INTRODUCTION

Pulmonary hypertension (PH) is characterized by elevated mean pulmonary artery pressure (mPAP) of ≥25 mmHg at rest during right-sided cardiac catheterization (RSCC) (1). PH is a life-threatening condition that ultimately causes right ventricular failure and death. Since the prognostic evaluation is critical for PH, several risk assessment tools were developed to predict its prognosis and optimize treatment (2-7).

RSCC is accepted as the gold standard diagnostic tool for the definitive diagnosis of PH and used for prognostic purposes (1). The pulmonary to systemic flow (Qp/Qs) ratio is a calculation for estimating the direction and severity of shunting, especially in congenital heart diseases. This ratio is typically calculated using the Fick method (8), and it is essential in the differential diagnosis and management of PH in patients with left-to-right shunts (9). We routinely calculate the Qp/Qs ratio to avoid missing any left-to-right shunts in patients with precapillary PH. However, the pulmonary artery oxygen saturation (SpaO₂) was lower than the mixed venous oxygen saturation (SmvO₂) calculated using the formula; hence, the Qp/Qs ratio was calculated as less than “1” in some patients despite the absence of any detectable shunt. We hypothesized that this observation might have prognostic significance; however, to the best of our knowledge, it has not been investigated yet. Therefore, we aimed to investigate the prognostic value of the Qp/Qs ratio in patients with precapillary PH without any left-to-right shunt.

METHODS

Study Population

This retrospective cohort study was conducted in the Department of Cardiology of Dokuz Eylül University Hospital. This study was approved by the Local Ethics Committee. Informed consent was obtained for the RSCC procedure from all patients.

The medical records of 225 consecutive patients who underwent RSCC combined with oximetric study through the Fick method (8) for differential diagnosis of PH were screened from the hospital database. All patients were diagnosed with precapillary PH by an algorithm recommended in the guideline (1). After excluding 52 patients with confirmed left-to-right shunt not only through the oximetric analysis but also with other diagnostic modalities, the remaining 173 patients with precapillary PH were considered for the final analysis. Precapillary PH was defined as mPAP ≥25 mmHg along with pulmonary artery wedge pressure (PAWP) ≤15 mmHg (1).

Transthoracic Doppler Echocardiography

Thorough transthoracic echocardiography that specifically focused on investigating the function and pressure within the right side of the heart was performed by using a Philips HD11 XE Ultrasound system with 3.2 MHz transducer (Philips Healthcare, Best, Netherlands).

Data Collection and Patient Follow-up

All patients were routinely evaluated every 3 months in the PH outpatient clinic. The functional capacity (FC) of the patients was recorded according to the World Health Organization (WHO) functional classification (10). Results of the 6-min walking distance (6MWD) test, echocardiographic values, and laboratory parameters were obtained. All-cause mortality was noted during follow-up, and patients were compared as survivors versus nonsurvivors for analysis.

Right-Sided Cardiac Catheterization

All patients underwent RSCC at rest that was performed by experienced cardiologists. Neither sedation nor supplemental oxygen was administered during the study. Pressure records and the oximetric study were performed with multipurpose angled catheters (end hole only). The right atrial pressure and PAP, along with the PAWP, were recorded. Blood samples from the pulmonary artery, right atrium, right ventricle, superior vena cava (SVC), inferior vena cava (IVC), and systemic artery were obtained routinely, and the Qp/Qs ratio was calculated using the following formula: systemic artery oxygen saturation - SmvO₂/pulmonary artery wedge oxygen saturation - SpaO₂ (8). To calculate SmvO₂, this formula was used: [(3×SVC oxygen saturation (SsvcO₂) + IVC oxygen saturation (SıvcO₂))/4] (11). In cases with no record of the pulmonary artery wedge saturation, it was assumed to be similar to the systemic artery oxygen saturation. The cardiac index was calculated by dividing Qs values by the measure of the total surface area of the body. Transpulmonary gradient determined by subtracting PAWP from mPAP was divided by Qp to calculate the pulmonary vascular resistance (PVR).

