Robert J. Fragen

Midazolam: pharmacology and uses.

Midazolam is an imidazobenzodiazepine with unique properties when compared with other benzodiazepines. It is water soluble in its acid formulation but is highly lipid soluble in vivo. Midazolam also has a relatively rapid onset of action and high metabolic clearance when compared with other benzodiazepines. The drug produces reliable hypnosis, amnesia, and antianxiety effects when administered orally, intramuscularly, or intravenously. There are many uses for midazolam in the perioperative period including premedication, anesthesia induction and maintenance, and sedation for diagnostic and therapeutic procedures. Midazolam is preferable to diazepam in many clinical situations because of its rapid, nonpainful induction and lack of venous irritation. Compared with thiopental, midazolam is not as rapid acting nor predictable in hypnotic effect. It will not replace thiopental as an induction agent. Advantages of midazolam over thiopental are those of the more versatile pharmacologic properties of a benzodiazepine compared with a barbiturate such as amnestic and anxiolytic properties. Midazolam should be a useful addition to the formulary.

Ketorolac tromethamine as compared with morphine sulfate for treatment of postoperative pain

Ketorolac tromethamine, a nonnarcotic, prostaglandin synthesis‐inhibiting analgesic, was compared with morphine sulfate for relief of moderate to severe postoperative pain. The 155 patient participants received single intramuscular doses of either ketorolac, 10, 30, or 90 mg, or morphine, 6 or 12 mg, administered in a double‐blind, randomized fashion. Pain scores (verbal and visual analog) were recorded at baseline and assessed at 30 minutes and then hourly to 6 hours. Pain relief was rated at the same times. Ketorolac, 90 and 30 mg, was rated significantly better than morphine, 6 mg, at each assessment interval after 1 hour. Ketorolac, 90 and 30 mg, was rated similarly to morphine, 12 mg, for the first 3 hours and better than morphine, 12 mg, 4 hours after injection. There were no serious side effects reported. The only side effect reported in more than 3% of patients was 8% somnolence with morphine. This study shows ketorolac to be a safe and effective analgesic for relief of postoperative pain.

Effects of Etomidate on Hormonal Responses to Surgical Stress

The hormonal responses to surgical stress were examined in 10 patients scheduled for elective gynecologic laparotomy. Anesthesia was induced with either thiopental, 4 mg/kg, or etomidate, 0.35 mg/kg, and maintained with nitrous oxide and enflurane. Plasma cortisol, aldosterone, ACTH, and catecholamines were measured during the 24 h after the induction of anesthesia. The catecholamine responses of the patients whose anesthesia was induced with either drug were similar. The plasma ACTH concentrations for the etomidate group were greater than baseline values and the concentrations in the thiopental group (P < 0.05) in the fourth and fifth hours. In the patients receiving thiopental, both cortisol and aldosterone concentrations were greater than the baseline value (P < 0.05) in the second to fourth hours after induction. In the etomidate group, the plasma concentrations of cortisol were less than baseline values (P < 0.05) in the first and second hours after induction of anesthesia and both cortisol and aldosterone were lower than those in the thiopental group (P < 0.05) in the half to fourth hours after induction. These results confirm an earlier report of the suppression of cortisol after etomidate administration and, because aldosterone also was suppressed, suggests that etomidate exerts its effect by inhibiting early stages of steroidogenesis in the adrenal cortex.

The Pharmacokinetics of Dexmedetomidine in Volunteers with Severe Renal Impairment

Dexmedetomidine, an &agr;2-adrenergic agonist with sedative and analgesic properties, is mainly cleared by hepatic metabolism. Because the pharmacokinetics of dexmedetomidine have not been determined in humans with impaired renal function, we studied them in volunteers with severe renal disease and in control volunteers. Six volunteers with severe renal disease and six matched volunteers with normal renal function received dexmedetomidine, 0.6 &mgr;g/kg, over 10 min. Venous blood samples for the measurement of plasma dexmedetomidine concentrations were drawn before, during, and up to 12 h after the infusion. Two-compartmental pharmacokinetic models were fit to the drug concentration versus time data. We also determined its hemodynamic, respiratory, and sedative effects. There was no difference between Renal Disease and Control groups in either volume of distribution at steady state (1.81 ± 0.55 and 1.54 ± 0.08 L/kg, respectively; mean ± sd) or elimination clearance (12.5 ± 4.6 and 8.9 ± 0.7 mL · min−1 · kg−1, respectively). However, elimination half-life was shortened in the Renal Disease group (113.4 ± 11.3 vs 136.5 ± 13.0 min;P < 0.05). A mild reduction in blood pressure occurred in most volunteers. Although most volunteers were sedated by dexmedetomidine, renal disease volunteers were sedated for a longer period of time.

