Mild therapeutic hypothermia for survivors of cardiac arrest

This chapter reviews some of the methods and the evidence behind the use of therapeutic hypothermia in comatose survivors of cardiac arrest. Another, much larger chapter, reviews the physiology of hypothermia in general. Given the excitement generated by this therapy, and given the fact that it is probably the only useful thing we can do for the cardiac arrest survivor, the college examiners have dedicated an understandable attention to it in the SAQs.

• Question 21 from the second paper of 2021
• Question 9 from the first paper of 2015
• Question 20 from the second paper of 2006
• Question 2 from the first paper of 2002

This chapter begins with a stereotyped answer to a "critically evaluate" question, and then degenerates into what can only be described as a rant. The time-poor exam candidate may wish to limit their reading to the first subheading.

A critical evaluation of therapeutic hypothermia in cardiac arrest survivors

Rationale for therapeutic hypothermia in the cardiac arrest survivor

• Therapeutic hypothermia has been advanced as a means of improving survival and good neurological outcome following cardiac arrest.
• Hypothermia modulates the activity of body proteins and electrolytes.
• This modulation is thought to have some beneficial effects in scenarios where inflammatory damage is anticipated.
• This also involves the down-modulation of the overall metabolic rate, which decreases the metabolic demands of the organism in situations where supply of metabolic substrate may be compromised.
• Decrease in oxygen consumption matches decreased demand with decreased supply in "penumbra" areas, at the watersheds, where hypoxic injury has caused oedema

Advantages of therapeutic hypothermia in the recovery from cardiac arrest

• Decreased granulocyte migration into the brain tissue.
• Decreased cerebral oedema
• Intrinsic anticonvulsant effects of hypothermia

Disadvantages of therapeutic hypothermia following cardiac arrest

• Decreased rate of drug metabolism
• Impaired immunity
• Decreased cardiac output and bradycardia
• Prolongation of QT
• Risk of arrhytmias
• Increased hematocrit and blood viscosity
• Hyperglycaemia
• Counterproductive energy expenditure via shivering

Evidence for and against therapeutic hypothermia following cardiac arrest

• Pseudorandomised unblinded trial in 1996 showed promising results
• Bernard et al (2002), in a small study (n=77) demonstrated a marked difference in survival (26% vs 49%) in out of hospital VF arrest survivors using 33°C.
• HACA trial (2002) in a small study (n=134) demonstrated good neurological outcomes in 55% of cooled patients, vs. 39% of non-cooled patients.
• TTM trial (2013) in a larger and more methodologically robust study (n=950) had demonstrated non-inferiority of a more conservative hypothermia (36°C), in terms of mortality.
• HYPERION trial (2019), specifically among patients with nonshockable rhythm (n=584) , found a benefit to good neurological outcome (10.2% vs 5.7%) using 33°C.
• TTM2 trial (2021), the largest so far (n=1861) had further demonstrated that merely maintaining normothermia (under 37.8°C) was also non-inferior to using  33°C (54% vs 54% mortality).

Professional organisation-level support for this practice

• ESC (2021) recommend 32 and 36 °C for at least 24 hours
• AHA (2020) recommend TTM 
• AHA (2015) had specifically recommended 32-36° C
• ARC recommended 32-36° C in 2016 (and that was their last update)

How did they come up with this?

Since the Russians started burying their dead soldiers in the snow at part of routine resuscitation, there has been interest in hypothermia as an adjunct to cardiac arrest management. After a few unsuccessful attempts to use low temperature treatments to arrest the growth of cancer, the fact that it decreases the metabolic activity of the brain was demonstrated in dogs, moneys and groundhogs. The authors cooled the animals down to 20 degrees and performed surgery on their myocardia, with cardiac standstill lasting up to 13 minutes. The results were incredible for the times. At 18 months follow up, one of the post-cardiotomy monkeys was acting as a mascot at a naval station, and appeared "normal in all respects".

