419

Management of labor in Eisenmenger syndrome with inhaled nitric oxide

Karin M. Lust, MB, BS, Robert J. Boots, MD, Mark Dooris, MD, and John Wilson, MD

Herston, Queensland, Australia

Administration of nitric oxide by means of inhalation during the labor of a woman with Eisenmenger’s syn-drome caused by an atrial septal defect resulted in improved oxygenation and initial pulmonary arterial pres-sure. She gave birth to a live infant at 34 weeks’ gestation but died of worsening pulmonary hypertension andheart failure 21 days post partum. (Am J Obstet Gynecol 1999;181:419-23.)

Key words: Eisenmenger’s syndrome, labor, nitric oxide, pulmonary hypertension

The risk for maternal and infant morbidity and deathassociated with pregnancy among patients with pre-exist-ing cardiovascular disease depends on the underlyingcardiac lesion, the functional derangement produced bythe lesion, the development of pregnancy-related compli-cations, and New York Heart Association functionalclass.1, 2 Other poor prognostic indicators of right-to-leftcardiac shunts include hematocrit >0.6, arterial oxygensaturation <80%, right ventricular hypertrophy, andepisodes of syncope.3, 4

Atrial septal defects of the secundum type are a com-mon congenital cardiac lesion, occurring among 10% ofpregnant patients with congenital heart disease.2 In se-ries of patients with pulmonary hypertension Wood5

found that the average age at presentation of uncompli-cated cases of atrial septal defect was 26 years, 35 yearswhen Eisenmenger’s reaction was present. Wood5 de-fined Eisenmenger’s syndrome as “pulmonary hyperten-sion due to high pulmonary vascular resistance with re-versed or bidirectional shunt at the aorto-pulmonary,ventricular, or atrial level.” The development of pul-monary hypertension complicating atrial septal defect isrelatively uncommon and does not usually occur untilthe fourth decade of life.6, 7 However, there are numer-ous case reports of Eisenmenger’s syndrome caused byatrial septal defect among young women during preg-nancy.2, 8-13 The maternal mortality rate among patientswith Eisenmenger’s syndrome during pregnancy variesfrom 11% to 70%.1, 8, 11, 12, 14-16 Vaginal delivery is associ-ated with a 34% mortality rate compared with 75% for ce-sarean delivery.1, 9, 11, 14, 17

Case reportA 29-year-old primigravid woman was referred at 26

weeks’ gestation for evaluation of dyspnea at rest and pal-pitations. Progressive exertional dyspnea had developedover the preceding 6 years. The dyspnea had worsenedduring pregnancy. Minor exertion caused regular palpi-tations. There was no history of chest pain. At age 23years, a heart murmur and cardiomegaly had been foundon a chest radiograph. She was advised that the murmurwas congenital and that no further evaluation or treat-ment was necessary. There was no history of use of rape-seed oil, appetite suppressants, or crotalaria alkaloid.There were no symptoms of collagen vascular disease orvenous thromboembolism. The rest of the medical his-tory and the family medical history were unremarkable.Clinical examination showed that the 45-kg patient hadcentral cyanosis on room air and clubbing of the fingersand toes. Pulmonary hypertension with right ventricularfailure was present. The gravid uterus corresponded withgestational age. An electrocardiogram revealed rightventricular hypertrophy and strain.

Arterial blood gas evaluation on room air at admis-sion showed pH 7.43, PO2 64 mm Hg, PCO2 33 mm Hg,and bicarbonate 21 mmol/L. A full blood cell count re-vealed a hemoglobin value of 14.3 g/dL and hematocritof 0.42. Serum iron, ferritin, and folate levels were withinnormal limits. An echocardiogram showed gross rightventricular dilatation and a large atrial septal defect. Aright-to-left shunt and moderate tricuspid regurgitationwith severe pulmonary hypertension were present. Anautoantibody screen that included tests for the lupus an-ticoagulant and anticardiolipin antibody had negative re-sults. Protein S, protein C, antithrombin III, activatedprotein C resistance, and human immunodeficiencyvirus serologic results were normal. No thrombi were de-tected in the lower limbs at ultrasonographic examina-tion. Lung volumes were normal.

