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From the Department of Anesthesia, University of British Columbia and British Columbia's Children Hospital, Vancouver, B.C. Canada.
Dr. L.D. Scheepers, British Columbia's Children's Hospital, Department of Anaesthesia, 4480 Oak Street, Room 1L2, Vancouver, B.C. V6H 3V4 Canada. Phone: 604-875-2711; Fax: 604-875-3221; E-mail: louissch{at}home.iatronet.net
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kg–1.
Methods: Following institutional approval and informed written consent, 11 ASA physical status I-II patients, aged two to six years, undergoing general anesthesia for dental surgery were recruited. After induction, 40 µgkg–1 flumazenil Anexate®, Roche, 0.1 mgmL–1 (0.4 mLkg–1)) were administered via a syringe as drops, prior to nasal intubation. Venous plasma samples were drawn prior to administration of flumazenil (t=0), and then at 2, 4, 6, 8, 10, 15, 20, 30, 40, 60, and 120 min thereafter. The plasma samples were immediately processed by the on-site laboratory and then stored at -70°C, before batch analysis via high performance liquid chromatography assay. Pharmacokinetic data calculations were performed using WinNonLin software (Scientific Consulting Inc.).
Results: Eleven patients were studied, but data for one patient were discarded due to insufficient sampling. The median age was 4.3 yr (range 3 to 6), with a median weight of 18.9 kg (range 14.9 to 22.2). There were seven boys and three girls. Mean Cmax was 67.8 ngmL–1 (SD 41.9), with Tmax at two minutes. The calculated half-life was 122 min (SD 99).
Conclusion: The mean plasma concentrations of flumazenil attained were similar to those reported after intravenous administration, and may be sufficient to antagonize the side-effects of benzodiazepines. This route of administration may be useful when the intravenous route is not readily available.
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In addition, there is no standard intravenous pediatric flumazenil dose reported. The therapeutic clinical dose in adults is 20 µgkg–1, with a maximum intravenous bolus dose of 0.2 mg.5,6 In another study, the mean dose required to antagonize midazolam-induced anesthesia in children was 24 µgkg–1 (SD 19).7 The suggested neonatal dose is also 20 µgkg–1.8 Based on these studies, the intravenous therapeutic dose in children was assumed to be 20 µgkg–1. Since intranasally administered midazolam has a bioavailability between 32-57%,1,9 and flumazenil is structurally related to midazolam (Figure 1
), a bioavailability of 50% was assumed for intranasally administered flumazenil. Consequently, in order to determine the plasma concentrations of flumazenil after intranasal administration in pediatric patients, a dose of 40 µgkg–1 (0.4 mLkg–1) was selected.
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kg–1 propofol, 3 µgkg–1fentanyl and 0.2 mgkg–1 mivacurium, 40 µgkg–1, 0.1 mgmL–1 flumazenil (Anexate®, Roche,(0.4 mLkg–1)) was administered via a syringe as drops, prior to nasal intubation. The first four patients received the total flumazenil dose via one nostril, while in the other patients it was divided equally between each nostril. Anesthesia was maintained with halothane, 0.5-2%, in nitrous oxide and oxygen. Venous plasma samples were drawn, via an indwelling Jelco® (Johnson and Johnson) catheter, before administration of flumazenil (t=0), and then at 2, 4, 6, 8, 10, 15, 20, 30, 40, 60, and 120 min thereafter. Prior to venous sampling, 2 ml dead space fluid was withdrawn from the Jelco® and discarded, and immediately thereafter the catheter was flushed with 3 ml normal saline to maintain patency. All samples were drawn in the operating room. The plasma samples were immediately processed by the on-site laboratory and then stored at -70°C, before batch analysis via high performance liquid chromatography (HPLC) assay.
The plasma flumazenil concentrations were determined by a HPLC assay published previously,10 and was linear at concentrations ranging from 2 to 200 ngmL–1. Inter- and intra-day coefficients of variation for accuracy and precision of the flumazenil assay, as measured using quality control samples (2 to 100 ngmL–1), were <4%.
Pharmacokinetic parameters were calculated from the plasma concentration-time data using a non-compartmental model with extravascular input (WinNonLin, Scientific Consulting Inc. Apex, North Carolina).
