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Education  |   October 2003
Effect of Nitroglycerin Inhalation on Patients with Pulmonary Hypertension Undergoing Mitral Valve Replacement Surgery
Author Affiliations & Notes
  • Nurgul Yurtseven, M.D.
    *
  • Pelin Karaca, M.D.
    *
  • Mehmet Kaplan, M.D.
  • Vedat Ozkul, M.D.
    *
  • Abdullah K. Tuygun, M.D.
  • Tamer Aksoy, M.D.
    *
  • Sevim Canik, M.D.
  • Ercument Kopman, M.D.
    †§
  • *Attending Anesthesiologist, ‡Chief, Department of Anesthesiology and Reanimation. †Deceased, §Professor, Department of Anesthesiology and Reanimation, †Attending Surgeon, Department of Cardiovascular Surgery.
  • Received from the Dr. Siyami Ersek Thoracic and Cardiovascular Surgery Hospital, Istanbul, Turkey.
Article Information
Education
Education   |   October 2003
Effect of Nitroglycerin Inhalation on Patients with Pulmonary Hypertension Undergoing Mitral Valve Replacement Surgery
Anesthesiology 10 2003, Vol.99, 855-858. doi:
Anesthesiology 10 2003, Vol.99, 855-858. doi:
IN patients with mitral valve disease, the presence of pulmonary hypertension (PHT) is important because it affects prognosis. After cardiac surgery, it may be necessary to treat right ventricular failure caused by PHT. 1 
Recent literature documents the use of inhaled nitric oxide 2–4 in the treatment of PHT; however, it requires a complicated and expensive apparatus. 5 PHT is usually treated with intravenous vasodilators, but their use is limited because of their systemic effects. Although it is well known that intravenous nitroglycerin decreases systemic blood pressure and pulmonary arterial pressures, 2,6–8 little is known about the effects of inhaled nitroglycerin on PHT.
This study was undertaken to determine whether inhaled nitroglycerin lowers pulmonary vascular resistance in patients with PHT after mitral valve replacement.
Materials and Methods
After obtaining ethics committee approval (Istanbul, Turkey), 20 patients with PHT (12 female and 8 male) were enrolled in this study, and informed consent was taken from all patients. Their ages were between 19–46 yr. All patients had undergone mitral valve replacement (70% for mitral stenosis, 30% for mitral regurgitation). Left ventricle ejection fractions were over 40% in all patients, and their mean pulmonary arterial pressures were higher than 25 mmHg during both the preoperative and postoperative periods.
Anesthesia was induced with intravenous fentanyl (20 μg/kg) and propofol (2 mg/kg). Muscle relaxation was provided with pancuronium (0.1 mg/kg). Anesthetic maintenance was ensured with fentanyl infusion (0.3–1.0 μg · kg−1· min−1), isoflurane (0.4–1.0%), and propofol (1 mg/kg). During the first 8 postoperative hours, patients were sedated with 2 μg · kg−1· h−1fentanyl, and the study was continued at this time. The patients were ventilated with 40% oxygen. Tidal volume was set at 10 ml/kg. Respiratory rate was adjusted to establish an arterial carbon dioxide tension and arterial pH of approximately 35 mmHg and 7.40, respectively.
The measured hemodynamic parameters were heart rate, mean arterial pressure, mean pulmonary artery pressure, central venous pressure, and pulmonary capillary wedge pressure. Cardiac output determinations were made in triplicate at the end of expiration by a thermodilution technique using 10 ml iced dextrose, 5%, in water, each time using a cardiac output computer (Baxter Healthcare Corporation, Cardiovascular Group Edwards Critical Care Vigilance, Irvine, CA). The mean of the three readings was taken as the cardiac output for each time. Cardiac index, systemic vascular resistance, and pulmonary vascular resistance were derived from the measured hemodynamic variables using standard formulae.
Before the inhalation of nitroglycerin (at T0), basal heart rate, mean arterial pressure, mean pulmonary artery pressure, central venous pressure, pulmonary capillary wedge pressure, cardiac index, pulmonary vascular resistance, and systemic vascular resistance were measured.
Then, 2.5 μg/kg nitroglycerin, nebulized by a 2-l/min air jet device shown in figure 1(Ref. 41883, MICRO MIST Small Volume Nebulizer; Hudson Respiratory Care Inc., Temecula, CA) was inhaled by the patient from the inspiratory limb of the ventilator. The previous measurements were again performed at the first (T1), third (T2), and fifth (T3) hours after the beginning of this treatment and 1 h after the end of nitroglycerin inhalation (T4).
Fig. 1. The device used for nitroglycerin administration.
