In newborns with a functional single ventricle and

Transcription

1 Pulmonary Vascular Resistance of Children Treated With Nitrogen During Early Infancy Ronald W. Day, MD, Alan J. Barton, MD, Theodore J. Pysher, MD, and Robert E. Shaddy, MD Division of Pediatric Cardiology, Primary Children s Medical Center, University of Utah, Salt Lake City, Utah Background. We have empirically used supplemental nitrogen in newborns with a functional single ventricle and ductal-dependent systemic perfusion to prevent pulmonary vasodilation and deliver a greater proportion of flow to the systemic circulation. Thus, we reviewed patient outcome to determine whether adverse pulmonary vascular effects may be associated with this therapy. Methods. From December 1991 to December 1995, the fraction of inspired oxygen was adjusted, with supplemental nitrogen if necessary, to maintain an oxygen saturation near 75% in 20 newborns awaiting heart transplantation. Medical records were reviewed to evaluate (1) the duration of nitrogen therapy, (2) pulmonary vascular histology, (3) postoperative pulmonary hemodynamics, and (4) survival. Results. Thirteen patients underwent heart transplantation, 4 patients died without surgical intervention, and 3 patients underwent late aortic reconstruction. Supplemental nitrogen was used without exceeding a fraction of inspired oxygen of 0.21 for 38 6 days. One patient had evidence of changes of potentially irreversible pulmonary vascular disease. Pulmonary vascular resistance was not increased long-term in surviving patients. Conclusions. Supplemental nitrogen can be used to maintain a systemic oxygen saturation near 75% for an extended period in newborns with ductal-dependent systemic perfusion with no long-term adverse effect on pulmonary vascular resistance. (Ann Thorac Surg 1998;65:1400 4) 1998 by The Society of Thoracic Surgeons In newborns with a functional single ventricle and severe systemic outlet obstruction, the ductus arteriosus must remain patent to maintain systemic perfusion. Regional differences in vascular resistance then determine how the cardiac output is distributed between the lung and other vital organs. Oxygen and lung distention decrease pulmonary vascular resistance after birth [1]. This increases ventricular volume and decreases the proportion of flow to the systemic circulation. Supplemental nitrogen and carbon dioxide acutely increase pulmonary vascular resistance and decrease the pulmonary systemic blood flow ratio [2 5]. At several neonatal transplant centers, the fraction of inspired oxygen is adjusted, with nitrogen if necessary, to maintain a systemic oxygen saturation near 75% in newborns with a functional single ventricle [6]. Unfortunately, pulmonary hypertension and medial hypertrophy develop after several days of sustained hypoxia in young animals [7, 8]. Thus, we reviewed the outcome of our patients to determine whether sustained alveolar hypoxia had an adverse effect on the pulmonary vascular histology, pulmonary hemodynamics, and survival of newborns awaiting heart transplantation. Accepted for publication Dec 31, Address reprint requests to Dr Day, Division of Pediatric Cardiology, Primary Children s Medical Center, 100 North Medical Dr, Salt Lake City, UT ( ron.day@hsc.utah.edu). Material and Methods This retrospective study was approved by the Research and Human Subjects Committee of Primary Children s Medical Center. From December 1991 to December 1995, 49 newborns were admitted to Primary Children s Medical Center with a functional single ventricle and ductal-dependent systemic perfusion. The parents of 20 patients elected an option for heart transplantation. All patients were treated with 0.02 to 0.1 g kg 1 min 1 prostaglandin E 1 to maintain a patent ductus arteriosus. All patients were predominantly supported with enteral nutrition. Digoxin and diuretics were used according to the judgment of the attending cardiologist. The fraction of inspired oxygen was adjusted to maintain oxygen saturations near 75% by pulse oximetry until the time of surgical intervention or death. If needed, supplemental nitrogen was delivered into the flow of inspired gas by mechanical ventilation, nasal cannula, or head box. The hematocrit was maintained greater than 40% by recombinant erythropoietin therapy or blood transfusion. Balloon atrial septostomy was performed if patients experienced pulmonary edema or required a high fraction of inspired oxygen secondary to left atrial hypertension by The Society of Thoracic Surgeons /98/$19.00 Published by Elsevier Science Inc PII S (98)

