Comparison of isoflurane and propofol–fentanyl anaesthesia in a swine model of asphyxia

T. Kurita*,1, K. Morita1, T. Kazama2 and S. Sato1

1 Department of Anesthesiology and Intensive Care, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Japan. 2 Department of Anesthesiology, National Defense Medical College, 3-2 Namiki, Tokorozawa 359-8513, Japan

*Corresponding author. E-mail: tadkur@hama-med.ac.jp

Accepted for publication: July 9, 2003


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Background. There have been few studies comparing the response to asphyxia and the effectiveness of typical cardiopulmonary resuscitation (CPR) using exogenous epinephrine administration and manual closed-chest compression between total intravenous anaesthesia (TIVA) and inhalational anaesthesia.

Methods. Twenty pigs were randomly assigned to two study groups anaesthetized using either 2% end-tidal isoflurane (n=10) or propofol (12 mg kg–1 h–1)–fentanyl (50 µg kg–1) (n=10). Asphyxia was induced by clamping the tracheal tube until the mean arterial pressure (MAP) decreased to 40% of the baseline value (40% MAP time). The tracheal tube was declamped at that point, and CPR was performed. Haemodynamic parameters and blood samples were obtained before the induction of asphyxia, at 1-min intervals during asphyxia, and 1, 2, 3, 5, 10, 30 and 60 min after asphyxia.

Results. TIVA maintained the MAP against hypoxia–hypercapnia stress significantly longer than isoflurane anaesthesia (mean (SD) 40% MAP time 498 (95) and 378 (104) s respectively). In all animals in the isoflurane group, spontaneous circulation returned within 1 min of the start of CPR. In six of the TIVA animals, spontaneous circulation returned for 220 (121) s; spontaneous circulation did not return within 5 min in the remaining four animals.

Conclusions. Although TIVA is less prone than isoflurane anaesthesia to primary cardiovascular depression leading to asphyxia, TIVA is associated with reduced effectiveness of CPR in which resuscitation because of asphyxic haemodynamic depression occurs.

Br J Anaesth 2003; 91: 871–7

Keywords: anaesthetics i.v.; anaesthetics i.v., propofol; anaesthetic techniques, inhalation; heart, resuscitation


