effect of nifedipine on physiologic shunting and oxygenation in chronic obstructive pulmonary...

Effect of NiMipine on Physiologic Shunting and Oxygenation in Chronic Obstructive Pulmonary Disease LALITKALRA,M.D., M.R.C.P.(U.K.),P~.D.,MICHAELF.BONE,D.C.H.,M.R.C.P., Dudley, United Kingdom

P~~POSB To amem changes in physiologic shunting and oxygenation following short-term treatment with nifedipine in patients with pulmonary hypertension secondary to chronic obstructive pulmonary dieease.

PATIEXUTS AND METH0D43,t%m@t~ in pubnonary vaseuIar preraeure, pulmonary vaacubu resistance, venous admixture, and systemic arterial oxygen tension following subbngual administration of 20 mg of nifedipine were stud- ied in 18 patients (13 men, 5 women; mean age of 59.7 [SD 7.21 years) using Swan-Ganx catbeter- ixatior~ Tboae patients had a mean peak expira- tory flow rate of 112 (SD 27) Lhin (msan 22.2 [SD 12.21% of predicted value), mean forced ex- piratory volume in 1 second (F’EVi) of 0.84 (SD 023) L (mean 312 [SD 8.51% of predicted value), mean FEVi/forood vital capacity ratio of 31.6 (SD 4.5), and moan carbon monoxide diffusing capacity of 6.8 (SD 1.36) mmol/min/kPa.

IUBXJLTB There was a significant decrease in moan pulmonary va8ouIa.r resistance (662 to 371 dyne seo.om-5) and a significant reduction in the moan pubnonary arterial prossure (mean 32.8 to 23.6 mm Hg). Pulmonary venous admixture however, increased significantly from the &se- line mean of 44.6% (SD 16.1) to a mean of,56% (SD 15.6), and the mean arterial oxygen tension decreased from 5.8 (SD 1.3) kPa to 4.5 (SD 0.8) kPa at 60 minutes following drug administration (p <O.OOl).

CONCLUSION: The role of IdfedipiIIe in the treatment of pulmonary hypertension secondary to chronic bronchitis may be Iimitod because of its deletorioua effect on venous admixture.

From the Department of Chest Medicine, Russells Hall Hospital, Dud- ley. West Midlands, United Kingdom.

Requests for reprints should be addressed to Lalit Kalra, M.D., M.R.C.P.(U.K.). Ph.D., Orpington Hospital, Sevenoaks Road, Orpington BR6 9JU, Kent, United Kingdom.

Manuscript submitted April 1. 1992, and accepted in revised form October 12. 1992.

R ecent years have seen a resurgence of interest in the use of vasodilators in patients with car

puhnonale secondary to chronic obstructive puhno- nary disease [l-5]. So far, long-term oxygen therapy is the only treatment shown by controlled trials to prolong survival in these patients [6-S]. Many other drugs, especially vasodilators such as nifedipine, have also been tested but have not been as success- ful as oxygen in improving survival in this popula- tion [1,3-5,8-U].

Although mortality has been linked to the severity of pulmonary hypertension in patients with car pulmonale secondary to chronic bronchitis and emphysema [12-151, unequivocal statistical proof cor- relating improvements in pulmonary hemodynam- its with increased survival is lacking [5]. It is quite possible that the benefits seen with oxygen therapy may be due not only to its effects on pulmonary pressures [16] but also to selective vasodilation of the pulmonary vascular bed that improves oxygen delivery to the tissues [9]. In contrast, vasodilators such as nifedipine may reduce oxygenation by increasing physiologic shunting in these patients, and, despite reducing pulmonary pressures, may be of limited value. There is little information on the ventilation-perfusion consequences of vasodilators, but some studies show a decrease in arterial oxygen content following treatment with nifedipine [5,17-191.

The aim of the present study was to assess changes in physiologic shunting as measured by venous admixture following short-term administration of nifedipine in patients with pulmonary hypertension secondary to chronic bronchitis and emphysema.

PATIENTS AND METHODS Right heart catheter studies were performed on

13 men and 5 women with an average age of 59.7 (SD 7.2) years. All patients were known to have severe chronic obstructive airway disease with car pulmonale, and their functional ability was restrict- ed to class 3 or 4 on the New York Heart Association scale despite maximal treatment. Pulmonary func- tion tests in these patients included timed spirome- try using a 13.5-L water-sealed spirometer and single-breath diffusing capacity for carbon monoxide.

