Population pharmacokinetics of intramuscular droperidol in acutely agitated patients.

BACKGROUND: Intramuscular droperidol is used increasingly for sedation of aggressive and violent patients. This study aimed to characterise the pharmacokinetics of intramuscular droperidol in these patients to determine how rapidly it is absorbed and the expected duration of measurable drug concentrations. METHODS: We undertook a population pharmacokinetic analysis of a subgroup of patients from a clinical trial comparing droperidol and midazolam: 17 receiving 5 mg and 24 receiving 10 mg droperidol. Droperidol was measured using high-performance liquid chromatography. Pharmacokinetic modelling was performed under a nonlinear mixed effects modelling framework (NONMEM v7.2). The model was used to simulate concentration time profiles of three typical doses, 5 mg, 10 mg and 10 mg + 10 mg repeated at 15 min. RESULTS: A two-compartment first-order input with first-order output model fitted the data best. The absorption rate constant was poorly characterised by the data and an estimate of the first order rate constant of absorption when fixed to 10 h-1 provided a stable model and lowest objective function. This represents extremely rapid absorption with a half-life of 5 min. The final model had a clearance of 41.9 l h-1 and volume of distribution of the central compartment of, 73.6 l. Median and interquartile range of initial (alpha) half-life was 0.32 h (0.26-0.37 h) and second (beta) half-life was 3.0 h (2.5-3.6 h). Simulations indicate that 10 mg alone provides an 80% probability of being above the lower limit of quantification (5 µg l-1 ) for 7 h, 2 h longer than for 5 mg. Giving two 10 mg doses increased this duration to 10 h. CONCLUSIONS: Intramuscular droperidol is rapidly absorbed with high therapeutic concentrations after 5 and 10 mg doses, and supports clinical data in which droperidol sedates rapidly for up to 6 h.

Ondansetron: a review of pharmacokinetics and clinical experience in postoperative nausea and vomiting.

INTRODUCTION: Postoperative nausea and vomiting (PONV) is associated with poor patient satisfaction and delayed recovery after general anesthesia. Multiple neurotransmitters are involved in the mediation of PONV but despite the introduction of new antiemetics, no completely effective drug exists for its prevention or treatment. AREAS COVERED: This review provides a detailed description of ondansetron's chemistry, pharmacokinetics, pharmacodynamics, toxicity and a brief review of clinical trials involving ondansetron and the management of PONV. We searched reviews, meta-analysis and randomized controlled trials (Medline, Embase and article reference lists). EXPERT OPINION: According to current literature, administering ondansetron 4 mg i.v. near the end of surgery provides sufficient protection against PONV in low- and moderate-risk patients, comparable to traditional antiemetics such as antihistamines and droperidol. High-risk patients require a multimodal approach since one quarter of them will not respond to monotherapy. In the future, transdermal formulation or formulations for nasal or buccal delivery will be available. The development of non-racemic mixture consisting of R-ondansetron would enhance the safety profile and probably the efficacy too.

Recomendaciones de prevención y tratamiento de las náuseas y vómitos postoperatorios y/o asociados a las infusiones de opioides / No disponible

