Tolazoline

Primary pulmonary hypertension (PPH) is often a fatal disease, with a majority of patients dying within 5 years.[1-3] It affects mostly young adults in their second to fourth decades[4] and follows a progressively downhill course culminating in right ventricular failure. Various forms of vasodilator therapy have been used in the past,[5] but a large series of patients would be required to determine their long-term efficacy. Acetylcholine, phentolamine, tolazoline and isoprenaline were initially used with conflicting results. Oral vasodilators such as hydralazine and captopril have also been used with early success, but their long-term use has been disappointing.[6,7] Recently Rich and Brundage[8] have shown sustained hemodynamic, symptomatic, and electrocardiographic improvement associated with the use of high-dose calcium channel blockers[8] and have also reported improved survival in a proportion of patients.[9] Long-term benefit with enhanced survival chance, however, seems to be confined to the group of patients who had a significant vasodilatory responsiveness to acute challenge with oral calcium channel blockers and also had a relatively preserved cardiac output. There remains a large proportion of patients with severe disease who have developed right ventricular dysfunction and are, therefore, not suitable for [CA.sup.++] channel blockers and require alternate therapies. Much attention has been placed recently on lung transplantation and novel therapies which combine both vasodilatory and antithrombotic actions.

NATURAL HISTORY/PROGNOSIS

Recent large scale reviews of patients with PPH have provided a clearer idea of the natural history of the disease. From these data, strategies of care have been formulated.

In a retrospective analysis of 120 patients with PPH, Fuster et al[1] reported only 21 percent survival after 5 years indicating an overall poor prognosis of this disease. There is a significant proportion of patients who do even less well if their pulmonary artery oxygen saturation is less than 63 percent; in this group, 3 years' survival chance is below 20 percent.[1] More recently, a larger study from the NIH registry comprising prospective follow-up of 194 patients estimated a median survival of 2.8 years.[3] In this study, prognosis was most closely related to right ventricular hemodynamic function; thus, patients with elevated right artial pressure (more than 20 mm Hg), impaired cardiac index (less than 2 L/min/[m.sup.2]), and mean pulmonary artery pressure in excess of 85 mm Hg were associated with poor survival chance. New York Heart Association (NYHA) class 3 or 4, presence of Raynauds phenomenon, and decreased diffusion capacity for carbon monoxide (DCO) were also associated with poor prognosis. This study, however, did not record pulmonary artery oxygen saturation.

In spite of an overall bleak outlook in PPH, there is a small proportion of patients, particularly those with a maintained cardiac output, where the disease progresses slowly leading to "spontaneous" recovery. Active vasodilator treatment for such patients may not be indicated.

ANTICOAGULANTS IN PPH TREATMENT

The cause of PPH is unknown, therefore, treatment is mainly aimed at alleviating the effects of pulmonary vasoconstriction and low cardiac output state. However, the presence of endothelial injury in the pulmonary vascular bed in conjunction with a low cardiac output makes these patients prone to develop pulmonary thrombi. The enhanced risk of intravascular thrombosis explains the valuable role of long-term anticoagulants in the treatment of PPH. There are now two large-scale studies[1,9] which have clearly demonstrated improved survival when patients are treated with anticoagulants.

VASODILATORS

Calcium channel blockers are currently the favored vasodilator treatment of PPH where right ventricular function is maintained with the cardiac index of more than 2 L/min/[m.sup.2] and right atrial pressure of less than 10 mm Hg. Their use is restricted to patients with mild to moderate disease where there is a demonstrable element of pulmonary vasodilatation to acute vasodilator challenge. There is no clear evidence as to the optimum dose of [Ca.sup.++] blocker which can be used without having adverse effects. However, high doses of [Ca.sup.++] channel blockers, such as 720 mg of diltiazem per day or 240 mg of nifedipine daily have been reported to improve symptoms and hemodynamics, as well as survival chance over 5 years.[8,9] Rich et al[8,9] demonstrated that improved mortality with high dose [Ca.sup.++] channel blockers was confined to the group of patients who dropped their pulmonary artery pressure and pulmonary vascular resistance by more than 20 percent when challenged with oral diltiazem or nifedipine. However, those patients who do not show significant acute vasodilatory responsiveness do not benefit from [Ca.sup.++] channel blockers.[10,11]

