The pharmacodynamic effect of a remifentanil bolus on ventilatory control.

BACKGROUND: In doses typically administered during conscious sedation, remifentanil may be associated with ventilatory depression. However, the time course of ventilatory depression after an initial dose of remifentanil has not been determined previously. METHODS: In eight healthy volunteers, the authors determined the time course of the ventilatory response to carbon dioxide using the dual isohypercapnic technique. Subjects breathed via mask from a to-and-fro circuit with variable carbon dioxide absorption, allowing the authors to maintain end-tidal pressure of carbon dioxide (PET(CO2)) at approximately 46 or 56 mm Hg (alternate subjects). After 6 min of equilibration, subjects received 0.5 microg/kg remifentanil over 5 s, and minute ventilation (V(E)) was recorded during the next 20 min. Two hours later, the study was repeated using the other carbon dioxide tension (56 or 46 mm Hg). The V(E) data were used to construct two-point carbon dioxide response curves at 30-s intervals after remifentanil administration. Using published pharmacokinetic values for remifentanil and the method of collapsing hysteresis loops, the authors estimated the effect-site equilibration rate constant (k(eo)), the effect-site concentration producing 50% respiratory depression (EC50), and the shape parameter of the concentration-response curve (gamma). RESULTS: The slope of the carbon dioxide response decreased from 0.99 [95% confidence limits 0.72 to 1.26] to a nadir of 0.27 l x min(-1) x mm Hg(-1) [-0.12 to 0.66] 2 min after remifentanil (P<0.001); within 5 min, it recovered to approximately 0.6 l x min(-1) x mm Hg(-1), and within 15 min of injection, slope returned to baseline. The computed ventilation at PET = 50 mm Hg (VE50) decreased from 12.9 [9.8 to 15.9] to 6.1 l/min [4.8 to 7.4] 2.5 min after remifentanil injection (P<0.001). This was caused primarily by a decrease in tidal volume rather than in respiratory rate. Estimated pharmacodynamic parameters based on computed mean values of VE50 included k(eo) = 0.24 min(-1) (T1/2 = 2.9 min), EC50 = 1.12 ng/ml, and gamma = 1.74. CONCLUSIONS: After administration of 0.5 microg/kg remifentanil, there was a decrease in slope and downward shift of the carbon dioxide ventilatory response curve. This reached its nadir approximately 2.5 min after injection, consistent with the computed onset half-time of 2.9 min. The onset of respiratory depression appears to be somewhat slower than previously reported for the onset of remifentanil-induced electroencephalographic slowing. Recovery of ventilatory drive after a small dose essentially was complete within 15 min.

Diphenylhydramine increases ventilatory drive during alfentanil infusion.

BACKGROUND: Diphenhydramine is used as an antipruritic and antiemetic in patients receiving opioids. Whether it might exacerbate opioid-induced ventilatory depression has not been determined. METHODS: The ventilatory response to carbon dioxide during hyperoxia and the ventilatory response to hypoxia during hypercapnia (end-tidal pressure of carbon dioxide [PETCO2] is approximately equal to 54 mmHg) were determined in eight healthy volunteers. Ventilatory responses to carbon dioxide and hypoxia were calculated at baseline and during an alfentanil infusion (estimated blood levels approximately equal to 10 ng/ml) before and after diphenhydramine 0.7 mg/kg. RESULTS: The slope of the ventilatory response to carbon dioxide decreased from 1.08+/-0.38 to 0.79+/-0.36 l x min(-1) x mmHg(-1) (x +/- SD, P < 0.05) during alfentanil infusion; after diphenhydramine, the slope increased to 1.17+/-0.28 l x min(-1) x mmHg(-1) (P < 0.05). The minute ventilation (VE) at PETCO2 approximately equal to 46 mmHg (VE46) decreased from 12.1+/-3.7 to 9.7+/-3.6 l/min (P < 0.05) and the VE at 54 mmHg (VE54) decreased from 21.3+/-4.8 to 16.6+/-4.7 l/min during alfentanil (P < 0.05). After diphenhydramine, (VE46 did not change significantly, remaining lower than baseline at 9.9+/-2.9 l/min (P < 0.05), whereas VE54 increased significantly to 20.5+/-3.0 l/min. During hypoxia, VE at SpO2 = 90% (VE90) decreased from 30.5+/-9.7 to 23.1+/-6.9 l/min during alfentanil (P < 0.05). After diphenhydramine, the increase in VE90 to 27.2+/-9.2 l/min was not significant (P = 0.06). CONCLUSIONS: Diphenhydramine counteracts the alfentanil-induced decrease in the slope of the ventilatory response to carbon dioxide. However, at PETCO2 = 46 mmHg, it does not significantly alter the alfentanil-induced shift in the carbon dioxide response curve. In addition, diphenhydramine does not exacerbate the opioid-induced depression of the hypoxic ventilatory response during moderate hypercarbia.

