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Canadian Journal of Anesthesia 47:265-272 (2000)
© Canadian Anesthesiologists' Society, 2000
Laboratory Investigations

Modifications of the hemodynamic consequences of theophylline intoxication with landiolol in halothane-anesthetized dogs

Shinji Takahashi, MD, Yoshitaka Fujii, MD, Takuo Hoshi, MD, Shin-ichi Inomata, MD, Masayuki Miyabe, MD and Hidenori Toyooka, MD

From the Department of Anesthesiology, University of Tsukuba, Institute of Clinical Medicine, Tsukuba, Ibaraki, 305-8575, Japan.

Address correspondence to: S Takahashi MD, Department of Anesthesia and Critical Care Medicine, Tsukuba Gakuen Hospital, Tsukuba, Ibaraki, 305 0854, Japan. Phone: 81-298-36-9597; Fax: 81-298-36-9583; E-mail: shinjitk{at}db3.so-net.ne.jp


   Abstract
TOP
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Purpose: To examine the effect of landiolol (ONO-1101), a new ultra-short acting, highly selective beta1 blocker, on hemodynamic response to acute theophylline intoxication in anesthetized dogs.

Methods: Thirty-four dogs were studied during halothane anesthesia. Aminophylline (50 mg•kg–1 over 20 min followed by infusion at 1.75 mg•kg–1•hr–1 ) was administered as a model of acute theophylline intoxication. Dogs were randomly enrolled into four landiolol groups (0, 1, 10, 100 µg•kg–1•min–1) to treat tachyarrhythmias. Hemodynamic variables, heart rate (HR), systemic blood pressure (SBP), pulmonary artery pressure, pulmonary artery occlusion pressure, and cardiac output (CO) were measured along with plasma concentrations of theophylline, epinephrine, and norepinephrine.

Results: After 60 min, plasma concentration of theophylline reached 46.6 ± 4.0 (mean ± SD) µg•ml–1, HR increased from 129 ± 21 to 193 ± 27 bpm (P < 0.0001) and CO increased from 1.6 ± 0.5 l•min–1 to 2.1 ± 0.4 l•min–1 (P < 0.0001), whereas SBP decreased from 139 ± 25 to 121 ± 25 mm Hg (P < 0.0001), with decreasing systemic vascular resistance. After intoxication, plasma epinephrine concentration increased from 125 ± 112 to 325 ± 239 pg•ml–1 (P < 0.0001), and norepinephrine concentration from 103 ± 61 to 133 ± 61 pg•ml–1 (P < 0.0011). Landiolol 10 µg•kg–1•min–1 decreased HR to pre-intoxication level, whereas HR returned to the intoxication baseline by 30 min after cessation of landiolol infusion.

Conclusions: Landiolol controlled tachyarrhythmias associated with theophylline toxicity. The optimal effective dose of landiolol was 10 µg•kg–1•min–1.


   Introduction
TOP
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
BETA-ADRENERGIC receptor blockers have been extensively used in the treatment of hypertension, effort angina, and cardiac arrhythmias.1,2 Various types of beta blocker have been developed, but their use has been limited because of undesirable properties, such as bronchoconstriction, prolonged hypotension, and myocardial depression, which is attributed to their long duration of action. Zaroslinski and co workers3 demonstrated that esmolol, an ultra-short acting, highly cardioselective beta-adrenergic receptor antagonist is effective in the treatment of critically ill patients. Several investigators have also documented that it controls hemodynamic changes in clinical situations.4–6 Another ultra-short acting beta blocker, landiolol (ONO-1101) {(-)-[(S)-2,2-dimethyl-1, 3-dioxolan- 4-yl] methyl 3-[4-[(S)-2-hydroxy-3-(2-morpholino carbonylamino) ethyl-amino] propoxy] phenylpropionate monohydrochloride}, has more potent cardiac properties than esmolol,7 and has been developed for application in the emergency treatment of tachyarrhythmias in animals.7–9 Theophylline toxicity induces severe tachyarrhythmias in humans10–12 and in an animal model.13 The purpose of this study was to examine the effect of landiolol on hemodynamics during acute theophylline intoxication in halothane-anesthetized dogs.