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Pharmacokinetic analysis of the data from all ten patients yielded a mean Cmax was 67.8 ngmL–1 (SD 41.9), at a Tmax of two minutes. Plasma flumazenil concentrations of each patient, as well as the sample mean, are displayed in Figure 2. The calculated pharmacokinetic data included a clearance of 200.6 mLmin–1 (SD 85.7), volume of distribution of 29.9 L (SD 20.4), and half-life of 122 min (SD 99). Data from the final six patients were reanalyzed as a subgroup distinct from the whole study group because the flumazenil dose was divided equally between the two nostrils in these patients. This subgroup analysis yielded a mean Cmax of 93.99 ngmL–1 (SD 22.4; Tmax at two minutes), and a mean calculated plasma half-life of 75 min (SD 65.7).
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kg–1 to 0.45 mgkg–1.13 These reactions were described as agitated excitement, restlessness, irritation, lack of co-operation, disorientation or confusion, emotional crying, and visual disturbances.13 Those patients that require urgent antagonism of BZD side-effects or of paradoxical reactions, will need rapid intravenous placement. This may be difficult in children, especially in a setting where non-anesthetists may not have the optimal skills or equipment available. An alternate emergency route of flumazenil administration may thus be useful in these situations.
This study aimed to establish whether 40 µgkg–1 flumazenil administered intranasally would result in plasma concentrations that are sufficient to antagonize adverse BZD reactions. However, therapeutic plasma flumazenil concentrations have not been accurately determined. Klotz et al.4 concluded that plasma concentrations of 10 to 20 ngmL–1 may effectively reverse BZD induced CNS depression. In another study, the mean plasma concentration of flumazenil required to reverse midazolam, as measured by the ability of the patient to identify him- or herself verbally after midazolam anesthesia, was 29.9 ngmL–1.14 Even though these studies reported mean plasma flumazenil concentrations, as opposed to individual patient responses, it is evident that attaining a plasma concentration of 10-30 ngmL–1 may result in clinical reversal of BZD side-effects. In our study, the mean Cmax was 67.8 ngmL–1, and was measured at two minutes after administration. Therefore, based on the reported therapeutic range of 10 - 30 ngmL–1,4,14 the administration of intranasal flumazenil is likely to clinically antagonize the BZD side-effects.
Using the intravenous formulation of flumazenil intranasally results in the administration of large volumes of solution. A toddler, aged two to three years, weighing approximately 15 kg, will receive 6 mL of solution. This may result in some oromucosal and gastric absorption, in addition to the proposed nasal mucosal absorption. In this study, three of the first four patients failed to achieve high plasma flumazenil concentrations. This may reflect individual patient pharmacokinetic variability, but may also be due to the technique of administration. The first four patients received the entire dose of flumazenil in one nostril and, given the large volumes, it is conceivable that some, if not most, of the flumazenil was absorbed via the gastrointestinal tract. This would result in first pass hepatic metabolism with reduced bioavailability, as reported by Klotz et al.,4 where oral flumazenil has a bioavailability of only 16%. Indeed, the pharmacokinetic analysis of the final six patients yielded a peak plasma concentration that was 50% greater than that of the whole study group. This is consistent with more complete absorption and reduced first pass hepatic metabolism as the flumazenil was absorbed via the nasal mucosa in these six patients. Consequently, to ensure reliable absorption of intranasal flumazenil, the dose should be divided equally between the two nostrils.
Intranasal flumazenil administration may theoretically produce laryngospasm or aspiration in semiconscious patients, especially considering the large volumes of solution being administered. Although this study was performed on supine anesthetized patients that had received neuromuscular paralysis, there was no evidence of aspiration at the time of intubation. However, when administering intranasal flumazenil, positioning the patient in the Trendelenburg or in the recovery position, may minimize this risk of aspiration. In addition, the selected dose of 40 µgkg–1 flumazenil in this study resulted in a mean plasma concentration that exceeded previously reported mean concentrations. A smaller dose, for example 20 µgkg–1, will result in less volume administered, and may further reduce the risk of aspiration, while still resulting in therapeutic plasma concentrations. However, this dose should be divided equally between the two nostrils to maximize the nasal mucosal surface area exposed to the drug.
