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Dobutamine potentiates the peripheral chemoreflex in patients with congestive heart failure
Journal of Cardiac Failure Vol. 9 No. 5 2003
Dobutamine Potentiates the Peripheral Chemoreflex in Patients With Congestive Heart Failure SONIA VELEZ-ROA, MD, PHILIPPE VAN DE BORNE, MD, PhD,1 VIREND K. SOMERS, MD, PhD2 Brussels, Belgium; Rochester, Minnesota
ABSTRACT Background: β-Adrenergic agonists may increase chemoreflex sensitivity to hypoxia in normal humans. Chemoreflex function is important in the pathophysiology of heart failure. Whether the β-1 agonist dobutamine, which is frequently administered to patients with heart failure, alters their chemoreflex sensitivity is not known. Methods: We tested the hypothesis that dobutamine increases chemoreflex sensitivity in patients with congestive heart failure (CHF) using a randomized, double-blinded, placebo-controlled study design. We assessed the influence of dobutamine on minute ventilation and hemodynamics during normoxic breathing and during peripheral chemoreflex deactivation by hyperoxia (100% O2) in 9 patients with CHF. Results: Dobutamine increased minute ventilation in patients with CHF (9.4 ⫾ 0.9 versus 8.4 ⫾ 0.7 L/min, P ⫽ .005) during normoxia. Peripheral chemoreflex deactivation by hyperoxia suppressed the ventilatory effects of dobutamine (10.4 ⫾ 1.4 L/min for dobutamine versus 10.0 ⫾ 1.2 L/min for placebo, P ⫽ .34). Conclusions: Dobutamine increases ventilation during normoxia, but not during hyperoxia in patients with CHF. We conclude that dobutamine enhances peripheral chemoreflex sensitivity in patients with congestive heart failure. Key Words: Chemoreflex sensitivity, congestive heart failure, dobutamine.
primarily to hypoxia,12,13 and exert powerful effects on ventilation and on autonomic cardiovascular control.1,2 Altered chemoreflex sensitivity to hypoxia could have clinically significant effects on breathing, hemodynamics, and neural circulatory control in patients with heart failure.3,14 These effects may influence both stability and clinical outcome in patients with cardiorespiratory compromise. We tested the hypothesis that dobutamine increases chemoreflex sensitivity in patients with CHF using a randomized, double-blinded, placebo-controlled study design. In 9 patients with CHF, we studied the effects of dobutamine on hemodynamics and on minute ventilation during room-air breathing and during hyperoxia. The effects of hyperoxia on the responses to dobutamine were examined to further clarify any effects of dobutamine on peripheral chemoreflex function. We hypothesized that any effects of dobutamine on ventilation mediated by the peripheral chemoreceptors, would be suppressed by hyperoxia by reducing tonic activation of the peripheral chemoreceptors.11–13,15
Chemoreflex function contributes importantly to cardiovascular regulation1–3 and may be especially significant in patients with cardiac and respiratory compromise.4 β-agonists may increase chemoreflex sensitivity to hypoxia in humans.5–7 Dobutamine has strong β-1 adrenergic agonist effects,8 and is frequently administered to patients with heart failure in intensive and coronary care units.9,10 Whether dobutamine affects chemoreflex function in patients with congestive heart failure (CHF) is not known. Patients with heart failure often have mild oxygen desaturation as a result of chronic lung edema.11 The peripheral chemoreceptors, located in the carotid bodies, respond From the 1Department of Cardiology, Erasme Hospital, Brussels, Belgium; 2Division of Cardiovascular Diseases and Division of Hypertension, Mayo Clinic, Rochester, Minnesota. Manuscript received January 16, 2003; revised manuscript received April 28, 2003; revised manuscript accepted May 2, 2003. These studies were supported by the Erasme Foundation, Belgium (S.V.-R.), the National Fund for Research and the Jacqueline Bernheim Award of the Foundation for Cardiac Surgery and the Mark Hurard Foundation, Belgium (P.v.d.B.). VKS is an Established Investigator of the American Heart Association and is also supported by NIH HL61560, HL65176, HL70602, and RR00585. Reprint requests: Sonia Velez-Roa, MD, Department of Cardiology, Erasme Hospital, 808 Lennik Road, 1070 Brussels, Belgium. 쑕 2003 Elsevier Inc. All rights reserved. 1071-9164/02/0905-0007$30.00/0 doi:10.1054/S1071-9164(03)00132-5
Methods Subjects Nine patients with congestive heart failure (8 men, aged 53 years; range 40–79 years,) were enrolled in the study. The cause
