Efficacy of sugammadex for the reversal of moderate and deep rocuronium-induced neuromuscular block in patients pretreated with intravenous magnesium: a randomized controlled trial.

BACKGROUND: Magnesium enhances the effect of rocuronium. Sugammadex reverses rocuronium-induced neuromuscular block. The authors investigated whether magnesium decreased the efficacy of sugammadex for the reversal of rocuronium-induced neuromuscular block. METHODS: Thirty-two male patients were randomized in a double-blinded manner to receive magnesium sulfate (MgSO4) 60 mg/kg or placebo intravenously before induction of anesthesia with propofol, sufentanil, and rocuronium 0.6 mg/kg. Neuromuscular transmission was monitored using TOF-Watch SX acceleromyography (Organon Ltd., Dublin, Ireland). In 16 patients, sugammadex 2 mg/kg was administered intravenously at reappearance of the second twitch of the train-of-four (moderate block). In 16 further patients, sugammadex 4 mg/kg was administered intravenously at posttetanic count 1 to 2 (deep block). Primary endpoint was recovery time from injection of sugammadex to normalized train-of-four ratio 0.9. Secondary endpoint was recovery time to final T1. RESULTS: Average time for reversal of moderate block was 1.69 min (SD, 0.81) in patients pretreated with MgSO4 and 1.76 min (1.13) in those pretreated with placebo (P = 0.897). Average time for reversal of deep block was 1.77 min (0.83) in patients pretreated with MgSO4 and 1.98 min (0.58) in those pretreated with placebo (P = 0.572). Times to final T1 were longer compared with times to normalized train-of-four ratio 0.9, without any difference between patients pretreated with MgSO4 or placebo. CONCLUSION: Pretreatment with a single intravenous dose of MgSO4 60 mg/kg does not decrease the efficacy of recommended doses of sugammadex for the reversal of a moderate and deep neuromuscular block induced by an intubation dose of rocuronium.

The first intravenous anaesthetic: how well was it managed and its potential realized?

Our speciality commonly traces its origin to a demonstration of the inhalation of ether by a patient undergoing surgery in Boston in 1846. Less well known is the demonstration of the i.v. injection of opium with alcohol into a dog in Oxford in 1656, leading to anaesthesia followed by full long-term recovery. After gaining i.v. access, a mixture of opium and alcohol was injected, resulting in a brief period of anaesthesia. After a period during which the dog was kept moving to assist recovery, a full recovery was made. Details from this momentous experiment allow us to compare the technique used with modern management. It is important to consider why there was a failure to translate the results into clinical practice and nearly 200 yr of potentially pain-free surgery. Possible factors include lack of equipment for i.v. access, lack of understanding of dose-response effects, and a climate of scientific discovery rather than clinical application. Given the current interest in total i.v. anaesthesia, it seems appropriate to identify its origins well before those of inhalation anaesthesia.

Intravenous lidocaine has no impact on rocuronium-induced neuromuscular block. Randomised study.

BACKGROUND: Intravenous lidocaine is increasingly used in surgical patients. As it has neuromuscular blocking effects, we tested the impact of an intravenous lidocaine infusion on the time course of a rocuronium-induced neuromuscular block. METHODS: Fifty-two adults undergoing surgery were randomly allocated to intravenous lidocaine 1.5 mg/kg followed by a continuous infusion of 2 mg/kg/h or physiological saline (control) throughout surgery. Anaesthesia was induced and maintained with a target-controlled propofol infusion and sufentanil. After loss of consciousness, rocuronium 0.6 mg/kg was given. Neuromuscular transmission was measured using train-of-four (TOF)-watch SX (Organon, Swords Co., Dublin, Ireland) acceleromyography. RESULTS: Onset time (to 95% depression of first twitch) was on average 113.9 s (standard deviation 35.3) with lidocaine and 119.5 s (44.9) with saline (P = 0.618). Total recovery time (TOF ratio 0.9) was on average 58.1 min (15.1) with lidocaine and 54.3 min (16.9) with saline (P = 0.394). Clinical duration (until first twitch has recovered to 25%) was on average 33.3 min (7.2) with lidocaine and 30.6 min (8.1) with saline (P = 0.21). Recovery index (time between 25% and 75% recovery of the first twitch) was on average 11.5 min (5.0) with lidocaine and 10.6 min (4.1) with saline (P = 0.458). Recovery time (between 25% recovery of the first twitch and TOF ratio 0.9) was on average 24.8 min (9.3) with lidocaine and 23.2 min (9.2) with saline (P = 0.541). CONCLUSION: A continuous intravenous infusion of lidocaine has no impact on the time course of the neuromuscular blockade induced by a standard intubation dose of rocuronium.

