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560 PART 5: Infectious Disorders

imaging studies. However, in many patients there are often clinical clues individuals. 65,66 When fever occurs within the first 72 hours after
that may point to a noninfectious cause of fever. brain injury, it is most often not due to infection. It remains unclear
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■ SURGICAL TRAUMA if fever is simply a marker of worse brain injury or if fever actually
aggravates neuronal injury. In one series of 260 patients with fever
Up to 30% of all surgical patients will develop fever in the first 72 hours within the first 24 hours of ischemic stroke, fever not due to infection
postoperatively. 55,56 The majority of these early febrile events are directly was independently related to worse neurologic outcome at 3 months,
however fever due to infection was not associated with poorer out-
due to either a surgically induced systemic inflammatory response or to 67
the lingering effects of anesthetic drugs. Both usually resolve without come. These data might suggest that noninfectious fever is simply a
marker of worse neurologic injury. In spite of the uncertainty regard-
specific interventions. Patients who develop benign postoperative
10
fever tend to be younger, have fewer comorbidities and have had less ing its pathologic role, it is accepted practice to treat fever in all types
of brain injury. The routine use of therapeutic hypothermia in patients
extensive surgery than patients who are subsequently found to have
an infection. Among patients with benign postoperative fever, the with severe brain injury is, however, more contentious. To date, there
55
are no large randomized trials that demonstrate survival benefit or
amplitude of temperature elevation has been observed to correlate with
the duration and extent of the surgical procedure. Available data do improved neurologic outcomes with the use of therapeutic hypo-
57
thermia in either traumatic brain injury or stroke. The therapeutic
not suggest that atelectasis causes fever. Postoperative infection is
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more common among patients who have had cancer surgery, a bowel application of induced hypothermia has become standard practice for
neuroprotection following in witnessed cardiac arrest. This practice is
resection, a longer duration of fever, a temperature above 38.5°C, or an
elevated white blood cell count. Extensive evaluations with cultures described in Chap. 26.
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and imaging may be avoided in the majority of patients with a low ■
pretest probability of infection. 59 VENOUS THROMBOEMBOLISM
■ DRUG FEVER It is best to consider that febrile patients with acute venous thromboem-
bolism have an alternative cause of fever. In a prospective study of 1847
Ten percent of all patients will experience a medication-induced fever consecutive patients undergoing evaluation for deep vein thrombosis
(DVT), the temperature for the 175 patients with acute DVT was 37.1 ±
sometime during a hospitalization. The diagnosis of drug fever is 0.6°C (only 0.2°C higher than those without DVT). Although this
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usually first suspected only after competing infectious diagnoses have difference was statistically significant, there was no temperature that
been excluded. Even then, making a definitive diagnosis of drug fever accurately differentiated patients who had DVT from those who did not.
can be difficult both because patients are often taking multiple suspect Among patients with proven DVT, the frequency of temperature read-
medications and because confirmation of the diagnosis of drug fever ings above 38.3°C was less than 5%. 68
requires withdrawal of the offending drug with resulting resolution of
There are many potential mechanisms of drug fever. First, a drug may ■
the fever. HEAT STROKE
insight a hypersensitivity reaction. Second, a patient may have a febrile Very high temperatures, that is, those above 41.1°C, are less commonly
reaction to a carrier molecule, a diluent, or a contaminant rather than due to infection. Rather, temperatures above this level are most often due
to the pharmacologically active drug. Third, some drugs may be ther- to excessive heat generation and/or an impairment of thermoregulation.
mogenic; that is, they may increase the metabolic rate. Fourth, a drug The differential diagnosis of severe hyperthermia includes heat stroke
may interfere with natural heat loss by impairing sweating or vasodila- (heat-related illness), serotonin syndrome, neuroleptic malignant syn-
tion. And finally, the mechanism of action of a drug (ie, bactericidal drome, and malignant hyperthermia. Heat-related illness is most likely
antibiotics) may lead to the secondary release of pyrogenic bacterial cell to occur when environmental heat exposure is combined with drugs that
wall components. are thermogenic or with drugs that impair cooling. Drugs with anticho-
The most common drugs to cause fever in the ICU include linergic action, stimulants such as methamphetamines, and diuretics
anticonvulsants, antibiotics, chemotherapeutics, diuretics, antihy- such as caffeine and alcohol are the most common culprits. Prompt
pertensives, antiarrhythmics, and heparin. These associations are diagnosis, fluid resuscitation, and rapid cooling are critical to prevent
undoubtedly partially related to how commonly these drugs are used. multiple organ failure.
the amplitude of temperature elevation, and the patient severity of ■ SEROTONIN SYNDROME
Unfortunately, the timing of the onset of fever, the pattern of fever,
illness do not help to discriminate between drug fever and an infec- Serotonin syndrome is an underrecognized cause of clinical deteriora-
tious cause of fever. Although the presence of a skin rash makes tion in the ICU. It may be precipitated by a long list of drugs that affect
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drug fever more likely, only a minority of patients with drug fever the serotonergic pathway (Table 63-2). It classically presents with signs
will have a rash. 61 of autonomic instability, increased muscle tone, altered mental status,
Sometimes overlooked is that many recreational drugs of abuse and fever. Because these signs are often already present among ICU
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have sympathomimetic action that can lead to severe temperature patients, affected individuals may fall below the threshold for detec-
elevations, especially when used in combination with drugs that tion unless clinical suspicion is high. Hyperthermia in serotonin
have anticholinergic activity. Recently, synthetic psychostimulants, syndrome is worsened by increased agitation and muscle contraction.
such as “bath salts” that contain mephedrone, have become popu- Treatment is focused on removal of the offending agent, supportive
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lar party drugs. When ingested these drugs can cause tachycardia, care, and benzodiazepines for agitation. Cyproheptadine, a nonspecific
hypertension, and temperature elevations as high as 42°C. Other serotonin antagonist with anticholinergic properties, can be employed
recreationally abused stimulants, such as cocaine, phencyclidine, in selected cases.
or methamphetamines, may also cause hyperthermia and may even
predispose to heat stroke. ■ NEUROLEPTIC MALIGNANT SYNDROME
■ CENTRAL NERVOUS SYSTEM DISEASE Like the serotonin syndrome, neuroleptic malignant syndrome (NMS)
is characterized by hyperthermia, increased muscle tone, autonomic
Fever is a common occurrence among neurocritical care patients, instability, and altered mental status. However, the pathogenesis of
especially those with traumatic brain injury, intraventricular hem- NMS relates to reduced dopaminergic activity in the central nervous
63
orrhage, or ischemic stroke. There is considerable epidemiologic system. Neuroleptic medications that have antidopaminergic effects
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evidence associating fever with worse outcomes among brain injured are the most common offending agents. Haloperidol has been most

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