- Email: [email protected]
Comparison of the recovery and respiratory effects of aminophylline and doxapram following total intravenous anesthesia with propofol and remifentanil
Journal of Clinical Anesthesia 25 (2013) 173–176
Contents lists available at SciVerse ScienceDirect
Journal of Clinical Anesthesia journal homepage: www.JCAfulltextonline.com
Original Contribution
Comparison of the recovery and respiratory effects of aminophylline and doxapram following total intravenous anesthesia with propofol and remifentanil☆,☆☆ Dae Woo Kim MD, PhD (Professor), Jin Deok Joo MD, PhD (Professor), Jang Hyeok In MD, PhD (Professor), Yeon Su Jeon MD, PhD (Professor), Hong Soo Jung MD (Clinical Assistant Professor), Kyeong Bae Jeon MD (Resident), Jae Sik Park MD (Resident), Jin Woo Choi MD, PhD (Associate Professor) ⁎ Department of Anesthesiology and Pain Medicine, The Catholic University of Korea St. Vincent Hospital, Suwon, 442–723, South Korea
a r t i c l e
i n f o
Article history: Received 1 November 2011 Received in revised form 4 July 2012 Accepted 12 July 2012 Keywords: Aminophylline Bispectral index monitoring Doxapram Propofol Remifentanil Total intravenous anesthesia
a b s t r a c t Study Objective: To compare the effects of aminophylline and doxapram on recovery, respiration, and bispectral index (BIS) values in patients after total intravenous anesthesia (TIVA) with propofol and remifentanil. Design: Prospective, randomized, blinded clinical trial. Setting: Operating room of a university hospital. Patients: 90 adult, ASA physical status 1 and 2 patients scheduled for elective laparoscopic vaginal hysterectomy. Interventions: TIVA was performed with the induction target of remifentanil 3 ng/mL and propofol 6 μg/mL, followed by the maintenance target of remifentanil 1–3 ng/mL and propofol 3–5 μg/mL at the effect site, and with BIS scores in 40–50 range. Patients were randomized to three groups to receive intravenous (IV) aminophylline 3 mg/kg (n = 30), IV doxapram 1 mg/kg (n = 30), or normal IV saline (control; n = 30). Measurements and Main Results: After administration of the study drugs, return to spontaneous ventilation differed significantly among the three groups. The times to eye opening and hand squeezing on verbal command were similar. The time to extubation was shortened in both the doxapram and aminophylline groups (P b 0.05). Tidal volumes were increased in the doxapram group at 5–14 minutes and the aminophylline group at 5–12 minutes (P b 0.05). Respiratory rates were increased at 2 to 8 minutes and then showed a decrease at the 12 to 14-minute mark in both the doxapram and aminophylline groups (P b 0.05). No difference was noted between the two groups. BIS values were increased in both the doxapram and aminophylline groups at 4–10 minutes (P b 0.05). Heart rates were increased in the doxapram group for the first 8 minutes and at 1–2 minutes in the aminophylline group (P b 0.05). Conclusion: Aminophylline 3 mg/kg or doxapram 1 mg/kg shortened the time to spontaneous ventilation and improved early recovery from TIVA without appreciable side effects. The more rapid emergence correlates with higher BIS values when compared with the saline control group. The arousal and respiratory effects of aminophylline were comparable to those of doxapram. © 2013 Elsevier Inc. All rights reserved.
1. Introduction Total intravenous anesthesia (TIVA) with propofol and remifentanil allows for rapid and predictable titration of anesthesia. However, we have noted a greater delay in return to spontaneous breathing after TIVA than with sevoflurane or desflurane anesthesia. Propofol is a potent intravenous (IV) anesthetic with dosedependent respiratory depression [1], and remifentanil produces
☆ Supported by grants from The Catholic University of Korea, St. Vincent Hospital, Suwon, Korea. ☆☆ The authors have no conflicts of interest to declare in relation to this article. ⁎ Correspondence: Jin Woo Choi, MD, PhD, 93–6, Chi-Dong, Paldal-Ku, Suwon, 442– 723, South Korea. Tel.: +82 31 249 7212; fax: +82 31 258 4212. E-mail address: [email protected] (J.W. Choi). 0952-8180/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jclinane.2012.07.005
similar dose-dependent respiratory depression [2]. The synergistic interaction of remifentanil and propofol in TIVA causes more depression of the ventilatory response to hypercapnia. Therefore, a pharmacological means to hasten recovery without side effects is desirable. Caffeine, like aminophylline, is a methylxanthine found in coffee and green tea, and it can partially antagonize the behavioral and hypnotic effects of ethanol [3–5]. Aminophylline, which is used clinically as a bronchodilator, centrally antagonizes adenosine, which is a very potent, endogenous central nervous system (CNS) depressant [6,7]. It was reported in 1981 that aminophylline antagonized the hypnotic action of diazepam [8]. Several clinical studies have suggested that aminophylline decreases the depth and duration of sedation produced by propofol [9]. Aminophylline is usually used in anesthetic practice to treat bronchospasm [10,11]; in preterm neonates it decreases the incidence of postoperative apnea [12–14].