2 Ann Thorac Surg DAY ET AL 1998;65: PVR AFTER NITROGEN THERAPY 1401 Table 1. Patient Characteristics Patient Diagnosis Days of Therapy N 2 N 2 /O 2 O 2 Histologic Changes PVR at 3 mo (Wood units) Outcome (age at death, days) 1 HLHS None Transplant, early death (34) 2 HLHS Transplant 3 TA, TGA, CoA Medial 2.31 Transplant 4 HLHS Transplant 5 HLHS Transplant 6 HLHS Transplant 7 HLHS Transplant 8 DILV, CoA Transplant, late death (490) 9 HLHS Medial and intimal Transplant, early death (28) 10 HLHS Transplant, late death (882) 11 HLHS Medial Transplant, late death (104) 12 HLHS Transplant 13 HLHS Medial, intimal, Transplant, early death (164) and occlusive 14 HLHS Aortic reconstruction, transplant, late death (550) 15 HLHS Medial 3.70 Aortic reconstruction 16 HLHS Medial Aortic reconstruction, early death (109) 17 l-tga Death before transplant (24) Aortic atresia 18 HLHS Medial Death before transplant (97) 19 HLHS Medial Death before transplant (55) 20 HLHS Medial Death before transplant (86) CoA coarctation of the aorta; DILV double-inlet left ventricle; HLHS hypoplastic left heart syndrome; Intimal intimal hyperplasia; Medial medial hypertrophy or extension of muscle into distal vessels; N 2 supplemental nitrogen without an inspired oxygen fraction 0.21; N 2 /O 2 an inspired oxygen fraction of 0.21 exclusively or alternating periods of supplemental nitrogen and supplemental oxygen; O 2 supplemental oxygen without an inspired oxygen fraction 0.21; Occlusive arteriolar occlusion; PVR pulmonary vascular resistance; TA tricuspid atresia; TGA transposition of the great arteries. Data Collection Medical records were reviewed to determine (1) age at the time of surgical intervention or death, (2) duration of therapy with supplemental nitrogen, (3) pulmonary vascular histology, (4) postoperative pulmonary hemodynamics, and (5) survival. The lung histology of 10 patients was reviewed by a pathologist who was unaware of the duration of supplemental nitrogen therapy. Unfortunately, the indications for lung biopsy were not well-defined. Lung tissue was obtained from 9 patients at the time of transplantation, initial palliation, or death before intervention. Lung tissue was obtained from an additional patient at the time of death 24 days after transplantation. Lung biopsy or autopsy tissue was immersed in 10% neutral buffered formalin without inflation, processed into paraffin, and stained with hematoxylin and eosin and Masson trichrome stains. Pulmonary vascular resistance and the ratio of pulmonary to systemic vascular resistance were initially determined by heart catheterization and the Fick method approximately 3 months after the operation. Hemodynamic measurements were repeated 1 year postoperatively and at 1-year intervals thereafter. Pulmonary vascular resistance was generally not evaluated before, or immediately after, surgical intervention. Statistical Analysis Numeric values are expressed as mean standard error of the mean. Serial hemodynamic measurements were compared by analysis of variance for repeated measures, and categorical comparisons were evaluated by factorial analysis of variance (Statview II, Abacus Concepts, Berkeley, CA). Significant results were determined by p less than or equal to 0.05 using a Scheffé F test. Potential correlations between preoperative factors and outcome measures were evaluated by linear regression analysis. Results The diagnosis of each patient is listed in Table 1. The majority of patients had a form of hypoplastic left heart syndrome. were transferred to Primary Children s Medical Center at an age of 3 1 days. Thirteen patients underwent heart transplantation at an age of days. Four patients died without surgical intervention at an age of days. Three patients

3 1402 DAY ET AL Ann Thorac Surg PVR AFTER NITROGEN THERAPY 1998;65: Five patients underwent balloon atrial septostomy or balloon dilation of the foramen ovale to alleviate left atrial hypertension associated with pulmonary edema or a high oxygen requirement. In 1 patient, left atrial hypertension and a high oxygen requirement persisted despite several attempts at balloon atrial septostomy and balloon dilation of the foramen ovale. Fig 1. Pulmonary vascular histology. An increase in medial thickness is present in pulmonary arterioles near the level of a respiratory bronchiolus. (Hematoxylin and eosin; original magnification, 100.) underwent aortic reconstruction and a systemic pulmonary shunt at an age of days after losing hope for eventual transplantation. One of these patients subsequently underwent heart transplantation 12 months thereafter. gained an average of 8 3 g of weight per day from the date of admission to the date of surgical intervention or death. No patient had clinical evidence of necrotizing enterocolitis. Table 1 lists the number of days that patients received (1) supplemental nitrogen without increasing the fraction of inspired oxygen more than 0.21 (mean, 38 6 days); (2) a fraction of inspired oxygen of 0.21 exclusively, or alternating periods of supplemental nitrogen and supplemental oxygen (mean, 14 3 days); or (3) supplemental oxygen