American Journal of Respiratory and Critical Care Medicine

This prospective and controlled pilot study evaluates the long-term effects of nocturnal oxygen therapy (NOT) on exercise endurance, hematology variables, quality of life, and survival of 23 adult patients (mean age, 32 ± 6 yr) with post-tricuspid congenital heart defects (ventricular septal defect = 10; patent ductus arteriosus = 13) and Eisenmenger Syndrome. All had pulmonary hypertension (mean pulmonary artery pressure = 88 ± 20 mm Hg), severe hypoxemia (PaO2 = 44 ± 5 mm Hg), and secondary erythrocytosis (hematocrit = 61.5 ± 7%). Exercise endurance (6-min walk test = 380 ± 88 m) was limited. In a random fashion, NOT was given to one group of patients (n = 12) but withheld from a comparable control group (n = 11). At 2 yr of close follow-up, two patients in the group of control patients, and three in the treatment group died. Mean survival estimates were similar in both groups (20.7 versus 20.8 mo; chi-square log-rank, 0.08; p = NS). Likewise, none of the hematology, exercise capacity, and quality of life variables examined showed statistically significant changes that were dependent on treatment regimen. We conclude that NOT does not modify the natural history of patients with advanced Eisenmenger Syndrome.

Keywords: Eisenmenger Syndrome; oxygen therapy; survival; congenital heart defects

The physiologic concept of Eisenmenger Syndrome (ES) was introduced by Paul Wood (1) in 1958 to refer to the presence of pulmonary hypertension at systemic level caused by a high pulmonary vascular resistance (PVR) with reversed or bidirectional shunts at aortopulmonary, ventricular, or atrial level. The same year, Heath and Edwards (2) established the pathology basis of hypertensive pulmonary vascular disease emphasizing the central role of obstruction in the pulmonary bed as the main underlying factor for the increased PVR in congenital heart defects (CHD).

Once fully developed, the presence of ES renders the underlying defect inoperable, limits the functional capacity of the patients, and establishes a poor survival prognosis (3-12). Except for the limited option of Heart-Lung transplantation or single-lung transplantation with repair of intracardiac defects (11, 12), the current management of adult patients with CHD and ES is rather disappointing. There is no consensus regarding the use of therapeutic interventions such as anticoagulants or vasodilators (3-5, 7). In most cases, nonsurgical therapy is symptomatic or directed at avoiding or ameliorating complications associated with hypoxia, congestive heart failure, infection, and hematologic abnormalities (3-5, 7, 9, 10).

Although there is evidence of the deleterious effect of a low arterial oxygen saturation on survival in ES (6) and recognition exists regarding the detrimental effects of exposure to hypoxic environments (altitude, aircraft traveling), the potential usefulness of interventions such as long-term oxygen therapy in the setting of ES has not been fully evaluated, perhaps as a result of the fact that long-term oxygen administration is an expensive form of treatment and also because reasonable doubts exist regarding its efficacy given the existence of a right-to-left shunt as the mechanism of hypoxemia in these patients.

It is true that right-to-left shunt is the main mechanism of hypoxemia in these patients; however, we have recently shown (13) that the simple fact of going from sitting to supine position may exert a detrimental effect on the oxygenation variables of patients with ES, and we also demonstrated that this deleterious effect was acutely relieved by oxygen administration through nasal prongs. Furthermore, in an interesting and challenging study by Bowyer and colleagues (14), the long-term administration of oxygen to children with pulmonary vascular disease (mostly nocturnal administration) resulted in a dramatic difference in the 5-yr survival of these children as compared with those who did not receive this form of therapy. Altogether, these two studies would suggest that correction of worsening nocturnal hypoxemia associated with supine position might influence the course of the pulmonary vascular remodeling and pulmonary hypertension as well as the systemic response to hypoxia that are characteristic of this disease.

On the basis of this rationale, and with the hypothesis that nocturnal oxygen therapy (NOT) would improve functional status, quality of life (QOL), and survival, we performed a prospective pilot study in which NOT was given to one group of patients but withheld from a similar control group with Eisenmenger Syndrome. By considering other trials of oxygen treatment in patients with chronic obstructive pulmonary disease (COPD) (15, 16), we expected that treatment for a minimum of 2 yr would be necessary to show a beneficial effect. For this reason, the design of the trial was based on two parallel groups without crossover or placebo.


