Pharmacokinetics of midazolam given as an intranasal spray to adult surgical patients.

The aim of this study was to determine the bioavailability and absorption kinetics of midazolam given as an intranasal (i.n.) spray. In addition, plasma concentrations of the active metabolite, 1-hydroxymidazolam, were measured to give an indication of enteral absorption. An i.v. and i.n. midazolam dose were given in a crossover study to 14 adult surgical patients. Individual uptake profiles of i.n. midazolam were estimated by numerical deconvolution. After an i.n. dose of 0.15 mg kg-1, maximum arterial plasma concentrations were 192 (SD 48) micrograms litre-1 at 14 (2) min. Uptake of midazolam was rapid and bioavailability was 83 (15)%. Formation of the 1-hydroxy metabolite after i.n. administration did not exceed that after the i.v. dose. This demonstrates that under optimal conditions absorption of midazolam via the nasal mucosa was virtually complete. In this case little midazolam was swallowed and subjected to first-pass metabolism in the liver and therefore pharmacologically important amounts of active metabolite were not produced. Routinely administering i.n. midazolam under the assumption that the bioavailability is approximately 50% (as reported previously in the literature) may lead to overdosing in some patients.

Cardiac output and organ blood flow in experimental septic shock: effect of treatment with antibiotics, corticosteroids, and fluid infusion.

Septic shock from intraperitoneal (i.p.) injection of live Escherichia coli bacteria in rats induces marked pathophysiological changes, including 40% decrease in plasma volume (PV), cardiac output, and oxygen consumption with 100% mortality within 24 hr. The present study evaluates cardiac output and organ blood flow before and after treatment of septic shock with an effective antibiotic (AB), plasma volume (PV) expansion, and corticosteroids (CS), alone and in combination. Treatment was initiated at 5.5 hr after bacterial injection, at a time when AB therapy did not improve 24 hr survival rate. Cardiac output decreased from 28.6 +/- 3.1 (SD) to 15.4 +/- 2.8 ml/min/kg (P less than .01) in septic rats concomitant with redistribution of blood flow from carcass to the heart, brain, intestines, liver, and adrenal glands. Absolute arterial blood flow increased only to the adrenal glands and the liver to 158% (P less than .01) and 167% (P less than .01) of control values, respectively. AB, CS, and Ringer's lactate (RL) alone or in combination did not significantly improve any organ blood flow compared to untreated septic animals but increased survival significantly to about 60% (P less than .01). Albumin (ALB) and CS in combination expanded PV to 138% (P less than .01), restored cardiac output to 100%, and achieved supranormal blood flow values to the brain (109%), liver (125%), small intestine (147%) (P less than .01), and kidneys (190%) (P less than .01) of preshock levels. More importantly, survival at 24 hr was 90% (9/10) (P less than .001). It is concluded that a colloid diluted in an electrolyte solution, combined with CS, and an effective antibiotic agent are necessary therapeutic ingredients for the successful recovery of experimental E. coli sepsis.

Ketamine monoanaesthesia for major surgery in epidermolysis bullosa. Case report.

A case report is presented of a patient with recessive dystrophic epidermolysis bullosa, who required anaesthesia for a major plastic surgery operation. The special anaesthetic problems are discussed, and ketamine monoanaesthesia is advocated when muscle relaxation is unnecessary. Glycopyrrolate was found to be an excellent antisialogenic agent.

Determination of methylprednisolone in rat tissue by high-performance liquid chromatography.

Methylprednisolone was determined in various types of rat tissue following an intravenous injection of methylprednisolone sodium succinate. Two modes of tissue work-up were investigated: digestion with subtilisin Carlsberg, a proteolytic enzyme, and homogenization with methanol. The final determination was by reversed-phase high-performance liquid chromatography with dexamethasone as internal standard. The extraction yields of methylprednisolone and dexamethasone from tissue homogenate and the extraction yield of methylprednisolone after incubation with viable tissue were determined. The experiments show that methylprednisolone and the internal standard are extracted in similar yields from tissue homogenates and that methylprednisolone can be recovered in a good yield after incubation with viable tissue, provided that the tissue does not have a high metabolic activity. There was a good agreement between the analytical results from the two different types of tissue work-up. The method of analysis proved feasible for pharmacokinetic work.

Charcoal hemoperfusion for treatment of serious carbamazepine poisoning.

A case of severe carbamazepine intoxication (total dose 80 g) is reported. Because of deep coma and cardiovascular symptoms, intensive care and hemoperfusion were employed. The carbamazepine hemoperfusion clearance rate was 80-90 ml/min, but due to a probable ongoing absorption from the gut the effect of hemoperfusion was limited. Long hemoperfusion periods are recommended due to the pharmacokinetic pattern of carbamazepine.

Rectal ketamine for induction of anaesthesia in children.