Effect of flumazenil on ventilatory drive during sedation with midazolam and alfentanil.

BACKGROUND: Patients who receive a combination of a benzodiazepine and an opioid for conscious sedation are at risk for developing respiratory depression. While flumazenil effectively antagonizes the respiratory depression associated with a benzodiazepine alone, its efficacy in the presence of both a benzodiazepine and an opioid has not been established. This study was designed to determine whether flumazenil can reverse benzodiazepine-induced depression of ventilatory drive in the presence of an opioid. METHODS: Twelve healthy volunteers completed this randomized, double-blind, crossover study. Ventilatory responses to carbon dioxide and to isocapnic hypoxia were determined during four treatment phases: (1) baseline, (2) alfentanil infusion; (3) combined midazolam and alfentanil infusions, and (4) combined alfentanil, midazolam, and "study drug" (consisting of either flumazenil or flumazenil vehicle) infusions. Subjects returned 2-6 weeks later to receive the alternate study drug. RESULTS: Alfentanil decreased the slope of the carbon dioxide response curve from 2.14 +/- 0.40 to 1.43 +/- 0.19 l.min-1.mmHg-1 (x +/- SE, P < 0.05), and decreased the minute ventilation at P(ET)CO2 = 50 mmHg (VE50) from 19.7 +/- 1.2 to 14.8 +/- 0.9l.min-1 (P < 0.05). Midazolam further reduced these variables to 0.87 +/- 0.17 l.min-1.mmHg-1 (P < 0.05) and 11.7 +/- 0.8 l.min-1 (P < 0.05), respectively. With addition of flumazenil, slope and VE50 increased to 1.47 +/- 0.37 l.min-1.mmHg-1 (P < 0.05) and 16.4 +/- 2.0l.min-1 (P < 0.05); after placebo, the respective values of 1.02 +/- 0.19 l.min-1.mmHg-1 and 12.5 +/- 1.2 l.min-1 did not differe significantly from their values during combined alfentanil and midazolam administration. The effect of flumazenil differed significantly from that of placebo (P < 0.05). Both the slope and the displacement of the hypoxic ventilatory response, measured at P(ET)CO2 = 46 +/- 1 mmHG, were affected similarly, with flumazenil showing a significant improvement compared to placebo. CONCLUSIONS: Flumazenil effectively reverses the benzodiazepine component of ventilatory depression during combined administration of a benzodiazepine and an opioid.

Sevoflurane versus isoflurane: induction and recovery characteristics with single-breath inhaled inductions of anesthesia.

Because of its nonpungent odor and low blood-gas solubility coefficient, sevoflurane might be an ideal drug for single-breath inhaled induction of anesthesia. Fifty ASA grade I-III ambulatory surgical patients (18-76 yr old) received a single-breath induction with either 5.0% sevoflurane or 5.0% isoflurane (randomized) in a 1:1 N2O/O2 mixture. Anesthesia was maintained with the same anesthetic in 70% N2O until the end of surgery, when anesthetics were abruptly discontinued. Induction times (loss of eyelash reflex) were similar for sevoflurane (75 +/- 3 s, mean +/- se) and isoflurane (67 +/- 4 s, P = not significant). Sevoflurane patients were less likely to have complications during induction (P < 0.005); coughing occurred more frequently with isoflurane (P < 0.001). During induction, heart rate increased with both sevoflurane (from 73 +/- 3 to 90 +/- 4 bpm, P < 0.05) and isoflurane (from 70 +/- 2 to 92 +/- 2 bpm, P < 0.05); the increase with isoflurane was greater than that with sevoflurane. Times to eye opening for sevoflurane (8.1 1 +/- 1.0 min) did not differ significantly from those for isoflurane (10.6 +/- 1.3 min). Patients opened their eyes at lower end-tidal minimum alveolar anesthetic concentration (MAC)-fractions of sevoflurane (0.12 +/- 0.01 MAC) than isoflurane (0.15 +/- 0.01 MAC, P < 0.01). During recovery, patients who received sevoflurane felt less clumsy (P < 0.001) and less confused (P < 0.005) but had higher pain scores (P < 0.005) than those who received isoflurane. Sevoflurane is more suitable than isoflurane for single-breath induction, because it produces a smoother induction with a lower incidence of complications and better patient acceptance.

