**4.3 Suspected cases and confounding factors during liver transplantation**

MH syndrome exhibits a wide range of symptoms including tachycardia, progressive elevation of the exhaled CO2, arrhythmias, hyperthermia, profuse sweating, fever up to 40ºC, cyanosis, poor skin perfusion and blood pressure instability31. The only physical sign typical of MH is muscular rigidity, although it may be hard to detect due to the limited access for physical evaluation. MMR may be observed upon anesthetic induction and is predictive of the syndrome32-33.

However, tachycardia, arrhythmias, poor skin perfusion, blood pressure instability and other subtle manifestations of the initial phase of HM are commonly observed during liver transplantation, as it involves large volume paracentesis, manipulation of major vessels, massive bleeding and reperfusion syndrome116. Inadequate anesthetic depth and pyrogenic reaction can mimic some of those symptoms.

Most of liver transplant patients are maintained normothermic with the aid of forced warm air mattresses. After the reperfusion, the graft begins to produce heat by its exothermic metabolic reactions and the addition of this new source of heat may lead to hyperthermia. However this temperature rise only begins lately in the course of the surgery, usually is minimized by turning off the mattresses and rarely exceeds 39ºC. Another potential source of confusion in the diagnosis of MH is the use of defective equipment for patient heating (leading to overheating and sweating) or poorly calibrated temperature monitors.

Some situations can induce severe intraoperative Systemic Inflammatory Response Syndrome (SIRS) during liver transplantation, like bacteremia/sepsis, acute rejection and graft non-function. Although SIRS may show up with hyperthermia117, other MH symptoms like severe hypercapnia are not usually present in these cases.

Hypercapnia may have several causes during liver transplantation, like intrinsic pulmonary diseases, accumulation of lung secretions in the airway, lung compression by retractors, inappropriate mechanical ventilation, exhaustion of soda lime and faulty carbon dioxide monitoring. However, after checking and solving all these issues, the maintenance of a progressive rise on end-tidal carbon dioxide becomes a strong indicator of malignant hyperthermia.

To make diagnosis even problematic, most early laboratory manifestations of malignant hyperthermia, such as respiratory and lactic acidosis and hyperkalemia, are also commonly observed in anesthesia for liver transplantation. The reasons for respiratory acidosis were described above. Lactic acidosis frequently results from the combination of tissue hypoperfusion and decreased hepatic clearance of lactate during the anhepatic phase. Hyperkalemia during liver transplantation may have several reasons, like poor baseline renal function, large and rapid transfusion of red cells and high-potassium content of preservation solutions. Nonetheless, mixed venous oxygen saturation (SvO2) may have a lower value when MH is suspected. Due to severe increase in cellular oxygen consumption,

MH syndrome exhibits a wide range of symptoms including tachycardia, progressive elevation of the exhaled CO2, arrhythmias, hyperthermia, profuse sweating, fever up to 40ºC, cyanosis, poor skin perfusion and blood pressure instability31. The only physical sign typical of MH is muscular rigidity, although it may be hard to detect due to the limited access for physical evaluation. MMR may be observed upon anesthetic induction and is

However, tachycardia, arrhythmias, poor skin perfusion, blood pressure instability and other subtle manifestations of the initial phase of HM are commonly observed during liver transplantation, as it involves large volume paracentesis, manipulation of major vessels, massive bleeding and reperfusion syndrome116. Inadequate anesthetic depth and pyrogenic

Most of liver transplant patients are maintained normothermic with the aid of forced warm air mattresses. After the reperfusion, the graft begins to produce heat by its exothermic metabolic reactions and the addition of this new source of heat may lead to hyperthermia. However this temperature rise only begins lately in the course of the surgery, usually is minimized by turning off the mattresses and rarely exceeds 39ºC. Another potential source of confusion in the diagnosis of MH is the use of defective equipment for patient heating

Some situations can induce severe intraoperative Systemic Inflammatory Response Syndrome (SIRS) during liver transplantation, like bacteremia/sepsis, acute rejection and graft non-function. Although SIRS may show up with hyperthermia117, other MH symptoms

