Pediatr Cardiol 20:224-226, 1999
`
`@;) Springer-Verlag New Yorio Inc. 1999
`
`Adverse Hemodynamic Effects Observed with Inhaled Nitric Oxide After
`Surgical Repair of Total Anomalous Pulmonary Venous Return
`
`A.M. Rosales,! J. Bolivar,2 R.P. Burke,3 A.C. Chang4
`'Division of Pediatric Medicine, Miami Children's Hospital, 3200 S.W. 60th Court, Suite 104, Miami, FL 33155-4070, USA
`2Division of Critical Care, Miami Children's Hospital, 3200 S.W. 60th Court, Suite 104, Miami, FL 33155-4070, USA
`'Division of Cardiovascular Surgery, Miami Children's Hospital, 3200 S.W. 60th Court, Suite 104,
`Miami, FL 33155-4070, USA
`-IDivision of Cardiology, Miami Children's Hospital, 3200 S.W. 60th Court, Suite 104, Miami, Pi. 33155-4070, USA
`
`Abstract. The following is a case report of a l-month-
`old patient who developed adverse hemodynamic sequel-
`ae during the use of nitric oxide (NO) in the postopera-
`tive period for pulmonary hypertension after correction
`of total anomalous pulmonary venous return. At the time
`of diagnosis, the patient had evidence of systemic right
`ventricular pressures estimated by continuous-wave
`Doppler. He was sedated and paralyzed for hyperventi-
`lation in preparation for surgery and underwent pulmo-
`nary vein confluence to left atrial anastomosis. Postop-
`erative pulmonary hypertension was managed by hyper-
`ventilation, sedation, and paralysis until a sudden onset
`of systemic-level pulmonary pressure required NO
`therapy. Satisfactory results were obtained in minutes,
`but a rebound pulmonary hypertension occurred with
`concomitant systemic hypertension and no radiographic
`changes. We suspected left atrial hypertension secondary
`to a sudden increase in pulmonary blood flow to an non-
`compliant left ventricle. Discontinuation of NO resulted
`in stabilization of the hemodynamic profile of the patient
`and he continued to be managed with paralysis, hyper-
`ventilation, and sedation. Based on this experience we
`suggest that NO should be used with caution in patients
`with obstructive lesions at the atrial level prior to surgery
`(mitral valve stenosis and cor triatriatum) or in patients
`with a poorly compliant left ventricle (cardiomyopathy
`and left ventricular dysfunction). These entities are un-
`able to ~olerate a sudden increase in pulmonary blood
`return thus creating paradoxical pulmonary hypertension.
`
`hypertension -
`Key words: Nitric oxide -Pulmonary
`Complications ~ Total anomalous venous connection
`
`Correspondence to: A.C. Chang
`
`Total anomalous pulmonary venous return (TAPVR) is a
`congenital heart defect that accounts for 1 % of all con-
`genital cardiac defects and can be associated with pul-
`monary hypertension secondary to obstruction to the pul-
`monary venous return. The pulmonary artery smooth
`muscle in T APVR can be hypertrophied; its hyperreac-
`tivity is thought to be responsible for the acute rises in
`pulmonary vascular resistance following corrective sur-
`gery. Pulmonary hypertension contributes significantly
`to postoperative morbidity and death and is usually man-
`aged with sedation/paralysis, hyperventilation/hyper-
`oxia, and inotropic support [5, 8].
`Current data support the use of inhaled nitric oxide
`(NO) in the treatment of pulmonary hypertension [4, 9].
`We report a case in which inhaled NO was intended to
`treat pulmonary hypertension following surgical correc-
`tion of T APVR but resulted in unexpected paradoxical
`pulmonary hypertension, most likely secondary to poor
`left heart compliance and excessive pulmonary blood
`flow.
`
`Case Report
`
`MR is a l-month-old white male born to a 39-year-old G2Pl mother
`via an uncomplicated normal spontaneous vaginal delivery with a birth
`weight of 3S60 g. He was admitted to the cardiac intensive car unit with
`a 2-day history of intermittent cyanosis and progressive respiratory
`distress.
`Initial laboratory data showed capillary blood gases as follows:
`pH, 7.20; pC°2' SS Torr; pO2' 11 Torr; and base deficit, -7.4 mEq/Lt.
`Further w6rkup demonstrated a hemoglobin of 7.7 mg/dl, hematocrit of
`23.2%, a platelet count of 88,OOO/UL, and a white blood cell count of
`12,300 cells/ILl. Antibiotic therapy with ampicillin and cefotaxime was
`administered for presumed sepsis. The chest roentgenogram showed
`diffuse interstitial edema with a normal cardiac silhouette. The elec-
`trocardiogram demonstrated right ventricular hypertrophy. The echo-
`cardiogram revealed the diagnosis of mixed TAPVR (three pulmonary
`
`
`
`~~~~
`
`
`
`
`
`IKARIA EXHIBIT 2005
`Praxair v. INO Therapeutics
`IPR2015-00529
`
`224
`
`

`

`Rosales et al.: Hemodynamic Complications of Nitric Oxide
`
`.
