Neurologic Status After Arrest
TTM is not recommended for patients who have clear return to baseline neurologic status after their arrest. Criteria for enrollment in the HACA trial was the inability to follow verbal commands; the Australian study used the more vague description of “unconscious,” and the recent TTM trial specified a Glasgow Coma Scale (GCS) less than 8. It is not known whether there is any benefit to TTM in patients who have less severe neurological examinations postreturn of spontaneous circulation (ROSC). The 2010 AHA guidelines recommend TH for patients who have a lack of meaningful response to verbal commands,5 and it is reasonable to apply this criteria to TTM in general. As for patients who may have received sedatives thereby confounding their presenting examination, it may be prudent to wait a reasonable period to see if they regain the ability to follow commands before deciding to cool. It is suggested not to provide TTM in patients who are severely neurologically impaired at baseline, terminally ill, those for whom intensive care does not seem appropriate, or in whom they or their surrogates have indicated that they would not want intensive care.7
Location and Other Rhythms
In terms of location, the core studies were limited to out-of-hospital arrests. Accumulating evidence however supports TH for in-hospital arrests, and aside from the higher proportion of nonarrhythmic arrests there is no reason to believe the difference in physical location would have any detrimental impact on the therapy. Although TH is best established in VF and VT arrests, there has always been interest in its application to nonshockable rhythms. Irrespective of the dominant rhythm during cardiac arrest, ischemia and reperfusion injury occurs and may therefore be responsive to TH. The 2015 AHA guidelines gave a class I recommendation that all comatose patients post ROSC irrespective of rhythm receive TTM in the range between 32°C and 36°C.6 A large retrospective study in 2011 showed that TH was associated with improved outcomes in out-of-hospital nonshockable rhythms.8 However, a recent prospective review of a French registry from 2000 to 2009, did not find improved outcomes of TH in PEA/asystole patients.9 The authors raised the possibility that the anoxic/hypoxic insult in nonarrhythmic arrests is likely much greater and therefore may require deeper or longer periods of hypothermia to address. On the other hand, it is also possible that the risk-benefit ratio may simply be altered in this high-risk population and that PEA and asystole are better served by targeting a (potentially safer) temperature of 36°C. In conclusion, data supporting TH (33°C) in PEA/asystole are lacking and the benefit of TTM in general in this population is not clear. However, given the physiologic rationale for benefit of TH, it is arguable to target a potentially safer goal of 36°C.
Physiologic Effects of Cooling
The following sections on the physiologic effects of cooling refer mainly to a temperature of 33°C. The effects of minimal hypothermia (36°C) are less well characterized, but presumably milder.
Hypothermia raises systemic vascular resistance (SVR) but its effects on blood pressure are variable as are its effects on cardiac output. The hypothermic heart develops diastolic dysfunction and there is an expected and physiologically adaptive bradycardia. It is not uncommon to see heart rates (HRs) in the low 40s (occasionally high 30s) with core temperatures of 33°C. Artificially elevating the HR could result in worsening contractility and cardiac output.10 Therefore, it is not recommended to treat bradycardia (with catecholamine infusions or pacing) unless evidence suggests it is directly responsible for poor perfusion. Mild TH has an antiarrhythmic effect and suppresses the development of ventricular arrhythmias. But overcooling should be avoided because a core temperature under 30°C frequently results in cardiac arrhythmias including spontaneous VF.11
Although initial studies excluded hemodynamically unstable patients, increasing experience shows the safety in TH even in very unstable patients. A case series of patients in cardiogenic shock postcardiac arrest from acute coronary syndrome (ACS) on multiple vasopressors/inotropes including a large percentage requiring intra-aortic balloon pumps reported the safety of TH.12 Another study of cardiac arrest patients from ACS suggests that TH may have a favorable impact on the hemodynamics of cardiogenic shock. Hypothermic patients had a higher SVR and HR. But more surprisingly, they also had improved cardiac output and index13 (as measured by a minimally invasive cardiac output monitoring device and echocardiography).
The brain is particularly sensitive to ischemic injury and temperature. For every decrease in 1°C, brain metabolism decreases by 6% to 7%.1 There is abundant evidence that hyperthermia is associated with poor outcomes after many different brain injured states (stroke, traumatic brain injury). Postcardiac arrest cerebral edema may be more common than readily recognized and hypothermia is very effective in lowering intracranial pressure (ICP). Lastly, TH may provide an anti-antiepileptic effect.14
It has been long recognized that hypothermia potentiates coagulopathy during trauma and surgery. Accidental hypothermia is widely considered a marker of mortality in trauma victims, as well as a marker of morbidity during surgery. The oft-repeated bloody vicious triad of trauma “hypothermia, coagulopathy, and acidosis,” is thought critical to avoid. Studies of TH effects on coagulation demonstrate a prolongation of prothrombin time (PT) and activated partial thromboplastin time (aPTT), as well as reversible thrombocytopenia and platelet dysfunction.15 A mild prolongation of time to clot formation, but not clot propagation or clot firmness using more sophisticated clotting testing (ROTEM) has also been found.16 However, while unintentional hypothermia may be important to avoid during massive resuscitation of a bleeding patient, the clinical relevance of its effects on coagulopathy in controlled hypothermic conditions however is less clear. Importantly, major clinical studies have not shown a significant increase in bleeding. There is accumulated experience of TH safely being applied concurrent with heparinization for pulmonary embolism, as well as in extremely anticoagulated patients with ACS (who may receive aspirin, clopidogrel, or heparin). Routine intensive care unit (ICU) procedures such as arterial and venous catheterization should not be affected by TH. In summary, the coagulopathy of TH is well tolerated, and safe with concurrent anticoagulation, but should be considered contraindicated in patients who arrest secondary to bleeding, especially those with ongoing uncontrolled bleeding. TH at 36°C is expected to have trivial effects on coagulation.
A major concern is the effect of TH on potassium. Induction of hypothermia drives intracellular flux of potassium and the reverse occurs upon rewarming. Hypokalemia on induction is usually not a huge problem, but caution and possibly intervention should be taken in the hyperkalemic patient before rewarming. Magnesium levels mimic potassium, falling on cooling and rising again on rewarming. Hypophosphatemia is also common but rarely a problem. Hypothermia also inhibits insulin sensitivity and release leading to hyperglycemia.15 TH may lead to an increase in urine output, dubbed the “cold diuresis.” Whether this is related to a more centrally distributed circulation or a direct tubular effect is not clear.
TH is thought to be immunosuppressive but the degree is not well characterized, and may do not have clinical relevance. Pneumonia is common after cardiac arrest in general, and it is unclear if TH increases that risk. It is possible that TH can indirectly lead to an increase in infections by requiring sedation, paralysis, and mechanical ventilation.
As temperature falls the solubility of gases in the blood decreases. Temperature uncorrected arterial blood gases (ABGs) therefore overestimate both Pco2 and Po2. The patient therefore may have a slight respiratory alkalosis and be slightly more hypoxemic. The significance of this effect is unknown, and it is controversial whether to aim for a normal pH (pH stat) or normal CO2 (alpha stat) level during TH. It is likely that the impact is more important at deeper levels of hypothermia used during cardiopulmonary bypass. This author recommends addressing the pH/Pco2 on the uncorrected ABG as you would any other critically ill patient, but aim for a slightly higher Po2 than normal (ie, 70 mm Hg) to give buffer room.
In summary, TH routinely leads to well-tolerated bradycardia and electrolyte shifts. Other effects such as coagulopathy, immune suppression, and acid-base imbalances, are uncommon severe problems. TH effects on any of these conditions are expected to be minimal.