section name header

Information

  1. Hyperthermia-Related Drug Reactions are a broad category that often results in patients being admitted to the ICU. These are hyperthermic states and not the result of hypothalamic dysregulation as seen in infections, and therefore antipyretics are not indicated nor effective.
    1. Malignant hyperthermia is caused by an autosomal dominant trait which, when exposed to certain provoking agents (succinylcholine or inhaled volatile anesthetics), leads to a systemic hypermetabolic state in skeletal muscle due to excessive calcium release. This may result in increased oxygen utilization and CO2 production, lactic acidosis, hyperthermia, and/or disseminated intravascular coagulation (DIC). Early presentation includes spasm of masseter muscles, tachypnea, and rigidity, while diagnostic testing will commonly show elevated end-tidal CO2, hyperkalemia, and evidence of rhabdomyolysis. Hyperthermia is a late finding. Death is typically from cardiac dysrhythmias and multi-organ failure. Immediate administration of dantrolene has reduced the mortality rate to less than 5%. Dantrolene should be administered as an initial IV bolus of 2.5 mg/kg, doses of 1 to 2.5 mg/kg may be repeated until signs of hypermetabolism resolve or until a total of 10 mg/kg of dantrolene has been administered. Following clinical stabilization, dantrolene 1 mg/kg every 6 hours should be given for 24 hours. Additional supportive therapy to address hyperkalemia, bleeding, and prevent kidney damage is also indicated. Further information and 24-hour support are provided by the Malignant Hyperthermia Association of the United States (Website: www.mhaus.org; US Phone Number: 1-800-644-9737; International Phone Number: 001-209-417-3722).
    2. Neuroleptic malignant syndrome (NMS) is an uncommon but serious condition that occurs in patients taking antidopaminergic drugs, most frequently antipsychotics. This syndrome can also present after the abrupt discontinuation of dopamine agonists. The mechanism for NMS is believed to be related to an acute decrease in dopaminergic activity in the hypothalamus and striatum leading to impaired thermoregulation and muscle rigidity. This is typically a diagnosis of exclusion; patients present initially with muscle rigidity and altered mental status, later developing hyperthermia and autonomic instability. NMS typically develops insidiously over days to weeks. Treatment includes supportive care, active cooling, and benzodiazepines for agitation and decreasing sympathetic outflow. Administration of either bromocriptine and/or dantrolene may be considered in severe cases, but these interventions should be discussed with a toxicologist.
    3. Serotonin syndrome (SS) results from the increased serotonergic activity, predominantly at central 5-HT2A receptors. Drugs and substances associated with the development of SS include serotonin agonists (eg, triptans, buspirone, and LSD); serotonin reuptake inhibitors (eg, SSRIs, SNRIs, tramadol, and St. John’s wort); MAOIs (eg, selegiline, phenelzine, linezolid, and methylene blue); and drugs that increase serotonin release (eg, MDMA, dextromethorphan, and methadone). SS typically starts within 6 hours of exposure to the causative agent(s) and most commonly occurs in patients taking two or more serotonergic agents but can occur with exposure to a single agent. Patients may present with symptoms ranging from mild to life-threatening. Mild or early symptoms may include akathisia, nausea/vomiting, diarrhea, tremor, and/or diaphoresis. Patients may go on to develop hyperreflexia, altered mental status, inducible or sustained clonus, muscle rigidity, and hyperthermia. Serotonin syndrome is a clinical diagnosis based on signs/symptoms and exposure to at least one serotonergic agent. The Hunter Serotonin Toxicity Criteria (Table 31.3) have largely replaced the Sternbach Criteria in clinical practice to aid in the diagnosis of SS. Treatment includes the removal of offending agent(s), supportive care, benzodiazepines for agitation, and active cooling. Although supportive care is the mainstay of treatment, cyproheptadine, chlorpromazine, and dantrolene can be considered in refractory cases.
    4. Anticholinergic syndrome results from exposure to excessive amounts of drugs with anticholinergic properties (eg, antihistamines, TCAs, neuroleptics, atropine, scopolamine, and antispasmodics). Symptoms include agitation, confusion, hyperthermia, dry mouth, blurred vision, tachycardia, flushing, and urinary retention. Toxicity occurs secondary to antagonism of peripheral and/or central muscarinic receptors. Initial treatment is primarily supportive, consisting of active cooling and benzodiazepines. Physostigmine is an acetylcholinesterase inhibitor that crosses the blood-brain barrier and helps increase acetylcholine levels centrally and peripherally. Studies have shown that it is more effective than benzodiazepines at treating delirium and agitation due to anticholinergic toxicity. The starting dose is typically 1 mg over 5 minutes, which may be repeated every 10 minutes as needed. Physostigmine is relatively short acting, and its effects may diminish over time. Some medications, specifically TCAs, may cause ECG changes (ie, QRS or QTc prolongation) and physostigmine should typically be avoided until these alterations have resolved.
    5. Drug fevers are not uncommon in the ICU. They have a typical onset of 7 to 10 days after exposure. Many antimicrobials, antineoplastics, nonsteroidal anti-inflammatory drugs, and immunosuppressants are known causative agents, and symptoms resolve soon after the drug is discontinued.
  2. Propofol-Related Infusion Syndrome (PRIS) was first defined in 1998 in the pediatric population as refractory bradycardia progressing to asystole with any of the following: severe metabolic acidosis, rhabdomyolysis, lipemia, or fatty liver. The specific mechanism of how PRIS develops is not clear, though it is believed to be due to defects in the mitochondrial respiratory chain. Cardiac dysfunction or Brugada-like ECG changes may be seen and may indicate impending instability. Treatment includes stopping propofol, supportive care, and HD. Inotropes demonstrate little benefit, though pacing and extracorporeal membrane oxygenation has been used in case reports. Ultimately, prevention is the best measure by limiting prolonged propofol use and utilizing high-carbohydrate, low-fat nutrition. Monitoring serum triglycerides may allow for early detection of patients at risk of developing PRIS. In order to minimize the risk of developing PRIS, it is generally recommended to keep doses less than 80 μg/kg/min.
  3. Anaphylaxis and Anaphylactoid Reactions are indistinguishable in presentation, differing only in that anaphylactoid reactions are not IgE mediated. The incidence of anaphylaxis and related hospitalizations have increased globally for many years. Overall, foods and stinging insects represent the most frequent causes of anaphylaxis in children, whereas medications and stinging insects are the most common triggers in adults.
    1. The most common presenting signs and symptoms are urticaria and angioedema (88%), followed by dyspnea and wheezing (47%), whereas dizziness, syncope, and hypotension (33%) are less commonly seen. Gastrointestinal complaints such as nausea, vomiting, diarrhea, and abdominal pain are important to identify but are only present in 30% of patients.
    2. Early identification of anaphylaxis is critical, and the National Institute of Allergy and Infectious Diseases (NIAID) diagnostic criteria are highly sensitive. Cardiac and respiratory arrest can occur within 5 minutes of onset, and nearly 50% of deaths occur in the first hour. Immediate administration of epinephrine (0.3 mg or 0.01 mg/kg up to 0.5 mg IM) is the most effective and life-saving intervention. Some patients may require repeated dosing of IM epinephrine and ultimately a continuous infusion. Antihistamines and steroids are frequently used in clinical practice, but these medications should not be used in place of epinephrine as they are slower acting and there is no strong evidence to support their use in the management of anaphylaxis. If possible, obtain a serum tryptase within 2 hours of symptom onset (Table 31.4) .