Beneficial Effects of Inhaled Nitric Oxide in Adult Cardiac Surgical Patients

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1 Beneficial Effects of Inhaled Nitric Oxide in Adult Cardiac Surgical Patients Thomas S. Maxey, MD, Christopher D. Smith, MBBS, FRACS, John A. Kern, MD, Curtis G. Tribble, MD, David R. Jones, MD, Irving L. Kron, MD, and Ivan K. Crosby, MBBS, FRCS Division of Thoracic and Cardiovascular Surgery, Department of Surgery, University of Virginia Health Care System, Charlottesville, Virginia Background. Pulmonary hypertension with associated right ventricular dysfunction may complicate the postoperative cardiac patient despite maximum pharmacologic and ventilatory support. The purpose of this study was to retrospectively review our experience with inhaled nitric oxide (INO) in adult postoperative cardiac patients with pulmonary hypertension. Methods. We retrospectively reviewed the medical records of 17 adult cardiac patients treated with INO postoperatively between November 1998 and February The INO was used to manage pulmonary hypertension postoperatively in patients who had undergone coronary artery bypass graft (CABG) (n 13), valve operation (n 3), and combined CABG/aortic valve replacement (n 1). Hemodynamic and respiratory measurements before INO and again 6 hours after administration were examined. Student s t test was used to analyze the data. Presented at the Forty-seventh Annual Meeting of the Southern Thoracic Surgical Association, Marco Island, FL, Nov 9 11, Address reprint requests to Dr Crosby, Division of Thoracic and Cardiovascular Surgery, Department of Surgery, Box , University of Virginia Health System, Charlottesville, VA 22908; ikc2n@ virginia.edu. Results. Inhaled nitric oxide (20 ppm to 30 ppm) was administered for a median duration of 30.2 hours. The group, as a whole, demonstrated a significant decrease in both mean pulmonary artery pressure and right ventricular stroke work index. In addition, a significant increase in posttherapeutic cardiac index and PaO 2 /FiO 2 ratio was observed. The vasodilatory effects of nitric oxide were specific to the pulmonary circulation as no significant change in mean arterial pressure was noted. Overall mortality was 6%. Conclusions. Inhaled nitric oxide effectively and selectively lowered right ventricular afterload and right ventricular work in critically ill adult cardiac patients with acute pulmonary hypertension. (Ann Thorac Surg 2002;73:529 33) 2002 by The Society of Thoracic Surgeons Right ventricular contractile function has been previously considered unimportant for maintenance of pulmonary blood flow and cardiac output. The concept of the dispensable right ventricle, [1] however, is not applicable in the presence of pulmonary hypertension or left heart failure. The use of intravenous vasodilators may improve right ventricular function; however, the systemic hypotension associated with them may further impair myocardial perfusion and ventricular function. Use of inhaled nitric oxide (INO) to manage acute pulmonary hypertension was described by Fratacci and colleagues [2] in an animal model. Since then, several investigative studies have evaluated the role of INO in pulmonary hypertension associated with adult respiratory distress syndrome (ARDS), persistent pulmonary hypertension of the newborn, chronic obstructive pulmonary disease, and coronary artery bypass grafting [3 6]. Inhaled nitric oxide is a potent dilator of pulmonary vessels. After inhalation into the alveolus, NO produces smooth muscle relaxation by increasing intracellular levels of cgmp within the pulmonary vascular smooth muscle. As the NO further diffuses into the vessel lumen, it is bound to and inactivated by hemoglobin. The bound hemoglobin is converted to methemoglobin and further reduced to nitrates and nitrites. The vasodilatory effects of INO are, therefore, localized to the pulmonary vasculatuar and are short lived, because the half-life of cgmp is less than 1 minute. This allows the near immediate cessation of INO effects when NO is removed from the circuit [7, 8]. We hypothesized that INO could improve pulmonary hypertension and lead to overall improved cardiac function in cardiac surgical patients. Thus, the purpose of this study was to evaluate the hemodynamic effects of INO in adult cardiac surgery patients. Material and Methods We retrospectively reviewed the medical records of surgical patients who received INO during their postoperative course during a 16-month period at the University of Virginia Health Science Center. The therapeutic application of INO in this setting was to manage acute pulmonary hypertension and right heart dysfunction. All study patients had coronary or valvular disease. The indication for INO therapy in all patients was acute pulmonary 2002 by The Society of Thoracic Surgeons /02/$22.00 Published by Elsevier Science Inc PII S (01)