   Methods
TOP
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Animal preparation
The study protocol was approved by our institutional animal care committee. Thirty-four adult mongrel dogs of either sex and weighing 9.5-13.5 kg were anesthetized with 25 mg•kg–1 pentobarbital iv. The trachea of each dog was intubated with a cuffed endotracheal tube, and the lungs were mechanically ventilated (Harvard Model 613® Apparatus Company, Chicago, USA) at tidal volume of 15 ml•kg–1 at a respiratory rate sufficient to maintain normoventilation. End-tidal CO2 tension was continuously monitored. Anesthesia was maintained with 1.2 MAC (1.0% at end-tidal concentration) halothane in oxygen. These concentrations were monitored with a respiratory/anesthetic gas analyser (Capnomac Ultima®, Datex instrumentarium, Helsinki, Finland) calibrated with a standard gas. The femoral artery and vein were cannulated for arterial blood pressure monitoring, blood sampling, and drug and fluid administration. Drug infusions were delivered via motor driven syringe pumps (Termo Model STC-523®, Tokyo, Japan). The contralateral femoral vein was cannulated with a pulmonary artery catheter (Swan-Ganz Catheter®, Baxter Healthcare Corporation Edwards Critical-Care Division, Santa Ana, CA, USA) to measure pulmonary artery pressure, pulmonary artery occlusion pressure, central venous pressure, cardiac output and blood temperature (Cardiac Output Computer 7350®, Arrow, Reading, PA, USA). Lead II of the ECG was monitored continuously and recorded (Polygraph 7747 Amplifier Case®, San-ei, Tokyo, Japan). Additional monitoring included arterial blood gas analysis, electrolyte and hemoglobin concentrations (Ciba Coring 288 Blood Gas System®, Ciba Corning Diagnostics Corp. Medfield, MA, USA). Maintenance fluid (Ringer's lactate solution) was administered at a rate of 10 ml•kg–1•hr–1. Metabolic acidosis (base excess < -10.0) was corrected with sodium bicarbonate as required. Serum potassium concentration was maintained between 3.5-4.5 mEq•l–1 by infusing KCl as required. Arterial pH, PO2, and serum sodium concentration were maintained within the range of 7.35-7.45, 100-200 mm Hg, 135-145 mEq•l–1, respectively. During the study, blood temperature was maintained between 36.5-38.5°C using a hot-water pad. After at least 90 min of stabilization of halothane-oxygen anesthesia, measurements of all hemodynamic variables including heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean blood pressure (MBP), central venous pressure (CVP), mean pulmonary artery pressure (MPAP), pulmonary artery occlusion pressure (PAOP), cardiac output (CO) and plasma concentration of catecholamines (epinephrine and norepinephrine) were taken to define the pre-intoxication baseline. Systemic vascular resistance (SVR) and pulmonary vascular resistance (PVR) were derived according to the following equation: and .

Theophylline intoxication
The model of acute theophylline toxicity was made using the method described by Gaar et al.14 Aminophylline was administered as an iv infusion at a dose of 50 mg•kg–1 body weight over 20 min. This was followed by continuously administering 1.75 mg•kg–1•hr–1 aminophylline throughout the experiment. This dose design was based on the knowledge of the volume of distribution and the elimination characteristics, to achieve serum theophylline concentration >35 µg•ml–1, which were considered to be in the toxic range. Hemodynamic variables were measured every 10 min until 60 min after the beginning of aminophylline administration. Blood sampling for measuring of plasma concentrations of catecholamines and theophylline was performed at least 60 min after theophylline-intoxication.

