Contribution of the active metabolite M1 to the pharmacological activity of tesofensine in vivo: a pharmacokinetic-pharmacodynamic modelling approach.

BACKGROUND AND PURPOSE: Tesofensine is a centrally acting drug under clinical development for Alzheimer's disease, Parkinson's disease and obesity. In vitro, the major metabolite of tesofensine (M1) displayed a slightly higher activity, which however has not been determined in vivo. The aims of this investigation were (i) to simultaneously accomplish a thorough characterization of the pharmacokinetic (PK) properties of tesofensine and M1 in mice and (ii) to evaluate the potency (pharmacodynamics, PD) and concentration-time course of the active metabolite M1 relative to tesofensine and their impact in vivo using the PK/PD modelling approach. EXPERIMENTAL APPROACH: Parent compound, metabolite and vehicle were separately administered intravenously and orally over a wide dose range (0.3-20 mg kg(-1)) to 228 mice. Concentrations of tesofensine and M1 were measured; inhibition of the dopamine transporter was determined by co-administration of [(3)H]WIN35,428 as the pharmacodynamic measure. KEY RESULTS: Pharmacokinetics of tesofensine and M1 were best described by one-compartment models for both compounds. Nonlinear elimination and metabolism kinetics were observed with increasing dose. The PK/PD relationship was described by an extended E(max) model. Effect compartments were used to resolve observed hysteresis. EC(50) values of M1, as an inhibitor of the dopamine transporter, were 4-5-fold higher than those for tesofensine in mice. CONCLUSIONS AND IMPLICATIONS: The lower potency of M1 together with approximately 8-fold higher through steady-state concentrations suggest that M1 did contribute to the overall activity of tesofensine in mice.

Pharmacodynamic models for the cardiovascular effects of moxonidine in patients with congestive heart failure.

AIMS: To assess the pharmacodynamics of moxonidine in patients with functional NYHA Class II-III congestive heart failure (CHF). METHODS: A parallel population pharmacokinetic/pharmacodynamic (PK/PD) analysis was performed to assess the effect of moxonidine (0.1, 0.2, 0.3 mg twice daily) and placebo treatment on plasma noradrenaline (NA) levels, standing systolic blood pressure (SBP), and heart rate (HR) over 12 weeks in 97 patients with CHF using a parallel group design with dose escalation. A sequential analysis was also developed, where the relative changes in NA concentration were related to both SBP and HR. RESULTS: In the parallel PD analysis, an effect delay was shown for all three end points (NA, SBP, and HR). An inhibitory Emax model was used to characterize the concentration-effect relationships. For SBP and HR, the EC50 value increased over time. For NA, there was a positive baseline drift over the 12 weeks; this was interpreted as disease progression. Moxonidine delayed this increase by 9.8 weeks. For SBP, there was a circadian pattern at baseline. In the sequential PD analysis, the relationship between the drug response (NA) and SBP or HR was best described by an inhibitory Emax model. No effect delays between the response and effects were found. CONCLUSIONS: Effects of moxonidine on NA, SBP, and HR could be quantified by an effect compartment model in the presence of disease progression and circadian variations. Disease progression, as judged by increasing NA levels with time, was delayed by moxonidine. A direct relationship was found between NA and SBP/HR.

Comparison of manual versus ambulatory blood pressure measurements with pharmacokinetic-pharmacodynamic modeling of antihypertensive compounds: application to moxonidine.