Fig. 1. The device used for nitroglycerin administration.
Fig. 1. The device used for nitroglycerin administration.
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Arterial and mixed venous blood samples were drawn during each assessment point and immediately analyzed by the Stat Profile-M (Nova Biomedical, Boston, MA). Besides the evaluation of arterial carbon dioxide tension (Paco2; mmHg) and mixed venous oxygen saturation (Svo2), arteriovenous oxygen content difference (AvḊo2), pulmonary shunt fraction (Qs/Qt), and arterial oxygen tension/fraction of inspired oxygen (Pao2/Fio2) ratio were calculated by standard formulas.
Statistical Analysis
Statistical procedures were performed using SPSS 10.0 (Statistical Package for the Social Sciences; SPSS Inc., Chicago, IL). Data are expressed as mean ± SD and compared at T0, T1, T2, T3, and T4. The variables were analyzed with repeated-measures one-way analysis of variance. Post hoc  comparisons were performed using the Student-Newman-Keuls test. P  value of less than 0.05 was considered to indicate statistical significance.
Results
The hemodynamic parameters are shown in table 1. There were no statistically significant differences at T0, T1, T2, T3, and T4with respect to heart rate, mean arterial pressure, central venous pressure, pulmonary capillary wedge pressure, cardiac index, and systemic vascular resistance (P  > 0.05). Inhaled nitroglycerin produced significant reduction in mean pulmonary artery pressure and pulmonary vascular resistance. Mean pulmonary artery pressure and pulmonary vascular resistance returned to prenitroglycerin values 1 h after withdrawal of inhaled nitroglycerin. We did not observe any rebound PHT during this period. Mean pulmonary artery pressure and pulmonary vascular resistance were significantly lower at T1, T2, and T3compared to T0and T4(P  < 0.001). There were no statistically differences between T0and T4with respect to all parameters obtained.
Table 1. Hemodynamic Data
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Table 1. Hemodynamic Data
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Gas exchange data are shown in table 2. Inhaled nitroglycerin increased the Pao2/Fio2ratio at T1, T2, and T3when compared to T0and T4. In addition, it also decreased the Qs/Qt ratio during the same periods (P  < 0.05). Gas exchange values were similar at T0and T4. There were no statistically significant differences at T0, T1, T2, T3, and T4with respect to Paco2tension, Svo2, and AvḊo2(P  > 0.05).
Table 2. Gas Exchange Data
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Table 2. Gas Exchange Data
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Discussion
Although the mechanism changes according to the primary pathology, PHT is usually the endpoint of mitral valve disease. 9,10 At least three pathophysiologic mechanisms contribute to the PHT seen in longstanding valvular disease. These are increased left atrial pressure transmitted retrograde into the pulmonary circulation, vascular remodelling of the pulmonary vasculature in response to chronic obstruction to pulmonary venous drainage (fix component), and pulmonary arterial vasoconstriction (reactive component). PHT is usually a reflex in origin during the immediate postoperative period. However, in time, other morphologic changes take place. 11,12 
The treatment of mitral valvular disease is usually mechanical. In addition to original pathology, cardiopulmonary bypass itself might contribute to the increased mean pulmonary arterial pressure in this group of patients. Several days or even weeks might be required for the increased pulmonary vascular resistance to return to normal after valve replacement. Unfortunately, control of pulmonary vascular resistance in such patients may be a problem. Thus, patients undergoing valve surgery most often require pulmonary vasodilator therapy during the immediate postoperative period. 13 
However, PHT is not always associated with increased pulmonary vascular resistance. Congestive heart failure induces a postcapillary PHT characterized by pulmonary vasodilatation and normal pulmonary vascular resistance. Selective vasodilators, such as nitroglycerin, do not induce any further dilation. Therefore, in planning a therapy regimen in patients with PHT, the primary etiologic factor is important. 11,12 
Vasodilator agents are one of the therapeutic options in PHT. Recently, inhalation of nitric oxide has become a popular treatment modality in experimental models of PHT. 2,3 However, nitric oxide inhalation may have toxic adverse reactions, and the application requires expensive and complicated systems. 5 
On the other hand, nitroglycerin is metabolized to nitric oxide, which is a potent vascular smooth muscle relaxant in the vascular endothelial cells. 3 In addition, administration of nitroglycerin is easier compared to nitric oxide. Although inhalation of high concentrations of nitric oxide can be lethal because of severe acute pulmonary edema and methemoglobinemia, 14 there is little evidence of toxicity when the concentration is below 50 ppm. 15 There is no study showing toxicity of nitroglycerin inhalation in the literature. This is most probably because of the use of doses of nitroglycerin lower than the intravenous doses that are reported to be toxic. Nitroglycerin doses of 5 mg kg−1day−1and over should be avoided to prevent significant methemoglobinemia. 16 Intravenous infusion of nitroglycerin is used commonly to treat PHT; however, it not only decreases pulmonary artery pressure but also systemic blood pressure. Recently, it has been shown that nitroglycerin inhalation is free of this side effect. 5,17 Therefore, in this study, we used nitroglycerin inhalation to reduce pulmonary artery pressure in patients with PHT. Our results demonstrate that inhaled nitroglycerin, after mitral valve replacement surgery, produces significant reductions in mean pulmonary artery pressure and pulmonary vascular resistance without affecting mean arterial pressure, systemic vascular resistance, or cardiac index. The decline in mean pulmonary artery pressure and pulmonary vascular resistance was found to be statistically significant (P  < 0.001). These results are similar to those of Gong et al.  5 that in dogs with experimentally induced PHT, inhalation of nebulized nitroglycerin decreases mean pulmonary artery pressure, diastolic pulmonary artery pressure, and systolic pulmonary artery pressure without affecting systolic arterial pressure, diastolic arterial pressure, mean arterial pressure, systemic vascular resistance, or cardiac output.
