APSF NEWSLETTER February 2021 PAGE 41 Drug-Induced MH-like Syndromes in the Perioperative Period by Charles Watson, MD; Stanley N. Caro!, MD; and Henry Rosenberg, MD MALIGNANT HYPERTHERMIA VS. anticholinergic e!ects are relatively contraindi- prochlorperazine can also trigger NMS. These DRUG!INDUCED MH!LIKE SYNDROMES cated because they inhibit heat dissipation and are often given perioperatively for nausea or Anesthesia professionals recognize malig- sweating.4 Dantrolene sodium is a specific anti- nausea prophylaxis. The onset of hypermeta- nant hyperthermia (MH) in the perioperative dote to the MH crisis because of its direct action bolic signs with fever, abnormal muscle activity period as a rapidly progressing, life-threatening, on muscle, but it may also be helpful in control- (including rigidity), and abnormal mentation can hypermetabolic syndrome that’s triggered in ling fever caused by muscle hyperactivity and be seen within hours and up to one or two the muscle of genetically susceptible individu- heat production caused by these CNS and weeks after neuroleptics are started. Progres- als by potent inhalational anesthetic agents other problems.5-8 sion of these signs is usually reversed over time and/or succinylcholine. Unless recognized and The volunteer MH Hotline that is supported by when the causative agents are discontinued, treated expeditiously by withdrawal of the trig- donations and the Malignant Hyperthermia but unrecognized NMS can progress to muscle gering agent(s), intravenous dantrolene sodium Association of the United States [MHAUS] injury, cardiorespiratory failure, and death. Pri- and other supportive measures, MH crisis has a receive calls from anesthesia and surgical practi- mary treatment requires early diagnosis, neuro- high morbidity and mortality. Evolving signs of tioners, perioperative nursing sta!, and others leptic withdrawal, and supportive medical care. MH include rapidly rising temperature, heart with questions about the recognition and man- In the absence of randomized controlled trials, rate (HR), CO2 production, end-tidal CO2, respi- agement of MH crises, post-crisis management, benzodiazepines, dopaminergic drugs like bro- ratory rate (RR), spontaneous or required and other conditions that resemble MH. (https:// mocriptine or amantadine, dantrolene, and ECT minute ventilation, increased muscle tone with www.mhaus.org) Review of MH Hotline calls (electroconvulsive therapy) have been rigidity, and multiple organ system failure shows that some of these calls are associated employed with varying success. Neither labora- (MOSF). Muscle injury can lead to renal failure, with MH-like conditions that are drug- or toxin- tory tests nor presenting symptoms make the even when the MH crisis is treated e!ectively. induced (unpublished data-author’s personal diagnosis of NMS. Diagnosis requires a thor- Fever with unmet metabolic demand together communication with MHAUS Hotline Database). ough medical history and examination together with cardiac and microcirculatory failure can with elimination of other organic or drug- lead to coagulopathy, hepatic dysfunction, Drug-induced, MH-like syndromes include induced conditions.9,10 If NMS is suspected, the other MOSF, and death.1,2 Neuroleptic Malignant Syndrome (NMS), Parkin- Neuroleptic Malignant Syndrome Information sonism/Hyperthermia Syndrome (PHS), Sero- Service (NMSIS) sponsored by MHAUS pro- MH is best known by anesthesia profession- tonin Syndrome (SS), baclofen withdrawal, vides literature, and email and telephone sup- als because it is triggered by anesthetic drugs. intoxication caused by stimulants like amphet- port through its website (www.NMSIS.org) Since anesthesia intervention causes an MH amine, MDMA and cocaine, and psychoactive crisis, it has become an anesthetic-related prob- drugs like phencyclidine (PCP, “angel dust”) and PARKINSONISM!HYPERTHERMIA lem. But there are other drug-induced hyper- lysergic acid diethylamide (LSD) (see Table 2). SYNDROME "PHS# metabolic conditions that are caused by While the clinical setting of these is most often PHS is caused by withdrawal of centrally abnormal central nervous system (CNS])activity not perioperative and the presentation may not acting dopaminergic drugs that control the and have signs resembling those of an MH be so fulminant as classic MH, these conditions muscle rigidity, motor retardation, and other crisis (See Table 1).3 Moreover, anesthetic drugs also can pose life-threatening medical prob- symptoms of Parkinson’s disease. Symptoms or interventions may contribute to or precipitate lems that the anesthesia and surgical team often fluctuate and drug dosing may vary these. Such CNS crises can present in the have to address intra- and postoperatively. And, because patients