OBJECTIVES: To compare the results of the pharmacokinetic-pharmacodynamic analyses of 24-hour ambulatory blood pressure measurements and manual blood pressure data in patients receiving moxonidine. METHODS: 32 patients with borderline to mild-to-moderate hypertension were enrolled in a double-blind, placebo-controlled phase II study. After receiving placebo for 1 week (run-in phase), the patients were randomly allocated to the placebo or the 0.6-, 0.9-, or 1.2-mg dose groups. Placebo and moxonidine were administered once daily for 1 week (drug-treatment phase). Four 24-hour ambulatory blood pressure measurement profiles were obtained for each individual. Plasma samples (n = 9) and four measurements of manual blood pressure were taken at the start and end of the drug-treatment phase. Two additional manual blood pressure measurements were taken during the run-in and drug-treatment phases. RESULTS: Pharmacokinetics was described by a one-compartment model. For the 24-hour ambulatory blood pressure measurements, baseline circadian patterns were described with a two-cosine function model that included interindividual and interoccasion variability. Pharmacodynamics was described with use of an effect-compartment model [k(e0) = 0.37 (1/h)] and an Emax model. For diastolic blood pressure the maximum drug-induced decrease (Emax) was 30.9 mm Hg and the steady-state plasma drug concentration eliciting half of maximum effect (C50) was 1.33 microg/L. Interindividual variability was estimated for ke0 (24.8%) and Emax (33.3%). For the manual blood pressure measurements, data was described by a time-invariant baseline model combined with an effect-compartment model and an Emax model. Mean population estimates were in agreement with those obtained during the analysis of 24-hour ambulatory blood pressure measurements. However, interindividual variability could be estimated for the baseline parameter only. CONCLUSIONS: Although similar typical population estimates for the drug action-related parameters were obtained with use of manual blood pressure data and 24-hour ambulatory blood pressure measurements, the latter allowed for a more detailed description of the individual pharmacodynamic profiles because interindividual variability in pharmacodynamic parameters could be estimated together with increased precision in parameter estimates.

Population pharmacokinetic-pharmacodynamic modeling of moxonidine using 24-hour ambulatory blood pressure measurements.

OBJECTIVES: To develop a model for 24-hour ambulatory blood pressure measurements (ABPM) that can be applied in a pharmacokinetic-pharmacodynamic model. METHODS: Four different data sets were prepared from 2 studies to accommodate different modeling strategies. In study A, a double-blind placebo-controlled study in 47 patients, 24-hour ABPM profiles (74 to 99 measurements per profile) were obtained during the placebo run-in phase and after 3, 5, and 11 weeks during the treatment. Three to 5 plasma samples were taken. Cosine and polynomial models were evaluated to describe the circadian rhythm in blood pressure based on 3 data sets (1: only run-in data; 2: only placebo data; 3: all data). In study B, a double-blind placebo-controlled study in 94 patients, two 24-hour ABPM profiles per patient (during placebo run-in and after 8 weeks) were recorded and randomly reduced to 15 measurements per profile to evaluate the robustness of the baseline model. RESULTS: The mean moxonidine clearance was 35 L/h, and the volume of distribution was 132 L. The final baseline model consisted of 2 cosine terms with fixed-effect parameters for rhythm-adjusted 24-hour mean blood pressure, amplitude, phase, and period; random-effect parameters for interindividual variability in rhythm-adjusted 24-hour mean, amplitude, and clock time; and interoccasion variability in rhythm-adjusted 24-hour mean and clock time. The final baseline model was combined with an Emax model for the drug effect. An effect compartment was used (kco = 0.198 h-1). The maximum decrease in diastolic blood pressure (Emax) was 16.7%, and EC50 was 0.945 microgram/L. CONCLUSION: The pharmacokinetic-pharmacodynamic model for 24-hour ABPM can be used to estimate the concentration-effect relationship of antihypertensive drugs.

Dose-related hemodynamic and electrocardiographic effects of the calcium promoter BAY y 5959 in the presence or absence of congestive heart failure.