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Dobutamine Increases Chemoreflex Sensitivity of heart failure was ischemic heart disease (n ⫽ 5) or idiopathic (n ⫽ 4). Left ventricular ejection fraction, determined by a resting radionuclide ventriculogram or echocardiography, was 21 ⫾ 2%. They were in class II (n ⫽ 3), III (n ⫽ 5) and IV (n ⫽ 1) of the New York Heart Association classification. All CHF patients were on standard heart failure treatment including angiotensin-converting enzyme inhibitors, β-blockers, and diuretics; 8 received spironolactone, and 4 received digoxin. Patients were on stable dose of βblockers for a minimum of 8 weeks before the participation in the study. The Ethical Committee of our institution approved the study protocol and informed consent was obtained from each patient. Measurements We obtained continuous recordings of minute ventilation (pneumotachometer, Medical Electronic Equipment, Brussels, Belgium), end-tidal PCO2 (Normocap 200 Capnometer, Datex-Ohmeda, Hatfield, UK), O2 saturation (N100C pulse oximeter, Nellcor, Pleasanton, California), and the electrocardiogram (Siemens, Munich, Germany). Mean arterial blood pressure (MBP; Physiocontrol Colin BP-880 sphygmomanometer, COLIN Corp, Komaki City, Japan) was measured every 3 minutes during normoxia and every minute during hyperoxia. All recordings were acquired on a Mac Lab 8/s data acquisition system. Protocol The protocol used to test the chemoreflex responses was identical to that used in previous studies (Fig. 1).11,16,17 A venous catheter was inserted into a basilic vein. Either dobutamine (5 µg/kg/min in 5% glucose solution) or placebo (identical volumes of 5% glucose solution) was infused continuously according to a randomized double-blind protocol. The subjects started to breathe across a low-resistance mouthpiece with a nose clip to ensure exclusive mouth breathing 10 minutes after the initiation of the dobutamine or placebo infusion. This period ensured that the hemodynamic effects produced by the infusion had been reached and were stable. We subsequently waited 5 more minutes, during which ventilation was allowed to stabilize and reach baseline values. This allowed the subject to habituate progressively to the recording conditions. The rest of the protocol then consisted
Fig. 1. Protocol of the study.
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of a sequence of 5 minutes of normoxic breathing and a sequence of 5 minutes of hyperoxic breathing (100% O2). We randomized both the order of the placebo and dobutamine infusions as well as the other of the hyperoxic/normoxic breathing sequences. A recovery period of 15 minutes was allowed between 2 sequences of gas mixture exposure and a recovery period of 20 minutes was allowed between 2 infusions (Fig. 1). Statistical Analysis Results are expressed as mean ⫾ SEM. Comparisons between the variables under dobutamine and under placebo infusions were performed with Student’s paired t tests (2-tailed). Significance was assumed at P ⬍ .05.
Results Effects of Dobutamine during Normoxia
Dobutamine increased minute ventilation when the patients with CHF were breathing room air (9.4 ⫾ 0.9 versus 8.4 ⫾ 0.7 L/min, P ⫽ .005). This occurred despite a tendency toward a slight increase in oxygen saturation (96.6 ⫾ 0.4% under dobutamine versus 96.3 ⫾ 0.3% under placebo, P ⫽ .08). Dobutamine did not affect MBP, heart rate, or end-tidal PCO2 during normoxia (Table 1). Effects of Dobutamine during Hyperoxia
Hyperoxic breathing increased ventilation to a similar level during both infusions (10.4 ⫾ 1.4 L/min for dobutamine versus 10.0 ⫾ 1.2 L/min for placebo, P ⫽ .34) and suppressed the differences in minute ventilation that were observed between dobutamine and placebo during normoxia. Dobutamine did not affect MBP, heart rate, or end-tidal PCO2 during hyperoxia (Table 2). Discussion The novel finding of this double-blind, randomized, placebo-controlled study is that dobutamine enhances arterial
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Table 1. Effects of Dobutamine During Normoxia (n ⫽ 9)* Normoxia Placebo Minute ventilation (L/min) MBP (mm Hg) HR (bpm) PCO2 (mm Hg) SaO2 (%)
8.4⫹/⫺0.7 79⫹/⫺4 68⫹/⫺4 32⫹/⫺0.8 96.3⫹/⫺0.3
Normoxia Dobutamine 9.4⫹/⫺0.9 83⫹/⫺5 67⫹/⫺5 32⫹/⫺1 96.6⫹/⫺0.4
P .005 .26 .42 .37 .08
*Results are expressed as mean ⫹/⫺ SEM. MBP, mean arterial blood pressure, HR, heart rate; PCO2, end-tidal PCO2; SaO2, arterial oxygen saturation.
