April 2011 Critical Care Journal Club

Reference as : Raschke RA. April 2011 Critical Club Journal Club. Southwest J Pulm Crit Care 2011;2:59-64. (Click here for PDF version )

This month’s Journal club focused on a couple of recent articles from the trauma literature.   Even though we don’t often have primary responsibility for the care of trauma patients, it’s important for the fellows to know about major advances in the field.  It’s also useful to consider how the trauma intensivists might deal differently than we would in areas of shared interest, such as hemorrhagic shock, and prevention of VAP.  Corey Detlefs MD – a senior member of our trauma team – was kind enough to join us to help lend perspective to our discussion.  Dr. Bajo, our senior intensivist, Dick Gerkin MD, our statistician, and Dr. Robbins all participated.    

The CRASH-2 Investigators.  The importance of early treatment with tranexamic acid in bleeding patients: an exploratory analysis of the CRASH-2 randomized controlled trial.  Lancet 2011; 377:1096-101.  (Click here for the abstract of the manuscript)

A difficult study for us to review.  Tranexamic acid is an inhibitor of fibrinolysis, and the original CRASH-2 study was a multicenter RCT with over 20,000 patients that showed a significant reduction in all cause mortality (RR 0.91 p=0.0035) when tranexamic acid was given to trauma patients who were bleeding or at risk for bleeding.  This study we reviewed is a re-analysis of the CRASH-2 data to determine if the observed benefit was due to a decrease in hemorrhagic death.  This makes sense since the original hypothesis was that tranexamic acid might prevent bleeding.  What confused us right from the start is that we apparently are not using tranexamic acid in our trauma patients – and we weren’t sure whether this was because the original study just hasn’t impacted bedside practice yet, or whether there was some reason to reject the conclusion of the original study based on critical appraisal. 

The study is quite impressive at face value.  It was conducted in 274 hospitals in 40 countries, and randomized 20,211 patients to tranexamic acid vs. placebo.  This did not seem like a data-dredging expedition - It makes sense to perform a re-analysis of death due to hemorrhage.  A subgroup analysis (that was planned a-priori) also made sense.  This examined the relationship between delay in treatment and benefit. 

The method of the original study was not fully reiterated in this re-analysis, but the general method and statistics seem appropriate.  The study showed a reduction in the risk of bleeding death (RR 0.85, 95% CI 0.76-0.96, p=0.0077).  The study showed strong evidence that this benefit depended on how rapidly the treatment was given p<0.0001, with the best benefit in patients who received it within 1 hour of injury (RR 0.68, 95% CI 0.57-0.82, p<0.0001).  These findings are not only highly statistically significant, but they are biologically plausible.  The main problem with the results is that the effect size is extremely small.  The absolute reduction in bleeding death observed in the treatment group is only 0.8%, so the number needed to treat is 125.  Thus, although statistically significant, the potential clinical benefit for an individual patient is quite small - more on this later, in our review of statistics for the month.

Roquilly A et al.  Hydrocortisone therapy for patients with multiple trauma.  JAMA 2011; 305:1201-9. (Click here for abstract of manuscript)

This was a randomized controlled trial that enrolled 150 trauma patients from 7 centers in France.  Patients were assigned to receive hydrocortisone infusions for a week, versus placebo infusions.  The main outcome measure was the incidence of hospital acquired pneumonia within 28 days.

Leaving out the unnecessary “modified” analysis, the study showed that steroids reduced hospital acquired pneumonia by about half (p=0.007), reduced ventilator length-of-stay (LOS) by 4 days (p=0.001), and reduced ICU LOS by 6 days (p=0.03).

But the study has some problems.  The authors provide some background for why they thought steroids might prevent pneumonia, but the biological plausibility seems a stretch.  Approximately 80% of potentially eligible patients failed to meet stringent inclusion/exclusion criteria, narrowing the generalizability of the study.  The diagnosis of hospital-based pneumonia is based on individual criteria that lack specificity – theoretically, even if the only action hydrocortisone produced was amelioration of fever, the apparent rate of pneumonia would decline, since fever is one of criteria for diagnosis of pneumonia.

But perhaps the strongest reason to doubt the conclusions of this study is historical.  Dozens of studies, over decades, have examined possible therapeutic effects of steroids in critically-ill patients.  Early enthusiasm is almost always followed by disappointment.  This study cannot be appraised without considering this history.  It would indeed be surprising if further studies unequivocally confirm these findings. 

