08 - caring for children in a persistent vegetative state complex but manageable

Editorials

Dexmedetomidine: Do we know enough?*

Pediatric critical care practitio-ners are faced with the need toprovide optimal sedation, anal-gesia, and anxiolysis whileavoiding the many serious side effectsattendant to unplanned deep sedation.Several categories of pediatric patientsare especially challenging in that regard.Children with borderline cardiovascularfunction may experience a difficult-to-predict life-threatening decompensationwith sedation. Those with airway anoma-lies or increased secretions may developairway compromise. Finally, in manyperi-extubation patients, finding theright balance between treating pain andanxiety while avoiding respiratory depres-sion may be a formidable task.

Dexmedetomidine, a sedative, anxio-lytic, and analgesic agent approved by theU.S. Food and Drug Administration forshort-term sedation of initially intubatedand mechanically ventilated adults in theintensive care setting, may also be appro-priate for the difficult-to-sedate child. Aselective 2-adrenergic agonist akin toclonidine, but with eight times the affin-ity for the 2-receptor, it induces seda-tion by acting on the 2-receptors in thelocus ceruleus (1) and analgesia by stim-ulating 2-receptors of the spinal cord(2). Although some dexmedetomidine-mediated respiratory depression has beenreported in healthy adults, it is minimaland not clinically significant at recom-mended doses (2, 3). In our experience,infants and children receiving dexme-detomidine are easily arousable whenstimulated. In a recent study from ourinstitution, dexmedetomidine was usedsuccessfully as the primary sedative anal-gesic in both intubated (13%) and extu-

bated (87%) children recovering fromcardiothoracic surgery (4).

Dexmedetomidine decreases the cir-culating plasma catecholamines and at-tenuates the response to surgical traumain adults (5, 6) and children (7). However,it may cause hypotension and bradycardia(8), especially when administered withnegative chronotropes or vagotonic med-ications (9, 10). Generally, its hemody-namic effects are dose- and rate-of-infusionrelated and nearly alwayspredictable (11).

Dexmedetomidines sedative and anxi-olytic properties and its limited cardiore-spiratory effects have appealed to pediat-ric intensivists and anesthesiologists.Recent reports have highlighted its use asan anesthetic adjunct for pediatric pa-tients undergoing neurologic (12) or car-diac (7) surgery. Others have describedits benefits as a primary or adjunct seda-tive for intubated or unintubated chil-dren recovering from cardiothoracic (4,13) or airway surgery (14) and burns (15).Its use to facilitate a difficult extubationin the critically ill pediatric patient (13,16) by maintaining a level of sedation andpain control, but not respiratory depres-sion, and by calming the sympatheticstorm associated with extubation (17) isespecially unique. It has been used as asole sedative for noninvasive proceduresand an adjunct for invasive procedures(11). Finally, it is effective as treatment ofwithdrawal in pediatric intensive careunit patients (18, 19).

However, dexmedetomidine is a rela-tively new agent, which to date has noFood and Drug Administration-approvedpediatric indications (11) and which, toour knowledge, has not been studied inchildren by the Food and Drug Adminis-tration. Thus, the pediatric-specific as-pects of dexmedetomidines pharmacoki-netics and pharmacodynamics are stillpoorly understood and, in practice, arebeing approximated by extrapolatingfrom adult data.

In this issue of Pediatric Critical CareMedicine, we read a report by Dr. Dazand colleagues (20), who studied thepharmacokinetics of dexmedetomidine in

ten pediatric intensive care unit (ICU)patients (aged 4 months to 7.9 yrs) fol-lowing surgical intervention. The chil-dren were treated by continuous infu-sions of dexmedetomidine at 0.20.7g/kg per hr. The infusions started in theoperating room at the discretion of theattending anesthesiologist and continuedin the pediatric ICU. They were titrated toeffect by the nursing staff according to aproscribed algorithm based on a modifiedRamsay scale and the patients level ofsedation. The infusion was continued forup to 24 hrs at the discretion of theattending pediatric intensivist, and thepatients were eligible to receive supple-mental morphine or midazolam for anal-gesia or anxiolysis at the discretion of thenursing staff. All but one of the patientsreceived additional morphine and midazo-lam; one patient required fentanyl infusion,and another was given a short course ofpropofol for extubation. The serum concen-tration of dexmedetomidine was measuredat predetermined times.

The calculated parameters in thisstudy included mean clearances of 0.570.4 L/kg per hr, steady-state volumes ofdistribution of 1.53 0.37 L/kg, and ter-minal elimination half-life of 2.65 0.88hrs. As the authors state, these findingsare comparable with those of the adultvalues (21, 22). They are also close tothose reported by Petroz and colleagues(23) in 30 children aged 212 yrs. Theauthors suggest that similar weight-based dosing of dexmedetomidine can beused in infants, children, and adults be-cause of similar clearance values. Thiscontrasts with the experience with otherdrugs in which higher clearance valuesnecessitate higher drug doses when ad-justed for weight.

Pharmacokinetic studies in childrenshould be performed to target dosing thatwill achieve appropriate sedation levelswithout undue risk. Dr. Daz and col-leagues study of dexmedetomidine phar-macokinetics in infants and children isimportant, and their data are a significantcontribution to our understanding ofhow to use this unique and promisingagent in pediatrics. However, several as-

*See also p. 419.Key Words: dexmedetomidine, 2-agonist; phar-

macokinetics; child; sedation; anxiolysis; side effectsFor information regarding this article, E-mail:

[email protected] 2007 by the Society of Critical Care

Medicine and the World Federation of Pediatric Inten-sive and Critical Care Societies

DOI: 10.1097/01.PCC.0000269380.66845.21

492 Pediatr Crit Care Med 2007 Vol. 8, No. 5

pects must be carefully considered. Thestudy included a very small sample ofchildren, among whom 40% were infants.Although the authors state that the dexme-detomidine clearance among the infants(0.52 L/kg per hr) was similar to thatamong the older children (0.61 L/kg perhr), they provide no statistical analysis tosupport their claim. The observed widevariation in drug clearance (0.40.82 L/kgper hr) and in volume of distribution (0.10.68 L/kg) suggests that larger trials withspecific stratification of subjects by age maybetter determine age-related differences inclearance and validation of the use of sim-ilar weight-based dosing strategies in bothadult and pediatric patients. Nearly everychild in this study received supplementalsedatives or analgesics, or both, so it isdifficult to fully accept the authors claimthat the dexmedetomidine concentrationin these patients was truly therapeutic. Tobetter judge dexmedetomidines efficacy itmay have been advantageous to include acontrol postsurgical group treated solelywith morphine andmidazolam and to showthat the use of the supplemental agents inthe dexmedetomidine group was signifi-cantly less. Alternatively, it may have beenhelpful to list the amounts of midazolam,morphine, fentanyl, and propofol given toeach child, so that readers could comparethem, albeit imperfectly, with their ownexperience.

Michael D. Tsifansky, MDDepartment of Critical Care

MedicineCardiac Intensive Care

DivisionHeart CenterUniversity of PittsburghPittsburgh, PA

Carol G. Schmitt, PharmDDepartment of PharmacyChildrens Hospital ofPittsburgh

Pittsburgh, PA

Ricardo A. Munoz, MDDepartment of Critical Care

MedicineCardiac Intensive Care

DivisionHeart CenterUniversity of PittsburghPittsburgh, PA

REFERENCES

1. Kamibayashi T, Maze M: Clinical uses of al-pha2-adrenergic agonists. Anesthesiology2000; 93:13451349

2. Ebert TJ, Hall JE, Barney JA, et al: The effectsof increasing plasma concentrations ofdexmedetomidine in humans. Anesthesiol-ogy 2000; 93:382394

3. Belleville JP, Ward DS, Bloor BC, et al: Ef-fects of intravenous dexmedetomidine in hu-mans. I. Sedation, ventilation, and metabolicrate. Anesthesiology 1992; 77:11251133

4. Chrysostomou C, Di Filippo S, Manrique AM,et al: Use of dexmedetomidine in childrenafter cardiac and thoracic surgery. PediatrCrit Care Med 2006; 7:126131

5. Talke P, Chen R, Thomas B, et al: The he-modynamic and adrenergic effects of periop-erative dexmedetomidine infusion after vas-cular surgery. Anesth Analg 2000; 90:834839

6. Jalonen J, Hynynen M, Kuitunen A, et al:Dexmedetomidine as an anesthetic adjunctin coronary artery bypass grafting. Anesthe-siology 1997; 86:331345

7. Mukhtar AM, Obayah EM, Hassona AM: Theuse of dexmedetomidine in pediatric cardiacsurgery. Anesth Analg 2006; 103:5256

8. Bloor BC, Ward DS, Belleville JP, et al: Ef-fects of intravenous dexmedetomidine in hu-mans. II. Hemodynamic changes. Anesthesi-ology 1992; 77:11341142

9. Ingersoll-Weng E, Manecke GR Jr, Thistleth-waite PA: Dexmedetomidine and cardiac ar-rest. Anesthesiology 2004; 100:738739

10. Berkenbosch JW, Tobias JD: Development ofbradycardia during sedation with dexmedeto-midine in an infant concurrently receivingdigoxin. Pediatr Crit Care Med 2003;4:203205

11. Tobias JD: Dexmedetomidine: Applications inpediatric critical care and pediatric anesthe-

siology. Pediatr Crit Care Med 2007;8:115131

12. Everett LL, van Rooyen IF, Warner MH, et al:Use of dexmedetomidine in awake craniot-omy in adolescents: report of two cases. Pae-diatr Anaesth 2006; 16:338342

13. Chrysostomou C, Zeballos T: Use of dexme-detomidine in a pediatric heart transplantpatient. Pediatr Cardiol 2005; 26:651654

14. Hammer GB, Philip BM, Schroeder AR, et al:Prolonged infusion of dexmedetomidine forsedation following tracheal resection. Paedi-atr Anaesth 2005; 15:616620

15. Walker J, Maccallum M, Fischer C, et al:Sedation using dexmedetomidine in pediat-ric burn patients. J Burn Care Res 2006;27:206210

16. Guler G, Akin A, Tosun Z, et al: Single-dosedexmedetomidine reduces agitation and pro-vides smooth extubation after pediatric ad-enotonsillectomy. Paediatr Anaesth 2005;15:762766

17. Kulkarni A, Price G, Saxena M, et al: Difficultextubation: Calming the sympathetic storm.Anaesth Intensive Care 2004; 32:413416