2 530 MAXEY ET AL Ann Thorac Surg INO IN CARDIAC SURGERY PATIENTS 2002;73: arterial hypertension (defined as mean pulmonary artery pressure [MPAP] of higher than 25 mm Hg) and associated ventricular dysfunction with or without associated hypoxia. Transesophageal echocardiogram was used to quantify right ventricular dysfunction before initiating INO therapy. An attending cardiac surgeon made all the clinical and therapeutic decisions and was involved in all aspects of care throughout the treatment period. Written consent for nonapproved use of INO was obtained in all cases. The delivery of INO to the patients in this study was accomplished using the INOvent delivery system for NO therapy (INO Therapeutics, Inc, Clinton, NJ) [7]. The system incorporates a dual channel design consisting of both a delivery and monitoring component. The delivery component uses an injector module responsible for maintaining a constant concentration of NO in the inspiratory limb of the breathing circuit. The monitoring component uses a gas sampling system connected to gas-measuring cells that allows the continuous monitoring of NO, NO 2, and O 2 from the patient s inspiratory gas flow. The system was calibrated and maintained following the recommendations of the manufacturer and used with gas cylinders containing 800 parts per million (ppm) of NO. The injector module of the INOvent delivery system was placed at the proximal end of the inspiratory limb of the breathing circuit, and a gas-sampling line was placed at the distal end of the inspiratory circuit. Adjustments were made to the Fio 2 delivery system to account for the dilutional effect of the nitric oxide on the inspired gas. The starting dose of INO in all patients was 20 ppm. The dose of INO was then titrated accordingly to maintain normal pulmonary artery pressures. Patients remained on INO therapy until their hemodynamic status improved; at that time, they were slowly weaned from therapy. In some patients INO had to be readministered secondary to refractory pulmonary hypertension after therapy ended. Hemodynamic measurements [MPAP, right ventricular stroke work index (RVSWI), mean arterial pressure, cardiac index, and the Pao 2 /Fio 2 ratio] were collected before the initiation of INO. These data were then compared with the same hemodynamic measurements 6 hours after the start of therapy. These two data sets were then analyzed by a Student s t test, with a p value of less than 0.05 considered statistically significant. Results This cohort included 17 patients whose demographics are listed in Table 1. Thirteen patients received coronary revascularization; 3 patients had valve replacements (one aortic valve replacement, two mitral valve replacements); and 1 patient had a combined coronary revascularization and aortic valve replacement. All patients were placed on cardiopulmonary bypass. The dose of INO in all but 2 patients was started and maintained at 20 ppm. One patient was immediately weaned to a dose of 10 ppm, and the other was increased to 30 ppm shortly after Table 1. Patient Demographics Variable therapy started. The mean duration of therapy was 30.2 hours (range 6 to 92 hours). Administration of INO resulted in a significant reduction in MPAP in all patients, with a mean reduction from 35.3 mm Hg before INO to 22.7 mm Hg after administration (p 0.001). Similarly, 16 of the 17 study patients had significant reductions in RVSWI. The mean reduction was from 6.0 to 3.1 g beat 1 m 2 (p 0.005) with INO therapy. Despite the reduction in pulmonary afterload and improved right ventricular function, the mean arterial pressure increased in 12 patients, stayed the same in 1 patient, and decreased slightly in 4 patients. The increase in the mean arterial pressure for the whole group did not reach statistical significance. Although we expected INO to affect primarily pulmonary circulation, an analysis of the group showed an improvement in the left ventricular function, with an increase in the cardiac index from a mean of 2.3 L min 1 m 2 pre-ino infusion to 3.1 L min 1 m 2 postinfusion (p 0.012). This increase in cardiac index was present for the entire group and the coronary bypass cohort, but was not increased significantly in the valve cohort. Figure 1 shows hemodynamic measurements before and 