Noninvasive Tests for Responsiveness of Pulmonary Hypertension to Oxygen

III. ~§~

------4

clinical inVeSligaliOnS Noninvasive Tests for Responsiveness of Pulmonary Hypertension to Oxygen* Prediction of Survival in Patients with Chronic Obstructive Lung Disease and Cor Pulmonale Kumar Ashutosh, M.D.;t and Milton Dunsky, M.D.:t.

Response of mean pulmonary artery pressure (PAP) to breathing oxygen for 24 hours was measured in 43 patients with chronic obstructive pulmonary disease and cor pulmonale (COPD-CP). Considering a ~5 mm Hg fall in PAP after breathing 28 percent oxygen for 24 hours to be a significant response to oxygen administration, 25 and 18 patients were identified as responders (R) and nonresponders (NR), respectively. Oxygen consumption at the end of a symptom-limited maximum exercise (V02 peak) and right (RVEF) and left ventricular (LVEF) ejection fractions by nuclide ventriculography (NVC) were also obtained, and the changes (L\) in RVEF-and LVEF after 48 hours of oxygen breathing recorded. All patients were prescribed continu-

ous long-term domiciliary oxygen therapy (CLTO) and followed up as outpatients. Thirty-three patients have completed the follow-up for three years or until their deaths. The R showed a markedly higher survival compared to the NR at 1,2, and3years. A high V02 peak (>6.5 ml min -I kg") was significantly associated with R status and also predicted two- and three-year survival. A baseline EF or ~EF of right or left ventricles could not be used to predict either the response of PAP to O 2 or the long-term survival, although ~LVEF was significantly higher in the R. Response of PAP to breathing O 2 for 24 hours is a reliable indicator of at least three-year survival with CLTO, which can be predicted noninvasively by baseline V02 peak.

Continuous long-term oxygen therapy (CLTO) is widely used in the treatment of patients with cor pulmonale (CP) secondary to chronic obstructive pulmonary disease (COPD).l However, many patients continue to do poorly in spite of CLTO, 2.3 and identify-

requires pulmonary arterial catheterization, an invasive procedure with a definite morbidity and even poten tial mor tal ity.Y which limits its clinical usefulness. Our preliminary observations suggested that a change in the left ventricular ejection fraction (LVEF) determined by 99mTc nuclide ventriculography (NVC) on breathing 28 percent oxygen for 48 hours and the symptom-limited maximum oxygen consumption determined by an incremental workload exercise (\70 2 peak) could indicate a good response to oxygen therapy and predict two-year survival. 5 The current study was undertaken to test the value of these noninvasive measurements in predicting responsiveness of PAP to oxygen and long-term survival with CLTO in patients with COPD-C~ We also intended to test whether the predictive value of PAP for survival continued to be significant over a longer period of follow-up and whether the severity of pulmonary hypertension influenced the predictive value of this measurement.

For editorial comment see page 387 ing these patients would be helpful not only as a guide to prognosis but also for planning additional therapeutic measures. 4 We previously reported" that a ~5 mm Hg fall in the mean pulmonary artery pressure (PAP) on breathing 28 percent oxygen for 24 hours is a significant predictor of two-year survival in patients with COPD-CP who are treated with CLTO and probably indicates the responsiveness of the pulmonary artery' pressure (PAP) to oxygen administration. However, measurement of PAP *From the Pulmonary Disease Section, Department of Medicinet, and Department of Nuclear Medicinef, Veterans Administration Medical Center and SUNY Health Science Center at Syracuse, NY. Manuscript received October 27; revision accepted January 8. Reprint requests: Dr. Ashutosh, VA Medical Center, 800 Irving Avenue, Syracuse 13210

MATERIALS AND METHODS

Patients attending the Chest Clinic at the Veterans Administration CHEST I 92 I 3 I SEPTEMBER, 1987