The patient was admitted to the hospital from 26weeks’ gestation onward. Her care included bed rest,oxygen to maintain oxygen saturation >90%, and thera-peutic systemic heparinization. Serial ultrasono-graphicscans revealed adequate fetal development and growth.

From the Royal Brisbane Hospital and the Royal Women’s Hospital.Received for publication June 25, 1998; revised January 22, 1999; ac-cepted March 8, 1999.Reprint requests: R. Boots, MD, Intensivist and Thoracic Physician, 7GIntensive Care Unit, Royal Brisbane Hospital, Herston Rd, Herston,Queensland, 4029 Australia. E-mail: bootsr@health.qld.gov.au.Copyright © 1999 by Mosby, Inc.0002-9378/99 $8.00 + 0 6/1/98386

Dyspnea increased as the pregnancy progressed.Episodes of central chest pain of sudden onset with in-creased shortness of breath occurred and settled with in-creased oxygen therapy.

A consulting team included the patient’s midwife, anintensive care specialist, a cardiologist, an obstetric physi-cian, a neonatologist, and an anesthetist. Elective vaginaldelivery at 34 weeks’ gestation was planned. The patientreceived prophylaxis with intramuscular betamethasonefor fetal lung maturity and amoxicillin and gentamicinfor bacterial endocarditis. Heparin infusion was stoppedthe morning of induction. Labor was induced with in-travaginal prostaglandin E2. Epidural anesthesia withfentanyl and bupivacaine 0.1% was begun after the onsetof labor. The patient was transferred to the intensive careunit at the onset of contractions. Labor was monitored bymeans of cardiotocography, echocardiography, oximetry,and pulmonary artery catheterization.

Administration of 900 ppm nitric oxide through anasal cannula was begun. Mixed expired gas was analyzedwith a chemiluminescence monitor with hourly determi-nation of methemoglobin level. Nitric oxide flow rate wastitrated to a maximal reduction in pulmonary artery pres-sure and improved gas exchange. After the start of ad-ministration of 5 ppm nitric oxide, pulmonary arterialpressure fell from 85/42 mm Hg to 65/45 mm Hg. PaO2on a rebreather mask at 15 L/min increased from 66 mmHg to 143 mm Hg. The patient could breathe sponta-neously and was able to communicate easily with her fam-ily and midwife. She stayed in a private, air-conditionedroom. Room concentrations of nitric oxide and nitrogendioxide ranged from 20 to 50 ppb. Methemoglobin level

remained <5%. Fig 1 summarizes the hemodynamic andoxygenation progress through labor.

Oxygenation was well maintained throughout laborwith a fraction of inspired oxygen of 0.8. During labor,pulmonary pressure increased to 117/36 mm Hg; sys-temic pressure was 112/70 mm Hg at delivery.Administration of nebulized prostacyclin to 20 ng/kg perminute was unsuccessful in reducing pulmonary arterialpressure. Intravenous administration of prostacyclin to 5ng/kg per minute resulted in systemic hypotension andtype II deceleration on the cardiotocogram without anychange in pulmonary arterial pressure. When the cervixwas fully dilated, the patient underwent artificial ruptureof the membranes and ventouse delivery. Ten unitsSyntocinon was given with delivery of the anterior shoul-der followed by infusion of 40 units over 8 hours. A 1823-g female infant was delivered with Apgar scores of 10 atboth 1 and 5 minutes. The neonatal course was uncom-plicated.

