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APSF3601 Reprint

APSF3601 Reprint

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- can also trigger NMS. These DRUG!INDUCED MH!LIKE SYNDROMES cated because they inhibit heat dissipation and are often given perioperatively for 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 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 ) 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 (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 . 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 , 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 -blocking drugs like tated by drugs commonly given or withheld in trol during emergence delirium, for antiemetic or neuroleptics like . 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 drugs have been designed to Rising Temperature NMS is a life-threatening condition caused by manipulate CNS levels. These drugs that block central dopamine, PHS is include the Selective Serotonin Reuptake Inhib- itors (SSRIs), Selective Reup- caused by withdrawal of dopaminergic therapy. Tachypnea For this reason, complete discontinuation of take Inhibitors (SNRIs), tricyclic , 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. /Hypotension Commonly used anesthetic adjuvant drugs and "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 mental status, nergic drugs. Serotonin or 5-hydroxytrypta- lation of mood, appetite, sleep, some cognitive autonomic dysfunction, hypotension, neuro- mine, a monoamine derived from , is functions, platelet aggregation, and smooth muscular rigidity, agitation, ocular and periph- a in the brain, gut, and on muscle contraction of uterus, bronchi, and small eral clonus, diaphoresis, and fever.

Table 2: Drug-Induced MH Look-Alike Conditions.

Probable Syndrome Drug Cause Implicated Drugs Factors Onset Signs & Symptoms NMS CNS Neuroleptics like haloperidol. Dehydration, 1–2 weeks Fever, hypermetabolism, dopamine Dopamine blocking antiemetics like overdose, rigidity, shivering, abnormal deficit & prochlorperazine increasing or mixed CNS, unstable BP, rising drug doses creatinine kinase, MOSF PHS Dopamine Parkinsonian dopaminergic Abrupt Hours to As above deficit withdrawal discontinuation, days dehydration & stress SS CNS & SSRIs, SNRIs, , MAOIs, TCAs, Overdose or 1–24 hours As above & myoclonus, peripheral some anesthetic adjuvants, increasing doses, agitation, confusion, dilated serotonin methylene blue, some OTC drugs like multidrug pupils, GI symptoms, evolving excess loperamide, dextromethorphan interactions MOSF Baclofen Withdrawal Baclofen Pump failure, Hours to Hypertension, rigidity, prescription stop days dysautonomia, depressed CNS, coagulopathy, & MOSF Direct CNS Amphetamines, dexamphetamine, Dehydration, stress, Hours Hyperdynamic circulation, & CNS & MDMA, cocaine other illness fever, sweating, pupillary stimulants peripheral dilatation, cardiorespiratory, & e!ects MOSF PCP Direct CNS PCP or “angel dust” Dehydration, stress, Hours Slurred speech, abnormal & other illness gait, rigidity, sweating, peripheral hypersalivation, convulsions, e!ects coma, MOSF LSD Direct CNS LSD & LSD preparations Dehydration, major Hours Hallucinations, rigidity, & stress, intercurrent psychosis, CNS depression, peripheral illness respiratory arrest, e!ects coagulopathy, MOSF Table Abbreviations: NMS (neuroleptic malignant syndrome), CNS (Central Nervous System), MOSF (multiple organ system failure), PHS (Parkinsonism- Hyperpyrexia Syndrome), SS (Serotonin Syndrome), SSRIs (selective serotonin reuptake inhibitors), SNRIs (selective norepinephrine reuptake inhibitors), Triptans (a class of Triptamine-based drugs used to abort & cluster ), TCAs (tricyclic antidepressants), MAOIs (Monoamine Oxidase Inhibitors), OTC (sold without prescription “over the counter”), GI (gastrointestinal), MDMA (3,4-methylenedioxy-methamphetamine or "ectasy"), PCP (phen- cyclidine or “angel dust”), LSD (lysergic acid diethylamide). See “MH-like Syndromes,” Next Page APSF NEWSLETTER February 2021 PAGE 43

