case report a minimal-invasive metabolic test detects...

Hindawi Publishing CorporationCase Reports in AnesthesiologyVolume 2013, Article ID 953859, 4 pageshttp://dx.doi.org/10.1155/2013/953859

Case ReportA Minimal-Invasive Metabolic Test DetectsMalignant Hyperthermia Susceptibilityin a Patient after Sevoflurane-Induced Metabolic Crisis

Frank Schuster, Stephan Johannsen, and Norbert Roewer

Department of Anesthesia and Critical Care, University of Wuerzburg, Oberduerrbacher Street 6, 97080 Wuerzburg, Germany

Correspondence should be addressed to Frank Schuster; schuster [email protected]

Received 17 July 2013; Accepted 27 August 2013

Academic Editors: A. Han, H. Shankar, and C.-S. Sung

Copyright © 2013 Frank Schuster et al.This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Malignant hyperthermia is a rare but life-threatening complication of general anesthesia in predisposed patients usually triggeredby potent inhalation anesthetics and/or the depolarizing muscle relaxant succinylcholine. The authors present a case of delayedsevoflurane-inducedmalignant hyperthermia in a 21-year-oldmale patient that was sufficiently treated by discontinuation of triggeragent application and dantrolene infusion. After surviving an MH episode diagnostic procedures are indicated to increase patientsafety. In the presented case, the use of a novel minimal-invasive metabolic test with intramuscular injection of halothane andcaffeine successfully confirmed MH susceptibility and hence might be an alternative for invasive in vitro contracture testing inselected cases.

1. Introduction

Malignant hyperthermia (MH) is a rare but potentiallylethal pharmacological induced disease of skeletal muscle.Exposure to triggering agents such as volatile anestheticsand/or the depolarizing muscle relaxant succinylcholine mayinduce a hypermetabolic muscular syndrome characterizedby hypoxemia, hypercapnia, tachycardia, muscular rigidity,acidosis, hyperkalemia, and hyperthermia, due to an uncon-trolled sarcoplasmic calcium release via functionally alteredryanodine receptors subtype 1 or dihydropyridine receptors[1]. Currently, the in vitro contracture test (IVCT) requiringan open muscle biopsy is the only reliable procedure todiagnoseMHsusceptibility in affected patients.However, dueto its invasive characteristics this test is associated with severerisks to the patients, for example, wound infections, postoper-ative bleeding, or persistent dysesthesia. Important progresswas made within the last years by screening for causativeMH mutations, which allows a genetic diagnosis in 30% to50% of MH families [2]. Unfortunately, a negative geneticresult does not sufficiently exclude MH susceptibility andhence must be confirmed by IVCT [3]. Recently, a minimal-invasive metabolic test was proposed to analyze muscular

alterations in MH patients under in vivo conditions. Thelocal monitoring of interstitial lactate concentrations afterpharmacological stimulation induced by MH trigger agentsallowed a differentiation betweenMH susceptible (MHS) andMH nonsusceptible (MHN) patients [4].

In the presented case report, we used this minimal-inva-sive test to screen for MH susceptibility in a patient whodeveloped clinical sings of MH during general anesthesiawith sevoflurane while undergoing an elective shoulderarthroscopy.

2. Case Presentation

2.1. Intra- and Postoperative Course. With approval of thelocal ethics committee (application number: 263/11, ethicscommittee of the University of Wuerzburg), we report thecase of a 21-year-old male patient weighting 100 kg, whowas scheduled for elective shoulder arthroscopy. Neither thepatient nor his family had any history of neuromusculardisease or MH. According to the medical records, the patientunderwent two uneventful anesthesias using halothane com-bined with oxygen (O

2) and nitrous oxide (N

2O) for cleft

lip revision at the age of 5 months and at the age of 4

2 Case Reports in Anesthesiology

years, respectively.The preoperative laboratory examinationswere within normal values. Initial heart rate (95 bpm), bloodpressure (145/80mmHg), and peripheral oxygen saturation(96%) were unremarkable. Anesthesia was induced by intra-venous application of 0.1mg/kg piritramid, an initial bolus of2.5mg/kg propofol followed by an additional application of1.5mg/kg propofol, and 1.5mg/kg succinylcholine. To securepatient’s airways, a size 8,0mm cuffed endotracheal tube wasinserted after direct laryngoscopy. Afterwards, anesthesia wasmaintained by sevoflurane 1.5 vol% supplemented byO