393

Medical Center at Syracuse were selected for the study on the basis of the presence of CO PD as determined by a forced expiratory volume in one second (FEV 1) <70 percent of predicted and FEV/ forced vital capacity (FVC) ratio <65 percent, arterial P0 2 (PaOJ of less than 60 mm Hg at rest or exercise, and present or past clinical evidence of right heart failure as documented by peripheral edema, neck vein engorgement, and right ventricular gallop. Patients with any evidence of left ventricular or myocardial disease by history, physical examination, radiologic assessment of the heart, or ECG were excluded from the study. Patients already being treated with LID or suffering from an acute illness ofany kind were also excluded. Subjects selected for the study underwent a 99mtechnetiumlabeled red blood cell (RBC) nuclide ventriculography (NVG) by an equilibrium-gated technique." After IV administration of stannous pyrophosphate, RBCs were labeled by IV administration of20mCi of 99m'fc pertechnetate. The radioactivity was measured over the precordium after one hour of injection by a single-crystal gamma camera. The borders of right and left ventricles were defined in left anterior oblique projection, and the systolic and diastolic volumes were estimated by computer analysis (Brattle EKG, Medical Data Computer System) of the nuclide counts over the respective ventricles. Ejection fraction (EF) was defined as the fractional change in the venticular volumes and was calculated as (diastolic volume - systolic volume)/(diastolic volume). All measurements were made by the same investigator (M. D.) using the same criteria for defining the left and right ventricular borders. With experience, the reproducibllity of the measurement of RVEF was brought to ±.02 for the same study. If a greater variation between different measurements was found, the average of two closest readings was taken as the Elf: The maximum variation noted in RVEF measurement within the same study was .06 in one instance. After completion of the NVG procedure, patients performed symptom-limited maximum exercise at a workload of25 to 50 W on a bicycle ergometer by the method previously described." Oxygen consumption (VoJ at rest and exercise was measured using 30second collections of expired gas in airtight collecting bags, Tissot spirometer for measuring gas volumes, and a mass spectrometer (Perkins Elmer) for measuring fractional concentration of oxygen and carbon dioxide in the expired air samples. V0 2 over the last 30 seconds of exercise was recorded as the symptom-limited peak oxygen consumption (V02 peak). Arterial blood gases were collected at rest and at the end of exercise. After four to six hours of complete bed rest following the exercise, a right heart catheterization was performed using a balloon-tipped, How-directed catheter and right atrial, right ventricular, pulmonary arterial, and pulmonary capillary wedge pressures were recorded. Cardiac output (CO) was obtained as an average offive closest values from a total of seven measurements made by thermodilution technique. Right atrial, right ventricular, systolic, diastolic, and mean PAP and pulmonary capillary wedge pressures were recorded. All of the above measurements were made with zero reference point at midthorax in the supine position and during a relaxed pause in respiration at functional residual capacity. Patients in whom the pulmonary capillary wedge pressure was found to be > 15 mm Hg or those in whom the mean PAP was <20 mm Hg were excluded from the study. The remaining patients were then given 28 percent oxygen to breathe continuously through a Venturi mask except during meals, when oxygen was administered by nasal cannula at the rate of2 Umin. All of the above measurements were repeated the next day, after about 24 hours, and the pulmonary arterial catheter was removed. Patients continued to breathe 28 percent oxygen, and NVG was repeated the next morning, ie, about 48 hours after the first procedure. The LVEF and right ventricular ejection fraction (RVEF) were again estimated. The patients were divided into two groups, responders (R) and nonresponders (NR), consisting of patients with ~5 (R)and <5 (NR) mm Hg fall in mean pulmonary artery pressure (PAP), respectively, 394

