Timothy W. Higenbottam

Inhaled nitric oxide as a cause of selective pulmonary vasodilatation in pulmonary hypertension

The acute effects of inhaled nitric oxide (NO) (40 ppm in air) on pulmonary (PVR) and systemic (SVR) vascular resistance were compared with those of an intravenous infusion of prostacyclin (24 micrograms/h) in 8 patients with severe pulmonary hypertension and 10 cardiac patients with normal values of PVR. 10 healthy volunteers were studied non-invasively. In the patients with pulmonary hypertension, PVR fell significantly after inhaled NO and after prostacyclin. PVR also fell significantly in the cardiac patients after inhaled NO. Although SVR fell substantially after prostacyclin in patients with pulmonary hypertension, inhaled NO had no effect on SVR in any patient or volunteer. Inhaled NO therefore seems to be both a selective and effective pulmonary vasodilator.

INTERNATIONAL GUIDELINES FOR THE SELECTION OF LUNG TRANSPLANT CANDIDATES

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Impairment of endothelium-dependent pulmonary-artery relaxation in chronic obstructive lung disease

BACKGROUND Endothelial cells release endothelium-derived relaxing factor (EDRF) in a variety of vascular beds, including the pulmonary circulation. However, the role of EDRF-mediated pulmonary-artery relaxation in chronic hypoxic lung disease is unknown. METHODS We studied endothelium-dependent relaxation mediated by EDRF in vitro in pulmonary arteries that had been obtained from 22 patients undergoing heart-lung transplantation for end-stage chronic obstructive lung disease. Control pulmonary arteries were obtained from 15 patients undergoing lobectomy for lung carcinoma who did not have evidence of other chronic lung disease. The responses of all vascular rings (external diameter, 1.2 to 3.4 mm) to the endothelium-dependent vasodilators acetylcholine and adenosine diphosphate were studied immediately after lung excision. RESULTS Pulmonary arterial rings from the patients with chronic lung disease developed a greater tension (2.19 +/- 0.16 g) in response to phenylephrine (10(-6) M) than the rings from control patients (1.28 +/- 0.18 g, P less than 0.05). Inhibition of EDRF synthesis by treatment with NG-monomethyl-L-arginine (10(-4) M) eliminated this difference, increasing the tension in the rings from the controls (P less than 0.01) but not in those from the patients with chronic lung disease. Rings from control patients relaxed in response to cumulative doses (10(-10) to 10(-5) M) of acetylcholine (maximal relaxation, 81.3 +/- 3.9 percent) and adenosine diphosphate (maximal relaxation, 85.3 +/- 2.6 percent). By contrast, rings from patients with chronic obstructive lung disease achieved only 41.3 +/- 4.8 percent of maximal relaxation in response to acetylcholine (n = 32) and 49.4 +/- 5.5 percent in response to adenosine diphosphate (n = 24) (P less than 0.001, as compared with control rings). Rings from both the controls and the patients with chronic lung disease relaxed similarly in response to the endothelium-independent vasodilator sodium nitroprusside (10(-4) M). There was an inverse correlation between the degree of intimal thickening and the level of maximal relaxation of the rings from the patients with chronic lung disease (r = -0.60, P less than 0.001). Maximal relaxation was also related directly to the partial pressure of arterial oxygen before transplantation (r = 0.68, P less than 0.01) and inversely to the partial pressure of arterial carbon dioxide before transplantation (r = -0.55, P less than 0.01), but not to the forced expiratory volume in one second (r = 0.19, P not significant). CONCLUSIONS Endothelium-dependent pulmonary-artery relaxation in vitro is impaired in arteries from patients with end-stage chronic obstructive lung disease. Such impairment may contribute to the development of pulmonary hypertension in chronic hypoxic lung disease.

Worsening of pulmonary gas exchange with nitric oxide inhalation in chronic obstructive pulmonary disease

BACKGROUND Inhalation of nitric oxide (NO) causes selective pulmonary vasodilation and improves arterial oxygenation in acute respiratory distress syndrome. But some patients do not respond or gas exchange worsens when inhaling NO. We hypothesised that this detrimental effect might be related to the reversion of hypoxic vasoconstriction in those patients where this mechanism contributes to ventilation-perfusion (V(A)/Q) matching. METHODS We studied 13 patients with advanced chronic obstructive pulmonary disease (COPD). We compared their responses to breathing room air, NO at 40 parts per million in air, and 100% O2. Changes in pulmonary haemodynamics, blood gases, and V(A)/Q distributions were assessed. FINDINGS NO inhalation decreased the mean (SE) pulmonary artery pressure from 25.9 (2.0) to 21.5 (1.7) mm Hg (p = 0.001) and PaO2 from 56 (2) 53 (2) mm Hg (p = 0.014). The decrease in PaO2 resulted from worsening of V(A)/Q distributions, as shown by a greater dispersion of the blood-flow distribution (logSD Q) from 1.11 (0.1) to 1.22 (0.1) (p = 0.018). O2 breathing reduced the mean pulmonary arterial pressure to 23.4 (2.1) mm Hg and caused greater V(A)/Q mismatch (logSD Q, 1.49 [0.1]). The intrapulmonary shunt on room air was small (2.7 [0.9]%) and did not change when breathing NO or O2. INTERPRETATION We conclude that in patients with COPD, in whom hypoxaemia is caused essentially by V(A)/Q imbalance rather than by shunt, inhaled NO can worsen gas exchange because of impaired hypoxic regulation of the matching between ventilation and perfusion.

