Category: Cardiac Arrest

Very little can reliably be espoused as beneficial in out-of-hospital cardiac arrest: high-quality CPR, and defibrillation of malignant arrhythmias. For each of these, the sooner the better. The remainder of Advanced Cardiac Life Support? Meh.

This population-based survey out of Japan looks at the increasing availability of automated electronic defibrillators for the lay public, frequency of their use, and impact on neurologic survival following OHCA. Between 2005 and 2013, the number of bystander-witnessed events in which an AED delivered a shock increased linearly from a mere 40 patients to 829 patients. Overall good or moderate cerebral performance at hospital discharge in those patients was 38.5%, including an astounding 46.6% in non-elderly adults. By comparison, bystander-witnessed OHCA patients found to be in ventricular fibrillation whose first shock was delivered by EMS demonstrated a CPC good or moderate of only 18.2%.

By all clinical measures, then, AEDs and early defibrillation in bystander-witnessed OHCA is a splendid thing. The authors estimate that public-access AEDs accounted for 201 additional neurologically-intact survivors annually in Japan by 2013.

One small catch – it required an installed base of 428,821 AEDs to garner this small benefit. Considering most AEDs are priced well over USD$1000, this represents at least half-a-billion $USD investment for the 800-odd additional neurologically intact survivors identified during the study period. The magnitude of individual benefit is high – but it’s not cheap!

“Public-Access Defibrillation and Out-of-Hospital Cardiac Arrest in Japan”

http://www.nejm.org/doi/full/10.1056/NEJMsa1600011

If a little bit of cooling – or at least Targeted Temperature Management – can preserve brain function, why not start it when the brain is most susceptible to injury? Why not start it when CPR is in progress, and the initial injury from poor perfusion begins?

That was, essentially, the question asked by the RINSE Trial, which randomized out-of-hospital cardiac arrest patients to either rapid infusion of cold saline or standard “ambient” fluid administration. Eligible patients received an initial round of CPR, defibrillation if indicated, and epinephrine if indicated, and were then randomized to one of the two arms.

Unfortunately, there’s not much in this trial favoring the intervention. RINSE was stopped early after receiving hospitals changed their temperature management protocols following the publication of TTM, but still managed to randomize 1,198 patients with similar baseline characteristics between cohorts. About half of patients had non-shockable rhythms, and pre-hospital results were similar. The other half, however, had shockable rhythms, and an excess of 10.2% of these patients died at the scene after cold saline infusion was initiated. Thus, the only trend observed here is one favoring standard care.

There are a few quirks to consider. Only a little more than 10% of all potentially eligible OHCA were enrolled, with no information regarding the unenrolled cohort or reasons for exclusion. The temperature difference between the two groups, based on pre-hospital tympanic membrane measurements, was only 0.7°C. Lastly, the primary outcome measure used was survival to hospital discharge, and not one of neurologic function – which may have been better aligned with the underlying neuropreservation hypothesis.

Regardless, there certainly isn’t anything here to trump up enthusiasm for further exploration, even if the magnitude of harm observed probably exceeds the expected effect of their intervention.

“Induction of Therapeutic Hypothermia During Out-of-Hospital Cardiac Arrest Using a Rapid Infusion of Cold Saline (The RINSE Trial)”

http://circ.ahajournals.org/content/early/2016/08/25/CIRCULATIONAHA.116.021989

The prehospital game has always been muddy, particularly when it comes to the various pharmacologic interventions fixed in the constellation of Advanced Life Support.  You could – and some have – go as far as to say virtually nothing in the armamentarium of prehospital care has been proven to improve meaningful survival following cardiac arrest.

This latest evidence drop is the ALPS trial from the Resuscitation Outcomes Consortium – amiodarone, lidocaine, or placebo in patients with shock-refractory ventricular fibrillation/ventricular tachycardia.  The underlying physiologic theory would be that there’s a period of time between onset of VF/VT and death where drugs are the answer.  Early on, an appropriately delivered shock solves the disorganized electrical problem.  Later on, after the intracellular rigor sets in, nothing will be reliably beneficial.  In some intervening period, there is hope that amiodarone or lidocaine provides a little extra stabilization to help a shock take hold.