Las náuseas y los vómitos postoperatorios (NVPO) producen malestar e insatisfacción del paciente y aumentan la necesidad de cuidados. La infusión de opiáceos, frecuente como tratamiento analgésico postoperatorio, puede inducir náuseas y/o vómitos (NV). Este trabajo tiene como objetivo el desarrollo de recomendaciones de prevención y tratamiento de ambos problemas. Con este fin se constituyó un Grupo de Trabajo de acuerdo con los estatutos de la Sociedad Española de Anestesiología y Reanimación. Dicho grupo realizó una evaluación crítica de artículos relevantes sobre el manejo de las NV perioperatorios precoces y tardíos tanto en adultos como en niños. Tras varias reuniones y discusión se acordaron las siguientes recomendaciones (resumen): 1. Todos los pacientes sometidos a cirugía deben ser evaluados respecto al riesgo de desarrollar NVPO. Se recomiendan las escalas de Apfel et al. para adultos y de Eberhart et al. para niños, ambas son útiles y fáciles de aplicar; 2. En los adultos con riesgo moderado o alto y en todos los niños se deben adoptar medidas de reducción del riesgo basal; 3. La profilaxis con un fármaco es útil en pacientes de riesgo bajo (Apfel 1 o Eberhart 1) sometidos a anestesia general. En los demás pacientes se debe realizar profilaxis con 2 o más fármacos y reducir el riesgo basal (abordaje multimodal); 4. Dexametasona, droperidol y ondansetrón (setrones en general) tienen similar eficacia. La elección de fármaco debe tener en consideración factores individuales en cada paciente; 5. El tratamiento de las NVPO establecidas debe hacerse preferentemente con un fármaco diferente al empleado en la profilaxis. El fármaco más efectivo es el ondansetrón; 6. Debe evaluarse la posibilidad de NVPO tras el alta del paciente en cirugía ambulatoria o en la sala de hospitalización en cirugía con ingreso. No existen evidencias suficientes para formular una estrategia de prevención de las NV tardíos; 7. El fármaco de elección en la prevención de las NV asociadas a infusión de opiáceos es droperidol (AU)

Postoperative nausea and vomiting (PONV) causes patient discomfort, lowers patient satisfaction, and increases care requirements. Opioid-induced nausea and vomiting (OINV) may also occur if opioids are used to treat postoperative pain. These guidelines aim to provide recommendations for the prevention and treatment of both problems. A working group was established in accordance with the charter of the Sociedad Española de Anestesiología y Reanimación. The group undertook the critical appraisal of articles relevant to the management of PONV and OINV in adults and children early and late in the perioperative period. Discussions led to recommendations, summarized as follows: 1) Risk for PONV should be assessed in all patients undergoing surgery; 2easy-to-use scales are useful for risk assessment: the Apfel scale for adults and the Eberhart scale for children.2) Measures to reduce baseline risk should be used for adults at moderate or high risk and all children. 3) Pharmacologic prophylaxis with 1 drug is useful for patients at low risk (Apfel or Eberhart 1) who are to receive general anesthesia; patients with higher levels of risk should receive prophylaxis with 2 or more drugs and baseline risk should be reduced (multimodal approach). 4) Dexamethasone, droperidol, and ondansetron (or other setrons) have similar levels of efficacy; drug choice should be made based on individual patient factors. 5) The drug prescribed for treating PONV should preferably be different from the one used for prophylaxis; ondansetron is the most effective drug for treating PONV. 6) Risk for PONV should be assessed before discharge after outpatient surgery or on the ward for hospitalized patients; there is no evidence that late preventive strategies are effective.7) The drug of choice for preventing OINV is droperidol (AU)

Droperidol and ondansetron-induced QT interval prolongation: a clinical drug interaction study.

BACKGROUND: Droperidol and ondansetron have previously been found to prolong the QT interval in the treatment of postoperative nausea and vomiting. However, this adverse effect has never been confirmed and compared with both drugs under controlled conditions. The objective was to study the effects of droperidol and ondansetron alone or in combination on QT interval duration in healthy subjects. METHODS: Sixteen healthy volunteers, eight males and eight females, were enrolled in this prospective, double-blind, randomized, placebo-controlled study. Subjects received 1 mg droperidol, 4 mg ondansetron, 1 mg droperidol plus 4 mg ondansetron, or a placebo, intravenously in a crossover design. Fridericia-corrected QT interval (QTcF) and plasma concentrations were measured repeatedly during 10 h at each study period. The primary endpoint was the maximal placebo time-matched and baseline-subtracted QTcF prolongation (DeltaDeltaQTcF). RESULTS: Compared with placebo, both droperidol and ondansetron significantly prolonged the QTcF interval. DeltaDeltaQTcF prolongation was 25 +/- 8 ms after droperidol, significantly greater than the 17 +/- 10-ms prolongation with ondansetron (P = 0.014). The combination of droperidol and ondansetron significantly increased the mean maximal DeltaDeltaQTcF by 28 +/- 10 ms. The combination induced greater QTcF prolongation compared with ondansetron alone (P = 0.001), but not with droperidol alone (P = 0.33). There was no significant pharmacokinetic interaction between droperidol and ondansetron. CONCLUSIONS: Under controlled conditions, both droperidol and ondansetron either alone or in combination induced significant marked QTc interval prolongation. However, the combination of both drugs did not significantly increase QTc prolongation compared with that induced by droperidol alone.