Issues surrounding lethal injection as a means of capital punishment.

Lethal injection as a method of state-sanctioned capital punishment was initially proposed in the United States in 1977 and used for the first time in 1982. Most lethal injection protocols use a sequential drug combination of sodium thiopental, pancuronium bromide, and potassium chloride. Lethal injection was originally introduced as a more humane form of execution compared with existing mechanical methods such as electrocution, toxic gassing, hanging, or firing squad. Lethal injection has not, however, been without controversy. Several states are considering whether lethal injection meets constitutional scrutiny forbidding cruel and unusual punishment. Recently in the case of Ralph Baze and Thomas C. Bowling, Petitioners, v John D. Rees, Commissioner, Kentucky Department of Corrections et al, the United States Supreme Court upheld the constitutionality of the lethal injection protocol as carried out in the Commonwealth of Kentucky. Most of the debate has surrounded the dosing and procedures used in lethal injection and whether the drug combinations and measures for administering the drugs truly produce a timely, pain-free, and fail-safe death. Many have also raised issues regarding the "medicalization" of execution and the ethics of health care professionals' participation in any part of the lethal injection process. As a result of all these issues, the future of lethal injection as a means of execution in the United States is under significant scrutiny. Outcomes of ongoing legislative and judicial reviews might result in cessation of lethal injection in totality or in alterations involving specific drug combinations or administration procedures.

The effect of hepar magnesium on seasonal fatigue symptoms: a pilot study.

OBJECTIVES: To evaluate the effect of the anthroposophic drug hepar magnesium D10 intravenously administered on seasonal fatigue symptoms. DESIGN: Time series with two measurements per week, starting before onset of treatment until three measurements after finishing treatment in a regular way. SETTINGS: Six anthroposophic general practitioner practices in the Netherlands. SUBJECTS: Twenty-three (23) patients with seasonal fatigue symptoms. INTERVENTIONS: Hepar magnesium D10 intravenously administered every week. OUTCOME MEASURES: Mean division of 24 hours in categories: sleep, rest, everyday activities, and activities that require a large effort; fatigue-related single questions: unusual emotional response to events, problems with short-term memory, the degree to which fatigue after effort continues for longer than 2 hours, the degree to which people at the end of the day have a complete lack of energy; and the degree to which people are still fit after the evening meal; Multidimensional Fatigue Index: general fatigue, physical fatigue, reduced activity, reduced motivation, and mental fatigue; subjective experiences with regard to the effect of the treatment. RESULTS: (1) No changes in division in 24-hour categories were found; (2) pretreatment versus post-treatment analyses (after 1 and 2.5 weeks, at the end of treatment, and 1.5 weeks after the end of treatment) demonstrated overall large statistically significant differences. Eighteen (18) of 22 patients (82%) who completed the final questionnaire judged that treatment overall had been effective for their fatigue symptoms. Nine (9) patients (41%) judged a strong improvement and 9 patients (41%) a light improvement as a result of the treatment. Four (4) patients reported no change. On average, patients received treatment 4.5 times. CONCLUSIONS: There are clear indications that hepar magnesium D10 intravenously administered can have a positive effect on subsyndromal seasonal affective disorder symptoms of fatigue. A more controlled trial is indicated to study the (long-term) effects of hepar magnesium.

Lethal injection for execution: chemical asphyxiation?

