volume 83 · no. 3 · march 2017€¦ · ecmo patients with, unfortunately, conflict-ing findings...

V O L U M E 8 3 · N o. 3 · M A R C H 2 0 1 7

248ORIGINAL ARTICLESThe effect of routine availability of sugammadex on postoperative respiratory complications: a historical cohort studyOlesnicky BL, Traill C, Marroquin-Harris FB

255Altered liver function in patients undergoing veno-arterial extracorporeal membrane oxygenation therapyBlandino Ortiz A, Lamanna I, Antonucci E, Pozzebon S, Dell’Anna AM, Vincent JL, de Backer D, Taccone FS

266Propofol sedation reduces diaphragm activity in spon-taneously breathing patients: ultrasound assessmentRocco M, Maggi L, Ranieri G, Ferrari G, Gregoretti C, Conti G, De Blasi RA

274Comparison of two different forms of sevoflurane for anesthesia maintenance and recoveryYanli Y, Ozdemir M, Bakan N, Yuruk CT, Yildirim A, Cetinkaya AO

239EDITORIALSIs life worth living? It all depends on the liverScolletta S, Biancofiore G

242TAP block in neonates: need to think beyond effec-tivenessSola C, Vega E, Ingelmo P

244Turning sedation into comfort analgesia: another skill to learn for the intensivistBertini P, Guarracino F

246Injury-induced immunosuppression: are we finally on the right track?Busani S, Cossarizza A, Girardis M

MINERVA ANESTESIOLOGICA

Vol. 83 March 2017 No. 3

CONTENTS

Vol. 83 - No. 3 MINERVA ANESTESIOLOGICA I

OFFICIAL JOURNAL OF ITALIAN SOCIETY OF ANESTHESIOLOGY, ANALGESIA,RESUSCITATION AND INTENSIVE CARE (SIAARTI)

ITALIAN JOURNAL OF ANESTHESIOLOGY AND ANALGESIAMONTHLY JOURNAL FOUNDED IN 1935 BY A. M. DOGLIOTTI

OFFICIAL JOURNAL OF ITALIAN SOCIETY OF ANESTHESIOLOGY, ANALGESIA,RESUSCITATION AND INTENSIVE CARE (S.I.A.A.R.T.I.)

CONTENTS

II MINERVA ANESTESIOLOGICA March 2017

282Transversus abdominis plane block for postoperative analgesia in neonates and young infants: retrospective analysis of a case seriesKendigelen P, Tütüncü C, Ashyralyyeva G, Ozcan R, Emre S, Altindas F, Kaya G

288REVIEWSUtilizing Bi-Spectral Index (BIS) for the monitoring of sedated adult ICU patients: a systematic reviewBilgili B, Montoya JC, Layon AJ, Berger AL, Kirchner HL, Gupta LK, Gloss DS

302Biological markers of injury-induced immunosup-pressionRouget C, Girardot T, Textoris J, Monneret G, Rimmelé T, Venet F

315EXPERTS’ OPINIONSOpioid-less perioperative careCata JP, Bugada D, de Andrés J

321Regional anesthesia and antithrombotic agents: instructions for useScibelli G, Maio L, Savoia G

336LETTERS TO THE EDITORCervical facet joint syndrome: a possible cause of chronic cervicobrachial painPiraccini E, Byrne H, Maitan S

337Analysis of cerebral glucose metabolism in patients with post-operative cognitive dysfunctionHerter JM, Brenscheid N, Nienhaus L, Dieterich C, Weckesser M, van Aken H

338A scope on esophageal damage associated with rou-tine transesophageal echocardiography use in cardiac surgeryAbraham P, Siegenthaler N, Giraud R, Bendjelid K

340Perioperative management of a patient with cold agglutinin disease undergoing segmental hepatec-tomyCao X, White PF, Ma H

341TOP 50 MINERVA ANESTESIOLOGICA REVIEWERS

About the cover: the cover shows the diaphragmatic thickening at end-inspiration (TEI) at T0 (before propofol infusion) and at T1 (1 min after reaching level 1 on the OAAS scale before gastric probe insertion). The study confirms that US was a suitable and well-tolerated technique for measuring diaphragmatic activity during a routine clinical procedure. For more informa-tion, see article by Rocco M. et al. (pages 266-73).

V O L U M E 8 3 · N o. 3 · M A R C H 2 0 1 7

EDITORIAL BOARD

EDITOR IN CHIEFF. CavaliereRoma, Italy

General Critical CareAssociate Editor

E. De Robertis (Napoli, Italy)Section Editor

G. Biancofiore (Pisa, Italy)

Circulation Critical CareSection Editor

S. Scolletta (Siena, Italy)E. Bignami (Milano, Italy),

Respiration Critical CareSection Editor

S. Grasso (Bari, Italy)P. Terragni (Sassari, Italy),

Neurocritical CareSection Editor

F. S. Taccone (Brussels, Belgium)

Section EditorA. Giannini (Milano, Italy)

Section EditorM. Allegri (Parma, Italy)F. Coluzzi (Roma, Italy)

ETHICS PAIN

Section EditorB. M. Cesana (Brescia, Italy)

MEDICAL STATISTICS

General AnesthesiaAssociate Editor

M. Rossi (Roma, Italy)Section Editor

E. Cohen (New York, USA)P. Di Marco (Roma, Italy)

J. T. Knape (Utrecht, The Netherlands)O. Langeron (Paris, France)

P. M. Spieth (Dresden, Germany)

Pediatric AnesthesiaSection Editor

M. Piastra (Roma, Italy)

Obstetric AnesthesiaSection Editor

E. Calderini (Milano, Italy)

Regional AnesthesiaSection Editor

A. Apan (Giresun, Turkey)M. Carassiti (Roma, Italy)

CRITICAL CARE ANESTHESIA

MANAGING EDITORA. Oliaro

Torino, Italy

MINERVA ANESTESIOLOGICAITALIAN JOURNAL OF ANESTHESIOLOGY AND ANALGESIA

MONTHLY JOURNAL FOUNDED IN 1935 BY A. M. DOGLIOTTIOFFICIAL JOURNAL OF ITALIAN SOCIETY OF ANESTHESIOLOGY, ANALGESIA,

RESUSCITATION AND INTENSIVE CARE (S.I.A.A.R.T.I.)

Vol. 83 - No. 3 MINERVA ANESTESIOLOGICA V

This journal is PEER REVIEWED and is quoted in:

Current Contents, SciSearch, PubMed/MEDLINE, EMBASE, Scopus

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Vol. 83 - No. 3 MiNerVa aNestesiologica 239

ment/therapy for the diseased liver; 3) the liver cannot be routinely monitored with the same precision and intensity that is nowadays pos-sible for other organs and functions, namely the lungs and the cardiovascular system.

in this issue of Minerva Anestesiologica, Blandino ortiz et al. aimed at studying the liv-er dysfunction that may affect patients under-going venous-arterial ecMo in terms of oc-currence, time-course and impact on survival.3 the key points of their study are: 1) although an elevation of liver enzymes can occur in the majority (65%) of the patients not all of them show the signs of hypoxic hepatitis; 2) elevat-ed liver enzymes can normalize quickly (with-in five days since ECMO initiation); 3) there is a lack of association between alteration of liver enzymes and poor outcome.

as noticed by the authors, only few other studies are available about liver dysfunction in ECMO patients with, unfortunately, conflict-ing findings due to methodological, study pop-ulations and definitions heterogeneity. There-fore, the conclusion they drew — i.e. further studies are needed in order to better investigate the association between ecMo and liver out-comes — was inevitable. still, Blandino ortiz et al. are to be commended for bringing to our attention the key topic of how liver function

the use of extracorporeal membrane oxy-genation (ecMo) seems to be an impor-

tant issue for clinicians: a literature search with ecMo as a key word in the title including pa-pers published from January 2014 until octo-ber 2016 yielded 359 articles, 17 reviews, and 16 editorials. Such a figure depicts the constant evolution through the years showed by ecMo from technical and clinical points of view. ac-cordingly, despite the fact that this technique is resource-intensive and requires significant in-stitutional commitment and well-trained staff, the use of ecMo has been rapidly increasing in high-income countries with a rising evi-dence that it ensures clear benefits in patients with different acute illnesses including cardiac arrest and cardiogenic shock.1

Nevertheless, although in-hospital com-plications and mortality of patients receiving ecMo decreased over time, they still remain an important issue.1, 2 among the different or-gan dysfunctions possibly affecting patients undergoing ecMo, liver failure can represent a severe, life-threatening event. this is mainly due to three factors: 1) the liver plays a piv-otal role in almost any body metabolic and immune pathway; 2) there is no specific treat-

E D I T O R I A L

is life worth living? it all depends on the liver

sabino scolletta 1, gianni BiaNcoFiore 2 *

1Unit of cardiovascular anesthesia and critical care, Department of Medical Biotechnology, azienda ospedaliera Universitaria senese, siena, italy; 2Unit of anesthesia and critical care for general, Vascular and transplantation surgery, azienda ospedaliera Universitaria Pisana, Pisa, italy*Corresponding author: Gianni Biancofiore, Unit of Anesthesia and Critical Care for General, Vascular and Transplantation Surgery, Azienda Ospedaliera Universitaria Pisana, Cisanello, 56100 Pisa, Italy. E-mail: [email protected]

anno: 2017Mese: MarchVolume: 83No: 3rivista: Minerva anestesiologicacod rivista: Minerva anestesiol

lavoro: 11864-Mastitolo breve: liVer DYsFUNctioN iN PatieNts oN ecMoprimo autore: scollettapagine: 239-41citazione: Minerva anestesiol 2017;83:255.

comment on p. 255.

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240 MiNerVa aNestesiologica March 2017

liver, which are considered to be of outstanding significance in deterioration of liver function in the critically-ill.6

Finally, there is a very specific feature of the liver that frustrates our efforts in shedding more light on how to better assess liver function in critically-ill patients. the liver participates in host defense and tissue repair through hepatic cell cross-talk, which controls most of the co-agulation and inflammation processes. When this control system becomes inadequate or in-effective, as is the case of the possible ecMo-related hypoperfusion/hyperinflammation, a secondary hepatic dysfunction may occur and may sometimes lead to bacterial product spill-over, enhanced procoagulant and inflamma-tory processes, and, in turn, be responsible for multiple organ failure and death.7, 8 the liver suffers the consequences of shock- or hyper-inflammation-inducing circumstances, which alter hepatic circulation parameters, oxygen supply and inflammatory responses at the cel-lular level. Moreover, the liver is an orchestra-tor of metabolic arrangements, which promote the clearance and production of inflammatory mediators, the scavenging of bacteria, and the synthesis of acute-phase proteins. therefore, the liver can both promote and become a tar-get for remote organ dysfunction. accordingly, with the currently-available technology and laboratory tests, it is nearly impossible to dis-criminate whether an altered liver function is “primary” or “secondary”.

given the above premises, we agree with William James, the “father of American psy-chology,” who stated: “Is life worth living? It all depends on the liver.” More efforts need to be made in the future to better understand how such a pivotal organ works and fails.

References 1. ouweneel DM, schotborgh JV, limpens J, sjauw KD,

Engström AE, Lagrand WK, et al. extracorporeal life support during cardiac arrest and cardiogenic shock: a systematic review and meta-analysis. intensive care Med 2016;42:1922-34.

2. Ventetuolo ce, Muratore cs. extracorporeal life sup-port in critically ill adults. am J respir crit care Med 2014;190:497-508.

3. Blandino ortiz a, lamanna i, antonucci e, Pozzebon s, Dell’anna aM, Vincent Jl, et al. altered liver func-

can be assessed, monitored and possibly pre-served in critically-ill patients, with or without ecMo as a treatment.

Preserving liver function is of great impor-tance in patients on ecMo, as in some cases the liver dysfunction can be secondary to spe-cific technical aspects. For instance, in patients supported by ecMo placement of cannulas at the level of suprahepatic veins might de-termine liver dysfunction, due to inadequate venous drainage. thus, correct positioning of the cannula tip in the inferior vena cava must be confirmed to avoid cannulation of one of the hepatic veins.4 echocardiography plays a key role in avoiding such an issue, as it has the ability to determine the exact position of the cannula. in addition, serial echocardiograms might serve to monitor cardiac chamber size to ensure adequate emptying of the ventricles, thus facilitating unloading of the heart. in this view, central venous pressure (cVP) provides additional information on venous stasis in pa-tients on ecMo, as high cVP values could indicate impairment either in the portal blood drainage or right ventricular failure. also, a rise in cVP in the setting of stable settings may be indicative of a mechanical obstructive pro-cess, which can affect liver function as well.5

studying the liver with its pleiotropic func-tions is not easy and rapid and repeated assess-ments of surrogates for global liver function in the critically ill are difficult to achieve.6 real-time monitoring of liver function in critically-ill patients is currently not available. in general, the results of different tests may vary consider-ably, since they assess different hepatic partial functions, which makes comparison difficult. on the one hand, conventional static param-eters, such as bilirubin and transaminases, are generally too slow to fit real-time monitoring. on the other hand, the so-called “dynamic tests” that rely on clearance, elimination or metabolite formation can respond more rapidly to changes associated to critical illness than conventional tests, but they are characterized by inherent di-agnostic fuzziness regarding discrimination of perfusion to function abnormalities. Moreover, no validated biomarkers are currently available to monitor non-parenchymal functions of the

liVer DYsFUNctioN iN PatieNts oN ecMo scolletta


6. Kortgen a, recknagel P, Bauer M. How to assess liver function? curr opin crit care 2010;16:136-41.

7. Dhainaut JF, Marin N. Mignon a,Vinsonneau c. Hepatic response to sepsis: interaction between coagulation and inflammatory processes Crit Care Med 2001;29:S42-7.

8. Robinson MW, Harmon C, O’Farrelly C. Liver immunol-ogy and its role in inflammation and homeostasis. Cell Mol immunol 2016;13:267-76.

tion in patients undergoing veno-arterial extracorpor-eal membrane oxygenation therapy. Minerva anestesiol 2017;83:255-65.

4. Douflé G, Roscoe A, Billia F, Fan E. Echocardiography for adult patients supported with extracorporeal mem-brane oxygenation. crit care 2015;19:326.

5. chung M, shiloh al, carlese a. Monitoring of the adult patient on venoarterial extracorporeal membrane oxy-genation. Sci World J 2014;2014:393258.

Conflicts of interest.—The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.Article first published online: January 25, 2017. - Manuscript accepted: January 10, 2017. - Manuscript revised: January 2, 2017. - Manuscript received: December 12, 2016.(Cite this article as: Scolletta S, Biancofiore G. Is life worth living? It all depends on the liver. Minerva Anestesiol 2017;83:239-41. Doi: 10.23736/s0375-9393.17.11864-X)

242 Minerva anestesiologica March 2017

try, received doses potentially associated with last.3

several case reports of last have been published after performing taP blocks in adults.4-6 Pharmacokinetic studies have con-firmed that a single dose of 2.5 to 3 mg/kg of levobupivacaine or ropivacaine can easily reach plasmatic concentration associated with neurological toxicity.7-9 a recent pharmacoki-netic study, confirmed the rapid and early rise of la plasma concentration following taP block in neonates.10 Moreover, due to an im-mature hepatic metabolism, low plasma con-centration of the la binding proteins and the lack of fully developped nerve fibers, neonates are at greatest risk of la toxicity.11 therefore, a reduction of the concentration and the total dose of the LA are essential in this specific population.

currently, the use of Us has become the gold standard for regional anesthesia procedures in pediatric patients, including taP blocks.12 the key of the block’s success relies on the accu-rate placement of the la solution in the fascial layer that separates the internal oblique and the transverse abdominal muscles.13 as dem-onstrated by Kendigelen et al., the distance from the skin to the taP is often a few mil-limeters in neonates. the peritoneum, liver,

the transversus abdominis plane (taP) block has become a widely used regional

anesthesia technique for perioperative pain management in a variety of abdominal surger-ies and patients, from neonates to adults. near-ly twenty years after the first description by Rafi 1 and in spite of an important increase in its use and indications, surprisingly a number of unknowns are still unresolved. in the current issue of Minerva Anestesiologica, Kendigelen et al. described the use of ultrasound (Us) to perform taP blocks in neonates and reported its benefits in this high-risk population.2 none-theless, this technique could provide a safe and effective perioperative pain management only if we consider its challenging technical and pharmacological aspects in the neonatal population.

one of the greatest concerns in regional anesthesia in neonates is how to be effective with the lowest dose of local anesthetic (la) in order to avoid local anesthetic systemic tox-icity (last). a recent analysis of taP blocks included in the Pediatric regional anesthesia network (Pran) database, highlighted the potential risk of last in children. nearly 135 of 1994 children included in the regis-

E D I T O R I A L

taP block in neonates: need to think beyond effectiveness

chrystelle sola 1, 2, eduardo vega 2, 3, Pablo ingelMo 2 *

1Pediatric anesthesia Unit, Department of anesthesiology and critical care Medicine, Montpellier University Hospital, Montpellier, France; 2Department of anesthesia, Montreal children’s Hospital, Montreal, Qc, canada; 3Department of Anesthesiology, School of Medicine, Pontifical Catholic University of Chile, Santiago, chile*corresponding author: Pablo ingelmo, Department of anesthesia, Montreal children’s Hospital, 1001 Decarie Boulevard (H4a3J1) Montreal, Qc, canada. e-mail: [email protected]

anno: 2017Mese: Marchvolume: 83no: 3rivista: Minerva anestesiologicacod rivista: Minerva anestesiol

lavoro: 11848-Mastitolo breve: taP block in neonatesprimo autore: solapagine: 242-3citazione: Minerva anestesiol 2017;83:282.

comment on p. 282.

Minerva anestesiologica 2017 March;83(3):242-3DOI: 10.23736/S0375-9393.17.11848-1

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taP BlocK in neonates sola

vol. 83 - no. 3 Minerva anestesiologica 243

infants: retrospective analysis of a case series. Minerva anestesiol 2017;83:282-7.

3. long JB, Birmingham PK, De oliveira gs, Jr., schalden-brand KM, suresh s. transversus abdominis plane block in children: a multicenter safety analysis of 1994 cases from the pran (pediatric regional anesthesia network) da-tabase. Anesth Analg 2014;119:395-9.

4. Griffiths JD, Le NV, Grant S, Bjorksten A, Hebbard P, royse c. symptomatic local anaesthetic toxicity and plasma ropivacaine concentrations after transversus ab-dominis plane block for caesarean section. Br J anaesth 2013;110:996-1000.

5. Scherrer V, Compere V, Loisel C, Dureuil B. Cardiac ar-rest from local anesthetic toxicity after a field block and transversus abdominis plane block: a consequence of miscommunication between the anesthesiologist and sur-geon. A A Case Rep 2013;1:75-6.

6. Weiss e, Jolly c, Dumoulin Jl, Meftah rB, Blanie P, la-loe Pa, et al. convulsions in 2 patients after bilateral ul-trasound-guided transversus abdominis plane blocks for cesarean analgesia. reg anesth Pain Med 2014;39:248-51.

7. torup H, Mitchell aU, Breindahl t, Hansen eg, rosen-berg J, Moller aM. Potentially toxic concentrations in blood of total ropivacaine after bilateral transversus ab-dominis plane blocks; a pharmacokinetic study. eur J Anaesthesiol 2012;29:235-8.

8. Miranda P, corvetto Ma, altermatt Fr, araneda a, echevarria gc, cortinez li. levobupivacaine absorp-tion pharmacokinetics with and without epinephrine dur-ing tap block: analysis of doses based on the associated risk of local anaesthetic toxicity. eur J clin Pharmacol 2016;72:1221-7.

9. Griffiths JD, Barron FA, Grant S, Bjorksten AR, Hebbard P, royse cF. Plasma ropivacaine concentrations after ultrasound-guided transversus abdominis plane block. Br J Anaesth 2010;105:853-6.

10. suresh s, De oliveira gs, Jr. Blood bupivacaine concen-trations after transversus abdominis plane block in neo-nates: a prospective observational study. anesth analg 2016;122:814-7.

11. el-Boghdadly K, chin KJ. local anesthetic systemic toxicity: continuing professional development. can J anaesth 2016;63:330-49.

12. Johr M. regional anaesthesia in neonates, infants and children: an educational review. eur J anaesthesiol 2015;32:289-97.

13. suresh s, chan vW. Ultrasound guided transversus ab-dominis plane block in infants, children and adolescents: a simple procedural guidance for their performance. Pae-diatr anaesth 2009;19:296-9.

spleen or even the kidney, are never very far away from the target plane. therefore, the use of an appropriate needle’s size (24 or 25 G), an extremely careful skin puncture and real-time needle advancement visualization, done by a pediatric anesthesiologist with experience in sonoanatomy, will increase the safety of the procedure.

the choice of the regional anesthesia tech-nique should include the surgical site, the severity of the surgical insult, the clinical characteristics of the patient and the benefit risk ratio. a multimodal analgesia program including taP block provide an effective an-algesia and could be considered as the first option for minor abdominal surgery in small children. it could also be considered as a safe alternative to major abdominal surgery when an epidural technique is not feasible or con-traindicated.

the study by Kendigelen et al. highlight the place of peripheral regional analgesia in neonates as an effective tool for improving perioperative pain control and reduce analge-sics requirement after surgery. taP blocks in neonates could be recommended when is per-formed with the appropriate expertise, using proper equipment and taking special attention to the dose of la.

References 1. An R. Abdominal field block a new approach via the lum-

bar triangle. Anaesthesia 2001;56:1024-6. 2. Kendigelen P, tütüncü c, ashyralyyeva g, ozcan r,

emre s, altindas F, et al. transversus abdominis plane block for postoperative analgesia in neonates and young

Conflicts of interest.—The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.Article first published online: January 25, 2017. - Manuscript accepted: January 10, 2017. - Manuscript revised: January 2, 2017. - Manuscript received: December 4, 2016.(Cite this article as: sola c, vega e, ingelmo P. taP block in neonates: need to think beyond effectiveness. Minerva anestesiol 2017;83:242-3. DOI: 10.23736/S0375-9393.17.11848-1)


overcome. sedation should be secondary to pain relief and should aim to the restoration of sleep and wake alternation. on the other hand, adequate analgesia can contribute to early weaning from mechanical ventilation, mobilization, improvement in communication with the family or the care givers and proper rehabilitation.

in our opinion, especially in a period of reduced resources in the health care environ-ment in general and in particular in the acute care setting, specific attention should be ad-dressed to reduce the human and economic costs of a prolonged icU stay, and proper analgosedation is indeed one of the major de-terminants. What emerges from the present study is that the current understanding of Bis and its interaction with sedative or general anesthetics, is not helping the quest to con-quer adequate sedation in the icU, probably because sedation itself is inadequate in most of the situations.

since we are moving to a condition where comfort is considered the best care for our pa-tients, we cannot rely on a single device or a technique to monitor it. instead, we should fo-cus on finding other means to proper detect the lack of comfort in our critically ill patient, in order to assure improved quality of care.

it is good practice to provide adequate seda-tion in the critically ill in the intensive care

Unit (icU). nevertheless, over the last few years, sedation in the icU has passed from a concept of deep irresponsive state, or induced coma, to the need for the patient to reach a state of adequate analgosedation. together with this latter idea, the concept of comfort in the icU was born. the Bispectral index (Bis) is a well-known tool utilized by anesthesiologists to monitor the depth of anesthesia and titrate general anesthetics in the operating theatre. in this issue of Minerva Anestesiologica,1 Bilgili et al. reviewed the literature on Bis utility in order to provide proper sedation to critically-ill patients. the overall evidence of this review is quite inconclusive. the Bis technique in-deed, although beneficial in the avoidance of inadequate anesthesia levels in paralyzed pa-tients 2 is poorly applicable in the icU setting in which patients are complex and with several comorbidities.

recently, an interesting concept developed across the intensivists: it was called ecasH,3 which stands for “early comfort using anal-gesia, minimal sedatives and maximal Hu-mane care”. according to this idea the con-cept of deep sedation in the icU is completely

E D I T O R I A L

turning sedation into comfort analgesia: another skill to learn for the intensivist

Pietro Bertini *, Fabio gUarracino

cardiothoracic anesthesia and intensive care Medicine Unit, Department of anesthesia and critical care Medicine, University Hospital of Pisa, Pisa, italy*corresponding author: Pietro Bertini, cardiothoracic anesthesia and intensive care Medicine Unit, Department of anesthesia and critical care Medicine, University Hospital of Pisa, via Paradisa 2, 56124 cisanello (Pi), italy. e-mail: [email protected]


lavoro: 11716-Mastitolo breve: FroM seDation to coMFort analgesiaprimo autore: Bertinipagine: 244-5citazione: Minerva anestesiol 2017;83:244-5

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comment on p. 288.

FroM seDation to coMFort analgesia Bertini


2. tasaka cl, Duby JJ, Pandya K, Wilson MD, a Hardin H. inadequate sedation During therapeutic Paralysis: Use of Bispectral index in critically ill Patients. Drugs real World outcomes 2016;3:201-8.

3. vincent Jl, shehabi Y, Walsh ts, Pandharipande PP, Ball Ja, spronk P, et al. comfort and patient-centred care without excessive sedation: the ecasH concept. inten-sive care Med 2016;42:962-71.

References

1. Bilgili B, Montoya Jc, layon aJ, Berger al, lester Kirchner H, gupta lK, et al. Utilizing bi-spectral in-dex (Bis) for the monitoring of sedated adult icU pa-tients: a systematic review. Minerva anestesiol 2017; 83:288-301.

Conflicts of interest.—The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.Article first published online: October 13, 2016. - Manuscript accepted: October 12, 2016. - Manuscript revised: October 6, 2016. - Manuscript received: september 21, 2016.(Cite this article as: Bertini P, guarracino F. turning sedation into comfort analgesia: another skill to learn for the intensivist. Min-erva anestesiol 2017;83:244-5. Doi: 10.23736/s0375-9393.16.11716-X)


the role of the possible markers of immuno-suppression expressed by B and/or t lympho-cytes has been also reviewed in detail, along with a novel transcriptomic view that would allow the identification of genes that are up or down-regulated during a stressing insult.

in addition to molecules and cells described by rouget et al.,4 further bio-markers may be helpful for identifying an hypo-reactive state of the immune system. a low plasma concen-tration of the different isotypes of endogenous immunoglobulins at the onset and throughout the course of sepsis has been associated to an increased risk of mortality in septic patients.6, 7 Due to the pleiotropic effects of immunoglobu-lins in the inflammatory-immune response, the reasons and the true meaning of this associa-tion are still debated. However, several mecha-nisms by which immunoglobulins may exert anti-apoptotic effects of different immune cells populations have been identified in preclinical models. therefore, a decreased immunoglobulin plasma levels could facilitate a boost of apop-tosis that has been recognized as an important cause of major immune dysfunction during late phases of sepsis.8, 9 remaining on apoptosis, caspase 1 is a key component of inflammasomes that trigger a potent proinflammatory response, ultimately inducing a type of cell death defined “pyroptosis”.10, 11 in addition to its role as mark-er of an excessive pro-inflammatory condition,

in critically ill patients multiple stress events such as infection, trauma, surgery and burn

may lead to dysregulation of the immune re-sponse with an excessive pro-inflammatory phase and/or a prolonged and profound dys-function in immune response. this latter, called immune-paralysis, predisposes patient to secondary life-threatening infections and seems to be crucial for long-term outcomes in patients surviving to first hit.1 Moreover, due to impairment in the innate and adaptive im-munity, antibiotic therapy alone may result ineffective in immunosuppressed patients. therefore, early detection of immune dysfunc-tion and its support by specific strategies may be the key for improving survival.2, 3

in the last years the awareness of the pivotal role of immunity in acute illnesses has led to significant advances in the identification of biomarkers useful for the assessment of the immune system competence in critically ill pa-tients. in the current issue of Minerva Anestesi-ologica, rouget et al.4 provided a detailed and exhaustive review of these biomarkers. the authors focused on immature granulocytes, quantitative and qualitative alterations in den-dritic cells, monocytes human leucocytes anti-gen DR, anti-inflammatory interleukins and the recent concept of leucocyte reprogramming.5

e d i t o r i a l

injury-induced immunosuppression: are we finally on the right track?

stefano BUsani 1, andrea cossariZZa 2, Massimo girarDis 1 *

1intensive care Unit, University of Modena and reggio emilia, Modena, italy; 2Department of Pathology and immunology, University of Modena and reggio emilia, Modena, italy*corresponding author: Massimo girardis, cattedra di anestesia e rianimazione, azienda ospedaliera Universitaria di Modena, l.go del Pozzo, 71, 41100 Modena, italy. e-mail: [email protected]


lavoro: 11632-Mastitolo breve: inJUrY-inDUceD iMMUnosUPPressionprimo autore: BUsanipagine: 246-7citazione: Minerva anestesiol 2017;83:246-7

Minerva anestesiologica 2017 March;83(3):246-7Doi: 10.23736/s0375-9393.16.11632-3


comment on p. 302.

inJUrY-inDUceD iMMUnosUPPression BUsani


Conflicts of interest.—The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.Article first published online: October 20, 2016. - Manuscript accepted: October 19, 2016. - Manuscript revised: October 17, 2016. - Manuscript received: august 5, 2016.(Cite this article as: Busani S, Cossarizza A, Girardis M. Injury-induced immunosuppression: are we finally on the right track? Min-erva anestesiol 2017;83:246-7. Doi: 10.23736/s0375-9393.16.11632-3)

references 1. Pop-vicas a, opal sM. the clinical impact of multidrug-

resistant gram-negative bacilli in the management of sep-tic shock. virulence 2014;5:206-12.

2. venet F, lukaszewicz ac, Payen D, Hotchkiss r, Mon-neret g. Monitoring the immune response in sepsis: a rational approach to administration of immunoadjuvant therapies. curr opin immunol 2013;25:477-83.

3. Delano MJ, Ward Pa. sepsis-induced immune dysfunc-tion: can immune therapies reduce mortality? J Clin In-vest 2016;126:23-31.

4. rouget c, girardot t, textoris J, Monneret g, t ri, venet F. Biological markers of injury-induced immuno-suppression. Minerva anestesiol 2017;83:302-14.

5. shalova in, lim JY, chittezhath M, Zinkernagel as, Beasley F, Hernandez-Jimenez e, et al. Human mono-cytes undergo functional re-programming during sepsis mediated by hypoxia-inducible factor-1alpha. immunity 2015;42:484-98.

6. Bermejo-Martin JF, rodriguez-Fernandez a, Herran-Monge r, andaluz-ojeda D, Muriel-Bombin a, Merino P, et al. immunoglobulins igg1, igM and iga: a syner-gistic team influencing survival in sepsis. J Intern Med 2014;276:404-12.

7. Justel M, socias l, almansa r, ramirez P, gallegos Mc, Fernandez v, et al. igM levels in plasma predict outcome in severe pandemic influenza. J Clin Virol 2013;58:564-7.

8. Busani s, Damiani e, cavazzuti i, Donati a, girardis M. intravenous immunoglobulin in septic shock: review of the mechanisms of action and meta-analysis of the clini-cal effectiveness. Minerva anestesiol 2016;82:559-72.

9. leentjens J, Kox M, van Der Hoeven Jg, netea Mg, Pickkers P. immunotherapy for the adjunctive treatment of sepsis: from immunosuppression to immunostimula-tion. Time for a paradigm change? Am J Respir Crit Care Med 2013;187:1287-93.

10. Kepp o, galluzzi l, Zitvogel l, Kroemer g. Pyropto-sis - a cell death modality of its kind? Eur J Immunol 2010;40:627-30.

11. Wallach D, Kang tB, Dillon cP, green Dr. Programmed necrosis in inflammation: Toward identification of the ef-fector molecules. science 2016;352:aaf2154.

12. le Bourhis l, guerri l, Dusseaux M, Martin e, soudais c, lantz o. Mucosal-associated invariant t cells: uncon-ventional development and function. trends immunol 2011;32:212-8.

13. grimaldi D, le Bourhis l, sauneuf B, Dechartres a, rousseau c, ouaaz F, et al. Specific MAIT cell behaviour among innate-like t lymphocytes in critically ill patients with severe infections. intensive care Med 2014;40:192-201.

14. Hamers l, Kox M, Pickkers P. sepsis-induced immuno-paralysis: mechanisms, markers, and treatment options. Minerva anestesiol 2015;81:426-39.

15. Boomer Js, to K, chang Kc, takasu o, osborne DF, Walton aH, et al. immunosuppression in patients who die of sepsis and multiple organ failure. JaMa 2011;306:2594-605.

persisting high level of caspase 1 could be also considered an early indicator of immune system hypo-reactivity. a further potential marker of immune dysfunction might be mucosal-associ-ated invariant t (Mait) cells, a population of t lymphocytes that express a semi-invariant t cell receptor. an important role of Mait cells in the early stages of bacterial infections has been postulated 12 and a recent study showed that critically ill patients with persistent Mait cells depletion display a high susceptibility to develop hospital acquired infections.13

a proper evaluation of hyper or under-acti-vation of the host immune system may provide a better comprehension of the pathobiology changes occurring in sepsis as well as in other conditions such as trauma, burn and surgery, and may finally guide to a tailored therapeutic approach.14 For instance, the traditional strat-egy aimed to suppress the immune system by inhibition of inflammatory mediators could be helpful in patients with an overwhelming pro-inflammatory state, but may be harmful in patients with a suppressed immune response.15

the review by rouget et al.4 provides a straightforward analysis on the rationale for use and the feasibility of measuring immune-competence at the bedside. Unfortunately, most of the biomarkers described requires sophisticated techniques such as flow cytom-etry, immunohistochemistry, cytokine elisa arrays or rna analysis for gene expression. Despite many of these procedures are com-plex and have a high cost, we believe that the evaluation of the immune response is today mandatory for a proper management of septic patients. To this aim, official guidelines or con-sensus conferences are urgently needed to pro-vide clinicians with a sort of “immunoscope” to monitor critically-ill patients and treat them. The future in which specific therapies will be tailored on a sound evaluation of patient patho-biology could be around the corner.


feeling that the rate of clinically significant re-sidual paralysis is less than 1%.16

rPoc has been linked to postoperative mor-bidity. the majority is respiratory in nature, re-flecting the impairment of laryngeal reflexes and swallowing function 17, 18 and the impairment of hypoxic respiratory drive at TOF ratio (TOFR) <0.9.19 Postoperative pulmonary complications

residual postoperative curarization (RPOC) after anesthesia is a common and pre-

ventable problem. the incidence in the pub-lished literature ranges from 13-89%.1-14 with a meta-analysis showing an overall incidence of RPOC (as defined by train-of-four [TOF] <0.9) of 41.3%.15 Despite this, anesthetists un-derestimate the incidence of rPoc, with most

O R I G I N A L A R T I C L E

the effect of routine availability of sugammadex on postoperative respiratory complications: a historical cohort study

Benjamin l. olesnicKY *, Catherine TRAILL, Frank B. MARROQUIN-HARRIS

Northern Sydney Anesthetic Research Institute, Department of Anesthesia, Royal North Shore Hospital, Sydney, australia*corresponding author: Benjamin l. olesnicky, northern sydney anesthetic research institute, Department of anesthesia, royal North Shore Hospital, Reserve Road, St Leonards, Sydney, 2065 Australia. E-mail: [email protected]


lavoro: 11489-Mastitolo breve: SUGAMMADEX IN POSTOPERATIVE RESIDUAL CURARIZATIONprimo autore: olesnicKYpagine: 248-54citazione: Minerva anestesiol 2017;83:248-54

a B s t r a c tBACKGROUND: Postoperative residual curarization is a preventable cause of postoperative morbidity. although sug-ammadex has been shown to reduce the risk of residual curarization, it has not yet been shown if this directly translates to a reduction in morbidity. We aimed to demonstrate whether the introduction of unrestricted sugammadex for routine reversal changed the incidence of postoperative respiratory diagnoses and the rate of airway and respiratory complica-tions in the postoperative care unit.METHODS: A historical cohort study of 1257 patients who underwent general surgical or ear, nose and throat procedures before and after the introduction of unrestricted availability of sugammadex. Patient records were used to identify the incidence of postoperative in-hospital respiratory diagnoses and of airway complications in post-anesthesia care unit, the pattern of muscle relaxant use and the relative costs associated with the routine availability of sugammadex.RESULTS: Unrestricted sugammadex availability was associated with a significant reduction in the rate of a postopera-tive in-hospital respiratory diagnosis (odds ratio [OR] 0.20; 95% CI: 0.05-0.72, P=0.01). Furthermore, the use of sugam-madex itself was also associated with a reduction in in-hospital respiratory diagnoses (OR=0.26; 95% CI: 0.08-0.94, P=0.04). Unrestricted sugammadex was also associated with a decrease in the need for manual airway support in the recovery room (3.2% vs. 1.1%, P=0.02) and a decrease in patients being transferred intubated to ICU (5.5% vs. 1.3%, P<0.001).CONCLUSIONS: Unrestricted sugammadex availability is associated with a reduction in postoperative respiratory com-plications. a well-designed, prospective randomized trial is needed to provide further validation of the data.(Cite this article as: Olesnicky BL, Traill C, Marroquin-Harris FB. The effect of routine availability of sugammadex on post-operative respiratory complications: a historical cohort study. Minerva anestesiol 2017;83:248-54. Doi: 10.23736/s0375-9393.16.11489-0)Key words: Cohort studies - Delayed emergence from anesthesia - Humans - Postoperative care - Gamma-cyclodextrins.

Minerva Anestesiologica 2017 March;83(3):248-54Doi: 10.23736/s0375-9393.16.11489-0

© 2016 EDIZIONI MINERVA MEDICAonline version at http://www.minervamedica.it

SUGAMMADEX IN POSTOPERATIVE RESIDUAL CURARIZATION olesnicKY


sentation of the volume of cases at our institu-tion, and the cohorts were limited to general and ent cases to select groups with a high in-cidence of muscle relaxant use. In addition, the same three-month period (August to October) was chosen in both years to minimize interfer-ing factors such as seasonal variation of diseases and to allow for six months of “familiarization” after the introduction of routine sugammadex.

Paper patient medical records were retrieved and accessed to record patient data, and to look for in-hospital respiratory diagnoses, as defined from the medical coding sheet (ICD-9 codes; 465-66, 480-88, 518). Additionally, recovery room notes were reviewed to record the need for airway support (manual, oropharyngeal or endotracheal airways), any documented satu-ration <90%, the need for reintubation and the need for unplanned intensive care unit (ICU) admission. the anesthetic chart was analyzed to record the use and dose of muscle relaxant and the use of reversal agents, the type of anes-thetic given (volatile based anesthesia vs. total intravenous anesthesia, TIVA) and the use of intraoperative neuromuscular twitch (NMT) monitoring.

a simple cost analysis was performed by multiplying the percentage of patients receiv-ing each nMBD or reversal agent by the cost of an individual ampoule of drug (or multi-plied by two where glycopyrrolate was used, to represent the standard dose of two am-poules). This approximated a total cost per 100 patients. the drug cost was provided by hospi-tal pharmacy as at February 2014.

Statistical analysis

Data was entered into an Excel spreadsheet and analyzed using Excel for Mac 2008 and SPSS v.22. Significance of effect for continu-ous data was determined using two-tailed stu-dent’s t-test. categorical data was analyzed for significance using χ2 tests (or Fisher’s exact tests when any group N.<5). Binomial logistic regression was used to determine the effects of age, ASA, the use of suxamethonium, the use of NMT monitoring, the type of relaxant and type of reversal used on the dependent

are postulated to arise from either increased atelectasis and/or micro-aspiration following inadequate reversal. rPoc has been directly associated with increased critical and hypoxic events in the PACU,20-23 and with longer term increased risk of pulmonary complications 24 and radiographic chest X-ray 25 changes.

Most studies into the effects of rPoc have investigated anticholinesterase drugs as rever-sal agents. Sugammadex differs as it produces rapid termination of neuromuscular blockade via formation of one-to-one complexes with aminosteroid neuromuscular blocking drugs (NMBDs).26, 27 Published studies investigating the effect of sugammadex have consistently shown a reduction in rPoc incidence.13, 25, 28 Despite this, evidence that links sugammadex use to a reduction in clinically relevant mor-bidity is limited and of low quality.29-31

We performed a retrospective analysis of two cohorts of general surgical and ear, nose and throat (ENT) patients, prior to and after the introduction of unrestricted sugammadex at our institution. the primary outcome measured was any in-hospital respiratory diagnosis. our hypothesis was that the introduction of routine sugammadex would lead to a reduction in re-spiratory diagnoses. additionally, we sought to identify differences in the incidence of airway and respiratory events in the postoperative care unit (PACU), changes in the pattern of muscle relaxant use, the incidence of unplanned ICU admissions and in the use of intraoperative monitoring of neuromuscular function. Finally, we aimed to perform a simple cost analysis based on the changed patterns of drug use.