Landiolol infusion during theophylline intoxication
At least 60 min after intoxication of theophylline, stabilization of the intoxicated state was defined as HR and SBP that remained within 10% variation over five minutes. After measurements of hemodynamic baseline variables, dogs were assigned randomly to one of four landiolol groups: 0 µg•kg–1•min–1 group (n = 9), 1 µg•kg–1•min–1 group (n = 9), 10 µg•kg–1•min–1 group (n = 8), and 100 µg•kg–1•min–1 group (n = 8). Landiolol was administered for 30 min. Hemodynamic variables were measured before, 15, and 30 min after landiolol administration. Hemodynamic variables were also measured 15 and 30 min after landiolol cessation. Blood samples for measuring the plasma concentration of catecholamines and theophylline were obtained at the end of infusion of landiolol. Then, the samples for measuring catecholamine concentration were withdrawn into plastic tubes containing EDTA-2Na. These were then centrifuged at 3000 rpm for 10 min at 2°C to separate the plasma. Epinephrine and norepinephrine in deproteinized plasma were determined by an automated double-column HPLC system (Model CA825®, Tosho Co., Ltd., Tokyo, Japan). This assay system is based on the trihydroxyindole reaction, and has a limit of sensitivity of 5 pg•ml–1 for epinephrine and inter and intra-assay variations are less than 3%. Blood samples for measuring the plasma concentration of theophylline were withdrawn into plastic tubes and were then centrifuged at 3000 rpm for 10 min at 2°C to separate the plasma. Plasma concentrations were measured by enzyme multiplied immunoassay technique (Model 7170®, Hitachi Co., Ltd., Tokyo, Japan).

The data were expressed as mean ± SD. Statistical analysis was performed using a commercially available software package (StatView® Ver.4.5, Abacus Concepts, Inc., Berkeley, CA, USA). Hemodynamic parameters, catecholamines and theophylline concentrations, at different doses of landiolol were analyzed using analysis of variance (ANOVA) with Bonferroni's correction. The data of each group were analyzed using paired t test. P value of < 0.05 was considered significant.


   Results
TOP
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Theophylline intoxication
The hemodynamic changes after theophylline infusion are shown in Table IGo. Post-intoxication values obtained 60 min after administration of aminophylline, showed increases in HR and CO, and decreases in SBP, DBP, MBP, SVR, and PVR from baseline values. These hemodynamic changes continued during theophylline infusion (Figure 1Go). After theophylline intoxication, plasma epinephrine concentrations increased from 125 ± 112 pg•ml–1 at baseline to 325 ± 239 pg•ml–1, and plasma norepinephrine concentrations increased from 103 ± 61 to 133 ± 61 pg•ml–1 (Table IGo). Plasma theophylline concentration reached >35 µg•ml–1 in all animals and the mean theophylline concentration after theophylline intoxication was 66.8 ± 12.8 µg•ml–1 at 30 min after theophylline infusion, and 46.7 ± 4.0 µg•ml–1 at 60 min after theophylline infusion. Dysrhythmias associated with theophylline intoxication were observed in eight of 34 (23%) animals.


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  		TABLE I Hemodynamic changes after theophylline intoxication
 


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  		FIGURE 1 Upper panel: Changes in heart rate (HR), systolic blood pressure (SBP), and cardiac output (CO) after iv injection of aminophylline in halothane-anesthetized dogs. Values are mean ± SD. *P < 0.05 vs baseline (preinjection) values.

Middle panel:Changes in systemic vascular resistance (SVP) after iv injection of aminophylline in halothane-anesthetized dogs. Values are mean ± SD. *P < 0.05 vs baseline (preinjection) values.

Lower panel:Changes in pulmonary vascular resistance (PVR) after iv injection of aminophylline in halothane-anesthetized dogs. Values are mean ± SD. *P < 0.05 vs baseline (preinjection) values.

