**4.6.2 Postoperatively**

1. **Observation and monitoring:** as much as 25% of patients with MH will present a recrudescence of the syndrome several hours after its initial control133. As a result, authors recommend observation in Intensive Care Units for 24-72 hours postoperatively32. Samples for blood gases, electrolytes, creatine kinase, coagulation profile and blood and urine myoglobin should be collected every 6-12 hours76,131. Habitually, immediate postoperative tests show evidence of hepatic injury (increased liver enzymes) and coagulopathy. Such profile mainly results of the ischemic injury to the graft and is self-limited when the graft begins to work. When MH occurs during liver transplantation, it is not clear if dantrolene can make these abnormalities more severe nor if it can contribute to graft dysfunction. Irrespective of these uncertainties, the postoperative management is similar: graft function should be closely followed, dantrolene doses should be minimized to control symptoms and supportive treatment should be instituted. Liver biopsy has a limited value in this scenario, since the histopathological patterns of dantrolene hepatotoxicity are comparable to the ones usually observed in liver transplantation and the treatment choice does not change. If severe graft dysfunction ensues despite minimal use of dantrolene, retransplantation should be considered.


#### **4.7 Perioperative management of liver transplantation candidates susceptible to malignant hyperthermia**

Patients at risk for MH may be identified based on data collected on preoperative evaluation, like clinical symptoms, presence of muscular disease and personal and family history of previous anesthetics (see preoperative evaluation section). CHCT is indicated in patients preoperatively deemed at risk for MH, postoperatively in patients with a typical MH crisis during liver transplantation and the relatives of the patients with a positive CHCT. Anesthesia for liver transplantation in patients with some risk factors for MH must be free of succinylcholine and halogenated inhalational agents. Additionally, dantrolene must be immediately available in the operating room. Besides this, some precautions have to be taken with the anesthesia machine. Avoidance of succinylcholine is an easy to deal issue. However, avoidance of vapor anesthetics is more challenging because anesthesia machines retain anesthetic vapors long after discontinuation. Instructions for clearing residual anesthetic gases include removal or disabling of vaporizers, flushing the machine with a fresh gas flow rate more than 10 L.min-1 using the ventilator for at least 20 min, and replacement of the fresh gas outlet hose, carbon dioxide absorbent, and anesthesia circuit. The goal is to decrease the residual anesthetic vapor concentration within the breathing circuit. These precautions represent the standard of care for the management of MHsusceptible patients. These instructions for purging anesthetic gases were derived from studies designed to optimize gas clearance in older generation machines. Modern anesthesia workstations are more complex and contain more gas absorbing materials. The current guidelines are inadequate to prepare newer generation workstations, which require more time for purging anesthetic gases, autoclaving or replacement of parts, and modifications to the gas delivery system. As a result, institutions must develop protocols that individualize their own new generation anesthesia machines136.

#### **5. Conclusion**

410 Liver Transplantation – Basic Issues

2. **Postoperative dantrolene therapy:** in liver transplant patients, after initial control of MH, dantrolene should be reserved for recrudescences (to minimize liver toxicity). The

3. **Mechanical ventilation weaning:** one of the most reported side-effects of dantrolene is muscle weakness, which may persist up to 24-48h after the last dose. Although some authors objectively demonstrated strength reduction with clinically used doses of dantrolene60, no studies of pulmonary function have been performed in patients after MH crises, dantrolene therapy and intensive care management. As a result, careful attention with respiratory function is essential in these patients, especially during weaning of mechanical ventilation or in patients with borderline respiratory function,

4. **Refer patient and family to MH Testing Center for contracture or DNA testing**134-135**.** 

Patients at risk for MH may be identified based on data collected on preoperative evaluation, like clinical symptoms, presence of muscular disease and personal and family history of previous anesthetics (see preoperative evaluation section). CHCT is indicated in patients preoperatively deemed at risk for MH, postoperatively in patients with a typical MH crisis during liver transplantation and the relatives of the patients with a positive CHCT. Anesthesia for liver transplantation in patients with some risk factors for MH must be free of succinylcholine and halogenated inhalational agents. Additionally, dantrolene must be immediately available in the operating room. Besides this, some precautions have to be taken with the anesthesia machine. Avoidance of succinylcholine is an easy to deal issue. However, avoidance of vapor anesthetics is more challenging because anesthesia machines retain anesthetic vapors long after discontinuation. Instructions for clearing residual anesthetic gases include removal or disabling of vaporizers, flushing the machine with a fresh gas flow rate more than 10 L.min-1 using the ventilator for at least 20 min, and replacement of the fresh gas outlet hose, carbon dioxide absorbent, and anesthesia circuit. The goal is to decrease the residual anesthetic vapor concentration within the breathing circuit. These precautions represent the standard of care for the management of MHsusceptible patients. These instructions for purging anesthetic gases were derived from studies designed to optimize gas clearance in older generation machines. Modern anesthesia workstations are more complex and contain more gas absorbing materials. The current guidelines are inadequate to prepare newer generation workstations, which require more time for purging anesthetic gases, autoclaving or replacement of parts, and modifications to the gas delivery system. As a result, institutions must develop protocols that individualize

