**2. Physiologic effects of therapeutic hypothermia**

Before discussing the specific effects of therapeutic hypothermia on drug disposition and response, it is important to first recognize the general physiologic changes that occur in therapeutic hypothermia patients during induction, maintenance, and rewarming. In a broad sense, therapeutic hypothermia is defined as a core temperature less than 35.0C. Moreover, there are different degrees of hypothermia which incur a range of neuroprotection and adverse physiologic effects. Hypothermia can be divided based on the degree of cooling and include mild hypothermia, moderate hypothermia, and severe hypothermia. It is generally accepted that mild hypothermia occurs when a subject is cooled to a temperature of 32-34C whereas moderate hypothermia is at a temperature range of 30 – 32C. Severe, or "deep" hypothermia, is defined as cooling to a temperature below 30C. Furthermore, therapeutic hypothermia undergoes different lengths of cooling depending on the subject population. Adult cardiac arrest patients typically undergo therapeutic hypothermia for 24-48 hours, whereas neonates with HIE are cooled for 72 hours. The duration of cooling is largely based on the design of randomized control trials which demonstrated outcome benefits.

Although these temperatures tend to be generally accepted, it is important to note that these categories can be arbitrary across studies and require verification of temperature and duration in the currently published literature. In order to normalize the temperatures discussed in this chapter, we have focused predominately on the effects seen within mild hypothermia (32-34C), since this is the clinically relevant temperature range that has been proven to afford neuroprotection without adverse physiologic consequences to patients in the ICU.

a. Cardiovascular effects

*Hemodynamic Effects:* Hypothermia has been linked to changes in myocardial function. Mild hypothermia induces a decrease in heart rate, but produces an overall increase in the contractility of the heart in sedated patients. Systolic function will improve, but diastolic function may decrease. Some patients may experience an increase in blood pressure while others may see no change in blood pressure. Overall, cardiac output will decrease along with the heart rate. However, the subsequent hypothermia-induced decrease in metabolic demand tends to equal or exceed the decrease in cardiac output, thus keeping the balance between supply and demand constant. Generally, cold diuresis occurs early during cooling and is of a relatively short duration.

In some cases, the heart rate may be artificially increased by drugs or external pacing. However, the effect of hypothermia on myocardial contractility has convoluted results under artificial stimulation. Two pre-clinical studies showed that under normothermic conditions an increase in heart rate led to an increase in cardiac output and myocardial 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.

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 clinical trials evaluating the safety of mild therapeutic hypothermia.

#### b. Renal effects

132 Therapeutic Hypothermia in Brain Injury

demonstrated outcome benefits.

a. Cardiovascular effects

and is of a relatively short duration.

the ICU.

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.

Before discussing the specific effects of therapeutic hypothermia on drug disposition and response, it is important to first recognize the general physiologic changes that occur in therapeutic hypothermia patients during induction, maintenance, and rewarming. In a broad sense, therapeutic hypothermia is defined as a core temperature less than 35.0C. Moreover, there are different degrees of hypothermia which incur a range of neuroprotection and adverse physiologic effects. Hypothermia can be divided based on the degree of cooling and include mild hypothermia, moderate hypothermia, and severe hypothermia. It is generally accepted that mild hypothermia occurs when a subject is cooled to a temperature of 32-34C whereas moderate hypothermia is at a temperature range of 30 – 32C. Severe, or "deep" hypothermia, is defined as cooling to a temperature below 30C. Furthermore, therapeutic hypothermia undergoes different lengths of cooling depending on the subject population. Adult cardiac arrest patients typically undergo therapeutic hypothermia for 24-48 hours, whereas neonates with HIE are cooled for 72 hours. The duration of cooling is largely based on the design of randomized control trials which

Although these temperatures tend to be generally accepted, it is important to note that these categories can be arbitrary across studies and require verification of temperature and duration in the currently published literature. In order to normalize the temperatures discussed in this chapter, we have focused predominately on the effects seen within mild hypothermia (32-34C), since this is the clinically relevant temperature range that has been proven to afford neuroprotection without adverse physiologic consequences to patients in

