PulmCrit- DEXACET: Four grams of acetaminophen a day keeps the delirium away?

Background

Acetaminophen, pain, and ICUs

For decades, acetaminophen has been regarded as the first rung of the analgesic ladder. It has a nearly unparalleled risk/benefit profile when dosed correctly (it’s not tremendously effective, but it is extraordinarily safe). Theoretically, acetaminophen should be used very broadly among critically ill patients with pain.

However, this isn’t the case. A survey of Canadian intensive care units found that 85% of patients received opioids, while only 25% received acetaminophen.¹ This has been my experience as well: opioids are used broadly, whereas acetaminophen is prescribed erratically (and usually in a PRN fashion for fever, rather than a scheduled fashion for analgesia).

Why isn’t acetaminophen used more often for pain? A few possibilities may include:

The perception that acetaminophen is ineffective, adding little to opioids.
Concern that scheduled acetaminophen could mask fever and thereby obscure the diagnosis of infection.
Lack of high-quality evidence that acetaminophen improves patient-centered outcomes among the critically ill.
Concern regarding the use of acetaminophen in patients with cirrhosis or severe alcoholism.

IV acetaminophen

In 2011, intravenous acetaminophen was approved by the FDA for use in the United States. It has been used in over 80 countries since 2002, but the United States was late to the party.² The existence of an expensive form of acetaminophen was beneficial for research, because it spurred many pharma-sponsored trials of the drug.

RCTs and meta-analyses regarding intravenous acetaminophen demonstrated that it does work as an analgesic in a variety of contexts (e.g. it decreases opioid requirements).^3–6 This comes as no surprise, because acetaminophen has been used as an analgesic for over half a century. Nonetheless, it is nice to see this validated in prospective, placebo-controlled RCTs.

While these studies did show that IV acetaminophen reduces opioid requirements, questions remain regarding the degree of improvement in patient-centered outcomes (e.g. nausea/vomiting). In short, is the efficacy of acetaminophen substantial enough to be clinically meaningful? (regarding question #1 above). It’s possible that acetaminophen causes a statistically significant reduction in opioid use, without yielding clinically meaningful benefit. To date, results have been somewhat conflicting.^7–9 No study has carefully looked at delirium – which is a significant complication of opioid use.

DEXACET trial

This is a single-center prospective RCT evaluating different strategies for sedation and analgesia following cardiothoracic surgery.¹⁰ It has a 2×2 factorial design, where patients were randomized into one of four groups:

Patients were randomized to receive either propofol or dexmedetomidine for up to six hours postoperatively.
Patients were randomized to receive 1 gram acetaminophen IV q6hr for 48 hours or placebo.

Assignment of patients to the placebo vs. acetaminophen groups was blinded. However, assignment to dexmedetomidine vs. placebo couldn’t be blinded (because propofol’s white color is easily identified).

Groups were well matched at baseline, albeit equally lacking in diversity:

Results are shown below. There was no statistically significant impact of using propofol or dexmedetomidine. This may be explained by the very short duration of sedation that patients were exposed to (usually under six hours).

The primary endpoint was acetaminophen’s effect on delirium. Acetaminophen did cause a statistically and clinically significant reduction in the incidence of delirium (from 28% to 10%). A quick back-of-the-envelope calculation shows:

p = 0.019 using Fisher’s Exact Test¹¹
Fragility index is 2.
Number needed to treat (NNT) is six.

Reduction in delirium is probably explained by the reduction in opioid use among patients treated with acetaminophen (although additional mechanisms, such as reduced inflammation and antipyretic effects, are certainly possible). Among patients treated with acetaminophen, reduced delirium translated into a shorter ICU length-of-stay. Time-to-event analysis confirms these findings:

Conclusions on the DEXACET trial

This study shows that acetaminophen reduces the rate of delirium, possibly by reducing the use of opioid. Statistically this is not an extremely robust trial (with a fragility index of two).

From a Bayesian perspective, prior studies indicate that acetaminophen reduces opioid use. This makes it likely that acetaminophen would reduce delirium. Therefore, the study’s conclusions appear valid (even without definitive statistics). However, it should be recognized that this study alone constitutes only a moderate level of evidence and should ideally be replicated.¹²

Intravenous vs. oral acetaminophen?

Many studies (including DEXACET) are pharma-sponsored studies of IV acetaminophen. Unfortunately, IV acetaminophen is bizarrely expensive in the United States (due partially to a price hike by Mallinckrodt pharmaceuticals, its cost in the US is ~10 times higher than in Australia).¹³ Would oral acetaminophen work equally well?

