Ro 15-1788 for postoperative recovery

In a double-blind randomised study, 100 women who underwent induced abortion under midazolam anaesthesia were given the benzodiazepine antagonist Ro 15-1788 or placebo after termination of anaesthesia. Recovery was assessed by means of a modified Steward coma scale. Following incremental doses of Ro 15-1788, 56% of the patients were fully awake within 3 minutes and 92% after 5 minutes, which was significant compared to the placebo group. The median duration of amnesia was 91 minutes after Ro 15-1788 compared to 121 minutes in the placebo group (p less than 0.001). The median dose of Ro 15-1788 was 0.4 mg. A slight positive correlation between total dose of Ro 15-1788 and total amount of midazolam was found. Nausea and/or vomiting were found to be more frequent in the Ro 15-1788 group, but otherwise we found no differences between groups with regard to either side effects or cardiorespiratory function. Ro 15-1788 is evidently an effective antagonist to the sedation induced by midazolam.     

RO 15-1788 ANTAGONIZES THE EFFECTS OF DIAZEPAM IN MAN WITHOUT AFFECTING ITS BIOAVAILABILITY

In 8 double-blind, placebo-controlled three-way cross over study,the efficacy of Ro 15–1788 200 mg, a new benzodiazepineantagonist, in blocking the amnesic, cognitive, psychomotorand subjective effects of diazepam 20 mg, was investigated ina group of six healthy male volunteers. The amnesic effectsof diazepam were markedly attenuated by the combined administrationof Ro 15–1788. The psychomotor and subjective effectsof diazepam by mouth were most pronounced 2.5 h after administration.Concurrent oral administration of Ro 15–1788 completelyprevented these effects at 2.5 h. Plasma diazepam concentrationsobserved after administration of the combination of diazepamand the antagonist did not differ from those observed followingdiazepam alone.     

DEPRESSION OF NOCICEPTIVE SYMPATHETIC REFLEXES BY THE INTRATHECAL ADMINISTRATION OF MIDAZOLAM

The effect of the intrathecal administration of midazolam 0.5–1.0mg in 1–2 ml of physiological saline solution, has beenobserved on responses evoked in renal sympathetic nerves bysupramaximal electrical stimulation of radial and tibial nerves.In artificially ventilated dogs anaesthetized with a-chloralose,the intrathecal administration of midazolam caused a markeddepression of reflexes evoked from the tibial nerve but hadno effect on either spontaneous sympathetic activity or reflexesevoked by radial nerve stimulation. Neither the small amount(1–2 ulitre) of benzyl alcohol, present as a preservative(administered intrathecally), nor midazolam 1 mg kg^–1i.v. caused any significant depression of the evoked somato-sympatheticreflexes. The effects of intrathecal midazolam were reversedby the benzodiazepine antagonists Ro 15–1788 1 mg kg^–1i.v. and Ro 15–3505 1–2 mg kg^–1 i.v. but notby naloxone 2 mg i.v. It is suggested that the antinociceptiveeffect of locally applied midazolam could be the result of anon-opioid GABA-mediated system which may have implicationsin the management of pain. ^*Present address: Tel-Aviv Medical Centre and Tel-Aviv MedicalSchool, Tel-Aviv, Israel.     

The effect of Ro15-1788 (Anexate) on conscious sedation produced with midazolam

A double-blind cross-over randomised study was performed to investigate whether Ro15-1788 (Anexate) adequately reversed the conscious sedation with midazolam so that patients were clinically recovered and fit for discharge quicker than when midazolam was used alone. Twenty-eight healthy patients between 18 and 34 years sedated with midazolam for bilateral 3rd molar surgery, one side being operated on at each visit. Ro15-1788 or normal saline (placebo) was given at the end of the surgical procedure at the first visit and the alternative at the second visit. Recovery with Ro15-1788 was significantly quicker than with the placebo, both by subjective (86%) and objective (93%) evaluation. Patients' evaluation indicated that only 61% were more alert at home with Ro15-1788. Postoperative adverse effects were similar in both groups.     