BACKGROUND: Lethal injection for execution was conceived as a comparatively humane alternative to electrocution or cyanide gas. The current protocols are based on one improvised by a medical examiner and an anesthesiologist in Oklahoma and are practiced on an ad hoc basis at the discretion of prison personnel. Each drug used, the ultrashort-acting barbiturate thiopental, the neuromuscular blocker pancuronium bromide, and the electrolyte potassium chloride, was expected to be lethal alone, while the combination was intended to produce anesthesia then death due to respiratory and cardiac arrest. We sought to determine whether the current drug regimen results in death in the manner intended. METHODS AND FINDINGS: We analyzed data from two US states that release information on executions, North Carolina and California, as well as the published clinical, laboratory, and veterinary animal experience. Execution outcomes from North Carolina and California together with interspecies dosage scaling of thiopental effects suggest that in the current practice of lethal injection, thiopental might not be fatal and might be insufficient to induce surgical anesthesia for the duration of the execution. Furthermore, evidence from North Carolina, California, and Virginia indicates that potassium chloride in lethal injection does not reliably induce cardiac arrest. CONCLUSIONS: We were able to analyze only a limited number of executions. However, our findings suggest that current lethal injection protocols may not reliably effect death through the mechanisms intended, indicating a failure of design and implementation. If thiopental and potassium chloride fail to cause anesthesia and cardiac arrest, potentially aware inmates could die through pancuronium-induced asphyxiation. Thus the conventional view of lethal injection leading to an invariably peaceful and painless death is questionable.

[Pharmacokinetic study on baicalin of Qingkailing injection in rats].

OBJECTIVE: Studying the metabolic pharmacokinetic of baicalin of Qingkailing injection in rat, to search for effector substance of Qingkailing injection in vivo. METHOD: Qingkailing sterile injection powder was given by caudal vein, then blood, liver and lung were collected in various time, the concentration of baicalin from samples were determined by HPLC-MS. Pharmacokinetic evaluation was carried out using the 3P87. RESULT: After Qingkailing injection, Baicalin was consistent with two-compartment model in rat. 45 min, the concentration of baicalin in hepatic tissue reached maximum, followeded by decrease sharply, 120 min began to rise slowly, present double hump phenomenon. In lung, baicalin concentration was far more than in liver, was eliminated more slowly, but they have the same t(max). CONCLUSION: After Qingkailing injection, baicalin distributed quickly to liver and lung, baicalin is one of effector substance of qingkailing injection in vivo. Baicalin might have hepatoenteral circulation.

Narcotic use in southeast Asia and afterward. An interview study of 898 Vietnam returnees.

From all US Army enlistees leaving Vietnam in September 1971, a random sample of 943 men was selected. Of these, 470 represented a "general" sample of all enlistees returning at that time, and 495 represented a "drug positive" sample whose urine samples had been positive for opiates at the time of departure. We attempted to locate and personally interview all of the men in the samples. Results indicate that before arrival, hard drug use was largely casual, and less than 1% had ever been addicted to narcotics. In Vietnam, almost half of the general sample tried narcotics and 20% reported opiate addiction. After return, usage and addiction essentially decreased to pre-Vietnam levels. We discuss the use of nonnarcotic drugs, predictors and correlates of drug use in the samples, and the relationship of drugs to post-Vietnam social adjustment.

A new method for studying the relationship between hepatic uptake of drugs and their pharmacodynamic effects in anaesthetized cats.

1 A new in vivo experimental method is described whereby the liver can be temporarily excluded from the general circulation by means of a portocaval shunt operation. The influence of this manoeuvre upon the effects of pancuronium and Org 6368 was investigated using the tibialis muscle preparation of anaesthetized cats. 2 The procedure also allowed intraportal injections of the drugs to be made so that the effect of first-passage uptake by the liver could be compared with hapatic exclusion in the same animal. 3 Hepatic exclusion greatly increased the duration of action of both drugs. Whereas intraportal injection did not significantly alter the effect of pancuronium on the tibialis muscle, the effect of Org 6368 was greatly diminished when given by this route. 4 The liver appears to tolerate short periods of hepatic exclusion and it is concluded that this technique may become a useful tool for studying the handling of drugs by this organ.

Intravenous pancuronium bromide for fetal neuromuscular blockade during intrauterine transfusion for red-cell alloimmunization.

