Ketamine Clinical Trials
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Organisation Name: Leiden University Medical Center
Overal Status: Open for patient inclusion
Start Date: 2011-11-14
Lead Sponsor: Leiden University Medical Center
Brief Summary: Postoperative sedation in patients requiring care in the intensive care unit (ICU) generally is achieved with the administration of short acting intravenous hypnotic agents that often are combined with longer acting morphinomimetic analgesics.
Propofol is an often used intravenous anesthetic agent with strong sedative effects with a rapid onset and short duration of action and a preferable recovery profile. Propofol that exerts its action through facilitation of the GABAA receptor, is widely used as sedative for induction and maintenance of anesthesia but also as sedative agent in patients in the ICU or PACU. Next to its sedative effects, propofol exhibits significant side effects jeopardizing hemodynamic stability and spontaneous respiration. These side effects are relatively mild in otherwise healthy patients but may induce serious unwanted effects in critically ill patients. Blood pressure is reduced in the presence of propofol both through direct vasodilatation as well as by myocardial depression. The respiratory depressant effects of propofol are central of origin and result in a reduced response to arterial pCO2 and may become clinically evident as a reduction in minute ventilation. Ketamine, a NMDA-receptor antagonist is another commonly used intravenous anesthetic agent with strong analgesic effects. Next to its analgesic and sedative effects S(+)-ketamine has hallucinogenic properties that limit its use in awake patients. In patients sedated through coadministration of an intravenous hypnotic agent like propofol, ketamine may however, be advantageous for it combines its sedative-analgesic properties with hemodynamic stimulatory effects that may reduce the hemodynamic side effects of intravenous hypnotic agents and may even limit the requirements of sympaticomimetics. In addition, several studies suggest that ketamine may attenuate the inflammatory response to cardiac surgery as induced by blood contact with the surface of the extracorporeal circuit apparatus, surgical trauma and reperfusion injury.
The pharmacodynamic interaction between 2 agents acting at similar receptor systems is often additive. This, in contrast to the interaction between agents that propagate their effect at different receptor sites that often is found to be synergistic. Synergism implies that one needs less of the combination of two agents than expected from the potency of the two agents separately. Because propofol is known for its action at the GABAA receptor and ketamine for its antagonism of the NMDA receptor one may expect the interaction between these agents to be synergistic. Next to the pharmacodynamic interaction propofol and ketamine may well also affect each other distribution and/or clearance and thus may also affect each other’s pharmacokinetics. The hemodynamic stimulatory effects of ketamine may influence the distribution and hepatic clearance of propofol. Propofol is known as a high hepatic extraction ratio drug, its clearance therefore may be sensitive to changes in hepatic blood flow.
In summary, propofol and ketamine may well be a promising anesthetic combination for sedation of patients after cardiac surgery ((coronary artery bypass grafting (CABG) and aortic valve surgery) in the ICU. This study aims to evaluate the interaction between these 2 agents with respect to their pharmacokinetics (distribution, redistribution and elimination) and pharmacodynamics (sedation, hemodynamic side effects and attenuation of the inflammatory response) in patients after cardiac surgery.
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