Materials and methods

Following local ethics approval (Northern Sydney Local Health District Human Research ethics committee, ref. 1210-377M, approved 10/08/2013), electronic operating theatre data-bases were accessed to extract all general surgi-cal and ent patients undergoing surgery over two corresponding three month periods before and after the introduction of unrestricted sugam-madex (February 2011). The three-month study period was chosen to offer a reasonable repre-

olesnicKY SUGAMMADEX IN POSTOPERATIVE RESIDUAL CURARIZATION


with a reduction of in-hospital respiratory diag-noses (OR=0.26; 95% CI: 0.08-0.94; P=0.04). Increasing age (OR=1.05; 1.02-1.08; P<0.01) and the use of more than one non-depolariz-ing muscle relaxant (OR=21.2; 2.78-161.2; P<0.01) were both associated with an increase in the likelihood of a respiratory diagnosis.

The binomial logistic regression model fit well with the data using the Hosmer-Lemeshow goodness of fit test (χ2=6.74, df=8; P=0.57). The model explained 19.7% (Nagelkerke R2) of the variance in respiratory diagnoses and correctly classified 97.6% of cases.

Figure 1 shows the use of muscle relax-ants in the two cohorts. Where it was used, the mean dose of rocuronium was unchanged from 54.6±22.9 mg to 54.7±24.3 mg per case (P=0.22), while vecuronium use per case was 8.0±3.3 mg in the 2010 cohort and 8.9±5.5 mg in the 2011 cohort (P=0.06). There was no dif-ference in the use of nMt monitoring between the two groups (12.7% vs. 12.7%, P=0.98).

Figure 2 shows the use of reversal agents in the two cohorts.

There was a significant difference in the type of anesthetic between the two cohorts, with the percentage of patients receiving volatile based general anesthesia increasing from 69.9% to 77.5% (P=0.01), while TIVA decreased from 27.9 to 21.8% (P=0.03). Combined TIVA/vol-atile anesthesia was unchanged (2.2 vs. 0.7%, P=0.07).

variable of in-hospital respiratory diagnosis. to ensure the assumption of independence of measurement in the variables was met, regres-sion analysis was performed after removing patients with more than one operation during the analysis period (patients only had their first anesthetic during the three-month period in-cluded in the analysis).

Results

there were 1281 cases eligible for inclusion in the study. 24 patient files were unable to be obtained despite repeated requests for access (12 in each cohort), resulting in 1257 cases available for review. of these 1257 cases, a total of 922 received a nMBD as part of their anesthetic and were included in further analy-sis. table i shows the numbers in each cohort and the patient demographic data.

the rate of in hospital respiratory diagnosis was non-significantly reduced after the intro-duction of unrestricted sugammadex (3.3% vs. 1.6%, P=0.13).

after correcting for potential confound-ers, the cohort with unrestricted sugammadex availability was significantly associated with a reduction in the rate of in-hospital respiratory diagnosis (odds ratio [OR] 0.20; 95% CI: 0.05-0.72; P=0.01), giving a relative risk of 0.21 (0.05-0.73).32 regression analysis also showed the use of sugammadex itself was associated

Table I.—�Number of cases and demographic data of cases analyzed.

2010(pre-

sugammadex)

2011(post-

sugammadex)P value

n. cases 514 767Unable to get files 12 12Cases with relaxant used 362 (70.4%) 560 (73.0%) 0.31n. patients 350 526Age (mean±SD) 50.5±20.3 50.2±20.0 0.78Male 51.1% 51.4% 0.92asa score

asa 1 102 (28.2%) 184 (32.9%) 0.13asa 2 163 (45.0%) 251 (44.8%) 0.95asa 3 90 (24.9%) 114 (20.4%) 0.11asa 4 7 (1.9%) 11 (2.0%) 0.97

All values are presented as number (percentage of cases), where no otherwise specified.

Figure 1.—Difference between two cohorts in percentage use of different neuromuscular blocking agents before and after the routine introduction of sugammadex.*Significant difference between the two cohorts (P<0.05).

Before after

rocuroniumvecuroniumcisatracuriumSuxamethonium



ble iii. there was an overall cost difference of AU$ 1390.86 per 100 patients between the two cohorts, with the increased cost predominantly due to the increased use of sugammadex in the 2011 cohort.

Discussion

The use of sugammadex has been associated with a reduced incidence of rPoc, and rPoc has been associated with postoperative mor-bidity, but there is little evidence directly link-ing sugammadex use to a reduction in postop-erative morbidity.

We found that the unrestricted availability of sugammadex for neuromuscular blockade reversal was associated with a reduction in the risk of an in-hospital respiratory diagnosis by 79%. In addition, the use of sugammadex it-self was associated with a 74% reduction in the odds of in-hospital respiratory diagnosis.

the incidence of postoperative respiratory complications in our study was based on docu-mentation on the medical coding sheet, which would not be expected to capture “mild” cases of respiratory impairment. This would explain why our rate of respiratory diagnoses of 3.3% to 1.6% sits on the lower end of with rates re-ported in the literature of 2-40%.33, 34

several other positive postoperative out-comes were realized. The first of these was a significant reduction in the need for manual airway support in PACU in the 2011 cohort compared to the 2010 cohort (1.08% versus 3.22%). We hypothesize that this is due to less rPoc, leading to improved muscle tone and maintenance of a patent airway by patients. of note, the reduction in documented manu-

Fewer patients were transferred intubated to the ICU; 7/560 (1.3%) in the 2011 cohort, compared with 20/362 (5.5%) cases in 2010 (P<0.001).

the incidence of respiratory complications in those patients who went to the PACU unit is shown in table ii. of note, the unrestricted use of sugammadex was associated with a signifi-cant decrease in the need for manual airway support in the PACU unit.

the total cost of each nMBD and rever-sal agent per 100 patients is presented in ta-

Figure 2.—Difference between two cohorts in percentage use of different neuromuscular reversal agents before (2010) and after (2011) the routine introduction of sugammadex.neo/glyco: neostigmine/glycopyrrolate; neo/atropine: ne-ostigmine/atropine; neo: neostigmine alone; neo/glyco/atro: neostigmine/glycopyrrolate/atropine.*Significant difference between the two cohorts (P<0.05).

Table II.—�PACU events in the cohort prior to (2010) and following (2011) the introduction of routine su-gammadex use.

2010 2011 P value

any documented airway complication in PACU

1 (0.29%) 8 (1.45%) 0.16

Unplanned ICU admission 1 (0.29%) 5 (0.90%) 0.41Arrival in PACU with ETT 3 (0.88%) 1 (0.18%) 0.15need for reintubation in

PACU0 0

need for manual airway support

11 (3.22%) 6 (1.08%) 0.02

need for oropharyngeal airway

3 (0.88%) 1 (0.18%) 0.09

Documented spo2<90% 3 (0.88%) 4 (0.72%) 0.99Values are presented as number (percentage of cases). Significance testing into differences between the two group (χ2 contingency ta-bles, or using Fisher’s exact test where any N.<5).

Table III.—�Total cost of relaxant and reversal agents per 100 patients in the period prior to (2010) and fol-lowing (2011) the introduction of routine availability of sugammadex.

2010 cohort 2011 cohort

rocuronium AU$ 96.26 AU$ 262.45vecuronium AU$ 1331.81 AU$ 572.13cisatracurium AU$ 111.28 AU$ 27.02neo/glyco/atropine AU$ 601.09 AU$ 59.68Sugammadex AU$ 36.00 AU$ 2646total cost AU$ 2176.43 AU$ 3567.29

Suga

mmadex

neo/g

lyco

no rev

ersal

neo/a

tropin

e

neo

neo/gl

yco/a

tro

20102011



sugammadex increased from 0.8% in 2010 to 58.8% in 2011. in both cohorts, there was an absence of documented reversal in almost 40% of cases.

along with this change in choice of nMBDs and reversal agents, there was a significant dif-ference in the type of anesthesia administered. Between the cohorts, the use of volatile anes-thesia increased from 69.9% to 77.5%, while there was a decrease in tiva from 27.9% to 21.8%. the rate of combined tiva/volatile an-esthesia did not change. the reason for this is unclear. it has been shown that anesthesia with sevoflurane, when compared with a TIVA an-esthetic, results in significantly greater impair-ment in bronchociliary clearance, which could have implications for postoperative respiratory complications.36 We showed a reduction in re-spiratory diagnoses despite the reduction in tiva anesthesia, and regression analysis did not show an association between the type of anesthesia given and the occurrence of a respi-ratory diagnosis.

We did not find any change in the use of for-mal NMT monitoring (12.7% versus 12.7%, P=0.98) between the two cohorts. In keep-ing with previous studies, the overall use of nMB monitoring was low.37 suggestions have been made that the lack of routine monitoring of neuromuscular function is the single most important contributing factor contributing to rPoc,38, 39 however, a meta-analysis in failed to show any reduction in roPc with nMt monitoring.15 We also did not show any as-sociation between the use of nMt monitoring and postoperative respiratory diagnosis.

the introduction of routine sugamma-dex was associated with an extra cost of AU$ 1390.86 per 100 patients. However, with the average increased hospital costs (reported in 2006) of postoperative complications rang-ing from US$ 4868 for ventral incisional her-nia repair to US$ 20,486 for colonic resection procedures,40 the prevention of respiratory complications in one patient would potentially offset the extra cost in over one hundred pa-tients.

there are several potential limitations to our study. Firstly, the results may not be generaliz-

al airway support in the PACU from 2010 to 2011 coincided with the changing of hospital PACU data entry from a paper to a computer based system. Potentially, the change in data entry systems may have led to a reduced rate of documentation of the use of manual airway support (but not of any of the other measured PACU events), accounting for the fewer re-ported cases. on the other hand, it could also have lead to an increased rate of documenta-tion and the true reduction in the need for air-way support may be greater than shown.

Another somewhat unexpected finding was a significant decrease in the number of patients transferred directly to the ICU intubated in the 2011 cohort compared with the 2010 cohort (1.3% versus 5.5%). This may reflect a more aggressive extubation strategy in 2011, i.e., sicker patients who would normally be left in-tubated are given a “trial of extubation” with increased physician confidence in the reversal technique. there were no patients in either cohort requiring re-intubation in the PACU or in unplanned ICU admission between the two groups.

With the introduction of unrestricted avail-ability of sugammadex, there where changes in the clinical practice of the anesthetists and the type of anesthetic administered. The first is the change in the use of nMBDs. there was a large increase (44.2%) in the use of rocuroni-um, with a decrease in the use of vecuronium (32%) and cisatracurium (11.1%). The most likely reason for this likely the high affinity of sugammadex for reversal of rocuronium-induced neuromuscular blockade.35 there was no change in the use of suxamethonium as an initial NMBD (7.2% versus 9.1%, P=0.3), sug-gesting that despite having a fast onset and a rapid and effective reversal agent, rocuronium was not viewed at this institution as an accept-able substitution for suxamethonium in the performance of a rapid sequence induction.

in conjunction with the change in nMBD choice over the studied time period, was a sig-nificant move toward the use of sugammadex for nMBD reversal in place of a more tradi-tional combination of neostigmine/atropine or neostigmine/glycopyrrolate. the use of



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11. Butterly a, Bittner ea, george e, sandberg Ws, eiker-mann M, Schmidt U. Postoperative residual curariza-tion from intermediate-acting neuromuscular blocking agents delays recovery room discharge. Br J anaesth 2010;105:304-9.

12. Schreiber JU, Mucha E, Fuchs-Buder T. Residual paraly-sis following a single dose of atracurium: results from a quality assurance trial. eur J anaesthesiol 2010;27:993-4.

13. cammu gv, smet v, De Jongh K, vandeput D. a pro-spective, observational study comparing postoperative residual curarisation and early adverse respiratory events in patients reversed with neostigmine or sugammadex or after apparent spontaneous recovery. anaesth intens care 2012;40:999.

14. Fortier LP, McKeen D, Turner K, de Médicis É, Warriner B, Jones PM, et al. the recite study: a canadian pro-spective, multicenter study of the incidence and sever-ity of residual neuromuscular blockade. anesth analg 2015;121:366-72.

15. Naguib M, Kopman AF, Ensor JE. Neuromuscular moni-toring and postoperative residual curarisation: a meta-analysis. Br J anaesth 2007;98:302-16.

16. naguib M, Kopman a. a survey of current Management of Neuromuscular Block in the United States and Europe. anesth analg 2010;111:110-19.

17. Eriksson LI, Sundman E, Olsson R, Nilsson L, Witt H, ekberg o, et al. Functional assessment of the pharynx at rest and during swallowing in partially paralyzed hu-mans: simultaneous videomanometry and mechanomy-ography of awake human volunteers. anesthesiology 1997;87:1035-43.

18. Sundman E, Witt H, Olsson R, Ekberg O, Kuylenstierna

able to all surgical patients, as this study only included general surgical and ent cases. sec-ondly, despite correcting for known confound-ers, there is always the possibility that other unmeasured differences between the groups exist that help explain the difference between groups. thirdly, and most importantly, the ret-rospective nature of this study means we can only postulate an association between the rou-tine use of sugammadex and the decrease in postoperative respiratory complications rather establish a causative effect.

Conclusions

this paper provides evidence that unre-stricted sugammadex use is associated with a reduction in postoperative respiratory morbid-ity. this unrestricted use is associated with an increased drug cost, but this would likely be offset by potential savings in the treatment of postoperative respiratory complications. the data presented is retrospective in nature and relies on medical record documentation and needs to be validated by a well-designed, pro-spective randomized trial.

Key messages

— residual paralysis following inter-mediate duration muscle relaxants is a common problem.

— residual paralysis has been linked with postoperative morbidity.

— Sugammadex has been shown to reduce the rate of residual paralysis when compared with neostigmine.

— this paper provides evidence that su-gammadex use is associated with reduced postoperative morbidity when compared with neostigmine or no reversal.

References

1. Kaan N, Kocaturk O, Kurt I, Cicek H. The incidence of residual neuromuscular blockade associated with single dose of intermediate-acting neuromuscular blocking drugs. Middle east J anaesthesiol 2012;21:535-41



29. Martinez-Ubieto J, Ortega-Lucea S, Pascual-Bellosta A, arazo-iglesias i, gil-Bona J, Jimenez-Bernardo t, et al. Prospective study of residual neuromuscular block and postoperative respiratory complications in patients re-versed with neostigmine versus sugammadex. Minerva anestesiol 2016;82:735-42.

30. Llauradó S, Sabaté A, Ferreres E, Camprubí I, Cabrera a. Postoperative respiratory outcomes in laparoscopic bariatric surgery: comparison of a prospective group of patients whose neuromuscular blockade was reverted with sugammadex and a historical one reverted with ne-ostigmine. rev esp anestesiol reanim 2014;61:565-70.

31. Ledowski T, Falke L, Johnston F, Gillies E, Greenaway M, De Mel a, et al. retrospective investigation of post-operative outcome after reversal of residual neuromuscu-lar blockade: sugammadex, neostigmine or no reversal. eur J anaesthesiol 2014;31:423-9.

32. Znamg J, Yu KF. What’s the relative risk? A method of converting the odds ratio in cohort studies of common outcomes. JaMa 1998;280:1690-1.

33. rock P, rich PB. Postoperative pulmonary complica-tions. curr op anaesthesiol 2003;16:123-32.

34. Qasseem AM, Snow V, Fitterman N, Hornbake Er, Law-rence va, smetana gW, et al. risk assessment for and strategies to reduce perioperative pulmonary complica-tions for patients undergoing noncardiothoracic surgery: a guideline from the american college of Physicians. annals intern Med 2006;144:575-80.

35. Suy K, Morias K, Cammu G, Has P, van Duijnhoven WGF, Heeringa M, et al. effective reversal of moder-ate rocuronium- or vecuronium-induced neuromuscular block with sugammadex, a selective relaxant binding agent. survey of anaesthesiol 2008;52:187-8.

36. ledowski t, Paech M, Patel B, schug s. Bronchial mu-cus transport velocity in patients receiving propofol and remifentanil versus sevoflurance and remifentanil anaes-thesia. anaesth analg 2006;102:1427-30.

37. videria r, vieira J. What rules of thumb do clini-cians use to decide whether to antagonise nondepolar-izing neuromuscular blocking drugs? Anaesth Analg 2011;113:1192-6.

38. eriksson li. evidence-based practice and neuromuscular monitoring: it’s time for routine quantitative assessment. anaesthesiology 2003;98:1037-9.

39. viby-Mogensen J. Postoperative residual curarization and evidence-based anaesthesia. Br J anaesth 2000;84:301-3.

40. Dimick JB, Weeks WB, Karia rJ, Das s, campbell DA Jr. Who pays for poor surgical quality? Building a business case for quality improvement. J am coll surg 2006;202:933-7.

r, eriksson li. the incidence and mechanisms of pha-ryngeal and upper esophageal dysfunction in partially paralyzed humans. Pharyngeal videoradiography and si-multaneous manometry after atracurium. anesthesiology 2000;92:977-84.

19. Eriksson LI. Reduced hypoxic chemosensitivity in par-tially paralysed man. A new property of muscle relax-ants? Acta Anaesthesiol Scand 1996;40:520-3.

20. Bissinger U, Schimek F, Lenz G. Postoperative residual paralysis and respiratory status: a comparative study of pancuronium and vecuronium. Physiol res 2000;49:455-62.

21. Murphy GS, Szokol JW, Franklin M, Marymont JH, avram MJ, vender Js. Postanesthesia care unit recov-ery times and neuromuscular blocking drugs: a prospec-tive study of orthopedic surgical patients randomized to receive pancuronium or rocuronium. anesth analg 2004;98:193-200.

22. Murphy GS, Szokol JW, Marymont JH, Greenberg SB, avram MJ, vender Js. residual neuromuscular blockade and critical respiratory events in the postanesthesia care unit. anesth analg 2008;107:130-7.

23. sauer M, stahn a, soltesz s, noeldge-schomburg g, Mencke T. The influence of residual neuromuscular block on the incidence of critical respiratory events. a randomised, prospective, placebo-controlled trial. eur J anaesthesiol 2011;28:842-8.

24. Berg H, Roed J, Viby-Mogensen J, Mortensen CR, Eng-baek J, skovgaard lt, et al. residual neuromuscular block is a risk factor for postoperative pulmonary compli-cations. a prospective, randomized, and blinded study of postoperative pulmonary complications after atracurium, vecuronium and pancuronium. acta anaesthesiol scand 1997;41:1095-103.

25. Ledowski T, Hillyard S, O’Dea B, Archer R, Vilas-Boas F, Kyle B. Introduction of sugammadex as standard re-versal agent: impact on the incidence of residual neu-romuscular blockade and postoperative patient outcome. indian J anaesth 2013;57:46-51.

26. Naguib M. Sugammadex: another milestone in clini-cal neuromuscular pharmacology. anaesth analg 2007;104:575-81.

27. Welliver M, McDonough J, Kalynych n, redfern r. Dis-covery, development, and clinical application of sugam-madex sodium, a selective relaxant binding agent. Drug Des Devel ther 2008;2:49-59.

28. Brueckmann B, sasaki n, grobara p, li MK, Woo t, de Bie J, et al. Effects of sugammadex on incidence of postoperative residual neuromuscular blockade: a rand-omized, controlled study. Br J anaesth 2015;115:743-51.

Authors’ contributions.—Benjamin L. Olesnicky was involved in the design of the study, data collection, collation and analysis and preparation of the manuscript. Catherine Traill was involved in data collection, collation and preparation of the manuscript. Frank B. Marroquin-Harris was involved in data collation, analysis and preparation of the manuscript.Funding.—Funding was entirely provided through the Department of Anesthesia at Royal North Shore Hospital. None of the con-tributors received any fees or funding for performance of this study.Conflicts of interest.—The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.Acknowledgments.—Dr Blake Kesby and Dr Simon Collins were involved in data collection.Article first published online: October 5, 2016. - Manuscript accepted: October 4, 2016. - Manuscript revised: September 13, 2016. - Manuscript received: June 17, 2016.


cently, extracorporeal membrane oxygenation (ecMo) has become increasingly used in pa-tients of severe cardio-pulmonary failure not responsive to conventional therapy.2 the im-provement in equipment and increased experi-ence in several specialized high-volume cen-ters has allowed the extension of its indication

since the first successful use of an artificial heart/lung apparatus by John gibbon in

1953, the extracorporeal circulation technique has been optimized and its applicability ex-panded to multiple clinical settings.1 More re-


altered liver function in patients undergoing veno-arterial extracorporeal

membrane oxygenation therapyaaron BlaNDiNo ortiZ 1, irene laMaNNa 1,

elio aNtoNUcci 1, selene PoZZeBoN 1, antonio M. Dell’aNNa 1, Jean-louis ViNceNt 1, Daniel de BacKer 1, 2, Fabio s. taccoNe 1 *

1Department of intensive care, erasme Hospital, Université libre de Bruxelles (UlB), Brussels, Belgium; 2Department of intensive care and emergency, cHirec, Hopital de Braine-l’alleud Waterloo, Braine-l’alleud, Belgium*corresponding author: Fabio s. taccone, Department of intensive care, Hôpital erasme, Université libre de Bruxelles (UlB), route de lennik 808, 1070 Brussels, Belgium. e-mail: [email protected]


lavoro: 11442-Mastitolo breve: liVer FailUre aND ecMoprimo autore: BlaNDiNo ortiZpagine: 255-65citazione: Minerva anestesiol 2017;83:255-65

a B s t r a c tBacKgroUND: Multiple organ dysfunction can occur in patients undergoing veno-arterial extra corporal membrane oxygenation (Va-ecMo); however, liver function has not been well studied in this setting.MetHoDs: in a review of our institutional ecMo database (N.=162), we collected aspartate (ast) and alanine (alt) transaminases, total bilirubin and international normalized ratio (iNr) at time of ecMo initiation (baseline) and once daily during therapy in patients who survived for at least 24 hours. Elevated liver enzymes (ELE) were defined if AST and/or ALT were >200 UI/L, and acute liver failure (ALF) as the presence of an INR ≥1.5, new onset encephalopathy and an elevated total bilirubin concentrations.resUlts: on a total of 80 patients undergoing Va-ecMo, 69 patients met the inclusion criteria (cardiogenic shock, N.=52; refractory cardiac arrest, N.=15; cardiac failure following severe arDs, N.=2). of them, 45 (65%) had early ele after ecMo initiation (median highest ast and alt were 528 [251-2606] Ui/l and 513 [130-1031] Ui/l, respectively). two thirds of patients with ele (N.=30) had a progressive reduction in ast and alt, but the levels were normalized only after 5 (5-6) days. among patients with ele, 21/45 (47%) had ast and/or alt levels above >1000 Ui/l. a total of 14/69 (20%) patients developed ALF. However, mortality rate was not significantly higher in patients with ELE or ALF when compared to others.coNclUsioNs: a substantial proportion of patients needing Va-ecMo have early ele, which usually improves over days. the prognostic implications are not evident.(Cite this article as: Blandino ortiz a, lamanna i, antonucci e, Pozzebon s, Dell’anna aM, Vincent Jl, et al. altered liver function in patients undergoing veno-arterial extracorporeal membrane oxygenation therapy. Minerva anestesiol 2017;83:255-65. Doi: 10.23736/s0375-9393.16.11442-7)Key words: extracorporeal membrane oxygenation - liver failure - enzymes - treatment outcome.

Minerva anestesiologica 2017 March;83(3):255-65 Doi: 10.23736/s0375-9393.16.11442-7


comment in p. 239.

BlaNDiNo ortiZ liVer FailUre aND ecMo


ings in this setting and the large heterogeneity in the definition of liver dysfunction, the aim of this study was to evaluate the occurrence and time-course of ischemic liver dysfunction in adult patients undergoing Va-ecMo as well as its impact on survival.


Study population

this study was performed in the 35-bed De-partment of Medico-surgical intensive care of the erasme University Hospital in Brus-sels, Belgium. in this institution, the ecMo program was initiated in November 2008 and substantially increased (>35 cases/year) since 2010. We reviewed our database of adult (>18 years) patients who were treated with Va-ecMo from November 2008 until December 2013. We excluded from the analysis patients who survived less than 24 hours to analyze the time-course of liver function and to avoid oth-er factors (e.g. massive bleeding, decision of life-sustaining therapies in case of brain death) than liver dysfunction to influence patients’ outcome. the study was approved by the eth-ics committee of erasme Hospital, which waived the need for informed consent.

ECMO management

indications for ecMo were recorded in the database. Va-ecMo was mainly implanted with a percutaneous procedure using heparin-coated cannulas (18-22 Fr arterial cannula and 22-25 Fr venous cannula, Medtronic, Minne-apolis MN, Usa). However, in patients who could not be weaned from cardio-pulmonary bypass (cPB), a central cannulation was per-formed directly by cardiac surgeons. a cen-trifugal blood pump (revolution blood pump, sorin, Milan, italy) was initially set at a blood flow of 3.5-5.0 L/min (based on the body sur-face area). ecMo priming consisted of 700 ml of Plasmalyte solution (Baxter Healthcare Corporation, Deerfield, IL, USA). In patients showing clinical signs of limb hypoperfusion, the leg was perfused with an anterograde sin-

to other conditions.3-7 according to the extra-corporeal life support organization registry, ecMo has been used in over 73,000 cases since 1990; 25% of them were adult critically ill patients, 70% were eventually weaned and 58% were discharged or transferred to a reha-bilitation center after the icU stay.8

Patients receiving ecMo often have other organ dysfunctions, which may be, at least in part, due to the low cardiac output state and severe hypoxemia before ecMo initiation.9 Moreover, prolonged ecMo therapy is often complicated by a systemic inflammatory reac-tion with persistent vasoplegia and coagulopa-thy, which can contribute to the development of multiple organ failure.10 as an example, neurological complications related to the ecMo implantation (e.g. seizures, cerebral infarctions or hemorrhage) can be observed in 5-8% of adult patients 11 and are associated with lower survival rates. acute kidney injury (aKi) may develop in more than 30% of pa-tients receiving ecMo 9, 12 and has been also associated with a worse outcome.

Few data are available on the impact of al-tered liver function in patients with ecMo. in a retrospective analysis of 69 consecu-tive adult patients treated with veno-arterial ecMo (Va-ecMo), Heilmann et al. reported that hepatic failure (defined as increased trans-aminases and bilirubin), even when occurring concomitantly with increased inflammatory state and altered acid–base balance, was not associated with poor outcome.13 in a more re-cent single-center retrospective cohort study including a total of 132 patients (N.=54 on Va-ecMo, N.=64 on veno-venous ecMo, N.=14 with sequential therapy), Mazzeffi et al. reported that approximately 10% developed acute liver failure (defined as increased biliru-bin and iNr with acute encephalopathy) and had a high mortality.14 chen et al. showed that in patients suffering from acute myocardial infarction complicated with refractory shock necessitating Va-ecMo, the combination of renal, hepatic (e.g. bilirubin ≥6.0 mg/dL) and neurological dysfunction was more common in non-survivors than in survivors.15

Considering the limited and conflicting find-

liVer FailUre aND ecMo BlaNDiNo ortiZ


transaminases, lactate dehydrogenase (lDH, normal values < 200 Ui/l), prothrombin time (Pt, normal values >70%), the international normalized ratio (INR, normal values ≤1.2), total bilirubin (normal values ≤1.2 mg/dL) and fibrinogen (normal values >150 mg/dL) at time of ecMo initiation (baseline) and then once daily during the following days during ecMo therapy. We also collected admission and maximal concentrations of total creatine phosphokinase (cK) and troponin t (tnt), as markers of concomitant muscular and myocar-dial injury.

Definitions

considering that the main mechanisms of liver damage in Va-ecMo patients is severe hypoperfusion or shock state,18 we used liver transaminase enzymes to characterize the isch-emic injury. elevated liver enzymes (ele) were arbitrarily defined by the elevation of ast and/or alt were >200 Ui/l. this cut-off was selected to identify “mild” ischemic liver injury in this setting. among patients with ele and according to recommended cut-offs,18 we defined “hypoxic hepatitis” (HH) as an in-crease in ast and/or alt above 20 times the upper normal ranges (≤50 UI/L), e.g. >1000 Ui/l. We also reported the time to the highest ast and/or alt values since ecMo imple-mentation. We considered as “normalized” liver enzymes as ast/alt value <100 Ui/l, as most of these patients may present with he-molysis and persistent transaminase above 50 Ui/l, independently from liver hypoxia. the time to normalized liver enzymes was also re-corded. Finally, as ast/alt assessment is not accurate to provide significant information on liver function, we defined ALF using previous-ly published criteria, which included an iNr ≥1.5, new onset encephalopathy (defined as a patient not obeying to orders) and an elevated total bilirubin in absence of chronic liver dis-ease.19

Massive bleeding was defined as transfu-sion of >10 rBc units in 24 hours or >4 rBc units in 1 hour.20 DIC was defined according to standard criteria.21 acute kidney injury

gle lumen 8-Fr catheter (arrow inc., reading, Pa, Usa) at the end of ecMo implantation. a heat exchanger (Hico Variotherm 550; Hirtz, cologne, germany) was used on the ecMo circuit to maintain body temperature at 37 °c (or at 33 °c for 24 hours in patients after cardiac arrest). Monitoring of cardiac func-tion, and in particular the impact of ecMo on left ventricular afterload, was performed in all patients using repeated echocardiography and/or a pulmonary artery catheter. systemic anticoagulation was achieved by intravenous administration of unfractionated heparin; how-ever, anticoagulation was not given to patients resuscitated from cardiac arrest during the first 24 hours after ECMO implantation or in those patients having bleeding and needing red blood cell transfusions. Mean arterial pressure (MaP) was maintained >70 mmHg by adjust-ing ECMO blood flow (up to a maximum of 5 l/min) and/or by giving norepinephrine. Pa-tients with major bleeding were treated with fluids and blood products (to keep the hemo-globin level >7 g/dl and the ratio between rBc and fresh frozen plasma close to 1 after the fourth unit).

Data collection

We collected demographic characteristics, presence of pre-existing chronic diseases (on hospital or icU admission, whichever came first) and admission diagnosis for all patients. severity of illness was assessed on the day 1 of ecMo using the acute Physiology and chronic Health evaluation (aPacHe) ii score 16 and the sequential organ Failure as-sessment (soFa) 17 scores. We recorded the need for mechanical ventilation (MV), vaso-active drugs, blood transfusions and the oc-currence of systemic complications [massive bleeding, infections (site and pathogens), he-molysis, disseminated intravascular coagula-tion (Dic)], length of intensive care unit (icU) stay and overall icU mortality. ecMo data were also recorded, including blood flow, gas and oxygen flow, multiple runs and duration of ecMo support. to assess liver function, we collected aspartate (ast) and alanine (alt)



Va ecMo included peripheral cannulation (femoro-femoral) except in 3 patients after cardiac surgery (central ecMo). the median duration of ecMo was 6 (3-9) days and the icU length of stay was 12 (7-21) days. in 13 patients (19%) treated for refractory cardiac arrest, 24-hour hypothermia (body tempera-ture 32-34 °c) was used during ecMo. the median of aPacHe ii score was 23; only two patients had pre-existing liver cirrhosis (both child-Pugh a). overall icU mortality was 54% (N.=37). at ecMo implantation, all pa-tients were on mechanical ventilation, while 66 (96%) and 58 (84%) were on vasopressor and inotropic therapy, respectively. Median lactate levels were 5.0 (2.9-9.4) meq/l. the median initial ECMO blood flow, gas flow and Fio2 were 4.0 (3.0-4.0) l/mim, 3.0 (2.0-4.5) l/min and 1.0 (0.8-1.0), respectively.

a total of 45 (65%) patients had ele; me-dian ast and alt at ecMo initiation were 92 (48-503) Ui/l and 81 (33-283) Ui/l, re-spectively while the highest ast and alt val-ues during ecMo were 528 (251-2606) Ui/l and 513 (130-1031) Ui/l, respectively. the median time to ele development was 2 (0-2) days and the time to the highest ast/alt values was 2 (1-3) days. Figure 1 shows the time-course over the first 3 days of AST, ALT, bilirubin and iNr of patients with and with-out ELE; no significant difference in INR and bilirubin between groups was observed. also, fibrinogen levels were similar between ELE and no-ele groups (on admission: 215 (177-322) mg/dl vs. 236 (176-307) mg/dl; lowest value: 139 (89-195) mg/dl vs. 145 (100-223) mg/dl, respectively). of all the patients with ele, 30 (67%) showed a progressive reduc-tion in ast and alt; however the median time to normalized ast/alt levels was 5 (4-6) days. Patients with ele had similar clinical and ecMo characteristics than those without ele (tables i, ii). overall mortality rate was higher, although not statistically significant, in ele patients than others (27/45, 60% vs. 10/24, 42%, P=0.21, Figure 2).

among the 45 patients with ele, 25 (56%) had the criteria for HH. aPacHe ii score — 23 (16-28) vs. 25 (22-28) — on ecMo inser-

(AKI) was defined according to AKIN crite-ria.22 Hemolysis was defined as an LDH ≥600 iU/l and total bilirubin >1.2 mg/dl, without considering the reticulocyte count as erythro-poiesis may be impaired during critical illness. Potential hepatotoxic drugs/interventions in-cluded paracetamol, β-lactams or quinolones, trimetoprim-sulfametoxazol (tMP-sMZ), isoniazid, azoles, metronidazole, amiodarone, some chemotherapy, parenteral nutrition and anti-epileptic drugs.


statistical analyses were performed using iBM sPss statistics 21 for Windows. Descrip-tive statistics were computed for all study vari-ables. a Kolmogorov-smirnov test was used, and histograms and normal-quartile plots were examined to verify the normality of distribution of continuous variables. Data are presented as count (percentage), mean±sD or median (25th-75th percentiles). Differences between groups were assessed using a Fisher’s exact test for categorical variables and student t-test or a Mann-Whitney for continuous variables, if nor-mally or not normally distributed, respectively. Data from repeated measures were analyzed us-ing a two-way analysis of variance (aNoVa), with correction for missing values, followed by a Bonferroni post-hoc analysis to evaluate dif-ferences between groups for each time point (parametric tests). a Friedman test for repeated measurements in non-parametric variables was used, followed by a post-hoc Dunn’s test to an-alyze differences at each time point. a P<0.05 was considered as statistically significant.

Results

on a total of N.=162 included in our da-tabase, 82 patients underwent veno-venous ecMo and were then excluded. among the 80 patients treated with Va-ecMo, 11 were excluded because of early death (10 after ecPr) and 69 patients were eventually ana-lyzed (table i); 52 patients had cardiogenic shock, 15 refractory cardiac arrest and 2 severe arDs associated with myocardial depression.



Table I.—�Characteristics of the study population. Data are reported as count (percentage) or median (IQRs).all patients

(N.=69)ele

(N.=45)No-ele(N.=24)

alF(N.=14)

No-alF(N.=55)

age, years 53 (40-60) 52 (39-62) 54 (42-58) 53 (38-61) 53 (41-59)Body weight, kg 75 (70-80) 75 (70-82) 70 (67-85) 73 (67-82) 75 (70-80)Male, N. (%) 48 (70) 31 (69) 17 (71) 9 (64) 39 (71)Medical admission, N. (%) 61 (88) 40 (89) 21 (88) 12 (86) 49 (89)comorbid diseases

Heart disease, N. (%) 8 (12) 5 (11) 3 (13) 2 (14) 6 (11)Diabetes, N. (%) 6 (9) 4 (9) 2 (8) 1 (7) 5 (9)coPD/asthma, N. (%) 3 (4) 2 (4) 1 (4) - 3 (5)chronic renal disease, N. (%) 2 (3) 1 (2) 1 (4) - 2 (4)liver cirrhosis, N. (%) 2 (3) 1 (2) 1 (4) 1 (7) 1 (2)cancer, N. (%) 7 (10) 3 (7) 4 (17) 1 (7) 6 (11)immunosuppressive agents, N. (%) 9 (13) 4 (9) 5 (21) 2 (14) 7 (12)

on ecMo insertionaPacHe ii score 24 (18-28) 24 (18-28) 23 (19-26) 25 (17-28) 23 (19-29)lactate, meq/l 5.0 (2.9-9.4) 5.0 (2.9-9.4) 6.8 (3.1-9.1) 3.2 (2.4-8.9) 6.1 (3.0-9.4)ecPr, N. (%) 15 (22) 10 (22) 6 (25) 1 (7) 14 (25)cK, Ui/l 813 (487-1765) 813 (567-1077) 762 (436-1796) 837 (713-1887) 813 (452-1061)tnt, ng/l 215 (115-431) 217 (105-415) 212 (167-474) 177 (120-403) 217 (124-438)

During ecMo therapyinfections, N. (%) 51 (74) 32 (71) 20 (83) 12 (86) 39 (71)severe bleeding, N. (%) 30 (43) 18 (40) 12 (50) 4 (29) 26 (47)Dic, N. (%) 11 (16) 8 (18) 3 (13) 1 (7) 10 (18)Hemolysis, N. (%) 3 (4) 2 (4) 1 (4) 1 (7) 2 (4)total rBc transfused, N. # 6 (3-9) 5 (3-10) 6 (4-9) 5 (3-8) 6 (4-10)total FFP transfused, N. # 7 (4-11) 7 (4-10) 7 (3-11) 6 (3-11) 7 (3-11)Norepinephrine therapy, N. (%) 66 (96) 42 (93) 24 (100) 14 (100) 52 (95)Maximum Ne dose, mcg/min # 70 (25-137) 83 (30-128) 45 (19-180) 45 (26-96) 78 (25-141)Dobutamine therapy, N. (%) 58 (84) 39 (87) 19 (79) 12 (86) 46 (84)Maximum DB therapy, mcg/kg/min # 15 (10-20) 18 (10-20) 14 (5-20) 20 (12-20) 15 (10-20)MV, N. (%) 69 (100) 45 (100) 24 (100) 14 (100) 55 (100)Hypothermia, N. (%) 13 (19) 7 (16) 7 (29) 2 (14) 11 (20)aKi, N. (%) 39 (57) 26 (58) 12 (50) 7 (50) 32 (58)crrt, N. (%) 32 (46) 21 (47) 10 (42) 5 (36) 27 (49)Duration of ecMo, days 6 (3-9) 6 (3-9) 5 (3-8) 7 (4-10) 5 (3-9)Multiple ecMo, N. (%) 15 (22) 10 (22) 4 (16) 2 (14) 13 (24)Peak cK, iU/l 1100 (913-1967) 1450 (913-2017) 1044 (883-1910) 1272 (912-1887) 1100 (913-1992)Peak tnt, ng/l 389 (215-678) 355 (210-678) 413 (264-695) 380 (221-750) 389 (216-675)at least one hepatotoxic drug, N. (%) 69 (100) 45 (100) 24 (100) 14 (100) 55 (100)Paracetamol, N. (%) 30 (44) 19 (42) 12 (50) 4 (29) 26 (47)β-lactams/quinolones, N. (%) 66 (96) 42 (93) 24 (100) 13 (93) 53 (96)sMt/tMt, N. (%) 1 (1) - 1 (4) - 1 (2)isoniazid, N. (%) - - - - -azoles, N. (%) 9 (13) 6 (13) 3 (13) - 9 (16)Metronidazole, N. (%) 4 (6) 1 (2) 3 (13) - 4 (7)amiodarone, N. (%) 43 (62) 27 (60) 15 (63) 12 (86) 31 (56)chemotherapy, N. (%) 7 (10) 3 (7) 4 (17) 1 (7) 6 (11)PN, N. (%) - - - - -aeDs, N. (%) 6 (9) 4 (9) 3 (13) 2 (14) 4 (7)

outcomesele, N. (%) 45 (65) 45 (100) - 11 (79) 34 (61)alF, N. (%) 14 (20) 11 (24) 3 (13) 14 (100) -HH, N. (%) 25 (39) 25 (56)* - 11 (79) * 14 (31)icU length of stay, days 12 (7-21) 12 (8-20) 15 (7-20) 10 (7-20) 12 (7-22)icU mortality, N. (%) 37 (54) 27 (60) 10 (42) 7 (50) 30 (55)

coPD: chronic obstructive pulmonary disease; sMt/tMt: sulfamethoxazole/trimethoprime; aPacHe: acute physiology and chronic health evaluation; ecPr: extracorporeal cardiopulmonary resuscitation; Dic: disseminated intravascular coagulation; MV: mechanical ventilation; aKi: acute kidney injury; crrt: continuous renal replacement therapy; ele: elevated liver enzymes; HH: hypoxic hepatitis; alF: acute liver failure; icU: intensive care Unit; PN: parenteral nutrition; aeDs: antiepileptic drugs; rBc: red blood cells; FFP: fresh frozen plasma; Ne: norepinephrine; DB: dobutamine; cK: creatine kinase; tnt: troponin t.#Over the first 3 days of ECMO. P<0.05 (ELE vs. no-ele/alF vs. no-alF).



tion as well as the occurrence of ecPr (6/25 vs. 4/20), bleeding (12/25 vs. 6/20), Dic (5/25 vs. 3/20) or the use of vasopressors (22/25 vs. 20/20) and inotropic agents (21/25 vs. 18/20) were similar between ele patients with and without HH. all other demographics and co-morbidities were also similar between groups (data not shown). Bilirubin (on admission: 1.3 [0.8-2.0] mg/dl vs. 0.6 [0.4-1.2] mg/dl, P=0.002; highest value: 4.2 [2.4-9.9] mg/dl vs. 1.5 [0.9-2.4] mg/dl, P<0.001) and iNr levels (on admission: 2.0 [1.5-2.8] vs. 1.5 [1.1-1.8], P=0.001; highest value: 3.6 [2.7-6.1] vs. 1.9 [1.6-2.8], P<0.001) were higher in patients with ele and HH when compared to those with ELE without HH, while fibrinogen lev-els were similar. the proportion of patients showing normalized liver enzymes was lower, although not statistically different, in ele pa-tients with HH when compared to ele with-out HH (14/25 vs. 16/20; P=0.11), while the time to normalized liver enzymes was similar: 5 (4-6) vs. 5 (4-5) days, respectively. Mortality rate was higher, although not statistically sig-nificant, in ELE patients with HH when com-pared to those with ele without HH (18/25, 72% vs. 9/20, 45%, P=0.12).

a total of 14 (20%) patients had alF; pa-tients with alF had similar characteristics than those without alF (tables i, ii). How-ever, initial ast (591 [47-2026] Ui/l vs. 80 [44-312] Ui/l; P=0.001) and alt (377 [43-1983] vs. 65 [26-162] Ui/l; P=0.002) values were higher in alF patients than others, while total bilirubin and iNr were similar. the me-dian time to alF development was 2 (1-2) days. among those 14 patients, 12 (86%) had the criteria for HH. Mortality rate was similar between patients with and without alF (7/14, 50% vs. 30/55, 55%, P=0.77).