18. Baddigam K, Russo P, Russo J, et al: Dexme-detomidine in the treatment of withdrawalsyndromes in cardiothoracic surgery pa-tients. J Intensive Care Med 2005; 20:118123

19. Tobias JD: Dexmedetomidine to treat opioidwithdrawal in infants following prolonged se-dation in the pediatric ICU. J Opioid Manag2006; 2:201205

20. Daz S, Rodarte A, Foley J, et al: Pharmaco-kinetics of dexmedetomidine in postsurgicalpediatric intensive care unit patients: Pre-liminary study. Pediatr Crit Care Med 2007;8:419424

21. Dutta S, Karol MD, Cohen T, et al: Effect ofdexmedetomidine on propofol requirementsin healthy subjects. J Pharm Sci 2001; 90:172181

22. Venn RM, Karol MD, Grounds RM: Pharma-cokinetics of dexmedetomidine infusions forsedation of postoperative patients requiringintensive caret. Br J Anaesth 2002; 88:669675

23. Petroz GC, Sikich N, James M, et al: A phaseI, two-center study of the pharmacokineticsand pharmacodynamics of dexmedetomidinein children. Anesthesiology 2006; 105:10981110

493Pediatr Crit Care Med 2007 Vol. 8, No. 5

Using a computer-driven system to wean children frommechanical ventilation*

I n this issue of Pediatric CriticalCare Medicine, Dr. Jouvet and col-leagues (1) authored an imperfectbut interesting pilot study of aclosed-loop mechanical ventilation sys-tem. They recognize the limitations oftheir study, which include a nonrandomdesign, selection of patients who werelikely close to successful weaning and ex-tubation, use of historical controls, lowclinician compliance with the study andcontrol protocols, elimination of somepatients from the study protocol beforeextubation was achieved, and otherslisted in their article. Although the au-thors describe this protocol as closedloop, it was only partially a closed-loopprotocol since physicians made the judg-ment to extubate children and had tomanually change the mode of mechanicalventilation when end-inspiratory plateaupressure exceeded 27 cm H2O. Neverthe-less, the protocol did function duringpressure support weaning as a closed-loop controller and achieved a median of1.5 ventilator-setting changes per hour.This rate of ventilator setting changewould be unlikely to be achieved underusual clinical circumstances because ofclinician time constraints. Bedside clini-cians would not likely make changes sofrequently. More frequent assessmentsand changes should provide better con-trol under usual systems control theoryconsiderations. In spite of its limitations,this report is a contribution and shouldstimulate discussion regarding protocoluse in critically ill children.

The protocol of Dr. Jouvet and col-leagues (1) appears to be adequately ex-plicit, leading to specific and replicablechanges in pressure support when theinput data describe a specific patientstate. This attribute of replicability is un-usual and deserves emphasis (2). Most

guidelines and protocols are not replica-ble because they depend on bedside clini-cian judgment for many decisions. Theseclinician judgments become incorporatedin the protocol rules. Since these judg-ments occur in a variable manner, it isnot possible to describe the protocol rulescompletely. Consequently, the experi-mental or clinical care method cannot bereproduced. Absent replication of themethod, clinical investigators are notable to replicate an experiment. Thisleads medical research into a dilemma.Science generally requires replicability ofexperimental methods and results beforeembracing new information in the refer-ence works of the scientific domain (37).Our inability to replicate many medicalexperiments contributes to conflictingexperimental results and confusion re-garding best therapeutic choices.

Replicability is a requirement of themost credible experiments in part be-cause the signal-to-noise ratio for manyclinical investigations is low (8). For thesignal of interest (the signal) to be de-tected among the many unwanted signalsin nature (the noise), the signal-to-noiseratio must exceed 1 and should be maxi-mized. This can be achieved by increasingthe signal, reducing the noise, or both.Replicable protocols can increase the sig-nal through increased consistency andadherence to the protocol rules associ-ated with the intervention. Replicableprotocols can also reduce the noisethrough increased consistency in admin-istration of confounding variables thatoperate as cointerventions (nonexperi-mental interventions that can influenceoutcome) (8).

Cointerventions can introduce sys-tematic noise (bias) into clinical investi-gations in ways difficult to detect. Forexample, widely taught fluid assessmentconcepts include an analytical schemethat addresses three major fluid and elec-trolyte factors: effectiveness of the arte-rial circulation, extracellular fluid vol-ume, and state of hydration, reflected byserum osmolality or serum sodium con-centration) (912). This three-fold con-ceptual scheme seems to be frequentlyignored in fluid and electrolyte problemassessment and management. For exam-

ple, a pediatric publication used the tau-tology hypernatremic dehydration todescribe both dehydration (hypernatre-mia) and extracellular fluid volume con-traction (13). Equivocal use like this ofthe term dehydration contributes to con-fusion in the medical community. Thisconfusion can lead to experimental bias,because fluid therapy can be an impor-tant cointervention in clinical trials ofmechanical ventilation (14). Other fre-quently unrecognized cointerventions in-clude vasodilator therapy, since differentclasses of vasodilators may affect arterialoxygenation differently (15).

Dr. Jouvet and colleagues (1) recog-nize that they have addressed only someof the important mechanical ventilationrequirements. They only focus on alveo-lar ventilation and acid-base balance vari-ables (respiratory rate, tidal volume, andend-tidal partial pressure of CO2). Theyplan to include oxygenation variables infuture versions of the protocol. It will bevaluable to also consider protocol rulesfor those cointerventions that might alterclinical outcomes and obscure the effectof experimental interventions. The au-thors mention developing rules for seda-tion. These and rules for fluid manage-ment and rules for hemodynamic supportall appear likely to be important for con-trolling cointerventions in clinical trialsof mechanical ventilation. This is a largetask but one that will likely bring impor-tant dividends in the form of increasedscientific rigor and increased credibilityof experimental results.

One additional and quite importantbenefit of protocols, like that of Dr. Jou-vet and colleagues (1), is the exportabletool that houses the protocol rules. Thistool can, in principle, be exported fromthe clinical experimental environment tothe clinical care environment. It couldenable practitioners to replicate themethod used in a clinical study. Thiswould be a direct response to the chal-lenge of translating research results intoclinical practice. Enabling practitionersto use, in usual clinical care, the methodsemployed in clinical research would be arevolutionary step in healthcare delivery.This domain of translational research has

*See also p. 425.Key Words: mechanical ventilation; closed-loop

protocol; weaning; extubationThe author has not disclosed any potential con-

flicts of interest.Copyright 2007 by the Society of Critical Care


DOI: 10.1097/01.PCC.0000282161.09886.08


hardly been touched. It seems to be anattractive pursuitone likely to lead tolarge future dividends.

Alan H. Morris, MDPulmonary DivisionLDS Hospital and University of UtahSalt Lake City, UT

REFERENCES

1. Jouvet P, Farges C, Hatzakis G, et al: Wean-ing children from mechanical ventilationwith a computer-driven system (closed-loopprotocol): A pilot study. Pediatr Crit CareMed 2007; 8:425432

2. Morris A: Developing and implementingcomputerized protocols for standardizationof clinical decisions. Ann Intern Med 2000;132:373383

3. Babbie E: Survey Research Methods. Bel-mont, CA, Wadsworth, 1990

4. Guyatt G, Sackett D, Cook D: Users guide tothe medical literature: II. How to use an

article about therapy or prevention: B. Whatwere the results and will they help me incaring for my patient? JAMA 1994; 271:5963

5. Giancoli D: Physics. Third Edition. Engle-wood Cliffs, NJ, Prentice Hall, 1995

6. Emanuel EJ, Wendler D, Grady C: Whatmakes clinical research ethical? JAMA 2000;283:27012711

7. Hawe P, Shiell A, Riley T: Complex interven-tions: How out of control can a randomisedcontrolled trial be? BMJ 2004; 328:15611563

8. Morris A: The importance of protocol-directed patient management for research onlung-protective ventilation. In: Ventilator-Induced Lung Injury. Dreyfuss D, Saumon G,Hubamyr R (Eds). New York, Taylor & Fran-cis, 2006, pp 537610

9. Windus D: Fluids and electrolyte manage-ment. In: Manual of Medical Therapeutics.25th Edition. Orland M, Saltman R (Eds).Boston, Little, Brown, 1986, pp 4056

10. Levinsky N: Fluids and electrolytes. In: Har-

risons Principles of Internal Medicine. 12thEdition. Wilson J, Braunwald E, IsselbacherK (Eds). New York, McGraw-Hill, 1991, pp278283

11. DeVita M, Michelis M: Perturbations in so-dium balance. Clin Lab Med 1993; 13:135148

12. Rose B: Clinical Physiology of Acid-Base andElectrolyte Disorders. Fourth Edition. NewYork, McGraw-Hill, 1994

13. Chilton L: Prevention and management ofhypernatremic dehydration in breast-fed in-fants. West J Med 1995; 163:7476

14. The National Heart Lung and Blood Insti-tute Acute Respiratory Distress SyndromeClinical Trials Network: Comparison oftwo fluid-management strategies in acutelung injury. N Engl J Med 2006; 354:25642575

15. Wood G: Effect of antihypertensive agents onthe arterial partial pressure of oxygen andvenous admixture after cardiac surgery. CritCare Med 1997; 25:18071812

Its not easy to save a life*

They did not let me throw a pitch in a college baseball game until I had repeatedly demonstrated my skills with thousands ofpractice pitches.Lou Halamek, Stanford neonatologist, medical educator, and former college pitcher.

I n this issue of Pediatric CriticalCare Medicine, Dr. Grant and col-leagues (1) suggest that the Pedi-atric Advanced Life Support(PALS) course needs resuscitation be-cause of its inability to provide for sus-tainable knowledge of detailed algo-rithms, sufficient technical skills, orconfidence in resuscitation. Perhapstheir expectation that pediatric residentscould be adequately trained by this cur-riculum in the management of pediatriccardiopulmonary arrests was misguided.