after breathing 28 percent oxygen for 24 hours. Also, patients with a V0 2 peak of ~6.5 mllmin -1 kg- 1 were classified as having high V0 2 peak compared with those in whom this was lower than the above value. These criteria separating R from NR and patients with high V0 2 peak from those with low V0 2 peak were determined in our previous study" and were followed unchanged during the present work. All patients were prescribed CLID by nasal cannula to be taken at the rate 2 Lpm continuously or for at least 20 hours daily and were followed up by the investigators in the Chest Clinic of the SVAMC at two- to three-month intervals or sooner, if required on the basis of their clinical condition. Compliance was monitored by interviewing the patients, reports by visiting nurses, and by the amount of oxygen used by the patients as determined by the monies paid to the oxygen supply companies by the VA. The difference between two groups was statistically analyzed using Student's t test for unequal numbers of unpaired observations and from X2 with Yates' correction using 2 X 2 contingency table." Sensitivity, specificity, positive and negative predictive values, and efficiency of tests were calculated using Bayes' theorem.P'" Ninetyfive percent confidence range for the predictive values of tests were calculated using "exact" confidence limits for binomial distribution

tables."

RESULTS

Since our earlier report on 28 patients, 15 new patients were recruited for the study. As the new patients were similar in all other respects to the previous ones, the data on all 43 patients were combined for analysis. NVC was not available in 22 patients studied earlier and had to be discarded on two of the remaining 21 patients, as one was inadvertently digitalized between the first and second study, and another patient could not lie down for NVC during the second study. Hence, the NVC measurements pertain to only 19 patients. Baseline measurements on these patients are shown in Table 1. R had significantly higher hemoglobin (Hb) and \70 2 peak. & and NR were similar in all other respects. All were elderly male veterans. All had been heavy cigarette smokers in the past and claimed to have quit or markedly reduced smoking once CLTO was Table I-Selected Measurements (Mean ± SD) in Responders (R) and Nonresponders (NB) R No. Age, yr FEV 1 L FVC,L Hb Resting Pa02 , mm Hg PaC02 , mm Hg Exercise Pa02 , mm Hg PAE mm Hg CO, Umin PVR, dynes sec cm -5 V02 peak, ml/min " kg" LVEF, % RVEF, %

NR

25 18 59.4±7.55 61.9±4.95 0.85±0.20 0.76±0.57 1.94±0.75 2.05±0.58 17.4±2.1 14.9±1.7 54.6±8.20 53.8±17.6 47.0±7.91 5O.8± 11.0 49.0±6.0 45.6±9.0 37.3 ± 10.8 33.2 ± 10.14 5.48± 1.67 5.33± 1.63 471.5 ± 172.9 413.4 ± 110.8 8.61 ± 3.15 6.65 ± 3.52 53.3± 11.9 55.4± 11.6 19.5± 15.7 24.4± 15.4

P Value <0.3 <0.5 <0.5 <0.001* <0.5 <0.2 <0.2

<0.3

<0.5 <0.2 <0.05* <0.5 <0.5

*Statistically significant. Responsiveness of PulmonaryHypertension to Oxygen (Ashutosh, Dunsky)

Table 2-Changes in Selected Patient Measurements (Mean±SD) After Breathing 28% OJ/or 24 to 48 Hours

