Ann Thorac Surg
`1995;60:1791-3
`
`CASE REPORT SHAH ET AL
`NO AND REFRACTORY PULMONARY HYPERTENSION
`
`1791
`
`cations usually develop in newborns or infants [5]. Our
`case demonstrates that bleeding complications due to
`gastric mucosa in an esophageal duplication can occur
`even in the fetal period.
`
`References
`1. Holcomb GW, Gheissaryi A, O'Neill JA, Shorter NA, Bishop
`HC. Surgical management of alimentary tract duplications.
`Ann Surg 1989;209:167-74.
`2. Ware GW, Conrad HA. Thoracic duplication of alimentary
`tract. Am J Surg 1953;86:264-72.
`3. Bissler JJ, Klein RL. Alimentary tract duplications in children.
`Clin Pediatr 1988;27:152-7.
`4. Adzick NS. Fetal thoracic lesions. Semin Pediatr Surg 1993;2:
`103-8.
`5. Macpherson RI, Reed MH, Ferguson CC. Intrathoracic gas-
`trogenic cysts: a cause of lethal pulmonary hemorrhage in
`infants. J Assoc Can Radiol 1973;24:362-9.
`6. Chitale AR. Gastric cyst of the mediastinum. J Pediatr 1969;
`75:104-10.
`7. Burgher DP, Carachi R, Beattie TJ. Foregut duplication cysts
`presenting as neonatal respiratory distress and haemoptysis.
`Thorax 1994;49:287-8.
`8. Page US, Bigelow JC. A mediastinal gastric duplication lead-
`ing to pneumonectomy. J Thorac Cardiovasc Surg 1967;54:
`291-4.
`
`Nitric Oxide Treatment for
`Pulmonary Hypertension After
`Neonatal Cardiac Operation
`Aamir S. Shah, MD, Arthur J. Smerling, MD, Jan M.
`Quaegebeur, MD, and Robert E. Michler, MD
`Division of Cardiothoracic Surgery and Department of
`Anesthesiology, College of Physicians and Surgeons,
`Columbia University, New York, New York
`
`This report describes a newborn with transposition of
`the great arteries who underwent a Blalock-Taussig
`shunt with transient improvement in oxygenation, but
`required emergent insertion of a central shunt later the
`same day due to progressive hypoxia and cardiac arrest.
`Two hours after central shunt insertion, sudden episodes
`of hypoxia and hypotension developed that were resis-
`tant to all pharmocologic therapy. Inhaled nitric oxide (25
`ppm) was then administered with dramatic improvement
`in oxygenation and hemodynamics within minutes. The
`patient's condition stabilized after these measures, and
`nitric oxide therapy was discontinued after 2 days.
`(Ann Thorac Surg 1995;60:1791-3)
`
`p ulmonary hypertension after congenital cardiac op-
`
`erations in pediatric patients is a potentially fatal
`complication [11. Therapy with vasodilators such as pros-
`Accepted for publication May 31, 1995.
`Address reprint requests to Dr Michler, Division of Cardiothoracic
`Surgery, Columbia-Presbyterian Medical Center, 177 Fort Washington
`Ave, New York, NY 10032.
`
`0003-4975195159.50
`SSDI 0003-4975(95)00657-7
`
`Fig 2. Chest roentgenogram taken immediately after birth showing
`the right hemithorax filled by a mass.
`
`caval obstruction or cardiac compression from extreme
`mediastinal shift [4]. Although our fetus had no signs of
`hydrops, he was treated by serial thoracocenteses be-
`cause of the massive mediastinal shift, to prevent pulmo-
`nary hypoplasia. According to the experience of Adzick
`[4], serial thoracocenteses are ineffective because of rapid
`reaccumulation of cyst fluid. Thoracoamniotic shunts
`seem to be more effective, but are difficult to place, can
`lead to premature rupture of membrane, and are prone
`to migration and occlusion [4].
`Esophageal duplications present with different symp-
`toms depending on localization, size, and mucosal char-
`acteristics. Large cysts usually present with respiratory
`distress. Small ones may be found as asymptomatic
`masses on chest roentgenograms. Peptic complications
`can occur if the mucosal lining of the esophageal dupli-
`cation is gastric tissue. This is described in about one
`third of the cases [1]. The acid and pepsin secretions may
`digest the cyst's mucosal lining locally, causing peptic
`ulceration or producing mucosal necrosis. Among 81
`cases of thoracic duplications collected by Ware and
`Conrad [2], peptic ulcers developed in 14, and 5 of these
`cases ended fatally. These ulcers may perforate into
`different organs: esophagus, tracheobronchial tree, and
`pleural space. Perforation into the esophagus causes
`hematemesis or melena [5, 6l. When the cyst ruptures
`into the tracheobronchial tree, hemoptysis becomes the
`prominent symptom [6, 7]. Fatal hemorrhage into the
`bronchial tree has been recorded [5], and partial pulmo-
`nary resection or pneumonectomy has been lifesaving in
`some cases [8]. Rupture into the pleural space causes
`chemical pleurisy, pneumothorax, or empyema ]5].