chemoreflex sensitivity in patients with heart failure. Indeed, dobutamine increased minute ventilation during normoxic breathing in patients with CHF. This occurred despite similar levels of arterial oxygen saturation during both infusions. The effect of dobutamine on ventilation was eliminated by chemoreflex deactivation using 100% O2.11–13,15 All these findings argue for a selective potentiation of arterial chemoreflex sensitivity by dobutamine in patients with CHF. Dobutamine is widely used in the intensive and critical care settings, particularly in patients with CHF and cardiorespiratory compromise.9,10 Peripheral chemoreflex sensitization by dobutamine may have important clinical implications in patients with CHF. Enhanced ventilation during dobutamine could improve oxygenation in heart failure patients but may also be deleterious by increasing muscle respiratory fatigue. Although in the acute setting the hemodynamic benefits of the administration of dobutamine should likely override the potential negative effects on respiratory muscle fatigue, this effect may become particularly relevant with chronic use of the drug, which is strongly discouraged by the American College of Cardiology/American Heart Association’s most recent guidelines and is indicated only as a palliative intervention in end-stage heart failure.18 Dobutamine use may also be important in heart failure patients or in critically ill patients with sleep-disordered breathing. CHF patients have a high prevalence of central and obstructive apneas.4,19 Chemoreflex-mediated sympathetic activation and vasoconstriction in response to apneic events are thought to contribute to the pathophysiology and progression of heart failure in patients with disordered breathing.4,14,20 These responses to hypoxemia and apnea are likely to be exacerbated by concomitant use of dobutamine and consequent chemoreflex potentiation. Table 2. Effects of Dobutamine During Hyperoxia (n ⫽ 9)* Hyperoxia Placebo Minute ventilation (L/min) MBP (mm Hg) HR (bpm) PCO2 (mm Hg) SaO2 (%)
10⫹/⫺1.2 80⫹/⫺3 66⫹/⫺4 29⫹/⫺1 98.1⫹/⫺0.3
Hyperoxia Dobutamine 10.4⫹/⫺1.4 84⫹/⫺5 65⫹/⫺4 29⫹/⫺1 98.0⫹/⫺0.2
Dobutamine may also have proarrhythmic properties. Potentiated increases in sympathetic activity in response to acute oxygen desaturation in hemodynamically unstable heart failure patients could further enhance the arrhythmogenic effects of dobutamine. Thus care should be taken to maintain optimal21,22 oxygenation in patients with heart failure receiving dobutamine. Mechanisms
The pathophysiology of the β-adrenergic influence on arterial chemoreceptor sensitivity is not well understood. The carotid bodies are the most important arterial chemoreceptors. They are located in the carotid bifurcation and contain 2 different cell types.23,24 Type I cells, or glomus cells, are the sensitive cells. They contain synaptic vesicles with important amounts of catecholamines. They are surrounded by type II cells or sustentacular cells. These 2 cell-types form clusters and are in contact with several fenestrated capillaries, whose proximity minimizes diffusion pathway for blood stimuli. Decreases in arterial blood PO2 content, reversibly inhibit the outwardly directed K+ current, creating depolarization of the cellular membrane that will lead to the opening of Ca++ channels with an increase of intracellular calcium and consequent neurosecretion.12 The neurotransmitters released (primarily dopamine and norepinephrine) may have a modulating influence on the afferent nerve traffic from glomus cells, by an effect on blood flow or on oxygen consumption by the carotid body and they could also sensitize the chemoreceptors to other stimuli. Thus β-adrenergic agents may stimulate ventilation by activating the same adrenergic receptor mechanism leading either to a direct activation of the chemoreceptors or to a sensitization to hypoxic stimuli.5 Dobutamine increases oxygen consumption (VO2) and oxygen delivery (DO2).25,26 The positive correlation between VO2 and DO226 and the fact that, in normoxic conditions, arterial oxygen saturation increases during dobutamine infusion (from 96.8 ⫾ 0.02 to 97.8 ⫾ 0.01%, P ⬍ .01)25 suggests that the administration of this drug does not produce tissue oxygen debt.26 In our study oxygen saturation tended also to increase with dobutamine during normoxia (from 96.3 ⫾ 0.3 to 96.6 ⫾ 0.4, P ⫽ .08). Thus the increase in minute ventilation observed in our study during dobutamine infusion cannot be explained by an increase in VO2. Dobutamine impairs arterial baroreflex sensitivity in normal humans.27 There is evidence that the baroreceptors inhibit chemoreflex function.1,2 Baroreflex inhibition with dobutamine may thus have also conceivably contributed to enhanced peripheral chemoreflex drive in our patients.
P .34 .21 .51 .85 .50
*Results are expressed as mean ⫹/⫺ SEM. MBP, mean arterial blood pressure, HR, heart rate; PCO2, end-tidal PCO2; SaO2, arterial oxygen saturation.