Discussion

in our experience, ele occurs in about two thirds of patients undergoing Va-ecMo, and 56% of them also have the criteria for HH. also, alF occurred in 20% of patients, mostly in patients with HH. similar demographics, clinical, hemodynamic and ecMo character-

Figure 1.—a) time-course of ast and alt in patients with and without elevated liver enzymes (ele); B) time-course of iNr and total bilirubin in patients with and without el-evated liver enzymes (ele).

Figure 2.—icU mortality according to the presence of el-evated liver enzymes (ele), hypoxic hepatitis (HH) or acute liver failure (alF).

a

B

tran

sam

inas

es (i

U/l

)

no-ele

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ele

ele

Bilirubin (mg/dl)

ast

Day 1

Day 1

Day 1

Day 1

Day 2

Day 2

Day 2

Day 2

Day 3

Day 3

Day 3

Day 3

alt

iNr

ele HH alF

Yes No80

70

60

50

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30

20

10

0

icU

Mor

talit

y (%

)



nificant reduction in the portal vein flow, which will contribute to diminished hepatic oxygen supply and cause centro-lobular damage.25 the biological hallmark of hypoxic liver cell necrosis is a massive increase in serum ast/alt levels, which exceeds >10 times the up-per limit of normal values in half of patients.23 overall, the survival to hospital discharge of patients suffering from HH is estimated around 50%.23 Moreover, HH is also a known and treatable cause of alF; however, the diagno-sis of alF remains challenging as some of its typical biological alterations, such as spontane-ous hypoglycemia, high levels of serum ammo-nia, lactic acidosis and coagulation disorders, are not always present or distinguishable from liver abnormalities due to the underlying criti-cal illness.26 in our study, elevation of ast and alt was frequent and in more than half of cas-es these abnormalities met the criteria for HH.

istics were observed among groups. compli-cations rates and mortality were not different.

among splanchnic organs, the liver appears to be the most vulnerable to hypoperfusion. the so-called “ischemic” or “hypoxic” hepatitis oc-curs every 2.5 of every 100 icU admissions and is typically associated with an acute car-diac event (e.g. low cardiac output, cardiogenic shock or cardiac arrest) in almost 80% of cases; also, about 53% of these patients present a doc-umented hypotensive event of any duration.23 interestingly, venous congestion is also an im-portant determinant for hypoxic liver injury during hypotension; any higher pressures in the venous system of the body will interfere with portal circulation because of the low-pressure gradient and the absence of a valvular mecha-nism available in this circulation.24 Moreover, the intense adrenergic and neuroendocrine re-sponses to circulatory failure may induce a sig-

Table II.—�Hemodynamics and ECMO characteristics over the first 3 days of therapy, according to the presence of liver abnormalities.

Variable group Day 1 Day 2 Day 3 aNoVa *

MaP, mmHg ele 76 (71-86) 74 (70-85) 81 (73-86) 0.53No-ele 80 (74-88) 73 (69-81) 79 (72-89)

alF 83 (75-86) 73 (67-77) 80 (67-84) 0.16No-alF 78 (73-87) 74 (70-85) 80 (72-88)

Hr, bpm ele 90 (77-108) 88 (76-109) 85 (72-103) 0.41No-ele 102 (80-116) 85 (78-109) 99 (79-113)

alF 92 (68-118) 84 (68-119) 91 (78-115) 0.76No-alF 92 (79-108) 88 (77-105) 85 (71-105)

cVP, mmHg ele 12 (9-14) 12 (10-17) 12 (9-15) 0.61No-ele 10 (8-12) 10 (8-15) 12 (10-15)

alF 12 (10-12) 11 (8-12) 12 (10-13) 0.28No-alF 11 (9-14) 12 (10-17) 12 (9-15)

lactate, meq/l ele 5.0 (2.9-9.4) 3.0 (1.4-4.6) 2.2 (1.2-3.1) 0.79No-ele 7.2 (3.1-9.2) 2.4 (1.1-4.7) 1.5 (1-2.4)

alF 3.2 (2.4-9.1) 2.2 (1.3-5.0) 2.2 (1.2-2.4) 0.71No-alF 6.1 (3.2-9.4) 3.3 (1.3-4.6) 2.0 (1.1-2.9)

Hemoglobin, g/dl ele 9.4 (8.4-12.3) 9.1 (8.6-10) 9.2 (8.6-9.9) 0.13No-ele 8.7 (8.0-10.8) 8.8 (8.0-9.3) 8.6 (8.1-9.1)

alF 10.1 (8.4-12.3) 10.1 (8.5-11.3) 9.0 (8.6-10.1) 0.34No-alF 9.1 (8.2-11.1) 9.0 (8.4-9.6) 8.7 (8.2-9.5)

ECMO blood flow, L/min ele 3.7 (3.0-4.0) 4.0 (3.1-4.1) 4.1 (3.2-4.2) 0.54No-ele 3.6 (3.2-4.2) 3.8 (3.2-4.0) 3.8 (2.9-4.0)

alF 3.8 (3.1-4.0) 4.1 (3.4-4.2) 4.0 (3.4-4.3) 0.34No-alF 3.6 (3.1-4.1) 4.0 (3.2-4.1) 4.0 (3.1-4.1)

ecMo Fio2 ele 1.0 (0.5-1.0) 1.0 (0.6-1.0) 1.0 (0.6-1.0) 0.74No-ele 0.7 (0.5-1.0) 0.7 (0.6-0.8) 0.7 (0.6-0.8)

alF 1.0 (0.6-0.8) 1.0 (0.6-0.7) 1.0 (0.6-0.7) 0.81No-alF 1.0 (0.5-1.0) 1.0 (0.6-0.9) 1.0 (0.6-1.0)

MaP: mean arterial pressure; cVP: central venous pressure; Hr: heart rate; ele: elevated liver enzymes; alF: acute liver failure.* comparing ele vs. no-ele and alF vs. no-alF (group and time interaction).



Mazzefi et al.14 used a similar definition for alF than ours but reported a lower inci-dence (8%); the hospital mortality rate was higher in alF patients when compared to oth-ers (81% vs. 46%, P=0.001). Nevertheless, cardiogenic shock, with subsequent “hypoxic liver injury”, occurs more frequently among VA-ECMO patients while Mazzeffi et al. in-cluded also VV-ecMo patients, who are at lower risk of liver hypoperfusion.14 interest-ingly, the mortality rate was similar in their study (49%) and in ours (54%), even though we included only Va-ecMo patients, who are expected to have a higher mortality than VV-ecMo.34, 35 Moreover, in the absence of other demographic, clinical and hemodynamic data, it is difficult to understand the reasons for a higher mortality rate in the alF group in the Mazzeffi’s Study,14 as well as whether alF was an independent determinant of mor-tality or represented just a marker of sever-ity (e.g. multiple organ failure occurring af-ter cardiogenic shock). in a second study by Heilmann et al.,13 liver dysfunction, and not alF, was evaluated by the assessment of in-creased ast, alt or total bilirubin. the oc-currence of these abnormalities was around 40% but it included also mild alterations of liver enzymes without significant clinical rel-evance and might explain the lack of correla-tion with mortality in this cohort.14 in another study, chen et al. analyzed the occurrence of ALF using the specific hepatic SOFA sub-score;15 15/36 patients eventually developed alF during their icU stay and their mortal-ity was higher than in patients without alF. Nevertheless, only ecPr patients treated with Va-ecMo were included in this study; in the setting of prolonged resuscitation after car-diac arrest, hypoxic liver injury is not a rare complication and is triggered by the duration of resuscitation attempts and is also associ-ated with increased icU mortality.36 thus, it is difficult to extrapolate these findings to a more heterogeneous population of Va-ecMo patients, including post-cardiotomy heart fail-ure and acute myocardial infarction. Finally, in a single-center study (N.=240), roth et al. reported that alkaline phosphatase and to-

the high prevalence of HH among patients with ele could be explained by the severity of the circulatory failure, which required ecMo after failure of medical therapy. Nevertheless, we did not directly assess liver blood flow nei-ther quantify hepatic hypoxia. as an example, the use of indocyanine green plasma disappear-ance rate (icg-PDr) can 27 or the measurement of supra-hepatic vein saturation or transcutane-ous hepatic near-infrared spectroscopy may provide more information on liver function and perfusion.28, 29 Nevertheless, these tools are not easily available and the diagnosis of HH is still largely based on the measurement of ast/alt levels.

We did not find any particular differences in demographics, clinical or ecMo characteris-tics between patients with and without ele or with and without alF. in particular, although it is recommended to keep central venous pres-sure (cVP) as low as possible to preserve portal circulation in the case of liver hypoperfusion,25 similar cVP values were observed between groups in this study. Also, ECMO flow, which is obviously a determinant of splanchnic per-fusion, was similar among groups. We could not assess global flow as measurement of car-diac output during Va-ecMo is extremely biased by several confounders.30 interestingly, normalization of liver enzymes alterations oc-curred in most patients, although it required several days. the mechanisms undergoing re-duction of liver enzymes are largely unrecog-nized in this setting, and are probably related to the improvement in liver perfusion and oxy-genation due to the optimization of systemic hemodynamics using Va-ecMo. it is possible that a reduction in inflammation and immune dysregulation, as shown in acute on chronic liver failure,31 or the activation of adult liver stem/progenitor cells 32 could also contribute to hepatic recovery. importantly, as some of these patients underwent ecPr and may suf-fer from persistent and extended post-anoxic brain injury, clinicians should recognize that Va-ecMo can adequately support liver func-tion for several days so that some of these pa-tients may become potential liver donors after complete functional recovery.33



function.18 similarly, one may argue that co-agulation disorders could be due to ecMo implementation; however, in a recent study, ecMo therapy, at least when initiated for respiratory support in adults, did not influ-ence coagulation parameters.39 Forth, we did not routinely perform morphologic exams of the liver (e.g. ultrasound); however, hepatic echography may be of interest to exclude other causes of ischemic liver injury (vascular clot-ting) and to identify signs of chronic liver dis-ease and have a limited diagnostic/prognostic role in the setting of HH.18 Finally, our study cohort included only 69 patients; we excluded patients who died early and who may have presented with a multiple organ failure since the admission. Nevertheless, early mortality is usually related to the severity of the initial in-jury rather than to organ failures. Moreover, as no previous study had used the same definition of ele, we could not perform a sample size calculation to assess the validity of our analy-sis, which might be then underpowered. Fi-nally, the generalizability of our results might be limited, as the study population was quite heterogeneous and findings reflect the experi-ence at a single center.

Conclusions

liver dysfunction during ecMo should be further evaluated in prospective large studies to better investigate its association with out-come.

Key messages

— in this study, elevation of liver en-zymes occurred in 65% of patients.

— among patients with elevation of liver enzymes, 21/45 (47%) had the criteria of hypoxic hepatitis.

— two thirds of patients with elevated liver enzymes had a normalization of this alteration within 5 days since ecMo ini-tiation.

— alteration of liver enzymes was not associated with poor outcome.

tal bilirubin were the strongest predictors for 30-day mortality among patients undergoing Va-ecMo therapy following cardiovascu-lar surgery.37 Furthermore, derangements of these liver variables are also caused by sep-sis or iatrogenic pharmacological effects in this patients’ population and may not reflect liver hypoperfusion.38 thus, differences in ALF definition and heterogeneity with other cohorts may explain the conflicting data with previous studies, where ALF was significantly associated with poor outcome.

Limitations of the study

this study has several limitations. First, we did not assess serum ammonium levels and the occurrence of encephalopathy could be due to other reasons (e.g. post-anoxic injury, sepsis) than alF. similarly, most of these patients re-ceived sedative agents that may confound the assessment of encephalopathy. other potential pre-existing diseases (e.g. microvascular dis-ease, aging) might also interfere with the di-agnosis of liver encephalopathy, also because we could not collect specific data on minimal alterations of consciousness or delirium. De-spite all these limitations, the same defini-tion of alF has also been previously used in critically ill patients undergoing Va or VV-ecMo.14 second, some increase in bilirubin levels could be due to hemolysis, and we did not routinely measure free hemoglobin or hap-toglobin in all patients. these limitations may also explain why we observed three patients with the alF criteria but without ele. third, the accuracy of alF diagnosis could be altered by concomitant acute myocardial or muscular injuries, which may also induce elevation of AST/ALT or bilirubin. However, no signifi-cant difference in cK and tnt concentrations were observed between patients with alF or ELE and others. Moreover, although signifi-cant increase of alt/ast without elevation of bilirubin may suggest a “non-hepatic” in-volvement, the definition of hypoxic hepatic injury still relies on transaminase assessment while jaundice is generally rare and transient and occurs only in case of severe loss of liver



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Authors’ contributions.—Aaron Blandino Ortiz and Irene Lamanna equally contributed as first author.Conflicts of interest.—The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.Article first published online: November 18, 2016. - Manuscript accepted: November 17, 2016. - Manuscript revised: November 11, 2016. - Manuscript received: May 20, 2016.


in normal subjects has led some investigators to examine diaphragmatic contractility during different settings.2‑7

a few studies have evaluated the effect of sedative drugs on diaphragmatic activity 8‑10 using diaphragmatic electrical activity (eadi) in different clinical situations. However, there

the diaphragm is a dome-shaped fibro-muscular partition between the thoracic

and abdominal cavities. it is undeniably the most important respiratory muscle in humans and the linear relationship between inspired volume and hemi‑diaphragmatic movement in both supine and sitting positions 1 observed


Propofol sedation reduces diaphragm activity in spontaneously breathing

patients: ultrasound assessmentMonica rocco 1 *, luigi Maggi 1, giorgio ranieri 1, giovanni Ferrari 2,

cesare gregoretti 3, giorgio conti 4, roberto a. De Blasi 1

1intensive care Unit, Department of surgical and Medical science and translational Medicine, sapienza University, rome, italy; 2Department of Pneumology, Mauriziano Hospital, turin, italy; 3intensive care Unit, Department of Biopathology and Medical Biotechnologies (DiBiMed), P. giaccone Polyclinic, University of Palermo, Palermo, italy; 4intensive care Unit, Department of anesthesia and intensive care, sacro cuore catholic University, rome, italy*corresponding author: Monica rocco, intensive care Unit, Department of surgical and Medical science and translational Medi‑cine, sapienza University, rome, italy. e‑mail: [email protected]


lavoro: 11615‑Mastitolo breve: ProPoFol‑relateD reDUceD DiaPHragM activitYprimo autore: roccopagine: 266‑73citazione: Minerva anestesiol 2017;83:266‑73

a B s t r a c tBacKgroUnD: the diaphragm is the most important respiratory muscle in humans, and the close relationship between inspired volume and diaphragmatic movement in normal subjects has led to investigations into diaphragmatic activity using ultrasound, during spontaneous breathing and sedative drug infusion.MetHoDs: a total of 36 consecutive patients undergoing diagnostic procedures under deep propofol sedation were studied. Ultrasound measurements included the following: diaphragmatic thickening end‑inspiration (tei) and end‑expiration (TEE). Diaphragmatic thickening fraction (DTF) was calculated from [(TEI − TEE) / TEE] at various time points (at T0 basal; at T1 during propofol infusion; at T2 awakening). Oxygen was administered at 4 L/min, and oxygen saturation (spo2), end tidal co2 (etco2) and respiratory rate (rr) were recorded.resUlts: tei, and tee decreased by 26.7% and 17.4%, respectively, during propofol infusion (t0 versus t1) (P<0.001), and rapidly recovered at t2 (22.7% and 15.8%). at procedure end (t0 versus T2), TEI maintained a significant reduction (10%, P<0.001), whereas tee recovered completely. DtF decreased by 56.7% at t1 (P<0.001) but increased by 76.9% (P=0.001) at t2. recovery after awakening (t0 versus t2) did not reach the baseline value, with a 23.4% difference (P<0.001). spo2 remained above 96% and etco2 below 43 mmHg with no desaturation episodes observed.conclUsions: our study showed that deep propofol sedation affects muscle activity in healthy patients. While dia‑phragmatic strength decreased during sedation, there was no clinically relevant effect on spo2. The study also confirmed that ultrasound is suitable for measuring diaphragm activity during a normal clinical procedure.(Cite this article as: rocco M, Maggi l, ranieri g, Ferrari g, gregoretti c, conti g, et al. Propofol sedation reduces diaphragm activity in spontaneously breathing patients: ultrasound assessment. Minerva anestesiol 2017;83:266‑73. DOI: 10.23736/S0375-9393.17.11615-9)Key words: Propofol ‑ Deep sedation ‑ Diaphragm ‑ Ultrasonography.

Minerva anestesiologica 2017 March;83(3):266‑73DOI: 10.23736/S0375-9393.17.11615-9

© 2017 eDiZioni Minerva MeDicaOnline version at http://www.minervamedica.it

ProPoFol‑relateD reDUceD DiaPHragM activitY rocco

vol. 83 ‑ no. 3 Minerva anestesiologica 267

of anesthesiologists (asa) grade 1; age >18 years; normal cardiac, pulmonary, hepatic, and renal function; and absence of neurologi‑cal and muscular diseases. exclusion criteria were: lack of informed consent or patients re‑ceiving premedication or anticholinergic drugs were excluded from the study.

sedation was provided by an anesthesiolo‑gist using a target controlled infusion (tci) (Marsh pharmacokinetic model) of intrave‑nous (iv) propofol at an effect site concentra‑tion of 3 μg/mL 17 (alaris asena PK pump, alaris Medical UK ltd, Basingstoke, UK). the infusion was continued throughout the endoscopic procedure, and the infusion rate was adjusted to obtain level 1 according to the Observer’s Assessment of Alertness/Seda‑tion (oaas) scale.18 Patients requiring >4 or <2 μg/mL or endotracheal intubation for any cause were withdrawn from the study.

oxygen was administered at a rate of 4 L/min via nasal cannula. oxygen saturation (spo2), end tidal co2 (etco2) and respiratory rate (rr) were recorded. Hypoventilation was considered when spo2 fell below 95% and/or etco2 rose above 43 mmHg. all hypoventila‑tion episodes were recorded. Ultrasonography was performed by a specialist well trained in diaphragmatic Us, using a Mylab 30 gold Ul‑trasound (esaote, genoa, italy). all diaphrag‑matic measurements were obtained in milli‑meters, and patients were scanned in the left lateral decubitus position.

some authors 19 recommend measuring the thickness of the right rather than the left hemi‑diaphragm as the latter is often challenging to visualize and measure.

Diaphragmatic thickening was studied in B‑mode in the zone of apposition (Zoa) to the rib cage from the 8th to the 9th right intercostal space.20, 21 Using a linear 10 MHz probe, the diaphragmatic muscle was observed as an an‑echogenic central layer between two echogen‑ic layers consisting of the diaphragmatic pleu‑rae and peritoneum. Many studies 19, 20, 22, 23 have shown that measurements of diaphragm thickness in the Zoa are reliable and repro‑ducible, as assessed by either intra‑observer or inter‑observer reproducibility.20, 24

are no data available on diaphragmatic activity during sedation for non‑invasive procedures in spontaneous breathing patients.

sedation outside the operating room for inva‑sive and non‑invasive procedures is a growing reality involving both anesthesiology and other specialties. this in turn has led to concern due to potential life‑threatening complications re‑lated to some commonly used sedative drugs.11

Ultrasound (Us) provides a simple, non‑invasive method of assessing the strength and movement of the diaphragm,12, 13 thus, simpli‑fying the study of this muscle, which is other‑wise carried out using invasive methods rarely used in clinical practice. the Us diagnostic method was proposed in 1985 14 for the study of diaphragmatic motion (DM) and in the 1990’s for the assessment of its contractility (diaphragmatic thickness, Dt).15 cohen et al. demonstrated that Dt could be assessed over a wide range of lung volumes, from residual volume to total lung capacity.16 thickening fraction (tF) was reported to be a good indi‑cator of diaphragmatic strength.15 this latter diaphragmatic measurement can be obtained in M‑mode and has been reported to be useful in evaluating muscle function and its contribu‑tion to the respiratory workload.13

the aim of this prospective observational study was to use Us to assess the effect of deep propofol sedation on diaphragmatic contractil‑ity in spontaneously breathing patients under‑going elective endoscopic procedures and its consequences on the respiratory system.


the study was approved by the appropriate institutional review Board (irB) of sapienza University of rome (no 208012015) and writ‑ten informed consent was obtained from all subjects. a total of 36 consecutive patients (19 women and 17 men, aged 53±12 years, with a Body Mass Index [BMI] of 23.8±3.6) were enrolled between august and september 2015; all patients underwent elective diagnostic esophagogastroduodenoscopy (egDs) with co2 insufflation under deep propofol seda‑tion. inclusive criteria were: american society

rocco ProPoFol‑relateD reDUceD DiaPHragM activitY


ference, and a maximum within group sD dif‑ference of 0.08% considering an alpha error <0.05. shapiro‑Wilk’s test was used to assess normal data distribution. a one‑way analysis of variance (anova) was used to test differ‑ences in the repeated measurements in normal‑ly distributed variables and Bonferroni’s post-hoc test was used to compare the data at each time point. For non‑normally distributed data we used Wilcoxon’s test. Data are expressed as mean±sD and P values less than 0.05 were considered statistically significant. Data were analyzed using Medcalc software for Windows v. 12.0 (Medcalc, Mariakerke, Belgium).

Results

none of the patient dropped out of the study. changes in all variables during propofol infu‑sion are shown in table i, and in Figures 1 and 2. DtF decreased by 56.7% during propo‑fol target delivery (t0 versus t1) (P<0.001), whereas, after awakening (t1 versus t2), DtF increased by 76.9% (P<0.001). after awaken‑ing, recovery did not reach baseline value, with a 23.4% difference (t0 versus t2) (P<0.001).

in addition, following propofol administra‑tion (t0 versus t1), tei decreased by 26.7%

Measurements of diaphragmatic thicken‑ing were obtained at end‑inspiration (tei) and end‑expiration (tee). the diaphragmatic thickening fraction (DtF), which represents the index of diaphragmatic efficiency,23 was calculated as:

DTF = [(TEI − TEE) / TEE].Measurements were performed at three dif‑

ferent time points: t0, before propofol infu‑sion; t1, 1 minute after reaching level 1 on the oaas scale before gastric probe insertion; and t2, 5 minutes after reaching level 5 on the oaas scale post‑endoscopic procedure. all measurements assessed before and after seda‑tion (t0 and t2) were obtained during normal quiet breathing.

the primary endpoint was the change in diaphragmatic contractility in spontaneously breathing patients sedated with propofol. the secondary endpoint was the incidence of hy‑poventilation episodes.


Based on preliminary results, we determined that a sample size of 36 patients would have 100% power to detect a minimum 15% tF dif‑

Table I.—�Changes in all variables at different study times.variables t0 t1 t2 P value

tei (mm) 3.0±0.5 2.2±0.5 2.7±0.5 t0 vs. t1: P<0.001t0 vs. t2: P=0.002t1 vs. t2: P<0.001

tee (mm) 2.3±0.4 1.9±0.4 2.2±0.4 t0 vs. t1: P<0.001t0 vs. t2: P=0.06t1 vs. t2: P<0.001

DtF 0.3±0.07 0.13±0.06 0.23±0.07 t0 vs. t1: P<0.001t0 vs. t2: P<0.001t1 vs. t2: P=0.002

saturation (%) 99.4±0.6 96.9±0.8 99.3±0.7 t0 vs. t1: P<0.001t0 vs. t2: P=1t1 vs. t2: P<0.0001

etco2 (mmHg) 37.6±0.9 41.8±1.0 38.2±0.7 t0 vs. t1: P<0.001t0 vs. t2: P<0.001t1 vs. t2: P<0.001

rr (bpm) 12.6±1 20.9±1.5 12.8±0.9 t0 vs. t1: P<0.001t0 vs. t2: P=1t1 vs. t2: P<0.001

Data presented as mean±sD.t0: before propofol infusion; t1: 1 minute after reaching level 1 on the oaas scale before gastric probe insertion; t2: 5 minutes after reach‑ing level 5 on the oaas scale post‑endoscopic procedure; tei: thickening end‑inspiration; tee: thickening end‑expiration; DtF: diaphrag‑matic thickening fraction; etco2: end tidal co2; rr: respiratory rate.



15.8% of tee. at the end of the procedure (t0 versus t2), tei maintained a statistically significant reduction (10%, P<0.001), whereas tee completely recovered (P=0.06).

in 15 of 36 patients tei measurements were repeated 5 minutes after t2 and 100% recov‑ery was observed.

Mean spo2 level was consistently above 96%, etco2 was below 43 mmHg and no de‑saturation episodes were noted in the studied patients. respiratory rate increased from 12.6 to 20.9 breaths/min after propofol adminis‑tration (T1) returning to 12.8 breaths/min at awakening (t2).

Discussion

The main findings in the present study were the following:

— a significant change in diaphragmatic contractility was noted during propofol infu‑sion with a site concentration of 3.0±1 μg/mL;

— a decrease in DtF of 56.7% at t1 was observed and a 23.4% difference at t2 was maintained;

— a significant increase in respiratory rate at t1 was noted, which returned to normal values at t2, suggesting that propofol infu‑sion induced an alteration in neuro‑ventilatory coupling due to a transient, albeit significant, reduction in diaphragmatic contractility;

— only a small decrease in spo2 and a small increase in etco2 were observed which were not clinically significant.

(P<0.001) (Figure 3), and tee was reduced by 17.4% (P<0.001). at awakening, (t1 ver-sus T2) we observed a statistically significant diaphragmatic recovery of 22.7% of tei and

Figure 1.—changes in diaphragmatic thickening at end‑in‑spiration (tei) (a), end‑expiration (tee) (B), and diaphrag‑matic thickening fraction (DtF) (c) at different study times.t0: before propofol infusion; t1: 1 minute after reaching level 1 on the oaas scale before gastric probe insertion; t2: 5 minutes after reaching level 5 on the oaas scale post‑endoscopic procedure.

Figure 2.—change in oxygen saturation, end tidal co2, and respiratory rate.Black dots are spo2 (mean, sD); white triangles are etco2 (mean, sD); white dots are rr (mean, sD).a

B

c



crease in diaphragmatic electrical activity after 1 mg/kg of propofol administered as a bolus in 20 children ventilated with neurally‑adjusted ventilator assist (nava) in a Pediatric inten‑sive care Unit 370 seconds after drug infusion due to respiratory depression. in our study, respiratory rate increased significantly at T1 when DtF, tei and tee decreased, suggest‑ing compensation of the related tidal volume reduction. etco2 showed a small but non‑clin‑ically significant increase during T1, suggest‑ing that alveolar ventilation was maintained. spo2 showed only a small change which was not clinically significant.

in addition, the tci delivery system would have guaranteed a lower stable and effective propofol concentration leading not only to re‑spiratory depression, but to a transient reduc‑tion in diaphragmatic contractility partially counterbalanced by a transient increase in re‑spiratory rate.

DtF did not reach baseline value at t2, maintaining a 23.4% difference. aliverti et al.34 during propofol anesthesia (2-5 mg/kg in 1 minute to achieve central effect/apnea) ob‑served a decrease in end‑expiratory chest wall volume, with a more pronounced effect on the diaphragm than on the rib cage muscles. of note, when breathing was restored after apnea (maintaining doses of 6-9 mg/kg/h continu‑

several animal 25‑27 and human studies 15 have underlined the effect of propofol on dia‑phragmatic contractility. sedation for diag‑nostic and interventional procedures is now current practice in many settings, and in some instances, gastroenterologists or nurses rou‑tinely administer sedation for upper and lower endoscopy.28 as respiratory depression is the most prominent adverse effect of sedation/an‑esthesia with propofol, minimum monitoring guidelines 29‑32 ensure patient safety outside the operating room.

recent guidelines of the european society of gastrointestinal endoscopy (esge) recom‑mend the administration of propofol by a non‑anesthesiologist through perfusion systems as target controlled infusion (tci) to increase safety.31 tci systems are designed to facilitate the delivery of IV anesthetics efficiently and safely, utilizing the effect site concentration. We chose tci methods using the Marsh pharmaco‑kinetic model to reduce the well‑known tran‑sient central depressant effect on respiration 33 and the 20‑30% incidence of apnea which is dose‑ and injection‑velocity‑dependent.

During the infusion of propofol at a site con‑centration of 3.0±1 μg/mL, DTF decreased by 56.7% at T1 with a significant increase in re‑spiratory rate.

amigoni et al.10 reported a relevant de‑

Figure 3.—Diaphragmatic thickening at end‑inspiration (tei) at t0 (before propofol infusion) (a) and at t1 (1 minute after reaching level 1 on the oaas scale before gastric probe insertion) (B). D: diaphragm; l: liver; ∇: pleura layer; Δ: peritoneum layer.

a

t0 t1

B



inter‑observer reproducibility of diaphrag‑matic ultrasound in measuring thickness as many other studies have already studied this parameter 23, 24 and placement of the patient in the left decubitus position meant that we were obliged to study the right diaphragm; never‑theless, some studies have shown the right hemidiaphragm to be the easiest side to assess this muscle.19

thirdly, propofol can have a potential dual effect on respiratory drive and diaphragmatic activity. although previous studies 11, 13, 39 demonstrated that propofol can reduce P0.1, this variable was not measured in this study. in addition, our results suggest that propofol infu‑sion, at those site concentrations, may induce an alteration in neuro‑ventilatory coupling due to a transient, albeit significant, reduction in diaphragmatic contractility without affecting respiratory drive. our main aim was to assess diaphragmatic thickness changes during deep propofol sedation and whether this reduction in strength would affect muscle activity in healthy patients undergoing a common endo‑scopic procedure.

Moreover, the egDs procedures uses insuf‑flation of carbon dioxide (CO2) that, at the end of the procedure, is partially inhaled by fiber‑optic tool and partially proceed in the bowel. carbon dioxide, unlike air, is rapidly cleared from the colon by passive absorption 150 times faster than nitrogen for the higher solubility of co2 in water 40, 41 and easily expired through the respiratory tract without a significant rise above normal co2 levels also in an unselected population.42

Different studied have showed no significant residual gas on plain radiograph taken 30 min‑utes 43 or 1 hour after procedures.44 For all these reasons, we assume that our third measurement was performed in absence of abdominal dis‑tension but we cannot exclude that a residual distension could have influenced our third mea‑surement having a confounder influence.

in addition, we studied only asa1 patients with normal respiratory function and further studies are necessary to evaluate the impact of these complex physiological changes on patients with pre‑existing respiratory complications.

ous infusion) breathing was initiated by the rib cage muscles producing a lower tidal volume but higher respiratory rate.

in addition, inter‑subject variability ob‑served in our study during quiet breathing in healthy subjects was consistent with data from other studies which described subjects who either did not use their diaphragm at all or had minimal contraction rather than normal contraction. Harper et al.12 conducted a large patient population survey which showed no significant difference between sides or across age groups, but wide variability in diaphrag‑matic contractility during quiet breathing was found, thus providing a wide database of healthy controls for future use in the evalu‑ation of diaphragmatic dysfunction. Mccool et al.35 analyzed the cause of this variability and confirmed that the dimensions of the dia‑phragm and thoracic cavity vary with the size of individuals, which is consistent with the principles of elastic similarity, and can predict a wide range in trans‑diaphragmatic pressure (Pdi) among normal individuals, which is al‑most independent of body size.


our study has important limitations.Firstly, we did not use conventional methods

to assess diaphragmatic function, including Pdi measurements, phrenic nerve stimulation or fluoroscopy.36 these methods, in addition to being invasive, are uncomfortable and cumber‑some for studying ambulatory procedures such as sedation for endoscopic procedures. We used B‑mode ultrasound, which has greater anatom‑ical definition of muscle and its adjacent struc‑tures, and a wider panoramic view, compared with M‑mode.18, 25, 37 as suggested by Ferrari et al.,38 B‑mode diaphragm ultrasound is a sim‑ple, rapid, reproducible, and non‑invasive test that can be repeated several times, without risk to patients, and provides important information on respiratory function. it was demonstrated 38 that diaphragm ultrasound measurements cor‑related with lung volumes and maximal inspi‑ratory pressure (Pimax).

secondly, in this study, we did not assess



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Finally, the potential effect of airway ob‑struction on diaphragmatic motion has also raised concern. although propofol may cause airway obstruction during deep sedation, we did not observe snoring in any of our patients during the procedure. in addition, spontaneous breathing was always maintained, no desatu‑ration episodes were observed in the studied patients and mean etco2 was always below 43 mmHg.45

Conclusions

in conclusion, while diaphragmatic strength decreased during sedation, there were only marginal and non-significant effects on SpO2 and etco2 and a transient increase in respira‑tory rate. Our study also confirmed that US was a suitable and well‑tolerated technique for measuring diaphragmatic activity during a routine clinical procedure.

Key messages

— Propofol decreases diaphragmatic strength during light sedation, but in asa 1 patients strength variation has only a mar‑ginal and non‑relevant effect on spo2 and etco2, due to a transient increase in respi‑ratory rate.

— Propofol sedation in spontaneous breathing critically ill patients must be carefully considered as a decrease in dia‑phragmatic strength could be deleterious. Further studies are required.

— Diaphragmatic ultrasound (DUs) is a non‑invasive real‑time technique suit‑able for assessing diaphragmatic strength in several clinical settings. Diaphragmatic dysfunction is often under diagnosed and DUs can be useful for assessing diaphrag‑matic thickness in mechanically ventilated patients or as a weaning index. Data from the present study may extend the applica‑tion of DUs to study the effect of sedative drugs on the diaphragm in order to better assess patient safety.



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Conflicts of interest.—The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.Article first published online: February 8, 2017. - Manuscript accepted: January 26, 2017. - Manuscript revised: January 24, 2017. - Manuscript received: July 30, 2016.


Químicos e Farmacêuticos, rio de Janeiro, Brazil), as a stabilizer, have recently become available in some countries.1‑3 although ge‑neric versions of sevoflurane are considered therapeutically equivalent to the original form, these are different in respect of synthesis meth‑ods, formulation characteristics and conditions of storage.

There are two brands of sevoflurane on the Turkish market: Sevoflurane Likid® 100% (abbott laboratories, istanbul, turkey), which is the original form, and sojourn® (Adeka İlaç

sevoflurane is a commonly used inhalation anesthetic in worldwide anesthesia prac‑

tice. This product was first synthesized in the Usa, then developed in 1990 by Maruishi Pharmaceuticals in Japan. It was first market‑ed by abbott laboratories in 1995, under the trademark Ultane and worldwide as sevoflu‑rane.1, 2 Forms of sevoflurane with a low wa‑ter content (eraldin®, laboratorios richmond/Minrad, Buenos aires, argentina; sevoness®, Baxter, Deerfield, IL, USA) or added pro‑pylene glycol (sevocris®, cristália Produtos


Comparison of two different forms of sevoflurane for anesthesia maintenance and recovery

Yonca Yanli 1 *, Mehtap OZDEMİR 1, nurten BaKan 1, cafer t. YUrUK 1, ahmet YilDiriM 1, ali o. cetinKaYa 2

1Department of anesthesiology and reanimation, Umraniye training and research Hospital, istanbul, turkey; 2Department of anesthesiology and reanimation, Beykoz state Hospital, istanbul, turkey*corresponding author: Yonca Yanli, Department of anesthesiology and reanimation, Umraniye training and research Hospital, Yenisehir Mah. Kagnıcı Yolu Sok, 7000A Residence No. 215, Atasehir-Istanbul, Turkey. E-mail: [email protected]


lavoro: 11406‑Mastitolo breve: coMParison oF tWo ForMs oF sevoFlUraneprimo autore: Yanlipagine: 274‑81citazione: Minerva anestesiol 2017;83:274‑81

a B s t r a c tBACKGROUND: Sevoflurane is a commonly used inhalation agent. There are two forms of sevoflurane in Turkey. The aim of this study was to evaluate the effects of original versus generic sevoflurane products on hemodynamics, time to reach 1 MAC level, inspired and expired sevoflurane levels and postoperative recovery profile.MetHoDs: seventy patients undergoing general anesthesia were divided into two groups as group sevo or group sojo. after intravenous induction of anesthesia (with the same drugs in both groups), inhalation anesthetic was started. Hemo‑dynamic parameters, Bispectral index (BIS), time to reach 1MAC level, inspired and expired sevoflurane levels, percent vaporizer concentration of sevoflurane, additional remifentanil doses were recorded. In the awakening period, decreasing times of Mac 0.5, 0.4, 0.3, Bis levels, sedation‑agitation and aldrete scores were recorded.resUlts: the time to reach 1Mac level was shorter in group sevo than in group sojo (P=0.01). the fractions of in‑spired sevoflurane levels were higher at 4, 6, 8, 10, 15, 30, 35, and 45 minutes, the fractions of expired sevoflurane levels were higher at 4, 6, 8, 10, 15, and 20 minutes in group sevo (P<0.05). in the awakening period and postoperatively, there were no differences in recorded parameters between the groups.conclUsions: although there are differences in maintenance period of the anesthesia, the two products seem to be comparable routine anesthesia practice. But further studies are needed to enhance our knowledge.(Cite this article as: Yanli Y, ozdemir M, Bakan n, Yuruk ct, Yildirim a, cetinkaya ao. comparison of two different forms of sevoflurane for anesthesia maintenance and recovery. Minerva Anestesiol 2017;83:274-81. DOI: 10.23736/S0375-9393.16.11406‑3)Key words: Inhalation anesthetics - Sevoflurane - General anesthesia - Consciousness monitors.

