PULMONARY HYPERTENSION

Adam D. Lichtman, MD, Guest Reviewer

Miller OI, Tang SF, Keech A, et al: Inhaled nitricoxide and prevention of pulmonary hypertension af-ter congenital heart surgery: A randomized doubleblind study. Lancet 356:1464-1469, 2000

In this randomized, double-blind clinical trial, 124 infants scheduledfor repair of large ventricular or atrioventricular septal defects in thesetting of high pulmonary arterial pressure, high pulmonary blood flow,or both were randomized to receive either inhaled nitric oxide orplacebo. The number of pulmonary hypertensive crises (PHTC), hoursreceiving study gas, and hours spent in the intensive care unit werefollowed in the 2 groups. The study showed that infants receivinginhaled nitric oxide had fewer PHTC (p � 0.045) and shorter times tomeet criteria for extubation (p � 0.019). No important toxic effectswere seen.

Implication: In infants undergoing cardiac surgery for congenitaldefects at high risk for PHTC, routine use of inhaled nitric oxide canreduce the chances of perioperative PHTC and shorten the time toextubation.

Deb B, Bradford K, Pearl RG: Additive effects ofinhaled nitric oxide and intravenous milrinone inexperimental pulmonary hypertension. Crit CareMed 28:795-799, 2000

Pulmonary hypertension was induced in mechanically ventilated andanesthetized rabbits by a continuous infusion of U46619 (a thrombox-ane A2 mimetic). Then inhaled nitric oxide (INO) was added to theinspired gas mixture, and hemodynamic measurements were obtained.Mean arterial pressure (MAP), pulmonary artery pressure (PAP), pul-monary vascular resistance (PVR), systemic vascular resistance (SVR),and cardiac output (CO) measurements were obtained before and afterthe initiation of INO. Milrinone was given intravenously as a loadingdose followed by 3 to 30 �g/kg/min. Hemodynamic measurementswere obtained with and without INO at each dose of milrinone. Duringchemically induced pulmonary hypertension, INO decreased PAP andPVR but did not affect MAP, SVR, or CO. Milrinone dose-dependentlydecreased PAP, PVR, MAP, and SVR with an increase in CO. At eachdose of milrinone, INO further decreased PVR but not SVR. Milrinoneat 30 �g/kg/min in combination with INO decreased PVR a total of68% so that PAP and PVR decreased to baseline values.

Implication: Similar studies in humans may show that milrinone plusINO has additive effects on lowering PAP and PVR in patients withpulmonary hypertension.

Ziesche R, Petkov V, Wittmann K, et al: Treatmentwith epoprostenol reverts nitric oxide non-respon-siveness in patients with primary pulmonary hyper-tension. Heart 83:406-409, 2000

In this clinical trial, 7 patients with primary pulmonary hypertensionwho had been primary nonresponders to inhaled nitric oxide were givenintravenous epoprostenol and were followed for 13 to 29 months. Aftertreatment, the patients underwent right heart catheterization to deter-mine pulmonary vascular reactivity to nitric oxide. After epoprostenoltherapy, inhaled nitric oxide resulted in an increase in arterial oxygensaturation (p � 0.01), an increase in cardiac index (p � 0.05), adecrease in mean pulmonary artery pressure, and a decrease in totalpulmonary vascular resistance (p � 0.01).

Implication: Long-term treatment with epoprostenol reverts nonre-sponsiveness to inhaled nitric oxide in patients with primary pulmonaryhypertension. The use of intravenous prostaglandins in addition toinhaled nitric oxide raises interesting questions regarding use ascombination therapy. More studies are needed to examine whether useof inhaled nitric oxide and intravenous prostaglandins would be worth-while for treatment of intraoperative pulmonary hypertension.

