CJA
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Résumé de cet Article
Right arrow Full Text (PDF)
Right arrow Additional material
Right arrow Submit a scholarly reply
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Takahashi, S.
Right arrow Articles by Toyooka, H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Takahashi, S.
Right arrow Articles by Toyooka, H.
Canadian Journal of Anesthesia 50:830-834 (2003)
© Canadian Anesthesiologists' Society, 2003
Cardiothoracic Anesthesia, Respiration and Airway

Milrinone attenuates the negative inotropic effects of landiolol in halothane-anesthetized dogs

[La milrinone atténue les effets inotropes négatifs du landiolol chez des chiens anesthésiés avec de l’halothane]

Shinji Takahashi, MD, Yoshitaka Fujii, MD, Takuo Hoshi, MD, Aki Uemura, MD, Masayuki Miyabe, MD and Hidenori Toyooka, MD

From the Department of Anesthesiology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Japan.

Address correspondence to: Dr. Shinji Takahashi, Department of Anesthesiology, Institute of Clinical Medicine, University of Tsukuba, Tenodai 1-1-1, Tsukuba-city 305-8575, Japan. Phone and FAX: 81-29-853-3092; E-mail: shinjitk{at}md.tsukuba.ac.jp


   Abstract
TOP
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Background: Clinical use of high dose beta-blocker therapy is limited by excessive negative inotropic effects. Previous studies suggest that milrinone may be of utility in limiting the inotropic but not the chronotropic effects of beta blockers. We examined the hemodynamic effects of co-administration of a new potent selective beta1 blocker, landiolol, and milrinone in halothane-anesthetized dogs.

Methods: Eighteen adult mongrel dogs were anesthetized with 1.2 MAC halothane. Hemodynamic measurements were made at baseline, 30 min after starting the milrinone (0.5 µg•kg-1•min-1) or normal saline infusion (n = 9 in each), then 30 min after each change in the dose of landiolol infusion. The tested doses of landiolol were 10, 100, and 1000 µg•kg-1•min-1.

Results: Landiolol (>= = 10 µg•kg-1•min-1) has significant and comparable negative chronotropic effects in both groups of dogs. While it also has significant negative inotropic effects in both groups, such effects are significantly attenuated in the dogs treated with milrinone.

Conclusion: Milrinone is effective to attenuate the negative inotropic effects of landiolol in halothane-anesthetized dogs.


   Introduction
TOP
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
BETA-ADRENERGIC receptor blockers have been used widely in the treatment of tachycardia and dysrhythmias.1,2 Recent reports3–6 demonstrated that the prophylactic administration of beta-adrenergic blockers in patients with ischemic heart disease reduced the incidence of postoperative ischemic events and reduced mortality.

Landiolol, a new ultra-short acting, highly cardioselective beta-adrenergic receptor antagonist, is effective in the treatment of tachyarrhythmias in animals.7,8 While landiolol is more potent than esmolol7 in terms of chronotropy, it also has less effects on blood pressure than esmolol in anesthetized rabbits.9 Although there have been great advances in cardiac surgical techniques in the past decade, postoperative support with inotropic agents is still frequently necessary.10 Further, intraoperative prevention of hypotension and arrhythmias and maintenance of cardiac output (CO) are critical in terms of patient outcome.

Milrinone is a well-known phosphodiesterase III-inhibitor that has a potent positive inotropic effect and is used to maintain CO, both intraoperatively and postoperatively.11 However, the favourable effect of milrinone on CO may be negated by increases in heart rate (HR; and subsequent increases in myocardial oxygen consumption) that sometimes accompany its administration.12 The present study investigated the hemodynamic effects of the co-administration of landiolol and milrinone in halothane-anesthetized dogs. We hypothesized that milrinone would prevent the negative inotropic effects of landiolol but preserve the ability of landiolol to achieve optimal HR control.


