Cooling After Cardiac Arrest – The Sclerosis of Therapeutic Fashion

The story of how an ineffective therapy persisted for decades

A recent reversal in an established practice in cardiology provides a beautiful example of how biased science, intellectual conflict of interest, and intervention bias can mislead medical practice—for two decades.

The reversed practice involves the care of survivors of cardiac arrest. It’s called targeted temperature management or induced hypothermia. More simply: cooling.

As an arrhythmia consultant, I am often asked to see survivors of cardiac arrest in the ICU. What you see is a spectacle: the patient is sedated, paralyzed, connected to the cooling apparatus and almost always attended by an ICU staff member.

Whenever I see something this labor-intensive and aggressive, I wonder about the evidence. The Neutral Martian part of my brain asks: does all this stuff really help?

The short answer is no, it doesn’t.

Be sure, the relevance of this story extends beyond the specifics of one ICU therapy—as most of us aren’t ICU clinicians.

The big story is how an aggressive practice became the therapeutic fashion despite shoddy evidence. And then, even when published evidence showed that it didn’t work, the practice persisted.

There are four chapters to this story:

Chapter 1: The Plausibility Tailwind:

Cardiac arrest causes the brain to be deprived of oxygen and nutrients. The longer the period of no blood flow, the more the brain injury.

Rapid cooling may lower the demand for nutrients and reduce brain injury. Cooling, for instance, is used during surgery that transiently stops blood flow to the brain. Animal studies suggested that cooling mitigated brain damage after cardiac arrest.

In other words: cooling after cardiac arrest makes sense. Since organ injury occurs when demand for nutrients outstrips supply, cooling reduces demand and that may reduce brain injury.

The problem is that cooling a human being is no small thing. Getting down to 33 degrees requires placing the patient on a cooling system, with pads wrapped around the body. This induces shivering—which is then suppressed with heavy sedation and paralytic agents.

Then there is the fact that normal body functions are optimized at 37° degrees (C). Cooling can affect blood pressure, increase the risk of infection, lower heart rate, induce arrhythmia and prolong the time to waking.  Cooling is also labor intensive—more blood draws, monitoring and staff time.

Chapter 2: The 2002 Studies:

In 2002, the New England Journal of Medicine published two studies suggesting cooling improved outcomes in survivors of cardiac arrest.

An Australian study (Bernard et al) compared just 77 patients and found that survival with good neurologic function occurred in 49% of the cooling arm vs 26% in the control arm. The authors made cautious conclusions, calling their observations “preliminary,” using the phrase “appears to improve outcomes” to describe their findings.

The second study, called the Hypothermia after Cardiac Arrest or HACA study, compared cooling in 275 patients. A favorable neurologic outcome was noted in 55% in the cooled group vs 39% in the normal temperature group. In addition, the rate of death was also 14% lower in the cooling arm.

Both these trials were susceptible to bias. For instance, neither trial used blinding in the decision to withdraw care. Proponents of cooling might have been less willing to withdraw care in patients assigned to the cooling arm. The most glaring concern: the large reductions in death (14% in the HACA trial) look highly suspicious as an outlier, because no ICU therapy, ever, has ever achieved such a reduction.

The weaknesses of these two studies mattered not. Cooling became the standard of care for more than a decade until the next trial came in 2013.

Chapter 3: The 2013 Study:

The TTM trial compared 33 degrees to 36 degrees in post-cardiac arrest survivors in a larger sample of 975 patients. In this more rigorous test, there were no differences in death or neurologic function. Plus, the cooling arm had more adverse events. The authors concluded that TTM provided no evidence that targeting 33 degrees conferred any benefit over 36 degrees.

You would think this would have been it for cooling. But it was not. Cooling patients remained the norm. Guidelines recommended either 33 or 36 degrees.

Intensivist Josh Farkas, MD, posits that cooling persists because of status quo bias. I recently took an American Heart Association course on advanced cardiac life support and cooling was recommended.

Chapter 4: The 2021 Study

Seven years after the nonsignificant TTM trial, NEJM published the TTM2 trial, which enrolled 1850 post-cardiac arrest survivors to either 33 degrees vs normothermia (prevention of fever). The authors also blinded clinicians and families to the decision to withdraw care.

The results were clear: no difference in death nor neuro outcomes. There were more arrhythmias, greater use of paralytics and longer time on the ventilator in the cooling arm.

Any neutral observer would think that this would be the end of cooling patients who survive cardiac arrest. The invasive more aggressive strategy makes no difference in outcomes, causes more adverse effects, and requires more nursing care. There were now two large rigorous trials showing no benefit.

But I wonder.

The editorial accompanying the stunningly clear TTM2 trial portends the difficulty in de-adopting ensconced therapy.

The key takeaway from the TTM2 trial for clinicians should be that targeted temperature management involving pharmacotherapy, device cooling, and timely neurologic prognostication is a crucial treatment strategy to improve outcomes in patients who have had a cardiac arrest.

The target temperature, at the discretion of the clinician, could be 33°C, 36°C, or 37.5°C or less.

Really?

Take-Homes

The original Barnard et al trial in 2002 explicitly warned that these were preliminary data. But the two early trials, however flawed, established cooling as the therapeutic fashion. So strong was that fashion, that the nonsignificant results of the 2013 TTM trial did not shake it.

And now, even after the second large nonsignificant TTM2 trial, it may still be difficult to de-adopt cooling to 33 degrees as an intervention.

The cooling story underscores two important biases that doctors (and patients) ought to be aware of.

The first is over-confidence. In a recent survey study, Dan Morgan and colleagues, found that clinicians massively overestimate benefits of treatments. His study involved simple therapies such as statins and blood pressure control, but I would guess that bigger aggressive interventions engender even more overconfidence.

The other factor is intervention bias.

Clinicians favor errors of commission more than omission. Using conditional arguments and observational data, my friend and frequent co-author Andrew Foy, along with Ed Filippone, MD, made a strong case for intervention bias in Medicine. And it’s not merely defensive medicine. It’s as if we come pre-programmed to intervene.

What’s unusual about cooling is that—unlike many other low-value therapies (think vascular screening)-- financial conflict of interest does not seem to be a factor.

Rather, cooling persists more from a deeply engrained intellectual conflict—as in, this makes sense, we’ve done it forever, and we ought to continue doing it. This thinking likely has beneficent intent: cardiac arrest survivors have a poor prognosis, so more must be better.

But the two recent large TTM trials show that more is not better; it’s worse. Higher costs, more adverse effects and no benefits in efficacy.

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De-adoption of aggressive cooling to 33 degrees will eventually occur. The new standard of care will become maintenance of normal temperature and avoidance of fever.

After a few years, the practice of cooling will be forgotten—like the error of treating PVCs after MI. But I think this history should be preserved, for the sake of learning.

The lessons here are many: the danger of accepting interventions based on flawed studies and plausibility; the power of therapeutic fashion, the overconfidence and intervention bias of doctors, but mostly the incredible power of proper randomized controlled trials to teach us what works and what does not.

This story makes the case of having evidence from proper randomized trials before adopting an expensive aggressive intervention.