Wednesday, 24 April 2019

Changing target temperature from 33 to 36 in the ICU management of OHCA: a before and after study

I’ve always been skeptical of the original studies claiming efficacy of therapeutic hypothermia for out-of-hospital cardiac arrest (OHCA).

Image result for the alfred hospital
Two small studies published in 2002 demonstrated a profound treatment effect that caused most of the world to change practice.

Anytime you see a small RCT claiming results that are too good to be true, you need to think that the results are exactly that. Medical reversal is common and much of what is published in the medical literature turns out to be wrong.

Along came Nielsen’s study of Targeted Temperature Management (TTM) in 2013 and most of us reversed back to normothermia. However, several studies have indicated that it is difficult to keep patients at this warmer temperature and there are concerns about fever & possible worse outcomes.
The Alfred Hospital in Melbourne conducted a retrospective before and after study after they changed their targeted temperature from 33 to 36 degrees. They describe their experience and try to compare outcomes.

Over a 30-month period they had 76 patients with OHCA due to ventricular fibrillation. There were 24 in the before group and 52 in the after.

After the TTM change, less patients got active cooling (100% vs. 70%), less time was spent at the target temperature (87% vs. 50%) and fever rates went up from zero to 19%.

The authors compare the before and after outcomes and state there was a trend towards better outcomes with the before group.

Fortunately, the conclusion in the manuscript is appropriately measured:

After the change from a TTM target of 33 to 36 we report low compliance with target temperature, higher rates of fever, and a trend towards clinical worsening in patient outcomes. Hospitals adopting the 36 target temperature need to be aware that this target may not be easy to achieve and requires adequate sedation and muscle relaxant to avoid fever.

I would go a step further.

A small retrospective before and after study can be rather problematic. With such small numbers it is very likely the groups were different; akin to comparing apples to oranges. No amount of adjustment for confounding factors will fix this.

So, I don’t think we should be taking anything away from the trend toward benefit. Much better-quality evidence from the TTM trial shows there is none.

There are also some potential harms noted in this study. They note patients in the 33 degree arm were intubated a full day longer, experienced more shivering, bleeding requiring transfusion and pneumonia.

What’s the take home message?

Overall this was a small study in a single centre that is poor quality evidence to inform practice. It demonstrates it is more difficult to keep patients at a higher target temperature. Whether this has any impact on real patient outcomes is not known but I think unlikely.


Bray J, Stub D, Bloom JE, et al. Changing target temperature from 33 to 36 degrees in the ICU management of out-of-hospital cardiac arrest: A before and after study. Resus 2017;113:39-43. [link to article]

Coronary Angiography after Cardiac Arrest without STEMI

Well regarded guidelines recommend immediate coronary angiography in patients who present with STEMI and cardiac arrest. But what about those that don’t have STEMI? Should they also go to the cath lab?

This RCT conducted in 19 centres in the Netherlands attempted to answer this question.

These researchers randomised 552 patients to immediate vs. delayed angiography.

The inclusion criteria were comatose survivors of out-of-hospital cardiac arrest (OHCA) that had shockable rhythms and return of spontaneous circulation. Patients were excluded if they had STEMI in the ED, shock, or an obvious non-cardiac cause of arrest.

The study was powered to detect a whopping 40% difference between the groups. Of course, it is quite ambitious to think immediate angiography would be so efficacious. Therefore, the study had an “adaptive design” that allowed for an increase in sample size if they detected a trend towards benefit during an interim analysis of the first 400 patients. (Kinda sounds like cheating… but I get it)


Those Dutch know how to conduct a study (must be something in the Heineken).

Adherence to protocol was fantastic. Median time to angiography was about 45 minutes in the immediate group and about 5 days in the delayed.

Acute thrombotic occlusion of a coronary vessel was found in a small minority of patients. Only 3.4% in the immediate and vs. 7.6% in the delayed. As such PCI and CABG was performed less than a third of the time.

I think you know where this is going… this was a negative study.

At 90 days 64% of the immediate group and 67% of the delayed group were alive.
So what should we conclude?

I think it is safe to say that we should not send all patients with OHCA without STEMI to the cath lab.

But one of the major challenges with evidence-based medicine is extrapolating the results of a study to the individual patient in front of us. 

What about the patient with some degree of hemodynamic or electrical instability? Or what about lots of dynamic ST and T wave changes on the ECG (of course this could also come from intracranial catastrophe)? What if they just smell like a coronary occlusion?

In summary, don’t send all patients to the cath lab. But I think we should still consider it on an individual basis. Now back to my Grolsch...


Lemkes JS, Janssens GN, van der Hoeven NW, et al. Coronary Angiography after Cardiac Arrest without ST-Segment Elevation. N Engl J Med 2019;380:1397-1407. [link to article]

Effect of a Resuscitation Strategy Using Capillary Refill Time vs. Lactate in Patients with Septic Shock: The ANDROMEDA-SHOCK Trial

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Can capillary refill time (CRT) replace serum lactate as a resuscitation target in septic shock?

