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* From the Departments of Anesthesiology, Taipei Medical University Hospital, and
Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.
Address correspondence to: Dr. Chao-Shun Lin, Department of Anesthesiology, Taipei Medical University Hospital, 252 Wu-Hsin Street, Taipei, Taiwan 110. Phone: 886-2-27372181, ext. 1212; Fax: 886-2-27367344; E-mail: soon.lin{at}msa.hinet.net
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Abstract |
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Methods: Upon completion of surgery under sevoflurane anesthesia, 60 adult patients were randomly allocated to receive either doxapram hydrochloride 1 mg·kg–1 iv or saline placebo. Clinical recovery from anesthesia was assessed by time to eye opening on verbal command, hand squeezing on command, time to extubation, and the Aldrete recovery score. Bispectral index values, systolic blood pressure, and heart rate were recorded at baseline (before anesthesia), during surgery, and every minute for 15 min after administration of the study drug.
Results: Time to eye opening was shorter in the doxapram group compared with the control group (6.9 ± 2.2 min vs 9.9 ± 3.1 min, P < 0.05). Mean bispectral index scores were also higher in the doxapram group compared with the saline placebo seven to eight minutes following administration of the study medication (P < 0.05). More rapid emergence was associated with a greater increase in heart rate with doxapram (P < 0.05 compared with placebo), but no differences in systolic blood pressure responses were observed in comparison with placebo.
Conclusion: We conclude that doxapram 1 mg·kg–1 hastens early recovery from sevoflurane anesthesia, and this arousal effect correlates with higher bispectral index values.
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Methods |
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After recording baseline vital signs and BIS values, anesthesia was induced with thiopental 4 mg·kg–1 iv and fentanyl 100 µg iv. Endotracheal intubation was facilitated with succinylcholine 1 mg·kg–1 iv. After intubation the inspiratory and expiratory concentrations of oxygen and sevoflurance were monitored. Anesthesia was maintained with sevoflurane 2–3% end-tidal concentration with oxygen, titrated to maintain BIS scores in the range of 45–50. Incremental doses of atracurium 0.1 mg·kg–1 iv were given as required to maintain adequate muscle relaxation. No additional opioid was used during surgery. During the last 30 min of the operation no further muscle relaxant was administered, and anesthesia was continued with assisted ventilation to maintain end-tidal CO2 values between 35–40 mmHg. Five minutes prior to anticipated completion of surgery, sevoflurane was discontinued and the patient’s lungs were ventilated with 100% oxygen at a fresh gas flow rate of 5 L·min–1 Guided by a train-of-four neuromuscular blockade monitor (TOF-Guard, Organon Teknika BV, Boxtel, Netherlands) reversal of residual neuromuscular block was achieved with neostigmine 0.05 mg·kg–1 iv and atropine 0.01 mg·kg–1 iv.
Patients were next randomly divided into two groups of equal size according to a computerized randomization table. The control Group C patients (n = 30) received normal saline iv, and Group D patients (n = 30) received doxapram 1 mg·kg–1 iv (Nhwa Pharma Corporation, Xuzhou, China) in identically appearing syringes. Study medication or placebo was administered by a dedicated research assistant who was blinded to the syringe contents, which were administered immediately after discontinuation of sevoflurane. Recovery from anesthesia was assessed by a blinded anesthesiologist. The following parameters were evaluated: eye opening on verbal command; hand squeezing in response to verbal command, and time to extubation of the trachea after discontinuation of the anesthetic gas. Heart rate, systolic blood pressure, BIS values, and SpO2 values were determined before, and every five minutes during surgery, then every minute after the injection of the study drugs for 15 min. End-tidal CO2 concentration and end-expiratory concentration of sevoflurane were also recorded from the time of study drug injection to the time of extubation. Aldrete recovery scores13 were recorded upon arrival in the postanesthesia care unit (PACU) and at the time of discharge from PACU. Patients were questioned specifically about any recall or awareness during anesthesia or any abnormal psychological feeling during emergence.