Minerva anestesiologica 2017 March;83(3):274‑81Doi: 10.23736/s0375‑9393.16.11406‑3


coMParison oF tWo ForMs oF sevoFlUrane Yanli


neurological, cardiac or mental diseases, Body Mass index (BMi) >35 kg/m2, procedures last‑ing more than two hours or shorter than 45 minutes, the usage of neuroleptics, benzodiaz‑epines, anticonvulsant or other similar medica‑tions that might interfere with the inhalation characteristic of sevoflurane. None of the pa‑tients received any premedication.

in the operating theatre, venipuncture (18 gauge) was performed and hydration was initi‑ated with 4 ml/kg/h lactate ringer’s solution. standard clinical anesthesia monitoring with 3‑lead electrocardiography (ecg), noninva‑sive (systolic, mean, diastolic) blood pressure (niBP), peripheral oxygen saturation (spo2), temperature and Bispectral index analysis (Bis) were applied before the induction of anesthesia. Body temperature was maintained within normal limits using a warm blanket.

anesthesia induction was performed with propofol 3 mg/kg, rocuronium bromide 0.4 mg/kg and remifentanil 1 µg/kg. no inhaled agent was administered during induction. two min‑utes after the induction of anesthesia, the lMa was inserted smoothly on the first or second attempt by an experienced anesthetist. if the lMa could not be inserted on the second at‑tempt, the patient was excluded from the study. the patients were divided randomly (with sealed envelope) into two groups: the sevo group (n.=35) and the sojo group (n.=35). Sevoflurane was administered to the patients in group sevo and sojo at vaporizer dial to 1.5% concentration in n2o/o2 (50%/50%) mixture. Fresh gas flow was set at 6L/min. Ventilation of the lungs was maintained by an anesthetic machine (Fabius plus‑Dräger Medical gmbH, lübeck, germany) using volume‑controlled ventilation mode with tidal volume 7 ml/kg. the respiratory frequency was adjusted to keep the end‑tidal concentrations of carbon dioxide (etco2) between 30‑35 mmHg. no other iv drug was used and the vaporizer dial was not changed until the sevoflurane concen‑tration reached 1 Mac level. Maintenance of anesthesia was adjusted to keep the Bis levels between 40 and 60. if the Bis level exceeded 60 or blood pressure or heart rate increased 20% from baseline; remifentanil bolus dose of

sanayi, samsun, turkey), which is a generic form. these two products are different in syn‑thesis, storage and water content.1, 3 the dif‑ference in water content of the two sevoflurane formulations is important. Sevoflurane under‑goes chemical degradation which can cause potentially toxic different compounds such as Lewis and hydrofluoric acids. Water functions as a stabilizer, preventing acid degradation of the products.1‑3 the original form of sevo‑flurane contains 300 ppm water whereas the generic form has <130‑ppm water.1 although there have been a few in-vitro studies in litera‑ture investigating the effects and the differenc‑es of filling devices of the two forms of sevo‑flurane, the number of in-vivo studies is very limited.1, 2, 4‑6 it has been speculated that these differences in water content lead to different clinical and anesthetic effects of sevoflurane. in a clinical study of pediatric population, it was pointed out that the water content of sevo‑flurane affected the fractions of inspired and expired sevoflurane in the awakening period.5

the aim of this study, was to evaluate whether there was any difference between original and generic products of sevoflurane in the time taken to reach 1 MAC level at a fixed vaporizer setting. secondary endpoints were to determine any effect on inspired and expired fractions (inhalation characteristics) during the maintenance of anesthesia and decreasing times of Mac 0.5 to 0.3 in the awakening pe‑riod in adults.


approval for the study was granted by the ethics committee of Umraniye research Hos‑pital (2013‑18) and the turkey Ministry of Health, clinical Drug research center (clini‑cal trial registration no.: 2013–PMs–17). in‑formed consent was obtained from each pa‑tient. this prospective study comprised 70 asa (american society of anesthesiologists) i or ii, patients aged 18‑65 years, who were scheduled to undergo lower abdominal or uro‑logical surgery (herniorrhaphy and ureterolith‑otripsia) under general anesthesia using clas‑sic lMa. exclusion criteria were patients with

Yanli coMParison oF tWo ForMs oF sevoFlUrane


evaluated immediately after the transfer of the patient to the recovery room and at the 60th minute postoperatively. adverse events such as respiratory tract irritation (coughing, laryn‑gospasm or breath holding) and nausea/vomit‑ing were recorded.

the vaporizers of the two products used in the study were different but were of the same make (vapor 2000, Dräger Medical gmbH). all of them had been in use for between 6‑12 months and were also calibrated. each vapor‑izer was provided by the manufacturer and checked as appropriate to the product. the an‑esthesiologist was not informed of which form of sevoflurane was used.


the ncss (number cruncher statistical system) 2007 and Pass (Power analysis and sample size) 2008 statistical software pro‑grams were used to calculate the power of the study. according to the results of a pilot study of the time to reach 1 Mac level, delta was calculated as 95 seconds with standard devia‑tion (SD): 140, assuming an α level of 0.05 and a power of 0.80, thus a minimum of 35 patients should be enrolled in each group for the study. For the inspired fraction of sevoflu‑rane, at the time points where the difference was statistically significant, the post-hoc pow‑er was calculated in the range of 68.4‑96.7% and for the expired fraction of sevoflurane, in the range of 65.8‑97.8%. When evaluating the study data descriptive statistical methods were used to express the results as mean±sD. For

1 µg/kg was injected to maintain appropriate anesthetic level and recorded as an analgesic. similarly, if the Bis level decreased to 40 or blood pressure or heart rate decreased 20% from baseline, the vaporizer dial of sevoflu‑rane was reduced to 1.2% and recorded.

the heart rate (Hr), niBP, spo2, and Bis values were recorded 2 minutes before anes‑thesia induction, then at 4, 6, 8, and 10 min‑utes after induction and subsequently every 5 minutes during anesthesia. the time to reach 1 Mac was recorded from opening the vapor‑izer to the time when end‑tidal gas concentra‑tion reached 1 Mac level for each product. the etco2, fraction of inspired and expired sevoflurane, percent concentration of (vapor‑izer settings) sevoflurane were recorded after induction and during the anesthesia period. the spirometric data were obtained using a scio Four oxiplus spirometry device (Dräger Medical gmbH, lübeck, germany) and re‑corded on an anesthesia monitor.

at the end of the operation, the vaporizer was turned off and mechanical ventilation was continued with o2/air (50%/50%). in the awakening period, decreasing times of Mac 0.5, 0.4, 0.3 and Bis levels at those times were recorded. no verbal or tactile stimulations were administered in this period. the lMa was re‑moved with the cuff inflated 7 while the patient was breathing spontaneously. the sedation‑agitation levels were assessed with the riker sedation‑agitation score (sas) 8 (table i) at the time of Mac=0.3 and after the removal of lMa. Patients were then transferred to the re‑covery room. Modified Aldrete scores 9 were

Table I.—� Riker Sedation Agitation Score.score state Description

7 Dangerous agitation Pulling at et tube, trying to remove catheters, climbing over bed rail, striking at staff, thrashing side‑to‑side

6 very agitated requiring restraint and frequent verbal reminding of limits, biting et tube5 agitated anxious or physically agitated, calms to verbal instructions4 calm and cooperative calm, easily arousable, follows commands3 sedated Difficult to arouse but awakens to verbal stimuli or gentle shaking, follows simple commands

but drifts off again2 very sedated arouses to physical stimuli but does not communicate or follow commands, may move

spontaneously1 Unarousable Minimal or no response to noxious stimuli, does not communicate or follow commandset: endotracheal.



Results

Both groups comprised 35 asa i‑ii patients. No significant differences were determined between the groups in demographic data and duration of anesthesia (P>0.05) (table ii). Hr, niBP, spo2 and etco2 were similar and with‑in the physiological range in both groups at all times (P>0.05).

after induction, the time to reach 1 Mac level was shorter in the sevo group (6.3±2.4 minutes) than in the sojo group (8.5±5.2 minutes) (P=0.01) (Figure 1). the fractions of inspired and expired sevoflurane were also different between the groups. the fractions of inspired sevoflurane were higher and statisti‑cally significant at 4, 6, 8, 10 15, 30, 35, and 45 minutes during anesthesia in the sevo group compared to the sojo group (P<0.05) (Fig‑ure 2). The fractions of expired sevoflurane were higher at 4, 6, 8, 10, 15 and 20 minutes in the sevo group (P<0.05) (Figure 3).

although the percentage vaporizer concen‑trations of sevoflurane required to maintain Bis levels between 40 and 60 were recorded at higher levels in the sojo group than in the Sevo Group, the differences were not signifi‑cant (P>0.05). the Bis levels were similar in both groups at all recorded times (P>0.05). thirteen additional remifentanil boluses were administered (once in 7 patients, twice in 3 pa‑tients) in the sojo group, and 9 boluses (once in 9 patients) in the sevo group. six patients from the sevo group and 5 from the sojo group required additional analgesia (twice in 2 patients) while undergoing herniorrhaphy.

qualitative analysis of data with normal distri‑bution between the groups, the student’s t‑test was used to compare with normal distribution the parameters while Mann Whitney U‑test was used for comparison of the parameters not showing normal distribution. Fisher’s exact test and Yates continuity correction test were used for comparison of the qualitative data. a P value <0.05 was considered statistically sig‑nificant.

Table II.—�Demographic data and duration of sur-gery (mean±SD) or number (P>0.05).

sevo group sojo group P value

age (years) 43±14 42±12 0.84<40 years (n.) 16 18 0.81>40 years (n.) 19 17Weight (kg) 78±15 72±13 0.07Height (cm) 168±8 148±9 0.72Duration of surgery (min) 49±25 48±20 0.84sex, M/F 24/11 20/15 0.46

Figure 1.—time to reach 1 Mac level.columns represent means; vertical lines correspond to 1 sD.*P=0.01.

Figure 2.—Inspired sevoflurane fractions (%).columns represent means; vertical lines correspond to 1 sD.*P<0.05; **P<0.01.

Figure 3.—Expired sevoflurane fractions (%).columns represent means; vertical lines correspond to 1 sD.*P<0.05; **P<0.01.

tim

e (m

in)

time (min) time (min)Insp

ired

sevo

flura

ne fr

actio

ns (%

)

Expi

red

sevo

flura

ne fr

actio

ns (%

)

sevo groupsojo group

sevo groupsojo group

sevo group

sojo group



tidal concentration, is independent of gender, duration of anesthesia and type of surgery.12 Age and temperature are known to influence Mac and Mac‑awake in humans.12‑15 in or‑der to maintain a Bis level of 40‑60 in adults, the required percent end‑tidal concentrations of sevoflurane have been reported between 1.04% and 1.81% in several studies.14, 16‑18 as there was a wide but not extreme age range in the current study, the sevoflurane vapor‑izer dial was initially set to 1.5% to obtain 1 Mac level. the number of patients younger and older than 40, gender, duration of anes‑thesia and type of surgery were similar in both groups.

There are two forms of sevoflurane avail‑able in turkey. even though these two prod‑ucts are rated therapeutically equivalent, there are some differences. Original sevoflurane is manufactured using a single‑step process, con‑tains 300‑ppm water and is packaged in a plas‑tic polymer bottle. Generic sevoflurane is man‑ufactured using a three‑step process, contains an average of <130‑ppm water and is pack‑aged in a glass bottle.3 Both the original and generic products have a high purity of sevo‑flurane with low variation.2 the differences in water contents of the two forms of sevoflurane have been the main topic of discussion rather than their purity. Sevoflurane is susceptible to chemical degradation. the degradation prod‑ucts of sevoflurane are Lewis acids and hydro‑fluoric acid.1‑3, 11 if these acids are inhaled, they may cause respiratory irritation. Water inhibits such degradation.1, 3, 6, 11 In-vitro studies have demonstrated that degradation products of the different water content of sevoflurane can in‑fluence hydrofluoric acid concentration, pH or compound a production.1, 2, 4 the clinical implications of these differences are unknown.

the number of patients (P=0.78) and the num‑ber of additional boluses (P=0.21) were simi‑lar between the groups.

During the awakening period, the decreasing times of Mac 0.5, 0.4, 0.3 were recorded as longer in the original form. these differences were not significant (P>0.05) (Table III). SAS were similar at the time of Mac=0.3 (P=0.46) and removal of the LMA (P=0.43). No signifi‑cant difference was determined compared to nausea (P=1). Modified Aldrete scores were comparable immediately after transfer to the recovery room (P=0.23) and at the 60th minute postoperatively (P=0.79). no signs of respira‑tory tract irritation such as coughing, laryn‑gospasm or breath holding were observed in either group.

Discussion

the results of this study showed that the time to reach 1 Mac level was shorter and that the fractions of inspired and expired sevoflurane were higher in the original product compared with the generic product.

Sevoflurane is less irritating to the respira‑tory tract and provides a rapid, smooth induc‑tion and recovery from anesthesia than many other agents.10, 11 Due to its low blood solubil‑ity, recovery from anesthesia is rapid.4, 6, 10 the factors affecting inspirational concentration of sevoflurane are fresh gas flow rate, the volume of the breathing system and any absorption by the machine or breathing circuit.11 the major factor affecting alveolar concentration is the anesthetic uptake. this is affected by solubility in the blood, alveolar blood flow and the par‑tial pressure difference between alveolar gas and venous blood. the awakening concentra‑tion of sevoflurane, which is defined as the end

Table III.—�During the awakening period, the decreasing times of MAC 0.5, 0.4, 0.3 and BIS levels. The times rep-resent as minutes (mean±SD) (P>0.05).

Mac 0.5 Mac 0.4 Mac 0.3

time (min) Bis time (min) Bis time (min) Bis

sojo group 0.8±0.2 47.3±10.0 1.2±0.3 49.1±9.2 1.7±0.5 51.9±10.9sevo group 1.2±2.4 46.3±9.3 1.6±0.9 49.3±10.9 2.3±1.6 51.0±12.1P value 0.08 0.7 0.1 0.91 0.27 0.73



could be considered to be related to their for‑mulation characteristics especially the water content and solubility. nevertheless, it is dif‑ficult to say exactly what caused the observed differences in the current study design. new technology, and target controlled anesthesia machines allow entry of the desired alveolar partial pressure (Fa) of the inhaled agent, and manage fresh gas flow rate and agent admin‑istration rates.20 However, inspired anesthesia concentration is still important with the a con‑ventional delivery system.

During the awakening and recovery period the sas and aldrete scores were similar in both groups. no signs of respiratory tract ir‑ritation such as coughing, laryngospasm or breath holding were observed in either group.

in this study, there was no measurement of the time to eye‑opening, or of the fraction of inspired and expired sevoflurane after discon‑tinuation of sevoflurane in both groups. The times to decreasing Mac and Bis levels from 0.5 to 0.3 were recorded. even though the de‑creasing times of Mac levels tended to be lon‑ger in the original form, the differences were not significant.

coppens et al.21 indicated that rapid se‑quence induction with remifentanil, propofol and rocuronium can be applied without dan‑gerous hemodynamic and arousal responses. in the current study, it was aimed to obtain excellent conditions for the induction period and remifentanil was administered to both groups. However, no other remifentanil bolus was used until the inhalation agent reached 1 Mac level. Previous studies in literature have stated that remifentanil could affect Mac levels of inhalation anesthetics.22, 23 Despite this knowledge, in the current study, inspired and expired sevoflurane fractions were higher in the sevo group when the vaporizer was set to the same dial to obtain Bis levels between 40‑60. in addition, the number of patients who received remifentanil and the number of additional bolus doses were no different be‑tween the groups. thus, it was thought that the use of remifentanil did not affect the in‑halation characteristics of the two groups in this study.

there have been a limited number of in-vivo studies evaluating the clinical effects of different sevoflurane forms.5, 6 in a study by otsuki et al.,6 equipotent doses of two differ‑ent forms of sevoflurane on a pig model were determined to have similar effects on hemo‑dynamics. in the current study, the parameters such as Hr, blood pressure and etco2 that could alter the pharmacokinetics were similar in both groups.

tomal et al.5 evaluated two different forms of sevoflurane (with 300-ppm water or 260-ppm propylene glycol as a stabilizer) on a pediatric population and found that a greater number of children required an additional bolus of sevoflu‑rane to maintain the same anesthesia level in the generic group. at the end of the anesthesia, de‑spite the same concentration in vaporizer dial, the median fractions of inspired and expired sevoflurane were higher and BIS levels were lower in the original sevoflurane group than in the generic sevoflurane group. In the current study, higher inspired and expired sevoflurane fractions were recorded in the original sevoflu‑rane product, whereas percent vaporizer con‑centrations were similar between the groups at all times. in addition, the recorded time to reach 1 Mac level was shorter in the sevo group than in the sojo group (6.3 versus 8.5 minutes). Hor‑witz et al.19 reported the time to reach 1 Mac as 6.2 minutes using fixed vaporizer dial in the original form with 1 L/min fresh gas flow rate.

All these findings are surprising. In the cur‑rent study, a standardized anesthesia regimen was applied and the depth of anesthesia was controlled by monitoring the Bis. the factors that affect inspirational concentration of sevo‑flurane, such as fresh gas flow rate and the vol‑ume of the breathing system, and hemodynam‑ics and respiratory parameters which affect the pharmacokinetics of sevoflurane were similar between the groups. Furthermore, the vapor‑izers used in this study were provided and checked by the manufacturer for each product. tomal et al.5 reported similar results in pedi‑atric patients with propylene glycol additive sevoflurane on discontinuation of sevoflurane at the end of the anesthesia. therefore, in the light of the literature results, these differences



3. Baker MT. Sevoflurane: Are there differences in prod‑ucts? anesth analg 2007;104:1447‑51.

4. li Y, li Yc, Zhang Yn, liu sJ, Zhou YM, Wang cs, et al. Degradation products of different water content sevoflurane in carbon dioxide absorbents by gas chro‑matography‑mass spectrometry analysis. chin Med J 2011;124:1050‑4.

5. tomal crg, da silva agP, Yamashita aM, de an‑drade Pv, Hirano Mt, tardelli Ma, et al. assessment of induction, recovery, agitation upon awakening, and consumption with the use of two brands of sevoflu‑rane for ambulatory anesthesia. rev Bras anestesiol 2012;62:154‑72.

6. otsuki Da, Fantoni Dt, Holms c, auler Joc Jr. Mini‑mum alveolar concentrations and hemodynamic effects of two different preparations of sevoflurane in pigs. Clin‑ics 2010;65:531‑7.

7. Deakin cD, Diprose P, Majumdar r, Pulletz M. an in‑vestigation into the quantity of secretions removed by in‑flated and deflated laryngeal mask airways. Anaesthesia 2000;55:478‑80.

8. riker, rr, Picard, Jt, Fraser gl. Prospective evaluation of the sedation‑agitation scale for adult critically ill pa‑tients. critical care Medicine 1999;27:1325‑9.

9. aldrete Ja. the post‑anesthesia recovery score revisited. J clin anesth 1995;7:89‑91.

10. Patel SS, Goa KL. Sevoflurane. A review of its pharma‑codynamic and pharmacokinetic properties and its clini‑cal use in general anaesthesia. Drugs 1996;51:658‑700.

11. Morgan ge, Mikhail Ms, Murray MJ, larson cP. sec‑tion ii – clinical Pharmacology, inhalational anesthetics. in: clinical anesthesiology. third edition. lange Medi‑cal Books; 2002. p. 127‑50.

12. Katoh T, Suguro Y, Ikeda T, Kazama T, Ikeda K. Influ‑ence of age on awakening concentrations of sevoflurane and isoflurane. Anesth Analg 1993;76:348-52.

13. eger ei 2nd. age, Minimum alveolar anesthetic concen‑tration, and minimum alveolar anesthetic concentration‑awake. anesth analg 2001;93:947‑53.

14. Matsuura t, oda Y, tanaka K, Mori t, niskikawa K, asada a. advance of age decreases the minimum al‑veolar concentrations of isoflurane and sevoflurane for maintaining bispectral index below 50. Br J anaesth 2009;102:331‑5.

15. Katoh T, Bito H, Sato S. Influence of age on hypnotic requirement, bispectral index, and 95% spectral edge fre‑quency associated with sedation induced by sevoflurane. anesthesiology 2000;92:55‑61.

16. olofsen e, Dahan a. the dynamic relationship between end-tidal sevoflurane and isoflurane concentrations and bispectral index and spectral edge frequency of the elec‑troencephalogram. anesthesiology 1999;90:1345‑53.

17. Wang Hl, Yang l, guo XY, Zhang lP, Bi ss, lu W. Response surface analysis of sevoflurane-remifentanil in‑teractions on consciousness during anesthesia. chin Med J 2012;125:2682‑7.

18. nickalls rWD, Mapleson WW. age‑related iso‑Mac charts for isoflurane, sevoflurane and desflurane in man. Br J anaesth 2003;91:170‑4.

19. Horwitz M, Jakobsson JG. Desflurane and sevoflurane use during low- and minimal-flow anesthesia at fixed va‑porizer settings. Minerva anestesiol 2016;82:180‑5.

20. Hendrickcx J, Peyton P, carette r, De Wolf a. inhaled anaesthetics and nitrous oxide: complexities overlooked: things may not be what they seem. eur J anaesthesiol 2016;33:611‑9.

21. coppens MJ, versichelen lF, Mortier eP, struys MM. Do we need inhaled anaesthetics to blunt arousal, haemo‑dynamic responses to intubation after i.v. induction with propofol, remifentanil, rocuronium? Br J anaesth 2006;97:835‑41.


a limitation of this study was that sevo‑flurane consumption was not measured. In a study by tomal et al.5 sevoflurane consump‑tion was evaluated and no difference was found between the two products. However, it was emphasized that the short duration of an‑esthesia and the calculation method of sevoflu‑rane consumption might have been insufficient to demonstrate significant differences in sevo‑flurane consumption.

Conclusions

in conclusion, inspired and expired sevo‑flurane fractions were observed to be higher and the time taken to reach 1 Mac level was shorter in the original form than in the generic form. therefore, anesthesiologists should pay attention to these features when using different preparations of sevoflurane. Further extensive, evidence‑based studies are required to enhance the knowledge of this subject.

Key messages

— At a fixed vaporizer dial, the time to reach 1 Mac level was shorter in the origi‑nal form than in the generic form.

— the fractions of inspired and expired sevoflurane were recorded at higher levels in the original form during the maintenance of anesthesia.

— No significant difference was ob‑served in the recovery scores and adverse reactions between the two forms of sevo‑flurane during the awakening and recovery period.

References

1. Kharach eD, subbarao gn, cromack Kr, stephens Da, Saltarelli MD. Sevoflurane formulation water content in‑fluences degradation by lewis acids in vaporizers. Anesth analg 2009;108:1796‑802.

2. Yamakage M, Hirata n, saijo H, satoh Ji, namiki a. analysis of the composition of ‘original’ and generic sevoflurane in routine use. Br J Anaesth 2007;99:819-23.



HK, et al. Remifentanil decreases sevoflurane require‑ments to block autonomic hyperreflexia during transure‑thral litholapaxy in patients with high complete spinal cord injury. anesth analg 2011;112:191‑7.

22. glass Ps, gan tJ, Howell s, ginsberg B. Drug inter‑actions: volatile anesthetics and opioids. J clin anesth 1997;9:18s‑22s.

23. Yoo KY, Jeong cW, Kim sJ, Jeong st, Kim WM, lee

Conflicts of interest.—The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.Congresses.—this study was presented as a poster presentation at the 47th national congress of the turkish society of anesthesiol‑ogy and reanimation, which was held in 2013 in antalya, turkey.Article first published online: December 6, 2016. - Manuscript accepted: December 1, 2016. - Manuscript revised: November 8, 2016. ‑ Manuscript received: april 27, 2016.


in neonates and infants is important for the surgical outcome. the pain management has some challenges, because of the physiologi-cal and pharmacological differences of this developmental stage. inadequate postop-erative analgesia in neonates and infants in-creases the stress response and also increases morbidity and mortality.3 the intravenous

neonates can start to feel pain at XXiii-XXiv weeks gestation. Untreated pain-

ful procedures in neonates can lead to chang-es in behavior and learning in the long term that can provoke cognitive and neurological impairment.1, 2 the postoperative analgesia


transversus abdominis plane block for postoperative analgesia in neonates and young infants:

retrospective analysis of a case seriesPinar KenDigelen 1 *, cigdem tÜtÜncÜ 1, gulruh asHYralYYeva 1,

rahsan oZcan 2, senol eMre 2, Fatis altinDas 1, guner KaYa 1

1Department of anesthesia and intensive care, cerrahpasa Medical Faculty, istanbul University, istanbul, turkey; 2Department of Pediatric surgery, cerrahpasa Medical Faculty, istanbul University, istanbul, turkey*corresponding author: Pinar Kendigelen, Department of anesthesia and intensive care, cerrahpasa Medical Faculty, istanbul Uni-versity, istanbul, turkey. e-mail: [email protected]


lavoro: 11420-Mastitolo breve: taP BlocKs in neonates anD YoUng inFantsprimo autore: KenDigelenpagine: 282-7citazione: Minerva anestesiol 2017;83:282-7

a B s t r a c tBacKgroUnD: the effectiveness of the transversus abdominis plane (taP) block in children has been well character-ized in literature. However, there are only few reports about taP block in the neonates and low birth weight groups. this is a retrospective observational analysis of ultrasound – assisted taP blocks in neonates and young infants. the aim of this study was to analyze retrospectively the analgesic effectiveness of taP block in neonates and infants undergoing abdominal and inguinal surgeries.MetHoDs: thirty-four cases of neonates and infants to (whom) taP block was applied, were retrospectively analyzed. the taP block was performed postoperatively in supraumbilical surgeries and preoperatively in infraumbilical surgeries. the taP block was applied with 0.8 ml/kg-1 of 0.25% bupivacaine in unilateral approach and 1.6 ml/kg-1 of 0.125% bupivacaine in bilateral approach. the cries Pain scale was used for postoperative pain measurement of neonates.resUlts: the patient’s age ranged from 2 to 88 day-old with a mean (sD) of 36.2(24.2). eleven of them were premature babies. the weight ranged from 1.6 to 5.8 with a mean (sD) of 3.7 kg (1.1). twenty-nine patients were extubated at the end of the surgery and the other patients within 12 hours. 67.7% infants required no additional postoperative analgesic in 24 hours and none of them required narcotic analgesics.conclUsions: our conclusion is that the use of taP blocks results in low analgesic requirements and a low incidence of postoperative intubation and mechanical ventilation in neonates and infants. it should be considered in this age group of child for postoperative analgesia.(Cite this article as: Kendigelen P, tütüncü c, ashyralyyeva g, ozcan r, emre s, altindas F, et al. transversus abdominis plane block for postoperative analgesia in neonates and young infants: retrospective analysis of a case series. Minerva ane-stesiol 2017;83:282-7. Doi: 10.23736/s0375-9393.16.11420-8)Key words: nerve block - infant, newborn - abdominal wall.

comment in p. 242.



taP BlocKs in neonates anD YoUng inFants KenDigelen


monitors. anesthesia was maintained with 2% end-tidal concentration of sevoflurane in air/oxygen (Fio2=0.4) and remifentanil infusion. Patients were mechanically ventilated using a pressure-controlled mode. the etco2 was maintained between 32 and 38 mm/Hg. the subcostal approach in supraumbilical surger-ies (duodenal atresia, pyloric stenosis, biliary atresia and choledoc cyst) and midaxillary or posterior approach in infraumbilical surgeries (inguinal hernia, pyeloplasty, and colostomy) were preferred for taP block. the taP block was performed postoperatively in supraum-bilical surgeries as surgical incision was at the same location of block and preoperatively in infraumbilical surgeries as location of surgical incision was at different places. the block was performed by using a high frequency linear probe (esaoteMylab5-la523e) and needle of 24G cannula (Vasofix® certo, Braun, Mel-sungen, germany) with attached short and thin extension line, after cleaning the skin with chlorhexidine. the needle was advanced at 10-20 degree angle to Usg probe with the in-plane approach after internal oblique and transversus abdominis muscle layers were vi-sualized. the target area between these two muscles was confirmed in all cases by inject-ing 0.5 ml 0.9% nacl. the 0.8 ml/kg of 0.25% bupivacaine solution for unilateral and 1.6 ml/kg of 0.125% bupivacaine in totally for bilateral taP block were received.

Patients were transferred to nicU or ward depending on the age and surgery after opera-tion. the cries Pain scale (crying, requires increased oxygen administration, increased vi-tal signs, expression, and sleeplessness) was used by trained nurses for pain measurement for postoperative 24 hours. the cries Pain scale for 32 weeks of gestational age to 6 months in-cludes five categories: severity of crying; O2 re-quirement; increased vital signs; facial expres-sion; and sleeplessness each with 0 to 2 level and scores range from zero to 10.8, 9 Patient have been received paracetamol (10 mg/kg iv) with a cries score>4. the remifentanil infusion for intubated patient and iv tramadol (1-2 mg/kg) for non-intubated patient were administrated with a cries score>7.

analgesia may have respiratory and metabolic problems with immature organ systems.3, 4 especially, systemic opioids may cause respi-ratory depression and increases ventilator du-ration. regional analgesia could conveniently provide pain relief and a comfortable postop-erative period. However, due to the small size of the structure, differences in the resistance of tissues, a variety of indication limitations complicates and needs experience for this procedure in neonates. the regional anesthet-ic techniques start to performed commonly after the begin of Usg guidance, especially in children. some studies show that taP block can reduce the pain in some specific surgical procedures in children.5 Until now, only few case reports were published about taP block in neonates and low birth weight groups.4, 6, 7 the performing taP block in ne-onates are challenging because of their small size and small distances between adjacent critical structures. the Ultrasound (Usg) can assist and facilitate the performance of taP block. the main purpose of this study is to evaluate the postoperative analgesic ef-fectiveness of taP block in neonates and in-fants. in addition, the type of surgeries whom taP block was performed, the approach of taP block, the analgesic requirement during 24-hour postoperative period and the extuba-tion time were evaluated.


this study was approved by ethical Board of our institution (no: 83045809/604.01/02) and all available data between november 2014 and January 2016 was retrospectively collected. any informed consent from human subjects was obtained as required. The infants younger than 3 months, who underwent any abdominal and inguinal surgeries under gen-eral anesthesia and applied taP block for pain management were included. Data were collect-ed by reviewing patients’ anesthetic, postop-erative neonatal intensive care Unit (nicU) and ward records. general anesthesia was in-duced by sevoflurane (4-5%) and rocuronium (0.6-1 mg/kg) after the application of standard

KenDigelen taP BlocKs in neonates anD YoUng inFants


the 32.3% of patients required one (6 patients) or two doses (5 patients) of paracetamol (10 mg/kg iv) in 24 hours. none of them required opioid analgesics in postoperative period. the postoperative sedation was not used in nicU due to early weaning plan. the opioid infusion (remifentanil) was not needed in patients with cries score <7.

Discussion

neonates with congenital anomalies may need surgical repairs in early life period. Pain management of neonatal patient after the sur-gery is a challenging process. inadequate treat-ment of pain has negative outcomes for neo-nates and infants. Pain experiences in neonatal period have long term effects on the develop-ment of pain processing, neuroendocrine and immune systems. Further, this experience have caused emotional, behavioral and learning dis-abilities.1-3

the systemic opioid usage is limited in neo-nates, due to the respiratory depression and side effects.4 continuously using the opioids to pro-vide sufficient analgesia may extend the dura-tion of mechanical ventilation and the extubation time. the patient is already extubated; opioids increase the risk of apnea, which requires close monitoring even minor surgery such as inguinal hernia repairing. in our study, none of patients required opioid analgesics in postoperative pe-riod; therefore most patients were extubated at end of surgery or within 12 hours. Paracetamol, is an alternative intravenous drug, may not pro-vide a sufficient analgesia.

Results

We are presenting our experiences in thirty-four cases of neonates and infants whom ap-plied taP block. all available data was col-lected between november 2014 and January 2016. thirty-four patients who underwent ul-trasound assisted taP block for pain manage-ment after abdominal and inguinal surgeries were investigated. Patients’ characteristics are presented in table i.

all patients who underwent infra-umbilical surgeries were extubated in operating room. the patients who underwent supra-umbilical surgeries, especially low birth weight prema-ture babies were extubated in nicU after suc-cessful spontaneous breathing trials.

the additional analgesics were administrat-ed in patient with cries score >4 (Figure 1).

Table I.—�Patients’ characteristics.Mean (sD) (Min-max)

age (day) 36.2 (24.2) 2-88Weight (kg) 3.7 (1.1) 1.6-5.8type of surgical procedure n. %

DuodenoduodenostomyKasai’s techniquePyloromyotomyPyeloplastyHigh ligationcolostomyRoux-enY hepaticojejunostomyJejunojejunostomy

4534

12321

11.814.7

8.811.835.3

8.85.92.9

taP block approach n. %

subcostalPosteriorMidaxillary

141010

41.229.429.4

Unilateral/Bilateral 23/11 67.7/32.3extubation time n. %

in operating roomPostop. 2nd hourPostop. 3rd hourPostop. 12th hour

29311

85.38.82.92.9

Postoperative analgesic requirement n. %

subcostal approachMidaxillary approachPosterior approachtotal

911

11 32.4

Postconceptional age (week), Median (iQr):43[39-47]Preterm/term (n.): 11/23Data are reported as number and %, mean (sD), median [iQr].

Figure 1.—the patients who need (cries score >4) and do not need the analgesic administration (cries score <4)

>4

<4

cries

postoperative time point24hr16hr12hr8hr

40

30

20

10

0

num

ber o

f pat

ient

s req

uirin

g an

alge

sic



were feasible. it is recommended that an ex-perienced anesthesiologist should perform the taP block, especially in low birth weight neo-nates.4, 6, 7 We used iv cannula needle, which is sharply pointed and clearly visualized by Usg. We utilized this needle to decrease the risk of intra-abdominal perforation, due to the elasticity of the skin of neonates. to our knowledge, one of our patients with duode-nal atresia was only reported with the lowest weight (1.6 kg) neonate that had the taP block (Figure 2). in this case, the distance from skin to taP was very short (3 mm) and very careful application was needed to avoid the puncture of peritoneum.

Fredrickson et al. firstly performed preop-erative taP block in four neonates undergoing hernia repair. they concluded that taP block is feasible in the neonate and provides effec-tive intraoperative analgesia.4

Jacops et al., performed preoperative taP block in both five neonates and infants un-dergoing abdominal surgery. they concluded that taP block can be promising in this age of groups due to reduction in requirement of neuraxial techniques and opioids.7

Bielsky et al. also performed bilateral taP block in two neonates who had an urgent co-lostomy. they reported that no additional dos-es of analgesics were received in postoperative 24-hours.12

The central neuraxial blocks are not the first choice due to technical difficulties and inad-equate coagulation factors in neonates. Periph-eral nerve blocks can be used when neuraxial block is not desired.9 according to aDarPeF study, neuraxial techniques have an incidence of complications that is seven times that of the peripheral regional techniques. complications of epidural anesthesia are higher in children below 6 months old, being four times that of the over 6 months old.9 anatomical relation-ships and landmarks are different and the dis-tance from skin to epidural space is very small (in infants >6 months is 1 mm/kg). caudal block is also most common regional anesthesia technique in children. the termination of dura and spinal cord in the spinal canal in infants are lower than adults (dura s4-spinal cord l3 at birth).10, 11 therefore the technique for ac-cessing the epidural space should be careful to avoid inadvertent dural puncture or spinal cord damage. It is difficult to place small diameter needles and catheters into subarachnoid space. in addition, small catheters may be kinked, dis-connected, dislodged and occluded easily.11

the taP block was primarily performed in children by Fredrickson et al.4 there are few published reports about taP block in neonates for postoperative analgesia. small infants could be technically challenging due to size and closeness of critical structures but blocks

Figure 2.—Distance between surface and taP was 3 mm and from taP to peritoneum was less than 1 mm in neonate with 1.6 kg of weight.

KenDigelen taP BlocKs in neonates anD YoUng inFants


the thickness of abdominal wall is very slim in this age of groups. those needles have to be inserted parallel to the probe in low angle. We have to be very careful especially during performance of block with subcostal approach due to near adjacency of subcostal abdominal wall to liver and spleen (Figure 2). Besides, the volume of saline which is given to control nee-dle placement has to be much lesser as it can increase the total volume in such low weight patients.

Prospective randomized controlled trial is more preferable, therefore retrospective de-scription, different types of surgeries, varied approaches of performance and variation of time when taP block performed may be con-stitute the limitations of our study.

We did not experience any complications in our cases. long et al. reported one blood aspi-ration and one peritoneal punction from 1994 patients whom performed taP block. they notified that the overall complication rate is 0.3% for taP block in their study. they con-cluded that safety should not be the major con-cerns. Despite, long and et al. reported that so many different dosages of local anesthetic agents were used for taP block. according to their reports, in one study within 135 cases, the dosage of bupivacaine (>2 mg/kg) that admin-istrated was unsafe.5 suresh et al. studies the plasma level of local anaesthetic agent after performance of taP block with dosage of 1 ml/kg 0.125% bupivacaine in neonates. they reported that the plasma level of bupivacaine was significantly much lower from toxic dos-ages. However, the analgesic effects of taP block with that dosage and volume was not investigated.2

We reached an adequate analgesia with our dosage and volume within the limits of the maximal dosage. the risk of last is also present with boluses of local anesthetic so, continuous infusions may be advantage for more prolonged analgesia.13 For this reason, it is an important issue to determine reliable therapeutic range of local anesthetics, espe-cially in premature and low weight neonates.

We followed the cries scores postopera-tively for all cases. the most of patients did not need any analgesics in postoperative 24-hours (Figure 1, table i). the dermatomal block of the abdominal wall may not cut off this ma-jor abdominal surgery pain, but it reduces an-algesic requirements and expected extubation time. Most of our patients were extubated at end of the surgery or within 12 hours. the pa-tients with biliary atresia, choledoc cyst and anal atresia needed paracetamol (10 mg/kg one or two doses) in our series. the paracetamol was received to nine of 11 patients whom taP block were applied with subcostal approach.

We preferred to perform taP block post-operatively in supraumbilical and preopera-tively in infraumbilical incisions. the subcos-tal approach was applied for supraumbilical incision. We considered that local anesthetic solution might be disintegrated from the transversus abdominis plane due to surgical incision at the same location of block that may be the reason of inadequate block, when it is performed preoperatively. therefore, we preferred to perform subcostal approach post-operatively. We cannot compare the various approaches due to small numbers and dissim-ilar surgeries. although, most block failures were performed by subcostal approach. this can be attributed to any several possibilities: 1) this approach less reliable; 2) surgical inci-sion was higher than taP block can cover; 3) the surgeries for which we performed a sub-costal taP, were more invasive (e.g. Kasai procedure).

the non-extubated patients in nicU whom regional block (neuraxial or peripheric) is not performed may routinely need sedation and remifentanil infusion. so, it can prolong post-operative extubation period. Even sufficient success of taP block with subcostal approach is not observed in patients who underwent su-praumbilical surgeries, positive affects as re-duction in paracetamol administration, no need of opioids, shorten extubation period cannot be underestimated. the mid axillary approach may be added to subcostal approach due to in-crease success of taP block in patients who will have major supraumbilical surgeries.



References

1. roofthooft DW, simons sH, anand KJ, tibboel D, van Dijk M. Eight years later, are we still hurting newborn infants? neonatology 2014;105:218-26.

2. suresh s, De oliveira gs Jr. Blood bupivacaine concen-trations after transversus abdominis plane block in ne-onates: a prospective observational study. anesth analg 2016;122:814-7.

3. lönnqvist Pa, Morton ns. Postoperative analgesia in in-fants and children. Br J anaesth 2005;95:59-68.

4. Fredrickson MJ, seal P. Ultrasound-guided transversus abdominis plane block for neonatal abdominal surgery. anaesth intensive care 2009;37:469-72.

5. long JB, Birmingham PK, De oliveria gs Jr, schalden-burg KM, suresh s. transversus abdominis plane block in children: a multicenter safety analysis of 1994 cases from the Pran (Pediatric regional anesthesia network) database. anesth analg 2014;119:395-9.

6. Fredrickson M, seal P, Houghton J. early experience with the transversus abdominis plane block in children. Paediatr anaesth 2008;18:891-2.

7. Jacobs a, Bergmans e, arul gs, thies Kc. the trans-versus abdominis plane (taP) block in neonates and in-fants-result of an audit. Paediatr anaesth 2011;21:1078-80.

8. Krechel sW, Bildner J. cries: a new neonatal postop-erative pain measurement score initial testing of validity and reliability. Paediatr anaesth 195;5:53-61.

9. ecoffey c, lacroix F, giaufré e, orliaguet g, courrèges P; association des anesthésistes réanimateurs Pédi-atriques d’expression Française (aDarPeF). epidemi-ology and morbidity of regional anesthesia in children: a follow-up one-year prospective survey of the French-language society of Paediatric anaesthesiologists (aDarPeF). Pediatr anesth 2010;20:1061-9.

10. Jöhr M. regional anesthesia in neonates, infants and chil-dren. eur J anaesthesiol 2015;32:289-97.

11. Morton ns. local and regional anaesthesia in infants. contin educ anaesth crit care Pain 2004;4:148-51.

12. Bielsky a, efrat r, suresh s. Postoperative analgesia in neonates after major abdominal surgery: ‘TAP’ our way to success! Paediatr anaesth 2009;19:541-2.

13. Walker BJ, long JB, De oliveira gs, szmuk P, setia-wan c, Polaner DM, et al. Peripheral nerve catheters in children: an analysis of safety and practice patterns from the pediatric regional anesthesia network (Pran). Br J anaesth 2015;115:457-62.

Conclusions

there are only few reports about taP block in the neonates and low birth weight groups. this study was analyzed the analgesic effec-tiveness of taP block in neonates and infants that pain control is challenging process. it would be more precise to say that, taP block decrease postoperative analgesic requirements in neonates and young infants undergoing ab-dominal and inguinal surgeries. the minimally invasive and safe analgesic techniques can be solution for postoperative pain management in neonates and young infants. therefore, taP block should be considered in this age group for postoperative analgesia.

Key messages

— the transversus abdominis plane (taP) block has shown analgesic effec-tiveness in abdominal wall surgery both in adults and children.

— Postoperative pain management of neonates is still not developed enough and becomes a key issue.

— Postoperative pain management of neonates has challenges. the simplest ef-fective and safe technique should be used.

— in this group of ages, taP block should be performed to minimize the opi-oid and analgesic requirements in neonates undergoing abdominal surgeries.