174
D.W. Kim et al. / Journal of Clinical Anesthesia 25 (2013) 173–176
Doxapram is a central and peripheral respiratory stimulant and a nonspecific CNS stimulant, which antagonizes the hypnotic or respiratory depressant effect of anesthetics such as diazepam, barbiturates, and halothane [15–18]. This study was designed to compare the effects of aminophylline and doxapram on recovery, respiration, and bispectral index (BIS) monitoring in patients following TIVA with propofol and remifentanil. 2. Materials and methods This prospective, randomized, blinded clinical study was approved by the Institutional Review Board of the Catholic University of Korea St. Vincent Hospital, and written, informed consent was obtained from all patients. A total of 90 ASA physical status 1 and 2 patients without cardiovascular, pulmonary, or neurological diseases, who were scheduled for elective laparoscopic vaginal hysterectomy, were enrolled. No premedication was given. In the operating room, a routine monitoring system was attached to each patient, including continuous electrocardiography, noninvasive arterial blood pressure (BP), pulse oximetry, and capnography. To evaluate the depth of anesthesia, a BIS monitor (A-3000; Aspect Medical Systems, Norwood, MA, USA) was used. Patients were randomized to three groups according to a computer-generated table of random numbers. The aminophylline group (n = 30) received IV aminophylline 3 mg/kg, the doxapram group (n = 30) received IV doxapram 1 mg/kg, and the control group (n = 30) received normal IV saline. Induction was performed with a target-controlled infusion (TCI) of remifentanil, followed by propofol (Orchestra Infusion Workstation V03.OS-1; Fresenius, Vial, France), which included a protocol in the infusion instrument that was chosen by the Schnider model for propofol and the Minto model for remifentanil. Target-controlled infusion mode was used on both effect-site concentration infusions. The induction target of remifentanil was 3 ng/mL and propofol 6 μg/mL, followed by a maintenance target of remifentanil 1–3 ng/mL and propofol 3–5 μg/mL at the effect site; during the operation, these infusions were titrated to maintain BIS scores in the 40–50 range. Neuromuscular blockade was obtained with rocuronium 0.6 mg/ kg. After endotracheal tube insertion, ventilation was adjusted to maintain end-tidal CO2 at 35 ± 5 mmHg using 2 L/min of oxygen (O2) and 2 L/min of room air. During the last 30 minutes of the operation, no additional muscle relaxant was administered. At 10 minutes before the end of surgery, neuromuscular block was reversed with IV pyridostigmine 0.2 mg/kg and glycopyrrolate 0.04 mg/kg to allow for the return to spontaneous breathing. At the end of surgery, the propofol and remifentanil infusions were stopped and the study drug was given intravenously over one minute. Recovery from anesthesia was assessed by an anesthesiologist who was unaware of patients’ study group allocations. The following parameters were evaluated: time to return to spontaneous breathing, eye opening on verbal command, hand squeezing on verbal command, and tracheal extubation after administration of the study drug. Heart rate (HR), BP, and BIS values were determined before surgery and at 5-minute intervals during surgery. At each minute after injection of the study drug, for a period of 16 minutes the abovementioned parameters were determined. Respiratory rate (RR) and tidal volume (VT) were also recorded from the time of injection of the study drug to extubation. To estimate group size, a pilot study was conducted to measure the time it took for the occurrence of spontaneous breathing for 10 patients in the control group. The standard deviation (SD) of the time to return to spontaneous breathing was 2.2 minutes. For our power calculation, we assumed an equal SD for the time to return to spontaneous breathing in the other two groups. We wanted to show a difference of two minutes among the three groups in the time to
return to spontaneous breathing. With a two-tailed α = 0.05 and a power of 80%, 25 patients per group were needed. Assuming the possibility of patients being excluded from the study, we enrolled 30 patients per group. Data are expressed as means and SD. Demographic data were analyzed by x 2-test. Heart rate, BP, BIS values, RR, and VT were all analyzed by repeated-measures analysis of variance (ANOVA); the Newman-Keuls test was applied when ANOVA reached significance. The time to return to spontaneous breathing, eye opening on verbal command, hand squeezing on verbal command, and extubation were also compared using repeated-measures ANOVA. In all tests, a P-value b 0.05 was considered significant. 3. Results Patient characteristics were comparable among the three groups, with no significant differences noted (Table 1). After study drug administration, the return to spontaneous breathing occurred first in the doxapram group, then the aminophylline group, and finally the control group, with significant differences noted among the three groups. Eye opening and hand squeezing on verbal command were observed in the same order, with significant differences noted among the three groups. However, the time to extubation was significantly shorter in the doxapram and aminophylline groups versus the control group (P b 0.05; Table 2). Tidal volumes after study drug injection were increased significantly in the doxapram group, at 5–14 minutes, and in the aminophylline group, at 5–12 minutes, when compared with the control group. Respiratory rates were increased significantly at 2–8 minutes and decreased significantly at 12–14 minutes in both the doxapram and aminophylline groups versus the control group (P b 0.05; Fig. 1). However, there were no differences between the doxapram and aminophylline groups. With respect to BIS, no significant differences were noted among the three groups at baseline, ie, before injection of the study drugs. BIS values after injection of the study drugs were increased significantly in both the doxapram and aminophylline groups when compared with the control group at 4–10 minutes (P b 0.05), with no intergroup differences observed between the doxapram and aminophylline groups. Heart rates after study drug injection were increased significantly in the doxapram group for the first 8 minutes and at 1– 2 minutes in the aminophylline group when compared with the control group (P b 0.05; Fig. 2). However, there was no significant difference in BP among the three groups. 4. Discussion The synergistic interaction of remifentanil and propofol in TIVA causes a greater depression of the ventilatory response to hypercapnia, further delaying recovery. It therefore seemed logical to evaluate whether recovery from TIVA, with a rapid recovery profile, might be modified by a CNS stimulant such as aminophylline or doxapram. The main finding of this study was that both the aminophylline and Table 1 Patient characteristics
Age (yrs) Height (cm) Weight (kg) Duration of anesthesia (min)
Control group (n = 30)
Doxapram group (n = 30)
Aminophylline group (n = 30)
42.2 158.2 57.0 86.1
40.0 161.5 57.7 82.2
43.1 158.3 57.8 99.2
± 10.2 ± 4.8 ± 10.0 ± 28.6
± 11.3 ± 6.0 ± 8.7 ± 30.9
± 7.8 ± 5.6 ± 8.6 ± 15.9
Values are means ± SD. The control group received normal intravenous (IV) saline, the aminophylline group received IV aminophylline 3 mg/kg, and the doxapram group received IV doxapram 1 mg/kg.
D.W. Kim et al. / Journal of Clinical Anesthesia 25 (2013) 173–176 100
Table 2 Recovery time Aminophylline group (n = 30)
Time to spontaneous breathing (min) 8.6 ± 2.3 3.1 ± 1.5⁎ 4.4 ± 1.9 Eye opening on verbal command (min) 11.1 ± 2.0 6.29 ± 2.1⁎ 8.95 ± 3.7†,‡ Hand squeezing in response to 11.9 ± 2.0 7.55 ± 2.0⁎ 9.81 ± 3.6†,‡ verbal command (min) Extubation (min) 12.6 ± 2.3 8.70 ± 1.9⁎ 10.20 ± 3.7‡ †,‡
Values are means ± SD. The control group received normal intravenous (IV) saline, the aminophylline group received IV aminophylline 3 mg/kg, and the doxapram group received IV doxapram 1 mg/kg. ⁎ P b 0.05 doxapram vs control group. † P b 0.05 doxapram vs aminophylline group. ‡ P b 0.05 aminophylline vs control group.