IN VIVO INTERACTIONS BETWEEN THE BENZODIAZEPINE ANTAGONIST Ro 15-1788 AND THE STEROID ANAESTHETIC ALTHESIN IN RATS

Althesin and 16-alphaxalone have been used alone and in combinationwith the benzodiazepine antagonist Ro 15–1788 to investigateany protective effect these drugs might have against bicuculline-induced convulsions in rats. We found that Althesin providedgood protection against bicuculline- induced convulsions whichwas enhanced when Ro 15–1788 was also present. 16- Alphaxalonelacks the anaesthetic properties of Altbesin, but did have someactivity in preventing bicuculline-induced convulsions, althoughit was less effective than Althesin. Its action was not enhancedby treatment with Ro 15–1788. Although we have no definitiveexplanation of these results, it is possible that when Ro 15–1788is used clinically, it may interact with other drugs not relatedchemically to the benzodiazepines.     

HAEMODYNAMIC EFFECTS OF DILTIAZEM DURING FENTANYL-NITROUS OXIDE ANAESTHESIA: An In Vivo Study in the Dog

The haemodynamic effects of diltiazem were studied in six dogsduring fentanyl-nitrous oxide (in oxygen) anaesthesia. A bolusof diltiazem 300 µg kg^–1 was given, followed byinfusions at 30, 60 and 90 µg kg^–1 min^–1 whichproduced plasma diltiazem concentrations of 392±30, 908±54and 1483±134 ng ml^–1, respectively. Diltiazem significantlyreduced systemic vascular resistance index, mean arterial pressure,heart rate and PR interval. The decrease in afterload increasedcardiac index, since there was little change in myocardial contractility(LV dP/dt). Five dogs developed second degree atrioventricular(AV) block in association with the highest dose. Administrationof calcium chloride 20 mg kg^–1 did not reverse the haemodynamicor electrophysiological effects of diltiazem. Isoprenaline increasedheart rate and restored sinus rhythm in four dogs with AV block. Presented in part at the 59th International Anesthesia ResearchSociety Congress, Houston, Texas, 1985.     

CLINICAL EVALUATION OF A SPECIFIC BENZODIAZEPINE ANTAGONIST (RO 15-1788): Studies in Elderly Patients after Regional Anaesthesia under Benzodiazepine Sedation

The efficacy, usefulness and side effects of RO 15-1788 (RO),a specific benzodiazepine (BZD) antagonist, have been evaluated.Sixty-two patients (ASA l-lll, mean age 72±9 yr) scheduledfor urological surgery under regional anaesthesia and BZD sedationreceived placebo or RO in a randomized, double-blind fashionat the end of the procedure, folio wing sedation with midazolam.When compared with placebo, RO improved alertness and collaborationfor 15 min, and suppressed anterograde amnesia for 60 min. Nomajor side effect was noted, although five patients became anxiousafter administration of RO. Two cases of a paradoxical reactionto midazolam were treated successfully by RO.     

The effectiveness of the benzodiazepine antagonist Ro 15-1788 after the induction of anesthesia with midazolam

The benzodiazepine antagonist Ro 15-1788 has now been added to the series of antagonists which have been routinely used for a long time. In the present prospective, randomized double-blind study, it is investigated whether Ro 15-1788 is able to antagonize the effect of midazolam applied at a dosage of 0.2 mg/kg for induction of anesthesia. PATIENTS, MATERIAL and METHODS: Thirty female patients (age between 19 and 44 years) undergoing laparoscopy were included in the study. Premedication consisted of an oral dose of 2 mg flunitrazepam given on the evening before the intervention and a 7.5 mg oral dose of midazolam 45 min prior to the induction of anesthesia. After preoxygenation, midazolam was given intravenously at a dose of 0.2 mg/kg body weight for induction of anesthesia. Following extubation either Ro 15-1788 at a dosage of 0.2 mg (2 ml) or an adequate volume of placebo was given according to a randomized double-blind scheme. Those patients whose vigilance status did not change received either Ro 15-1788 or placebo every 60 s up to a maximum total dose of 10 ml. Prior to induction of anesthesia, 5 min after midazolam dosing, prior to and 5, 15, 30, 60 and 120 min after the application of Ro 15-1788, the following parameters were assessed using a multistep rating scale: degree of sedation, comprehension and collaboration, orientation in space and time, anterograde amnesia as well as blood pressure and heart rate.(ABSTRACT TRUNCATED AT 250 WORDS)     