Intravenous pancuronium bromide was administered into the umbilical cord by funipuncture to effect temporary fetal paralysis. Neuromuscular blockade was achieved in 12 fetuses undergoing a total of 34 intrauterine procedures for the treatment of severe red-cell alloimmunization. The same initial dose of 0.2 mg/kg fetal weight estimated by ultrasound was used in all cases, but anemic fetuses did not resume movement for prolonged periods. A relationship among fetal hematocrit, adjusted dose, and duration of paralysis was described by the equation: Duration (hours) = 5.24 + 10.30 adjusted dose (mg/kg) - 0.16 hematocrit (%) (R2 = 0.49; P less than .001). Intravenous pancuronium was found to be a safe and effective method for cessation of fetal movement during intrauterine procedures.

Fatal falciparum malaria among narcotic injectors.

Eleven narcotic injectors from a prison in Saigon were hospitalized with falciparum malaria. Coma and intense parasitemia were common and eight patients died soon after admission. Two of three autopsied cases also had purulent pulmonary infections. No non-addicted prisoners were hospitalized for malaria. Nine more unsuspected falciparum infections were found among 29 other addicts in the prison. The clustering of malaria infections among narcotic injectors who had not been in malarious areas indicates that the malaria was transmitted by the common use of needles and syringes. Cerebral malaria in an addict may be misdiagnosed as drug intoxication. Malaria surveillance is recommended for the increasing addict population in the cities of Southeast Asia.

Pharmacokinetic and pharmacodynamic characteristics of ganirelix (Antagon/Orgalutran). Part I. Absolute bioavailability of 0.25 mg of ganirelix after a single subcutaneous injection in healthy female volunteers.

OBJECTIVE: To assess the absolute bioavailability of ganirelix (Antagon/Orgalutran; NV Organon, Oss, the Netherlands) after a single SC injection. DESIGN: Randomized, crossover, pharmacokinetic study. SETTING: Phase I clinical research unit. PATIENT(S): Nineteen healthy female volunteers of reproductive age. INTERVENTION(S): Two separate injections of 0.25 mg of ganirelix were given, one subcutaneously and one intravenously, with a washout period of 1 week between injections. Blood samples were taken for assessment of serum ganirelix concentrations, and blood pressure, heart rate, and adverse events were monitored. MAIN OUTCOME MEASURE(S): Pharmacokinetic parameters. RESULT(S): Fifteen subjects were evaluated. The mean concentration-time profile after SC administration was comparable to that after IV administration. The mean (+/- SD) peak concentration and time of occurrence after SC administration were 14.8+/-3.2 ng/mL and 1.1+/-0.3 hours, respectively. The mean (+/- SD) half-lives after IV administration and SC administration were highly similar (12.7+/-3.7 hours and 12.8+/-4.3 hours, respectively). Mean (+/- SD) AUC0-infinity (area under the concentration-time curve) values of 105+/-11 ng/mL x hours and 96+/-12 ng/mL x hours were calculated for IV administration and SC administration, respectively, resulting in an absolute mean (+/- SD) bioavailability of 91.3%+/-6.7%. Both treatments were well tolerated. CONCLUSION(S): Ganirelix is absorbed rapidly and extensively after SC administration, resulting in a high absolute bioavailability of >90%.

Role of adenosine in functional hyperemia in skeletal muscle as indicated by pharmacological tools.

The hypothesis that adenosine mediates blood flow increments in contracting skeletal muscle was evaluated by intravital microscopy of the microcirculation in the tenuissimus muscle of anesthetized rabbits. Motor nerve stimulation elicited muscle contractions and frequency-dependent arteriolar dilatation, particularly in terminal arterioles. The pulse duration (0.05 ms) and voltage (1.5-5 V) precluded activation of vasoconstrictor fibers, as also indicated by the lack of effect of phentolamine on resting vascular tone and on the hyperemic response to nerve stimulation. The specific adenosine receptor antagonist, 1,3-dipropyl-8-p-sulfo-phenylxanthine (DPSPX; 10(-5) M), attenuated the hyperemic response to muscle contractions. The adenosine uptake inhibitor dipyridamole (10(-8)-10(-6) M) dose-dependently dilated microvessels, an effect prevented by DPSPX (10(-5) M). Moreover, dipyridamole (10(-7) M) augmented contraction-induced hyperemia. The enhancement by dipyridamole was reversed by DPSPX (10(-5) M). The effects of adenosine uptake inhibitor and antagonist were invariably more marked in terminal than in transverse arterioles, and also more pronounced at higher stimulation frequencies. Motor nerve stimulation failed to induce alterations in vascular diameters when the neuromuscular junction was blocked by pancuronium. Thus, our observations indicate that functional hyperemia after motor nerve-induced contractions of the skeletal muscle was of postjunctional origin. Apparently, activation of adenosine receptors was responsible for a part of the evoked vasodilation.