*Hemodynamic Effects:* Hypothermia has been linked to changes in myocardial function. Mild hypothermia induces a decrease in heart rate, but produces an overall increase in the contractility of the heart in sedated patients. Systolic function will improve, but diastolic function may decrease. Some patients may experience an increase in blood pressure while others may see no change in blood pressure. Overall, cardiac output will decrease along with the heart rate. However, the subsequent hypothermia-induced decrease in metabolic demand tends to equal or exceed the decrease in cardiac output, thus keeping the balance between supply and demand constant. Generally, cold diuresis occurs early during cooling

In some cases, the heart rate may be artificially increased by drugs or external pacing. However, the effect of hypothermia on myocardial contractility has convoluted results under artificial stimulation. Two pre-clinical studies showed that under normothermic conditions an increase in heart rate led to an increase in cardiac output and myocardial

**2. Physiologic effects of therapeutic hypothermia** 

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 receptor levels.

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 filtration.

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

hypothermia on the active process of tubular secretion has only been studied preclinically in rats. This study used fluorescein isothiocyanate (FITC)-dextran to measure glomerular filtration and phenolsulfonphthalein (PSP) to measure renal tubular secretion in mildly hypothermic versus normothermic rats. The results showed no change in FITC-dextran clearance, but a significant change in the renal clearance of PSP. These results provide further evidence that the passive process of renal filtration is unaffected by mild hypothermia, whereas, active renal tubular secretion is decreased during cooling. There are, however, a limited number of studies published to date and whether or not these initial evaluations remain true clinically will depend on more extensive assessments of the effects of mild hypothermia on renal drug elimination processes.

Therapeutic Hypothermia: Implications on Drug Therapy 135

**Volume of Distribution** **Protein Binding** 

0.35 L/kg 92% 3-10

2 - 3 L/kg 47% 2-3 hrs

1 - 4.7 L/kg 30-40% 2-3 hrs

0.19 L/kg 77-91% 1.5-2.7

1.5 L/kg 60-80% 1.5–2.0

CYP3A4 0.2 - 0.4 L/kg 60 - 80% 51-80

CYP2D6/Renal 0.25 L/kg 30% 84-131

**Halflife** 

mins

hrs

mins

hrs

mins

mins

hrs

hrs

contribution by active transport mechanisms for some drugs. Also similar to the kidney, cooling was shown to affect active drug transport via the ABCB1 transporter, more commonly known as P-glycoprotein, *in vitro*. However, no affect of cooling has been reported on passive diffusion, thereby, suggesting that passive processes are unaltered and active drug transport may be impaired during cooling. Further physiological factors that affect absorption include the pH of various biological compartments and the blood flow at the site of absorption. The physiochemical properties of the drug, such as its pKa and lipid solubility, in combination with the compartmental pH, will influence the extent of which the drug will distribute into a given compartment. It is expected that some drugs will have increased absorption while others may have decreased absorption during cooling depending on pH, lipophilicity, and primary site of GI absorption; however, no studies to date have thoroughly evaluated if these anticipated changes occur *in vivo* under mild hypothermic conditions. The effects of hypothermia on drug disposition and response will

> **Pathway(s) of Elimination**

esterases in blood and tissue

CYP2B6 & CYP2C9

Renal elimination &

CYP3A4 (minor)

Fentanyl Hepatic: 75% CYP3A4 4 - 6 L/kg 80-85% 3-12 hrs Propofol Hepatic: 90% CYP2B6/UGT 60 L/kg 95-99% 30-60

Dexmedetomidine Hepatic: 95% CYP2A6 118 - 152 L/kg94% 2-2.67

Midazolam Hepatic: 63 - 80% CYP3A4 1 - 3.1 L/kg 95% 1.8-6.4

Lorazepam Hepatic: 88% Conjugation 1.3 L/kg 91% 9-19 hrs

(minor)

CYP3A4

Bile

be further addressed in the next section.