Acute Vasodilator Trial With Prostacyclin

Intravenously administered prostacyclin ([PGI.sub.2]) was used as an agent to test vasodilatory responsiveness during right heart catheterization. Prostacyclin is an arachidonic acid metabolite involving cyclo-oxygenase pathway. It is a potent vasodilator with a short half-life of approximately 5 min, and therefore, quite useful for a diagnostic study as any adverse effect can be quickly reversed by stopping the infusion. Due to its rapid onset of action, it is also possible to titrate an effective dose to achieve pulmonary vasodilation in a relatively short period of a catheter study.[12] Prostacyclin was first used in 1980 as a pulmonary vasodilator in a child.[13] Since then, many centers have started to use [PGI.sub.2] routinely to assess vasodilatory capacity of pulmonary vasculature. After baseline hemodynamic measurements, [PGI.sub.2] is commenced at approximately 2 ng/kg/min and increased by 1 to 2 ng/kg/min after every 5 to 15 min until there is more than a 20 percent fall in pulmonary vascular resistance (PVR) or the patient gets unacceptable side effects such as headache, flushing, or hypotension. The pulmonary vasodilatory capacity during catheter study may be useful in predicting clinical response to long-term vasodilator therapy,[10,11] particularly in early stages of the disease. However, in more severe disease, this hypothesis may not necessarily apply as we have seen comparable or even better results to [PGI.sub.2] treatment in patients with severe PPH failing to show acute vasodilatory responsiveness.[14,15]

Long-term Treatment With Prostacyclin

Continuous [PGI.sub.2] infusion was first used at our center in a moribund patient with PPH[16] who showed remarkable improvement with this form of treatment. This was followed by a study comprised of ten patients with severe PPH, and the majority of them responded well to [PGI.sub.2] therapy showing significant improvement in exercise tolerance and well-being.[17] Such improvement may not be confined to patients showing pulmonary vasodilatory response to acute [PGI.sub.2] infusion but may also occur in other patients with severe disease. We have recently demonstrated doubling of survival chance in the first year for patients with severe PPH treated with long-term [PGI.sub.2] infusion.[15] Enhanced survival was particularly greater in patients without any pulmonary vasodilatory capacity. This suggests that [PGI.sub.2] may not be acting simply as a pulmonary vasodilator but may also have additional effects. It is likely that [PGI.sub.2] displays antithrombotic properties or even has a role in vascular remodelling and rehabilitation of diseased endothelium. Rubin et al[18] have shown sustained hemodynamic and symptomatic improvement in a randomized study of PPH cases using long-term [PGI.sub.2] infusion. They have demonstrated a significant fall in PVR (from 21.6 to 13.7 limits) after 8 weeks of [PGI.sub.2] treatment as compared to no significant shift in PVR (from 20.6 to 20.4) in the conventional therapy group over the same period.

As [PGI.sub.2] is quite expensive and has to be self-administered by patients through an indwelling central vein cannula, its use is restricted to patients with severe disease. These patients have evidence of right ventricular failure, mixed venous oxygen saturation of less than 63 percent, and would otherwise have a poor chance of survival. These patients are generally considered for heart-lung or single lung transplantation. Prostacyclin may not only help to stabilize their condition before suitable donor organs are available but also enhances their chances to get a transplant by improving survival.[19]

Iloprost

Although [PGI.sub.2] is a useful diagnostic and theraputic agent, its use is not without limitations. As presently formulated it tends to lose its efficiency if left at room temperature for more than 12 h, and it has to be protected from the light. It needs to be administered intravenously and is also quite expensive. Iloprost is a synthetic analogue of [PGI.sub.2][20,21] which does not fulfill all the requirements but is a step forward. It is relatively more stable with a half life of approximately 13 min.[21] It can be stored at room temperature and has an oral bioavailability of 13 percent[22] indicating that an oral preparation might be possible. In preliminary studies, we have demonstrated its potent pulmonary vasodilatory effects[23] as well as improved exercise tolerance[24] in severe PPH which was comparable to [PGI.sub.2].