In short, hypothermia seemed as a promising method to keep the vital organs alive under conditions of poor or absent cardiac output. There was a direct link to cardiac arrest from this. The intensive care community swooned with the intoxicating promise of an actual management strategy for cardiac arrest survivors. Shortly after the groundhogs were defrosted, Williams and Spencer (and then Bensen and colleagues) attacked post-cardiac arrest patients with ice baths and rectal thermometers. Williams and Spencer reported on a case series of patients described as "coloured" who were subjected to cooling with temperature ranging from 30 to 33 degrees, and without paralysis. Miraculously, these people recovered with minimal deficits. Bensen and friends did something similar and reported a survival rate improvement from 14 to 50%. However, the technique was fraught with complications, the most significant being ventricular fibrillation and staphylococcal pneumonia. The complications were sufficiently fearsome, and the technique sufficiently unfamiliar, for the entire thing to be abandoned for about 30 years.

The technique was resuscitated (forgive the pun) in 1996. Promising results (in terms of neurological outcome) were published, and interest in therapeutic hypothermia was rekindled; to such an extent that in 2003 the AHA included it in their guidelines for managing post-cardiac arrest patients.

Contraindications to therapeutic hypothermia

Firstly, let us exclude from cooling those post-arrest patients who wake up, pull off their defib pads, and thank their rescuers. Clearly hypothermia is contraindicated if there is already good neurological outcome.

Of the comatose post-arrest patients, you would not want to cool those who have uncontrollable bleeding. The colder they get, the less their platelets will aggregate, and the less fibrinogen they will synthesise, which means that their bleeding will not get any more controllable. Originally, the trials of therapeutic hypothermia had excluded haemodynamically unstable patients and pregnant women; we now have sufficient successful case reports to include these groups of patients, if cooling is the thing you want to continue doing.

Methods of lowering body temperature

Let's say you decided to cool the patient. First, you must convince yourself that you are measuring the core body temperature, rather than some sort of surface temperature. Nasogastric probes are available, but their disadvantage lies in their tendency to measure the warmed humidified gases in the endotracheal tube (where the temperature is a balmy 38 degrees or so). The bladder probes which double as IDCs are probably better at picking up core body temperature.

However, the oesophagus remains the site of choice for core body temperature measurements. The argument for this rests on the concept that the most physiologically important temperature in this whole cooling process is the temperature of the myocardium (seeing as that is where the worst complications will come from).

The typical means of lowering body temperature is ice packs and a water-cooled blanket.

Alternative (more awesome) means of inducing hypothermia include using ice water for body cavity irrigation, using ice-cold dialysate fluid for CVVHDF, and cooling an entire ECMO circuit.

A CICM fellowship exam question (Question 16 from the first paper of 2012) has forced me to review these methods, and as a result a handy table is available, detailing the advantages and disadvantages of various cooling methods. This table is based on an even better table from a 2009 article by Kees Polderman and Herold Ingeborg.

