Does Length of TTM Matter after Cardiac Arrest?

Targeted temperature management, sometimes conflated with therapeutic hypothermia, is part of modern resuscitation guidelines in post-arrest care. There are, however, many aspects of this therapy for which the details remain hazy, including: how long? 24 hours? 48 hours? Or, as in neonates, 72 hours?

This is the “Time-Differentiated Therapeutic Hypothermia” trial, a randomized, single-blind comparison between TTM – in this case, TH at 33°C – treatment for 24 hours versus 48 hours following resuscitation from cardiac arrest. These authors randomized 355 eligible survivors to ICU admission into two generally similar arms, most of whom received their assigned treatment without protocol violations. A great deal of data on survival, adverse events, and other secondary features are presented, and the short of it is: probably no difference. Similar proportions of patients in each arm had cerebral performance scores of 1 or 2 at six months, which was the primary outcome. Mortality at six months was also similar, as was, generally speaking, adverse events. Confidence intervals, however, were quite wide – for example, the relative risk for CPC 1 or 2 was 1.08 with 95% CI of 0.93 to 1.25, the top end of which represents a fairly meaningful difference. However, given the Bayesian pre-test likelihood of such an advantage, the null hypothesis is the clear winner. One clear loser: ICU length-of-stay, and by association, healthcare costs, which will obviously favor the group with a shorter period of TTM.

Some comments on Twitter were overjoyed at six-month survival figures approaching 70% as indicative of advances in post-arrest care. Unfortunately, these are more reflective of their exclusion criteria – which entailed non-cardiac causes of arrest, asystole rhythms, vasopressor-resistant shock, extended pre-ROSC resuscitation times, and a host of other items representing dire prognoses. These are the “best of the best”, which is reasonable to try and reduce heterogeneity and other random effects on outcome measures.

Lastly, it is reasonable to note one of the elements of causality generally entails a dose-response relationship, in which the magnitude of exposure to a beneficial therapy relates in some fashion a continuum of outcomes. Lacking such an apparent relationship, as in this trial, does not refute an association between TTM/TH and improved outcomes, but certainly continues to raise points regarding the precise elements of post-arrest care resulting in improved outcomes. Cooling to 33°C does not appear to confer an advantage to 36°C, nor does an extended exposure to the treatment. What is it really, then, that helps achieve the greater proportion of CPC 1 and 2 survivors?

“Targeted Temperature Management for 48 vs 24 Hours and Neurologic Outcome After Out-of-Hospital Cardiac Arrest”

The Shenfu Wave Continues

It was just a few months ago where I featured a brief review of Shenfu injection for the treatment of patients with septic shock. The conclusion: promising, yet – possibly because I’m simply culturally obtuse – a healthy dose of skepticism seems warranted.

This is another example of Shenfu injection in a randomized, controlled trial – this time for in-hospital cardiac arrest. Shenfu, just to recap:

Shenfu injection (SFI), produced by using multistage counter current extraction and macroporous resin adsorption technology, is a well-known TCM formulation containing ginseng (Panax; family: Araliaceae) and aconite (Radix aconiti lateralis preparata, Aconitum carmichaeli Debx; family: Ranunculaceae). Ginsenosides and aconite alkaloids are the main active ingredients in Shenfu.

In this trial, patients were randomized – in open-label fashion – to either a post-resuscitation bundle, or the same bundle plus twice-daily 100mg Shenfu infusions. Treatment was continued for 14 days or transfer out of the ICU, whichever came first.

These authors assessed 1,022 patients, 44 of whom were not randomized because consent could not be obtained. The remaining 978 were allocated to the two arms, approximately 35 of whom in each group died before receiving the study intervention. Baseline characteristics, adjudicated cause of arrest, presenting rhythm, and follow-up care were similar between the two groups. The most common rhythm, by far, was asystole, at ~82% of each group.

The winner, again, is the Shenfu injection cohort, by far. 28-day survival was 42.7% versus 30.1%, 90-day survival was 39.6% vs. 25.9%, median ventilation and hospital length of stay were ~4 days shorter, and hospital costs reflected these shorter time periods. Not only was survival improved, but a greater proportion of survivors were discharged with cerebral performance scores of 1 or 2, rather than with severe disability or coma.

There are obvious limitations, the lack of blinding for the treating physicians most potentially biasing. However, this is, again, a large effect size for a very meaningful outcome. Considering the other utter rubbish otherwise approved and marketed in modern medicine, it should be prioritized, to say the least, to further evaluate in a prospective fashion – particularly outside of China.

Now, if we wanted to get television-miracle levels of survival, we should just combine this with high-dose Vitamin C therapy!

