Category: Cardiac Arrest

Saving Lives with Lifesaving Devices

Automated electronic defibrillators are quite useful in many cases of out-of-hospital cardiac arrest – specifically, those so-called “shockable rhythms” in which defibrillation is indicated. Ventricular fibrillation, if treated with only bystander conventional cardiopulmonary resuscitation, has dismal survival. However, when no AED is available, the issue is mooted.

This is an interesting simulation exercise looking to improve access to AEDs such that availability might be improved in cases of cardiac arrest. These authors pulled every AED location in Denmark, along with the locations of all OHCAs between 2007 and 2016. Then, they used all OHCA from 1994 until 2007 as their “training set” to help derive an optimal location for AED placement with which to simulate. Optimal AED placements were dichotomized into “intervention #1” and “intervention #2” based on whether their building location provided business-hours access, or 24/7 access.

In the “real world” of 2007 to 2016, AED coverage of OHCA was 22.0%, leading to 14.6% bystander defibrillation. Based on their simulations and optimization, these authors propose potential 33.4% and 43.1% coverage, depending on business hours, leading to increases in bystander defibrillation of 22.5% and 26.9%. This improved coverage and bystander defibrillation would give an absolute increase in survival, based on the observed rate, of 3.4% and 4.1% over the study period.

This is obviously a simulation, meaning all these projected numbers are ficticious and subject to the imprecision of the inputs, along with extrapolated outcomes. However, the underlying principle of trying to intelligently match AED access to OHCA volume is certainly reasonable. It is hard to argue against distributing a limited resource in some data-driven fashion.

“In Silico Trial of Optimized Versus Actual Public Defibrillator Locations”
https://www.sciencedirect.com/science/article/pii/S0735109719361649

Shocked: To the Cath Lab?

Just a couple weeks ago, I pointed out a recent evidence summary regarding the utility of cardiac catheterization following out-of-hospital cardiac arrest. The general between-the-lines theme of the article: sure seems useful, but the observational evidence is potentially really biased.

This, the Coronary Angiography after Cardiac Arrest (COACT) trial, is one of the randomized trials noted in that aforementioned evidence review. These authors conducted a randomized, multi-center trial enrolling patients with out-of-hospital cardiac arrest, shockable initial rhythms, unconscious on ED arrival, but no ST-segment elevation. Based on their survey of the literature, they gave themselves an 85% power to detect a 13% absolute difference in survival to 90 days, and enrolled 552 patients over three years. Patients undergoing early coronary angiography did so generally within 2 hours, while those in the delayed strategy – if they underwent angiography at all – did so several days later.

Overall – no difference. Survival to 90 days did not differ between groups at 64.5% for immediate angiography and 67.2% for delayed, nor did any secondary outcomes regarding post-resuscitation morbidity or neurologic survival. Of course, the key element being: unless an intervention occurs, there likely won’t be any effect. Only about a third of patients in each group underwent revascularization during their hospital stay, meaning any difference in overall survival would ultimately need be affected by outcomes in this specific population. Absent a massive effect size, the results observed are basically as expected.

So, I think the basic takeaway here is – within the limitations of this small sample – immediate angiography is not supported as a universal strategy for patients with OHCA, shockable rhythms, and lack of ST-segment elevation. It appears either a delayed strategy, or one guided by yet-to-be-determined clinical features, is preferred.

“Coronary Angiography after Cardiac Arrest without ST-Segment Elevation”

https://www.nejm.org/doi/full/10.1056/NEJMoa1816897

The “OHCA to the Cath Lab?” Update

STEMI: cardiac catheterization.

Out of hospital arrest: now what?

This scientific statement provides a lovely – and detailed – overview of the state of the science regarding which survivors of cardiac arrest should be considered for cardiac catheterization. They start with the easiest of answers: arrest with return of circulation and ST-segment elevation on a 12-lead ECGs are likely to benefit from catheterization. Then, patients with persistent ventricular fibrillation or ventricular tachycardia are, similarly, highly likely to have coronary artery disease and a suspected culprit lesion precipitating their arrest.