 
Landiolol infusion during theophylline intoxication
The hemodynamic changes after administration and cessation of landiolol are shown in Table IIGo. Decreases in HR were observed in the groups that received >= 10 µg•kg–1•min–1 landiolol (Figure 2Go). These decreased HR values during landiolol were not different from pre-intoxication values. There were no differences among the groups in terms of SBP, DBP, MBP, CVP, PAP, PAOP, CO, SVR and PVR after landiolol administration. However, decreases in SBP were observed compared with intoxication baseline (immediately before administration of landiolol) in the group receiving 10 µg•kg–1•min–1 landiolol. Decreases in SBP, DBP, MBP and MPAP were observed compared with baseline after theophylline in the group receiving 100 µg•kg–1•min–1 landiolol. On the other hand, no differences in CO were observed compared with intoxication baseline in the group receiving 100 µg•kg–1•min–1 landiolol. Treatments with landiolol did not change SVR, PVR, CVP, or PAOP in any group (Table IIGo). In the control group, increases in HR, PAP, and PAOP were observed compared with intoxication baseline during observation.


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  		TABLE II Variables after treatment and cessation of landiolol
 


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  		FIGURE 2 Changes in heart rate (HR, upper panel), systolic blood pressure (SBP, middle panel), and cardiac output (CO, lower panel) after iv injection of landiolol during theophylline intoxication in halothane- anesthetized dogs. Infusions of landiolol were continued for 30 min. Values are mean ± SD. *P < 0.05 vs landiolol 0 µg•kg–1•min–1 according to post-hoc comparison.

 
After cessation of landiolol, HR returns to the intoxication baseline value by 30 min with the exception of the group receiving 100 µg•kg–1•min–1 landiolol. (Figure 2Go) However, in the group receiving 100 µg•kg–1•min–1 landiolol, HR returned to the intoxication baseline value within 60 min after cessation of landiolol.

Plasma epinephrine and norepinephrine concentrations were not affected by administration of landiolol (Table IIIGo). Plasma theophylline concentrations of all subjects remained within the toxic range (>35 µg•ml–1) through the study, and there were no differences among the groups after landiolol administration (Table IVGo).


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  		TABLE III Plasma concentrations of epinephrine, and norepinephrine during theophylline intoxication
 

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  		TABLE IV Plasma concentrations of theophylline during theophylline intoxication
 
Dysrhythmia disappeared after landiolol administration (1 µg•kg–1•min–1) in five of eight dogs. In the remaining three dogs without landiolol treatment, dysrhythmias lasted throughout the study.


   Discussion
TOP
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The findings of the present study are as follows: first, administering aminophylline (50 mg•kg–1 loading dose plus 1.75 mg•kg–1•hr–1 maintenance dose) induced acute cardiovascular theophylline intoxication: second, administrating 10 µg•kg–1•min–1 landiolol during theophylline intoxication decreased HR to pre-intoxication level.

As previously described by Gaar et al.,14 the plasma theophylline concentrations were >35 µg•ml–1 for five hours during intoxication. In this study, plasma theophylline concentrations achieved 46.7 ± 4.0 (mean SD) µg•ml–1 at the time of commencing landiolol infusion and were maintained above the toxic level (>35 µg•ml–1) in all animals.

A characteristic progression of symptoms in theophylline intoxication has been described.11,13 Initial cardiovascular signs and symptoms include mild tachycardia and slight hypertension. In the most severe intoxications, severe tachycardia, cardiac arrhythmia, hypotension, and peripheral vascular collapse may occur. In this study, we found severe tachycardia, hypotension, decreases in SVR and PVR, and an increase in CO during infusion. These hemodynamic changes associated theophylline agree with the report of Kearney et al.13 Tachycardia during theophylline intoxication occurs by a direct effect of theophylline on the sinus node, an increase in sympathetic nervous system activity, or an increase in catecholamines.10,13 In this study, plasma concentrations of catecholamines increased from baseline values after administration of aminophylline. The findings are consistent with reports that theophylline increased circulating levels of catecholamines.10,11,13 The increases in plasma catecholamine concentrations correlated with the dose-related increases in HR observed during their study, supporting the hypothesis that the cardiovascular effects of theophylline may be mediated in part by the beta-adrenergic system.