OBJECTIVES: The aim of this study was to assess the cardiovascular effects of BAY y 5959, a calcium promoter modulating myocardial calcium channels, in the presence or absence of congestive heart failure. BACKGROUND: There is still a clinical need for short-term administration of intravenous positive inotropes. BAY y 5959 was developed as a new approach to increase myocardial performance by selectively enhancing calcium influx in the myocytes. METHODS: Forty-one patients (21 without and 20 with congestive heart failure) were studied in an open label, dose-ranging study. Hemodynamic variables (including left ventricular [LV] angiography) and plasma samples were obtained at baseline and after 20 min of intravenous infusion of BAY y 5959 at doses ranging from 0.25 to 4.5 microg/kg body weight per min. RESULTS: In both study groups, BAY y 5959 produced dose-dependent increases in the indexes of inotropic state, without affecting isovolumetric relaxation rate. The magnitude of the response was comparable in patients with or without heart failure (average 38% increase in maximal first derivative of LV pressure [dP/dt max] at plasma levels of 100 microg/liter). BAY y 5959 also induced mild but statistically significant bradycardia and significantly decreased end-systolic volume while producing a leftward shift of the pressure-volume loop. Mean aortic pressure was unaffected at doses up to 3.0 microg/kg per min, and cardiac index improved in patients with heart failure at doses of 2.0 microg/kg per min (+23%, p < 0.05). However, at a dose of 4.5 microg/kg per min, mean aortic pressure and LV systolic wall stress increased, suggesting systemic vasoconstriction. The QT interval was also prolonged significantly at most doses. CONCLUSIONS: BAY y 5959 exhibits positive inotropic effects in patients with and without heart failure. The optimal response--combining bradycardia, reduced preload and improved cardiac output--appeared to be achieved at a dose of approximately 2.0 microg/kg per min. The impact of QT prolongation with regard to potential antiarrhythmic or proarrhythmic effects is unclear at this time.

Pharmacokinetic-pharmacodynamic modelling as a tool to evaluate the clinical relevance of a drug-food interaction for a nisoldipine controlled-release dosage form.

OBJECTIVE: Nisoldipine, a calcium antagonist of the dihydropyridine class, has been used in the treatment of hypertension and angina pectoris. A new controlled-release dosage form (nisoldipine coat-core, NCC) has been developed to allow once daily dosing. In addition to a formal food interaction study as requested by regulatory authorities for controlled-release dosage forms, a subsequent study was conducted to determine the clinical relevance of the changes in nisoldipine plasma concentration vs time profiles seen in the food effect study. METHODS: After a placebo run-in phase of 6 days, 12 hypertensive patients started treatment with 20 mg NCC once daily (days 0-3, 5-6, 8-9). On days 4, 7 and 10 the NCC was substituted for 5, 10 and 20 mg nisoldipine solution, respectively, in order to obtain nisoldipine plasma concentration vs time profiles comparable to the ones resulting from the concomitant intake of food and NCC. Simultaneous measurements of blood pressure (BP) and nisoldipine concentration were performed on days 3, 4, 7 and 10. RESULTS: The relationship between nisoldipine plasma concentrations and percentage reduction in BP [diastolic (DBP) and systolic (SBP), supine and standing] could be described by an Emax model. The mean maximum reduction (Emax) relative to baseline was about 36.4% and 37.7% (DBP, supine and standing) and 27.9% and 29.2% (SBP, supine and standing), respectively. The interindividual variability (% CV) in Emax was low, ranging from 17.6% to 28.8%. The mean nisoldipine plasma concentration corresponding to 50% of the maximum effect (EC50) ranged between 0.99 and 2.62 micrograms.l-1 with a pronounced interindividual variability (% CV) of 89.5-108.8%. Mean Cmax values after administration of the 30 and 40 mg NCC together with food were 4.5 and 7.5 micrograms.l-1, respectively. Based on the concentration-effect relationship established in the present study, the effect achieved with a concentration of 7.5 micrograms.l-1 will be about 77% of Emax for DBP and about 88% of Emax for SBP, respectively. CONCLUSION: At the time of maximum plasma concentration the additional decrease in BP relative to baseline due to the food effect will be about 7-15% for DBP and 3-9% for SBP. After administration of the 10 mg solution with a mean Cmax of 8.7 micrograms.l-1, only headache and flush with mild severity have been reported as adverse events. These maximum concentrations are comparable to Cmax values seen after intake of 40 mg NCC with food. With regard to heart rate (HR) there were distinct differences between the two formulations: Following administration of 5, 10 and 20 mg nisoldipine solution, there were dose-dependent increases in HR by a maximum of 4, 12 and 16 beats.min-1, respectively, whereas the HR profile for the NCC was similar to that seen under placebo treatment.