These authors performed a prospective, double-blinded, placebo-controlled, randomized trial with three arms to compare each antiarrhythmic therapy to placebo.  With a 90% power to detect a 6% survival to hospital discharge between arms, these authors enrolled 3,026 patients.  Groups were generally well-balanced for important prognostic features, adjunctive treatments, and post-admission care.  But, unfortunately, the survival advantage seen was 3.2% for amiodarone and 2.6% for lidocaine – meaning the confidence intervals each cross unity and the p-values are 0.08 and 0.16, respectively.

So, we have, yet again, a study that provides more to argue about than to inform practice.  Delving into the secondary outcomes and the supplementary appendix, it is clear that both antiarrhythmic drugs are doing something.  Patients receiving the active arms in the trial required fewer shocks, received fewer doses of alternative antiarrhythmic drugs (e.g., magnesium, procainamide), and had significantly higher rates of hospital admission – 45.7% vs. 47.0% as. 39.7% for amiodarone, lidocaine, and placebo, respectively.  However, all these advantages on the front-end decayed into smaller and smaller absolute differences on the back end – where mRS 3 or better discharge status was only 18.8% vs. 17.5% vs. 16.6%.

The glass half-full look at this is: even though it’s not statistically significant, even a couple percentage points of life vs. death represents a couple thousand additional neurologically intact survivors each year.  The glass half-empty look at this is: 26.9% of the amiodarone group required immense resource outlay and ICU care and was still ultimately dead or disabled, along with 29.5% of the lidocaine group, but only 23.1% of the placebo group.

These data suggest many reasonable choices may be made.  The signal may not be strong enough, and the downstream costs high enough, that a case could be made to dramatically curtail use of both active drugs.  Or, specific instances of use or delivery improvements could be proposed, based on other survival signals hidden in the secondary data.  Finally, costs, ease of use, and other secondary signals could make dueling cases to discontinue use of one of the two active drugs.

I think these drugs probably have value – but, their value won’t be maximized until in-hospital care produces either a better yield of neurologically intact survivors or better prognosticates resuscitation to reduce ultimate resource utilization.

“Amiodarone, Lidocaine, or Placebo in Out-of-Hospital Cardiac Arrest”
https://www.ncbi.nlm.nih.gov/pubmed/27043165

This brief article bubbled back up to the surface the other day, with a colleague claiming an “NNT of 5” for mortality for antibiotic prophylaxis following cardiac arrest.  An NNT of 5 is excellent, mortality is a bad thing – so why aren’t we doing this?

This is a retrospective review of 138 patients resuscitated from OHCA and admitted to a British ICU, all receiving therapeutic hypothermia, stratified by receipt of antibiotics within 7 days of the ICU stay.  Mortality was 56.6% in those receiving antibiotics and 75.3% for those not receiving antibiotics, thus the independent association with antibiotics use and survival with an NNT of 5.

This is, unfortunately, an egregious example of an abstract exaggerating and misleading from the correct conclusion, including the authors own results and discussion.  Any mortality difference between groups occurred in the first 3 days following admission – thus, immortal time bias, as those patients who could receive antibiotics were, by definition, those who lived long enough to receive them.  This fact is ultimately reflected in the presented results, in which the Cox proportional hazards model identified no significant predictive effect of antibiotics on survival.  However, the authors – particularly in the abstract – focus on the superficial mortality observation, and inappropriately promote the potential value of prophylactic antibiotic use.  This supposed NNT of 5 is nonsense, and ought never have been published.

Don’t just read the abstract!

Also, editors of Resuscitation, don’t let authors write such abstracts!

“Early antibiotics improve survival following out-of hospital cardiac arrest”

A staple of resuscitative care, epinephrine is enshrined in the ACLS algorithms for the pulseless patient.  And, what seems to be clear – flogging the heart with vasoactive agents produces, at least, a temporary physiologic response.  Unfortunately, such sympathomimetic abuse results in multiple adverse effects, included coronary and cerebral vasoconstriction – and the net effect, perhaps, is negative.

This is a retrospective review of 1,556 patients admitted to a “cardiac arrest center” in Paris, France, evaluating cerebral performance outcomes depending upon pre-hospital administration of epinephrine.  Of the 1,134 patients who received epinephrine, 17% ultimately had good outcome.  Of the remaining 422 patients who did not receive epinephrine, 63% ultimately had good outcome.  The authors also demonstrate worsening outcomes for epinephrine administration in a dose-dependent fashion.  Cheers.