Methods of Inducing Therapeutic Hypothermia

METHOD	ADVANTAGES	DISADVANTAGES
Air cooling by skin exposure	Easy, cheap, and without procedural risk Cooling rate is around 0.5°C per hour	Not very effective. And you cannot rewarm them this way.
Air cooling with electric fans	Easy, cheap, and without procedural risk Cooling rate is around 1.0°C per hour	As you fan the patient, you blow aerosolised pathogens all around your ICU, which is a potential infection risk. And you cannot rewarm them this way.
Evaporative air cooling by skin exposure with alcohol, water, sponge baths etc	Easy, cheap, and without much procedural risk. Cooling rate is around 1.0°C per hour	Labour intensive. The patient ends up wet - that may be a major problem for patients with wounds. Alcohol is not benign, it may absorb into eroded skin areas and it may irritate. Electrical safety becomes a concern with exposed transvenous or epicardial pacing wires. And you cannot rewarm them this way.
Air cooling with an inflatable blanket	Easy, cheap, and without procedural risk Frequently the ICU will already have one. Cooling rate is around 0.5°C per hour. One can change the air temperature, and rewarm the patient in this fashion.	Not any more effective effective than cooling by passive air-skin exposure.
Specially designed air-cooling beds (with an air-pumped inflating mattress)	Without procedural risk, and potentially offering a protection against pressure areas. Cooling rate is around 1.0°C per hour. One can change the air temperature, and rewarm the patient in this fashion.	Expensive and noisy. Not available everywhere
Surface cooling by ice packs	Easy and cheap. Cooling rate is around 1.0°C per hour	Labour intensive. Uneven cooling - some areas may have little cooling while other areas may develop frostbite or pressure areas.
Surface cooling by immersion in cold water	Rapid cooling rate: around 8-10°C per hour Cold water is inexpensive. It may be possible to rewarm the patient this way by changing the bath temperature.	Impractical for large patients - this technique may only be suitable for infants and children. The patient ends up wet - that may be a major problem for patients with wounds. Unusual problems arise with attempting to ventilate a partially submerged patient. Electrical safety becomes a concern with exposed transvenous or epicardial pacing wires.
Surface cooling by skin contact with circulating cold water in a cooling blanket	Good cooling rate: around 1.5°C per hour Cold water is inexpensive. Changing the water temperature can be used to rewarm the patient. Some systems can be coupled in feedback with a temperature probe for more accurate temperature maintenance	Labour-intensive Initially, takes some time to reach he desired temperature
Surface cooling by skin contact with circulating cold water in a cooling vest	Rapid cooling rate: around 8-10°C per hour Cold water is inexpensive. Changing the water temperature can be used to rewarm the patient. Some systems can be coupled in feedback with a temperature probe for more accurate temperature maintenance	The cooling blankets may be reusable, but the jackets are not -and these can be expensive. The jackets may leave marks on the skin, and theoretically could cause pressure areas
Infusion of cold fluids	Easy and cheap. Good cooling rate: 2.5-3.0°C per hour	A large volume of fluid needs to be infused; this may result in electrolyte derangement and fluid overload. The patient cannot be rewarmed in this way. Also, there is little control over the temperature which is achieved in this way. Lastly, exposure of the myocardium to a jet of cold fluid may result in arrhythmias and asystole.
Peritoneal lavage with cold fluids	Potentially, a good cooling rate	Invasive, requires some surgical expertise. Infused cold fluids will be absorbed to some extent, giving rise to electrolyte abnormalities. The patient cannot be rewarmed in this way.
Intravascular cooling catheters: baloons filled with cold saline, metal catheters for heat exchange,	Good cooling rate: around 2.0°C per hour Most of these double as central lines, offering central venous access and central temperature monitoring	Invasive, expensive, and disposable. Catheter-related thrombosis may be an issue.
Extracorporeal circuit cooling	Rapid cooling rate: around 4-6°C per hour Convenient if the patient is already on ECMO or CVVHDF; little additional workload. The patient can also be rewarmed in this way.	Very invasive. Major disadvantage due to the need for anticoagulation.
Antipyretic drugs	Easy and cheap.	Poor cooling rate: 0.1-0.5°C per hour

How low can you go?

The trials which have made this technique so popular have targeted a modest decrease in core body temperature, down to 32-34 C. ILCOR guidelines recommend you don't go lower than 32°, beyond which point arrhythmias and coagulopathy await. Recent evidence suggests that maintaining a low-normal body temperature of 36° is probably at least as good as cooling to 33° in terms of mortality and neurological outcome.

For how long do you cool them?

The optimal duration of hypothermia has not yet been agreed upon. Certainly, the first trial seems to have only cooled the patients for the first 12 hours. Subsequently, studies have focused on 12 to 24 hour ranges. The AHA guidelines recommend this as the ideal period.

What is the evidence for the use of therapeutic hypothermia in post-arrest patients?

Methodological problems abound in hypothermia literature, which is par for the course in the historically murky waters of post-resuscitation care. There are few high quality studies because no investigator dares tread from the beaten path lest they sink gurgling into the swamp of resuscitation ethics. Let us examine these valiant attempts.

Bernard et al (from Melbourne, Australia) performed their trial on 77 men and women who had out-of-hospital VF arrests. This sample group were randomised in a wholly non-random way, without allocation concealment: the decision to cool or not to cool was made according to a calendar, on the basis of whether the date was odd or even.

But let us ignore that for a second. The exclusion criteria clearly make this an "efficacy" rather than an "effectiveness" trial. The patients were very carefully selected. I suppose the most delicate problem was the hemodynamic stability of the patients. Only the stable ones qualified for cooling. All those VF arrests which occurred due to massive coronary events (why, that's the majority of them) who come to ED in cardiogenic shock - excluded. Non-VF arrests? Excluded. Drug overdose or head injury? Excluded.

In short, only out of hospital VF arrest patients with strong spontaneous circulation by the time of presentation were included. And some might argue that this is the group who would do well anyway. But I digress.

The study protocol was to cool the patients as soon as possible down to a temperature of 33 degrees, and then to keep them at this temperature until 12 hours post admission has elapsed.