Kaul TK, Fields BL: Postoperative acute refractoryright ventricular failure: Incidence, pathogenesis,management and prognosis. Cardiovasc Surg 8:1-9,2000

A complex complication of cardiac surgery is right ventricularfailure. Rarely seen in isolation, right ventricular failure is seen mostoften after cardiac transplantation, after left ventricular assist deviceplacement, and in combination with pre-existing left ventricular failure.Treatment is often difficult. In this review, the authors discuss thecauses, management, and prognosis of acute postoperative right ven-tricular failure. Therapies discussed include vasodilators, mechanicalsupport, right ventricular assist devices, and surgical redirection ofcaval blood flow.

Implication: Aggressive early treatment of patients with postopera-tive right ventricular failure may help to offset the poor salvage rate inthis group of patients. This article discusses the causes of right ven-tricular failure and the treatment options available in postoperativeadult cardiac surgical patients.

Cowen KN, Heilbut A, Humpl T, et al: Completereversal of fatal pulmonary hypertension in rats by aserine elastase inhibitor. Nat Med 6:698-702, 2000

Progressive pulmonary hypertension is associated with increasedserine elastase activity and the deposition of the smooth muscle cellsurvival factor tenascin-C. Tenascin-C amplifies the response ofsmooth muscle cells to growth factors. Studies of organ cultures ofhypertrophied rat pulmonary arteries have shown that serine elastaseinhibitors suppress tenascin-C and induce smooth muscle apoptosis.This induced cell death initiates the regression of vessel wall hyper-trophy. In this study, after the chemical induction of pulmonary hyper-tension in rats, a serine elastase inhibitor was administered. After 1week of treatment, 92% of treated rats had survived compared with39% of untreated rats. After 2 weeks of treatment, pulmonary arterypressure had normalized. Survival was 86% in the treated group com-pared with 0% in the untreated group.

Implication: In an animal model, pulmonary hypertension can bereversed completely after treatment with a serine elastase inhibitor. Inthe future, it may be possible to reverse pulmonary hypertension inhumans by using this new class of drugs. Much work remains beforehuman trials, although the early animal work is promising.

Jiang ZY, Costachescu T, Derouin M: Treatment ofpulmonary hypertension during surgery with nitricoxide and vasodilators. Can J Anaesth 47:552-555,2000

This article describes the presentation and treatment of a patient withsecondary pulmonary hypertension that presented for noncardiac sur-gery. The patient’s preoperative pulmonary artery pressures (PAP)were 55/24 mmHg. Nitric oxide was given intraoperatively, with aresultant reduction in PAP. After the initiation of surgery, the patientdeveloped atrial fibrillation with a slow ventricular rate and hypoten-sion. A dipyridamole bolus normalized systemic pressure and increasedheart rate and cardiac output but did not alter the PAP. A nitroglycerin

399LITERATURE REVIEW

infusion was added to this therapeutic regimen resulting in a sustaineddecrease in PAP and increase in systolic blood pressure.

Implication: The authors show that in combination with inhalednitric oxide, dipyridamole does not augment thenitric oxide–induced de-crease in PAP but does increase cardiac output and improves hemo-dynamic stability. Inhaled nitric oxide, nitroglycerin, and dipyridamolewhen used in combination have a beneficial effect on pulmonary andsystemic hemodynamics in patients with pulmonary hypertension.

Krowka MJ: Pulmonary hypertension: Diagnosticsand therapeutics. Mayo Clin Proc 75:625-630, 2000

Pulmonary hypertension is the end result of multiple diseases orsyndromes, including primary cardiac diseases, pulmonary thrombo-

embolism, parenchymal lung disease, and sleep apnea. This reviewconcentrates on the most common causes of pulmonary hypertension,screening and diagnostic tests, and approved and investigational treat-ment options.

Implication: A concise review is provided of the causes, diagnosticmodalities, and treatments of the most common causes of pulmonaryhypertension.

Papers reviewed in this issue were selected from those published inthe following journals: American Heart Journal, Annals of Surgery,Canadian Journal of Anaesthesia, Cardiovascular Surgery, Circula-tion, Clinical Science(Colch), Critical Care Medicine, Heart, Lancet,Mayo Clinic Proceedings,and Nature Medicine.

doi: 10.1053/jcan.2001.23337

400 LITERATURE REVIEW