Pharmacologic considerations for therapeutic hypothermia

Cooling the core body temperature to 32^oC to 34^oC in post-cardiac arrest patients with an initial rhythm of ventricular fibrillation or pulseless ventricular tachycardia has demonstrated favorable neurologic outcomes and is recommended by the American Heart Association’s post-cardiac arrest care guidelines.

Patients undergoing therapeutic hypothermia or targeted temperature management present unique challenges in drug absorption, metabolism and elimination that result from disease manifestations and lower body temperature. Understanding the complex physiologic changes, potential complications and altered pharmacodynamics in these patients aid in appropriate dosing and drug monitoring. Effects of cooling on drug activity will be discussed for each of the three primary phases in managing patients undergoing therapeutic hypothermia: induction, maintenance and re-warming.

Michaiah G. Parker, PharmD

Induction phase

The goal with therapeutic hypothermia is to achieve a target temperature of 32^oC to 34^oC. This should be achieved as quickly as possible after cardiac arrest to optimize patient outcomes. As the temperature is lowered, the body attempts to conserve heat through cutaneous vasoconstriction that occurs at a core temperature around 36.5^oC and increases heat production through shivering around 35.5^oC. Rapidly reaching the target temperature will stabilize fluid loss and intracellular shifts, diminish or stop shivering, and reduce significant hemodynamic changes. Shivering is an undesirable effect in patients with neurologic and/or post-hypoxic injury because it is linked to hemodynamic and respiratory responses that can double the metabolic rate and delay achieving the target cooled temperature.

The greatest risks during induction include: cold diuresis leading to hypovolemia and hypotension; bradycardia and decreased cardiac output; electrolyte disorders; an impaired coagulation cascade; shivering, insulin resistance and hyperglycemia; and a suppressed inflammatory response, thereby potentially increasing infection risk. These physiologic effects also persist in both the maintenance and re-warming phases.

Common agents to counteract shivering include sedatives, anesthetics, opiates and neuromuscular blocking agents. Therapeutic hypothermia not only affects serum levels and drug clearance due to metabolic slowing of liver enzyme systems, but the pharmacodynamics of various drugs also change. One or two single-bolus doses of a neuromuscular blocking agent, such as cisatracurium at 0.15 mg/kg or vecuronium at 0.1 mg/kg, can help achieve faster time to goal temperature while passing quickly through the shivering threshold. However, it is important to have sedation on board before initiating these agents because this may lend an additional benefit of suppressing shivering.

Unlike postoperative patients, intentionally cooled patients do not experience the same effects of sedation and mechanical ventilation such as increased work of breathing and oxygen consumption. Sedation will need to be continued throughout the maintenance and re-warming phases. Fentanyl and midazolam can be effective in controlling shivering, and although midazolam is metabolized hepatically to an active metabolite, the half-life of this metabolite in a cooled patient remains shorter than the half-life of lorazepam.

Strategies to combat metabolic changes include using bolus doses when possible, or if an infusion is required, utilizing lower doses to prevent or minimize drug accumulation and prolonged recovery time when re-warmed. In most cases, therapeutic hypothermia increases drug levels or enhances the effects of drugs, including fentanyl, midazolam, vecuronium and atracurium.

Maintenance phase

Once at target temperature, shivering and hemodynamic monitoring are of importance. If shivering persists once goal temperature is achieved, some adjunctive agents may be considered. Buspirone with or without meperidine (as needed) bolus doses (reduced for renal function impairment), a dexmedetomidine infusion or a continuous infusion of a low-dose neuromuscular blocking agent may be initiated. Because meperidine reduces the shivering threshold as low as 33^oC, it is possible that patients on this agent may continue to experience shivering at the target temperature.

EEG monitoring is helpful for patients receiving meperidine due to concerns of increased seizure risk and should be standard practice for any patient on a continuous neuromuscular blockade infusion. Advantages of dexmedetomidine, an alpha 2-adrenergic agonist, are that it does not have associated respiratory depression, it is short-acting, and it is easily titratable despite cooling; however, it may precipitate bradycardia. Propofol, although beneficial for shivering suppression, has predictable hypotensive effects and may not be ideal if the patient requires pressor support.

If hypotension persists, vasopressors are often initiated after fluid resuscitation has taken place. Some vasoactive drugs such as epinephrine and norepinepherine may have a blunted effect from the cooling, but because the half-life of these agents is increased, higher concentrations may still be achieved with the same dose. Thus, lower doses of vasopressors may be sufficient in cooled patients to achieve a goal mean arterial pressure of more than 65 mm Hg. Because cooling has little effect on medications used in arrhythmia management, the treatment of these agents remains unchanged.

Re-warming phase

Re-warming is important with respect to targeted drug toxicity because the reduced drug elimination from the induction phase can continue to elevate concentrations as re-warming occurs. Slow re-warming at a rate of 0.2^oC to 0.5^oC per hour will help prevent shivering, better preserve neuroprotective effects from hypothermia and allow the body to normalize. Continuing lower doses of sedatives is appropriate in this phase, but because the neuromuscular blocking agent half-life can double in a cooled patient, discontinuing these infusions at the initiation of re-warming is appropriate.

If shivering occurs during re-warming, the use of bolus doses of neuromuscular blockade will suffice. Due to the extracellular shift of potassium in re-warming, hyperkalemia may occur. Maintaining potassium, magnesium, phosphorous and calcium levels during maintenance and re-warming will help prevent rapid and large electrolyte changes. Rebound hyperthermia with temperatures of at least 37.6^oC should be identified and treated because this may increase oxygen consumption and is associated with worse outcomes. Administering adjunctive acetaminophen as needed for up to 72 hours after re-warming may also be beneficial.

In conclusion, research continues to investigate the specific effect of as needed on drug activity. Due to hepatic injury and renal failure typically associated with cardiac arrest, as well as the effects of cooling that slow metabolic processes, dose reductions and drug monitoring become paramount to prevent drug toxicity and adverse effects in cooled patients.

For more information:

• Arpino P. Pharmacotherapy. 2008;28:102-111.
• Bjorksten R. Anesth Analg. 2001;93:1233-1239.
• Peberdy M. Circulation. 2010;122:S768-S786.
• Polderman K. Crit Care Med. 2009;37:1101-1120.
• Tortorici M. Crit Care Med. 2007;35:2196-2204.
• Weant K. Pharmacotherapy. 2010;30:831-841.

Michaiah G. Parker, PharmD, is a cardiology critical care clinical specialist at the CJW Medical Center in Richmond, Va.

Rhonda M. Cooper-DeHoff, PharmD, MS, is associate professor, department of pharmacotherapy and translational research, College of Pharmacy, and division of cardiovascular medicine, College of Medicine, University of Florida, Gainesville. Dr. Cooper-DeHoff is Cardiology Today’s Pharmacology Consult column editor and a member of the CHD and Prevention section of the Cardiology Today Editorial Board.

Disclosures: Drs. Cooper-DeHoff and Parker report no relevant financial disclosures.