`Unlike unruptured esophageal duplication cysts,
`which should be easily identifiable mediastinal masses,
`ruptured cysts may be obscured by the adjacent pleural
`and pulmonary disease. The fluid content of the cyst may
`be partially evacuated and replaced by air, thus resem-
`bling a lung or mediastinal abscess [5, 7]. Peptic compli-
`
`© 1995 by The Society of Thoracic Surgeons
`
`Ex. 2026-0001
`
`

`
`1792
`
`SHAH ET AL
`CASE REPORT
`NO AND REFRACTORY PULMONARY HYPERTENSION
`
`Ann Thorac Surg
`1995;60:2791-3
`
`tacyclin is often limited by systemic hypotension. Nitric
`oxide (NO) has been reported to cause selective pulmo-
`nary vasodilation without significant systemic effects
`when administered as an inhalational agent [2-5]. In a
`study of 11 patients with pulmonary hypertension under-
`going cardiac catheterization at our institution (7 with
`idiopathic primary pulmonary hypertension, 4 with as-
`sociated congenital heart disease), both inhaled NO (20
`to 80 ppm) and prostacyclin were found to significantly
`reduce pulmonary arterial pressures [2]. However, unlike
`prostacyclin, which caused a significant reduction in
`mean arterial pressure, NO was not found to have any
`appreciable systemic effects.
`A 3.5-kg full-term male infant with Apgar scores of 8 and
`8 at 1 and 5 minutes was noted to be cyanotic at 2 hours
`of life. The 0 2 saturation (SaO2) was 80% on room air
`with arterial blood gas values as follows: pH, 7.37; carbon
`dioxide
`tension, 39 mm Hg; and oxygen
`tension,
`42 mm Hg. Mechanical ventilation was initiated, and
`transthoracic echocardiography at another institution re-
`vealed transposition of the great arteries. Prostaglandin E
`(0.2
`/xg-kg 1.min 1) and dopamine
`(5 /~g'kg 1
`min 1) were given without significant improvement
`(SaO2, 60% to 70% on an inspired oxygen fraction of 1.0),
`and the patient was transferred to Columbia-Presbyte-
`rian Medical Center for further treatment.
`Echocardiography on arrival revealed transposition of
`the great arteries, subvalvular pulmonary stenosis with a
`40 mm Hg gradient, a large ventricular septal defect,
`good ventricular function, and a patent ductus arteriosus.
`Balloon atrial septostomy with a 5F catheter was success-
`fully performed, with the SaO 2 improving to 84% imme-
`diately after the procedure. A progressive decline in SaO 2
`(SaO2, 68% to 70%) and clinical condition necessitated
`placement of a right modified Blalock-Taussig shunt on
`the second day of life.
`Intraoperative anesthetic management included the
`administration of high doses of fentanyl and ventilation
`with an inspired oxygen fraction of 1.0. The chest was
`entered through a right thoracotomy in the fourth inter-
`costal space. Findings included a right-sided aortic arch,
`and a pulmonary artery of normal size. A 4-rnm thin-
`walled Gore-Tex graft (W. L. Gore & Assoc, Flagstaff, AZ)
`was interposed between the origin of the right subclavian
`artery and the right pulmonary artery. The SaO2 im-
`proved to 85%. The prostaglandin infusion was discon-
`tinued and the patient returned to the intensive care unit.
`Approximately 1 hour postoperatively significant hy-
`poxemia developed with an oxygen tension of 17 mm Hg.
`Prostaglandin E administration was reinstituted with no
`improvement in oxygenation. The Blalock-Taussig shunt
`could not be visualized by echocardiography. The patient
`was taken emergently to the operating suite for place-
`ment of another shunt. Cardiopulmonary arrest devel-
`oped en route, and the patient was placed emergently on
`cardiopulmonary bypass during the arrest.
`A 4-mm Gore-Tex graft was inserted from the right
`posterolateral aorta to the anterior aspect of the pulmo-
`
`nary artery using continuous 7-0 polypropylene suture. A
`small patent ductus arteriosus was ligated. Excellent flow
`was noted in the shunt, but initial attempts to wean the
`patient from cardiopulmonary bypass failed due to low
`0 2 saturations. Therefore, a 5-mm shunt was inserted in
`place of the 4-ram shunt using the same technique. There
`was excellent filling of the pulmonary vessels. Elevated
`pulmonary vascular resistance was suspected and
`treated by high-dose narcotic analgesia with fentanyl,
`sodium bicarbonate to correct an acid-base imbalance,
`and hyperventilation with an inspired oxygen fraction of
`1.0. The patient was eventually weaned with difficulty
`from cardiopulmonary bypass. Despite this large central
`shunt the SaO 2 remained between 70% and 80%.
