Pathophysiologically, there are several ways in which poison exposure and toxicity may result in hyperthermia. By alteration of normal mental state, cognition, and psychomotor agitation, patients may be unaware of own temperatures or that of their surroundings. They may fail to avoid exercise or activity in hot ambient environments, become unable to leave the environment, or continue to exert themselves while restrained. Examples include becoming comatose in a closed automobile during daytime, and comatose on a hot surface such as asphalt, where heat gain by conduction may occur quickly. Commonly, this may occur with drugs of abuse such as ethanol, cocaine, opioids, and PCP. Psychomotor agitation associated with drugs of abuse may also result in significant heat production.
Such cases are understandably more common in warmer months, summer in the Northern hemisphere and winter in the Southern hemisphere. A clear relationship between deaths from cocaine hyperthermia and ambient temperature exists: Deaths from cocaine hyperthermia in New York City, for example, dramatically peak during the warmest summer months and are rare during other times.31 This is likely true for other drugs that cause psychomotor agitation and hyperthermia, as well.
Other pathophysiologic mechanisms for hyperthermia include uncoupling of oxidative phosphorylation, such as with salicylate or dinitrophenol toxicity; increased metabolism, such as from thyroid hormone or thyroid extract toxicity; impaired sweating, such as from antihistamines and anticholinergics; vasoconstriction due to α-adrenergic agonism, such as from amphetamines, cocaine, pseudoephedrine, and other sympathomimetics. Malignant hyperthermia (MH), resulting from ryanodine receptor dysfunction, as well as serotonin syndrome (SS) and neuroleptic malignant syndrome (NMS), is discussed later in this chapter.
Although different pathophysiology underlies the manner in which hyperthermia is reached, the initial acute treatments are similar. The temperature at which permanent neurologic injury will occur in any patient cannot be known, but a core temperature of 107°F or 42°C warrants active cooling, preferably by immersion in ice or an ice bath. Tepid sponging, mist spray and fans, or other less effective measures should only be used in the extraordinary instance when true ice immersion cannot be achieved.
A simple method of ice immersion is placing the patient in a partially closed body bag enclosed with ice. Covering the patient in ice and wrapping in a sheet or blanket is also suitable, understanding that this will quickly result in water pooling on the floor surrounding the patient as the ice melts. If a cholera bed is available, this aids in collection of melting ice water and is preferable from a nursing and housekeeping perspective. Using immersion makes cardiopulmonary monitoring more difficult.
Typically patients with hyperthermia resulting from psychomotor agitation, hypermetabolism, or uncoupled oxidative phosphorylation do not typically feel uncomfortable in an ice pack or ice bath. After some period of time when the temperature decreases, they may communicate that they feel cold or uncomfortable, and this often correlates with reaching a goal temperature of 100–102°F. Care should be taken to carefully monitor patients to avoid overcooling below normal body temperature.
Treatment of psychomotor agitation should include chemical restraint by benzodiazepine administration. Use of haloperidol is contraindicated for this purpose as it lowers seizure threshold, results in increased incidence of cardiac dysrhythmia, and impairs heat dissipation. In cases of true MH, dantrolene is indicated. Dantrolene is often errantly used for hyperthermia from causes other than MH, in which there is no potential benefit and thus the small risk of use is not justified. Use of COX inhibitors such as aspirin, acetaminophen, ibuprofen, ketorolac, naproxen, or others plays no role whatsoever in toxin-induced hyperthermia.
Hyperthermic Syndromes: Serotonin Syndrome, Neuroleptic Malignant Syndrome, and Malignant Hyperthermia
SS, NMS, and MH are toxin-induced illnesses that result in hyperthermia by different mechanisms (Table 41-6). These syndromes have significant overlap in clinical presentation, but careful evaluation can clearly differentiate between them. Hotline numbers for the Neuroleptic Malignant Syndrome Information Service are 1-888-667-8367 and 1-315-464-4001. Another hotline to aid in management of MH is the Malignant Hyperthermia Association of the United States, which can be reached at 1-800-644-9737 or 1-315-434-7079. These services are intended to provide advice about diagnosis and management of NMS and MH, respectively. They are supported by medical toxicologists and are able to assist in differentiating NMS, MH, and SS, and to make treatment recommendations.
