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Anesth Analg 2003;97:456-460
© 2003 International Anesthesia Research Society

ANESTHETIC PHARMACOLOGY

Intravenous Alprostadil, an Analog of Prostaglandin E1, Prevents Thiamylal-Fentanyl-Induced Bronchoconstriction in Humans

Zen’ichiro Wajima, MD PhD*, Toshiya Shiga, MD PhD||, Tatsusuke Yoshikawa, MD PhD{dagger},§, Akira Ogura, MD PhD*, Kazuyuki Imanaga, MD*, Tetsuo Inoue, MD PhD*, and Ryo Ogawa, MD PhD{ddagger}

*Department of Anesthesia, Chiba Hokusoh Hospital, Chiba, Japan; {dagger}Department of Anesthesia, Tama-Nagayama Hospital; {ddagger}Department of Anesthesiology, Nippon Medical School; §Department of Anesthesiology, Tokyo Jikeikai Medical School, Tokyo, Japan; and ||Center for Anesthesiology Research, The Cleveland Clinic Foundation, Ohio

Address correspondence and reprint requests to Zen’ichiro Wajima, MD, PhD, Department of Anesthesia, Chiba Hokusoh Hospital, Nippon Medical School, 1715, Kamagari, Inba-mura, Inba-gun, Chiba 270–1694, Japan. Address e-mail to HFB01245{at}nifty.com


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Prostaglandin (PG) E1 relaxes airway smooth muscle in animals. However, no clinical data have been published on the bronchorelaxant effects of IV alprostadil, an analog of PGE1. We have described experimental thiamylal-fentanyl-induced bronchoconstriction in humans; we now report the effect of IV alprostadil on thiamylal-fentanyl-induced bronchoconstriction. Thirty-two patients were allocated randomly to a control group (n = 16) and alprostadil group (n = 16). Anesthesia was induced with thiamylal 5 mg/kg and vecuronium 0.3 mg/kg and maintained with a continuous infusion of thiamylal 15 mg · kg-1 · h-1. The lungs of the patients were ventilated with 50% nitrous oxide in oxygen. Twenty minutes after the induction of anesthesia, patients in the control group were given a continuous infusion of normal saline 20 mL/h, and those in the alprostadil group received a continuous infusion of alprostadil 0.2 µg · kg-1 · min-1 (20 mL/h), both for 60 min. Both groups were then given fentanyl 5 µg/kg. Systolic and diastolic arterial blood pressure, heart rate, mean airway resistance (Rawm), expiratory airway resistance (Rawe), and dynamic lung compliance (Cdyn) were measured at the baseline, just before the fentanyl injection (T30), at three consecutive 6-min intervals after fentanyl injection (T36, T42, and T48), and 30 min after fentanyl injection (T60). Baseline Rawm, Rawe, and Cdyn values were comparable between groups. In the control group, both Rawm and Rawe were significantly increased at T36–60, and Cdyn was significantly decreased at T36–60 compared with the baseline. Patients given alprostadil showed no change in Rawm, Rawe, or Cdyn at T36–60. Thus, IV alprostadil seems to have a bronchodilator effect in humans.

IMPLICATIONS:IV alprostadil, an analog of prostaglandin E1, prevents thiamylal-fentanyl-induced bronchoconstriction in humans. This finding suggests that IV alprostadil has a bronchodilator effect.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Prostaglandins (PG) affect airway caliber causing either bronchoconstriction or bronchodilatation (1). The E-series PG relax airway smooth muscle, and prostacyclin reverses bronchospasm induced by acetylcholine, histamine, and PG F2{alpha}. Therefore, PG may be useful in the treatment of human asthma (1).

PGE1 relaxes vascular and airway smooth muscle (2–6), and IV PGE1 may produce direct relaxant effects on bronchoconstriction induced by histamine (7) and serotonin (8) in a dog model. However, no clinical data have been published on the bronchorelaxant effects of IV alprostadil, an analog of PGE1. We investigated whether IV alprostadil prevents thiamylal-fentanyl-induced bronchoconstriction, which has been shown to be safe and ethical for human experimentation (9,10).


   Methods
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 Abstract
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 Methods
Results
 Discussion
 References
 
Thirty-two nonsmoking, ASA physical status I or II patients scheduled for elective minor surgery were included in this study. The study protocol was approved by our IRB, and written informed consent for the prolongation of anesthesia was obtained from each patient. The exclusion criteria were any clinical or radiological abnormality of the respiratory system, suspected (history of atopy) or overt (history of wheezing) bronchial hypersensitivity, history of reactive airway disease, or treatment with bronchodilators such as ß-adrenoceptor antagonist. The patients were randomly allocated to a control group (n = 16) or an alprostadil group (n = 16).

