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.

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A randomized double-blind comparison of ondansetron and metoclopramide in the prophylaxis of emesis induced by cyclophosphamide, fluorouracil, and doxorubicin or epirubicin chemotherapy.

Journal of Clinical Oncology ◽

10.1200/jco.1990.8.6.1063 ◽

1990 ◽

Vol 8 (6) ◽

pp. 1063-1069 ◽

Cited By ~ 81

Author(s):

J Bonneterre ◽

B Chevallier ◽

R Metz ◽

P Fargeot ◽

E Pujade-Lauraine ◽

...

Keyword(s):

Group Analysis ◽

Loading Dose ◽

Breast Cancer Patients ◽

Double Blind ◽

Parallel Group ◽

Blind Comparison ◽

Prophylaxis Of Emesis ◽

To Receive ◽

Blind Crossover Study ◽

Double Blind Crossover Study

Seventy-five breast cancer patients scheduled to receive a first course (in a new cycle) of cyclophosphamide, fluorouracil, and doxorubicin (FAC) or epirubicin (FEC) participated in a double-blind crossover study to compare the antiemetic efficacy and safety of ondansetron (GR38032), a 5-hydroxytryptamine3 (5-HT3) receptor antagonist, and metoclopramide. Ondansetron was given as an 8 mg loading dose (4 mg intravenously [IV] plus 4 mg orally) before chemotherapy followed by 8 mg every 8 hours orally for 3 to 5 days. Metoclopramide was given as an 80 mg loading dose (60 mg IV plus 20 mg orally) before chemotherapy followed by 20 mg every 8 hours orally for 3 to 5 days. A "period" interaction in the analysis of emetic response in the first 24 hours necessitated a parallel group analysis of first treatments only, 68 patients being assessable for this parameter. In the first 24 hours, complete or major control (zero to two emetic episodes) of emesis was achieved in 30 of 35 (86%) patients receiving ondansetron and in 14 of 33 (42%) patients receiving metoclopramide (P less than .001). Ondansetron was also more effective in reducing acute nausea. On days 2 to 3, the complete or major responses were significantly better with ondansetron (81% v 65%; P = .033), but there was no statistical difference in the control of nausea. There was a significant patient preference for ondansetron (63% v 26%; P = .001). Extrapyramidal reactions were observed in two metoclopramide treatments; both treatments were otherwise well tolerated. These results are consistent with serotonin (5-HT), being a significant neurotransmitter of cyclophosphamide/doxorubicin- or epirubicin/fluorouracil-induced emesis.

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Co-Phenylcaine Spray: can we improve the taste? A randomised, double-blind, crossover study

The Journal of Laryngology & Otology ◽

10.1017/s0022215117001359 ◽

2017 ◽

Vol 132 (2) ◽

pp. 138-142

Author(s):

S Bailey ◽

B Panizza ◽

P Cabot ◽

B Wallwork

Keyword(s):

Crossover Study ◽

Nasal Spray ◽

Patient Experience ◽

Washout Period ◽

Sensory Attributes ◽

Satisfaction Score ◽

Double Blind ◽

To Receive ◽

Blind Crossover Study ◽

Double Blind Crossover Study

AbstractObjective:Co-Phenylcaine Forte is a nasal spray routinely prescribed by otolaryngologists in Australia. The taste of Co-Phenylcaine Forte is typically described as unpleasant. This study sought to improve the overall patient experience associated with Co-Phenylcaine Forte by generating a Co-Phenylcaine Forte formulation, referred to as Co-Phenylcaine Zest, which contains an added vanilla flavour and masking agent.Methods:Participants were randomised to receive two actuations of Co-Phenylcaine Forte in each nostril followed by two actuations of Co-Phenylcaine Zest, or vice versa. There was a 6–36-hour washout period between each treatment. After the administration of each spray, participants completed a questionnaire to rate various sensory attributes of each formulation on seven-point ordinal scales. Patients reported their overall formulation preference after receiving both treatments.Results:A total of 86 participants completed the trial. Seventy-four per cent of patients preferred Co-Phenylcaine Zest, 21 per cent preferred Co-Phenylcaine Forte and 5 per cent had no preference (p < 0.001). The satisfaction score associated with Co-Phenylcaine Zest was 1.22 points greater than with Co-Phenylcaine Forte (p < 0.001).Conclusion:A novel formulation of Co-Phenylcaine Forte was created by adding a flavour and a masking agent; this formulation was preferred by most patients.

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The Pharmacodynamic Effect of a Remifentanil Bolus on Ventilatory Control

Anesthesiology ◽

10.1097/00000542-200002000-00020 ◽

2000 ◽

Vol 92 (2) ◽

pp. 393-393 ◽

Cited By ~ 67

Author(s):

H. Daniel Babenco ◽

Pattilyn F. Conard ◽

Jeffrey B. Gross

Keyword(s):

Carbon Dioxide ◽

Respiratory Depression ◽

Response Curve ◽

Time Course ◽

Ventilatory Response ◽

Minute Ventilation ◽

Effect Site ◽

Ventilatory Drive ◽

Ventilatory Depression ◽

Carbon Dioxide Response

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.