Effects of Hyperoxia on Ventilation
The peripheral arterial chemoreceptors have some activity during normoxia, called the “resting drive.” They are influenced primarily by arterial oxygen saturation, but also in a minor manner by the CO2 arterial concentration.13 Hyperoxia selectively suppresses the activity of the peripheral chemoreceptors.11–13,15 Conversely, hyperoxia
Dobutamine Increases Chemoreflex Sensitivity
increases ventilation in normal subjects,28,29 probably through a mechanism mediated by the central chemoreceptors known as the Haldane effect.30 Oxygenated hemoglobin has a lower transport capacity for tissue CO2 than does nonoxygenated hemoglobin. During hyperoxia, consequent increases in brain tissue CO2 may cause stimulation of central chemoreceptors. Thus the increased ventilation measured during hyperoxia is probably not mediated by the peripheral chemoreceptors. Hyperoxia would be expected to suppress any facilitatory effects of dobutamine on the peripheral chemoreceptors. The lack of differences in ventilation between dobutamine and placebo during hyperoxia in our patients suggests that the increase in ventilation observed with dobutamine during normoxic breathing is due to a sensitization of the peripheral chemoreceptors. In conclusion, our study suggests that dobutamine increases the sensitivity of the peripheral chemoreceptors in patients with heart failure. Clinicians should be aware of this effect and should seek to maintain optimal oxygenation in hypoxemic patients and in patients with sleep-disordered breathing who are receiving dobutamine. Acknowledgments We are indebted to Dr. Karen Pickett for editorial assistance and to Franc¸oise Pignez for the drawing of the figures.
References 1. Heistad DD, Abboud FM, Mark AL, Schmid PG. Interaction of baroreceptor and chemoreceptor reflexes: modulation of the chemoreceptor reflex by changes in baroreceptor activity. J Clin Invest 1974;53: 1226–1236. 2. Somers VK, Mark AL, Abboud FM. Interaction of baroreceptor and chemoreceptor reflex control of sympathetic nerve activity in normal humans. J Clin Invest 1991;87:1953–7. 3. Ponikowski P, Peng Chua T, Piepoli M, Ondusova D, Webb-Peploe K, Harrington D, et al. Augmented peripheral chemosensitivity as a potential input to baroreflex impairment and autonomic imbalance in chronic heart failure. Circulation 1997;96:2586–94. 4. Naughton MT, Bradley TD. Sleep apnea in congestive heart failure. Clin Chest Med 1998;19:99–113. 5. Heidstad DD, Wheeler RC, Mark AL, Schmid PG, Abboud FM. Effects of adrenergic stimulation on ventilation in man. J Clin Invest 1972;51: 1469–1475. 6. Yoshiike Y, Susuki S, Watanuki Y, Okubo T. Effects of fenoterol on ventilatory responses to hypoxia and hypercapnia in normal subjects. Thorax 1995;50:139–42. 7. Leitch AG, Clancy LJ, Costello JE, Flenley D. Effects of intravenous infusion of salbutamol on ventilatory response to carbon dioxide and hypoxia on heart rate and plasma potassium in normal men. BMJ 1976;1:365–7. 8. Goodman Gilman A, Rall TW, Nies AS, Palmer T. Goodman and Gilman’s the pharmacological basis of therapeutics. 8th ed. New York: Pergamon Press; 1990. 9. Lowes BD, Tsvetkova T, Eichhorn EJ, Gilbert EM, Bristow MR. Milrinone versus dobutamine in heart failure subjects treated chronically with carvedilol. Int J Cardiol 2001;81:141–9.