Conflicts of interest.—The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.Article first published online: November 11, 2016. - Manuscript accepted: November 10, 2016. - Manuscript revised: September 19, 2016. - Manuscript received: May 7, 2016.


significant care is required to ensure appro-priate use of sedative/analgesics in these pa-tients. However, determining the appropriate level of sedation based on clinical sedation scales (CSSs) may be difficult at higher levels of sedation.1 The use of an objective monitor of sedation, continuous Bispectral (BIS) Index

in mechanically ventilated patients, sedative/analgesic agents are often used to minimize

discomfort of the endotracheal tube, ventila-tor, and the underlying pathologic process. Because of related complications and cost,

R E V I E W

Utilizing Bi-Spectral Index (BIS) for the monitoring of sedated adult ICU patients: a systematic review

Beliz BILGILI 1, Juan C. MONTOYA 2, A. Joseph LAYON 3 *, Andrea L. BERGER 4, H. Lester KIRCHNER 4, Leena K. GUPTA 5, 6, David S. GLOSS 7

1Anesthesiology and Critical Care Medicine, Marmara University Teaching and Education Hospital, Istanbul, Turkey; 2Department of General Internal Medicine, The Geisinger Clinic, Danville, PA, USA; 3Department of Critical Care Medicine, The Geisinger Clinic, Danville, PA, USA; 4Center for Health Research, Division of Medicine, The Geisinger Clinic, Danville, PA, USA; 5Critical Care Medicine, The Geisinger Clinic, Danville, PA, USA; 6Regional Medical Center of San Jose, San Jose, CA, USA; 7Department of Neurology, The Geisinger Clinic, Danville, PA, USA*Corresponding author: A. Joseph Layon, Department of Critical Care Medicine, The Geisinger Clinic, 100 North Academy Avenue, MC 20-37, Danville, PA 17822 – 2037, USA. E-mail: [email protected]

Anno: 2017Mese: MarchVolume: 83No: 3Rivista: Minerva AnestesiologicaCod Rivista: Minerva Anestesiol

Lavoro: 10886-MAStitolo breve: Utilizing Bi-Spectral Index (BIS) for the monitoring of sedated adult ICU patientsprimo autore: BILGILIpagine: 288-301citazione: Minerva Anestesiol 2017;83:288-301

A B S T R A C TBACKGROUND: The ideal level of sedation in the ICU is an ongoing source of scrutiny. At higher levels of sedation, the current scoring systems are not ideal. BIS may be able to improve both. We evaluated literature on effectiveness of BIS monitoring in sedated mechanically ventilated (MV) ICU patients compared to clinical sedation scores (CSS).EVIDENCE ACQUISITION: For this systematic review, full text articles were searched in OVID, MEDLINE, EM-BASE, and Cochrane databases from 1986-2014. Additional studies were identified searching bibliographies/abstracts from national/international Critical Care Medicine conferences and references from searched articles retrieved. Search terms were: “Clinical sedation scale”, “Bi-Spectral Index”, “Mechanical ventilation”, “Intensive Care Unit”. Included were prospective, randomized and non-randomized studies comparing BIS monitoring with any CSS in MV adult (>18 year old) ICU patients. Studies were graded for quality of evidence based on bias as established by the GRADE guide-lines. Additional sources of bias were examined.EVIDENCE SYNTHESIS: There were five studies which met inclusion criteria. All five studies were either unclear or at high risk of bias for blinding of participants and blinding of outcome assessment. All papers had at least one source of additional high risk, or unclear/unstated bias.CONCLUSIONS: BIS monitoring in the mechanically ventilated ICU patient may decrease sedative drug dose, recall, and time to wake-up. The studies suggesting this are severely limited methodologically. BIS, when compared to subjec-tive CSSs, is not, at this time, clearly indicated. An appropriately powered randomized, controlled study is needed to determine if this monitoring modality is of use on the ICU.(Cite this article as: Bilgili B, Montoya JC, Layon AJ, Berger AL, Kirchner HL, Gupta LK, et al. Utilizing Bi-Spectral Index (BIS) for the monitoring of sedated adult ICU patients: a systematic review. Minerva Anestesiol 2017;83:288-301. DOI: 10.23736/S0375-9393.16.10886-7)Key words: Consciousness monitors - Deep sedation - Respiration, artificial.

Minerva Anestesiologica 2017 March;83(3):288-301DOI: 10.23736/S0375-9393.16.10886-7

© 2016 EDIZIONI MINERVA MEDICAOnline version at http://www.minervamedica.it

Comment in p. 244.

UTILIZING BI-SPECTRAL INDEx (BIS) FOR THE MONITORING OF SEDATED ADULT ICU PATIENTS BILGILI

Vol. 83 - No. 3 Minerva anestesiologica 289

Evidence acquisition

Protocol and registration

We developed a systematic review proto-col with pre-specified inclusion and exclusion criteria for study selection, outcome measure-ments and analysis. The project was registered with PROSPERO (www.crd.york.ac.uk), # CRD42015017267.

Eligibility criteria

Type of sTudies

All prospective randomized controlled tri-als evaluating and comparing the effect of BIS monitoring in sedated, MV ICU patients with any of the CSSs were pre-planned to be in-cluded. If there were an inadequate number of prospective randomized studies — less than 5 to 8 — we considered it acceptable to include non-randomized prospective studies. No lan-guage, publication status or publication date restrictions were imposed. Correlation studies of BIS and CSSs were excluded since this was not an objective of this review.

Type of parTicipanTs

Adults (>18 years old) admitted to the ICU requiring sedation/analgesia for MV were in-cluded. Non-ventilated patients were excluded.

Type of inTervenTion

The intervention (BIS monitored) group compared any version of BIS monitors to CSSs.

Type of comparaTor

The control group included any CSS, such as Ramsay Sedation Scale (RSS), Richmond Agitation Sedation Scale (RASS), Sedation Agitation Scale (SAS), and Glasgow Coma Scale (GCS). Some studies used physiologic parameters — blood pressure, heart rate, respi-ratory rate and anxiety — to titrate sedative/an-algesics/anesthetic in the control group.4, 10, 16

monitoring, well established in the operating rooms (OR),2-5 has not been adequately stud-ied in the intensive care unit (ICU).

While utilization of physiologic param-eters — such as variation in blood pressure, heart rate, and respiratory rate — or a change in the sympathetic response resulting in tear-ing, sweating, and/or restlessness may be used to titrate sedative/analgesic medication, these are suboptimal in ensuring amnesia and analgesia in patients unable to express their discomfort. A more optimal manner to assess the depth of sedation in MV ICU patients is via one of a number of computed clinical se-dation scores (CSSs).6 Interobserver variabil-ity has been a concern with the use of these CSSs, with potential for decreased reliability and validity,7 resulting in an over- or under-sedated patient.8

As of the date of this writing, we have found no systematic review or meta-analysis report-ing on which sedation assessment modality or tool is best suited for critically ill, MV ICU pa-tients. In 2013 the American College of Criti-cal Care Medicine (ACCM) Pain, Agitation and Delirium (PAD) study performed a limited meta-analysis of the effect of sedative choice on ICU length of stay, but did not evaluate the influence of sedation tools — CSS versus eeg based tools — on ICU-related outcomes.9

Over-sedated patients may have delayed weaning,10 an increased incidence of ventila-tor associated events from prolonged mechani-cal ventilation 10 and increased drug use and costs.10, 11 Conversely, under-sedated patients may suffer anxiety and agitation, and a re-sultant increased incidence of adverse events such as awareness and recall, post-traumatic stress disorder, and delirium, as well as — po-tentially — an inappropriate use of neuromus-cular blocking agents (NMBAs).11, 12

This systematic review of sedation assess-ment modalities — CSS’s versus BIS moni-toring — in MV ICU patients is performed to ascertain whether BIS monitoring, compared with commonly used CSSs, provides signifi-cant benefit in clinically measurable outcomes: amount of sedatives/analgesics, ventilator days, ICU and hospital LOS and mortality, and complications such as delirium and recall.

BILGILI UTILIZING BI-SPECTRAL INDEx (BIS) FOR THE MONITORING OF SEDATED ADULT ICU PATIENTS


Study selection

Eligibility assessment and data abstrac-tion were performed independently in an un-blinded standardized manner by two re-viewers, and repeated by a second set of two reviewers. Abstracted data included eligibil-ity criteria, baseline characteristics, interven-tions, outcomes, and methodological quality. Instances of disagreement between the re-viewers were resolved by consensus among the investigators.

Inclusion criteria

Participants: adults (>18 years old) admitted to the ICU requiring sedation and MV.

Intervention: BIS monitoring.Comparison: Sedation monitoring using a

CSS.Design: Randomized controlled trials; two

prospective observational studies16, 17 were also included.

Outcome: All outcomes. We pre-planned to accept any acceptable measure of effect, including, but not limited to, risk ratio, odds ratio or risk difference for binary outcomes, difference in means for continuous outcomes, hazard ratio for time-to-event outcomes.

Exclusion criteria

Studies done in the operation room (OR) or post anesthesia care unit (PACU), ICU pa-tients not requiring MV, correlation studies of BIS with CSSs, any study involving Pedi-atric patients, any study involving non-ICU patients.

Data collection

daTa collecTion process

A data extraction sheet (based on the Co-chrane consumers and Communication Re-view Group’s data extraction template) was developed. One review author extracted the following data (Study characteristics, study environment, study methods and study qual-

Type of ouTcome measures

The primary outcome measure was ICU LOS.10 Secondary outcome measures included duration of MV, sedative/analgesic dosage/cost, presence or absence of delirium, and in-fection.11-13

Information sources

The search strategy for studies in this sys-tematic review was both automated and man-ual. We used electronic databases, reviewing reference from the lists of articles searched to identify trials to be included in the system-atic review. For the automated search, the da-tabases used included the digital libraries of PubMed, CCRCT (Cochrane Central Register of Controlled Trials via the Cochrane Library), CDSR (Cochrane Database of Systematic Re-views via the Cochrane Library), Ovid, Med-line and EMBASE. No language limitations were applied. The titles and abstracts of identi-fied references were reviewed, and reference lists of pertinent trials and systematic reviews were used to identify additional studies.

We also searched conference proceedings of the American Thoracic Society (1994-2013), Society of Critical care Medicine (1994-2013), European Society of Intensive Care Medicine (1994-2013) and American College of Chest Physicians (1994-2013). We searched for unpub-lished and ongoing trials in www.clinicaltrials.gov. We contacted the manufactures of commer-cially available BIS monitoring devices for pub-lished and unpublished data (Aspect, Colorado).

Search

With the guidance of an expert medical li-brarian, we searched for eligible studies us-ing the following Medical Subject Heading groupings “bi-spectral index AND sedation scale AND intensive care unit AND mechani-cal ventilation” (Supplementary Tables I, II online content only). For EMBASE, we used the same MESH terms as in OVID MEDLINE. The same search criteria were used across da-tabase resources.



and inclusion/exclusion criteria, study envi-ronment (describing the type of hospital and country), and the design and details of random-ization procedure (Tables I, II, Supplementary Table III, online content only). Data were also extracted regarding the study quality indica-tors and statistical analysis tool used as well as details of CSS used, sedatives and narcot-ics used, dosages and frequency of administra-tion. We extracted details of BIS monitoring equipment, including the type of BIS monitor and software version. The individual study au-

ity indicators) from the included studies and a second author checked the extracted data; this process was then repeated by a second group of two authors. Data were independently ex-tracted from all studies fulfilling inclusion cri-teria.

Data elements

Data extracted from the studies included the study population demographics, age, gen-der, diagnosis, co-morbidities, length of stay

Table i.—�Characteristics of the included studies - method.Altaba Tena, et al.17 Kaplan, et al.16 Zhao, et al.14 Olson, et al.13 Weatherburn, et al.10

Aim of study To determine if BIS use results in reduction of time spent on MV and reduced ICU length of stay, reduced early and late pneumonia development, reduced sedative dose, and complications?

To determine whether BIS-monitored titration of sedatives in ICU patients on continuous infusions of sedatives and paralytics was cost effective and reduced the incidence of the recall phenomenon.

To compare the value of BIS monitoring and SAS in guiding ICU sedation therapy for the patients undergoing short-term MV.

To assess whether monitoring sedation status using BIS as an adjunct to clinical evaluation was associated with a reduction in the total amount of sedative drug used in a 12 hour period.

To assess the effectiveness of the BIS monitor in supporting clinical sedation management decisions in mechanically ventilated ICU patients.

Study design Prospective observational Prospective observational

Prospective RCT Prospective RCT Prospective RCT

Method of recruitment

Not clear; appears to use BIS “when available” and based upon opinion of attending physician. All monitored via RASS.

Month 1 and 2 Control group, Month 3 and 4 Intervention arm

Not clear Unclear. Informed consent from Patient’s legal representative.

All eligible patients were recruited within 24 hours.

Study period July 2009 to November 2010.

4 consecutive months

March 2008 to Feb 2009

Undefined Undefined

Inclusion criteria Medical-surgical patients admitted in the ICU in a level 2-3 teaching hospital, use of MV for at least 24 hours.

SICU patients All adult patients aged between 18-60, admitted between Mar. 2008 and Feb. 2009 who received MV for more than 12 hours in ICU.

Adult MV patients admitted to the neurocritical care unit of a tertiary care hospital with a primary neurological or neurosurgical diagnosis and currently on propofol infusion?

All MV, likely to be ventilated for greater than 12 hours and receiving continuous infusion of Morphine and Midazolam.

Exclusion criteria

Under 18 years old or older than 80, postsurgical patients extubated in less than 3 hours, patients with a neurological condition (ischemic or hemorrhagic or trauma) because of risk of developing intracranial hypertension that can require deeper levels of sedation.

Severe brain injury with GCS <8

Patients with disturbance of consciousness, cardiovascular and cerebrovascular diseases, and liver/kidney diseases which can possibly impair the metabolism of the propofol and midazolam.

Frontal brain injury, required deep (barbiturate coma) sedation or were admitted for status epilepticus.

Intracranial injury, neurological disorder and facial burns.



Table ii.—�Characteristic of included studies.Altaba Tena, et al.17 Kaplan, et al.16 Zhao, et al.14 Olson, et al.13 Weatherburn, et al.10

ParticipantDescription Mechanically ventilated

Patients admitted to a Medical-Surgical ICU in a Level 3-4 Teaching Hospital

SICU patients Patients admitted by ICU at Beijing Tong Ren Hospital.March 2008 to February 2009.

Adult mechanically ventilated Patients admitted to the NeuroCritical Care Unit with primary neurological / neurosurgical diagnosis & receiving IV propofol.

Control: “Standard Care”.BIS: Continuous monitoring until extubation or tracheostomy.

Number N.=85Control-54BIS – 31

N.=57Control-31BIS-26

N.=105SAS-63BIS-42

N.=6735-Ramsay Score32-BIS

N.=5025-Control25-BIS

Age >18 and <80 years(no mean given)

Unspecified SAS: 39.2±10.4BIS 39.5+7.8

Ramsay: 54.8±15.1BIS: 57.8±19.8

Control: 50±22BIS: 57±21

Gender MaleControl: 57.4%BIS: 77.4%(P=0.05)

Unspecified Male 101Female 4

MaleRamsay: 40%BIS: 50%

MaleControl: 68%BIS: 64%

Severity of illness

Comorbidities given Unspecified APACHE II:SAS: 4.2±2.3BIS: 3.6±2.6

APACHE IV:Ramsay: 67.4±20.3 BIA: 75.6±21.8Admit GCS:Ramsay: 8.4+2.6BIS: 7.6+2.7

APACHE II: median (IQR)Control: 14 (11, 20)BIS: 14 (11, 19)

Frequency of BIS monitoring

Upon admission and at 24 hours

Unspecified Hourly Unspecified Every 1 hour

controlCSS used rass Vital signs

changes after stimulation

sas Ramsay Hourly subjective clinical assessment – HR, BP, Consciousness Level & Pupillary Size

Duration CSS monitoring

Unspecified Unspecified From the ICU admission to 0600 the next day.

12 hours Unspecified

Sedative used Midazolam/propofol Lorazepam, Midazolam, and Propofol

Midazolam/propofol

Propofol Midazolam

Narcotic used Morphine Morphine Fentanyl Fentanyl prn MorphineNMB used Cisatracurium Yes, unspecified Unspecified Unspecified UnspecifiedGoals of

sedationBIS of 40-60 Control: Vital

Signs after Stimulation.BIS: 70-80

SAS: 3-4BIS: 50-70

Ramsay Score = 4BIS between 60-70

Control: Normal HR, BP, LOC, & Pupillary SizeBIS: >70

Duration of sedation

Weaning left up to physician judgment.

Unspecified Median (IQR)SAS: 16 hours (13, 18)BIS: 14 (12.9, 17.1)

12 hours Until extubation or tracheostomy

OutcomePrincipal

outcomeLength of MV Cost

effectiveness of sedative and paralytic agents

Dosage of midazolam and propofol.Duration of MV and Sedation

Total dose of sedative drug used in 12 hours. Overall sedative use

Total amount of sedative, Amount of sedative administered over time

Secondary outcome

ICU stay, incidence of early and late pneumonia, dose of sedatives, costs, complications

Incidence of recall

Mean recovery time. Under sedation event

Length of MV and icU los



Planned method of analysis

While meta-analysis was our goal, extreme variability, inconsistency and heterogeneity across the studies made this impossible.

Evidence synthesis

Study selection

Of 385 potential studies, we identified 63 citations 7-14, 16-71 from search of electronic bib-liographic databases. Five studies 10, 13, 14, 16, 17 met the inclusion criteria after excluding cor-relation articles, trials involving pediatric pa-tients and duplicates; because there were only three randomized, controlled trials, we includ-ed two prospective observational studies 16, 17 in this systematic review (Figure 1). These five trials were included in qualitative synthesis and systematic review. While there was gener-al agreement amongst all the reviewers, minor differences were resolved with the help of the

thor’s conclusions, study limitations, and other remarks were also noted.

Risk of bias in individual studies

The assessment of the risk of bias of indi-vidual studies included the following: random sequence generation, allocation concealment (a method in which researchers are unable to influence whether the patients end in treated or the control group), blinding of personnel and participants, blinding of outcome assessment, incomplete outcome data, selective report-ing (ORBIT classification),15 other sources of bias, and a priori protocol/analysis plan. Two authors assessed the risk collaboratively (DG and AJL).

Summary measures

Effect on ICU LOS was the primary measure of BIS utilization when compared to CSSs.

Figure 1.—PRISMA Flow Diagram for Study selection.

Records identified through database searching

#42 PubMed + #318 Medline + #21 EMBASE (n = 381)

Additional records identified through other sources (n = 4)

Total number of Records (n = 385) After duplicates #24 removed

(n = 361)

Records screened for eligibility (n = 63)

#298 Total Articles excluded due to: -‐ Correlation studies -‐ Pediatric patients -‐ Post Anesthesia Care Unit -‐ Non Mechanical ventilated

Articles assessed for eligibility (n = 31)

Articles excluded based on inclusion criteria (n = 32)

Studies included in qualitative synthesis (n = 5)

Studies included in quantitative synthesis (n = 0)

Articles excluded based on close reading of methods

(n = 26)

(N.=381)(N.=4)

(N.=361)

(N.=63)

(N.=31)

(N.=5)

(N.=0)

(N.=32)

(N.=26)

(N.=385)



related to the CSS used. In general, outcome measures were not defined well; there were a limited number of studies for each outcome. While bias varied by study, all studies were ei-ther unclear or at high risk of bias with blind-ing of participants and personnel, and blinding of outcome assessment (Supplementary Table IV, online content online).


We could not reliably combine studies in a way that made scientific sense. Studies used different outcome measures, and were silent on, or used different, BIS monitors, which may have included a different algorithm to calcu-late sedation level. Moreover, the duration of the BIS monitoring was individualized by the study. Thus, we felt combining such overtly different studies could be potentially mislead-ing.

Discussion

bis characTerisTics

The BIS was introduced by Aspect Medical Systems in 1994 as a novel way to algorith-mically measure the level of consciousness of a patient under general anesthesia by using a limited montage electroencephalogram. This is used in conjunction with other physiologic monitoring, such as electromyography, to esti-mate the depth of anesthesia and thereby mini-mize the possibility of intraoperative aware-ness. The US Food and Drug Administration (FDA) cleared BIS monitoring in 1996 for assessing the hypnotic effects of general anes-thetics and sedatives. BIS is a practical, pro-cessed EEG parameter that measures the direct effects of sedatives on the brain. It is applied using a frontal montage and provides objec-tive information about an individual patient’s response to sedation/anesthesia.

BIS was initially devised to monitor depth of anesthesia in the OR, as it was intended to replace or supplement Guedel’s classifica-tion system for determining anesthetic depth. Use of the BIS monitor is thought to reduce

other investigators. Data was further analyzed in regards to clinical and physiologic attributes of the included studies, statistical tools used and conclusions provided by the authors.

Outcome

The main outcome was ICU LOS.10 Other outcomes assessed were level of sedation, dos-age of sedatives, duration of MV and adverse events such as delirium, infections, extubation failure, and mortality.11, 12

We accepted the author’s goals of seda-tion, which were varied. We also considered other physiologic outcomes such as physi-ologic changes in blood pressure, HR, time to awakening and factors such as usage of daily sedation interruption and daily delirium as-sessment. Only one of the studies had a daily morning sedation interruption or daily delirium screening. Finally, we evaluated for adverse events, including ventilator associated events — which included early and late VAP — bac-teremia, catheter associated-urinary tract in-fection (CA-UTI), technical complications and equipment use characteristics, including the comfort level and experience of the nurse in using the BIS monitor.

In general, there were hints that the use of BIS in the critically ill adult ICU patient was associated with use of lesser amounts of seda-tives,13 at lesser cost and with less recall;14, 16 decreased MV days;14 less delirium and a short-er time to wakeup.13, 14 Although flawed, the study of Mahmood and colleagues 72 — not part of our analysis — showed a decrease in the use of sedation and analgesia, decrease in agitation and failure to extubate as well as the need for tracheostomy, and an approximate 4 day decreased length of stay. While these data cannot be taken as final, they are indications that this modality of monitoring requires rigor-ous study to determine its usefulness.

Risk of bias within studies

There was variability with regard to the in-tervention group, which had different versions of the BIS monitor. Control group variance was



per group, but randomization was stopped in interim analysis because of the statistical sig-nificance achieved.

Zhao et al.14 randomized patients to receive midazolam or propofol sedation. Sedation was suspended hourly and titrated to goals of BIS 50-70, SAS 3-4. The authors showed some dif-ferences in BIS-treated versus SAS treated pa-tients. Percent total time under sedation, pro-pofol and midazolam doses were all higher in the BIS group (P<0.05). However, the median time to wake-up was less in the BIS group (0 versus 15 minutes, P<0.05).

Weatherburn’s study 10 was a prospective randomized trial in which patients sedated with morphine and midazolam were random-ized to sedation titration based on a BIS score of greater than 70, or subjective clinical as-sessment which could be augmented based on clinician preference with a sedation scoring tool. The investigators found no differences in the total amount of sedation administered, nor in days of mechanical ventilation, or ICU length of stay. Among secondary outcomes, they did find that the amount of morphine used in BIS patients significantly increased over time (P<0.02 after Bonferoni correction).

There were two abstracts included in this review. Both were considered to be at high risk of bias as the provided information was considered inadequate. In the prospective ob-servational study by Altaba Tena et al.17 of 85 patients, there were not significant differences in duration of ventilation, total dose of seda-tives, ventilator-associated pneumonia, or ICU or hospital length of stay. In Kaplan and Bai-ley’s 16 prospective cohort trial, patients with GCS <9 were treated on alternating months ei-ther via apparent patient comfort guided by vi-tal sign changes or using a BIS value between 70-80. There were significant differences in amount of sedation used and in the number of patients who recalled a frightening/painful ex-periences.

A study — which was not part of our origi-nal evaluation — of interest is that by Mah-mood et al.72 These investigators evaluated 110 traumatized patients, of whom 50% were from motor vehicular crashes, and 88% had

the incidence of intraoperative awareness dur-ing anesthesia.4 Titrating anesthetic agents to a specific BIS index during general anesthesia in adults allows the anesthesiologist/anesthetist to adjust the amount of anesthetic agent to the needs of the patient, potentially resulting in a more rapid emergence from anesthesia. There are a wide range of BIS modules available cur-rently on the market, including — in the USA — Phillips, GE, Datex-Ohmeda, Dräger Medi-cal, Space labs, Nihon Kohden, Dixtal and Da-tascope.5

The key application of BIS monitoring is objective assessment of sedation in the pa-tient’s intraoperative and immediate peri-oper-ative phase in the OR and recovery room. The not-so-established, and less frequent, usage of BIS is in the ICU, in postoperative patients who may have received neuromuscular block-ade, close monitoring of sedation level in drug induced coma, and for sedation purpose during bedside procedures. It is in these areas that the utility of BIS could be explored.

Summary of evidence

This systematic review on comparison of diagnostic properties and efficacy of BIS monitoring and CSS is the first to summarize available validation studies. We found 5 stud-ies 10, 13, 14, 16, 17 each of which evaluating differ-ent outcomes (Table III).

Among the included studies, Olson’s was a prospective study randomizing patients to Ramsay scale or BIS monitoring in addition to Ramsay Scale.13 The study began at 08.00 after consent was obtained. All patients were sedated with propofol. Patients had sedation stopped every 2 hours. Nurses were instructed to dose the propofol infusion to obtain a score of 4 in the control group, or a Ramsay score of 4 and a BIS value between 70 and 80 in the BIS monitoring group. The primary end-point was the total dose of sedative medication used in 12 hours. There was an approximate 50% reduction in the amount of sedation used: BIS-augmentation 93.5±86.3 mL, Ramsay scale alone 157.8±119.2 mL (P=0.0146). The study’s power analysis suggested 45 patients



Table iii.—�Results.Name of study/outcomes Intervention Control P Comments

3a. ALTABA TENA 17 N.=31 N.=54Ventilator days Median (IQR) 4 (1, 10) 4 (2, 10.75) 0.33 nsEarly VAP N, (%) 3 (10%) 7 (13.5%) 0.46 nsLate VAP 3 (9.7%) 11 (21.2%) 0.14 nsDosages propofol (mcg) 1996 (800, 4800) 4160 (1860, 6375) 0.15 nsDosages midazolam (mg) 155 (55, 279) 137 (54, 420) 0.87 nsDosages morphine (mg) 77 (33, 240) 96 (44, 214) 0.93 nsDosage cisatracurium (mg) 22.5 (10, 100) 42 (10, 100) 0.73 nsBacteremia 4 (13.3%) 12 (25%) 0.16 nsUti 1 (3.3%) 4 (7.7%) 0.39 nsTracheostomy 1 (3.2%) 6 (11.5%) 0.18 nsAKI 15 (18%) 19 (22.8%) 0.1 nsFailure to extubate 7 (11.1%) 14 (22.2%) 0.5 nsLOS ICU days 7.5 (2, 17) 7.5 (4, 19) 0.51 nsLOS Hospital days 20 (12, 36) 20 (9, 32) 0.57 nsMortality ICU 12 (14.1%) 16 (18.8%) 0.26 ns

3b. KAPLAN 16 N.=26 N.=31Sedative cost per patient $ 669±1362 $ 819±2045 >0.05 18% reduction in cost, NSLorazepam 18% reduction in

usage<0.05 Significant Difference

Midazolam 18% reduction in usage

<0.05 Significant Difference

Propofol 47% reduction in usage

<0.05 Significant Difference

Under sedated ** 15% who appeared sedated were less sedated by BIS

Over sedated ** 54% of BIS-monitored patients required less sedation than initially predicted by staff

Recall(frightening/painful events)

4% 18% <0.05 Significant difference

3c. ZHAO (14) N.=42 N.=63% total time under sedation 75.2% 52.8 <0.01 Significant differenceTime period 1 sedated 78.6% 22.2% <0.01 Significant differenceTime period 2 sedated 88.1% 20.6% <0.01 Significant differenceTime period 3 sedated 81.0% 31.7% <0.01 Significant differenceRestlessness after Suction 81% 79.4% > 0.05 nsIncreased endotracheal tube resistance 71.4% 74.6% > 0.05 nsPain free during sedation 92.8% 93.6% > 0.05 nsDelirium after extubation 4.8% 1.6% > 0.05 nsMidazolam (mg/kg/hr) 0.1±0.02 0.09±0.02 <0.05 Significant differencePropofol (mg/kg/hr) 0.95±0.23 0.86±0.2 <0.05 Significant differenceDuration of mechanical ventilation

(median, interquartile range), hrs16.5 (14.5, 19) 17.0 (15, 19) > 0.05 ns

Sedation time (median, IQR), hrs 14 (12.9, 17.1) 16 (13, 18) > 0.05 nsTime to wake-up (median, IQR), min 0 (0, 20) 15 (0, 47) <0.05 Significant difference

(To be continued)



ing in the ICU, there is a compelling rationale to use BIS only in ICU patients in a properly powered randomized prospective trial. The clinical experience of one of the authors (AJL), using BIS in the ICU, leads us to think that this modality of monitoring will advantageous in decreasing ventilator days and drug dosages while preventing under-sedation.


The limitations of this systematic review are significant, as there were few studies meeting the inclusion criteria. Of the studies included, each had significant methodological limitations. Ad-ditionally, because of the heterogeneity between the studies regarding the CSS, BIS equipment, ICU setting and statistical analytical tools used, it is not possible to say with any confidence that BIS monitoring improves patient outcomes. More appropriately designed trials are required

suffered head injury; average Glasgow Coma Scale score was 6.9±2.7. While the bias in this study is as remarkable as its results — there was no mention of randomization nor how it was done if it was done, there was no power analysis, and there was, finally, no mention of how the BIS was used nor the BIS value that was aimed for — use of BIS in this study re-sulted in a decrease in the use of sedation and analgesia, a decrease in agitation, failure to extubate, and tracheostomy, and an approxi-mate 4 day decreased length of stay. While this study has its flaws, it is of great interest.

While BIS monitoring in the mechanically ventilated ICU patient may decrease seda-tive drug dose,10, 14, 16, 72 recall,16 and time to wake-up,14 given the limitations of the studies and the decided lack of significant differences when using BIS alone or BIS-augmentation of standard clinical care, combined with the po-tential applicability of this mode of monitor-

Table iii.—�Results (continues).Name of study/outcomes Intervention Control P Comments

3d. Olson 13 N.=32 N.=35Dose of propofol in 12 hr (mL) 93.5±86.3 157.9±119.2 0.0146 BIS augmented group needed

half the sedative dosesRate of infusion of propofol(mcg/kg/min)

14.6±12.2 27.9±20.5 0.0026

Risk of propofol infusion exceeding manufacturer’s recommended dosing guide (4 mg/kg/hr) %

0 subjects, 0% 8 subjects, 23% 0.0052 Non BIS group significantly more likely to receive Propofol at rates that exceeded manufacturer’s recommended doses

Mean recovery time (min) 1.2±2.08 7.5±7.54 <0.0001 BIS augmented group had a rapid emergence from sedation

Number of under sedation events 0 0 BIS augmented group appeared safe

Fentanyl used mcg/12 hr 200 350 nsWeatherburn 10 N.=25 N.=25Sedative dosage – midazolam(mean, 95% confidence intervals)

18.4 (10.9 – 30.9)

14.6 (8.8 – 24) 0.85 No significant differences in sedation/analgesia total doses. When doses of midazolam (P=0.03) and morphine (P=0.005) were trended over time in ICU, BIS- patients received more of both drugs

Analgesic – morphine 22.6 (14.9 – 34.5)

26.6 (17.5 – 40.4) 0.67

Mechanical ventilation (mean [SD], days)

7.0±0.6 7.0±0.8 0.71 No significant difference

ICU LOS (Median, [IQR] days) 12 (6, 18) 8 (4, 14) 0.2 No significant differenceNote: Information taken from data / Tables in the original articles and / or after telephonic discussion with authors.



pharmacological action different than the po-tent inhaled anesthetic agents. It is possible that different sedatives and analgesics will have a variable effect on the BIS-calculated sedation value, and may require differential validation. Future studies need to focus on the BIS monitoring of patients in different critical care settings, specifically, patients who are in the neuro-critical care unit or who have suf-fered cerebro-vascular accidents, traumatic brain injuries, and so forth.

Larger studies are required with better con-trol of variables to adequately assess the in-fluence of BIS monitoring on under-sedation, over-sedation, incidence of delirium, and out-comes resulting from prolonged duration of sedation and ICU LOS. In the context of these further studies, we recommend evaluation of infectious complications in BIS-monitored pa-tients as well. It is intuitive — even if poten-tially incorrect — that if there is a decrease in the sedative dosage in the BIS group, there will be fewer ventilator days, a lesser incidence of ventilator associated events and, potentially, other infectious complications.

Key messages

— BIS monitoring in the mechanically ventilated ICU patient may decrease seda-tive drug dose, recall, and time to wake-up. The studies suggesting this are severely limited.

— BIS, when compared to subjective CSSs, is not, at this time, clearly indicated.

— An appropriately powered random-ized, controlled study is needed to deter-mine if this monitoring modality is of use in the ICU.

— Until this study is performed, we rec-ommend that BIS be used cautiously in the ICU population.

References 1. Micek S, Barnes BJ, Grauer DW, Johnson DC. Long-

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to assess the efficacy of BIS monitoring in differ-ent ICU populations and settings.

Strengths

This systematic review was exhaustive, with strict inclusion and exclusion criteria used. Additionally, the senior investigators have ex-tensive experience in neuromonitoring and uti-lization of perioperative BIS monitoring. Most importantly, this systematic review points out the need for a well-designed, randomized, con-trolled trial.

Conclusions

We performed a systematic review of ran-domized trials comparing CSSs with BIS in mechanically ventilated ICU patients. We found numerous issues related to study design, conduct, and quality that, to a great extent, dispute their validity and generalizability in evaluating how, or whether, BIS modality of sedation monitoring has a significant effect on clinical outcomes.

Implications for practice

BIS does not appear to be indicated based on the included studies; a properly powered ran-domized controlled study is needed. Indeed, the American College of Critical Care Medicine (ACCM), the Society of Critical Care Medi-cine (SCCM), the American College of Chest Physicians (ACCP), and the American Society of Health System Pharmacists (ASHP), in their clinical practice guideline for the sustained use of sedatives and analgesics in the critically ill patient point out that the routine use of BIS in the ICU is not recommended.73

Future research

The reliability of BIS has been questioned, in part, because its numerical calculation does not rely on an underlying physiological model of how the brain functions, nor on how aware-ness is generated. Additionally, the BIS value is insensitive to the commonly used anesthetic agent ketamine, which has a mechanism of



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56. Jaber S, Bahloul H, Guetin S, Chanques G, Sebbane M, Eledjam JJ. Effects of music therapy in intensive care unit without sedation in weaning patients versus non-ventilated patients. Ann Fr Anesth Reanim 2007;26:30-8.

57. Ma PL, Zhao JZ, Su JW, Li Q, Wang Y. Comparison of reliability of bispectral index and sedation-agitation scale in assessing the depth of sedation in patients treated with mechanical ventilation. Zhongguo Wei Zhong Bing Ji Jiu Yi xue 2006;18:323-6.

58. Vet NJ, Ista E, de Wildt SN, van Oijk M, Tibboel D, de Hoog M. Optimal sedation in pediatric intensive care patients: a systematic review. Intensive Care Med 2013;39:1524-34.

59. Roberts DJ, Haroon B, Hall RI. Sedation for critically ill or injured adults in the intensive care unit: a shifting para-digm. Drugs 2012;72:1881-916.

60. Cidoncha EL, Mencia S, Riano B, Urbano J, Lopez – Herce J, Carrillo A. The assessment of sedation in the critically ill child on mechanical ventilation during tra-cheal suction. Ann Pediatr (Barc) 2009;70:218-22.

61. Hernandez-Gancedo CI, Pestana D, Pena N, Royo C, Perez-Chrzanowska H, Criado A. Monitoring sedation in critically ill patients: bispectral index, Ramsay and ob-server scales. Eur J Anaesthesiol 2006;23:649-53.

62. De Jong MM, Burns SM, Campbell ML, Chulay M, Grap MJ, Pierece CN, et al. Development of the Ameri-can Association of Critical-Care Nurses’ sedation as-sessment scale for critically ill patients Am J Crit Care 2005;14:531-44.

63. Long D, Horn D, Keogh S. A survey of sedation assess-ment and management in Australian and New Zealand paediatric intensive care patients requiring prolonged mechanical ventilation. Aust Crit Care 2005;18:152-7.

64. De Gaudio AR, Rinaldi S. Sedation in PACU: Indica-tions, monitoring, complications. Curr Drug Targets 2005;6:729-40.

65. Roustan JP, Valette S, Aubas P, Rondouin G, Capdevila x. Can electroencephalographic analysis be used to de-termine sedation levels in critically ill patients? Anesth Analg 2005;101:1141-51.

66. Deogaonkar A, Gupta R, DeGeorgia M, Sabharwal V, Gopakumaran B, Schubert A, et al. Bispectral Index monitoring correlates with sedation scales in brain-in-jured patients. Crit Care Med 2004;32:2403-6.

67. Liu LL, Gropper MA. Postoperative analgesia and seda-tion in the adult intensive care unit: a guide to drug selec-tion. Drug 2003;63:755-67.

68. Sessler CN, Gosnell MS, Grap MJ, Brophy GM, O’Neal PV, Keane KA, et al. The Richmond Agitation-Sedation Scale – Validity and reliability in adult intensive care unit patients. Am J Respir Crit Care Med 2002;166:1338-44.

69. Dewlin JW, Fraser GL, Kanji S, Riker SS. Sedation assessment in critically ill adults. Ann Pharmocother 2001;35:1624-32.

34. de Wit M, Best AM, Epstein SK, Greenblatt DJ. Loraz-epam concentrations, pharmacokinetics and pharmaco-dynamics in a cohort of mechanically ventilated ICU patients. Int J Clin Pharmocol Ther 2006;44:466-73.

35. Consales G, Chelazzi C, Rinaldi S, De Gaudio AR. Bispectral Index compared to Ramsay score for sedation monitoring in intensive care units. Minerva Anestesiol 2006;72:329-36.

36. Turkmen A, Altan A, Turgut N, Vatansever S, Gokkaya S. The correlation between the Richmond agitation-sedation scale and bispectral index during dexmedetomidine seda-tion. Eur J Anaesthesiol 2006;23:300-4.

37. Twite MD, Zuk J, Gralla J, Friesen RH. Correlation of the Bispectral Index Monitor with the COMFORT scale in the pediatric intensive care unit. Pediatr Crit Care Med 2005;6:648-53.

38. Riker RR, Fraser GL. Monitoring sedation, agitation, an-algesia, neuromuscular blockade, and delirium in adult I CU patients. Semin Respir Crit Care 2001;22:189-98.

39. Tonner PH, Wei C, Bein B, Weiler N, Paris A, Scholz J. Comparison of two bispectral index algorithms in moni-toring sedation in postoperative intensive care patients. Crit Care Med 2005;33:580-84.

40. Olofsson K, Alling C, Lundberg D, Malmros C. Abol-ished circadian rhythm of melatonin secretion in sedated and artificially ventilated intensive care patients. Acta Anaesthesiol Scand 2004;48:679-84.

41. Tobias JD, Berkenbosch JW. Sedation during mechani-cal ventilation in infants and children: dexmedetomidine versus midazolam. South Med J 2004;97:451-5.

42. de Wit M, Epstein SK. Administration of sedatives and level of sedation: comparative evaluation via the Seda-tion-Ag i tation Scale and the Bispectral Index. Am J Crit Care 2003;12:343-8.

43. Crain N, Slonim A, Pollack MM. Assessing sedation in the pediatric intensive care unit by using BIS and the COMFORT scale. Pediatr Crit Care Med 2002;3:11-4.

44. Mondello E, Siliotti R, Noto G, Cuzzocrea E, Sciollo G, Trimarchi G, et al.Bispectral Index in ICU: correlation with Ramsay Score on assessment of sedation level. J Clin Monit Comput 2002;17:271-7.

45. Cavaliere F, Antonelli M, Arcangeli A, Conti G, Costa R, Pennisi MA, et al. A low-dose remifentanil infusion is well tolerated for sedation in mechanically ventilated, critically-ill patients. Can J Anaesth 2002;49:1088-94.

46. Frenzel D, Greim CA, Sommer C, Bauerle K, Roewer N. Is the bispectral index appropriate for monitoring the sedation level of mechanically ventilated surgical I CU patients? Intensive Care Med 2002;28:178-83.

47. Berkenbosch JW, Fichter CR, Tobias JD. The correla-tion of the bispectral index monitor with clinical seda-tion scores during mechanical ventilation in the pediatric intensive care unit. Anesth Analg 2002;94:506-11.

48. Riker RR, Fraser GL, Simmons LE, Wilkins ML. Vali-dating the Sedation-Agitation Scale with the Bispectral Index and Visual Analog Scale in adult ICU patients after cardiac surgery. Intensive Care Med 2001;27:853-8.

49. Simmons LE, Riker RR, Prato BS, Fraser GL. Assessing sedation during intensive care unit mechanical ventila-tion with the Bispectral Index and the Sedation-Agitation Scale. Crit Care Med 1999;27:1499-504.

50. da Silva C, Alves MM, El Halal MG, dos Pinheiro SS, Carvalho PR. A comparison of gradual sedation levels us-ing the Comfort-B scale and bispectral index in children on mechanical ventilation in the pediatric intensive care unit. Rev Bras Ter lntensiva 2013;25:306-11.

51. Vaschetto R, Cammarota G, Colombo D, Longhini F, Grossi F, Giovanniello A, et al. Effects of propofol on patient-ventilator synchrony and interaction during pres-sure support ventilation and neurally adjusted ventilatory assist. Crit Care Med 2014;42:74-82.



72. Mahmood S, Parchani A, El-Menyar A, Zarour A, Al-Thani H, Latifi R. Utility of Bispectral index in the man-agement opf multiple trauma patients. Surg Neurol Int 2014;5:141-52.

73. Barr J, Fraser GL, Puntillo K, Ely EW, Gelinas C, Dasta JF, et al. Clinical practice guidelines for the Management of Pain, Agitation, and Delirium in Adult Patients in the Intensive Care Unit. Crit Care Med 2013;41:263-306.