Long term intravenous prostaglandin (epoprostenol or iloprost) for treatment of severe pulmonary hypertension

Objective To investigate the relation between the severity of pulmonary hypertension and the outcome of medical treatment. Methods 98 patients with primary pulmonary hypertension—nine (6%) with systemic disease and pulmonary hypertension and 39 (27%) with thromboembolic pulmonary hypertension—received medical treatment and were followed between 1982 and 1995. They were given long term intravenous prostaglandin treatment (either epoprostenol (n = 61) or iloprost (n = 13)) or conventional treatment with oral anticoagulants (n = 24) with or without calcium channel blockers. Event-free survival was measured to death or transplant surgery, or pulmonary thromboendarterectomy. Results Prognosis (hazard ratio) was affected by: New York Heart Association grade, 1.52 (95% confidence interval 1.11 to 2.09); mixed venous oxygen saturation (Svo 2%), 0.97 (0.95 to 0.98); cardiac index, 0.72 (0.49 to 1.06); mean right atrial pressure, 1.04 (1.01 to 1.07); and pulmonary vascular resistance, 1.02 (1.00 to 1.04). The median event-free survival time of patients with Svo 2< 60% was 239 days (0 to 502) on conventional treatment (n = 22) and 585 days (300 to 870) on prostaglandin treatment (n = 42). No difference was seen in patients with Svo 2⩾ 60% between conventional treatment and prostaglandin treatment, survival being 1275 days (732 to 1818; (n = 48)) and 986 days (541 to 1431; n = 30)), respectively. Capacity for pulmonary vasodilatation did not predict outcome of treatment. Conclusions Continuous intravenous prostaglandins were more effective than anticoagulants, with or without calcium channel blockers, in prolonging survival in patients with right heart failure. In these patients a capacity to vasodilate did not predict outcome from medical treatment.

Development of bronchiolitis obliterans syndrome in recipients of heart-lung transplantation : Early risk factors

Given the internationally recognized definition of bronchiolitis obliterans syndrome (BOS) and longer follow up of heart-lung transplant recipients, it is possible to establish some of the major risk factors for development and progression of BOS. Between April 1984 and 31 December 1993, 157 patients underwent heart-lung transplantation; 126 survived at least six months after operation and so were at risk of developing BOS. The following early risk factors were assessed for development of BOS grade 1 (21-35% decline in FEV1) and progression from grade 1 to grade 2 (36-50% decline in FEV1): age, gender and underlying diagnosis of the recipient, evidence of acute rejection and cytomegalovirus (CMV) infection within 6 months of operation, peak FEV1 achieved, age and gender of the donor, cold ischemic time of the graft, and matching of CMV serological status and HLA antigens of donor and recipient. The number of acute rejection episodes observed remained the single most important determinant of development of BOS grade 1 (relative risk 1.17 (1.06, 1.29), P=0.002) and progression to BOS grade 2 (relative risk 1.58 (1.02, 2.46), P=0.03). No other factors were significantly related to development or progression of BOS, although both evidence of CMV infection and disease and the number of HLA mismatches increased the risk. Bronchiolitis obliterans syndrome is a major problem for medium-to-long-term survivors of cardiothoracic transplantation. Acute rejection early after transplantation is a sensitive prognostic indicator of subsequent functional decline and requires prompt attention.

Risk factors for obliterative bronchiolitis in heart-lung transplant recipients.

Obliterative bronchiolitis is the major cause of death of long-term survivors of heart-lung transplantation. Of our first 75 patients who have received heart-lung transplantation, 38 have been followed for a year or longer. Eight patients developed clinical evidence of obliterative bronchiolitis within 15 months of transplantation, of whom four died with postmortem confirmation of extensive obliterative bronchiolitis, interstitial and pleural fibrosis, and vascular sclerosis in the heart and lungs. One further patient died before one year after chronic rejection. All nine patients had evidence on transbronchial biopsy of submucosal fibrosis and vascular sclerosis. Twelve of our remaining patients have shown similar areas of lung fibrosis on transbronchial biopsy, and the other eighteen are well and without fibrosis on transbronchial biopsy. Studies of the 274 biopsies obtained from 38 patients confirmed rejection on 182 occasions with more frequent, more persistent, and more severe rejection in the chronic rejection group than in the without-fibrosis or lung fibrosis groups. Opportunistic infection resulted in pneumonia on 19 occasions, and were most commonly found in lung fibrosis patients. We conclude that obliterative bronchiolitis is the likely outcome in patients with early, poorly controlled, severe rejection.

