Without evidence of benefit, an intervention should not be presumed to be beneficial or safe.

- Rogue Medic

Do Paralytics Improve Outcomes Following Resuscitation?

ResearchBlogging.org
 

This study will get some people excited because of an impressive p value for an odds ratio of improved cardiac arrest outcomes – 7.23 (1.56–33.38) p = 0.01.

NMBs (NeuroMuscular Blockers/Blockade) are paralytic drugs that are used to prevent movement by the patient. Does this study truly show that immediate use of NMBs improves neurologically intact survival from cardiac arrest?
 

Side effects of therapeutic hypothermia include an increased risk for arrhythmia, infection or bleeding, and shivering.6 [1]

 

NMBs could cause worse outcomes from therapeutic hypothermia use following ROSC (Return Of Spontaneous Circulation).
 

the American Heart Association (AHA) has recommended minimizing the use of NMB in post-CA patients or avoiding it altogether.11 [1]

 

Is this enough to get the AHA to change their minds?
 

We included patients who were 18 years of age or older who had suffered OHCA with sustained ROSC (defined as the presence of palpable pulses for >20 min) and who were comatose (not following commands) upon presentation to the NPARC hospital.[1]

 

That is an unusual definition of comatose. It would be interesting to know how many patients had a GCS (Glasgow Coma Score) of at least 8, but were not following commands. Many people are taught that a low GCS means that we should intubate. The mnemonic Less than 8 – intubate, is taught as if it is a substitute for a thorough assessment.

Maybe not following commands is the right metric to use for administration of NMBs, but we might want to describe this level of consciousness with a term other than coma. There is a lot of connotation associated with coma that might complicate decisions about treatment. If we use NMBs for patients with ROSC and a motor score of less than 6, will some people start to use a motor score of less than 6 for intubation with NMBs? RSI (Rapid Sequence Induction/Intubation) is the use of NMBs to facilitate intubation. A better question is How many of us will do this?, rather than Will any of us will do this?
 

Continuous neuromuscular blockade is associated with decreased mortality in post-cardiac arrest patients - Fig 1
 

Impressive.

So why am I suggesting caution?
 

Compared to those who did not receive sustained NMB, patients with 24-h NMB had shorter intervals from collapse-to-ROSC (13 min [IQR: 9–25] versus 22 min [IQR: 13–30]; p = 0.04) and higher baseline blood pH values (pH = 7.30 [IQR: 7.26–7.36] versus 7.22 [IQR: 7.12–7.31]; p = 0.04). There was a lower incidence of chronic obstructive pulmonary disease in patients with NMB compared to patients without NMB (0% versus 22%; p = 0.02).[1]

 

Time to ROSC demonstrates one of the problems with small numbers. The IQRs (InterQuartile Ranges) do not show that much difference, but the median times to ROSC are much farther apart. 22 minutes is in the middle of the 13-30 minute IQR for control patients, but 13 minutes is much quicker than the middle of the IQR for NMB patients.

Why does this matter?

The control patients appear to be evenly distributed around 22 minutes from collapse to ROSC, but the NMB patients had an uneven distribution that masks a tendency toward much quicker ROSC.
 

It is also odd that the group with the smaller numbers has a narrower IQR. Is this because of some uncontrolled variable in choosing which patients received early, sustained NMB treatment?
 

This is a post hoc analysis of data collected for a study with a different hypothesis, so the best that can be stated is that immediate NMB use (continued for 24 hours) is a promising treatment for further study.

Another big problem with this study is that it is so small. 18 patients received NMBs. The authors started the paper by mentioning that there are 400,000 cardiac arrests in the US each year. We need to demonstrate benefit on much more than 18 patients, regardless of p value, if we are going to start using this treatment outside of controlled trials.
 

There were 77 (69%) patients documented to have received NMB at any point within the first 24 h following ROSC. A portion of these patients (18/111, 16%) patients had NMB initiated immediately and sustained for a minimum duration of 24 h following return of circulation.[1]

 

This is not really a study comparing NMB use with absence of NMBs. This is a study comparing immediate NMB use that was continued for at least 24 hours against control group patients – most of whom received NMBs, but did not meet the full criteria for inclusion in the study group.

How different were the treatments? We do not know.

59 out of the 111 patients in the No NMB group received NMBs.

53% of the No NMB group did receive NMBs, just not for at least 24 hours and/or not immediately following ROSC. Correction – 15:20 7/08/2013.

59 out of 93 patients in the No NMB group received NMBs.

63% of the No NMB group did receive NMBs, just not for at least 24 hours and/or not immediately following ROSC.
 

The following is the main limitation pointed out by the authors.
 

An important limitation of this observational study is the uncertainty about why NMB was used in certain patients. It is possible that patients with more intact reflexes, shivering or spontaneous movement were more likely to receive NMB than patients with less vigorous neurological examinations. Thus, the possibility remains that patients without sustained NMB were less responsive (i.e., worse neurological status) and therefore did not clinically require continued therapy therefore creating selection bias. Finally, whether heavy sedation in the post-CA period would confer similar results is possible but has yet to be explored.[1]

 

Is a good physiologic explanation is leading them to minimize the weaknesses of this study? I don’t know, but they are not recommending anything other than more study, which is a reasonable conclusion for this study.

Unfortunately, the abstract presents a different conclusion – a conclusion that assumes too much.

I would discuss the physiology that is the basis for this study, but with no clear evidence of benefit and a lot of evidence that the data are misleading, there is no reason to spin tales about any possible mechanism(s).

The hypothesis is still essentially untested.

Footnotes:

[1] Continuous neuromuscular blockade is associated with decreased mortality in post-cardiac arrest patients.
Salciccioli JD, Cocchi MN, Rittenberger JC, Peberdy MA, Ornato JP, Abella BS, Gaieski DF, Clore J, Gautam S, Giberson T, Callaway CW, Donnino MW.
Resuscitation. 2013 Jun 21. doi:pii: S0300-9572(13)00331-6. 10.1016/j.resuscitation.2013.06.008. [Epub ahead of print]
PMID:23796602[PubMed – as supplied by publisher]
 

The National Post-Arrest Research Consortium (NPARC) is a clinical research network conducting research in post-cardiac arrest care. The network consists of four urban tertiary care teaching hospitals and was established to evaluate treatment strategies for individuals who are successfully resuscitated after out-of-hospital cardiac arrest. The current investigation is a post hoc analysis of a prospectively conducted NPARC trial evaluating mitochondrial injury in post-cardiac arrest patients (NIH 3UL1RR031990-02S1).

Salciccioli JD, Cocchi MN, Rittenberger JC, Peberdy MA, Ornato JP, Abella BS, Gaieski DF, Clore J, Gautam S, Giberson T, Callaway CW, & Donnino MW (2013). Continuous neuromuscular blockade is associated with decreased mortality in post-cardiac arrest patients. Resuscitation PMID: 23796602

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