What do we know about pediatric car-diopulmonary arrests? Reanimating apulseless, apparently dead child is noteasy. For pediatric out-of-hospital arrests,less than one third attain return of spon-taneous circulation, and 5% to 15% sur-vive to hospital discharge (2). For pediat-ric in-hospital cardiac arrests, the datafrom the National Registry of Cardiopul-monary Resuscitation (CPR) indicate thatabout one half to two thirds of the chil-dren attain return of spontaneous circu-lation and 27% survive to hospital dis-charge (3). This is not a job for a rookie.Even all-stars fail most of the time.Chest compressions, airway manage-ment, and other complex diagnosticand therapeutic skills should not de-pend on a resident alone. Perhaps thegold standard should include an expe-rienced physician in the hospital 24/7.Children at high risk for cardiac arrestshould be at centers that are preparedto provide excellent CPR and advancedlife support, much like children withtrauma should get their care at atrauma center.

There are four phases to cardiac ar-rest: prearrest, no flow, low flow, andpostresuscitation. Most pediatric cardiacarrests are due to progressive respiratoryfailure or circulatory shock. Early recog-nition and treatment of respiratory fail-ure and shock in the prearrest phase canprevent most cardiac arrests. The PALScourse was initially developed with thispurpose in mind, and this approach is acentral tenet of medical emergency teamsand rapid response teams.

The no-flow phase demands promptrecognition and intervention. In hospi-tals, the no-flow phase of untreated car-diac arrest should be avoided by monitor-ing high-risk patients in an intensive careunit (ICU). More than 80% of in-hospitalpediatric cardiac arrests are in a moni-tored unit, and outcomes from ICU ar-rests are superior to those from non-ICUarrests, presumably because of minimiz-ing the no-flow phase and providing bet-ter resuscitative efforts (3). Perhaps anin-hospital non-ICU cardiac arrest shouldbe considered a potentially avoidabledeath, requiring a root cause analysis.

*See also p. 433.Key Words: cardiac arrest; cardiopulmonary resus-

citation; medical education; resuscitation; pediatric ad-vanced life support; residency training

Dr. Berg has received grant funding fromMedtronic and Laerdal to study piglet CPR and defi-brillation. He was also the former chair of the PediatricResuscitation Committee of the American Heart Asso-ciation and is currently a member of this committee.Dr. Theodorou has not disclosed any potential conflictsof interest.

Copyright 2007 by the Society of Critical CareMedicine and the World Federation of Pediatric Inten-sive and Critical Care Societies

DOI: 10.1097/01.PCC.0000282162.31615.38


The entire cardiac output during thelow-flow phase depends on CPR: Pushhard for adequate stroke volume, pushfast for adequate heart rate, allow chestrecoil for venous return, minimize inter-ruptions in compressions, and avoid over-ventilation/high intrathoracic pressure,which may impede venous return. In-hospital and out-of-hospital basic life sup-port for adults is typically inadequate (4, 5).Providers do not push fast enough, do notpush hard enough, and allow too manyinterruptions in compressions for rhythmdetection, airway management, and vascu-lar access. Although pediatric CPR data arelimited, it appears that pediatric CPR is alsosuboptimally performed (6).

Finally, postresuscitation ischemia-reperfusion injuries routinely result inpostarrest myocardial dysfunction, oftenresult in neurologic injuries, and may leadto multiple organ system failure. The main-stays of postresuscitation care include ef-fective hemodynamic support, conservativeneurointensive care, and consideration ofinduced hypothermia. Extracorporeal lifesupport is increasingly provided in pediat-ric ICUs as an aggressive approach to suc-cessfully resuscitate children from pro-longed cardiac arrests and maintainpostresuscitation hemodynamic support (7).

How should we train healthcare pro-fessionals to provide the excellent carenecessary to bring a dead child back tolife? Practice, practice, practice. Becauseoptimal pediatric advanced life supportfor a child in cardiac arrest requires awhole team, much of that practice shouldbe as a team. PALS courses can be oneimportant part of this process. However,

only a few hours of a PALS course arefocused on cardiopulmonary resuscita-tion. Approximately 2% of children ad-mitted to pediatric ICUs have a cardiacarrest (8). Therefore, pediatric ICUs with1,000 admissions per year only have 20children arrest per year. Not surprisingly,relatively few residents, junior nurses,pharmacists, and respiratory therapistshave many experiences providing cardio-pulmonary resuscitation. Therefore, opti-mal training requires frequent mockcodes and simulation training with entireresuscitation teams, preferably in thePICU and using the same equipment thatwill be used in a real resuscitation.

What should we expect of the PALScourse? Students should learn to recog-nize and treat respiratory failure, shock,and cardiac arrest. These issues should bereinforced with repetitive case-based sce-narios. Students should also learn how tofunction effectively as a team. The newPALS course available since 2006 was de-veloped with these goals in mind. Hope-fully, it will better prepare residents,nurses, and others for preventing pediat-ric cardiac arrests and managing pediat-ric cardiopulmonary resuscitations. Wewant the PALS course to be like springtraining: a beginning, not an end in itself.For best results, the PALS course willprovide a foundation in the multiply iter-ative preparation of pediatric providers tosave a childs life.

Robert A. Berg, MD, FCCMAndreas A. Theodorou, MD,

FCCMSteele Childrens Research

Center

University of ArizonaCollege of Medicine

Tucson, AZ

REFERENCES

1. Grant EC, Marczinski CA, Menon K: UsingPALS in pediatric residency training: Does thecurriculum need resuscitation? Pediatr CritCare Med 2007; 8:433439

2. Donoghue AJ, Nadkarni V, Berg RA, et al:Out-of-hospital pediatric cardiac arrest: Anepidemiologic review and assessment of cur-rent knowledge. Ann Emerg Med 2005; 46:512522

3. Nadkarni VM, Larkin GL, Peberdy MA, et al:First documented rhythm and clinical out-come from in-hospital cardiac arrest amongchildren and adults. JAMA 2006; 295:5057

4. Abella BS, Alvarado JP, Myklebust H, et al:Quality of cardiopulmonary resuscitation dur-ing in-hospital cardiac arrest. JAMA 2005; 293:305310

5. Valenzuela TD, Kern KB, Clark LL, et al: In-terruptions of chest compressions duringemergency medical systems resuscitation.Circulation 2005; 112:12591265

6. Berg RA, Sanders AB, Milander M, et al:Efficacy of audio-prompted rate guidance inimproving resuscitator performance of car-diopulmonary resuscitation on children.Acad Emerg Med 1994; 1:3540

7. Morris MC, Wernovsky G, Nadkarni VM:Survival outcomes after extracorporeal car-diopulmonary resuscitation instituted dur-ing active chest compressions following re-fractory in-hospital pediatric cardiac arrest.Pediatr Crit Care Med 2004; 5:440446

8. Slonim AD, Patel KM, Ruttimann UE, et al:Cardiopulmonary resuscitation in pediatricintensive care units. Crit Care Med 1997; 25:19511955


Caring for children in a persistent vegetative state: Complex butmanageable*

Technological advancements inpediatric critical care have sig-nificantly improved survivalrates of critically ill children.Surviving the admission to an intensivecare unit, however, can be dramatic forsome children and their parents, partic-ularly those children surviving in a per-sistent vegetative state (PVS). To date,little is known about the incidence andprevalence of PVS in children and the lifeexpectancy of these children (13). Evenless is known about where these childrenare cared for during their prolonged re-covery period, if recovery ever occurs. Formost children in a PVS, the pediatric in-tensive care unit is the likeliest place tostart recovery. After stabilization, how-ever, the pediatric intensive care unit set-ting seems nonoptimal for these chil-dren. These children are thereforetransferred to step-down or high-careunits. Eventually, in some countries thedischarge home can be realized, given awell-organized community healthcare sys-tem allowing for life-sustaining interven-tions at home. Regardless where, caring forchildren in PVS is challenging for nurses,physicians, and parents.

The article by Mses. Montagnino andEthier (4) in this issue of Pediatric Crit-ical Care Medicine describes experiencesof eight nurses who care for neurologi-cally devastated children. The authorsused a qualitative phenomenologic de-sign to gain a deeper understanding ofthe impact on nurses. In-depth inter-views revealed that the routine care ofchildren in PVS is not the major issuethat bothers them. Of the six themes thatemerged, support of the parents and thenurses moral distress deserve specialattention to manage the complex careprocess.

Building up a nurseparent relation-ship and exploring the role of partnershipmight help nurses to understand contex-tual factors to support parents. In an-other qualitative study, parents acknowl-edged that trust, respect, and empathy fortheir child are important characteristicsfor partnership in care (5). Negotiationand support seem to be attributes neces-sary for nurses to guide parents in theirpsychological and emotional well-being.But how parents feel about and cope witha child in a PVS is not known, and has notbeen studied before. However, Drs. Tom-linson and Harbaugh (6) developed andtested the 14 item FamilyNurse Bound-ary Ambiguity Scale for pediatric inten-sive care units in a convenient sample of107 mothers and 49 fathers. This toolillustrates the family functioning and re-sponse to the critical care environment.The roles of parents and caregivers caneasily be determined on a shared basis,thus clarifying the boundaries betweenfamilies and nurses. This may then limitconflicts between parents and profession-als, leaving time for a positive interfacewith parents. Ultimately, harmoniouscollaboration might not only benefit thefamilys well-being, but also support thecomfort of the nurses and physicians.

Moral distress is a sort of suffering andis often related to ethical dilemmas thatnurses experience in practice. Ultimately,distress in daily work can lead to burn-out and decreased job satisfaction. It caneven develop into a causative agent innursing turnover. Surely, critical carenursing cannot afford for this to happen,given the global nursing shortage.

In the study of Mses. Montagninoand Ethier (4), nurses described moralstress as the powerless feeling of beingrequired to continue life support thatthey perceived as inappropriate in casesof PVS. In fact, moral distress is a hid-den danger not only for the nurses, butalso for children and their parents. Ithas been documented that moral dis-tress influences the nurses emotionaland social well-being, possibly affectingthe delivery of patient care (7). Theeffects can lead to nurses requesting tobe relieved of taking care of a patient orto less intense interaction with the par-

ents (8). Such developments might leadto negative feelings within the health-care team. Once a team is affected by atwister of negative feelings or moralsuffering, group cohesion is put underpressure. A call for support is thenneeded, which can be formal, informal,regular, or irregular. Critical carenurses seem to prefer peer support byexperienced colleagues, which may re-sult in a strong group alliance (9). TheRise Above Moral Distress model, devel-oped by the American Association ofCritical-Care Nurses, can be used toachieve positive change within ahealthcare team (10). By asking the na-ture of the distress, affirming moraldistress, assessing the sources, and act-ing upon these, the model aims to serveas a catalyst to move the critical careteam forward and to create a healthyenvironment. The help of experiencednurses and nurse leaders is necessary toinfluence attitudes and to empower col-leagues toward advanced directives andparticipation in ethics discussions.