without decreasing the fraction of inspired oxygen less than 0.21 (mean, 16 5 days). were supported by mechanical ventilation for 15 4 days and were extubated for 54 8 days. Eight patients received recombinant erythropoietin therapy. Pulmonary Vascular Histology and Hemodynamics The changes in pulmonary vascular histology are described in Table 1 for the 10 patients who underwent lung biopsy or autopsy. Figure 1 shows evidence of medial hypertrophy in the distal arterioles of patient 13. Areas of intimal hyperplasia and arteriolar occlusion were also identified in this patient with persistent left atrial hypertension who was treated predominantly with supplemental oxygen including a 5- to 6-week period of mechanical ventilation with a fraction of inspired oxygen of 1.0. The degree of medial hypertrophy was less severe in other patients. Serial measurements of pulmonary vascular resistance for each surviving patient are shown in Figure 2. Approximately 3 months after surgical intervention, the mean pulmonary vascular resistance ( Wood units) and the mean ratio of pulmonary to systemic vascular resistance ( ) were only mildly increased. With time, there was a trend toward normal pulmonary vascular resistance. However, there were no significant differences between serial measurements. There were only weak correlations between initial values of pulmonary vascular resistance 3 months after surgical intervention and the duration of supplemental nitrogen (r ; p 0.04) and age at the time of the operation (r ; p 0.06). There were no significant correlations between subsequent measurements of pulmonary vascular resistance and the duration of supplemental nitrogen. Postoperative measurements of pulmonary vascular resistance were not influenced by the duration of mechanical ventilation, preoperative erythropoietin therapy, or a history of left atrial hypertension requiring balloon atrial septostomy. Fig 2. Serial measurements of pulmonary vascular resistance. The individual (A) and mean (B) serial measurements of pulmonary vascular resistance (PVR) are illustrated for surviving patients. Pulmonary vascular resistance is mildly increased 3 months after transplantation; however, there is a trend toward normal PVR thereafter. Hemodynamic measurements were performed at months (n 11), months (n 10), months (n 7), months (n 6), months (n 3), and 60 months (n 1). (Wood units mm Hg min m 2 /L.)

4 Ann Thorac Surg DAY ET AL 1998;65: PVR AFTER NITROGEN THERAPY 1403 Mortality There have been 12 deaths. Patient 13 died of right heart failure secondary to pulmonary hypertension. Of note, this is the same patient who had histologic evidence of advanced pulmonary vascular disease. Two patients could not be weaned from cardiopulmonary bypass after transplantation as a result of acute graft failure. One patient could not be weaned from cardiopulmonary bypass after aortic reconstruction as a result of global heart dysfunction. Four patients died before a suitable donor was available. Death was attributed to sepsis in 2 patients, refractory heart failure secondary to severe tricuspid valve regurgitation in 1 patient, and a restrictive ductus arteriosus in 1 patient. An autopsy was performed on 3 of these 4 patients. Lung histology identified changes of medial hypertrophy that were similar to the vascular changes in patients who underwent transplantation or late palliation. Four patients died of allograft rejection 24 days to 27 months after transplantation. One of these patients underwent transplantation after initial palliation by aortic reconstruction. Comment In neonatal transplantation candidates, consistent levels of hypoxemia were maintained by adjusting the fraction of inspired oxygen. Extended periods of alveolar hypoxia were required to maintain systemic oxygen saturations near 75% in many patients. Pulmonary hypertension was a factor in one early death; however, there were no long-term, adverse effects of nitrogen therapy on pulmonary vascular resistance. All patients had a functional single ventricle with ductaldependent systemic perfusion and were listed during the neonatal period as candidates for heart transplantation. Unfortunately, an average of 2 months passed before patients died or an appropriate donor was identified. Three patients underwent late aortic reconstruction. Our patients had similar cardiac defects. However, we have not studied enough patients to determine whether differences in gestational age, preoperative left atrial pressure, postoperative medications, the degree of allograft rejection, or other patient characteristics may influence postoperative hemodynamics and survival. A patent ductus arteriosus was maintained in all patients by a continuous infusion of prostaglandin E 1.Itisnot known whether prostaglandin E 1 had a greater vasodilatory effect on the pulmonary or the systemic