PLASMA CONCENTRATIONS OF METHADONE DURING POSTOPERATIVE PATIENT-CONTROLLED EXTRADURAL ANALGESIA

Plasma concentrations of methadone were measured by gas chromatographyin 16 patients receiving extradural methadone by continuousinfusion for relief of postoperative pain. Venous blood sampleswere taken after a loading dose of extradural methadone 2 mgand during infusion of 0.46 mg h^–1 plus patient-controlledincrements of 0.2–1 mg. Mean (SD) plasma concentrationof methadone was 9.8 (2.1) ng ml^–1 at 15 min; this didnot change significantly during the first 2 h, after which itincreased gradually to 32.2 (4.6) ng ml^–1 (P < 0.001)at the end of 24 h. The mean quantity of extradural methadonerequired to produce effective analgesia was 10.3 (1.8) mg duringthe first 12 h after operation and 6 (1.0) mg for the subsequent12 h. The mean amount of methadone for effective analgesia onthe second day was 7.6 (1.1) mg. No adverse effects were detectedduring the 2–3 days of methadone therapy. Plasma concentrationof methadone increased significantly during patient-controlledinfusion of extradural methadone in the first 24 h after operation,suggesting rapid vascular uptake. Systemic activity of the drugcontributes to the analgesic effect of extradural methadone. Presented in part at the Vth Congress of the International Associationfor the Study of Pain, Hamburg, West Germany, 1987.     

SEDATION DURING SPINAL ANAESTHESIA: COMPARISON OF PROPOFOL AND MIDAZOLAM

Propofol and midazolam were compared in 40 patients undergoingorthopaedic surgery under spinal anaesthesia. An infusion ofeither 1% propofol or 0.1% midazolam was given at a rate adjustedto maintain a similar level of sedation. The mean time to reachthis required level was similar in both groups. Quality andease of control of sedation were good in all patients. A meaninfusion rate of 3.63 mg kg^–1 h^–1 was required forpropofol and 0.26 mg kg^–1 h^–1 for midazolam. Immediaterecovery, as judged by ability to open eyes and recall dateof birth, was significantly more rapid following propofol (P< 0.0001). Similarly, restoration of higher mental functionwas significantly faster following propofol, measured by choicereaction time and critical flicker fusion threshold. Amnesiafor the immediate postoperative period was significantly greaterafter midazolam (P = 0.0001). ^*Present address: Department of Anaesthetics, Royal Infirmary,Edinburgh. Present address: Intensive Therapy Unit, Western General Hospital,Edinburgh.     

Benzodiazepine antagonist Ro 15-1788

In a double-blind, randomised trial the efficacy and safety of Ro 15-1788, a new benzodiazepine antagonist, was assessed in forty adults undergoing gastroscopy under diazepam sedation. Criteria of efficacy were the degree of sedation and anterograde amnesia. There was a significantly faster recovery of the patients after the injection of 0.6-1.0 mg of Ro 15-1788 than after placebo. Patients were awake shortly after Ro 15-1788, but remained drowsy or asleep after placebo administration. There were no side effects of note.     