The study series comprised 23 patients in whom pulmonary arterial hypertension (PAH) associated with CHD and ES was diagnosed at our institution between May 1996 and November 1997 and who were followed through November 1999. In most of these patients the diagnosis had been established previously and they had been followed at our outpatient clinic of adult patients with CHD.

Entry and exclusion criteria are shown in Table 1. Patients considered for the trial were all adults 20 to 50 yr of age with CHD and PAH because of pulmonary vascular disease severe enough to preclude surgery. Anatomic diagnoses, as documented by right heart catheterization and/or echocardiography, were restricted to only post-tricuspid shunts, namely, ventricular septal defect (VSD) and patent ductus arteriosus (PDA). Evidence of predominant right-to-left shunt, as assessed by the echocardiography findings, and also the existence of hypoxemia and secondary erythrocytosis, were part of the ES diagnostic criteria.


Entry Criteria
 Age: between 20 and 50 yr
 Clinical diagnosis of Eisenmenger Syndrome
  VSD or PDA by right heart catheterization or echocardiography
  Pulmonary arterial hypertension
  Secondary erythrocytosis
 Residence: Mexico City and places nearby (mean altitude: 2,240 m)
 Clinical stability
Exclusion Criteria
 Clinical evidence of diseases capable of influencing the course of the disease
  Obesity (> 20% of ideal weight)
  Clinical evidence of sleep apnea
  Evidence of obstructive/restrictive lung disease
 Other diseases that might be expected to influence morbidity, mortality,    compliance with therapy, or ability to give informed consent.

Definition of abbreviations: PDA = patent ductus arteriosus; VSD = ventricular septal defect.

To be included in the study the patients had to be residents of Mexico City and places nearby (mean altitude; 2,240 m above sea level). They also had to be nonsmokers, defined as those who have never smoked or have smoked less than one cigarette or equivalent a day for as long as 1 yr. To enter the trial, patients had to be in a stable condition as defined by the absence of heart failure and/or respiratory infection in the 4 wk prior to the study.

Patients were excluded if they had any clinical or functional evidence of parenchymal (obstructive/restrictive) lung diseases, or other diseases capable of influencing the course of the disease such as obesity (> 20% of ideal weight), and sleep apnea.


Baseline studies included a complete history and physical examination, complete blood count, measurements of blood urea nitrogen and creatinine, uric acid and serum electrolytes, twelve-lead electrocardiogram (ECG), chest radiograph, and two-dimensional Doppler echocardiography. Repeat right heart catheterization was not part of the baseline procedures. For hemodynamic assessment we used the variables measured at diagnostic catheterization. Pulmonary vasoreactivity testing with 100% oxygen or with vasodilators was not performed. Lung function was assessed by standard spirometry and arterial blood gas (ABG) analysis. ABG measurements were performed in every patient at rest, first in the sitting and then in the supine position (13). The exercise endurance of the patients was assessed through a 6-min walk protocol (17). The patient's quality of life (QOL) was assessed by the administration of the questionnaire described by Guyatt and colleagues (18) that has been translated into Spanish and validated by Mejı́a-Alfaro and colleagues (19) in a Mexican population of patients with chronic respiratory failure. This QOL measure involves the assessment of four distinct aspects of the usual daily activity: dyspnea (range, 5 to 35), fatigue (range, 4 to 28), emotional (range, 7 to 49), and control (range, 4 to 28). The range of values obtained in each of these components is variable, with lowest values representing the worst condition. The degree of dyspnea during usual daily activities was also independently assessed by using a visual analog scale (VAS) (range, 0 to 10), as described by McGavin and colleagues (20), which has also been validated in a Mexican population of patients with interstitial lung disease (21). Finally, we also used a similar VAS (range, 0 to 10) to evaluate the degree of fatigue immediately after the 6-min walk test.

Patients were followed clinically and noninvasively at our outpatient clinic at 4-mo intervals for as long as 2 yr. Clinical status of the patients, exercise endurance, QOL, and hematology variables were all reassessed during these evaluations.

Our institutional ethics and clinical investigation committees approved all procedures. The rationale for oxygen treatment, and the controlled nature of the study were fully explained to the patients, and their consent was obtained. We made clear that the potential benefits of oxygen therapy were unproved. Patients who agreed to participate in the trial were then allocated to the treatment or control group by means of a table of random numbers (22).