doxapram groups hastened the return to spontaneous breathing. The more rapid emergence correlates with higher BIS values. A clinical maintenance infusion of propofol results in a dosedependent decrease in VT [19]. Remifentanil affects respiration by activating μ-opioid receptors, as expressed on the respiratory neurons in the brainstem [20,21]. As a consequence, ventilation is depressed and arterial carbon dioxide increases [22]. The peak respiratory depression of remifentanil occurred at 5 minutes after each dose of remifentanil. Recovery from remifentanil-induced respiratory depression was rapid, and minute ventilation returned to baseline in 8 minutes (range 5–15 min) after the infusion was stopped [23]. The dose-dependent respiratory depressant effects from propofol
A
90
a,c a,c
80
Bispectral index
Doxapram group (n = 30)
a,c
a,c
a,c
70
60
50 Saline control group
40
Doxapram group Aminophylline group
30 100
B a,b a,b
90
Heart rate (bpm)
Control group (n = 30)
175
a,c
a,b a,c
a,b
2
3
a,b
80
70
60 0
1
4
5
6
8
10
12
14
16
Time (min) 700
A
Fig. 2. Changes in Bispectral Index and heart rate after study drug administration. Error bars = SD. aP b 0.05 doxapram vs control group. bP b 0.05 doxapram vs aminophylline group. cP b 0.05 aminophylline vs control group.
a,c a
a,c
600
Tidal volume (mL)
a,c
500 a,c
a,c
400
300
200
Saline control group
100 30
B
Doxapram group
Respiratory rate (breaths/min)
Aminophylline group 25 a,c
a,c a,c a,c
20
a,c
a,c
a,c
15
a,c
10
5 0
1
2
3
4
5
6
8
10
12
14
16
Time (min) Fig. 1. Changes in tidal volume and respiratory rate after study drug administration. Error bars = SD. aP b 0.05 doxapram vs control group. bP b 0.05 doxapram vs aminophylline group. cP b 0.05 aminophylline vs control group.
and remifentanil (measured arterial blood concentration range: propofol 0–2.6 μg/mL, remifentanil 0–2.0 ng/mL) were strikingly synergistic, with clinically important respiratory depression at already low doses [24]. The effects of aminophylline (85% theophylline, 15% ethylendiamine) are very similar to those of caffeine. The main action of theophylline is direct relaxation of the smooth muscles of the bronchial airways and pulmonary blood vessels. It acts as a bronchodilator in anesthetic practice to treat asthma or bronchospasm [10,11], and in preterm neonates to decrease the incidence of postoperative apnea [12–14]. Several clinical studies have suggested that aminophylline decreases the depth and duration of sedation produced by propofol or antagonizes the effects of propofol [9]. Turan et al [25] showed that aminophylline shortened recovery times and consequently improved cognitive functions after sevoflurane anesthesia. BIS values are higher during the first 12 minutes of recovery when compared with those for placebo [26]. Stirt reported that IV aminophylline 2 mg/kg may be used to antagonize morphine anesthesia and respiratory depression in a patient with no other obvious cause of CNS depression [27]. Porkka-Heiskanen [28] reported that antagonism of adenosine by theophylline is well known and results in excitatory effects on neuronal activity, which stimulates the CNS to induce vigilance and increase the time spent awake. Doxapram is a central and a peripheral respiratory stimulant as well as a nonspecific CNS stimulant. Its ventilatory stimulant action occurs by an increase in VT, with little effect on RR [29–32]. As expected, our data showed that after administration of doxapram and aminophylline, return to spontaneous breathing occurred first in the doxapram group, then the aminophylline group, and then the control group, with significant differences noted among the three groups. Tidal volume and RR also were increased in the same corresponding order.
176
D.W. Kim et al. / Journal of Clinical Anesthesia 25 (2013) 173–176
Wu et al [33] showed that administration of doxapram 1 mg/kg hastened early recovery from sevoflurane anesthesia, and that this arousal effect correlated with higher BIS values. In another paper, Wu et al [34] reported that IV administration of doxapram 1 mg/kg or aminophylline 2 mg/kg hastened early recovery from sevoflurane anesthesia; this effect correlated well with higher BIS values. The arousal effects of doxapram and aminophylline appear to be similar. Aminophylline increases mean arterial blood pressure, left ventricular (LV) systolic pressure, and HR, and reduces LV end-diastolic diameter [35]. Turan et al [36] reported that HR increased with aminophylline in their study. A number of adverse effects have been reported with doxapram, such as tachycardia, cardiac arrhythmia, hypertension, hallucinations, and excitation [16,18,37]. In our study, after injection of the study drugs HR values were increased significantly in the doxapram group for the first 8 minutes and in the aminophylline group at 1–2 minutes, when compared with the control group. However, there was no significant difference in BP among the three groups. To study the hastening of recovery from anesthesia with BIS, Turan et al [25,26] and Hupfl et al [38] gave IV aminophylline 5 mg/kg or 3 mg/kg. As our finding was in accordance with those reports, we chose a smaller dose of aminophylline, 3 mg/kg. Noe et al [40] observed electroencephalographic (EEG) changes, which were indicative of arousal with intraoperative administration of IV doxapram 0.5 mg/kg at the end of surgery with thiamylal or halothane-nitrous oxide anesthesia. However, they did not elaborate on the specific EEG patterns. Roy and Stullken [41] reported conversion of the EEG to an awake pattern in dogs after the administration of IV doxapram 1 mg/kg during halothane anesthesia. Wu et al [33] showed that IV doxapram 1 mg/kg hastened recovery time in patients receiving sevoflurane anesthesia, an improvement that was also reflected in higher BIS scores. Since there has been no report in humans on the equivalent potency between doxapram and aminophylline in recovery of anesthesia, we used a single, lower dose of doxapram, 1 mg/ kg, or aminophylline 3 mg/kg, which are effective in reversing anesthetic effects without adverse responses [17,26,27,36–39]. In conclusion, the administration of aminophylline 3 mg/kg or doxapram 1 mg/kg at the end of TIVA hastened respiration and improved early recovery from TIVA without appreciable side effects. The more rapid emergence correlated with higher BIS values. The arousal and respiratory effects of aminophylline were comparable to those of doxapram. Acknowledgments The statistical analyses were performed in this study under the advice of the Catholic Medical Center Clinical Research Coordinating Center. References [1] Kashiwagi M, Osaka Y, Onimaru H, Takeda J. Optical imaging of propofol-induced central respiratory depression in medulla–spinal cord preparations from newborn rats. Clin Exp Pharmacol Physiol 2011;38:186–91. [2] Coda BA. Opioids. In: Barash PG, Cullen BF, Stoelting RK, Cahalan MK, Stock MC, editors. Clinical Anesthesia. 6th Ed. Philadelphia: Lippincott Williams & Wilkins; 2009. p. 465–97. [3] El Yacoubi M, Ledent C, Parmentier M, Costentin J, Vaugeois JM. Caffeine reduces hypnotic effects of alcohol through adenosine A2A receptor blockade. Neuropharmacology 2003;45:977–85. [4] Hasenfratz M, Bunge A, Dal Prá G, Bättig K. Antagonistic effects of caffeine and alcohol on mental performance parameters. Pharmacol Biochem Behav 1993;46: 463–5. [5] Rush CR, Higgins ST, Hughes JR, Bickel WK, Wiegner MS. Acute behavioral and cardiac effects of alcohol and caffeine, alone and in combination, in humans. Behav Pharmacol 1989;4:562–72. [6] Arvidsson S, Niemand D, Martinell S, Ekström-Jodal B. Aminophylline reversal of diazepam sedation. Anaesthesia 1984;39:806–9.