Intravenous droperidol: a review of its use in the management of postoperative nausea and vomiting.

Droperidol (Dehydrobenzperidol, Dehidrobenzoperidol, Dridol, Droleptan, Inapsine) is a dopamine D(2) receptor antagonist that has been widely used in adults and children for the prevention and treatment of postoperative nausea and vomiting (PONV) over several decades and, more recently, for the prevention of opioid-induced PONV during patient-controlled analgesia (PCA) in adults. In well controlled clinical trials of patients undergoing surgery, the efficacy of single-dose intravenous (IV) droperidol in preventing PONV was similar to that of ondansetron and dexamethasone. Droperidol significantly reduced opioid-induced PONV in adults during PCA and had a morphine-sparing effect. Droperidol is generally well tolerated and the incidence of adverse effects is similar to that observed with placebo and the serotonin 5-HT(3) receptor antagonists (setrons). Guidelines recommend that, in adults, droperidol monotherapy be considered for those at moderate risk of PONV, and droperidol in combination with a setron and/or dexamethasone be considered for patients at moderate or high risk of PONV. In children with moderate or high risk of PONV, droperidol is recommended for first-line use in some countries, and second-line use in others.

Successful protocol of anaesthesia for measuring transepithelial nasal potential difference in spontaneously breathing mice.

Numerous difficulties arise during in vivo measurements of transepithelial nasal potential difference (PD) in mice, such as inadequate duration and depth of anaesthesia, bronchoaspiration of solutions perfused in the nose, and respiratory and/or cardiovascular depression. Anaesthesia was induced in adult C57 mice with intraperitoneal injection of a combination of fentanyl, droperidol and medetomidine, each of these at either a small dose (0.20, 10 and 0.33 mg/kg, respectively) or at a large dose (0.40, 20 and 0.40 mg/kg, respectively), combined with a fixed dose of 0.375 microg clonidine. In order to establish a pharmacokinetic-pharmacodynamic relationship, blood concentrations of the first three drugs were measured in 24 animals by liquid-chromatography tandem mass spectrometry. At the end of the experiment, naloxone, a competitive morphinic antagonist, and atipamezole, an alpha-2 adrenergic antagonist, were administered. Bronchoaspiration was prevented by tilting the animal head downwards and by absorbing the excess fluid from the opposite nostril and from the oral cavity. Optimal assessment of anaesthesia associated with regular respiration, loss of blink, pupillary and pedal withdrawal reflexes was obtained with doses of fentanyl, droperidol and medetomidine corresponding to 0.20, 20 and 0.40 mg/kg, respectively. Blood concentrations of fentanyl around 17 ng/mL induced loss of respiratory efforts and were followed by death during the experiment. Integrity of ion transport was demonstrated under continuous perfusion by successive depolarization after amiloride and repolarization after chloride-free solution. The combination investigated in this study lead to adequate surgical anaesthesia (stage III, plane 2) for prolonged nasal PD measurements in spontaneously breathing mice.

Randomized clinical trial comparing intravenous midazolam and droperidol for sedation of the acutely agitated patient in the emergency department.