Effect of dexmedetomidine on the minimum alveolar concentration (MAC) of sevoflurane in adults age 55 to 70 years

STUDY OBJECTIVE To determine the effect of two target dexmedetomidine infusions (0.3 ng/ml and 0.6 ng/ml) on the minimal alveolar concentration (MAC) of sevoflurane in adults age 55 to 70 years. DESIGN Prospective, randomized, placebo-controlled study. SETTING University-affiliated hospital. PATIENTS 45 ASA physical status I and II adults, age 55 to 70 years, undergoing elective surgery with at least a 3 inch skin incision. INTERVENTIONS Patients were given a dexmedetomidine or placebo infusion for at least 15 minutes before anesthetic induction with sevoflurane in oxygen by face mask. After tracheal intubation, a target sevoflurane concentration was maintained for 15 minutes while the dexmedetomidine or placebo infusion continued to run. MEASUREMENTS AND MAIN RESULTS At the time of skin incision, two observers independently determined movement or nonmovement to the incision. Blood samples for dexmedetomidine were taken before the infusion and at the time of skin incision. The dexmedetomidine plasma concentrations were 0 before infusion with all treatment groups. At the time of incision, they were 0 in the placebo group, 0.39 +/- 0.13 ng/ml in the 0.3 ng/ml target group, and 0.7 +/- 0.13 ng/ml in the 0.6 ng/ml target group. The MAC of sevoflurane was 1.83% in the placebo group, 1.78% in the 0.3 ng/ml target dexmedetomidine group, and 1.51% in the 0.6 ng/ml target dexmedetomidine group. CONCLUSIONS Dexmedetomidine 0.7 ng/ml decreased the MAC of sevoflurane by 17%, whereas there was no difference between the placebo and the dexmedetomidine 0.39 ng/ml group.

Dose-ranging study in younger adult and elderly patients of ORG 9487, a new, rapid-onset, short-duration muscle relaxant

The purpose of this multicenter, randomized, assessor-blind placebo-controlled study was to determine which of five doses of the new, rapid-onset neuromuscular relaxant, ORG 9487, provided both good to excellent tracheal intubating conditions 60 s after administration and a clinical duration of action <20 min in 120 younger (aged 18-64 yr) and 61 elderly (aged 65-85 yr) adult patients. Anesthesia was induced with fentanyl (2-5 micro g/kg) and thiopental (3-6 mg/kg) and maintained with N2 O/O2 and a propofol infusion (50-300 micro g [centered dot] kg-1 [centered dot] min-1). Neuromuscular train-of-four (TOF) monitoring by electromyography (Datex Relaxograph) commenced immediately after anesthetic induction and was followed, within 30 s, by one of five doses of ORG 9487 (0.5, 1.0, 1.5, 2.0, 2.5 mg/kg) or a placebo. Tracheal intubation was attempted at 60 s and again, in the case of failure, at 90 s. Conditions were assessed with a 4-point scale. Maximum block, clinical duration (time to 25% T1 recovery), and recovery (TOF >or=to 0.7) were measured. Dose-dependent changes were observed in tracheal intubating conditions and neuromuscular block. Good to excellent intubating conditions at 60 s were present in most younger adult (52 of 60) and elderly (26 of 31) patients administered doses >or=to1.5 mg/kg. Mean clinical durations <20 min were observed in adult patients at doses up to 2.0 mg/kg and in geriatric patients up to 1.5 mg/kg. Thus, doses of 1.5-2.0 mg/kg ORG 9487 enabled both rapid tracheal intubation and a short clinical duration of action in adult and elderly patients. (Anesth Analg 1997;84:1011-8)

A Water-soluble Benzodiazepine, RO 21–3981, for Induction of Anesthesia

Diazepam, a benzodiazepine, is widely used to produce basal narcosis prior to anesthesia because of its effectiveness and lack of cardiorespiratory side effects. The venous irritation or occasional phlebitis related to its insolubility in water is a distinct drawback.1–3 Dilution of diazepam and prior administration of a local anesthetic have been used to decrease the pain on injection.4 These maneuvers, however, do not prevent phlebitis in the veins of animals.4 A new water-soluble benzodiazepine, RO 21–3981 (8-chloro-6(2-fluorophenyl)-l -methyl-4H-imidazo-[l,5-a][l,4]benzodiazepine maleate), has been shown in animal studies to have central nervous system depressant properties similar to those of diazepam but with approximately twice the potency.§ Based upon unpublished studies,§ 0.15 mg/kg is the suggested induction close of RO 21–3981. We compared RO 21–3981, diazepam, and thiopental as agents for the intravenous induction of general inhalational anesthesia and evaluated the differences in induction times, cardiorespiratory changes, venous irritation, retrograde or antegrade amnesia, and patient acceptability.

