Category: Sepsis

C1-Esterase Inhibitor Might Improve Some Sepsis Outcomes

…or it might not.  This is a tiny study using a very expensive medication that probably works only on a few patients, but it’s interesting nonetheless.

As part of the inflammatory cascade, C1-esterase inhibitor (C1INH) modulates the coagulation cascade, impacts leukocyte activation, enhances bactericidal activity, and prevents endotoxin shock in sepsis models.  So, sounds like a good thing – let’s give it to patients and see what happens!

This was an open-label, randomized, controlled study in Moscow and St. Petersburg with 62 ICU patients – 20 controls and 42 treatment patients – that met inclusion criteria.  There were, unfortunately, a lot of differences between the control group and the treatment group.  These differences included a lot more post-operative patients, much more pneumonia, and more on the ventilator, and probably favored the treatment group.  The mortality is way better for the treatment group – 12% dead versus 45% – but it’s simply impossible to attribute all the effects to C1INH with all the other confounding differences.

That being said, this study is consistent the effects from other small studies.  Therefore, we will likely hear more about C1INH after larger, manufacturer-sponsored trials also undoubtedly find a way to spin positive results.

“C1-esterase inhibitor infusion increases survival rates for patients with sepsis”
www.ncbi.nlm.nih.gov/pubmed/22080632

Another Call to Retire Dopamine

The slow, gradual shift from dopamine to norepinephrine as the vasopressor of choice in septic shock has another piece of ammunition – this time a meta-analysis of the observational and randomized trials.

They perform two separate analyses – an analysis of five observational trials and an analysis of six randomized trials.  They find heterogeneity and no difference in the observational analysis – and then drop the observational trial responsible for the heterogeneity, and find an RR for mortality of 1.23 favoring norepinephrine.  Then, with the randomized trials, they find an RR for mortality of 1.10 favoring norepinephrine.  The RR for arrhythmias associated with dopamine use was 2.34 in their pooled analysis.

Of the RCTs, most of the patients came from one trial with 1044 patients and includes four trials with fewer than 50, so it’s not exactly as though this analysis adds a lot of statistical power – but it’s enough to reinforce the trends from each trial.

It is reasonable to suggest that norepinephrine is superior to dopamine – but I would also suggest the magnitude of that difference, given the data we have so far, has only been shown to be small.

“Dopamine versus norepinephrine in the treatment of septic shock: A meta-analysis”
http://www.ncbi.nlm.nih.gov/pubmed/22036860

No Reversing The Harm of Etomidate

A small, but growing body of evidence is starting to correlate the physiologic adrenal suppression of etomidate with worsening clinical outcomes.  This study is a French prospective cohort that really likes etomidate for RSI, so, they decided to ask the question whether a continuous hydrocortisone infusion has any substantial effect on cardiovascular parameters in the setting of etomidate use.

Short answer, no.

Their randomized groups are awfully small – 45 patients in each group – so their power to detect a difference is not great.  But, at the minimum, there’s no profoundly obvious difference or any seemingly clinically significant trend between the two groups.

I trained using etomidate for everyone, but I’ve almost completely moved to alternative agents, ketamine being the most prominent of those agents.  Most significantly, ketamine differs from the other agents in terms of having analgesic properties as well, and I think it is reasonable to provide some treatment for the pain associated with laryngoscopy.  There is evidence that ketamine is a myocardial depressant and may be deleterious in patients with limited cardiac reserve, but so far in limited literature it holds up clinically well against etomidate and midazolam.

“Corticosteroid after etomidate in critically ill patients: A randomized controlled trial”
http://www.ncbi.nlm.nih.gov/pubmed/21926601

“Intubating ICU patients with ketamine: adverse effects that can occur.”
http://www.ncbi.nlm.nih.gov/pubmed/18079246

Algorithmic Approach To Detect Sepsis Fails

I was asked to blog about this little article – since it lies at the intersection of Emergency Medicine and informatics.

So, that feeling you get when you look at a patient who is obviously ill?  Computers don’t have that yet.  These folks tried to encapsulate that feeling of “sick” vs. “not sick” into the criteria for severe sepsis, which includes SIRS and hypotension.  The hope was that an algorithmic approach that automatically recognized the vital sign and physiologic criteria for SIRS would trigger reminders to clinicians that would spark them to initiate certain quality care processes sooner.
Out of 33,460 patients processed by the system, 398 triggered the system.  Less than half (46%) of those were true positives.  To follow that up, they tried to evaluate their system for sensitivity and specificity by pulling 1 week’s worth of data (1,386 patients) for closer review – and they found the system generated 6 false positives, 7 true positives, and 4 false negatives.  And those numbers speak for themselves.
Looking back at their four quality measures, they all showed a trend towards improvement – unfortunately three of their four quality measures don’t even have a theoretical connection to improved outcomes.  Chest x-ray, blood cultures, and measuring a serum lactate are all clinically relevant in certain situations, but they are all diagnostic and management decisions independent of “quality”.  Antibiotic administration, however, is part of EGDT for sepsis (for what it’s worth), and that trended towards improvement (OR 2.8, CI 0.9 to 8.6).  
But the final killer?  “In approximately half of patients electronically detected, patients had been detected by caregivers earlier”.  So, clinicians were receiving automated pages suggesting they might consider an infectious cause to hypotension, probably while already placing central lines for septic shock.
Great concept – but automated systems just don’t yet have robust, rapid, high-quality inputs like those a clinician gets just by walking in the room.  But, EM physicians in busy departments overlook things – and a well-designed system might in the future help catch some of those misses.
“Prospective Trial of Real-Time Electronic Surveillance to Expedite Early Care of Severe Sepsis.”