EFFECTS OF MIDAZOLAM ON MEDIAN NERVE SOMATOSENSORY EVOKED POTENTIALS

We have studied the effect of i.v. midazolam on median nervesomatosensory evoked potentials (SSEP) in 10 unpremedicatedadults. Anaesthesia was induced with midazolam by bolus administration(0.2 mg kg^–1) followed by infusion (5 mg h^–1). Thelatency and amplitudes of the SSEP responses over the secondcervical vertebrae (SC2) and sensory cortex (P17, N20, P25)were recorded before and for 10 min after induction. Data wereanalysed over that period for time-related alterations. Smallbut statistically significant increases in latency of the corticalN20 (P < 0.005) and P25 (P < 0.001) waves and interwaveconduction times of SC2 to P25 (P < 0.005) and N20 to P25(P < 0.021) were observed. Cortical amplitude (N20–P25)decreased significantly (P < 0.012), to approximately 60%of baseline. These results demonstrated that midazolam produceda depression of cortical SSEP amplitude without clinically significantalterations in latency. Presented in part at the Annual Meeting of the InternationalAnesthesia Research Society in San Diego, California, March1988.     

POSTOPERATIVE ANALGESIA AFTER PAEDIATRIC ORCHIDOPEXY: EVALUATION OF A BUPIVACAINE-MORPHINE MIXTURE

The value of combining morphine with bupi-vacaine for caudalanalgesia was investigated. Thirty children, undergoing orchidopexy,received a caudal block of 0.125% bupivacaine with or withoutmorphine 0.05 mg kg^–1. Analgesia, side-effects, ventilatoryfrequency and oxygen saturation (Sa_o2) were recorded after operation.None of the 15 patients receiving the bupivacaine-morphine mixturerequired postoperative opioids, whereas eight of 15 patientsreceiving bupivacaine alone needed additional opioid analgesia.The incidence of side effects after surgery was similar forthe two groups and there was no detectable difference in ventilatoryfrequency or Sa_o2. The pilot study to this paper was presented to the AnaestheticResearch Society and subsequently published in British Journalof Anaesthesia 1989; 62: 221P.     

Assessment of the efficacy and tolerance of a benzodiazepine antagonist (Ro 15-1788)

The aim of this study was to evaluate the efficacy and the tolerance of Ro 15-1788, a specific benzodiazepine antagonist, in reversing the effects of midazolam. Six healthy male volunteers (mean age 32 +/- 3 years; mean weight 75.5 +/- 5 kg) took part in this study. Two of the three following drugs: midazolam (0.15 mg X kg-1), Ro 15-1788 (0.1 mg X kg-1) or placebo, diluted in 10 ml isotonic saline, were injected intravenously in 15 s at 5 min intervals in a double-blind manner in each subject during six randomized sessions: midazolam-placebo; Ro-placebo; placebo-midazolam; placebo-Ro; midazolam-Ro; Ro-midazolam. At least four days were allowed between each session for each subject. The evaluation of the effects on the central nervous system was as follows. At the time of injection of the first drug and, if possible, at the time of injection of the second drug, the subject was asked to count aloud to 150. The following variables were timed: start of dysarthria, cessation of counting, abolition and duration of absence of the ciliary reflex and duration of induced sleep. Retrograde and anterograde amnesia were evaluated by the recall of a playing card and a number. Haemodynamic effects (variations of systolic and diastolic pressures and pulses rate) as well as respiratory ones (apnoea) were also studied.(ABSTRACT TRUNCATED AT 250 WORDS)     

BETA-ADRENOCEPTOR BLOCKADE, ALPHA-STIMULATION AND CHANGES IN PLASMA POTASSIUM CONCENTRATION AFTER SUXAMETHONIUM ADMINISTRATION IN DOGS