Oxygen Administration

Oxygen treatment was supplied by either oxygen concentrators or large-capacity stationary cylinders installed in the patient's home with outlets to the bedroom. Nasal cannulas were used in all patients. Patients in the treatment group received oxygen for at least 8 h a day, always including the sleeping hours. The dose of oxygen for these patients was determined according to the response to oxygen obtained at baseline either by ABG analysis or by pulse oxymetry at night. The flow of oxygen that better improved arterial oxygen saturation (from 79 ± 6.5 to 88 ± 6.0% in the group as a whole) was employed. A flow rate of 2 to 3 L/min was usually required. All patients in the treatment group were closely followed by one of the investigators (JA) at monthly intervals to assess compliance. In each visit, the adequate performance of the equipment was assessed, and the patient was questioned about the number of hours for which oxygen was used, the frequency of equipment breakdowns, and nights missed because of holidays.

Statistical Analysis

Comparison between treatment and control groups data was made using Student's t test for unpaired data. Comparison between baseline and postintervention data (at 2 yr of follow-up) were made using Student's t test for paired data. Significance was defined as a two-tailed p value < 0.05. Descriptive variables are presented as mean value ± SD.

Mortality data were monitored at regular intervals throughout the trial to detect treatment differences as soon as possible. Survivorship of all patients at the end of follow-up regardless of the extent of their participation was ascertained by individual follow-up observations. For survival analysis we used the date of entry into the trial as an index for determining survival. The Kaplan-Meier method was used to estimate overall survival distribution in the treatment and control groups (23). Univariate analysis based on the Cox proportional hazards model was used to examine the relation between survival and selected demographic, medical history, pulmonary function, laboratory, and hemodynamic variables measured at baseline (23).

Demographic Characteristics

All 23 patients with ES were Hispanics with a mean age of 32 ± 6 yr; range, 20 to 43; 17 (74%) were female, six were male. There were 10 patients with VSD and 13 with PDA. As a group, patients with ES entering the trial all had PAH with a mean pulmonary artery pressure (Ppa) of 88 ± 20 mm Hg, severe hypoxemia (PaO2 = 44 ± 5 mm Hg) (24), and secondary erythrocytosis (hemoglobin = 19.4 ± 2.5 g/dL; hematocrit = 61.5 ± 7%) (25). Exercise endurance, as assessed by a mean 6-min walk test of 380 ± 88 m, was sharply limited. After randomization, 12 patients received oxygen, 11 patients forming the control group.

The demographic, clinical, and functional data of patients with ES at baseline are shown in Table 2. Patients in the group receiving NOT were comparable to control group in terms of age, residence altitude, Ppa, PaO2 , hematocrit level, functional class, and exercise endurance. Baseline parameters assessing QOL were also similar in both groups. PDA was more frequent in the treated group, whereas VSD was more frequent in the control group.


Patient No.Age (yr/sex)DiagnosisAge at DiagnosisAltitude Residence (m) Ppa(mm Hg)PaO2 (mm Hg)HCT (%)6-min Walk (m)Outcome
Patients receiving nocturnal oxygen therapy
 140/FVSD372,240 875157.5468Survived
 330/FPDA262,240 814457.0432Survived
 433/FVSD 72,240 704663.4432Survived
 534/FPDA181,610 914159.8432Survived
 741/FPDA212,240 803965.5306Died at 15 mo
 927/FPDA202,240 683866.1216Died at 9 mo
 1332/MPDA142,240 794174.5360Survived
 1632/FPDA242,240 963555.5432Died at 12 mo
 1820/FPDA 82,3991474950.9432Survived
 2136/FVSD212,309 714953.3432LFW at 4 mo
 Mean31.93VSD202,206 9043.560.3372
 ± SD 5.79PDA 9 194 24 4.9 6.5  88
Patients without nocturnal oxygen therapy
 640/FVSD102,240 685447.7432Survived
 828/FPDA232,476 834856.8396Survived
 1029/FVSD232,651 904263.0432LFW at 5 mo
 1430/FPDA212,240 634969.8396Survived
 1728/FPDA282,240 734668.5144Survived
 1921/MVSD131,2481004269.0468LFW at 7 mo
 2034/FVSD312,240 704353.4432Survived
 2230/MVSD282,2401174166.8432Died at 4 mo
 2338/MVSD302,240 953768.0468Died at 10 mo
 Mean32.67VSD232,209 8644.562.9389
 ± SD 6.54PDA 7 346  17.5 4.8 7.5 92
p =  0.78  0.30.98    0.67  0.64  0.38  0.64

Definition of abbreviations: HCT = hematocrit; LFW = lost to follow-up; Ppa = mean pulmonary artery pressure. For other definitions, see Table 1.