After flumazenil administration in anesthesia, the most common side effect is nausea (10.8%).15 Other effects include tears, tremors, dizziness and anxiety (all in <1% of patients).15 Furthermore, flumazenil has a half-life of 0.7 to 1.3 hr,4 which is less than the half-life of midazolam of 1.5 to 3.5 hr.16 Consequently, resedation may occur once the flumazenil is metabolized. In our study, mean plasma concentrations of flumazenil was maintained above the therapeutic levels of 10-30 ngmL–1 for at least 20 min. This should provide sufficient time to establish secure intravenous access and adequate patient monitoring to detect possible resedation.
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kg–1, result in mean plasma concentrations similar to those obtained after intravenous administration, and may be sufficient to antagonize BZD induced side-effects. This route of administration may be useful to reverse adverse effects resulting from oral midazolam administration in situations when intravenous access is not readily available. However, further studies to evaluate the clinical effects of intranasal flumazenil administration in non-anesthetized patients are required.
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Accepted for publication November 6, 1999.
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2 Malinovsky J-M, Populaire C, Cozian A, Lepage J-Y, Lejus C, Pinaud M. Premedication with midazolam in children. Effect of intranasal, rectal and oral routes on plasma midazolam concentrations. Anaesthesia 1995; 50: 351–4.[Medline]
3
Ricou B, Forster A, Brückner A, Chastonay P, Gemperle M. Clinical evaluation of a specific benzodiazepine antagonist (Ro 15-1788). Studies in elderly patients after regional anaesthesia under benzodiazepine sedation. Br J Anaesth 1986; 58: 1005–11.
4 Klotz U, Kanto J. Pharmacokinetics and clinical use of flumazenil (Ro 15-1788). Clin Pharmacokinet 1988; 14: 1–12.[Medline]
5 Amrein R, Hetzel W, Hartmann D, Lorscheid T. Clinical pharmacology of flumazenil. Eur J Anaesthesiol 1988; S2: 65–80.
6 Perry HE, Shannon MW. Diagnosis and management of opioid- and benzodiazepine-induced comatose overdose in children. Curr Opin Pediatr 1996; 8: 243–7.[Medline]
7
Jones RDM, Lawson AD, Andrew LJ, Gunawardene WMS, Bacon-Shone J. Antagonism of the hypnotic effect of midazolam in children: a randomized, double-blind study of placebo and flumazenil administered after midazolam-induced anaesthesia. Br J Anaesth 1991; 66: 660–6.
8 Richard P, Autret E, Bardol J, et al. The use of flumazenil in a neonate. J Toxicol Clin Toxicol 1991; 29: 137–40.[Medline]
9 Walbergh EJ, Wills RJ, Eckhert J. Plasma concentrations of midazolam in children following intranasal administration. Anesthesiology 1991; 74: 233–5.[Medline]
10 Vletter AA, Burm AG, Breimer LTM, Spierdijk J. High-performance liquid chromatographic assay to determine midazolam and flumazenil simultaneously in human plasma. J Chromatogr 1990; 530: 177–85.[Medline]
11 Van Der Bijl P, Roelofse JA. Disinhibitory reactions to benzodiazepines: a review. J Oral Maxillofac Surg 1991; 49: 519–23.[Medline]
12 Bailey PL, Pace NL, Ashburn MA, Moll JWB, East KA, Stanley TH. Frequent hypoxemia and apnea after sedation with midazolam and fentanyl. Anesthesiology 1990; 73: 826–30.[Medline]
13 Roelofse JA, Stegmann DH, Hartshorne J, Joubert JJ. Paradoxical reactions to rectal midazolam as premedication in children. Int J Oral Maxillofac Surg 1990; 19: 2–6.[Medline]
14
Jones RDM, Chan K, Roulson CJ, Brown AG, Smith ID, Mya GH. Pharmacokinetics of flumazenil and midazolam. Br J Anaesth 1993; 70: 286–92.
15 Philip BK. Drug reversal: benzodiazepine receptors and antagonists. J Clin Anesth 1993; 5: 46S–51.[Medline]
16 Breheny FX. Reversal of midazolam sedation with flumazenil. Crit Care Med 1992; 20: 736–9.[Medline]
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