Now, the raw outcomes for this were quite good. 49% of cooled patients went home or to rehab, whereas of the non-cooled group only 26% we so lucky. The odds ratio for a good outcome with this cooling protocol is about 5.8, which makes it a damn good treatment effect. These were clinically meaningful outcome measures.

Hypothermia for patients with non-VF and in-hospital arrest

Though the good quality studies were predominantly in haemodynamically stable survivors of out-of-hospital VF arrest, the AHA recommended therapeutic hypothermia be offered to survivors of arrest from any cause, in or out of hospital. However, the evidence for this is poor. Most of the studies on which this recommendation rests are either observational studies or trials with historical control groups; most have a substantial risk of bias and very small sample size, which makes it difficult to take them seriously. A good review in Critical Care discussed the contemporary evidence and concluded that, though overall the evidence was poor, the pooled results trend towards a 15% reduction of in-hospital mortality among the hypothermia group, albeit without much improvement in neurological outcome.

Interestingly, though the authors suggested a randomised trial with N=1100 would be sufficiently powered to detect a treatment effect, they also suggest that the evidence for benefit is sufficient to derail such a trial on ethical grounds. This basically implies that at this stage, it was seen as unethical to withhold therapeutic hypothermia from non-VF arrest survivors.  Fortunately, TTM came along, and reintroduced a bit of equipoise. It was therefore possible to run the HYPERION trial (2019), specifically looking at  patients with nonshockable rhythm (n=584) , found a benefit to good neurological outcome (10.2% vs 5.7%) using 33°C. 

Benefits of mild therapeutic hypothermia in the post-arrest patient

Table 17.4 in the old (6th) edition Oh's Manual listed the benefits in a concise fashion. Instead of reproducing it, I will merely mention a few of the salient features. 

For one, the decrease in oxygen consumption (by 6-7% per degree below 37) matches decreased demand with decreased supply in "penumbra" areas, at the watersheds, where hypoxic injury has caused oedema,.

The overall decrease in enzyme activity and protein synthesis is likely responsible for the decreased expression of adhesion molecules on the endothelia of cerebral vessels, and thus there is a decrease in granulocyte migration into the brain tissue. This results in decreased oedema, and this it decreases intracranial pressure.

Furthermore, hypothermia has some intrinsic anticonvulsant effects (as the decreased metabolic activity of neurons tends to protect them from becoming "overexcited" and thus limits the production of epileptiform discharges).

Anticipated complications of mild therapeutic hypothermia

Again, Oh's manual lists these with exhausting attention to detail. I will focus on the most important ones:

Bradycardia	The lower the temperature, the slower the rhythm.
QTc prolongation	The QT interval is prolonged by even more than one would expect from the bradycardia.
Arrhythmia	Typically, in this "mild" range of hypothermia, one only encounters atrial fibrillation, which is typically slow.
Vasoconstriction	The peripheral vessels become constricted, and this drives the blood pressure up, which (if you have a crappy left ventricle) is not ideal. One may wish to start some antihypertensives, if one does not wish to struggle against this afterload.
Neutropenia and thrombocytopenia	Both the number and the function of these cells decreases.
Coagulopathy	Clotting factors lose activity with decreasing temperature; however this should not be a major issue at temperatures as high as 33 degrees.
Decreased gut motility	If nothing else is working, nor will the gut be working. Bacterial overgrowth results (I imagine they are more resistant than us to these temperature fluctuations)
Hyperglycaemia	In part, this may be due to the poor cellular reactivity to insulin; but no doubt decreased whole-body glucose consumption is also involved.
Cold diuresis	The cooled patient will pee torrentially. The tubules rely on ion channels and ATP-powered pumps to drive the resorption of water; as their metabolic activity decreases, so the resorption becomes impaired. Furthermore, a chilled tubule is much less responsive to vasopressin, and less vasopressin is synthesised by the hypothermic pituitary gland. In any case, the hypothermia patient is a rich source of dilute urine.
Shivering and lactic acidosis	This threat is pretty much always is completely abolished by the use of neuromuscular junction blockers. There is a frequently mention caveat to this - if your patient is having a seizure, you will not know about it if they are paralysed.
Electrolyte derangement	Hypokalemia and hypophosphataemia are usually associated with cooling; renal losses may be responsible.