Compliance with NOT in the group of treatment was very good. All patients used the prescribed regimen of oxygen therapy from 8 to 10 h during sleep. There were no complications associated with the long-term use of nasal oxygen therapy. Performance of the equipment to deliver treatment was also adequate.

Treatment other than oxygen included anticoagulants (n = 8), diuretics (n = 6), digoxin (n = 6), angiotensin-converting enzyme inhibitors (n = 5), and aspirin (n = 5), which were almost equally distributed between NOT and control groups. Although therapeutic phlebotomies were discouraged, they were performed in both NOT (two patients), and control (three patients) groups during the trial.


The 23 patients were followed for an average of 19.8 mo. Fifteen patients (62.5%) survived the whole period of the trial (24 mo). Three patients (16.6%), one in the NOT group and two in the control group, abandoned the trial or were lost to follow-up at 4, 5, and 7 mo, respectively.

Over the whole period of the trial a total of five patients (21.7%) died, three in the NOT group and two in the control group. Lifetime cumulative survival rates for patients in both groups are shown in Figure 1. Mortality in both treated and control groups was very similar. Mean survival time for the patients who received NOT was 20.73 mo (range, 9 to 24 mo; 95% confidence interval (CI), 17.48 to 23.97), not statistically different from the 20.77 mo mean survival time for patients in the control group (range, 4 to 24 mo, 95% CI, 16.69 to 24.85); chi-square log-rank, 0.08; p = NS.

Patients who died did so at hospital and the causes of death were recorded as pneumonia and/or pulmonary hemorrhage (n = 3) and stroke (n = 2). No postmortem studies were performed in any of these patients.

Eighteen of the 23 patients either survived (n = 15) or abandoned (n = 3) the trial and, as mentioned, five (21.7%) died. Of all recorded variables at baseline in surviving (mean survival = 21.4 ± 6 mo) and dead (mean survival = 10 ± 4 mo) patients shown in Table 3, there were significant differences (p < 0.05), respectively, in baseline PaO2 (45.8 ± 3.8 versus 38 ± 2.2 mm Hg), and the degree of dyspnea at baseline as assessed by the visual analog scale (VAS) (4.88 ± 1.56 versus 6.2 ± 0.41) between the two groups. The degree of fatigue after the 6-min walk test at baseline, as assessed by the VAS (3.6 ± 2.68 versus 5.8 ± 1.78), and also the mean red cell corpuscular volume (CV) at baseline (84.5 ± 6.9 versus 74.6 ± 8.2 fL) tended to be different between surviving and dead patients and almost reached statistical significance.


VariableAliveDeadp Value
Age, yr31.88 ± 6.1833.6 ± 5.770.582
Age at diagnosis, yr20.77 ± 9.1124.6 ± 4.330.207
Altitude residence, m2198 ± 3072240 ± 00.574
6-min walk test, m383 ± 85370 ± 1060.822
Fatigue (VAS) at walk test, 0–10  3.6 ± 2.685.8 ± 1.780.058
Dyspnea (VAS), 0–10 4.88 ± 1.566.2 ± 0.410.005
Ppa, mm Hg 87 ± 2291 ± 180.69
FVC, % pred 92 ± 1981 ± 140.190
FEV1, % pred 84 ± 1971 ± 170.194
FEV1 / FVC, % 81 ± 6.982.6 ± 6.60.744
PaO2 , mm Hg45.8 ± 3.838 ± 2.20.000
PaCO2 , mm Hg 32.5 ± 2.8933.2 ± 4.50.776
Hemoglobin, g/dl 19.7 ± 2.6518.6 ± 1.670.276
Hematocrit, % 60.7 ± 7.3164.6 ± 4.870.200
CV, fL84.5 ± 6.974.6 ± 8.20.051
Uric acid, mg/dl 6.52 ± 2.157.60 ± 2.50.421
QOL questionnaire
 Dyspnea, 5 to 3519.61 ± 4.818.2 ± 2.160.360
 Fatigue, 4 to 28 17.8 ± 4.9815.4 ± 2.190.123
 Control, 4 to 2819.77 ± 4.8517.2 ± 3.270.197
 Emotional, 7 to 49 33.7 ± 9.7530.2 ± 5.540.318

Definition of abbreviations: CV = mean corpuscular volume; Ppa = mean pulmonary artery pressure; QOL = quality of life; VAS = visual analog scale.