2/N2O

and application of 0.05mg/kg piritramid if needed. Duringthe initial period of surgery, hemodynamic and metabolicparameters were within normal limits with end-tidal carbondioxide values between 38 and 39mmHg. Suddenly, after290min a slightly increase of heart rate from 60 bpm to80 bpm and a rise in systolic blood pressure from 120mmHgto 135mmHg were noticed. Furthermore, end-tidal carbondioxide concentration rapidly increased from 39mmHg to85mmHg within 5min after the onset of sinus tachycardia.Simultaneously, oxygen saturation decreased from 98% to93%. Unfortunately, there was no monitoring of body tem-perature, but the attending anesthesiologist observed anddocumented warming of head and chest during this episode.After MH was suspected, the anesthesiologist immediatelystopped sevoflurane and hyperventilated the patient with100% oxygen (25 L/min). In addition, 240mg dantrolene wasapplied twice and anesthesia was continued intravenouslyby infusion of 5mg/kg/h propofol and repeated fentanylapplications. After these interventions, hemodynamic andmetabolic parameters were stabilized within 10min.The sur-gical procedure was stopped, and the patient was transferredto the intensive care unit (ICU) in stable conditions.

Laboratory analyses performed after admission to theICU detected a significant rhabdomyolysis with crea-tine kinase levels about 20.000U/L and a hyperkalemia(6.4mmol/L). Further laboratory data were unremarkable.Interestingly, blood gas analysis drawn one hour after theMH suspected event did not show signs of metabolic orrespiratory acidosis. Four hours after the admission, thepatient was extubated without neurological deficits.

3. Diagnostic Findings

Due to the suspected MH event, the patient was informedabout the possible risk of MH susceptibility and a diagnosticworkup was recommended. Hence, after written and oralinformed consent of the patient, we decided to performthe recently developed minimal-invasive metabolic test threedays after the suspected MH episode. In brief, after regionalanesthesia of the skin, two microdialysis probes with asemipermeable membrane for measurement of interstitialmetabolites were inserted into the lateral vastus muscleand perfused with 1 𝜇L/min Ringer’s solution. 15min afterequilibration either a single bolus of 200𝜇L halothane 4 vol%dissolved in soy bean oil or 200𝜇L caffeine 80mM wasinjected into the muscular tissue. Dialysate samples werecollected after 15-minute intervals, and lactate concentra-tion was measured spectrophotometrically. If lactate values

exceeded a threshold of 2.8mM after halothane or 1.6mMafter caffeine, which had been defined by a previous set oftests, MH susceptibility was assumed [4]. Prior to halothaneor caffeine application, the baseline lactate levels did not sig-nificantly differ between both microdialysis probes (0.4mMversus 0.8mM). After halothane injection the lactate valuessignificantly increased to a maximum of 3.7mM. Similarly,caffeine induced a significant increase of lactate to 3.1mM(Table 1).

Even though MH susceptibility had been confirmed bythis metabolic test, the patient decided to undergo furtherdiagnostic testing due to personal reasons. Due to theMH suspected course of the described case and to avoidinvasive IVCT, we determined to screen the hotspots of theryanodine receptor subtype 1 gene forMH related alterations.Unfortunately, genetic analysis did not detect MH associatedmutations. Hence, twelve weeks after theMH suspected eventan open muscle biopsy and IVCT according to publishedguidelines of the European MH Group were performed atour lab [3]. In few words, 2.5 g muscle tissue was excised ofthe left vastus lateral muscle after femoral nerve block. Singlemuscle bundles weremounted in a tissue bath and exposed toincremental concentrations of caffeine (0.5; 1; 1.5; 2; 3; 4; and32mM) or halothane (0.11; 0.22; 0.44; and 0.66mM) at 3minintervals. Since significant contractures ≥ 2mN occurred atthe defined threshold concentrations of caffeine 2mM andhalothane 0.44mM, the MH-susceptibility of the patient wasconfirmed (Table 2).

4. Discussion

Malignant hyperthermia is a rare but life-threatening com-plication of general anesthesia usually triggered by volatileanesthetics and/or succinylcholine in susceptible patients.While genetic frequency of MH predisposition is stated tobe 1 : 2.000, the prevalence of MH-episodes varies regionallybetween 1 : 10.000 and 1 : 220.000 [5].