Most adverse effects of beta blocker use are related to interference with beta2 mediated function including bronchodilation and vasodilation.1,2 Thus, to avoid these disadvantages, selective beta1 blockade is required. Landiolol has been developed as an ultra-short acting beta blocker, and has been reported to be nine times more potent than esmolol.7 In addition to these properties, landiolol has highly selective beta1-adrenoceptor activity (beta1/beta2-receptor activity (ß1/ß2) = 255) which studied in vitro with guinea pig right atria and trachea strips.7 Its beta1 selectivity is greater than that of other beta blockers, such as esmolol (ß1/ß2 = 33) and propranolol (ß1/ß2 = 0.68).7 Thus, the high cardioselectivity of landiolol may produce beneficial effects in some patients with bronchial asthma.

Beta2 adrenergic receptors exist on vascular smooth muscle and exert a vasodilating effect. Propranolol, a non- selective beta adrenergic receptor antagonist, reverses the effects of theophylline-induced hypotension, because of the increase in SVR associated with its beta2-blocking effects.13 By contrast, landiolol, even in the highest dose (100 µg•kg–1•min–1), did not affect the decrease in SVR associated with theophylline in this study. A lack of effect of landiolol on SVR was demonstrated previously in pentobarbital anesthetized dogs even after 3000 µg•kg–1•min–1 administration.15

Landiolol did not decrease plasma concentrations of norepinephrine in this study. This is in agreement with finding that esmolol, a selective beta1 blocker, did not affect plasma concentrations of norepinephrine.14 These results suggest that beta1 does not mediate facilitation of norepinephrine from sympathetic nerve terminal. Dahlof et al.16 demonstrated that selective beta1 blocker does not decrease stimulation-evoked norepinephrine overflow, compared with control experiments. They concluded that norepinephrine release could be enhanced by activation of prejunctonal beta2 adrenoceptors in vivo.16

We found that landiolol reversed the tachycardia induced by theophylline in a dose dependent manner. Consequently, 10 µg•kg–1•min–1 landiolol is considered to be the optimal effective dose for suppressing an increase in HR during theophylline intoxication. On the other hand, 10 µg•kg–1•min–1 landiolol did not affect CO compared with intoxication baseline. Thus, landiolol attenuated the positive chronotropic effect of theophylline without blocking the positive inotropic effect.

Dysrhythmias were observed in eight of 34 (23%) halothane-anesthetized dogs during intoxication of theophylline in this study. However, Gaar et al.14 showed no dysrhythmia associated theophylline in alpha chloralose-anesthetized dogs. This difference is considered to be the use of anesthetics, especially halothane. We have previously demonstrated that epinephrine causes dysrhythmias in halothane-anesthetized dogs, and that 10 µg•kg–1•min–1 landiolol prevents such dysrhythmias.17 In this study, the dose of 1 µg•kg–1•min–1 landiolol controlled dysrhythmias associated with theophylline intoxication.

In conclusion, landiolol controlled tachyarrhythmias during theophylline intoxication. The optimal effective dose of landiolol, which decreases HR during intoxication, is determined 10 µg•kg–1•min–1.


   Acknowledgments
 
The authors acknowledge Ono Pharmaceutical Co., Ltd. Osaka, Japan, for supplying landiolol (ONO-1101).

Accepted for publication November 26, 1999.