The use of oral transmucosal fentanyl citrate for painful procedures in children.

OBJECTIVE: To investigate the efficacy and safety of oral transmucosal fentanyl (OTFC) in providing analgesia and sedation for painful diagnostic procedures in children. DESIGN: Randomized, placebo-controlled clinical trial. METHOD: Forty-eight children referred to the University Connecticut Division of Pediatric Hematology/Oncology for bone marrow aspiration or lumbar puncture were randomized to receive either OTFC (15 to 20 micrograms/kg) or a placebo lollipop. Thirty minutes after administration, the procedure was begun. An anesthesiologist monitored the child's heart rate, blood pressure, and oxygen saturation every 10 minutes. At the conclusion of the procedure, the nurse, the child's parent, and all children over 8 years of age were asked to rate the pain associated with the procedure using a 1 to 10 visual analogue scale. Young children (less than 8) used a modified scale, the Oucher, yielding a 0 to 5 score. RESULTS: Significant differences in pain ratings between the OTFC and placebo groups were noted on the pain scores of the parents (P = .005), nurses (P = .001), younger children (P = .006), and older children (P = .013), and median pain scores in the OTFC group were reduced to tolerable levels. Vomiting (P = .003) and itching (P = .001) were more common in the OTFC group, but no clinically significant vital sign deviations occurred. CONCLUSION: OTFC is safe and effective for use in relieving the pain of pediatric procedures, but frequency of vomiting may restrict its clinical usefulness.

Diphenhydramine enhances the interaction of hypercapnic and hypoxic ventilatory drive.

BACKGROUND: Although diphenhydramine is frequently used to treat pruritus and nausea in patients who have received neuraxial opioids, there are no data regarding its effect on ventilatory control. We conducted the current study to evaluate the effects of diphenhydramine on hypercapnic and hypoxic ventilatory control in healthy volunteers. METHODS: First, we measured the steady-state ventilatory response to carbon dioxide during hyperoxia with an end-tidal carbon dioxide tension of 46 or 54 mmHg (alternate subjects) in eight healthy volunteers. We then determined the hypoxic ventilatory response during isocapnic rebreathing at the same carbon dioxide tension. After a 10-min recovery period, we repeated the steady-state and hypoxic ventilatory response measurements at the other carbon dioxide tension (54 or 46 mmHg). Ten minutes after subjects received diphenhydramine 0.7 mg.kg-1 intravenously, we repeated this sequence of ventilatory measurements. RESULTS: Under hyperoxic conditions (inspired oxygen fraction > 0.5) diphenhydramine did not affect the ventilatory response to hypercapnia. Similarly, at an end-tidal carbon dioxide tension of 46 mmHg, neither the slope nor the position of the hypoxic ventilatory response curve changed significantly after diphenhydramine. However, at an end-tidal carbon dioxide tension of 54 mmHg, the slope of the hypoxic ventilatory response increased from 1.28 +/- 0.33 to 2.13 +/- 0.61 l.min-1.%SpO2(-1) (mean +/- standard error), and VE at an arterial hemoglobin oxygen saturation of 90% increased from 31.2 +/- 3.1 to 43.1 +/- 5.4 l.min-1). CONCLUSIONS: We conclude that although it did not affect the ventilatory response to carbon dioxide during hyperoxia or the ventilatory response to hypoxia at an end-tidal carbon dioxide tension of 46 mmHg diphenhydramine augmented the hypoxic response under conditions of hypercapnia in our young healthy volunteers. Although these findings may help to explain the apparent safety of diphenhydramine, they may not be applicable to debilitated patients or those who have received systemic or neuraxial ventilatory depressants.