Table 41-6. Comparison of Findings in Serotonin Syndrome, Neuroleptic Malignant Syndrome, and Malignant Hyperthermia ||Download (.pdf)
Table 41-6. Comparison of Findings in Serotonin Syndrome, Neuroleptic Malignant Syndrome, and Malignant Hyperthermia
|Illness||Onset||Mental Status||Muscular Changes||Vital Signs||Offending Agent(s)||Treatment|
|Serotonin syndrome||Hours||Confused, agitated||Twitching, fasciculation, shivering, hyperreflexia||Severe hyperthermia, hypertension, tachycardia, hypotension, and bradycardia when deteriorating||Serotonergic medications and drugs of abuse||Cyproheptadine, active cooling|
|Neuroleptic malignant syndrome||Days||Catatonic, mute||Catatonic, lead-pipe rigidity||Mild hyperthermia <102.5°F||Neuroleptic antipsychotic agents, withdrawal of anti-Parkinson dopamine agonists||Bromocriptine|
|Malignant hyperthermia||Minutes to hours||Poorly defined, patient usually sedated or anesthetized||Rigidity, may not be present if already paralyzed|
- Elevated EtCO2
- Severe hyperthermia
|Inhalational anesthetics, succinylcholine||Dantrolene, active cooling|
Onset of illness and progression of illness are distinct for SS, NMS, and MH. SS develops over hours and universally <24 hours after exposure to the serotonin agonist. SS is rapidly progressive, and can quickly transition from mild illness to critical instability or death in hours. This helps differentiate from NMS, which develops over days, and for which both the progression and resolution occur over a more prolonged time period. MH develops more acutely than both SS and NMS, within minutes to hours, and nearly universally within 12 hours of exposure to the causal medication(s). It may rapidly progress and rapidly dissipate. As a result, initial diagnosis and treatment of MH infrequently involves emergency medicine or critical care physicians, usually occurs in operating rooms or postoperative recovery rooms, and is overseen by anesthesiologists managing the patient at that time.
SS results from excess serotonergic agonism, typically as a result of exposure to two or more serotonin agonists or massive exposure to a single serotonin agonist. It characteristically causes mental status changes, autonomic hyperactivity, and neuromuscular abnormalities. Alteration of mental status usually does not involve coma or impaired consciousness. Typically it is anxiety, disorientation, psychomotor agitation, and hyperalertness, with patients startling easily. The neuromuscular findings may be hyperreflexia, clonus, tremor, muscle rigidity, myoclonus, hyperreflexia, and a unique form of shivering that is sometimes rhythmic and progressive along the torso, similar to that of a dog shaking water from its coat. Autonomic manifestations are tachycardia and hypertension, with hyperthermia.
To fulfill Hunter criteria to diagnose SS, the patient must have been exposed to a serotonergic medication or drug, and have any of the following: (1) spontaneous clonus; (2) inducible clonus plus agitation or diaphoresis; (3) ocular clonus plus agitation or diaphoresis; (4) tremor and hyperreflexia; (5) hypertonia; (6) temperature >38°C plus ocular clonus or inducible clonus.
Laboratory abnormalities include myoglobinuria, elevated creatine phosphokinase (CPK), and hyperkalemia. In suspected cases, obtain blood gas analysis with lactate concentration, serum electrolytes, liver function tests, and CBC.
Treatment of SS includes maintaining vital signs within acceptable limits, including cooling to <39°C (102.2°F), and use of benzodiazepines, as well as possibly cyproheptadine. Benzodiazepines treat agitation, serve as muscle relaxants, and are useful because the CNS side effects of benzodiazepines do not overlap with CNS changes that result from SS. Lorazepam 0.05–0.1 mg/kg IV is given every 20–30 minutes until clinical effect is reached, followed by repeat administration at the appropriate dose in 2- to 6-hour periods. Diazepam 0.1–0.5 mg/kg may also be used, with initial doses repeated every 10–15 minutes and repeat dosing every 1–2 hours as needed. If benzodiazepines fail to sedate thoroughly, cyproheptadine is given empirically in adults as a 12-mg initial dose followed by 2 mg every 2 hours until symptoms resolve. Dosing would be modified on a weight basis in children.
Cyproheptadine is only available in a PO formulation, but can be crushed and injected down a nasogastric tube to patients with altered mental status. Medications such as chlorpromazine and olanzapine should not be used, since they lower seizure threshold and increase risk of developing NMS.
Neuroleptic Malignant Syndrome
NMS is an extrapyramidal syndrome associated with hyperthermia, muscle rigidity, autonomic instability, and altered mental status. This occurs predominantly with use of antipsychotics and less commonly when anti-Parkinson dopamine agonists are withdrawn.
NMS occurs in particular with potent antipsychotics such as haloperidol and fluphenazine, and with depot formulations such as long-acting depot haloperidol injection, but it has been reported to occur from all classes of neuroleptic drugs, as well as new atypical antipsychotic agents.
Epidemiologically, NMS occurs more commonly in males and in younger patients, but can occur in any gender or age patient. NMS is an idiosyncratic reaction, meaning it is not dose dependent. It may occur with the first dose of medication or may occur in a patient who has been receiving the medication for years without any adverse side effects. NMS occurs more frequently within the first 2 weeks of initiating a neuroleptic or antipsychotic treatment, with depot injection use, and with rapid dose escalation. The pathophysiology and etiology of NMS are unknown, but are widely believed to be mediated by central dopamine antagonism.