It should, yes. Available RCTs comparing oral versus intravenous acetaminophen have detected no difference in efficacy.^14–20 Perhaps in the immediate post-operative period before return of gut function, IV acetaminophen has a transient advantage. However, overall both forms seem to work equally well.

It would be great to see an RCT which shows that oral acetaminophen when used as an analgesic reduces opioid requirements and delirium in critical illness. However, it’s unclear whether anyone will ever fund such a study.

Needed research: acetaminophen-acetylcysteine combination therapy

N-acetylcysteine is available over the counter at minimal cost. It replenishes hepatic glutathione levels, therefore preventing or treating acetaminophen toxicity (more on this here). Theoretically, co-administration of acetaminophen and N-acetylcysteine could greatly reduce the risk of acetaminophen toxicity. This could allow for acetaminophen to be used in patients with cirrhosis or hepatic injury at standard doses (e.g. 4 grams daily).

The concept of co-administering acetaminophen and N-acetylcysteine is an old idea.²¹ In mice, pre-treatment with n-acetylcysteine prevents toxicity from even a very high acetaminophen dose.²² An RCT was designed to investigate this at Columbia University, but wasn’t completed due to logistic problems (NCT01137591).

This idea has languished due to its low cost and lack of corporate sponsorship. If successful, a study on acetylcysteine/acetaminophen (e.g. 1000 mg/1500 mg q6hr) could be more useful than yet another trial on IV acetaminophen. As we are increasingly moving away from opioids in all venues, a high-dose acetaminophen option could be welcome.²³

Acetaminophen has previously been shown to be an effective analgesic which can reduce opioid consumption.
DEXACET shows that in a cohort of critically ill post-cardiothoracic surgery patients, IV acetaminophen reduced the incidence of delirium. This suggests that acetaminophen use may offer meaningful, patient-oriented benefit.
Although DEXACET was performed with IV acetaminophen, other studies have found equivalent efficacy between either oral or intravenous forms.
Acetaminophen is probably an under-utilized analgesic among critically ill patients. For maximal efficacy, oral acetaminophen should be given in substantial doses in a scheduled fashion (e.g. 1 gram q6-q8 hours scheduled, not 650 mg q8hr PRN).
DEXACET isn’t incredibly robust statistically (fragility index of two). However, it validates longstanding principles of analgesia (specifically, the “analgesic ladder”). Until further evidence is available, it’s sensible to use these principles in clinical practice. This isn’t a revolution, but rather a reminder of first principles.

Reengineering the analgesic ladder for critically ill patients (PulmCrit)

References & notes

Burry L, Williamson D, Perreault M, et al. Analgesic, sedative, antipsychotic, and neuromuscular blocker use in Canadian intensive care units: a prospective, multicentre, observational study. Can J Anaesth. 2014;61(7):619-630. [PubMed]

Nishimoto R. OFIRMEV: an old drug becomes new again. Anesth Prog. 2014;61(3):99-102. [PubMed]

Dixon J, Ashton F, Baker P, Charlton K, Bates C, Eardley W. Assessment and Early Management of Pain in Hip Fractures: The Impact of Paracetamol. Geriatr Orthop Surg Rehabil. 2018;9:2151459318806443. [PubMed]

Guo H, Wang C, He Y. A meta-analysis evaluates the efficacy of intravenous acetaminophen for pain management in knee or hip arthroplasty. J Orthop Sci. 2018;23(5):793-800. [PubMed]

Lee Y, Yu J, Doumouras A, et al. Intravenous Acetaminophen Versus Placebo in Post-bariatric Surgery Multimodal Pain Management: a Meta-analysis of Randomized Controlled Trials. Obes Surg. February 2019. [PubMed]

Shi S, Wang X, Song J, Guo S, Chen Z, Wang Y. Efficacy of intravenous acetaminophen in multimodal management for pain relief following total knee arthroplasty: a meta-analysis. J Orthop Surg Res. 2018;13(1):250. [PubMed]

Memis D, Inal M, Kavalci G, Sezer A, Sut N. Intravenous paracetamol reduced the use of opioids, extubation time, and opioid-related adverse effects after major surgery in intensive care unit. J Crit Care. 2010;25(3):458-462. [PubMed]

Jelacic S, Bollag L, Bowdle A, Rivat C, Cain K, Richebe P. Intravenous Acetaminophen as an Adjunct Analgesic in Cardiac Surgery Reduces Opioid Consumption But Not Opioid-Related Adverse Effects: A Randomized Controlled Trial. J Cardiothorac Vasc Anesth. 2016;30(4):997-1004. [PubMed]

Cattabriga I, Pacini D, Lamazza G, et al. Intravenous paracetamol as adjunctive treatment for postoperative pain after cardiac surgery: a double blind randomized controlled trial. Eur J Cardiothorac Surg. 2007;32(3):527-531. [PubMed]

10.

