Acetaminophen for Fever

You bring up a common question asked regarding acetaminophen and febrile patients. You are correct in stating that it can be a useful tool in treating symptomatic febrile patients, but sometimes this is not always necessary.

Firstly, let’s look at some specific definitions:

Fever: Fever is an elevation in core body temperature above the daily range for an individual. Fever is regulated at the level of the hypothalamus. The thermostat setting in the hypothalamic thermoregulatory center shifts upwards during a fever, for example, from 37 to 39°C. Elevated levels of prostaglandin E2 (PGE2) in the hypothalamus appear to be the trigger for raising the set-point. Once the hypothalamic set-point is raised, this activates neurons in the vasomotor center to commence vasoconstriction and warm-sensing neurons to slow their firing rate and increase heat production in the periphery.

Hyperpyrexia: Hyperpyrexia is the term for an extraordinarily high fever (>41.5°C), which can be observed in patients with severe infections but can also occur in patients with central nervous system (CNS) hemorrhages.

Hyperthermia: Hyperthermia includes heat stroke syndromes, certain metabolic diseases, and the effects of pharmacologic agents that interfere with thermoregulation. In contradistinction to fever, the setting of the thermoregulatory center during hyperthermia remains unchanged (ie: at normothermic levels), while body temperature increases in an uncontrolled fashion and overrides the ability to lose heat. Exogenous heat exposure and endogenous heat production are two mechanisms by which hyperthermia can result in dangerously high internal temperatures.

Fever is a normal response to infection and itself does not directly cause harm and therefore medication to lower body temperatures is not always required. However, antipyretics are particularly useful in relieving systemic symptoms such as headaches, myalgias, and arthralgias. Providers often elect to treat fever to prevent adverse physiological consequences of fever. However, there is no data that definitively suggest benefit from treatment. In a systematic review and meta-analysis of 16 randomized controlled trials that included over 2400 hospitalized patients with fever, there was no difference in mortality between those who received treatment for fever and those who did not (23% mortality rate in both groups). There was also no difference in serious adverse events (24% rate of serious adverse events in both groups). Additionally, there has been no documented evidence surrounding a reduction in seizure occurrence/recurrence with the use of antipyretics in febrile children.

Physiological effects of elevated core temperature, whether fever or hyperthermia, include increased demand for oxygen and aggravation of preexisting cardiac or pulmonary disease. In healthy subjects, the temperature-pulse relationship is linear with an increase in heart rate of eight beats/minute for each 1°C rise in core temperature, although the amount of increase varies based on age and body mass index (BMI). For every increase of one degree above 37°C, there is a 13 percent increase in O2 consumption. Something to consider for symptomatic febrile patients with pre-existing cardiac and respiratory challenges.

Additionally, there is no definitive clinical data that suggest treatment of fever harms patients either. Theoretically, treating fever may reduce any physiological benefits of fever. In animal studies, there are reports that temperatures in the febrile range may be beneficial during infectious challenges. In addition, in vitro cultures of animal or human cells at elevated temperature suggest a heightened immune response as well as increased bactericidal killing of microorganisms during infection. However, there are no studies demonstrating that fever itself facilitates recovery from infection or acts as an adjunct to the immune system. And another thing to consider, when treating fever, it is often prudent to treat only when the temperature reaches a predesignated threshold. Continuous fever suppression may impair the ability to monitor the response to treatment of the underlying disease process.

Looking specifically at the antipyretic medications that paramedics carry there are the NSAIDs which are potent antipyretics because they inhibit cyclooxygenases (COX-1 or COX-2), an enzyme that promotes the synthesis of prostaglandin E2 (PGE2). The substrate for cyclooxygenase is arachidonic acid released from the cell membrane, and this release is the rate-limiting step in the synthesis of PGE2. Conversely, acetaminophen is a poor cyclooxygenase inhibitor in peripheral tissue and does not display any anti-inflammatory activity. However, acetaminophen is oxidized in the brain by the p450 cytochrome system, and the oxidized form inhibits cyclooxygenase activity.

However, like all medications, antipyretics can have associated risks and side effects. Aspirin and other NSAIDs have excellent antipyretic capabilities, however, they can cause gastrointestinal upset, renal complications, and antiplatelet effects. Acetaminophen is known to cause hepatotoxicity, especially in individuals with chronic liver disease, older age, or malnutrition and in those taking medications or herbal products that interfere with the metabolism of acetaminophen. For patients at increased risk of side effects from antipyretics, one class of antipyretic may be favored over the other.

Lastly, to note, acetaminophen is recommended as the primary antipyretic. NSAIDs are highly effective but are associated with a higher risk of adverse events. If better fever control is needed than achieved with monotherapy, combination therapy with acetaminophen and an NSAID may be more effective. There are, however, no randomized trials comparing acetaminophen with NSAIDs, or specific NSAIDS to each other, for fever reduction.

In conclusion, while treatment of fever is considered patient-centered care, there is currently no evidence that outlines that it is related to specific improved outcomes. We applaud your enthusiasm about this topic and want to inform you that this is a medical directive that is being considered for future iterations of the ALS PCS. The process takes time to include a thorough search of the literature and medicine. In the meantime, we encourage you to continue to patch for those patients that you believe could benefit from acetaminophen for fever.