[7] Krintel JJ, Wegmann F. Aminophylline reduces the depth and duration of sedation with barbiturates. Acta Anaesthesiol Scand 1987;31:352–4. [8] Stirt JA. Aminophylline is a diazepam antagonist. Anesth Analg 1981;60:767–8. [9] Sakurai S, Fukunaga A, Fukuda K, Kasahara M, Ichinohe T, Kaneko Y. Aminophylline reversal of prolonged postoperative sedation induced by propofol. J Anesth 2008;22:86–8. [10] Seidenfeld JJ, Jones WN, Moss RE, Tremper J. Intravenous aminophylline in the treatment of acute bronchospastic exacerbations of chronic obstructive pulmonary disease. Ann Emerg Med 1984;13:248–52. [11] Migliori C, Garzoli E, Spinoni V, Chirico G. Aminophylline treatment of refractory bronchospasm in mechanically ventilated neonates: case report. Med Sci Monit 2007;13:CS93–6. [12] Sims C, Johnson CM. Postoperative apnoea in infants. Anaesth Intensive Care 1994; 22:40–5. [13] Martin RJ, Abu-Shaweesh JM. Control of breathing and neonatal apnea. Biol Neonate 2005;87:288–95. [14] Crean PM. Anaesthesia for the prematurely born infant. Trends in Anaesthesia and Critical Care 2000;11:245–9. [15] 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. [16] Siker ES, Mustafa K, Wolfson B. The analeptic effects of doxapram hydrochloride on thiopentone induced depression. Br J Anaesth 1964;36:216–23. [17] Gupta PK, Dundee JW. Hastening of arousal after general anaesthesia with doxapram hydrochloride. Br J Anaesth 1973;45:493–6. [18] Stephen CR, Talton I. Investigation of doxapram as a postanesthetic respiratory stimulant. Anesth Analg 1964;43:628–40. [19] Goodman NW, Black AM, Carter JA. Some ventilatory effects of propofol as sole anaesthetic agent. Br J Anaesth 1987;59:1497–503. [20] Dahan A, Aarts L, Smith TW. Incidence, reversal, and prevention of opioid-induced respiratory depression. Anesthesiology 2010;112:226–38. [21] Pattinson KT. Opioids and the control of respiration. Br J Anaesth 2008;100: 747–58. [22] Dahan A, Teppema LJ. Influence of anaesthesia and analgesia on the control of breathing. Br J Anaesth 2003;91:40–9. [23] Glass PS, Hardman D, Kamiyama Y, et al. Preliminary pharmacokinetics and pharmacodynamics of an ultra-short-acting opioid: remifentanil (GI87084B). Anesth Analg 1993;77:1031–40. [24] Nieuwenhuijs DJ, Olofsen E, Romberg RR, et al. Response surface modeling of remifentanil-propofol interaction on cardiorespiratory control and bispectral index. Anesthesiology 2003;98:312–22. [25] Turan A, Memiş D, Karamanlioglu B, Colak A, Pamukçu Z, Turan N. Effect of aminophylline on recovery from sevoflurane anaesthesia. Eur J Anaesthesiol 2002;19:452–4. [26] Turan A, Memiş D, Karamanlýodthlu B, Pamukçu Z, Süt N. Effect of aminophylline on bispectral index. Acta Anaesthesiol Scand 2004;48:408–11. [27] Stirt JA. Aminophylline may act as a morphine antagonist. Anaesthesia 1983;38: 275–8. [28] Porkka-Heiskanen T. Adenosine in sleep and wakefulness. Ann Med 1999;31: 125–9. [29] Hirsch K, Wang SC. Selective respiratory stimulating action of doxapram compared to pentylenetetrazol. J Pharmacol Exp Ther 1974;189:1–11. [30] Scott RM, Whitwam JG, Chakrabati MK. Evidence of a role for the peripheral chemoreceptors in the ventilatory response to doxapram in man. Br J Anaesth 1977;49:227–31. [31] Nishimura N, Fujii S, Chiba T, Zen K, Kusunoki H. Re-evaluation of intravenous drip infusion of doxapram–a double-blind method. Masui 1974;23:328–32. [32] Hunt CE, Inwood RJ, Shannon DC. Respiratory and nonrespiratory effects of doxapram in congenital central hypoventilation syndrome. Am Rev Respir Dis 1979;119:263–9. [33] Wu CC, Mok MS, Chen JY, Wu GJ, Wen YR, Lin CS. Doxapram shortens recovery following sevoflurane anesthesia. Can J Anaesth 2006;53:456–60. [34] Wu CC, Lin CS, Wu GJ, et al. Doxapram and aminophylline on bispectral index under sevoflurane anaesthesia: a comparative study. Eur J Anaesthesiol 2006;23: 937–41. [35] Rutherford JD, Vatner SF, Braunwald E. Effects and mechanism of action of aminophylline on cardiac function and regional blood flow distribution in conscious dogs. Circulation 1981;63:378–87. [36] Turan A, Kasuya Y, Govinda R, et al. The effect of aminophylline on loss of consciousness, bispectral index, propofol requirement, and minimum alveolar concentration of desflurane in volunteers. Anesth Analg 2010;110:449–54. [37] Riddle PL, Robertson GS. Use of doxapram as an arousal agent in outpatient general anaesthesia. Br J Anaesth 1978;50:921–4. [38] Hupfl M, Schmatzer I, Buzath A, et al. The effects of aminophylline on bispectral index during inhalational and total intravenous anaesthesia. Anaesthesia 2008;63: 583–7. [39] Kanemaru Y, Nishikawa K, Goto F. Bispectral index and regional cerebral oxygen saturation during propofol/N2O anesthesia. Can J Anaesth 2006;53:363–9. [40] Noe FE, Borrillo N, Greifenstein FE. Use of a new analeptic, doxapram hydrochloride, during general anesthesia and recovery. Anesth Analg 1965;44:206–13. [41] Roy RC, Stullken EH. Electroencephalographic evidence of arousal in dogs from halothane after doxapram, physostigmine, or naloxone. Anesthesiology 1981;55: 392–7.