April 1993 The American Journal of Medicine Volume 94 419

EFFECT OF NIFEDIPINE ON PHYSIOLOGIC SHUNTING IN COPD / KALRA AND BONE

Spirometric indices, calculated from the best of three satisfactory breaths, showed a mean peak ex- piratory flow rate of 112 (SD 27) L/min (mean 22.2 [SD 12.21% of predicted value), mean forced expira- tory volume in 1 second (FEVi) of 0.84 (SD 0.23) L (mean 31.2 [SD 8.51% of predicted value), and mean FEVJforced vital capacity ratio of 31.6 (SD 4.5). The mean carbon monoxide diffusing capacity, de- termined in duplicate using 0.3% carbon monoxide and holding breath for 10 seconds [20], was 6.8 (SD 1.96) mmol/min/kPa in these patients. The values of carbon monoxide diffusing capacity were uncor- rected for hemoglobin or alveolar volume, but none of the patients had anemia or pneumonectomy.

Infection was excluded on the basis of history, clinical examination, chest radiograph, total/differ- ential white blood cell counts, and sputum micros- copy and culture for pathogens. Patients with evidence of left ventricular hypertrophy or myocardial disease on electrocardiography, a cardiothoracic ratio greater than 0.55 on chest radiograph, or left ventricular ejection fraction less than 50% at rest on M-mode echocardiography were excluded from the study. Treatment with theophylline was stopped 48 hours prior to the procedure, but other bronchodi- lators and steroids were continued to ensure maxi- mum achievable ventilation. The objective, tech- nique, and possible complications of Swan-Ganz catheterization were fully explained to the patients and consent was obtained prior to the procedure. The study was approved by the Ethics Committee of the Dudley Health Authority.

Procedure Patients were transferred to the intensive care

unit for the procedure. A percutaneous polythene catheter was inserted into the radial artery and a triple-lumen Swan-Ganz catheter was introduced into the pulmonary artery under constant pressure wave monitoring using the right jugular approach. The position of the catheter was confirmed by a chest radiograph. Systemic and pulmonary arterial pressures were measured directly using transducers corrected for patient position and atmospheric pressure. Values for pressure were averaged for three successive respiratory cycles. Blood gas analysis of various samples was done in duplicate using a semiautomatic blood gas analyzer (Corning, model 168).

Cardiac output was measured in triplicate by the thermodilution method using 10 mL of 5% dextrose at 4OC [21]. The Spectramed Haemopro I hemodynamic profile computer was used, which automati- cally calculates cardiac output by means of the Stewart-Hamilton formula [22]. Radial and pulmonary arterial blood samples were evaluated for arte-

420 April 1993 The American Journal of Medlclne Volume 94

rial and mixed venous blood gas values respectively. Pulmonary (PVRI) and systemic vascular resis- tances (SVRI) were calculated using the formulas:

PVRI = 8O(PAP - PAWP)/cardiac index

SVRI = 80(Ao - R&/cardiac index

where PAP = pulmonary artery pressure; PAWP = pulmonary artery wedge pressure; Ao = mean systemic arterial pressure; RA = right atrial pressure; and cardiac index = cardiac output/body surface area [23].

Physiologic shunting was calculated as the sum of anatomic shunting and venous admixture. It was assumed that anatomic shunting was constant and did not contribute significantly to subsequent changes in physiologic shunting. Venous admixture was defined as the degree of admixture of mixed venous blood with pulmonary end-capillary blood that would be required to produce the observed difference between the arterial and pulmonary end- capillary POz and represents the “shunt-like effect” due to areas of decreased ventilation/perfusion ratio [24]. Venous admixture was calculated by the formula:

Q,/Q, = (Cc’Op - CaOz)/(Cc’Oz - CvOJ

where Qs is the flow through the shunt, Qt is the cardiac output, Cc’02 is the oxygen content of the end-pulmonary capillary blood, CaOs is the oxygen content of the arterial blood, and CvOz is the oxygen content of the mixed venous blood. The oxygen contents of arterial and mixed venous blood were calculated from respective oxygen tensions using the oxygen dissociation curve and corrected for hemoglobin and pH. End-pulmonary capillary oxygen content was calculated from the alveolar air equa- tion assuming that end-pulmonary capillary oxygen tension was equal to the alveolar oxygen tension and the pH was the same as the arterial pH [24].

