Effect of voriconazole and fluconazole on the pharmacokinetics of intravenous fentanyl

Conclusion Both voriconazole and fluconazole delay the elimination of fentanyl significantly. Caution should be exercised, especially in patients who are given voriconazole or fluconazole during long-lasting fentanyl treatment, because insidiously elevated fentanyl concentration may lead to respiratory depression

Voriconazole and fluconazole increase the exposure to oral diazepam

Conclusion Both voriconazole and fluconazole considerably increase the exposure to diazepam. Recurrent administration of diazepam increases the risk of clinically significant interactions during voriconazole or fluconazole treatment, because the elimination of diazepam is impaired significantly

Ketamine: A Review of Clinical Pharmacokinetics and Pharmacodynamics in Anesthesia and Pain Therapy

Ketamine is a phencyclidine derivative, which functions primarily as an antagonist of the N-methyl-d-aspartate receptor. It has no affinity for gamma-aminobutyric acid receptors in the central nervous system. Ketamine shows a chiral structure consisting of two optical isomers. It undergoes oxidative metabolism, mainly to norketamine by cytochrome P450 (CYP) 3A and CYP2B6 enzymes. The use of S-ketamine is increasing worldwide, since the S(+)-enantiomer has been postulated to be a four times more potent anesthetic and analgesic than the R(-)-enantiomer and approximately two times more effective than the racemic mixture of ketamine. Because of extensive first-pass metabolism, oral bioavailability is poor and ketamine is vulnerable to pharmacokinetic drug interactions. Sublingual and nasal formulations of ketamine are being developed, and especially nasal administration produces rapid maximum plasma ketamine concentrations with relatively high bioavailability. Ketamine produces hemodynamically stable anesthesia via central sympathetic stimulation without affecting respiratory function. Animal studies have shown that ketamine has neuroprotective properties, and there is no evidence of elevated intracranial pressure after ketamine dosing in humans. Low-dose perioperative ketamine may reduce opioid consumption and chronic postsurgical pain after specific surgical procedures. However, long-term analgesic effects of ketamine in chronic pain patients have not been demonstrated. Besides analgesic properties, ketamine has rapid-acting antidepressant effects, which may be useful in treating therapy-resistant depressive patients. Well-known psychotomimetic and cognitive adverse effects restrict the clinical usefulness of ketamine, even though fewer psychomimetic adverse effects have been reported with S-ketamine in comparison with the racemate. Safety issues in long-term use are yet to be resolved

Enhancement of GABAergic activity:neuropharmacological effects of benzodiazepines and therapeutic use in anaesthesiology

GABA is the major inhibitory neurotransmitter in the central nervous system (CNS). The type A GABA receptor (GABAAR) system is the primary pharmacological target for many drugs used in clinical anesthesia. The α1, β2, and γ2 subunit-containing GABAARs located in the various parts of CNS are thought to be involved in versatile effects caused by inhaled anesthetics and classic benzodiazepines (BZD), both of which are widely used in clinical anesthesiology. During the past decade, the emergence of tonic inhibitory conductance in extrasynaptic GABAARs has coincided with evidence showing that these receptors are highly sensitive to the sedatives and hypnotics used in anesthesia. Anesthetic enhancement of tonic GABAergic inhibition seems to be preferentially increased in regions shown to be important in controlling memory, awareness, and sleep. This review focuses on the physiology of the GABAARs and the pharmacological properties of clinically used BZDs. Although classic BZDs are widely used in anesthesiological practice, there is a constant need for new drugs with more favorable pharmacokinetic and pharmacodynamic effects and fewer side effects. New hypnotics are currently developed, and promising results for one of these, the GABAAR agonist remimazolam, have recently been published.</p

Predictive equations over-estimate the resting energy expenditure in amyotrophic lateral sclerosis patients who are dependent on invasive ventilation support

BackgroundAmyotrophic lateral sclerosis (ALS) is a form of degenerative motor neuron disease. At the end stage of the disease artificial feeding is often required. Nevertheless, very little is known about the energy demand of those ALS patients who are chronically dependent on tracheostomy intermittent positive pressure ventilation. The objective of our study was to clarify the resting energy expenditure (REE) in mechanically ventilated ALS patients.MethodsWe measured the REE of five ALS patients (four men, one female) twice during a 12 month-period using indirect calorimetry with two sampling flow settings (40 L/min and 80 L/min). The measured REEs (mREE) were compared with values calculated using five different predictive equations.ResultsThe mean (± SD) of all mREEs was 1130 ± 170 kcal/d. The measurements with different flow settings and at different time instances provided similar results. The mean of mREEs was 33.6% lower, as compared to the mean calculated with five different predictive equations REE (p ConclusionsThe mREE values were significantly lower for every patient than all the predicted ones. Determination of daily nutrition with predictive equations may therefore lead in mis-estimation of energy requirements. Because ALS patients may live years with artificial ventilation their nutritional support should be based on individual measurements. However, further study is needed due to the small number of subjects.</p