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10. Yamani MH, Haji SA, Starling RC, Albert N, Knack DL, Joung JB. Comparison of dobutamine-based and milrinone-based therapy for advanced decompensated congestive heart failure: hemodynamic efficacy, clinical outcome, and economic impact. Am Heart J 2001;142:998– 1002. 11. van de Borne P, Oren R, Anderson EA, Mark AL, Somers VK. Tonic chemoreflex activation does not contribute to elevated muscle sympathetic nerve activity in heart failure. Circulation 1996;94:1325–8. 12. Gonzalez C, Almaraz L, Obeso A, Rigual R. Oxygen and acid chemoreception in the carotid body chemoreceptors. TINS 1992;15:146–52. 13. Duffin J. Continuing medical education. The chemoreflex control of breathing and its measurement. Can J Anaesth 1990;37:933–42. 14. van de Borne P, Oren R, Abouassaly C, Anderson E, Somers VK. Effect of Cheyne Stokes respiration on muscle sympathetic activity in severe congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 1998;81:432–6. 15. Narkiewicz K, van de Borne P, Montano, Philips B, Somers VK. Contribution of tonic chemoreflex activation to sympathetic activity and blood pressure in patients with obstructive sleep apnea. Circulation 1998;97:943–5. 16. Narkiewicz K, Pesek CA, van de Borne P, Kato M, Somers VK. Enhanced sympathetic and ventilatory responses to central chemoreflex activation in heart failure. Ciculation 1999;100:262–7. 17. van de Borne P, Oren R, Mark AL, Somers VK. Dopamine depresses minute ventilation in patients with heart failure. Circulation 1998;98: 126–131. 18. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult. Executive summary a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines. Circulation 2001;104:2996–3007. 19. Teramoto S, Ouchi Y. Clinical significance of arterial blood gas analysis for detection and or treatment of central apnea in patients with heart failure. Circulation 1999;99:2709–12. 20. Lafranchi PA, Braghiroli A, Bosimini E, Mazzuero G, Colombo R, Donner CF, Giannuzi P. Prognostic value of nocturnal Cheyne-Stokes respiration in chronic heart failure. Circulation 1999;99:1435–40. 21. Haque WA, Boehmer J, Clemson BS, Leuenberger UA, Silber DH, Sinoway LI. Hemodynamic effects of supplemental oxygen administration in congestive heart failure. J Coll Cardiol 1996;27:353–7. 22. Mak S, Azavedo ER, Liu PP, Newton GE. Effect of hyperoxia on left ventricular function and filling pressures in patients with and without congestive heart failure. Chest 2001;120:467–73. 23. DeKock LL, Dunn AEG. Ultrastructure of carotid body tissue as seen in serial sections. Nature 1964;202:821–6. 24. McDonald DM. Peripheral chemoreceptors. Structure-function relationships of the carotid body. Regulation of breathing. In: Hornbein TF, editor. Regulation of Breathing, Part I. New York: Marcel Dekker; 1981. p. 105–319. 25. De Backer D, Berre J, Moraine JJ, Melot C, Vanfraechem J, Vincent JL. Effects of dobutamine on the relationship between oxygen consumption and delivery in healthy volunteers: comparison with sodium nitroprusside. Clin Sci 1996;90:105–11. 26. Bhatt SB, Hutchinson RC, Tomlinson B, Oh TE, Mak M. Effect of dobutamine on oxygen supply and uptake in healthy volunteers. Br J Anaesth 1993;69298–303. 27. van de Borne P, Heron S, Nguyen H, Unger P, Leeman M, Vincent JL, et al. Arterial baroreflex control of the sinus node during dobutamine exercise stress testing. Hypertension 1999;33:987–91. 28. Becker HF, Polo O, McNamara SG, Berthon-Jones M, Sulivan CE. Ventilatory response to isocapnic hyperoxia. J Appl Physiol 1995;78:696– 701. 29. Becker HF, Polo O, McNamara SG, Berthon-Jones M, Sulivan CE. Effect of different levels of hyperoxia on breathing in healthy subjects. J Appl Physiol 1996;81:1683–90. 30. Christiansen J, Douglas CG, Haldane JS. The absorption and dissociation of carbon dioxide by human blood. J Physiol Lond 1914;48: 244–271.
Dobutamine Potentiates the Peripheral Chemoreflex in Patients With Congestive Heart Failure SONIA VELEZ-ROA, MD, PHILIPPE VAN DE BORNE, MD, PhD,1 VIREND K. SOMERS, MD, PhD2 Brussels, Belgium; Rochester, Minnesota
ABSTRACT Background: β-Adrenergic agonists may increase chemoreflex sensitivity to hypoxia in normal humans. Chemoreflex function is important in the pathophysiology of heart failure. Whether the β-1 agonist dobutamine, which is frequently administered to patients with heart failure, alters their chemoreflex sensitivity is not known. Methods: We tested the hypothesis that dobutamine increases chemoreflex sensitivity in patients with congestive heart failure (CHF) using a randomized, double-blinded, placebo-controlled study design. We assessed the influence of dobutamine on minute ventilation and hemodynamics during normoxic breathing and during peripheral chemoreflex deactivation by hyperoxia (100% O2) in 9 patients with CHF. Results: Dobutamine increased minute ventilation in patients with CHF (9.4 ⫾ 0.9 versus 8.4 ⫾ 0.7 L/min, P ⫽ .005) during normoxia. Peripheral chemoreflex deactivation by hyperoxia suppressed the ventilatory effects of dobutamine (10.4 ⫾ 1.4 L/min for dobutamine versus 10.0 ⫾ 1.2 L/min for placebo, P ⫽ .34). Conclusions: Dobutamine increases ventilation during normoxia, but not during hyperoxia in patients with CHF. We conclude that dobutamine enhances peripheral chemoreflex sensitivity in patients with congestive heart failure. Key Words: Chemoreflex sensitivity, congestive heart failure, dobutamine.