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Treatment of Bulimia with Desipramine: A Double-Blind Crossover Study

The Canadian Journal of Psychiatry ◽

10.1177/070674378803300211 ◽

1988 ◽

Vol 33 (2) ◽

pp. 129-133 ◽

Cited By ~ 61

Author(s):

Jane Barlow ◽

Jane Blouin ◽

Arthur Blouin ◽

Edgardo Perez

Keyword(s):

Clinical Effect ◽

Eating Attitudes ◽

Tricyclic Antidepressant ◽

Normal Weight ◽

Crossover Design ◽

Double Blind ◽

Reverse Sequence ◽

To Receive ◽

Blind Crossover Study ◽

Double Blind Crossover Study

The purpose of this study was to evaluate the effect of desipramine, a tricyclic antidepressant with relatively specific noradrenergic effects, on bulimic behaviour, eating attitudes, and mood. Using a double-blind crossover design, 47 normal weight bulimics were randomly assigned to receive either desipramine (150 mg/day)for six weeks, no drug for three weeks, followed by placebo for six weeks, or the reverse sequence. At weeks 0, 2, 4, 6, 9, 11, 13, and 15, each subject was assessed using the EDI, SCL-90, POMS and binge records. Plasma desipramine levels were obtained at weeks 4 and 13. Twenty-four subjects completed the entire fifteen week protocol, while 23 dropped out. Desipramine was significantly more effective than placebo in reducing the frequency of weekly hinging, weekly vomiting, and the fatigue scale of the POMS. No significant effect of the drug was obtained on the EDI or the SCL-90. The clinical effect was modest. Desipramine's antibulimic effects were not associated with an alleviation of depressive symptoms.

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Diphenhydramine Increases Ventilatory Drive during Alfentanil Infusion

Anesthesiology ◽

10.1097/00000542-199809000-00013 ◽

1998 ◽

Vol 89 (3) ◽

pp. 642-647. ◽

Cited By ~ 8

Author(s):

H. Daniel Babenco ◽

Robert T. Blouin ◽

Pattilyn F. Conard ◽

Jeffrey B. Gross

Keyword(s):

Carbon Dioxide ◽

Ventilatory Response ◽

Minute Ventilation ◽

Blood Levels ◽

Ventilatory Responses ◽

Ventilatory Drive ◽

Before And After ◽

End Tidal ◽

Carbon Dioxide Response ◽

Ventilatory Response To Hypoxia

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.

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Pharmacokinetics and Tolerability of Factor XIII Concentrates Prepared from Human Placenta or Plasma: a Crossover Randomised Study

Thrombosis and Haemostasis ◽

10.1055/s-0038-1649787 ◽

1995 ◽

Vol 74 (02) ◽

pp. 622-625 ◽

Cited By ~ 29

Author(s):

H H Brackmann ◽

R Egbring ◽

A Ferster ◽

P Fondu ◽

J M Girardel ◽

...

Keyword(s):

Factor Xiii ◽

Bleeding Events ◽

Serious Adverse Events ◽

Double Blind ◽

Randomised Study ◽

The Mean ◽

Blind Crossover Study ◽

Double Blind Crossover Study ◽

Fxiii Activity ◽

Observation Period

SummaryThe pharmacokinetics and tolerability of factor XIII (FXIII) from plasma were compared with those of FXIII from placenta in a randomised, double-blind, crossover study involving 13 patients with congenital FXIII deficiency. Both FXIII activity and FXIII antigen were monitored. No difference was seen in the mean half-lives of the two preparations (9.3 days and 9.1 days for plasma and placenta FXIII activity, respectively). Response was similar for both preparations, but was slightly greater for FXIII from plasma.Similar results were found for recovery (65% vs 60%). The area under the data completed by extrapolation was significantly higher for FXIII from plasma. No differences between preparations in terms of efficacy or tolerability were observed. It can be concluded that treatment with FXIII concentrate from plasma is as efficient as with FXIII concentrate from placenta in terms of recovery and half-life. Both preparations were equivalent in terms of safety during the observation period. With the administration of monthly injections of approximately 30 U/kg serious bleeding events were prevented and no other serious adverse events occurred.

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Inhibition of Spontaneous Platelet Aggregation by Sulfinpyrazone

Thrombosis and Haemostasis ◽

10.1055/s-0038-1666900 ◽

1979 ◽

Vol 42 (02) ◽

pp. 621-625 ◽

Cited By ~ 1

Author(s):

G G Nenci ◽

G Agnelli ◽

M Berrettini ◽

P Parise ◽

E Ballatori

Keyword(s):

Platelet Aggregation ◽

Crossover Study ◽

Double Blind ◽

Platelet Aggregability ◽

Initiation Of Therapy ◽

Spontaneous Platelet Aggregation ◽

Blind Crossover Study ◽

Double Blind Crossover Study

SummaryIn a randomized double-blind crossover study in 16 patients with enhanced in vitro spontaneous platelet aggregation, sulfinpyrazone proved to be effective in normalizing platelet aggregability within 4 days after initiation of therapy.

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