70. Campbell ML, Bizek KS, Thill M. Patient responses during rapid terminal weaning from mechanical ventila-tion – A prospective study. Crit Care Med 1999;27:73-7.

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Conflicts of interest.—The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.Author’s contributions.—Juan C. Montoya, Leena K. Gupta, H. Lester Kirchner, and A. Joseph Layon conceived of and designed the study. Juan C. Montoya and Leena K. Gupta initially reviewed the literature and provided initial evaluation of included papers; A. Joseph Layon, Beliz Bilgili, and David S. Gloss re-evaluated the literature search and the included and excluded papers; H. Lester Kirchner and Andrea L. Berger were statistical consultants for the study.All the authors assisted in the writing, reviewing, and editing of the paper; all authors approved the final manuscript. All the authors attest to the integrity of the manuscript.Article first published online: June 17, 2016. - Manuscript accepted: June 15, 2016. - Manuscript revised: May 23, 2016. - Manuscript received: August 19, 2015.For supplementary materials, please see the online version of this article.


cal care medicine, mortality remains high and often not related to the initial injury, but rather to secondary events — especially infections — that occur during the immunosuppression period.9 Mechanisms of this immunoparaly-sis and therapeutic opportunities have been recently published in the particular field of sepsis.10 in the present review, we will focus on cellular biomarkers of injury-induced im-munosuppression resulting from various forms of severe injuries. Unless specified, all studies cited in the present review involved intensive care patients.

the immune system response to major in-juries often leads, after an initial hyper-

activation, to an incompetent and hyporeactive immune status (Figure 1). this injury-induced immunosuppression has been described in the past decades in various clinical settings, such as septic shock,1 severe trauma,2 severe burns,3 or major surgery.4 When persistent or intense, immune paralysis is associated with the devel-opment of secondary infections and pejorative outcomes.5-8 Despite recent advances in criti-

R E V I E W

Biological markers of injury-induced immunosuppression

christelle roUget 1-3, thibaut girarDot 1-3, Julien teXtoris 1-3, guillaume Monneret 1, 2, 4, thomas riMMelÉ 1-3, Fabienne venet 1, 2, 4 *

1Joint research Unit, Hospices civils de lyon, BioMérieux, edouard Herriot Hospital, lyon, France; 2eaM Pathophysiology of injury-induced immunosuppression, UcBl1-Hcl-BioMérieux, lyon, France; 3anesthesiology and intensive care Department, Hospices civils de lyon, edouard Herriot Hospital, lyon, France; 4immunology laboratory, Hospices civils de lyon, edouard Herriot Hospital, lyon, France*corresponding author: Fabienne venet, laboratoire commun de recherche Hcl-BioMérieux, Hôpital edouard Herriot, Pavillon P, 5 place d’arsonval, 69437 lyon cedex 3, France. e-mail: [email protected]


lavoro: 11268-Mastitolo breve: Biological MarKers oF inJUrY-inDUceD iMMUnosUPPres-sionprimo autore: roUgetpagine: 302-14citazione: Minerva anestesiol 2017;83:302-14

a B s t r a c tsevere injuries, such as severe sepsis, burn, trauma and major surgery, lead to an overlapping development of pro- and anti-inflammatory responses. It is now well established that these injuries are associated with the secondary development of immune suppression, which results in significant morbidity and mortality. Recent data suggest that immunostimu-latory drugs might prevent these complications. However, intensive care patients are heterogeneous, making patient stratification essential for a targeted treatment. In the present review, we discuss potential biomarkers of injury-induced immunoparalysis, mainly focusing on these that have been associated with poor outcome in various clinical settings. We namely present clinical data on monocyte human leukocyte antigen Dr, lymphopenia, PD-1/PD-l1 and transcriptomic approach.(Cite this article as: rouget c, girardot t, textoris J, Monneret g, rimmelé t, venet F. Biological markers of injury-induced immunosuppression. Minerva anestesiol 2017;83:302-14. Doi: 10.23736/s0375-9393.16.11268-4)Key words: Wounds and injuries - sepsis - immunosuppression - Biomarkers - Monitoring, immunologic.



comment in p. 246.

Biological MarKers oF inJUrY-inDUceD iMMUnosUPPression roUget


(granulocyte–macrophage colony-stimulating factor) therapy enables to shorten the time of mechanical ventilation and hospital/intensive care unit stay.15 Because of the aforementioned heterogeneity, critically ill patients may not all benefit from immunostimulatory drugs. therefore, clinicians need to know the particu-lar immune status of each patient in real time to propose the best personalized care. Finally, markers of patient immune status could be used to monitor treatment efficacy or side effects.

Biomarkers of injury-induced immunosuppression

Innate immunity

Neutrophils aNd immature graNulocytes

Neutrophils represent the first line of innate immune defense against infection and are the most abundant leukocyte subset. Paradoxi-cally, data about injury-induced neutrophil alterations are scarce. sepsis leads to the mas-sive recruitment of immature neutrophils. the immature granulocyte fraction can be assessed by a blood cell analyzer, expressing the result in Delta neutrophil index (Dn), which inde-pendently correlates with 28-day mortality in patients with sepsis.16 consistently, Mare et al. found a significantly lower immature granulo-cyte count in the >4-week survival group com-pared with the patients who died within the first week of sampling.17

We recently studied functional neutrophil alterations during sepsis-induced immunosup-pression (day 3-4 and day 6-8), on 43 septic shock patients and 23 healthy volunteers.18 a high immature granulocyte count was associ-ated with mortality. in addition, we performed a global evaluation of the neutrophil alterations in septic shock, and highlighted a markedly al-tered neutrophil chemotaxis (reduced integrin, selectin, and chemokine receptor expression with altered ex vivo migration in response to dif-ferent chemo attractants) and oxidative burst, also associated with mortality. conversely, and in accordance with the work of Drifte et al.,19 phagocytose and activation capacities were

Need for biomarkers

even considering the same diagnosis, there is a huge clinical and biological diversity re-sulting from the complex and highly dynamic interaction between host and injury. the panel of disease severity and patients’ comorbidities increases even more this heterogeneity. this has been suggested to participate in the failure of clinical trials in septic shock. in line, icU patients’ immune status is heterogeneous but cannot be determined based on clinical signs. Biomarkers of patients’ immune status could help patient stratification such as proposed in the Piro (predisposition, insult, response, and organ dysfunction) score.11

reversing and/or shortening the immuno-paralysis phase might be of crucial interest to improve patients’ outcomes.12 For instance, one of these promising immunoadjuvant thera-pies is interferon-gamma (IFNγ). It has been shown to restore the expression of transcripts associated with the development of immuno-suppression in an ex vivo monocyte endotoxin tolerance model.13 IFNγ also partially reversed sepsis-induced immunoparalysis in a human in vivo model of gram negative sepsis.14 We can also refer to the work of Meisel et al., who have shown that mHla-Dr guided gM-csF

Figure 1.—Simplified description of immune response to injury: a complex balance.After injury, inflammatory and immunosuppressive pro-cesses coexist (dotted lines), with an usual initial proinflam-matory and lately anti-inflammatory resultant (continuous line). severe injuries lead to a biphasic situation, with a long lasting immunoparalysis following the initial inflammatory burst. Both extreme pro- and anti-inflammatory states lead to unfavorable outcome (dashed lines).

Hom

eost

asis

early death

late death

Anti inflammatory response

time

Pro inflammatory response

roUget Biological MarKers oF inJUrY-inDUceD iMMUnosUPPression


overall, mHla-Dr is a robust prognostic marker of mortality and secondary infections in a broad variety of injury contexts. Multi-center clinical trials are still needed to define precise cut-off values, as they may depend on the type of injury.

IL10 and IL10/TNF ratio

interleukin 10 (il10) is a powerful anti-in-flammatory mediator, which namely suppress-es dendritic cell and macrophage functions. Many different cell populations may be in-volved in its synthesis, such as monocytes, and its regulation is complex.27 in a septic shock population, Monneret et al. showed that il10 correlates with Hla-Dr expression and that values were significantly higher among non-survivors.28 interestingly, il10 elevation was already significantly associated to mortality at time of admission and il10 remained higher during 15 days in the non-survivor group. these results were consistent with previous literature regarding il10 dosage 29-31 or il10 mrna measurement.32-34 the association be-tween il10 and septic complication or mortal-ity was also described in burned patients35, 36 and in trauma patients.37 il10 may therefore constitute an early marker of forthcoming im-munoparalysis. some authors also evaluated IL10/TNF ratio, which reflects the pro/anti-inflammatory balance and also correlates with unfavorable outcome.28-30

Other monocyte-related markers

During sepsis, monocytes show not only im-paired antigen presentation, but also decreased pro-inflammatory response, as assessed by the down-regulation of surface markers such as cD10, cD86, cD14, gM csF receptor, or cX3cr1.38-43 For all these markers, a reduced expression was associated with mortality. to our knowledge, none of them has been associ-ated with poor prognosis in surgical, burn or trauma context.

another interesting monocyte surface pro-tein is PD-l1. this marker will be discussed

preserved, indicating that neutrophil function is reconfigured rather than globally suppressed.

impaired neutrophil chemotaxis, altered phagocytosis and bacterial killing were also described in burn 20-23 and trauma patients.24 However, the possible association between neutrophils and mortality/morbidity has only been investigated in sepsis.17, 18

moNocytes

Monocytes are myeloid cells which play a central role in innate immunity. these circulat-ing cells are also able to release pro and anti-inflammatory molecules. After injury, many aspects of monocyte physiology have been studied.

HLA-DR

one of the most promising biomarkers of injury-induced immunoparalysis is monocyte human leukocyte antigen Dr (mHla-Dr). as developed elsewhere, monocytes from septic patients display an altered antigen pre-sentation, related to lower expression of ma-jor histocompatibility (MHc) class ii system. this decrease in cell-surface expression of mHla-Dr is a marker of monocyte dysfunc-tion, objectified by lower synthesis of pro-in-flammatory cytokines in response to bacterial challenges, lower proliferation rate, and inter-estingly recovery of monocyte functions after restoration of normal mHla-Dr levels after treatment ex vivo and in vivo.25

low mHla-Dr expression has been as-sociated to both mortality and secondary in-fections in various clinical backgrounds: sep-tic shock, severe burn, trauma, pancreatitis, cirrhosis etc. For instance, gouel-chéron et al. observed that after severe trauma, a ratio of mHla-Dr expression between day 3 and day 2 below 1.2 is an independent predictor of septic complication with an odd ratio of 5 (95% ci [1.6; 19], P=0.008) after multivariate analysis.26 similarly, venet et al. reported an association between mHla-Dr decrease and severity as well as secondary septic shock after severe burn injury.6



that was chosen (day 0). Further multicentric clinical trials are warranted to confirm the prognostic value of this functional approach in different injury contexts, and to determine its optimal timing.

deNdritic cells

Dendritic cells (Dcs) are professional an-tigen-presenting cells (aPcs), playing a key role in linking innate and adaptive immune systems. Dcs capture and process antigens, before migrating to lymph nodes, where they present antigens to lymphocytes.

literature provides strong evidences for both quantitative and qualitative Dc altera-tions after injury. Hotchkiss et al. showed a dramatic reduction in the number of follicular Dcs in septic patients compared with con-trols.55 MHc class ii expression by Dcs was also lower in septic patients. this is consis-tent with the observation that circulating Dc count is lower in septic shock patients than in controls (shocks other than septic) as early as day 1, and persistent low circulating myeloid Dc count is associated with nosocomial infec-tion.56 Furthermore, Dc loss in septic patients is higher in non-survivor septic patients than in survivors and is inversely correlated with severity scores.57

after surgery, Dc count increases acutely, and then drops below preoperative levels on days 2-3.58 surgery-induced Dc depletion is associated with IL12 — a pro-inflammatory cytokine — deficiency.59 Dc functional im-pairment has also been observed in trauma patients with an in vitro reduced differentia-tion into Dcs, a lower il12 production, and an impaired t cell proliferation.60 Further-more, life span and signaling function of Dcs may be altered by trauma.61 consistently, severe burn patients displayed early low Dc count.62 in addition Dcs from burn patients had impaired reactivity, an anti-inflammatory phenotype, and dysfunctional t cell-priming ability.63

to sum up, functional and quantitative im-pairments of Dcs have been observed in many

in a following subsection, together with the protein it binds.

cD163 is a scavenger receptor expressed on monocytes, macrophages, and dendritic cells. it is also known as haptoglobin-hemo-globin receptor, and also exists as a soluble form, scD163, which is shed into plasma after stimulation by mediators of inflammation.44 three clinical studies in septic populations showed that monocyte expression of cD163, or scD163 level, were higher in non-survi-vors,45-47 even at early time points. neverthe-less, cD163 has not been evaluated in severe burn, surgery or trauma.

Functional testing: endotoxin tolerance

Functional approaches may be interest-ing, for they give an insight into in vivo cell response to an immune challenge. Monocytes from septic patients have been particularly studied; they display a predominantly anti-in-flammatory phenotype, this observation leads to the concept of leukocyte reprogramming.48 Indeed, these cells release less pro-inflamma-tory mediators (such as tnF, il6 or il12) and as much or even slightly more anti-inflamma-tory molecules (il10, il1ra).48 this reduced responsiveness after lPs stimulation has been described as Endotoxin Tolerance. Hence, this method may reveal immune paralysis. endotoxin tolerance has also been described in severe trauma 49, 50 as well as in major sur-gery.51, 52

clinical impact of this reprogramming has been recently studied. in a heterogeneous pe-diatric population with multiple organ failure syndrome, Hall et al. found an association between a reduced ex vivo lPs-induced tnF response (in whole blood, on day 7 after ad-mission) and increased nosocomial infection (rr 3.3 [1.8-6.0]) and mortality (rr 5.8 [2.1-16]).53 conversely, van vught et al. observed an endotoxin tolerant phenotype on septic pa-tient monocytes, but it was not associated with the development of nosocomial infections.54 as suggested by the authors, this negative result may be related to the early time point



Neutrophil-to-lymphocyte ratio.—another way to take into consideration lymphopenia is to use the neutrophil-to-lymphocyte ratio (ntl).72 From a pathophysiological perspec-tive, NTL reflects the complex balance be-tween inflammatory insult and immune sup-pression. In clinical setting, NTL was first investigated in abdominal surgery. increased nlr after digestive surgery was associated with an increased risk of complications or death.73-75 Moreover, time points and cut-offs were very heterogeneous among these studies, and cancer in itself may interfere with ntl.

three clinical studies recently assessed ntl in the icU. in cirrhotic patients with acute complication, high nlr at day 1 was associated with mortality in a multivariate lo-gistic regression.76 a retrospective study sug-gested that ntl at admission is associated with 28-day mortality in unselected critically ill patients, however this association was not observed in the septic patient subgroup.77 ri-ché et al. refined this result in a septic shock cohort. they highlighted a reversed ntl evo-lution according to the timing of death:78 early death was associated with low ntl at admis-sion, whereas late death (≥day 5) was associ-ated with high ntl between day 1 and day 5.

all in all, ntl is an easy and affordable biomarker which may be of interest to detect immune failure, yet the best timing and cut-offs are still to be determined, and, like mH-la-Dr, these parameters may depend on the clinical situation.

regulatory t cells

Regulatory T cells (Tregs) are a very specific subset of t cells, crucial for immune tolerance and homeostasis. indeed, they inhibit the acti-vation and proliferation of most of the other im-mune cells, by directly killing cytotoxic cells, inhibiting their cytotoxic production, and se-creting immunomodulatory cytokines (TGFβ, il10).79 as presented recently, the percent-age of tregs increases after the onset of septic shock,80 burn and trauma. the enhancement of their suppressive functions and the relative and

different injury situations, and may be key players of injury-induced immune paralysis. As murine administration of purified DCs64, 65 and of Dc growth factor (Fms-related tyrosine kinase 3 ligand, Flt3-l)66, 67 reversed mortal-ity and secondary sepsis, monitoring and tar-geting Dcs represent a promising therapeutic strategy.

Adaptive immunity: T and B cells

lymphocytes are central actors in immu-nity, acting as both effectors and regulators. not only are they quantitatively altered during injury, but they also display functional anoma-lies.

cell couNts

Lymphopenia.—apoptosis-related loss of immune cells is an important feature of injury-induced immune paralysis. this cell loss af-fects both t cells (except for treg cells) and B cells. lymphopenia is a hallmark of sirs and septic syndrome, and has also been de-scribed in trauma, burn and surgical patients. at day 4 of sepsis, lymphopenia was inde-pendently associated with 28-day and 1-year survival and severe lymphopenia was associ-ated with increased development of second-ary infections.68 in this study, lymphopenia at admission was not associated with mortality, contrary to the results presented by chung et al.69 consistently, in emergency general surgi-cal patients, lymphopenia was independently associated with increased in-hospital mortality (or 3.5 [1.7-7.3]).70 in trauma as well, failure to normalize lymphopenia in severely injured patients is associated with significantly higher mortality,71 and with higher rate of nosocomial infections after multivariate analysis (personal data). Moreover, lymphocyte count is cheap and included in routine biology. However, most of the severely injured patients display lymphopenia, which may limit its discriminat-ing power. Effective stratification strategies in-cluding lymphopenia are still to be determined.



cD4+ t cells during the early stage of sepsis was associated with severity and 28-day mor-tality.93

ctla-4 and Btla might constitute inter-esting biomarkers for injury-induced immune paralysis, but data are still scarce. to address this question, more clinical studies are needed, including the monitoring of nosocomial infec-tions, and exploring a wider range of injuries. other negative immune regulators have been proposed, such as lymphocyte-activation gene 3 (lag-3) or t-cell immunoglobulin and mucin domain 3 (Havcr2, also known as tiM3), as their expression is increased in septic patients presenting an exhausted t cell phenotype.94

PD-1/PD-L1.—another promising bio-marker is PD-1 (for Programmed Death one, official symbol PDCD1). The protein is ex-pressed on the cell membrane of lymphocytes, myeloid and dendritic cells. it binds two li-gands: PD-l1 (cD274, also known as B7-H1), PD-l2 (PDcD1lg2, also known as B7-Dc or cD273). Both belong to the B7:cD28 fam-ily,95 and are expressed by epithelial, endothe-lial and antigen presenting cells. this complex pathway is involved in co-ligation with t cell receptor and leads to lower cytokine produc-tion and to an inhibition of cellular prolifera-tion, negatively controlling the immune re-sponse.

a murine PD-1 knock-out model exposed to sepsis showed lower mortality and decreased bacterial burden and inflammatory response, in link with a macrophage dysfunction.96 in clinical setting, Zhang et al. provided evi-dence for an up-regulation of PD-1 on t cells and PD-l1 on monocytes of 19 septic shock patients. interestingly, PD-l1 blockade leads to a decreased apoptosis of t cells after tnF stimulation or t cell receptor ligation.97 guig-nant et al. found consistent results, and high-lighted a correlation between increased PD-1, mortality and nosocomial infections after sep-tic shock.98 in this study, trauma patients did not express increased PD1 or PD-l1, contrary to the results presented elsewhere.87

absolute elevation in their count were associat-ed with mortality in burn.81 chen et al. also de-scribed a significant association between Treg count increase at day 7 and mortality in icU patients with sepsis.82 cD39+ treg cells form a specific subset displaying increased suppres-sive skills. in septic patients, increased expres-sion of cD39+ tregs was associated with mor-tality and severity of sepsis.83

conversely, after traumatic brain injury, the level of circulating tregs was positively as-sociated with neurologic recovery and lower hospital mortality.84 indeed, treg action is thought to be neuroprotective because, in this context, a down-regulation of inflammation may promote cell survival.

as a conclusion, tregs may play a role in in-jury-induced immunosuppression, given their important regulatory properties.

iNcreased co-iNhibitory receptors

CTLA-4, BTLA.—after antigen recognition, t cell full activation depends on the balance between co-stimulatory and co-inhibitory sig-nals. ctla4 — cytotoxic t lymphocyte-as-sociated antigen 4 — is expressed in t cells and delivers a negative signal to the primed lymphocyte,85 directly antagonizing the co-stimulatory receptor cD28, and participating in t cell tolerance. ctla-4 expression is in-creased after burn injury,86 after trauma-hem-orrhage,87, 88 and in sepsis, and inhibits immune cell functions.89 inoue et al. showed a dose-dependent effect of anti-ctla-4 on survival in a rodent model of sepsis,90 with decreased cD8+ and cD4+ lymphocyte apoptosis. con-sistently, blockade of ctla-4 improved sur-vival in rodent fungal sepsis.89 to date, no data is available in human clinical setting regarding its prognostic value.

B and t lymphocyte attenuator (Btla) is also a lymphocyte inhibitory receptor, ex-pressed in a wide range of cells. Btla de-creases cytokine production and inhibits survival signaling in cD4+ lymphocytes.91 consistently with previous literature,92 shao et al. showed that lower percentage of Btla+/



driven by an indirect mechanism: in an ex vivo human model derived from endotoxin toler-ance, Poujol et al. suggested that lPs priming indirectly impairs lymphocyte functions by re-ducing aPcs capacity to activate t cells.102, 103 nevertheless, such functional approaches are time-consuming, as proliferation requires sev-eral days of incubation. this precludes most applications in clinical settings.

STAT5 phosphorylation.—stat5 (sig-nal transducer and activator of transcrip-tion 5) is a key molecule for the response to il7. its phosphorylation occurs in response to the recruitment of IL7R and reflects the acti-vated status of the cell. stat5 phosphoryla-tion (pstat5) is enhanced by ex vivo rhil7 (recombinant human il7) in septic shock pa-tients.100 low doses of rhil7 preferentially sustain effector t cells activation, whereas rhil2 activates regulatory t cells.104 a pilot study from our team suggested that pstat5 in septic shock patients was higher in survivors. non-survivors failed to phosphorylate stat5 in effector t cells in response to rhil7.105 in-terestingly, pSTAT5 can be assessed by flow cytometry on whole blood samples, making it suitable for daily clinical practice.

b cells

regarding B cells, human data are limited. B lymphocytes are a heterogeneous cell popu-lation; they can not only differentiate into im-munoglobulin secreting plasma cells, but they also produce cytokines and present antigens. However, their role in the pathogenesis of in-jury-induced immunosuppression has not been firmly established. Sepsis-induced cell deple-tion also deeply affects B cells, but this has not been specifically associated with mortality.106 interestingly, patterns in B subset distribution and activation were different between survi-vors and non survivors. at time of admission, a high percentage of cD23+ (a marker of activa-tion and regulation) B cells appeared to be as-sociated with good outcome, whereas cD80+ (a t cell co-stimulation marker) and cD95+ (a

PD-1/PD-l1 expression on immune cells was also increased after surgery, and correlates with the severity of surgical trauma.99 similar-ly, t cell apoptosis was partially reversed by anti-PD-1 antibody. overall, these data indi-cate that PD-1 might be an attracting biomark-er for injury-induced immunosuppression.

cd127

interleukin 7 (il7) is an essential cyto-kine involved in survival, development and maturation of t and B cells. it binds to a het-erodimeric receptor, consisting of an alpha chain (IL7Rα, also known as CD127) and a gamma chain (cD132), the latter is common to several interleukin receptors. administra-tion of il7 restored lymphocyte functions in septic patients.100 il7 level and cD127 were not associated with mortality in this study. interestingly, a high level of soluble fraction of CD127 (sCD127) was significantly associ-ated with the development of nosocomial in-fection. recently, in a larger cohort of septic shock patients, Demaret et al. found a signifi-cant association between increased plasmatic scD127 (at day 1 and day 3) and mortality.101 However, the function and the regulation of scD127 and of cD127 are still widely un-known. soluble cD127 could be an interest-ing biomarker for identification of a group of patients presenting with higher risk of second-ary infections or mortality, but it is unclear whether it is involved in immune paralysis pathophysiology.

FuNctioNal testiNg

T cell proliferation.—another hallmark of sepsis is the decreased lymphocyte prolifera-tion in response to stimulation. Yet, lympho-cyte proliferation is a fundamental part of im-mune response. its decrease has been described in sepsis, trauma, severe burn, and after major surgery. it has been associated with nosoco-mial infections, poor outcome and multiorgan failure syndrome.25 recent data suggested that reduced lymphocyte proliferation may be



nomics, transcriptomics and proteomics have expanded rapidly within the past years. tran-scriptomic approach evaluates the transcripts (messenger rna, also known as mrna) for many genes. assuming that certain genes may be over- or under- expressed in reaction to injury, researchers expect to find or confirm diagnostic, prognostic and follow-up mark-ers, and to progress in pathophysiologic un-derstanding. Being able to guide therapeutic strategies disclosing patient immune profile is a seducing concept, however actual scientific knowledge is far from achieving this goal.108 still, literature dealing with injury-induced im-munoparalysis and transcriptome is abundant (table i).

General clinical data

as reported by Xiao et al., leukocytes of in-jured patients (in this study, severe trauma and burns) responded to stress by a global repri-

marker of apoptosis susceptibility) B cell per-centages were associated with increased 28-day mortality. the reason of this observation remains to be elucidated. recently, only B cell and cD16- monocyte counts were associated with increased mortality.107, 108 consequently we may hypothesize that, similarly to other immune cells, B cell functional and quantita-tive alterations may play a role in injury-in-duced immune dysfunction. thus, it might be interesting to shed light on B cell involvement and to develop B cell markers.

Both innate and adaptive immunity: transcriptomic approach

the host response to injury involves nu-merous intricate pathways (e.g. immune, neurologic and endocrine systems).2 given this complexity, rather than focusing on very specific markers, some researchers have re-cently aimed for a systemic perspective. ge-

table i.—�Biomarkers: feasibility and clinical evidence.

Biomarker associated clinical outcome laboratory technique

approximate minimal turn-around time

Possible in routine?

innate immunity

Pnn ↑ immature forms Death Fc, hematological analyzers

1h30 Yes

Monocytes ↓ mHLA-DR Death, Hai Fc, iHc, Pcr 1h30 YesscD127 Few data. Death? elisa 5h no

endotoxin tolerance Conflicting data cell culture + elisa 3 days no↑ PD-L1 Hai Fc, iHc 1h30 not yet

il10 ad il10/tnF Death elisa or comparable method

5h no

Dc ↓ DC count Death, Hai Fc 1h30 not yetFunction :

il-12 synthesis, proliferation

no cell culture, elisa 3 days no

adaptive immunity

all lymphocytes lymphopenia Death Fc, hematological analyzers

30 min Yes

ntl Death Fc, hematological analyzers

30 min Yes

↑ CTLA4, BTLA Few data Fc, iHc 1h30 not yet↑ PD-1 Death Fc, iHc 1h30 not yetcD127 Death, Hai Fc, iHc 1h30 not yet

t cells Proliferation Death, Hai, MoF cell culture + Fc 3 days notregs ↑ Treg percentage Death Fc 1h30 not yet

Both transcriptomic cD74, cX3cr1 Few data. Death? qrt Pcr 3h* Possiblymicroarray 3 days no

Hai: healthcare-associated infections; MoF: multi organ failure; Pnn: polynuclear neutrophils; Dc: dendritic cells; tregs: regulator t cells; mHla-Dr: monocyte human leukocyte antigen Dr; PD-1: programmed death one; PD-l1: programmed death ligand one; il: interleukin; TNFα: tumor necrosis factor alpha; NLT: neutrophil to lymphocyte ratio; CTLA4: cytotoxic T lymphocyte-associated antigen 4; BTLA: B and T lymphocyte attenuator; FC: flow cytometry; IHC: immunohistochemistry; ELISA: Enzyme-Linked ImmunoSorbent Assay.* if a unitized industrial method were developed.



cyte subpopulations. it is involved in adhesion and migration of leukocytes and is thought to amplify pro-inflammatory immune response. in a microarray study, we observed an 8-fold increase of cX3cr1 in survivors compared with non survivors, which corresponded to the highest factor of change.114 We later re-ported that cX3cr1 (mrna and protein) was strongly down-regulated in monocytes.43 con-sistently, this down-regulation was associated with mortality.

although these data are preliminary, both examples suggest that transcriptomic approach may allow to discover and to evaluate new bio-markers of immunoparalysis.

Conclusions

In parallel with explosive inflammatory pro-cesses, injury causes major immune dysfunc-tions leading to a significant morbi-mortality. innate and adaptive immunity may both be severely compromised, in different extents de-pending on the patient immune profile. Being able to detect and follow immunoparalyzed patients and dysfunction subtypes is an impor-tant issue, for a targeted immunostimulating treatment may improve greatly their outcome. to date, available markers have a prognostic value, but researchers now aim to develop diagnostic tools. such biomarkers could help targeting diagnosis procedures, allowing the clinician to define patients at risk to develop opportunistic infections. the most promising markers — i.e. markers both associated with clinical outcome in several types of injury and performable on routine basis — are decreased mHla-Dr and lymphopenia. in the light of the complexity of injury-induced immune re-sponse, combinations of biomarkers may rep-resent an interesting line of investigation.

this review outlines current knowledge on biomarkers of injury-induced immunosuppres-sion. it was not intended to be an in-depth sur-vey of the whole subject and does not represent an exhaustive listing of studies in the field. We sincerely apologize for works not cited in this manuscript.

oritization affecting >80% of the cellular func-tions and pathways.109 authors refer to this phenomenon as “genomic storm”. researchers observed simultaneous increase in expression of innate immune genes and suppression of adaptive immunity, in both injury situations. this supports the hypothesis of a common be-havior, which would not rely on the stress type. this novel paradigm has also been described after severe blunt trauma 110 and in sepsis.111

Xiao et al. studied differentially expressed genes in complicated (recovery >14 days, no recovery, or death) versus uncomplicated clin-ical recovery (recovery in <5 days). interest-ingly, authors highlighted an up-regulation of pro-inflammatory pathways in the complicated group, associated with down-regulated antigen presentation and t cell regulation.

to date, the literature gives many other ex-amples of the ability of the transcriptomic ap-proach to analyze the patient’s immune status in a global way. as proposed by rittirsch et al. in trauma patients, the combination of clini-cal and transcriptomic markers may represent an even more interesting tool.112 Further stud-ies are needed to develop predefined set of markers and to evaluate their predictive value regarding the diagnosis and prognosis of im-mune dysfunction.

Examples of transcriptomic-discovered mark-ers: CD74, CX3CR1

cazalis et al. used transcriptomic approach in a more targeted manner. in a prospective septic shock cohort, they investigated the link between MHc class ii-related gene ex-pression (by qrt-Pcr) and mortality at day 28.113 among these, low cD74 at day 3 after the onset of shock was associated with 28-day mortality after multivariate logistic regression analysis (or 3.4 [1.2 to 9.8], P=0.026). cD74, also called Hla-Dr antigen-associated in-variant chain, is a protein involved in MHc ii heterodimer synthesis and export towards the cell surface. cD74 still needs validation in a larger multicenter study.

cX3cr1 is a chemokine receptor expressed on monocytes, nK cells, and some lympho-



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Key messages

— injury-induced immunosuppression is a healthcare burden; patients suffering from it may benefit from immunostimulat-ing treatments.

— Biomarkers of injury-induced immu-nosuppression are needed to specifically identify those patients that may benefit from immunoadjuvant therapies.

— For now, the most promising bio-markers are low mHla-Dr, lymphopenia and increased PD-1/PD-l1 pathway.

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74. Forget P, Dinant v, De Kock M. is the neutrophil-to-lymphocyte ratio more correlated than c-reactive protein with postoperative complications after major abdominal surgery? PeerJ 2015;3:e713.

75. Jaramillo-reta KY, velázquez-Dohorn Me, Medina-Franco H. neutrophil to lymphocyte ratio as predictor of surgical mortality and survival in complex surgery of the upper gastrointestinal tract. rev investig clínica organo Hosp enfermedades nutr 2015;67:117-21.

76. Moreau n, Forget P, Wittebole X, laterre P, castanares-Zapatero D. neutrophil-to-lymphocyte ratio is associ-ated with mortality in critically-ill cirrhotic patients. intensive care Med exp 2015;3:a688.

77. salciccioli JD, Marshall Dc, Pimentel M, santos MD, Pollard t, celi l, et al. the association between the neutrophil-to-lymphocyte ratio and mortality in criti-cal illness: an observational cohort study. crit care 2015;19:13.

78. riché F, gayat e, Barthélémy r, le Dorze M, Matéo J, Payen D. reversal of neutrophil-to-lymphocyte count ratio in early versus late death from septic shock. crit care 2015;19:439.

79. Kessel a, Bamberger e, Masalha M, toubi e. the role of t regulatory cells in human sepsis. J autoimmun 2009;32:211-5.

80. venet F, chung c-s, Kherouf H, geeraert a, Malcus c, Poitevin F, et al. increased circulating regulatory t cells (CD4+CD25+CD127−) contribute to lymphocyte



107. Park sH, Park Bg, Park cJ, Kim s, Kim DH, Jang s, et al. an extended leukocyte differential count (16 types of circulating leukocytes) using the cytodiff flow cytomet-ric system can provide informations for the discrimina-tion of sepsis severity and prediction of outcome in sep-sis patients. cytometry B clin cytom 2013 [epub ahead of print].

108. amit i, regev a, Hacohen n. strategies to discover regulatory circuits of the mammalian immune system. nat rev immunol 2011;11:873-80.

109. Xiao W, Mindrinos Mn, seok J, cuschieri J, cuenca ag, gao H, et al. a genomic storm in critically injured humans. J exp Med 2011;208:2581-90.

110. vanzant el, lopez cM, ozrazgat-Baslanti t, Ungaro r, Davis r, cuenca ag, et al. Persistent Inflamma-tion, immunosuppression and catabolism syndrome after severe Blunt trauma. J trauma acute care surg 2014;76:21-30.

111. cazalis M-a, lepape a, venet F, Frager F, Mougin B, vallin H, et al. early and dynamic changes in gene expression in septic shock patients: a genome-wide ap-proach. intensive care Med exp 2014;2:20.

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with increased mortality, nosocomial infection and im-mune dysfunctions in septic shock patients. crit care 2011;15:r99.

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100. venet F, Foray a-P, villars-Méchin a, Malcus c, Poitevin-later F, lepape a, et al. il-7 restores lym-phocyte functions in septic patients. J immunol 1950 2012;189:5073-81.

101. Demaret J, villars-Méchin a, lepape a, Plassais J, vallin H, Malcus c, et al. elevated plasmatic level of soluble il-7 receptor is associated with increased mortality in septic shock patients. intensive care Med 2014;40:1089-96.

102. Wolk K, Döcke WD, Baehr v von, volk H-D, sabat r. impaired antigen presentation by human monocytes dur-ing endotoxin tolerance. Blood 2000;96:218-23.

103. Poujol F, Monneret g, Pachot a, textoris J, venet F. al-tered t lymphocyte Proliferation upon lipopolysaccha-ride challenge ex vivo. Plos one 2015;10;e0144375.

104. Dupont g, Demaret J, venet F, Malergue F, Malcus c, Poitevin-later F, et al. comparative dose-respons-es of recombinant human il-2 and il-7 on stat5 phosphorylation in cD4+FoXP3- cells versus regu-latory t cells: a whole blood perspective. cytokine 2014;69:146-9.

105. Demaret J, Dupont g, venet F, Friggeri a, lepape a, rimmelé t, et al. stat5 phosphorylation in t cell subsets from septic patients in response to recombi-nant human interleukin-7: a pilot study. J leukoc Biol 2015;97:791-6.

106. Monserrat J, de Pablo r, Diaz-Martín D, rodríguez-Zapata M, de la Hera a, Prieto a, et al. early altera-tions of B cells in patients with septic shock. crit care 2013;17:r105.

Conflicts of interest.—christelle rouget and Julien textoris are employees of Biomérieux sa. thibaut girardot, Julien textoris, guillaume Monneret, thomas rimmelé and Fabienne venet are employees of the Hospices civils De lyon. Fabienne venet and guil-laume Monneret are the inventors of patent families covering markers cited in this paper. this does not alter the authors’ adherence to all the journal policies on sharing data and materials.Article first published online: June 17, 2016. - Manuscript accepted: June 15, 2016. - Manuscript revised: May 4, 2016. - Manuscript received: February 12, 2016.


the goal of this perspective report is to pres-ent the foundational concepts of perioperative opioid-less (conscious) analgesia.

Opioid-free or opioid-less anesthesia/analgesia: reasons and speculations

the concept of opioid-free anesthesia has re-cently gained interest among anesthesiologists, surgeons, and other perioperative physicians because of the growing evidence from a large number of clinical studies that have demon-strated the beneficial effects of opioids reduc-tion in the context of surgery. Furthermore, the minimization of the use of opioids during the perioperative period is one of the cornerstones elements of the “enhanced recovery after sur-gery” programs. However, it is important to

to date, opioids are the most commonly pre-scribed intravenous analgesic during major

surgery because of their high potency in com-parison to other analgesics. While opioids are typically given in adjunction to general anes-thetics, they also play a role in regional anesthe-sia techniques since they can be administered as a sole agent or in combination with local anes-thetics or other adjuvant analgesic drugs.

The first clinical reports of opioid-free anes-thesia can be dated to more than 100 years ago when first Corning and then Kreis reported the use of neuraxial anesthesia for surgical proce-dures.1, 2 in 1933, Dogliotti published a manu-script on “a new method of block anesthesia, segmental peridural spinal anesthesia”.3 in that work, the author did not comment on the need of opioids during surgery.

E X P E R T S ’ O P I N I O N

opioid-less perioperative careJuan P. cata 1-3 *, Dario BUgaDa 3-5, Jose de aNDrÉs 3, 6

1Department of anesthesiology and Perioperative Medicine, M.D. anderson cancer center, Houston, tX, Usa; 2anesthesiology and surgical oncology research group, Houston, tX, Usa; 3siMPar group, Parma, italy; 4Department of surgical sciences, University of Parma, Parma, italy; 5Department of anesthesia, icU and Pain therapy, Parma University Hospital, Parma, italy; 6Department of anesthesia, critical care and Multidisciplinary Pain Management, Valencia University general Hospital, Valencia, spain*corresponding author: Juan P. cata, Department of anesthesiology and Perioperative Medicine, the University of texas, M.D. anderson cancer center, Houston, tX, Usa. e-mail: [email protected]


lavoro: 11698-Mastitolo breve: oPioiD-less PerioPeratiVe careprimo autore: catapagine: 315-20citazione: Minerva anestesiol 2017;83:315-20

a B s t r a c topioids are the most frequently administered analgesics in the perioperative period. the analgesic potency of opioids is without question. While the “opioid-free” or “opioid-less perioperative care” concept is not a reality in most surgical centers of the United States and other developed countries, there is a significant number of healthcare problems (i.e., ad-verse events, opioid-induced hyperalgesia and opioid diversion) related to the indiscriminate use of opioids that warrants the implementation of multimodal analgesia strategies. although it has been suggested an association between the use of opioids and cancer progression, there is a need of well-designed studies to confirm that association.(Cite this article as: cata JP, Bugada D, de andrés J. opioid-less perioperative care. Minerva anestesiol 2017;83:315-20. Doi: 10.23736/s0375-9393.16.11698-0)Key words: opioid analgesics - Perioperative care - Drug-related side effects and adverse reactions.



cata oPioiD-less PerioPeratiVe care


highlight that notion of opioid-free anesthesia should be extended into the immediate and in-termediate postoperative period, thus perhaps the concept should be coined as “opioid-free” or “opioid-less perioperative care”.

there are at least 3 important reasons to understand why an opioid-free or opioid-less perioperative care could become a reality and all of them are relevant to patient care issues and healthcare policies (Figure 1). Firstly, there is growing evidence indicating that pa-tients who receive large doses of opioids dur-ing their perioperative hospital admission not only experience inadequate pain control but they are also at risk for developing an impor-tant number of opioid-related adverse events (oraDes), an increase in the risk of mortal-ity and an incremented cost of care. secondly, the so-called “opioid epidemic” in the Usa has been linked to the misuse and diversion of opioids prescribed in the perioperative period. and thirdly, there are some concerns regarding the use of opioids in cancer patients since these drugs could be associated with tumor growth and cancer recurrence.

ORADEs, inadequate analgesia, hyperalgesia and high costs of care

Opioids are associated with significant ad-verse events (i.e., ileus, nausea and vomit-ing, respiratory depression) mostly seen when they are administered in moderate-to-large amounts. However, the administration of opi-

Figure 1.—How perioperative opioids can negatively impact the health care costs.

oids in low quantities can cause oraDes in patients with comorbidities known to affect their metabolism or enhance their affinity to the opioid receptors. For instance, the require-ments of intrathecal opioids are lower in obese than non-obese parturient women. as another example, elderly patients have a higher risk of developing oraDes because of the con-comitant use of multiple drugs, drug-drug in-teractions (psychoactive drugs in particular), diminished renal clearance, and possibly de-creased hepatic function.