Factors Associated with Mortality

Univariate analysis of the relation between mortality and variables measured at entry into the study are shown in Table 4. Mortality was not associated with treatment regimen. Baseline sitting PaO2 (hazard ratio = 0.64) and baseline CV (hazard ratio = 0.9) both had a protective effect against the risk of death. A baseline sitting PaO2 < 40 mm Hg was the most significant predictor of mortality among patients with ES. For illustration, the Kaplan-Meier survival curve for patients with ES according to baseline PaO2 (< 40 and > 40 mm Hg) is shown in Figure 2.


VariableHazard Ratio (95% CI)p Value
Demographic and treatment
 Age, yr1.03 (0.89 to 1.19)0.66
 Age at diagnosis, yr1.04 (0.94 to 1.16)0.38
 Male sex2.04 (0.34 to 12.2)0.43
 VSD diagnosis0.87 (0.14 to 5.24)0.88
 Altitude residence, m1.00 (0.99 to 1.00)0.62
 No NOT0.77 (0.12 to 4.62)0.77
Functional status and hemodynamics
 6-min walk test (m)0.99 (0.98 to 1.00)0.88
Ppa, mm Hg1.00 (0.96 to 1.04)0.72
Laboratory variables
 Hemoglobin, g/dl0.83 (0.56 to 1.21)0.34
 Hematocrit, %1.07 (0.93 to 1.22)0.32
 CV, fL0.90 (0.82 to 0.99)0.03
 Uric acid, mg/dl1.20 (0.81 to 1.72)0.35
Pulmonary function tests and gas exchange
 FVC, % pred0.97 (0.93 to 1.02)0.32
 FEV1, % pred0.97 (0.93 to 1.01)0.25
 FEV1/FVC, %1.04 (0.90 to 1.20)0.57
 PaO2 , mm Hg0.64 (0.46 to 0.88)0.007
 PaO2 < 40 mm Hg28.5 (3.03 to 269)0.003
 PaCO2 , mm Hg0.97 (0.69 to 1.35)0.87

Definition of abbreviations: NOT = nocturnal O2 therapy. For other definitions, see Tables 1 and 3.

Effects of Treatment on Physiologic Variables

The effects of NOT on functional, QOL, hematology, PFT, and other laboratory variables listed in Table 5 were examined by comparing baseline and follow-up data in individual patients who completed the trial. None of the variables examined showed statistically significant changes that were dependent on treatment regimen.


Treatment GroupNo Treatment Group
BeforeAfterp valueBeforeAfterp value
 6-min walk, m385 ± 82391.5 ± 780.84355 ± 100396 ± 510.31
QOL questionnaire
 Dyspnea18.3 ± 4.9 20.3 ± 4.60.2819.1 ± 4.420.8 ± 4.80.28
 Fatigue18.5 ± 4.0 17.2 ± 4.80.6216.6 ± 6.616.4 ± 4.70.94
 Emotional 33 ± 9.8 33.2 ± 6.50.9534.8 ± 8.635.5 ± 6.90.74
 Control19.8 ± 3.8 20.4 ± 3.30.8219.3 ± 5.721.0 ± 5.10.38
 Hemoglobin, g/dl19.5 ± 2.4 19.5 ± 3.10.9519.6 ± 3.120.1 ± 2.30.39
 Hematocrit, %60.4 ± 6.8 62.1 ± 100.5060.7 ± 8.662.2 ± 7.90.24
 CV, fL 83 ± 6.0 80.2 ± 100.3984.6 ± 8.683.4 ± 8.00.13
 Uric acid, mg/dl 6.5 ± 1.6  6.6 ± 1.70.605.7 ± 2.16.2 ± 2.40.52
 BUN, mg/dl15.1 ± 12 18.1 ± 150.3514.0 ± 5.116.8 ± 5.20.16
 Creatinine, mg/dl0.95 ± 0.3 1.01 ± 0.40.690.94 ± 0.30.83 ± 0.30.34
Pulmonary function
 FVC, % pred78.5 ± 19  78 ± 270.8999 ± 10 95 ± 8.10.06
 FEV1, % pred70.4 ± 20 71.6 ± 250.6787.8 ± 1186.8 ± 110.60
 FEV1/FVC, %89.2 ± 6.2 89.6 ± 6.70.8091 ± 6.0 92 ± 6.20.21
 PaO2 , mm Hg45.1 ± 3.7 42.5 ± 4.80.1046.4 ± 4.345.4 ± 5.00.34
 PaCO2 , mm Hg33.2 ± 2.8 33.2 ± 6.10.9933 ± 2.0 33 ± 2.50.88