Patients were allowed 30 minutes to stabilize after insertion of catheters, following which baseline determinations were performed. Heart rate, blood pressure, and respiratory rate were monitored to ensure steady-state conditions for hemodynamic and oxygenation measurements. A single dose of nifedipine 20 mg was given sublingually, and observations were repeated at 30-minute intervals for 3 hours. Means and standard deviations were com- puted for variables measured. Significance of changes observed during repetitive measurements within individuals was assessed by two-way analysis of variance using a computerized statistical pro- gram (Minitab).

EFFECT OF NIFEDIPINE ON PHY9lOLOGE SHUNTING IN COPD / KALRA AND BONE

QslQt 44.6 (16.1) 54.1 (8.3) 56.0 (15.6) 55.8 (18) 54.1 (9.8) 46.3 (17.8) 3-5 % <O.OOl

\P = pulmonary artery pressure: PAWP = pulmonary artery wedge pressure; PVRI = pulmonary vascular resistance index; Pa02 = artenal oxygen tension; PaC02 = arterial carbon dioxide tension Qr /Qt = calculated pulmonary venous admrxture. *\I ‘S

‘alues in parentheses are standard deviations. ignificance determed using two-way analysis of variance. p co.05 if f(5,17) >4 34.

TABLE I

Hemodynamic and Oxygenation Response to Nifedipine 20 mg in 18 Patients With Pulmonary Hypertension Secondary to Chronic Obstructiie Airway Disease*

Measure 0 30

Minutes Normal 60 90 120 180 Range Units VaPuet

PAP

Systolic 46.9 (15.4) 31.5 (10.11 35.2 (8.7) 31.1 (8.7) 34.2 (7.7) 41.2 (13.2) mm Diastolic 24.9 (8.9) 16.0 (5.1) 15.8 (5.0) 18.1 (8.8) 19.7 (6.4) 22.0

Hg (8.4)

l&3$ mm E

Mean 32.8 (10.7) 21.5 (6.2) 23.6 (6.4) 22.6 (9.3) 24.3 (8.7) 30.6 Hg

(7.7) 10-22 mm Hg <O.Ol

PAWP 9.4 (7.7) 7.3 (4.9) 8.4 (4.3) 8.7 (4.3) 8.6 (3.9) 8.8 (6.3) 5-13 mm He NS

PVRI 562 (173) 386 (118) 371 (148) 357 (176) 394 (163) 492 (164) 225-315 dyne sec.cm-5 < 0.005

Pa02 5.8 (1.3) 4.5 (0.9) 4.5 (0.8) 4.8 (1.5) 4.8 (0.7) 5.5 (0.9) 11-13 kPa < 0.001

PaC02 6.6 (0.7) 6.6 (0.6) 6.6 (0.4) 6.5 (0.7) 6.3 (0.5) 6.3 (0.7) 4-6 kPa NS

RESULTS Baseline observations showed moderate to severe

pulmonary hypertension, increased pulmonary vascular resistance, increased venous admixture, and hypoxemia in all patients (Table I). The peak effect of nifedipine on pulmonary hemodynamic and oxygenation parameters was seen 30 to 60 minutes after administration of the drug and lasted for 3 hours. Mean pulmonary vascular resistance decreased (p <0.005) and was associated with a significant reduction in mean pulmonary arterial pressure (p <O.Ol). Mean pulmonary venous admixture increased (p <O.OOl) and mean Pa02 decreased significantly in these subjects (Table I). PaCO2 levels were unaffected and remained unchanged during the period of observation. Heart rate, blood pressure, and respiratory rate did not vary significantly during oxygenation determinations.

Systemic vascular resistance decreased from 1,456.0 (SD 196.3) to 927.8 (SD 97.7) dyne sec.cmV5 and the mean systemic arterial pressure fell from 88.3 (SD 5.8) to 71.6 (SD 6.6) mm Hg at 30 minutes, but the mean cardiac index increased from 3.24 (SD 0.18) to 4.38 (0.36) L/min/m2. These values remained unchanged during the rest of the study.

