Category: Resuscitation

Winter Recap

Spring is here down in this nuclear-free hemisphere. This blog is still effectively in stasis – but the productivity continues elsewhere!

Don’t forget the Annals of Emergency Medicine Podcast, a lighthearted feel-good romantic comedy with Rory Spiegel, available for free on your choice of streaming platforms:

Bimonthly #FOAMed in ACEPNow:

And, lastly, everyone’s favorite part of their residency curriculum, the Annals of Emergency Medicine Journal Club – in which we update folks from the wider world of medical literature in concise summaries for emergency medicine practice:

Enjoy!

🤷‍♂️ Vitamins in Sepsis Again

The VITAMINS trial was not the only trial investigating the efficacy of the hydrocortisone/vitamin C/thiamine cocktail in severe sepsis – and will thus not be the last word on the matter, by any chance. This is one of what is sure to be a slow trickle of other relevant data – as much as anything can break through the cacophony of the coronavirus pandemic.

This is a small trial, just 137 patients, and they used ascorbic acid 1,500 mg q6h, thiamine 200 mg q12, and hydrocortisone 50 mg q6h or a matching saline placebo for a four day course of treatment. Open-label corticosteroids were permissible per the clinical judgement of treating clinicians. The primary outcome was – wait for it – resolution of shock and change in SOFA score. This is, unfortunately, a change from their original primary outcome – in-hospital mortality. The original primary outcome is not mentioned in their manuscript, however, and includes a power calculation based on their secondary outcome – and this power calculation serendipitously matches their original anticipated study size as seen on clinicaltrials.gov.

There are circumstances in which changing the primary outcome is reasonable based on new, outside information obtained during the course of a study. That is not the case here. Moreover, and less appetizing, the new primary outcome is conveniently the only outcome measured significantly favoring the intervention. The authors tracked WBC counts, platelet counts, lactates, SOFA scores, fluid balance, procalcitonin clearance, ICU length-of-stay, hospital mortality, ICU mortality, and more, ad nauseaum. It is clear their original primary outcome would not have reached statistical significance because mortality was far too low – 16% with the intervention, 19% for control – based on sample size. However, the correct thing to do is simply run the trial out and have a reasonable academic discussion of the observed findings, not change to a disease-oriented surrogate.

Because, after all this, the authors make a fair bit of hay of their observed difference in shock resolution, a finding favoring the intervention by nearly a day. However, there were differences[1] in the groups at baseline specifically regarding the initiation of vasopressors – and this probably trickles down to the duration of vasopressors, as well. This study probably mostly shows just how difficult it is to do a study in intensive care, and how robust a sample size is required. Giving patients vitamins is unlikely to cause specific harms, but it doesn’t seem to be all that helpful. Remember – reliably useful treatments give reliably positive results.

“Outcomes of Metabolic Resuscitation Using Ascorbic Acid, Thiamine, and Glucocorticoids in the Early Treatment of Sepsis: The ORANGES Trial”
https://www.sciencedirect.com/science/article/pii/S0012369220304554

  1. Differences reported with a p-value, no less. There is no reason to report p-values for baseline characteristics in a randomized trial. A p-value here describes the likelihood an observation occurred by chance alone, but, obviously, because it was randomized, the chance it occurred by chance alone is 100%.

Stayin’ Alive Below 65

Just a quick note looking at this lovely trial hypotension trial, evaluating potential use of lower mean arterial pressure targets in elderly patients receiving vasopressors.

Quick summary: Less is more. With a primary outcome of 90-day mortality, outcomes were no worse in patients randomized to a MAP target of 60-65 mmHg rather than “usual care” (≥65 mmHg) – 41.0% vs. 43.8% (-2.85%, 95%CI -6.75 to 1.05). Stated in formal terms, however, the trial failed to demonstrate a statistically significant difference between the treatment arms, and the confidence interval crosses unity. That said, I certainly agree with the accompanying editorial – it should be considered likely there is a potential advantage to “permitting” hypotension, rather than being hedging against intermittent dips. This trial wouldn’t go so far as to say the 65 mmHg is not the MAP target – patients in the “permissive” cohort still had a mean MAP on vasopressors of 66.7 mmHg, while those in the usual care arm trended higher at 72.6 mmHg – but, additional work looking at lower targets is reasonable.

There are, of course, minor oddities to be observed when considering how (or if) to generalize these data. While 78% of patients received norepinephrine, the second-most popular vasopressor was metaraminol, a predominately alpha agonist, used in almost a third of those randomized. Interestingly, fewer than half the patients enrolled were in “septic shock” by Sepsis-3 definitions, while only another quarter were noted to have “sepsis (not in shock)”. Finally, while the findings are generally consistent across all age cohorts, the mean age is ~75, and nearly 75% of those screened were excluded for one of many reasons.

This study is a lovely demonstration of a rather straightforward underlying principle – MAP is not a measure of tissue perfusion, and is used rather as a surrogate for the ultimately-important microvascular circulation. Making big tubes run at a higher pressure at the expense of clamping down little tubes may be harmful – hence the rationale for this trial, and future ones.