Subramaniam B, Shankar P, Shaefi S, et al. Effect of Intravenous Acetaminophen vs Placebo Combined With Propofol or Dexmedetomidine on Postoperative Delirium Among Older Patients Following Cardiac Surgery: The DEXACET Randomized Clinical Trial. JAMA. 2019;321(7):686-696. [PubMed]

11.

This is higher than the reported p-value in the manuscript of 0.01. The manuscript is vague about what statistical test was used here, stating “Differences in categorical variables, including the primary outcome (in-hospital delirium), were assessed with a chi-squared test (or a 2-tailed Fisher exact test when cell counts were small).” It appears that the authors used an uncorrected Chi-square test to obtain a p-value of 0.01. Given the small number of events (as few as six), an uncorrected Chi-square might under-estimate the p-value here.

12.

In a prior publication regarding this study, the authors wrote “Depending on what this study shows, the obvious next step will be a larger multicenter trial.”(PMID 29333240). However, now that the authors and industry sponsors have obtained a positive study in JAMA, enthusiasm for a replication study will rapidly wane. In particular, this would seem to be an unwise investment for industry sponsors.

13.

Chiam E, Weinberg L, Bellomo R. Paracetamol: a review with specific focus on the haemodynamic effects of intravenous administration. Heart Lung Vessel. 2015;7(2):121-132. [PubMed]

14.

Gollamudi J, Marks S. Oral versus Intravenous Acetaminophen #302. J Palliat Med. 2016;19(2):231-232. [PubMed]

15.

Fenlon S, Collyer J, Giles J, et al. Oral vs intravenous paracetamol for lower third molar extractions under general anaesthesia: is oral administration inferior? Br J Anaesth. 2013;110(3):432-437. [PubMed]

16.

Liang L, Cai Y, Li A, Ma C. The efficiency of intravenous acetaminophen for pain control following total knee and hip arthroplasty: A systematic review and meta-analysis. Medicine (Baltimore). 2017;96(46):e8586. [PubMed]

17.

Hickman S, Mathieson K, Bradford L, Garman C, Gregg R, Lukens D. Randomized trial of oral versus intravenous acetaminophen for postoperative pain control. Am J Health Syst Pharm. 2018;75(6):367-375. [PubMed]

18.

Furyk J, Levas D, Close B, et al. Intravenous versus oral paracetamol for acute pain in adults in the emergency department setting: a prospective, double-blind, double-dummy, randomised controlled trial. Emerg Med J. 2018;35(3):179-184. [PubMed]

19.

Sun L, Zhu X, Zou J, Li Y, Han W. Comparison of intravenous and oral acetaminophen for pain control after total knee and hip arthroplasty: A systematic review and meta-analysis. Medicine (Baltimore). 2018;97(6):e9751. [PubMed]

20.

Nichols D, Nadpara P, Taylor P, Brophy G. Intravenous Versus Oral Acetaminophen for Pain Control in Neurocritical Care Patients. Neurocrit Care. 2016;25(3):400-406. [PubMed]

21.

Mehrpour O, Ballali-Mood M. Why not formulate an acetaminophen tablet containing N-acetylcysteine to prevent poisoning? J Med Toxicol. 2011;7(1):95-96. [PubMed]

22.

James L, McCullough S, Lamps L, Hinson J. Effect of N-acetylcysteine on acetaminophen toxicity in mice: relationship to reactive nitrogen and cytokine formation. Toxicol Sci. 2003;75(2):458-467. [PubMed]

23.

It’s controversial if and where an analgesic ceiling exists for acetaminophen. Some evidence suggests that 1000 mg is below the analgesic ceiling, with higher doses being potentially more effective (PMID 9516030). Currently this is an irrelevant question because higher doses of acetaminophen could cause hepatic injury. If acetaminophen/acetylcysteine could be shown to be safe, this could potentially open the door for investigating the use of higher doses of acetaminophen for various types of pain.