Recommended dosages of analgesic and sedative drugs in intensive care result in a low incidence of potentially toxic blood concentrations.

Background: Standard dosages of analgesic and sedative drugs are given to intensive care patients. The resulting range of blood concentrations and corresponding clinical responses need to be better examined. The purpose of this study was to describe daily dosages, measured blood concentrations, and clinical responses in critically ill patients. The purpose was also to contribute to establishing whole blood concentration reference values of the drugs investigated. Methods: A descriptive study of prospectively collected data from 302 admissions to a general intensive care unit (ICU) at a university hospital. Ten drugs (clonidine, fentanyl, morphine, dexmedetomidine, ketamine, ketobemidone, midazolam, paracetamol, propofol, and thiopental) were investigated, and daily dosages recorded. Blood samples were collected twice daily, and drug concentrations were measured. Clinical responses were registered using Richmond agitation-sedation scale (RASS) and Numeric rating scale (NRS). Results: Drug dosages were within recommended dose ranges. Blood concentrations for all 10 drugs showed a wide variation within the cohort, but only 3% were above therapeutic interval where clonidine (57 of 122) and midazolam (38 of 122) dominated. RASS and NRS were not correlated to drug concentrations. Conclusion: Using recommended dose intervals for analgesic and sedative drugs in the ICU setting combined with regular monitoring of clinical responses such as RASS and NRS leads to 97% of concentrations being below the upper limit in the therapeutic interval. This study contributes to whole blood drug concentration reference values regarding these 10 drugs.

Thiopental versus propofol on the outcome of the newborn after caesarean section: An impact study.

BACKGROUND: In 2011, the company that produced thiopental in France and in the United States stopped its marketing. Because of limited evidences, the choice of the best induction agent for caesarean section remains controversial, especially in emergency. The objective of this study was to compare the effects of propofol versus thiopental on the Apgar score of the newborn. METHODS: Newborns delivered by elective or emergency caesarean section under general anaesthesia in a university hospital were included from January 2009 to December 2013. Two periods, according to the hypnotic drug used, were compared in this before-and-after comparative study: thiopental before May 2011 and propofol after. The primary outcome was to compare the proportion of newborns with a 5-minute Apgar Score < 7 between both groups. RESULTS: 367 newborns were enrolled, 178 in thiopental group and 189 in propofol group. Demographic and clinical characteristics were similar in both groups. The occurrence of a 5-minute Apgar Score less than 7 was not influenced by the use of propofol (OR 1.40 [CI 95% 0.90-2.20] P = 0.135). Blood gas analyses and admission's rate in neonatal intensive care unit were similar in both groups. CONCLUSIONS: Thiopental and propofol do not appear to present significant difference in term of outcome of the newborn after caesarean section. In this situation, propofol may probably be a reliable alternative to the supply reduction of thiopental imposed by forces. Prospective studies are required to confirm the safety of propofol, particularly in the long term.

POST-ANESTHETIC REHABILITATION PERIODS AND ANESTHESIA DOSAGE FOR LAPAROSCOPIC CHOLECYSTECTOMY: RELATIONSHIP TO THE TOTAL OXIDATIVE CAPACITY OF LIVER.

Analysis of the results of pharmacological phenotyping using antipyrine test prior to providing anesthesia for laparoscopic cholecystectomy showed that trimeperidine (promedol) dosing with allowance for the total oxidative capacity of liver and the patient mass allows the periods of post-anesthetic rehabilitation to be controlled. Clear algorithm of trimeperidine dosing based on established indices of the total oxidative capacity of liver and is yet nor developed because of restricted sampling set. The obtained results show expediency of using and studying antipyrine test as a simple, cheap, and informative method of individual anesthesia dosing for increasing the adequacy of general anesthesia.

Protein-bound drugs are prone to sequestration in the extracorporeal membrane oxygenation circuit: results from an ex vivo study.