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Total intravenous anaesthesia (TIVA) with propofol and opioids effectively obtunds the adrenergic response to surgical stress with a concomitant reduction in plasma catecholamine concentrations.14 On the basis of their study examining the effects of anaesthetic method on outcome variables associated with asphyxia-induced cardiac arrest, Jasani and colleagues5 reported that the anaesthetic method affects endogenous plasma epinephrine concentrations, the incidence of ventricular fibrillation and time to cardiac arrest. If adrenergic activation in response to hypoxia–hypercapnia stress depends on anaesthetic method, differences in haemodynamic responses and catecholamine secretion may occur between TIVA and inhalational anaesthesia in cases of asphyxia. Hypoxia produces an increase in plasma propofol concentrations during constant infusion.6 Furthermore, we have recently reported that low cardiac output induces high plasma propofol concentrations.7 These changes in propofol kinetics can depress myocardial function and may negatively affect the resuscitation outcome in cases of upper airway crisis during TIVA. The first objective of the present study was to assess the characteristics of isoflurane and propofol–fentanyl anaesthesia in response to asphyxial stress, and the second objective was to investigate the effectiveness of typical cardiopulmonary resuscitation (CPR) using exogenous epinephrine and manual closed-chest compression in anaesthetized swine.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
This study was approved by our institutional ethics committee (Committee on Animal Research, Hamamatsu University School of Medicine, Hamamatsu, Japan). Twenty swine (body weight range, 23.0–39.0 kg; mean (SD), 29.4 (3.9) kg) were studied. General anaesthesia was induced by the inhalation of isoflurane (5%) in oxygen 5 litres min–1 using a standard animal mask. After tracheostomy, anaesthesia was maintained with end-tidal isoflurane 2% and an oxygen–air mixture (fraction of inspired oxygen, 0.6) via mechanical ventilation. A peripheral venous catheter (20 gauge) was placed in the right dorsal ear vein, and an infusion of lactated Ringer’s solution was maintained at the rate of 10 ml kg–1 h–1. End-tidal carbon dioxide was maintained between 4.7 and 5.3 kPa. Lead II of an electrocardiogram (ECG) was monitored with subcutaneous electrodes introduced into the legs. A pulmonary artery catheter (5 F, 4 lumen; Nihon Kohden, Tokyo, Japan) was inserted via the right jugular vein and a catheter (18 gauge) was placed in the right femoral artery. Blood temperature was maintained between 38.0 and 39.0°C with heating lamps. Swine were assigned randomly to continue isoflurane (n=10) or to change to propofol–fentanyl anaesthesia (n=10). In the isoflurane group, anaesthesia was maintained for 100 min before asphyxia was induced by a tracheal tube clamp. In the propofol–fentanyl group, another peripheral venous catheter (20 gauge) was placed in the left dorsal ear vein and was used for propofol and fentanyl infusion. Propofol and fentanyl were administered by two separate infusion pumps (TE-312; Terumo, Tokyo, Japan) at 12 mg kg–1 h–1 and 50 µg kg–1 respectively over 100 min. Twenty minutes after the start of propofol and fentanyl administration, inhalation of isoflurane was stopped and animals were ventilated with an oxygen–air mixture (fraction of inspired oxygen 0.6). Blood samples were collected from the femoral artery at 0, 20, 40, 60, 80 and 100 min to measure plasma propofol concentrations, which were confirmed as reaching a pseudo-steady-state concentration before asphyxia. Propofol concentrations were assayed by high-performance liquid chromatography according to the method of Plummer.8 The lower limit of detection was 15 ng ml–1 and the mean intra-assay coefficient of variation was 7.0%. After preparation, the animals were paralysed with pancuronium 4 mg to prevent gasping and heparin 100 U kg–1 was administered to prevent intracardiac clot formation. After haemodynamic stability had been obtained, asphyxia was induced by clamping the tracheal tube. The end point was determined by decreasing the mean arterial pressure (MAP) to 40% of the value obtained before clamping the tracheal tube in our preliminary studies; this end point was chosen for the present study because asystole or pulseless electrical activity occurs soon after this point. When this end point was achieved (continuous infusion of propofol was stopped in the TIVA group), mechanical ventilation was resumed with oxygen 100% (without isoflurane), and epinephrine 0.02 mg kg–1 was administered into the right atrium. Manual closed-chest CPR was then initiated. Chest compressions were performed by the same investigator in all animals at the rate of 100 compressions min–1. If asystole or pulseless electrical activity was present after 5 min of CPR, the experiment was terminated. Return of spontaneous circulation (successful CPR) was defined as an unassisted pulse with a systolic arterial pressure of >=80 mm Hg for 5 min. Inhalation of isoflurane (isoflurane group) or continuous infusion of propofol (TIVA group) was reinitiated when movement of the animal was observed or when 20 min had passed after the return of spontaneous circulation. Haemodynamic parameters were noted and blood samples (for the measurement of plasma propofol, plasma epinephrine and plasma norepinephrine concentrations) were obtained before the induction of asphyxia, at 1-min intervals up to the end point during asphyxia, and 1, 2, 3, 5, 10, 30 and 60 min after declamping of the tracheal tube. Plasma catecholamine concentrations were determined using high-performance liquid chromatography, with detection limits of 6 pg ml–1 for both epinephrine and norepinephrine. Coefficients of variation within assays were 1.6% for epinephrine and 2.4% for norepinephrine, and between assays they were 2.0% for epinephrine and 2.3% for norepinephrine. Cardiac output (CO) was measured by the thermodilution method before induction of asphyxia, 10 min after the declamping of the tracheal tube. CO was determined with a thermodilution computer (Cardiac Output Computer, MTC6210; Nihon Kohden) using cold glucose 5%, 5 ml, injected into the right atrium. Each CO value was measured four times and the mean of the last three values was recorded.