`The patient was stable for approximately 2 hours
`postoperatively, but then the SaO 2 suddenly dropped to
`less than 30% and was treated with hand ventilation. Two
`additional sudden episodes of severe hypoxia developed,
`followed by bradycardia, hypotension, and near death.
`These hypoxic paroxysms were not temporally related to
`interventions by the physician or nursing staff such as
`repositioning or suctioning, and responded to resuscita-
`tive efforts, which included chest compressions, hand
`ventilation, epinephrine and dobutamine infusions, va-
`sodilator therapy with tolazoline, and alkalinization of
`the blood. After three such paroxysms with marginal
`improvement after resuscitation, the patient remained
`hypotensive (systolic blood pressure, 30 to 40 mm Hg)
`and hypoxic (SaO 2 between 50% and 60%). Echocardiog-
`raphy revealed a right-to-left shunt across the atrial
`septum, moderate tricuspid regurgitation, no pericardial
`fluid collection, and slightly decreased ventricular func-
`tion. The cardiopulmonary deterioration was attributed
`to severe pulmonary hypertension resulting in a right-to-
`left intracardiac shunt. Inhalational NO therapy was
`instituted during the third hypoxic paroxysm at a con-
`centration of 25 ppm via the endotracheal tube. This
`resulted in almost immediate improvement in gas ex-
`change and hemodynamics. The oxygen tension
`in-
`creased to approximately 35 to 40 mm Hg (SaO2, 77% to
`80%) and
`the systolic pressure
`increased
`to 60 to
`65 mm Hg without additional inotropy. The patient's
`condition completely stabilized after NO infusion with-
`out further hypoxic paroxysms, and NO was decreased to
`20 ppm within 2 hours. Both NO and nitrogen dioxide
`(NO2) concentrations were measured continuously by
`chemiluminescence (model 42H; TEI Co, Franklin, MA)
`during inhalational NO therapy. The NO2 concentration
`was measured to be less than 1 ppm throughout the
`treatment period (with the accepted toxic threshold being
`5 ppm) [6]. Nitric oxide was administered as an investi-
`gational new drug under a research protocol approved by
`the Food and Drug Administration. Informed consent
`was obtained from the child's parents before initiation of
`NO therapy.
`The patient remained hemodynamically stable, and
`NO administration was discontinued on the second post-
`operative day. The SaO 2 was between 80% and 90%. The
`methemoglobin level did not exceed 1.8% in this patient
`
`Ex. 2026-0002
`
`

`
`Ann Thorac Surg
`1995;60:1791-3
`
`CASE REPORT SHAH ET AL
`NO AND REFRACTORY PULMONARY HYPERTENSION
`
`1793
`
`during NO therapy. Inotropic support was discontinued,
`and the ventilator was weaned to continuous positive
`airway pressure on the fourth postoperative day. Echo-
`cardiography on the ninth day revealed good ventricular
`function with both shunts patent. The patient was
`weaned off all ventilatory support by the 11th day. The
`patient became tachypneic over the next several days
`(respiratory rate, 60 to 70 breaths/min) with radiographic
`evidence of pulmonary overcirculation. Therapy with
`digoxin and furosemide was instituted with moderate
`benefit. On the 27th postoperative day, the patient un-
`derwent right heart catheterization for attempted coil
`embolization of the Blalock-Taussig shunt. The pulmo-
`nary arterial pressure was 40/30 mm Hg (approximately
`half of the systemic pressure) and both shunts were
`patent. Stable catheter position for coil delivery was
`unable to be achieved, and embolization was not per-
`formed. On the 36th postoperative day the patient un-
`derwent operative ligation of the central shunt. The SaO 2
`decreased from 96%
`to 92% on an
`inspired oxygen
`fraction of 0.4 after shunt
`ligation. The patient was
`extubated 1 day after central shunt ligation and dis-
`charged 13 days later.
`
`Comment
`Inhaled NO at a low concentration of 25 ppm caused
`rapid and complete reversal of paroxysmal pulmonary
`hypertensive crises in this newborn with complex con-
`genital heart disease after central shunt insertion. Nitric
`oxide is believed to have benefited this patient by reduc-
`ing pulmonary vascular resistance and reversing the
`right-to-left intracardiac shunt, resulting in more effec-
`tive pulmonary blood flow with a probable reduction of
`ventilation-perfusion mismatch, and improved hemody-
`namics. Inotropic and ventilatory support were signifi-
`cantly reduced immediately after NO therapy. There was
`no clinical evidence of NO or NO 2 toxicity.