`
`225
`
`~
`
`~
`
`~
`
`~
`
`~
`
`£Y.f-M--
`
`:;'
`
`27
`
`17
`
`-'\
`
`-L2-
`
`-21-
`
`-!..L-
`
`.--§.l.-
`
`-2L-
`
`-!1.--
`
`..~
`
`, ~/"\II"\\t\;--
`
`-!-
`
`1:00
`
`1:15
`
`1:30
`
`1:45
`
`2:00
`
`2:15
`
`2:30 2:45
`
`mon
`
`Fig. 1. Variation in systolic (S).
`mean (M). and diastolic (D). arterial
`blood pressure (ABP), pulmonary
`artery pressure (PAP), and central
`venous pressure (CVP) before. dur-
`ing, and after inhaled NO (see text
`for descriptions). The solid bar rep-
`resents initiation of inhaled NO treat-
`ment.
`
`into the ponal system, and the
`veins draining infradiaphragmatically
`remaining upper left pulmonary vein draining into the innominate
`vein); in addition, there was evidence of right hean dilatation, tricuspid
`regurgitation, and systemic right ventricular pressure (estimated by
`continuous-wave Doppler).
`The patient was sedated with fentanyl at 7 lI.g/kg/hr and paralyzed
`with vecuronium at 0.6 mgihr; he was also mechanically ventilated
`with the following ventilatory settings: FiO2' 1.0; lMV, 50 per minute;
`PIP, 30 cm; and PEEP, 5 cm. In addition, furosemide (0.4 mgihr),
`dopamine (10 1I.g/kg/min), and prostaglandin (0.02 1I.g/kg/min) were
`also administered.
`The patient underwent corrective surgery with pulmonary vein
`confluence to left atrial anastomosis; the left upper pulmonary vein was
`left intact. Immediately following surgery, the patient remained hemo-
`dynamically stable, supponed with epinephrine (0.05 1I.g/kg/min) and
`dopamine (7.5 1I.g/kg/min). During the first 36 hours following surgery,
`the pulmonary anery pressure ranged between one half and three quar-
`ters of systemic pressure, and the patient was managed with sedation,
`paralysis, and hyperventilation (with an anerial CO2 of 24-30 Torr).
`At about 36 hours in the postoperative period, the patient devel-
`oped sudden onset systemic-level pulmonary pressure with concomi-
`tant systemic hypotension (Fig. I); NO therapy at 80 ppm was promptly
`begun. Prior to NO therapy, anerial blood gas showed the following:
`pH, 7.47; paCO2, 26 Torr; paO2' 83 Torr; and a base deficit equivalent
`to -2.6 mEq/L. During the ensuing 15 minutes, both a decrease in the
`pulmonary anery pressure and an improvement in systemic pressure
`were observed. Anerial blood gas showed no significant changes in pH
`or paCO2, but paO2 increased to 364 Torr.
`These favorable changes were followed by an unexpected rise in
`pulmonary pressure (during a period of 15 minutes) that exceeded
`systemic-level pressure. This "rebound" pulmonary hypenension oc-
`curred with concomitant systemic hypotension and central venous pres-
`
`sure elevation to 16 mmHg. This phenomenon was not associated
`with any change in the administration of NO delivery or in the chest
`roentgenogram. Therapy with NO was discontinued based on the
`rationale
`that this latter episode of pulmonary hypertension may
`have been caused by left atrial hypertension secondary to a sudden
`increase in pulmonary blood flow into a noncompliant left atrium and
`ventricle.
`The suspension of NO therapy resulted in stabilization of the
`patient's hemodynamic profile. The patient remained in sedation!
`paralysis, hyperventilation, and inotropic support for an additional 3
`days. The remaining hospital course was uneventful and he was dis-
`charged 18 days after surgery on oral furosemide.
`
`Discussion
`
`Pulmonary hypertension is one of the leading causes of
`death and morbidity in children after cardiac surgery and
`is associated with preoperative intrinsic pulmonary vas-
`cular abnormality [4]. This abnormal pulmonary vascular
`endothelium is further damaged by cardiopulmonary by-
`pass. Vasodilators such as nitroprusside, tolazoline, or
`prostaglandin/prostacyclin can be effective in treating
`pulmonary hypertension but have unfavorable sequelae,
`such as increased intrapulmonary right-to-left shunting
`(as a result of indiscriminate vasodilatation of pulmonary
`vessels) and systemic hypotension.
`Current therapy for postoperative pulmonary hyper-
`
`~
`I
`
`IKARIA EXHIBIT 2005
`Praxair v. INO Therapeutics
`IPR2015-00529
`
`

`

`tension includes the use of NO, a biologic diatomic mol-
`ecule produced in the endothelium from L-arginine by
`the enzyme NO synthetase. Nitric oxide, previously
`known as endothelial-derived relaxing factor, stimulates
`guanylate cyclase to form cGMP, which in turn causes
`relaxation of the vascular smooth muscle by decreasing
`the concentration of free calcium in the smooth muscle
`cytosol [I, II]. Once inhaled, NO acts exclusively on the
`adjacent alveolar unit and is rapidly inactivated by he-
`moglobin, thus avoiding systemic hypotension. In addi-
`tion, since NO manifests its effects in better ventilated
`regions of the lung, it selectively dilates only the pulmo-
`nary vessels in these areas, thus maximizing ventilation!
