Page 82 - Journal of Special Operations Medicine - Summer 2015

by the FDA for fever reduction, a characteristic that For oral and IV routes, patients weighing at least 50kg
could be incorporated into a supportive care algorithm can receive 1g every 4 to 6 hours to a maximum of 4g
during field treatment of infection. per 24 hours. The minimum duration between doses is 4
hours except in cases with extreme renal impairment, in
which case dose frequency should be no sooner than ev-
Pharmacokinetics and Efficacy
ery 6 hours. Patients weighing less than 50kg and pedi-
Paracetamol is converted to acetaminophen in vivo by atric patients are dosed based on weight at 10 to 15mg/
plasma esterases. The standard dose is 1g, which pro- kg to a maximum of 75mg/kg per 24 hours. 2
duces a pharmacokinetic profile similar to the oral ab-
sorption of 0.5g of acetaminophen after the first hour. Adverse Effects
4
However, while oral acetaminophen is characterized by
slow onset of action and variable analgesic activity, IV The side-effect profile of acetaminophen suggests that it
administration results in faster onset, more predictable would be safe in combat trauma. It has not been associ-
pharmacokinetics, and reduced time to meaningful pain ated with the postoperative side-effects commonly as-
relief. Peak plasma concentration occurs 15 minutes sociated with opioids, including respiratory depression,
2,5
after administration, compared to about 60 minutes af- sedation, nausea and vomiting, pruritus, or urinary re-
ter oral, and 4 hours after rectal administration. Ad- tention. Likewise, it does not reduce glomerular filtra-
2
4,6
ditionally, IV acetaminophen avoids first-pass hepatic tion rate in patients with normal renal function. There
2
metabolism via portal circulation, which may reduce the is suggestion of a dose-dependent antiplatelet effect, due
potential for hepatic toxicity. 5 to weak inhibition of cyclooxygenase –1. However, this
effect is transient and minor relative to the anti-platelet
The mechanism by which acetaminophen produces an- effect caused by nonsteroidal anti-inflammatory drugs
algesia is not completely understood. The presumed (NSAIDs). 2
2
mechanism of action is selective inhibition of central
prostaglandin synthesis via the cyclooxygenase path- Perhaps the greatest concern of acetaminophen adminis-
way. However, it has also been suggested that acet- tration in a patient in shock is the risk of hepatotoxicity.
2,4
aminophen may activate descending serotonin-mediated The majority of acetaminophen-related cases of acute
inhibitory pain pathways as well as acting as a periph- liver failure are due to outpatient use in excess of the
eral anti-inflammatory agent. The central analgesic ef- recommended daily limit of 4g. At therapeutic dosing
6
5
fects are facilitated by acetaminophen’s ability to cross (up to 4g daily), acetaminophen is only rarely associated
the blood–brain barrier. 4 with hepatotoxicity, even in patients with underlying
liver conditions. In patients undergoing major surgery,
5
Given acetaminophen’s central effects, the IV route has including major orthopedic, open pelvic and open ab-
significant advantage over the oral route, due to ear- dominal procedures, thoracic and cardiac procedures,
lier and higher peak cerebrospinal fluid levels. In fact, and spine surgeries, there were no elevated liver enzyme
2
IV acetaminophen results in a higher maximum plasma levels in liver function test results or clinically relevant
concentration and shorter time to maximum concen- adverse effects versus control when IV acetaminophen
tration compared with oral formulation at equivalent was administered at a dosing regimen of 1g every 6
doses. These effects account for faster-acting analgesia hours or 650mg every 4 hours for 5 days. In another
5
and reduced time to meaningful pain control relative to study, no changes in renal or hepatic function relative
the oral route. 2 to placebo were found in orthopedic surgery patients
administered the bio-equivalent of 1g IV acetaminophen
Numerous studies have established the analgesic effect of every 6 hours for 24 hours.4 It should be noted that
IV acetaminophen in a variety of clinical situations. The the risk of hepatotoxicity in overdose is worsened by
initial randomized controlled trials demonstrated effi- alcohol consumption, a fact that has prompted the FDA
cacy of IV acetaminophen in major orthopedic surgery. to issue a consumer warning. So long as overdose is
1,7
10
Subsequent systematic review of placebo-controlled trials avoided, the risk of hepatotoxicity is probably minimal
for a variety of major surgeries demonstrated improved and, when weighed against its benefit of not causing se-
analgesia with IV acetaminophen. It reduced postopera- dation, the risk to benefit calculation probably favors its
8
tive morphine consumption after both orthopedic sur- use in combat trauma patients requiring pain control.
gery and spinal fusion surgery. It reduced meperidine
4,6
consumption, postoperative nausea and vomiting, and Although a 1g dose should have sufficient safety mar-
time to extubation in patients admitted to the intensive gin, limiting its use in cases of severe shock, would allow
care unit after major surgery. One study demonstrated its evaluation in field medicine. Recalling that the US
9
that 1g of IV acetaminophen produced postoperative an- Special Operations Command Tactical Trauma Proto-
algesia similar to 30mg of IV ketorolac. 2 cols (TTP) advocate for altered mental status and weak

72 Journal of Special Operations Medicine Volume 15, Edition 2/Summer 2015