INTRODUCTION: Vital drugs may be degraded or sequestered in extracorporeal membrane oxygenation (ECMO) circuits, with lipophilic drugs considered to be particularly vulnerable. However, the circuit effects on protein-bound drugs have not been fully elucidated. The aim of this experimental study was to investigate the influence of plasma protein binding on drug disposition in ex vivo ECMO circuits. METHODS: Four identical ECMO circuits comprising centrifugal pumps and polymethylpentene oxygenators and were used. The circuits were primed with crystalloid, albumin and fresh human whole blood and maintained at a physiological pH and temperature for 24 hours. After baseline sampling, known quantities of study drugs (ceftriaxone, ciprofloxacin, linezolid, fluconazole, caspofungin and thiopentone) were injected into the circuit to achieve therapeutic concentrations. Equivalent doses of these drugs were also injected into four polypropylene jars containing fresh human whole blood for drug stability testing. Serial blood samples were collected from the controls and the ECMO circuits over 24 hours, and the concentrations of the study drugs were quantified using validated chromatographic assays. A regression model was constructed to examine the relationship between circuit drug recovery as the dependent variable and protein binding and partition coefficient (a measure of lipophilicity) as explanatory variables. RESULTS: Four hundred eighty samples were analysed. There was no significant loss of any study drugs in the controls over 24 hours. The average drug recoveries from the ECMO circuits at 24 hours were as follows: ciprofloxacin 96%, linezolid 91%, fluconazole 91%, ceftriaxone 80%, caspofungin 56% and thiopentone 12%. There was a significant reduction of ceftriaxone (P = 0.01), caspofungin (P = 0.01) and thiopentone (P = 0.008) concentrations in the ECMO circuit at 24 hours. Both protein binding and partition coefficient were highly significant, with the model possessing a high coefficient of determination (R (2) = 0.88, P <0.001). CONCLUSIONS: Recovery of the highly protein-bound drugs ceftriaxone, caspofungin and thiopentone was significantly lower in the ECMO circuits at 24 hours. For drugs with similar lipophilicity, the extent of protein binding may determine circuit drug loss. Future clinical population pharmacokinetic studies should initially be focused on drugs with greater lipophilicity and protein binding, and therapeutic drug monitoring should be strongly considered with the use of such drugs.

Interaction of thiopental with esomeprazole in critically ill patients.

INTRODUCTION: Thiopental is a thiobarbiturate given in the case of brain injuries to reduce intracranial pressure and to manage cerebral ischemia. A pharmacokinetic model has been described previously in critically ill patients with a different therapeutic strategy. New treatment options prompted us to investigate if drug-drug interactions occur. A new model is proposed describing the influence of concomitant administration of esomeprazole on the distribution of thiopental. METHOD: The study population comprised 52 critically ill patients (body weight 47.1-114 kg) aged 18-78 years who had been admitted into the critical care unit for treatment of intracranial hypertension. A total mean dose of 282.8 ± 172.7 mg/kg was given in 96 ± 72 h. Pharmacokinetic analysis was performed by using a nonlinear mixed-effect population model. RESULT: A one-compartment open model with first-order elimination identified two covariates, namely, body weight on clearance and volume of distribution, and the administration of esomeprazole on volume of distribution. The mean values (% relative standard error) for total clearance (CL) and for central volume of distribution (Vd) in patients with and without concomitant esomeprazole were 5.3 L/h (9.2 %) and 256.1 (6.4 %) and 153.2 l (19.2 %), respectively. CONCLUSION: Based on these results, we conclude that concomitant administration of esomeprazole increases the volume of distribution and the half-live of thiopental. This drug-drug interaction should be considered when a target concentration has to be reached.

Effect of intermittent hypobaric hypoxia on efficacy & clearance of drugs.