Caring for children in a PVS is chal-lenging, particularly when all life-savinginterventions and therapies result in littleor no improvement. In the prolongedcare process, conflicts can easily arise be-tween the healthcare team and parents.Nevertheless, moral dilemmas and dis-tress are inherent in pediatric criticalcare. Responding to these difficulties orincongruity requires leadership to con-tinue the collaborative work based on re-spect, support, and empathy. Only thencan we succeed in providing optimal pa-tient care. Ultimately, the challenge is tofocus on all: children, parents, and ourpediatric critical care colleagues.

Jos M. Latour, RN, MSNSophia Childrens HospitalRotterdam, The Netherlands

REFERENCES

1. Ashwal S: Recovery of consciousness and lifeexpectancy of children in a vegetative state.Neuropsychol Rehabil 2005; 15:190197

2. Beaumont JG, Kenealy P: Incidence andprevalence of vegetative and minimally con-scious states. Neuropsychol Rehabil 2005;15:184189

*See also p. 440.Key Words: stress; nurses; parents; family; patient

care team; nurse-patient relations; ethicsThe author has not disclosed any potential con-



DOI: 10.1097/01.PCC.0000282166.84021.82


3. Lavrijsen JCM, van den Bosch JSG, KoopmansRTCM, et al: Prevalence and characteristics ofpatients in a vegetative state in Dutch nursinghomes. J Neurol Neurosurg Psychiatr 2005;76:14201424

4. Montagnino BA, Ethier AM: The experiencesof pediatric nurses caring for children in apersistent vegetative state. Pediatr Crit CareMed 2007; 8:440446

5. McIntosh J, Runciman P: Exploring the roleof partnership in the home care of children

with special health needs: Qualitative find-ings from two service evaluations. Int J NursStud 2007; In Press

6. Tomlinson PS, Harbaugh BL: Assessing am-biguity at the family-nurse boundary inter-face in pediatric health crisis. J Pediatr Nurs2004; 19:399410

7. Mekechuk J: Moral distress in the pediatricintensive care: The impact on pediatricnurses. Int J Health Care Qual Assur IncLeadersh Health Serv 2006; 17:16

8. Gutierrez KM: Critical care nurses percep-tions of and responses to moral distress. Di-mens Crit Care Nurs 2005; 24:229241

9. Cronqvist A, Ltzn K, Nystrm M: Nurseslived experiences of moral stress support inthe intensive care context. J Nurs Manag2006; 14:405413

10. Rushton CH: Defining and addressingmoral distress: Tools for critical care nurs-ing leaders. AACN Adv Crit Care 2006; 17:161168

Extracorporeal support for septic shock*

I n this issue of Pediatric CriticalCare Medicine, Dr. MacLaren andcolleagues (1) describe a series of45 children with profound septicshock refractory to conventional treat-ment, managed with venoarterial extra-corporeal circulation: extracorporeal lifesupport (ECLS) and extracorporeal mem-brane oxygenation (ECMO). Twenty-onechildren (47%) were discharged and sur-vived with no serious disability. These arevery impressive results, especially consid-ering that 18 were resuscitated from car-diac arrest, all had three or more organsfailing, and all were failing despite maxi-mal inotropic and pressor support. Al-though all had profound respiratory fail-ure, patients who presented with primarypneumonia and septic shock were ex-cluded from this group, to define thecharacteristics and results of ECLS man-agement of septic shock itself. The causeof septic shock was bacterial infection inall but one patient, with meningococcusand streptococcus predominating.

As ECLS was being developed, pro-found sepsis was initially considered acontraindication (2). However sepsis withshock and respiratory failure in new borninfants responded well during ECLS sup-port. The overall survival for this indica-tion is 75%, and sepsis is now a standardindication in neonates (3, 4) This group

of investigators from the Royal ChildrensHospital in Melbourne, Australia, havebeen leaders in evaluation of extracorpo-real support for sepsis in children (5, 6).This is a full review of their experienceand by far the largest experience withECLS management of septic shock in pe-diatrics in the literature. ECLS has beenproven very effective in prospective ran-domized trials in neonatal respiratoryfailure (79) and in a contemporarymatched pairs study in pediatric respira-tory failure (10). As the authors point out,there will not be a prospective random-ized trial of ECLS for septic shock inchildren for many reasons, but it is rea-sonable to ask what the survival mighthave been in this series without extracor-poreal support. Eighteen children were incardiac arrest, and we might assume thattwo could ultimately survive without dis-ability. Twenty-seven had three or moreorgans failing and were deteriorating de-spite maximal support, with an averagelactate of eight and negative buffer basedeviation of 10 meq/L. We might gener-ously estimate that a third of these chil-dren could have survived without severedisability. This gives us a total of 11 po-tential survivors of 45 (24%).

We can conclude that ECLS is effec-tive for children in septic shock, but whyshould it be? One reason is perfusion.With conventional treatment, systemicperfusion is maintained with high dosesof pressor and inotropic drugs, each ofwhich has its own deleterious side effects.Furthermore, profound respiratory fail-ure requires positive pressure ventilationat high mean intrathoracic pressures, de-creasing venous return and further in-creasing the need for fluid loading, ino-tropes, and pressors. All of this results inmetabolic acidosis secondary to poor res-

piration at the cellular level (includingthe myocardial cells), leading to the vi-cious cycle of septic shock. By taking overthe circulation with a mechanical pumpand taking over gas exchange with a me-chanical membrane lung, ECLS elimi-nates the iatrogenic problems of fluidoverload, high ventilator pressure andFIO2, and vasoactive drugs. Equally im-portant is simply buying time. The doctorhas time to identify the culprit bacteriaand institute culture-specific antibiotics.The patient has time to survive while thistreatment is undertaken. Futility (in theform of brain death or apparently irre-versible organ failure) becomes clear, andefforts are directed to truly salvageablepatients. Other less obvious factors thatmight be involved include systemic anti-coagulation (perhaps avoiding microvas-cular sludging and consumption coagu-lopathy), treatment of anemia (improvingsystemic oxygen delivery), treatment ofrenal failure and fluid overload (becausecontinuous hemofiltration is a simple ad-dition to the extracorporeal circuit), andperhaps removal of deleterious humoralmediators, some of which become dis-solved in the large plastic surfaces of theextracorporeal circuit.

Because this is a very experiencedteam, there were few complications ofextracorporeal support. The need for ox-ygenator, circuit, and pump changes iscommon and not a serious problem (al-though one patient died during a circuitchange, which is always a risk in patientswho are totally dependent on the extra-corporeal circuit). It is interesting thatchildren whose venous drainage cathe-ters were placed directly in the rightatrium via thoracotomy had a better sur-vival rate (73%) than children cannulatedthrough the neck vessels (44%). The flow

*See also p. 447.Key Words: sepsis; septic shock; extracorporeal

membrane oxygenation; extracorporeal life support;extracorporeal circulation

The author has not disclosed any potential con-flicts of interest.


DOI: 10.1097/01.PCC.0000282163.60836.2C


rate goals were set very high for this pop-ulation, and these goals are much moreeasily achieved with direct thoracotomyand cannulation of the atrium and aorta,which might account for improved results.The authors state that they are now usingthis approach by choice, and we look for-ward to seeing the results of a series ofpatients managed in that fashion.

The authors refer to guidelines fortreatment of septic shock in childrenpublished by the Society of Critical CareMedicine (11). Those guidelines include arecommendation to use ECLS when allother measures fail (a surprisingly per-ceptive recommendation, perhaps pre-scient of this report).

Dr. MacLaren and colleagues (1)present convincing evidence that extra-corporeal support is a valuable manage-ment technique in septic shock that isrefractory to conventional treatment.

Robert H. Bartlett, MDUniversity of Michigan

Medical Center

Department of SurgeryAnn Arbor, MI

REFERENCES

1. MacLaren G, Butt W, Best D, et al: Extracor-poreal membrane oxygenation for refractoryseptic shock in children: One institutionsexperience. Pediatr Crit Care Med 2007;8:447451

2. Bartlett RH: Extracorporeal Life Support forCardiopulmonary Failure. Current Problemsin Surgery. Vol. 27, No. 10, St. Louis, MO,Mosby-Year Book, 1990

3. Toomasian JM, Snedecor SM, Cornell R, etal: National experience with extracorporealmembrane oxygenation (ECMO) for newbornrespiratory failure: Data from 715 cases.ASAIO Trans 1988; 34:140147

4. Rich PB, Younger J, Soldes OS, et al: The useof extracorporeal life support for adult pa-tients with respiratory failure and sepsis.ASAIO J 1998; 44:263266

5. Beca J, Butt W: Extracorporeal membraneoxygenation for refractory septic shock inchildren. Pediatrics 1994; 93:726729

6. MacLaren G, Butt W: Extracorporeal mem-brane oxygenation and sepsis. Crit Care Re-susc, In Press

7. Bartlett RH, Roloff DW, Cornell RG, et al:Extracorporeal circulation in neonatal respi-ratory failure: A prospective randomizedstudy. Pediatrics 1985; 4:479487

8. ORourke PP, Crone R, Vacanti J, et al: Ex-tracorporeal membrane oxygenation andconventional medical therapy in neonateswith persistent pulmonary hypertension ofthe newborn: A prospective randomizedstudy. Pediatrics 1989; 84:957963

9. UK Neonatal ECMO Trial Group: UK collab-orative randomized trial of neonatal extra-corporeal membrane oxygenation. Lancet1996; 348:7582

10. Green TP, Timmons OD, Fackler JC, et al:The impact of extracorporeal membrane ox-ygenation on survival in pediatric patientswith acute respiratory failure: Pediatric Crit-ical Care Study. Crit Care Med 1996; 24:323329

11. Carcillo JA, Fields AJ: Clinical practice pa-rameters for hemodynamic support of pedi-atric and neonatal patients in septic shock.Crit Care Med 2002; 30:13651378

Probiotics in the critically ill: Handle with care!*

The gastrointestinal tract is acomplex ecosystem in whicha delicate balance exists be-tween the intestinal micro-flora and the host. The good microbesoutnumber the potentially pathogenicbacteria, live in symbiosis with the host,and provide many beneficial effects, in-cluding development of a competent im-mune system. These microbes produceseveral enzymes and biochemical path-ways to help in digestion; absorption ofcalcium, magnesium, and iron; and syn-thesis of short chain fatty acids and vita-mins. The gut microflora act as a physicalbarrier to invading pathogens as well asopportunistic bacteria by competing foradhesion sites. They also produce anti-bacterial substances, bacteriocins, and

lactic acid that make the environmentunsuitable for growth of potentiallypathogenic bacteria.