STUDY OBJECTIVE: We compare intravenous midazolam and droperidol for the onset of sedation of acutely agitated patients in the emergency department (ED). METHODS: This was a double-blind, randomized, clinical trial set in the ED of a university teaching hospital. Subjects were adults, acutely agitated because of mental illness, intoxication, or both, who received midazolam or droperidol, 5 mg intravenously, every 5 minutes until sedated. We analyzed time to sedation using survival analysis, median times to sedation, and proportions sedated at 5 and 10 minutes. RESULTS: Seventy-four patients received midazolam; 79 patients, droperidol. Survival analysis showed no difference in time to sedation (hazard ratio 0.86; 95% confidence interval [CI] 0.61 to 1.23), P=.42. Median time to sedation was 6.5 minutes for midazolam (median dose 5 mg) and 8 minutes for droperidol (median dose 10 mg), P=.075 (effect size 1.5 minutes; 95% CI 0 to 4 minutes). At 5 minutes, 33 of 74 (44.6%) patients from the midazolam group were adequately sedated compared with 13 of 79 (16.5%) patients from the droperidol group, a difference of 28.1% (95% CI 12.9% to 43.4%; P<.001). By 10 minutes, 41 of 74 (55.4%) from the midazolam group were sedated compared to 42 of 79 (53.2%) from droperidol, a difference of 2.2% (95% CI -14.9% to 19.3%; P=.91). Eleven adverse events occurred in the midazolam group and 10 in the droperidol group. Three patients required active airway management (3 patients with assisted ventilation and 1 patient intubated); all received midazolam. CONCLUSION: There is no difference in onset of adequate sedation of agitated patients using midazolam or droperidol. Patients sedated with midazolam may have an increased need for active airway management.

The inhibition of epidural morphine-induced pruritus by epidural droperidol.

UNLABELLED: IV droperidol inhibits epidural morphine-induced pruritus, but this effect disappears when the dose is increased from 2.5 to 5.0 mg. This study was performed to determine whether epidural droperidol would have a similar effect. In this double-blinded study, we enrolled 140 patients undergoing Cesarean delivery under epidural anesthesia who were randomly allocated to four groups. Anesthesia consisted of 150 mg of 0.5% bupivacaine with 1:200,000 epinephrine, with 2 mg of morphine and 0.0, 1.25, 2.5, or 5.0 mg of droperidol (Groups 1 to 4). During the postoperative period, patients were assessed for pruritus (absent, mild, moderate, or severe) and other untoward symptoms. The chi(2) test was used to compare the incidence of the side effects. For the analysis of pruritus, we used the Mantel-Haenszel test for linear association. Droperidol induced a dose-related reduction in the incidence of pruritus (P < 0.001). This reduction was independent of the incidence of somnolence, which increased with droperidol dose (P < 0.05 when the incidence of somnolence in Groups 1 and 4 was compared). We conclude that droperidol, in doses up to 5 mg epidurally, induces a dose-related reduction in the incidence of pruritus without inducing significant side effects. IMPLICATIONS: Epidural morphine is effective for pain control but yields some side effects, including pruritus, that can be severe. Studying patients undergoing Cesarean delivery, we found a dose-related reduction in the incidence of pruritus using epidural droperidol.

Droperidol elimination after cardiopulmonary bypass surgery.

A high-dose (0.75 to 2.8 mg/kg) pharmacokinetic study of droperidol was undertaken in patients during the recovery phase after cardiac surgery involving hypothermic cardiopulmonary bypass (CPB). The elimination half-life of droperidol in these patients, determined from concentration-time data obtained after CPB, was significantly prolonged relative to previously reported mean values in younger surgical patients not undergoing CPB and receiving lower doses of the drug (0.05-0.20 mg/kg). On stratification of the patients by droperidol dose, there was an inverse correlation between the size of the dose and the elimination half-life of droperidol: mean half-life decreased as mean dose increased. This difference in elimination half-life was not related to the duration of the CPB procedure, or the total anesthetic time, both of which were not significantly different between the patient groups receiving the three different doses of droperidol. The magnitude or duration of hypothermia after CPB did not differ between the three patient groups. The differences in half-lives are more likely due to the clinical condition of the patients, such that the patients who received the higher doses of droperidol were also judged clinically to be less ill and thus eliminated droperidol more efficiently. This hypothesis, however, could not be supported due to the small number of patients studied. The results obtained in this study indicate that droperidol elimination is significantly prolonged after high-dose administration to elderly patients undergoing hypothermic CPB procedures during cardiac surgery.