BACKGROUND & OBJECTIVES: People travelling to high altitude for occupational, recreational or religious purposes are mostly healthy and fit but sometimes they use drugs for common ailments like influenza, acute mountain sickness or chronic disease like diabetes. Limitation of oxygen at high altitude may compromise metabolism of drugs. Hence, we undertook this study to assess the effect of hypobaric hypoxia on some commonly used drugs in rats and rabbits. METHODS: Effect of intermittent hypobaric hypoxia on phenotypic expression of anesthetic drugs pentabarbitone, thiopentone and zoxazolamine (sleeping time) was assessed in rats exposed to 282.4 mm Hg equivalent to 25000 feet in a decompression chamber. Plasma clearance of some commonly used drugs was investigated in rabbits exposed to 429 mm Hg equivalent to 15000 feet. Pharmacokinetic parameters were computed by plotting drug concentration versus time curve on semi log scale. RESULTS: A significant delay in regaining rightening reflex was observed in rats exposed to intermittent hypobaric hypoxia in response to zoxazolamine, pentobarbitone and thiopentone sodium. Pharmacokinetics of acetyl salicylic acid, gentamicin, phenobarbitone and acetazolamide showed increase in plasma half life (t 1/2), decrease in elimination rate constant (k el) and hence prolonged residence of these drugs in hypoxic animals. INTERPRETATION & CONCLUSIONS: This experimental study showed that hypoxia altered therapeutic effectiveness and clearance of several drugs, in rats and rabbits exposed to intermittent hypobaric hypoxia. s0 uch studies need to be done in human volunteers to see the effect of hypoxia on pharmacokinetics of some common drugs.

Changes of blood endocannabinoids during anaesthesia: a special case for fatty acid amide hydrolase inhibition by propofol?

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: • Available data from animal studies suggest that the narcotic drug propofol interacts with the endocannabinoid system. Inhibition of enzymatic degradation of anandamide could explain some of the characteristics of propofol. Direct measurements have not been reported yet in humans. WHAT THIS STUDY ADDS: • Propofol does not change the time course of anandamide plasma concentrations during anaesthesia. Furthermore, propofol does not inhibit fatty acid amide hydrolase activity ex vivo or in vitro. Thus, specific characteristics of the narcotic drug propofol cannot be explained by peripheral inhibition of anandamide degradation in humans. AIMS: The aim of our study was to describe the time course of endocannabinoids during different anaesthesia protocols in more detail, and to challenge the hypothesis that propofol acts as a FAAH inhibitor. METHODS: Endocannabinoids were measured during the first hour of anaesthesia in 14 women and 14 men undergoing general anaesthesia with propofol and in 14 women and 14 men receiving thiopental/sevoflurane. We also incubated whole human blood samples ex vivo with propofol and the known FAAH inhibitor oloxa and determined FAAH enzyme kinetics. RESULTS: Plasma anandamide decreased similarly with propofol and thiopental/sevoflurane anaesthesia, and reached a nadir after 10 min. Areas under the curve for anandamide (mean and 95% CI) were 53.3 (47.4, 59.2) nmol l(-1) 60 min with propofol and 48.5 (43.1, 53.8) nmol l(-1) 60 min with thiopental/sevoflurane (P= NS). Anandamide and propofol plasma concentrations were not correlated at any time point. Ex vivo FAAH activity was not inhibited by propofol. Enzyme kinetics (mean ± SD) of recombinant human FAAH were K(m) = 16.9 ± 8.8 µmol l(-1) and V(max) = 44.6 ± 15.8 nmol mg(-1) min(-1) FAAH without, and K(m) = 16.6 ± 4.0 µmol l(-1) and V(max) = 44.0 ± 7.6 nmol mg( 1 ) min(-1) FAAH with 50 µmol l(-1) propofol (P= NS for both). CONCLUSIONS: Our findings challenge the idea that propofol anaesthesia and also propofol addiction are directly mediated by FAAH inhibition, but we cannot exclude other indirect actions on cannabinoid receptors.

Thiopentone elimination in newborn infants: exploring Michaelis-Menten kinetics.