During critical illness, the environ-ment of the human gut becomes hostileto existing microflora. The hostile envi-ronment is created by changes in nutri-ent availability, pH, oxygen concentra-tion, redox state, osmolality, andproduction of counter-regulatory hor-mones including catecholamines (endog-enous as well as exogenous) (1). Antibi-otic use and decreased gut motility incritical illnesses further alter the micro-bial flora. The microbes adapt and re-spond to the hostile environment (1).Studies indicate decreased gut motility,decreased numbers of anaerobes and lac-tobacilli, overgrowth of Escherichia coliin distal small intestine and colon, andbacterial translocation within hours afterinduction of acute pancreatitis in animalmodels, and loss of lactic acidproducingbacterial flora in critically ill patients af-ter a short stay in an intensive care unit(2, 3).

The extreme change in host environ-ment may force the good microbes to ex-press virulence genes for nutritional pur-

poses and self-protection (1). Variouspotentially pathogenic commensals areknown to induce virulence when theyreach a critical mass whenever opportun-ism or adversity arises. Salmonella, E. coli,Yersinia, and Pseudomonas aeruginosahave been shown to cause disruption inepithelial tight junction permeability, cyto-kine release, cell apoptosis, activation ofneutrophils, and bacterial translocation (1).

Exogenous supply of live micro-organisms with or without food for theflora (prebiotics) is being advocated formaintaining the balance of flora. Theselive micro-organisms, which when ad-ministered in adequate amounts confer ahealth benefit on the host have beenlabeled as probiotics by a joint workinggroup of the Food and Agriculture Orga-nization of the United Nations and WorldHealth Organization.

There are several commercially avail-able probiotics. These include variousLactobacillus strains (L. acidophilus, L.casei, L. bulgaricus, L. plantarum), Bi-fidobacterium strains (B. longun, B. in-fantis, B. breve), Streptococcus ther-mophilus, Saccharomyces boulardii andBacillus clausii. Lactobacilli are normal

*See also p. 452.Key Words: probiotics; children; intensive care;

nosocomial infectionsThe author has not disclosed any potential con-



DOI: 10.1097/01.PCC.0000282165.04260.59


inhabitants of the human intestine. L.plantarum 299v adheres to intestinalmucosa to reinforce the barrier function.Lactobacillus GG binds to the enteric ep-ithelium, inhibiting adhesion of patho-gens, producing bacteriocins to limit thegrowth of potentially pathogenic bacte-ria, competing with other bacteria forconsumption of monosaccharides andthereby slowing their growth, and eradi-cating Clostridium difficile in patientswith relapsing colitis (4). L. casei in-creases the level of circulating immuno-globulin A. L. acidophilus and B. bifidumappear to enhance the nonspecific phago-cytic activity of circulating blood granu-locytes. S. boulardii secretes a proteasethat causes proteolytic digestion of toxinsA and B of C. difficile.

Supplementation of B. lactis Bb12 inpreterm infants significantly reduced thecell counts of enterobacteria and Clos-tridium species. (5). Use of a multistrainprobiotic (Lactobacillus GG, L. acidophi-lus, S. thermophilus, BifidobacteriumB420) reduced potentially pathogenicbacteria in the noses (6) and in the naso-gastric aspirates of critically ill patients(7). In essence, probiotics including lac-tobacilli have the ability to reduce oreliminate potentially pathogenic organ-isms from the body; reduce or eliminatevarious toxins; release numerous nutri-ents, antioxidants, growth factors, andcoagulation factors; modulate the innateand adaptive immune defense mecha-nisms; and stimulate gastrointestinalmotility (8). This forms a valid concep-tual premise and rationale for use of pro-biotics for reducing infections in criti-cally ill patients.

Some studies have indeed strength-ened this premise. A randomized studyon 80 preterm infants with very low bodyweight showed that oral supplementationwith L. casei rhamnosus for 6 wks signif-icantly lowered the incidence and inten-sity of enteric colonization by Candidaspecies (9).

An article in this issue of PediatricCritical Care Medicine by Dr. Honeycuttand colleagues (10) raises the issue ofbenefit, or rather a lack of it, of probioticsin critically ill patients. A randomizedcontrolled trial to evaluate efficacy of aprobiotic L. rhamnosus GG (10 109

cells/capsule) to reduce nosocomial infec-tions had to be discontinued prematurelybecause of lack of benefit and concernabout increased risk of nosocomial infec-tions. Their findings are similar to thoseobserved in a double-blind randomized

study of preterm infants (gestational age33 wks and birth weight 1500 g) cov-ering 12 Italian neonatal intensive careunits (11). Bacterial sepsis was more fre-quent in the neonates receiving Lactoba-cillus GG (6 109 colony-forming units)daily till discharge (4.4%) than in theplacebo group (3.8%), although the dif-ference was not statistically significant.

A lack of benefit from enteral admin-istration of L. plantarum 299 v in criti-cally ill adult patients was shown in an-other randomized trial; there was nosignificant change in the intestinal mi-croflora, intestinal permeability, endo-toxin exposure, and septic morbidity andmortality (12).

In critically ill patients, those receiv-ing viable probiotics (3 treatments/dayfor 7 days) showed a significant enhance-ment of systemic immunoglobulin A andG concentration on day 7 as comparedwith patients receiving placebo or nonvi-able probiotic (13). However, the MultipleOrgan Dysfunction Score was not affectedby probiotic use.

Is it possible that the lack of clinicalbenefit in the above cited studies wasrelated to use of a single probiotic? In arandomized study of 65 critically ill, me-chanically ventilated, multiple-traumapatients, daily supplementation with asynbiotic formula containing four probi-otics (Pediococcus pentosaceus 5334,Leuconostoc mesenteroides 32771, L.paracasei subspecies 19, and L. planta-rum 362) was associated with a signifi-cant reduction in rate of infection (p .01), systemic inflammatory responsesyndrome, severe sepsis, and mortality, aswell as length of intensive care stay andmechanical ventilation, as compared withthe placebo group (14). The above studysuggests that a combination of multipleprobiotics had a more balanced/compre-hensive enhancement of immune re-sponse and achieved a therapeutic bene-fit. However, in a randomized controlledtrial on 90 critically ill adult patients,1-wk therapy with a synbiotic preparationconsisting of four probiotics (L. acidophi-lus La 5, B. lactis Bb12, S. themophilus,and L. bulgaricus) and oligofructose didnot change the clinical outcome in spiteof a favorable alteration in microbialcomposition of the upper gastrointestinaltract (7). Studies using different combi-nations are needed to define which pro-biotic combinations are most effective inprevention of infections.

The other issue raised by Dr. Honeycuttand colleagues (10) is the possibility of in-

creased risk of nosocomial infections withprobiotic use in critically ill patients. Anepidemiologic study from Spain identi-fied three patients with fungemia causedby S. cerevisiae, a probiotic used in Eu-rope. These patients had received S. bou-lardii via nasogastric tube for an averageof 8.5 days before the culture. Cases offungemia with S. cerevisiale followingenteral use of S. boulardii, some of themfatal, have been documented in the liter-ature. The strains from the probiotic cap-sule and isolate from the blood had iden-tical DNA fingerprinting (15).

However, in a prospective, pilot studyto establish clinical safety (defined as in-vasive infection/colonization) of probioticL. casei Shirota in 28 pediatric intensivecare patients, there was no evidence ofcolonization (on culture of surface swabsor endotracheal aspirates) or invasive in-fection (from culture of blood, urine, andsterile body fluid) (16). L. reuteri or B.lactis was safe and well tolerated in in-fants, and reduced counts of enterobacte-ria and clostridia in intestinal microfloraof preterm infants (5).

Are we being a bit overenthusiastic inusing probiotics? These are being pre-scribed for disorders without clear sup-porting evidence. Even in conditionswhere the evidence is thought to be ade-quate, there is need for more evidence.One such example is the use of probioticsin prevention of atopic/eczematous der-matitis in infants. Recent randomizedcontrolled trials have turned in contra-dictory results; one using a mix of fourprobiotic bacterial strains supports theiruse (17), the other using L. acidophilus(LAVRI-A1) blamed the probiotic for ahigher risk of cows milk sensitivity with-out reduction in the risk of atopic derma-titis (18, 19). Another example is the useof probiotics for prevention of antibiotic-associated diarrhea. Of the two recentmeta-analyses of published studies, onereviewed seven randomized controlledtrials, with 766 children, and concludedthat probiotics reduced risk of antibiotic-associated diarrhea (20), while the otherreviewed six, with 707 patients, using anintention to treat analysis approach anddid not find any benefit (21).

It is important to appreciate that pro-biotics are highly heterogeneous in com-position, biological activity, and dosage.Properties of probiotic species vary andcan be strain-specific. The effect of onemay not be generalized to others withoutseparate confirmation (22). Currentlyavailable strains and currently recom-


mended doses are not able to provideimmediate benefits and need rather long-term administration.

A thorough understanding of risk andbenefits is necessary before use of probi-otics in critically ill patients. Probioticsare appealing as simple, noninvasive,therapeutic agents to enhance naturalhost defense and prevent infection by re-creating natural and normal flora.However, in spite of a valid conceptualpremise, the envisioned therapeutic ben-efits have not been realized. More re-search is needed to address issues such asmechanism of action and role of specificprobiotic, alone or in combination, fordifferent indications. Well-designed, ran-domized, clinical trials are required tofurther define the role of probiotics aspreventive and therapeutic agents in crit-ically ill patients.