Pa02 , mm Hg PaC02, mm Hg PA~ mm Hg

PVR, dynes sec em -5 LVEF RVEF

R

NR

P Value

+21±14 + l.S±3 -9.64±6.5 -132.1±92.4 +.035±.076 -.024±.054

+16±11 +3±4.2 -0.27±2.51 -14.2±62.4 -.033±.061 - .0044± .041

<0.3 <0.2 <0.001* <0.001* <0.05* <0.4

*Statistically significant. instituted. It was not possible to determine the duration of COPD in these patients with precision, but they all had had respiratory symptoms for more than a decade. As mentioned earlier, all studies were done when the patients were in stable clinical condition and free from any overt acute illness. Table 2 shows the changes (d) in the different measurements after breathing 28 percent oxygen for 24 hours. As the Rand NR were defined on the basis of a fall in the pAP, the difference in the PAP and pulmonary vascular resistance (PVR) response to breathing oxygen between the two groups was expected. However, there was also significant difference in LVEF between the two groups. Thus, V02 peak, Hb, and LVEF were significantly different in the R and NR. Subjects with a V0 2 peak >6.5 ml/min " kg:', Hb 2:I8G, or LVEF >+0.01 were more likely to be R than NR (Table 3). No other measurement could differentiate between the two groups. Table 4 shows the sensitivity and specificity as well as the predictive values of noninvasive tests in identifying R and NR. V0 2 peak showed significant efficiency as a test (X2 = 4.49; p<. 05) in correctly identifying the two groups. Although LVEF had an overall efficiency of O. 79 in correctly identifying the R or NR patients, its usefulness as a test was limited, because if a change of at least 0.05 was considered to'be significant as is currently accepted.v" the efficiency of an increase in RVEF and/or LVEf in predicting PAP Table 3-Number ofB and NB Subjects Grouped According to the Results ofSelected Tests No. of Subjects Test

Result

R

NR

\702 peak, mllmin- 1 kg- 1

>6.5 <6.5 2=18 <18 2= + .01 <+.01 2:+.03 <+.03

15 5 11 13 8

5 10 0 15

Hb, G dl" 4LVEF

*p<.05. tp<.ool.

2

6 4

2

7 1 8

2

X

4.49* 7.45t 4.23* 2. 99(NS)

response to O 2 was only 0.68. Even using an increase of 0.03 as the criterion for improvement in ejection fraction, only six of ten (60 percent) R and one of nine (11 percent) NR showed an improvement in RVEF or LVEF (X2 = 2.99; NS). Thirty-five and 33 subjects have now been followed for at least two and three years, respectively, or until their deaths. These include ten additional subjects, five R and five NR, followed up for two years since our previous study. Of these ten subjects, two R and three NR have died within two years. The numbers are too small to be analyzed statistically. The remaining eight patients are alive at the time of writing with less than one year of follow-up. Percent survival with the passage of time of all patients in the two groups is shown in Figure 1. The R had a significantly higher survival compared with the NR at one year and thereafter throughout the period of follow-up. The survival curves of our patients are compared with the control male patients of the British Medical Research Council study" who did not receive oxygen. The NR show a much lower survival, even though they received CLTO. The R, on the other hand, not only have a significantly improved survival compared with these patients, but also their survival is similar to patients younger than 65 years of age treated with CLTO in the Nocturnal Oxygen Therapeutic Trial Group study," No difference between the subjects who survived for two years and those who did not was observed in age, NVG, FVC, PAE baseline P02 , hemoglobin, or cardiac output (Table 5). Table 6 shows the numbers of patients surviving for two and three years and their relationship with tests for prediction of survival. Response ofID to oxygen and to a lesser extent, \'02 peak showed statistically the most significant difference between survivors and nonsurvivors. An FEV1 of 0.85 L also separated survivors from nonsurvivors but at a lower level of significance compared with the above two tests. A greater number of patients with Pco, s50 mm Hg or d~F 2:0.03 survived than those with Pc02 >50 or dEF <0.03, but the difference was not significant. We also analyzed the response of PAP to oxygen and survival in patients grouped according to the severity of pulmonary hypertension. Twenty subjects, 14 Rand six NR, had baseline PAP >30 mm Hg. Nine (64 percent) R but none of the NR survived for three years (X2=4.65, p<.05). Fourteen patients (seven R and seven NR) had baseline PAP <30 mm Hg. Six (86 percent) R and one (14 percent) NR survived for three years (X2 = 4.53, p <.05), while seven R but only two (29 percent) NR survived for two years (X2 = 4.97, p <.05). Responsiveness of the PAP seemed to be important for survival irrespective of FEV 1 or PaC02 • Eight patients with FEV1 <0.85 and 'two patients with PaC02 CHEST / 92 /3/ SEPTEMBER, 1987

395

Table 4-Predictive Values ofTests for Identifying PAP BeaponsiveneBs*

Sens-Spec

Test V0 2 peak, >6.5 mVmin- kgdLVEF, ~ + .01 dRlLVEF, 2: + .05 dRlLVEF: 2: + .03 Hb,' ~18 gldl l