BACKGROUND: Thiopentone elimination has been described using Michaelis-Menten pharmacokinetics in adults after prolonged infusion or overdose, but there are few reports of elimination in neonates. METHODS: Time-concentration profiles for neonates (n=37) given single-dose thiopentone were examined using both first-order (constant clearance) and mixed-order (Michaelis-Menten) elimination processes using nonlinear mixed effects models. These profiles included a 33-week post-menstrual age (PMA) neonate given an overdose. A two-compartment mamillary model was used to fit data. Parameter estimates were standardized to a 70 kg person using allometric models. RESULTS: There were 197 observations available for analysis from neonates with a mean post-menstrual age of 35 (SD 4.5) weeks and a mean weight of 2.5 (SD 0.9) kg. They were given a mean thiopentone dose of 3 (SD 0.4) mg/kg as a rapid bolus. Clearance at 26 weeks PMA was 0.015 l/min/70 kg and increased to 0.119 l/min/70 kg by 42 weeks PMA. The maximum rate of elimination (V(max)) at 26 weeks PMA was 0.22 mg/min/70 kg and increased to 4.13 mg/min/70 kg by 42 weeks PMA. These parameter estimates are approximately 40% adult values at term gestation. The Michaelis constant (K(m)) was 28.3 [between subject variability (BSV) 46.4%, 95% confidence interval (CI) 4.49-99.2] mg/l; intercompartment clearance was 0.44 (BSV 97.5%, 95% CI 0.27-0.63) l/min/70 kg; central volume of distribution was 46.4 (BSV 29.2%, 95% CI 41.7-59.8) l/70 kg; peripheral volume of distribution was 95.7 (BSV 70.3%, 95% CI 61.3-128) l/70 kg. CONCLUSIONS: Both first-order and mixed-order processes satisfactorily described elimination. First-order elimination adequately described the time-concentration profile in the premature neonate given an overdose. Clearance is immature in the pre-term neonate although there is rapid maturation around 40 weeks PMA, irrespective of post-natal age.

Placental transfer and pharmacokinetics of thiopentone in newborn infants.

BACKGROUND AND OBJECTIVES: Thiopentone, a short-acting barbiturate, has been introduced as premedication for intubation in newborn infants. The objectives of this study were to assess the pharmacokinetics of thiopentone in newborn infants, and to unravel whether placental transfer of the drug should be taken into account if administered to infants exposed to it during delivery. METHODS: Plasma concentrations were assessed with high-pressure liquid chromatography in samples from delivering mothers (n=27) receiving a median dose of 5.5 mg/kg (range 3.8-7.7) thiopentone for Caesarean section in gestational week 37.6 (range 25.7-41.4) and from corresponding umbilical cord blood (n=28). In infants (n=30) born at 35.4 weeks gestation (range 27.9-42.0) undergoing surgery at a median postnatal age of 24.5 h (range 4-521), repeated blood levels were assessed after administering a dose of 3 mg/kg thiopentone on clinical indication before intubation (seven samples per infant from 5 min to 48 h after administration). RESULTS: The umbilical/maternal concentration ratio was 0.7, the mean concentration of thiopentone was 55.7 micromol/l (SD+/-15.3) in mothers and 39.3 micromol/l (SD+/-12.5) in venous cord blood. In newborn infants undergoing surgery, the terminal half-life of thiopentone was 8 h (interquartile range (IQR) 2.5-10.8), and clearance 0.092 l/min per kg/postnatal age in days (IQR 0.02-0.1). CONCLUSIONS: Thiopentone might be used as premedication for short-lasting intubation after birth, for example, for surfactant administration. During the first 4 h after birth the dose needs to be adjusted for maternal dosage as well as for the weight of the infant.

Thiopental pharmacokinetics in newborn infants: a case report of overdose.