Immunogenicity of synthetic HIV-1 gp120 V3-loop peptide-conjugate immunogens.

A successful prophylactic human immunodeficiency virus type 1 (HIV-1) vaccine must elicit an immune response that will prevent establishment of the persistent viral infection. The only response shown to be effective in this regard is virus-neutralizing antibody directed against the viral gp120 hypervariable V3-loop region. Conjugate immunogens, containing cyclic peptides representing the V3 determinant covalently bound to a carrier protein, were capable of eliciting virus-neutralizing antibodies. The consistency of the response was related to peptide size. The smaller cyclic peptides, expressing relatively conserved sequences from the V3-loop apex, were poor inducers of neutralizing activity. In contrast, the largest cyclic peptides mediated neutralizing responses that were similar to those observed and previously reported for intact gp120 immunogens. A cyclic synthetic peptide expressing most of the prototypic HIV-1 MN variant V3 determinant warrants further study as a potentially effective vaccine immunogen.

Propofol depresses the hypoxic ventilatory response during conscious sedation and isohypercapnia.

BACKGROUND: Propofol infusion at subanesthetic doses provides reliable conscious sedation. However, the ventilatory effects of sedative doses of propofol have not been established. The current study was conducted to determine the effects of propofol sedation on the hypoxic ventilatory response. METHODS: Eight healthy, male volunteers received 1 mg.kg-1 propofol followed by a propofol infusion adjusted to maintain a constant, subanesthetic level of sedation. Hypoxic ventilatory response was measured using an isocapnic rebreathing technique: while keeping PETCO2 constant (approximately 6 mmHg above prestudy baseline), the authors continuously recorded minute ventilation and tidal volume, as oxygen saturation (SpO2) decreased from 98 to 70%. Hypoxic response determinations were performed before and during propofol infusion, as well as 30 and 60 min after termination of the propofol infusion. RESULTS: The slope of the hypoxic ventilatory response curve (VE vs. SpO2) decreased from 0.88 +/- 0.15 to 0.17 +/- 0.03 l.min-1.%SpO2 -1 during propofol sedation (mean +/- SE). Thirty minutes after discontinuation of the propofol infusion, slope returned to its prepropofol value. In addition, minute ventilation at SpO2 = 90% decreased during propofol sedation, from 16.1 +/- 0.8 to 8.7 +/- 0.4 l.min-1, accompanied by a similar decrease in tidal volume at SpO2 = 90%, from 1,099 +/- 87 to 523 +/- 21 ml. Thirty minutes after discontinuation of the propofol infusion, these variables also returned to their prepropofol values. CONCLUSIONS: The authors concluded that propofol infusion for conscious sedation significantly decreases the slope and causes a downward shift of the hypoxic ventilatory response curve measured during isohypercapnia.

Sedative doses of propofol increase beta activity of the processed electroencephalogram.

The effects of sedative infusions of propofol on the processed electroencephalograms (EEG) of eight healthy male volunteers were studied. EEG data for aperiodic analysis were collected during three 5-min periods: before propofol, during propofol infusion, and 30 min after termination of the infusion. After an initial dose of 1 mg/kg, subjects received a propofol infusion titrated to produce a standard level of conscious sedation. The infusion rate was 84 +/- 27 micrograms.kg-1 x min-1 (mean +/- SE) and plasma propofol levels were 2180 +/- 43 ng/mL. Total EEG power, defined as the sum of the squares of peak-to-peak amplitudes during each 5-s epoch, increased from 1350 +/- 295 microV2 x epoch-1 to 9675 +/- 2390 microV2 x epoch-1 during the propofol infusion (P < 0.05); it returned to 1445 +/- 145 microV2 x epoch-1 30 min after the infusion was discontinued (P < 0.05 vs the result during propofol). The change in total power was accompanied by a change in the distribution of power within the EEG spectrum, as the fraction of activity in the beta-band (12-35 Hz) increased during the infusion from 23% +/- 3% to 44% +/- 5% (P < 0.05). Thirty minutes after the infusion was terminated, the distribution of activity within the EEG spectrum had reverted to pre-propofol patterns. The similarity of EEG effects seen with sedative doses of propofol and benzodiazepines suggests that these drugs may share some neurochemical effects.

