**4. The effects of therapeutic hypothermia on drug response**

In addition to the effects of therapeutic hypothermia on drug disposition and pharmacokinetics, hypothermia has also been associated with changes in drug response. The remainder of this section addresses drugs based on their therapeutic class and the current research showing changes in drug response. A summary of the clinical effects of hypothermia on drug response is given in Table 3.

Therapeutic Hypothermia: Implications on Drug Therapy 145

CYP2E1 and preclinical studies have demonstrated reduced CYP2E1 activity in the rat model during hypothermia. Thus, it is reasonable to postulate that the effects on isoflurane are likely due to pharmacokinetics. Future studies should investigate whether a decrease in CYP2E1

*Paralytics.* Drug response for the neuromuscular blocking agent vecuronium has been studied during therapeutic hypothermia. Mild hypothermia increased the duration of action of the second infusion of vecuronium in patients undergoing elective surgery. Another study saw a similar increase in the duration of action of vecuronium in healthy volunteers during mild hypothermia. An increased duration of action was also seen in atracurium during mild hypothermia. In these studies the increase in duration of action was due to increase concentrations of the paralytics due to reduced drug clearance (i.e. pharmacokinetics). No alteration in the pharmacodynamic response was observed under hypothermic conditions. Therefore, unlike morphine response, it appears that the

pharmacodynamic response to paralytics is not altered during mild hypothermia.

In summary, therapeutic hypothermia has been shown to affect the drug response of analgesics, sedatives, and paralytics. A reduction in drug metabolism and clearance may explain part of the response change particularly with paralytics. Conversely, a reduced affinity of morphine for the μ-receptor has been reported. Careful pharmacotherapeutic monitoring in the clinic during hypothermia treatment may be necessary to prevent a potential therapy-drug interaction caused by changes in both drug concentration and in

Therapeutic hypothermia has been shown to be a beneficial neuroprotective therapy in critical care. In addition to the benefits for therapeutic hypothermia, there are potential side effects that can also occur. The effect of hypothermia on drug metabolism and clearance can lead to elevations in drug concentrations. Recent studies have reported that the effect of hypothermia on drug metabolism and the degree of change can be specific for the metabolism and elimination route. A small number of studies have investigated the effect of hypothermia on drug response including analgesics, sedatives and paralytics. The effect on drug response may

However, the effect of therapeutic hypothermia on drug disposition and response is still significantly understudied. To date, little is still understood as to how therapeutic hypothermia affects the wide array of drugs administered to critically ill patients in the ICU. In order to safely use this therapy in patients, it is imperative that we further evaluate the potential alterations on drug metabolism and response. Larger clinical trials in humans are necessary before we can fully understand the effects of therapeutic hypothermia on drug pharmacokinetics. Ultimately by understanding the physiological effects of hypothermia, awareness of hypothermia's effect on drug pharmacokinetics, and learning the potential side effects, we will be able to more safely and effectively use this neuroprotective strategy

be due to pharmacokinetic and pharmacodynamics alterations during hypothermia.

activity is responsible for the decrease in isoflurane response.

drug response during cooling.

**5. Prospectus and future directions** 

in a wide range of critically ill patients.


**Table 3.** Summary of the findings of clinical studies evaluating the effects of therapeutic hypothermia on drug response.

*Analgesics/Sedatives.* Medications given for analgesia and sedation are largely hepatically metabolized and are one of the most commonly used class of drugs in the ICU. We previously mentioned in the drug metabolism section that morphine is one of the most extensively studied analgesics and undergoes predominately Phase II enzyme metabolism by UGT2B7. The effect of hypothermia on morphine response was evaluated in a dog model. In the hypothermic group, a significant decrease in mean arterial pressure was observed, whereas no change in mean arterial pressure was seen in the normothermic group. Another *in situ* study measured the potency of morphine in guinea pig ileum. This study saw a decrease in the affinity of morphine for its target μ-receptor when the temperature was decreased from 37°C to 30°C. In addition, this study reported an increase in morphine affinity for its receptor when the temperature was raised from 37C to 40C. This study indicates that during cooling, morphine affinity for the μ-receptor is decreased; therefore, it is likely that morphine receptor response would be reduced during hypothermia even though the concentrations of morphine are likely to be elevated due to reduced morphine clearance.

Another study evaluated the effect of hypothermia on the drug response to isoflurane in children. Liu *et al.* noted that the isoflurane requirement in children decreased by 5.1% per degree Celsius. Furthermore, the isoflurane minimum alveolar concentration values decreased from 1.69±0.14% to 1.22±0% at 37°C and 31°C, respectively. The pharmacokinetic properties of isoflurane were not evaluated in this study so the overall pharmacokinetic change relative to the drug response and dosage is not known so it is unclear if these alterations are due to altered pharmacokinetics or pharmacodynamics. Isoflurane is metabolized predominately by CYP2E1 and preclinical studies have demonstrated reduced CYP2E1 activity in the rat model during hypothermia. Thus, it is reasonable to postulate that the effects on isoflurane are likely due to pharmacokinetics. Future studies should investigate whether a decrease in CYP2E1 activity is responsible for the decrease in isoflurane response.

*Paralytics.* Drug response for the neuromuscular blocking agent vecuronium has been studied during therapeutic hypothermia. Mild hypothermia increased the duration of action of the second infusion of vecuronium in patients undergoing elective surgery. Another study saw a similar increase in the duration of action of vecuronium in healthy volunteers during mild hypothermia. An increased duration of action was also seen in atracurium during mild hypothermia. In these studies the increase in duration of action was due to increase concentrations of the paralytics due to reduced drug clearance (i.e. pharmacokinetics). No alteration in the pharmacodynamic response was observed under hypothermic conditions. Therefore, unlike morphine response, it appears that the pharmacodynamic response to paralytics is not altered during mild hypothermia.

In summary, therapeutic hypothermia has been shown to affect the drug response of analgesics, sedatives, and paralytics. A reduction in drug metabolism and clearance may explain part of the response change particularly with paralytics. Conversely, a reduced affinity of morphine for the μ-receptor has been reported. Careful pharmacotherapeutic monitoring in the clinic during hypothermia treatment may be necessary to prevent a potential therapy-drug interaction caused by changes in both drug concentration and in drug response during cooling.