Sunit Singhi, MDPostgraduate Institute of

Medical Education andResearch

Chandigarh, India

REFERENCES

1. Alverdy JC, Laughlin RS, Wu L: Influence ofthe critically ill state on host-pathogen inter-actions within the intestine: Gut-derived sep-sis redefined. Crit Care Med 2003; 31:598607

2. Leveau P, Wang X, Soltesz V, et al: Alter-ations in intestinal motility and microflora inexperimental acute pancreatitis. Int J Pan-creatol 1996; 20:119125

3. Wang X, Andersson R, Soltesz V, et al: Gutorigin sepsis, macrophage function, and ox-ygen extraction associated with acute pan-creatitis in the rat. World J Surg 1996; 20:299308

4. Doron S, Snydman DR, Gorbach SL: Lacto-bacillus GG: Bacteriology and clinical appli-cations. Gastroenterol Clin North Am 2005;34:483498

5. Mohan R, Koebnick C, Schildt J, et al: Effectsof Bifidobacterium lactis Bb12 supplementa-tion on intestinal microbiota of preterm in-fants: A double-blind, placebo-controlled,randomized study. J Clin Microbiol 2006; 44:40254031

6. Gluck U, Gebbers JO: Ingested probiotics re-duce nasal colonization with pathogenic bac-teria (Staphylococcus aureus, Streptococcuspneumoniae, and beta-hemolytic strepto-cocci). Am J Clin Nutr 2003; 77:517520

7. Jain PK, McNaught CE, Anderson AD, et al:Influence of synbiotic containing Lactobacil-lus acidophilus La5, Bifidobacterium lactisBb 12, Streptococcus thermophilus, Lacto-bacillus bulgaricus, and oligofructose on gutbarrier function and sepsis in critically illpatients: A randomised controlled trial. ClinNutr 2004; 23:467475

8. Bengmark S: Bioecologic control of thegastrointestinal tract: The role of flora andsupplemented probiotics and synbiotics.Gastroenterol Clin North Am 2005; 34:413436

9. Manzoni P, Mostert M, Leonessa ML, et al:Oral supplementation with Lactobacillus ca-sei subspecies rhamnosus prevents entericcolonization by Candida species in pretermneonates: A randomized study. Clin InfectDis 2006; 42:17351742

10. Honeycutt TCB, El Khashab M, Wardrop RMIII, et al: Probiotic administration and theincidence of nosocomial infection in pediat-ric intensive care: A randomized placebo-controlled trial. Pediatr Crit Care Med 2007;8:452458

11. Dani C, Biadaioli R, Bertini G, et al: Probiot-ics feeding in prevention of urinary tractinfection, bacterial sepsis, and necrotizingenterocolitis in preterm infants. A prospec-tive double-blind study. Biol Neonate 2002;82:103108

12. McNaught CE, Woodcock NP, Anderson AD:A prospective randomized trial of probioticsin critically ill patients. Clin Nutr 2005; 24:211219

13. Alberda C, Gramlich L, Meddings J, et al: Ef-fects of probiotic therapy in critically ill pa-tients: A randomized, double-blind, placebo-

controlled trial. Am J Clin Nutr 2007; 85:816823

14. Kotzampassi K, Giamarellos-Bourboulis EJ,Voudouris A, et al: Benefits of a synbioticformula (Synbiotic 2000Forte) in critically illtrauma patients: Early results of a random-ized controlled trial. World J Surg 2006; 30:18481855

15. Munoz P, Bouza E, Cuenca-Estrella M, et al:Saccharomyces cerevisiae fungemia: Anemerging infectious disease. Clin Infect Dis2005; 40:16251634

16. Srinivasan R, Meyer R, Padmanabhan R, etal: Clinical safety of Lactobacillus casei shi-rota as a probiotic in critically ill children.J Pediatr Gastroenterol Nutr 2006; 42:171173

17. Kukkonen K, Savilahti E, Haahtela T, et al:Probiotics and prebiotic galacto-oligosaccha-rides in the prevention of allergic diseases: Arandomized, double-blind, placebo-con-trolled trial. J Allergy Clin Immunol 2007;119:192198

18. Taylor AL, Dunstan JA, Prescott SL: Probi-otic supplementation for the first 6 monthsof life fails to reduce the risk of atopic der-matitis and increases the risk of allergensensitization in high-risk children: A ran-domized controlled trial. J Allergy Clin Im-munol 2007; 119:184191

19. Brouwer ML, Wolt-Plompen SA, Dubois AE,et al: No effects of probiotics on atopic der-matitis in infancy: A randomized placebo-controlled trial. Clin Exp Allergy 2006; 36:899906

20. Szajewska H, Ruszczynski M, Radzikowski A:Probiotics in the prevention of antibiotic-associated diarrhea in children: A meta-analysis of randomized controlled trials.J Pediatr 2006; 149:367372

21. Johnston BC, Supina AL, Vohra S: Probioticsfor pediatric antibiotic-associated diarrhea: Ameta-analysis of randomized placebo-con-trolled trials [published erratum appears inCMAJ 2006; 175:777]. CMAJ 2006; 175:377383

22. Boyle RJ, Robins-Browne RM, Tang ML:Probiotic use in clinical practice: What arethe risks? Am J Clin Nutr 2006; 83:12561264


Blood transfusions in patients with 22q11.2 deletion syndrome:Assessment of risk requires identification of the at-risk patient*

The risks and benefits of bloodtransfusion have increasinglybeen a topic for debate withinthe critical care communityover the past several years, with much ofthis debate focusing on identifying thosepatients who are most likely to benefitfrom the extra oxygen-carrying capacityprovided by packed red blood cell (pRBC)transfusions. Paradoxically, while this de-bate has been framed to demonstrate thesafety of a restrictive transfusion proto-col, it has in fact largely been fueled bystudies that have demonstrated an in-crease in morbidity and mortality in crit-ically ill patients who receive the mostpRBC transfusions (15). While in somecases this excess mortality can be linkedto well-known transfusion reactions (e.g.,acute hemolysis, transfusion-relatedacute lung injury), in general the causefor this observation is not clear. One pop-ular hypothesis is that the inclusion oflymphocytes and/or lymphocyte elabo-rated cytokines in the pRBC units resultsin a degree of immunosuppression, in-creasing the risk of infection in criticallyill patients (6, 7). Supporting this hypoth-esis are the results of limited studies insurgical patients demonstrating an im-proved outcome in patients who receivedleukocyte-depleted pRBC transfusions (8,9). In at-risk patients, who include neo-nates, patients with immunodeficiencies,and those with cardiac anomalies (partic-ularly those undergoing cardiac surgery),the transfusion of immunocompetentleukocytes (i.e., lymphocytes) has beenassociated with graft vs. host disease(transfusion associated-graft vs. host dis-ease; TA-GVHD) (10, 11). Gamma-irradi-ation of cellular blood products (RBCs,platelets, white blood cells) has beenrecommended to minimize the occur-

rence of TA-GVHD, which carries amortality approaching 100% in thesepatients. Included in these at-risk pa-tients are those with DiGeorge syn-drome, an inherited immunodeficiency.While the immune defect in DiGeorgesyndrome is variable, a consistent find-ing is a decrease in T-lymphocyte pop-ulations, particularly CD4()/CD25()regulatory T cells, which are importantin the prevention of autoimmunity(12). Interestingly, in a mouse model,the development of GVHD induced bydonor T lymphocytes can be preventedby infusions of human CD4()/CD25()regulatory T cells (13), raising the possi-bility that the deficiency of this popula-tion of T cells is related to the risk ofTA-GVHD.

In the current issue of Pediatric Crit-ical Care Medicine, Dr. Jatana and col-leagues (14) report on the transfusionevents and practices in 65 admissions of40 patients with a diagnosis of 22q11deletion. Patients with 22q11 deletionsyndrome include those with the velocar-diofacial syndrome, Shprintzen syndrome,conotruncal anomaly face syndrome, Cay-ler syndrome, CATCH syndrome, and theDiGeorge syndrome (15). Indeed, it hasbeen demonstrated that these disordersdefine the spectrum of anomalies inducedby gene deletion and that each of thesedisorders may express any of the constit-uent elements of the spectrum. Conse-quently, any patient with known or sus-pected 22q11.2 deletion syndrome is atrisk for the development of hypocalcemiaas a consequence of hypoparathyroidismand may reasonably be considered to havea degree of immunodeficiency as definedby the DiGeorge syndrome. Because ofthe risk of immune function abnormali-ties, all of these patients should receiveirradiated cellular blood products to min-imize the risk of developing TA-GVHD(10). In spite of a recommendation forsuch treatment, more than half of thepatients reported by Dr. Jatana and col-leagues (14) received nonirradiated bloodproducts during an admission to the pe-diatric intensive care unit (16 of 29 pa-tients; 55%) (14). Owing to the knownrisk of TA-GVHD, the authors institu-

tional blood bank had a prompt code toidentify del22q11.2 patients and instructstaff that these patients were only to re-ceive irradiated blood products in 20 ofthe 40 patients included in the report.Again, only one half (20 of 40) of theidentified patients with 22q11.2 deletionhad such a blood bank instruction inplace at the time of hospital admissioneven though each of the patients waseither known as having or suspected tohave this syndrome. While none of thepatients experienced a significant sideeffect from transfusion of nonirradiatedblood product, the authors correctlyidentify this lack of compliance withaccepted transfusion practice as result-ing from incomplete clinical informa-tion being transmitted to the bloodbank. While this may be an example ofno harm, no foul, it also represents afailure in physician-to-physician com-munication. Failure to identify theseat-risk patients to blood bank personnelresulted in a lack of adherence to ac-cepted transfusion guidelines and couldhave had severe consequences. We as aprofession cannot take comfort in the factthat there were no adverse consequences inthis patient cohort.

So, what is the take-home message ofthis study? First, in complex genetic ab-normalities, patients may present with abroad spectrum of clinical findings, andwe must be equally broad in our diagnos-tic and management strategies. Second,we must communicate sufficient clinicalinformation to others participating in thecare of these children to ensure that they,too, will make appropriate clinical deci-sions. And third, we must exercise duediligence to ensure that appropriatetreatment guidelines are followed toprovide maximum safety to the patientwhile simultaneously providing opti-mum treatment.

Robert I. Parker, MDDepartment of PediatricsStony Brook University

Cancer CenterSUNY at Stony Brook School

of MedicineStony Brook, NY

*See also p. 459.Key Words: DiGeorge syndrome; velocardiofacial

syndrome; 22q11.2 deletion; transfusion-associatedgraft vs. host disease

The author has not disclosed any potential con-flicts of interest.