**4.7 Perioperative management of liver transplantation candidates susceptible to** 

dosage regimen is recommended 1 mg.kg-1 every eight hours for 36 hours.

should be considered.

**malignant hyperthermia** 

like those neuromuscular disorders.

their own new generation anesthesia machines136.

severe nor if it can contribute to graft dysfunction. Irrespective of these uncertainties, the postoperative management is similar: graft function should be closely followed, dantrolene doses should be minimized to control symptoms and supportive treatment should be instituted. Liver biopsy has a limited value in this scenario, since the histopathological patterns of dantrolene hepatotoxicity are comparable to the ones usually observed in liver transplantation and the treatment choice does not change. If severe graft dysfunction ensues despite minimal use of dantrolene, retransplantation

Malignant hyperthermia is an inherited pharmacogenetic disorder of the skeletal muscle. It can be triggered by any halogenated inhalational agent or by succinylcholine. A mutation on the Ryanodine Receptor (RyR) may be the main causative factor, resulting in a defect of intracellular Ca2+ homeostasis. Besides muscle tissue, RyR's are present in hepatocytes. Dantrolene is the only available treatment for MH and is a unique muscle relaxant that interferes with excitation-contraction coupling by reducing the concentration of myoplasmic calcium. This drug seems to be hepatotoxic, although the exact mechanism is unclear. Preoperative evaluation of liver transplant candidates by anesthesiologist is critical to identify patients at risk or susceptible to MH. There is a significant overlap between the MH clinical manifestations and the usual physiological behavior during liver transplantation, and early clinical diagnosis is a challenge. Sustained and progressive increases in EtCO2, despite checking and solving other possible causes, should raise suspicion of MH. Treatment should be aimed towards discontinuing triggering agents, administering the antidote and instituting supportive measures. Due to its possible hepatotoxicity, dantrolene should be used in doses lower than usual and for shorter periods of time.

#### **6. Acknowledgements**

The authors would like to thank the bibliographical support kindly and patiently provided by Dr. Amir Mohamed El Shahawy, M.D.

#### **7. References**


[13] Williams CH, Houchins C, Shanklin MD. Pigs susceptible to energy metabolism in the fulminant hyperthermia stress syndrome. *Br Med J*. 1975; 3(5980): 411-3. [14] Benson BE. Dantrolene, in *Critical Care Toxicology: Diagnosis and Management of the* 

[15] Harrison GG: Control of the malignant hyperpyrexic syndrome in MHS swine by

[16] Dantrolene sodium approved for malignant hyperthermia. *FDA Drug Bull.* 1979; 9(5):

[17] Kolb ME, Horne ML, Martz R. Dantrolene in human malignant hyperthermia.

[18] Hirshey Dirksen SJ, Larach MG, Rosenberg H, et al. Future Directions in Malignant

[19] Heiman-Patterson TD, Rosenberg H, Fletcher JE, Tahmoush AJ. Halothane-caffeine contracture testing in neuromuscular diseases. *Muscle Nerve*. 1988; 11(5): 453-7. [20] Utili R, Boitnott JK, Zimmerman HJ. Dantrolene-associated hepatic injury: incidence

[21] Loke J, MacLennan DH. Malignant hyperthermia and central core disease: disorders of

[22] Abraham RB, Adnet P, Glauber V, et al. Malignant hyperthermia. *Postgrad Med J*. 1998;

[23] Hogan K. The anesthetic myopathies and malignant hyperthermia. *Curr Opin Neurol*.

[24] Monnier N, Krivosic-Horber R, Payen JF, et al. Presence of two different genetic traits in

[25] Britt BA, Endrenyi L, Peters PL, et al. Screening of malignant hyperthermia susceptible

[26] Sumitani M, Uchida K, Yasunaga H, Horiguchi H, Kusakabe Y, Matsuda S, Yamada Y.

