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Objective: To evaluate the effect of the non-steroidal anti-inflammtory drug carprofen on the lumbar cerebrospinal fluid (CSF) concentration of noradrenaline (NA) and serotonin (5-HT) in non-stimulated (Part I) and surgically stimulated (Part II) sheep., Methods: In a prospective controlled study the effects of a single intravenous (i. v.) bolus injection of 4 mg/kg carprofen (CARP; n = 14), 0.01 mg/kg fentanyl (FENT; n = 12) or 0.9 % saline solution (NaCl; n = 13) on lumbar CSF concentrations of NA and 5-HT were evaluated in non-stimulated sheep. In addition, CSF concentrations were evaluated in isoflurane-anaesthetised sheep at different time points T1 (30 min after i. v. treatment with 4 mg/kg carprofen [n = 8] or saline [n = 7], T2 (20 min of constant end-tidal isoflurane concentration of 2.4 %) and T3 (during stifle arthroscopy at 2.4 % end-tidal isoflurane)., Results: CSF concentrations of NA (NaCl: 170.23 +/- 16.86 pg/ml [x +/- SEM], CARP: 200.79 +/- 28.94 pg/ml, FENT: 209.58 +/- 27.67 pg/ml; p = 0.524) and 5-HT (NaCl: 2752.46 +/- 413.87 pg/ml, FENT: 2969.08 +/- 684.05 pg/ml, CARP: 3232.93 +/- 713.93 pg/ml; p = 0.978) were not significantly different between the three treatment groups of non-stimulated sheep. In the anaesthetised sheep, mean CSF-5-HT at T3 (NaCl: 6670.25 +/- 313.63 pg/ml; CARP: 4080.80 +/- 539.59 pg/ml) was significantly increased compared to T1 (NaCl: 2818.4 +/- 1104.54 pg/ml, p < 0.001; CARP: 2926.13 +/- 818.66 pg/ml, p = 0.022) and T2 (NaCl: 2593.67 +/- 618.89 pg/ml, p = 0.002; CARP: 2724.13 +/- 395.39 pg/ml, p = 0.012) in both treatment groups. Moreover, mean CSF-5-HT at T3 in the saline group was significantly higher (p = 0.006) compared to the CARP-group. Unlike changes in CSF-5-HT, no significant changes in mean CSF-NA were recorded neither within nor between the two treatment groups., Conclusion: During arthroscopy in isoflurane-anaesthetised sheep, surgical stimuli may significantly increase mean CSF-5-HT concentration. This effect can be attenuated by pre-treatment with 4 mg/kg carprofen intravenously. Therefore, the analgesic effects of carprofen may be at least in part mediated by central serotonergic mechanisms.

Objective: Monocytes play a crucial role in the immune response by recognition, ingestion, and intracellular killing of microorganisms. We investigated whether morphine and fentanyl influence CD 11b and CD35 surface receptor expression, phagocytic activity and superoxide anion generation of monocytes in a whole blood flow cytometric assay., Methods: Whole blood of 13 healthy volunteers was incubated with different morphine and fentanyl concentrations. Expression of surface receptors CD 11b and CD35 was determined by fluorochrome-labelled antibodies. Phagocytic activity was assessed by ingestion of fluorescent bacteria. Conversion of dihydrorhodamin served for oxidative burst measurements., Results: Morphine inhibited monocyte function in a concentration and time dependent manner. Morphine-induced changes were abolished by preincubation with the NO synthase inhibitor N-nitro-l-arginine as well as naloxone. Fentanyl failed to inhibit receptor expression, phagocytosis and reactive oxygen production by monocytes in clinically relevant as well as supraclinical concentrations., Conclusion: Our results suggest that these monocyte functions are inhibited by a morphine-stimulated NO release mediated by a mu opiate receptor subtype expressed on the surface of monocytes. In contrast, fentanyl did not share morphine's inhibitory effects on monocyte activity.

The artificially ventilated guinea pig was frequently used for neurophysiological and respiratory studies. This species is also preferable for an evaluation of hemoglobin based artificial oxygen carriers, because its oxygen hemoglobin binding is very similar to that of man. But the narcosis of this animal-species is very difficult, because of cardiorespiratory depression induced by conventional procedures. The following intraperitoneal administered neuroleptanesthesia was proved in guinea pigs: 0.2 mg Fentanyl (Janssen/D), 10 mg Droperidol (Janssen/D) and 400 mg Urethan in 10 ml isotonic sodium chloride solution per kg body weight. Our new animal model with a special valve system enables to assess the gas exchange under spontaneous breathing, cardiovascular and the acid-base parameters. The vital parameters of animals were stable over 6 hours and very close to those of awake animals, especially the arterial average blood pressure. For that reason, this established neuroleptanesthesia of guinea pigs is preferable for research purpose. The fasted animals show significantly decreased values of arterial blood pH (7,345 vs. 7401), of heart frequency (244 vs. 277 min(-1)), and of ventilation value (167 vs. 205 ml/min) compared to non-fasted animals.

Purpose: The present study investigates the effects of S-(+)-ketamine on cerebral blood flow (CBF) autoregulation in rats., Methods: Following IRB approval, 24 nonfasted male Sprague-Dawley rats were anesthetised with isoflurane, intubated and mechanically ventilated. Catheters were inserted into the right femoral artery, both femoral veins, and into the right jugular vein for drug administration, measurement of mean arterial blood pressure (MAP), and blood sampling. Cortical cerebral blood flow was measured using laser-Doppler-flowmetry (PF 403, Perimed). At the end of surgery isoflurane was discontinued and all animals were randomly assigned to one of the following anaesthetic treatments. In group 1 (n = 8, control), anaesthesia was maintained using fentanyl (10 micrograms/kg i.v. bolus, followed by 25 micrograms/kg/h i.v.) and N2O/O2 (FiO2: 0.3). In group 2 (n = 8) and group 3 (n = 8) animals received 0.5 mg/kg/min S-(+)-ketamine i.v. or 1.0 mg/kg/min S-(+)-ketamine i.v. and O2/air (FiO2: 0.3), respectively. CBF was tested by graded haemorrhage. Arterial blood gases, arterial pH, and pericranial temperature were controlled over time., Results: CBF autoregulation was maintained under low and high doses of S-(+)-ketamine compared to fentanyl/N2O-anaesthetised controls. However, low-dose S-(+)-ketamine shifted the autoregulatory curve towards higher MAP values., Conclusions: The present study indicates that autoregulatory cerebrovascular dilation is preserved with low and high doses of S-(+)-ketamine. Differences in the lower limit of CBF autoregulation may be consistent with an increased sympathetic tone induced by low doses of S-(+)-ketamine.

Both fentanyl and clonidine lead to a reduction of vigilance. We tested the influence of clonidine on a fentanyl induced change of vigilance using a cross-out concentration test (b-cross-out test). With local ethics committee approval, we conducted a randomised double-blinded cross-over study with 10 healthy male subjects (25-35 years old). Each volunteer received intravenously at two separate sessions 1.5 micrograms/kg fentanyl and 1.5 micrograms/kg fentanyl plus 3 micrograms/kg clonidine. For testing the level of vigilance a concentration test (b-cross-out) was used. The number of correctly revised marks was evaluated prior to drug administration (TI), directly after application, one hour later and two hours later. Our data underwent a multiple analysis of variance. With fentanyl two hours after application the mean increase of correctly revised marks was 12% when compared to those prior to application (p < 0.024). This means that with fentanyl a learning effect was achieved as described in the literature. With fentanyl and clonidine two hours after application, a decrease in vigilance of 7 1/4 in comparison with TI was seen (n.s.). This reduction of vigilance should be considered during the postoperative course and especially with regard to ambulant anaesthesia when using clonidine.

