Propofol and sepsis

Motivation: Sepsis is one of the most common issues in the ICU, and for any number of reasons, patients with sepsis also could require intubation and sedation. Practically speaking, propofol and midazolam are both commonly used in the ICU for septic patients who require sedation, weighing their risks and benefits in the individual patient. There are some benefits of propofol over midazolam in critical care patients in general (1), so I wondered whether there were risks associated with using propofol in the setting of sepsis. This discussion excludes the issue of contaminated propofol preparations. I found one paper that raised clinical concerns about the association between propofol and infection/sepsis.

Study:  Haddad S, Tamim H, Memish ZA, Arabi Y. Association of preservative-free propofol use and outcome in critically ill patients. Am J Infect Control. 2011 Mar;39(2):141-7. 

Design: Nested cohort study of patients who were enrolled in a randomized control trial on another topic (comparing different regimens of insulin therapy). Patients who were on propofol were compared to those who were not on propofol, in terms of baseline characteristics and outcomes. ICU-acquired infections were defined as those found at least 48 hours after ICU admission and up to 48 hours after discharge, while ICU-acquired sepsis was defined as per standard criteria (2).

Results: There were differences in baseline characteristics between the two groups of patients; compared to no propofol, propofol group were more likely to be mechanically ventilated but less likely to have severe illness, chronic renal disease, immunosuppression or cardiovascular disease. In adjusted statistical analysis, propofol use was associated with increased risk of ICU-acquired infection (95 CI 1.17-3.05, p=0.009), and ICU-acquired severe sepsis and septic shock (95 CI 1.12-3.28,p=0.02). There were no statistically significant differences in ICU or hospital length of stay or ICU or hospital mortality (2). 

Discussion: This study had convincing evidence as above for a relationship between propofol use and infections, and discusses potential reasons why propofol may be associated with increased risk of infectious including impairment of host immune cell function, increased lipid levels affecting mitochondrial oxygen use, growth of bacteria in propofol emulsion, increased lipid caloric intake (2); however, it is important to emphasize that these are potential reasons based on studies or observations in other contexts that are not necessarily generalizable to the septic ICU patient. In terms of study limitations, it is important to note that the study showed a statistical association (not causation) between use of propofol and increased risk of ICU-acquired infection or sepsis in a post-hoc study on a trial designed for another indication (2). Noted that this study did not compare propofol versus midazolam, nor did I find a similarly designed study for midazolam.

I was surprised to see that there were several animal studies that showed benefit of propofol (versus no propofol) in animal models of sepsis. A few examples of these studies are here; most of the sample sizes are modest. In an animal study specifically designed to study the effect of propofol on a rat model of sepsis (cecal ligation and puncture), rats treated with early or late propofol had statistically significant higher survival rates than rats without propofol treatment (3). Propofol-treated rats also had statistically significant lower levels of ALT, AST, BUN, Cr and CK (3). In the same rat model of sepsis, rats treated with propofol had improved hypotension, lower plasma levels of TNF-alpha, IL-6, and more suppression of NF-kappaB activation (4). Another study reported that midazolam had an overall anti-inflammatory effect in a macrophage cell line through various mechanisms (5).

Looking for more studies of animal models of sepsis and sedation, I found a paper on the same rat model of sepsis comparing the effects of propofol and midazolam on neutrophil function (6). In both early and late time points of sepsis, propofol and midazolam decreased hydrogen peroxide production by neutrophils with propofol associated with statistically signficantly more decreased production than midazolam (6). These results suggest at least in the in vitro context that propofol might attenuate neutrophil function in this rat model of sepsis, favoring midazolam over propofol if results could be extrapolated to clinical context (6). Also, it was very interesting to note in this study that there was negligible effect of the lipid propofol carrier on neutrophil hydrogen peroxide production (6).

Conclusion: Overall, there lacks definitive evidence comparing propofol and midazolam in ICU patients with sepsis; however, one clinical study brought up concerning associations between propofol and ICU-related infection (2), while one animal model study showed that midazolam would be better than propofol in rat models of sepsis as it interfered less with neutrophil function (6). These concerns should be taken into account when weighing the risks and benefits of midazolam versus propofol for the septic ICU patient.

References:

1.     Carrasco G, Molina R, Costa J, Soler JM, Cabré L. Propofol vs midazolam in short-, medium-, and long-term sedation of critically ill patients. A cost-benefit analysis. Chest. 1993 Feb;103(2):557-64.

2.     Haddad S, Tamim H, Memish ZA, Arabi Y. Association of preservative-free propofol use and outcome in critically ill patients. Am J Infect Control. 2011 Mar;39(2):141-7.

3.     Bao HG, Li S. Effects of propofol on the outcomes of rats with sepsis. J Surg Res. 2011 Jun 1;168(1):e111-5. doi: 10.1016/j.jss.2010.12.034. Epub 2011 Jan 22.

4.     Song XM, Wang YL, Li JG, Wang CY, Zhou Q, Zhang ZZ, Liang H. Effects of propofol on pro-inflammatory cytokines and nuclear factor kappaB during polymicrobial sepsis in rats. Mol Biol Rep. 2009 Nov;36(8):2345-51. doi: 10.1007/s11033-009-9456-z. Epub 2009 Feb 4.

5.     Kim SN, Son SC, Lee SM, Kim CS, Yoo DG, Lee SK, Hur GM, Park JB, Jeon BH. Midazolam inhibits proinflammatory mediators in the lipopolysaccharide-activated macrophage. Anesthesiology. 2006 Jul;105(1):105-10.

6.     Inada T, Taniuchi S, Shingu K, Kobayashi Y, Fujisawa J, Nakao S. Propofol depressed neutrophil hydrogen peroxide production more than midazolam, whereas adhesion molecule expression was minimally affected by both anesthetics in rats with abdominal sepsis. Anesth Analg. 2001 Feb;92(2):437-41.