Determination of droperidol in plasma by liquid chromatography.

A reversed-phase high performance liquid chromatographic method is described for the determination of droperidol concentrations in plasma. Following extraction, separation of droperidol and the internal standard flurazepam was achieved with a Spherisorb Nitrile, 5 microns, S5CN 250 mm x 4.6 mm column at 200 nm. The mobile phase was phosphate buffer (0.05 M, pH 2.4), acetonitrile and ethanol (65:20:15, v/v/v). The assay was rapid, sensitive and linear over the range 2-4000 ng ml-1. Precision of the assay expressed as the intra- and inter-day relative standard deviations (%RSD) did not exceed 10%. Flunitrazepam, midazolam and nitrazepam were also resolved with this technique and did not interfere with droperidol or flurazepam. Resolution of all five compounds was complete in less than 6 min. The assay was used to study the pharmacokinetics of high dose droperidol infusions during and after cardiac surgery.

El droperidol interactúa con receptores serotonérgicos y adrenoceptores Ó- cardiovasculares / Droperidol interactions with serotonergic and cardiovascular Ó adrenoceptors

En este trabajo se investigó si los receptores cardiovasculares de la serotonina (5-HT) son antagonizados por el droperidol. Los efectos de este fármaco sobre la vasopresión y el cronotropismo positivo obtenidos con la infusión intravenosa de noradrenalina (NA; 1 µg.kg-1.min-1), angiotensina II (1 µg.kg-1.min-1) y quipazina (100 µg.kg-1.min-1) se estudiaron en ratas desmeduladas. El droperidol (0.01 - 1 mg.kg-1,i.v.) revirtió los efectos presores de la NA y la quipazina en forma dependiente de la dosis. El pretratamiento con propranolol, bromefeniramina o atropina (1 mg.kg-1, i.v.; cada uno), no previno los efectos del neuroléptico. Por otra parte, el droperidol no modificó la respuesta presora de la angiotensina II, ni el cronotropismo de las drogas estudiadas. Se observó que los efectos inhibitorios del droperidol (DI50 141 µg/kg; LC 105-191) y de la ketanserina (Di50 110 µg/kg; LC 91-132) sobre la vasopresión de la quipazina, son similares; sin embargo, esta última no fue modificada por la prazosina. Estos resultados indican una interacción del droperidol con los reeptores vasculares 5-HT y confirman su capacidad para bloquear Ó-adrenoceptores

Nistagmo espontáneo y posicional por efecto de la intoxicación aguda por drogas y sustancias químicas en humanos / Spontaneous and positional nystagmus due to acute intoxication by drugs and chemical substances in human

Se realizó una intoxicación experimental en 70 personas jóvenes normales que produjo vértigo o desequilibrio. Se estudiaron dos parámetros: el nistagmo espontáneo y el posicional. Las drogas que se experimentaron fueron de uso común mientras que otras se usan por prescripción terapéutica. Estas drogas actúan sobre la homeostasis del sentido del equilibrio sea por efecto inhibitorio o exitatorio en diferentes niveles del sistema nervioso central. Las sustancias estudiadas fueron: alcohol, ketamina, pentobarbital, nicotina, xileno, etambutol, tricloroetileno, fentanil y droperidol. Todas las drogas, con excepción de la ketamina, produjeron nistagmo espontáneo y porsicional, en algunas personas contra la gravedad y en las otras a favor de ella. La información obtenida lo conduce a uno a predecir cuán mal se sentirá una persona después del uso de drogas como las fenotiazinas, dependiendo del nivel del sistema nervioso que es afectado o cuán bien se sentirá usando un agonista del GABA o un antagonista de acetilcolina, dependiendo del tipo del nistagmo espontáneo o posicional que afecte al paciente en el momento de usar alguna de estas drogas

The pharmacokinetics of droperidol in anesthetized children.