The main focus of this paper is to show regulative interactions between cardiac index (CI) and renal blood flow (RBF) with various intravenous anaesthetics under steady state conditions. Several experimental series were carried out on dogs with the following anaesthetic doses (as given per hour and per kilogram body weight-h-1 x kg-1): fentanyl 50 micrograms, ketamine 4 and 10 mg, and thiopentone 10 and 20 mg. The basic anaesthesia used was halothane (0.7 vol.%) in N2O/O2 (ratio about 3:1), because renal function, renal autoregulation and responsiveness to renally effective drugs remain nearly unaltered by this anaesthetic procedure. The experimental set-up allowed separate evaluation of effects caused by basic anaesthesia, by intravenous anaesthetic under examination or by the combination of both. All physiological parameters, such as blood gas parameters, plasma electrolytes and intravasal volume were kept in normal range throughout the experiments. Under all anaesthetics studied, RBF reflects the situation of general metabolism especially of cardiac output, as long as sympathetic innervation of the kidneys remains unaltered. Especially the relationship between RBF and CI corresponds with regulative effects in situations without anaesthesia. Within the blood pressure range of autoregulation RBF is greater under ketamine than normal and smaller under fentanyl and etomidate, whereas all other anaesthetics applied show no effect on RBF. Functional "denervation" of the kidney by means of epidural anaesthesia is capable of terminating those effects caused centrally by opioids and transmitted by sympathetic nerves. Diuresis is increased by thiopentone and by ketamine, whereas fentanyl reduces it. The activity of the plasma renin level does not correspond with the degree of renal vascular resistance. The effect of each anaesthetic drug on RBF has principally to be taken as regulative adaptation to altered circulatory conditions. Increasing plasma renin levels are mainly a compensatory reaction following a decline in arterial blood pressure due to anaesthesia induced sympathicolysis. With regard to renal function, the additional use of epidural anaesthesia (functional "denervation" of the kidney) can be recommended especially for highly invasive surgical procedures to antagonize reduction of RBF, which is often induced sympathetically by pain or by commonly used anaesthetic drugs.

The effects of the opioids alfentanil (A), fentanyl (F), and sufentanil (S) on cerebral blood flow (CBF) and intracranial pressure (ICP) have been discussed in several recent publications. The purpose of this review is to describe the results of studies in animals, healthy volunteers, and patients with and without intracranial diseases. Clinical relevance and mechanisms of the reported ICP and CBF increases are analysed. METHODS. Approximately 70 original articles and abstracts were retrieved by a systematic literature search using the key word list at the end of this abstract. The cited studies came from computerised database systems like Silver Platter and DIMDI, the SNACC reference list, and the bibliographies of pertinent articles and books. These studies were classified into three groups: significant increase of ICP and/or CBF; no significant or clinically relevant alterations; and significant decreases of ICP and/or CBF. RESULTS. The numerical relationship was 6:7:3 for A, 7:16:9 for F, and 5:11:8 for S. Increases of previously normal or only slightly elevated ICP were registered in some studies in connection with a decrease in mean arterial pressure (MAP). On the other hand, in patients with brain injury and elevated ICP opioids did not further increase ICP despite MAP decreases. In studies monitoring ICP and/or CBF continuously, transient and moderate increases of questionable clinical relevance became apparent a few minutes after bolus injection of opioids. Alterations of systemic and cerebral haemodynamics observed after bolus application were not registered during continuous infusion of A and S. DISCUSSION AND CONCLUSIONS. The cerebral effects of opioids are dependent on several factors, e.g., age, species, ventilation, anaesthesia before and during measurements, systemic haemodynamics, and underlying diseases. The probable mechanism of ICP increase during decreasing MAP is cerebral vasodilatation due to maintained autoregulation. With increasing severity of the cerebral lesion autoregulation is often disturbed. Therefore, ICP often remains unaltered despite MAP decreases. However, the resulting decrease in cerebral perfusion pressure makes such patients more susceptible to develop ischaemic neurological deficits. Induction of somatic rigidity or (with high doses) convulsions, exceeding the upper limit of autoregulation, histamine release, cerebral vasodilatation, increased cerebral oxygen consumption, or carbon dioxide accumulation during spontaneous breathing were discussed as mechanisms for transient ICP/CBF increases. It is concluded that opioids are often beneficial and not generally contraindicated for patients with cerebral diseases and compromised intracranial compliance. However, since negative side effects cannot be excluded, opioid effects and side effects should be monitored (MAP, ICP, cerebrovenous oxygen saturation, transcranial Doppler sonography) in patients at risk. It has to be stressed that opioids should be administered only to patients with stable haemodynamic situations and preferably in well-titrated, continuous infusions.

The introduction of the new opioid, sufentanil, into clinical practice should focus on the following questions: (1) What are the pharmacokinetic features of sufentanil that make it different from the well-established congeners alfentanil and fentanyl and open the way to new perspectives? and (2) Does sufentanil offer any particular advantages for specialised surgical procedures that make it the drug of first choice? Pharmacokinetics. Sufentanil is a potent analgesic with a very high receptor affinity and specificity, high lipid solubility, marked protein binding, and a shorter elimination half-life than fentanyl. Due to the high hepatic extraction ratio, metabolic degradation and elimination depend more on hepatic perfusion than on enzyme activity or renal clearance. However, changes in plasma protein concentration, volume of distribution, protein binding, or acid-base status may significantly alter the pharmacokinetic profile and prolong clinical effects. Pharmacodynamics. Several clinical trials have focused on the haemodynamic response to surgical manipulation, stress protection, induction time, and recovery time: 1. Induction of anaesthesia with low, medium, or high doses of sufentanil generally provide a stable haemodynamic profile comparable to that of fentanyl following intubation and surgical manipulation, even in cardiovascular risk patients. 2. Severe decreases in systolic blood pressure and bradycardia may occur in the dehydrated patient or in combination with vecuronium, however. 3. Despite some evidence of endocrinologic and metabolic stress protection in cardiac surgery in particular, an increase of hormonal stress parameters can only be ascertained prior to extracorporeal circulation. However, the clinical value of endocrinologic stress protection in terms of mortality and outcome has yet to be verified. 4. Induction time is significantly shorter with sufentanil compared to fentanyl, indicating a central sedative effect. 5. Despite experimental evidence of cerebral vasodilatation and increased intracranial pressure, there seems to be no disruption of cerebrovascular autoregulation in patients with normal intracerebral pressure. 6. Common side effects such as nausea, vomiting, and truncal rigidity occur in up to 30% of patients and are comparable to those after other opioids. 7. In the postoperative period the advantage of an intermediate elimination half-life seems to be out-weighed by the effects of volatile anaesthetics or sedatives on respiratory depression and postoperative recovery following balanced anaesthesia. 8. Epidural application of 10-50 micrograms sufentanil provides rapid and effective pain relief within 5-7 min for a period of 3-7 h. Doses of more than 50 micrograms seem to increase the risk of respiratory depression without further improvement of analgesia. Analgesia may be enhanced by combination with local anaesthetics or clonidine.(ABSTRACT TRUNCATED AT 400 WORDS)

