Malignant Hyperthermia - Rishp

Malignant HyperthermiaMatthew AlcuskyPharmD, MS StudentUniversity of Rhode IslandJuly, 2013

Financial DisclosureI have no financial obligations to disclose.

Outline Introduce malignant hyperthermia including itscauses and implications Describe the underlying pathophysiology Detail the clinical presentation of MH Summarize the necessary pharmacological andnon-pharmacological treatment of MH Highlight necessary considerations with the use ofdantrolene Discuss recrudescence

Malignant Hyperthermia A life threatening reaction that is most oftentriggered by the use of inhalational anesthetics Estimated incidence of 1 in 5,000 to 1 in100,000 anesthesia inductions Early recognition and treatment is essential inreducing morbidity and mortality Screening patients for past anesthesia historyand family history, as well as conductingtesting on at risk individuals is necessary toreduce MH occurrenceRosenberg H, Davis M, James D, Pollock N, Stowell K. Malignanthyperthermia. Orphanet J Rare Dis. 2007 Apr 24;2:21. Review.

Drugs Triggering Malignant Hyperthermia neSevoflurane Succinylcholineonly non-inhalationalanesthetic that triggersMH Nitrous Oxide- onlyinhalational anestheticthat does not causeMHHopkins PM. Malignant hyperthermia: pharmacology of triggering. Br JAnaesth. 2011 Jul;107(1):48-56. doi: 10.1093/bja/aer132. Epub 2011May 30. Review.

Pathophysiology MH partially attributed to a dominant mutation inthe ryanodine receptror 1 (RYR1)– Ryanodine receptors are activated by elevatedCa2 levels, known as store overload inducedcalcium release (SOICR)– Mutant receptors are activated by lower Ca2 levels– Volatile anesthetics further lower the SOICRthresholdMacLennan DH, Chen SR. Store overload-induced Ca2mutations release as a triggering mechanism for CPVT and MH episodes causedby in RYR and CASQ genes. J Physiol. 2009 Jul 1;587

Pathophysiology In MH, the Ca2 level repeatedly exceeds thelowered SOICR threshold, increasing cytosolCa2 concentrations– Increased muscle contracture,hypermetabolism– ATP hydrolysis by myosin causes hyperthermia Dantrolene is a RYR1 receptor antagonist, inhibitsSOICRMacLennan DH, Chen SR. Store overload-induced Ca2mutations release as a triggering mechanism for CPVT and MH episodescaused by in RYR and CASQ genes. J Physiol. 2009 Jul 1;587

Testing for MHCaffeine HalothaneContracture Test Gold standard Requires muscle biopsy,invasive False negativesextremely rare 80% specific, 20% falsepositivesRYR Genetic Testing At least 29 identifiedcausative mutations inRYR Presence of any isdiagnostic for MH Absence of mutation,must complete musclebiopsyMHAUS Guidelines: Testing for Malignant HyperthermiaSusceptibility. Malignant Hyperthermia Association of the UnitedStates. Web. MHAUS.org .

Non-Trigger Anesthetic Agents Thiopental pe localanesthetics Nitrous oxide,ketamine Prophylaxis with IVdantrolene is notnecessary if thesesafe agents are usedin patients with ahistory of MHRosenberg H, Davis M, James D, Pollock N, Stowell K. Malignanthyperthermia. Orphanet J Rare Dis. 2007 Apr 24;2:21. Review.

Malignant Hyperthermia:Clinical PresentationEarly SignsLater SignsMetabolic Tachypnea, elevated CO2production and increased O2consumption Combination metabolic andrespiratory acidosis Profuse sweating and mottling ofskinCardiovascular Tachycardia ArrythmiasMuscle Masseter spasm if succinylcholinehas been given Generalized muscle rigidity Rapid increase in coretemperature (1-2 degrees Celsiusevery 5 min)RhabdomyolysisGrossly elevated blood CPK andmyoglobin levelsDarkly colored urineHyperkalemiaSevere cardiac arrythmiasDisseminated intravascularcoagulationGlahn KP, Ellis FR, Halsall PJ, Müller CR, Snoeck MM, Urwyler A, WapplerF;European Malignant Hyperthermia Group. Recognizing and managing amalignanthyperthermia crisis: guidelines from the European MalignantHyperthermia Group.Br J Anaesth. 2010 Oct;105(4):417-20.

Differential Diagnosis Insufficient anesthesiaand/or analgesia Infection or septicemia Insufficient ventilation,anesthetic machinemalfunction Anaphylactic reaction Pheochromocytoma Thyroid Crisis Cerebral Ischemia Neuromusculardisorders Elevated end tidal CO2due to laparoscopicsurgery Use of drugs of abuse Malignant neurolepticsyndromeGlahn KP, Ellis FR, Halsall PJ, Müller CR, Snoeck MM, Urwyler A,Wappler F;European Malignant Hyperthermia Group. Recognizing andmanaging a malignanthyperthermia crisis: guidelines from the EuropeanMalignant Hyperthermia Group.Br J Anaesth. 2010 Oct;105(4):417-20.

Variable Onset ofMalignant Hyperthermia The inhalationalanesthetics arecapable of initiating aMH reaction withinminutes of exposureto hours after theinitial exposureHopkins PM. Malignant hyperthermia: pharmacology of triggering. BrJ Anaesth. 2011 Jul;107(1):48-56. doi: 10.1093/bja/aer132. Epub2011 May 30. Review.