Pharmacokinetics of ciprofloxacin in pediatric cystic fibrosis patients.

The pharmacokinetic characteristics of ciprofloxacin were studied in 10 children with cystic fibrosis, aged from 6 to 16 years, who had completed the standard regimen of intravenous ceftazidime and amikacin. The aim of the investigation was to derive dosing guidelines for young cystic fibrosis patients to be treated with ciprofloxacin. Each child received ciprofloxacin given as two 30-min infusions (10 mg/kg of body weight each) 12 h apart; this was followed by the administration of oral ciprofloxacin (15 mg/kg every 12 h). Blood samples were taken after both infusions and after the first oral dose. A total of 232 ciprofloxacin concentrations (203 concentrations in plasma and 29 concentrations in urine) were analyzed by use of NONMEM and a two-compartment body model with seven parameters: total body clearance (CL), volume of the central compartment (V2), volume of the peripheral compartment (V3), intercompartmental clearance, renal clearance, absorption rate constant, and bioavailability. The influences of weight (range, 18 to 42 kg) and age (range, 6 to 16 years) were investigated. CL (in liters per hour) was found to be linearly correlated with weight (typical value of CL = 8.8 + 0.396. WT, where WT is weight; (interindividual coefficient of variation, 7.8%). V2 and V3 were directly proportional to weight, with slopes of 0.7 and 1.3 liters/kg, respectively. Interindividual variabilities were calculated to be 22.6 and 14.9% for V2 and V3, respectively. No dependency of the other pharmacokinetic parameters on age or weight was seen. Because of the high correlations between age and weight, only one covariable was necessary. Weight had the strongest effect. Bioavailability (population mean) was estimated to be 61.8%, and renal clearance (population mean) was estimated to be 11.4 liters/h. The residual (intraindividual) variability was 31.9%. The protein binding was about 34%, which is similar to the results obtained for adults. In order to define the appropriate dosage regimen for children suffering from cystic fibrosis, a formula was derived so that steady-state concentrations, similar to those obtained in adults after the administration of dosages of 400 mg three times daily intravenously and 750 mg twice daily orally, could be reached. The calculated total daily dose increased with increasing body weight. Given as milligrams per kilogram of body weight, the calculated dosage regimens suggest that for younger children (weight range, 14 to 28 kg), 28 to 20 mg/kg orally twice daily should be given, and for older children (weight range, 28 to 42 kg), 20 to 15 mg/kg orally twice daily should be given. For intravenous administration, dosages of 15 to 10 mg/kg twice daily are sufficient.

Pharmacokinetics, safety and tolerability of the orally administered receptor antagonist of cysteinyl-leukotrienes BAY x 7195 in single-dose escalation studies.