[27] Brady JE, Sun LS, Rosenberg H, Li G. Prevalence of malignant hyperthermia due to anesthesia in New York State, 2001-2005. *Anesth Analg*. 2009; 109(4): 1162-6. [28] Ording H.Incidence of malignant hyperthermia in Denmark. *Anesth Analg*. 1985; 64(7):

[29] Pollock AN, Langton EE, Couchman K, Stowell KM, Waddington M. Suspected

[30] Simões CM, Koishi GN, Rozatti M, Amaral JL. Are we prepared to diagnose and manage malignant hyperthermia? *Rev Bras Anestesiol.* 2003; 53(2): 248-57. [31] Larach MG, Brandom BW, Allen GC, Gronert GA, Lehman EB. Cardiac arrests and

malignant hyperthermia families: implication for genetic analysis, diagnosis, and incidence of malignant hyperthermia susceptibility. *Anesthesiology*. 2002; 97(5):

families by creatine phosphokinase measurement and other clinical investigations.

Prevalence of malignant hyperthermia and relationship with anesthetics in Japan: data from the diagnosis procedure combination database. *Anesthesiology*. 2011;

malignant hyperthermia reactions in New Zealand. *Anaesth Intensive Care*. 2002;

deaths associated with malignant hyperthermia in north america from 1987 to 2006:

Hyperthermia Research and Patient Care. *Anesth Analg*. 2011 Jun 27. [Epub ahead

dantrolene sodium. *Br J Anaesth*. 1975; 47: 62-65.

and character. *Gastroenterology*. 1977; 72:610.

*Can Anaest Soc J*. 1976; 23(3): 263–284.

Ca2+ release channels. *Am J Med.* 1998; 104: 470–486.

*Anesthesiology.* 1982; 56: 254-262.

2005: 1589-1594.

27.

of print]

74: 11–17.

1067–1074.

114(1): 84-90.

30(4): 453-61.

700-4.

1998; 11: 469–476.

*Critically Poisoned Patient*, Benson BE, Brent J et al (Eds). Mosby, Philadelphia, PA,

a report from the north american malignant hyperthermia registry of the malignant hyperthermia association of the United States. *Anesthesiology*. 2008;108(4): 603-11.


[50] Lee YS, Kim WY, Lee SH, Baek SM, Ok SJ, Kim JH, Park YC. A case of malignant

[51] Chen PL, Day YJ, Su BC, Lee PC, Chen CY. Delayed onset of sevoflurane-induced

[52] Bonciu M, de la Chapelle A, Delpech H, Depret T, Krivosic-Horber R, Aimé MR. Minor

[53] Wedel DJ, Gammel SA, Milde JH, Iaizzo PA. Delayed onset of malignant hyperthermia

[54] Wappler F, Fiege M. Is desflurane a "weak" trigger of malignant hyperthermia? *Anesth* 

[55] Hoenemann CW, Halene-Holtgraeve TB, Booke M, Hinder F, Daudel F, Reich A, Van

[56] Fernandes CR, Azevedo DM, Gomes JM, et al. Malignant hyperthermia in a liver transplant patient: a case report. *Transplant Proc*. 2007; 39(10): 3530-2. [57] Metterlein T, Schuster F, Kranke P, Hager M, Roewer N, Anetseder M. Magnesium does

[58] MacKenzie AE, Allen G, Lahey D, Crossan ML, Nolan K, Mettler G, Worton RG,

[59] Metterlein T, Hartung E, Schuster F, Roewer N, Anetseder M. Sevoflurane as a potential

[60] Flewellen EH, Nelson TE, Jones WP et al. Dantrolene dose response in awake man:

[61] Lerman J, McLeod ME, Strong HA. Pharmacokinetics of intravenous dantrolene in

[62] Lietman PS, Haslam RH, Walcher JR. Pharmacology of dantrolene sodium in children.

[63] Ellis KO, Wessels FL. Muscle relaxant properties of the identified metabolites of dantrolene. *Naunyn Schmiedebergs Arch Pharmacol*. 1978; 301: 237–240. [64] Dykes MH. Evaluation of a muscle relaxant: dantrolene sodium (Dantrium). *JAMA*.