Statistical Analysis

Statistical analyses were performed using SPSS 25.0 (institutionally registered software). Normality was assessed with the Kolmogorov-Smirnov test. Data were reported as percentages for categorical variables and mean ± standard deviation or median (interquartile range) for continuous variables. Student’s t-test or Mann-Whitney U test was used to compare continuous variables, and the appropriate chi-squared test was performed to compare categorical variables. To predict mortality, the optimal cutoff threshold for the Qp/Qs ratio was obtained by analyzing the receiver operating characteristics (ROC) curve. The Kaplan-Meier analysis with a cutoff value of 0.90 for the Qp/Qs ratio was used to designate the survival curves. Logistic regression analyses were performed to define predictors of mortality. Variables with p-value <0.1 in the univariate regression analysis were included in the multivariate logistic regression analysis. For all statistical analyses, p-value of ≤0.05 was accepted as significant.

RESULTS

This study included 45 men and 128 women, with a mean age of 60.2±15.5 years. The follow-up duration ranged from 25 months to 128 months. A total of 74 (42.7%) deaths were noted during the follow-up. Baseline demographics and clinical and echocardiographic comparisons of survivors versus nonsurvivors are presented in Table 1. According to functional class, 91.8% of the nonsurvivors and 54.5% of the survivors had WHO FC III-IV. Nonsurvivors had significantly lower 6MWD, tricuspid annular plane systolic excursion, and right ventricular outflow tract maximum systolic velocity values. Pericardial effusion more frequently occurred in nonsurvivors, and they had significantly higher brain natriuretic peptide and lactate dehydrogenase levels (Table 1).

Baseline hemodynamic data obtained from RSCC are shown in Table 2. Nonsurvivors had significantly lower Qp and Qp/Qs ratio (3.52±1.48 vs. 4.53±1.43, p<0.001; 0.76±0.19 vs. 1.02±0.07, p<0.001) than survivors, respectively. The mPAP and PVR levels were significantly higher in nonsurvivors.

The multivariate logistic regression analysis showed that the Qp/Qs ratio and poor FC (WHO FC III-IV) (p=0.002, p<0.001 respectively) were independent predictors of mortality (Table 3). The optimal Qp/Qs cutoff for predicting mortality was 0.90 with 76% sensitivity and 98% specificity (area under the curve=0.845, 95% CI: 0.778-0.913, p<0.001) based on the ROC curve analysis (Figure 1). The Kaplan-Meier analysis of Qp/Qs >0.90 and Qp/Qs ≤0.90 yielded diverging survival curves (p<0.001) (Figure 2). Qp/Qs ≤0.90 was noted in 34.7% of the patients, and Qp/Qs ratio ≤0.90 was significantly more common in nonsurvivors than in survivors (75.7% vs. 4%; p<0.001).