Drug-Induced Hypermetabolic Syndromes May Present in the Perioperative Setting

From “MH-like Syndromes,” Preceding Page Baclofen is commonly given orally or by direct for elective surgery. Just as some patients pre- Onset can be abrupt following drug adminis- injection/infusion into cerebrospinal fluid by medicate themselves with or “medical” tration or overdose. SS can present as a hyper- anesthesia and other specialists to control marijuana prior to surgery in order to control thermic, hypermetabolic syndrome that’s spasticity seen following CNS damage in condi- anxiety, habitual users of these psychoactive di"cult to distinguish from NMS, PHS, and MH. tions like cerebral palsy, spinal cord injury, and drugs may do the same. While initial subjective As with NMS and PHS, progression of symp- dystonia. Since anesthesia pain specialists use symptoms vary as each of these drugs takes baclofen, it isn’t that uncommon for other anes- effect, all may produce signs of sympathetic toms may lead to cardiorespiratory failure, thesia practitioners to become involved in hyperactivity, abnormal motor activity, fever, muscle damage, multiple organ injury, and pump refills, assessment of a malfunctioning and hypermetabolism with cardiorespiratory death. The incidence of SS may be underesti- baclofen pump, or a baclofen prescription for a and MOSF in the perioperative period. Patients mated, possibly because of mild cases that are colleague. Hence it’s important for members of presenting for surgery with abnormal menta- overlooked or because more serious presenta- the anesthesia care team to know that the MH- tion, signs of sympathetic hyperactivity, and tions can mimic other causes. Hence it may be like syndrome following acute baclofen with- other unusual symptoms that are not caused by that SS is more common in the perioperative drawal, with relative CNS deficiency of GABA, their primary medical problem should have toxi- period than we know. It is important for anes- can be dramatic with fever, abnormal menta- cology screening if at all possible. thesia practitioners to remember that a number tion, autonomic hyperactivity, respiratory dis- of anesthetic adjuvant drugs we commonly use tress, rhabdomyolysis, and coagulopathy. CONCLUSION: can precipitate or increase risk of SS. Treatment Treatment involves supportive medical care While anesthesia professionals know MH as requires cessation of all drugs that contribute to and reinstitution of baclofen therapy.23 a perioperative crisis, it is important to be aware serotonin excess together with supportive ther- of other drug-induced hypermetabolic syn- apy.15,16 Although unproven, some authorities RECREATIONAL DRUGS dromes that may be seen in the perioperative recommend use of the central 5-hydroxytrip- Selected CNS stimulants used for “recre- setting. Indeed, commonly used anesthetic tamine 2a receptor blocker, , ation” or in overdose cause hypermetabolic adjuvant drugs may contribute to or precipitate because the 5 hydroxytriptamine 2a receptor is conditions that may resemble MH crisis through some of these. Dantrolene sodium is the critical thought to be one of the primary central activa- direct peripheral and CNS effects. These drug for treatment of MH crisis, but it is non- tors of hyperthermia in SS.16,21,22 include amphetamines, dextroamphetamine, specific in that it may ameliorate some of the methamphetamine, MDMA (methylene-dioxy- hypermetabolic signs of other conditions. BACLOFEN WITHDRAWAL methamphetamine), cocaine, and psychoactive Because these can closely mimic the MH crisis NMS and MH-like reactions have been drugs like PCP and LSD. Although a drug his- and dantrolene may control some of the symp- reported following baclofen withdrawal. tory and toxicology screening usually identify toms, misdiagnosis as MH could delay or pre- Baclofen enhances the central effects of such problems before emergency surgery for vent other e!ective treatment. gamma-aminobutyric acid (GABA), an inhibitory trauma or other acute conditions, “recreational” Charles Watson, MD, is a volunteer MH Hotline central nervous system (CNS) neurotransmitter. use may be encountered in patients scheduled Consultant for the Malignant Hyperthermia Association of the United States (MHAUS), Sher- Table 3: Some Drugs that Cause or Potentiate Serotonin Syndrome. burne, NY. Anesthesia Stanley Caro!, MD, is professor of psychiatry at Antidepressants Triptans Adjuvants Miscellaneous the University of Pennsylvania School of Medi- SSRIs Cocaine cine and director of the Neuroleptic Malignant Citalopram Meperidine Syndrome Information Service (NMSIS) and an o"cer of MHAUS. Methadone Dextromethorphan Ergot Henry Rosenberg, MD, is the president of 5-hydroxytryptophan MHAUS. Linezolid Fentanyl Loperamide Drs. Watson and Rosenberg have no conflicts of interest. Methylene blue Dr. Caroff is a consultant for Neurocrine SNRIs St. John’s wort Biosciences, Teva Pharmaceuticals. He has also received research grants from Neurocrine Biosciences, Osmotica Pharmaceuticals, Eagle Pharmaceuticals. Tricyclics REFERENCES 1. Rosenberg H, Davis M, James D, et al. Malignant hyperther- MAOIs mia. Orphanet Journal of Rare Diseases. 2007:2:21. Phenelzine 2. Rosenberg H, Hall D, Rosenbaum H. Malignant hyperther- mia. In: Brendt J, ed. Critical Care Toxicology. Elsevier- Tranylcypromine Mosby; 2005:291–304. Abbreviations: SSRIs (selective serotonin reuptake inhibitors), SNRIs (selective norepinephrine reuptake inhibitors), MAOIs (monoamine oxidase inhibitors). See “MH-like Syndromes,” Next Page APSF NEWSLETTER February 2021 PAGE 44