`It is likely that the cardiopulmonary arrest suffered en
`route to the operating suite before central shunt insertion
`was due to an unrecognized pulmonary hypertensive
`crisis. At that time the cause of cardiopulmonary deteri-
`oration was thought to be secondary to Blalock-Taussig
`shunt occlusion. This error in diagnosis made by a team
`experienced in the management of congenital heart dis-
`ease underscores the difficulty in detecting this condition
`in the postoperative setting after a palliative shunt pro-
`cedure and stimulated the presentation of this case
`report.
`We have reported previously the induction of selective
`pulmonary vasorelaxation without significant systemic
`effects by inhaled NO in patients evaluated for pulmo-
`nary hypertension [2]. Nitric oxide causes smooth muscle
`relaxation through a cyclic guanosine monophosphate-
`mediated mechanism, and may cause selective pulmo-
`nary vasorelaxation when administered as an inhala-
`tional agent by diffusing directly into the smooth muscle
`of the pulmonary vascular bed [7]. The inactivation of NO
`by binding to hemoproteins may account for its lack of
`appreciable systemic effects [7, 8].
`
`Reversal of pulmonary hypertension with low-dose
`inhalational NO (20 ppm) has been reported in pediatric
`patients after operations for congenital heart disease [3,
`9, 10]. In these reports, pulmonary hypertension was
`refractory to conventional therapeutic measures but re-
`sponded to low-dose inhalational NO. Inhaled NO has
`been shown to cause selective reversal of acute and
`chronic pulmonary hypertension in large animal models
`and has also been reported to improve pulmonary hy-
`pertension in pediatric patients with idiopathic primary
`pulmonary hypertension and adult respiratory distress
`syndrome [4, 5, 11, 12].
`Inhaled NO administered in low doses may play a
`critical role in improving gas exchange and hemodynam-
`ics in newborn surgical patients with refractory pulmo-
`nary hypertensive crises. Its administration may be less
`frequently associated with systemic hypotension, which
`can limit the use of other vasodilafing agents.
`
`References
`1. Hopkins RA, Bull C, Haworth SG, de Leval MR, Stark J.
`Pulmonary hypertensive crises following surgery for con-
`genital heart defects in young children. Eur J Cardiothorac
`Surg 1991;55:628-34.
`2. Smerling AJ, Stennet R, Ho JWS, et al. A comparison of
`inhaled nitric oxide and intravenous prostacyclin for acute
`testing of pulmonary, vascular reactivity. Anesthesiology
`1994;81:A1366.
`3. Journois D, Pouard P, Mauriat P, Malhere T, Vouhe P, Safran
`D. Inhaled nitric oxide as a therapy for pulmonary hyper-
`tension after operations for congenital heart defects. J Tho-
`rac Cardiovasc Surg 1994;107:1129-35.
`4. Frostell C, Fratacci MD, Wain JC, Jones R, Zapol WM.
`Inhaled nitric oxide: a selective pulmonary vasodilator re-
`versing hypoxic pulmonary vasoconstriction. Circulation
`1991;83:2038- 47.
`5. Zayek M, Cleveland D, Morin FC. Treatment of persistent
`pulmonary hypertension in the newborn lamb by inhaled
`nitric oxide. J Pediatr 1993;122:743-50.
`6. Centers for Disease Control. Recommendations for occupa-
`tional safety and health standard. MMWR 1988;37:21.
`7. lgnarro LJ, Lippton H, Edwards JC, et al. Mechanism of
`vascular smooth muscle relaxation by organic nitrates, ni-
`trites, nitroprusside, and nitric oxide: evidence for the in-
`volvement of S-nitrosothiols as active intermediates. J Phar-
`macol Exp Ther 1981;218:739-49.
`8. Palmer RMJ, Ferrige AG, Moncada S. Nitric oxide release
`accounts for the biological activity of endothelium-derived
`relaxing factor. Nature 1987;327:524-6.
`9. Selld6n H, Winberg P, Gustafson LE, Lundell B, B66k K,
`Frostell CG. Inhalation of nitric oxide reduced pulmonary
`hypertension after cardiac surgery in a 3.2 kg infant. Anes-
`thesiology 1993;78:577-80.
`10. Berner M, Beghetti M, Ricou B, Rouge JC, Pretre R, Friedli B.
`Relief of pulmonary, hypertension after closure of a large
`ventricular septal defect using low dose inhaled nitric oxide.
`Intensive Care Med 1993;19:75-7.
`11. Abman SH, Griebel JL, Parker DK, Schmidt JM, Swanton D,
`Kinsella JP. Acute effects of inhaled nitric oxide in children
`with severe hypoxemic respiratory failure. J Pediatr 1994;124:
`881-8.
`12. Roberts JD, Polaner DM, Lang P, Zapol WM. Inhaled nitric
`oxide in persistent pulmonary hypertension of the newborn.
`Lancet 1992;340:818-9.
`
`Ex. 2026-0003