Contents lists available at SciVerse ScienceDirect
Journal of Clinical Anesthesia journal homepage: www.JCAfulltextonline.com
Original Contribution
Comparison of the recovery and respiratory effects of aminophylline and doxapram following total intravenous anesthesia with propofol and remifentanil☆,☆☆ Dae Woo Kim MD, PhD (Professor), Jin Deok Joo MD, PhD (Professor), Jang Hyeok In MD, PhD (Professor), Yeon Su Jeon MD, PhD (Professor), Hong Soo Jung MD (Clinical Assistant Professor), Kyeong Bae Jeon MD (Resident), Jae Sik Park MD (Resident), Jin Woo Choi MD, PhD (Associate Professor) ⁎ Department of Anesthesiology and Pain Medicine, The Catholic University of Korea St. Vincent Hospital, Suwon, 442–723, South Korea
a r t i c l e
i n f o
Article history: Received 1 November 2011 Received in revised form 4 July 2012 Accepted 12 July 2012 Keywords: Aminophylline Bispectral index monitoring Doxapram Propofol Remifentanil Total intravenous anesthesia
a b s t r a c t Study Objective: To compare the effects of aminophylline and doxapram on recovery, respiration, and bispectral index (BIS) values in patients after total intravenous anesthesia (TIVA) with propofol and remifentanil. Design: Prospective, randomized, blinded clinical trial. Setting: Operating room of a university hospital. Patients: 90 adult, ASA physical status 1 and 2 patients scheduled for elective laparoscopic vaginal hysterectomy. Interventions: TIVA was performed with the induction target of remifentanil 3 ng/mL and propofol 6 μg/mL, followed by the maintenance target of remifentanil 1–3 ng/mL and propofol 3–5 μg/mL at the effect site, and with BIS scores in 40–50 range. Patients were randomized to three groups to receive intravenous (IV) aminophylline 3 mg/kg (n = 30), IV doxapram 1 mg/kg (n = 30), or normal IV saline (control; n = 30). Measurements and Main Results: After administration of the study drugs, return to spontaneous ventilation differed significantly among the three groups. The times to eye opening and hand squeezing on verbal command were similar. The time to extubation was shortened in both the doxapram and aminophylline groups (P b 0.05). Tidal volumes were increased in the doxapram group at 5–14 minutes and the aminophylline group at 5–12 minutes (P b 0.05). Respiratory rates were increased at 2 to 8 minutes and then showed a decrease at the 12 to 14-minute mark in both the doxapram and aminophylline groups (P b 0.05). No difference was noted between the two groups. BIS values were increased in both the doxapram and aminophylline groups at 4–10 minutes (P b 0.05). Heart rates were increased in the doxapram group for the first 8 minutes and at 1–2 minutes in the aminophylline group (P b 0.05). Conclusion: Aminophylline 3 mg/kg or doxapram 1 mg/kg shortened the time to spontaneous ventilation and improved early recovery from TIVA without appreciable side effects. The more rapid emergence correlates with higher BIS values when compared with the saline control group. The arousal and respiratory effects of aminophylline were comparable to those of doxapram. © 2013 Elsevier Inc. All rights reserved.
1. Introduction Total intravenous anesthesia (TIVA) with propofol and remifentanil allows for rapid and predictable titration of anesthesia. However, we have noted a greater delay in return to spontaneous breathing after TIVA than with sevoflurane or desflurane anesthesia. Propofol is a potent intravenous (IV) anesthetic with dosedependent respiratory depression [1], and remifentanil produces
☆ Supported by grants from The Catholic University of Korea, St. Vincent Hospital, Suwon, Korea. ☆☆ The authors have no conflicts of interest to declare in relation to this article. ⁎ Correspondence: Jin Woo Choi, MD, PhD, 93–6, Chi-Dong, Paldal-Ku, Suwon, 442– 723, South Korea. Tel.: +82 31 249 7212; fax: +82 31 258 4212. E-mail address: [email protected] (J.W. Choi). 0952-8180/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jclinane.2012.07.005
similar dose-dependent respiratory depression [2]. The synergistic interaction of remifentanil and propofol in TIVA causes more depression of the ventilatory response to hypercapnia. Therefore, a pharmacological means to hasten recovery without side effects is desirable. Caffeine, like aminophylline, is a methylxanthine found in coffee and green tea, and it can partially antagonize the behavioral and hypnotic effects of ethanol [3–5]. Aminophylline, which is used clinically as a bronchodilator, centrally antagonizes adenosine, which is a very potent, endogenous central nervous system (CNS) depressant [6,7]. It was reported in 1981 that aminophylline antagonized the hypnotic action of diazepam [8]. Several clinical studies have suggested that aminophylline decreases the depth and duration of sedation produced by propofol [9]. Aminophylline is usually used in anesthetic practice to treat bronchospasm [10,11]; in preterm neonates it decreases the incidence of postoperative apnea [12–14].