The primary end-point of this study was defined as the time to achieve eye opening to verbal command. Applying an a priori power analysis, at least 22 patients had to be enrolled in each treatment group to provide 80% power to detect a difference at 
= 0.05. Data are expressed as mean and standard deviation. Demographic data and Aldrete scores were analyzed by the Chi-square test. Bispectral index values, end-tidal CO2, end-expiratory sevoflurane concentration, heart rate, and systolic blood pressure were analyzed by repeated-measures analysis of variance (ANOVA) and the Newman-Keuls test was applied when ANOVA was significant. Times to eye opening, response to verbal command, and extubation were also compared using repeated-measures ANOVA. Data are presented as mean ± standard deviation, and statistical significance was assumed when P < 0.05.
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). Groups were also comparable with respect to duration of anesthesia, end-tidal CO2 values, and end-tidal sevoflurane concentrations (Table I). No patient received any medication during the course of anesthesia, which was not specified by the study protocol.
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). Mean BIS scores were similar in doxapram and control groups prior to administration of the study drug. While BIS scores recovered rapidly upon discontinuation of sevoflurane, BIS scores were significantly higher in the doxapram group compared with placebo seven to eight minutes post-drug administration (P < 0.05). Beyond nine minutes, there were no differences in mean BIS scores between groups (Figure 1).
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). Changes in systolic blood pressure were similar in the two groups during emergence from anesthesia (Figure 3).
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Discussion |
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Doxapram is a central and peripheral respiratory stimulant and a nonspecific CNS stimulant. It is presently approved for the treatment of acute respiratory failure, postoperative respiratory depression, neonatal apnea of prematurity, and postanesthetic shivering. In the 1970s and up to the 1980s doxapram was not infrequently used as an analeptic antagonizing the hypnotic and/or respiratory depressant effects of sedatives such as diazepam, opioids, barbiturates and inhalation anesthetics commonly used at that time.10,14,15 With the introduction of selective antagonist drugs it is now well recognized that antagonism of opioids should be achieved with either naloxone or naltrexone, and antagonism of benzodiazepines can be achieved with flumazenil. However, there is a paucity of useful agents with reasonable safety profiles to antagonize the CNS depressant effects of inhalational anesthetics. Physostigmine has been used in the past, but this drug is now no longer available.
Recently, Turan et al. demonstrated that aminophylline 5 mg·kg–1 iv hastens recovery from sevoflurane anesthesia.16 Sevoflurane, with a blood/gas coefficient of 0.65, has a rapid induction time and a generally rapid recovery.17 However, slow recovery following sevoflurane is observed occasionally, and a pharmacological means to hasten recovery in such circumstances, without side effects, might be desirable and clinically useful. It therefore seemed logical to evaluate whether recovery from an inhaled anesthetic with a rapid recovery profile can be modified by a CNS stimulant such as doxapram, and whether BIS values correlate with the observed clinical response.18,19 Noe et al. observed electroencephalogram (EEG) changes indicative of arousal with intraoperative administration of doxapram 0.5 mg·kg–1 iv at the end of surgery under thiamylal or halothane-N2O anesthesia. However, these investigators did not elaborate on the specific EEG patterns.20 Roy and Stullken reported conversion of the EEG to an awake pattern in dogs under steady state halothane anesthesia, within 22 ± 3 sec following administration of doxapram 1 mg·kg–1 iv.21 In our study we found that doxapram 1 mg·kg–1 iv hastened recovery time in patients receiving sevoflurane anesthesia, and this improvement was also reflected in higher BIS scores. The arousal effect of doxapram appears to be directly related to its CNS stimulating effect, since both the end-tidal CO2 and the end-expiratory concentrations of sevoflurane were similar between groups. The observed changes in BIS values, attaining a significant between-groups difference within seven minutes, coincided with clinical signs of awakening. There were no episodes of recall/awareness or any other psychological reactions possibly related to the administration of doxapram. Of equal importance, there was no "re-narcotization" effect after doxapram’s response had dissipated. Aldrete scores in the PACU showed no difference between the doxapram and placebo groups, and all the patients were discharged uneventfully.