UNLABELLED: Thiopental may be used for sedation before intubation in newborn infants. A boy, born at 33 weeks of gestation (gw); birth weight 2435 g, was prescribed thiopental 3 mg/kg before intubation. He developed temporary hypotension and oxygen desaturation, and remained unconscious for longer than expected with a suppressed electroencephalography for 48 h. Serum thiopental concentration was 82, 59, 42 and 32 micromol/L after 20 min and 6, 24 and 68 h respectively. Serum concentrations from five newborn infants at the same time points after intubation with the same thiopental dose were used as reference values, and indicated a 10-fold overdose in the index case. The cause of the overdose could not be identified. The infant recovered; cerebral magnetic resonance imaging at the age of 42 gw and psychomotor development at 2 years were normal. These results show that thiopental concentrations are variable in neonates and there is a high risk of dosage error as no specific paediatric formulation is available. CONCLUSION: Well-designed procedures and continuous education are required to prevent errors and adverse events during drug delivery to newborn infants. To develop a safe method of administration for thiopental, an extended pharmacokinetic and pharmacodynamic study in neonates is warranted.

A critical review: does thiopental continuous infusion warrant therapeutic drug monitoring in the critical care population?

Thiopental is a barbiturate used in traumatic brain injuries (TBIs) to reduce intracranial pressure (ICP) and to manage cerebral ischemia. As thiopental follows Michaelis-Menten kinetics, therapeutic drug monitoring (TDM) has been used in practice to improve efficacy and reduce adverse effects. However, its role is still debatable, and TDM is not widely practiced. Current evidence suggests that thiopental therapy may improve mortality and functional outcome in a subpopulation of patients with severe TBI with elevated ICP refractory to conventional medical therapy. Several analytical methods are available to quantify thiopental concentrations. This review uses a previously published 9-step decision-making algorithm to determine whether TDM of thiopental in TBI is warranted. There seems to be poor correlation between thiopental concentration and pharmacological response in terms of neurological response, ICP, electroencephalography, and drug toxicity. There is no established therapeutic range for thiopental continuous infusion due to a wide range of plasma concentrations corresponding to efficacy (25-50 mg/L) and toxicity (30-70 mg/L) and the resulting overlap between the 2. Thiopental exhibits intrapatient and interpatient variability due to age, obesity, renal and hepatic dysfunction, Michaelis-Menten kinetics, and hepatic enzyme autoinduction. Available evidence suggests that TDM of thiopental continuous infusion is not beneficial in improving efficacy or avoiding toxicity. There are however 2 possible scenarios in which TDM may provide additional information to sound clinical judgment. The first is providing patient-specific plasma target concentration to guide titration of therapy. The second scenario is differentiating between brain death and barbiturate-induced coma.

How does obesity affect residence time dispersion and the shape of drug disposition curves? Thiopental as an example.

The effect of obesity on the shape of drug disposition curves was explained using the residence time concept without assuming well-mixed compartments. The mean (MDRT) and relative dispersion (RD2(D)) of disposition residence time of drug were predicted as function of percentage body fat by lumping the organs into fat and nonfat tissues, utilizing the fact that MDRT and RD2(D) act as a scale and shape parameter of disposition curves, respectively. The longer sojourn time of lipophilic drugs in adipose tissue leads to an increase in RD2(D) when the fraction of body fat increases. This explains the change in the shape of disposition curves observed in obese patients, where the increase in MDRT is accompanied by a proportionately great prolongation of the terminal half life. The model also predicts a decrease in whole body distribution clearance with increasing residence time dispersion (RD2(D)).

Thiopental and halothane dose-sparing effects of magnesium sulphate in dogs.