For definition of abbreviations, see Table 3.

To our knowledge, this is the first controlled trial of long-term nocturnal oxygen therapy in adult patients with Eisenmenger Syndrome. Patients included in our study were probably representative of a group of patients with post-tricuspid congenital heart disease and advanced pulmonary vascular disease. The selection criteria ensured that the patients had severe PAH, significant hypoxemia, and secondary erythrocytosis. Patients at this stage, usually have reduced exercise tolerance, a poor quality of life, and a grave outlook in terms of survival (4-8, 10-12).

Patients were randomized successfully. At baseline, there was no significant difference between NOT and control groups with regard to the demographic, functional, and hematology variables listed in Table 2. The oxygen delivered by nasal prongs was well tolerated. The treatment was acceptable, and compliance of the patients was good, probably as a result of the close follow-up of the patients and also because of the expected benefit from this form of therapy. Therapy other than NOT included the medications usually prescribed in this type of patients (7), it was equally distributed in both groups and, therefore, could not have biased our results.

At 2 yr of follow-up, mortality in the NOT group was not different from that in the control group. Likewise, the rate of change in other hematology (hemoglobin and hematocrit levels) and functional variables appears to be independent of treatment assignment. This somehow disappointing result differs from that obtained in the study of Bowyer and colleagues (14), the only previously reported experience with long-term oxygen therapy in the setting of CHD. In that study, performed in children with CHD and pulmonary vascular disease, long-term oxygen therapy (mostly nocturnal) resulted in a dramatic 5-yr survival difference between treated and control groups. Important differences between the two studies include a different age and, therefore, a possible different stage of the disease, and also a longer period of follow-up in the study of Bowyer and colleagues. An earlier stage in the children, as compared with our adult population, is suggested by the lower level of baseline Ppa (50 versus 88 mm Hg), and also by the still significant hemodynamic response to oxygen breathing in most of the children. Likewise, different from patients in our series, only five of the 21 children had increased levels of hemoglobin and/or hematocrit at baseline suggesting a smaller degree of right-to-left shunt in this pediatric population (14). It is likely that the potential benefits of oxygen therapy shown at an earlier stage of the disease are lost once pulmonary vascular resistance becomes fixed, as a result of a significant component of structural vascular changes (2, 3, 26), and a predominant right-to-left shunt ensues. In this regard, it has to be stressed that most patients in our study had a very low PaO2 at baseline, as a reflection of significant right-to-left shunt, and, although statistically significant, the change in PaO2 from sitting to supine position (from 44 ± 4.9 to 42.7 ± 5.3 mm Hg; p < 0.05) was probably of little clinical significance (13).

We believe that a 2-yr follow-up period was long enough to show any potential difference in terms of quality of life, functional status, hematology variables, and survival between treated and control patients. In the study of Bowyer and colleagues (14), a clearcut difference in survival was evident from the first year of treatment. Likewise, significant differences in survival appeared after 500 d of long-term oxygen therapy in the setting of chronic obstructive pulmonary disease (COPD) (15, 16). We could not find a good reason to prolong the trial as we did not observe any significant difference, neither in mortality nor in the rate of change of other important hematology and functional variables between treated and control patients. It appears then that severely afflicted patients with ES such as the ones in our study are unlikely to benefit from this form of long-term NOT. The current existence of relatively new and promising therapeutic strategies in the setting of CHD and ES (26, 27) was another reason not to prolong the trial.