   Methods
TOP
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
This present study was approved by the Institutional Animal Care Committee. Eighteen adult mongrel dogs of either gender, weighing 12 to 16 kg (13.2 ± 1.5 kg mean ± SD), were included in the study. Animal preparation was similar to that described previously.8,13 Animals were anesthetized with 25 mg•kg-1 pentobarbital iv, the trachea intubated with a cuffed tracheal tube, and the lungs ventilated mechanically. Anesthesia was maintained with 1.2 MAC (1.0% end-tidal concentration) halothane in oxygen. An 18-gauge catheter was inserted into the femoral artery for continuous blood pressure monitoring and intermittent blood sampling. Another 18-gauge catheter was inserted into a femoral vein for drug and fluid administration. Drug infusions were delivered via motor driven syringe pumps (Termo Model STC-523®, Tokyo, Japan). A 7-Fr pulmonary artery catheter (Baxter Edwards Critical Care, Irvine, CA, USA) was inserted via a femoral vein and floated to the wedge position. Lead II of the electrocardiogram, arterial blood pressure (systolic, mean, and diastolic blood pressure), HR, mean pulmonary artery pressure (MPAP), pulmonary artery occlusion pressure (PAOP), and central venous pressure (CVP) were monitored continuously and recorded (Polygraph 7747 Amplifier Case®, San-ei, Tokyo, Japan). CO was determined as the mean of three measurements determined by thermodilution using iced saline (Cardiac Output Computer 7350®, Arrow, Reading, PA, USA). Additional monitoring included arterial blood gas analysis, and electrolyte and hemoglobin concentration determination (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 to 7.45, 100 to 200 mmHg, and 135 to 145 mEq•L-1, respectively. During the study, blood temperature was maintained between 36.5 to 38.5°C using an electric heating blanket. After at least 90 min of stabilization after initiating halothane-oxygen anesthesia, measurements of all hemodynamic variables were performed to define baseline values. Systemic vascular resistance (SVR) and pulmonary vascular resistance (PVR) were derived according to the following equation: SVR = {(mean blood pressure; MBP-CVP) x 80}/CO, and PVR = {(MPAP-PAOP) x 80}/CO. After measurements of baseline hemodynamic variables, dogs were randomly assigned according to computer-generated random numbers into one of two groups (n = 9 in each): 1) a milrinone group, or 2) a control (normal saline) group.

The dogs in the control group received iv normal saline (10 mL bolus injection over five minutes, followed by a continuous infusion of 5 mL•hr-1). The dogs in the milrinone group received milrinone as an iv infusion (50 µg•kg-1 body weight in 5 mL over five minutes, followed by a continuous infusion of 0.5 µg•kg-1•min-1 milrinone). The investigators who injected the drug and observed the hemodynamic changes were blinded to the treatment group of the dogs. Thirty minutes after milrinone or saline infusion, hemodynamic variables were measured. After measurements of hemodynamic baseline variables (landiolol 0 µg•kg-1•min-1), 10 µg•kg-1•min-1 of landiolol was administered for 30 min in each group. Hemodynamic variables were measured before and at 15 and 30 min after landiolol administration. At least 30 min after cessation of landiolol, hemodynamic measurements were repeated using the same protocol with an increasing concentration of landiolol (100 then 1000 µg•kg-1•min-1) in the same dogs.

The data are expressed as mean ± SD. Statistical analysis was performed using a commercially available software package (StatView®, Ver.5.0, Abacus Concepts, Inc., Berkeley, CA, USA). Hemodynamic variables between the groups were analyzed using analysis of variance (ANOVA) with Bonferroni’s correction. Data from each group were analyzed using paired t test. P value of < 0.05 was considered significant.


   Results
TOP
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Hemodynamic changes after saline or milrinone infusions are summarized in Table IGo. There were no significant differences between groups in the pre-treatment values. Thirty minutes after administration of milrinone, measurements revealed increases in HR and CO, and decreases in CVP, MPAP, PAOP and SVR when compared to pre-treatment values. Systolic blood pressure (SBP), MBP and diastolic blood pressure (DBP) values showed no change. Hemodynamic variables did not change significantly after saline infusion in the control group.