Inhaled Nitric Oxide for PPH

Endothelium-derived nitric oxide (ENDO)[25] is an extremely labile gas with a half life in biological systems of only a few seconds. After its release from the endothelial cells, it is quickly diffused into the underlying vascular smooth muscle cells where it promotes vascular relaxation by causing a rise in cyclic 3,5 guanosine monophosphate.[26] It has negligible action beyond its site of release as it is rapidly inactivated by hemoglobin for which it has a high affinity. Indeed, it is the fastest known ligand of hemoglobin. Inhaled nitric oxide would approach the vascular smooth muscle cells of resistance pulmonary arteries albuminally from the membranous bronchioli. It therefore does not come into contact with blood. We have demonstrated selective pulmonary vasodilatory effect of inhaled NO (40 ppm in air) in patients with PPH, compatible to [PGI.sub.2].[27] Frostell et al[28] have shown pulmonary vasodilation by inhaled NO (80 ppm in air) in sheep where it caused a significant reversal of hypoxic vasoconstriction.[28] Vasodilation achieved with inhaled NO was comparable to [PGI.sub.2]. A similar effect has also been shown in infantile pulmonary hypertension.[29] It seems that inhaled NO has a potential to be used as a treatment of pulmonary hypertension once a safe and effective delivery system becomes available. Studies so far have been only short-term. However, long-term, possibly domiciliary-inhaled NO may soon become available for treatment.

LUNG AND HEART-LUNG TRANSPLANTATION IN PPH

There are a number of patients with PPH who follow a progressively downhill course in spite of the drug therapy and are considered for heart-lung transplantation (HLT).[30] Some of them are likely to benefit more from surgery than others. Relatively younger patients free of any other systemic disease are likely to do better. At our center, patients with evidence of right ventricular failure, an [SvO.sub.2] of less than 63 percent and functional class III to IV are considered for heart-lung transplantation. Other factors such as age (usually less than 50 years), psychosocial circumstances, and any nonreversible organ dysfunction or systemic disease are also considered. For single-lung transplantation (SLT), it is important to exclude any significant coronary artery disease by performing coronary angiography.

During the last few years, survival chances post-HLT have significantly improved to 65 percent over 3 years by virtue of effective immunosuppression regimen and early detection of graft rejection using periodic transbronchial pulmonary biopsies.[31,32] Biopsies would also be good at picking up pulmonary infection[33-36] which would otherwise be difficult to differentiate from rejection[37,38] and may prove fatal if not treated adequately.[39] Better techniques of preservation and distant procurement of the donor organs, as well as use of [PGI.sub.2] in perfusing the heart-lung grafts have also contributed to improved survival postoperatively.[40,41]

The role of SLT is being evaluated currently. Hemodynamic benefits post-SLT have been demonstrated in moderately severe pulmonary hypertension,[42] and some of the early evidence from Pasque et al[43] also cautiously supports this option. However, problems of acute pulmonary edema in the single transplanted lung may lessen the success of this form of transplant surgery.

Once the role of SLT is established in pulmonary hypertension, it would lead to more effective use of the scarce donor organs[44] as only one lung would be required per patient and a heart-lung block from one donor might be used for three recipients. This would also eliminate the risk of graft-related coronary occlusive disease[45] in SLT recipients.

FUTURE TREATMENTS

There are many new ideas emerging which concern the vasoactive and platelet regulatory factors released by the endothelin. In addition to vasodilatory agents, antagonists to vasoconstrictors are now being described. Of interest are the antagonists of endothelin-1, one of the most powerful vasoconstrictors. A cyclic neuropeptide (BE-18257B) is a selective antagonist for ETA receptor, and it is found in Streptomyces misakienesis.[46] It can displace ET-1 from the receptor or vascular smooth muscle and antagonizes its pressor effects.[47] The importance of these results is the view that ET-1 may play a part in human PPH.[48]

REFERENCES

[1] Fuster V, Steele PM, Edwards WD, Gersh BJ, McGoon MD, Frye RL. Primary pulmonary hypertension: natural history and the importance of thrombosis. Circulation 1984; 70:580-87

[2] Voelkel NF, Reeves JT. Primary pulmonary hypertension. In: Moser KM, ed, Pulmonary vascular diseases. New York: Marcel Dekker, 1979; 573-628

[3] D'Alonzo GE, Barst RJ, Ayres SM, Bergofsky EH, Brundage BH, Detre KM. Survival in patients with primary pulmonary hypertension. Ann Intern Med 1991; 115:343-49

[4] Rich S, Dantzker DR, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, et al. Primary pulmonary hypertension: a national prospective study. Ann Intern Med 1987; 107:216-23

[5] Rich S, Brundage BH. The pharmacologic treatment of primary pulmonary hypertension. In: Bergofsky EH, ed., Abnormal pulmonary circulation. New York: Churchill Livingstone, 1986; 283-311

[6] Hermiller JB, Bambach D, Thompson MJ, Huss P, Fontana ME, Magorien RD, et al. Vasodilators and prostaglandin inhibitors in primary pulmonary hypertension. Ann Intern Med 1982; 97:470-89