Our results are also different from those obtained in trials using either nocturnal or continuous long-term oxygen therapy in the setting of COPD, in which this form of treatment resulted in a significant improvement in the quality of life and survival of patients afflicted by this disease (15, 16). Although significant hypoxemia is a marker of both Eisenmenger syndrome and advanced COPD, the main pathophysiologic mechanism involved in the genesis of hypoxemia (right-to-left shunt versus abnormal V˙/Q˙ distribution) differs considerably in both diseases. Accordingly, the response to oxygen administration is also quite different in both settings, and this fact alone may explain the different results. Another difference between our study in patients with ES and those in patients with COPD is with regard to the prescribed treatment regimens. Patients in our study received oxygen exclusively during sleep, whereas patients with COPD treated with oxygen in the British (16) and in the North American (15) studies received this form of therapy for at least 13 to 15 h, and the maximum benefit in terms of quality of life and survival was observed with the continuous (24 h) form of treatment. We used only NOT because it is more acceptable to the patients and mainly because we wanted to know if the relief of nocturnal hypoxemia or the hypoxemia associated with supine position (13) could prevent progression of the disease. Patients with ES, however, suffer oxygen disaturation day and night and they are in fact more likely to do so with normal daily activities, particularly those requiring any form of physical activity. A more continuous form of oxygen administration might be required in this severely ill population.

The importance of the degree of hypoxemia at baseline as a predictor of survival in patients with ES is strongly emphasized by the results of the present study. A baseline PaO2 < 40 mm Hg in our ES population, regardless the form of treatment, was associated with a higher likelihood of death before 1 yr. The importance of a low PaO2 as a prognostic marker of poor survival in this population has been emphasized in previous studies (4, 6). Thus, this simple measurement might be a useful way to identify the precise timing for interventions such as lung or heart-lung transplantation in the Eisenmenger Syndrome population (11, 12). The true usefulness of this parameter, however, needs to be assessed either prospectively or in studies involving a larger population of patients (7). Interestingly, baseline CV was also associated with survival. A higher CV at baseline had a protective effect against the risk of death. In other words, patients with lower values of CV as a reflection of iron deficiency, either as a result of poor iron intake or repeated phlebotomy, are at a higher risk of death. The deleterious effects of iron deficiency on erythrocyte's intrinsic viscosity and oxygen transport in the ES population have been previously established (5, 28).

Study Limitations

Besides a relatively small sample size, there are two other limitations in our study. First, a placebo arm (administering “air” to the control group) was not included. Second, only patients with a very advanced disease, living at high altitude, were included in the trial. Therefore, conclusions derived from the present study should be judged in the context of these limits.

Long-term nocturnal oxygen therapy was not effective in modifying the natural history of a group of patients with post-tricuspid CHD and advanced ES studied at an altitude of 2,240 meters over sea level. Our study, however, does not provide a definite answer with regard to the potential benefits of a continuous (24 h a day) form of oxygen therapy, or its effects in a population of patients with a less advanced stage of the disease, or even on the evaluation of this form of therapy in a lower altitude environment.

Supported in part by a research grant from the Fundación UNAM-Banamex.