Statistical analysis
Data are expressed as mean (SD). Heart rate (HR), MAP, plasma epinephrine concentration and plasma norepinephrine and propofol concentrations were analysed by repeated-measures one-way analysis of variance (ANOVA). If ANOVA was found to be significant, Scheffé’s F-test was performed to compare the difference in values at each time. Differences in HR, MAP and plasma epinephrine, norepinephrine and propofol concentrations between groups were analysed using two-factor ANOVA with repeated measures on one factor. If ANOVA was found to be significant, an unpaired t-test was performed to compare the difference in values at each relevant time point between groups. Differences in demographic variables between the two groups were evaluated using the unpaired t-test for dependent samples. Fisher’s exact probability test was used to test for differences among groups with respect to the rate of successful CPR and the time to resuscitation. A P-value of less than 0.05 was considered statistically significant.


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Table 1 shows basic characteristics of the isoflurane and TIVA groups before asphyxia. There were no significant differences between the groups. Figure 1 shows the time courses of MAP (A) and HR (B) after tracheal tube-clamping (post-clamp time) in the isoflurane and TIVA groups. In both groups, MAP initially increased after the start of asphyxia, then decreased. The peak MAP in the isoflurane group was reached at 2 min (99 (18) mm Hg; increased 38% from the baseline) and that in the TIVA group at 4 min (115 (30) mm Hg; increased 37% from the baseline). In the isoflurane group, HR changed similarly to the MAP, with a peak value reached at 2 min (152 (23) beats min–1; increased 27% from the baseline), after which a decrease was observed. In the TIVA group, HR did not change significantly until 4 min after the start of asphyxia, after which it gradually decreased. Plasma epinephrine concentrations increased significantly in both groups, increases in the TIVA group being greater than those in the isoflurane group (Fig. 2A). Plasma norepinephrine concentrations also increased significantly in both groups, increases in the TIVA group being greater than those in the isoflurane group (Fig. 2B).


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Table 1 Baseline (pre-asphyxia) variables in the two anaesthetic groups
 


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Fig 1 (A) Effect of tracheal tube-clamping (post-clamp time) on mean arterial pressure (MAP) in the isoflurane and TIVA groups. #P<0.05 vs MAP at 0 min in the isoflurane group; ##P<0.05 vs MAP at 0, 1 and 3 min in the isoflurane group; ###P<0.05 vs MAP at 0, 1 and 2 min in the TIVA group. (B) Effect of post-clamp time on heart rate in both groups. #P<0.05 vs HR at 3 min in the isoflurane group; ##P<0.05 vs HR at 0 and 3 min in the isoflurane group.

 


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Fig 2 (A) Effect of tracheal tube-clamping (post-clamp time) on plasma epinephrine concentration in the isoflurane and TIVA groups. #P<0.05 vs plasma epinephrine concentrations at 0, 1 and 2 min in the isoflurane group; ##P<0.05 vs plasma epinephrine concentrations at 0, 1 and 2 min in the TIVA group. (B) Effect of post-clamp time on plasma norepinephrine concentration in both groups. #P<0.05 vs plasma norepinephrine concentrations at 0, 1 and 2 min in the isoflurane group; ##P<0.05 vs plasma norepinephrine concentrations at 0, 1, 2 and 3 min in the TIVA group.