View this table:
[in this window]
[in a new window]
  		TABLE I Hemodynamic changes after saline/milrinone treatment
 
Hemodynamic changes after administration of landiolol are shown in the FigureGo. Significant decreases in HR and CO were observed in both groups after administration of >= = 10 µg•kg-1•min-1 landiolol, and there was no significant difference in HR, SBP, DBP, MBP, CVP, PAP, PAOP, or PVR between the two groups after landiolol administration (Table II, available as additional material at www.cja-jca.org). The administration of 0.5 µg•kg-1•min-1 milrinone attenuated the decrease in CO seen with the administration of landiolol (FigureGo), while SVR decreased with the administration of milrinone (100 µg•kg-1•min-1 or more). There were no unexpected deaths in either group of animals, and dysrhythmia did not occur.



View larger version (22K):
[in this window]
[in a new window]
  		FIGURE Percent changes in heart rate (HR), systolic blood pressure (SBP), cardiac output (CO), and systemic vascular resistance (SVR) from baseline values after iv injection of landiolol. Values are mean ± SD. *P < 0.05 vs baseline value. {dagger}P < 0.05 vs the control group.

 

   Discussion
TOP
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The present study demonstrated that chronotropic control was achieved with a landiolol dose of 10 µg•kg-1•min-1. These results are consistent with our previous report13 that a 10 µg•kg-1•min-1 dose of landiolol suppressed tachycardia-induced theophylline intoxication. In another report,14 Sugiyama et al. demonstrated that the isoproterenol-induced increase in HR was halved by 1.5 ± 0.9 µg•kg-1•min-1 of landiolol or by 9.3 µg•kg-1•min-1 of esmolol in halothane-anesthetized dogs. Thus, landiolol was six times more potent than esmolol in attenuating increases in HR. The present study also demonstrated that milrinone (0.5 µg•kg-1•min-1) did not alter the ability of landiolol to control HR.

Sasao et al.9 demonstrated that 300 µg•kg-1•min-1 esmolol produced hypotension in rabbits, while 300 µg•kg-1•min-1 landiolol had no effect on blood pressure. In our study, 1000 µg•kg-1•min-1 landiolol produced a 20% decrease in SBP from baseline value. Although milrinone has a potent vasodilating effect that occasionally induced hypotension, the change in blood pressure with landiolol was not altered by the co-administration of 0.5 µg•kg-1•min-1 milrinone.

Milrinone administration resulted in a 44% increase in CO, while landiolol produced a dose-dependent decrease in CO. However, when landiolol was administered in animals that also received milrinone, CO was maintained.

Propranolol is a non-selective beta-adrenergic receptor antagonist (beta1/beta2-receptor activity (ß1/ß2) = 33)7 that results in increased SVR secondary to its beta2-blocking effects.15 In contrast, landiolol is a highly selective beta1-adrenergic receptor antagonist (ß1/ß2 = 255)7 that had a minimal effect on SVR in pentobarbital-anesthetized dogs, even with high-dose administration.15 The present study observed an increase in SVR in the saline-treated animals with landiolol 100 µg•kg-1•min-1 but showed no change with landiolol administration in the milrinone-treatment group.

Carceles et al.16 demonstrated that GI104313, a chimeric molecule containing a combined phosphodiesterase-inhibiting pyradazinone and a blocking phenoxypropanolamine, induced a decrease in arrhythmia and mortality that was not associated with changes in ventricular cyclic nucleotide content in rats. Recent knock-out mouse studies suggested that specific beta1-adrenergic receptor blockade, and not beta2 blockade, was responsible for cardioprotection and prevention of myocyte apoptosis.17 Further investigation is necessary to prove the efficacy of combined phosphodiesterase inhibition and beta blockade in ischemic hearts.