Whereas the efficacy of flumazenil (Fl) for improving vigilance in the presence of other benzodiazepine agonists (BZA) is undoubted, its effect on BZA- and/or opioid agonists (OA)-induced respiratory depression is the subject of controversies. Some authors describe an improvement of a midazolam (Mi)-induced increase in paCO2, whereas others cannot find any influence on diazepam-induced respiratory depression. In two studies in which Fl was used to antagonize Mi/Fentanyl (Fe) anaesthesia we found even worse oxygen saturation values than with placebo (Pl). All our previous studies indicate a slight intrinsic activity of Fl on respiration in the presence of opioids. We therefore investigated the influence of Fl and Pl on expiratory pCO2 and oxygen saturation (SAT). METHODS. A group of 15 male, healthy volunteers aged 20-30 years gave written informed consent to participate in this double blind study, which was approved by our Institutional Review Board. Each subject received 3 micrograms/kg body wt. Fe + 0.5 mg Fl and 1 week later 3 micrograms/kg body wt. Fe + 5 ml NaCl 0.9% (Pl) i.v., in random order. They were undisturbed and breathed spontaneously. The following parameters were measured: SAT, pCO2 and heart rate (HR) continuously, using a pulse oximeter (SAT, H) and CO2 infrared absorption monitor (Oscar, Messrs., Datex). The blood pressure was recorded before and after a 5-min preinjection period (baseline) and at the end of the procedure (25 min). The data were stored in a microcomputer (Multitalent, Messrs. ZAK) and transmitted to a PC after each trial. STATISTICS. The groups were compared with the Wilcoxon rank sum test. P less than 0.05 is significant. RESULTS. In trials 1 and 2 there was an increase of pCO2 and a drop in SAT. The changes in pCO2 and SAT were more pronounced after Fe+Fl in 12 subjects (80%), as against 1 subject with the opposite result. There were 2 subjects who showed no difference between trials 1 and 2. The combination of Fe and Fl caused significantly higher increases in pCO2 (P = 0.007) and more pronounced decreases in SAT (P = 0.04) than Fe and Pl. DISCUSSION. These results indicate a slight enhancement of Fe-induced respiratory depression by Fl. In a previous study it could be shown that Fl antagonized the respiratory depressive effect of Mi, but baseline paCO2 was not completely recovered. In previous studies respiratory function impaired by Mi+Fe was initially improved by Fl, but rebound effects on SAT were observed, which were more pronounced than those after Pl. Therefore, respiratory function must be closely monitored in Fl-antagonized patients after Mi/Fe anaesthesia.

The intracranial hemodynamic and metabolic effects of 20 micrograms/kg sufentanil were studied in ten mongrel dogs. Anesthesia was maintained with 0.7 vol.% end-tidal isoflurane and 50% nitrous oxide in oxygen. Catheters were inserted into both femoral arteries and veins, the superior sagittal sinus, the left atrium, and the lateral cerebral ventricle for blood pressure measurement, arterial and sagittal sinus blood sampling, radioactive microsphere injections, and intracranial pressure (ICP) monitoring. Cardiac output (CO) was measured using an electromagnetic flow probe on the pulmonary artery. Following baseline measurements, sufentanil was injected and data were recorded at 5, 15, and 30 min. RESULTS. In group 1 (n = 5) blood pressure was not controlled, while in group 2 (n = 5) blood pressure was maintained at baseline level with a phenylephrine infusion. Arterial blood pressure decreased by 32% in response to sufentanil in group 1 and remained constant in group 2 according to the protocol. CO decreased by 40%-50% in both groups. Regional and global cerebral blood flow (CBF) decreased by 25%-40% with no difference between groups. The cerebral hemodynamic changes were associated with a decrease of 35%-40% in cerebral oxygen consumption. ICP did not change over time. DISCUSSION. These data are in contrast to studies in dogs, where sufentanil produced non-dose-dependent increases in CBF and ICP. Our results are more consistent with studies in humans and rats where administration of sufentanil was associated with either no change or decreases in cerebral hemodynamics, metabolism, and ICP. We conclude that in dogs with normal intracranial physiology sufentanil decreases regional and global CBF in response to a decrease in cerebral metabolic demand without significantly affecting ICP.

Use of the benzodiazepine antagonist flumazenil may inhibit the effects of benzodiazepines in a competitive manner. The only known partially agonistic effect of flumazenil is a weak anticonvulsive action at high doses. However, reports have claimed that flumazenil reduces the MAC of isoflurane in animal studies. Other reports have found that antagonizing midazolam-induced sedation or anesthesia by flumazenil led to an increase in respiratory depression. The aim of this study was to examine whether flumazenil i.v. increases fentanyl-induced respiratory depression. METHODS. In two separate sessions, ten healthy young volunteers were given either 0.0027 mg/kg fentanyl alone or 0.0027 mg/kg and 1 mg flumazenil i.v. over 4 min each time. The CO2 rebreathing method was used to determine the ventilatory response. RESULTS. Fentanyl alone brought about a significant reduction in CO2 response, characterized by a shift to the right and a decrease in the slope of the rebreathing curve (from 1.95 +/- 0.76 l.min-1.mmHg-1 to 0.86 +/- 0.53 l.min-1.mmHg-1). The infusion of additional flumazenil caused similarly significant respiratory depression (from 2.21 +/- 1.0 l.min-1.mmHg-1 to 0.77 +/- 0.38 l.min-1.mmHg-1). In both groups changes persisted for at least 120 min. No statistically significant differences between the two groups could be detected. CONCLUSION. Flumazenil does not enhance fentanyl-induced respiratory depression. Flumazenil's weak, partially agonistic action is therefore of no clinical importance.

Numerous reports have concluded that propofol is suitable for maintenance of anesthesia by continuous infusion. The aim of this study was to evaluate the use of propofol and fentanyl for coronary bypass surgery in patients with good left ventricular function. The effects of this anesthetic combination on quality of anesthesia, hemodynamic status, and endocrine and metabolic responses were assessed. Postoperative recovery and side effects were also noted. The effects were compared with those of a standard method using etomidate, midazolam, and fentanyl. METHODS. Twenty patients who presented for aortocoronary bypass surgery (NYHA class II-III) were randomly allocated to one of two groups: propofol-fentanyl (group A) or etomidate-midazolam-fentanyl (group B). In each patient the dosage of the drugs was adjusted to obtain the optimum responses during induction and maintenance. RESULTS. Propofol in combination with fentanyl diminished mean arterial pressure (-28.7%) and heart rate (-17.3%) when used for induction in patients with ischemic heart disease, even in low doses and with slow administration. In 5 of the 10 patients it was impossible to prevent a critical fall in coronary perfusion without active intervention. However, during maintenance anesthesia, stable circulatory parameters were obtained with both drug regimens. Clinical signs thought to reflect myocardial ischemia were not observed. In both groups reductions in basal and stimulated catecholamine secretion were demonstrated. Similarly, perioperative cortisol secretion was reduced with both techniques. Despite all the complicated metabolic inhibitory effects seen, preoperative hormonal levels were restored within 1 h of the end of anesthesia. The magnitude and duration of the metabolic changes were found to be related to the duration of surgery. There was no evidence of non-homogeneous tissue perfusion as assessed by increases in lactate concentration, cardiac ischemia, or liver dysfunction in any of the patients. There were no postoperative complications in either group, but the return of consciousness, adequate spontaneous ventilation, and psychomotor activity was more rapid in the propofol patients. CONCLUSION. In summary, it can be concluded that a propofol infusion technique positively enhances the recovery period after cardiac surgery and provides good control during anesthesia. However, the use of propofolfentanyl for induction of anesthesia in patients with limited coronary perfusion is not recommended because of its hypotensive effect.