Bando et al.  17 compared nitroglycerin infusion and inhalation in doses of 1 and 2.5 μg · kg−1· min−1, respectively, in dogs with hypoxic pulmonary vasoconstriction and reported that nitroglycerin inhalation in doses of 2.5 μg · kg−1· min−1decreased mean arterial pressure, mean pulmonary artery pressure, and pulmonary vascular resistance but did not affect cardiac output. The same doses of nitroglycerin infusion did not decrease mean pulmonary artery pressure but decreased mean arterial pressure. They concluded that inhalation of nitroglycerin is more effective in pulmonary circulation when compared to nitroglycerin infusion.
Omar et al.  18 investigated the effects of nitroglycerin inhalation in PHT resulting from congenital cardiac defects and reported decreases in systolic pulmonary artery pressure and mean pulmonary artery pressure as a result of nitroglycerin administration; however, heart rate, systolic arterial pressure, and mean arterial pressure were not affected. Therefore, the literature supports the theory that nitroglycerin inhalation can be a less expensive, easy, and effective alternative for PHT therapy when compared with nitric oxide inhalation.
Inhaled nitroglycerin produces vasodilatation of pulmonary vasculature adjacent to well-ventilated alveoli, increases blood flow to these areas, and preferentially shunts blood away from poorly ventilated regions; thus, it matches ventilation/perfusion and reduces intrapulmonary shunt. This results in improved oxygenation and reduced pulmonary vascular resistance and right ventricular afterload.
In conclusion, nitroglycerin inhalation decreases mean pulmonary artery pressure, pulmonary vascular resistance, and Qs/Qt ratio without affecting heart rate, mean arterial pressure, central venous pressure, pulmonary capillary wedge pressure, systemic vascular resistance, or cardiac output after mitral valve replacement surgery. In addition, inhalation of nitroglycerin increases the Pao2/Fio2ratio. Thus, it can be used as alternative mode of therapy in patients with PHT associated with mitral valve diseases.
It is known that at low doses, nitroglycerin acts as a venodilator, whereas at high doses it becomes an arteriodilator. Because mean arterial pressure was not affected by the doses used in this study, we assume that nitroglycerin acts as a venodilator at this dose, but in this study design, it is not possible to predict the exact dose reaching the distal lung. This can be regarded as a drawback of our study. Therefore, further randomized trials are needed.