Effect of nitrous oxide on cisatracurium infusion demands: a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Recent studies have questioned our previous understanding on the effect of nitrous oxide on muscle relaxants, since nitrous oxide has been shown to potentiate the action of bolus doses of mivacurium, rocuronium and vecuronium. This study was aimed to investigate the possible effect of nitrous oxide on the infusion requirements of cisatracurium.</p> <p>Methods</p> <p>70 ASA physical status I-III patients aged 18-75 years were enrolled in this randomized trial. The patients were undergoing elective surgery requiring general anesthesia with a duration of at least 90 minutes. Patients were randomized to receive propofol and remifentanil by target controlled infusion in combination with either a mixture of oxygen and nitrous oxide (Nitrous oxide/TIVA group) or oxygen in air (Air/TIVA group). A 0.1 mg/kg initial bolus of cisatracurium was administered before tracheal intubation, followed by a closed-loop computer controlled infusion of cisatracurium to produce and maintain a 90% neuromuscular block. Cumulative dose requirements of cisatracurium during the 90-min study period after bolus administration were measured and the asymptotic steady state rate of infusion to produce a constant 90% block was determined by applying nonlinear curve fitting to the data on the cumulative dose requirement during the study period.</p> <p>Results</p> <p>Controller performance, i.e. the ability of the controller to maintain neuromuscular block constant at the setpoint and patient characteristics were similar in both groups. The administration of nitrous oxide did not affect cisatracurium infusion requirements. The mean steady-state rates of infusion were 0.072 +/- 0.018 and 0.066 +/- 0.017 mg * kg-1 * h-1 in Air/TIVA and Nitrous oxide/TIVA groups, respectively.</p> <p>Conclusions</p> <p>Nitrous oxide does not affect the infusion requirements of cisatracurium.</p> <p>Trial registration</p> <p>ClinicalTrials.gov NCT01152905; European Clinical Trials Database at <url>http://eudract.emea.eu.int/2006-006037-41</url>.</p

Using respiratory rate and thoracic movement to assess respiratory insufficiency in amyotrophic lateral sclerosis: a preliminary study

ackgroundHypoventilation due to respiratory insufficiency is the most common cause of death in amyotrophic lateral sclerosis (ALS) and non-invasive ventilation (NIV) can be used as a palliative treatment. The current guidelines recommend performing spirometry, and recording nocturnal oxyhemoglobin saturation and arterial blood gas analysis to assess the severity of the hypoventilation. We examined whether the respiratory rate and thoracic movement were reliable preliminary clinical signs in the development of respiratory insufficiency in patients with ALS.MethodsWe measured the respiratory rate and thoracic movement, performed respiratory function tests and blood gas analysis, and recorded subjective hypoventilation symptoms in 42 ALS patients over a 7-year period. We recommended NIV if the patient presented with hypoventilation matching the current guidelines. We divided patients retrospectively into two groups: those to whom NIV was recommended within 6 months of the diagnosis (Group 1) and those to whom NIV was recommended 6 months after the diagnosis (Group 2). We used the Mann Whitney U test for comparisons between the two groups.ResultsThe mean partial pressure of arterial carbon dioxide in the morning in Group 1 was 6.3 (95% confidence interval 5.6–6.9) kPa and in Group 2 5.3 (5.0–5.6) kPa (p = 0.007). The mean respiratory rate at the time of diagnosis in Group 1 was 21 (18–24) breaths per minute and 16 (14–18) breaths per minute in Group 2 (p = 0.005). The mean thoracic movement was 2.9 (2.2–3.6) cm in Group 1 and 4.0 (3.4–4.8) cm in Group 2 (p = 0.01). We observed no other differences between the groups.ConclusionsPatients who received NIV within six months of the diagnosis of ALS had higher respiratory rates and smaller thoracic movement compared with patients who received NIV later. Further studies with larger numbers of patients are needed to establish if these measurements can be used as a marker of hypoventilation in ALS.</p

Validation of indirect calorimetry for measurement of energy expenditure in healthy volunteers undergoing pressure controlled non-invasive ventilation support

The aim of this validation study was to assess the reliability of gas exchange measurement with indirect calorimetry among subjects who undergo non-invasive ventilation (NIV). Oxygen consumption (VO2) and carbon dioxide production (VCO2) were measured in twelve healthy volunteers. Respiratory quotient (RQ) and resting energy expenditure (REE) were then calculated from the measured VO2 and VCO2 values. During the measurement period the subjects were breathing spontaneously and ventilated using NIV. Two different sampling air flow values 40 and 80 l/min were used. The gas leakage from the measurement setup was assessed with a separate capnograph. The mean weight of the subjects was 93 kg. Their mean body mass index was 29 (range 22-40) kg/m(2). There was no statistically significant difference in the measured values for VO2, VCO2, RQ and REE during NIV-supported breathing and spontaneous breathing. The change of sampling air flow had no statistically significant effect on any of the above parameters. We found that REE can be accurately measured with an indirect calorimeter also during NIV-supported breathing and the change of sampling air flow does not distort the gas exchange measurement. A higher sampling air flow in indirect calorimetry decreases the possibility for air leakages in the measurement system and increases the reliability of REE measurement