After delivery the patient continued with a fraction ofinspired oxygen of 0.8 and nitric oxide at 10 ppm.Pulmonary arterial pressure gradually decreased to68/35 mm Hg (82/25 mm Hg at the beginning of labor).Cardiac output improved from 2.24 L/min to 4.7 L/min(3.4 L/min at the beginning of labor) by 24 hours afterdelivery. The second postpartum day was complicated bypersistently heavy vaginal bleeding and supraventriculartachycardia without clinical change in oxygenation or ev-idence of heart failure. Pulmonary arterial pressure in-creased to 109/67 mm Hg and cardiac output to 6.2L/min during supraventricular tachycardia. The bleed-ing settled with Syntocinon infusion, and the uterus be-

420 Lust et al August 1999Am J Obstet Gynecol

Fig 1. Chart of progress through labor. Delivery occurred at time 0. s, Systolic; PAP, pulmonary arterial pressure; d, di-astolic; m, mean value.

came well contracted. The supraventricular tachycardiasettled with administration of digoxin and amiodaroneinfusion. Pulmonary arterial pressure and cardiac outputreturned to previously stable values. The pulmonary arte-rial catheter was removed after 60 hours.

Syntocinon was continued for 48 hours. A vaginal ex-amination did not reveal any focal source of bleeding.Curettage was not performed because of the perceivedrisks of anesthesia and the clinical response toSyntocinon. Heparin 5000 units subcutaneously every 6hours was continued until heparinization was completeon postpartum day 2. Heparin administration was discon-tinued on days 7 to 9 because of persistent vaginal bleed-ing. By 10 days post partum, the hemoglobin level hadfallen by 3 g/dL, and a transfusion was administered.Therapeutic anticoagulation was resumed on postpar-tum day 10. Amiodarone infusion was stopped on post-partum day 5 because of first-degree heart block.

Seven days after delivery a Johnson transtracheal oxy-gen catheter (Cook Critical Care, Bloomington, Ind) wasinserted while the patient was under local anesthesia tocontinue nitric oxide at 10 ppm. On postpartum day 14progressive hypoxemia developed with clinically increas-ing pulmonary arterial pressure. Echocardiography re-vealed worsening right ventricular function, severe tri-cuspid regurgitation, and an estimated right ventricularsystolic pressure between 110 and 120 mm Hg.Intravenous prostacyclin, sublingual nifedipine, nitricoxide to 80 ppm, and aminophylline did not reduce pul-monary arterial pressure. Because of progressive hy-potension, intravenous administration of norepineph-rine was begun. The patient was accepted for heart-lungtransplantation. Her condition deteriorated, and shedied 21 days post partum. Postmortem examination wasdeclined by the family.

Comment

The role of anticoagulation in the care of pregnant pa-tients with Eisenmenger’s syndrome remains controver-sial. It has been shown that in situ thrombi may developand may worsen pulmonary hypertension.9, 16, 18

Anticoagulation is recommended to prevent thrombusformation and is generally well tolerated. The cessationof heparin administration during postpartum hemor-rhage may contribute to the rapid progression of pul-monary hypertension.

Inhaled nitric oxide is a potent and selective pul-monary vasodilator for patients with pulmonary hyper-tension.19-23 Endothelium-dependent relaxation of pul-monary arteries is impaired in Eisenmenger’ssyndrome.24 Direct inhalation of nitric oxide may there-fore reduce pulmonary hypertension and improve oxy-genation because of optimization of ventilation-perfu-sion relations. Inhaled nitric oxide also has anantithrombotic effect.25 Inhaled nitric oxide has beenused as a bridge to heart-lung transplantation20 but hasnot been described in the management of labor.

For our patient continuous inhalation of nitric oxidemarkedly reduced initial pulmonary arterial pressureand improved oxygenation. Pulmonary arterial pressureincreased throughout labor, as would be expected for in-creasing cardiac output in the presence of fixed pul-monary resistance. Oxygenation was well maintainedthroughout labor and delivery, and by 24 hours after de-livery, cardiac output remained improved and increasedpulmonary diastolic pressure reflected possible postpar-tum fluid shifts.