   References
TOP
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
1 Frishman WH. Clinical differences between beta-adrenergic blocking agents: implications for therapeutic substitution. Am Heart J 1987; 113: 1190–8.[Medline]

2 Kendall MJ. Clinical relevance of pharmacokinetic differences between beta blockers. Am J Cardiol 1997; 80: 15J–19J.[Medline]

3 Zaroslinski J, Borgman RJ, O'Donnell JP, et al. Ultra-short acting beta blockers: a proposal for the treatment of the critically ill patient. Life Sci 1982; 31: 899–907.[Medline]

4 Gold MI, Sacks DJ, Grosnoff DB, Herrington C, Skillman CA. Use of esmolol during anesthesia to treat tachycardia and hypertension. Anesth Analg 1989; 68: 101–4.[Medline]

5 Dyson A, Isaac PA, Pennant JH, Giesecke AH, Lipton JM. Esmolol attenuates cardiovascular response to extubation. Anesth Analg 1990; 71: 675–8.[Abstract/Free Full Text]

6 Vucevic M, Purdy GM, Ellis FR. Esmolol hydrochloride for management of the cardiovascular stress responses to laryngoscopy and tracheal intubation. Br J Anaesth 1992; 68: 529–30.[Abstract/Free Full Text]

7 Iguchi S, Iwamura H, Nishizaki M, et al. Development of a highly cardioselective ultra short-acting ß- blocker, ONO-1101. Chem Pharm Bull 1992; 40: 1462–9.

8 Muraki K, Nakagawa H, Nagano N, et al. Effects of ONO-1101, a novel beta-antagonist, on action potential and membrane currents in cardiac muscle. J Pharmacol Exp Ther 1996; 278: 555–63.[Abstract/Free Full Text]

9 Motomura S, Hagihara A, Narumi Y, Hashimoto K. Time course of a new ultrashort-acting ß- adrenoceptor-blocking drug, ONO-1101: comparison with those of esmolol and propranolol by using the canine isolated, blood-perfused heart preparations. J Cardiovasc Pharmacol 1998; 31: 431–40.[Medline]

10 Atuk NO, Blaydes MC, Westervelt FB Jr, Wood JE Jr. Effect of aminophylline on urinary excretion of epinephrine and norepinephrine in man. Circulation 1967; 35: 745–53.[Abstract/Free Full Text]

11 Vaucher Y, Lightner ES, Walson PD. Theophylline poisoning. J Pediatr 1977; 90: 827–30.[Medline]

12 Vestal RE, Eiriksson CE Jr, Musser B, Ozaki LK, Halter JB. Effect of intravenous aminophylline on plasma levels of catecholamines and related cardiovascular and metabolic responses in man. Circulation 1983; 67: 162–71.[Abstract/Free Full Text]

13 Kearney TE, Manoguerra AS, Curtis GP, Ziegler MG. Theophylline toxicity and beta-adrenergic system. Ann Intern Med 1985; 102: 766–9.

14 Gaar GG, Banner W Jr, Laddu AR. The effects of esmolol on the hemodynamics of acute theophylline toxicity. Ann Emerg Med 1987; 16: 1334–9.[Medline]

15 Shiroya T, Matsumori Y, Sawada S, et al. Effect of ONO-1101, an ultra-short acting ß1-blocker, on cardiohemodynamics in anesthetized dogs. (Japanese) The Clinical Research 1997; 31: 2949–65.

16 Dahlöf C, Kahan T, Åblad B. Prejunctional. ß2-adrenoreceptor blockade reduces nerve stimulation evoked release of endogenous noradrenaline in skeletal muscle in situ. Acta Physiol Scand 1987; 129: 499–503.[Medline]

17 Takahashi S, Fujii Y, Inomata S, Miyabe M, Toyooka H. Landiolol increases a dysrhythmogenic dose of epinephrine in dogs during halothane anesthesia. Can J Anesth 1999; 46: 599–604.[Abstract/Free Full Text]




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 Canadian J. AnesthesiaHome page
S. Takahashi, Y. Fujii, T. Hoshi, A. Uemura, M. Miyabe, and H. Toyooka
Milrinone attenuates the negative inotropic effects of landiolol in halothane-anesthetized dogs: [La milrinone attenue les effets inotropes negatifs du landiolol chez des chiens anesthesies avec de l'halothane]
Can J Anesth, October 1, 2003; 50(8): 830 - 834.
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