Remifentanil versus alfentanil in a balanced anesthetic technique for total abdominal hysterectomy.

STUDY OBJECTIVES: To compare the intraoperative effects and recovery characteristics of remifentanil hydrochloride and alfentanil when administered as part of balanced anesthesia, and to assess the effects of an additional remifentanil infusion administered as analgesic pretreatment before removal of the uterus. DESIGN: Multicenter, double-blind, randomized, parallel-group study. SETTING: Two university hospitals. PATIENTS: 35 ASA physical status I, II, and III women scheduled for elective total abdominal hysterectomy with general endotracheal anesthesia. INTERVENTIONS: Patients were premedicated with midazolam 0.05 mg/kg intravenously (i.v.). Anesthesia was induced with thiopental 2 mg/kg, vecuronium 0.15 mg/kg, and a single dose of opioid over 60 seconds (Pump 1): remifentanil 2 micrograms/kg (Remi/Placebo and Remi/Remi groups) or alfentanil 50 micrograms/kg (Alf/Placebo group). Anesthesia was maintained with a nitrous oxide/oxygen mixture (66:34 ratio) and a continuous opioid infusion: remifentanil 0.25 microgram/kg/min (Remi/Placebo and Remi/Remi) or alfentanil 0.5 microgram/kg/min (Alf/Placebo). At skin incision, a second blinded drug infusion was also initiated (Pump 2): remifentanil 0.25 microgram/kg/min (Remi/Remi) or saline placebo (Remi/Placebo and Alf/Placebo). Intraoperative responses were controlled with single doses of opioid and/or rate titrations via Pump 1. Pump 2 was terminated on removal of the uterus. Pump 1 was terminated at skin closure. MEASUREMENTS AND MAIN RESULTS: The mean (+/- SD) opioid infusion rates administered for the duration of Pump 2 to suppress responses to removal of the uterus were 0.49 +/- 0.27 microgram/kg/min, 1.99 +/- 1.34 micrograms/kg/min, and 0.49 +/- 0.07 microgram/kg/min for the Remi/Placebo, Alf/Placebo, and Remi/Remi groups, respectively. At these rates, similar proportions of patients in the Remi/Placebo (67%) and the Alf/Placebo (60%) groups had responses. Fewer patients had responses in the Remi/Remi group (8%) compared with the Remi/Placebo and Alf/Placebo groups (p < 0.05). The mean total opioid doses used during maintenance were 84.6 micrograms/kg (Remi/Placebo), 393 micrograms/kg (Alf/Placebo), and 68.7 micrograms/kg (Remi/Remi). Awakening times were significantly shorter (p < 0.05) in the remifentanil population compared with the alfentanil population, but discharge times were similar. More patients received naloxone to reverse opioid effects in the alfentanil population (60%) than in the remifentanil population (20%) (p < 0.05). CONCLUSIONS: A mean remifentanil infusion of 0.49 microgram/kg/min is as effective as a mean alfentanil infusion of 1.99 micrograms/kg/min in suppressing intraoperative responses. Doubling of the remifentanil infusion to 0.5 microgram/kg/min before the major stress event improves suppression of responses and lowers intraoperative use of remifentanil without prolonging recovery times. Remifentanil allows faster awakening times than alfentanil, but preemptive administration of postoperative analgesics is recommended to facilitate discharge.

Dose comparison of remifentanil and alfentanil for loss of consciousness.

