Piritramide and alfentanil display similar respiratory depressant potency.

BACKGROUND: The question whether some opioids exert less respiratory depression than others has not been answered conclusively. We applied pharmacokinetic/pharmacodynamic (PKPD) modeling to obtain an estimate of the C50 for the depression of CO2 elimination as a measure of the respiratory depressant potency of alfentanil and piritramide, two opioids with vastly different pharmacokinetics and apparent respiratory depressant action. METHODS: Twenty-three patients received either alfentanil (2.3 microg x kg(-1) x min-1, 14 patients, as published previously) or piritramide (17.9 microg x kg(-1) x min(-1), nine patients) until significant respiratory depression occurred. Opioid pharmacokinetics and the arterial PCO2 (PaCO2) were determined from frequent arterial blood samples. An indirect response model accounting for the respiratory stimulation due to increasing PaCO2 was used to describe the PaCO2 data. RESULTS: The following pharmacodynamic parameters were estimated with NONMEM [population means and interindividual variability (CV)]: k(elCO2) (elimination rate constant of CO2) 0.144 (-) min(-1), F (gain of the CO2 response) 4.0 (fixed according to literature values) (28%), C50 (both drugs) 61.3 microg l-1 (41%), k(eo alfentanil) 0.654 (-) min(-1) and k(eo piritramide) 0.023 (-) min(-1). Assigning separate C50 values for alfentanil and piritramide did not improve the fit compared with a model with the same C50. CONCLUSION: Since the C50 values did not differ, both drugs are equally potent respiratory depressants. The apparently lower respiratory depressant effect of piritramide when compared with alfentanil is caused by slower equilibration between the plasma and the effect site. Generalizing our results and based on simulations we conclude that slowly equilibrating opioids like piritramide are intrinsically safer with regard to respiratory depression than rapidly equilibrating opioids like alfentanil.

Pharmacokinetic-pharmacodynamic modeling of the respiratory depressant effect of alfentanil.

BACKGROUND: Although respiratory depression is the most well-known and dangerous side effect of opioids, no pharmacokinetic-pharmacodynamic model exists for its quantitative analysis. The development of such a model was the aim of this study. METHODS: After institutional approval approval and informed consent were obtained, 14 men (American Society of Anesthesiologists physical status I or II; median age, 42 yr [range, 20-71 yr]; median weight, 82.5 kg [range, 68-108 kg]) were studied before they underwent major urologic surgery. An intravenous infusion of alfentanil (2.3 microg x kg(-1) x min(-1)) was started while the patients were breathing oxygen-enriched air (fraction of inspired oxygen [FIO2 = 0.5) over a tightly fitting continuous positive airway pressure mask. The infusion was discontinued when a cumulative dose of 70 microg/kg had been administered, the end-expiratory partial pressure of carbon dioxide (PE(CO2) exceeded 65 mmHg, or apneic periods lasting more than 60 s occurred During and after the infusion, frequent arterial blood samples were drawn and analyzed for the concentration of alfentanil and the arterial carbon dioxide pressure (PaCO2). A mamillary two-compartment model was fitted to the pharmacokinetic data. The PaCO2 data were described by an indirect response model The model accounted for the respiratory stimulation resulting from increasing PaCO2. The model parameters were estimated using NONMEM. Simulations were performed to define the respiratory response at steady state to different alfentanil concentrations. RESULTS: The indirect response model adequately described the time course of the PaCO2. The following pharmacodynamic parameters were estimated (population means and interindividual variability): EC50, 60.3 microg/l (32%); the elimination rate constant of carbon dioxide (Kel), 0.088 min(-1) (44%); and the gain in the carbon dioxide response, 4(28%) (fixed according to literature values). Simulations revealed the pronounced role of PaCO2 in maintaining alveolar ventilation in the presence of opioid. CONCLUSIONS: The model described the data for the entire opioid-PaCo2 response surface examined. Indirect response models appear to be a promising tool for the quantitative evaluation of drug-induced respiratory depression.

[Anesthesia with propanidid in a liposomal preparation. An experimental study in swine]. / Anästhesie mit Propanidid in liposomaler Zubereitung. Eine experimentelle Studie am Schwein.

