**1. Introduction**

130 Therapeutic Hypothermia in Brain Injury

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#### **1.1. Overview of drug disposition and response in critically ill patients**

Therapeutic hypothermia has been growing in use over the past several years. Proven efficacy of therapeutic hypothermia in pediatric hypoxic-ischemic encephalopathy (HIE) patients and adult out-of-hospital cardiac arrest (CA) patients has led to expanding clinical implementation in both large and small hospitals. Furthermore, its use to control intracranial pressure (ICP) in brain injured patients, as well as ongoing experimental studies for a variety of other conditions, have led to increased use of therapeutic hypothermia in the intensive care unit (ICU). With increased implementation comes a growing need to understand the ramifications of therapeutic hypothermia on other important factors of ICU care. One such factor is drug disposition and efficacy changes in the hypothermic patient. Specifically, clinical practitioners have postulated the question, "Should drug doses be altered during or after cooling in patients receiving therapeutic hypothermia?" The purpose of this chapter is to explore this question and present the current understanding of the effects of mild therapeutic hypothermia on the processes of absorption, distribution, metabolism and excretion, as well as provide specific evidence of drugs with altered and unaltered pharmacokinetics.

The question of altered drug disposition and response in patients receiving therapeutic hypothermia is particularly important due to the wide array of drugs used in critically ill patients. Critically ill patients are known to have a high rate of adverse drug events. This high rate of adverse drug events is due, in part, to the plethora of medications used for analgesia/sedation, paralysis, control of seizure activity, blood pressure, treatment of arrhythmias, control of blood clotting, antibiotics, and delirium prevention. Table 1 provides a list and details the pharmacokinetic characteristics of the medications commonly administered to critically ill patients organized by class of compound. From this table, it is

© 2013 Anderson and Poloyac, licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 Anderson and Poloyac, licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

clear that many of these drugs have large volumes of distribution, are extensively bound to plasma proteins, and require hepatic metabolism as a primary mechanism of elimination.

Therapeutic Hypothermia: Implications on Drug Therapy 133

contractility. In contrast, when heart rate was increased under mild hypothermic conditions there was a decrease in myocardial contractility. The same results were reported in a clinical study in patients undergoing cardiac surgery. When heart rate was not increased artificially, mild hypothermia improved myocardial contractility. Thus, in most patients heart rate should be allowed to decrease with temperature without any serious adverse complications. *Electrocardiographic Effects:* Mild hypothermia has also been associated with abnormal heart rhythms. During cooling, hypothermia causes an increase in plasma norepinephrine levels and activation of the sympathetic nervous system. This leads to constriction of peripheral vessels and a shift of the blood from small, peripheral veins to centrally located veins in the core compartment of the body. Ultimately, this results in an increase in venous return which leads to mild sinus tachycardia. As temperature continues to drop even further below 35C, the heart rate begins to slow to a below normal rate eventually leading to what is known as sinus bradycardia. The heart rate will continue to decrease progressively as temperature drops to 33C and below. The mechanism behind this is a decrease in the rate of spontaneous depolarization of cardiac cells in combination with prolonged duration of action potentials. These electrocardiogram changes usually do not require treatment and in

most cases a patient's heart rate should be allowed to decrease with cooling.

clinical trials evaluating the safety of mild therapeutic hypothermia.

b. Renal effects

receptor levels.

filtration.

Furthermore, some studies have linked hypothermia to an increased risk for arrhythmias. However, hypothermia-induced arrhythmias generally only apply to moderate to deep hypothermia, particularly when temperatures reach less than 30°C. During deep hypothermia, a patient is at higher risk to develop atrial fibrillation or ventricular fibrillation if temperatures reach as low as 28°C. Since temperatures are maintained at greater than 30°C in the ICU, few cases of hypothermia-induced arrhythmias have been observed in

Therapeutic hypothermia also has physiologic effects on renal function. During cooling, an increase in urinary output, known as cold diuresis, may occur. Cold diuresis results from a combination of an increase in venous return, a decrease in antidiuretic hormone, tubular dysfunction, and decreased levels of antidiuretic hormone and renal antidiuretic hormone

Renal elimination can be divided into passive filtration, active tubular secretion and active tubular reabsorption. Passive glomerular filtration does not seem to be affected by therapeutic hypothermia. One clinical study investigated the effects of mild hypothermia on renal filtration by measuring serum creatinine levels and creatinine clearance in subjects with and without hypothermic treatment. The study found no change in creatinine clearance between the two groups and concluded that cooling does not impair renal

Although passive processes of renal filtration do not seem to be significantly altered, some published evidence does suggest that the active processes of tubular secretion and reabsorption may be altered by mild hypothermia. To date, the effect of therapeutic