 
Table 2 shows 40% MAP time, plasma catecholamine and propofol concentrations at 40% MAP time, coronary perfusion pressure (CPP) at the start of CPR, CPR outcome, and CO 10 min after CPR (n=6). The TIVA group maintained MAP significantly longer than the isoflurane group (498 (95) and 378 (104) s respectively). Plasma concentrations of both epinephrine and norepinephrine at 40% MAP time were significantly greater in the TIVA group than in the isoflurane group. Although CPP was not significantly different between groups, CPP in the unsuccessful CPR animals receiving TIVA (10 (12) mm Hg) was significantly lower than that in the successful animals receiving TIVA (46 (25) mm Hg) (data not shown in tables). In the isoflurane group, spontaneous circulation returned in all animals within 1 min after the start of CPR. In the TIVA group, spontaneous circulation returned within 1 min in three animals and between 1 and 5 min in three animals; the mean time for spontaneous circulation return was 220 (121) s. In four animals, spontaneous circulation did not return within 5 min of CPR (two animals were asystole and two had MAP <=30 mm Hg). Although the ratios of successful CPR between both groups were not statistically different (P=0.09), the TIVA group required longer for spontaneous circulation to return than the isoflurane group. CO 10 min after CPR in the TIVA group (n=6) was significantly lower than that in the isoflurane group. In the entire isoflurane group, anaesthesia was reinitiated after movement was observed (353 (114) s). In the TIVA group, no animals were observed to produce any movement within 20 min, and continuous infusion of propofol was restarted 20 min after CPR. Plasma propofol concentrations increased after the start of constant infusion and reached a pseudo-steady state at 100 min (5.8 (2.5) µg ml–1, data not shown).


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Table 2 40% MAP time, plasma epinephrine and plasma norepinephrine concentrations at 40% MAP time and CPR outcome of each anaesthetic method. 40% MAP time=mean arterial pressure time decrease to 40% of the baseline value; 40% epinephrine=plasma epinephrine concentration at 40% MAP time; 40% norepinephrine=plasma norepinephrine concentration at 40% MAP time; 40% propofol concentration=plasma propofol concentration at 40% MAP time. {dagger}Compared with successful CPR; {ddagger}compared with successful CPR within 5 min (>1 min); *statistically significant.
 
After tracheal tube-clamping, plasma propofol concentrations gradually increased with the progression of asphyxia (Fig. 3A). Plasma propofol concentration 4 min after asphyxia (at the time of the observed peak MAP) and at 40% MAP time were 10.1 (3.8) and 14.7 (4.8) µg ml–1 respectively. Figure 3B shows the changes in plasma propofol concentrations in the successful and unsuccessful TIVA groups after tracheal tube declamping. In the unsuccessful group, plasma propofol concentrations did not change and high concentrations were maintained. Plasma propofol concentrations of the CPR-unsuccessful animals during CPR were 19.5 (6.6) µg ml–1. In contrast, plasma propofol concentrations in the successful group gradually decreased until the restart of propofol infusion at 20 min, and the lowest concentration was 2.2 (0.8) µg ml–1, at 10 min. Plasma propofol concentrations in the successful group at 2, 3 and 5 min were significantly lower than those in the unsuccessful group.



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Fig 3 (A) Effect of tracheal tube-clamping (post-clamp time) on plasma propofol concentration. #P<0.05 vs plasma propofol concentrations at 0, 1, 2 and 3 min. (B) Effect of tracheal tube-declamping (post-declamp time) on plasma propofol concentration in unsuccessful CPR cases in the TIVA group (TIVA-unsuccess) and successful CPR cases in the TIVA group (TIVA-success). #P<0.05 vs plasma propofol concentration at 0, 1 and 2 min in TIVA-success; ##P<0.05 vs plasma propofol concentration at 0, 1, 2 and 3 min in TIVA-success. *P<0.05 between groups.

 

    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The effects of acute hypoxia and hypercapnia appear to cause direct depression of both cardiac muscle and vascular smooth muscle; however, they also cause reflex stimulation of the sympathoadrenal system, which compensates to a greater or lesser extent for the primary cardiovascular depression.9 10 The rapid release of catecholamines in response to stress induced by asphyxia was observed in both the TIVA and isoflurane groups, and plasma epinephrine and norepinephrine concentrations in both groups increased similarly for 2 min after asphyxia was initiated; however, after 2 min, plasma catecholamine concentrations in the TIVA group continued to increase at a greater rate than that observed in the isoflurane group. In the TIVA group, plasma epinephrine and norepinephrine concentrations at the time of reaching 40% baseline MAP were significantly greater than those in the isoflurane group. Although the maximum rate of increase in MAP did not differ between the two groups (38 and 37% increase from the baseline respectively), the MAP response in the TIVA group was slower than that in the isoflurane group. Moreover, in the TIVA group, HR did not increase, rather slowly decreasing. These results indicate that TIVA diminishes haemodynamic responsiveness to endogenous catecholamine concentrations, and maintains a relatively low cardiac oxygen demand compared with isoflurane, although catecholamine secretion is maintained. As a result, TIVA was shown to be advantageous with regard to maintaining haemodynamics against the development of asphyxia-induced stress.