The experimental protocol is shown in Figure 1 and is similar to that of our reported studies (9,10). Anesthesia was induced with thiamylal 5 mg/kg, and IV vecuronium 0.3 mg/kg was given to facilitate oral endotracheal intubation with a disposable endotracheal tube (internal diameter, 8 mm). Anesthesia was maintained with a continuous infusion of thiamylal 15 mg · kg-1 · h-1. The lungs of the patients were ventilated using a semiclosed circle system (Ohmeda Modulus® CD Anesthesia System, Ohmeda, Madison, WI) delivering 50% nitrous oxide in oxygen at a fresh gas flow of 6 L/min (tidal volume, 8 mL/kg; inspiratory-expiratory ratio, 1:2; respiratory rate, 10 breaths/min).



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  		Figure 1. Anesthesia was induced with thiamylal 5 mg/kg and vecuronium 0.3 mg/kg IV. In both groups, a 15 mg · kg-1 · h-1 continuous infusion of thiamylal followed anesthetic induction. In the control group, continuous normal saline injection was started at 0 min (baseline), whereas the alprostadil group received continuous alprostadil injection. For both groups, IV fentanyl was administered just after the measurement at 30 min (T30). Measurements were conducted at 0 (baseline), 30 (T30), 36 (T36), 42 (T42), 48 (T48), and 60 (T60) min.

 
Twenty minutes after the induction of anesthesia, patients in the control group received a continuous infusion of normal saline 20 mL/h, and those in the alprostadil group received a continuous infusion of alprostadil 0.2 µg · kg-1 · min-1 (20 mL/h) for 60 min (until the end of the study). Fifty minutes after the induction of anesthesia, patients in both groups received fentanyl 5 µg/kg IV. Systolic and diastolic arterial blood pressure, heart rate, mean airway resistance (Rawm), expiratory airway resistance (Rawe), and dynamic lung compliance (Cdyn) were measured at baseline, just before fentanyl injection (T30), at 3 consecutive 6-min intervals after fentanyl injection (T36, T42, and T48), and 30 min after fentanyl injection (T60). Rawm, Rawe, and Cdyn were measured and analyzed by a CP-100 pulmonary function monitor (Bicore, Irvine, CA) attached to a flow transducer (VarFlex®, Bear Medical Systems, Inc, Palm Springs, CA) and an esophageal balloon catheter (SmartCath®, Bear Medical Systems, Inc) (9–18).

If mean arterial blood pressure decreased to less than 60 mm Hg, IV phenylephrine (bolus or continuous) was administered. The plasma concentrations of norepinephrine and epinephrine were measured at baseline and T36. They were assayed in duplicate by high-pressure liquid chromatography (19). The study was completed before surgery was started.

Differences in sex were compared using {chi}2 analysis. Unpaired t-tests were used to compare differences in age, weight, and height. Intragroup comparisons of systolic and diastolic arterial blood pressure, heart rate, Rawm, Rawe, and Cdyn were performed by two-way analysis of variance for repeated measures and paired t-tests with Bonferroni’s correction. Intragroup comparisons of plasma epinephrine and norepinephrine concentrations were performed by paired t-tests. Between-group comparisons were made at each time point by unpaired t-test. The mean ± SD was given for each value. A value of P < 0.05 was considered statistically significant.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
There were no demographic differences between groups (Table 1). At baseline, both groups had comparable arterial blood pressure, heart rate, Rawm, Rawe, and Cdyn values (Table 2). Baseline Rawm was 7.9 ± 3.1 cm H2O·L-1·s-1 in the control group and 8.0 ± 2.4 cm H2O · L-1 · s-1 in the alprostadil group. Baseline Rawe was 8.0 ± 2.9 cm H2O · L-1 · s-1 in the control group and 8.4 ± 2.1 cm H2O · L-1 · s-1 in the alprostadil group. Baseline Cdyn was 102 ± 42 mL/cm H2O in the control group and 95 ± 37 mL/cm H2O in the alprostadil group. Systolic and diastolic arterial blood pressure decreased significantly from baseline in both groups after the induction of anesthesia (Table 2). Heart rate in the control group remained unchanged throughout the study, but was increased significantly more than the baseline rate after T30 in the alprostadil group (Table 2), and heart rate at T30 and T36 was faster in the alprostadil group than in the control group. Rawm in the control group increased significantly at T36–60 compared with baseline values, but it remained unchanged in the alprostadil group (Table 2). Rawm was higher in the control group than in the alprostadil group at T36, T48, and T60 (Table 2). Rawe also increased significantly at T36–60 compared with the baseline in the control group but did not change in the alprostadil group (Table 2). Rawe was higher in the control group than in the alprostadil group at T36–48 (Table 2). Cdyn in the control group decreased significantly at T36–60 compared with the baseline value, but it increased significantly at T30 in the alprostadil group (Table 2).


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  		Table 1. Demographic Data
 

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  		Table 2. Changes in Hemodynamic Status, Mean Airway Resistance, Expiratory Airway Resistance, and Dynamic Compliance
 
Baseline plasma epinephrine concentrations were comparable between groups (Table 3). In the control group, the T36 plasma epinephrine concentration was less than the baseline level, whereas in the alprostadil group, the plasma epinephrine concentration did not change at T36 (Table 3). The baseline plasma norepinephrine concentration was comparable between groups (Table 3). In the control group, T36 plasma norepinephrine concentration was smaller than the baseline concentration, whereas in the alprostadil group, T36 plasma norepinephrine concentration was larger than at the baseline level (Table 3).