can become relatively insen- extended perioperative period with MH-like of course, these evolving drug-induced prob- sitive to dopaminergic drugs. Dopaminergic signs of hypermetabolism (elevated HR, RR, lems should be di!erentiated from inflamma- drugs are sometimes stopped during acute temperature, and carbon dioxide production), tory and central neurologic e!ects of organic hospitalization for medical or surgical condi- abnormal motor activity, abnormal mentation, conditions like encephalitis, sepsis, CNS tions or preoperatively in order to minimize their and progressive cardiorespiratory failure. abscess, tumor, head trauma, and some autonomic side e!ects. PHS, a semi-acute con- Although these drug-induced crises are more strokes. Also, confusion, together with hyper- commonly seen by emergency medicine, neu- dition that resembles NMS and MH, may follow metabolism is seen with thyrotoxicosis, heat- sudden withdrawal of Parkinsonian drug ther- rology, psychiatry, and critical care providers as stroke, and untreated lethal catatonia. evolving medical emergencies, they can also apy. It is reported in up to 4% of patients in present around the time of surgery. Central NEUROLEPTIC!MALIGNANT whom dopaminergic drugs are acutely discon- drug-related hypermetabolic conditions are SYNDROME "NMS# tinued and approximately a third of patients who develop the syndrome have long-term important to anesthesia professionals because NMS is a relatively rare condition associated 11 they can be seen in the perioperative period, with administration of chronic or increasing sequellae. Fever, abnormal muscle activity, are not MH (although they may resemble MH), doses of neuroleptic drugs that block dopami- and other signs of hypermetabolism together and may have di!erent management require- nergic activity in the brain. Neuroleptics are with autonomic instability are seen. PHS may ments if morbidity and mortality are to be given for sedation, behavioral control, and be facilitated by dehydration, infection, and avoided. Although these are not caused primar- management of psychotic disorders. Postop- other system stresses, or following administra- ily by anesthetic drugs, some can be precipi- eratively they may be used for behavioral con- tion of central dopamine-blocking drugs like tated by drugs commonly given or withheld in trol during emergence delirium, for antiemetic droperidol or neuroleptics like haloperidol. It the perioperative period. Fever associated with properties, or in the ICU following surgery. can also be induced in Parkinson’s patients MH crisis and these central hypermetabolic Individuals who take these drugs, and are ill, after sudden loss of deep brain stimulation conditions respond poorly to antipyretic drugs. dehydrated, agitated, or catatonic are more (DBS) for Parkinson’s disease or following Anticholinergic and antipsychotic drugs with susceptible to NMS. “Occult” neuroleptics like See “MH-like Syndromes,” Next Page APSF NEWSLETTER February 2021 PAGE 42 MH-like Syndromes (Cont.) 15 From “MH-like Syndromes,” Preceding Page Table 1: MH-Like Signs and Symptoms. blood vessels. Consequently, a number of implantation of electrodes for DBS.12,13 While antidepressant drugs have been designed to Rising Temperature NMS is a life-threatening condition caused by manipulate CNS serotonin levels. These drugs that block central dopamine, PHS is Tachycardia include the Selective Serotonin Reuptake Inhib- itors (SSRIs), Selective Norepinephrine Reup- caused by withdrawal of dopaminergic therapy. Tachypnea For this reason, complete discontinuation of take Inhibitors (SNRIs), tricyclic antidepressants, Increasing Hypercarbia—Especially with and monoamine oxidase inhibitors (MAOIs). dopaminergic therapy in the perioperative Fixed, Controlled Ventilation period should be avoided, if at all possible. Also, The incidence of SS has been reported as those patients who have had their Parkinsonian Confusion, Agitation, Altered Mentation 0.9–2% of patients on chronic therapy and as drugs discontinued in the perioperative period, Muscle Rigidity, Cramping, Tremor, high as 14–16% after overdose.16 SSRIs and should restart therapy as soon as possible.14 Spasms SNRIs are most commonly associated with SS. Hypertension/Hypotension Commonly used anesthetic adjuvant drugs and SEROTONIN SYNDROME "SS# Cardiac Arrhythmia other major classes of drugs—including some SS is usually seen when several drugs that sold without prescription—may contribute to or increase central serotonin levels are given con- precipitate SS (see Table 3).17-20 comitantly, but it may also occur following a platelets. Serotonin modulates a broad array of single dose or overdose of one or more seroto- central and peripheral actions that include regu- SS may present with altered