Target temperature management in critically ill patients

Definitions

Hypothermia is defined as a core body temperature lower than 36°C, regardless of the cause. Within hypothermia we can still distinguish mild (i.e., between 35°C and 32°C), moderate (i.e., between 32°C and 28°C), severe (i.e., between 28°C and 24°C), and profound (i.e., <24°C) hypothermia.

The concept of target temperature management (TTM) includes the use of induced hypothermia (i.e., cooling procedures initiated to provide brain and/or organ protection in different clinical scenarios), followed by or combined with an active control of temperature (i.e., normothermia and avoidance of fever) after hypothermia over a defined period.

Physiology and pathophysiology

Hypothermia has been considered over decades as a potential therapeutic strategy for different purposes, including pain management, hemorrhagic control, tetanus treatment, and neuroprotection; however, its applicability remained limited by the difficulties in achieving and maintaining a given temperature threshold (in particular for nonsedated patients) and in managing related adverse effects. As a matter of fact, only “moderate hypothermia” was initially considered to be effective ; nevertheless, in the last few decades, the report of beneficial effects of “mild hypothermia” in some clinical settings, together with the advances in medical technologies providing adequate temperature management, has significantly contributed to spread the research and implementation of TTM worldwide.

Most studies have focused on the effects of hypothermia/TTM on the brain, considering its high sensitivity to ischemic injury. When the brain temperature is reduced, its metabolic rate slows down by 6%–10% for each degree, thereby diminishing oxygen consumption and carbon dioxide (CO ₂ ) production and the reperfusion injury. Indeed, after a period of blood flow reduction, a complex cascade of events triggered by the reperfusion starts within minutes and can persist up to 72 hours, increasing the degree of ischemic injury. These mechanisms include (1) an increase of the inflammatory response accompanied by increased cerebral blood flow (hyperemic phase); (2) an increase in cellular Ca ²⁺ influx that is responsible, along with the cellular metabolic failure, for mitochondrial dysfunction; (3) a decrease in intracellular pH; (4) the release of glutamate in the extracellular space in the brain, determining a state of persistent neuronal hyperexcitability; (5) blood-brain barrier disruption with augmented permeability; (6) augmented production of free radicals; and (7) increase in programmed cell death (apoptosis). Moreover, hyperthermia, which is either caused by the inflammation after reperfusion or by direct hypothalamic damage, which is involved in the tight temperature regulation in humans, occurs frequently in the postreperfusion phase; as hyperthermia is independently associated with worse outcome and can also exacerbate the magnitude of the secondary brain damage, ^, it sounds logical to control body and brain temperature in brain-injured patients.

In particular, hypothermia can mitigate several of these phenomena, thus limiting the installation of a vicious circle by which the organ damage can further progress despite optimal medical treatment. In particular, in the acute phase (i.e., first minutes to hours), hypothermia would contribute to reducing reperfusion injuries by reducing the cerebral metabolic rate and the release of excitatory amino acids, decreasing free radical production and inflammation, and attenuating pro-apoptotic signals. Subsequently, in the subacute phase, hypothermia can counteract the occurrence of brain edema (i.e., hours to days), and it can favor neuronal repair (i.e., following days and weeks). As body temperature is a major determinant of all biochemical reactions and interactions in the human organism, inducing hypothermia modifies the entirety of the biologic processes thorough the body ( Table 39.1 ).

The first effect triggered by the temperature drop is the appearance of shivering, which generally manifests as the core temperature becomes lower than 35.5°C ⁴ : that is, one degree below the vasoconstriction threshold. Shivering is the physiologic attempt to restore core temperature by causing an increase in heat production by involuntary movements, but also determines increase in work of breathing, heart rate, and myocardial oxygen consumption. These effects could complicate the induction phase of hypothermia (i.e., prolonged time to target temperature) and should be treated promptly to avoid an undesired increase in the metabolic rate in injured organs. Several options could be considered, including pharmacologic therapy and direct surface counter-warming, as summarized in Table 39.2 .

The induction of hypothermia can induce some cardiovascular alterations, including an increase in cardiac systolic function associated with a mild impairment in diastolic function despite a reduction in heart rate. However, the cardiovascular effects of hypothermia could be different in critical illness: In survivors after cardiac arrest, cooling to 33°C has been shown to increase contractility and improve recovery from cardiac arrest–related dysfunction when applied for more than 48 hours. Pulmonary effects of TTM are tightly related to the decrease in oxygen demand and CO ₂ production by the entire body. These variations must be taken into account to adequately adjust ventilatory parameters in order to avoid deleterious shifts in arterial partial pressure of CO ₂ (PCO ₂ ) or pH. Several aspects of the immunologic response are also modified by hypothermia, raising concerns about a higher incidence of infections. Fortunately, large trials using mild TTM did not show any difference in the rate of infections. Nevertheless, perioperative hypothermia has been associated with an increased risk for surgical wound infection when compared with normothermia. Also, platelet count and function appear to be decreased when core temperature decreases below 35°C, whereas coagulation appears to be affected significantly only for temperatures below 33°C. ^, Reassuringly, despite these alterations no significant increase in spontaneous bleeding or hemorrhage rate has been found in large trials on the use of mild TTM in comatose survivors after cardiac arrest or after traumatic brain injury (TBI). ^, Hypothermia can induce electrolyte abnormalities and increase the sensitivity to them. Specifically, potassium, magnesium, and phosphate depletion could cause serious adverse effects, including life-threatening arrhythmias, both during the induction and the rewarming phase and must then be monitored closely. Hyperglycemia, caused by decreased insulin sensitivity occurring during hypothermia, is common particularly in the induction phase and is associated with poor neurologic outcome, whereas hypoglycemia caused by increased insulin sensitivity may occur during the rewarming phase, especially if the rewarming rate is too fast. The overall changes in enzymatic (i.e., liver) and tubular (i.e., kidney) functionality can reduce the blood clearance of several medications during hypothermia ; thus when TTM is applied, possible alteration in drug pharmacodynamics must be taken into account. Lastly, TTM can slow bowel and gastric function, promoting ileus and delayed gastric emptying, which in turn must not be considered a contraindication to nasogastric feeding when indicated.

Clinical application of hypothermia/TTM in cardiac arrest