Numerous factors may have contributed to progres-sion of pulmonary hypertension 14 days after deliverythat resulted in heart failure and death. These includepostpartum blood loss that contributed to decreased pul-monary blood flow. The patient never had clinical hypo-volemia, and pulmonary diastolic pressure remained ele-vated throughout the postpartum period. The patienthad an arrhythmia, but this was associated with increasedcardiac output. Both of these events may contribute tothe development of in situ pulmonary thrombi and wors-ening pulmonary hypertension.

Pregnancy and labor impose increased strain on pa-tients with a fixed resistance in the pulmonary circula-tion. Blood volume is increased 50% over nonpregnantvalues. Stroke volume and cardiac output increase in thefirst and second trimesters and again during labor.Elevation in pulmonary arterial pressure causes rightventricular enlargement, arrhythmia, and heart failure.Right to left shunting with worsening hypoxemia is en-hanced by the normal decrease in systemic vascular resis-tance associated with pregnancy or by increases or reduc-tions in right ventricular preload in an alreadycompromised ventricle. During labor, uterine contrac-tion causes autotransfusion and may increase cardiacoutput by 25%. This increases pulmonary arterial pres-sure and may precipitate heart failure or arrhythmia.Decreases in cardiac output may occur in the secondstage of labor as a result of the increased intrathoracicpressure of bearing down. In the third stage of labor au-totransfusion of 500 mL may occur. Stroke volume andcardiac output gradually return to normal within 2 weeksof delivery. These factors may contribute to maternaldeath during pregnancy and labor. Patients withEisenmenger’s syndrome remain at risk for thromboem-bolism with an estimated risk as high as 30% to 70% inthe immediate postpartum period.26

The delivery of nitric oxide through a nasal cannulaand a transtracheal catheter has been described.21 It wasuseful to this patient because it allowed her to communi-cate with her family and take regular fluids and nourish-ment. The concentration of nitric oxide delivered withthese methods depends greatly on minute volume.Monitoring with mixed expired gas is confounded by thegreat absorption of nitric oxide into the pulmonary cir-

Volume 181, Number 2 Lust et al 421Am J Obstet Gynecol

culation. Methemoglobin monitoring is mandatory inthis circumstance. The use of a pharyngeal catheter andan electrochemical cell nitric oxide monitor with an airpump to deliver mixed expired gas to the monitor(NoxBox; Bedfront Scientific, Kent, United Kingdom)results in a faster response time for tidal concentrationmeasurement and the opportunity for continuous mea-surement. This is the only useful way of monitoring spon-taneously breathing patients with transtracheal catheters.The use of a transtracheal catheter is protective againstsudden hypoxic crises and increases in pulmonary arter-ial pressure associated with removal of a mask deliverysystem. The environmental concentrations of nitricoxide and nitrogen dioxide were well below recom-mended industrial standards.27

Our patient was monitored in the intensive care unitfor the day of delivery and for the 21 days until she died.Invasive monitoring was continued for 48 hours after de-livery. Pulmonary arterial wedge pressures were not regu-larly obtained during or after delivery because of theheightened risk for pulmonary artery rupture and thelack of reliability of these values in reflecting left ventric-ular end-diastolic volume in patients with pulmonary vas-cular disease.28 During this period assessment for poten-tial heart-lung transplantation continued. Nitric oxidewas continued through a transtracheal catheter to main-tain oxygenation and for any additional benefit in reduc-ing pulmonary arterial pressure and risk for pulmonaryvessel thrombosis.