[7] Rich S, Martinez J, Lam W, Rosen KM. Captopril as treatment for patients with pulmonary hypertension: problem of variability in assessing chronic drug treatment. Br Heart J 1982; 48:272-77

[8] Rich S, Brundage BH. High-dose calcium channel-blocking therapy for primary pulmonary hypertension: evidence for long-term reduction in pulmonary arterial pressure and regression of right ventricular hypertrophy. Circulation 1987; 76:135-41

[9] Rich S, Kaufmann E, Levy P. The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N Engl J Med 1992; 327:76-81

[10] Reeves JT, Groves BM, Turkevich D. The case for treatment of selected patients with primary pulmonary hypertension. Am Rev Respir Dis 1986; 134:342-46

[11] Roskovec A, Stardling JR, Shepherd G, MacDermot J, Oakley CM, Dollery CT. Prediction of favourable response to long term vasodilation of pulmonary hypertension by short term administration of epoprostenol (prostacyclin) or nifedipine. Br Heart J 1988; 59:696-705

[12] Higenbottam T. The place of prostacyclin in the clinical management of primary pulmonary hypertension. Am Rev Respir Dis 1987; 136:782-85

[13] Watkins WD, Peterson MB, Crone RK, Shannon DC, Levine L. Prostacyclin and prostaglandin [E.sub.1] for severe idiopathic pulmonary artery hypertension [letter]. Lancet 1980; 1:1083

[14] Butt AY, Higenbottam TW, Cremona G, Takao M, Glanville C, McMahon A. Acute pulmonary vasodilation does not predict successful response to long term vasodilation in severe pulmonary hypertension. Thorax 1993; 48:465

[15] Higenbottam TW, Scott JP, Spiegelhalter D, Fuster V, Dinh-Xuan AT, Caine N, et al. The value of prostacyclin (epoprosteral) and heart-lung transplantation in severe pulmonary hypertension. Br Heart J 1993; 70:366-70

[16] Higenbottam TW, Wheeldon D, Wells F, Wallwork J. Long-term treatment of primary pulmonary hypertension with continuous intravenous epoprostenol (prostacyclin). Lancet 1984; 1:1046-47

[17] Jones DK, Higenbottam TW, Wallwork J. Treatment of primary pulmonary hypertension with intravenous epoprostenol (prostacyclin). Br Heart J 1987; 57:270-78

[18] Rubin LJ, Mendoza J, Hood M, McGoon M, Barst R, Williams WB, et al. Treatment of primary pulmonary hypertension with continuous intravenous prostacyclin (epoprostenol). Ann Intern Med 1990; 112:485-91

[19] Cremona G, Higenbottam TW, Scott JP. Continuous intravenous infusion of prostacyclin ([PGI.sub.2]) improves survival in primary pulmonary hypertension [abstract]. Am Rev Respir Dis 1991; 143:A180

[20] Schror K, Darius H, Matzky R, Ohlendorf R. The antiplatelet and cardiovascular actions of a new carbacyclin derivative (ZK36374)-equipotent to PG12 in vitro. Arch Pharmacol 1981; 316:252-55

[21] Kaukinen S, Ylitalo P, Pessi T, Vapaatolo H. Hemodynamic effects of iloprost, a prostacyclin analogue. Clin Pharmacol Ther 1984; 36:464-69

[22] Krause W, Humpel M, Hoyer GA. Biotransformation of the stable prostacyclin analogue, iloprost, in the rat. Drug Metab Dispos 1984; 12:645-51

[23] Scott JP, Higenbottam TW, Wallwork J. The acute effect of the synthetic prostacyclin analogue iloprost in primary pulmonary hypertension. Br J Clin Pharmacol 1990; 6:231-34

[24] Dinh Xuan AT, Higenbottam TW, Scott JP, Morrison HM, Cremona G, Wallwork J. Effects of long-term treatment with iloprost, a prostacyclin analogue, on exercise tolerance in patients with primary pulmonary hypertension [abstract]. Am Rev Respir Dis 1990; 141:A889

[25] Palmer RMJ, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 1987; 327:524-26

[26] Dinh-Xuan AT, Higenbottam TW. Non-prostanoid endothelium-derived vasoactive factors. J Int Med Res 1989; 17:305-15

[27] Pepke-Zaba J, Higenbottam TW, Dinh-Xuan AT, Stone D, Wallwork J. Inhaled nitric oxide as a cause of selective pulmonary vasodilation in pulmonary hypertension. Lancet 1991; 338:1173-74