primarily to hypoxia,12,13 and exert powerful effects on ventilation and on autonomic cardiovascular control.1,2 Altered chemoreflex sensitivity to hypoxia could have clinically significant effects on breathing, hemodynamics, and neural circulatory control in patients with heart failure.3,14 These effects may influence both stability and clinical outcome in patients with cardiorespiratory compromise. We tested the hypothesis that dobutamine increases chemoreflex sensitivity in patients with CHF using a randomized, double-blinded, placebo-controlled study design. In 9 patients with CHF, we studied the effects of dobutamine on hemodynamics and on minute ventilation during room-air breathing and during hyperoxia. The effects of hyperoxia on the responses to dobutamine were examined to further clarify any effects of dobutamine on peripheral chemoreflex function. We hypothesized that any effects of dobutamine on ventilation mediated by the peripheral chemoreceptors, would be suppressed by hyperoxia by reducing tonic activation of the peripheral chemoreceptors.11–13,15
Chemoreflex function contributes importantly to cardiovascular regulation1–3 and may be especially significant in patients with cardiac and respiratory compromise.4 β-agonists may increase chemoreflex sensitivity to hypoxia in humans.5–7 Dobutamine has strong β-1 adrenergic agonist effects,8 and is frequently administered to patients with heart failure in intensive and coronary care units.9,10 Whether dobutamine affects chemoreflex function in patients with congestive heart failure (CHF) is not known. Patients with heart failure often have mild oxygen desaturation as a result of chronic lung edema.11 The peripheral chemoreceptors, located in the carotid bodies, respond From the 1Department of Cardiology, Erasme Hospital, Brussels, Belgium; 2Division of Cardiovascular Diseases and Division of Hypertension, Mayo Clinic, Rochester, Minnesota. Manuscript received January 16, 2003; revised manuscript received April 28, 2003; revised manuscript accepted May 2, 2003. These studies were supported by the Erasme Foundation, Belgium (S.V.-R.), the National Fund for Research and the Jacqueline Bernheim Award of the Foundation for Cardiac Surgery and the Mark Hurard Foundation, Belgium (P.v.d.B.). VKS is an Established Investigator of the American Heart Association and is also supported by NIH HL61560, HL65176, HL70602, and RR00585. Reprint requests: Sonia Velez-Roa, MD, Department of Cardiology, Erasme Hospital, 808 Lennik Road, 1070 Brussels, Belgium. 쑕 2003 Elsevier Inc. All rights reserved. 1071-9164/02/0905-0007$30.00/0 doi:10.1054/S1071-9164(03)00132-5
Methods Subjects Nine patients with congestive heart failure (8 men, aged 53 years; range 40–79 years,) were enrolled in the study. The cause
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Dobutamine Increases Chemoreflex Sensitivity of heart failure was ischemic heart disease (n ⫽ 5) or idiopathic (n ⫽ 4). Left ventricular ejection fraction, determined by a resting radionuclide ventriculogram or echocardiography, was 21 ⫾ 2%. They were in class II (n ⫽ 3), III (n ⫽ 5) and IV (n ⫽ 1) of the New York Heart Association classification. All CHF patients were on standard heart failure treatment including angiotensin-converting enzyme inhibitors, β-blockers, and diuretics; 8 received spironolactone, and 4 received digoxin. Patients were on stable dose of βblockers for a minimum of 8 weeks before the participation in the study. The Ethical Committee of our institution approved the study protocol and informed consent was obtained from each patient. Measurements We obtained continuous recordings of minute ventilation (pneumotachometer, Medical Electronic Equipment, Brussels, Belgium), end-tidal PCO2 (Normocap 200 Capnometer, Datex-Ohmeda, Hatfield, UK), O2 saturation (N100C pulse oximeter, Nellcor, Pleasanton, California), and the electrocardiogram (Siemens, Munich, Germany). Mean arterial blood pressure (MBP; Physiocontrol Colin BP-880 sphygmomanometer, COLIN Corp, Komaki City, Japan) was measured every 3 minutes during normoxia and every minute during hyperoxia. All recordings were acquired on a Mac Lab 8/s data acquisition system. Protocol The protocol used to test the chemoreflex responses was identical to that used in previous studies (Fig. 1).11,16,17 A venous catheter was inserted into a basilic vein. Either dobutamine (5 µg/kg/min in 5% glucose solution) or placebo (identical volumes of 5% glucose solution) was infused continuously according to a randomized double-blind protocol. The subjects started to breathe across a low-resistance mouthpiece with a nose clip to ensure exclusive mouth breathing 10 minutes after the initiation of the dobutamine or placebo infusion. This period ensured that the hemodynamic effects produced by the infusion had been reached and were stable. We subsequently waited 5 more minutes, during which ventilation was allowed to stabilize and reach baseline values. This allowed the subject to habituate progressively to the recording conditions. The rest of the protocol then consisted
Fig. 1. Protocol of the study.