BACKGROUND: Propanidid was widely used as a short-acting i.v. anaesthetic until it was withdrawn due to severe haemodynamic side effects. It was presumed that anaphylactoid reactions with massive histamine release were caused by the solvent cremophor rather than by propanidid itself. A new liposomal preparation of propanidid was examined in this animal study and compared with propanidid in cremophor solution and with propofol. METHODS: Eighteen pigs were randomly assigned to one of the following groups: Group 1 (n = 6): Propanidid in liposomal preparation (PropaLip; Braun Melsungen, Germany). Anaesthesia was induced with 60 mg/kg, followed by continuous infusion of 400 mg/kg.h. Group 2 (n = 6): Propanidid in cremophor solution (PropaCrem; Sombrevin, Gedeon Richter, Budapest) 15 mg/kg, 100 mg/kg.h. Group 3 (n = 6): Propofol (Disoprivan, Zeneca, Plankstadt, Germany) 5 mg/kg, 20 mg/kg.h. After induction and tracheal intubation, the animals were ventilated with 50% oxygen in air. Basic monitoring included noninvasive blood pressure measurements, electrocardiographic monitoring, and capnography. In a short surgical procedure, arterial and pulmonary artery catheters were placed via the right carotid artery and right internal jugular vein, respectively. As soon as the animals responded to a pain stimulus a second anaesthetic induction was performed, followed by a 60-min continuous infusion of the agent studied with invasive haemodynamic monitoring including arterial and pulmonary arterial pressures and cardiac output. Blood samples were taken for the measurement of serum levels of adrenaline, noradrenaline, cortisol, aldosterone, adrenocorticotropic hormone, and histamine. RESULTS: Intubation conditions and quality of anaesthesia were best in propofol animals, followed by PropaCrem animals. In spite of the large dose of 410 mg/kg.h, resulting in a volume load of as much as 16.4 ml/kg.h, the PropaLip animals showed evidence of poor anaesthetic quality. In group 1 we recorded the highest increases in heart rate (91 vs. 115/min), cardiac output (5.4 vs. 7.7 l/min), plasma catecholamine levels, and histamine concentrations (124-268 ng/ml). CONCLUSIONS: In our animal study, propanidid in liposomal preparation failed to show promise as a new anaesthetic agent. Our results are discussed in view of a drug targeting the cells of the reticuloendothelial system, especially the liver, where liposomes are eliminated from the blood. This may result in the transport of propanidid to one of its major places of inactivation.

Opiate modulation of the stress-induced increase of vasoactive intestinal peptide (VIP) in plasma.

Vasoactive intestinal peptide (VIP) has a variety of extra-intestinal actions which are typical of the body's reaction to stress, such as lipolysis, glycogenolysis and modulation of anterior pituitary hormone secretion. Serial VIP plasma concentrations in patients undergoing major laparotomies were determined. The influence of the mu-receptor agonist, fentanyl, on intra-operative changes was investigated and compared to a control group receiving halothane anesthesia. Plasma levels of typical "stress hormones" cortisol and catecholamines were also monitored for additional information on the extent of perioperative stress. VIP levels increased intraoperatively in the halothane group from 5.9 +/- 4.6 to 15.3 +/- 5.3 pmol/l. Cortisol and catecholamine levels showed a similar increase. The intraoperative VIP increase in the fentanyl group was significantly smaller: 3.5 +/- 1.9 to 7.3 +/- 3.6 pmol/l. Anesthesia itself did not affect VIP concentrations as shown by constant levels during a 30 minute preoperative control period. The observed increases of VIP plasma concentration are thought to reflect a possible role for VIP in the hormonal metabolic response to stress. The attenuation of the increase by fentanyl might be due to a direct opiate action on VIP release.

[Rewarming from moderate to deep hypothermia: plasma catecholamine content, metabolism and circulatory function. 2 case reports]. / Wiedererwärmung bei mittlerer bis tiefer Hypothermie: Plasma-Katecholamin-Verhalten, Metabolismus und Kreislauffunktion. 2 Fallberichte.

Two patients were rewarmed from hypothermia (esophageal temperature 27.2 degrees C, 27.5 degrees C respectively). The first case suffered from head-injury after alcohol ingestion and was deeply comatose. A metabolic or cardiovascular regulatory response to cold was not observed in this patient. The relationship between esophageal temperature and whole-body-oxygen consumption was quantified with a Q10 of 2.75 during rewarming (27.2-37.2 degrees C). His epinephrine levels were greatly elevated to 1,000 pg/ml whereas norepinephrine levels were only moderately increased to 250 pg/ml. Premature ventricular contractions (PVCs) during intubation or from the pulmonary artery catheter were not observed. The second patient was a 87 year old man with accidental hypothermia. He exhibited shivering at an esophageal temperature of 27.5 degrees C which indicated persistent thermoregulation. In contrast to the first case his norepinephrine levels were elevated to 1,500 pg/ml and his epinephrine levels only to 450 pg/ml. After onset of surface rewarming an additional increase in norepinephrine levels was observed and an increasing rate of PVC's (15/min) recorded, which ceased when temperature returned to normal. Our observations indicate that part of the cardiac complications during rewarming from deep hypothermia may result from thermoregulation and additional catecholamine liberation.

[The effects of midazolam on the general, coronary and cerebral circulation (author's transl)]. / Midazolam: Wirkung auf allgemeine, coronare und cerebrale Hämodynamik.

The effects of midazolam (0.3 mg/kg body weight) on cardiovascular haemodynamics, coronary blood flow and cerebral blood flow were studied in fentanyl/halothane anaesthetized and artifically ventilated dogs. There was only a slight decrease in mean aortic pressure and dp/dtmax. Heart rate, cardiac output, coronary bood flow and myocardial oxygen consumption essentially remained unchanged. Cerebral blood flow and cerebral oxygen consumption did not change significantly. Cerebral perfusion pressure slightly decreased due to a reduction in mean aortic pressure. Our results demonstrate that midazolam in induction doses exerts only minimal efffects on the general, coronary and cerebral circulation. Midazolam might be of benefit in clinical practice due to its rapid onset, short duration of action, minimal cardiovascular side effects and water solubility. However, these results from experimental animals have to be confirmed in man.