Despite the large use of opioids for periop-erative analgesia, more than 75% of the pa-tients undergoing surgery report inadequate pain relief. in a recent study by Mudumbai et al., the authors found that the median time-to-opioid-cessation after surgery was 15 days in opioid-naïve patients and even longer in those taking opioids preoperatively.4 These findings confirm that even when postoperative pain is poorly managed, the need for opioids is still long. in addition, patients with inadequately treated postsurgical pain are more likely to re-ceive large doses of opioids and have a higher risk for developing postoperative persistent pain.5 as a result, these patients will be more likely to be readmitted to the hospital or seek consultation with pain physicians. Both, read-missions and expert consultations are associ-ated with an increase in the costs of care.

the use of potent opioids in the periopera-tive period appears to be a linked to the devel-opment of chronic surgical pain. a recent study has demonstrated that the use of “strong” opi-oids is associated with a 30% increase in the chances to develop chronic postmastectomy pain.6 it remains uncertain whether opioids are directly linked with the development of persis-tent pain but it is well-known that the amount of opioid used perioperatively correlates with inadequately treated pain.7 opioids can per se trigger hyperalgesia, this phenomenon is also known as opioid-induced hyperalgesia (oiH). all opioids can cause oiH however, there is evidence to conclude that the administration of remifentanil and fentanyl in high doses is strongly associated with oiH.8, 9 it is worth noticing that because of the ultra-short anal-

opioid-related adverse events

Prolonged lenght of

hospital stay

DiversionabuseDeath

cancerrecurrence?

MorbidityMortality

PerioPeratiVe oPioiD Use

iNcreaseD cost oF care

oPioiD-less PerioPeratiVe care cata


authorities and agencies including the United states center for Disease control have called for the creation of quality improvement and patient education programs dedicated to moni-tor and reduce inadequate opioid prescribing strategies. Perhaps, one the first step towards this goal would be the use of aggressive non-opioid based analgesic techniques specifically designed to provide opioid-free or opioid-less perioperative care.

Opioids and cancer outcomes

a body of growing evidence indicates that opioids have significant effects on several steps of carcinogenesis and cancer progres-sion and in some instances can be associated with cancer recurrence.11-13 opioids receptors, and in particular mu opioid receptors (Mor), have been found in malignant cells including prostate cancer cells, glioblastoma cells, lung adenocarcinoma cells and breast cancer cells. In-vitro studies have shown that activation of Mor induce cleavage of the DNa and stimu-late phosphorylation/activation of src, gab-1, Pi3 kinase, akt and stat3 via the interaction with the epidermal growth factor receptor in human lung cancer cells.14-17

Mors are also present in lymphocytes that participate in the active process of eliminating cancer cells. although the evidence remains controversial, some studies indicate that mor-phine and fentanyl can facilitate tumor spread by diminishing the killing activity of natural killer cells.18-20 opioids can also impact the an-giogenesis process. While long-term exposure or high-doses of opioids impair angiogenesis, short-term treatment of human umbilical vein cells with physiological concentrations of en-domorphin-1 and -2 increase cell proliferation, migration, and adhesion.21

although the evidence from basic science data points towards a predominant protumoral effect of opioids, the clinical data have shown mixing results. in patients with non-small cell lung cancer, most studies point towards an as-sociation between the use of opioids and worse survival outcomes.13, 22-24 in patients who had radical prostatectomy, fentanyl did not have a

gesic effect of remifentanil patients often ex-perience an abrupt cessation in analgesia that can lead to high postoperative pain scores and large opioid consumption in the immediate postoperative period.10 Hence, the ultra-short duration of analgesia of remifentanil should not be confused with its hyperalgesic effects. to complicate matters, the addition of opioids with long-lasting analgesic (i.e.. hydromor-phone) effects during the infusion of remi-fentanil does not improve postoperative pain scores or reduce opioid consumption immedi-ately following surgery.10

in most modern healthcare systems, the in-creased costs associated with opioids based anesthesia or analgesia is multifactorial. First, patients who develop oraDes stay longer in the hospital than those without complications, which it can increase the costs of hospitaliza-tion. as an example, patients who had oraDes following total joint arthroplasty were approxi-mately 8 times more likely to have a prolonged hospital course in comparison to those without adverse events. to add complexity to the mat-ter, opioid selection also appears to influence outcomes. a recent study that demonstrated a decrease in the use of morphine but at the ex-pense of an increase in the prescription of hy-dromophone, also showed that a higher rate in the use of rescue analgesics, a longer length of stay and a higher rate of readmissions to the hospital. all of these factors have been linked to an increase in the cost of care.

inadequately treated postoperative pain, acute tolerance, lack of understanding of opi-oid selection and oiH can explain why some patients are often discharged from the hospital with large counts of opioids pills. as a conse-quence, the risk of drug misuse and diversion is high. it is worth noticing that oxycodone and hydrocodone (two of the most commonly pre-scribed opioids in the perioperative period) are the most frequent drugs associated with diver-sion, abuse, and overdose.

Because of the potential devastating con-sequences associated with oraDes such as respiratory depression, the increased costs associated with them, and the recent rise in opioid-related abuse and overdose, several



evidence to indicate opioid-free anesthesia in patients undergoing oncologic procedures. However, opioids should be used with cau-tious in this population of patients to minimize oraDes and facilitate postsurgical recovery. oncological patients who require adjuvant therapy are more likely to initiate their treat-ment soon after surgery if they experience an uneventful recovery.

Multimodal analgesia: the cornerstone of opioid-free or opioid-less perioperative care

Perioperative multimodal analgesia refers to the use of a variety of pharmacological and non-pharmacological therapies with two ma-jors goals: 1) to improve postoperative anal-gesia, and 2) reduce oraDes (Figure 2).32-35 Most studies indicate that those patients who have undergone surgery in the context of mul-timodal analgesia and have received none or extremely low doses opioids experience a bet-ter surgical recovery, develop fewer oraDes and are discharged earlier from the hospital.

When indicated, regional anesthesia and an-algesia even in combination with general anes-thesia should be one the key components of any multimodal opioid-free/-less analgesia tech-nique.36-40 Neuraxial and peripheral nerve an-esthesia techniques as well as newer strategies such as wound infiltration, the transverse ab-dominis plane block and scalp blocks have dem-onstrated to reduce opioid consumption. local anesthetics alone or in combination with sys-temic adjuvant drugs such ketamine, clonidine/dexmedetomidine, lidocaine, gabapentinoids, acetaminophen or cyclo-oxygenase inhibitors have been successfully used for opioid-free an-esthesia/analgesia techniques. For instance, we have demonstrated a reduction of 84% in the in-traoperative consumption of morphine equiva-lents in patients undergoing hyperthermic cyto-reductive abdominal surgery by using combined general-epidural anesthesia in conjunction with oral celecoxib, tramadol and pregabalin and the systemic infusion of lidocaine, dexmedeto-midine and/or ketamine.41 similar results have been found in patients undergoing hepatobili-ary surgery and gynecological surgery (Drs José

significant impact on the survival of patients while sufentanil was associated with a 7-fold increase in the risk of cancer recurrence.25, 26 on the other hand, 2 large cohort studies that included women with breast cancer did not support the association between the use of opi-oids and shorter survival.27, 28 lastly, we dem-onstrated that the use of intraoperative opioids was an independent factor of cancer progres-sion in patients that had surgery for squamous cell carcinoma of the larynx.11

in 2006, exadaktylos et al.published a ret-rospective study suggesting an association be-tween the use of regional analgesia and fewer recurrences after breast cancer surgery.29 the authors hypothesized that a reduction in opi-oid use in women who had regional anesthe-sia contributed to their findings. Following that initial publication, a growing number of retrospective studies tried to replicate the find-ings by exadktylos et al., but unfortunately the results of those reports are conflicting. For in-stance, a recent study from our group found no evidence of a lower rate of recurrence in wom-en who had paravertebral analgesia for breast cancer surgery despite a substantial reduction in opioids.30 similar results were reported for prostate cancer.31 We hypothesize that the con-troversial findings among different studies are due to cancer type, regional anesthesia-tech-nique- and surgery-specific factors.

summarizing, although the basic science evidence suggest that opioids have protu-moral effects, there is no convincing clinical

Figure 2.—How multimodal analgesia can improve care in the perioperative period.

Multimodal analgesia

opioid less use

Better outcomes

lowercosts

PerioPeratiVe care

oPioiD-less PerioPeratiVe care cata


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although most of the non-opioid analge-sics used during and immediately after surgery have shown opioid-sparing effects, their effi-cacy is limited to a short period of time that do not last beyond hospital stay, which increases the chance of opioid prescription.42, 43 For in-stance, ketamine during and after (72 hours) scoliosis surgery has failed to improve chronic pain outcomes and pregabalin does not provide protective effects against postmastectomy or posthoracotomy pain syndromes.44 therefore, a multimodal analgesia approach to provide ad-equate pain relief beyond the duration of hospi-talization is needed not only to avoid the devel-opment of postsurgical persistent pain but also to decrease the exposure of patients to opioids.

in conclusion, opioid-free or opioid-less perioperative care should be implemented to reduce orDaDes and decrease the costs as-sociated with them. the risks associated with drug diversion are far superior to the fear of inadequate analgesia when appropriate multi-modal anesthesia and analgesia techniques are used. although still controversial, the use of opioids during oncological surgery could be associated with an increase in recurrence in certain tumors.

Key messages

— opioids are the most commonly prescribed analgesics in the perioperative periods, but the healthcare costs associ-ated with opioids related adverse events are high.

— opioid-induced hyperalgesia, opi-oid misuse and diversion are the conse-quences of ineffective strategies of opioid based postoperative analgesia.

— large perioperative opioid use might have a negative impact in the sur-vival of patients with cancer.

— Multimodal analgesia modalities are essential to effectively implement opioid-less perioperative strategies.



Authors’ contributions.—All authors were involved in reviewing the literature; writing of the manuscript and final approval. Conflicts of interest.—The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.Article first published online: November 8, 2016. - Manuscript accepted: November 3, 2016. - Manuscript revised: October 19, 2016. - Manuscript received: september 5, 2016.

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23. Wang K, Qu X, Wang Y, Shen H, Liu Q, Du J. Effect of mu agonists on long-term survival and recurrence in Nonsmall cell lung cancer Patients. Medicine (Balti-more) 2015;94:e1333.

24. Maher DP, Wong W, White PF, McKenna R, Jr., Rosner H, shamloo B, et al.association of increased postop-erative opioid administration with non-small-cell lung cancer recurrence: a retrospective analysis. Br J anaesth 2014;113 suppl 1:i88-94.

25. scavonetto F, Yeoh tY, Umbreit ec, Weingarten tN, gettman Mt, Frank i, et al.association between neuraxi-al analgesia, cancer progression, and mortality after radi-cal prostatectomy: a large, retrospective matched cohort study. Br J anaesth 2014;113 suppl 1:i95-102.

26. Forget P, tombal B, scholtes Jl, Nzimbala J, Meulders c, legrand c, et al.Do intraoperative analgesics influ-ence oncological outcomes after radical prostatectomy for prostate cancer? eur J anaesthesiol 2011;28:830-5.

27. cronin-Fenton DP, Heide-Jorgensen U, ahern tP, lash tl, christiansen PM, ejlertsen B, et al.opioids and breast cancer recurrence: a Danish population-based co-hort study. cancer 2015;121:3507-14.

28. Forget P, Vandenhende J, Berliere M, Machiels JP, Nuss-baum B, legrand c, et al.Do intraoperative analgesics influence breast cancer recurrence after mastectomy? A retrospective analysis. anesth analg 2010;110:1630-5.

29. Exadaktylos AK, Buggy DJ, Moriarty DC, Mascha E, sessler Di. can anesthetic technique for primary breast cancer surgery affect recurrence or metastasis? anesthe-siology 2006;105:660-4.

30. cata JP, chavez-Macgregor M, Valero V, Black W, Black DM, goravanchi F, et al.the impact of Paravertebral Block analgesia on Breast cancer survival after sur-gery. reg anesth Pain Med 2016;41:696-703.

31. Lee BM, Singh Ghotra V, Karam JA, Hernandez M, Pratt g, cata JP. regional anesthesia/analgesia and the risk of


the highest bleeding risk is connected to po-sitioning and removing an epidural catheter, the lowest to the single-shoot spinal, while another variable is connected to the caliber of the needle used.2, 3 about 60-80% of all major bleedings is associated to hemostatic disorders or bleedings from the needle.4

Numerous studies on a high number of pa-tients have shown the relative safety of per-forming central blocks during an antiplatelet therapy, but the total number of enrolled pa-tients was relatively low.5 three spinal he-matomas during a therapy with ticlopidine or clopidogrel have been described.6-8 NsaiDs,

Performing neuraxial anesthesia in patients receiving antithrombotic drugs is contro-

versial due to the increased risk of spinal epi-dural hematoma.

The spinal hematoma, defined as a symp-tomatic bleeding internal to the neuraxis, is a rare and serious complication of the central anesthetic block. the actual incidence of such a complication is unknown. the probable in-cidence of major bleedings after performing a central block without specific risk factors has been approximately calculated as less than 1:220,000 for the spinal anesthesia and less than 1:150,000 for the epidural anesthesia.1

E X P E R T S ’ O P I N I O N

regional anesthesia and antithrombotic agents: instructions for use

gennaro sciBelli 1, lucia Maio 1, gennaro saVoia 2 *

1Department of anesthesia and intensive care, asl caserta, caserta, italy; 2Department of anesthesia and intensive care, aorN a. cardarelli, Naples, italy*corresponding author: gennaro savoia, Department of anesthesia and intensive care, aorN a. cardarelli, Naples, italy. e-mail [email protected]


lavoro: 11414-Mastitolo breve: regioNal aNestHesia aND aNtitHroMBotic ageNtsprimo autore: sciBellipagine: 321-35citazione: Minerva anestesiol 2017;83:321-35

a B s t r a c tthe use of anticoagulant agents represents a serious limitation of regional anesthesia, due to the risk of spinal hematoma. examining all the principles currently available, it has been possible to notice that published guidelines are very often incomplete or also differ significantly on the rules to be followed relating to a specific drug. A comparison was carried out between the guidelines of major scientific societies in order to take a practical and simple user guide which operators can consult. the more and more frequent occurrence of patients who undergo dual antiplatelet and need to be subjected to surgery was taken into account, considering regional anesthesia as a possible alternative to general anesthesia in condi-tions of election and not deferrable urgency. We describe the main anticoagulant drugs used in therapy. regarding the low-molecular-weight heparins, we have reported the most important properties, highlighting the substantial differences of their use detectable by comparison between american and european guidelines. a similar comparison has been made for the main antiplatelet drugs, including aspirin, and thrombin inhibitors. a particular chapter is dedicated to new oral anticoagulant drugs, especially for the low possibility of allowing regional anesthesia. the comparison between the main guidelines often highlights substantial disparities and weak evidences, so operators must carry out a careful risk-benefit analysis prior to regional anesthesia.(Cite this article as: scibelli g, Maio l, savoia g. regional anesthesia and antithrombotic agents: instructions for use. Min-erva anestesiol 2017;83:321-35. Doi: 10.23736/s0375-9393.16.11414-2)Key words: local anesthesia - spinal epidural hematoma - Fibrinolytic agents.

Minerva anestesiologica 2017 March;83(3):321-35 Doi: 10.23736/s0375-9393.16.11414-2


sciBelli regioNal aNestHesia aND aNtitHroMBotic ageNts


ment, these guidelines represent the reference point in the exercise of anesthetic activities in different countries, even if they contain indica-tions often unsupported by clear evidence, but, even more, significantly different indications which confuse the operators and we wanted to emphasize.

Precisely because of the reduced charac-teristics of systematic reviews held by these guidelines, and considering that no rcts have been published in the last two years regarding the use of anticoagulants in patients undergo-ing locoregional anesthesia, we believe that the current method to assign a score according to the PrisMa guidelines does not have the conditions to be applied, with no result except for considering all major guidelines currently in use as “insufficient.”

We have graded the level of recommenda-tions and the level of evidence using the defini-tions of the committee for Practice guidelines of the esc (table i).12

Low-molecular-weight heparins

With the release of low-molecular-weight heparins (lMWH) for general use in the Unit-ed states in May 1993, labeled indications included thromboprophylaxis at a scheduled dose of 30 mg every 12 hours, with the first dose administered as soon as possible after surgery. an alarming number of spinal epi-dural hematomas, some with permanent para-plegia, were reported,13 triggering a warning from the Us Food and Drug administration (FDa). the marked increase in the frequency

widely used in pain treatment protocols, are not anticoagulant drugs, but they, similarly to aspirin, interfere with platelet aggregation mechanisms. the administration of NsaiDs alone does not increase the bleeding risk, but it has been shown that the association with other anticoagulants increases the frequency of spontaneous hemorrhagic complications, bleeding at the injection sites and spinal hema-tomas.2, 9, 10

Due to its rarity, recommendations regard-ing neuraxial regional anesthetic procedures with concurrent thromboprophylaxis are not based on prospective randomized studies, but rather on case reports and expert opinions. the latter are based mainly on knowledge of the pharmacokinetics of the individual agents con-cerned. a rule of thumb adopted by most na-tional societies puts the time interval between cessation of medication and neuraxial block-ade at two times the elimination half-life of the drug. this approach has recently been recom-mended by others.11

We have carried out a broad review of the main anticoagulant drugs used in therapy, de-scribing the most important properties, with particular reference to the mechanisms of ac-tion and duration of their activity. therefore, we have analyzed the guidelines published by major scientific societies, comparing the rec-ommendations provided for the correct use of drugs and the relative levels of evidence.

Here we have considered and compared the main guidelines compiled by the main study groups and scientific associations in several american and european countries. in this mo-

Table I.—�Classes of recommendations and levels of evidence.

classes of recommendationsclass i Evidence and/or general agreement that a given treatment or procedure is beneficialclass ii Conflicting evidence and/or divergence of opinion about the usefulness/efficacy of the treatment

or procedureclass iia Weight of evidence/opinion in favor of usefulness/efficacyclass iib Usefulness/efficacy is less well established by evidence/opinionclass iii evidence or general agreement that the treatment or procedure is not useful or effective and in

some cases may be harmfullevel of evidence

level a Data derived from multiple randomized clinical trials or meta-analyseslevel B Data derived from a single randomized clinical trial or large non-randomized studieslevel c consensus of opinion of the experts and/or small studies, retrospective studies, registries

regioNal aNestHesia aND aNtitHroMBotic ageNts sciBelli


ous technique is selected, the epidural catheter may be left indwelling overnight, but must be removed before the first dose of LMWH. Ad-ministration of lMWH should be delayed for 2 hours after catheter removal;

— in case of single-daily dosing, the first postoperative lMWH dose should be admin-istered 6 to 8 hours postoperatively. the sec-ond postoperative dose should occur no sooner than 24 hours after the first dose. Indwelling neuraxial catheters may be safely maintained. However, the catheter should be removed a minimum of 10 to 12 hours after the last dose of lMWH. subsequent lMWH dosing should occur a minimum of 2 hours after catheter removal. No additional hemostasis-altering medications should be administered due to the additive effects.16

in europe, the widespread adoption of a sin-gle daily dose of enoxaparin 40 mg produced a lower incidence of complications. a retro-spective analysis in sweden found out that the risk was 1:156,000 after spinal anesthesia and 1:18,000 after epidural anesthesia, with bleeding occurring more rarely in obstetrics (1:200,000) than in female orthopedic patients undergoing knee arthroplasty (1:3600).17 risk factors for spinal hematoma after neuraxial regional anesthesia were identified as lack of guidelines, administration of antithrombotic agents, female sex, and difficult punctures. subsequent reports from various countries indicate that spinal epidural hematoma af-ter neuraxial blockade occurs in 1:2700 to 1:19,505 patients,18-21 with one report indicat-ing that hematoma may be more common after lumbar (1:1341) compared to thoracic epidural anesthesia (1:10,199).20

according to the european guidelines, to avoid bleeding complications, there should be a time interval of at least 12 hours between subcutaneous administration of lMWH at prophylactic doses and neuraxial blockade or removal of an epidural catheter 4, 22 (class iia, level c). if thromboprophylaxis with lMWH is prescribed in a twice-daily schedule, com-pared to a once daily regimen, the risk of epi-dural hematoma may be increased because the trough levels of anti-Xa activity are higher.23

of spinal hematoma in patients anticoagulated with lMWH prompted a reevaluation of the relative risks and benefits of neuraxial block-ade.14, 15 collation of these cases in the Usa allowed the risk of spinal epidural hematoma during concurrent administration of lMWHs to be calculated at 1:40,800 for spinal anesthe-sia, 1:6600 for single-shot epidural anesthesia, and 1:3100 for epidural catheter anesthesia.13 What seems to be a relatively high incidence of bleeding has been attributed to the twice daily administration of lMWH, and the lack of recommendations at that time regarding time intervals between neuraxial puncture or catheter removal and thromboprophylaxis. the response in the Usa has been to introduce recommendations that are stricter than those in place in europe, proposing avoidance of lMWH the entire time epidural catheters are in place.14 in particular, the asra guidelines have consistently recommended against the administration of twice-daily lMWH in a pa-tient with an indwelling epidural catheter.14, 15 although once-daily lMWH dosing in the presence of an epidural catheter is safe, it has been recommended to be cautious if the patient has received an additional hemostasis-altering medications, including antiplatelet therapy.

the anesthetic management of the patient receiving lMWH suggested by the american society of regional anesthesia and Pain Med-icine mainly consists in the following points:

— in patients on preoperative lMWH thromboprophylaxis, needle placement should occur at least 10 to 12 hours after the lMWH dose;

— in patients receiving higher (treatment) doses of lMWH, a delay of at least 24 hours is recommended to ensure normal hemostasis at the time of needle insertion;

— in case of postoperative lMWH, pa-tients with postoperative lMWH thrombopro-phylaxis may safely undergo single-injection and continuous catheter techniques;

— in case of twice-daily dosing, the first dose of lMWH should be administered no ear-lier than 24 hours postoperatively. indwelling catheters should be removed before initiation of lMWH thromboprophylaxis. if a continu-



der development. the administration of these medications in combination with neuraxial an-esthesia must be carefully considered and we can apply lessons learned from the lMWH experience to develop initial management rec-ommendations 25 (table ii).

Fondaparinux

Fondaparinux, an injectable synthetic penta-saccharide, produces its antithrombotic effect through factor Xa inhibition.26 the eXPert study included a total of 5387 patients, among whom 1428 undergoing regional anesthesia procedures: a single dose of fondaparinux was omitted the evening before catheter re-moval 27 and this provided a time interval of 36 hours before catheter removal and 12 hours (6 hours according to the aas guidelines) 28 between catheter removal and the next dose of fondaparinux. Neuraxial regional anesthe-

in this situation, one dose of lMWH should be omitted creating a 24-hour time interval be-fore catheter removal and the subsequent dose (class iib, level c). similarly, when therapeu-tic doses of lMWH are administered once or twice daily, catheter placement or removal should also be delayed for at least 24 hours af-ter the last dose (class iia, level B).

a meta-analysis of preoperative versus post-operative studies shows that lMWH given 12 hours preoperatively does not reduce the risk of Vte compared to a postoperative regi-men.24 as antithrombotic drugs increase the risk of spinal epidural hematoma after neur-axial blockade, a postoperative start may be advantageous, especially in patients who are receiving also aspirin (class iib, level B).

spinal epidural hematoma is not restricted to lMWH and similar drugs, but can occur with any agent that interferes with hemostasis. New antithrombotic drugs are continually un-

Table II.—�Recommended time intervals before and after neuraxial puncture or catheter removal.time before puncture/catheter manipulation or removal

time after puncture/catheter manipulation or removal lab tests

Unfractionated heparins (for prophylaxis, ≤15,000 IU/day)

4-6 h 1 h Platelets during treatment for more than 5 days

Unfractionated heparins (for treatment)

iV 4-6 hsc 8-12 h

1 h1 h

aPtt, act, platelets

low-molecular-weight heparins (for prophylaxis)

12 h 4 h Platelets during treatment for more than 5 days

low-molecular-weight heparins (for treatment)

24 h 4 h Platelets during treatment for more than 5 days

Fondaparinux (for prophylaxis, 2.5 mg per day)

36-42 h 6-12 h (anti-Xa, standardised for specific agent)

rivaroxaban (for prophylaxis, 10 mg/day)

22-26 h 4-6 h (PT, standardised for specific agent)

apixaban (for prophylaxis, 2.5 mg b.i.d.)

26-30 h 4-6 h ?

Dabigatran (for prophylaxis, 150-220 mg)

contraindicated according to the manufacturer

6 h ?

coumarins INR≤1.4 after catheter removal iNrHirudins (lepirudin, desirudin) 8-10 h 2-4 h aPtt, ectargatroban 4 h 2 h aPtt, ect, actacetylsalicylic acid None Noneclopidogrel 7 days after catheter removalticlopidine 10 days after catheter removalPrasugrel 7-10 days 6 h after catheter removalticagrelor 5 days 6 h after catheter removalcilostazol 42 h 5 h after catheter removalNsaiDs None Noneact: activated clotting time; aPtt: activated partial thromboplastin time; ect: eparin clotting time; iNr: international Normalized ratio; NSAID: non-steroidal anti-inflammatory drug.all time intervals refer to patients with normal renal function.



catheter removal. other suggestions for next dose range from 2 to 12 hours.11, 28, 32

When used in patients with aFiB, if a neur-axial block for surgery is planned, the suggest-ed withdrawal time is 3.5-4 days.31, 33

rivaroxaban is a potent selective and re-versible oral activated factor Xa inhibitor. When used for thromboprophylaxis, rivar-oxaban is generally administered once a day, 10 mg within 6-10 hours after surgery for 5 weeks after hip replacement surgery and two weeks after knee replacement surgery.29

a minimum of 18 hours between the last dose of rivaroxaban (10 mg) and removal of an indwelling catheter, and a minimum of 6 hours before resumption of the drug has been recom-mended by the scandinavian society guide-lines.28 the european society guidelines rec-ommend an interval of 22 to 26 hours between the last dose of rivaroxaban and removal of an indwelling catheter (class iia, level c), and an interval of 4 to 6 hours between epidural cath-eter removal and the next dose of rivaroxaban (class iib, level c). these two recommenda-tions represent a two-half-life interval between rivaroxaban discontinuation and epidural cath-eter placement or removal. extreme caution is recommended when rivaroxaban is used in presence of neuraxial blockade (class iib, level c).25

rivaroxaban is given 1×20 mg for deep ve-nous thrombosis treatment or stroke preven-tion inpatients with nonvalvular aFiB. experts recommend rivaroxaban discontinuation for 2-3 days 32, 34, 35 before neuraxial puncture. experts’ opinions concerning resumption after catheter removal range from 5 to 24 hours.32, 34

apixaban is an oral, reversible, direct fac-tor Xa inhibitor related to rivaroxaban.30 it is given twice a day 2.5 mg within 12-24 hours after hip or knee replacement surgery for 32-38 days and 10-14 days, respectively.29 al-though the scandinavian guidelines 28 did not make recommendation on the interval between cessation of apixaban and neuraxial injection because of lack of available data, the euro-pean guidelines suggest a time interval of 26-30 hours between the last dose of apixaban (2.5 mg) and catheter withdrawal and that at

sia should not be performed when therapeutic doses of fondaparinux (5-10 mg/day) are em-ployed due to the substantial risk of accumula-tion (class iii, level c).25

New oral anticoagulants

the new oral anticoagulants (Noacs) cur-rently include thrombin inhibitor dabigatran and factor Xa inhibitors (rivaroxaban, apixa-ban, edoxaban).

the asra guidelines on regional anesthe-sia 16 did not make recommendations, proba-bly because of the lack of studies, whereas the european 25 and the scandinavian 28 guidelines based their recommendations on the half-life of the drugs. the european and scandinavian guidelines adopted a two-half-life interval be-tween discontinuation of the drugs and neur-axial injection.

current recommendations for neuraxial blocks with new oral anticoagulants are dif-ferent when they are used for postoperative thromboprophylaxis after hip or knee replace-ment or for prevention of thromboembolic dis-ease in patients with nonvalvular atrial fibril-lation (AFIB), because in the first case much lower doses are given compared with patients with aFiB.29

Dabigatran is an oral reversible monovalent thrombin inhibitor. the oral prodrug dabiga-tran etexilate is metabolized by plasma ester-ases into dabigatran.30 currently it is licenced to be given once daily 220 mg starting with 110 mg within 1-4 hours after surgery for 10 days after knee replacement surgery and for 28-35 days after hip replacement surgery, while is typically given 2×150 mg daily in aFiB patients.

the long (12-17 hours) half-life of dabiga-tran in healthy patients suggests a time inter-val of 34 hours (1-1.5 days) between the last dose of dabigatran and catheter manipulation or withdrawal. However, the manufacturer ad-vises against the use of dabigatran in the pres-ence of neuraxial blockade (class iii, level c).25, 31, 32 analyzing licensing studies involv-ing 4212 neuraxial blocks, the first dose of dabigatran was given at least 2h after epidural



clopidogrel), and platelet gP iib/iiia antago-nists (abciximab, eptifibatide, tirofiban) exert diverse effects on platelet function.

low-dose aspirin, when used for second-ary prophylaxis, has been shown to reduce the risk of stroke and myocardial infarction in the range of 25% to 30%.35-37 Furthermore, the discontinuation of aspirin for secondary pro-phylaxis is associated with significant risk 38 and a platelet rebound phenomenon may oc-cur, resulting in a prothrombotic state.39 When aspirin is used for primary prophylaxis, its value in preventing cardiovascular events is unclear.40, 41

Non-aspirin NsaiDs bind reversibly and competitively inhibit the active site of the coX enzyme. the degrees of reversible in-hibition of coX-1, after single doses of fre-quently used NsaiDs (diclofenac, ibuprofen, indomethacin, naproxen, and piroxicam), de-pend on the selected NsaiD and measured time frame in the first 24 hours.42

NsaiDs that selectively inhibit the enzyme coX-2 do not alter platelet function.43

asra and european guidelines recommend that central neuraxial blocks may be performed in individuals using aspirin or NsaiDs.16, 25 on the basis of the available data, NsaiDs, including aspirin, when given in isolation, do not increase the risk of spinal epidural hema-toma and are not a contraindication to neurax-ial block (class iib, level c). spinal anesthe-sia has better a support than the epidural one (class iib, level c).

to avoid any negative effect of NsaiDs on platelet function and neuraxial block, it is

least one dose should be omitted (class iib, level c). after catheter withdrawal, the next dose of apixaban may be given 4-6 hours later (class iib, level c).25 the scandinavian guide-lines recommend 6 hours after a neuraxial in-jection or catheter removal before resumption of the drug.28 extreme caution is recommend-ed when using neuraxial blockade in the pres-ence of apixaban (class iib, level c).

apixaban is given 2x5 mg daily for the pre-vention of stroke and systemic embolic disease in adult patients with nonvalvular aFiB. ex-pert opinions defining the time from Apixaban discontinuation to neuraxial block placement range from 3 to 4 days.32, 34

edoxaban, a new Xa inhibitor, has currently been approved in the Usa and Japan for the reduction in the risk of stroke and systemic embolic disease in patients with nonvalvular aFiB with a dose of 60 mg once a day. indwell-ing epidural or intrathecal catheters should not be removed earlier than 12 hours after the last administration of edoxaban and the next dose of edoxaban should not be administered earlier than 2 hours after the removal of the catheter. However, in analogy to expert reasoning with rivaroxaban and apixaban, edoxaban should be stopped 2 days before a neuraxial puncture or epidural catheter manipulation.29

in table iii the timing to be observed for a safe administration of these drugs is summarized.

Antiplatelet drugs

antiplatelet medications, including NsaiDs, thienopyridine derivatives (ticlopidine and

Table III.—�Simplified scheme of suggested times when neuraxial blocks are planned during NOACs administration.

Noac

Drug used for postoperative thromboprophylaxys(low doses)

Drug used for aFiB(high doses)

time before puncture/catheter manipulation or removal

time after puncture/catheter manipulation or removal

Drug withdrawal if neuraxial blocks are performed for surgery

Dabigatran 1-1.5 days 2 to 12 hours 3.5-4 daysrivaroxaban 22-26 hours e

18 hours s4-6 hours e6 hours s

2-3 days

apixaban 26-30 hours eNo data s

4-6 hours e6 hours s

3-4 days

edoxaban 12 hours 2 hours 2 daysNOAC: new oral anticoagulant; AFIB: nonvalvular atrial fibrillation.e european guidelines; s scandinavian guidelines.



drug,47, 48 has a rapid onset, 10 times greater than that of clopidogrel,49 and is a particularly potent antiplatelet agent. in view of this prop-erties, neuraxial anesthesia should be strongly discouraged during prasugrel treatment, unless a time interval of 7-10 days can be observed (class iii, level c),25 whereas the scandina-vian guidelines states that a 5-day stoppage may be sufficient.28

ticagrelor acts directly on the P2Y12 recep-tor. like prasugrel, it provides much faster, greater and more consistent P2Y12 inhibition than clopidogrel.49 However, neuraxial anes-thesia should be discouraged during treatment with ticagrelor, unless at least 5 days have lapsed since the last dose (class iii, level c).25 For resumption of the antiplatelet drug after a neuraxial procedure or catheter removal, the scandinavian guidelines recommended that the drug has to be started after catheter remov-al, whereas the european guidelines recom-mended 6 hours after catheter removal before prasugrel and ticagrelor can be started.25

Blocking the glycoprotein iib/iiia receptor, the final common pathway of platelet aggrega-tion, represents the most potent form of plate-let inhibition. it is reversible. after administra-tion, the time to normal platelet aggregation is 24 to 48 hours for abciximab and 4 to 8 hours for eptifibatide and tirofiban.50, 51 as glycopro-tein iib/iiia inhibitors are used only in acute coronary syndromes, in combination with anti-coagulants and aspirin, and as cardiac surgery procedures are usually conducted as emergen-cies with continuing anticoagulation, neuraxial blockade is contraindicated (class iii, level c). if a catheter has to be removed after their administration, most guidelines recommend waiting at least 48 hours after abciximab, and 8-10 hours after tirofiban or eptifibatide.52 Neuraxial techniques should be avoided until platelet function has recovered.

Thrombin inhibitors

Direct selective thrombin inhibitors in-clude recombinant hirudin derivatives (desi-rudin, lepirudin, and bivalirudin), indicated for thromboprophylaxis (desirudin) and Vte

sufficient to miss a dose the evening before a planned procedure or catheter removal.

the scandinavian guidelines for the perfor-mance of central neuraxial blocks in individuals using aspirin, based their recommendations on the indication for aspirin use and the daily dose. in individuals who take aspirin for secondary prevention, a shorter discontinuation time of 12 hours was recommended. For individuals who do not use aspirin for secondary prevention, the discontinuation time is 3 days unless the dose is greater than 1 g/day for which the discontinua-tion time is extended to 1 week.28

For NsaiDs, the scandinavian guideline recommendations are guided by the specific half-life for each drug.28

although the administration of aspirin alone does not appear to increase hematoma forma-tion, a higher rate of complications has been observed in both surgical and medical patients when heparins were administered concurrent-ly.3, 44 Because preoperative, versus postopera-tive, thromboprophylaxis is not proven to be beneficial,45 a cautionary approach in the pres-ence of aspirin would be to start Vte prophy-laxis postoperatively (class i, level B).

in patients who are receiving NsaiDs, we recommend against the performance of neur-axial techniques if the concurrent use of other medications affecting clotting mechanisms, such as oral anticoagulants, UFH, and lMWH, is anticipated in the early postoperative period because of the increased risk of bleeding com-plications.16

the thienopyridines block the aDP recep-tor, P2Y12 subtype.

ticlopidine has a long elimination half-life and causes an irreversible inhibition of platelet function.46 the european guidelines 25 suggest a time interval between discontinuation of this thienopyridine therapy and neuraxial blockade of 10 days, while the american guidelines 14 days.16

clopidogrel is a prodrug.47 Neuraxial anes-thesia should only be performed at least 7 days after the last intake (class iia, level c),16, 25 whereas the scandinavian guidelines noted that a 5-day interruption is probably adequate.28

Prasugrel, a novel thienopyridine, is a pro-



Table IV.—�Comparison of different guidelines in the management of patients receiving antithrombotic therapy.

antiplatelet medications subcutaneous UHF intravenous UHF lMWH Warfarin Fondaparinux Direct thrombininhibitors thrombolytics Herbal therapy

Dgai NsaiDs: no contraindi-cation; hold lMWH, fondaparinux 36-42 h.

thienopyridines and gP iib/ iiia are contrain-dicated

Needle placement 4 h after heparin; heparin 1 h after needle placement or catheter removal

Needle placement and/or catheter removal 4 h after discontinuing heparin, heparinize 1 h after neuraxial technique; delay bypass surgery 12 h if traumatic

Neuraxial technique 10-12 h after lMWH; next dose 4 h after needle or catheter placement Delay block for 24 h after therapeutic dose

iNr<1.4 for needle/catheter insertion and withdrawal

Needle placement 36-42 h after last dose, wait 6-12 h after catheter removal for subsequent dose

Needle placement 8-10 h after dose; de-lay subsequent doses 2-4 h after needle placement

absolute contraindica-tion

No contraindication

Bara NsaiDs: no contraindi-cation.

Discontinue ticlopidine 14 d, clopidogrel 7 d, gP iib/iiia inhibitors 8-48 h in advance

Not discussed Heparinize 1 h after neuraxial technique remove catheter during normal aPtt; reheparinize 1 h later

Neuraxial technique 10-12 h after lMWH; next dose 4 h after needle or catheter placement.

Delay block for 24 h after therapeutic dose


Needle placement 36 h after last dose. indwelling epidural catheter not recom-mended



Not discussed

asra NsaiDs: no contrain-dication.Discontinue ticlopidine 14 d, clopidogrel 7 d, gP iib/iiia inhibitors 8-48 h in advance

No contraindication with twice-daily dosing and total daily dose <10,000 U, consider delay heparin until after block if technical dif-ficulty anticipated.the safety of neu-raxial blockade in patients receiving doses >10,000 U of UFH daily, or more than twice daily dosing of UFH has not been established

Heparinize 1 h after neuraxial technique, remove catheter 2-4 h after last heparin dose; no mandatory delay if traumatic

twice-daily dosing: lMWH 24 h after surgery, regard-less of technique; remove neuraxial catheter 2 h before first LMWH dose.single-daily dosing: as per european statements but with no additional hemosta-sis-altering drugs.therapeutic dose: delay block for 24 h

Normal iNr (before neuraxial technique); remove catheter when INR≤1.5 (initiation of therapy)

single injection, atrau-matic needle placement or alternate thrombo-prophylaxis.avoid indwelling catheters

Insufficient information.suggest avoidance of neuraxial techniques


No evidence for manda-tory discontinuation be-fore neuraxial technique; be aware of potential drug interactions

cHest NsaiDs: no contrain-dication.Discontinue clopidogrel 7 d before neuraxial block

Needle placement 8-12 h after dose; subsequent dose 2 h after block or catheter withdrawal

Needle placement delayed until anticoagu-lant effect is minimal

Needle placement 8-12 h after dose; subsequent dose 2 h after block or catheter withdrawal. indwelling cath-eter safe with twice-daily dosing.therapeutic dose: delay block for 18+ h

avoid or limit epidural analgesia to <48 h. remove catheter when iNr<1.5

single-injection spinal safe.avoid epidural anal-gesia

Not addressed Not addressed Not addressed

esa NsaiDs: no contrain-dication.Discontinue ticlopidine 10 d, clopidogrel 7 d, gP iib/iiia inhibitors 8-48 h in advance

a time interval of 4-6 h between heparin admin-istration and puncture or catheter manipulation and withdrawal. Further administration of low-dose heparin at least 1 h after the block

a time interval of 4-6 h between heparin admin-istration and puncture or catheter manipulation and withdrawal. Further administration of low-dose heparin at least 1 h after the block.intraoperative heparini-zation is not a contrain-dication to neuraxial blockade

time interval of at least 12 h between sc administration of lMWH at prophylactic doses and neuraxial blockade or removal of an epidural catheter.twice-daily dosing: 24 h time interval before catheter removal and the subsequent dose.therapeutic doses once or twice daily: catheter place-ment or removal delayed for at least 24 h after the last dose.Next dose of lMWH at least 4 h after spinal/epidural puncture, or after removal of a spinal/epidural catheter


Needle placement 36 h after last dose, wait 12 h after catheter removal for subsequent dose.therapeutic doses: contraindication to neuraxial technique

Needle placement 8-10 h after dose; delay subsequent doses 2-4 h after needle placement





Table IV.—�Comparison of different guidelines in the management of patients receiving antithrombotic therapy.


Dgai NsaiDs: no contraindi-cation; hold lMWH, fondaparinux 36-42 h.

thienopyridines and gP iib/ iiia are contrain-dicated

Needle placement 4 h after heparin; heparin 1 h after needle placement or catheter removal

Needle placement and/or catheter removal 4 h after discontinuing heparin, heparinize 1 h after neuraxial technique; delay bypass surgery 12 h if traumatic

Neuraxial technique 10-12 h after lMWH; next dose 4 h after needle or catheter placement Delay block for 24 h after therapeutic dose


Needle placement 36-42 h after last dose, wait 6-12 h after catheter removal for subsequent dose



No contraindication

Bara NsaiDs: no contraindi-cation.

Discontinue ticlopidine 14 d, clopidogrel 7 d, gP iib/iiia inhibitors 8-48 h in advance

Not discussed Heparinize 1 h after neuraxial technique remove catheter during normal aPtt; reheparinize 1 h later

Neuraxial technique 10-12 h after lMWH; next dose 4 h after needle or catheter placement.