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of a sequence of 5 minutes of normoxic breathing and a sequence of 5 minutes of hyperoxic breathing (100% O2). We randomized both the order of the placebo and dobutamine infusions as well as the other of the hyperoxic/normoxic breathing sequences. A recovery period of 15 minutes was allowed between 2 sequences of gas mixture exposure and a recovery period of 20 minutes was allowed between 2 infusions (Fig. 1). Statistical Analysis Results are expressed as mean ⫾ SEM. Comparisons between the variables under dobutamine and under placebo infusions were performed with Student’s paired t tests (2-tailed). Significance was assumed at P ⬍ .05.
Results Effects of Dobutamine during Normoxia
Dobutamine increased minute ventilation when the patients with CHF were breathing room air (9.4 ⫾ 0.9 versus 8.4 ⫾ 0.7 L/min, P ⫽ .005). This occurred despite a tendency toward a slight increase in oxygen saturation (96.6 ⫾ 0.4% under dobutamine versus 96.3 ⫾ 0.3% under placebo, P ⫽ .08). Dobutamine did not affect MBP, heart rate, or end-tidal PCO2 during normoxia (Table 1). Effects of Dobutamine during Hyperoxia
Hyperoxic breathing increased ventilation to a similar level during both infusions (10.4 ⫾ 1.4 L/min for dobutamine versus 10.0 ⫾ 1.2 L/min for placebo, P ⫽ .34) and suppressed the differences in minute ventilation that were observed between dobutamine and placebo during normoxia. Dobutamine did not affect MBP, heart rate, or end-tidal PCO2 during hyperoxia (Table 2). Discussion The novel finding of this double-blind, randomized, placebo-controlled study is that dobutamine enhances arterial
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Table 1. Effects of Dobutamine During Normoxia (n ⫽ 9)* Normoxia Placebo Minute ventilation (L/min) MBP (mm Hg) HR (bpm) PCO2 (mm Hg) SaO2 (%)
8.4⫹/⫺0.7 79⫹/⫺4 68⫹/⫺4 32⫹/⫺0.8 96.3⫹/⫺0.3
Normoxia Dobutamine 9.4⫹/⫺0.9 83⫹/⫺5 67⫹/⫺5 32⫹/⫺1 96.6⫹/⫺0.4
P .005 .26 .42 .37 .08
*Results are expressed as mean ⫹/⫺ SEM. MBP, mean arterial blood pressure, HR, heart rate; PCO2, end-tidal PCO2; SaO2, arterial oxygen saturation.
chemoreflex sensitivity in patients with heart failure. Indeed, dobutamine increased minute ventilation during normoxic breathing in patients with CHF. This occurred despite similar levels of arterial oxygen saturation during both infusions. The effect of dobutamine on ventilation was eliminated by chemoreflex deactivation using 100% O2.11–13,15 All these findings argue for a selective potentiation of arterial chemoreflex sensitivity by dobutamine in patients with CHF. Dobutamine is widely used in the intensive and critical care settings, particularly in patients with CHF and cardiorespiratory compromise.9,10 Peripheral chemoreflex sensitization by dobutamine may have important clinical implications in patients with CHF. Enhanced ventilation during dobutamine could improve oxygenation in heart failure patients but may also be deleterious by increasing muscle respiratory fatigue. Although in the acute setting the hemodynamic benefits of the administration of dobutamine should likely override the potential negative effects on respiratory muscle fatigue, this effect may become particularly relevant with chronic use of the drug, which is strongly discouraged by the American College of Cardiology/American Heart Association’s most recent guidelines and is indicated only as a palliative intervention in end-stage heart failure.18 Dobutamine use may also be important in heart failure patients or in critically ill patients with sleep-disordered breathing. CHF patients have a high prevalence of central and obstructive apneas.4,19 Chemoreflex-mediated sympathetic activation and vasoconstriction in response to apneic events are thought to contribute to the pathophysiology and progression of heart failure in patients with disordered breathing.4,14,20 These responses to hypoxemia and apnea are likely to be exacerbated by concomitant use of dobutamine and consequent chemoreflex potentiation. Table 2. Effects of Dobutamine During Hyperoxia (n ⫽ 9)* Hyperoxia Placebo Minute ventilation (L/min) MBP (mm Hg) HR (bpm) PCO2 (mm Hg) SaO2 (%)
10⫹/⫺1.2 80⫹/⫺3 66⫹/⫺4 29⫹/⫺1 98.1⫹/⫺0.3
Hyperoxia Dobutamine 10.4⫹/⫺1.4 84⫹/⫺5 65⫹/⫺4 29⫹/⫺1 98.0⫹/⫺0.2