Several investigators have reported that TIVA with propofol and opioids effectively blunts the adrenergic response to surgical stress, with a consecutive reduction in plasma catecholamine concentrations.13 Minami and colleagues11 have reported that propofol at an anaesthetic concentration of 10–30 µmol litre–1 reduces catecholamine secretion in cultured bovine adrenal medullary cells. Our finding appears to contradict these reports. However, because asphyxia is extremely serious and maximum stress is involved in cases of severe hypoxia–hypercapnia, we cannot simply compare responses to this kind of stress with those to other stresses. In fact, plasma catecholamine concentrations in the present study reached approximately 100 times the concentrations noted in studies of other stresses, such as surgery, hypoglycaemia, myocardial infarction and chromaffin tumour.12 We are able to conclude that propofol and fentanyl administered at anaesthetic concentrations cannot sufficiently suppress plasma catechol amine secretion in response to asphyxia, even if the response is reduced more or less. In the present study, we administered fentanyl 50 µg kg–1 before asphyxia occurred. As an additional experiment in the present study, we administered fentanyl 150 µg kg–1 in another five swine to examine whether the dose of fentanyl affected catechol amine secretion. Plasma epinephrine concentrations (pg ml–1) were 124 (114) (before), 432 (775) (1 min), 9696 (20 740) (2 min), 31 514 (26 065) (3 min) and 56 193 (30 194) (4 min). Plasma norepinephrine concentrations were 216 (79) (before), 684 (627) (1 min), 8792 (11 262) (2 min), 47 788 (19 585) (3 min) and 100 492 (51 144) (4 min) pg ml–1. Even threefold doses of fentanyl could not suppress plasma catecholamine secretion in response to asphyxia. The minimum alveolar concentration (MAC) for isoflurane administration to swine has been reported by Lerman and colleagues as 1.48 (0.21)%.13 We used 2% end-tidal isoflurane (1.3 MAC) to maintain anaesthesia. However, few reports concerning anaesthetic depth have employed total i.v. anaesthetics in animal models. Although the MAP and HR in the TIVA group before asphyxia were both slightly, if not significantly, greater than those in the isoflurane group, no movement was observed in response to the same surgical stimuli. Furthermore, baseline plasma epinephrine and norepinephrine concentrations between groups were similar. Anaesthetic depth before asphyxia appeared to be comparable between groups. Plasma propofol concentrations increased gradually with the progression of asphyxia. Yamamoto and colleagues6 have reported the results of an animal study evaluating the effects of hypoxia and hyperoxia on the pharmacokinetics of propofol emulsion. They found that hypoxia causes both an accumulation of propofol in the blood and a reduction in propofol clearance. These changes are due to decreased hepatic blood flow and low cellular energy in the liver. We have recently reported that CO influences plasma propofol concentrations during constant infusion, and that plasma propofol concentrations rapidly increase and decrease with decreasing and increasing CO respectively.7 Acute respiratory acidosis initially increases CO;14 CO then decreases with the progression of asphyxia. Plasma norepinephrine concentrations gradually increase with the progression of asphyxia. Two minutes after tracheal tube-clamping, plasma norepinephrine concentrations had already reached 5821 (7165) pg ml–1 (almost the same concentration as that observed in association with a chromaffin tumour).12 Not only the change in CO (including the decrease in hepatic clearance), but also the rapid decrease in the propofol distribution volume induced by high plasma norepinephrine concentrations may cause accumulation of propofol during asphyxia. Although plasma propofol concentrations in the unsuccessful group at the start of CPR (16.7 (3.1) µg ml–1) tended to be greater than those in the successful group (13.4 (5.5) µg ml–1) (Fig. 3B), the 40% MAP time in the unsuccessful group (460 (96) s) was not longer than that in the successful group (523 (93) s). However, norepinephrine concentrations at 40% MAP time in the unsuccessful group (20.9 (8.3) pg ml–1) tended to be greater than those in the successful group (17.2 (15.8) pg ml–1). These findings may also suggest that high plasma norepinephrine concentrations cause high plasma propofol concentrations. Because our study simulated unexpected upper-airway trouble during anaesthesia, we did not stop continuous infusion of propofol during asphyxia. As a supplementary experiment in the present study, in four of six swine with successful CPR the tracheal tube was reclamped 60 min after the first tracheal tube-declamping (the initiation of CPR). Just before the second clamping, continuous propofol infusion was stopped and plasma propofol concentrations were measured before and at 1-min intervals after the second clamping. Plasma propofol concentrations (µg ml–1) were 4.5 (1.0) (before), 2.0 (0.1) (1 min), 1.7 (0.2) (2 min), 1.8 (0.1) (3 min) and 2.0 (0.2) (4 min). Plasma propofol concentrations before asphyxia were significantly greater than those 1, 2, 3 and 4 min after the second clamping. When the continuous infusion of propofol was stopped just before asphyxia, plasma propofol concentrations did not increase.