DOI: 10.1097/01.PCC.0000282160.62532.6A


REFERENCES

1. Napolitano LM, Corwin HL: Efficacy of redblood cell transfusion in the critically ill. CritCare Clin 2004; 20:255268

2. Taylor RW, OBrien J, Trottier SJ, et al: Redblood cell transfusions and nosocomial infec-tions in critically ill patients. Crit Care Med2006; 34:23022308

3. Hebert PC, Blajchman MA, Cook DJ, et al: Doblood transfusions improve outcomes relatedto mechanical ventilation? Chest 2001; 119:18501807

4. Robinson WP III, Ahn J, Stiffler A, et al:Blood transfusion is an independent predic-tor of increased mortality in nonoperativelymanaged blunt hepatic and splenic injuries.J Trauma 2005; 58:437444

5. Malone DL, Dunne J, Tracy JK, et al: Bloodtransfusion, independent of shock severity, isassociated with worse outcome in trauma.J Trauma 2003; 54:898905

6. Brand A: Immunological aspects of bloodtransfusions. Transplant Immunol 2002; 10:183190

7. Vamvalas EC: Possible mechanisms of allo-geneic blood transfusion-associated post-operative infection. Transfus Med Rev 2002;16:144160

8. Bilgin YM, van de Watering LM, Eijsman L,et al: Double-blind, randomized controlledtrial on the effect of leukocyte-depletederythrocyte transfusions in cardiac valve sur-gery. Circulation 2004; 109:27552760

9. van Hilten JA, van de Watering LM, vanBockel JH, et al: Effects of transfusion withred cells filtered to remove leukocytes: Ran-domized controlled trial in patients undergo-ing major surgery. BMJ 2004; 328:11281

10. Parshuram C, Doyle J, Lau W, Shemie SD:Transfusion-associated graft versus host dis-ease. Pediatr Crit Care Med 2002; 3:5762

11. Rosen NR, Weidner JG, Boldt HD, et al: Pre-vention of transfusion-associated graft-

versus-host disease: Selection of an adequatedose of gamma radiation. Transfusion 1993;33:125127

12. Sullivan KE, McDonald-McGinn D, ZackaiEH: CD4() CD25() T-cell production inhealthy humans and in patients with thymichypoplasia. Clin Diagn Lab Immunol 2002;9:11291131

13. Mutis T, van Rijn RS, Simonetti ER, et al:Human regulatory T cells control xenogeneticgraft-versus-host disease induced by autolo-gous T cells in RAG2/ gammac/ immu-nodeficient mice. Clin Cancer Res 2006; 12:55205505

14. Jatana V, Gillis J, Webster, B, et al: Deletion22q11.2 syndromeImplications for the in-tensive care physician. Pediatr Crit Care Med2007; 8:459463

15. Robin NH, Shprintzen RJ: Defining the clin-ical spectrum of deletion 22q11.2. Pediatrics2005; 147:9096

Steroids use in pediatric cardiac surgery: More questions*

Cardiopulmonary bypass (CPB)is a technique commonly per-formed for pediatric cardiacsurgery, although there stillare complications related to its use. As-sociated with CPB use is a whole-bodyinflammatory response characterized byboth cell and protein activation. Themain triggering events of this systemicinflammatory response are: surgicaltrauma, blood contact with surfaces ofCPB circuit, ischemia-reperfusion injury,and endotoxemia. These multiple syner-gistic stimuli to the inflammatory cas-cade amplify the process, leading to or-gan dysfunction and postoperativemorbidity (1, 2, 3). Among the problemsrelated to CPB and systemic inflamma-tory response we have myocardial, pul-monary, and renal dysfunction; neuro-logic alteration; coagulation disorder;hepatic dysfunction; adrenal insuffi-ciency; and multiple organ failure (4, 5).

Systemic inflammatory response andmultiple organ failure are most promi-nent at 8 hrs to 24 hrs after CPB (4). Inparticular, respiratory failure was one ofthe first CPB complications described.Changes in alveolararterial oxygenation,intrapulmonary shunt, pulmonary edemaseverity, and lung compliancealongwith increased pulmonary vascular resis-tance, extended tracheal intubation, andmechanical ventilation timereflect thepulmonary dysfunction related to CPB (5,6). Specifically concerning pulmonarydysfunction, Dr. Bronicki et al. (7)showed that in children submitted to car-diac surgery under CPB, dexamethasonedecreased length of ventilation and low-ered alveolararterial oxygen gradients.

A variety of methods have been triedto reduce the detrimental physiologic ef-fects, from avoidance of CPB through useof biocompatible CPB circuits to pharma-cologic agents. One obvious anti-inflam-matory option would be the use of ste-roids that mainly up-regulate RNAtranscription in the cell nucleus, andthereby modulate protein synthesis andmolecular pathways.

Although a topic of debate, over thelast few years the use of steroids in pedi-atric CPB has been slowly but steadilyreinforced. However, the available studiesdiffer widely, mainly concerning the typeof steroid, the dose and method of admin-

istration, the timing of the administra-tion (pre-, intra-, and postoperative), andthe clinical and laboratory parametersused to measure the therapeutic response(813). We should note that steroidsgiven during the surgery may be removedby the ultrafiltration during CPB. Theexisting studies also vary on their results,some favorable to the use of steroids,others not. Recently in Pediatric CriticalCare Medicine, Dr. Checchia et al. (14)performed an international survey to de-termine how steroids are used in pediat-ric CPB. The authors concluded that, al-though steroids are widely used, theirutilization is quite variable, and that welack multicenter, randomized, placebo-controlled trials to determine whether ornot steroids are beneficial in the clinicalsetting.

Additionally, the harmful effects (suchas hyperglycemia, immunosuppressiondue to suppression of T-cell function, im-paired wound healing, peptic ulcer, sup-pression of pituitaryadrenal axis andmetabolic effects, and other long-termeffects) of the steroid use also should beevaluated, although they are generallyviewed as acceptable risks (4, 6).

In this issue of Pediatric Critical CareMedicine, Dr. Santos and colleagues (15)further foster the discussion of steroiduse, introducing the inhaled route intothis already complex equation. Aiming to

*See also p. 465.Key Words: cardiac surgery; intensive care medi-

cine; postoperative care; corticosteroids; cardiopulmo-nary bypass; systemic inflammatory response; infants

The authors have not disclosed any potential con-flicts of interest.


DOI: 10.1097/01.PCC.0000282164.16664.5D


control the pulmonary injury and inflam-matory mediator production, and havingin the background the rationale localdrug, local effects, the authors adminis-tered budesonide to children submittedto cardiac surgery after CPB. They werenot able to demonstrate a measurable ef-fect on lung compliance, oxygenation, orproduction of inflammatory mediators.

At this point, several issues are raised.The low pulmonary volumes and capaci-ties (low tidal volume and low vital andfunctional residual capacity) of the in-fant, along with the high respiratory ratethat results in a low inspiratoryexpira-tory ratio, lead to a low residence time foraerosol particles and, therefore, a lowpulmonary deposition of these particles.In fact, 1% of the nominal dose is de-livered (16). Apart from the low pulmo-nary deposition, high interpatient and in-trapatient variability challenges anefficient aerosol delivery to infants. Toovercome these problems, one must rec-ognize and understand the distinct fac-tors that may influence aerosol pulmo-nary deposition: type of ventilator andventilation variables, ventilator circuitcharacteristics and the position of theaerosol device in it, size and type of theendotracheal tube, use of nebulizer ormetered-dose inhaler, heat and humidifi-cation, gas density, and the drug formu-lation. So, have we delivered the drugefficiently to the lungs? On the otherhand, it should be noted that the amountof drug received per kilogram by infantsis higher than in adults.

Considering that the effects of CPB aresystemic and that the limited systemicabsorption of inhaled drugs minimizes

systemic effects, do we really want to de-liver steroids only to the lungs? And inthe light of the available evidence, finally,the most difficult question: Do steroidsreally benefit children submitted to car-diac surgery with CPB?

Werther Brunow de Carvalho,MD, PhD

Marcelo Cunio MachadoFonseca, MD, MSc

Federal University of SoPaulo

So Paulo, Brazil

REFERENCES

1. Wan S, LeClerc JL, Vincent JL: Inflammatoryresponse to cardiopulmonary bypass: Mech-anisms involved and possible therapeuticstrategies. Chest 1997; 112:676692

2. Chaney MA: Corticosteroids and cardiopul-monary bypass: A review of clinical investi-gations. Chest 2002; 121:921931

3. Paparella D, Yau TM, Young E: Cardiopulmo-nary bypass induced inflammation: Patho-physiology and treatment. An update. EurJ Cardiothorac Surg 2002; 21:232244

4. Ando M, Park IS, Wada N, et al: Steroidsupplementation: A legitimate pharmaco-therapy after neonatal open heart surgery.Ann Thorac Surg 2005; 80:16721678

5. Stayer SA, Diaz LK, East DL, et al: Changesin respiratory mechanics among infants un-dergoing heart surgery. Anesth Analg 2004;98:4955

6. Whitlock RP, Rubens FD, Young E, et al: Pro:Steroids should be used for cardiopulmonarybypass. J Cardiothorac Vasc Anesth 2005;19:250254

7. Bronicki RA, Backer CL, Baden HP, et al:Dexamethasone reduces the inflammatoryresponse to cardiopulmonary bypass in chil-dren. Ann Thorac Surg 2000; 69:14901495

8. Trotter A, Muck K, Grill HJ, et al: Gender-

related plasma levels of progesterone, inter-leukin-8, and interleukin-10 during and aftercardiopulmonary bypass in infants and chil-dren. Crit Care 2001; 5:343348

9. Varan B, Tokel K, Mercan S, et al: Systemicinflammatory response related to cardiopul-monary bypass and its modification bymethyl prednisolone: High dose versus lowdose. Pediatr Cardiol 2002; 23:437441

10. Lindberg L, Forsell C, Jogi P, et al: Effects ofdexamethasone on clinical course, C-reactiveprotein, S100B protein, and von Willebrandfactor antigen after paediatric cardiac sur-gery. Br J Anaesth 2003; 90:728732

11. Schroeder VA, Pearl JM, Schwartz SM, et al:Combined steroid treatment for congenitalheart surgery improves oxygen delivery andreduces postbypass inflammatory mediatorexpression. Circulation 2003; 107:28232828

12. Checchia PA, Backer CL, Bronicki RA, et al:Dexamethasone reduces postoperative tropo-nin levels in children undergoing cardiopul-monary bypass. Crit Care Med 2003; 31:17421745

13. Gessler P, Hohl V, Carrel T, et al: Adminis-tration of steroids in pediatric cardiac sur-gery: Impact on clinical outcome and sys-temic inflammatory response. PediatrCardiol 2005; 26:595600

14. Checchia PA, Bronicki RA, Costello JM, et al:Steroid use before pediatric cardiac opera-tions using cardiopulmonary bypass: An in-ternational survey of 36 centers. Pediatr CritCare Med 2005; 6:441444

15. Santos AR, Heidemann SM, Walters HL III,et al: The effect of inhaled corticosteroid onpulmonary injury and inflammatory media-tor production after cardiopulmonary bypassin children. Pediatr Crit Care Med 2007;8:465469

16. Fink JB: Aerosol delivery to ventilated infantand pediatric patients. Respir Care 2004; 49:653665


Surfactant treatment of aspiration-induced lung injury inchildren*

The value of surfactant therapyin the neonatal setting for thetreatment of infant respiratorydistress syndrome is well es-tablished (1). However, based on phase IIIstudies, surfactant therapy for acute lunginjury in adults has not resulted in areduction in the duration of mechanicalventilation or an improvement in survival(2, 3). Nevertheless, extrapolation of theresults of adult trials of acute lung injuryto children with acute lung injury shouldbe done with caution. Although there aresimilarities between lung injury in adultsand children, one recent prospectivestudy of 324 pediatric patients with acutelung injury noted some differences. Forexample, unlike most adult studies, theinitial severity of hypoxemia in acutelung injury is an independent predictor ofmortality in children (4).

