Endogenous pyrogens released by leukocytes in response to infection, drugs, blood products, or other stimuli cause fever by stimulating cerebral prostaglandin E synthesis and as a result raise the hypothalamic temperature set point.7 Antipyretic agents including acetaminophen, aspirin, and other nonsteroidal anti-inflammatory drugs (NSAIDs) are believed to block this process by inhibiting cyclooxygenase-mediated prostaglandin synthesis in the brain, resulting in a lowering of the hypothalamic set point. This activates the body's two principal mechanisms for heat dissipation: vasodilation and sweating.7 The effectiveness of antipyretic agents is tightly linked to conditions where thermoregulation is intact. Therefore, they are more likely to be ineffective in brain-injured patients with impaired thermoregulatory mechanisms. Corticosteroids also have antipyretic properties but are not used clinically to treat fever because of their side effects.
Whether acetaminophen alone is more effective than placebo for treating fever in adult ICU patients is still unclear. The majority of studies have been conducted in the pediatric population, where weight-adjusted doses have been shown to be effective in reducing fever. In the adult neurocritical care population, acetaminophen has been most widely studied in an attempt to maintain normothermia in patients with acute stroke. Koennecke and Leistner8 showed that treatment with acetaminophen in a daily dose of 4000 mg resulted in a substantial reduction of the proportion of patients with body temperatures over 37.5°C (the amount of temperature reduction was not reported). Kasner et al9 observed a difference of 0.2°C in body temperature in favor of treatment with acetaminophen (approximately 4 g per day) as compared to placebo in patients with hemorrhagic or ischemic stroke, although not statistically significant. Two recent phase II studies have demonstrated that perhaps a higher dose of acetaminophen (6000 mg per day) is more effective in maintaining normothermia/preventing fever. Based on the results from these studies, a large phase III study assessing the ability to maintain normothermia after acute ischemic stroke is under way.10
Ibuprofen has been widely studied in the pediatric population, with equivalent or superior efficacy as compared to acetaminophen. However, only one randomized, controlled study has been conducted in adult patients with brain injury, which demonstrated that ibuprofen (2400 mg per day) was not shown to be better than acetaminophen or placebo in maintaining normothermia after ischemic stroke.10 A recent small randomized study of a continuous infusion of diclofenac sodium (0.04 mg/kg per hour) was found to be effective in reducing the burden of fever and number of febrile events in critically injured traumatic brain injury (TBI) and subarachnoid hemorrhage (SAH) patients.11 Although no adverse effects related to increasing hemorrhage rates were reported, larger studies are needed before this therapy can be widely utilized.
External cooling reduces body temperature by promoting heat loss without affecting the hypothalamic set point. Four modes of heat transfer constitute the basis of interventions to promote heat loss: (1) evaporation (eg, water sprays or sponge baths); (2) conduction (eg, ice packs, water-circulating cooling blankets, immersion); (3) convection (eg, fans, air-circulating cooling blankets); and (4) radiation (ie, exposure of the skin).12 In patients with temperature elevations caused by impaired thermoregulation, such as what occurs after brain injury, antipyretic agents are usually ineffective, and temperature reduction may only be achieved by external cooling. However, external cooling can result in reflex shivering and vasoconstriction as the body attempts to generate heat and counteract the cooling process.
Few controlled studies have evaluated the efficacy of external cooling interventions for lowering body temperature in humans. Previous experimental studies have shown that the combination of evaporative and convection cooling, with water sprays or sponging and forced airflow, is more effective than conduction cooling or either method alone for reducing temperature in non–brain-injured patients with hyperthermia.13 In a study of febrile neurocritical care patients treated with acetaminophen, air-blanket cooling had a small benefit that did not reach statistical significance.14
Water-circulating cooling blankets, a form of conductive cooling, are the most commonly used treatment for acetaminophen-refractory fever in critically ill adults. However, there are few data regarding their efficacy. Two small controlled studies have evaluated external cooling in adult ICU patients. One study compared the use of acetaminophen alone with tepid water sponging or with a water-circulating cooling blanket in febrile neurologic patients and found no difference between the three treatments.15 Another study of febrile patients under sedation, analgesia, and mechanical ventilation found that ice-water sponging was superior to two IV NSAIDs16 in a nonrandomized crossover study. A large observational study found no difference in the mean cooling rate in febrile ICU patients treated with or without water-circulating cooling blankets.17 A feature commonly found with water circulating blankets is the wide fluctuations in temperature that occur, with temperature overshoot being very common.
Recent engineering advancements have introduced a new set of surface-cooling blankets that are much more efficient at achieving and maintaining normothermia (Figure 19-2). Each system works by utilizing tightly wrapped pads that circulate cold water to promote conductive heat loss. In a randomized controlled trial of 53 neurologically injured patients that had a fever (temperature ≥ 38.3°C) for at least 2 hours after the administration of 650 mg of acetaminophen were randomized to treatment with an advanced cooling blanket system or a conventional water-circulating cooling blanket. Despite having a slightly higher baseline mean temperature, patients treated with the advanced system experienced a 75% reduction in fever burden and became normothermic faster than the control group, despite a significantly higher rate of shivering.18
Food and Drug Administration–approved temperature-modulation devices. A. Gaymar surface-cooling device using wrap-around pads. B. Cincinnati Sub-Zero surface-cooling device using a cool blanket. C. Medivance Arctic Sun, surface temperature modulation using conductive gel pads. D. Philips InnerCool RTx endovascular system using a conductive metal catheter. E. Zoll intravascular temperature management system using balloon catheters.
Over the past few years, a number of intravascular devices have become available to lower body temperature (Figure 19-2). They all work to control fever by directly lowering the blood temperature with cooled saline, which circulates through balloons or channels around an intravascular catheter. While there is no direct contact with the blood, the cold saline solution extracts heat from the blood, thus lowering body temperature.13
Infusion of 4°C normal saline is an appealing option because it is inexpensive and easy to administer in the critical care setting. The use of cold saline boluses has recently been studied and advocated for the induction of hypothermia in cardiac arrest patients.19 A small case series also found the rapid infusion of large-volume cold saline to be a safe and effective method to achieve normothermia in select brain-injured patients.20 In addition to its rapid onset, the large volume of infusion can help offset the fluid imbalance that may be observed during the induction of hypothermia. Therefore, the administration of large-volume cold saline could be considered during the induction phase of fever control.
The nurse administers 1000 mg of acetaminophen through the patient's nasogastric tube. Cultures from blood, urine, sputum, and CSF were sent to the laboratory. All the lines were inspected and were noted not to appear infected. A decision is made to initiate aggressive fever control to maintain normothermia with an advanced temperature-modulating device.