0.75-0.66 0.80-0.77 0.50-0.89 0.60-0.88 0.44-1.00

l

Positive Predictive Value 0.75 0.80 0.83 0.85 1.00

Negative Predictive Value

(.51-.91) (.44-.97) (.28-.99) (.42-.99) (.71-1.0)

0.66 0.77 0.61 0.66 0.57

Efficiency

(.38-.88) (.40-.97) (.29-.82) (.35-.91) (.33-.71)

0.71 0.79 0.68 0.74 0.67

(.54-.85)t (.54-.94)t (.38-.83) (.40-.91) (.48-.79)

*Sens = sensitivity; Spec = Specificity; RlLVEF = change in RVEF and/or LVEF; V0 2 peak = oxygen consumption during symptom-limited maximum exercise. Numbers in parentheses indicate ±95% confidence range. tStatistically significant (p<.05).

>50 survived for two years. All except one were R. Similarly, two patients with FEVl >0.85 and six patients with PaC02 <50 died within two years. All of them were NR. Table 7 gives the sensitivity, specificity, and positive and negative predictive values for survival and efficiency of selected tests. Ninety-five percent confidence ranges for predictive values are also shown. Highest predictive values are noted for PAP response and V02 peale The FEVl also has Significant predictive values but is less efficient than PAP or V0 2 peak. The Pe02 and EF have lower predictive values which are not significant. Thirteen subjects in whom both V0 2 peak and NVC were obtained have been followed up for two years. Three subjects who had both a significant improvement in NVC and a high V0 2 peak are alive at the end of two years. On the other hand, all three subjects in whom there was no improvement in NVC and the V0 2 peak was <6.5 ml/min " kg- l were dead less than one year after the study. Six other subjects had an improvement in NVC but had a low V0 2 peak. One subject had a high V02 peak but showed no improvement in NVC. Two of these subjects died before completion of twoyear follow-up, and the remaining five have survived for two years or more. The present work extends the findings of our previTable 5-Selected Baseline Measurements (Mean ± SD) and Two-year Survival

No. Age, yr P~ mean, mm Hg FEV l , L FVC,L VOl peak, mVmin- l kg"! POI' mm Hg Peot , mm Hg Hb, g/dl " LVEF, % RVEF, % *Statistically significant.

100

co > .>

Nonsurvivors P Value

21 14 59.5±6.4 59.3±5.8 34.15± 11.33 33.14± 12.12 0.68±0.29 1.01±0.54 2.14±0.86 1.72±0.60 8.89±3.81 5. 72± 1.17 54.0±8.2 52.2± 10.6 44.2±8.5 51.4±7.2 16.3±2.5 15.8±2.3 51.3±9.13 49.5± 12.1 24.6±9.91 23.3± 13.5

<0.05 <0.05 <0.01* <0.1 <0.01* <0.5 <0.02* <0.5 <0.05 <0.5

80

~

~

(J)

DISCUSSION

Survivors

ous reports that a significant fall (~5 mm Hg) in PAP is a reliable predictor of prolonged survival in patients with COPD-CP who are treated with CLTO. In addition, this study shows that the strong correlation between the' PAP response to oxygen and prolonged survival persists for at least three years, with high positive and negative predictive values and is noted in patients with both severe and mild grades of pulmonary hypertension irrespective of the baseline pulmonary function tests or the results of arterial blood gas analyses. The specific purpose of this study was to develop noninvasive tests which could predict the responsiveness of PAP to oxygen in patients with COPD-CE Two tests which appeared promising in our previous study" were examined and their correlation with an R or NR status and with two-year survival indicated that a ml" kg:' min-I) identified a high V0 2 peak (~6.5 favorable response to oxygen and predicted long-term survival with positive and negative predictive values

60

+--'

c o

Q)

40

~

(1)

0...