vascular beds. The fraction of inspired oxygen was adjusted to maintain a systemic oxygen saturation near 75% by continuous pulse oximetry. The actual fraction of inspired oxygen was unknown when nitrogen was delivered in air by nasal cannula, particularly as patients matured and developed an increase in oral breathing. Newborns with a functional single ventricle require a long-term method of controlling the distribution of flow to the pulmonary and systemic vascular beds before transplantation. Carbon dioxide can be used to increase pulmonary vascular tone [2 5]. However, compensatory changes may limit pulmonary vasoconstriction by normalizing blood ph and carbon dioxide tension unless ventilation is controlled. By decreasing the alveolar oxygen, supplemental nitrogen offers a simple method of increasing pulmonary vascular resistance without assisted ventilation or frequent blood gas measurements. Nonetheless, arterial oxygenation should be evaluated periodically to confirm the accuracy of pulse oximetry. Animal models of single ventricle pathophysiology provide support that supplemental nitrogen increases pulmonary vascular resistance, increases the relative distribution of flow to the systemic circulation, and decreases the ventricular volume load [3 5]. Riordan and associates [9] have also shown that oxygen delivery is generally optimal when flow is distributed equally between the pulmonary and systemic circulations. Optimal oxygen delivery corresponded with a systemic arterial oxygen saturation near 75% to 80% in their study. However, they recommend that the venous oxygen saturation also be used to determine the optimal pulmonary to systemic blood flow ratio. In newborns with ductal-dependent systemic perfusion, we have previously used Doppler ultrasonography to show that supplemental nitrogen acutely decreases diastolic flow reversal in the descending aorta [10]. This noninvasive finding suggests that supplemental nitrogen may improve the distribution of flow to the systemic circulation. However, controlled studies have not been performed in humans to determine whether maintaining an oxygen saturation of 75% with supplemental nitrogen decreases morbidity and mortality during the preoperative period. Necrotizing enterocolitis has been observed in patients with hypoplastic left heart syndrome before and after palliation by aortic reconstruction and a systemic pulmonary shunt [11]. Our patients tolerated enteral feedings and gained weight without this complication despite sustained hypoxemia. It is possible that bowel perfusion and oxygen delivery are improved by increasing pulmonary vascular resistance and decreasing diastolic flow reversal in the systemic circulation. Pulmonary Vascular Histology and Hemodynamics In normal newborns, preacinar arteries are muscular and initially thick-walled [12]. Within 4 months, the muscular thickness of these vessels decreases and smooth muscle extends into the acinar arteries [12]. In children with congenital heart disease and pulmonary hypertension, a lack of normal muscular regression or an increase in muscular hypertrophy and peripheral extension may be observed [13, 14]. Thus, it is not surprising that histologic changes consistent with mild pulmonary vascular disease were seen in several of our patients. However, the lung vessels of our patients were not distended at uniform pressures at the time of fixation and a detailed morphometric analysis was not performed. Further, a larger

5 1404 DAY ET AL Ann Thorac Surg PVR AFTER NITROGEN THERAPY 1998;65: study is needed to identify or exclude significant correlations between histologic findings, pulmonary hemodynamics, and survival. Pulmonary vascular disease may result from chronic alveolar hypoxia. Animal models have shown that pulmonary hypertension results from sustained exposure to supplemental nitrogen [7, 8]. Hypoxia causes an increase in medial thickness and abnormal extension of smooth muscle into distal arterioles [7]. In our patients, the potential effects of sustained alveolar hypoxia may have been attenuated by the concurrent use of prostaglandin E 1, which inhibits smooth muscle proliferation [15]. An important distinction between the effects of alveolar hypoxia and hypoxemia may exist. The alveolar oxygen tension has a greater effect on pulmonary vascular resistance than the pulmonary and bronchial arterial oxygen tensions [16, 17]. Alveolar and arterial oxygen tensions are both decreased in most animal models of hypoxia-induced pulmonary hypertension. If pulmonary vascular disease is mediated by pulmonary arterial hypoxemia, patients with a functional single ventricle and ductaldependent systemic perfusion may be at little risk because a pulmonary arterial oxygen saturation of 75% is normal. One patient had histologic evidence of occlusive changes in the pulmonary