Malignant hyperthermia

The incidence of MH is 1 per 100,000 general anesthetics delivered in hospitals and 0.31 per 100,000 anesthetics delivered in ambulatory care centers.^[1] Although observed so infrequently that many career anesthesiologists never encounter a single case, MH accounted for 1% of all anesthesia-related mortality in the United States between the years 1999 and 2005.^[2] The incidence of cardiac arrest during an episode of MH is 2.7%.^[3] While most episodes of MH present in the operating room during the anesthetic, MH can rarely be initially recognized in the postoperative setting either as the initial episode or a recrudescence of previously treated crisis.^[4–12] A recent observational study suggests that delayed presentation of MH to the second or third hour of the anesthetic is becoming more frequent.^[13] Modern anesthetics might not be as strongly triggering for MH, and contemporary presentations of the syndrome are more indolent, increasing the likelihood of late recognition. Prompt diagnosis and therapy greatly reduces mortality, so it is important that clinicians caring for surgical patients recognize the syndrome (Table 24.1).

MH susceptibility is inherited in an autosomal dominant fashion and is thought to be caused by a mutation in the type 1 ryanodine receptor. This abnormality results in abnormal calcium transport and sustained muscle contraction with resultant rigidity and hyperthermia. Several genetic mutations have been identified that increase sensitivity to “triggering agents” including all volatile anesthetics and the depolarizing muscle relaxant succinylcholine.

The earliest clinical signs include elevated end-tidal CO₂, tachycardia, and muscle rigidity. Untreated, the syndrome progresses to acidosis, renal failure, rhabdomyolysis, hyperkalemia, and cardiac arrhythmias. Metabolic acidosis and respiratory acidosis occur simultaneously. A 1994 consensus conference led to the formulation of a set of diagnostic criteria.^[14] The higher the score (greater than 6 following), the more likely a reaction constituted MH.

If recognized in the postoperative setting, treatment must be instituted rapidly with an intravenous (IV) loading dose of dantrolene 2.5 mg/kg. Each 20 mg vial of dantrolene must be dissolved in 60 ml of sterile water for injection. Preparation of dantrolene may take 20 minutes or more. In July 2014, the US Food and Drug Administration approved a new formulation of dantrolene (Ryanodex®, Eagle Pharmaceuticals, Woodcliff Lake, NJ), which is packaged in a 250 mg vial that requires reconstitution in only 5 ml sterile water and can be prepared in under 1 minute. Although clinical experience is limited, this formulation may improve outcomes by allowing faster treatment. Periodic readministration of dantrolene may be needed for several days to prevent recurrence. Cooling measures should be instituted to decrease core body temperature. Frequent monitoring of arterial blood gas, serum electrolytes, and coagulation studies should be performed. Sodium bicarbonate should be administered to treat hyperkalemia and metabolic acidosis as needed. An arterial line for frequent blood sampling and close monitoring of blood pressure would be beneficial. End-tidal CO₂ monitoring is helpful in monitoring response to therapy if available, but PaCO₂ may be monitored by frequent arterial blood gas sampling instead. Urine output should be maintained to prevent acute renal failure from rhabdomyolysis.

Neuroleptic malignant syndrome

NMS may occur after administration of medications that block the dopaminergic system. Haloperidol and chlorpromazine carry the highest risk, but metoclopramide, lithium, desipramine, phenelzine, reserpine, tetrabenazine, and abrupt discontinuation of levodopa have all been implicated in NMS.^[15] The pathogenesis is thought to possibly be a result of neuroleptic-induced alteration of central neuroregulatory mechanisms versus an abnormal reaction of predisposed skeletal muscle. Diagnosis is made by confirming the presence of three major criteria, or two major and four minor criteria (see Table 24.2).

Management should include discontinuation of the offending agent, supportive care (i.e. mechanical ventilation, antiarrhythmic medication, pacing), and dantrolene 1 to 2.5 mg/kg IV repeated to a maximum of 10 mg/kg daily, slowly tapered over 10 days. Bromocriptine 2.5 mg by mouth every 6 to 8 hours and amantadine 100 mg by mouth every 12 hours are alternative pharmacological therapies.