174
D.W. Kim et al. / Journal of Clinical Anesthesia 25 (2013) 173–176
Doxapram is a central and peripheral respiratory stimulant and a nonspecific CNS stimulant, which antagonizes the hypnotic or respiratory depressant effect of anesthetics such as diazepam, barbiturates, and halothane [15–18]. This study was designed to compare the effects of aminophylline and doxapram on recovery, respiration, and bispectral index (BIS) monitoring in patients following TIVA with propofol and remifentanil. 2. Materials and methods This prospective, randomized, blinded clinical study was approved by the Institutional Review Board of the Catholic University of Korea St. Vincent Hospital, and written, informed consent was obtained from all patients. A total of 90 ASA physical status 1 and 2 patients without cardiovascular, pulmonary, or neurological diseases, who were scheduled for elective laparoscopic vaginal hysterectomy, were enrolled. No premedication was given. In the operating room, a routine monitoring system was attached to each patient, including continuous electrocardiography, noninvasive arterial blood pressure (BP), pulse oximetry, and capnography. To evaluate the depth of anesthesia, a BIS monitor (A-3000; Aspect Medical Systems, Norwood, MA, USA) was used. Patients were randomized to three groups according to a computer-generated table of random numbers. The aminophylline group (n = 30) received IV aminophylline 3 mg/kg, the doxapram group (n = 30) received IV doxapram 1 mg/kg, and the control group (n = 30) received normal IV saline. Induction was performed with a target-controlled infusion (TCI) of remifentanil, followed by propofol (Orchestra Infusion Workstation V03.OS-1; Fresenius, Vial, France), which included a protocol in the infusion instrument that was chosen by the Schnider model for propofol and the Minto model for remifentanil. Target-controlled infusion mode was used on both effect-site concentration infusions. The induction target of remifentanil was 3 ng/mL and propofol 6 μg/mL, followed by a maintenance target of remifentanil 1–3 ng/mL and propofol 3–5 μg/mL at the effect site; during the operation, these infusions were titrated to maintain BIS scores in the 40–50 range. Neuromuscular blockade was obtained with rocuronium 0.6 mg/ kg. After endotracheal tube insertion, ventilation was adjusted to maintain end-tidal CO2 at 35 ± 5 mmHg using 2 L/min of oxygen (O2) and 2 L/min of room air. During the last 30 minutes of the operation, no additional muscle relaxant was administered. At 10 minutes before the end of surgery, neuromuscular block was reversed with IV pyridostigmine 0.2 mg/kg and glycopyrrolate 0.04 mg/kg to allow for the return to spontaneous breathing. At the end of surgery, the propofol and remifentanil infusions were stopped and the study drug was given intravenously over one minute. Recovery from anesthesia was assessed by an anesthesiologist who was unaware of patients’ study group allocations. The following parameters were evaluated: time to return to spontaneous breathing, eye opening on verbal command, hand squeezing on verbal command, and tracheal extubation after administration of the study drug. Heart rate (HR), BP, and BIS values were determined before surgery and at 5-minute intervals during surgery. At each minute after injection of the study drug, for a period of 16 minutes the abovementioned parameters were determined. Respiratory rate (RR) and tidal volume (VT) were also recorded from the time of injection of the study drug to extubation. To estimate group size, a pilot study was conducted to measure the time it took for the occurrence of spontaneous breathing for 10 patients in the control group. The standard deviation (SD) of the time to return to spontaneous breathing was 2.2 minutes. For our power calculation, we assumed an equal SD for the time to return to spontaneous breathing in the other two groups. We wanted to show a difference of two minutes among the three groups in the time to
return to spontaneous breathing. With a two-tailed α = 0.05 and a power of 80%, 25 patients per group were needed. Assuming the possibility of patients being excluded from the study, we enrolled 30 patients per group. Data are expressed as means and SD. Demographic data were analyzed by x 2-test. Heart rate, BP, BIS values, RR, and VT were all analyzed by repeated-measures analysis of variance (ANOVA); the Newman-Keuls test was applied when ANOVA reached significance. The time to return to spontaneous breathing, eye opening on verbal command, hand squeezing on verbal command, and extubation were also compared using repeated-measures ANOVA. In all tests, a P-value b 0.05 was considered significant. 3. Results Patient characteristics were comparable among the three groups, with no significant differences noted (Table 1). After study drug administration, the return to spontaneous breathing occurred first in the doxapram group, then the aminophylline group, and finally the control group, with significant differences noted among the three groups. Eye opening and hand squeezing on verbal command were observed in the same order, with significant differences noted among the three groups. However, the time to extubation was significantly shorter in the doxapram and aminophylline groups versus the control group (P b 0.05; Table 2). Tidal volumes after study drug injection were increased significantly in the doxapram group, at 5–14 minutes, and in the aminophylline group, at 5–12 minutes, when compared with the control group. Respiratory rates were increased significantly at 2–8 minutes and decreased significantly at 12–14 minutes in both the doxapram and aminophylline groups versus the control group (P b 0.05; Fig. 1). However, there were no differences between the doxapram and aminophylline groups. With respect to BIS, no significant differences were noted among the three groups at baseline, ie, before injection of the study drugs. BIS values after injection of the study drugs were increased significantly in both the doxapram and aminophylline groups when compared with the control group at 4–10 minutes (P b 0.05), with no intergroup differences observed between the doxapram and aminophylline groups. Heart rates after study drug injection were increased significantly in the doxapram group for the first 8 minutes and at 1– 2 minutes in the aminophylline group when compared with the control group (P b 0.05; Fig. 2). However, there was no significant difference in BP among the three groups. 4. Discussion The synergistic interaction of remifentanil and propofol in TIVA causes a greater depression of the ventilatory response to hypercapnia, further delaying recovery. It therefore seemed logical to evaluate whether recovery from TIVA, with a rapid recovery profile, might be modified by a CNS stimulant such as aminophylline or doxapram. The main finding of this study was that both the aminophylline and Table 1 Patient characteristics
Age (yrs) Height (cm) Weight (kg) Duration of anesthesia (min)
Control group (n = 30)
Doxapram group (n = 30)
Aminophylline group (n = 30)
42.2 158.2 57.0 86.1
40.0 161.5 57.7 82.2
43.1 158.3 57.8 99.2
± 10.2 ± 4.8 ± 10.0 ± 28.6
± 11.3 ± 6.0 ± 8.7 ± 30.9
± 7.8 ± 5.6 ± 8.6 ± 15.9
Values are means ± SD. The control group received normal intravenous (IV) saline, the aminophylline group received IV aminophylline 3 mg/kg, and the doxapram group received IV doxapram 1 mg/kg.
D.W. Kim et al. / Journal of Clinical Anesthesia 25 (2013) 173–176 100
Table 2 Recovery time Aminophylline group (n = 30)
Time to spontaneous breathing (min) 8.6 ± 2.3 3.1 ± 1.5⁎ 4.4 ± 1.9 Eye opening on verbal command (min) 11.1 ± 2.0 6.29 ± 2.1⁎ 8.95 ± 3.7†,‡ Hand squeezing in response to 11.9 ± 2.0 7.55 ± 2.0⁎ 9.81 ± 3.6†,‡ verbal command (min) Extubation (min) 12.6 ± 2.3 8.70 ± 1.9⁎ 10.20 ± 3.7‡ †,‡
Values are means ± SD. The control group received normal intravenous (IV) saline, the aminophylline group received IV aminophylline 3 mg/kg, and the doxapram group received IV doxapram 1 mg/kg. ⁎ P b 0.05 doxapram vs control group. † P b 0.05 doxapram vs aminophylline group. ‡ P b 0.05 aminophylline vs control group.