Rectal premedication with atropine and diazepam and rectal induction of anaesthesia with ketamine have been used in 30 healthy children undergoing minor surgery. The anticholinergic and sedative effects of the premedication were satisfactory. Induction of anaesthesia was smooth with no adverse circulatory or respiratory effects. No psychotomimetic side-effects were seen, and analgesia persisted into the recovery period. Plasma concentrations of ketamine and norketamine were measured in eight children and revealed a pharmacokinetic pattern indicating comparatively low bioavailability probably due to incomplete absorption from the rectum and a high 'first-pass' metabolism. The technique of rectal administration of ketamine needs further pharmacokinetic evaluation before it can be generally recommended.

Pharmacodynamic and pharmacokinetic interactions between ketamine and diazepam.

Anaesthesia with continuous i.v. ketamine and 65% nitrous oxide in oxygen was given to a total of 49 patients undergoing major abdominal surgery. A control group was premedicated with atropine and other groups received in addition rectal diazepam or clorazepate i.v. For further patients had been on oral diazepam or barbiturates for 1-14 years; as premedication they received atropine alone. The anaesthetic technique gave good operative conditions in the 4 groups of patients. The haemodynamic stimulation of ketamine was significantly reduced in patients premedicated with diazepam. Psychotomimetic side effects were not prominent in any of the groups. Patients premedicated with diazepam required a lower rate of ketamine infusion as compared to controls during the initial 30 min of anaesthesia. The patients in the other groups did not differ from the control group in this respect. There were large differences in metabolic pattern between the groups. As compared to the controls, the patients on long-term diazepam or barbiturates had high concentrations of hydroxylated metabolites, with levels higher than that of norketamine. The patients pretreated with diazepam had very low plasma levels of hydroxylated metabolites. Clorazepate premedication did not significantly affect the metabolism of ketamine. The biological half-life of ketamine was significantly increased in the diazepam-treated group, and it was shortened in those on long term treatment with barbiturates or diazepam.

Central haemodynamics and regional blood flow during halothane-nitrous oxide anaesthesia and controlled ventilation. An experimental study in the rat.

The haemodynamic effects of halothane-N2O/O2 anaesthesia with controlled ventilation were studied in rats, using the microsphere method. Mean arterial blood pressure was significantly reduced but only minor effects on cardiac output (CO), heart rate, and systemic vascular resistance were seen. During anaesthesia, there were significantly increased fractions of CO delivered to brain, lungs, small intestine and liver (hepatic artery), while the fractions to spleen, stomach and carcass were decreased. Fractional distribution and regional blood flow to heart, kidneys, adrenals and preportal area remained unchanged. When anaesthesia was prolonged from 60 to 90 min, no further changes in central or regional haemodynamics were seen. Considering the minor effects on central haemodynamics and the absence of changes in central and regional haemodynamics at 60 and 90 min, this anaesthesia model should be useful in experimental research.

Influence of ketamine on non-pregnant uterus in vivo.

This investigation was performed to evaluate the effect of ketamine anesthesia on non-pregnant uterine activity. Seven healthy non-pregnant women took part in the study. Anesthesia was induced with an i.v. bolus injection of ketamine 2 mg/kg and maintained with a continuous i.v. ketamine infusion, mean dosage 39 micrograms/kg/min. Before induction of anesthesia, each patient was placed in the lithotomy position, and a catheter fitted with two microtransducers for monitoring of intra-uterine pressures was fed through the cervix into the uterine cavity. For determination of plasma concentrations of ketamine and norketamine, venous blood samples were collected. The assay was based on a gas-liquid chromatographic technique. It was found that ketamine induced an increased uterine activity, both in basal tone and intensity of contractions. Only minor effects on the frequency were observed. This stimulatory effect was simultaneous with a hemodynamic stimulation with increases in heart rate and arterial blood pressure, and with the peak plasma concentration of ketamine.

Influence of ketamine anesthesia on cardiac output and tissue perfusion in rats subjected to hemorrhage.

Ketamine anesthesia has been considered suitable for use in patients suffering from acute hypovolemia. Using a microsphere technique, fractional distribution of cardiac output and tissue perfusion were determined in rats subjected to moderate (10 ml/kg), or severe (bled to 60 torr systolic arterial pressure) hemorrhage. In the moderate bleeding bleeding experiments, rats under ketamine anesthesia were compared to awake rats as well as to awake normovolemic rats. In the severe bleeding experiments, rats under ketamine anesthesia were compared to rats under barbiturate anesthesia. Following moderate bleeding the ketamine group had a significantly large cardiac output and higher arterial pressure than the unanesthetized group. There were no major differences in the fractional distribution of cardiac output, although tissue perfusion in the ketamine group was significantly larger in heart, kidneys, skin, and small intestine. The shed blood volume necessary to reach 60 torr in systolic arterial pressure was 36 per cent of normal blood volume in the ketamine group, and 23 per cent in the barbiturate group. In spite of the greater blood loss, rats under ketamine anesthesia displayed significantly larger cardiac output and a higher elevation of arterial pressure 20 min after the hemorrhage. In the ketamine group, fractional distribution of cardiac output favored the internal organs as opposed to an increase in the carcass in the barbiturate group. The ketamine anesthetized rats had a significantly larger perfusion to most organs, including heart, kidneys, and brain. It is concluded from this study that in rats experiencing acute hypovolemia blood flow to vital organs and cardiac output are well maintained under ketamine anesthesia.