“Efficacy and Safety of Combination Therapy of Shenfu Injection and Postresuscitation Bundle in Patients With Return of Spontaneous Circulation After In-Hospital Cardiac Arrest: A Randomized, Assessor-Blinded, Controlled Trial”

Taking Post-Arrest to the Cath Lab

There has been a fair bit of debate regarding the utility of taking post-arrest patients to cardiac catheterization. Clearly, ST-elevation myocardial infarction should receive intervention – although, it can sometimes be challenging to identify on post-arrest EKG. Much less has been determined regarding the treatment of those without STEMI.

This is – as is most of the relevant literature – a retrospective review of patients with cardiac arrest, as identified from a multi-center therapeutic hypothermia registry. These authors record the location of arrest, previously known coronary artery disease, the initial rhythm as shockable or unshockable, and EKG findings. They defined clinically important CAD by the presence of an intervention following cardiac catheterization, including PCI, stenting, or coronary artery bypass grafting.

Entertainingly, the authors hypothesis is “the incidence of coronary intervention would be uncommon (<5%)” – which, if it truly is their hypothesis, it is contradicted by most of their citations, including a meta-analysis citing an overall incidence of CAD in post-arrest patients ranging from 59-71%. Regardless, there were 1,396 patients with known initial rhythms, about 2/3rds of which were non-shockable. About 60% of shockable rhythms and 20% of unshockable rhythms underwent cardiac catheterization. After removing those with obvious STEMI on their EKG, there were 97 patients in their cohort of interest, 24 (24.7%) of whom underwent intervention.

This, therefore, is the “unexpectedly high” incidence of coronary intervention in this non-shockable rhythm cohort without STEMI on EKG. However, as these authors do appropriately note, these data should not specifically inform practice change. The findings in those patients undergoing catheterization are skewed by selection bias, including measured and unmeasured confounders influencing the decision to take patients for potential intervention. In an older population characteristic of a cardiac arrest cohort, some coronary disease is likely on any diagnostic test – and, in this clinical context, it seems intervention would be much more likely than not. Finally, intervention does not equate to a culprit lesion for cardiac arrest, further distancing these results as a surrogate for patient-oriented outcomes.

Despite the “surprise” these authors report, they likely overestimate any evidence for benefit in this post-arrest population, and better characterization of specific high-yield circumstances is needed.

“Incidence of coronary intervention in cardiac arrest survivors with non-shockable initial rhythms and no evidence of ST-elevation MI (STEMI)”

Just How Many Lives Do AEDs Save?

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”

Not Seeing Any Value in RINSE

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)”

Amiodarone, Lidocaine, or … Nothing

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”

New Text Message: Be a Hero! Go!

This pair of articles from the New England Journal catalogues, happily, the happy endings expected of interventions undertaken to increase early bystander CPR.

The first article simply describes a 21 year review of outcomes in Sweden following out-of-hospital cardiac arrest, measuring by 30-day survival in patients who received bystander CPR prior to EMS arrival, with those who did not.  In this review, 14,869 cases received CPR prior to EMS arrival, with a 30-day survival of 10.5%.  The remaining 15,512 cases did not receive CPR prior to EMS arrival, and survival was 4.0%.  This advantage remained, essentially, after all adjustments.  Thus, as expected, bystander CPR is good.

The second article is the magnificent one, however.  In Stockholm, 5,989 lay volunteers were recruited and trained to perform CPR.  Each of these volunteers also consented to make themselves available by contact on their mobile phone to perform CPR in case of a nearby emergency.  Patients with suspected OHCA were geolocated, along with those enrolled in the study, and randomized into two groups to either contact nearby volunteers, or not.  In the intervention group, 62% received bystander CPR, compared with 48% of the controls.  The magnitude of this difference was statistically significant, but, however, the survival difference of 2.6% (CI -2.1 to 7.8) favoring the intervention was not.

But, I think we can pretty readily agree – if bystander CPR improves survival, and text messages to nearby volunteers improves bystander CPR – it’s a matter of statistical power, not futility of the intervention.  If the cost of recruiting and contacting CPR-capable volunteers is low, it is likely increased neurologically-intact survival is the result.

This a an excellent initiative I hope is copied around the world.

“Early Cardiopulmonary Resuscitation in Out-of-Hospital Cardiac Arrest”

“Mobile-Phone Dispatch of Laypersons for CPR in Out-of-Hospital Cardiac Arrest”

Antibiotics, Therapeutic Hypothermia, and Damned Lies (Statistics)

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”

emlitofnote will be on holiday hiatus until December 29th.  Cheers!

All Falling Apart for Epinephrine

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?”

More Futility for Mechanical CPR

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”