Unlabelled: AIM OF THE INVESTIGATION: The effects of fentanyl on spontaneous respiration have been investigated in both animals and humans. The investigations in humans have been performed under circumstances and using methods that do not relate the results to clinical practice, e.g., predicting the effects of opioids used for postoperative pain relief on the ward. We investigated the effects of fentanyl on mechanical parameters, oxygen saturation (SAT), and end-expiratory CO2 (exCO2) in humans., Methods: Fifteen male volunteers took part in this study, which was approved by the local ethics committee. Each received 3 micrograms/kg fentanyl intravenously after 5 min measurement of base-line values and were observed for 30 min. We continuously registered thoracic (A1) and abdominal (A2) extension and respiratory rate (RR) using piezoceramic elements. SAT, heart rate (HR), and exCO2 were measured with a pulse oximeter and infrared absorption (OSCAR, Datex). All data were transferred to a high-performance microcomputer (Multitalent, ZAK). The statistical analysis included descriptive and correlation statistics., Results: After the injection of fentanyl A1, A2, RR, HR, and SAT were reduced; exCO2 increased. After a few minutes A1 increased, occasionally exceeding the base-line value. A2, RR, HR, and SAT increased without reaching base-line values. ExCO2 remained increased. The best overall correlation was found between A2 and SAT (r = 0.87)., Discussion: As far as comparable, our results are in accordance with those of the majority of other investigators. The difference between thoracic and abdominal extension, the latter being closely correlated with tidal volume, has not previously been described quantitatively. We attribute this result to the different innervation of the phrenic and intercostal nerves. Whereas the influence of fentanyl on SAT and exCO2 during the first 8 min can easily be explained, the varying behavior in the following minutes has not previously been described and may be due to the different binding characteristics of O2 and CO2. Alteration of the CNS setting for pCO2 may also contribute to this result. The time course of the measured parameters seems to be of clinical importance for the detection of respiratory problems in spontaneously breathing patients.

Sufentanil, a synthetic opioid that is 5-10 times as potent as fentanyl, has been suggested for use during neurosurgical procedures because it maintains cardiovascular stability and produces hypnosis without the use of additional anesthetic agents. Doses as low as 2.5 micrograms.kg-1 are reported to create deep levels of anesthesia as demonstrated by EEG changes to high-amplitude delta-waves. However, there are no reports concerning the effects of sufentanil on blood flow and metabolism in the human brain. The present study was designed to investigate the influence of high-dose sufentanil-O2 anesthesia on the cerebral circulation, metabolism, and the cerebrovascular response to CO2 in man. METHODS. Nine male and 2 female patients between 41 and 60 years of age who were scheduled for coronary artery bypass surgery were studied. Premedication consisted of flunitrazepam 2 mg orally and piritramide 15 mg and promethazine 50 mg i.m. 1 h before arrival in the induction room. Measurements were performed with the patients awake (I), after sufentanil 10 micrograms.kg-1 as an induction dose followed by 0.15 micrograms.kg-1.min-1 as an infusion with normocapnia (pa CO2 42.1 +/- 2 mmHg) (II), during hypercapnia (pa CO2 53.7 +/- 3.5 mmHg) (III), and during hypocapnia (pa CO2 31.7 +/- 2 mmHg) (IV). Cerebral blood flow (CBF) was measured using the argon wash-in technique. Cerebral venous blood was obtained from a catheter in the superior bulb of the right internal jugular vein. Cerebral metabolic rates of oxygen (CMRO2) glucose (Mgluc) lactate (CMlac) were calculated by multiplying the arterial-cerebral venous oxygen and substrate differences by CBF. The Anaerobic Index was calculated from the equation avD lactate x 100/2 x avD glucose = ANI (%) Cerebral electrical activity was recorded by aperiodic analysis of the EEG (Lifescan). RESULTS AND DISCUSSION. In the EEG sufentanil anesthesia was characterized by a decrease in the number of high-frequency waves and an increase in the number and amplitude of delta-waves, a pattern that did not change throughout the study period. Concomitantly, under normocapnic conditions high-dose sufentanil led to the significant decrease in CBF by 29% accompanied by an 18% increase in cerebral vascular resistance (CVR). CMRO2 decreased by 22% while CMRgluc and CMRlac changed only insignificantly such that the ANI, which represents the percentage of anaerobically metabolized glucose, essentially remained unchanged. Mean perfusion pressure declined by 18% but stayed within the range of autoregulation. Hypoventilation (III) was followed by an 82% increase in CBF as a result of a 55% reduction in CVR, whereas cerebral metabolic parameters did not show important changes when compared to measurement II. Hyperventilation (IV), on the other hand, produced a distinct fall in CBF by 56% to a value that was 21% below the one obtained under normocapnia. This was due to an increase in CVR of the same magnitude. There was a 31% rise in CMRO2, resulting in a decrease in cerebral venous oxygen tension, but in no case did it fall below the critical value of 20 mmHg at which tissue hypoxia becomes severe. Although CMRlac increased and CMRgluc did not significantly change, the ANI remained essentially unchanged, which suggests a predominantly aerobic metabolism. The increase in metabolic activity with sufentanil during hypocapnia might be caused by an alkalosis-induced stimulation of glycolysis. It might also be related to a reduction in the depth of anesthesia, although neither the EEG nor the hemodynamic parameters indicated this. This study shows that the coupling between CBF and metabolism is well maintained and that the cerebrovascular response to CO2 is unimpaired during high-dose sufentanil anesthesia.

A group of 36 patients in the last trimester of pregnancy and scheduled for cesarean section were examined during the induction of standardized general anesthesia (methohexitone 1.5 mg/kg, succinylcholine 1.5 mg/kg). No other inhalation anesthetics than N2O/O2 (50%:50%) were administered. In addition, 18 of the women received 0.005 mg/kg fentanyl prior to intubation. The remaining 18 patients served as a control group. In the study group maternal fentanyl plasma levels were determined 1 min after injection and again at the time of omphalotomy (radioimmunoassay). Immediately after clamping of the umbilical cord the fetal fentanyl plasma levels and the pH, pCO2 and pO2 values in both umbilical vein and artery were measured. The feto-maternal ratio and the fetal uptake were calculated. RESULTS. Maternal fentanyl plasma levels decreased significantly, from 7.84 (3.55-17.24) ng/ml 1 min after injection to 5.92 (2.01-14.15) ng/ml during omphalotomy. The corresponding fentanyl plasma levels in the umbilical vein were 2.08 (0.88-3.42) ng/ml. The feto-maternal ratio was 0.44 (0.08-1.00). The induction-delivery time ranged from 2 to 8 min. There was a significant correlation between umbilical-venous fentanyl concentration and the induction-delivery time: the longer the induction-delivery time the lower the fentanyl concentration in the umbilical vein. The 1-min Apgar score was 8 (5-9), the 5-min Apgar score 9 (8-10) and the 10-min Apgar score 10 (9-10) in neonates born to the fentanyl group. Only the 1-min Apgar score was significantly lower than in the control group.(ABSTRACT TRUNCATED AT 250 WORDS)

In 36 patients with acquired heart disease effects of 0.15 mg/kg piritramide on hemodynamics, inotropic state and myocardial oxygen consumption were investigated during and after cardiac surgery (basic neuroleptanalgesia). It could be demonstrated, that piritramide is not inducing any negative inotropic effects compared to a control group (n = 36) and a fentanyl group (0.003 mg/kg, n = 31). There were only small changes in HR, SV, PRA and PLA. A slight decrease in Part, PLV, and arterial perfusion pressure during extracorporeal circulation is interpreted as a peripheral vasodilatation. The resulting decrease in heart work caused a significant decrease in myocardial oxygen consumption (-18%), which is of special advantage in patients with coronary heart disease.