arterioles and died of right heart failure early after transplantation. This patient had severe pulmonary venous hypertension secondary to a restrictive foramen ovale despite attempts at balloon septostomy and balloon dilation. Further, prolonged hyperoxia and assisted ventilation may have contributed to the pulmonary vascular changes of this patient [18]. The mean pulmonary vascular resistance and ratio of pulmonary to systemic vascular resistance were only mildly elevated in surviving patients 3 months after surgical intervention. There was also a weak correlation between the duration of supplemental nitrogen and baseline pulmonary vascular resistance 3 months after the operation. However, there was a progressive trend toward normal values thereafter. These findings are consistent with animal studies showing that pulmonary hypertension resolves when supplemental nitrogen is withdrawn [19]. Mortality The majority of deaths were not related to right heart failure. Thus, it is unlikely that our use of supplemental nitrogen had an adverse effect on early or late postoperative survival. Conclusions We conclude that supplemental nitrogen can be used to maintain a systemic oxygen saturation near 75% for an extended period in newborns with ductal-dependent systemic perfusion with no long-term adverse effect on pulmonary vascular resistance. Chronic animal models or controlled human studies are needed to determine whether preoperative morbidity and mortality are decreased by carefully adjusting the fraction of inspired oxygen to maintain an optimal balance in perfusion to the pulmonary and systemic circulations. References 1. Teitel DF, Iwamoto HS, Rudolph AM. Changes in the pulmonary circulation during birth-related events. Pediatr Res 1990;27: Jobes DR, Nicolson SC, Steven JM, Miller M, Jacobs ML, Norwood WI. Carbon dioxide prevents pulmonary overcirculation in hypoplastic left heart syndrome. Ann Thorac Surg 1992;54: Mora GA, Pizzaro C, Jacobs ML, Norwood WI. Experimental model of single ventricle. Influence of carbon dioxide on pulmonary vascular dynamics. Circulation 1994;90:II Reddy VM, Liddicoat JR, Fineman JR, McElhinney DB, Klein JR, Hanley FL. Fetal model of single ventricle physiology. Hemodynamic effects of oxygen, nitric oxide, carbon dioxide, and hypoxia in the early postnatal period. J Thorac Cardiovasc Surg 1996;112: Riordan CJ, Randsbaek F, Storey JH, Montgomery WD, Santamore WP, Austin EH. Effects of oxygen, positive endexpiratory pressure, and carbon dioxide on oxygen delivery in an animal model of the univentricular heart. J Thorac Cardiovasc Surg 1996;112: Razzouk AJ, Chinnock RE, Gundry SR, Bailey LL. Cardiac transplantation for infants with hypoplastic left heart syndrome. Prog Pediatr Cardiol 1996;5: Haworth SG, Hislop AA. Effect of hypoxia on adaptation of the pulmonary circulation to extra-uterine life in the pig. Cardiovasc Res 1982;16: Fike CD, Kaplowitz MR. Effect of chronic hypoxia on pulmonary vascular pressures in isolated lungs of newborn pigs. J Appl Physiol 1994;77: Riordan CJ, Randsbaek F, Storey JH, Montgomery WD, Santamore WP, Austin EH. Balancing pulmonary and systemic arterial flows in parallel circulations: the value of monitoring systemic venous oxygen saturations. Cardiol Young 1997;7: Day RW, Tani LY, Minich LL, et al. Congenital heart disease with ductal-dependent systemic perfusion: Doppler ultrasonography flow velocities are altered by changes in the fraction of inspired oxygen. J Heart Lung Transplant 1995;14: Hebra A, Brown MF, Hirschl RB, et al. Mesenteric ischemia in hypoplastic left heart syndrome. J Pediatr Surg 1993;28: islop A, Reid L. Pulmonary arterial development during childhood. Branching pattern and structure. Thorax 1973;28: Heath D, Edwards JE. The pathology of hypertensive pulmonary vascular disease. Circulation 1958;18: Rabinovitch M, Haworth SG, Castañeda AR, Nadas AS, Reid LM. Lung biopsy in congenital heart disease. A morphometric approach to pulmonary vascular disease. Circulation 1978;58: Huttner JJ, Gwebu ET, Panganamala RV, Milo GE, Cornwell DG. Fatty acids and their prostaglandin derivatives: inhibitors of proliferation in aortic smooth muscle cells. Science 1977;197: Marshall C, Marshall B. Site and sensitivity for stimulation of hypoxic pulmonary vasoconstriction. J Appl Physiol 1983;55: Marshall BE, Marshall C, Magno M, Lilagan P, Pietra GG. Influence of bronchial arterial PO 2 on pulmonary vascular resistance. J Appl Physiol 1991;70: Jones R, Zapol WM, Reid L. Pulmonary artery remodeling and pulmonary hypertension after exposure to hyperoxia for 7 days. A morphometric and hemodynamic study. Am J Pathol 1984;117: Abraham AS, Kay JM, Cole RB, Pincock AC. Haemodynamic and pathological study of the effect of chronic hypoxia and subsequent recovery of the heart and pulmonary vasculature of the rat. Cardiovasc Res 1971;5: