Fever during anesthesia.
Management: Fever may be commonly observed in the Post-Anesthesia Care Unit (PACU) and early postoperative period owing to inflammatory mediators released by surgical trauma. An acute postoperative fever caused by an elevated thermostatic set-point requires no treatment. The routine use of laboratory and radiological tests to work-up postoperative fevers may not be cost effective. Diagnostic work-ups for early postoperative fever rarely discover treatable causes.[6,7] Multiple studies over the past three decades have concluded that positive blood cultures in the first 48 hours after surgery do not change outcome when obtained for the evaluation of fever among adult patients without other constitutional symptoms consistent with infection,[8] and more recent data suggest this may also be true for pediatric patients.[9]
Aspiration pneumonitis: The aspiration of gastric contents into the trachea and lower respiratory tract may occur if regurgitation occurs while protective airway reflexes are depressed. The acidity of the gastric contents may induce chemical injury of the tracheobronchial tree and pulmonary parenchyma with a subsequent inflammatory reaction. Clinically, this may be referred to by the eponym “Mendelson syndrome” after the author of the classic description in obstetrical patient populations.[10] Larger volumes and lower pH of the aspirate and the presence of particulate matter are correlated with more severe lung injury. Aspiration pneumonitis is rare, with an incidence of 1:895 emergency and 1:3,688 elective surgeries.[11]
Most perioperative aspiration is subclinical and asymptomatic. In one large retrospective study, 62% of witnessed perioperative aspiration displayed no clinical sequelae.[11] Hypoxia and dyspnea are the cardinal symptoms of severe cases, but fever may also be present owing to the inflammatory response. The fever of aspiration pneumonitis is typically low grade. Arterial blood gas may demonstrate hypoxia with increased alveolar–arterial gradient, and chest X-ray may show infiltrates in the posterior segment of the upper lobes or apical segments of the lower lobes if the aspiration occurs while the patient is supine.[12,13]
Unfortunately, efforts to prevent perioperative aspiration are not universally successful. The prohibition against eating before elective surgery does not ensure an empty stomach, nor does it reduce gastric acid content. In fact, the ingestion of clear liquids 2 hours prior to surgery may promote gastric emptying and reduce gastric residual volumes.[14] While the risk may be highest during airway manipulation, regurgitation and leakage around an endotracheal cuff may occur at any point during the anesthetic. Cricoid pressure has been used for decades during endotracheal intubation to lessen the risk of regurgitation by compressing and occluding the esophagus between the trachea and the vertebrae, but recent magnetic resonance imaging studies have suggested that the esophagus actually lies lateral to the trachea in more than half the population and cricoid pressure may shift it laterally in over 90%.[15] It is also important to emphasize that aspiration may occur after surgery, particularly if emesis occurs while mental status and protective airway reflexes are diminished. As much as 10% of perioperative aspiration occurs more than 5 minutes after tracheal extubation.[11]
Management: The acidity of gastric contents generally renders them sterile and treatment is supportive. If an aspiration event is witnessed, fiber-optic bronchoscopy may be useful to remove gastric contents or particulate matter from the airway by suctioning. Patients taking H2-antagonists or proton pump inhibitor medications may have less gastric acidity, lessening the chemical pneumonitis, but increasing the likelihood of gastric colonization with bacteria. However, empiric antibiotic therapy has not been shown to improve outcome after aspiration and may select for subsequent infection with more virulent pathogens.[12]
Iatrogenic: Medication associated
Central anticholinergic syndrome: This complication occurs with the administration of medications with centrally acting anticholinergic effects. “Anti” medications including antidepressants, antihistamines, antipsychotics, and anticholinergics may precipitate the syndrome. Anticholinergics may be administered during the anesthetic for a variety of reasons. Atropine and scopolamine have been implicated in causing central anticholinergic syndrome. Glycopyrrolate does not cross the blood–brain barrier and should not contribute to the syndrome. Clinical manifestations can include fever, variable central nervous system disturbances ranging from delirium and agitation to coma, tachycardia, and hypertension with a wide pulse pressure. While mild fever is more common, hyperpyrexia occurs in approximately 25% of patients with this syndrome.[16]
Management: There are no clinical tests to verify this diagnosis; however, the rapid resolution of symptoms, including defervescence, with the administration of physostigmine 1–2 mg IV is both therapeutic and diagnostic.[16] Physostigmine has been associated with both severe bronchospasm and profound bradycardia and should not be administered more quickly than 1 mg/min.
Drug-induced fever: Many medications may induce fever due to hypersensitivity reactions. Penicillins and cephalosporins administered for wound prophylaxis are the perioperative medications most frequently implicated in causing hypersensitivity-mediated fever.[17] The preoperative use of psychotropic medications and illicit drug use may cause temperature elevation in the postoperative period for the trauma patient or surgical patient undergoing emergency procedures. Cocaine may cause temperature elevation. The mechanism appears to be impairment of thermoregulatory mechanisms rather than increased heat production by the body and occurs primarily in warm environments.[18] Methylenedioxymethamphetamine (ecstasy) is also implicated in hyperpyrexia with acute intoxication, but the mechanism appears to be increased heat production.[19] Similarly, phencyclidine[20] and amphetamine[21] may cause fever.
Management: Identification and cessation of the causative medication is the treatment of drug-induced fever. This may be challenging with the polypharmacy of the perioperative period. A preoperative urine drug screen, if available, may provide evidence of illicit drug use.
Alcohol withdrawal syndrome: Abrupt cessation of chronic alcohol intake can produce an alcohol withdrawal syndrome which begins within 5–10 hours of the decreased intake and may present in the early postoperative period. Severely affected individuals may begin to experience withdrawal while plasma ethanol levels are still measurable. Signs and symptoms include tremors, agitation, anxiety, tachycardia, tachypnea, and an increased core body temperature. More than two-thirds of affected patients display only low-grade temperature elevations (37–37.9 °C). Among the one-fifth of patients who experience temperature greater than 38.0 °C, most do not experience the fever spike until 48 hours of abstinence, and three-quarters of these patients have an infectious source (catheter phlebitis, urinary tract infection, or pneumonia).[22] The most severe form of withdrawal, delirium tremens, refers to the mental confusion and fluctuating levels of consciousness associated with the above symptoms. Delirium tremens occurs most commonly in males over the age of 30 years. Most will have a prior history of alcohol withdrawal syndrome.
Management: Benzodiazepines are used for prophylaxis and treatment of alcohol withdrawal syndrome. Diazepam 5 to 10 mg IV or lorazepam 2 to 4 mg IV may be used for the treatment of mild alcohol withdrawal syndrome. Both need to be titrated to effect, with considerable inter-patient variability in effect. Clinical caution must be exercised to avoid over-sedation in patients who may also have concurrent hepatic insufficiency related to alcoholism. Oxazepem 15 to 30 mg by mouth every 6 to 8 hours may be administered for prophylaxis or treatment of mild cases in patients able to tolerate oral medications. While most withdrawal syndromes are managed with return of withdrawn medication, administering ethanol for alcohol withdrawal syndrome is a historical practice now considered inferior to benzodiazepine therapy.[23] Benzodiazepines are the mainstay of treatment for delirium tremens as well, but propofol, dexmedetomidine, and barbiturates are also infrequently employed as adjuvant therapy.
Malignant hyperthermia (MH): MH is triggered by one of a variety of mutations of the ryanodine receptor that have been identified as causing a rise in intracellular calcium levels in response to the administration of succinylcholine and/or inhalational anesthetics. This initiates a hypercatabolic state which presents as tachycardia, tachypnea, muscle rigidity, acidosis, increased oxygen consumption, increased carbon dioxide production, and hyperthermia. An increase in carbon dioxide production may be the first clinical sign if end-tidal carbon dioxide exhalation is being monitored. Hyperthermia is a late sign, and the syndrome derives its name from a historical era when early diagnosis was not possible.
MH occurs with an incidence of 1 in 15,000 anesthetics administered to children and 1 in 50,000 anesthetics administered to adults in North America.[24] MH is one of the most feared diagnoses in a patient with an acute rise in body temperature in the perioperative setting, but it rarely presents de novo after surgery. In a recent review of the 528 cases reported to the North America Malignant Hyperthermia Registry, less than 2% occurred after surgery and in none of these cases was fever the presenting symptom.[25] However, recrudescence of MH occurs in nearly 25% of episodes and the diagnosis must be considered if the patient received treatment intraoperatively.
Management: If MH is suspected after surgery, immediate consultation with the anesthesiologist is mandatory. Prompt treatment with dantrolene 2.5 mg/kg IV can be life-saving. Dantrolene should be repeated until signs of MH are reversed and may require a cumulative dose of 30 mg/kg. Each 20 mg vial of dantrolene must be dissolved in 60 ml of sterile water for injection, which is a labor intensive process that may take 20 minutes or more to prepare the initial bolus dose. 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. Dantrolene 1 mg/kg may be administered every 6 to 8 hours for 2 to 3 days to prevent recrudescence. Sodium bicarbonate may be administered intravenously to treat hyperkalemia and metabolic acidosis, and to alkalinize the urine if myoglobinuria is present. Other supportive measures include vigorous aggressive hydration, control of dysrhythmia (but avoidance of calcium channel blockers), and aggressive total body cooling to 38 °C. A urinary catheter will aid in diagnosis of myoglobinuria and allow for accurate measures of urine output and guide fluid resuscitation. Serial mixed venous blood gases and potassium measurements are necessary as aggressive treatment of hyperkalemia with glucose, insulin, bicarbonate, and hyperventilation should be employed. Baseline laboratory values including creatinine, coagulation tests, creatinine kinase, and liver function tests should also be obtained. The MH Hotline is available to assist with the diagnosis and treatment of possible cases.