The hemodynamics and the myocardial oxygen consumption during sleep and induction of anesthesia was studied in 10 patients with good left heart function (group I) and in 8 patients with bad left function (group II). Anesthesia was induced with diazepam (0.1 mg/kg BW), fentanyl (0.01 mg/kg BW), etomidate (0.2 mg/kg BW), and pancuronium (0.1 mg/kg BW). Four min after induction under ventilation with mask the cardiac index (CI) in both groups and the whole body oxygen consumption (VO2) diminished in exact the same degree. After intubation in patients of group I the CI and the VO2 decreased further, the arterio-venous oxygen content difference (avDO2) remained constant. In patients of group II the CI decreased to 0.9 1/min x m2, the avDO2 increased to 9.9 Vol%.

Favorable clinic experiences with an anaesthetic involving rohypnol (flunitrazepam) and fentanyl led to an investigation of the haemodynamic effect of this procedure in a group of 9 geriatric patients, aged from 86 to 95 years. Anaesthesia was induced with 0.5 mg rohypnol and 0.1 to 0.2 mg fentanyl depending on the narcotic effect of rohypnol, intubation was performed under relaxation with suxamethonium and long term relaxation was achieved with pancuronium. The patients were normoventilated with nitrous oxide/oxygen. The individual values of the changes in cardiac output and total peripheral resistance showed a great variation. There was a significant correlation between the relative changes in mean arterial pressure and total peripheral resistance (r = 0.69, p less than 0.05) but no correlation between mean arterial pressure and cardiac output (r = 0.09). This indicates that the pronounced drop in arterial pressure which occurred in 4 patients can be explained by a decrease in total peripheral resistance. Careful dosage of the drugs, in particular of fentanyl, and knowledge of adequate measures to treat a decrease in blood pressure if it occurs, appears to be a prerequisite for the use of this type of anaesthesia in poor risk patients.

This study compared both etomidate and methohexitone for intravenous anaesthesia with alfentanil and nitrous oxide/oxygen in 2 X 20 patients scheduled for ENT-surgery, in a double blind, random fashion. Apart from the alternative use of etomidate and methohexitone the anaesthetic procedure did not differ: After a small dose of alfentanil anaesthesia was induced by a bolus dose of the hypnotic followed by a continuous infusion of the drug. In case of inadequate analgesia alfentanil was injected. This technique provided a good quality of anaesthesia and a remarkable cardiovascular stability. Critical arterial pressures or heart rates never occurred. During the operation patients receiving etomidate exhibited a moderate rise in blood pressure and a significantly lower heart rate than patients anaesthetised with methohexitone. After some 90 min of anaesthesia patients awoke on the average 7 min after the end of the operation and could be extubated at once. During the first three postoperative hours there was no difference in recovery between groups. Whereas half an hour postoperatively the capacity of immediate memory was limited to 44 bit following etomidate and 48 bit following methohexitone, i.e. to 47 and 54% of its normal capacity, there was only a minimum but significant impairment of cerebral function after 3 h. There was no difference in the need for alfentanil. The dosage of etomidate and methohexitone was lowe than that reported in the literature. It proved to be impossible for the anaesthetist to decide which drug he was using. Hence both anaesthetic techniques compare favourably with each other.

Ocular pressure was measured in 60 patients under neuroleptanalgesia with three different modes of induction (N2O, ketamine, thiopentone), during abdominal operations lasting at least one hour. The effect of premedication, of three different induction agents and of decurarisation on intraocular pressure were tested. It became apparent that after premedication and during the induction stage a decline of intraocular pressure (IOP) occured but did not last longer than 60 minutes. Decurarisation had no influence on the IOP. The causes of these changes and discussed.

In the electric field the solid blood components will move to the anode because of their negative surface charge. When influenced by a direct current of constant force and duration a thrombus differing in size will develop depending on the composition of the coagulation system. This regularity could be used for diagnostic purposes. By means of experiments with animals and clinical examinations the development of the "electro-clot" is observed in vitro before and after the administration of heparin. In addition, the behaviour of the thrombus developed in vitro in the electric field is checked in patients affected with obstructive lung diseases. Here a correlation existing between the mass of the thrombus and hematocrit could be proved.

The influence of several anaesthetic methods on the tonus of the sphincter of Oddi was investigated in 45 selected patients undergoing cholecystectomy (halothane; fentanyl; fentanyl-droperidol (DHB); all in combination with N2O:O2 and relaxant). The fentanyl collective showed a significant rise of the common bile duct pressure, while the fentanyl-DHB and the halothane collectives did not show any statistical difference in their parameters. From these results neuroleptanalgesia appears to be a surtable method for biliary surgery.

Equipotent analgesic doses of sulfentanil and fentanyl showed similar effects in 281 cases of clinical neuroleptanalgesia. In rabbits equimolecular doses of sulfentanil induced a deeper narcotic effect (burst suppression) than fentanyl. This supports the thesis of a coincidental increase of analgesic potency and narcotic effect in agonistic opioids. In equipotent doses the conventional EEG and the amplitude-frequency-spectra are equal. Quantificated analyses and statistical calculations show essentially similar changes in animal: - Fentanyl as well as sulfentanil changes only the dominant frequency in the theta-bands. - The percentage value increases only in the sigma-band, doesn't change in the alpha- and beta1-band and decreases in the theta-band, beta2--and beta3-band. - The power of sigma rises by a potency of ten in both substances; the change in the other frequencies shows similar sizes. Fentanyl and sulfentanil do not coure differences in the EEG.

1. Electroencephalographic activity was registered in healthy subjects before, during and 90 minutes after intravenous injections of sufentanil and fentanyl. 2. With a dosage of ratio of 1:10, i.e., 0.025 mg/70 kg body weight sufentanil: 0.25 mg/70 kg body weight fentanyl as well as 0.015 mg/70 kg body weight sufentanil: 0.15 mg/70 kg body weight fentanyl, sufentanil was hypnotically more potent from fentanyl. 3. Sufentanil acts more powerfully on the respiratory regulation than does fentanyl. Periods of apnoea occur more frequently but can be interrupted by external psychophysiological stimulation. 4. The evaluation of indices of certain EEG-waves, characterizing well defined electroencephalographic stages corresponding to the waking-sleeping-behaviour confirmed the visual over-all analysis of the EEG-stages. 5. Physiological observations on heartrate, systemic blood pressure, rapid eye movements during wakefulness, and slow eye movements during sleepiness showed no reliable differences between sufentanil and fentanil. The systematically documented symptoms and vegetative signs of subjects also showed neither differences nor side-effects.