[65] Morgan KG, Bryant SH. The mechanism of action of dantrolene sodium. *J Pharmacol Exp* 

[66] Yamaguchi N, Igami K, Kasai M. Kinetics of depolarization-induced calcium release from skeletal muscle triads *in vitro*. *J Biochem (Tokyo)*. 1997; 121: 432-439. [67] Coronado R, Morrissette J, Sukhareva M, Vaughan DM. Structure and function of

*Anesthesiol*. 2010; 59 Suppl: S6-8.

*Paediatr Anaesth*. 2007; 17(2): 180-2.

swine. *Anesthesiology*. 1993; 78(6): 1138-44.

*Analg*. 2003; 97(1): 295; author reply 295.

hyperthermia. *Anesth Analg*. 2011; 112(5): 1174-8.

2007; 45(3): 189-93.

*Analg*. 2003; 96(1): 165-7.

*Anesthesiology*. 1991; 75(1): 4-8.

children. *Anesthesiology*. 1989; 70: 625–9.

*Arch Phys Med Rehabil*. 1974; 55(8): 388-92.

ryanodine receptors. *Am J Phys*. 1994; 266: C1485–504.

275–80.

1975; 231: 862-4.

*Ther*. 1977; 201(1): 138-47.

hyperthermia during anesthesia induction with sevoflurane -A case report. *Korean J* 

juvenile malignant hyperthermia after second exposure. *Acta Anaesthesiol Taiwan*.

increase of endtidal CO2 during sevoflurane-induced malignant hyperthermia.

induced by isoflurane and desflurane compared with halothane in susceptible

Aken H. Delayed onset of malignant hyperthermia in desflurane anesthesia. *Anesth* 

not influence the clinical course of succinylcholine-induced malignant

MacLennan DH, Korneluk R. A comparison of the caffeine halothane muscle contracture test with the molecular genetic diagnosis of malignant hyperthermia.

replacement for halothane in diagnostic testing for malignant hyperthermia susceptibility: results of a preliminary study. *Minerva Anestesiol*. 2011; 77(8): 768-73.

Implications for management of malignant hyperthermia. *Anesthesiology* 1983; 39:


[86] Sorensen EM, Acosta D. Comparison of dantrolene sodium with erythromycin estolate using primary cultures of rat hepatocytes. *Drug Chem Toxicol*. 1985; 8: 219-37. [87] Inan S, Wei H. The cytoprotective effects of dantrolene: a ryanodine receptor antagonist.

[88] Ogburn R, Myers R, Burdick G. Hepatitis associated with dantrolene sodium. *Ann* 

[90] Wilkinson SP, Portmann B, Williams R. Hepatitis from dantrolene sodium. *Gut*. 1979;

[91] Abernathy CO, Utili R, Zimmerman HJ, Ezekiel M. The effects of dantrolene sodium on

[92] Fitzgibbons DC. Malignant hyperthermia following preoperative oral administration of

[93] Donegan JH, Danegan WL, Cohen EB. Massive hepatic necrosis associated with

[94] Lundia SR, Uden DL, Hanson RF. Dantrolene-associated hepatitis. *Drug Intell Clin* 

[95] Cornette M, Gillard C, Borlee-Hermans G. Hépatite toxique mortelle associée al'usage

[96] Shih TH, Chen KH, Pao YY, et al. Low-dose dantrolene is effective in treating

after liver transplantation: case report. *Transplant Proc*. 2010; 42(3): 858-60. [97] Della Rocca G, De Flaviis A, Costa MG, Chiarandini P, Pompei L, Venettoni S. Liver

[98] Claxton BA, Cross MH, Hopkins PM. No response to trigger agents in a malignant

[99] Iaizzo PA, Kehler CH, Carr RJ, Sessler DI, Belani KG. Prior hypothermia attenuates malignant hyperthermia in susceptible swine. *Anesth Analg*. 1996; 82: 803-9. [100] Kunst G, Graf BM, Schreiner R, Martin E, Fink RH. Differential effects of sevoflurane,

[101] Urwyler A, Deufel T, McCarthy T, West S. Guidelines for molecular genetic detection of susceptibility to malignant hyperthermia. *Br J Anaesth*. 2001; 86: 283-7. [102] Steadman RH. Anesthesia for liver transplant surgery. *Anesthesiol Clin North Am*. 2004;

[103] Liu H, Lee SS. Acute-on-chronic liver failure: the heart and systemic hemodynamics.