A study involving 20 mongrel dogs tested the hypotheses thatbeta-adrenoceptor blockade or alpha-adrenoceptor stimulationmay potentiate and prolong the increase in plasma potassiumconcentration after suxamethonium administration, and that thebeta effect is beta₂-receptor mediated. Propranolol 0. 5 mgkg^–1 altered the time to peak increase in plasma concentrationof potassium after suxamethonium, but did not increase peakconcentrations. In controls, the maximum change (0. 83 mmollitre^–1) occurred at 3 min, while in propranolol-treateddogs the peak change (0. 96 mmol litre^–1 occurred at 30min. Similar results were obtained when metoprolol 0. 25 mgkg^–1 and ICI 118551 0. 1 mg kg^–1 were used, respectively,as selective betax- and beta₂-adrenoceptor blockers. The increasesin potassium concentration following suxamethonium in the metoprololgroup (0. 98 mmol litre^–1) and the ICI 118551 group (0.82 mmol litre^–1) reached maximum concentrations at 30min compared with the controls (0. 79 mmol litre^–1) whichachieved a maximum at 3 min. Phenylephrine was infused at 8fig kg^–1 min^–1 to produce alpha stimulation. Theinfusion alone altered plasma concentrations of potassium, butthe haemodynamic changes were such that conclusions as to theeffect of alpha-stimulation on release of potassium after suxamethoniumcould not be reached. ^*Present address: Department of Anaesthesia, The London Hospital,London El IBB. Presented in part at the Annual Scientific Meeting of the Associationof Anaesthetists of Great Britain and Ireland, September 1985and at the 60th Congress of the International Anesthesia ResearchSociety, Las Vegas, march 1986.     

REVERSAL OF MIDAZOLAM SEDATION WITH ANEXATE

Anexate (Ro 15–1788) a specific benzodiazepine antagonist,was assessed for its action in reversing midazolam-induced sedation.Sixty-five patients undergoing prostatic surgery under subarachnoidanaesthesia received midazolam for intraoperative sedation (meandose 16 mg) followed by either active drug (anexate) or placebogiven as a randomized, double-blind i. v. injection. The anexatedose sufficient to reverse sedation (0.36±0.09 mg), producedimmediate and dramatic improvements in ability to comprehendand obey commands, in orientation in time and space and in degreeof anterograde amnesia. These changes remained significantlydifferent from the control group for 60 min after injection.There was no effect on arterial pressure, heart rate or ventilatoryrate and no anxiety states were observed. After initial completeawakening, sedation increased gradually in drug-treated patients,while in the control group, sedation scores and cognitive testingscores all diminished over the 4-h study period. Anexate usedin doses up to 0.5 mg provided safe and effective antagonismof midazolam-induced sedation in a clinical setting.     

ALCOHOL AFTER SEDATION WITH I.V. MIDAZOLAM-FENTANYL: EFFECTS ON PSYCHOMOTOR FUNCTIONING

Patients who arrive home several hours after outpatient surgerymay drink alcohol. The extent to which residual drugs used inoutpatient surgery interact with alcohol is not known. The purposeof this study was to determine if two i. v. drugs commonly usedtogether in outpatient surgery, midazolam and fentanyf. haveresidual effects which would interact with alcohol drunk 4 hafter injection. Twelve healthy male volunteers participatedin a double-blind, randomized, placebo-controlled and cross-overstudy. Subjects were studied four times successively with aperiod of 1 week between trials. On each day of testing, thesubjects received randomly, by slow i.v. injection (30 s), eithersaline followed immediately by saline, or midazolam 0.1 mg kg^–1followed immediately by fentanyl 2 µg kg^–1. Fourhours after the injection, the subjects consumed a beveragewhich either did or did not contain alcohol 0.7g kg^–1.Before and 1, 3, 5 and 7 h after injection (and before and 1and 3 h after consumption of beverage), psychomotor performanceand mood were assessed. While both the combination midazolam-fentanyland alcohol had independent effects on the dependent measuresin this study, there was no interaction between midazolam-fentanyland alcohol (no potentiating of effects of alcohol by i.v. sedation).We conclude that the effects of benzo-diazepines and opioidsthat are short-acting and used in outpatient surgery have probablydissipated by the time a patient arrives home, and that effectsfrom alcohol ingested at home will probably not be affectedby recent administration of these drugs. Presented in part at the American Society of AnesthesiologistsAnnual Meeting, Las Vegas, U.S.A. 1990.     