Despite the wide use of droperidol to reduce nausea and vomiting in children, its pharmacokinetics have not been described in pediatric patients. Twelve ASA Class I-II children, undergoing tonsillectomy and adenoidectomy, received standardized anesthesia; none of the children received premedication. After induction of general anesthesia, droperidol (0.05 mg/kg) was injected intravenously as a bolus. Droperidol plasma concentrations were determined by radioimmunoassay. Pharmacokinetic data were analyzed by model-independent methods. The pharmacokinetic parameters (mean +/- SD) for the studied population were elimination half-life: 101.5 +/- 26.4 min, mean residence time: 127.2 +/- 28.6 min, volume of distribution at steady state: 0.58 +/- 0.29 L/kg and clearance: 4.66 +/- 2.28 mL.kg-1 x min-1. The clearance and volume of distribution at steady state values are lower than those reported for the adult population, and they apparently decreased in a parallel fashion. The smaller volume of distribution at steady state is consistent with the lipophilic distribution of droperidol and the reduced content of adipose tissue in children. The elimination half-time and mean residence time values are similar to those reported previously for adults. The relatively short half-life of droperidol for our pediatric population does not explain its extended antiemetic action. It does, however, reaffirm that the pharmacokinetic duration of a drug's action is only one of the determinants of its clinical duration.

Simultaneous high-performance liquid chromatographic assay of droperidol and flunitrazepam in human plasma. Application to haemodilution blood samples collected during clinical anaesthesia.

A simultaneous assay for droperidol and flunitrazepam by high-performance liquid chromatography has been developed and applied to blood samples collected during an acute normovolemic haemodilution under general anaesthesia. Haemodilution blood samples were stored at +4 degrees C to be transfused, if required, to a patient during the post-surgical phase. A C18 Supelclean cartridge was used for solid-phase extraction, and the recoveries were 74% and 89%, respectively, for droperidol and flunitrazepam. Compounds were chromatographed on a C18 Novapak column at 250 nm, with a mobile phase of acetonitrile-10 mM ammonium acetate buffer (pH 6.7) (45:55, v/v). Nitrazepam was used as the internal standard. For both drugs, the assay was linear up to 500 micrograms/l, and the detection limits were 20 and 10 micrograms/l for droperidol and flunitrazepam, respectively, and their observed levels in haemodilution samples were 93 +/- 82 micrograms/l and 76 +/- 107 micrograms/l, respectively. Some of the values for flunitrazepam were higher than the minimal efficient concentration, defined as the plasma level observed at the time of the patient wakening from anaesthesia (12 +/- 4 micrograms/l). According to our results, haemodilution sampling can be performed before induction of anaesthesia. When the blood is collected after the anaesthetic induction, it seems necessary to determine levels of the two drugs in haemodilution samples to avoid side-effects.

Pharmacokinetics of droperidol in surgical patients under different conditions of anaesthesia.

The pharmacokinetics of droperidol were studied in 42 surgical patients using doses of 5, 10 and 15 mg i.v., in association with neuroleptanalgesia or volatile anaesthetics. Plasma concentrations of droperidol were measured by radioimmunoassay. During neuroleptanalgesia, droperidol kinetics were linear over the dose range tested: the overall mean elimination half-life was 127 min, Vdss 103 litre and the plasma clearance 732 ml min-1. The kinetics of droperidol were similar under neuroleptanalgesia and under anaesthesia with halothane or enflurane. There was no significant correlation between the volume of distribution or clearance with age (14-65 yr) or body weight (48-90 kg).