Increased bleeding during liver resection in ethanol-intoxicated rats.

The effect of ethanol intoxication on hemostasis after liver resection was studied in the rat. Plasma levels of ethanol were within the range of those found in ethanol intoxication in man. Bleeding time and blood loss were significantly increased, whereas hemoglobin and hematocrit values were decreased after resection in intoxicated animals compared to controls. APT-times and platelet counts did not differ significantly between the two groups of rats. ADP- and collagen-induced platelet aggregation was slightly inhibited one hour after ethanol administration in non-operated animals. A decrease in pH, such as observed in intoxicated animals, did not affect hemostasis. Distribution of cardiac output was significantly altered ethanol intoxication. Renal blood flow was increased by 54%, blood flow in the hepatic artery by 40% and in the portal vein by 47%.

Tissue perfusion and distribution of cardiac output during ketamine anesthesia in normovolemic rats.

Based on previous clinical experience, an anesthetic technique for the rat, using ketamine, has been evaluated. The method comprised an i.v. bolus injection of 30 mg/kg for induction and an i.v. continuous infusion of 1.5 mg/kg/min for maintenance of anesthesia. Minor differences in ketamine metabolism between man and the rat are discussed. It appears that a higher ketamine concentration at the receptor site was required in the rat as compared to man. During ketamine anesthesia in the rat, fractional distribution of cardiac output and regional tissue perfusion were determined with the aid of the microsphere method. The study showed increased fractions to the heart, brain and tongue. The carcass fraction was elevated shortly after induction but reduced during steady-state anesthesia. Stomach, bowel and kidneys received reduced fractions early, but after these fractions returned to their initial levels. As a consequence of the increased cardiac output, regional tissue perfusion was increased in practically all organs.

Ketamine infusions: pharmacokinetics and clinical effects.

The clinical effects and pharmacokinetics of ketamine, administered as an i.v. infusion, were studied in 31 patients. Anaesthesia was induced with ketamine 2 mg kg-1 i.v. and maintained using an i.v. infusion of ketamine, supplemented by nitrous oxide. The plasma concentrations of ketamine, nor-ketamine and dehydro-nor-ketamine were analysed using gas-liquid chromatography. The average maintenance dose of ketamine was 41 +/- 21 microgram kg-1 min-1, but there was an obvious decrease in the dose required as anaesthesia progressed. This dose gave a stable plasma concentration of ketamine of 9.3 +/- 0.8 mumol litre-1. Patients recovered at 2.7 +/- 0.9 mumol litre-1. Plasma half-life of ketamine was 79 +/- 8 min. Maximum concentration of nor-ketamine was 4.7 +/- 2.4 mumol litre-1 and of dehydro-nor-ketamine 3.2 +/- 1.9 mumol litre-1. There were transient increases (15-30% of pre anaesthetic values) in arterial pressure, heart rate and cardiac output during operation. No post-operative respiratory depression was seen.

Evaluation of the microsphere method for determination of cardiac output and flow distribution in the rat.

The radioactive microsphere technique was applied to determine simultaneous cardiac output and flow distribution in the rat. Left ventricular injections of large numbers of microspheres were given, without significant adverse effects, allowing determination of flow to organs and tissues with low perfusion rates. In order to determine coronary blood flow it was necessary to excise the inner lining of the left ventricle, thus eliminating activity from deposits of microspheres. Cardiac output determination showed less variation with the sampling catheter in the abdominal aorta than in the femoral artery. It is concluded that the microsphere method can be conveniently used for hemodynamic studies in the rat, and that the abdominal aorta is the preferred site for the placement of the reference catheter in the rat.

Evaluation of catheter-manometer systems for adequate intravascular blood pressure measurements in small animals.

Various catheter-manometer systems possible for intravascular blood pressure measurments on rats have been elaborated and tested in vitro and in vivo. Using a pressure-step calibrator, it was observed from in vitro studies that microtransducers had superior frequency response compared to conventional transducers. Of the catheters tested, Pe-90 tapered to a 40 mm tip with an inner diameter of 0.3 mm had the best frequency response as judged from fall and settling times. Because of the damping effect, tapering increased fall time to 1.8 ms, which was still quite acceptable. By the same token settling time was minimized to 22.4 ms. With a special calculation method the theoretical percentile fault of the recordings was estimated to be 9.66%. When the measurement error was calculated from the actual in vivo recordings, it was found to be no more than 2.7%. These results show that the technique described is adequate for continuous intravascular blood pressure recordings on small animals. Finally it is emphasized that careful handling of the catheters and avoidance of stopcocks and air bubbles are essential for obtaining accurate and reproducible values.