Leave it to the South Americans to try to figure this one out… ¡Vamonos Amigos!

This was an RCT conducted in 28 ICU’s in Chile, Argentina, Uruguay, Ecuador and Colombia. (¿Valididad externa?)

424 adult patients were randomised to a resuscitation protocol aimed at either normalising CRT vs. normalising or decreasing lactate levels.

The study was powered to detect an absolute reduction of 28-day mortality by 15%. Of course, this is crazy… nothing would be expected to work this well. As such, this study was always at a high risk of a type II error (i.e. not finding a difference when one truly exists). ¿Vamonos?

Out of interest, the CRT involved training and standardisation as follows

...CRT was measured by applying firm pressure to the ventral surface of the right index finger distal phalanx with a glass microscope slide. The pressure increased until the skin was blank and then maintained for 10 seconds. The time for return of the normal skin color was registered with a chronometer, and refill time greater than 3 seconds was defined as abnormal.

Once again, the primary outcome was all cause mortality at 28 days. There were lots of prespecified secondary outcome measures.


By day 28, a total of 35% in the CRT group vs 43 % in the lactate group had died (hazard ratio, 0.75 [95% IC, 0.55 to 1.02]; P=.06; risk difference, -8.5% [95% CI, -18.2% to 1.2%]

P value was 0.06. Therefore, a negative study…

This highlights the silly dichotomous nature that we attribute to P values. Less than 0.05 means “something important” whereas above 0.05 means nothing… totalmente loco amigo.

0.05 has always been a single arbitrary cut-off of probability. It tells us nothing about the effect size, whether a study was powered correctly or whether the outcomes are clinically important. It doesn’t tell us about bias, confounding, reverse causality or if the correct statistical analysis was used. The reverence we hold to P values must stop!

In the end, this study produces quite a bit of noise in favour of capillary refill time as a target for resuscitation. But perhaps it highlights the lack of utility of lactate. To be fair, we would never use a single marker in isolation. So perhaps this is all a bit silly… almost as silly as the title, ANDROMEDA-SHOCK trial.



Hernandez G, Ospina-Tascon G Damiani LP, et al. Effect of a Resuscitation Strategy Targeting Peripheral Perfusion Status vs Serum Lactate Levels on 28-Day Mortality Among Patients with Septic Shock: The ANDROMEDA-SHOCK Randomized Clinical Trial. JAMA. 2019;321:654-64. [link to article]

Tuesday, 23 April 2019

Bag-Mask Ventilation during Tracheal Intubation of Critically Ill Adults: A tack in the coffin of RSI

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“Rapid sequence induction” is intended to decrease pulmonary aspiration during endotracheal intubation. Classily it requires a period of apnoea during which time we wait for the paralytic agent to take effect. No breaths are given for fear of insufflating the stomach and increasing the risk of aspiration.

But what if this period of apnoea is worse that the theoretical risk of aspiration? Herein lies a decent research question.

But spoiler… this was not fully addressed with this study.

This RCT in 7 ICU’s in the USA randomised 401 adult patients to BVM or no ventilation between induction and laryngoscopy. They excluded patients at high risk for aspiration (i.e. ongoing emesis, bowel obstruction, haematemesis etc.)

The primary outcome was lowest oxygen saturation. They also looked at many secondary outcomes and rates of pulmonary aspiration.


Those that got BVM had lower rates of hypoxemia. Rates of severe hypoxemia (sats less than 80%) were 11% in the BVM group but 23% in the no-ventilation group. This is hardly surprising but ultimately is not a patient-oriented outcome.

As expected, the incidence of pulmonary aspiration was quite low. It was noted in 5 (2.5%) patients in the BVM group vs. 8 (4%) in the apnoea group. With such small numbers, obviously this is not statistically significant.

The authors state the following:

Given the low incidence of operator-reported aspiration during tracheal intubation of critically ill adults, determining whether bag-mask ventilation increases the relative risk of aspiration by 50% would require a trial enrolling approximately 4000 patients.


I don’t think we’ll see this trial anytime soon.

There were a number of limitations in this trial. It was performed only in ICU’s, high risk patients were excluded, no blinding, the gold standard for aspiration is problematic, etc.

Do we have an answer? Is RSI dead?

Not really. But perhaps this is a tack (but not a nail) in the coffin of RSI.

Ultimately, I think we can use our common sense and cater to the individual patient. Those that are hypoxic are probably fine to have some BVM. Hold off on those where oxygenation is ok and/or high risk for aspiration.


Casey JD, Janz DR, Russell DW, et al. Bag-Mask Ventilation during Tracheal Intubation of Critically Ill Adults. N Engl J Med 2019;380:811-21. [link to article]