Influence of carbamazepine on the dose-response relationship of vecuronium

We have determined the cumulative dose-response relationshipfor vecuronium from the evoked compound electromyogram of thehypothenar muscles in eight patients who were receiving carbamazepine.The ED₅₀, ED₉₀ and ED₉₅ were 29, 52 and 64 µg kg^–1,respectively, and were significantly different (P < 0.05)from those of a control group (ED₅₀, ED₉₀ and ED₉₅ 21, 36 and44 µg kg^–1, respectively). (Br. J. Anaesth. 1994;72: 125–126) Presented at the 10th World Congress of Anaesthesiologists,The Hague, The Netherlands, June 1992.     

PHARMACOKINETICS OF ALFENTANIL IN TOTAL I. V. ANAESTHESIA

Alfentanil was administered, together with midazolam, as partof a total i.v. anaesthetic technique. The pharmacokineticsof alfentanil were determined in 10 female patients undergoinglower abdominal surgery. The dose regimen of alfentanil, basedon simulation studies, consisted of a two-stage infusion followingan initial bolus dose. The kinetics of alfentanil were describedby a linear twocompartment open model. The total plasma clearanceranged between 93 and 431 ml min^–1 (mean 249 ml min^–1).The apparent volume of distribution at steady-state ranged between0. 27 and 0. 64 litre kg^–1 (mean 0.44 litre kg^–11).The apparent volume of distribution (Vd^ß) was 0.58litre kg^–1, resulting in a terminal half-life of 112 min.Alfentanil concentrations at the time of extubation and postoperativeanalgesic requirements were also monitored. Good correlationbetween respiratory depression and plasma alfentanil concentrationwas found. Neither lower abdominal surgery nor the simultaneousadministration of midazolam seemed to affect the kinetics ofalfentanil as compared with results from studies in healthyvolunteers. The short haIf-life of alfentanil, resulting froma small volume of distribution, makes it suitable as part ofa total i.v. technique. Consideration must be paid, however,to interindividual differences in the pharmacodynamic responseand in plasma clearance. Presented in part at the third World Conference on ClinicalPharmacology and Therapeutics, Stockholm, Sweden, July 27-August1, 1986.     

HAEMODYNAMIC EFFECTS OF A PROLONGED INFUSION OF PROPOFOL AS A SUPPLEMENT TO NITROUS OXIDE ANAESTHESIA: Studies in Association with Peripheral Arterial Surgery

The haemodynamic effects of propofol at two infusion rates (54–65and 108–130 µg kg^–1 min^–1) have beenstudied during peripheral arterial surgery in eight elderlypatients premedicated with morphine sulphate 0.15 mg kg^–1.The haemodynamic response to laryngoscopy and intubation waspartially suppressed: neither arterial pressure nor heart rateexceeded awake values. During stable anaesthesia at the lowerinfusion rate before surgery, systolic (SAP) and diastolic (DAP)arterial pressures were significantly decreased from awake values(SAP: –47%; DAP: –46%) as a result of decreasesin cardiac output (–32%) and systemic vascular resistance(SVR) (–9%). During surgery, with either spontaneous (SV)or intermittent positive pressure (IPPV)ventilation, both infusionrates were associated with decreases in arterial pressures whencompared with the awake state. Cardiac output was decreased(SV: –35%, IPPV: –36%) and SVR increased (SV: +22%,IPPV: +45%) at the lower infusion rate; similar changes wereobserved during the faster infusion rate. Presented in part at the Annual Scientific Meeting of the EuropeanAcademy of Anaesthesiology, Basel, September 1985 (Monk et al.,1986).