Dobutamine may also have proarrhythmic properties. Potentiated increases in sympathetic activity in response to acute oxygen desaturation in hemodynamically unstable heart failure patients could further enhance the arrhythmogenic effects of dobutamine. Thus care should be taken to maintain optimal21,22 oxygenation in patients with heart failure receiving dobutamine. Mechanisms
The pathophysiology of the β-adrenergic influence on arterial chemoreceptor sensitivity is not well understood. The carotid bodies are the most important arterial chemoreceptors. They are located in the carotid bifurcation and contain 2 different cell types.23,24 Type I cells, or glomus cells, are the sensitive cells. They contain synaptic vesicles with important amounts of catecholamines. They are surrounded by type II cells or sustentacular cells. These 2 cell-types form clusters and are in contact with several fenestrated capillaries, whose proximity minimizes diffusion pathway for blood stimuli. Decreases in arterial blood PO2 content, reversibly inhibit the outwardly directed K+ current, creating depolarization of the cellular membrane that will lead to the opening of Ca++ channels with an increase of intracellular calcium and consequent neurosecretion.12 The neurotransmitters released (primarily dopamine and norepinephrine) may have a modulating influence on the afferent nerve traffic from glomus cells, by an effect on blood flow or on oxygen consumption by the carotid body and they could also sensitize the chemoreceptors to other stimuli. Thus β-adrenergic agents may stimulate ventilation by activating the same adrenergic receptor mechanism leading either to a direct activation of the chemoreceptors or to a sensitization to hypoxic stimuli.5 Dobutamine increases oxygen consumption (VO2) and oxygen delivery (DO2).25,26 The positive correlation between VO2 and DO226 and the fact that, in normoxic conditions, arterial oxygen saturation increases during dobutamine infusion (from 96.8 ⫾ 0.02 to 97.8 ⫾ 0.01%, P ⬍ .01)25 suggests that the administration of this drug does not produce tissue oxygen debt.26 In our study oxygen saturation tended also to increase with dobutamine during normoxia (from 96.3 ⫾ 0.3 to 96.6 ⫾ 0.4, P ⫽ .08). Thus the increase in minute ventilation observed in our study during dobutamine infusion cannot be explained by an increase in VO2. Dobutamine impairs arterial baroreflex sensitivity in normal humans.27 There is evidence that the baroreceptors inhibit chemoreflex function.1,2 Baroreflex inhibition with dobutamine may thus have also conceivably contributed to enhanced peripheral chemoreflex drive in our patients.
P .34 .21 .51 .85 .50
*Results are expressed as mean ⫹/⫺ SEM. MBP, mean arterial blood pressure, HR, heart rate; PCO2, end-tidal PCO2; SaO2, arterial oxygen saturation.
Effects of Hyperoxia on Ventilation
The peripheral arterial chemoreceptors have some activity during normoxia, called the “resting drive.” They are influenced primarily by arterial oxygen saturation, but also in a minor manner by the CO2 arterial concentration.13 Hyperoxia selectively suppresses the activity of the peripheral chemoreceptors.11–13,15 Conversely, hyperoxia
Dobutamine Increases Chemoreflex Sensitivity
increases ventilation in normal subjects,28,29 probably through a mechanism mediated by the central chemoreceptors known as the Haldane effect.30 Oxygenated hemoglobin has a lower transport capacity for tissue CO2 than does nonoxygenated hemoglobin. During hyperoxia, consequent increases in brain tissue CO2 may cause stimulation of central chemoreceptors. Thus the increased ventilation measured during hyperoxia is probably not mediated by the peripheral chemoreceptors. Hyperoxia would be expected to suppress any facilitatory effects of dobutamine on the peripheral chemoreceptors. The lack of differences in ventilation between dobutamine and placebo during hyperoxia in our patients suggests that the increase in ventilation observed with dobutamine during normoxic breathing is due to a sensitization of the peripheral chemoreceptors. In conclusion, our study suggests that dobutamine increases the sensitivity of the peripheral chemoreceptors in patients with heart failure. Clinicians should be aware of this effect and should seek to maintain optimal oxygenation in hypoxemic patients and in patients with sleep-disordered breathing who are receiving dobutamine. Acknowledgments We are indebted to Dr. Karen Pickett for editorial assistance and to Franc¸oise Pignez for the drawing of the figures.
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