20 0

6······6 COT

.'--.

BMRC-C

0---0

R

~.~

NR

0

2

3

Years FIGURE1. Survival curves in the responders (R) and non responders (NR). Asterisks, significant differences in survival between the Rand NR in our patients. Curves are compared with survival in untreated male patients (BMRC-C) with COPD-CP in British Medical Research Council Study" and in younger patients «65 years) treated with continuous oxygen therapy (COT N01T) in the noctural oxygen therapy trial study (Anthonisen et a116). Responsiveness of Pulmonary Hypertension to Oxygen (Ashutosh, Dunsky)

Table 6-Number ofSurvioon and Non-aurviOOn After two and ria,.. Yean ofFollow-up in Patienta Grouped According to tlee Baulta ofDifftmmt Predicting Tem Survivors Test PA~

2;-5 <-5

mm Hg

V02 peak, ml min- l kg- l

~6.5

<6.5 2;0.85 <0.85 <50 2;50 2;.03 <.03

FEV l , L PaCO t , mm Hg ~EF

Nonsurvivors

)(2

2 Yr

3 Yr

2 Yr

3 Yr

2 Yr

3 Yr

17 4 13 4 13 8 14 3 5 2

15 1 11 2 10 6 12 2 2 1

4 10 3 10 2 12 6 8 2 1

6 11 4 11 4 13 7 8 3 4

7.54*

9.7t

6.42t

7.21*

5.95t

4.62+

3.64

3.31

0.24

0

*p<.Ol. tp<.OOl. tStatistically significant (p<.05).

of prognostic significance. The significant predictive values of FEV. and V02 peak as we noted are in agreement with the above-mentioned studies. The significance of the present study lies in showing that the fall in PAP after breathing 28 percent O 2 for 24 hours is a more efficient test for long-term survival than any other baseline pulmonary function test, and further, among the noninvasive tests, V02 peak has the best correlation with the responsiveness of PAP to O 2 , Although all subjects with Hb ===18 G percent were R, the predictive value ofHb for identifying R from NR was only 0.67 (95 percent confidence interval, 0.48 to 0.79; NS), because an almost equal number of R and NR had Hb <18 G percent. Similary, Hb did not reliably predict two- or three-year survival in our study. We are unable to explain why the subjects with Hb ===18 G percent were invariably R. Incidence of smoking or intercurrent infections was similar in both groups. Phlebotomy is seldom used in our institution and was not responsible for the lower Hb in patients.

almost equal to that of a direct measurement of PA~ But, in contrast to our preliminary impression, NVG alone could not be used as a test for identification of the PAP response to oxygen or long-term survival, mainly due to an inability to detect small changes in EF: However, presence of both a high V02 peak and an increase in RVEF or LVEF was associated with favorable PAP response to oxygen and two-year survival and their absence with poor response to oxygen and early death in our group of patients. Predictive value of the combination of V02 peak and 4EF may be better defined if a larger number of patients were studied. In addition, measurements of EF during exercise might yield useful information, but our study protocol did not allow us to perform this experiment. The FEV1 has been shown to be an important predictive test for long-term survival by many investigators.2.16.21.22 Other measurements including PaC02 , RBC mass," maximum work capacity," and change in PAP with time'':" have also been found to be

Table 7-SeMitivity, Specificity and Predictive Value.

Test ~PAP,

- 5 mm Hg

VOl peak, 6.5 ml/min " kg- l FEVl , 0.85 L

PaCO t , 50 ~EF

.03

Duration of Survival, yr

Sensitivity

Specificity

2 3 2 3 2 3 2 3 2 3

0.81 0.93 0.76 0.84 0.61 0.62 0.82 0.85 0.71 0.66

0.71 0.64 0.77 0.73 0.85 0.76 0.57 0.53 0.60 0.57

ofSelected TeBta·

Positive Predictive Value 0.81 0.71 0.81 0.73 0.86 0.71 0.70 0.63 0.71 0.40

(.58-.94) (.48-.89) (.54-.96) (.49-.91) (.59-.98) (.42-.92) (.46-.88) (.38-.84) (.30-.96) (.05-.85)

