ICU JC 10/13/11

Therapeutic hypothermia in action

Dr. Xuan presented a retrospective study of therapeutic hypothermia (TH) after cardiac arrest due to PEA and asystole.

It is well-established that therapeutic hypothermia following out-of-hospital arrest due to shockable rhythms is associated with improved neurological outcome in survivors, and current AHA guidelines recommend cooling for twenty-four hours in any unconscious survivor of out-of-hospital VF arrest.  However, it is not clear whether this benefit extends to inpatients, or to patients presenting with non-shockable rhythms.

This trial assessed data prospectively collected at Hartford Hospital in Connecticut to determine whether the introduction of a cooling protocol for patients resuscitated from non-shockable rhythms changed outcomes for those patients.  The trial group was compared to a group of historical controls, and the investigators claimed to have found a statistically significant difference in neurological outcome, which is consistent with the results of other observational studies and meta-analyses.  However, the study had a number of limitations which came out in the discussion which followed Dr. Brah's presentation.

Dr. Bhuket emphasized how important it is to carefully review the baseline characteristics of the treatment and control groups in any type of trial ("Always look at Table 1").  He pointed out that in this study, the two groups differed markedly in age, presenting rhythm, whether the arrest was witnessed, and other characteristics presumably important to the outcomes observed.  He also drew attention to the fact that the authors are employed to promote the device used to induce hypothermia in the study.

Dr. Subramanian noted that, given that medical care is always changing, the use of "historical controls" is always perilous.  She wondered whether it's genuinely plausible that over the six-year period during which data were collected, nothing changed in post-cardiac arrest care at Hartford hospital besides the use of therapeutic hypothermia, and whether this might further confound the results. 

The expert consensus was that there may be reasons to use therapeutic hypothermia after resuscitation from a non-shockable rhythm, but that they should not be drawn from a study with as many methodological limitations as this one.

It's worth noting that there are two typos in this article in its present form:

1. The authors say that they calculated a NNT from the "absolute risk ratio."  This is an accidental compound of "absolute risk reduction," which is what you calculate the NNT from, and "relative risk ratio," which has nothing to do with absolute risk changes.  When I contacted Dr. Lundbye, he confirmed that this was a typographical error.
2. The NNT to achieve "one favorable neurological outcome" is given as 5.  However, if you calculate it from the data in presented in the paper, it's actually 6.  The difference is trivial in this instance, but reminds us to check others' work rather than accepting it without question.

Curare (source of the first NMJ blockers)

Dr. Indulkar presented a randomized, controlled trial of cisatracurium in early ARDS which tested the hypothesis that early paralysis might confer improved 90-day mortality.

Patients randomized to the treatment arm received cisatracurium besylate for 48 hours.  In an effort towards blinding, the investigators prohibited the use of peripheral nerve stimulators to objectively confirm paralysis, and patients randomized to the control group received a placebo infusion.  The authors managed to demonstrate a statistically significant difference only in "adjusted" 90-day mortality (although the difference in crude mortality was nearly significant with a p value of 0.08), and in some of their secondary end points.  The discussion focused on the validity of the study's results, and some important points came up.

Dr. Schub and Dr. Sackrin agreed that it would be very premature to implement early paralyis in ARDS on the basis of this study for several reasons.  First, Dr. Sackrin noted, the test used to establish the incidence of ICU-acquired paresis was crude and the investigators may therefore have underestimated the harm associated with their treatment.  He also noted that it would be hard to generalize the results to our patients, since we use vecuronium almost exclusively in patients with normal renal function. 

Dr. Feeney, who had pulled the article's enormous appendix and read through its long tables of vent-setting data, pointed out something very interesting: the proposed mechanism of increased survival in the trial was improved patient/ventilator synchrony.  However, there are no differences in the vent data between the two group suggesting a higher prevalence of dysynchrony in the control group - so that mechanism isn't supported by their actual data.  He also thought generalization to our patients would be problematic, because the data in the appendix showed oxygen saturations much higher than those we typically aim for in ARDS and a general reliance on a high FiO2, low PEEP ventilation strategy, which is also significantly different from our practice.

Dr. Subramanian drew attention to three important problems with the article:

1. The Kaplan-Meier survival curve presented in Figure 2 shows a divergence in probability of survival at 12 days.  However, the drug was given only in the first 48 hours.  This makes a neat causal relation difficult to imagine, and should make one suspect the presence of unmeasured confounders.
2. Cisatracurium is associated with tachyphylaxis, and because objective measurements of paralysis were not allowed, it's impossible to know who was actually paralyzed.
3. The assumptions about mortality used to power the study turned out to be incorrect, so the study itself was ultimately underpowered to demonstrate its primary outcomes.
   

Child in a Ugandan hospital

Dr. Brah presented a trial which compared bolus fluid resuscitation to no specific fluid resuscitation therapy in febrile, hypotensive children presenting to district hospitals in three East African countries.

This was a prospective, multi-center, open-label trial comparing fluid resuscitation with boluses of either normal saline or 5% albumin.  Children with severe febrile illness and impaired perfusion were included; children were excluded if they had severe malnutrition, gastroenteritis, non-infectious causes of shock, or contraindications to volume-expansion.  All participating children received antibiotics, antipyretics, antimalarials and other standard therapies for severe infection according to national guidelines.

Why, you may be asking yourself, was this study, which looked at rural African children, presented at a meeting attended exclusively by internists practicing in an American city?  Because of its alarming and unexpected results.

48-hour mortality in the saline-bolus group was 10.5%, in the albumin-bolus group it was 10.5%, and in the control group it was 7.3%, suggesting an absolute risk increase of about 3% associated with fluid resuscitation.  They also observed a risk increase of 4% at 4 weeks for death, neurologic sequelae, or both in the two resuscitation groups.  Subgroup analysis did not identify any group for which fluid resuscitaion was beneficial.  Interestingly, most deaths were not obviously associated with the recognized ill-effects of over-resuscitation in children, e.g. pulmonary edema and elevated ICP.

This article generated a very lively discussion. 

Dr. Rose and Dr. Schub were deeply concerned about the ethics of the study.  Dr. Rose expressed doubt that legitimate informed consent could have really been obtained under the conditions which prevailed at the study centers, while Dr. Schub saw serious problems testing a therapy with predictable adverse effects (such as pulmonary edema) in the absence of means for dealing with them (such as positive-pressure ventilation).

Dr.s Feeney, Subramanian, Sackrin, and Fried agreed that the study was primarily interesting as a hypothesis-generator, and because it calls into question ideas which have become axiomatic in the treatment of sepsis.  Dr. Feeney pointed out that, a few decades ago, a similar orthodoxy prevailed about the beneficial effects of blood transfusion - an orthodoxy which has been completely overturned by an increasingly robust body of evidence.  He quoted one of Dr. Schub's favorite aphorisms, which states that "the half-life of medical truth is about three years." "Why," he asked, "does God make you anemic?  Why does God make you hypotensive?"
While declining to add to Dr. Feeney's theological speculations, Dr. Sackrin called the study's results "humbling."  Finally, Dr. Subramanian pointed out that one plausible mechanism for the increase in observed mortality might be rapid hemodilution, since the excess mortality was mainly observed in children presenting with a hemoglobin level less than 5 grams per deciliter.