Nowadays, due to continuous progress in anesthesia, itseems that the incidence of fulminant MH crisis decreases.Since the potent MH trigger halothane is no longer usedin clinical routine in industrialized countries, the presentlyutilized inhalation anesthetics appear to delay the onsetof MH or lead to abortive MH reactions with alleviatedsymptoms. For instance, Hopkins and colleagues reportedthat the onset of MH was significantly faster after halothaneexposure (median: 20min, range: 5–45min) compared tosevoflurane (median: 60min, range: 10–210min) [6]. Hence,the intraoperative course in the presented case with devel-opment of MH signs 290min after induction of generalanesthesia seems consistent with these findings. However, insome cases application of sevoflurane inducesMH symptomswithin few minutes [7].

In addition, anesthesiologistsmust be aware that previousuneventful anesthesia does not excludeMH susceptibility [8].On average, susceptible patients undergo three uneventfulanesthesias until the first MH episode occurs [5]. In thiscontext, it is not surprising that the presented patient reportedtwo unremarkable anesthesias in the past. The underlying

Case Reports in Anesthesiology 3

Table 1: Local lactate increase following interstitial application of 200𝜇L caffeine 80mM and 200 𝜇L halothane 4 vol%.

Time 0min 15min 30min 45min 60min 75minCaffeine 80mM 0.4mM 0.6mM 0.7mM 2.7mM 3.1mM 2.7mMHalothane 4 vol% 0.8mM 0.7mM 0.9mM 2.1mM 3.7mM 2.8mM0min: baseline lactate levels; 15min: time point of caffeine or halothane injection.

Table 2: In vitro contracture test results. A contracture ≥ 2mN at the defined threshold concentrations of caffeine 2mM and halothane0.44mM confirmed MH susceptibility.

Caffeine Predrug 0,5mM 1mM 1,5mM 2mM 3mM 4mM 32mMTest 1 14.0mN 13.5mN 15.6mN 19.6mN 25.6mN 29.1mN 29.1mN 144mNTest 2 12.7mN 12.2mN 13.0mN 17.8mN 24.7mN 35.7mN 32.2mN 209mNHalothane Predrug 0,11mM 0,22mM 0,44mM 0,66mMTest 1 11.6mN 23.0mN 35.1mN 32.1mN 26.5mNTest 2 19.1mN 20.9mN 28.1mN 29.5mN 26.8mN

pathomechanism why some patients develop MH duringthe first exposition to triggering agents while others do notstill remains unclear. A possible explanation might be thepresence of an individual compensation mechanism at acellular level loweringmyoplasmic calcium concentrations inthese patients.

Based on these observations, attending anesthesiologistsmust keep in mind that MH may occur at any time duringgeneral anesthesia and prior unremarkable anesthesias, arenot a prove for the absence of MH susceptibility.

In case of a suspected MH, application of trigger agentsmust be discontinued immediately and causal therapy bydantrolene infusion should be initiated to avoid serious harmto the patient [9]. The mode of action of dantrolene is basedon inhibition of the sarcoplasmic calcium release duringan MH episode without increasing sarcoplasmic calciumreuptake [10]. The return of metabolic parameters to normalvalues reflects the therapeutic success of MH treatment,comparable to the absent of metabolic or respiratory acidosisin the presented case.

Due to the possible risk in case of future anesthesia,patients should be referred to a MH-center to initiate furtherdiagnostics after surviving a suspected MH event. In thereported case, the authors decided to apply a novel minimal-invasive metabolic test with intramuscular halothane andcaffeine injection to screen for MH susceptibility. Basedon the metabolic alterations in the course of an MHepisode, measurement of interstitial lactate concentrationwas assumed as a suitable method to detect MH in affectedpatients. The measured increase of local lactate concentra-tions following halothane and caffeine application clearlyindicated the diagnosis “MHS” in our patient. In contrastto the IVCT, the metabolic test is less invasive; since theinduced metabolic reactions are limited to an area < 10mmaround the inserted microdialysis probes and due to theexpected dilutional effects of the administered drugs in thetissue, serious systemic, or local adverse effects are unlikely[11]. Furthermore, previous histological examination of ratmuscular tissue after application of caffeine 80mM revealedonly unspecific morphological changes [12].

AlthoughMH susceptibility was proven by the metabolictest, the patient decided to undergo further diagnostic testing.Due to the clinical course of the reported MH reaction andin contrast to the diagnostic guidelines of the EuropeanMH Group, we decided to perform genetic screening atfirst. Unfortunately, no mutation of the ryanodine receptorsubtype 1 could be detected in the patient. Hence, IVCT wascarried out eight weeks after the suspicious event, since theabsence of a mutation does not reliably exclude MH [13].