MH-like Syndromes (Cont.-References)

From “MH-like Syndromes,” Preceding Page 9. Caro! SN, Rosenberg H, Mann SC, et al. Neuroleptic malig- 17. Nguyen H, Pan A, Smollin C, et al. An 11-year retrospective nant syndrome in the perioperative setting. Am J Anesthe- review of cyproheptadine. J Clin Pharm Ther. 2019;44:327– 3. Parness J, Rosenberg H, Caro! SN. Malignant hyperthermia siology. 2001; 28: 387–393. 334. doi: 10.1111/jcpt.12796 and related conditions. In: Kellum JA, Fortenberry JD, Fuchs BD & Shaw A, eds. Clinical Decision Support: Critical Care 10. Caro! SN. Neuroleptic malignant syndrome. In: Mann SC, 18. Basta MN. Postoperative serotonin syndrome following Medicine. Wilmington, Delaware: Decision Support in Med- Caro! SN, Keck PE, Lazarus A, eds. Neuroleptic Malignant methylene blue administration for vasoplegia after cardiac icine, LLC: 1913. Syndrome and Related Conditions. 2nd Ed. Washington, surgery: a case report and review of the literature. Semin DC: American Psychiatric Publishing; 2003:1–44. 4. Mann SC. Thermoregulatory mechanisms and antipsy- Cardiothoracic Vasc Anes. 2020: 1089253220960255. chotic drug-related heatstroke. In: Mann SC, Caroff SN, 11. Newman EJ, Grosset DG, Kennedy, PGE. The parkinson- (pre-pub) Keck PE, Lazarus A, eds. Neuroleptic Malignant Syndrome ism-hyperpyrexia syndrome. Neurocrit Care 2009;10:136– 19. Orlova Y, Rizzoli P, Loder E. Association of coprescription of and Related Conditions. 2nd Ed. Washington, DC: American 140. antimigraine drugs and selective serotonin reuptake Psychiatric Publishing; 2003:45–74. 12. Artusi CA, Merola A, Espay AJ, et al. Parkinsonism-hyperpy- inhibitor or selective norepinephrine reuptake inhibitor anti- 5. Goulon M, de Rohan-Chabot P, Elkharrat D, et al. Beneficial rexia syndrome and deep brain stimulation. J Neurol. 2015; depressants with serotonin syndrome. JAMA Neurol. e!ects of dantrolene in the treatment of neuroleptic malig- 262:2780–2782. 2018;75:566–572. Neurology. nant syndrome: a report of two cases. 13. Caro! SN. Parkinsonism-hyperthermia syndrome and deep 20. Boyer EW, Shannon M. The serotonin syndrome. N Engl J 1983;33:516–518. brain stimulation. Can J Anaesth. 2017;64:675–676. Med. 2005;352:1112–1120. 6. Pawat SC, Rosenberg H, Adamson R, et al. Dantrolene in 14. Newman EJ, Grossett DG, Kennedy PG. The parkinsonism- 21. Simon L, Kennaghan M. Serotonin syndrome [review]. Stat- the treatment of refractory hyperthermic conditions in criti- hyperpyrexia syndrome. Neurocrit Care. 2009;10:136–140. Pearls. NCBI Bookshelf. 2020:5. Published Jan 2020, cal care: a multicenter retrospective study. Open Journal of Accessed October 2020. Anesthesiology. 2015;5:63–71. 