Contribution of brain injury to hypertension following intravenously-administered pancuronium in rats.

Abnormal hypertension sometimes occurs following intravenous administration (i.v.) of pancuronium in patients with brain injury. The present experiment was designed to determine whether brain injury contributes to the hypertensive response of i.v. pancuronium. Forty-six Wister strain rats were studied, of which 39 had induced brain injury at (a) upper pons (b) midbrain (c) thalamus region (excluding hypothalamus) and (d) cerebellum or a combination of these sites. The injury was made by single insertion of a 22 Gauge needle through the skull surface. The quantity of pancuronium solution administered i.v. in each case was 1.0 ml containing either 0.8 mg/kg or 8 mg/kg of pancuronium. Group A (n = 7) had no brain injury and the mean arterial pressure (MAP) did not change following i.v. administration of pancuronium. In Group B (n = 9) (a+b+c, 8.0 mg/kg) MAP rose from 90.9 +/- 15.4 to 102 +/- 22.0 mmHg and in Group C (n = 7) (a+b+c, 0.8 mg/kg) MAP rose from 148.4 +/- 13.3 to 160 +/- 14.4 mmHg. In Group D (n = 5) (b+c, 8.0 mg/kg) MAP remained unchanged. In Group E (n = 5) (a, 8.0 mg/kg) MAP rose from 130.3 +/- 18.7 to 146 +/- 27.6 mmHg and in Group F (n = 6) (a, 0.8 mg/kg) MAP rose from 129.7 +/- 15.6 to 135.8 +/- 13.8 mmHg. In Group G (n = 7) (d, 8.0 mg/kg) MAP remained unchanged. Since the MAP was elevated in only those groups that received injury in the upper pons, we concluded that injury in the upper pons can lead to hypertension following i.v. administration of pancuronium.

Plasma concentrations of 3-keto-desogestrel after oral administration of desogestrel and intravenous administration of 3-keto-desogestrel.

The plasma concentrations of 3-keto-desogestrel have been measured by radioimmunoassay in a crossover study in nine healthy female volunteers given oral desogestrel (150 micrograms) and ethinyloestradiol (30 micrograms) and intravenous (i.v.) 3-keto-desogestrel (150 micrograms) and ethinyloestradiol (30 micrograms). Bioavailability ranged between 40.0 and 113% with a mean value ( +/- SD) of 76.1 +/- 22.5%. Only 3 subjects had a bioavailability of less than 70%. There was no significant difference in the elimination half life of 3-keto-desogestrel which was 12.6 +/- 4.1h following i.v. administration and 11.9 +/- 4.1h after oral administration of desogestrel.

PIP: In order to define its bioavailability, plasma concentration of 3-keto-desogestrel, the active metabolite of the progestogen desogestrel, was radioimmunoassayed in 9 women after a single iv dose of 150 ug or a single oral dose of 150 ug in combination with 30 ug ethinyl estradiol. Desogestrel is 13-ethyl-11-methylene-18, 19-dinor-17alpha-preg-4-en-20-yn-17-ol, the progestogen in the effective combined oral contraceptive Marvelon (Organon). The drug was given early in the menstrual cycle to each woman twice in a crossover design, 4 weeks apart. Bioavailability was calculated as the ratio of area under the plasma concentration time curve of the oral to the area under the curve of the iv dose. There was no significant difference in the elimination half-life of 3-keto-desogestrel by oral or iv administration: 11.9 and 12.6 hours. Mean plasma clearance, calculated by dose given divided by area under the curve, was 12.13 1/hour by oral, and 8.7 by iv routes. Bioavailability ranged from 40 to 113%, a wide individual variation, as seen in previous studies. Although mean bioavailability was 76%, the value was above 70% in 6 women, and 40.0, 54.7 and 64.1% in 3 others. This indicates that bioconversion was near quantitative. The reason for the variation cannot be ascertained from these data. Despite variability in bioavailability, the desogestrel combined oral contraceptive is reported to be very effective, as well as less androgenic than pills containing levonorgestrel.