BAY x 7195 is a novel receptor antagonist of cysteinyl-leukotrienes currently under development for the treatment of asthma. It is effective in antagonizing the leukotriene-D4 induced bronchoconstriction in healthy volunteers following oral administration. The pharmacokinetics, safety and tolerability of the drug were investigated in six partially placebo-controlled studies in healthy volunteers with single oral administration of a 50, 100, 250, 500 and 1000 mg dose as a tablet. The drug was well tolerated. The only remarkable adverse event was diarrhea in one volunteer receiving the highest dose of 1000 mg. There were no additional clinically relevant changes in any safety parameter including laboratory values. Concentrations of BAY x 7195 were determined in plasma and urine by high performance liquid chromatography with fluorescence detection and plasma-concentrations were further evaluated by compartmental and non-compartmental methods. The concentration vs time profiles of the drug were biphasic with a dominant t1/2 of 0.5-2 h and a terminal t1/2 of 5-10 h. Pharmacokinetics were linear in the investigated range of doses. In spite of substantial inter-subject variability intra-individual variability in AUC and Cmax was reasonable. In general, the concentration vs time profiles could be described with a 2-compartment body model. However, in some cases the occurrence of second and third concentration maxima necessitated the use of a multiple segment absorption model to accomplish a good fit to the data. Enterohepatic recirculation following glucuronidation of the drug is the likely reason for the multiple peaks. Urinary excretion of BAY x 7195 and its glucuronide metabolite was negligible the amount excreted into urine from 0 to 48 h being < 0.1% of the dose. The low renal clearance of BAY x 7195 (< or = 0.07 ml/min) is suggestive of significant reabsorption in the renal tubuli taking into account that the expected renal clearance for a drug with 99.5% protein binding is about 0.6 ml/min.

Nitrous oxide is a potent cerebrovasodilator in humans when added to isoflurane. A transcranial Doppler study.

Nitrous oxide during neurosurgical procedures is almost always given in combination with either volatile or intravenous anesthetics. The modifying influence of such interventions has been studied clinically and in experimental settings; the reported findings, however, are inconsistent. The present study compares the cerebrovascular effects of MAC equivalent concentrations of isoflurane alone and isoflurane plus nitrous oxide. Twenty lumbar laminectomy patients randomized either to receive isoflurane or isoflurane plus nitrous oxide were investigated over a dose range from 0.5 to 1.5 MAC. A transcranial Doppler (TCD) ultrasonography device was used to measure cerebral blood flow velocity (CBFV) in the right middle cerebral artery (MCA) as an index of anesthetic-induced alterations in cerebral blood flow (CBF). A small but marginally significant decrease in CBFV at 1 MAC and no change at 1.5 MAC occurred in the isoflurane anesthetized patients. In contrast, a small but significant increase in CBFV at 1 MAC and a very significant increase at 1.5 MAC occurred in the isoflurane plus nitrous oxide anesthetized patients. Nitrous oxide added to an isoflurane anesthetic regimen is concluded to be a potent vasodilator. In addition, the vasodilating effects of nitrous oxide were not uniform; they progressively increased with an increasing isoflurane concentration.

Pharmacokinetic development of quinolone antibiotics.

A prerequisite for the pharmacokinetic development of quinolone antibiotics is a sensitive and accurate method for the quantification of the drug in biological fluids. Both, a drug specific (e.g. HPLC) and a drug non-specific but effect related assay (e.g. bioassay) should be used during early clinical development to detect major active metabolites. The basic pharmacokinetic behavior of the drug is investigated as part of the early phase I program, where single and multiple ascending dose studies are performed to characterize the safety and tolerability of the quinolone in healthy volunteers. Further pharmacokinetic studies are performed to describe the absolute bioavailability, dose proportionality, pharmacokinetics in young and elderly, male and female volunteers. The suitability of the clinical dosage from must be evaluated in comparison to an oral solution and by quantification of the effect of food on bioavailability. The characterization of the absorption in different parts of the gastrointestinal tract may be valuable for dosage form optimization. In order to start phase IIb clinical trials, the potential of possible drug-drug interactions with antacids, cimetidine, theophylline and warfarin has to be evaluated. This can be done by in vitro and in vivo preclinical experiments, before formal clinical-pharmacology studies are performed. Further pharmacokinetic characterization (e.g. studies in special subpopulation, extended interaction studies, total recovery using 14C-labelled compound, blister fluid penetration) will be done parallel to the phase II/III development program. During these efficacy and safety trials blood samples should be obtained and PK-parameters can be calculated using sparse data analysis methods like non-linear mixed effect modeling (NONMEM) or Bayesian methods to characterize the pharmacokinetics in the target population.

Effects of ketamine on cerebral blood flow velocity in humans. Influence of pretreatment with midazolam or esmolol.