**Primary Route of Elimination** 

Remifentanil Hepatic: 90% Metabolized by

Ketamine Hepatic CYP3A4 (major),

Morphine Hepatic: 90% UGT2B7, CYP2C,

3 – 35% Hepatic: 15%

15% Bile: 5 – 10%

Lidocaine Hepatic: 90% CYP1A2 (major),

Renal: 33% Hepatic: Minimal

Vecuronium Bile: 30 – 50% Renal:

Pancuronium Renal: 50 – 70% Hepatic:

Rocuronium Bile: Extensive

**ANALGESICS /SEDATIVE**

**PARALYTICS** 

**ANTI-ARRYTHMICS**

#### c. Electrolyte effects

Therapeutic hypothermia also alters electrolyte levels such as magnesium, potassium, and phosphate. During cooling, electrolytes shift from the bloodstream to the intracellular compartment. The low level of electrolytes remaining in the bloodstream increases a patients risk for hypokalemia. During rewarming, the opposite effect is seen and potassium, as well as other electrolytes, is released back into the bloodstream from the intracellular compartment. If the patient is rewarmed too quickly, potassium levels will increase abruptly in the bloodstream and the patient may become hyperkalemic. To avoid hyperkalemia, a slow and consistent rewarming period is necessary to allow the kidneys to excrete the excess potassium. Furthermore, frequent lab electrolyte assessments are needed to account for shifts in systemic electrolyte concentrations.

#### d. Body metabolism & drug clearance effects

Hypothermia has been shown to decrease the metabolic rate by approximately 8% per 1C drop in body temperature. A similar decrease in oxygen consumption and carbon dioxide production is observed. This decrease in metabolic rate arises from a global decrease in the rate of drug metabolism by the liver because the majority of the metabolic reactions in the liver are enzyme-mediated. The rate of these enzyme-mediated reactions is highly temperature sensitive; thus the rate of these reactions is significantly slowed during hypothermia. Hypothermia-induced reductions in clearance have been shown for a number of commonly used ICU sedatives such as propofol; opiates such as fentanyl and morphine; midazolam; neuromuscular blocking agents such as vecuronium and rocuronium; and other drugs such as phenytoin (Refer to Table 1). The specific alterations in drug metabolism and clearance will be further addressed in the upcoming sections of this chapter.

e. Gastrointestinal effects

Gastrointestinal (GI) motility decreases with mild hypothermia. In some cases, decreased motility leads to mild ileus which typically occurs at temperatures less than 32°C. Other physiological factors play a large role in the extent to which drugs and nutrients are absorbed across the gut wall. As with drug excretion in the kidney, drug absorption across the intestinal membranes depends primarily on passive diffusion with significant contribution by active transport mechanisms for some drugs. Also similar to the kidney, cooling was shown to affect active drug transport via the ABCB1 transporter, more commonly known as P-glycoprotein, *in vitro*. However, no affect of cooling has been reported on passive diffusion, thereby, suggesting that passive processes are unaltered and active drug transport may be impaired during cooling. Further physiological factors that affect absorption include the pH of various biological compartments and the blood flow at the site of absorption. The physiochemical properties of the drug, such as its pKa and lipid solubility, in combination with the compartmental pH, will influence the extent of which the drug will distribute into a given compartment. It is expected that some drugs will have increased absorption while others may have decreased absorption during cooling depending on pH, lipophilicity, and primary site of GI absorption; however, no studies to date have thoroughly evaluated if these anticipated changes occur *in vivo* under mild hypothermic conditions. The effects of hypothermia on drug disposition and response will be further addressed in the next section.

134 Therapeutic Hypothermia in Brain Injury

c. Electrolyte effects

of mild hypothermia on renal drug elimination processes.

shifts in systemic electrolyte concentrations.

e. Gastrointestinal effects

d. Body metabolism & drug clearance effects

hypothermia on the active process of tubular secretion has only been studied preclinically in rats. This study used fluorescein isothiocyanate (FITC)-dextran to measure glomerular filtration and phenolsulfonphthalein (PSP) to measure renal tubular secretion in mildly hypothermic versus normothermic rats. The results showed no change in FITC-dextran clearance, but a significant change in the renal clearance of PSP. These results provide further evidence that the passive process of renal filtration is unaffected by mild hypothermia, whereas, active renal tubular secretion is decreased during cooling. There are, however, a limited number of studies published to date and whether or not these initial evaluations remain true clinically will depend on more extensive assessments of the effects