BACKGROUND: This study evaluated the efficacy and safety of remifentanil, a potent mu agonist opioid with a rapid onset and offset of effect, as a sole induction agent for loss of consciousness (LOC) and compared it with alfentanil. METHODS: Remifentanil and alfentanil were administered intravenously over 2 min in ascending doses (remifentanil 2, 3, 4, 5, 6, 8, 10, 15, 20 microg/kg; alfentanil 40, 60, 80, 100, 120, 160, 200 microg/kg) to unpremedicated healthy patients. Patients were observed for rigidity and LOC for 30 s after the end of infusion. If patients had not lost consciousness, 2 mg x kg(-1) x min(-1) thiopental was administered until LOC was achieved. Arterial blood samples, obtained at specified time intervals, were analyzed for remifentanil and alfentanil whole-blood concentration. Blood pressure and heart rate were also recorded at preset time intervals. RESULTS: Neither drug could reliably produce LOC. With both drugs, there was a dose-dependent decrease in thiopental requirements and a dose-dependent increase in the incidence and severity of rigidity (P < 0.05). The median effective dose (ED50) for LOC with remifentanil was 12 microg/kg, and for alfentanil it was 176 mcrog/kg. The median effective concentration (EC50; whole-blood concentration) of remifentanil was 53.8 ng/ml and for alfentanil it was 1,012 ng/ml. Minimal hemodynamic changes were observed after either drug was given. CONCLUSIONS: Remifentanil is 15 times more potent than alfentanil, based on the ED50 to achieve loss of response to a verbal command and 20 times more potent than alfentanil based on the EC50. Neither opioid is suitable as a sole induction agent.

A multicenter evaluation of total intravenous anesthesia with remifentanil and propofol for elective inpatient surgery.

Remifentanil is a mu-opioid receptor agonist with a context sensitive half-time of 3 min and an elimination half-life < or = 10 min. This study sought to evaluate the efficacy of remifentanil and propofol total intravenous anesthesia (TIVA) in 161 patients undergoing inpatient surgery. Remifentanil 1 microgram/kg was given intravenously (i.v.) followed by one of two randomized infusion rates: small dose (0.5 micrograms.kg-1.min-1) or large dose (1 microgram.kg-1.min-1). Propofol (0.5-1.0 mg/kg i.v. bolus and 75 micrograms.kg-1.min-1 infusion) and vecuronium were also given. Remifentanil infusions were decreased by 50% after tracheal intubation. End points included responses (hypertension, tachycardia, and somatic responses) to tracheal intubation and surgery. More patients in the small-dose than in the large-dose group responded to tracheal intubation with hypertension and/or tachycardia (25% vs 6%; P = 0.003) but there were no other differences between groups in intraoperative responses. Recovery from anesthesia was within 3-7 min in both groups. The most frequent adverse events were hypotension (systolic blood pressure [BP] < 80 mm Hg or mean BP < 60 mm Hg) during anesthesia induction (10% small-dose versus 15% large-dose group; P = not significant [NS]) and hypotension (27% small-dose versus 30% large-dose group; P = NS), and bradycardia (7% small-dose versus 19% large-dose group; P = NS) during maintenance. In conclusion, when combined with propofol 75 micrograms.kg-1.min-1, remifentanil 1 microgram/kg i.v. as a bolus followed by an infusion of 1.0 microgram.kg-1.min-1 effectively controls responses to tracheal intubation. After tracheal intubation, remifentanil 0.25-4.0 micrograms.kg-1.min-1 effectively controlled intraoperative responses while allowing for rapid emergence from anesthesia.

Naloxone-induced and spontaneous reversal of depressed ventilatory responses to hypoxia during and after continuous infusion of remifentanil or alfentanil.

Remifentanil is a new mu opioid analgesic of the synthetic phenylpiperidine class. It has an extremely short half-life (10-20 min) due to its breakdown by nonspecific estrases. We studied the effects of continuous infusion of remifentanil, compared with alfentanil, on the respiratory response to hypoxia. In addition, we examined the efficacy of naloxone to reverse remifentanil-mediated depression of respiration. Spontaneous recovery after the end of the infusion was also assessed. Twelve adult males participated in the study. On three sessions, separated by 7 to 14 days, the participants received continuous infusion over 240 min of alfentanil (0.5 microgram/kg/min), remifentanil (0.025 microgram/kg/min) or remifentanil (0.1 microgram/kg/min). Naloxone (6 micrograms/kg) was given at 95 min. On a fourth session, remifentanil (0.1 microgram/kg/min) was infused and placebo was given instead of naloxone. Base-line hypoxic challenge was induced at 30 min before starting the infusion. Eight hypoxic challenges were conducted at 10 min after starting the infusion and half-hourly thereafter. Two postinfusion challenges were performed at 250 and 280 min. The slope (liter/min/SPO2) of the ventilatory response and the predicted ventilation at SPO2 of 80% (VE80) (liter/min) significantly decreased during the infusion with remifentanil and alfentanil. A significant difference was noted between the two doses of remifentanil. Naloxone administration was associated with reversal of the depressed hypoxic responses during the infusion of alfentanil and the low dose of remifentanil. Termination of remifentanil infusion was associated with a prompt spontaneous recovery of the blunted hypoxic responses that was not detected with alfentanil.(ABSTRACT TRUNCATED AT 250 WORDS)