During normoventilation and 'light', haemodynamically stable, steady-state anaesthesia with isoflurane 0.3%, the effect of ketamine intravenously was investigated in 24 patients randomly assigned to one of the following groups: group 1 (control group) no ketamine, group 2 (ketamine group) ketamine 2 mg.kg-1, group 3 (ketamine/midazolam group) ketamine 2 mg.kg-1 after pretreatment with midazolam and group 4 (ketamine/esmolol group) ketamine 2 mg.kg-1 while maintaining mean arterial blood pressure at a preketamine level with esmolol. Ketamine-induced cerebrovascular changes were measured by means of transcranial Doppler ultrasonography. Control readings in patients without ketamine challenge demonstrated stable cardiovascular and cerebrovascular baseline conditions. Cerebral blood flow velocity and mean arterial blood pressure, however, significantly increased after administration of ketamine without pretreatment. The increase in cerebral blood flow velocity could not be blocked by maintaining mean arterial blood pressure at baseline value with esmolol. In contrast, the effects of ketamine on cerebral blood flow velocity and mean arterial blood pressure were prevented by prior administration of midazolam. The results suggest that ketamine may significantly influence intracerebral haemodynamics via a direct drug effect rather than via a secondary effect due to changes in arterial carbon dioxide and/or mean arterial blood pressure.

Safety in the operating theatre--part 1: interpersonal relationships and team performance.

NASA: The authors examine the application of interpersonal human factors training on operating room (OR) personnel. Mortality studies of OR deaths and critical incident studies of anesthesia are examined to determine the role of human error in OR incidents. Theoretical models of system vulnerability to accidents are presented with emphasis on a systems approach to OR performance. Input, process, and outcome factors are discussed in detail.^ieng

Human factors and safety in emergency medicine.

A model based on an input process and outcome conceptualisation is suggested to address safety-relevant factors in emergency medicine. As shown in other dynamic and demanding environments, human factors play a decisive role in attaining high quality service. Attitudes held by health-care providers, organisational shells and work-cultural parameters determine communication, conflict resolution and workload distribution within and between teams. These factors should be taken into account to improve outcomes such as operational integrity, job satisfaction and morale.

Spinal anaesthesia with 29 gauge Quincke point needles and post dural puncture headache in 2,378 patients.

Two thousand three hundred and seventy-eight spinal anaesthetics using a 29 G Quincke point needle were administered in a District Hospital between May 1983 and December 1991. The overall post dural puncture headache rate (PDPH) was 1.2% with a maximum of 2.5% in patients between age 30 and 39. PDPH was related to the experience of using 29 G needles (0.5% in consultants versus 2.0% in trainees, P < 0.05).

Biopharmaceutical aspects of anti-infective therapy at the extremes of age.

Optimal anti-infective therapy at the extremes of age can be supported by the development of appropriate dosage forms. With regard to neonates, infants and children an oral liquid formulation appears to be superior compared with standard formulations such as tablets and capsules, since individualized dosing by body weight or body surface area is more easily achieved. Reformulation of marketed dosage forms, such as crunched tablets or opened capsules, by the hospital pharmacist may result in stability and bioavailability problems and therapeutic failures may be the consequence. With regard to the elderly a reduction in dosing frequency and individualized dosing are important in order to increase compliance. A reduction of dosing frequency can be achieved by oral controlled-release dosage forms, which are designed to release the drug in small amounts at predefined rates. However, to permit ease of swallowing they require a relative small daily dose together with excipients. In addition absorption must occur throughout the entire gastrointestinal tract; this is not the case for several antibiotics. Various advantages and disadvantages of oral liquid and oral controlled-release dosage forms are discussed. In the development of an oral formulation, in addition to a standard tablet a variety of information, such as physico-chemical characteristics, pharmacokinetics and pharmacodynamics must be available. Physico-chemical disadvantages can largely be solved by advanced pharmaceutical concepts, such as the pro-drug approach, complex formation or coprecipitation, which are discussed. Using ciprofloxacin with its long lasting and extremely bitter taste as an example, the pharmaceutical development of an oral liquid formulation and the pharmacokinetic investigations in healthy volunteers are described.