As another random aside, I might make a note here for aspiring researchers – the guidelines will frequently tell you where knowledge gaps exist. The 2012 Surviving Sepsis guidelines gave the MAP >65 target a “1C” recommendation, with “1” meaning consensus for the recommendation was strong, but “C” meaning the evidence was weak. Looking at guideline recommendations and their accompanying level of evidence provides: 1) clues as to which clinical questions are important enough to be addressed by guidelines, and 2) the gaps in the evidence. Guideline authors will even, frequently, explicitly call out certain clinical questions for further study. I wouldn’t go so far as to call it a roadmap to clarifying the important questions in your specialty, but it certainly could be fertile.

“Effect of Reduced Exposure to Vasopressors on 90-Day Mortality in Older Critically Ill Patients With Vasodilatory Hypotension”
https://jamanetwork.com/journals/jama/fullarticle/2761427

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

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

Anything But Crystalloid

The balanced transfusion ratio has been in vogue for many years in military settings (read: whole blood), but, until recently, less popular with civilians. There are probably still kinks to be worked out with respect to improving the value of resource consumption in massive transfusion, but, at the least, it appears roughly equivalent ratios of plasma to blood cells are beneficial.

So, given the opportunity, why not initiate this sort of balanced resuscitation in the prehospital setting?

This somewhat messy and heterogenous trial does precisely that – randomizing 523 unstable trauma patients to either standard resuscitation or transfusion of 2 units of FFP, followed by standard resuscitation. The randomization took place in clusters at the aeromedical transport base level, and included bases whose initial protocol included PRBC transfusions for eligible patients. In these instances, the FFP was transfused first, and then the PRBCs. Additionally, 111 of the enrolled aeromedical transports were transfers from an outlying hospital. This meant the pre-enrollment resuscitation could be virtually any permutation of potential volume replacement. While the two groups were roughly balanced as far as etiologies of trauma, injury severity, and other baseline features, the initiation of FFP prior to standard resuscitation did skew the numbers with respect towards prehospital PRBCs, as they had to wait until the intervention transfusion was complete.

Overall, 24-hour mortality was 22% in the “standard care” group and 14% in the plasma group. Only a handful of potentially transfusion-related adverse events occurred, and this early survival advantage proved durable through the length of follow-up. There is enough in the pre-specified subgroup analysis to fuel any number of editorials, other retrospective analyses, and homegrown inclusion or exclusion criteria for prehospital FFP – but, overall, this grossly consistent with our priors for a survival advantage associated with balanced transfusions.

Now, what we really need, is a plasma product with a better shelf-life ….

“Prehospital Plasma during Air Medical Transport in Trauma Patients at Risk for Hemorrhagic Shock”

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

The Definitive Word on Steroids in Septic Shock

As the authors say in their introduction, glucocorticoids have been in and out of favor as adjunctive treatment of patients in septic shock for over 40 years. Various trials have found results both favoring and discounting their utility – leading, finally, to this trial to end all trials: ADRENAL.

Of course, there’s hardly ever any such definitive thing in medicine – but this is as close as it comes. This multi-center, multi-country, blinded, placebo-controlled, randomized trial evaluated the use of hydrocortisone in critically ill patients on vasopressors in septic shock. Patients were randomized to receive either 200mg of hydrocortisone daily as continuous infusion, or placebo. The primary outcome was 90-day mortality, with multiple secondary outcomes regarding length of ICU stay, hemodynamics, and others.

With 3,800 patients enrolled, this trial – if any could ever say to do so – should be essentially the final word with regard to detecting any significant difference in outcomes. And the final answer is: choose your own adventure!

For the primary outcome, there was no statistically significance difference in mortality at 90 days – 27.9% in the hydrocortisone cohort, and 28.8% with placebo. Looking at secondary outcomes, the results here tended to favor hydrocortisone – a slightly faster resolution of shock, shorter ICU stays, and, oddly, decreased transfusion requirements. The purist would say: negative trial. The Bayesian would say: this doesn’t change my prior opinion. The answer is, probably, somewhere in between.

Effectively, when a massive trial fails to find a difference, there is still the possibility of there actually being a difference – but any magnitude of effect is likely to be quite small. “Small” in this case, looks to be on the order of numbers-needed-to-treat ranging from 20 to 200, depending on the outcome. To take this into context, the much lauded WOMAN trial celebrating tranexamic acid found only a 0.4% absolute reduction in death due to bleeding. Hydrocortisone, similarly, is inexpensive, displayed few serious adverse effects, and even a small advantage with regard to an outcome such as mortality ought to be considered valuable.

Thus, the choose your own adventure. I tend to feel this is a reasonable treatment adjunct, but, as far as moving the needle on outcomes, there are many other higher-yield clinical interventions to prioritize above hydrocortisone. The critically ill are complex, and there are many aspects to high-quality intensive clinical and nursing care that have a greater impact on ultimate outcomes. To spend much time engaged in debate regarding hydrocortisone should be done only to the extent it does not distract and detract from other, more important aspects of their care.

“Adjunctive Glucocorticoid Therapy in Patients with Septic Shock”

http://www.nejm.org/doi/full/10.1056/NEJMoa1705835

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