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We had the opportunity at this point to pick Dr. Detlef’s brain regarding resuscitation in the trauma ICU, and I’m going to depart from discussion of specific articles for a moment to recall some of his comments.  Most came forth during our discussion of the CRASH-2 study.  One of the fellows pointed out that hemorrhagic shock in the trauma ICU is not all that different than hemorrhagic shock in the medical unit.  With that in mind, Dr. Detlef’s comments bear consideration.

One of the current concepts in trauma resuscitation came from observational data gathered by the military in Iraq and Afghanistan in regards to administration of whole blood.  Whole blood is generally not available in most stateside institutions, but the trauma intensivists have increasingly favored the concept of “whole blood equivalent” when transfusing blood products to patients with life-threatening hemorrhage.  This entails giving a 1:1:1 ratio of packed red blood cells, fresh frozen plasma, and single donor platelets. 

“Permissive hypotension” is another interesting concept in the trauma literature related to hemorrhagic shock.  This strategy involved intentional under-resuscitation – only giving the minimal amount of IV fluids and pressors necessary to maintain life until the source of bleeding is surgically controlled.  This is based on the concepts that early normotension may increase locally-uncontrolled bleeding, and that massive crystalloid administration might have deleterious effects.

These concepts are not yet supported by strong experimental data.  They should be considered as interesting hypotheses that might lead to future research.  Thanks Dr. Detlefs. 

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Back to the articles:  Brief mentions:

Tierney LM et al.  Case 10-2011: A woman with fever, confusion, liver failure, anemia and thrombocytopenia.  New Engl J Med 2011;364:1259-70. (Click here for abstract of the CPC). This CPC was included to point out that secondary hemophagocytic lymphohistiocytosis (HLH) can present as SIRS / severe sepsis / septic shock in adults.  The diagnosis should be suspected when such a patient fails to improve with antibiotics, and multisystem organ failure with bi- or pancytopenia develops.  Bone marrow aspiration is often key to the diagnosis.  Secondary HLH is likely an under-appreciated clinical syndrome.  We have recognized several cases in the past two years. 

Dallas J et al.  Ventilator- in a mixed surgical and medical ICU population.  Chest  2011;139:513-8. (Click here for abstract of manuscript) I thought the concept of ventilator-associated tracheobronchitis (VAT) was interesting.  Essentially, the diagnostic criteria are the same as for VAP, except without lung infiltrates.  From a bedside perspective, this distinction seems impractical.  Few of our ICU patients have clear chest x-rays.  Fleeting infiltrates of unclear significance are commonly seen, and may be attributable to non-infectious processes in many cases.  The author’s conclusion that VAT should be treated with antibiotics may turn out to be proven someday, but is entirely unsupported by their data. 

Levitan RM, et al.  The complexities of tracheal intubation with direct laryngoscopy and alternative intubation devices.  Ann Emerg Med 2011;57:240-47. (Click here for abstract of manuscript) This article is worth reviewing if you are considering purchasing a laryngoscope with advanced optics, like a Glidescope® or C-mac®.   It reviews theoretical and clinical pros and cons of each of the devices.  The gist of the literature in this regard seems to be that these devices should be made available in institutions where physicians might be called upon to manage difficult airways, and that intensivists should pursue experience in their use. 

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Biostatistics comments:

Number needed to treat (NNT)

From: The CRASH-2 Investigators.  The importance of early treatment with tranexamic acid in bleeding patients: an exploratory analysis of the CRASH-2 randomized controlled trial.  Lancet  2011;377:1096-101. 

The NNT is a statistic used to express effect size.  It expresses the number of patients that would have to undergo a therapy in order to prevent a single bad outcome.   It is especially useful in very large clinical trials (like the CRASH-2 study; N = 20,211). Very large clinical trials tend to have enormous power.  Power is the ability to statistically demonstrate a difference when it really exists. This sounds like a good thing, and it usually is.  However, the power of a study is largely dependent on the effect size and sample size.  Thus, when a study has lots of power because of a huge sample size, it may yield a significant p value, even when the effect size is very small. This is why pharmaceutical companies invest millions of dollars to achieve a huge sample size (as in CRASH-2), when they suspect the benefit of their drug is very small.  In such cases, the statistical and clinical significance should be considered. 

NNT is mathematically defined as 1/(absolute effect size).  In CRASH-2, the absolute effect size is the difference in bleeding rates between the treatment and control groups (5.7% - 4.9% = 0.8% = 0.008).    1/0.008 = 125.  Thus the NNT is 125.  You have to give tranexamic acid to 125 patients in order to save one bleeding death.    

Robert A. Rashke MD, Critical Care Journal Club Editor