`perfusion matching. For these reasons, NO is thought to
`be superior to conventional vasodilating agents.
`Previous reports on the use of inhaled NO did not
`disclose adverse hemodynamic profile in patients [4, 9].
`In our patient, the initial response to NO was a signifi~
`cant decrease in pulmonary artery pressure with an in-
`crease in arterial oxygen content, indicating improved
`pulmonary blood flow. The subsequent paradoxical pul-
`monary hypertension was not caused by alteration in the
`administration of NO or by the extrinsic factors (such as
`atelectasis or pneumothorax). We speculated that NO
`induced a pulmonary hypertensive crisis by acutely in-
`creasing pulmonary blood flow and therefore preload
`into a relatively noncompliant left atrium and ventricle.
`The left atrium in T APVR, due to failure of inclusion of
`the common pulmonary veins during embryological de-
`velopment, is 50% of the expected size; although surgi-
`cal repair improves the capacity of the left atrium, its
`compliance remains relatively impaired [6]. With the ad-
`ministration of inhaled NO, the increase in pulmonary
`venous return resulted in left atrial hypertension and sub-
`sequent reflex pulmonary venous and arterial vasocon-
`striction.
`In addition to T APVR after surgery, there are other
`pathophysiologic states in which NO therapy and an in-
`crease in pulmonary blood flow could be detrimental,
`including (I) left atrial obstructive lesions (such as mitral
`stenosis or supramitral ring) prior to relief of obstruction
`and (2) left ventricular dysfunction and/or dilated car-
`diomyopathy with decreased ventricular compliance and
`suboptimal diastolic function [2, 10]. These patients may
`not tolerate an acute increase in preload to the left atrium
`
`Pediatric Cardiology Vol. 20, No.3, 1999
`
`or ventricle and therefore could develop an abrupt in-
`crease in left atrial pulmonary arterial pressures and pul-
`monary edema.
`In summary, while inhaled NO has been found to be
`of benefit in the treatment of pulmonary hypertension in
`children with congenital heart disease, paradoxical pul-
`monary hypertension can occur in certain pathophysi-
`ologic states as a result of this therapy.
`
`Acknowledgments. The authors would like to acknowledge the help of
`JoAnn Nieves and Xavier Hernandez with the inhaled nitric oxide
`protocol.
`
`References
`
`I. Anggaard E (1994) Nitric oxide: mediator, murderer, and medi-
`cine. Lancet 343: 1199-1206
`2. Bocchi EA, Bacal F, Auler lunior 10, et aI. (1994) Inhaled nitric
`oxide leading to pulmonary edema in stable severe heart failure.
`Am J Cardiol 74:70-72
`3. Cobanoglu A, Menashe VD (1993) Total anomalous pulmonary
`venous connection in neonates and young infants: repair in the
`current era. Ann Thorac Surg 55:43-48
`4. 10urnois D, Pouard P, Maunat P, et aI. (1994) Inhaled nitric oxide
`as a therapy for pulmonary hypenension after operations for con-
`genital heart defects. J Thorac Cardiovasc Surg 107: 1129-1135
`5. Lupineni FM, Kulik Tl, Beekmann RH III, Crowley DC, Bove EL
`(1993) Correction of total anomalous pulmonary venous connec-
`tion in infancy. J Thorac Cardiovasc Surg 106:880-885
`6. Minich LL, Tani LY, Hawkings lA, McGough EC (1995) Abnor-
`mal Doppler pulmonary venous flow patterns in children after
`repaired total anomalous pulmonary venous connection. Am J Car-
`diol 75:6O6-{i10
`7. Okamoto K, Sato T, Kurosr M, et al. (1994) Successful use of
`inhaled nitric oxide for the treatment of severe hypoxemia in an
`infant with total anomalous pulmonary venous return. Anesthesi-
`ology 81:256-259
`8. Raisher BD, Grant lW, Martin TC, Strauss AW, Spray TL (1992)
`Complete repair of total anomalous pulmonary venous connection
`in infancy. J Thorac Cardiovasc Surg 104:443-448
`9. Robens ill
`lr, Lang P, Bigatello LM, Vlahakes Gl, Zapol WM
`(1993) Inhaled nitric oxide in congenital heart disease. Circulation
`87:447-453
`10. Semigran Ml, Cockrill BA, Kacmarek R, et aI. (1994) Hemody-
`namic effects of inhaled nitric oxide in heart failure. J Am Coli
`Cardiol 24:982-988
`II. Syder SH, Bredt DS (1992) Biological roles of nitric oxide. Sci Am
`266:68-71,74-77
`
`.
`
`I
`
`IKARIA EXHIBIT 2005
`Praxair v. INO Therapeutics
`IPR2015-00529
`
`226
`
`