A number of adverse effects have been reported with the use of doxapram, most noticeably tachycardia, cardiac arrhythmia, hypertension, hallucinations, excitation, anxiety reactions, and even panic attacks.7,9,10 More recently, Rosenberg et al. described the response of a doxapram infusion in an elderly patient following a laparotomy. The patient suffered a cerebrovascular accident, which the authors postulated may have been related to doxapram administration.22 In an animal study, Uehara et al. demonstrated that a large dose of doxapram (50 mg·kg–1) given prior to bilateral carotid artery occlusion accentuates white matter damage in the neonatal rat.23 This seems to indicate that doxapram in large doses may render the brain more vulnerable to ischemic damage. For our investigation, we elected to use a modest single dose of doxapram 1 mg·kg–1 which had previously been shown to be effective in reversing anesthetic effects, without adverse responses.7–10 However, benefits must always be weighed against potential risks, and we would only consider using small doses of doxapram in patients where recovery from inhalational anesthesia is unexpectedly prolonged.
The clinical significance of our observations must be considered in light of that fact that doxapram is no longer commonly used. We believe that our study provides clinically relevant information regarding the correlation between the BIS and the CNS arousal effect of a CNS stimulant. The BIS has been shown to be a useful guide in monitoring anesthetic recovery without drug intervention.18,19 and we have been able to demonstrate that BIS reflects changes during recovery from anesthesia following administration of an analeptic drug.
In conclusion, we have shown that administration of doxapram 1 mg·kg–1 iv hastens early recovery from sevoflurane anesthesia, without appreciable side effects. The more rapid emergence correlates with higher BIS values when compared to placebo.
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Footnotes |
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Accepted for publication November 7, 2005. Revision accepted December 20, 2005.
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References |
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2 Kato H, Buckly JP. Possible sites of action of the respiratory stimulant effect of doxapram hydrochloride. J Pharmacol Exp Ther 1964; 144: 260–4.
3 Hirsch K, Wang SC. Selective respiratory stimulating action of doxapram compared to pentylenetrorazaol. J Pharmacol Exp Ther 1974; 189: 1–11.
4 Mitchell RA, Herbert DA. Potencies of doxapram and hypoxia in stimulating carotid-body chemoreceptors and ventilation in anesthetized cats. Anesthesiology 1975; 42: 559–66.[Medline]
5 Scott RM, Whitwan JG, Chakrabarti MK. Evidence of a role for the peripheral chemoreceptors in the ventilatory response to doxapram in man. Br J Anaesth 1977; 49: 227–31.
6 Po BT, Watson RL, Hansen HR. Arousal time following intravenous anesthetic agents, methohexital and thiopental: effect of doxapram hydrochloride. Anesth Analg 1968; 47: 446–51.
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15 Allen CJ, Gough KR. Effect of doxapram on heavy sedation produced by intravenous diazepam. Br Med J (Clin Res Ed) 1983; 286: 1181–2.
16 Turan A, Memis D, Karamanlyoglu B, Colak A, Pamukcu Z, Turan N. Effect of aminophylline on recovery from sevoflurane anaesthesia. Eur J Anaesthesiol 2002; 19: 452–4.[Medline]
17 Miller RD. Anesthesia, 5th ed. Philadelphia, PA: Churchill Livingstone; 2000: 2226–7.
18 Anderson RE, Barr G, Assareh H, Jakobsson J. The AAI index, the BIS index and end-tidal concentration during wash in and wash out of sevoflurane. Anaesthesia 2003; 58: 531–5.[Medline]
19 Muncaster AR, Sleigh JW, Williams M. Changes in consciousness, conceptual memory, and quantitative electroencephalographical measures during recovery from sevoflurane-and remifentanil-based anesthesia. Anesth Analg 2003; 96: 720–5.
20 Noe FM, Borrillo N, Greifenstein FE. Use of a new analeptic, doxapram hydrochloride, during general anesthesia and recovery. Anesth Analg 1965; 44: 206–13.[Medline]
21 Roy RC, Stullken EH. Electroencephalographic evidence of arousal in dogs from halothane after doxapram, physostigmine, or naloxone. Anesthesiology 1981; 55: 392–7.[Medline]
22 Rosenberg J, Kristensen PA, Pedersen MH, Overgaard H. Adverse events with continuous doxapram infusion against late postoperative hypoxaemia. Eur J Clin Pharmacol 1996; 50: 191–4.[Medline]
23 Uehara H, Yoshioka H, Nagai H, et al. Doxapram accentuates white matter injury in neonatal rats following bilateral carotid artery occlusion. Neurosci Lett 2000; 281: 191–4.[Medline]
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