Serotonin syndrome

Monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibitors (SNRIs) may trigger serotonin syndrome through excessive stimulation of central and peripheral postsynaptic 5-HT_2A receptors. The risk is increased when multiple medications modulating serotonin pathways are used in combination. Many surgical patients are on chronic SSRI or TCA therapy and are at increased risk for developing perioperative serotonin syndrome during the polypharmacy of the postoperative period. Serotonin syndrome may be triggered by cocaine, amphetamine, the street drug ecstasy, L-tryptophan, and buspirone among outpatients.^[16] The surgical patient taking SSRIs, TCAs, or MAOIs is placed at risk from the many serotonergic medications commonly administered in the perioperative period, including opioids. Serotonergic opioids including fentanyl, tramadol, oxycodone, methadone, dextromethorphan, meperidine, codeine, and buprenorphine have been reported to contribute to the development of serotonin syndrome.^[17] These medications are only weakly serotonergic, and the syndrome is rare after anesthesia and surgery. The combination of SSRI and intraoperative methylene blue was reported to cause serotonin syndrome in a susceptible individual.^[18]

Excessive serotonin activity has cognitive, autonomic, and somatic effects. Patients may exhibit peripheral or ocular clonus, agitation, diaphoresis, tremor, tachycardia, hyperreflexia, hypertonism, shivering, diarrhea, and body temperature >38 °C. A diagnosis of serotonin syndrome by Hunter criteria may be made by a history of serotonergic agents and at least one of the following signs: clonus (spontaneous, inducible, ocular), agitation, autonomic dysfunction (hyperthermia), tremor, or hyperreflexia.^[18]

Management involves cessation of serotonergic medications and supportive care. Severely affected patients may require mechanical ventilation and/or dialysis, anticonvulsants if seizures develop, and propranolol to treat tachycardia. Severe cases may be treated with cyproheptadine 2 mg PO in incremental doses until symptoms resolve (max dose 12 to 32 mg/day) or chlorpromazine 50 to 100 mg IV if unable to take oral medications.^[16]

Opioid-induced rigidity

Opioid-induced rigidity is sometimes observed following induction of general anesthesia. This often occurs within 60 to 90 seconds of IV administration of sufentanil, fentanyl, alfentanil, or remifentanil.^[19–21] It can lead to difficulty with bag mask ventilation. Characteristics include chest wall rigidity, wrist flexion, closure of vocal cords, hoarseness, reduced pulmonary compliance and decreased functional residual capacity, and occasionally tonic-clonic movements. It has been linked to elevated central venous pressures and increased pulmonary vascular resistance.

Occurrence is dependent on dose, anatomical patient considerations, concomitant muscle relaxant use, and patient age. The mechanism of opioid-induced rigidity is poorly understood, but may be related to activation of GABAergic interneurons in the striatum and nucleus pontis raphe of the brain. It is common practice for anesthesiologists to administer a priming dose of non-depolarizing paralytic agent or succinylcholine to facilitate ventilation after large IV doses of opioids.

Rarely, rigidity is present on emergence from general anesthesia,^[22] and in exceptionally rare circumstances this has been reported to occur more than 3 hours after the last dose of opioid.^[23] Awareness of this syndrome is therefore important for clinicians caring for the surgical patient. When rigidity interferes with breathing, naloxone 4 mg IV should be administered.

Antidopaminergic medication effects

Dopamine antagonists or drugs with antidopaminergic side effects can cause extrapyramidal side effects, which can manifest as a number of related movement disorders, including Parkinsonism which includes rigidity, bradykinesia, and tremor. Many perioperative medications may cause extrapyramidal side effects, including droperidol,^[24] ondansetron,^[25] and metoclopramide.^[26] Additionally, abrupt discontinuation of anti-Parkinsonian medications, especially levodopa, can lead to spastic rigidity in the perioperative period if the patient is unable to take oral medications for a prolonged period of time. Management of acute extrapyramidal symptoms is administration of diphenhydramine 50 mg IV.