Rat tissue homogenates were used to study fentanyl biotransformation. The liver was shown to be the most important metabolizing organ, whereas extrahepatic metabolism occurred only to a minor degree in the kidneys. The products of oxidative desalkylation, phenylacetic acid and norfentanyl, could be identified as well as small amounts of p-hydroxy-(phenethyl)fentanyl, which is pharmacologically still active. Major sex differences were observed, male rats showing nearly twice as much activity as female animals. Several anaesthetic agents, often used in combination with fentanyl, were tested with respect to their influence on fentanyl metabolism. Most of them caused an inhibition of biotransformation and/or variations in product distribution, when they were added to in-vitro incubations or given to the animals prior to enzyme preparation. This experimental design proved to be useful as a screening method to predict metabolic drug interactions. Halothane and enflurane, which are strong inhibitors in rats, were demonstrated to delay fentanyl metabolism in man, too. Fentanyl plasma levels under halothane anaesthesia were found to be more than twice as high as during neuroleptanaesthesia. The importance of other agents, e.g. ketamine, promethazine or local anaesthetics, remains to be examined. Variations of biotransformation reactions among patients as well as the reported drug interactions might explain some differences in fentanyl blood concentrations reported in the past, but must also be taken into account when intensity and duration of effects or side-effects are discussed.

Changes of EEG and cEEG have been studied in two groups of patients (n=16) premedicated with 2 ml Thalamonal iv. (dosage: 5 mg droperidol; 0.1 mg fentanyl). Study group A consisted of patients, whose age ranged from 20 to 50 years, in study group B the patients' ages were avove 70 years. EEG and cEEG observation time was 15 min in general; in a few cases on hour. Changes in clinical behaviour were registered; blood pressure and pulse-rate measurements were taken at regular intervals. The base line electroencephalogram of twelve patients was unremarkable. Four elder patients of group B showed deviations from normal. Characteristic changes in the electroencephalogram after the tested premedication were: a decent accentuation and a light shifting to lower frequency of alpha-activity; in addition a light increase of delta-frequency. In good correlation to these findings were the clinical effects of sedation and light sleep. Light side effects in behaviour were seen in one patient. The tested disage of Thalamonal i.v. lowered the blood pressure particularly in younger patients.

Studies of blood volume (Evans blue), haematocrit, arterial blood and central venous pressure (CVP) were performed in 37 patients aged 61 to 80 years, 15 h (time I) and 15 min (time II) before, and 20 min after (time III) induction of neuroleptanalgesia (NLA) with fentanyl 0.004 mg and droperidol 0.2 mg per kg body weight. The patients underwent total hip arthroplasty for degenerative joint disease. 11 male and 11 female patients had no other medical disorders ("normal" group). 6 had considerable obesity and 9 had hypertension. The mean blood volume was lower in the female patients in comparison with the male patients and lower in the obese and hypertensive patients in comparison with the "normal" subjects. Between time I and II there was little decrease of blood and plasma volume and increase of haematocrit in the "normal" group. In the hypertensive patients the reverse was true. During this time the mean blood pressure decreased in the hypertensive patients only. CVP remained unchanged in each group. Between time II and III blood pressure and CVP decreased in all groups studied. A haemodilutional effect of NLA expressed by significant decrease of haematocrit and increase of blood and plasma volume was observed in each group. After induction of NLA we found a close correlation of CVP, systolic and diastolic blood pressure with blood volume. These observations firmly suggest that NLA expands vascular capacity. Consequently NLA may lead to a marked fall of blood pressure in hypovolaemic patients. This is important, particularly in hypertensive patients who usually have low blood volumes.

On 10 patients who had to undergo a ca. 4 hour operation of the lower abdominal region, the pattern of catecholamine excretion before, during and after operation was traced. 1. A decrease of systolic blood pressure on average of 80 mm Hg, in correlation to the concentration of Halothane and Thalamonal, was recorded. 2. The excretion of adrenaline and noradrenalin was significantly lower during anaesthesia as compared with the initial value, suggesting a depression of sympathoadrenal system. 3. The postoperative amount of adrenaline and especially noradrenaline increased markedly, when anaesthesia worn off, postoperative shivering started, and surgical wounds caused pain. 4. The excretion of urine during operation was slightly reduced, the renal output showed normal amounts, when calculated up to 24 hours. The results show, that the combined use of halothane an thalamonal because of its depressant effects on the sympathoadrenal system is capable of reducing the liberation of catecholamines during anaesthesia.

The effects of sufentanil (0.7 microgram/kg) and fentanyl (7 microgram/kg) on general and coronary haemodynamics and myocardial metabolism were studied in 6 and 9 patients without cardiovascular disease. Both drugs produced a slight reduction in heart rate, cardiac index and mean aortic pressure, whilst peripheral vascular resistance remained unchanged. There was a decrease in dp/dtmax and a slight increase in LVEDP suggesting minimal depression of myocardial contractility. Myocardial blood flow and myocardial oxygen uptake slightly decreased due to reduction in pressure-, volume- and frequency-load and dp/dtmax. With both drugs arterial concentrations of glucose, lactate, pyruvate and free fatty acids and their myocardial uptake did not change significantly. Clinically equi-anaesthetic doses of sufentanil and fentanyl produced almost identical effects on general and coronary haemodynamics. With regard to the cardiovascular actions sufentanil offers no advantage over fentanyl.

In 70 patients (maxillo-facial-, neurosurgical-, abdominal- and gynaecological operations) the technique of "analgetic anaesthesia" using high doses of fentanyl (0.025 mg/kg body weight) and naloxone as its antagonist (0.02 mg/kg body weight) has been employed. All patients were artificially ventilated with N2O/O2 in a 3:1 ratio. Muscle relaxation was achieved with pancuronium-bromide (0.08 mg/kg). The patients had no apparent heart or lung disease. The youngest patient was 4 years of age, the oldest 82 years of age (average age 48.9). The necessity for a reinjection of fentanyl (half the initial dose) was determined by continously monitoring heart rate. This variable appeared to be the most subtle index indicating a reduction in analgesia. Sufficient analgesia was maintained once the heart rate stayed 20% below preanaesthetic levels. At the end of the operation naloxone reversed the respiratory depression. There was no evidence indicating postoperative pain, which may have required administration of additional analgesics. If deep analgesia was maintained up to the last surgical procedures no emesis appeared in the post operative period. The incidence of emesis was higher 10% compared to the classical neuroleptanalgesia with droperidol this was often noted in cases where blood accumulated in the stomach (maxillo-facial operations) (70%). In 3% of all cases psychomotor agitation with delirium appeared right after the injection of naloxone. This lasted for about 15 minutes. We suspect that due to the sudden and powerful effect of naxolone, in replacing fentanyl from its receptor site, acute withdrawal symptoms may be precipitated.