DISCUSSION

Hemodynamic parameters obtained from RSCC are valuable for predicting the prognosis of PH (1). The Fick method relies on measuring oxygen concentrations in blood samples obtained by a catheter positioned at several points and serves as a reference procedure for the evaluation of blood flow (Qp/Qs) (8) and shunts (9). Qp, Qs, and Qp/Qs ratio are routinely calculated in patients with PH, except in settings with technical obstacles in our clinic. In real-life practice, without any shunting, the Qp/Qs ratio should be equal to 1. However, during routine RSCC procedures in patients with high-risk status and precapillary PH, the Qp/Qs ratio calculated using the Fick method was <1. SpaO₂ was lower than SmvO₂ calculated using the formula; therefore, the Qp/Qs ratio was calculated as <1. In the absence of shunting, the downward deviation of the Qp/Qs value from the expected normal value of 1 might initially appear to be strange in a closed-loop system and might be ignored as test result variability. However, the Qp/Qs ratio calculated using the Fick method is based on oxygen consumption, and the main determinant of this ratio is a difference between SpaO₂ and SmvO₂. Moreover, SmvO₂ is measured directly from the pulmonary artery (12) or calculated using a formula (11). However, various potential flow sources such as the coronary sinus (CS) can be neglected by calculating SmvO₂ from SsvcO₂ and SıvcO₂. This may not matter in patients with normal cardiac function. However, this phenomenon becomes important in patients with heart failure (13). CS oxygen saturation (ScsO₂) was a strong predictor of the severity of heart failure due to deranged metabolic demands (14). Similarly, we thought that in the presence of right ventricular dysfunction caused by a chronic pressure overload in PH, the metabolic demand of the right ventricle increases, and it may result in reduced ScsO₂. This causes a difference between SpaO₂ and SmvO₂ calculated using the formula. A study that supported our hypothesis showed that the major reason for the calculation between average venous oxygen saturation and SpaO₂ was the deoxygenated blood of the CS in patients who underwent cardiac surgery (15). While the contribution of deoxygenated blood derived from the myocardium via the CS to venous SO₂ can be taken into account in the measurement of SmvO₂ from the pulmonary artery, the effect of the myocardium can be ignored in the measurement of SO₂ from the central veins. Therefore, direct measurement of SmvO₂ through pulmonary artery catheterization is more accurate in patients with critical illness (16), including patients undergoing cardiac surgery and/or patients with impaired cardiac function (17,18). The contribution of CS drainage to venous SO₂ could have significant effects in the late stages of PH that might also serve as a basis for the Qp/Qs deviation in the Fick method (19). In the present study, we think that the SpaO₂ value is lower than that of SmvO₂ because of right ventricular dysfunction in patients with precapillary PH. The low SpaO₂ indicates that the heart cannot meet the tissue oxygen demand. The Qp/Qs ratio was calculated as <1 because a low SpaO₂ and, not surprisingly, decreased Qp/Qs ratio was an independent predictor of mortality. Similarly, SpaO₂ was shown to be a more valuable prognostic factor than the cardiac index in patients with PH (20).

Study Limitations

This retrospective cohort analysis had several limitations. First, our study was conducted on a limited number of patients from a single center without any data about treatment-related issues, which can potentially influence outcomes. Second, blood samples from the CS were not obtained. Analyses of ScsO₂ that can reflect an intrinsic error in the calculation of SmvO₂ should be ideally incorporated in the final evaluation of patients with PH and right ventricular dysfunction. However, the potential value of this issue in calculating the Qp/Qs ratio through the Fick method remains to be established. Third, we could not compare SmvO₂ with SpaO₂ because of the absence of oxygen saturation values in our hospital records. Fourth, thermodilution, which is the preferred method for determining cardiac output in patients with PH (19), was not utilized in this cohort because it was not available during the study period. Therefore, we could not compare the cardiac output obtained by thermodilution with Qp and Qs calculated using the Fick method. Essentially, further prospective randomized controlled studies with larger sample sizes are strongly recommended for the validation of the results of this study.

CONCLUSION

In this study, decreased Qp/Qs ratio calculated using the Fick method was an independent predictor of mortality in patients with precapillary PH without left-to-right shunts. This prognostic implication was based on the difference between SpaO₂ and SmvO₂ calculated using the formula. Nevertheless, it remains to be elucidated whether this is a reflection of an intrinsic methodological flaw in the Fick method.

ETHICS

Ethics Committee Approval: This retrospective cohort study was conducted in the Department of Cardiology of Dokuz Eylül University Hospital. This study was approved by the Local Ethics Committee (no: 2018/07-32, date: 15.03.2018).

Informed Consent: Informed consent was obtained for the RSCC procedure from all patients.

Authorship Contributions

Surgical and Medical Practices: B.Ş., Concept: B.Ş., B.A., E.Ö., Design: B.Ş., B.A., M.B.Y., M.B., C.S., Data Collection or Processing: B.Ş., B.A., E.Ö., D.S., B.Ö.K., K.C.T., Analysis or Interpretation: B.Ş., B.A., M.B.Y., E.Ö., D.S., B.Ö.K., B.Ac., M.B., C.S., Literature Search: B.Ş., Writing: B.Ş., B.A., M.B.Y., E.Ö., D.S., B.Ö.K., B.Ac., K.C.T., M.B., C.S.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study received no financial support.