6 hours after INO therapy. The effect of INO infusion on arterial oxygenation was quantified using the Pao 2 /Fio 2 ratio. For the entire cohort, the ratio increased significantly from 183 to 254 (p 0.04). Although the coronary bypass and valve cohorts each demonstrated increased Pao 2 /Fio 2 ratios, neither reached statistical significance. Mean methemoglobin concentration was 1.9% before INO administration and remained unchanged throughout the treatment course. Mortality Sixteen of 17 patients (94.1%) survived to hospital discharge. The single death occurred in a coronary bypass patient who underwent emergent revascularization for a high-grade left main coronary lesion. This death occurred 10 hours postoperatively, despite maximal pharmacologic support. Cost The average duration of INO therapy was 30.2 hours, and the average cost for the medication was US$6,417 (range US$3,000 to US$15,000). Comment Value Mean age (years) 64 Male-Female ratio 1.9:1 Mean preoperative LVEF 35% Urgent or emergent 6/17 (35.3%) LVEF left ventricular ejection fraction. Adult cardiac patients may develop right ventricular dysfunction for various reasons during the perioperative period. In the absence of pulmonary hypertension or left

3 Ann Thorac Surg MAXEY ET AL 2002;73: INO IN CARDIAC SURGERY PATIENTS 531 Fig 1. Hemodynamic effects of inhaled nitric oxide (INO) before and 6 hours after initiation of therapy. Mean pulmonary artery pressure (PAP, p 0.01); right ventricular stroke work index (RVSWI, p 0.01); mean arterial pressure (MAP, p 0.24); cardiac index (p 0.05); Pao 2 /Fio 2 ratio (p 0.05). ventricular dysfunction, this change may not cause important hemodynamic compromise. In the setting of elevated right ventricular afterload or coexisting left ventricular dysfunction, the right ventricle may be unable to generate the required stroke volume to achieve adequate pulmonary flow. Diminished pulmonary flow subsequently leads to a lower preload and decreased cardiac output [9]. The hemodynamic implications of right ventricular dysfunction depend not only on the degree of myocardial contractile dysfunction but also on the loading conditions imposed on the right ventricle. Pulmonary vascular resistance is the primary determinant of right ventricular afterload; thus, reducing pulmonary resistance may improve right ventricular performance. Intravenous pharmacologic agents such as nitroglycerin, sodium nitroprusside, dobutamine, and milrinone all produce pulmonary vasodilation. Use of these agents, however, may be limited by systemic vasodilation and hypotension. Furthermore, these agents produce pulmonary vasodilation to both the ventilated and nonventilated alveoli leading to an increased shunt fraction. Clinical use of INO has been reported predominantly in neonates with persistent pulmonary hypertension and hypoxic respiratory failure [4]. In that population, INO has been shown to reduce the need for extracorporeal membrane oxygenation [10]. In adults, INO has been used to manage ARDS; however, the application of INO remains controversial and has not been shown conclusively to afford improved outcome [11]. In adult patients undergoing cardiac operation, INO has been reported to manage early right ventricular dysfunction after heart transplant [12] and other cardiothoracic operation procedures [13 17]. We used INO in a subset of cardiac operation patients who exhibited pulmonary hypertension (MPAP higher than 25 mm Hg) and evidence, by transesophageal echocardiogram, of right ventricular dysfunction. All patients were on moderate to maximum amounts of inotropic support and vasodilatory agents when systemically tolerated. Administration of INO in our series significantly reduced right ventricular afterload, with a 36% reduction in MPAP in all patients. These reductions translated into significantly reduced RVSWI in the coronary artery bypass grafting subgroup, but not in the valvular diseased patients. A similar response, in mitral valve replacements, was noted by Girard and colleagues [18], who attributed an attenuated response with INO to structural remodeling secondary to chronic pulmonary hypertension. It has been suggested that some of the vasodilatory effects of INO relate to improved concurrent hypoxia. In fact, much of the data regarding INO are obtained from hypoxic patients. However, INO has been shown to reduce pulmonary vascular resistance in patients with normal arterial oxygenation [19]. Our data support these findings, as most of our patients were not hypoxic, per se, but did have significant increases in the Pao 2 /Fio 2 ratio (182 