Now, the trickier issue remains what to do with those who do not have ST-segment elevation on their ECG. Pooled data from registry and observational studies indicates the prevalence of coronary artery disease is between 25-50%, while a potential culprit lesion is identified about 25-35% of the time. The data from these same studies indicates a substantial survival advantage for those – and this is the key word – selected for cardiac catheterization, and in whom percutaneous coronary intervention is performed. The authors go on to note at least nine randomized trials are underway or planned to address the utility of catheterization in the subgroup without STE.

Lastly, the authors note the emerging role of VA-ECMO in cardiac arrest. With only a handful of patients from observational registries, survival with cerebral performance category 1 or 2 has been observed in 15-40% of patients. This is, again, likely subject to selection bias, but remains a potentially promising approach. The ARREST trial, evaluating such a strategy, is ongoing with completion expected in 2023.

At the minimum, it is a worthwhile review article for anyone looking to catch up to speed – even if there isn’t much within to change current thinking or practice, at the moment.

“The Evolving Role of the Cardiac Catheterization Laboratory in the Management of Patients With Out-of-Hospital Cardiac Arrest A Scientific Statement From the American Heart Association”
https://www.ahajournals.org/doi/10.1161/CIR.0000000000000630

All Hail the Female Resuscitationist

There has been more than one instance recently of observed associations between female gender and improved outcomes. Female physicians have lower rates of 30-day mortality and readmission rates for hospitalized elderly, and have better outcomes among female patients with acute myocardial infarction.

Now, another set of data showing improved survival after in-hospital cardiac arrest.

This is a retrospective review of 1,082 in-hospital cardiac arrests between 2005 and 2017 in which the gender of the code team leader could be ascertained. The minority – 30.2% – were led by a female physician. Location within the hospital, shockable rhythm, time of day, and patient age were similar between the male and female physician-led cardiac arrest cohorts. With male physicians, ROSC was 71.7% and survival to discharge was 29.8%, bested by female physicians with 76.8% ROSC and 37.3% survival. In a sample size this small, there are many potentially unmeasured confounders regarding the underlying health and type of arrest that may have contributed to the baseline likelihood of ROSC and survival – but this is still quite the interesting association.

Unfortunately, this brief analysis cannot tweeze out specifically why the female physician-led cohort had better outcomes. Their data set recorded compression depth and rate, and these were effectively the same – but they do not have medication use, timing, and other relevant attributes for evaluation. They make some further associations between physician and nurse gender, but the confidence intervals simply explode regarding whether any observed survival advantage may have occurred by chance alone.  I expect other inpatient cardiac arrest registries or databases may have more granular data to either confirm or refute this association – and, hopefully, if such an association continues to be observed, to better determine the practice patterns associated with any increased survival.

Lastly, it is reasonable to be concerned regarding publication bias relating to these such reports of gender-based outcomes.  It is probably editorially more interesting – and certainly seems more likely to get picked up by the lay press – to report associations favoring the female gender than the other way around.  Perhaps a bit more research seems warranted before condemning men to the scrap heap of history.  I hope, for my own sake!

“Female Physician Leadership During Cardiopulmonary Resuscitation Is Associated With Improved Patient Outcomes”
https://journals.lww.com/ccmjournal/Abstract/onlinefirst/Female_Physician_Leadership_During_Cardiopulmonary.96124.aspx

Homeopathy and Cardiac Arrest

Following up on the most recently published prehospital trials, we’re going back to an article published a few months ago. We’ve seen the data regarding epinephrine versus placebo – some does something, nothing does nothing, but the benefit of either strategy is debatable. Is there a better way?

This little retrospective report looks at the middle ground – a “well, let’s try and give a little less” protocol implemented in the King County prehospital system. Moving from their original protocol based on 1mg dosing with intervals indicated by rhythm, they halved it to 0.5mg. This resulted in patients generally getting a mean dose of epinephrine of about 2.5-3mg per arrest, rather than the 3.5-4mg total prior to implementation.

Did any outcome – survival, or, more importantly, neurologically-intact
survival – change? Not reliably, no.