A Randomized, Double-blind Evaluation of Ketorolac Tromethamine for Postoperative Analgesia in Ambulatory Surgery Patients

BackgroundGiven he trend toward early discharge of patients after surgery and the inherent adverse effects of opioid analgesics, we compared a new nonsteroidal antiinflammatory drug, ketorolac tromethamine, given intravenously (iv) and then orally, with two commonly prescribed opioid analgesics in ambulatory patients for up to 1 week after surgery. MethodsIn this study Incorporating a double-blind, multidose design, 221 patients who had moderate or severe pain after surgery were randomized to one of three treatment groups: group K30 received 30 mg iv ketorolac twice, then 10 mg iv every 30 min as required to control pain, up to six doses, followed by 10 mg oral ketorolac every 4–6 h; group F50 received 50 μg iv fentanyl at the same time intervals as in group K30, followed by 60 mg codeine plus 600 mg acetaminophen (C + A) orally every 4–6 h; and group F10 received the same combination as did group F50, but only 10 Mg fentanyl per dose. ResultsCompared with 50 Mg fentanyl iv, 30 mg iv ketorolac provided delayed but otherwise equivalent analgesic effects and was associated with similar side effects. Compared with C + A, 10 mg oral ketorolac was associated with a lower Incidence of nausea and somnolence and earlier return of bowel function but not better pain relief, drug tolerabllity, quality of life, or psychologic well-being. ConclusionsKetorolac, when used in an iv and then oral sequence, is a safe and effective analgesic in the ambulatory surgery setting. It has a slower onset than fentanyl, but causes fewer side effects than C + A.

Determinants of thiopental induction dose requirements

Dose requirements for thiopental anesthetic induction have significant age- and gender-related variability. We studied the association of the patient characteristics age, gender, weight, lean body mass, and cardiac output with thiopental requirements. Doses of thiopental, infused at 150 mg/min, required to reach both a clinical end-point and an electroencephalographic (EEG) end-point were determined in 30 males and 30 females, aged 18--83 yr. Univariate least squares linear regression analysis revealed outliers in the relationships of age, weight, lean body mass, and cardiac output to thiopental dose at clinical and EEG endpoints. Differential weighting of data points minimized the effect of outliers in the construction of a robust multiple linear regression model of the relationship between several selected independent variables and the dependent variables thiopental dose at clinical and EEG endpoints. The multiple linear regression model for thiopental dose at the clinical end-point selecting the regressor variables age, weight, and gender (R2 = 0.76) was similar to that for age, lean body mass, and gender (R2 = 0.75). Thiopental dose at the EEG end-point was better described by models selecting the variables age, weight, and cardiac output (R2 = 0.88) or age, lean body mass, and cardiac output (R2 = 0.87). Although cardiac output varied with age, age always remained a selected variable. Because weight and lean body mass differed with gender, their selection as variables in the model eliminated gender as a selected variable or minimized its importance.

Continuous intravenous infusion of rocuronium (ORG 9426) in patients receiving balanced, enflurane, or isoflurane anesthesia.

BackgroundRocuronium (ORG 9426) Is a new nondepolarizing neuromuscular blocking agent with a rapid onset and an intermediate duration of action. This study obtains the infusion requirements of rocuronium in 30 patients in whom anesthesia was maintained with barbiturate-nitrous oxide-opioid, nitrous oxide and enflurane, or nitrous oxide and isoflurane. MethodsFor all 30 patients, anesthesia was induced with intravenous thiopental and fentanyl, followed by 0.45 mg/kg rocuronium. Patients were randomly allocated to receive either: 1) nitrous oxide in 40% oxygen supplemented with fentanyl, thiopental, and droperidol (balanced anesthesia), 2) 1.25 MAC enflurane-nitrous oxide, or 3) 1.25 MAC isoflurane-nitrous oxide. Once blockade had recovered to 95% depression of twitch height, muscle relaxation was maintained by continuous Infusion of rocuronium, adjusted to maintain mechanical twitch response at 95% depression. ResultsAt 90 and 120 min, the enflurane and isoflurane groups had lower Infusion requirements than those receiving barbiturate-nitrous oxide-opioid anesthesia (P < 0.02), but these did not differ significantly between the two volatile agents. Final infusion requirements (mean ± SD) were 9.8 ± 3.7, 5.9 ± 3.1, and 6.1 ± 2.7 μg·kg-1·min-1 for the groups receiving barbiturate-nitrous oxide-opioid, enflurane, and isoflurane anesthesia, respectively. Spontaneous recovery began soon after termination of the infusion; in all patients, twitch tension equaled 10% of control within 5 min. ConclusionsThe infusion requirements to maintain 95% twitch depression approximated 10 μg·kg-1·min-1 during barbiturate-nitrous oxide-opioid anesthesia. These requirements were reduced by 40% during anesthesia involving enflurane or isoflurane.