doxapram groups hastened the return to spontaneous breathing. The more rapid emergence correlates with higher BIS values. A clinical maintenance infusion of propofol results in a dosedependent decrease in VT [19]. Remifentanil affects respiration by activating μ-opioid receptors, as expressed on the respiratory neurons in the brainstem [20,21]. As a consequence, ventilation is depressed and arterial carbon dioxide increases [22]. The peak respiratory depression of remifentanil occurred at 5 minutes after each dose of remifentanil. Recovery from remifentanil-induced respiratory depression was rapid, and minute ventilation returned to baseline in 8 minutes (range 5–15 min) after the infusion was stopped [23]. The dose-dependent respiratory depressant effects from propofol
A
90
a,c a,c
80
Bispectral index
Doxapram group (n = 30)
a,c
a,c
a,c
70
60
50 Saline control group
40
Doxapram group Aminophylline group
30 100
B a,b a,b
90
Heart rate (bpm)
Control group (n = 30)
175
a,c
a,b a,c
a,b
2
3
a,b
80
70
60 0
1
4
5
6
8
10
12
14
16
Time (min) 700
A
Fig. 2. Changes in Bispectral Index and heart rate after study drug administration. Error bars = SD. aP b 0.05 doxapram vs control group. bP b 0.05 doxapram vs aminophylline group. cP b 0.05 aminophylline vs control group.
a,c a
a,c
600
Tidal volume (mL)
a,c
500 a,c
a,c
400
300
200
Saline control group
100 30
B
Doxapram group
Respiratory rate (breaths/min)
Aminophylline group 25 a,c
a,c a,c a,c
20
a,c
a,c
a,c
15
a,c
10
5 0
1
2
3
4
5
6
8
10
12
14
16
Time (min) Fig. 1. Changes in tidal volume and respiratory rate after study drug administration. Error bars = SD. aP b 0.05 doxapram vs control group. bP b 0.05 doxapram vs aminophylline group. cP b 0.05 aminophylline vs control group.
and remifentanil (measured arterial blood concentration range: propofol 0–2.6 μg/mL, remifentanil 0–2.0 ng/mL) were strikingly synergistic, with clinically important respiratory depression at already low doses [24]. The effects of aminophylline (85% theophylline, 15% ethylendiamine) are very similar to those of caffeine. The main action of theophylline is direct relaxation of the smooth muscles of the bronchial airways and pulmonary blood vessels. It acts as a bronchodilator in anesthetic practice to treat asthma or bronchospasm [10,11], and in preterm neonates to decrease the incidence of postoperative apnea [12–14]. Several clinical studies have suggested that aminophylline decreases the depth and duration of sedation produced by propofol or antagonizes the effects of propofol [9]. Turan et al [25] showed that aminophylline shortened recovery times and consequently improved cognitive functions after sevoflurane anesthesia. BIS values are higher during the first 12 minutes of recovery when compared with those for placebo [26]. Stirt reported that IV aminophylline 2 mg/kg may be used to antagonize morphine anesthesia and respiratory depression in a patient with no other obvious cause of CNS depression [27]. Porkka-Heiskanen [28] reported that antagonism of adenosine by theophylline is well known and results in excitatory effects on neuronal activity, which stimulates the CNS to induce vigilance and increase the time spent awake. Doxapram is a central and a peripheral respiratory stimulant as well as a nonspecific CNS stimulant. Its ventilatory stimulant action occurs by an increase in VT, with little effect on RR [29–32]. As expected, our data showed that after administration of doxapram and aminophylline, return to spontaneous breathing occurred first in the doxapram group, then the aminophylline group, and then the control group, with significant differences noted among the three groups. Tidal volume and RR also were increased in the same corresponding order.
176
D.W. Kim et al. / Journal of Clinical Anesthesia 25 (2013) 173–176
Wu et al [33] showed that administration of doxapram 1 mg/kg hastened early recovery from sevoflurane anesthesia, and that this arousal effect correlated with higher BIS values. In another paper, Wu et al [34] reported that IV administration of doxapram 1 mg/kg or aminophylline 2 mg/kg hastened early recovery from sevoflurane anesthesia; this effect correlated well with higher BIS values. The arousal effects of doxapram and aminophylline appear to be similar. Aminophylline increases mean arterial blood pressure, left ventricular (LV) systolic pressure, and HR, and reduces LV end-diastolic diameter [35]. Turan et al [36] reported that HR increased with aminophylline in their study. A number of adverse effects have been reported with doxapram, such as tachycardia, cardiac arrhythmia, hypertension, hallucinations, and excitation [16,18,37]. In our study, after injection of the study drugs HR values were increased significantly in the doxapram group for the first 8 minutes and in the aminophylline group at 1–2 minutes, when compared with the control group. However, there was no significant difference in BP among the three groups. To study the hastening of recovery from anesthesia with BIS, Turan et al [25,26] and Hupfl et al [38] gave IV aminophylline 5 mg/kg or 3 mg/kg. As our finding was in accordance with those reports, we chose a smaller dose of aminophylline, 3 mg/kg. Noe et al [40] observed electroencephalographic (EEG) changes, which were indicative of arousal with intraoperative administration of IV doxapram 0.5 mg/kg at the end of surgery with thiamylal or halothane-nitrous oxide anesthesia. However, they did not elaborate on the specific EEG patterns. Roy and Stullken [41] reported conversion of the EEG to an awake pattern in dogs after the administration of IV doxapram 1 mg/kg during halothane anesthesia. Wu et al [33] showed that IV doxapram 1 mg/kg hastened recovery time in patients receiving sevoflurane anesthesia, an improvement that was also reflected in higher BIS scores. Since there has been no report in humans on the equivalent potency between doxapram and aminophylline in recovery of anesthesia, we used a single, lower dose of doxapram, 1 mg/ kg, or aminophylline 3 mg/kg, which are effective in reversing anesthetic effects without adverse responses [17,26,27,36–39]. In conclusion, the administration of aminophylline 3 mg/kg or doxapram 1 mg/kg at the end of TIVA hastened respiration and improved early recovery from TIVA without appreciable side effects. The more rapid emergence correlated with higher BIS values. The arousal and respiratory effects of aminophylline were comparable to those of doxapram. Acknowledgments The statistical analyses were performed in this study under the advice of the Catholic Medical Center Clinical Research Coordinating Center. References [1] Kashiwagi M, Osaka Y, Onimaru H, Takeda J. Optical imaging of propofol-induced central respiratory depression in medulla–spinal cord preparations from newborn rats. Clin Exp Pharmacol Physiol 2011;38:186–91. [2] Coda BA. Opioids. In: Barash PG, Cullen BF, Stoelting RK, Cahalan MK, Stock MC, editors. Clinical Anesthesia. 6th Ed. Philadelphia: Lippincott Williams & Wilkins; 2009. p. 465–97. [3] El Yacoubi M, Ledent C, Parmentier M, Costentin J, Vaugeois JM. Caffeine reduces hypnotic effects of alcohol through adenosine A2A receptor blockade. Neuropharmacology 2003;45:977–85. [4] Hasenfratz M, Bunge A, Dal Prá G, Bättig K. Antagonistic effects of caffeine and alcohol on mental performance parameters. Pharmacol Biochem Behav 1993;46: 463–5. [5] Rush CR, Higgins ST, Hughes JR, Bickel WK, Wiegner MS. Acute behavioral and cardiac effects of alcohol and caffeine, alone and in combination, in humans. Behav Pharmacol 1989;4:562–72. [6] Arvidsson S, Niemand D, Martinell S, Ekström-Jodal B. Aminophylline reversal of diazepam sedation. Anaesthesia 1984;39:806–9.