These data provide only the lowest level of evidence as applied to determining the most advantageous use of epinephrine in the prehospital setting. This neither confirms nor refutes the premise of their practice change, and provides little specific insight into where the serial dilution of epinephrine loses its potency. There may yet be a sweet spot where return of spontaneous circulation occurs with minimal collateral damage, but we’ll need to wait for future research to provide additional data.

“Lower-dose epinephrine administration and out-of-hospital cardiac arrest outcomes”
https://www.ncbi.nlm.nih.gov/pubmed/29305926

The Great Prehospital Airway Debate

… is over! With another 12,000 patients included in two prospective, randomized trials, we’ve finally arrived at unassailable conclusions regarding optimal airway management in the context of out-of-hospital cardiac arrest.

Or, as usual, not.

These two trials, AIRWAYS-2 from the United Kingdom and PART from the United States, randomized paramedics and emergency medical services agencies to routinely providing either endotracheal intubation or a supraglottic airway. The details of both trials are a little bit different, but they are both effectively pragmatic approaches directing the first attempt at airway management in patients deemed eligible in non-traumatic OHCA.

AIRWAYS-2 enrolled over 9,000 patients while PART enrolled over 3,000, and their results were similar, but not precisely the same. The primary outcome for AIRWAYS-2 was “good outcome” (0-3) on the modified Rankin Scale at 30 days, which was achieved by the ETI cohort in 6.8% versus 6.4% with SGA. The primary outcome for PART was 72-hour survival, which was 15.4% in their ETI cohort versus 18.3% with SGA. For rough comparison’s sake, PART also recorded mRS at hospital discharge, which was 5.0% with ETI and 7.1% with SGA.

These are both incredibly messy trials with regard to delivery of the intervention. Substantial fractions of both cohorts in the AIRWAYS-2 trial did not ultimately receive an attempt at an advanced airway, including over a quarter of those randomized to ETI. Then, the success rate for ETI in PART was only 51%, as compared with 90% with SGA. It is an imposing task to parse through their flow diagrams of randomization, patient interventions, and outcomes in both the main body of the articles and in the supplemental material.

Ultimately, while these can be argued back-and-forth due to substantial underlying uncertainty, there is little evidence to suggest ETI should be favored over SGA. This ought not be terribly surprising, as we’ve already seen a trial of ETI versus bag-valve mask ventilation which was unable to conclusively support one method over the other. While these findings probably could be used to substantially affect paramedic training and procedures with respect to ETI, the better, remaining question is whether any advanced airway should be routinely attempted at all.

“Effect of a Strategy of a Supraglottic Airway Device vs Tracheal Intubation During Out-of-Hospital Cardiac Arrest on Functional Outcome: The AIRWAYS-2 Randomized Clinical Trial”

https://jamanetwork.com/journals/jama/fullarticle/2698493

“Effect of a Strategy of Initial Laryngeal Tube Insertion vs Endotracheal Intubation on 72-Hour Survival in Adults With Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial”

https://jamanetwork.com/journals/jama/fullarticle/2698491

Bring Back Your Dead

When you take vacation, the relentless march of the medical literature does not. Even though this blog is a week late to this party – an eternity in the world of rapid post-publication peer review – I would be remiss not to here briefly mention PARAMEDIC2.

This is, by far, the largest prospective, randomized, controlled trial of epinephrine in out-of-hospital cardiac arrest. Effectively the mainstay of resuscitation for many decades now, smaller trials and other post-hoc analyses have found inconsistent survival advantages associated with its use. Epinephrine, it has seemed, will flog the heart back into some level of cardiac output compatible with “life”. However, the other deleterious effects of epinephrine – or the context of the peri-arrest physiology – fails to produce an advantage with regard to neurologically-intact survival.

And that’s what we see, again, here.

This trial enrolled 8,014 patients with OHCA with the primary outcome being survival at 30 days. The intervention arm administered 1mg intravenous or intraosseous doses of epinephrine every 3 to 5 minutes during resuscitation or saline placebo. Secondary outcomes were survival to hospital admission, length-of-stay in the intensive care unit, and neurologic outcomes at hospital discharge and at 3 months. A “favorable” neurologic outcome was defined as a score of 3 or less on the modified Rankin scale, which is a little bit different than other trials using Cerebral Performance Category.