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  		Table 3. Plasma Epinephrine and Norepinephrine Concentrations
 
In the control group, the mean arterial blood pressure did not decrease to less than 60 mm Hg in any patient (phenylephrine was not administered), whereas in the alprostadil group, all patients required IV phenylephrine to maintain arterial blood pressure after fentanyl injection (T30) (total dose was 2.3 ± 1.0 mg). IV phenylephrine had no effect on Rawm, Rawe, or Cdyn values (data not shown).


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
These observations suggest that IV alprostadil, an analog of PGE1, has a bronchodilator effect in humans. We have shown that IV thiamylal and fentanyl induce mild to moderate bronchoconstriction (9,10), and we have advocated that our method, thiamylal-fentanyl-induced bronchoconstriction model, is another safe and effective method of studying bronchoconstriction in humans (9,10). Although we administered alprostadil for 30 min and then induced bronchoconstriction, we are not certain that this study is the optimal study protocol. However, we did demonstrate that alprostadil is a bronchodilator even in humans.

PGE1 is an agonist at the PGE2-sensitive receptor (subtype EP2) that activates adenylate cyclase to increase intracellular cyclic adenosine monophosphatase (cAMP), inducing smooth muscle relaxation (20,21). Therefore, increased intracellular cAMP may contribute to the spasmolytic effects we observed.

Previous in vitro studies have shown a direct relaxant effect of PGE1 on isolated airway smooth muscles (4,6). Hashimoto et al. (7) showed that a continuous IV infusion of PGE1 at 0.1 µg · kg-1 · min-1 in dogs increased bronchial cross-sectional area in a time-dependent fashion, with no changes in the plasma epinephrine concentrations. These findings suggest that PGE1 may produce direct bronchodilating effects both in vitro and in vivo.

Administration of IV phenylephrine, an {alpha}-adrenergic agonist, did not affect Rawm, Rawe, or Cdyn. Alprostadil stimulated norepinephrine release (Table 3). This release may result from baroreceptor reflexes because alprostadil produces vasodilation (2–6). Sympathetic influence on airway tone mainly depends on circulating catecholamines because direct sympathetic neural supply in the lung is limited (22). Rolla et al. (23) reported that nebulized nitroglycerine induced a better bronchodilation in patients with moderate asthma after pretreatment with aerosolized norepinephrine (0.04 mg). This dose did cause vasoconstriction; however, they did not report blood pressure, heart rate, or plasma norepinephrine concentrations (23). Although circulating catecholamine concentration is one of the most important factors controlling airway tone (22), norepinephrine release may not be involved in the observed bronchodilation, and we concluded that the spasmolytic effect of alprostadil observed in this study was not caused by the small increase in norepinephrine. Hashimoto et al. (7,8) noted that PGE1 may have direct bronchodilatory effects because PGE1 at 0.1 and 1.0 µg/kg produced significant bronchodilation without increasing plasma catecholamines.

Hashimoto et al. (7) showed that an IV bolus of PGE1 increased the percentage of bronchial cross-sectional area dose-dependently (range was 0.01–10 µg/kg) against histamine-induced bronchoconstriction, and they reported that the percentage of bronchial cross-sectional area increased dose-dependently against serotonin-induced bronchoconstriction after PGE1 infusion (range was as above) (8). We chose the clinical maximum dose of IV alprostadil (0.2 µg · kg-1 · min-1) (24) to achieve the maximum effect.

One disadvantage of IV alprostadil (0.2 µg · kg-1 · min-1) is the risk of decreasing blood pressure; in the alprostadil group, IV phenylephrine was required to maintain blood pressure. However, the decrease may also have been caused by the fentanyl or the depth of anesthesia. We assume that if anesthesia had been maintained by thiamylal alone, IV phenylephrine might have been unnecessary. We therefore believe that the effects of alprostadil on blood pressure would pose a problem only for patients under deep anesthesia or those with hypovolemia.

In conclusion, IV alprostadil, an analog of PGE1, has produced a spasmolytic effect in a state of thiamylal-fentanyl-induced bronchoconstriction under endotracheal intubation in humans, and it is presumed that this effect is mainly caused by increasing the intracellular cAMP of the airway smooth muscle. This result may have implications that alprostadil pretreatment of patients with a history of asthma before the induction of anesthesia and tracheal intubation would be beneficial and advantageous. Moreover, alprostadil seems to be useful as a bronchodilator to treat bronchial asthma, similar to other drugs that increase intracellular cAMP. This drug may be effective in patients with bronchial asthma who fail to respond to ß-stimulants.


   Footnotes
 
Presented, in part, at the International Anesthesia Research Society 75th Clinical and Scientific Congress, Ft. Lauderdale, Florida, March 2001.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication March 13, 2003.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press