Ketamine and midazolam decrease cerebral blood flow and consequently their own rate of transport to the brain: An application of mass balance pharmacokinetics with a changing regional blood flow

Abstract

Mass balance pharmacokinetics, with simultaneous blood sampling from an artery and the internal jugular vein, was used to characterize the cerebral uptake of ketamine, norketamine, and midazolam in normoventilated pigs. Intravenous injections of ketamine or midazolam decreased the cerebral blood flow (CBF) by one third, as measured by intermittent 133Xe washout. By means of pharmacodynamic models, the effects on the CBF could be predicted from the arterial drug concentrations. The high-resolution CBF vs. time curves thus generated allowed the calculation of cerebral drug levels from arterio-venous concentration gradients in spite of a continuously changing regional blood flow. By their effects on the CBF, ketamine and midazolam decrease their own rate of transport to the brain, the immediate 30-35% drops in CBF giving similar reductions in initial net influx of drug. Physiological pharmacokinetic models assuming a constant regional blood flow are therefore not appropriate. Under clinical conditions, the CBF is determined mainly by the effects of the anesthetics and by the arterial CO2 tension. CBF changes in either direction influence the transport of drugs to the brain and may consequently result in impaired or exaggerated drug effects.

Protective effects of S(+) ketamine and atropine against lethality and brain damage during soman-induced status epilepticus in guinea-pigs

“…Along with these experimental results, the fact that the administration of KET with a benzodiazepine, either midazolam (Dorandeu et al, 2005) or diazepam (Ballough et al, 2006), increases protection seems to contradict the importance of KET or S-KET brain concentrations. It has been reported that midazolam and KET, injected separately, decrease their own rate of transport into the brain (Björkman et al, 1992) and that diazepam would counteract the increase of cerebral blood flow induced by KET (Werner et al, 1997). Thus, a complete pharmacokinetic study during soman poisoning and SE is necessary to assess KET or S-KET concentrations in different brain structures, with or without a benzodiazepine.…”

The Cerebrovascular Response to Ketamine

“…[18][19][20]35,46 Four of the 5 studies demonstrated a global decrease in CBF after ketamine on 131 Xe CT approaching up to 30%. [18][19][20]35,46 Four of the 5 studies demonstrated a global decrease in CBF after ketamine on 131 Xe CT approaching up to 30%.…”

“…Within the 38 animal studies identified, 18-55 the majority of cases measured CBF response to ketamine, and to other anesthetic agents, utilizing imaging [18][19][20][21][22][23][24][25][26][27][28][29]32,33,[35][36][37][38][41][42][43][44][45][46][47][48][49][50]52,55 : 131 Xe CT, PET, SPECT, indocyanine green (ICG) angiography, and magnetic resonance imaging (MRI). Less commonly utilized methods included radioactive microsphere-based CBF determination, ultrasound-based flow probes, 14 C-iodoantipyrine autoradiography, diffuse correlation spectroscopy, and direct measurements through sinus cannulation among others.…”

Swine models in the design of more effective medical countermeasures against organophosphorus poisoning

“…Recently, Burbridge et al (2004) described the complex intracranial arterial anatomy in swine. Brain perfusion flow rates are important parameters for the toxicokinetics of OPs and the pharmacokinetics of treatment drugs (Lundeen et al, 1983;Bjorkman et al, 1992).…”