Of course, it should follow naturally the patients receiving epinephrine probably did so because they were judged to need it – whereas, contrariwise, those not receiving epinephrine probably did not receive it because they were sufficiently stable.  And, then, failure to achieve initial return of spontaneous circulation begets additional doses of epinephrine.  Thus, you have a selection bias in which sicker patients were naturally allocated to epinephrine and less-sick patients to non-treatment – and an accounting for the dose-response relationship.  The authors perform multiple adjustments and propensity matches in an attempt to prove the outcome disparity durable to these validity challenges, but the astute reader may find them insufficient.

This study, nor any of the observational studies preceding it, definitively prove the harms of use of epinephrine pre-hospital outweighs the benefits.  I have, at least, stopped routinely using epinephrine in undifferentiated cardiac arrest, and rather try to select specific patients for whom the underlying etiology seems appropriate.

“Is Epinephrine During Cardiac Arrest Associated With Worse Outcomes in Resuscitated Patients?”

A few weeks ago we reported on the use of the LUCAS-2 for crushing the thorax, resulting in significant internal injuries.  None of these injuries were judged to have contributed to any patient’s demise – but, still, concerning.  This could be more forgivable if there were other advantages, say, survival.

Unfortunately, yet again, mechanical CPR fails to demonstrate superiority.

This is the PARAMEDIC trial, from the Lancet, a cluster-randomized trial aiming to demonstrate the superiority of the LUCAS-2 device as compared to manual CPR.  Based on a deployment of 143 available LUCAS devices, these authors compared 1,652 patients randomized to attempt device deployment compared with 2,819 in a control group.  There were no important differences in the baseline characteristics of the two groups, and other measures of initial treatment were similar.  And, in the end, there was no difference between initial return of circulation, event survival, 30-day survival, 3-month survival, or 12-month survival (all dismal).

The mildly interesting aspect to this trial is that it was not directly a test of the LUCAS device – but, rather, a pragmatic trial comparing deployment with LUCAS as an option with deployment without.  Thus, 638 patients in the clusters randomized to include the LUCAS device received manual compressions.  However, on multiple causal effect analyses, no advantage was detected from cases in which the LUCAS device was used, nor was a selection bias apparent.

In the absence of efficacy data, use of mechanical devices is defended primarily on the basis of convenience – freeing up hands for other tasks.  However, this argument fails in the face of these data – as it does not appear the handsfree advantage, when available, results in improved patient outcomes.

“Mechanical versus manual chest compression for out-of-hospital cardiac arrest (PARAMEDIC): a pragmatic, cluster randomised controlled trial”
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)61941-3/fulltext

The anecdotal experiences and reports from survivors of cardiac arrest are diverse, yet frequently describe common themes.  Detailed memories, “near death experiences” of entering another world, and sights and sounds from the arrest context are frequently reported.  And, what better place to collect cardiac arrest events than in a hospital?

As one might imagine, the population available for such interviews is rather limited – so it requires a massive undertaking, in this case, a four-year prospective evaluation across 15 hospitals in the U.S., UK, and Austria.  Essentially, the local investigator at each institution received notification of every adult, in-hospital cardiac arrest.  Survivors were identified and interviews conducted as soon as feasible, given continued comorbid illness.

Out of 2,060 cardia arrests, only 330 were eligible for study inclusion.  Investigators conducted 140 interviews – and only 55 had any memories.  Of these, 53 had detailed memories, whether unrelated or classic “crossing-over” phenomena – but nothing relating to the circumstances of their arrest event.  Only two patients had detailed memories of the circumstances of their event – one set of memories was not able to be verified, but the authors were able to fully verify the other set of memories by interview of the resuscitation staff.

So, essentially, very rarely do patients have any recollection of their arrest event.

Interestingly, one part of this study attempted to verify the veracity of the “floating above and watching” aspect of some individual’s arrest recollections.  The authors constructed shelves in areas thought most likely to have cardiac arrest, and then placed objects on the shelf that would only be visible from a perspective near the room ceiling.  Unfortunately, 70% of the cardiac arrests in this study occurred in locations where there were no shelves, including both arrests with detailed recollection.

“AWARE—AWAreness during REsuscitation—A prospective study”
http://www.ncbi.nlm.nih.gov/pubmed/25301715