A lack of uniform methodology used in the assessment of moderate doses of sufentanil in combination with non-depolarizing neuromuscular blocking drugs formed the basis of the current study which compared under randomized conditions the effects of sufentanil-pancuronium versus sufentanil-vecuronium on hemodynamics, intubating conditions and chest wall rigidity during induction of anesthesia. MATERIAL and METHODS. One hundred and twenty ASA physical status I and II patients aged between 20 and 40 years of age who were undergoing elective urological surgery were included in the study. Premedication consisted of 0.15 mg kg-1 diazepam, given orally 60 min prior to induction of anesthesia. Patients were randomly divided into eight groups of 15 each to receive 0.5 microgram kg-1 sufentanil or placebo in combination with pancuronium (groups I-IV) or vecuronium (groups V-VIII) Within each group, patients were randomly allocated to receive the relaxant either as a single bolus dose of 0.095 mg kg-1 pancuronium or 0.1 mg kg-1 vecuronium, or in divided doses (the priming principle), the smaller priming dose (0.015 mg kg-1 pancuronium or 0.015 mg kg-1 vecuronium) being administered 2 min before induction of anesthesia with 5 mg kg-1 thiopentone, followed by the second intubating dose of 0.080 mg kg-1 pancuronium or 0.085 mg kg-1 vecuronium. To maintain blind study conditions in the groups, the patients given the relaxants in one dose were given an equivalent volume of saline 2 min prior before 5 mg kg-1 thiopentone. Intubating was attempted 60 s after administration of the main dose of the relaxant, and conditions were assessed on a four-point scale: excellent, satisfactory, fair, or poor. Neuromuscular transmission was monitored with the Datex Relaxograph, a neuromuscular transmission analyzer, that utilizes the integration of the EMG response. Producing train-of-four (TOF) stimuli, with a pulse width of 100 microseconds and a frequency of 2 Hz every 20 s the following parameters were recorded by the Datex Relaxograph: The percentage of first twitch amplitude compared with the reference (T1), and the train-of-four (TOF) ratio, i.e., the ratio of last twitch height to first height. Measurements were taken after premedication in the operating room, the value which served as a baseline (t0), 1 min after sufentanil or placebo (t1), 1 min after priming or placebo (t2), 1 min after thiopentone (t3), and 1 min after intubation (t4).(ABSTRACT TRUNCATED AT 400 WORDS)

Changes of plasma amino acids in animal studies were observed after administration of different narcotic drugs. In a randomised study the effects of neuroleptic anaesthesia and general anaesthesia with halothane on free plasma amino acids in respect to liver toxicity were investigated in patients during microsurgery of the middle ear. 24 hours postoperatively in both groups a significant increase of branched chain amino acids and of phenylalanine as metabolic sign of stress was found. Typical changes of amino acids as shown in hepatic failure could not be seen in both groups. The study showed that none of the narcotics used had a toxic effect on liver function as measured by the levels of free plasma amino acids and that for disagrees with the results of animal studies.

The effects of a combination of etomidate (1.0 mg/kg bw) and fetanyl (0.005 mg/kh bw) on haematology, blood gases, acid-base balance and haemodynamics were investigated in 8 mongrel dogs. The only significant change in haematology was leucopenia. Blood gas values and acid-base balance initially showed a depression of respiration and a tendency to slight metabolic acid dosis. Decreased heart rate caused diminution of cardiac output, while systemic and pulmonary resistance as well as stroke volume were not altered significantly.

The influence of clinically relevant concentrations of fentanyl, alfentanil, morphine, pethidine, and buprenorphine on polymorphonuclear neutrophilic granulocyte (PMN) adherence was investigated in vitro by using nylon fibre columns. Since none of the drugs produced any significant (p less than 0.05) change of adherence, no evidence of opioid mediated increased risk of postoperative bacterial infection could be found.

105 patients were given diazepam-fentanyl anaesthesia and the respiratory values were studied spirometrically before the operation, after intramuscular premedication and postoperatively (i.e. after additional doses of diazepam during induction). The occurrence of respiratory depression which has been reported by some authors was confirmed. Blood gas analyses performed in 79 patients during the recovery period showed a significant improvement after the patients had been made to breathe deeply for five minutes. The results confirm the observations made in more than 12000 patients who had this type of anaesthesia that they must be kept under surveillance during the first 30-40 minutes in the recovery ward, but can then be returned to the ward.

Reflex changes in the heart frequency, blood pressure and respiratory frequency induced by slow changes of the blood volume are observed in the aesthetized European hamster (Cricetus cricetus L.). Tachycardia, hypertension and hyperpnoe occured during intravenous infusion and bradycardia, hypotension and respiratory inhibition during hemorrhages or local distensions of the junction between the superior vena cava and the right atrium. Various receptor organs of the heart and the great vessels and sympathetic as well as parasympathetic effector mechanisms were involved in the reflex effects. An activation of efferent vagal fibers decreased blood pressure and heart frequency; an excitation of efferent sympathetic fibers increased blood pressure and heart frequency.

In 8 volume expanded dogs with an equilibrium between input and renal output of sodium and water neuroleptanalgesia of 6 hours duration with a total of 9 mg/kg of droperidol and 0.35 mg/kg of fentanyl was performed. Under anaesthesia GFR was increased by about 10% (p less than 0,02) compared with the conscious state, whilst renal sodium and water excretion was reduced by about 50%. From this we conclude that active tubular transport of sodium is augmented under neuroleptanalgesia. Due to decreased excretion, retention of sodium and water increased during anaesthesia changes of functional ECFV tending into the same direction. Plasma volume and intravascular protein did not change under neuroleptanalgesia compared with the conscious state. Urine osmolality and negative free water clearance (TcH2O) increased by about 60% under droperidol and fentanyl. In volume expanded dogs under neuroleptanalgesia intravenous application of 0.5-1.0 mg of atropine resulted in a temporary water diuresis.

The acute effect of Fentanyl and Althesin upon haemodynamics, inotropism of the heart and myocardial oxygen consumption has not been studied in man so far. Healthy premedicated pateints (n = 16) were lightly anaesthetized with nitrous oxide-oxygen (ratio 2:1), 0.3 Vol.-% forane and 0.3 Vol.-% halothane respectively. In order to avoid any interference with respiratory depression all subjects were normoventilated via an orotracheal tube. In a circulatory steady state a single dose of 0.01 mg/kg Fentanyl (n = 7) and 0.075 mg/kg Althesin (n = 9) respectively was injected intravenously within 20 sec. After the application of Fentanyl there was a delayed (5th min) fall in blood pressure by 23%, which was due to a reduction in total peripheral resistance (12%) and in cardiac output (thermodilution technique) by 13%. The decrease in cardiac output was the result of a bradycardia (18%). Considering heart rate, pre- and afterload simultaneously, the fall in max dp/dt (catheter-tip manometer) by 20% could not be explained as a decrease in myocardial contractility. The altered haemodynamics led to a decrease of the myocardial oxygen consumption (control 6.4 ml O2/min x 100 g) by 31%. The energy demand of the heart was quantitatively calculated using the formula of the complex haemodynamic parameter developed by Bretschneider. Immediately after the administration of Althesin the cardiac output rose on account of tachycardia slightly, while stroke volume (19%), total peripheral resistance (32%) and mean arterial pressure (24%) reacted reversely. Since heart rate increased (11%), preload remainded unchanged and afterload decreased, the fall in dp/dt max (20%) has to be understood as a moderate reduction in myocardial inotropism. The energy demand of the heart decreased only initially by 15%. The clinical implications of the results were discussed.