COMMENTS Treatment with nifedipine was associated with

an increase in physiologic shunting as measured by pulmonary venous admixture resulting in a deterioration in arterial oxygen tension. This deterioration in oxygenation occurred despite a significant decrease in pulmonary vascular resistance and reduction in pulmonary arterial pressure in patients with chronic bronchitis associated with car pulmonale.

There is unequivocal evidence that long-term oxygen therapy increases survival in patients with car pulmonale secondary to chronic obstructive lung disease [6,7,9]. Since mortality is related to the severity of pulmonary hypertension in these patients [12-151, it was generally believed that the beneficial effects of oxygen were due to improvement in pulmonary hemodynamics [ 161. However, long-term oxygen therapy lasting 15 to 18 hours per day has its shortcomings and limita- tions [2]. Several alternative therapeutic options for correcting pulmonary hypertension in car pulmonale have been tried in recent years, but their effects remain controversial [l-5,10]. Short- term studies using nifedipine (10 to 20 mg sublingually) in patients with car pulmonale have shown a decrease in pulmonary vascular resistance with improvement in pulmonary hemodynamics and cardiac output [25-271. Long-term studies, however, suggest that treatment with nifedipine does not result in symptomatic improvement and patients continued to deteriorate clinical- ly despite persistent hemodynamic improvement [11,28,29].

Oxygen selectively vasodilates the pulmonary vascular bed, increasing oxygen delivery and mixed venous oxygen tension in addition to reducing ele- vated pulmonary artery pressures [9]. The superior- ity of oxygen over other vasodilators suggests that oxygen delivery, in addition to reduction in pulmonary arterial pressure, may contribute to improved survival [2]. In the absence of accurate noninvasive methods of assessing the complex dynamics of blood-gas exchange, most studies on pulmonary vasodilators have concentrated on the more immedi-

April 1993 The Amerlcen Journel of Medlclne Volume 94 421


ate problems of pulmonary hemodynamics rather than on oxygenation changes.

The effect of vasodilators on ventilation-perfusion imbalance is largely unknown. Increase in pulmonary vascular tone by almitrine-induced stimu- lation of peripheral chemoreceptors is known to improve gas exchange in patients with advanced obstructive airway disease [30]. It is also known that pulmonary vasodilation secondary to sodium nitroprusside infusion results in the opposite effect with aggravation of the ventilation-perfusion imbalance [31]. Improved oxygen delivery following nifedipine administration has been reported in healthy subjects in whom hypoxic pulmonary hypertension was induced during high-altitude studies [32,33]. An increase in carbon monoxide diffusing capacity after a low dose of nifedipine has also been reported in patients with car pulmonale [19], but most studies show a decrease in arterial oxygen saturation with nifedipine in these patients [5,25-271. A worsening of physiologic shunting was suspected but it was presumed that the improvement in cardiac output would improve overall oxygen delivery to the tissues [5,25].

This study shows a significant increase in venous admixture following nifedipine administration. The mechanism for this effect of nifedipine in patients with car pulmonale is a matter for specula- tion. Hypoxia increases cytoplasmic calcium con- centration in vascular smooth muscle cells by interfering with their ability to maintain trans- membrane gradients, thus activating the contrac- tion apparatus and producing sustained vasoconstriction [34]. Nifedipine has been shown to impair this hypoxic pulmonary vasoconstriction in a dose- dependent manner in animal models [35,36]. Indi- rect evidence suggests that a similar mechanism causing nonselective pulmonary vasodilation may operate in humans and would explain improvements in oxygenation seen in healthy subjects treat- ed with nifedipine during high-altitude studies [32,33]. However, in patients with car pulmonale, nifedipine-induced nonselective pulmonary vasodilation coupled with improved cardiac output would increase perfusion not only through well-ventilated but also through poorly ventilated alveoli, resulting in increased venous admixture and deterioration in oxygenation.

There is increasing evidence that changes in oxygen delivery following treatment with vasodilators are an important issue in pharmacologic management of pulmonary hypertension secondary to chronic bronchitis and emphysema. Although one possible mechanism for reduced oxygenation has been demonstrated in this study, further research and long-term controlled clinical trials, perhaps in

422 April 1993 The American Journal of Medicine Volume 94

combination with oxygen, are needed. Vasodilators should be used with caution in patients with car pulmonale until their benefits and, more impor- tantly, lack of significant adverse effects are un- equivocally established.

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effect of nifedipine on physiologic shunting and oxygenation in chronic obstructive pulmonary...

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