Phase I Trial to Determine Steady State Pharmacokinetics and Sedative Effects of Low Dose Ketamine Infusion

Background:

There has been an increasing awareness of the need for adequate sedation and analgesia in critically ill pediatric patients. The choices of treatment for pain are numerous, but in the Pediatric ICU parenteral opioids are most commonly used. At equipotent doses, all mu agonist opioids (morphine, fentanyl, meperidine and codeine) produce similar physiologic effects and side effects. Opioids can cause hypoventilation, hypotension, constipation, and may cause urinary retention. Patients receiving continuous opioid infusions experience not only these physiologic side effects, but also the side effects of dependence, tolerance and withdrawal. These lastly named side effects often complicate medical issues and contribute to longer ICU admissions.

There are numerous articles addressing the problem of opioid tolerance, dependence, and withdrawal . Despite repeated efforts, the mechanism of tolerance remains unclear. Current in-vitro and in-vivo investigations focus on five theories of opioid tolerance: receptor down-regulation, desensitization, internalization, alternative coupling, and functional antagonism. Recent studies suggest that receptor down-regulation is not the main mechanism in-vivo. Desensitization by receptor decoupling, receptor internalization and increased alternative coupling to stimulatory G-proteins have been demonstrated to be clinically insignificant. However, functional antagonism of the opioid effects seems to be clinically most important. This functional antagonism is mediated by the activation of N-methyl-D-aspartate (NMDA) receptors, up-regulation of adenylyl cyclase and nitric oxide synthase . Drugs blocking these mechanisms are promising in the treatment of opioid tolerance. Numerous in-vivo studies have focused on blocking the NMDA receptor. Studies in animals have shown a decrease in the development of opioid tolerance when NMDA antagonists are used . This effect has been escalated to the next level of investigation as several adult case reports and randomized controlled trials demonstrate patients receiving small, sub-anesthetic doses of ketamine respond with a subsequent dramatic decrease in opioid requirement. The doses of ketamine used in these case reports vary, from 1mg/kg/24 hours (0.04mg/kg/hr), to 0.1mg/kg/hr . Bell recently reviewed four randomized controlled trials in cancer patients receiving ketamine as an adjuvant to opioids for pain. Dosing and route of ketamine varied between trials. He cautiously concluded that there is promise in the potential efficacy of ketamine as an adjuvant to opioids for cancer pain . Another review reported that coadministration of ketamine reduced pain, analgesic consumption, and in some studies both . Suresh and Anand anecdotally report using 0.2mg/kg/hr-0.5mg/kg/hr in children with a resultant decreased need to escalate morphine infusion rates.

Part of the difficulty in determining an appropriate pediatric dose is the lack of clinical studies evaluating ketamine as adjuvant to opioids in children. There have been numerous attempts in adults to evaluate the effect of adding ketamine to opioids to improve pain management. Many of these studies were reviewed by Subraminiam. Of the fifty-seven studies reviewed, only seven used continuous infusion IV ketamine in addition to opioids. Of these seven studies, four reported significantly improved analgesia with the addition of ketamine. Of the fifty-seven studies, only four evaluated ketamine as an adjuvant to opioids in children. All of these studies were evaluating postoperative pain control and only one used continuous infusion ketamine. Of the four only one, evaluating preoperative ketamine administration, showed improvement in pain control .

In the future, we anticipate conducting a randomized, blinded, placebo controlled trial to evaluate the effect of low dose ketamine on the development of opioid tolerance. However, there is no standardized dose of ketamine for this role. The goal of this phase I trial to is to establish a dose of continuous infusion ketamine to be used in future studies, and to further the pharmacokinetic details of ketamine as a continuous infusion at this dose. There is currently no data describing the pharmacokinetics of low dose ketamine in children. These details would include plasma concentration, elimination rate, and half-life of ketamine and its primary metabolite norketamine. In addition to expanding the available data on ketamine this information could be useful in future studies. It has been reported that ketamine causes sedation in children at serum levels of 1 to 1.5 ug/ml, and that at levels less than 0.5ug/ml there are no sedative effects . The assumption can be made that at levels less than 1ug/ml ketamine is non-sedating, but this has not been tested.