Patients such as ours should be monitored closely in anintensive care unit. Aggressive management of factorsknown to result in worsening of shunt dynamics, such ashypoxemia, arrhythmia, fluid balance, and acidosis,should be undertaken, as should antibiotic prophylaxisfor infective endocarditis and careful anticoagulant ther-apy. The period of monitoring after delivery relates tothe severity of underlying cardiopulmonary disease. Ourpatient depended on nitric oxide for improved oxygena-tion and needed ongoing intensive care. The contribu-tion of the difficulties of anticoagulation therapy to theincrease in pulmonary arterial pressure is unclear.Clinicians should remain vigilant in ascertaining whichadults patients have congenital heart disease. Heart-lungtransplantation for Eisenmenger’s syndrome caused byan atrial septal defect is a reality, and patients who re-ceive transplants can have successful pregnancies.29

We concluded that care of pregnant patients withEisenmenger’s syndrome is improved by referral to a ter-tiary center with a multidisciplinary team that providesinvasive monitoring, vaginal delivery, and epidural anes-thesia. Inhaled nitric oxide may be used to improve oxy-genation and initially reduce pulmonary arterial pres-sure. Maintenance of improved oxygenation duringlabor and the postpartum period and the vasodilating

and antithrombotic effects of inhaled nitric oxide maylimit the increase in pulmonary arterial pressure ex-pected with increasing cardiac output throughout laboramong patients with fixed pulmonary vascular disease.Despite aggressive treatment with improved oxygenationand anticoagulation, the prognosis among these patientsremains poor. Death from arrhythmia and progressivepulmonary hypertension can occur before heart-lungtransplantation can be organized. Eisenmenger’s syn-drome remains a life-threatening condition in associa-tion with pregnancy. It is essential that patients known tohave this disease be offered appropriate counseling re-garding risk of pregnancy, methods of contraception,and early termination if contraception fails. Successfuldelivery may be enhanced by means of improved oxy-genation with inhaled nitric oxide for patients with pul-monary hypertension and hypoxemia.

REFERENCES

1. Gianopoulos J. Cardiac disease in pregnancy. Med Clin NorthAm 1989;73:639-51.

2. Shime J. Mocarski JM, Hasings D, Webb GD, McLaughlin PR.Congenital heart disease in pregnancy. Am J Obstet Gynecol1987;156:313-22.

3. Congenital heart disease after childhood: an expanding patientpopulation—22nd Bethesda Conference. J Am Coll Cardiol1991;18:311-42.

4. Elkayam U. Pregnancy and cardiovascular disease. In:Braunwald E, editor. Heart disease. 4th ed. Philadelphia: WBSaunders; 1992. p. 1790-809.

5. Wood P. The Eisenmenger’s syndrome. BMJ 1958;701-9,755-62.6. Douglas P. Heart disease in women. Philadelphia: FA Davis;

1989.7. Pitkin K. Pregnancy and congenital heart disease. Ann Intern

Med 1990;12:6445-54.8. Presbitero P, Rabajoli F, Somerville J. Pregnancy in patients with

congenital heart disease. Schweiz Med Wochenschr1995;125:311-5.

9. Jejamalar R, Sivanasaratnam V, Kuppuvelumani P. Eisenmengersyndrome in pregnancy. Aust N Z J Obstet Gynaecol1992:32:275-7.

10. Rao Usha R, Nalini V. Eisenmenger’s syndrome complicatingpregnancy. J Indian Med Assoc 1989;87:266-8.

11. Smedstad KG, Cramb R, Morison DH. Pulmonary hypertensionand pregnancy: a series of eight cases. Can J Anaesth1994;41:502-12.

12. Nelson G, Galea EG. Blunt A. Eisenmenger syndrome and preg-nancy. Med J Aust 1971;1:431-4.

13. Spinnato JA, Kraynack BJ, Wayne Cooper M. Eisenmenger syn-drome in pregnancy: epidural anaesthesia for elective caesareansection. N Engl J Med 1981;304:1215-7.