[104] Vincent JL, Gustot T. Sepsis and cirrhosis: many similarities. *Acta Gastroenterol Belg*.

[105] Liu LL, Niemann CU. Intraoperative management of liver transplant patients.

[106] Wu J, Zhu SM, He HL, Weng XC, Huang SQ, Chen YZ. Plasma propofol

concentrations during orthotopic liver transplantation. *Acta Anaesthesiol Scand.*

hyperthermia-susceptible patient. *Br J Anaesth*. 2002; 88: 870-3.

hyperthermia and hypercapnia, and seems not to affect recovery of the allograft

transplant quality and safety plan in anesthesia and intensive care medicine.

isoflurane, and halothane on Ca2+ release from the sarcoplasmic reticulum of

excretory function in the isolated perfused rat liver. *Toxicol Appl Pharmacol*. 1978;

[89] Schneider R, Mitchell D. Dantrolene hepatitis. *JAMA*. 1976; 235(15): 1590-1.

*Anesth Analg*. 2010; 111(6): 1400-10.

dantrolene. *Anesthesiology*. 1981; 54: 73-75.

*Transplant Proc*. 2010; 42(6): 2229-32.

dantrolene therapy. *Dig Dis Sci*. 1978; 23(Suppl.): 48-52.

du dantrolene. *Acta Neurol Belg*. 1980; 80: 336-347.

skeletal muscle. *Anesthesiology*. 1999; 91: 179-86.

*Curr Opin Crit Care*. 2011; 17(2): 190-4.

*Transplant Rev (Orlando)*. 2011; 25(3): 124-9.

*Intern Med*. 84: 53-54.

*Pharm*. 1977; 11: 278-280.

20: 33-36.

44(3): 441-52.

22(4): 687-711.

2010; 73(4): 472-8.

2005; 49(6): 804-10.


[123] Rosenberg H, Antognini JF, Muldoon S. Testing for malignant hyperthermia.

[124] Krivosic-Horber R. Malignant hyperthermia. Treatment of the acute episode. *Acta* 

[125] Krause T, Gerbershagen MU, Fiege M, Weisshorn R, Wappler F. Dantrolene: a review

[126] Rosenberg H, Davis M, James D, Pollock N, Stowell K. Malignant hyperthermia.

[127] Brandom BW. Recognition and treatment of Malignant Hyperthermia. ASA Refresher

[129] Baker KR, Landriscina D, Kartchner H, Mirkes DM. The Icarus effect: the influence of diluent warming on dantrolene sodium mixing time. *AANA J*. 2007; 75: 101-6. [130] Clavien PA, Harvey PR, Strasberg SM: Preservation and reperfusion injuries in liver

[131] Plattner O, Kurz A, Sessler DI, Ikeda T, Christensen R, Marder D, et al. Efficacy of

[132] Malignant Hyperthermia Association of the United States (2011). Medical

[133] Saltzman LS, Kates RA, Corke BC, Norfleet EA, Health KR. Hyperkalemia and

[134] Hopkins PM. Recrudescence of malignant hyperthermia. *Anesthesiology*. 2007; 106: 893-

[135] Hopkins PM. Malignant hyperthermia: advances in clinical management and

[136] Kim TW, Nemergut ME. Preparation of modern anesthesia workstations for malignant

[128] Gronert GA. Malignant hyperthermia. *Anesthesiology*. 1980; 53(5): 395–423.

intraoperative cooling methods. *Anesthesiology*. 1997; 87: 1089-95.

of its pharmacology, therapeutic use and new developments. *Anaesthesia*. 2004; 59:

allografts: an overview and synthesis of current studies. *Transplantation*. 1992; 53:

*http://medical.mhaus.org/index.cfm/fuseaction/Content.Display/PagePK/MedicalFAQs.cfm*

cardiovascular collapse after verapamil and dantrolene administration in the

hyperthermia-susceptible patients: a review of past and present practice.

*Anesthesiology*. 2002; 96: 232-7.

364-73.

957.

4.

(July 23, 2011)

*Anaesthesiol Belg.* 1990 ; 41: 83-86.

*Orphanet J Rare Dis*. 2007; 2: 21-34.

Courses in *Anesthesiology*. 2005; 33: 23-9.

Professionals' FAQs. [Online]. Available:

swine. *Anesth Analg*. 1984; 63: 473-8.

diagnosis. *Br J Anaesth*. 2000; 85: 118-28.

*Anesthesiology*. 2011; 114(1): 205-12.