1. Wood P. The Eisenmenger syndrome: or pulmonary hypertension with reversed central shunt. Br Med J 1958;2:701–709, 755–762.
2. Heath D, Edwards JEThe pathology of hypertensive pulmonary vascular disease: a description of six grades of structural changes in the pulmonary artery with special reference to congenital cardiac septal defect. Circulation181958533547
3. Collins-Nakai RL, Rabinovitch MPulmonary vascular obstructive disease. Cardiol Clin111993675687
4. Young D, Mark HFate of the patient with the Eisenmenger syndrome. Am J Cardiol281971658669
5. Daliento L, Somerville J, Presbitero P, Menti L, Brach-Prever S, Rizzoli G, Stone SEisenmenger syndrome. Factors relating to deterioration and death. Eur Heart J19199818451855
6. Saha A, Balakrishnan KG, Jaiswal PK, Venkitachalam CG, Tharakan J, Titus T, Kutty RPrognosis for patients with Eisenmenger syndrome of various aetilogy. Int J Cardiol451994199207
7. Cantor WJ, Harrison DA, Moussadji JS, Connelly MS, Webb GD, Liu P, McLaughlin PR, Siu SCDeterminants of survival and length of survival in adults with Eisenmenger Syndrome. Am J Cardiol841999677681
8. Clarkson PM, Frye RL, DuShane JW, Burchell HB, Wood EH, Weidman WPrognosis for patients with ventricular septal defect and severe pulmonary vascular disease. Circulation381968129135
9. Brickner ME, Hillis LD, Lange RACongenital heart disease in adults. First of two parts. N Engl J Med3422000256263
10. Brickner ME, Hillis LD, Lange RACongenital heart disease in adults. Second of two parts. N Engl J Med3422000334342
11. Hopkins WE, Ochoa LL, Richardson GW, Trulock EPComparison of the hemodynamics and survival of adults with severe primary pulmonary hypertension or Eisenmenger syndrome. J Heart Lung Transplant151996100105
12. D'Armini AM, Callegari G, Vitulo P, Klersy C, Rinaldi M, Pederzolli C, Grande AM, Fracchia C, Vigano MRisk factors for early death in patients awaiting heart-lung or lung transplantation. Experience at a single European Center. Transplantation661998123127
13. Sandoval J, Alvarado P, Martı́nez-Guerra ML, Gómez A, Palomar A, Meza S, Santos E, Rosas MEffect of body position changes on pulmonary gas exchange in Eisenmenger's syndrome. Am J Respir Crit Care Med159199910701073
14. Bowyer JJ, Busst CM, Denison DM, Shinebourne EAEffect of long term oxygen treatment at home in children with pulmonary vascular disease. Br Med J551986385390
15. Nocturnal Oxygen Therapy Trial Group. Continuous or nocturnal therapy in hypoxemic chronic obstructive lung disease: a clinical trial. Ann Intern Med 1980;93:391–398.
16. Report of the Medical Research Council Working Party. Long term domiciliary oxygen therapy in chronic hypoxic cor pulmonale complicating chronic bronchitis and emphysema. Lancet 1981;1:681–686.
17. Riley M, McParland J, Stanford CF, Nicholls DPOxygen consumption during corridor walk testing in chronic cardiac failure. Eur Heart J131992789793
18. Guyatt GH, Berman LB, Townsend M, Pugsley SO, Chambers LWA measure of quality of life for clinical trials in chronic lung disease. Thorax421987773778
19. Mejı́a-Alfaro R, Ramirez-Venegas A, Chapela R, Perez-Padilla R, Sánchez MC, Sansores RHValidity of a Spanish (Mexican) version of two instruments for measuring “quality of life” in patients with chronic respiratory failure (abstract). Am J Respir Crit Care Med1531996A427
20. McGavin CR, Artvinli M, Nave H, McHandy GIRDyspnea disability, and distance walked: comparison of estimates of exercise performance in respiratory disease. Br Med J221978241243
21. Ramirez-Venegas A, Sansores RH, Carrillo G, Salas J, Chapela R, Selman MValidaciòn de una escala analoga visual para medir disnea en pacientes con enfermedad pulmonar intersticial difusa. Rev Invest Clin461994479486
22. Dawson-Saunders B, Trapp RG. Bioestadı́stica Médica. El Manual Moderno. México DF; 1993.
23. Norusis MJ. The SPSS guide to data analysis for SPSS-PC+. Chicago, IL: SPSS Inc.; 1988.
24. Martı́nez-Guerra ML, Fernandez-Bonetti P, Balvanera AValores normales de algunas medidas de la función respiratoria en la Ciudad de México. Prensa Med Mex38197315
25. Ruiz-Arguelles GJ, Sanchez-Medal L, Loria A, Piedras J, Cordova MSRed cell indices in normal adults residing at altitudes from sea level to 2,670 m. Am J Hematol81980265271
26. Rabinovitch MPulmonary Hypertension: pathophysiology as a basis for clinical decision making. J Heart Lung Transplant11199910411053
27. Rosenzweig EB, Kerstein D, Barst RJLong term prostacyclin for pulmonary hypertension with associated congenital heart defects. Circulation99199918581865
28. Perloff JK, Rosove MH, Child JS, Wright GBAdults with cyanotic congenital heart disease. Hematologic management. Ann Intern Med1091988406413
Correspondence and requests for reprints should be addressed to Julio Sandoval, MD, FACC, Head, Cardiopulmonary Department, Instituto Nacional de Cardiologı́a Ignacio Chávez, Juan Badiano No. 1, Col. Seccion XVI, Tlalpan 14080, México D.F., México. E-mail:


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