Bioequivalence of a 17 beta-estradiol hydroxypropyl-beta-cyclodextrin complex in postmenopausal women.

Five postmenopausal women received single doses of a 0.675 mg estradiol hydroxypropyl-beta-cyclodextrin (estradiol-HP beta CD) sublingual tablet by the sublingual and oral route. A single dose of a 1 mg micronized estradiol tablet was given orally for comparison. Blood samples were obtained over 48 hours for measurement of estradiol, estrone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) concentrations. Sublingual administration produced faster and significantly higher peak estradiol concentrations than after oral administration of either estradiol-HP beta CD or micronized estradiol. The concentration-time area under the curve of estradiol after sublingual estradiol-HP beta CD was also significantly larger than after oral administration of either estradiol-HP beta CD or micronized estradiol, reflecting a larger estradiol bioavailability. The estradiol/estrone concentration ratio after sublingual estradiol-HP beta CD revealed a predominance of estradiol for the first 2 hours after the dose, followed by an estrone predominance. Both oral doses produced a predominant delivery of estrone to the systemic circulation. There was not difference in time-averaged LH suppression between the three phases. However, estradiol-HP beta CD sublingually produced greater FSH suppression than oral micronized estradiol.

Long-term suppression of recurrent genital herpes with acyclovir. A 5-year benchmark. Acyclovir Study Group.

BACKGROUND AND DESIGN: This multicenter trial (19 sites) was initiated in 1984 in more than 1100 immunocompetent individuals with a history of frequently recurring genital herpes (mean, > or = 12 episodes per year). The first year of this suppressive therapy trial was placebo controlled, with acyclovir being provided for episodic treatment in both groups. Thereafter, patients were treated with open-label acyclovir suppressive therapy on a long-term basis (400 mg twice daily) to continue to assess its long-term safety and efficacy. Complete data are available on 389 of the 430 patients who began the fifth year of the study. RESULTS: Patients were seen quarterly for review of diaries and clinical laboratory evaluations. The percentage of patients recurrence free for any 3-month quarter of the fifth year ranged from 86% to 90%. The mean annual number of recurrences per patient declined from 1.7 during the first year to 0.8 during the fifth year of suppressive therapy. The frequency of false prodromes has also decreased over time. More than 20% of the patients receiving suppressive therapy for 5 years have been recurrence free the entire time. The duration of herpetic outbreaks during suppressive therapy has not changed. CONCLUSION: This study extends the safety and efficacy profile of oral acyclovir in the suppression of genital herpes to 5 years. The majority of the patients were recurrence free on an annual basis during suppressive therapy. Therapy was well tolerated. Acyclovir usage was not associated with serious side effects or cumulative toxicity.

Continuous five-year treatment of patients with frequently recurring genital herpes simplex virus infection with acyclovir.