As mentioned, NMS may be differentiated from SS by timing of onset. NMS symptoms typically develop over several days, whereas SS develops over hours. Because NMS occurs in patients with psychiatric illness and is slower in onset, there is more likely to be delayed or missed diagnosis. Hyperthermia, altered mental status, autonomic instability, and muscle rigidity are universally present in patients with NMS.
Hyperthermia is usually not as extreme as with SS or NMS, with temperatures typically in the range of 38–39°C (100.4–102.2°F) and uncommonly greater than 40°C (104°F). Muscular rigidity with NMS is more catatonic, lead-pipe rigidity, whereas SS is associated with fasciculation, twitching, shivering, and hyperreflexia. Mental status changes are also more similar to those of catatonic states, and patients may be mute, stuporous, or comatose.
Lab testing is critical in management of NMS. Elevations of CPK may be severe. Rhabdomyolysis and myoglobinuric renal failure may result. Expectedly, associated electrolyte abnormalities may include hyperkalemia and mild elevations of lactate. Low serum iron concentration has >95% sensitivity in detecting NMS.32
Management of NMS includes immediate discontinuation of the offending drug and supportive care with correction of dehydration and electrolyte imbalance. Cooling to decrease temperature to acceptable range may be carried out by the physical methods mentioned earlier in this section. Pharmacologic treatment for NMS should be administered. Hyperthermia from NMS is usually less severe than SS, and typically will not require the aggressive measures to lower temperature that are commonly needed for SS.
Pharmacologic therapy for NMS includes bromocriptine, which agonizes dopamine receptors. This is only available as a PO formulation, and may be crushed and given by nasogastric tube. Dosing is 2.5 mg PO Q 6–8 hourly. It is recommended to continue this for 10–14 days after the symptoms of NMS have resolved. Amantadine may be used instead of bromocriptine. Benzodiazepines may also be used for muscle relaxation and to relieve psychomotor agitation. Lorazepam 2 mg IV/PO Q 6 h is typically effective, but this dose may be increased as necessary.
NMS resolution typically takes days to weeks, on average 5–15 days, to resolve. This is in contrast to SS, for which onset and resolution are often within hours.
MH is a hypermetabolic crisis typically encountered in the setting of anesthesia administration, and may be seen in genetically susceptible patients who receive inhalational anesthetics and/or succinylcholine. As previously mentioned, MH is rarely encountered in the emergency department or ICU setting, and is typically managed in the operative and postoperative setting. Because MH is the toxin-induced hyperthermic crisis that develops most rapidly, within minutes to hours, and is most likely to result in severe morbidity or mortality, clinicians who administer succinylcholine or manage postoperative patients should be aware of this entity and its management.
MH involves excessive release of calcium from the sarcoplasmic reticulum of myocytes, and an ensuing hypermetabolism that results in hypercarbia, mixed respiratory and metabolic acidosis, rhabdomyolysis, and hyperthermia that is sometimes severe, with temperatures rapidly rising up to 113°F. It is widely misunderstood and misstated that hyperthermia rapidly develops in patients with MH: in fact, hyperthermia and rhabdomyolysis may be the last of the clinical symptoms to become apparent, occurring after muscle rigidity, hypercarbia, and mixed respiratory and metabolic acidemia.
The earliest clinical indication of MH is often hypercarbia. There is no absolute Pco2 that is diagnostic, but a Paco2 >60–65 or end-tidal CO2 >55–60 in the absence of other obvious cause should be considered suggestive in postoperative patients. This hypercapnia may be managed by increasing minute ventilation, although the increases required by mechanical ventilation are often greater than would normally be expected. If the patient is not already being mechanically ventilated, he or she should be endotracheally intubated and mechanically ventilated with 100% FiO2, with a minute ventilation that corrects the Pco2 as reasonably as possible.
It is appropriate to correct hypercarbia, but investigation for other evidence of MH should be initiated. This includes physical exam to detect increased muscle tone; evaluation of arterial blood gas; urinary myoglobin, serum CPK, and serum potassium that may be associated with rhabdomyolysis; PT/PTT, INR, and fibrin split products to detect disseminated intravascular coagulation; and rectal or core temperature monitoring. Although hyperthermia is often not present when MH is initially suspected, when elevation of temperature does begin, it may be rapid, with temperatures rising as much as 2°F every 5 minutes.
At any time when MH is strongly suspected, any possible inciting medications should be discontinued and dantrolene administration should begin. Despite any other supportive care given, without dantrolene patients are extremely unlikely to survive MH.33 Prior to the development of dantrolene, 70% of cases of MH were fatal. With current supportive care and dantrolene administration in the United States, approximately 10% of cases are fatal.
Supportive care includes correcting hypercarbia, providing 100% oxygen to support the hypermetabolic state, correcting hyperkalemia and treating rhabdomyolysis, managing disseminated intravascular coagulation if it occurs, and, last, management of hyperthermia.
Use of active cooling as described in the beginning of this section is recommended in conjunction with dantrolene administration.