Negative Predictive Value 0.71 0.92 0.71 0.84 0.60 0.68 0.72

(.42-.92) (.61-1.00) (.61-1.00) (.57-.98) (.36-.80) (.~.87)

(.39-.94) ~.8O (.44-.97) 0.60 (.51-.95) 0.80 (.28-.99)

Efficiency 0.77 (.60-.90)t 0.79 (.61-.91)t

0.76 0.78 0.71 0.69 0.70 0.69 0.66 0.60

(.58-.90)1 (.59-.92)t (.54-.85)1 (.51-.84)1 (.52-.86) (.49-.85) (.26-.88) (.26-.88)

*Numbers in parentheses indicate 95% confidence range. tp<.OI. tp<.OOI0. IStatistically significant (p<.05). CHEST I 92 I 3 I SEPTEMBER. 1987

397

The lower Hb could be a reflection of the poorer general condition of the NR, but our study does not provide any data to support this speculation. The correlation of\102peak with the responsiveness of the. PAP to therapy has been also noted by others. Recently, D' Alonzo et al26 reported a significant association of \102 peak with responsiveness of the PAP to vasodilators. It is possible that both the \102 peak and the response of PAP to O 2or to vasodilator therapy are indicators of the severity and irreversibility of the pulmonary vascular abnormalities in patients with COPD-CE which might also explain their relationship with prognosis in these patients. An improvement in RVEF after breathing oxygen for 48 hours occurred only infrequently. Four and six of our 19 subjects showed improvement of>. 03 in RVEF and LVEF, respectively, after breathing O 2 for 48 hours. The lack of improvement in RVEF in most cases does not appear to be from limitations of the technique used, as this has been found satisfactory for detecting changes in RVEF by other workers. 9.10 Morrison et al27 have recently studied the change in RVEF after three months of O 2 therapy in patients with COPD-CP utilizing an equilibrium-gated steady-state NVC technique almost identical to that used by us. They also noted that the changes in RVEF did not correlate with those in the PA~ and six of their 12 patients showed no improvement in RVEF after three months of O 2 therapy. The lack of improvement in RVEF in the majority of patients probably indicates a reduced capacity of the right ventricular function to recover in patients with long-standing CE Presence of subclinical left ventricular dysfunction which improved with oxygen could explain the increase in LVEF in many of our patients. As we did not have a control group of patients not treated with CLlD, we are unable to draw any conclusions about whether CLlD was helpful in any of our subjects. However, as two- and three-year mortality in the R was only 20 percent and 30 percent, respectively, which is similar to patients treated with CLlD by other investigators" and is lower than even the lowest estimate of mortality in COPD-CP in some other studies,12.16.24.25 our results are compatible with an improvement in survival with CLlD in these patients. On the other hand, the 77 and 92 percent mortality seen within two and three years, respectively, in our NR patients is so high compared with patients with COPDCP treated without oxygen by other investigators3.21-23.25 that a favorable influence on survival by CLlD cannot be recognized. Although the results ofCLTO are very unsatisfactory in the Nfl, we do not recommend withholding CLlD therapy from these patients, because the possibility of some benefit from CLlD cannot be ruled out. However, if additional therapeutic measures, eg, reduction 398

of hematocrit;" diuretics," cardiac inotropic agents, 30 vasodilators," calcium antagonists or almitrine" are contemplated, their use should be especially valuable in these patients. Whether the above forms of treatment will in fact alter the natural history of the disease is unknown at this time, and clarification of their role awaits further research in this area. ACKNOWLEDGMENTS: The authors wish to thank Drs. J. H. Auchincloss, R. Gilbert, and H. Smulyan for their valuable criticisms and suggestions and the workers in the Word Processing Center and Ms. Linda Gomes for typing the manuscript.