This study presents data relative to the efficacy and safety following the continuous use of oral acyclovir in the treatment of genital herpes over a 5-year period. In this study, 1,146 patients (53% males; 47% females) were originally enrolled. These included patients with a history of frequently recurring genital herpes (mean > 12 episodes per year). During the first year, patients were randomized between those receiving 400 mg of acyclovir twice daily and an equal number receiving placebo. Additionally, acyclovir was utilized for episodic treatment (ES) in both groups. Thereafter, patients received open-label acyclovir suppressive therapy for the remainder of the study period. Complete data are available on 389 patients who completed the fifth year of therapy. All the participants who completed the fifty year of the study had completed either 4 or 5 years of daily suppressive acyclovir therapy. During the first year, a significant decrease in the frequency of recurrences in patients receiving continuous acyclovir (SS) was noted as compared to the placebo group (1.7 vs. 12.5 recurrences; P < 0.0001). From year one to the end of year three, a progressive decrease in the frequency of recurrences was noted in both groups. Yet, those patients who had received SS for the full 3 years had significantly fewer recurrences than those who had received ES in the first year (P = 0.05). During years four and five, the decrease in frequency of recurrences between the ES and SS groups was not significant.(ABSTRACT TRUNCATED AT 250 WORDS)

MK-927: a topical carbonic anhydrase inhibitor. Dose response and duration of action.

The dose response to a single topical administration of the carbonic anhydrase inhibitor MK-927 was investigated in 24 patients with primary open angle glaucoma or ocular hypertension. Three concentrations of MK-927 (2%, 1%, and 0.5%) and placebo were administered in a two-center, double-masked, randomized, placebo-controlled, four-period crossover study. MK-927 at the 0.5% concentration appeared to be minimally effective in reducing intraocular pressure. A single topical dose of 1% MK-927 resulted in a significantly greater percent reduction in intraocular pressure for up to 6 hours when compared with treatment with placebo. Similarly, a single dose of 2% MK-927 significantly lowered intraocular pressure for 8 hours compared with treatment with placebo. The pressure reduction from baseline measured 23.7% and 11.3% at 8 hours after instillation of a single drop of 2% MK-927. The medication was well tolerated and appeared to lower intraocular pressure in a dose-dependent fashion.

The effect of caffeine on intraocular pressure in glaucoma patients.

The authors investigated the effect of drinking regular coffee on intraocular pressure (IOP) using a single-masked randomized crossover study comparing coffee and herbal tea in 13 glaucoma patients. Intraocular pressure and blood pressure were monitored before ingestion of coffee or tea and at 30, 60, and 90 minutes after ingestion. The mean (+/- standard error of measurement) change in IOP 30, 60, and 90 minutes after ingestion for the coffee drinkers was 0.96 +/- 0.4, 1.38 +/- 0.53, and 1.04 +/- 0.37 mmHg, respectively. The mean change in IOP for the tea drinkers 30, 60, and 90 minutes after ingestion was 0.85 +/- 0.41, 0.23 +/- 0.36, and -0.42 +/- 0.44 mmHg, respectively. There was a statistically significant difference in the change in IOP at 90 minutes when comparing coffee to tea (P = 0.003) and no significant difference for 30 and 60 minutes. Although there was a statistically significant difference in IOP at 90 minutes between coffee and tea drinkers, the change was not clinically significant.

Near-total reduction in verapamil bioavailability by rifampin. Electrocardiographic correlates.

We evaluated the significance of the interaction between rifampin and verapamil in six volunteers who received single doses of verapamil, 10 mg intravenously (IV), then 120 mg orally two days later. Subjects were then given rifampin, 600 mg orally every day for 15 days. After 13 and 15 days of rifampin therapy, the IV and oral doses of verapamil were repeated. Electrocardiograms (ECG) were done and serum verapamil and norverapamil concentrations measured before and for 12 h after each dose. For IV verapamil, there was a small decrease in area under the serum concentration-time curve and an increase in clearance after rifampin therapy (p less than 0.05). There were no changes in elimination half-life, volume of distribution, or AUC for percentage of change in P-R interval-time curve (AUCPR). For oral verapamil, there were marked decreases in peak concentration, AUC, oral bioavailability (all p less than 0.005), and AUCPR (p less than 0.001) after rifampin treatment. There were no changes in time to peak concentration or elimination half-life. For oral verapamil, significant P-R interval prolongation occurred only before treatment with rifampin. The decrease in oral bioavailability and the abolition of ECG response confirm that a highly significant drug interaction exists between rifampin and verapamil given orally but not intravenously.