Neuroleptic malignant syndrome (NMS): NMS is characterized by increased heat generation and decreased heat dissipation caused by the inhibition of central dopamine receptors in the hypothalamus with the use of neuroleptic agents or the withdrawal of dopaminergic drugs. Older neuroleptic drugs are most often associated with NMS, but perioperative antidopaminergic agents including phenothiazines, haloperidol, prochlorperazine, and metoclopramide may precipitate NMS. NMS has clinical features similar to MH, but is a pharmacologically distinct entity which typically has a much more indolent onset. Unlike MH which typically occurs near the time of the triggering agent, the signs and symptoms of NMS generally occur over days to weeks with chronic therapy. NMS presenting in the early postoperative setting is very rare, but is occasionally reported.[26–32]
Management: Treatment is supportive and includes active cooling, antipyretic medications, and aggressive intravenous hydration to promote diuresis and reduce the risk of rhabdomyolysis-induced acute kidney injury. Dantrolone may be administered with good effect. For patients able to take oral medications, bromocriptine 2.5 mg by mouth every 6–8 hours and amantadine 100 mg by mouth every 12 hours may be prescribed.
Serotonin syndrome: Serotonin syndrome is believed to result from the hyperstimulation of central 5-HT2A receptors. Monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibitors (SNRIs) may trigger serotonin syndrome either individually or more frequently when administered in combination with other serotonergic medications. This hyperstimulation results in the triad of altered mental status, autonomic dysfunction, and neuromuscular excitability.[33] The clinical manifestations include myoclonus, agitation, abdominal cramping, hyperpyrexia, hypertension, rhabdomyolysis, and potentially death. Symptoms may be present in various combinations or severity, making the clinical presentation variable and confounding diagnosis. Fever or hyperpyrexia may be a prominent sign. The Hunter Criteria require both a history of serotonergic agent use and one or more of the following symptoms to make the diagnosis of serotonin syndrome: clonus (spontaneous, inducible, ocular), agitation, autonomic dysfunction (including fever), tremor, or hyperreflexia.[34] However, the Hunter Criteria must be applied cautiously in the perioperative period, since most surgical patients will have received at least one agent with serotonin effects, but many of these agents, including methylene blue,[35] and some opioids,[36–38] are only weakly serotonergic. Serotonin syndrome has been reported following the administration of ondansetron, palonosetron, dolasetron, and ganisetron either as sole agents or in combination with SSRIs, SNRIs, or MOAIs. Most reports to the Food and Drug Administration regarding serotonin syndrome and anti-HT3 have occurred in the PACU, so the clinician should have awareness of this possibility in the early postoperative course.[39]
| Serotonergic opioids |
|---|
| Fentanyl |
| Oxycodone |
| Methadone |
| Meperidine |
| Codeine |
| Dextromethorphan |
| Buprenorphine |
| Tramadol |
Management: If serotonin syndrome is suspected clinically, serotonergic medications should be discontinued. Mild to moderate serotonin syndrome will usually resolve with discontinuation of the precipitating medications. Severe serotonin syndrome, characterized by muscular rigidity, temperature >41.5 °C, seizures, or coma requires aggressive therapy. Cyproheptadine blocks serotonin production and should be administered orally (4 mg PO every 4 hours as needed, up to 20 mg in 24 hours). Chlorpromazine IV may be substituted if patients are unable to take oral medications. Seizures may be treated with benzodiazipines or antiepileptics.[33] Endotracheal intubation and mechanical ventilation may be necessary for extreme cases. Lipid rescue therapy has recently been reported in the treatment of serotonin syndrome.[40]
Iatrogenic: Not medication associated
Febrile non-hemolytic transfusion reaction: Febrile transfusion reactions are a result of antibody activation to donor leukocytes. Patients who have received multiple transfusions of red blood cells or platelets develop antibodies to the human leukocyte antigens in these products. Clinically, it is typically seen as a temperature rise of 1 °C within 4 hours, and patients usually defervesce within 48 hours.[41] Oral acetaminophen may alleviate discomfort associated with the fever, although treatment is not necessary.
Iatrogenic overwarming: Avoidance of unintended hypothermia is a component of modern anesthetic care. Many anesthetic agents cause vasodilation and redistribution of the heat from the body core to the periphery. This heat is ultimately lost through convection to the colder atmosphere in the operating room. Evaporation of skin preparations and insensible fluid loss from surgical incisions exposing the interior of the body to ambient temperature also have an important role in heat loss. Unintended hypothermia can have adverse effects upon wound perfusion and oxygenation and coagulation, cause patient discomfort and shivering postoperatively, precipitating myocardial ischemia, prolong anesthetic drug action, and increase length of stay in the PACU.[4] Forced air heating devices, increasing the ambient air temperature, fluid warming devices, and warming blankets are used to prevent hypothermia in the operating room. Inadvertent “overshooting” may increase body temperature beyond the normal range. In contradistinction to malignant hyperthermia, this anesthesia-related increase in body temperature has been whimsically termed “malignant heating pad.”[42]
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