[28] Frostell C, Fratacci MD, Wain JC, Jone R, Zapol WM. Inhaled nitric oxide, a selective pulmonary vasodilator reversing hypoxic pulmonary vasoconstriction. Circulation 1991; 83:2038-47

[29] Roberts JD, Polaner DM, Lang P, Zapol WM. Inhaled nitric oxide in persistent pulmonary hypertension of newborn. Lancet 1992; 340:818-19

[30] Reitz BA, Wallwork JL, Hunt SA, Pennock JL, Billingham ME, Oyer PE, et al. Heart-lung transplantation: successful therapy for patients with pulmonary vascular disease. N Engl J Med 1982; 306:557-64

[31] Higenbottam TW, Stewart S, Penketh ARL, Wallwork J. Transbronchial lung biopsy for the diagnosis of rejection in heart-lung transplant patients. Transplantation 1988; 46:532-39

[32] McCarthy PM, Starnes VA, Theodore J, Stinson EB, Oyer PE, Shumway NE. Improved survival after heart-lung transplantation. J Thorac Cardiovasc Surg 1990; 99:54-9

[33] Hutter JA, Scott J, Wreghitt T, Higenbottam T, Wallwork J. The importance of cytomegalovirus in heart-lung transplant recipients. Chest 1989; 95:627-631

[34] Smyth RL, Scott JP, Higenbottam TW, Wreghitt TG, Stewart S, Fradet G, et al. Experience of cytomeglovirus infection in heart-lung transplant recipients. Transplant Proc 1990; 22:1822-23

[35] Smyth RL, Higenbottam TW, Scott JP, Wreghitt TG, Stewart S, Clelland CA, et al. Herpes simplex virus infection in heart-lung transplant recipients. Transplantation 1990; 49:735-39

[36] Smyth RL, Scott JP, McGoldrick JP, Wallwork J, Higenbottam TW. Successful use of repeated transbronchial lung biopsies in a patient with multiple opportunistic infections. Respir Med 1989; 83:505-07

[37] Penketh ARL, Higenbottam TW, Hutter JA, Coutts C, Stewart S, Wallwork J. Clinical experience in the management of pulmonary opportunist infection and rejection in recipients of heart-lung transplants. Thorax 1988; 43:762-69

[38] Millet B, Higenbottam TW, Flower CDR, Stewart S, Wallwork J. The radiographic appearances of infection and acute rejection of the lung after heart-lung transplantation. Am Rev Respir Dis 1989; 140:62-7

[39] Brooks RG, Hofflin JM, Jamieson SW, Stinson EB, Remington JS. Infectious complications in heart-lung transplant recipients. Am J Med 1985; 79:412-22

[40] Hakim M, Higenbottam TW, Bethune D, Corg-Pearce R, English TA, Kneeshaw J, et al. Selection and procurement of combined heart and lung grafts for transplantation. J Thorac Cardiovasc Surg 1988; 98:474-79

[41] Wallwork J, Jones KD, Cavrocchi N, Hakim M, Higenbottam TW. Distant procurement of organs for clinical heart-lung transplantation using a single flush technique. Transplantation 1987; 44:654-58

[42] Doig JC, Corris PA, Hilton CJ, Dark JH, Bexton RS. Effect of single lung transplantation on pulmonary hypertension in patients with end stage fibrosing lung disease. Br. Heart J 1991; 66:431-34

[43] Pasque M, Trulock E, Kaiser L, Cooper JD. Single-lung transplantation for pulmonary hypertension: three-month hemodynamic follow-up. Circulation 1991; 84:2275-79

[44] Higenbottam T. Single lung transplantation and pulmonary hypertension. Br Heart J 1992; 67:121

[45] Mullins PA, Cary NA, Sharples L, Scott J, Aravot D, Large S, et al. Coronary occlusive disease and late graft failure after cardiac transplantation. Br Heart J 1992; 68:260-65

[46] Ihara M, Fukuroda T, Saeki T, Nishikibe M, Kojiri K, Suda H, et al. An endothelin receptor (ETA) antagonist isolated from Streptomyces misakiensis. Biochem Biophys Res Comm 1991; 178:132-37

[47] Youagisawa M, Kurchura H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988; 332:411-15

[48] Stewart DJ, Levy RD, Cernacek P, Longleben D. Inverse plasma endothelin-1 in pulmonary hypertension: marker or mediator of disease? Ann Intern Med 1991;114:464-69

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