Fluid Boluses Increase Mortality In Children

…or, at least, that’s the gist of the New England Journal Article making rounds in the news.

And, while a close reading of the article doesn’t offer great support for harm, it certainly supports saying that albumin, saline, or nothing were equivalent.

The absolute difference in survival was 3% – and, looking at the demographic breakdown, there were 2-3% differences or trends in favor of the control group regarding dehydration, acidemia, base-deficit, and bacteremia.  Enough that it lets me cling in denial to standard practice and teaching here in the U.S., in addition to whatever you want to say about external validity of a study in resource-poor settings in Africa.

It is an odd and unexpected finding, so say the least.  The authors attribute at least part of the unusual discovery to the high percentage of malaria cases they treated, and that fluid resuscitation in malaria is controversial – but regardless, this is going to be a frequently discussed study on the Pediatric Critical Care side of things for some time.  I also expect follow-up confirmatory studies to be a tough sell to U.S. IRBs.

http://www.nejm.org/doi/full/10.1056/NEJMoa1101549

Red Cell Distribution Width… Means What Now?

“Red cell distribution width is a robust predictor of… all-cause patient mortality.”

I saw this article when I was browsing abstracts, and I thought, “Huh!  That sounds interesting, though, probably not relevant.”

So, yes, increasing red cell distribution width is associated with increased mortality.  However – and this is something I’ve never seen before in an article – looking at the table describing the differences between their various divisions of RDW% – every other descriptive statistic is different between groups.  More septic patients with high RDW%.  More renal failure.  Differences in hematocrit.  More organ failure.  They claim by statistical multivariate massage, that RDW shakes out as an independent factor, but, sheesh…it’s almost like saying decrease in temperature is highly associated with death, when they’re cold because the blood isn’t circulating, the breathing has stopped, the brain has shut down, etc….

Another fine example of where reading the abstract is absolutely no replacement for perusing the article.

http://www.ncbi.nlm.nih.gov/pubmed/21532476

Pediatric Septic Shock Protocol

Another sort of goal-directed sepsis study, this time in Pediatrics at Primary Children’s.  They implemented a protocolized triage system in their ED designed explicitly identify more cases of sepsis – which led to increased percentages getting early fluid resuscitation, early lactate level measurements, and more frequently antibiotics in the first three hours.

But the net effect of all these interventions…the only detectable difference in their 345 patient cohort was improved length-of-stay for survivors, from IQR 103-328 hours pre-intervention to IQR 86-214 post-intervention.  Total hospital costs were not significantly different.  No change in mortality – which was already low at 7%.
So, yet again – adherence to “quality measures” has debatable clinical significance.

Procalcitonin Misleads Antibiotic Therapy In Sepsis

An important negative study of an inflammatory biomarker that’s been getting a fair amount of push.

It is absolutely true that procalcitonin levels may be elevated in an inflammatory states such as sepsis.  This group tried to make a clinically relevant protocol for procalcitonin trends by saying, if the procalcitonin level is not decreasing with current therapy, then antibiotic coverage should be expanded and aggressive testing should be undertaken to evaluate for missed source control.

Unfortunately, in the treatment arm where procalcitonin was used in clinical decision making, there was extensively greater broad-spectrum and multiple-antibiotic utilization without any demonstrated mortality benefit.  In addition, LOS and ventilator-depended days were longer in the procalcitonin arm.

There were very minor differences between the two groups, probably favoring the control, but not nearly enough to suggest that procalcitonin has any value in assessing failure of current therapy.

http://www.ncbi.nlm.nih.gov/pubmed/21572328

Early Antibiotics Show No Benefit in Sepsis

Interesting analysis of the EMSHOCKNET cohort, looking to see if there was any association between time to antibiotic administration and survival benefit in septic shock.

And, no.  Earlier antibiotic administration, as measured by arrival time in the the ED, showed no significant impact.

They do another secondary analysis where they try to say, well, if the patient received antibiotics before they met criteria for septic shock – then they had a 2.59 (1.17 – 5.74) OR for survival.  I’m not sure how to interpret this finding – perhaps because they looked at 10 different cut-off points for antibiotic administration, they found one that favored antibiotics by chance.

Or, perhaps antibiotics really aren’t the lynchpin in treating sepsis – if you can give antibiotics ahead of SIRS, perhaps you have a milder case – but once you have end-organ dysfunction, the interventions that target improving the physiologic changes of sepsis are more important.

http://www.ncbi.nlm.nih.gov/pubmed/21572327