15. Frazer A, Hensler JG. Serotonin involvement in physiologi- 7. Hadad E, Cohen-Sivan Y, Heled Y, et al. Clinical review: cal function and behavior. In: Siegel GJ, Agrano! BW, Albers 22. Nguyen H, Pan A, Smollin C, et al. An 11-year retrospective treatment of heat stroke: should dantrolene be considered? RW, et al., editors. Basic Neurochemistry: Molecular, Cellular review of cyproheptadine use in serotonin syndrome cases Crit Care. 2005;9:86–91. and Medical Aspects. 6th edition. Philadelphia: Lippincott- reported to the California Poison Control System. J Clin Raven; 1999. Available from: https://www.ncbi.nlm.nih.gov/ Pharm Ther. 2019:44;327–334. 8. Shih TH, Chen KH, Pao SC, et al. Low dose dantrolene is books/NBK27940/ Accessed December 12, 2020. e!ective in treating hyperthermia and hypercapnea, and 23. Co!ey RJ, Edgar TS, Francisco GE, et al. Abrupt withdrawal seems not to a!ect recovery of the allograft after trans- 16. Francescangeli J, Karamchandani K, Powell M, et al. The from intrathecal baclofen: recognition and management of plantation: case report. Transplantation Proceedings. 2010; serotonin syndrome: from molecular mechanisms to clinical a potentially life-threatening syndrome. Arch Phys Med 42:858–860. practice. Int J Mol Sci. 2019;20:2288. Rehabil. 2002;83:735–741.

Postoperative Anterior Neck Hematoma (ANH): Timely Intervention is Vital by Madina Gerasimov, MD, MS; Brent Lee, MD, MPH, FASA; and Edward A. Bittner, MD, PhD

INTRODUCTION An Anterior Neck Hematoma (ANH) can quickly progress to an airway obstruction that can occur at any time following a surgical inter- vention of the neck. Typically, most patients present within 24 hours of their original proce- dure.1 Patients with an ANH need swift inter- ventions to mitigate any life-threatening emergencies. We illustrate this important surgi- cal complication and its associated challenges with a specific case of ANH.

CASE STUDY A 49-year-old man underwent a total thyroid- ectomy for the diagnosis of thyroid cancer. His past medical history included transient ischemic attacks, hypertension, chronic obstructive pul- monary disease/asthma. He was a current heavy smoker whose preoperative included aspirin (81 mg) and an albuterol inhaler, which he took as needed. His labs were all within normal limits. After an uneventful surgery, the patient was discharged from the postanes- thesia care unit after five hours of observation and transferred to a surgical ward. The following day he complained of neck swelling, associated Figure 1: Arrows indicate active contrast extravasation from superior thyroid artery to the right of cricoid with pain, dysphagia, and odynophagia. He cartilage with hematoma formation anterior to the trachea. (P and I are not relevant to this illustration.) denied voice changes and di"culty breathing. See “Neck Hematoma,” Next Page

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