Delay block for 24 h after therapeutic dose


Needle placement 36 h after last dose. indwelling epidural catheter not recom-mended



Not discussed

asra NsaiDs: no contrain-dication.Discontinue ticlopidine 14 d, clopidogrel 7 d, gP iib/iiia inhibitors 8-48 h in advance

No contraindication with twice-daily dosing and total daily dose <10,000 U, consider delay heparin until after block if technical dif-ficulty anticipated.the safety of neu-raxial blockade in patients receiving doses >10,000 U of UFH daily, or more than twice daily dosing of UFH has not been established

Heparinize 1 h after neuraxial technique, remove catheter 2-4 h after last heparin dose; no mandatory delay if traumatic

twice-daily dosing: lMWH 24 h after surgery, regard-less of technique; remove neuraxial catheter 2 h before first LMWH dose.single-daily dosing: as per european statements but with no additional hemosta-sis-altering drugs.therapeutic dose: delay block for 24 h

Normal iNr (before neuraxial technique); remove catheter when INR≤1.5 (initiation of therapy)

single injection, atrau-matic needle placement or alternate thrombo-prophylaxis.avoid indwelling catheters

Insufficient information.suggest avoidance of neuraxial techniques



cHest NsaiDs: no contrain-dication.Discontinue clopidogrel 7 d before neuraxial block

Needle placement 8-12 h after dose; subsequent dose 2 h after block or catheter withdrawal

Needle placement delayed until anticoagu-lant effect is minimal

Needle placement 8-12 h after dose; subsequent dose 2 h after block or catheter withdrawal. indwelling cath-eter safe with twice-daily dosing.therapeutic dose: delay block for 18+ h

avoid or limit epidural analgesia to <48 h. remove catheter when iNr<1.5

single-injection spinal safe.avoid epidural anal-gesia

Not addressed Not addressed Not addressed

esa NsaiDs: no contrain-dication.Discontinue ticlopidine 10 d, clopidogrel 7 d, gP iib/iiia inhibitors 8-48 h in advance

a time interval of 4-6 h between heparin admin-istration and puncture or catheter manipulation and withdrawal. Further administration of low-dose heparin at least 1 h after the block

a time interval of 4-6 h between heparin admin-istration and puncture or catheter manipulation and withdrawal. Further administration of low-dose heparin at least 1 h after the block.intraoperative heparini-zation is not a contrain-dication to neuraxial blockade

time interval of at least 12 h between sc administration of lMWH at prophylactic doses and neuraxial blockade or removal of an epidural catheter.twice-daily dosing: 24 h time interval before catheter removal and the subsequent dose.therapeutic doses once or twice daily: catheter place-ment or removal delayed for at least 24 h after the last dose.Next dose of lMWH at least 4 h after spinal/epidural puncture, or after removal of a spinal/epidural catheter


Needle placement 36 h after last dose, wait 12 h after catheter removal for subsequent dose.therapeutic doses: contraindication to neuraxial technique

Needle placement 8-10 h after dose; delay subsequent doses 2-4 h after needle placement



(To be continued)



the first group, it is advisable to wait at least 8-10 hours — and longer if possible — be-tween the administration of these agents and neuraxial puncture, and to avoid combinations with other antithrombotic agents (class i, level c). in case of argatroban, when hepatic func-tion is good, normalization of the aPtt takes only 2-4 hours after the end of infusion, due to the short half-life of 35-45 minutes. For all

treatment (lepirudin) in patients with Hit type ii, and argatroban, approved for the treatment of Hit type ii.53, 54

if neuraxial blockade is considered, a dis-tinction needs to be made between patients with a history of Hit, who require only throm-boprophylaxis, usually with low-dose danapa-roid, and those with acute Hit type ii, in whom therapeutic anticoagulation is required.25 in

Table IV.—�Comparison of different guidelines in the management of patients receiving antithrombotic therapy (con-tinues).


siaarti NsaiDs: no contrain-dication.Discontinue ticlopidine 10-14 d, clopidogrel 7 d, gP iib/iiia inhibi-tors 8-48 h in advance

No contraindication with twice-daily dosing and total daily dose <10,000 U, consider delay heparin until after block.No other drugs

Heparinize 1 h after neuraxial technique; remove catheter 2-4 h after last heparin dose.No mandatory delay if traumatic

time interval of at least 12 h between sc administration of lMWH at prophylac-tic doses and neuraxial blockade or removal of an epidural catheter. Next dose of lMWH at least 6-8 h after spinal/epidural puncture, or after removal of a spinal/epidural catheter, thera-peutic doses once or twice daily: catheter placement or removal delayed for at least 24 h after the last dose.No spinal/epidural catheter if therapeutic doses continue


risk not evaluated risk not evaluated absolute contraindica-tion

Not addressed

ssai asa for secondary prevention: 12 h before neuraxial technique; asa for primary prevention: interruption 3 d before neuraxial technique or catheter removal.asa high doses: dis-continue 7 d.NsaiDs discontinua-tion before neuraxial technique: diclofenac, ibuprofen, ketoprofen 12 h, indomethacin, ketorolac, lornoxicam 24 h, naproxen 48 h, piroxicam, tenoxicam 2 wk, COX-2-specific inhibitors no effect on platelets.Discontinue ticlopidine and clopidogrel 5 d; dipyridamol: no interval required

Not discussed ≤5000 U (70 U/kg)/day.Needle placement and/or catheter removal 4 h after discontinuing heparin, normal aPtt and platelets; heparinize 1 h after neuraxial technique; >5000 U (70-100 U/kg)/day, same indications before, but heparinize 6 h after neuraxial technique; >100 U/kg/day, same recommendations, start epidural evening before surgery

≤5000 U or ≤40 mg/day neu-raxial technique 10 h after lMWH; next dose 6 h after needle or catheter placement >5000 U or >40 mg/day neu-raxial technique 24 h after lMWH; next dose 6 h after needle or catheter placement

recommended levels of iNr between 1.4 and 2.2 in relation to different levels of benefits from neuraxial techniques

Needle placement 36 h after last dose, wait 6 h after catheter removal for subsequent dose

Data not available absolute contraindica-tion.recommended mini-mum time intervals be-tween the last dose and cNB: 24 h for streptoki-nase and reteplase, 6 h for alteplase.Minimum time interval between neuraxial technique and iteration of the drugs: 10 d

Discontinue before neuraxial technique

UFH: unfractionated heparin; NSAID: non-steroidal anti-inflammatory drug; LMWH: low-molecular-weight heparin; GP: glycoprotein; aPtt: activated partial thromboplastin time; iNr: international Normalized ratio; cNB: central nerve block; Dgai: german society for anesthesiology and intensive care Medicine; Bara: Belgian association for regional anesthesia; asra: american society of regional

anesthesia and Pain Medicine; cHest: american college of chest Physicians; esa: european society of anaesthesiology; siaarti: italian society of anesthesiology and intensive care Medicine; ssai: scandinavian society of anaesthesiology and intensive care Medi-cine.



against the performance of neuraxial tech-niques in patients receiving thrombin inhibi-tors (grade 2c).16

Discussion

a comparison of various guidelines reveals similarities (table iV) in the management of patients who receive thrombolytics, UFH, and

drugs, a delay of at least 2-4 hours after neur-axial regional anesthesia should be observed (class iia, level c).

in the latter group of patients, there is a high risk of Vte if anticoagulation is interrupted (multiple organ failure, coagulation disorders), making neuraxial blockade inadvisable (class iii, level c).25

asra guidelines in all cases recommend

Table IV.—�Comparison of different guidelines in the management of patients receiving antithrombotic therapy (con-tinues).


siaarti NsaiDs: no contrain-dication.Discontinue ticlopidine 10-14 d, clopidogrel 7 d, gP iib/iiia inhibi-tors 8-48 h in advance

No contraindication with twice-daily dosing and total daily dose <10,000 U, consider delay heparin until after block.No other drugs

Heparinize 1 h after neuraxial technique; remove catheter 2-4 h after last heparin dose.No mandatory delay if traumatic

time interval of at least 12 h between sc administration of lMWH at prophylac-tic doses and neuraxial blockade or removal of an epidural catheter. Next dose of lMWH at least 6-8 h after spinal/epidural puncture, or after removal of a spinal/epidural catheter, thera-peutic doses once or twice daily: catheter placement or removal delayed for at least 24 h after the last dose.No spinal/epidural catheter if therapeutic doses continue


risk not evaluated risk not evaluated absolute contraindica-tion

Not addressed

ssai asa for secondary prevention: 12 h before neuraxial technique; asa for primary prevention: interruption 3 d before neuraxial technique or catheter removal.asa high doses: dis-continue 7 d.NsaiDs discontinua-tion before neuraxial technique: diclofenac, ibuprofen, ketoprofen 12 h, indomethacin, ketorolac, lornoxicam 24 h, naproxen 48 h, piroxicam, tenoxicam 2 wk, COX-2-specific inhibitors no effect on platelets.Discontinue ticlopidine and clopidogrel 5 d; dipyridamol: no interval required

Not discussed ≤5000 U (70 U/kg)/day.Needle placement and/or catheter removal 4 h after discontinuing heparin, normal aPtt and platelets; heparinize 1 h after neuraxial technique; >5000 U (70-100 U/kg)/day, same indications before, but heparinize 6 h after neuraxial technique; >100 U/kg/day, same recommendations, start epidural evening before surgery

≤5000 U or ≤40 mg/day neu-raxial technique 10 h after lMWH; next dose 6 h after needle or catheter placement >5000 U or >40 mg/day neu-raxial technique 24 h after lMWH; next dose 6 h after needle or catheter placement

recommended levels of iNr between 1.4 and 2.2 in relation to different levels of benefits from neuraxial techniques

Needle placement 36 h after last dose, wait 6 h after catheter removal for subsequent dose

Data not available absolute contraindica-tion.recommended mini-mum time intervals be-tween the last dose and cNB: 24 h for streptoki-nase and reteplase, 6 h for alteplase.Minimum time interval between neuraxial technique and iteration of the drugs: 10 d

Discontinue before neuraxial technique

UFH: unfractionated heparin; NSAID: non-steroidal anti-inflammatory drug; LMWH: low-molecular-weight heparin; GP: glycoprotein; aPtt: activated partial thromboplastin time; iNr: international Normalized ratio; cNB: central nerve block; Dgai: german society for anesthesiology and intensive care Medicine; Bara: Belgian association for regional anesthesia; asra: american society of regional

anesthesia and Pain Medicine; cHest: american college of chest Physicians; esa: european society of anaesthesiology; siaarti: italian society of anesthesiology and intensive care Medicine; ssai: scandinavian society of anaesthesiology and intensive care Medi-cine.



the following 12 months, and the patients show a high degree of compliance.64 a cardiologist should be consulted before any interruption of platelet aggregation inhibition, and clopidogrel with aspirin should be administered during the perioperative period (class i, level c).

the risk of preoperative withdrawal of an-tiplatelet drugs to perform a regional or neur-axial blockade is not justified, because clopi-dogrel withdrawal in case of unstable plaques or uncovered stents increases infarction and death rates 5-10 times. clopidogrel plus aspirin during the week preceding an operation is con-traindicated in all forms of regional anesthe-sia.14, 65 spinal hematoma has been described during clopidogrel treatment, but the risk of spinal or epidural hematoma with dual anti-platelet therapy is unknown.66 regional anes-thesia is commonly employed in patients with caD because of its protective cardiovascular effects. When compared to the cardiac death rates of general anesthesia, upper thoracic epi-dural anesthesia is known to decrease cardiac morbidity by 40%.67, 68 However, in a meta-analysis of 1173 patients, neuraxial blockade at levels below t6, alone or in combination with general anesthesia, do not reduce the car-diac risk,69 mortality, or infarction rate.67

Furthermore, in abdominal vascular surgery, a decrease in cardiac complication rate with combined anesthesia compared to general an-esthesia (10% vs. 18%), is clearly evident only in high-risk patients.67 since regional anesthe-sia is contraindicated (risk of spinal hemato-ma) in all subjects receiving clopidogrel plus aspirin during the week prior to surgery,14, 65 and since stopping clopidogrel, in the case of unstable plaques or uncovered stents, increases infarction and death rates by 5-10 times, more research work is urgently needed in the area.

Conclusions

the comparison of the guidelines of the main societies shows, for the majority of con-sidered anticoagulants, very strong differenc-es, particularly concerning the time intervals to be respected in carrying out regional anesthe-sia procedure. Furthermore, the evidences for

antiplatelet therapy. the asra guidelines for lMWH are much more conservative than the corresponding european statements owing to the large number of hematomas in North america. it is notable that an indwelling epi-dural catheter during single-daily dosing of lMWH is still considered safe in europe. However, if the patient is receiving antiplate-let therapy, lMWH will not be administered 24 hours before needle placement and/or cath-eter removal. an additional major difference is the management of the patient who receives fondaparinux. the german guidelines 55 allow maintenance of an indwelling epidural cath-eter, although this is recommended against in both the Belgian 56 and the asra statements. Finally, european guidelines support neurax-ial techniques (including continuous epidural analgesia) in the presence of direct thrombin inhibitors. However, this is relatively contrain-dicated by the asra guidelines.

a special case concerns patients undergoing dual antiplatelet therapy: patients with unstable coronary syndromes, previous percutaneous coronary interventions, and stent implantations, benefit from long-term dual platelet aggrega-tion inhibition with aspirin and clopidogrel.57

it is now well-established 58-60 that the du-ration of dual antiplatelet treatment among patients with Pcis and coronary stents is 4-6 weeks after bare metal stents (BMs) implan-tation, 3 months after sirolimus drug-eluting stents (Des) implantation, 6 months after pa-clitaxel Des implantation, and 3-6 months for second generation Des implantation. Patients with a drug-eluting stent are at risk for a partic-ularly long period, due to late and incomplete endothelialization.61

if this treatment combination is prematurely withdrawn following coronary intervention, the risk of acute stent thrombosis and myocardial infarction is substantially increased, with high mortality.62 this also appears to be the case even when perioperative bridging is carried out using heparin, and the platelet aggregation in-hibitors are only withdrawn very briefly.63 con-sequently, the american Heart association cur-rently recommends that drug-eluting stents are only used provided no surgery is planned within



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prescriptions to be taken are weak. therefore, the decision for or against regional anesthesia always requires a careful risk-benefit analysis, noting any history of bleeding, followed by a physical examination looking for signs of in-creased bleeding tendency, for example pete-chiae or hematoma (class i, level a).70 several conditions may be associated with altered co-agulation. these include the perioperative use of various anticoagulant drugs, low platelet count, renal and/or hepatic failure, chronic al-coholism, chronic steroid therapy, and periop-erative infusion of dextrans. laboratory tests, if indicated at all, should be appropriate to the individual (class i, level a).

the perioperative cessation of anticoagulant drugs to improve the safety of neuraxial block needs to be critically evaluated. an alterna-tive anesthetic technique should be used if it is judged that the administration of the antico-agulant must not be interrupted (class iia, level c).25 therefore, if neuraxial blockade is felt to be beneficial to a given patient, a spinal anes-thetic technique may be a valuable alternative as current data from the literature suggest that spi-nal puncture may be associated with lesser risk of spinal hematoma than epidural anesthesia.15

Finally, the guidelines are not intended to bypass clinical judgment. When the anesthe-siologist decides not to comply with these guidelines, the reasons should be noted in the patient’s chart.

Key messages

— a strong disparity often exists be-tween the guidelines of the main scientific societies, creating confusion among the operators in the choices of daily clinical practice.

— the evidence for prescriptions to be taken is weak.

— the decision for or against regional anesthesia always requires a careful risk - benefit analysis, especially in doubtful or controversial cases.

— in case of Noacs use, avoid region-al anesthesia procedures.



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69. Beattie Ws, Badner NH, choi P. epidural analgesia re-duces postoperative myocardial infarction: a meta-analy-sis. anesth analg 2001;93:853-8.

70. Pfanner g, Koscielny J, Pernerstorfer t, gütl M, Perger P, Fries D, et al. austrian society for anaesthesia, resusci-tation and intensive care. Preoperative evaluation of the bleeding history. recommendations of the working group on perioperative coagulation of the austrian society for anaesthesia, resuscitation and intensive care. anaesthe-sist 2007;56:604-11.

53. carswell ci, Plosker gl. Bivalirudin: a review of its po-tential place in the management of acute coronary syn-dromes. Drugs 2002;62:841-70.

54. greinacher a, lubenow N. recombinant hirudin in clinical practice: focus on lepirudin. circulation 2001;103:1479-84.

55. gogarten W, Van aken H, Büttner J, riess H, Wulf H, Buerkle H. regional anaesthesia and thromboembo-lism prophylaxis/anticoagulation. anesth intensivmed 1997;38:623-8.

56. Belgian guidelines concerning drug induced alterations of coagulation and central neuraxial anesthesia. acta anaesth Belg 2000;51:101-4.

57. Mehta sr, Yusuf s, Peters rJ, Bertrand Me, lewis Bs, Natarajan MK, et al. clopidogrel in Unstable angina to prevent recurrent events trial (cUre) investigators. effects of pretreatment with clopidogrel and aspirin fol-lowed by long-term therapy in patients undergoing per-cutaneous coronary intervention: the Pci-cUre study. lancet 2001;358:527-33.

58. acc/aHa/scai. guideline update for percutaneous coronary intervention. executive summary. J am coll cardiol 2006;47:216-35.

59. silber s, albertsson P, avile’s FF, camici Pg, colombo a, Hamm c, et al. task Force for Percutaneous coro-nary interventions of the european society of cardiol-ogy. guidelines for percutaneous interventions. the task Force for Percutaneous coronary interventions of the eu-ropean society of cardiology. eur Heart J 2005;26:804-47

60. aHa/acc. guidelines for secondary prevention for pa-tients with coronary and other atherosclerotic vascular disease: 2006 update. circulation 2006;113:2363-72.

61. Joner M, Finn a, Farb a, Mont eK, Kolodgie FD, ladich e, et al. Pathology of drug-eluting stents in humans: de-layed healing and late thrombotic risk. J am coll cardiol 2006;48:193-202.

62. Wilson sH, Fasseas P, orford Jl, lennon rJ, Horlocker t, charnoff Ne, et al. clinical outcome of patients under-

Conflicts of interest.—The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.Article first published online: December 16, 2016. - Manuscript accepted: December 5, 2016. - Manuscript revised: November 11, 2016. - Manuscript received: May 3, 2016.


© 2016 eDiZioni Minerva MeDicaonline version at http://www.minervamedica.itMinerva anestesiologica 2017 March;83(3):336Doi: 10.23736/s0375-9393.16.11671-2

cervical facet joint syndrome: a possible cause of chronic cervicobrachial pain

Dear editor,

We have read with keen interest the original article by aurini et al. about the treatment of chronic cervi-cobrachial pain (cBP) using ultrasound-guided perira-dicular injection of meloxicam.1

the paper reports excellent results in treating both patients with a herniated cervical disc (27%) or those with no structural cause for cBP (73%). the injections were performed at levels c5 to c7 which is consistent with the international literature which also demonstrates these roots as the most frequently involved in cBP.1, 2

We are highly appreciative of the comprehensive description of such a useful treatment option for this common disease and therefore we would like to give our contribution to the discussion to further improve the potential benefit of the treatment described.

our major concern regarding this paper is that it does not highlight cervical facet joint (cFJ) syndrome, nor does it describe its potential role in the genesis of cBP. the au-thors include peri-facet injections in the long list of treat-ments received by the patients without discussing it fully.1

according to the studies performed by Fukui et al. the referred pain arising from cFJ c4-c5, c5-c6 and c6-c7 can have clinical features partially similar to the cBP radiated to the upper extremities you have described.3

as 73% of your patients have no structural causes of cBP demonstrated by magnetic resonance imaging (Mri), the possibility of a cFJ syndrome should have been considered and diagnosed with a moderate to strong degree of accuracy using a medial branch block performed at the level of the suspected joint and the one above.4, 5

the ultrasound-guided approach described to perform periradicular injection is a safe approach to prevent in-traforaminal injection (1.5 cm away from the foramina), but requires a volume of drug (1 ml if one single nerve root is involved) that can spread and reach the close cer-vical facet, therefore it could partially explain the thera-peutic effect of your treatment in patients with negative Mri as usually the volume used to perform cervical periradicular injection varies between 0.25 and 0.5 ml.6

according to Manchikanti et al., there is no evidence

that common degenerative changes on cervical Mri correlate with neck symptoms except with disk hernia-tion and spondylosis (that usually cause radicular pain), thus the only way to exclude a cFJ syndrome in pa-tient without disk herniation should have been a medial branch block.4

this could have detected some cases of cFJ and changed treatment strategy by maybe considering the injection of meloxicam in the cFJ.

emanuele Piraccini 1, 2 *, Helen BYrne 3, stefano Maitan 1

1anesthesia and intensive care Unit, Department of surgery, g.B. Morgagni-Pierantoni Hospital, Forlì, italy;

2Young against Pain (YaP) italian group, Florence, italy;3Department of Medical Diagnostics, Kingsbridge

Private Hospital, Belfast, northern ireland, UK*corresponding author: emanuele Piraccini, anesthesia and intensive care Unit, Department of surgery, g.B. Morgagni-Pierantoni Hospital, viale Forlanini 34, 47100 Forlì, italy. e-mail: [email protected]

References

1. aurini l, Borghi B, White PF, tognú a, rossi B, Fini g, et al. treatment of chronic cervicobrachial pain with periradicular injection of meloxicam. Minerva anestesiol 2016;82:411-8.

2. radhakrishan K, litchy WJ, o’Fallon WM, Kurtland lt. epidemiology of cervical radiculopathy. a population based study from rochester, Minnesota, 1976 through 1990. Brain 1994;117:325-35.

3. Fukui s, ohseto K, shiotani M, Kenji o, Karasawa H, naganuma Y, et al. referred pain distribution of the cer-vical zygapophyseal joints and cervical dorsal rami. Pain 1996;68:79-83.

4. Manchikanti l, Hirsh Ja, Kaye aD, Boswell Mv. cer-vical zygapophysial (facet) joint pain: effectiveness of interventional management strategies. Postgrad Med 2016;128: 54-68.

5. Falco FJe, Manchikanti l, Datta s, Wargo BW, geffert s, Bryce Da, et al. systematic review of the therapeutic effectiveness of cervical facet joint interventions: an up-date. Pain Physician 2012;15:e839-68.

6. Waldmann sD. comprehensive atlas of ultrasound guid-ed pain management injection techniques. Philadelphia: lippincott Williams & Wilkins; 2014. p. 187-90.

Conflicts of interest.—The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.Article first published online: October 5, 2016. - Manuscript accepted: october 4, 2016. - Manuscript received: august 25, 2016.(Cite this article as: Piraccini e, Byrne H, Maitan s. cervical facet joint syndrome: a possible cause of chronic cervicobra-chial pain. Minerva anestesiol 2017;83:336. Doi: 10.23736/s0375-9393.16.11671-2)

L E T T E R S T O T H E E D I T O R


lavoro: titolo breve: primo autore: letters to tHe eDitorpagine: 336citazione: Minerva anestesiol 2017;83:336

letters to tHe eDitor


(FWT-II P=0.040 and FWT-III, P=0.032) were signifi-cantly worse in patients with PocD.

Patients positive for PocD (n.=10, 13 were dis-charge before scan or refused) were subjected to a FDg-Pet-ct scan and revealed impairment of glu-cose uptake in 5 of 10 cases (table i). We observed a generalized, global impairment of glucose uptake in 2 cases and patterns consistent with neurodegenerative disease in 3 cases, 2 consistent with alzheimer and 1 resembling fronto-temporal dementia. However, only 2 reached statistical significance using the Alzheimer-module (PalZ). We found that alterations went in line with differences in a test assessing executive functions postoperatively (RWT S, P=0.005) as well as signifi-cantly worse decline in scores assessing mental flexibil-ity (tMt-B, P=0.032).

taken together, our study shows that clinically

© 2016 eDiZioni Minerva MeDicaonline version at http://www.minervamedica.it Minerva anestesiologica 2017 March;83(3):337-8Doi: 10.23736/s0375-9393.16.11717-1

analysis of cerebral glucose metabolism in patients with post-operative cognitive dysfunction

Dear editor,

Postoperative cognitive dysfunction (PocD) is a perioperative complication of unknown etiology with an incidence of 25.8% among the elderly fol-lowing non-cardiac surgery.1 even though symp-toms may be temporary, association with premature retirement, prolonged dependency on social trans-fer payments and increased mortality have been reported.1, 2 of interest, recent studies have hypoth-esized a common pathophysiological mechanism of PocD and alzheimer’s disease.3, 4 an answer to the question whether sustained effects on the cen-tral nervous system as seen in these diseases are the pathophysiological foundation is essential for ef-fective prevention and treatment. FDg-Pet-ct is an established tool in the diagnosis of neurodegn-erative diseases, typically revealing hypometabolic regions in the posterior cingulate gyri, precuneus, and parietotemporal association cortices.5 as these changes precede the clinical onset, FDg-Pet-ct allows pre-clinical detection of these diseases.5 We here report a prospective pilotstudy using FDg-Pet-ct in patients with PocD to evaluate for pre-clinical neurodegenerative disease.

after approval from the institutional review board, informed written consent was obtained from 93 patients of 70 years and older undergoing ortho-pedic, urologic or visceral surgery with an expected operating room time >2 h. Patients with medication impairing cognitive functions or history of atrial fi-brillation, stroke, cardiac surgery, cerebrovascular disease, deep vein thrombosis or preexisting mental disorders were excluded. Patients were then subject-ed to a neuropsychological test battery based on pre-vious studies 1 prior to the day of surgery and 4 days after. twenty-three (24.7%) patients were excluded from the study due to cognitive impairment in the pre-test or due to refusal to re-test.

the incidence of PocD was 32.9% (n.=23) and did not differ in age, body mass index, gender, operating room time, frequency of combined anesthesia, social background, asa and nYHa scores, education level, anxiety, fatique, pain, depression scores, pre-operative test results, perioperative hemoglobin or crP. Postoper-ative scores assessing medium term memory (vlMt7, P=0.006 and vlMt W-F, P=0.003) and concentration

Table I.—�PET-CT results of patients with post-opera-tive dementia.

glucose uptake PMoD t-sum conclusion

1 Focal decrease temporo-ocipital left, borderline decrease temporo-polar right

normal report commensurate with age

2 Decrease temporo-mesial and basal


3 normal normal normal4 Discreet decrease

fronto-mesialnormal report commensurate

with age5 Decrease fronto-

mesial, temporalPositive Formally consistent

with fronto-temporal dementia, visual impression is a rather unspecific decrease of uptake

6 Decrease frontal and fronto-mesial, temporo-parietal, temporo-basal

Positive Formally consistent with alzheimer’s disease or fronto-temporal dementia, global hypometabolism

7 Focal decrease tempo-lateral right


8 Decrease temporo-parietal, cingulum

normal consistent with early onset alzheimer’s disease

9 Decrease frontal right and perisylvic, temporo-lateral

normal Significant unspecific, global decrease, not consistent with neurodegenerative disease

10 Decrease frontal, parietal

normal Borderline significant unspecific, global decrease, not consistent with neurodegenerative disease



© 2016 eDiZioni Minerva MeDicaonline version at http://www.minervamedica.it Minerva anestesiologica 2017 March;83(3):338-9Doi: 10.23736/s0375-9393.16.11683-9

a scope on esophageal damage associated with routine transesophageal echocardiography use in cardiac surgery

Dear editor,

We present the case of a 54-year-old man who’s been diagnosed with nsteMi and treated initially using as-pirin 100 mg/day and a heparin infusion 10,000 Units/day. This condition revealed at angiography a signifi-cant triple vessel coronary disease accessible to coro-nary artery bypass grafting.

The patient’s medical history was not significant ex-cept for tobacco and untreated hypercholesterolemia. the night before surgery, patient presented gastro in-testinal (gi) bleeding symptoms associated with a 2 g/dl decrease of hemoglobin. Preoperative labs results were protrombin time 88%, PTT: 100 secs, fibrinogen 5 g/l, when hemoglobin was 66 g/dl (versus 84 g/dl the day before) and platelets count was 373 g/l. Due to the mandatory context of early revascularization the patient was brought to the operating room for coronary revas-cularization first, and the GI evaluation was delayed to the postoperative time. after induction of general an-esthesia and orotracheal intubation an adult omniplan tee, 2 to 7 MHz Probe (Philips X7-2t tee ultrasound transducer, Philips, amsterdam, the netherlands) was inserted without difficulties. Perioperative imaging studies were easily obtain by both the resident and at-tending anesthesiologists. three-vessel coronary artery bypass grafting, was performed, with an aortic cross-clamp time of 60 min and a cardiopulmonary bypass time of 101 min. the tee probe remained in situ a total of two hours thirty and the acoustic power was from low to intermediate [mechanical index (Mi) between 0.1 and 0.5 with only one acquisition at 0.7]. the tem-perature (t°) sensor has never been upper than 39.2 °c. However, temperature gradient between tee Probe and body temperature during by-pass was superior to 5 °c.

at the end of the surgery, tee probe was removed easily with the tip in neutral position. the patient was transferred intubated and sedated to the intensive care Unit for postoperative care. a gi endoscopy was rapidly performed to check for any source of bleeding. a Forrest 2a gastric ulcer was also found to be responsible for the gi bleeding. interestingly, a 10 cm mucosal stripping was revealed, associated with several punctiform injuries of the anterior wall in middle third esophagus (Figure 1).

transesophageal echocardiography (tee) is a mini-mally invasive useful tool for intraoperative monitoring of patient undergoing cardiac surgery associated with

diagnosed PocD may in fact go in line with altera-tions of brain glucose metabolism, but that a statisti-cally significant number of patients does not reveal any impairment. therefore a pathophysiology con-stituting or resembling alzheimer’s disease can not fully explain the incidence of PocD. occurrence of the observed alterations, and their respective distri-bution patterns do not draw a homogenous picture and thus argue that PocD is a collective of hetero-geneous etiologies.

Jan M. Herter 1 *, niko BrenscHeiD 1, lydia nienHaUs 1, charlotte DietericH 1,

Matthias WecKesser 2, Hugo van aKen 1

1Department of anesthesiology, intensive care and Pain Medicine, University of Muenster,

Muenster, germany; 2clinic for nuclear Medicine, University of Muenster, Muenster, germany

*corresponding author: Jan M. Herter, Department: Department of anesthesiology, intensive care and Pain Medicine, Univer-sity Hospital Muenster, albert-schweitzer-campus 1, geb. a1, 48149 Muenster, germany. e-mail: [email protected]

References

1. Moller Jt, cluitmans P, rasmussen ls, Houx P, rasmus-sen H, canet J, et al. long-term postoperative cognitive dysfunction in the elderly isPocD1 study. isPocD in-vestigators. international study of Post-operative cogni-tive Dysfunction. lancet 1998;351:857-61.

2. steinmetz J, christensen KB, lund t, lohse n, rasmus-sen ls. long-term consequences of postoperative cogni-tive dysfunction. anesthesiology 2009;110:548-55.

3. Bilotta F, Doronzio a, stazi e, titi l, Fodale v, Di nino g, et al. Postoperative cognitive dysfunction: toward the alzheimer’s disease pathomechanism hypothesis. J alz-heimers Dis 2010;22(suppl 3):81-9.

4. Fodale V, Santamaria LB, Schifilliti D, Mandal PK. an-aesthetics and postoperative cognitive dysfunction: a pathological mechanism mimicking alzheimer’s disease. anaesthesia 2010;65:388-95.

5. Mosconi l, Berti v, glodzik l, Pupi a, De santi s, De leon MJ. Pre-clinical detection of alzheimer’s disease using FDg-Pet, with or without amyloid imaging. J alz-heimers Dis 2010;20:843-54.

Funding.—this work was conducted with support from Har-vard catalyst | the Harvard clinical and translational science center (ncrr and ncats, niH award Ul1 tr001102).Conflicts of interest.—The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.Acknowledgements.—in particular, we thank rie Maurer of the center for clinical investigation of Brigham and Women‘s Hos-pital for help with the statistical analysis.Article first published online: November 3, 2016. - Manuscript accepted: october 26, 2016. - Manuscript revised: october 19, 2016. - Manuscript received: september 21, 2016.(Cite this article as: Herter JM, Brenscheid n, nienhaus l, Diet-erich c, Weckesser M, van aken H. analysis of cerebral glucose metabolism in patients with post-operative cognitive dysfunc-tion. Minerva anestesiol 2017;83:337-8. Doi: 10.23736/s0375-9393.16.11717-1)



mucosal injury aspect immediately after a standard tee use for cardiac surgery and emphasize that shearing forces, associated to an inadequate probe mobilization in a locked position can lead to tearing of esophagus. Non pulsatile flow, prolonged cardio pulmonary bypass, mechanical compression and excessive heat are also fac-tors which can cause ischemic esophageal wall injury. therefore, safety measure to limit possible tee injury have been describe in Hilberath’s et al. work which rec-ommends several measures that can be taken to limit the risk for esophageal mucosa damage:3 keep the probe tip unlocked, use of the minimal acoustic power necessary to obtain adequate images, turn off the probe, and be careful for inadvertent heating of the probe.

Paul aBraHaM 1, 2 *, nils siegentHaler 1, raphael giraUD 1, Karim BenDJeliD 1

1intensive care Unit, University Hospital of geneva, geneva, switzerland; 2Department of anesthesiology and intensive care, centre

Hospitalier lyon sud, Pierre-Bénite, France *corresponding author: Paul abraham, service de soins in-tensifs, Hôpital Universitaire de genève, rue gabrielle-Perret-gentil 4, 1205 geneva, switzerland. e-mail: [email protected]

References

1. Min JK, spencer Kt, Furlong Kt, Decara JM, sugeng l, Ward rP, et al. clinical features of complications from transesophageal echocardiography: a single-cent-er case series of 10,000 consecutive examinations. J am soc echocardiogr off Publ am soc echocardiogr 2005;18:925-9.

2. Piercy M, Mcnicol l, Dinh Dt, story Da, smith Ja. Major complications related to the use of transesophageal echocardiography in cardiac surgery. J cardiothorac vasc anesth 2009;23:62-5.

3. Hilberath Jn, oakes Da, shernan sK, Bulwer Be, D’ambra Mn, eltzschig HK. safety of transesophageal echocardiography. J am soc echocardiogr off Publ am soc echocardiogr 2010;23:1115-27.

4. Urbanowicz JH, Kernoff rs, oppenheim g, Parnagian e, Billingham Me, Popp rl. transesophageal echocardiog-raphy and its potential for esophageal damage. anesthesi-ology 1990;72:40-3.

5. o’shea JP, southern JF, D’ambra Mn, Magro c, luis guerrero J, Marshall Je, et al. effects of prolonged transesophageal echocardiographic imaging and probe manipulation on the esophagus—an echocardiographic-pathologic study. J am coll cardiol 1991;17:1426-9.

Conflicts of interest.—The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.Article first published online: November 8, 2016. - Manuscript accepted: november 3, 2016. - Manuscript revised: october 14, 2016. - Manuscript received: august 30, 2016.(Cite this article as: abraham P, siegenthaler n, giraud r, Bendjelid K. a scope on esophageal damage associated with routine transesophageal echocardiography use in cardiac sur-gery. Minerva anestesiol 2017;83:338-9. Doi: 10.23736/s0375-9393.16.11683-9)

Figure 1.—a) endoscopic view of several punctiform in-juries * of approximately 5 mm diameter of the anterior and lateral wall in middle and inferior third esophagus; B) endoscopic view of a 10 cm mucosal stripping in the pos-terior wall of the midlle third esophagus with submucosal visualization.

a

B

complications incidence between 0.2% to 1.2%.1, 2 in-deed, the insertion and manipulation of the tee probe can cause oral, oropharyngeal, esophageal or/and gas-trointestinal tract injuries.3 Urbanowicz et al. have evaluated the pressure produced by contact between a transesophageal echocardiography (tee) probe and the esophagus as a factor sufficient to cause esophageal dam-age.4 Moreover, piezoelectric crystal vibration within the probe tip or by direct absorption of ultrasound energy may be responsible for thermal tissue injuries. although experimental studies have not demonstrated any histo-pathologic changes attributable to ultrasound energy in this settings,5 thermal injuries have been suspected in the setting of patients with severe atherosclerosis and possi-bly poorly vascularized upper gastrointestinal tract. the present case shows the possibly significant endoscopic



costeroids, rituximab and/or fludarabine are necessary prior to surgery.3

inadvertent perioperative hypothermia can occur dur-ing major surgical procedures.4 strict avoidance of hypo-thermia during the perioperative period is mandatory for patients with caD. in this case, a preoperative diagnosis of caD allowed necessary steps to be taken to avoid perioperative hypothermia and subsequent agglutina-tion and hemolysis. Prewarming of the operating room and application of warming devices before induction of anesthesia decreased the central to peripheral tempera-ture gradient, thereby minimizing core heat loss from thermal redistribution. in addition, the use of packed red blood cell transfusions was limited to avoid the introduc-tion of new antigens and complement factors. Warming measures should be continued postoperatively until nor-mal thermoregulation is restored and the patient is able to manage his/her own temperature control.

In conclusion, patients with clinically-significant caD require preoperative intervention with corticoste-roids, rituximab and fludarabine to suppress production of aberrant igM protein. careful temperature monitor-ing must be undertaken during the perioperative setting in conjunction with a preemptive warming strategy to avoid ca activation. a proactive perioperative manage-ment strategy allows patients with caD to safely un-dergo major surgical procedures.

Xuezhao cao 1, Paul F. WHite 2, Hong Ma 1 *1Department of anesthesiology, First

Hospital of china Medical University,shenyang, china; 2White Mountain institute, the sea ranch, ca, Usa

*corresponding author: Hong Ma, Department of anesthesiol-ogy, First Hospital of china Medical University, 155 nangjing north street, shenyang, liaoning, china. e-mail: [email protected]

References

1. Mcnicholl FP. clinical syndromes associated with cold agglutinins. transfus sci 2000;22:125-33.

2. Beebe Ds, Bergen l, Palahniuk rJ. anesthetic man-agement of a patient with severe cold agglutinin hemo-lytic anemia utilizing forced air warming. anesth analg 1993;76:1144-6.

3. swiecicki Pl, Hegerova lt, gertz Ma. cold agglutinin disease. Blood 2013;122:1114-21.

4. Forstot rM. the etiology and management of inadvertent perioperative hypothermia. J clin anesth 1995;7:657-74.

Conflicts of interest.—The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.Article first published online: November 9, 2016. - Manuscript accepted: november 8, 2016. - Manuscript revised: october 21, 2016. - Manuscript received: July 12, 2016.(Cite this article as: cao X, White PF, Ma H. Perioperative man-agement of a patient with cold agglutinin disease undergoing segmental hepatectomy. Minerva anestesiol 2017;83:340. Doi: 10.23736/s0375-9393.16.11563-9)

© 2016 eDiZioni Minerva MeDicaonline version at http://www.minervamedica.it Minerva anestesiologica 2017 March;83(3):340Doi: 10.23736/s0375-9393.16.11563-9

Perioperative management of a patient with cold agglutinin disease undergoing segmental hepatectomy

Dear editor,

cold agglutinin disease (caD) is an autoimmune he-molytic disease caused by the presence of cold-reacting autoantibodies.1 activation of cold agglutinins (cas) occurs when the patient’s body temperature falls below their thermal amplitude during an operation, leading to hemagglutination, hemolysis, and microvascular throm-bosis. Specific measures taken to prevent perioperative hypothermia were successfully used in a patient with caD undergoing segmental hepatectomy.

a 60-year-old male was scheduled for elective seg-mental hepatectomy. Based on the preoperative clini-cal and laboratory findings, a diagnosis of CAD was made. on the surgery day, the operating room was pre-warmed to 24 °c. Upper and lower body forced-air warming devices were applied during the periopera-tive period. Posterior skin surfaces were also warmed by a circulating-water mattress. All intravenous fluids and surgical irrigation solutions were pre-warmed to 39 °c. a Humid-ventFilter was placed in the airway circuit to humidify the anesthesia gases. esophageal and skin temperature was maintained above 36 °c. Warming measures were continued postoperatively for 24 hours. the patient made an uneventful recov-ery without evidence of hemolysis or microvascular thrombosis.

the severity of caD is dependent on the patient’s plasma titer of cas and their thermal amplitude (i.e., the highest temperature at which antibodies interact with red blood cells). Patients with a low titer of cas (≤256) and low thermal amplitude of CAs (≤30 °C) can safely undergo major surgery procedures without changes in standard clinical practice. However, patients with clinically-significant CAD (e.g., clinical signs of acrocyanosis of their extremities, a high titer of cas [≥512] and a high thermal amplitude of CAs [>30 °C]) can present a challenge for anesthesiologist due to their risk of intraoperative agglutination and hemolysis.2 screening for the presence of cold agglutinins involves obtaining a history related to acrocyanosis of their ex-tremities when exposed to the cold, positive bedside testing (e.g. the ice cube test and Ehrlich finger test), and high levels of plasma agglutinins. For clinically-relevant caD, prophylactic treatments including corti-

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