to 253, p 0.03). This finding can possibly be explained by improvements in ventilation-perfusion matching. These findings were less dramatic and not significant in the valve subgroup; however, oxygenation improved in all patients in this population. Concerns have been expressed that INO may cause myocardial depression. Acute pulmonary edema has been described with the use of INO [20]. Fullerton and colleagues [19] found that in patients with normal ventricular function the use of INO resulted in unchanged cardiac output. Other investigators have described improvements in right heart function and cardiac output in unstable patients with commencement of INO [13, 14]. Hare and colleagues [21] described this phenomenon as an increase in left heart preload secondary to improved pulmonary arterial resistance. Our series demonstrated a significant increase in cardiac index (2.3 to 3.1 L min 1

4 532 MAXEY ET AL Ann Thorac Surg INO IN CARDIAC SURGERY PATIENTS 2002;73: m 2, p 0.01). Although our data do suggest a statistically significant increase in cardiac index related to INO, no hard conclusions can be drawn, as all patients in this cohort were on some degree of inotropic support, which could account for these differences. There was, however, a trend to require less inotropic support once INO was administered, suggesting that improved pulmonary pressures positively influenced left ventricular dysfunction. The cost of INO therapy is considerable. Hospital storage of the delivery system alone is $3,000 per month. In addition, the cost of administering the drug is $3,000 for the first day, followed by $125 per hour until the end of therapy [7]. Outcome benefit was not an end point of this investigation, thus no related conclusions can be drawn from our data. The critical nature of the patients in this series is commonly seen in large university settings. Six of the 17 (35.3%) patients required emergent or urgent operations. Our review did not involve a control group of similarly ill patients with pulmonary hypertension who were not managed with INO therapy. Further prospective investigation into outcome benefits in this setting is warranted. Inhaled nitric oxide is an effective pulmonary vasodilator and its administration may be particularly beneficial in patients with right ventricular dysfunction. The therapy, however, is expensive both in set-up and delivery cost. Similar benefits have been identified with another selective pulmonary vasodilator, inhaled iloprost (prostacyclin analogue) in patients with primary pulmonary hypertension [22]. Further comparison of these two agents is warranted, assessing cost and effectiveness of use in cardiac surgical patients. References 1. Sade RM, CasteZeda AR. The dispensable right ventricle. Surgery 1975;77: Fratacci MD, Frostell CG, Chen TY, et al. Inhaled nitric oxide. A selective pulmonary vasodilator of heparin protamine vasoconstriction in sheep. Anesthesiology 1991;75: Rossaint R, Falke K, Lopez F, Slama K, Pison U, Zapol WM. Inhaled nitric oxide for the adult respiratory distress syndrome. N Engl J Med 1993;328: Kinsella JP, Neish SR, Shaffer E, Abman SH. Low-dose inhalational nitric oxide in persistent pulmonary hypertension of the newborn. Lancet 1992;340: Pepke-Zaba J, Higenbottam TW, Dinh-Xuan AT, Stone D, Wallwork J. Inhaled nitric oxide as a cause of selective pulmonary vasodilation in pulmonary hypertension. Lancet 1991;338: Fullerton DA, Jaggers J, Piedalue F, Grover FL, MacIntyre RC. Effective control of refractory pulmonary hypertension after cardiac operations. J Thorac Cardiovasc Surg 1997;113: INOmax (nitric oxide) for inhalation [package insert]. Clinton, NJ: INO Therapeutics, Inc; January Steudel W, Hurford WE, Zapol WM. Inhaled nitric oxide: basic biology and clinical applications. Anesthesiology 1999; 91: Morris JJ, Wechsler AS. Right ventricular performance and protection. Cardiac Surgery: State of the Art Reviews 1988;2: Hoffman GM, Ross GA, Day SE, Rice TB, Nelin LD. Inhaled nitric oxide reduces the utilization of extracorporeal membrane oxygenation in persistent pulmonary hypertension of the newborn. Crit Care Med 1997;25: Ferreira E, Shalansky SJ. Nitric oxide for ARDS what is the evidence? Pharmacotherapy 1999;19: Carrier M, Blaise G, Belisle S, et al. Nitric oxide inhalation in the treatment of primary graft failure after heart transplantation. J Heart Lung Transplant 1999;18: Bhorade S, Christenson J, O Connor M, Lavoie A, Pohlman A, Hall JB. Response to inhaled nitric oxide in patients with acute right heart syndrome. Am J Respir Crit Care Med 1999; 159: Bender