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16 Anthonisen NR, Wright EC, Hodgkin JE , IPPB Trial Group. Prognosis in chronic obstructive pulmonary disease . Am Rev Respir Dis 1986; 133:14-20 17 Steel RGD, Torrie JH. In : Principles and procedures of statistics , 1st ed . New York: McGraw Hill, 1960 18 Griner PF, Mayewski RJ, Mushlin AI, Greenland P. Principles of test interpretation: predictive values of diagnostic tests and procedures. Ann Intern Med 1981; 94(pt 2):565-70 19 Gaylen RS. False positives . Lancet 1974; 2:1081 20 Diem K, Lentner C. In : Scientific tables , Documenta Geigy. Ardsle y, NY: Geigy Pharmaceuticals, 1974 21 Bushy SF, Coates Of). The prognostic value of pulmonary function tests in emphysema, with special reference to arterial blood studies. Am Rev Respir Dis 1964; 90:553-63 22 Renzetti AD, McClement JH, Lilt BD. The Veterans Administration Cooperative Study of pulmonary function . Am J Med 1966; 41:115-29 23 Ude AC, Howard P. Controlled oxygen therapy and pulmonary heart failure . Thorax 1971; 26:572-78 24 Jones NL , Burrows B, Fletcher CH . Serial study of 100 patients with chronic airway obstruction in London and Chicago . Thorax 1967; 22:327-335 25 Weitzenblum E, Santigean A, Ehrhart M, Mammosser M, Hirth C, Roegel E. Long term course of pulmonary arterial pressure in chronic obstructive pulmonary disease . Am Rev Respir Dis 1984;

130:993-98 26 D'Alonzo GE , Gianotil, Dantzker DR. Noninvasive assessment of hemodynamic improvement during chronic vasodilator therapy in obliterative pulmonary hypertension . Am Rev Respir Dis 1986; 133:380-84 27 Morr ison DA, Henry R, Goodman H . Prelim inary study of the effects of low /low oxygen on oxygen delivery and right ventricular function in chronic lung disease . Am Rev Respir Dis 1986; 133:390-95 28 Weisse AB, Moschos CB, Frank MJ, Levinson MD. Cannila SE , Regan TJ. Hemodynamic effects of staged hematocrit reduction in patients with stable cor pulmonale and severely elevated hematocrit levels. Am J Med 1975; 58:92-98 29 Heinemann HO. Right-sided heart failure and the use of diuretics. Am J Med 1978; 64:367-70 30 Mathur P, Powles ACp' Pugsby SO, McEwan MP, Campbell EJM . Effect of digoxin on right ventricular funct ion in seve re chronic airflow obstruction. Ann Intern Med 1981: 95:283-88 31 Sirnonneau, Escourrou P, Duroux P, Lockhart A. Inhibition of hypoxic pulmonary vasoconstruction by nifedipine. N Engl J Med 1981; 304:1582-85 32 Arnaud F, Bertrand A, Charpin J, Decroix G, Guerrin F. Kalb JC, et aI. Almitrine bimasylate in long-term treatment of patients with chronic bronchitis. Bull Eur Physiopatho\ Respir 1982; 18 (suppl 4):87-93

Who are the pulmonary specialists in Tucson?

I need a cardiology consultant in Cleveland. How can I find qualified consultants in cardiothoracic surgery in the southwest suburbs of Boston?

THE NEW, COMPREHENSIVE 1988 ACCP MEMBERSHIP DIRECTORY The new Directory can answer your questions about referrals better than ever before . It will be an authoritative guide to current interests, residency and specialty training, education and principal specialty of qualified consultants in the US, Canada and worldwide. The Directory, an invaluable reference to members and colleagues, will now feature alphabetic, geographic and specialty listings for easier referral. FCCP: Cite these letters with pride. They represent peer recognition of your unique status as a consultant in the disciplines of the American College of Chest Physicians.

CHEST / 92 / 3 / SEPTEMBER . 1987

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