In the present study, we could not simply compare the resuscitation outcomes between groups because the resuscitations were initiated at 40% MAP time, which differed by approximately 2 min between groups. However, four of the 10 TIVA swine did not undergo a return of spontaneous circulation within 5 min, whereas all of the animals in the isoflurane group were successfully resuscitated within 1 min, although we did not perform a severe CPR protocol in either group, i.e. we did not maintain untreated asphyxic cardiac arrest. A CPP of 20 mm Hg is considered to be the approximate threshold needed for successful resuscitation.15 Diminished CPP during CPR, such as that due to sympathetic nervous blockage, renders resuscitation difficult.16 17 Our findings consistently demonstrated that CPP in the unsuccessful CPR group was significantly less than that in the successful CPR group. It is possible that increased endogenous plasma catecholamine concentrations actually limit the effectiveness of additional exogenous epinephrine as a result of down-regulation or uncoupling of receptors and/or low bioavailability.18 Additionally, the plasma propofol concentrations reached a level approximately three-fold those observed before asphyxia, while continuous infusion of propofol during asphyxia was maintained. This high plasma concentration might have caused the severe myocardial depression. Indeed, Zhou and colleagues19 have reported in an in vitro study that propofol decreased cardiac ß-adrenoceptor responsiveness. However, relatively high concentrations of propofol (5.5–45 µg ml–1) were required to antagonize ß-adrenoceptor binding and tissue responsiveness. This phenomenon may diminish the effectiveness of high plasma catecholamine concentrations (both endogenous and additional exogenous catecholamines).

In conclusion, propofol–fentanyl anaesthesia maintains haemodynamics against asphyxia-induced stress longer than isoflurane anaesthesia. Furthermore, propofol–fentanyl anaesthesia suppresses catecholamine secretion to a lesser extent than isoflurane anaesthesia. This is because the continuous infusion of propofol during asphyxia rapidly increases plasma propofol concentrations, possibly diminishing the effectiveness of both exogenously administered epinephrine and manual closed-chest compressions in cases necessitating resuscitation because of asphyxia-induced haemodynamic depression.