OBJECTIVE: To evaluate the effect of pre- and intraoperatively administered magnesium sulphate (MgSO(4)) on the induction dose of thiopental and of halothane for maintenance of anaesthesia in dogs undergoing ovariohysterectomy (OHE). STUDY DESIGN: Prospective, double-blind, randomized, placebo-controlled study. ANIMALS: Forty-six healthy, ASA physical status 1 dogs, scheduled for elective OHE. METHODS: The dogs were randomly assigned to receive a bolus of 50 mg kg(-1) MgSO(4) intravenously (IV), just before induction of anaesthesia, followed by a constant rate infusion (CRI) of 12 mg kg(-1) hour(-1) MgSO(4) intraoperatively (group Mg, n = 27) or a placebo bolus and CRI of 0.9% sodium chloride (NaCl) (group C, n = 19), approximately 30 minutes after premedication with acepromazine (0.05 mg kg(-1), intramuscularly, IM) and carprofen (4 mg kg(-1), subcutaneously, SC). Anaesthesia was induced with thiopental administered to effect and maintained with halothane in oxygen. End-tidal halothane (ET(hal)) was adjusted to achieve adequate depth of anaesthesia. Blood samples were obtained pre- and postoperatively for measurement of total serum magnesium concentration. RESULTS: The mean dose of thiopental was statistically lower (p < 0.0005) and the mean standardized ET(hal) concentration and end-tidal carbon dioxide partial pressure (Pe'CO(2)) areas under the curve were statistically smaller (p < 0.0005 and 0.014 respectively) in group Mg. Postoperatively the mean total serum magnesium concentration was statistically higher than the preoperative value (p < 0.0005) in group Mg, but not in group C. Nausea, associated with the MgSO(4) bolus injection, was observed in six dogs in group Mg, two of which vomited prior to induction of anaesthesia. CONCLUSIONS AND CLINICAL RELEVANCE: Magnesium sulphate administration reduced the induction dose of thiopental and ET(hal) concentration for maintenance of anaesthesia in dogs undergoing OHE. Observed side effects were nausea and vomiting.

A minimal physiological model of thiopental distribution kinetics based on a multiple indicator approach.

Currently available models of thiopental disposition kinetics using only plasma concentration-time data neglect the influence of intratissue diffusion and provide no direct information on tissue partitioning in individual subjects. Our approach was based on a lumped-organ recirculatory model that has recently been applied to unbound compounds. The goal was to find the simplest model that accounts for the heterogeneity in tissue partition coefficients and accurately describes initial distribution kinetics of thiopental in dogs. To ensure identifiability of the underlying axially distributed capillary-tissue exchange model, simultaneously measured disposition data of the vascular indicator, indocyanine green, and the marker of whole body water, antipyrine, were analyzed together with those of thiopental. A model obtained by grouping the systemic organs in two subsystems containing fat and nonfat tissues, successfully described all data and allowed an accurate estimation of model parameters. The estimated tissue partition coefficients were in accordance with those measured in rats. Because of the effect of tissue binding, the diffusional equilibration time characterizing intratissue distribution of thiopental is longer than that of antipyrine. The approach could potentially be used in clinical pharmacokinetics and could increase our understanding of the effect of obesity on the disposition kinetics of lipid-soluble drugs.

Cambios hemodinámicos durante la inducción anestésica con tiopental versus propofol en pacientes ASA I y II / Changes hemodinámics during the anesthesic induction with tiopental versus propofol in patients ASA I y II

Determinar los cambios hemodinámicos (frecuencia cardiaca y tensión arterial sistólica, diastólica y media) en la inducción anestésica con el uso de Tiopental versus Propofol en pacientes clasificados como ASA I y II de cirugía programada en el Hospital Universitario Fundación Santa Fe de Bogotá. Adicionalmente determinar el porcentaje requerido de medicamentos vasoconstrictores y líquidos endovenosos para contrarrestar la hipotensión generada por dichos inductores en los primeros 30 minutos de la anestesia. Metodología: experimento clínico aleatorizado controlado con muestreo secuencial por conveniencia. Se dividió en dos grupos, en el primero se realizó inducción anestésica con Tiopental Sódico (3-5 mg/kg) y el segundo con Propofol (1-2 mg/ kg), para evitar sesgos se estandarizó la técnica de inducción. Se midieron los cambios hemodinámicos (frecuencia cardiaca, tensión arterial sistólica, diastólica y media) realizándose un promedio de las tres primeras mediciones (T0) las cuales fueron previo a la inducción y sin la colocación de ningún fármaco, posteriormente se realizó la medición antes de la intubación y 3 minutos después de la colocación de relajante neuromuscular (T1), 3 (T2), 5 (T3), 10 (T4) y 15 minutos (T5) después de la intubación. Se cuantificó la cantidad de vasopresores y de líquidos endovenosos utilizados. Resultados: No se encontraron diferencias estadísticamente significativas en los parámetros hemodinámicos medidos, (p = 0,32) ni en el uso de vasoconstrictores (7 versus 8 por cien) (p= 0,69) o en la administración de líquidos endovenosos. Conclusiones: No hay diferencias clínicas ni estadísticamente significativas en los resultados encontrados entre el uso de Tiopental Sódico versus Propofol en pacientes clasificados como ASA I y II.