In this issue of Pediatric Critical CareMedicine, Dr. Marraro and colleagues (5)report favorable results from a small clin-ical trial that tested the potential value oftreating children who have aspiration-induced acute lung injury with saline la-vage with surfactant compared with acontrol group of patients. The authorsfound that the children treated withbronchial suction, saline lavage contain-ing surfactant, and then instillation ofsurfactant in affected lobes had improvedoxygenation, reduced days of mechanicalventilation, and reduced acquired lunginfection. The control group was treatedwith bronchial suction without lavage orsubsequent surfactant therapy. Therewere no deaths in either group. Althoughthe investigators are to be commendedfor carrying out a randomized clinicaltrial, there are important limitations tothis trial that should be appreciated.

First, the trial enrolled 20 children, asmall number of patients with a wide age

range. Second, the control group was nottreated with lavage. This is an importantomission because saline lavage itselfcould have some value in removing aspi-rated material from the distal airspaces.Third, while Curosurf (porcine surfac-tant, Chiesi Pharmaceutical, Spa, Parma,Italy) is a well accepted, surfactant prep-aration, the dosage for older children andadults is not as well established as it is fornewborns. Common practice would pre-scribe a dose of about 100 mg/kg in theneonatal setting of surfactant insuffi-ciency, or roughly 20 mg per lobe perkilogram of body weight, repeated onceor twice as indicated. In cases of inacti-vation of normal alveolar surfactant, asmight be anticipated with aspiration,higher doses have been recommended (6,7). In this study, the retained dosage isdifficult to estimate from the informationprovided. We calculate that 840 mg perlobe per kilogram of body weight mayhave been instilled, with surfactant fromthe initial lavage possibly adding another25%. Conceivably, this dosage could besufficient to stabilize the airspaces at lev-els of positive end-expiratory pressurenear 10 cm H2O, provided that residualaspiration materials and products of in-flammation did not markedly inhibit sur-factant function.

Another important concern is the fail-ure to standardize ventilation for all pa-tients with a lung-protective, low tidalvolume strategy. The results show thatpatients who were in the control groupended up with a significantly higher tidalvolume by 36 hrs compared with the sur-factant-treated group. The higher tidalvolume may have exacerbated the lunginjury. It is possible, of course, that thisdifference reflects improved lung func-tion and better compliance in the surfac-tant-treated group. However, the designof the study would have been improved ifboth patient groups were committedfrom the outset to a low tidal volumestrategy in the range of 67 mL/kg ofideal body weight with volume-dependentventilation, along with a plateau pressure30 cm of H2O. Since clinical trials inadults with lung injury have demon-strated the beneficial effects of a lung-protective ventilation strategy (8), clini-

cal trials in the pediatric population thattest new therapies, such as surfactant,should be designed so that both groupsare treated with a similar lung protectivestrategy.

Despite the limitations of this clinicaltrial, the results emphasize the impor-tance carrying out prospective clinicaltrials to test the potential value of surfac-tant therapy in pediatric lung injury out-side of the neonatal setting. There areseveral theoretical reasons why surfac-tant therapy might be beneficial in treat-ing direct lung injury from aspirationsyndrome of gastric contents. Surfactanttherapy could improve alveolar stabilityand gas exchange, and there might bebeneficial anti-inflammatory effects ofsurfactant as well (9). Interestingly, theonly positive result from a major trialwith the use of surfactant replacementtherapy in acute lung injury comes fromthe pediatric study by Willson et al. in2005 (10). In that trial, surfactant re-placement therapy was associated with adecrease in mortality, although there wasno difference in ventilator-free days. Inthe Willson study, Infasurf (calfactant;Forest Pharmaceuticals, St. Louis, MO) ata dosage of 200250 mg/kg was instilledinto the trachea without lavage. Approx-imately half of the children had pneumo-nia on entry into the trial; 10% hadaspiration-induced lung injury. The Will-son study included several patients whowere immunosuppressed, and the mor-tality was high (36% vs. 19% in the pla-cebo vs. treatment groups), whereasthere was no mortality in the trial by Dr.Marraro and colleagues (5).

The current clinical trial by Dr. Mar-raro and colleagues (5) suggests thatmore studies are warranted in the pedi-atric population of patients with acutelung injury to test the potential therapeu-tic value of surfactant therapy adminis-tered early in the course of the illness. Itmay be difficult to target patients whohave an aspiration syndrome alone be-cause of the limited number of patients,even if a multicenter trial is done. A morefeasible approach would be to target pa-tients with primary lung injury from ei-ther aspiration or pneumonia. In anyclinical trial, there will need to be appro-

*See also p. 476.Key Words: surfactant therapy; infant respiratory

distress syndrome; saline lavageThe authors have not disclosed any potential con-



DOI: 10.1097/01.PCC.0000282159.21812.CB


priate control groups for the surfactanttherapy, which should include a salinelavage control group if lavage is part ofthe treatment with surfactant. Also, someblinding procedure would be important,particularly since clinical outcomes willinclude factors that could be influencedby clinician bias, such as the timing forextubation. In addition, biochemical in-dexes of lung injury should be included.Several biological markers have proven tobe of value in adult studies and some havealso been identified to be of prognosticand pathogenetic significance in pediatriclung injury studies (11, 12) as well as instudies in adults with acute lung injury(13).

In recent years, there has been a grow-ing recognition of the need to focus clin-ical research and clinical trials on pediat-ric acute lung injury. Several pediatricintensivists have organized into a groupcalled the Pediatric Acute Lung Injuryand Sepsis Investigators (PALISI). Theseclinicians and investigators meet biannu-ally to foster clinical research and tocarry out clinical trials in pediatric acutelung injury. In 2006, PALISI and theARDS Network, supported by the Na-tional Heart Lung and Blood Institute,joined forces to organize a phase III clin-ical trial in children with acute lung in-jury. This is an encouraging developmentas there is a major need for more clinicalresearch and clinical trials for pediatric

acute lung injury.Michael A. Matthay, MDWilliam Taeusch, MD

Departments of Medicine,Anesthesia and Pediatrics

Cardiovascular ResearchInstitute

University of CaliforniaSan Francisco, CA

REFERENCES

1. Suresh GK, Soll RF: Overview of surfactantreplacement trials. J Perinatol 2005;25(Suppl 2):S40S44

2. Anzueto A, Baughman RP, Guntupalli KK, etal: Aerosolized surfactant in adults with sep-sis-induced acute respiratory distress syn-drome. Exosurf Acute Respiratory DistressSyndrome Sepsis Study Group. N Engl J Med1996; 334:14171421

3. Spragg RG, Lewis JF, Walmrath HD, et al:Effect of recombinant surfactant proteinC-based surfactant on the acute respiratorydistress syndrome. N Engl J Med 2004; 351:884892

4. Flori HR, Glidden DV, Rutherford GW, et al:Pediatric acute lung injury: Prospective eval-uation of risk factors associated with mortal-ity. Am J Respir Crit Care Med 2005; 171:9951001

5. Marraro GA, Marco L, Spada C, et al: Selec-tive medicated (normal saline and exogenoussurfactant) bronchoalveolar lavage in severeaspiration syndrome in children. Pediatr CritCare Med 2007; 8:476481

6. Hafner D, Beume R, Kilian U, et al: Dose-response comparisons of five lung surfactant

factor (LSF) preparations in an animal modelof adult respiratory distress syndrome(ARDS). Br J Pharmacol 1995; 115:451458

7. Findlay RD, Taeusch HW, Walther FJ: Sur-factant replacement therapy for meconiumaspiration syndrome. Pediatrics 1996; 97:4852

8. Ventilation with lower tidal volumes as com-pared with traditional tidal volumes for acutelung injury and the acute respiratory distresssyndrome. The Acute Respiratory DistressSyndrome Network. N Engl J Med 2000; 342:13011308

9. Lewis JF, Veldhuizen R: The role of exoge-nous surfactant in the treatment of acutelung injury. Annu Rev Physiol 2003; 65:613642

10. Willson DF, Thomas NJ, Markovitz BP, et al:Effect of exogenous surfactant (calfactant) inpediatric acute lung injury: A randomizedcontrolled trial. JAMA 2005; 293:470476

11. Flori HR, Ware LB, Glidden D, et al: Earlyelevation of plasma soluble intercellular ad-hesion molecule-1 in pediatric acute lunginjury identifies patients at increased risk ofdeath and prolonged mechanical ventilation.Pediatr Crit Care Med 2003; 4:315321

12. Flori HR, Ware LB, Milet M, et al: Earlyelevation of plasma von Willebrand factorantigen in pediatric acute lung injury is as-sociated with an increased risk of death andprolonged mechanical ventilation. PediatrCrit Care Med 2007; 8:96101

13. Ware LB: Prognostic determinants of acuterespiratory distress syndrome in adults: Im-pact on clinical trial design. Crit Care Med2005; 33:S217222


08 - caring for children in a persistent vegetative state complex but manageable

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