Patient-controlled analgesia in the terminally ill cancer patient.

Patient-controlled analgesia (PCA) is a relatively new therapeutic modality which has allowed postsurgical patients to safely and effectively self-administer doses of intravenous narcotics via a syringe pump and sequencing device. A pilot study was designed to evaluate PCA's safety and effectiveness in the terminally ill cancer patient. Eight patients whose chronic pain was not adequately controlled by oral narcotics were permitted to use PCA for a minimum of 48 hours. Respiratory rates, sedation rankings, and pain rankings indicated these patients achieved satisfactory analgesia with a minimum of sedation and experienced no respiratory depression. Three patients were switched to oral regimens using PCA dosing as a guide. Pain and sedation rankings were similar to those registered while exclusively on PCA. This self-dosing technique was judged to be safe, effective, and able to accommodate wide fluctuations in analgesic need when treating pain in the terminally ill cancer patient. The results obtained in these patients support further trials using PCA to individualize oral analgesic regimens.

Pharmacologic evaluation of loratadine (SCH 29851), chlorpheniramine and placebo.

The antihistaminic effect of loratadine (160 mg) was compared in twenty-four normal male volunteers to chlorpheniramine maleate (4 mg) and placebo in a double blinded 3-way cross-over study of latin square design. After receiving single oral doses of each medication, the wheal response to serial 0.1 ml intradermal histamine (2 micrograms) and saline (control) injections were recorded over a 24-h period. The calculated wheal areas were compared to base-line measurements. The results were analyzed by analysis of variance. Loratadine exhibited a more pronounced inhibition of histamine wheal formation than placebo or chlorpheniramine maleate (p less than 0.003). In contrast to chlorpheniramine maleate which had a duration of action of only 3 h, loratadine inhibited the response for the entire observation period between 1 and 24 h post-dose. Although sedation was observed less frequently with loratadine (Placebo, n = 2; chlorpheniramine, n = 3; and loratadine, n = 1), the relative incidence were not statistically significant.

Evaluation of 516 cardiopulmonary resuscitation attempts.

All adult cardiopulmonary resuscitations attended by the pharmacy department at a 486-bed tertiary-care institution were analyzed over a 24-month period. Data describing patient demographics, drug and equipment use, and patient survival were collected on 516 consecutive adult arrests. These data were recorded on a report form by a pharmacy technician and were classified as cardiac, respiratory, trauma, or other. Trauma included arrests caused by motor-vehicle accidents and gunshot wounds, and other included arrests caused by anaphylaxis or seizures. The majority of arrests (70%) were classified as cardiac, 24% as respiratory, and 6% as other. Overall, 54.5% of the patients suffering from arrests were resuscitated successfully. There was an equal distribution of arrests throughout the day. The mean duration of the resuscitation efforts was 38 minutes with a trend toward greater patient survival when resuscitation efforts lasted less than 15 minutes. Arterial blood-gas determinations were made in 81% of the arrests, defibrillations in 40%, and pacemaker or chest tube insertion in less than 10%. Sodium bicarbonate was the most frequently administered medication, followed by calcium salts and atropine sulfate. Lidocaine was used in 83% of the cases requiring antiarrhythmic therapy. Pressor support was required in 44.6% of the cases; norepinephrine bitartrate was the first-line pressor agent. Drugs not categorized as essential according to the American Heart Association's Advanced Cardiac Life Support (ACLS) standards were administered infrequently. Hospitals may benefit from arrest data in assessing their equipment and supply needs, staffing patterns, and personnel training programs.

Relationship between plasma morphine concentrations and pharmacologic effects in postoperative patients using patient-controlled analgesia.