Therapeutic hypothermia also alters electrolyte levels such as magnesium, potassium, and phosphate. During cooling, electrolytes shift from the bloodstream to the intracellular compartment. The low level of electrolytes remaining in the bloodstream increases a patients risk for hypokalemia. During rewarming, the opposite effect is seen and potassium, as well as other electrolytes, is released back into the bloodstream from the intracellular compartment. If the patient is rewarmed too quickly, potassium levels will increase abruptly in the bloodstream and the patient may become hyperkalemic. To avoid hyperkalemia, a slow and consistent rewarming period is necessary to allow the kidneys to excrete the excess potassium. Furthermore, frequent lab electrolyte assessments are needed to account for

Hypothermia has been shown to decrease the metabolic rate by approximately 8% per 1C drop in body temperature. A similar decrease in oxygen consumption and carbon dioxide production is observed. This decrease in metabolic rate arises from a global decrease in the rate of drug metabolism by the liver because the majority of the metabolic reactions in the liver are enzyme-mediated. The rate of these enzyme-mediated reactions is highly temperature sensitive; thus the rate of these reactions is significantly slowed during hypothermia. Hypothermia-induced reductions in clearance have been shown for a number of commonly used ICU sedatives such as propofol; opiates such as fentanyl and morphine; midazolam; neuromuscular blocking agents such as vecuronium and rocuronium; and other drugs such as phenytoin (Refer to Table 1). The specific alterations in drug metabolism and

Gastrointestinal (GI) motility decreases with mild hypothermia. In some cases, decreased motility leads to mild ileus which typically occurs at temperatures less than 32°C. Other physiological factors play a large role in the extent to which drugs and nutrients are absorbed across the gut wall. As with drug excretion in the kidney, drug absorption across the intestinal membranes depends primarily on passive diffusion with significant

clearance will be further addressed in the upcoming sections of this chapter.



Therapeutic Hypothermia: Implications on Drug Therapy 137

**Protein Binding** 

0.14 L/kg 99.5% 20-60

0.07 L/kg N/D 1-2 hrs

0.15 L/kg 50-80% 4.7-9

98% 6 hrs

50-70 L/kg 35% 12-17

9.5 - 21.7 L/kg90% 18 hrs

0.18 - 0.3 L/kg16% 36-80

0.46 L/kg 43-55% 2.6-3.2

1 L/kg 15-20% 8-12 hrs

**Halflife** 

hrs

Low 3-5 hrs

hrs

hrs

hrs

mins

hrs

hrs

**Volume of Distribution**

0.04 – 0.06 L/kg

CYP3A4/5 & CYP2J2 50 L/kg 92-95% 5-9 hrs

glomerular filtration 0.2 - 0.3 L/kg <30% 1.5-3

CYP2C19/CYP3A4 11 - 24 L/kg 98% 1 hr

**ANALGESICS /SEDATIVE**

**ANTI-PLATELET/ CLOTTING** 

**Primary Route of Elimination** 

Warfarin Hepatic: 92% Primarily CYP2C9

Heparin Hepatic Metabolized by

Dalteparin Hepatic: extensive Primarily by

Aspirin Hepatic Hydrolyzed by

Renal: 36%

Feces: 15%

Feces: 18%

Renal: 80 - 100%

Pravastatin Hepatic: Extensive Extensive first pass

Famotidine Renal: 25 - 70% glomerular filtration

Dabigatran Hepatic: 80% esterases and

Rivaroxaban Hepatic: Extensive

Haloperidol Hepatic: 50-60%

Pantoprazole Hepatic: 71%

MRP2: Multidrug resistance protein 2.