Hypercapnia may have several causes during liver transplantation, like intrinsic pulmonary diseases, accumulation of lung secretions in the airway, lung compression by retractors, inappropriate mechanical ventilation, exhaustion of soda lime and faulty carbon dioxide monitoring. However, after checking and solving all these issues, the maintenance of a progressive rise on end-tidal carbon dioxide becomes a strong indicator of malignant

To make diagnosis even problematic, most early laboratory manifestations of malignant hyperthermia, such as respiratory and lactic acidosis and hyperkalemia, are also commonly observed in anesthesia for liver transplantation. The reasons for respiratory acidosis were described above. Lactic acidosis frequently results from the combination of tissue hypoperfusion and decreased hepatic clearance of lactate during the anhepatic phase. Hyperkalemia during liver transplantation may have several reasons, like poor baseline renal function, large and rapid transfusion of red cells and high-potassium content of preservation solutions. Nonetheless, mixed venous oxygen saturation (SvO2) may have a lower value when MH is suspected. Due to severe increase in cellular oxygen consumption,

(leading to overheating and sweating) or poorly calibrated temperature monitors.

like severe hypercapnia are not usually present in these cases.

**4.3 Suspected cases and confounding factors during liver transplantation** 

drugs to administer to these patients115.

predictive of the syndrome32-33.

hyperthermia.

reaction can mimic some of those symptoms.

Local anesthetics, nondepolarizing muscle relaxants, barbiturates, benzodiazepines, droperidol, ketamine, nitrous oxide, opioids, propofol and vasoactive drugs are all safe the SvO2 of patients with MH is usually low. Such low values are not usually seen in liver transplantation, since cirrhotic patients generally have systemic shunts and a hyperdynamic circulation, yielding high values of SvO2118.

### **4.4 Intraoperative differential diagnosis**

Several disorders share similarities with MH and may be confused with the syndrome. Neuroleptic malignant syndrome is characterized by hyperthermia, acidosis, hyperkalemia and myoglobinuria following use of a wide variety of neuroleptics, especially haloperidol. Patients taking mono-amino-oxidase inhibitors who receive meperidine may present with hyperthermia, acidosis and an increase in creatine kinase concentration, what may become fatal. Other conditions that may resemble the MH situation include – but are not limited to – : iatrogenic overheating, thyroid storm in thyrotoxicosis, hypothalamic lesions, heat illness, pheochromocytoma, and intrathecal injection of high osmolar contrast agents, cocaine or ecstasy overdose, hypoxic encephalopathy and sudden cardiac arrest in a patient with occult myopathy119. None of these disorders, however, is frequent in liver transplant patients.

#### **4.5 Investigation of suspected cases**

Investigation of susceptibility should begin upon clinical suspicion during preoperative evaluation.

Creatine kinase (CPK) dosage during rest has been suggested as a component of a clinical grading scale to predict malignant hyperthermia susceptibility for patients with positive family history; increased resting values could suggest myopathy and MH susceptibility120. The use of this test is not recommended for the general population as it would yield an unacceptably high rate of false positive results. Cirrhotic patients habitually have reduced muscle mass and decreased exercise-tolerance, thus high CPK results in patients with positive family history are suggestive.

Caffeine-Halothane Contracture Test (CHCT) is considered the gold standard for the diagnosis of MH. This test, which uses a small piece of live muscle from biopsy, assesses the muscular contractility in response to increasing concentrations of halothane and caffeine exposure. It has a 97% sensitivity and 78% specificity121. Even in typical cases, CHCT is beneficial to guide the necessity of investigation of relatives. MH is inherited in an autosomal dominant pattern, meaning that if one of the parents has the disease, the risk of his or her passing it down to sons or daughters is 50 per cent122. Muscle biopsy for CHCT should be avoided in patients whose weight is less than 20 kg, patients under chronic dantrolene or calcium channel blocker therapy and in the first three months after a MH crisis, because muscle lesion may still be present123. A muscle sample is removed from the *vastus lateralis* or *medialis* or *rectus abdominis*. As the tests have to be finished up to five hours after its collection, patients have to be transported to specialized MH centers. The procedure is performed under general or regional anesthesia, obviously avoiding potentially trigerring agents and keeping dantrolene immediately available123. 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.
