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”

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”

Survival of the Intoxicated

We are mostly all familiar with the beneficial social outcomes associated with occasional alcohol use.  However, we also see the detrimental effects of chronic use in the context of comorbid disease states.

But, it’s apparently not all bad news in a medical sense.

This retrospective evaluation of patients admitted to medical and surgical critical care units in teaching hospitals in Boston simply tracked outcomes segregated by admission blood alcohol level.  Evaluating 11,850 admissions, most admitted patients had undetectable BAC, while 638, 703, and 1,226 patients fell into their three strata of increasing BAC.

Unsurprisingly, as most patients with the highest BAC had the fewest comorbid factors and were overwhelmingly admitted due to trauma, they had the lowest mortality in the unadjusted analysis.  However, across several different types of multivariate adjustment and propensity scoring, the same survival advantage held, although substantially weakened.

There is some school of thought alcohol confers a neuroprotective and anti-inflammatory effect in the setting of acute illness.  These retrospective data, fraught with potential confounders, are inadequate to conclusively confirm or refute such a hypothesis – but it is reasonable to suggest further study of underlying mechanisms may be warranted.

“Association between blood alcohol concentration and mortality in critical illness”

Not Much to Say About SPLIT

The Emergency Department is the land of fluid resuscitation.  The most typical resuscitation fluid tends to be 0.9% Normal Saline.  At simple face validity, this makes little sense as a volume expander – a poor mimic of basic physiology, and associated with an iatrogenic acidosis in large volumes.  Questions abound regarding the risks of renal failure associated with excessive saline administration, as compared to a more balanced or buffered solution.

This SPLIT trial, performed in intensive care units across New Zealand and Australia, provides little additional insight.  It is, happily, a lovely randomized, controlled, double-blind trial of fluid administration, comparing 0.9% NS with “buffered crystalloid”, also known as Plasma-Lyte.  Various outcomes measured changes in renal function, need for renal replacement therapy, and in-hospital mortality.

No differences.

But, also, not terribly generalizable.  Over 70% of these patients arrived to the ICU from the operating room, most of which was after elective surgery, most of which was cardiovascular.  Only 15% arrived from the Emergency Department, and only 4% carried a diagnosis of sepsis.  Patients also received only a median of 2 liters of fluid during their median of 1.5 days in the ICU.

It’s of mild interest to see no difference, but it does very little to further inform the sort of large-volume, rapid resuscitation routinely performed in the Emergency Department.

“Effect of a Buffered Crystalloid Solution vs Saline on Acute Kidney Injury Among Patients in the Intensive Care Unit The SPLIT Randomized Clinical Trial”

Also: for an excellent review of the “buffered crystalloid” solutions, visit

Is NODESAT Overhyped?

In the last few years, we’ve had a little bit of a sea-change in oxygenation during intubation.  We’ve stopped relying solely on pre-oxygenation to bridge our patients through apnea, and started providing passive oxygenation during intubation.  Usually supplied by high-flow nasal cannula, this takes advantage of physiology and diffusion to distribute oxygen into circulation.

But, as these authors state, the evidence for this practice is spotty – mostly observational evidence from controlled intubation settings.  Our critically-ill patients hardly have the same physiology as those undergoing elective airway procedures, and are generally less responsive to oxygenation adjuncts.  So, this is the FELLOW trial, a pragmatic, open-label randomized trial comparing apneic oxygenation vs. “usual care” – which was none.

With 150 patients in their intention-to-treat analysis, this cartoon sums up the results sufficiently:

Not much difference!

Their two groups were relatively well-balanced in terms of physiology and airway comorbidities.  The intubating operators were reasonably experienced (median >50 intubations), and 2/3rds of the patients were intubated on the first attempt.  There were probably no important differences in pre-oxygenation or procedural factors.

But, it is quite a small trial.  There are small differences here favoring the apneic oxygenation arm that simply might not reach statistical significance.  The exclusion criteria included “if the treating clinicians felt a specific approach to intra-procedural oxygenation or a specific laryngoscopy device was mandated for the safe performance of the procedure”, which could have introduced a selection bias.  The open-label effects may or may not be confounding.  The ICU environment and exclusion criteria also affect generalizability to the Emergency Department.

In the end, the answer is: apneic oxygenation still probably helps, particularly considering the pre-study evidence favored the intervention, and this one study does not move the needle much.  However, the observation here of a clinically unimportant effect size is not unreasonable.  If the effect size is small, the cost of an intervention becomes important.  However, in this case, the cost is fairly minimal – a small addition to set-up time and procedural complexity.  Considering the low cost and the post-test odds still favoring the intervention, it would be erroneous to stop providing apneic oxygenation based on this trial, and further study is indicated.