**MISCELLANEOUS**

Gentamicin

Piperacillin / Tazobactam

Clopidogrel Hepatic: Extensive CYP2C19, CYP3A4,

**Pathway(s) of Elimination** 

but also CYP2C19, CYP1A2, CYP2C8 &

heparinise; cleared

reticuloendothelial

desulfation and depolymerization

CYP1A2 and esterases

glucuronidation

Glucuronidation;

and tubular secretion

extraction by the liver

and tubular secretion

CYP3A4

Quetiapine Hepatic: 70 - 73% CYP3A4 6 - 14 L/kg 83% 6 hrs

Renal: 70 - 90% glomerular filtration

Vancomycin Renal: 40 - 100% glomerular filtration 0.2 - 1.25 L/kg30-55% 4 – 6

Corticosteroids Hepatic CYP3A4 Varies Varies Varies

Abbreviations: N/D: not determined; mins: minutes; hrs: hours; PGP: P-glycoprotein; UGT: UDP-galactose transporter; MAO: monoamine oxydase; COMT: catechol-O-methyltransferase; OATP: organic anion transporter;

**Table 1.** Pharmacokinetic characteristics of commonly used medications in critically ill patients

esterases in the liver to active metabolite

CYP3A4

via

system


Digoxin Renal: 55 – 80%

Valsartan Feces: 83%

Vasopressin Hepatic and Renal:

Carbamazepine Hepatic: 72%

Keppra Renal: 66% Hepatic:

Extensive

**Pressors and Iontropes**

**ANTI-CONVULSANT**

**Primary Route of Elimination** 

Bile: 6 – 8%

Verapamil Hepatic: 65 – 80% CYP3A4, CYP2C9/19;

Enalapril Hepatic: 60 - 70% Hydrolyzed in liver,

Epinephrine Hepatic & other tissues Metabolized by MAO

Norepinephrine Hepatic & other tissues Metabolized by MAO

Phenylephrine GI Tract: Extensive Metabolized by MAO

Milrinone Renal: 80 - 85% Primarily excreted as

Dopamine Hepatic: 80% Metabolized by MAO

Phenytoin Hepatic: Extensive CYP2C9, CYP2C19;

Phenobarbital Hepatic CYP2C9; UGT

Feces: 28%

minimal

Hepatic: 7-13%

**Pathway(s) of Elimination** 

glomerular filtration, PGP Transporter

PGP Transporter

Primarily excreted as unchanged drug; OATP/MRP2 Transporter

OATP/MRP2 Transporter

Metoprolol Hepatic: 95% CYP2D6 5.6 L/kg 15% 3-7 hrs

& COMT

& COMT

& COMT

Metabolized by vasopressinases

UGT Transporter

CYP3A4, CYP2C9; PGP/UGT Transporters

Primarily excreted as unchanged drug; some enzymatic hydrolysis

Transporter

& sulfotransferase

unchanged drug; Active tubular secretion

Amiodarone Hepatic: Extensive CYP3A4, CYP2C8 60 L/kg 33-65% 15-142

Diltiazem Hepatic: Extensive CYP450s 3 - 13 L/kg 77-93% 3-6.6

**Volume of Distribution** **Protein Binding** 

4 - 7 L/kg 25% 36-48

3.8 L/kg 90% 3-7 hrs

0.2 – 0.4 L/kg 50-60% 11 hrs

17 L/kg 95% 6 hrs

N/D N/D 2 mins

N/D N/D 2 mins

40 L/kg N/D 2-3 hrs

0.3 - 0.47 L/kg70% 1-3 hrs

1.8 - 2.5 L/kg N/D 9 mins

N/D N/D 10-20

0.5 - 1.0 L/kg 90% 7-42 hrs

0.5 – 1.9 L/kg 20-45% 2–7

0.8 - 2 L/kg 76% 25-65

0.7 L/kg < 10% 6-8 hrs

mins

days

hrs

**Halflife** 

days

hrs

hrs

**ANALGESICS /SEDATIVE**

**ANTI-**

**HYPERTENSIVE** 

Therapeutic Hypothermia: Implications on Drug Therapy 137

Abbreviations: N/D: not determined; mins: minutes; hrs: hours; PGP: P-glycoprotein; UGT: UDP-galactose transporter; MAO: monoamine oxydase; COMT: catechol-O-methyltransferase; OATP: organic anion transporter; MRP2: Multidrug resistance protein 2.

**Table 1.** Pharmacokinetic characteristics of commonly used medications in critically ill patients