Identification of HIV vaccine candidate peptides by screening random phage epitope libraries.

Most synthetic HIV-1 gp120 V3 loop peptides that are used as immunogens in experimental HIV-1 vaccine studies are modeled from the naturally occurring viral gp120 V3 loops. In experimental animals these immunogens generally elicit type (or variant)-specific neutralizing antibodies that are not broadly reactive among HIV-1 variants. In an attempt to find a more general structure for the V3 loop, we have obtained candidates that mimic V3 loop sequences by screening random epitopes displayed in a fusion phage 15-residue epitope library. Human monoclonal antibody 447-52D, a highly potent and broadly reactive virus-neutralizing antibody that recognizes the conserved V3 loop tip motif GPXR, was the probe. By using a screening method that was designed specifically for this work, we identified hundreds of reactive phage clones, 70 of which were sequenced. Over 98% of the epitopes contain the motif GPXR, yet none of the 70 are an identical match to any V3 variant loop described to date. One of these sequences was synthesized as the beta-maleimidopropionyl 15-mer peptide, covalently conjugated to a carrier and used to immunize rabbits. High anti-peptide titers were obtained in all animals with three of four individual responses also binding to a peptide that is representative of the "North American consensus" V3 loop. The sera from these three positive rabbits neutralized HIV-1 variant SF-2 in vitro. In addition, one of them was capable of neutralizing variant AL-1. Both of these variants are considered to have V3 loops of the North American consensus type. Thus, neutralizing responses were obtained by use of an immunogen that was selected for its ability to bind a broadly reactive human monoclonal antibody rather than modeled from an HIV-1 gp120 V3 loop sequence.

Immunization with recombinant BCG-SIV elicits SIV-specific cytotoxic T lymphocytes in rhesus monkeys.

Because the transmission of HIV is likely to occur through cell-associated virus, an effective HIV vaccine should be capable of eliciting HIV-specific CTL. We have employed the simian immunodeficiency virus (SIV)/rhesus monkey model to explore the use of the attenuated tuberculosis bacillus, Calmette Guérin bacillus (BCG), as a vaccine vehicle to elicit AIDS virus-specific CTL. BCG was engineered to express SIVmac gag under the control of hsp70 regulatory sequences. Immunization with this rBCG-SIVmac gag elicited MHC class I-restricted, CD8+ SIVmac gag-specific CTL in rhesus monkeys. In fact, SIVmac gag-specific CTL could be cloned readily from peripheral blood lymphocytes of these immunized monkeys. These findings provide further evidence for the power of BCG as a vaccine vector and its continued exploration as a vehicle for eliciting HIV-specific immunity.

The effect of flumazenil on midazolam-induced depression of the ventilatory response to hypoxia during isohypercarbia.

BACKGROUND: While flumazenil reverses benzodiazepine-induced sedation, its ability to antagonize the ventilatory depressant effects of benzodiazepines has not been fully established. A randomized, double-blind study was conducted to determine whether flumazenil effectively reverses midazolam-induced depression of the hypoxic ventilatory response. METHODS: Twelve healthy male volunteers received intravenous midazolam 0.12 +/- 0.01 mg.kg-1 followed by either flumazenil 1.0 mg or placebo. Hypoxic ventilatory response was measured using an isocapnic rebreathing technique: as Spo2 decreased to 70% VE and tidal volume were continuously recorded. Hypoxic response determinations were performed before and after midazolam, as well as 3, 30, 60, 120, and 180 min after flumazenil or placebo. RESULTS: After midazolam, the slope of the hypoxic ventilatory response curve (VE vs. SpO2) decreased to 0.59 +/- 0.05 (means +/- SE) times its premidazolam baseline; likewise, at Spo2 = 90%, minute ventilation (VE90) and tidal volume (TV90) decreased to 0.70 +/- 0.04 and 0.62 +/- 0.03 times baseline, respectively. Three minutes after flumazenil, the slope increased to 1.10 +/- 0.13 times baseline (P < 0.05 vs. postmidazolam), while following placebo, it was only 0.81 +/- 0.09 times baseline (P = NS vs. postmidazolam, P < 0.05 between treatments). VE90 and TV90, after flumazenil, increased to 1.45 +/- 0.15 and 1.27 +/- 0.09 times baseline, respectively (P < 0.05 vs. postmidazolam); these increases were significantly greater than the corresponding changes observed after placebo (P < 0.05 between treatments). CONCLUSIONS: It was concluded that, after sedation with midazolam, flumazenil causes a greater increase in hypoxic ventilatory response during isohypercarbic conditions than does placebo, and may, therefore, be useful in the treatment of midazolam-induced ventilatory depression.