References
Vlahakes GJ, Turley K, Hoffman JI: The pathophysiology of failure in acute right ventricular hypertension: Hemodynamic and biochemical correlations. Circulation 1981; 63: 87–95Vlahakes, GJ Turley, K Hoffman, JI
Van Obbergh LJ, Charbonneau M, Blaise G: Combination of inhaled nitric oxide with i. v. nitroglycerin or with a prostacyclin analogue in the treatment of experimental pulmonary hypertension. Br J Anaesth 1996; 77: 227–31Van Obbergh, LJ Charbonneau, M Blaise, G
Girard C, Lehot JJ, Pannetier JC, Filley S, Ffrench P, Estanove S: Inhaled nitric oxide after mitral valve replacement in patients with chronic pulmonary artery hypertension. A nesthesiology 1992; 77: 880–3Girard, C Lehot, JJ Pannetier, JC Filley, S Ffrench, P Estanove, S
Fullerton DA, Jones SD, Jaggers J, Piedalue F, Grover FL, McIntyre RC Jr: Effective control of pulmonary vascular resistance with inhaled nitric oxide after cardiac operation. J Thorac Cardiovasc Surg 1996; 111: 753–63Fullerton, DA Jones, SD Jaggers, J Piedalue, F Grover, FL McIntyre, RC
Gong F, Shiraishi H, Kikuchi Y, Hoshina M, Ichihashi K, Sato Y, Momoi MY: Inhalation of nebulized nitroglycerin in dogs with experimental pulmonary hypertension induced by U46619. Pediatr Int 2000; 42: 255–8Gong, F Shiraishi, H Kikuchi, Y Hoshina, M Ichihashi, K Sato, Y Momoi, MY
Schmid ER, Burki C, Engel MH, Schmidlin D, Tornic M, Seifert B: Inhaled nitric oxide versus intravenous vasodilators in severe pulmonary hypertension after cardiac surgery. Anesth Analg 1999; 89: 1108–15Schmid, ER Burki, C Engel, MH Schmidlin, D Tornic, M Seifert, B
Troncy E, Jacob E, Da Silva P, Ducruet T, Collet JP, Salazkin I, Charbonneau M, Blaise G: Comparison of the effect of inhaled nitric oxide and intravenous nitroglycerin on hypoxia-induced pulmonary hypertension in pigs. Eur J Anaesthesiol 1996; 13: 521–9Troncy, E Jacob, E Da Silva, P Ducruet, T Collet, JP Salazkin, I Charbonneau, M Blaise, G
Pearl RG, Rosenthal MH, Schroeder JS, Ashton JP: Acute hemodynamic effects of nitroglycerin in pulmonary hypertension. Ann Intern Med 1983; 99: 9–13Pearl, RG Rosenthal, MH Schroeder, JS Ashton, JP
Camara ML, Aris A, Padro JM, Caralps JM: Long-term results of mitral valve surgery in patients with severe pulmonary hypertension. Ann Thorac Surg 1988; 45: 133–6Camara, ML Aris, A Padro, JM Caralps, JM
Foltz BD, Hessel EA II, Ivey TD: The early course of pulmonary artery hypertension in patients undergoing mitral valve replacement with cardioplegic arrest. J Thorac Cardiovasc Surg 1984; 88: 238–47Foltz, BD Hessel, EA Ivey, TD
Fuster V, Alexander RW, O'Rouke RA, Roberts R, King SB III, Hein JJ, Wellens HJJ: Pulmonary hypertension, Hurst's The Heart, 10th edition. Edited by Rubin LJ. International edition, New York, McGraw-Hill, 2001, pp 1607–23
Bave AE, Geha AS, Hammond GL, Laks H, Naunheim KS: Acquired disease of the mitral valve, Glenn's Thoracic and Cardiovascular Surgery, 6th edition. Edited by Swain JA. Stamford, Appleton and Lange, 1996, pp 1943–59
Franco KL, Verrier ED: Inhaled nitric oxide in heart and lung surgery, Advanced Therapy in Cardiac Surgery, 1st edition. Edited by Fullerton DA. Hamilton, BC Decker, 1999, pp 335–46
Clutton-Brock J: Two cases of poisoning by contamination of nitrous oxide with higher oxides of nitrogen during anaesthesia. Br J Anesth 1967; 39: 388–92Clutton-Brock, J
Rossaint R, Falke KJ, Lopez F, Slama K, Pison U, Zapol WM: Inhaled nitric oxide for the adult respiratory distress syndrome. N Engl J Med 1993; 328: 399–405Rossaint, R Falke, KJ Lopez, F Slama, K Pison, U Zapol, WM
Harris JC, Rumack BH, Peterson RG, McGuire BM: Methemoglobinemia resulting from absorption of nitrates. JAMA 1979; 242: 2869–71Harris, JC Rumack, BH Peterson, RG McGuire, BM
Omar HA, Gong F, Sun MY, Einzig S: Nebulized nitroglycerin in children with pulmonary hypertension secondary to congenital heart disease. W V Med J 1999; 95: 74–5Omar, HA Gong, F Sun, MY Einzig, S
Bando M, Ishii Y, Kitamura S, Ohno S: Effects of inhalation of nitroglycerin on hypoxic pulmonary vasoconstriction. Respiration 1998; 65: 63–70Bando, M Ishii, Y Kitamura, S Ohno, S
Fig. 1. The device used for nitroglycerin administration.
Fig. 1. The device used for nitroglycerin administration.
Fig. 1. The device used for nitroglycerin administration.
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Table 1. Hemodynamic Data
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Table 1. Hemodynamic Data
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Table 2. Gas Exchange Data
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Table 2. Gas Exchange Data
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