KA, Alexander JA, Enos JM, Skimming JW. Effects of inhaled nitric oxide in patients with hypoxemia and pulmonary hypertension after cardiac surgery. Am J Crit Care 1997; 6: MacDonald PS, Keogh A, Mundy J, et al. Adjunctive use of inhaled nitric oxide during implantation of a left ventricular assist device. J Heart Lung Transplant 1998;17: Wagner F, Dandel M, Gunther G, et al. Nitric oxide inhalation in the treatment of right ventricular dysfunction after left ventricular assist device implantation. Circulation 1997; 96(Suppl):II Kemming GI, Merkel MJ, Schallerer A, et al. Inhaled nitric oxide (NO) for the treatment of early allograft failure after lung transplantation. Munich Lung Transplant Group Intensive Care Med 1998;24: Girard C, Lehot J-J, Pannetier JC, Filley S, Ffrench P, Estanove S. Nitric oxide after mitral valve replacement in patients with chronic pulmonary artery hypertension. Anesthesiology 1992;77: Fullerton DA, Jones SD, Jaggers J, Piedalue RRT, Grover FL, McIntyre RC Jr. Effective control of pulmonary vascular resistance with inhaled nitric oxide after cardiac operation. J Thorac Cardiovasc Surg 1996;111: Bocchi EA, Bacal F, Auler JO, de Carvalho MJ, Bellotti G, Pileggi F. Inhaled nitric oxide leading to pulmonary edema in stable severe heart failure. Am J Cardiol 1994;74: Hare JM, Shernan SK, Body SC, Graydon E, Colucci WS, Couper GS. Influence of inhaled nitric oxide on systemic flow and ventricular filling pressure in patients receiving mechanical circulatory assistance. Circulation 1997;95: Hoeper MM, Olscewski H, Ghofrani HA, et al. A comparison of the acute hemodynamic effects of inhaled nitric oxide and aerosolized iloprost in primary pulmonary hypertension. German PPH study group. J Am Coll Cardiol 2000;35: DISCUSSION DR FREDERICK L. GROVER (Denver, CO): Dave Fullerton presented a paper at this meeting several years ago about a prospective study he did in the operating room examining the effect of nitric oxide on patients who, after cardiopulmonary bypass had an MPAP of more than 30 mm Hg. He found a significant decrease in the pulmonary artery pressure and pulmonary vascular resistance in patients who had undergone coronary bypass grafting but no improvement in these measurements in patients who had undergone valvular procedures. Have you looked at the difference in response in your coronary group versus your valvular group? DR CROSBY: We did. Some individual patients in all the different subgroups did not seem to benefit from INO therapy.

5 Ann Thorac Surg MAXEY ET AL 2002;73: INO IN CARDIAC SURGERY PATIENTS 533 Generally speaking, however, the valvular patients did have a good reduction, as did many of the coronary patients. But we had only 6 valvular patients. DR CHRISTOPHER J. KNOTT-CRAIG (Oklahoma City, OK): I may be a little confused. If you take patients with right ventricular dysfunction and poor cardiac output and you give them a medication, in your case INO, and you see no difference in the cardiac index afterwards, how do you know that you have done any good apart from lowering the pulmonary artery pressure? Usually if you lower the pulmonary vascular resistance, you are trying to achieve a better cardiac output. If cardiac output or cardiac index does not change, how do you know that the INO made any difference at all? DR CROSBY: That is an interesting question. I think many of the patients did not have poor cardiac output. We were dealing with high pressures, pulmonary artery, and what we were trying to do was to lower those pressures. This was demonstrated nicely in the 3 patients who had left ventricular assist device insertion, in whom the cardiac output was okay, but the pulmonary vascular resistance was high. DR AHMED M. F. EL-WATIDY (Tabuk, Saudi Arabia): What was your definition of right ventricular dysfunction in this study and how did you diagnose it? My second question is about a subcategory of patients. There were 9 CABG patients who received NO. What was the reason for their right ventricular dysfunction and how did they respond to the NO? DR CROSBY: Thank you for your questions. Our definition of right ventricular dysfunction was pulmonary artery hypertension and high right-sided pressures. In the acute setting in the operating room, this condition was fairly obvious, and precipitated the trial of INO when other measures failed. In the coronary artery patients, if I understand your question correctly, sometimes the cause of the right ventricular hypertension was unknown, but it was dealt with in the same way. So I cannot say there was a common theme in the coronary patients.