[7] Krintel JJ, Wegmann F. Aminophylline reduces the depth and duration of sedation with barbiturates. Acta Anaesthesiol Scand 1987;31:352–4. [8] Stirt JA. Aminophylline is a diazepam antagonist. Anesth Analg 1981;60:767–8. [9] Sakurai S, Fukunaga A, Fukuda K, Kasahara M, Ichinohe T, Kaneko Y. Aminophylline reversal of prolonged postoperative sedation induced by propofol. J Anesth 2008;22:86–8. [10] Seidenfeld JJ, Jones WN, Moss RE, Tremper J. Intravenous aminophylline in the treatment of acute bronchospastic exacerbations of chronic obstructive pulmonary disease. Ann Emerg Med 1984;13:248–52. [11] Migliori C, Garzoli E, Spinoni V, Chirico G. Aminophylline treatment of refractory bronchospasm in mechanically ventilated neonates: case report. Med Sci Monit 2007;13:CS93–6. [12] Sims C, Johnson CM. Postoperative apnoea in infants. Anaesth Intensive Care 1994; 22:40–5. [13] Martin RJ, Abu-Shaweesh JM. Control of breathing and neonatal apnea. Biol Neonate 2005;87:288–95. [14] Crean PM. Anaesthesia for the prematurely born infant. Trends in Anaesthesia and Critical Care 2000;11:245–9. [15] 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. [16] Siker ES, Mustafa K, Wolfson B. The analeptic effects of doxapram hydrochloride on thiopentone induced depression. Br J Anaesth 1964;36:216–23. [17] Gupta PK, Dundee JW. Hastening of arousal after general anaesthesia with doxapram hydrochloride. Br J Anaesth 1973;45:493–6. [18] Stephen CR, Talton I. Investigation of doxapram as a postanesthetic respiratory stimulant. Anesth Analg 1964;43:628–40. [19] Goodman NW, Black AM, Carter JA. Some ventilatory effects of propofol as sole anaesthetic agent. Br J Anaesth 1987;59:1497–503. [20] Dahan A, Aarts L, Smith TW. Incidence, reversal, and prevention of opioid-induced respiratory depression. Anesthesiology 2010;112:226–38. [21] Pattinson KT. Opioids and the control of respiration. Br J Anaesth 2008;100: 747–58. [22] Dahan A, Teppema LJ. Influence of anaesthesia and analgesia on the control of breathing. Br J Anaesth 2003;91:40–9. [23] Glass PS, Hardman D, Kamiyama Y, et al. Preliminary pharmacokinetics and pharmacodynamics of an ultra-short-acting opioid: remifentanil (GI87084B). Anesth Analg 1993;77:1031–40. [24] Nieuwenhuijs DJ, Olofsen E, Romberg RR, et al. Response surface modeling of remifentanil-propofol interaction on cardiorespiratory control and bispectral index. Anesthesiology 2003;98:312–22. [25] Turan A, Memiş D, Karamanlioglu B, Colak A, Pamukçu Z, Turan N. Effect of aminophylline on recovery from sevoflurane anaesthesia. Eur J Anaesthesiol 2002;19:452–4. [26] Turan A, Memiş D, Karamanlýodthlu B, Pamukçu Z, Süt N. Effect of aminophylline on bispectral index. Acta Anaesthesiol Scand 2004;48:408–11. [27] Stirt JA. Aminophylline may act as a morphine antagonist. Anaesthesia 1983;38: 275–8. [28] Porkka-Heiskanen T. Adenosine in sleep and wakefulness. Ann Med 1999;31: 125–9. [29] Hirsch K, Wang SC. Selective respiratory stimulating action of doxapram compared to pentylenetetrazol. J Pharmacol Exp Ther 1974;189:1–11. [30] Scott RM, Whitwam JG, Chakrabati MK. Evidence of a role for the peripheral chemoreceptors in the ventilatory response to doxapram in man. Br J Anaesth 1977;49:227–31. [31] Nishimura N, Fujii S, Chiba T, Zen K, Kusunoki H. Re-evaluation of intravenous drip infusion of doxapram–a double-blind method. Masui 1974;23:328–32. [32] Hunt CE, Inwood RJ, Shannon DC. Respiratory and nonrespiratory effects of doxapram in congenital central hypoventilation syndrome. Am Rev Respir Dis 1979;119:263–9. [33] Wu CC, Mok MS, Chen JY, Wu GJ, Wen YR, Lin CS. Doxapram shortens recovery following sevoflurane anesthesia. Can J Anaesth 2006;53:456–60. [34] Wu CC, Lin CS, Wu GJ, et al. Doxapram and aminophylline on bispectral index under sevoflurane anaesthesia: a comparative study. Eur J Anaesthesiol 2006;23: 937–41. [35] Rutherford JD, Vatner SF, Braunwald E. Effects and mechanism of action of aminophylline on cardiac function and regional blood flow distribution in conscious dogs. Circulation 1981;63:378–87. [36] Turan A, Kasuya Y, Govinda R, et al. The effect of aminophylline on loss of consciousness, bispectral index, propofol requirement, and minimum alveolar concentration of desflurane in volunteers. Anesth Analg 2010;110:449–54. [37] Riddle PL, Robertson GS. Use of doxapram as an arousal agent in outpatient general anaesthesia. Br J Anaesth 1978;50:921–4. [38] Hupfl M, Schmatzer I, Buzath A, et al. The effects of aminophylline on bispectral index during inhalational and total intravenous anaesthesia. Anaesthesia 2008;63: 583–7. [39] Kanemaru Y, Nishikawa K, Goto F. Bispectral index and regional cerebral oxygen saturation during propofol/N2O anesthesia. Can J Anaesth 2006;53:363–9. [40] Noe FE, Borrillo N, Greifenstein FE. Use of a new analeptic, doxapram hydrochloride, during general anesthesia and recovery. Anesth Analg 1965;44:206–13. [41] Roy RC, Stullken EH. Electroencephalographic evidence of arousal in dogs from halothane after doxapram, physostigmine, or naloxone. Anesthesiology 1981;55: 392–7.