Although morphine is one of the oldest drugs known to man, it has only recently been used in large doses as an anesthetic agent. The main advantage is the cardiovascular stability. The purpose of this investigation was to study the circulatory response to high equianalgesic doses of morphine and meperidine. In 10 closed chest dogs during normoventilation and light background-anaesthesia (0.5 Vol. % halthane; N2O:O2 = 2:1) 2.0 mg/kg morphine and 15.0 mg/kg meperidine were given at random. Morphine produced a decrease in mean arterial blood pressure by 28%, which was paralleled by an identical fall in total peripheral resistance. No negative inotropic effects were found. In contrast to this, the severe hypotension developing with meperidine (decrease in blood pressure by 54%) was the result of peripheral vasodilatation (46%) and of myocardial depression indicated by a sharp drop in dp/dtmax (59%), dp/dtmax/IP (14%) and in left ventricular ejection fraction (33%). Utilizing the thermodilution technique, the cardiac output remained largely unaffected with both narcotic analgesics, as the increase in heart rate (morphine 27%; meperidine 101%) compensated for the fall in stroke volume (morphine 19%; meperidine 55%). In spite of the altered haemodynamics there was no change in the myocardial energy demand, which was adequately met by the coronary blood flow measured with the pressure-difference technique. Both, morphine and meperidine, produced initially an increase in coronary blood flow and coronary venous oxygen saturation indicating coronary vasodilation. While the mechanism for the change in cardiovascular status with high doses of morphine is vasodilatation probably due to histamine release, the results of this study suggest a peripheral as well as a central (myocardial depression) site of action with meperidine. The results obtained from this study were compared with the data from a previous investigation on equianalgesic doses of fentanyl and piritramide and their clinical implications were discussed.

This study was designed to differentiate possible amnesic effects of diazepam, flunitrazepam and fentanyl into impairment of storage, retention or retrieval of information and to correlate them with alterations in a vigilance task. 4 groups of 7 volunteers each were studied in a double-blind, random fashion. They performed a quasi continuous word recognition task i.e. after a preload list of 150 words played on a tape they had to indicate if the following words (grouped into 10 blocks of 100 words each) were new ones or had occurred already. Interposed were measurements of reaction time to a visual stimulus, and of concentration and short-time memory. During the experiment, unknown to the test person, diazepam 10 mg/70 kg, flunitrazepam 1 mg/70 kg, fentanyl 0.15 mg/70 kg or placebo were infused over 3 min. For evaluation of the word recognition task the d' index drawn from signal detection theory was employed. The results clearly indicated that both benzodiazepines specifically impair memory function the effect of flunitrazepam being more pronounced and longer in duration. Since retrieval of information learnt before administration of either drug was completely unaffected it was concluded that both drugs specifically influence encoding and registration of information. Reaction times were not significantly altered after diazepam, whereas they were prolonged by more than 50% after flunitrazepam indicating a pronounced sedative action of this drug. However, even during this period of maximal effect of flunitrazepam, recognition of words first presented prior to injection was not impaired.(ABSTRACT TRUNCATED AT 250 WORDS)

Somatosensory evoked potentials (SEP) at present seem to be the most reliable and accurate method for the investigation of compounds modulating pain sensation. Besides detecting changes in the duration and the potency of action of analgesics, their possible site of action in the sensory pathways may be derived by this method. In ten trials using two trained canines the efficacy and the duration of action of a new and short acting opioid, alfentanil was evaluated on SEP using cumulative doses (3, 30, 60, 120 micrograms/kg). Concomitantly arterial blood gases were analyzed for possible respiratory depressant effects. The results demonstrate that alfentanil induces a short lasting suppression of the N100 peak as well as a latency change of the N140 peak to N220, the latter lasting for more than 80 min. These effects saturate at doses higher than 30 micrograms/kg. The significant change in arterial blood gases - a fall in PaO2 and an increase in PaCO2 - are most prominent with 30 micrograms/kg and 120 micrograms/kg, respectively. It is of short duration and correlates with the suppression of the N100 peak. The latency changes seem to correlate with a marked sedatory effect. Due to the differential effects induced by the opioid, an interaction with different opioid subreceptor sites is postulated.

In 38 patients buprenorphine, meperidine and pentazocine were given in a single dose for postoperative pain relief 20 hours after the end of anaesthesia. Measuring the parameters of the high- and low-pressure system as well as the metabolism the authors found that the effects of these analgetic medicaments, intravenously injected were significantly influenced by fentanyl, halothane or diazepam, given under the course of operation. Especially buprenorphine, injected after epidural anaesthesia in combination with diazepam sedation, proved to have a rather negative effect, because it caused a strong depression of respiration and circulation. On the other hand buprenorphine had, given after neuroleptanaesthesia, a neutralizing - and pentazocine and pethidine in combination with neuroleptanaesthesia a stimulating influence on the circulation. After halothane-anaesthesia the effect of the analegtics on the cardiovascular system was, when buprenorphine was given, depressing and when pentazocine was given indifferent. Similar reactions, but more pronounced, could be seen in the epidural group. With certain reservations, caused by the preliminary character of this study, the following conclusions can be drawn for the anaesthetic practice: 1 Choosing analgetic drugs for postoperative pain relief, the anaesthesist has to be aware of the interactions, possibly resulting from the medicaments, given during anaesthesia. 2. The number of medicaments, given during anaesthesia, should be kept small, considering the eventual interactions and the unintentional secondary effects.

The action of etomidate, a short-acting non-barbiturate hypnotic agent, was studied in three groups of patients. Used alone for induction it did not significantly alter either the pulse rate or the diastolic blood pressure. Systolic blood pressure fell slightly, but became stable after 2 minutes. The pH of the arterial blood was not significantly altered. pO2 and pCO2 showed changes indicative of respiratory depression during induction (group 1). Etomidate combined with fentanyl caused a moderate, significant fall in both diastolic and systolic blood pressure, but did not affect the pulse rate (group 2). In view of its inconsiderable haemodynamic effects etomidate can be regarded as a safe agent for induction. In doses of 10-20 micrograms/kilogramme bodyweight/minute infusions of etomidate (combined with fentanyl and muscle relaxants) provide adequate basal narcosis for most routine surgical operations. It cannot, however, be considered the anaesthetic of choice for major abdominal surgery which requires deep analgesia and full muscular relaxation (group 3).

1. In healthy volunteers fentanyl (0.15 mg i.v.) induces a reduction of awareness and vigilance and in some persons a transition to sleepiness or sleep stages. The course of these changes with time can be shown in narcograms, consisting of vigilance indices which correspond to the different EEG-stages. 2. Naloxon (0.4--1.6 mg i.v.) reduces the hypnotic effect of fentanyl or antagonizes it completely. 3. Index values of rapid eye movements in wakefulness measured oculographically indicate a reduction of motor activity after administration of fentanyl, when stages of reduced vigilance appear. Injections of naloxone following later on diminish this effect of fentanyl or antagonize it completely, not so does levallorphan.

In 31 patients with congenital or acquired heart disease, functional class III NYHAC, effects of Sulfentanil (R 30730)--a new analgetic--on hemodynamics, inotropic state and myocardial oxygen consumption have been investigated intraoperatively, during extracorporeal circulation and postoperatively. Results are compared to a fentanyl-group and control-group. There was almost no change in cardiac index and stroke index. In comparison to fentanyl (dose relation fentanyl: sulfentanil = 10:1) there was a more pronounced decrease in aterial pressure, left ventricular pressure, peak dp/dt and myocardial oxygen consumption (-20%) in the sulfentanil-group. In contrast to the fentanyl-group there was, however, no increase in total pulmonary resistance with sulfentanil.