There are several notable limitations in this study. First, these studies were conducted on dogs with normal hearts and without cardiac insufficiency. The hemodynamic effects of landiolol and milrinone may differ in patients with severe cardiac disease and low CO. Second, we did not perform experiments with higher doses of milrinone. Increasing doses of milrinone may reverse the decrease in CO produced by landiolol. However, milrinone has a vasodilating effect and could also potentiate hypotension induced by landiolol. Third, this study was of short duration and did not address the long-term effects of treatment with these agents.

In conclusion, milrinone is effective to attenuate the negative inotropic effects of landiolol in halothane-anesthetized dogs.


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

Revision received July 4, 2003. Accepted for publication April 1, 2003.


   References
TOP
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
1 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]

2 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]

3 Urban MK, Markowitz SM, Gordon MA, Urquhart BL, Kligfield P. Postoperative prophylactic administration of ß-adrenergic blockers in patients at risk for myocardial ischemia. Anesth Analg 2000; 90: 1257–61.[Abstract/Free Full Text]

4 Raby KE, Brull SJ, Timimi F, et al. The effect of heart rate control on myocardial ischemia among high-risk patients after vascular surgery. Anesth Analg 1999; 88: 477–82.[Abstract/Free Full Text]

5 Poldermans D, Boersma E, Bax JJ, et al. The effect of bisoprolol on perioperative mortality and myocardial infarction in high-risk patients undergoing vascular surgery. N Engl J Med 1999; 341: 1789–94.[Abstract/Free Full Text]

6 Mangano DT, Layug EL, Wallace A, Tateo I. Effect of atenolol on mortality and cardiovascular morbidity after noncardiac surgery. N Engl J Med 1996; 335: 1713–20.[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 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]

9 Sasao J, Tarver SD, Kindscher JD, Taneyama C, Benton KT, Goto H. In rabbit, landiolol, a new ultra-short-acting ß-blocker, exerts a more potent negative chronotropic effect and less effect on blood pressure than esmolol. Can J Anesth 2001; 48: 985–9.[Abstract/Free Full Text]

10 Heames RM, Gill RS, Ohri SK, Hett DA. Off-pump coronary artery surgery. Anaesthesia 2002; 57: 676–85.[Medline]

11 Butterworth JF, Hines RL, Royster RL, James RL. A pharmacokinetic and pharmacodynamic evaluation of milrinone in adults undergoing cardiac surgery. Anesth Analg 1995; 81: 783–92.[Abstract]

12 Skoyles JR, Sherry KM. Pharmacology, mechanisms of action and uses of selective phosphodiesterase inhibitors. Br J Anaesth 1992; 68: 293–302.[Free Full Text]

13 Takahashi S, Fujii Y, Hoshi T, Inomata S, Miyabe M, Toyooka H. Modifications of the hemodynamic consequences of theophylline intoxication with landiolol in halothane-anesthetized dogs. Can J Anesth 2000; 47: 265–72.[Abstract/Free Full Text]

14 Sugiyama A, Takahara A, Hashimoto K. Electrophysiologic, cardiohemodynamic and ß-blocking actions of a new ultra-short-acting ß-blocker, ONO-1101, assessed by the in vivo canine model in comparison with esmolol. J Cardiovasc Pharmacol 1999; 34: 70–7.[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). Clin Res 1997; 31: 2949–65.

16 Carceles MD, Aleixandre F, Fuente T, Lopez-Vidal J, Laorden ML. Combined phosphodiesterase inhibition and ß-blockade in the GI104313, decreases ischemia-induced arrhythmias in the rat. Can J Anesth 2001; 48: 486–92.[Abstract/Free Full Text]

17 Zaugg M, Schaub MC, Pasch T, Spahn DR. Modulation of ß-adrenergic receptor subtype activities in perioperative medicine: mechanisms and sites of action. Br J Anaesth 2002; 88: 101–23.[Abstract/Free Full Text]





This Article
Right arrow Abstract Freely available
Right arrow Résumé de cet Article
Right arrow Full Text (PDF)
Right arrow Additional material
Right arrow Submit a scholarly reply
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Takahashi, S.
Right arrow Articles by Toyooka, H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Takahashi, S.
Right arrow Articles by Toyooka, H.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS