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.