Both cohorts were fairly evenly matched with regard to prognostic features, which is to say, they were basically terrible. Nearly 80% of the cohort had a non-shockable rhythm, although over 60% were witnessed arrest and had bystander CPR. Response times by ambulance to the scene were around 7 minutes, and 21 minutes elapsed between call and first use of trial medication.

Just as in the previous evidence, epinephrine functions as advertised – the return of spontaneous circulation in the prehospital setting was 36.3% with epinephrine, compared with 11.7% without. However, with every advancing time point, the gap between the arms narrowed. At hospital admission, epinephrine was favored 23.8% to 8.0%. Survival to hospital discharge favored epinephrine 3.2% to 2.3%, and then 3.0% to 2.0% at three months. Finally, neurologic outcomes were even more narrowly in favor of epinephrine at three months, 2.1% to 1.6%. Further splicing out the outcomes with regard to mRS, the small excess favoring epinephrine were those with mRS 3, whereas the small numbers with mRS 0,1 or 2 were effectively identical. Of note, from these 8,000 starting with cardiac arrest, only 27 survived with an mRS of 0. Bleak.

So, we’re effectively back where we started – but with the best evidence to date regarding the limitations of epinephrine. Giving epinephrine up-front is a rewarding, “life-saving!” experience for the initial treating providers. Unfortunately, the ultimate outcomes are effectively just as dismal – only vastly more costly in terms of real currency and resource utilization when epinephrine is featured. Until substantial advances can be made with regard to improving post-arrest functional outcomes, it is entirely reasonable to consider omitting epinephrine from resuscitation from out-of-hospital arrest.

“A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest”

https://www.nejm.org/doi/full/10.1056/NEJMoa1806842

A Non-Non-Answer in Airway Management in OHCA

In a lovely demonstration of the statistical inanity of non-inferiority trials, these authors present a simultaneously insightful and illogical data set examining airway management strategies during CPR in out-of-hospital arrest.

This is a clinical trial from France, randomizing patients out cardiac arrest to either bag-valve mask ventilation or placement of an advanced airway during CPR. Patients with significant challenges associated with BVM could cross over to ETI, and if patients achieved return of spontaneous circulation at any time, they were subsequently intubated as well. All emergency response and airway management was supervised by an emergency physician. Groups were fairly well matched by their randomization by center, and about 10% of the cohort crossed over to ETI from BVM due to failure of ventilation or gastric regurgitation.

Without wallowing too much in the statistical underpinnings, these authors defined a 1% absolute difference in favorable neurologic outcome at 30 days as their primary outcome measure for non-inferiority. Then, if non-inferiority was unable demonstrated, a test of difference would be performed for inferiority.

And, so, after all this, CPC 1-2 survival was: 4.2% in the BVM group and 4.3% in the ETI group, for a difference of 0.11% (1-sided 97.5% CI, −1.64% to infinity). It should be abundantly obvious that – considering the obviousness of their result and its gross failure to meet their statistical threshold – their sample size is completely inadequate. It then unsurprisingly follows their test of difference does not demonstrate inferiority of BMV as compared to ETI.

So, yes, BMV is not inferior, but not non-inferior, to ETI. This is why everyone hates Journal Club.

In the bigger picture, these data generally support deferring advanced airway placement during CPR. These authors did not observe any differences in low-flow time, even in their ETI group – but I would expect this might be a “best case scenario” with respect to minimal interruption and successful airway management.  Considering they have an EP assisting in the resuscitation and airway management, I would probably expect other settings are more prone to airway management failure and interruptions – and, really, the onus should be on those doing more to find solid data to back up their prehospital intervention.

“Effect of Bag-Mask Ventilation vs Endotracheal Intubation During Cardiopulmonary Resuscitation on Neurological Outcome After Out-of-Hospital Cardiorespiratory Arrest A Randomized Clinical Trial”
https://jamanetwork.com/journals/jama/article-abstract/2673550

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”

http://jamanetwork.com/journals/jama/article-abstract/2645105

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”
https://www.ncbi.nlm.nih.gov/pubmed/28661970