In postoperative patients using patient-controlled analgesia (PCA) to administer i.v. doses of morphine sulfate, respiratory rates and subjective rankings of pain, sedation, and liking for the drug were correlated with plasma morphine concentrations. In 12 patients selected before surgery, the initial morphine sulfate dose of 0.6 mg/sq m was increased or decreased as needed. Every two hours, cumulative morphine sulfate dose, respiratory rate, and sedation were recorded by the nurse, along with the patient's evaluation of pain and liking for the drug. Plasma was collected in the morning and evening during PCA therapy for morphine analysis. Data were analyzed by analysis of covariance. Dosing rates and rankings of pain, sedation, and liking decreased as a function of time postoperatively, but respiratory rates did not. Sedation and respiratory rates were independent of morphine concentration. Liking of the drug increased directly with plasma morphine concentration but decreased with time. A high level of pain was directly related to morphine use. For all significant relationships, there was high interpatient variability, with the exception of changes in pain rankings induced by morphine. Patients defined a minimum effective plasma morphine concentration of 20-40 ng/mL. The maximum plasma morphine concentration achieved by self-administration was 82 ng/mL. These postoperative patients used patient-controlled analgesia to deliver morphine sulfate i.v. for pain relief, not for euphoria, and did not exhibit sedation or respiratory depression. Morphine was consistently effective at plasma concentrations of 40 ng/mL or greater.

Nifedipine stability in cardioplegic solution.

The stability of nifedipine in cardioplegic solution was studied. Cardioplegic solutions containing nifedipine at 275 and 500 micrograms/liter were stored in plastic bags covered in brown plastic wrappers (1) under normal room light at 25 degrees C and (2) in a dark refrigerator at 4 degrees C. Samples were removed periodically for 48 hours. Infusions of cardioplegic solution containing 275 micrograms/liter were simulated using tubing and flow rates of 100, 200, and 300 ml/min; bags were covered with aluminum foil, while tubing was exposed to normal room lighting or yellow lighting, which does not degrade nifedipine. Gas chromatography was used for nifedipine assays. Nifedipine degraded more rapidly at 25 degrees C than at 4 degrees C. However, even when protected from light and refrigerated, nifedipine concentrations declined to less than 90% of original potency by approximately six hours after preparation. There was no significant degradation during the simulated infusion regardless of light exposure or flow rate. Cardioplegic solutions containing nifedipine should be prepared immediately before the surgical procedure, refrigerated until use, and protected from light until administration.

Extraordinary analgesic requirement in a patient previously unexposed to narcotics.

Patient-controlled analgesia (PCA) is a relatively new therapeutic modality that allows patients to administer doses of intravenous narcotics, using a syringe pump and sequencing device. We used PCA to deliver analgesic therapy to a 35-year-old man seriously injured in an aviation accident. Although the patient gave no previous history of narcotic use or abuse, he required morphine dosing rates as high as 56 mg/h to maintain adequate analgesia. The delivery of relatively high doses of narcotic was not accompanied by significant sedation, as might be expected. The patient underwent two surgical procedures while on PCA therapy. Following each procedure, dosing requirements increased, but within three days after each operation, dosing tapered. The patient was converted to oral hydromorphone therapy, which gradually was tapered and then discontinued. PCA should be considered a useful therapeutic adjunct in the management of patients refractive to empirical narcotic analgesic regimens.

Patient-controlled analgesia.

Patient-controlled analgesia is a relatively new and investigational technique that permits patients to treat pain by directly activating doses of intravenous narcotics. The technique was developed in response to the undertreatment of pain in hospitalized patients. Continuous narcotic infusion and intraspinal narcotic administrations also have the potential to provide continuous, uninterrupted analgesia, but do not allow simple dose attentuation to avoid overdosage. Patient-controlled analgesia is used to treat postoperative and labor pain and pain associated with terminal illness; it delivers analgesic more effectively with fewer side effects than conventional parenteral narcotic therapies. The technique is also an ideal investigative instrument for studying equianalgesic states. Several foreign-made devices are now being used under investigational sanctions in this country, and it is anticipated that several American manufacturers will be seeking regulatory approval to market the devices.