Time course of ventilatory depression following induction doses of propofol and thiopental.

To improve our understanding of the respiratory pharmacology of intravenous induction agents, the authors compared the acute effects of intravenous (iv) propofol 2.5 mg.kg-1 and iv thiopental 4.0 mg.kg-1 on the ventilatory response to CO2 (VeRCO2) of eight healthy volunteers. The slope of VeRCO2 decreased from 1.75 +/- 0.23 to a minimum of 0.77 +/- 0.14 1.min-1.mmHg-1 (mean +/- standard error) 90 s after propofol; similarly, the slope of VeRCO2 decreased from 1.79 +/- 0.22 to a minimum of 0.78 +/- 0.23 l.min-1.mmHg-1 30 s after thiopental. For both drugs, the slope was less than control in the 0.5-5-min period after injection (P less than 0.05). The slope returned to baseline within 6 min after thiopental; in contrast, after propofol, the slope remained less than control for the entire 20-min follow-up period (P less than 0.05 at 6-10, 11-15, and 16-20 min after injection). Also, from 6-10, 11-15, and 16-20 min after injection, the slope was less after propofol than at corresponding times after thiopental (P less than 0.05). Recovery of consciousness was approximately 4 min slower after propofol than after thiopental; nonetheless, awareness scores returned to baseline within 14 min after both drugs. The authors conclude that propofol 2.5 mg.kg-1 iv produces longer-lasting depression of VeRCO2 than a 4.0 mg.kg-1 iv dose of thiopental; after propofol, ventilatory depression may persist despite apparently complete recovery of consciousness.

Ibuprofen provides longer lasting analgesia than fentanyl after laparoscopic surgery.

The authors compared the analgesic efficacy of one dose of oral ibuprofen with that of intravenously administered fentanyl for relief of pain after outpatient laparoscopic surgery. Thirty healthy female patients received either 800 mg of oral ibuprofen preoperatively or 75 micrograms of intravenous fentanyl intraoperatively plus respective intravenous or oral placebos in a randomized, double-blind manner. Patients recorded their degree of pain and nausea in the recovery room, in the same-day surgery stepdown unit, during the ride home, and upon arrival at home. The postanesthesia care nurse recorded the amount of fentanyl and droperidol needed to treat pain and nausea in the recovery room. Patients who received ibuprofen were more comfortable in the stepdown unit (P less than 0.05) and after arrival home (P less than 0.05) than those in the fentanyl group. Additionally, patients who received ibuprofen had lower nausea scores in the step-down unit (P less than 0.05); this may have been related to the lower total fentanyl dose in these patients. The authors conclude that ibuprofen may be a useful alternative to fentanyl for providing postoperative analgesia for outpatient surgery.

Flumazenil antagonism of midazolam-induced ventilatory depression.