Impairment of pulmonary endothelium-dependent relaxation in patients with Eisenmenger's syndrome

A comparison has been made between the endothelium‐dependent relaxation of pulmonary arteries (PA) obtained at heart‐lung transplantation from 4 patients with Eisenmengers syndrome and secondary pulmonary hypertension, and PA obtained at lobectomy from 4 patients with lung carcinoma, the controls. All vascular rings were studied immediately after lung excision. PA rings from control patients dose‐dependently relaxed to cumulative doses of acetylcholine (ACh, 10−10 to 10−5 m), achieving a maximal relaxation of 80 ± 5% (mean ± s.e.mean) from precontraction with phenylephrine. By contrast, PA rings from Eisenmengers syndrome patients achieved a maximal relaxation of only 34 ± 12% (P < 0.05, unpaired t test), with even paradoxical contraction at high doses of ACh (10−6 to 10−5 m). Sodium nitroprusside (10−4 m) relaxed all PA rings, with and without endothelium (carefully removed before study), obtained from both control and Eisenmengers syndrome patients. These results provide the first evidence that endothelium‐dependent relaxation of PA mediated by endothelium‐derived relaxing factors is impaired in Eisenmengers syndrome patients with secondary pulmonary hypertension.

Prostacyclin (epoprostenol) and heart-lung transplantation as treatments for severe pulmonary hypertension

OBJECTIVE--To determine whether epoprostenol (prostacyclin, PGI2) or heart-lung transplantation (HLT), or both improves survival of patients with severe pulmonary hypertension. DESIGN--This was a prospective study where the effects of epoprostenol were compared with conventional treatment. Also, the benefits of epoprostenol and HLT were assessed by comparing survival in this group with that of 120 patients at the Mayo Clinic before HLT and epoprostenol treatment became available. PATIENTS AND INTERVENTIONS--Forty four patients were studied; 25 received continuous epoprostenol over a four year period (mean (SD) cardiac index 1.8 (0.4) 1 min-1 m-2 and mean (SD) pulmonary artery pressure (PAP) 70 (16) mm Hg) and 19 did not (cardiac index 2.1 (0.6) 1 min-1 m-2 and PAP 64 (13) mm Hg). Ten patients underwent HLT: seven had received epoprostenol, and three had not. RESULTS--The therapeutic intervention with epoprostenol, or HLT, or both improved survival compared with the Mayo clinic patients (p = 0.05). Most of the benefit was conferred by epoprostenol, which prolonged survival twofold from a median time of eight to 17 months and doubled the changes of successful HLT. The improved survival with epoprostenol was not related to its immediate capacity to cause pulmonary vasodilation. Those patients who had limited acute pulmonary vasodilation when treated with epoprostenol showed the greatest improvement in survival. CONCLUSIONS--These preliminary results indicate that those pulmonary hypertensive patients with the poorest chance of survival can be helped by epoprostenol and by HLT.

Effect of inhibitors of nitric oxide release and action on vascular tone in isolated lungs of pig, sheep, dog and man.

1. The actions of inhibitors of the release or action of nitric oxide (NO) on pulmonary vascular resistance (PVR) were investigated in lungs isolated from pig, sheep, dog and man. 2. In pig, sheep and human lungs perfused with Krebs‐dextran solution, both N omega‐nitro‐L‐arginine methyl ester (L‐NAME; 10(‐5) M) and Methylene Blue (10(‐4) M) increased basal PVR. This increase was reversed by sodium nitroprusside (10(‐5) M). In pig lungs N omega‐monomethyl‐L‐arginine (10(‐4) M) increased PVR by 154%. This increase was partially reversed by L‐arginine (10(‐3) M). L‐NAME had no effect in dog lungs. 3. Pulmonary artery pressure‐flow (PPA/Q) relationships were studied over a wide range of flows. In pigs, sheep and human lungs perfused with Krebs‐dextran solution, L‐NAME increased the PPA/Q slope. This increase was reversed by sodium nitroprusside. In dog lungs L‐NAME had no effect. 4. In blood‐perfused lungs, the respective responses to L‐NAME were similar to those observed with saline. Acute hypoxia in pig and dog lungs increased intercept pressure. Addition of L‐NAME during hypoxia increased the PPA/Q slope in both species. 5. In the human, there was no difference in the absolute increase of PVR or PPA/Q slope elicited by L‐NAME between hypertensive and control lungs. 6. We conclude that NO is continuously released in the pulmonary vascular bed of pig, sheep and humans under normoxic conditions. In dog lungs inhibition of NO synthesis increases PVR only under hypoxic conditions. In human lungs with pulmonary hypertension, NO is still released under basal conditions.