Comparison of two thiopental infusion rates for the induction of anaesthesia in dogs.

OBJECTIVE: To compare the induction dose requirements of thiopental using two different infusion rates for induction of anaesthesia in dogs. STUDY DESIGN: Prospective, randomized study. ANIMALS: Fifty, healthy (ASA I or II) client-owned dogs with a mean age of 4.1 years and a mean mass of 20.4 kg undergoing elective surgery. MATERIALS AND METHODS: Animals were randomly assigned to receive an infusion of 2.5% thiopental at a rate of either 0.1 ml kg(-1) minute(-1) or 0.4 ml kg(-1)minute(-1), 30-40 minutes after pre-anaesthetic medication with intramuscular acepromazine (0.025 mg kg(-1)) and pethidine (3.5 mg kg(-1)). Thiopental administration was controlled by a precision syringe driver. Statistical analyses of the results, using the outcome 'mg kg(-1) required for induction' (log-transformed) included unpaired t-tests for all categorical data (thiopental infusion rate, breed, sex, obesity, sedation quality) and univariable linear regression for continuous variables (mass, age). All variables were then considered in a multivariable linear regression model. The quality of induction with the two different infusion rates was also assessed. RESULTS: After controlling for quality of sedation, the thiopental induction dose requirement was significantly less (p < 0.001) with the slower infusion rate (median = 7.5 mg kg(-1); range 4.9-13.7) compared with the faster infusion rate (median =11.0 mg kg(-1); range 6.6-18.0). The quality of sedation also affected the dose required (p = 0.03). The slower infusion rate was associated with a significantly poorer induction quality (p = 0.03) [corrected] CONCLUSIONS: Slow thiopental infusion (0.1 ml kg(-1) minute(-1)) for anaesthesia induction after acepromazine/pethidine pre-anaesthetic medication reduced the induction dose requirement, although the quality of induction was inferior. CLINICAL RELEVANCE: The induction dose of thiopental was reduced with a slower administration rate and so slow administration is recommended in thiopental-sensitive animals.

Anesthesia in the obese patient: pharmacokinetic considerations.

The prevalence of obesity has increased 15% up to 20% and represents an important challenge for the anesthesiologist in drug-dosing management. The aim of this work is to provide an overview on physiological changes and pharmacokinetic implications of obesity for the anesthesiologist. Obesity increases both fat and lean masses; however, the percentage of fat tissue increases more than does the lean mass, affecting the apparent volume of distribution of anesthetic drugs according to their lipid solubility. Benzodiazepine loading doses should be adjusted on actual weight, and maintenance doses should be adjusted on ideal body weight. Thiopental sodium and propofol dosages are calculated on total body weight (TBW). The loading dose of lipophilic opioids is based on TBW, whereas maintenance dosages should be cautiously reduced because of the higher sensitivity of the obese patient to their depressant effects. Pharmacokinetic parameters of muscle relaxants are minimally affected by obesity, and their dosage is based on ideal rather than TBW. Inhalation anesthetics with very low lipid solubility, such as sevoflurane and desflurane, allow for quick modification of the anesthetic plan during surgery and rapid emergence at the end of surgery, hence representing very flexible anesthetic drugs for use in this patient population. Drug dosing is generally based on the volume of distribution for the loading dose and on the clearance for maintenance. In the obese patient, the volume of distribution is increased if the drug is distributed both in lean and fat tissues whereas the anesthetic drug clearance is usually normal or increased.