“Randomized Trial of Apneic Oxygenation during Endotracheal Intubation of the Critically Ill”

Central Line Showdown

Major complications related to insertion of central line catheters remain: infection, thrombosis, and “mechanical complications”(read: pneumothorax, arterial puncture).  And, central lines have three typical locations:  subclavian, jugular, and femoral.

Wouldn’t it be cute if each of these catheter insertion sites each had their own specific realm of superiority?

And, based on this randomized trial of 3,471 catheter insertion events, they just about do:

  • The femoral site has the fewest mechanical complications, but the most thrombosis (1.4%).
  • The subclavian site had the fewest infections (0.5%) and thrombotic events (0.5%), but the most mechanical complications (2.1%).
  • And the jugular site was essentially a middle ground between the two, although, had the greatest infection rate (1.4%).

However, many of these differences need be taken with a grain of salt.  Ultrasound was not mandated, which probably led to the unusual incidence of mechanical complications for the jugular approach.  Specific antimicrobial dressings were not used regularly.  There was a high rate of failure and crossover in the subclavian arm (14.7%).  Then, the number of complications for each were measured typically in the near-single digits, while 469 patients died before catheter removal – a large enough number of potentially unmeasured events to significantly affect the primary outcome.  Only symptomatic patients were screened for thrombosis – again, leaving many patients with potentially missed outcomes.

So, in the end, what’s likely best?  A skilled subclavian – or one guided by an ultrasound approach – is probably ideal, but should be avoided if clinician comfort is low.  Following that, an ultrasound-guided jugular approach is likely best.  It is not reasonable to suggest the femoral site would routinely be superior to either approach, but these very low rates of complications indicate it need not be shunned when clinically appropriate.

“Intravascular Complications of Central Venous Catheterization by Insertion Site”

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”

Chillin’ Children After OHCA

Once upon a time, many adults suffering an out-of-hospital cardiac arrest received therapeutic hypothermia with a target temperature of 33°C.  Then, along came the Targeted Temeperature Managment trial – in which 36°C seemed to be just as good as 33°C.  Now, just to throw another confounder in the mix, we have a trial comparing 33°C to “therapeutic normothermia” – 36.8°C – and we’re doing it in children to address concerns regarding generalizability from adults.

Very detailed summaries of the numbers, methods, and enrollment can be found on other #FOAMed sites – particularly St. Emlyns and ALiEM.  But, the high points:

  • Many – 1,355 – were screened, but ultimately only 260 were randomized and included in their primary analysis.
  • Adherence to temperature management protocols was good or adequate in ~90% of cases.
  • Hypothermia was implemented for 48 hours, followed by normothermia up to 120 hours total to match the normothermia group.
  • In contrast to adults, the great majority (72%) of this pediatric cohort suffered a respiratory arrest.

The outcome: no statistical difference, with 20% of the hypothermia group alive and functional at 1 year, compared with 12% of the normothermia group, a p-value of 0.14.  Regarding safety, arrhythmias and culture-proven infections favored the normothermia group, 1% vs. 5%, and 39% vs. 46%, but these also did not reach statistical significance.  Finally, both 28-day and 1-year mortality favored hypothermia, with an absolute difference of ~10% in each, but this was not statistically significant, either.

I will let the authors speak for me here:

“One important potential limitation of the trial is that, on the basis of the observed confidence limits for treatment differences, a potentially important clinical benefit cannot be ruled out despite the lack of a significant difference in the primary outcome measure. A larger trial might have detected or rejected a smaller intervention effect. Indeed, there was a significant difference in survival time with therapeutic hypothermia, although this was a secondary outcome measure.”

The relative likelihood of benefit for hypothermia in this trial was 1.54, with a 95% CI of 0.86 to 2.76.  Now, this result crosses 1, and therefore requires interpretation in two contexts.  The first is the normal distribution:

In which we visualize the frequency of potential outcomes, and the important realization the more frequent “true” outcome is most likely to occur near the center of the 95% CI range.

And, the more important context:

In which we interpret these data in the context of prior results, generalized from other settings.  In this case, our prevailing opinion is one in which we suspect hypothermia – with much uncertainty regarding the details – is beneficial.  As you can see, the effects of even “statistically significant” findings have only limited practical impact on the “good bet” or the “long shot”.  Hence, the results of this study – which simply barely fail to reject the null hypothesis – do not hardly move the needle against the prevailing opinion.

I tend to side with the authors of this “negative” study: it is mostly likely underpowered to detect the expected benefit, and it is still reasonable to cool children following OHCA.  There are many questions that remain regarding the temperature, duration, and other details – not limited only to children – but it would be erroneous to say this trial refutes the practice of hypothermia in children.

“Therapeutic Hypothermia after Out-of-Hospital Cardiac Arrest in Children”