Prolonged decrease in heart rate variability after elective hip arthroplasty.

The pattern of postoperative heart rate variability may provide insight into the response of the autonomic nervous system to anaesthesia and surgery. We have obtained spectral (fast Fourier transform) and non-spectral indices of heart rate variability from electrocardiographic recordings, sampled during continuous perioperative Holter monitoring in 15 otherwise healthy patients with an uncomplicated postoperative course, undergoing elective hip arthroplasty with either spinal or general anaesthesia. In both groups, total spectral energy (0.01-1 Hz), low-frequency spectral energy (0.01-0.15 Hz) and high-frequency spectral energy (0.15-0.40 Hz) decreased after surgery to 32% (95% confidence interval (CI) 10.5; P < 0.01), 29% (95% CI 12.5; P < 0.01) and 33% (95% CI 12.5; P < 0.01) of their preoperative values, respectively, and these indices remained suppressed for up to 5 days. Non-spectral indices decreased to a similar extent. These findings indicate a substantial and prolonged postoperative decrease in both parasympathetic and sympathetic influence on the sinus node.

External ophthalmoplegia after total intravenous anaesthesia.

Eye-opening and eye movements were assessed in 110 awake and cooperative ASA class 1 and 2 patients after elective ENT surgery with total intravenous anaesthesia using propofol, fentanyl and atracurium. Following tracheal extubation and after regaining consciousness 21 patients showed a complete transient bilateral inability to open their eyes combined with a total gaze paresis, while another 30 patients showed an impairment of eye-opening and/or eye movements to a lesser extent. In all patients affected symmetrical recovery of both impaired eye-opening and eye movements occurred during the following 20 min. The occurrence of ophthalmological symptoms was not related to the duration of anaesthesia or the propofol infusion rate. Thus a complex ophthalmological phenomenon occurred after total intravenous anaesthesia in approximately 50% of awake and cooperative patients. The aetiology of this phenomenon and the implications for the understanding of the mechanisms of general anaesthesia remain to be determined.

Haemodynamic response to fibreoptic versus laryngoscopic nasotracheal intubation under total intravenous anaesthesia.

Thirty ASA physical status I and II patients scheduled for elective maxillofacial surgery received total intravenous anaesthesia with propofol, fentanyl and atracurium and were randomly allocated to undergo either fibreoptic or orthodox nasotracheal intubation. Haemodynamic responses to intubation were similar for both techniques. The peak values for heart rate and blood pressure after induction were not significantly different from the baseline values for each group. There was no significant difference in the time required to complete intubation. SpO2 and end-tidal CO2 were similar for both techniques.

Cerebral vasomotor responsiveness to carbon dioxide is preserved during propofol and midazolam anesthesia in humans.

Carbon dioxide reactivity, as measured by transcranial Doppler ultrasonography, was determined during total intravenous anesthesia with propofol or midazolam in comparison with an awake control group. Thirty ASA physical status I neurosurgical patients undergoing lumbar laminectomy participated in the study. In randomized order they were subjected to a CO2 reactivity challenge, either under an intravenous anesthesia technique or in the awake state. CO2 reactivity was calculated in each study group as a relative change in middle cerebral artery (MCA) flow velocity per mm Hg change in end-tidal CO2 (PETCO2) (%/mm Hg). The cerebrovascular response to changes in CO2 was preserved during intravenous anesthesia. There was a significant difference (P < 0.05) in the reactivity slopes between the awake and the anesthetized patients with a small but not significant difference between the propofol and the midazolam group. We conclude that hypocarbia is effective in reducing cerebral blood flow velocity (CBFV) during intravenous anesthesia, either with propofol or midazolam.