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
1 Hoka S, Yamaura K, Takenaka T, et al. Propofol-induced increase in vascular capacitance is due to inhibition of sympathetic vasoconstrictive activity. Anesthesiology 1998; 89: 1495–500[ISI][Medline]

2 Daniel M, Eger EII, Weiskopf RB, et al. Propofol fails to attenuate the cardiovascular response to rapid increases in desflurane concentrations. Anesthesiology 1996; 84: 75–80[CrossRef][ISI][Medline]

3 Ng A, Tan SW, Lee HS, et al. Effect of propofol infusion on the endocrine response to cardiac surgery. Anaesth Intens Care 1995; 23: 543–7[ISI][Medline]

4 Schwall B, Jakob W, Sessler DI, et al. Less adrenergic activation during cataract surgery with total intravenous than with local anesthesia. Acta Anaesthesiol Scand 2000; 44: 343–7[CrossRef][ISI][Medline]

5 Jasani MS, Salzman SK, Tice LL, et al. Anesthetic regimen effects on a pediatric porcine model of asphyxial arrest. Resuscitation 1997; 35: 69–75[CrossRef][ISI][Medline]

6 Yamamoto K, Tsubokawa T, Yagi T, et al. The influence of hypoxia and hyperoxia on the kinetics of propofol emulsion. Can J Anaesth 1999; 46: 1150–5[Abstract]

7 Kurita T, Morita K, Kazama T, et al. Influence of cardiac output on plasma propofol concentrations during constant infusion in swine. Anesthesiology 2002; 96: 1498–503[CrossRef][ISI][Medline]

8 Plummer GF. Improved method for the determination of propofol in blood by high-performance liquid chromatography with fluorescence detection. J Chromatogr 1987; 421: 171–6[Medline]

9 Lehot JJ, Leone BJ, Foex P. Effect of altered PaO2 and PaCO2 on left ventricular function and coronary hemodynamics in sheep. Anesth Analg 1991; 72: 737–43[Abstract]

10 Rothe CF, Flanagan AD, Maass-Moreno R. Reflex control of vascular capacitance during hypoxia, hypercapnia, or hypoxic hypercapnia. Can J Physiol Pharmacol 1990; 68: 384–91[ISI][Medline]

11 Minami K, Yanagihara N, Segawa K, et al. Inhibitory effects of propofol on catecholamine secretion and uptake in cultured bovine adrenal medullary cells. Naunyn Schmiedebergs Arch Pharmacol 1996; 353: 572–8[ISI][Medline]

12 Cryer PE. Physiology and pathophysiology of the human sympathoadrenal neuroendocrine system. N Engl J Med 1980; 303: 436–44[ISI][Medline]

13 Lerman J, Oyston JP, Gallagher TM, et al. The minimum alveolar concentration (MAC) and hemodynamic effects of halothane, isoflurane, and sevoflurane in newborn swine. Anesthesiology 1990; 73: 717–21[ISI][Medline]

14 Walley KR, Lewis TH, Wood LDH. Acute respiratory acidosis decreases left ventricular contractility but increases cardiac output in dogs. Circ Res 1990; 67: 628–35[Abstract]

15 Kern KB, Niemann JT. Coronary perfusion pressure during cardiopulmonary resuscitation. In: Paradis NA, Halperin HR, Nowak RM, eds. Cardiac Arrest: the Science and Practice of Resuscitation Medicine. Baltimore: Williams & Wilkins, 1996; 270–85

16 Rosenberg JM, Wahr JA, Sung CH, et al. Coronary perfusion pressure during cardiopulmonary resuscitation after spinal anesthesia in dogs. Anesth Analg 1996; 82: 84–7[Abstract]

17 Rosenberg JM, Wortsman J, Wahr JA, et al. Impaired neuroendocrine response mediates refractoriness to cardiopulmonary resuscitation in spinal anesthesia. Crit Care Med 1998; 2: 533–7

18 Gonzalez ER, Ornato JP, Garnett AR, et al. Dose-dependent vasopressor response to epinephrine during CPR in human beings. Ann Emerg Med 1989; 18: 920–6[ISI][Medline]

19 Zhou W, Fontenot HJ, Wang SN, et al. Propofol-induced alterations in myocardial ß-adrenoceptor binding and responsiveness. Anesth Analg 1999; 89: 604–8[Abstract/Free Full Text]





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