Flumazenil, a benzodiazepine antagonist, reliably reverses midazolam-induced sedation; however, its effect on respiratory depression has not been established completely. Twelve healthy volunteers received sufficient midazolam (0.13 +/- 0.01 mg.kg-1 mean +/- SE) to render them unresponsive to verbal command; they then received flumazenil 1.0 mg or placebo (flumazenil vehicle) in a randomized, double-blind fashion. Ventilatory drive was measured before and after administration of midazolam, as well as 3, 30, 60, and 120 min after administration of flumazenil or placebo. Seven to 30 days later, the study was repeated, with subjects receiving placebo or flumazenil (whichever they had not received during their first trial). Midazolam caused significant decreases in the slope of the CO2 response (-29 +/- 5%; P less than 0.005); minute ventilation (VE) at end-tidal CO2 tension (PETCO2) = 46 mmHg (-28 +/- 4%; P less than 0.001), and tidal volume at PETCO2 = 46 mmHg (-44 +/- 4%; P less than 0.005). Three minutes after intravenous administration of flumazenil 1.0 mg, VE46 and tidal volume increased to 108 +/- 6% and 105 +/- 6%, respectively, of their premidazolam values; at the same time after administration of placebo, VE46 and tidal volume remained significantly depressed (between groups, P less than 0.005 for each variable). Thirty minutes later, these variables did not differ between groups, probably because the effects of flumazenil and midazolam were diminishing.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of epidural and patient-controlled intravenous morphine following joint replacement surgery.

The authors conducted a randomized, prospective study comparing epidural morphine with patient-controlled intravenous (iv) morphine in 30 patients recovering from total hip or total knee arthroplasty. Six, 18, and 24 hr postoperatively, patients used a 10 cm visual-analogue scale to indicate both their current degree of discomfort and the maximum discomfort they had experienced since the previous evaluation. Pain at the time of evaluation did not differ between patients receiving epidural (2.6 +/- 0.4 cm, mean +/- SEM) and patient-controlled iv morphine (3.4 +/- 0.3 cm). However, patients who received epidural morphine recalled less pain during the period preceding evaluation (4.2 +/- 0.5 cm) than did those receiving patient-controlled analgesia (5.5 +/- 0.4 cm, P less than 0.05). Patients receiving epidural morphine were more likely to require treatment for pruritus (4 of 15) than patients who received patient-controlled iv morphine (none of 15, P less than 0.05). Minimum respiratory rates were lower in patients receiving epidural morphine (15.0 +/- 0.3) than in those receiving patient-controlled analgesia (16.5 +/- 0.4, P less than 0.05), but no patients required treatment for respiratory depression. The authors conclude that epidural morphine may provide more consistent analgesia following joint replacement surgery than patient-controlled morphine; however, there is a higher incidence of side-effects with the epidural technique.

Granulocytic sarcoma of the ileum treated by bone marrow transplantation.

An 8-year-old boy with a granulocytic sarcoma of the proximal ileum metastatic to mesenteric lymph nodes was placed into complete remission with surgical excision of the primary tumor and conventional induction chemotherapy with daunorubicin and cytosine arabinoside. He was then treated with high dose cytosine arabinoside, fractionated total body irradiation, and allogeneic marrow transplantation from his 22-month-old brother who was completely matched at the major histocompatibility complex. Methotrexate was given following the transplant to prevent graft-versus-host disease (GVHD). His post-transplantation course was complicated by a transient autoimmune hemolytic anemia related to an ABO blood group incompatibility and hepatic fungal microabscesses which responded to Amphotericin therapy. Four years following the transplant the patient remains in complete remission. The prognosis for patients with granulocytic sarcoma has been poor although, perhaps, improved over the past decade. This is the first published case report of successful treatment of a granulocytic sarcoma of the ileum by allogeneic marrow transplantation.

Yeast-expressed p55 precursor core protein of human immunodeficiency virus type 1 does not elicit protective immunity in chimpanzees.

Yeast-expressed p55 precursor core protein of human immunodeficiency virus type 1 (HIV-1) was used to immunize chimpanzees. The animals developed high titers of antibodies to p55 as well as to the p24 and p17 mature cleavage products of the core precursor. Virus-neutralizing antibodies were not elicited. The induced immune responses did not prevent establishment of HIV-1 infection following challenge of one immunized chimpanzee with live virus.

Protective effect of a synthetic peptide comprising the complete preS2 region of the hepatitis B virus surface protein.

A peptide was synthesized containing the entire 55 amino acid residue sequence of the hepatitis B virus (HBV) surface antigen preS2 region (ad subtype). The unconjugated peptide was inoculated into four chimpanzees. Following multiple injections, all of the animals developed specific antipeptide antibodies that reacted with intact surface antigen particles bearing the preS2 moiety. All four peptide-inoculated animals were found to be protected from infection after intravenous challenge with live HBV of either the ad or ay subtypes.