Comparison of the onset, spontaneous recovery and train of four fade of the clinical neuromuscular block produced by pancuronium and pipecuronium.

The following study was performed to delineate the possible differences in the onset, recovery and "train of four" (TOF) fade characteristics of pancuronium (Pan) and pipecuronium (Pip). Eighty adult American Society of Anesthesiologists (ASA) class I and II surgical patients were studied with institutional approval. After premedication, general anesthesia was induced with thiopental sodium i.v. followed by N2/O2 halothane and fentanyl. The lungs were ventilated. Normocarbia and normothermia were maintained. Two groups of 40 patients received pancuronium (0.1 mg/kg i.v.) or pipecuronium (0.07 mg/kg i.v.). Neuromuscular block (NMB) was measured simultaneously by mechanomyography (MMG) and electromyographically (EMG) on the thumb adductor muscle. Supramaximal (TOF) stimuli were applied to the ulnar nerve every 20 seconds. The onset of neuromuscular blocking action, duration of action (to 25% recovery of twitch response). TOF fade during onset and up to 25% T1 response recovery, hemodynamic changes following induction of anesthesia and after the muscle relaxant and subsequent oral intubation were determined. Mean values and the differences in the two treatments groups were statistically analyzed. The onset of action of the two agents were similar: 3.62 +/- 0.02 minutes (MMG) and 4.94 +/- 0.05 minutes (EMG, Pan) and 3.74 +/- 0.02 minutes (MMG) and 4.36 +/- 0.012 minutes (EMG, Pip). TOF fade ratios during the onset phase were similar. TOF fade at the 25% twitch responses recovery level was 100% with the MMG responses and (96% (Pan) and 94.8% (Pip) with the EMG responses at the 25% twitch response recovery level. Hemodynamic changes were similar after the single dose administration of the bolus administration of the two NMB agents.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of prior administration of suxamethonium on non-depolarising muscle relaxants in the dog.

The depolarising muscle relaxant suxamethonium (0.3 mg kg-1) was administered to six dogs. At 50 per cent return of the neuromuscular activity, as measured by the train-of-four technique, a non-depolarising muscle relaxant was administered. Three drugs, alcuronium (0.1 mg kg-1), gallamine (1.0 mg kg-1) and pancuronium (0.06 mg kg-1) were injected intravenously. At the 50 per cent return of neuromuscular activity, atropine and neostigmine were administered to reverse the neuromuscular block. The duration of action of the three non-depolarising relaxants was reduced by the prior administration of suxamethonium.

Neuromuscular blocking action of vecuronium in the dog and its reversal by neostigmine.

Vecuronium bromide is one of a new series of competitive or nondepolarising muscle relaxants which is closely related chemically to pancuronium. Doses of 0.06, 0.1 and 0.2 mg kg-1 produced neuromuscular block in the anaesthetised dog. There were no observable effects on arterial blood pressure. The neuromuscular block was readily reversible with neostigmine preceded by atropine.

Ventilation and cardiovascular studies during mechanical control of ventilation in horses.

Eleven out of 12 horses were underventilating while breathing spontaneously during halothane anaesthesia with high arterial carbon dioxide tensions. In addition, large alveolar to arterial oxygen tension gradients were found to be present. Mechanically, controlled ventilation with an intermittent positive pressure of 20-30 cm H2O reduced arterial carbon dioxide levels to normal. The alveolar to arterial oxygen gradients did not increase and in some cases decreased. These (A - a) Po2 gradients were due mainly to true shunt of the order of 30 per cent and not to ventilation perfusion inequality.