14. Weiss BM, Atanassoff PG. Cyanotic congenital heart disease. JClin Anaesth 1993;5:332-41.

15. Midwall J, Jafin H, Herman MV, Kupersmith J. Shunt flow andpulmonary haemodynamics during labour and delivery in theEisenmenger’s syndrome. Am J Cardiol 1978;42:229-303.

16. Pitts JA, Crosby WM, Basta LL. Eisenmenger’s syndrome inpregnancy. Am Heart J 1977;93:321-6.

17. Gleicher N, Midwall J, Hochberger D, Jaffin H. Eisenmenger’ssyndrome in pregnancy. Obstet Gynaecol Surv 1979;34:721-41.

18. Heytens L, Alexander JP. Maternal and neonatal death associ-ated with Eisenmenger’s syndrome. Acta Anaesth Belg1986;37:45-51.

19. Pepke-Zaba J, Higenbottam TW, Dinh-Xuan AT, Wallork J.

422 Lust et al August 1999Am J Obstet Gynecol

Inhaled nitric oxide as a cause of selective pulmonary vasodi-latation in pulmonary hypertension. Lancet 1991;338:1173-4.

20. Snell GI, Salamonsen RF, Bergin P, Esmore DS, Khan S,Williams TJ. Inhaled nitric oxide used as a bridge to heart-lungtransplantation in a patient with end-stage pulmonary hyperten-sion. Am J Respir Crit Care Med 1995;151:1263-6.

21. Frostnell GC, Fratacci MD, Wain JC, Jones R, Zapol WM.Inhaled nitric oxide: a selective pulmonary vasodilator reversinghypoxic pulmonary vasoconstriction. Circulation 1991;83:2038-47.

22. Rich GF, Murphy JD, Roos CM, Johns RA. Inhaled nitric oxide:selective pulmonary vasodilation in cardiac surgical patients.Anesthesiology 1993;78:1028-35.

23. Barnes PJ, Belvisi MG. Nitric oxide and lung disease. Thorax1993;48:1034-43.

24. Dinh Xuan AT, Higenbottam TW, Celland C, Pepke-Zaba J,

Cremona G, Wallwork J. Impairment of pulmonary endothe-lium dependant relaxation in patients with Eisenmenger’s syn-drome. Br J Pharmacol 1989;99:9-10.

25. Moncada S, Higgs A. The L-arginine-nitric oxide pathway. NEngl J Med 1993;329:2002-10.

26. Yau G, Oh TE. Severe cardiac disease in pregnancy. In: Oh TE,editor. Intensive care manual. 4th ed. Boston: Butterworth–Heinemann; 1997. p. 499-501.

27. Etches PC, Finer NN, Ehrenkranz RA, Wright LL. Clinical mon-itoring of inhaled nitric oxide. Pediatrics 1995;95:620-1.

28. Gomersall CD, Oh TE. Haemodynamic monitoring. In: Oh TE,editor. Intensive care manual. 4th ed. Boston: Butterworth–Heinemann; 1997. p. 831-8.

29. Chinayon P, Sakornpant P. Successful pregnancy after heartlung transplantation. Asia Oceania J Obstet Gynaecol1991;20:275-8.

Volume 181, Number 2 Lust et al 423Am J Obstet Gynecol

Availability of Journal back issuesAs a service to our subscribers, copies of back issues of the American Journal of Obstetrics

and Gynecology for the preceding 5 years are maintained and are available for purchasefrom Mosby until inventory is depleted at a cost of $16 per issue. The following quantity dis-counts are available: one fourth off on quantities of 12 to 23 and one third off on quantitiesof 24 or more. Please write to Mosby, Inc, Subscription Services, 11830 Westline IndustrialDr, St Louis, MO 63146-3318, telephone (800)453-4351 or (314)453-4351, for informationon availability of particular issues. If back issues are unavailable from the publisher, photo-copies of complete issues may be purchased from Bell & Howell Information and Learning,300 N Zeeb Rd, Ann Arbor, MI 48106-1346. Telephone (734)761-4700.