Post-Operative Malignant Hyperthermia Cases of MH can present in the postoperativeperiod, but this is uncommon An analysis of the North American MHRegistry detected 10 of 528 suspected casesoccurring post-operatively Of these ten cases the longest latency timewas 40 minutes from completion of surgery In all 10 cases hyperthermia was not the initialpresenting signLitman RS, Flood CD, Kaplan RF, Kim YL, Tobin JR. Postoperativemalignant hyperthermia: an analysis of cases from the North AmericanMalignant Hyperthermia Registry. Anesthesiology. 2008 Nov;109

Treatment of AcuteMalignant Hyperthermia Begin treatment as soon as a MH crisis issuspected Immediately stop administration of triggeragents and change to non-trigger anesthesia Inform surgeon and terminate/postponesurgery Hyperventilate with 100% O2 using 2-3 timesthe normal minute volume Administer dantroleneMalignant Hyperthermia Association of the United States: EmergencyTherapy for Malignant Hyperthermia. Malignant HyperthermiaAssociation of the United States. Sherburne, NY. 2008.

Dantrolene: Dosing Dose of 2.5 mg/kg rapid IV push through largebore IV, no less than 1 mg/kg should be given Higher doses are often necessary and theinitial dose should be repeated until signs ofMH reversal The maximum dose is 10 mg/kg, althoughlarger doses up to 30mg/kg may be needed No dosage adjustment in renal failure, cautionin active hepatic diseaseMalignant Hyperthermia Association of the United States: EmergencyTherapy for Malignant Hyperthermia. Malignant HyperthermiaAssociation of the United States. Sherburne, NY. 2008.

Dantrolene: Preparation 20 mg vials, requiringdilution with at least 60mLs of sterilepreservative free water Incompatible with NS,D5W and other acidicsolutionsRevonto [Prescribing Information] Greenville, NC. DSMPharmaceuticals; 2009.

Dantrolene: Considerations Protect from light Vesicant!!! Storage is roomtemperature 6 hours expiration,prepare immediatelybefore use Do not prepareinfusion in glass(precipitates), usesterile plastic bags Prepare using PFsterile water, may addmultiple vials to bag ifneeded for infusionRevonto [Prescribing Information] Greenville, NC. DSMPharmaceuticals; 2009.

Treatment of AcuteMalignant Hyperthermia Administer bicarbonate for metabolic acidosis, 1-2mEq/kg if no blood gas values are available If temperature is 39 C, cool the patient applying iceto surface, lavage open cavities, infuse cold NS IV.Cease cooling once temperature is below 38 C Treat dysarrhythmias by addressing acidosis andhyperkalemia, use standard drug therapy except donot use calcium channel blockers in conjunctionwith dantrolene (cardiac arrest, hyperkalemia mayensue)Malignant Hyperthermia Association of the United States: EmergencyTherapy for Malignant Hyperthermia. Malignant HyperthermiaAssociation of the United States. Sherburne, NY. 2008.

Treatment of AcuteMalignant Hyperthermia Monitor: ETCO2, electrolytes, blood gases,CK, core temperature, urine output and color,coagulation studies A rise in CPK and/or K or a fall in urine outputto less than 0.5 mL/kg/hr requires induction ofdiuresis at a rate 1 ml/kg/hr Bicarbonate should also be given to alkalizethe urine and prevent myoglobinuria inducedrenal failureMalignant Hyperthermia Association of the United States: EmergencyTherapy for Malignant Hyperthermia. Malignant HyperthermiaAssociation of the United States. Sherburne, NY. 2008.

Management of Post-Acute Phaseof Malignant Hyperthermia Due to risk of recurrence, observe patient inICU for at least 24 hours Give dantrolene 1 mg/kg q 4-6 hours, or0.25 mg/kg/hr by infusion for at least 24hours. Further doses may be indicated. Continue to hydrate, alkalinize and givediuretics to prevent myoglobin precipitationin the renal tubulesMalignant Hyperthermia Association of the United States:Emergency Therapy for Malignant Hyperthermia. MalignantHyperthermia Association of the United States. Sherburne, NY.2008.

Recrudescence ofMalignant Hyperthermia The reoccurrence of signs and symptoms ofMH after completion of the initial episode One study of 308 reports of MH found 20%of cases recrudesced Mean time to recrudescence found to be 13hours, with a range of 2.5-72 hours 80% occurred within 16 hoursBurkman JM, Posner KL, Domino KB. Analysis of the clinicalvariables associated with recrudescence after malignanthyperthermia reactions. Anesthesiology. 2007 May;106(5):901-6

Factors Associated with Recrudescence

Malignant Hyperthermia Association of theUnited States (MHAUS) The goal of MHAUS is to promote optimumcare and scientific understanding ofMalignant Hyperthemia and relateddisorders Hotline available 24/7 : 1 (800) 644-9737 Office number for non-emergencies1-800-986-4287 www.mhaus.org"Contact - MHAUS." MHAUS. N.p., n.d. Web. 09 Jan. 2013.

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malignant hyperthermia: an analysis of cases from the North American Malignant Hyperthermia Registry. Anesthesiology. 2008 Nov;109. Treatment of Acute Malignant Hyperthermia Begin treatment as soon as a MH crisis is suspected . PowerPoint Presentation Author: Cindy Sabato