In summary, the authors present a case of a delayedsevoflurane-induced MH in a 21-year-old male patient, whowas sufficiently treated by dantrolene and discontinuationof trigger agent application. After surviving an MH episodediagnostic procedures are indicted to increase patient safety.In the presented case, the use of a novel minimal-invasivemetabolic test with intramuscular application of MH trigger-ing agents such as halothane and caffeine successfully provedMH susceptibility and hence might avoid invasive in vitrocontracture testing in selected cases.

Conflict of Interests

The authors declare that they have no competing interests.

Acknowledgments

The publication of this investigation was funded by theGerman Research Foundation (DFG) and the Universityof Wuerzburg in the funding programme Open AccessPublishing.

References

[1] F. Schuster and C. R. Muller-Reible, “Malignant hyperthermiadiagnostics, treatment and anaesthetic management,” Anas-thesiologie Intensivmedizin Notfallmedizin Schmerztherapie, vol.44, no. 11-12, pp. 758–763, 2009 (German).

[2] T. Girard, S. Treves, E. Voronkov, M. Siegemund, and A.Urwyler, “Molecular genetic testing for malignant hyperther-mia susceptibility,”Anesthesiology, vol. 100, no. 5, pp. 1076–1080,2004.

4 Case Reports in Anesthesiology

[3] F. R. Ellis, P. J. Halsall, and H. Ording, “A protocol for theinvestigation of malignant hyperpyrexia (MH) susceptibility.The European malignant hyperpyrexia group,” British Journalof Anaesthesia, vol. 56, no. 11, pp. 1267–1269, 1984.

[4] F. Schuster, T. Metterlein, S. Negele et al., “An in-vivo metabolictest for detecting malignant hyperthermia susceptibility inhumans: a pilot study,” Anesthesia and Analgesia, vol. 107, no.3, pp. 909–914, 2008.

[5] O. Bandschapp and T. Girard, “Malignant hyperthermia,” SwissMedical Weekly, vol. 142, no. 7, Article ID w13652, 2012.

[6] P. M. Hopkins, “Malignant hyperthermia: pharmacology oftriggering,” British Journal of Anaesthesia, vol. 107, no. 1, pp. 48–56, 2011.

[7] Y. S. Lee, W. Y. Kim, S. H. Lee et al., “A case of malignanthyperthermia during anesthesia induction with sevoflurane,”Korean Journal of Anesthesiology, vol. 59, pp. S6–S8, 2010.

[8] H. Adam, U. Gottschaldt, N. C. Pausch, H. Ruffert, and K. M.Sipli, “Fulminant MH crisis during the ninth general anaes-thesia,” Anasthesiologie, Intensivmedizin, Notfallmedizin undSchmerztherapie, vol. 42, no. 10, pp. 692–699, 2007 (German).

[9] K. P. E. Glahn, F. R. Ellis, P. J. Halsall et al., “Recognizing andmanaging amalignant hyperthermia crisis. Guidelines from theEuropean Malignant Hyperthermia Group,” British Journal ofAnaesthesia, vol. 105, no. 4, pp. 417–420, 2010.

[10] T. Krause, M. U. Gerbershagen, M. Fiege, R. Weißhorn, and F.Wappler, “Dantrolene—a review of its pharmacology, therapeu-tic use and new developments,” Anaesthesia, vol. 59, no. 4, pp.364–373, 2004.

[11] F. Schuster, H. Scholl, M. Hager, R. Muller, N. Roewer, andM. Anetseder, “The dose-response relationship and regionaldistribution of lactate after intramuscular injection of halothaneand caffeine inmalignant hyperthermia-susceptible pigs,”Anes-thesia and Analgesia, vol. 102, no. 2, pp. 468–472, 2006.

[12] F. Schuster, P. Tas, R. Muller, N. Roewer, and M. Anetseder,“Pharmacologic modulation of skeletal muscle metabolism:a microdialysis study,” Basic and Clinical Pharmacology andToxicology, vol. 98, no. 4, pp. 372–376, 2006.

[13] A. Urwyler, T. Deufel, T. McCarthy, and S. West, “Guidelinesfor molecular genetic detection of susceptibility to malignanthyperthermia,” British Journal of Anaesthesia, vol. 86, no. 2, pp.283–287, 2001.

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