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Critical care
Clinical characteristics of patients with a risk of pulmonary artery hypertension secondary to ARDS in a high-altitude area
  1. Peng Zhu1,
  2. Jing Zhu2,
  3. Shijun Tong1,
  4. Xiaobin She1,
  5. Zhenyuan Qi1,
  6. Qianjin Xu1,
  7. Zhongshan Shi3,
  8. Lining Si1,
  9. Ming Hou1,
  10. Guifen Gan1 and
  11. Chun Pan4
  1. 1Department of Critical Care Medicine, Qinghai University Affiliated Hospital, Xining, Qinghai, China
  2. 2Department of Cardiology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
  3. 3Department of Critical Care Medicine, People′s Hospital of Golmud City, Golmud, Qinghai, China
  4. 4Department of Critical Care Medicine, Health Management Center, University of Electronic Science and Technology of China Sichuan Provincial People's Hospital, Chengdu, Sichuan, China
  1. Correspondence to Dr Chun Pan; panchun1982{at}gmail.com

Abstract

Background Hypoxaemia plays an important role in the development of pulmonary artery hypertension (PAH). Patients with acute respiratory distress syndrome (ARDS) in a high-altitude area have different pathophysiological characteristics from those patients in the plains. The goal of our study was to explore the clinical characteristics of PAH secondary to ARDS in a high-altitude area.

Methods This was a prospective study conducted in the affiliated Hospital of Qinghai University. Two investigators independently assessed pulmonary artery pressure (PAP) and right ventricular function by transthoracic echocardiography. Basic information and clinical data of the patients who were enrolled were collected. A multivariable logistic regression model was used to evaluate the risk factors for PAH secondary to ARDS in the high-altitude area.

Results The incidence of PAH secondary to ARDS within 48 hours in the high-altitude area was 44.19%. Partial pressure of oxygen/fraction of inspired oxygen <165.13 mm Hg was an independent risk factor for PAH secondary to ARDS in the high-altitude area. Compared with the normal PAP group, the right ventricular basal dimensions were significantly larger and the right ventricular tricuspid annular plane systolic excursion was lower in the PAH group (right ventricular basal dimensions: 45.47±2.60 vs 40.67±6.12 mm, p=0.019; tricuspid annular plane systolic excursion (TAPSE): 1.82±0.40 vs 2.09±0.32 cm, p=0.021). The ratio of TAPSE to systolic PAP was lower in the PAH group (0.03±0.01 vs 0.08±0.03 cm/mm Hg, p<0.001).

Conclusions The incidence of PAH in patients with ARDS in our study is high. PAH secondary to ARDS in a high-altitude area could cause right ventricular dysfunction.

Trial registration number NCT05166759.

  • ARDS

Data availability statement

Data are available upon reasonable request. No data are available.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/bmjresp-2022-001475

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    WHAT IS ALREADY KNOWN ON THIS TOPIC

    • Patients with acute respiratory distress syndrome (ARDS) are often combined with acute cor pulmonale.

    WHAT THIS STUDY ADDS

    • Our study explored the influencing factors and right ventricular function of patients with a risk of pulmonary hypertension secondary to ARDS in a high-altitude area.

    HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

    • The right ventricular function of patients with pulmonary artery hypertension secondary to ARDS in high-altitude areas should not be ignored.

    Introduction

    Pulmonary artery hypertension (PAH) is an important complication of acute respiratory distress syndrome (ARDS). It has been reported that the incidence of PAH is 46.6% (14/30) and 92.2% (95/103) in patients with ARDS.1 2 Several mechanisms, including loss of lung volume, hypoxaemia, hypercapnia, overdistention and microthrombi, contribute to PAH secondary to ARDS.3 Pulmonary hypertension can lead to an increase in right heart afterload. Increased right heart afterload is associated with acute core pulmonale (ACP). A total of 22%–25% of patients with ARDS who underwent protective ventilation were found to develop ACP, which was associated with poor prognosis.4 5 Hypoxaemia is a clinical feature of ARDS, which plays an important role in the development of PAH. Therefore, the right ventricular (RV) function of patients with ARDS cannot be neglected.

    Patients with ARDS in a high-altitude area have different pathophysiological characteristics from those patients in the plains. High altitude is characterised by low atmospheric pressure and hypoxaemia. With increasing altitude, atmospheric pressure and oxygen concentration decrease. Compared with the patients in the plains, the oxygen partial pressure of the healthy people living in the high-altitude area is lower, which means that patients with ARDS in the high-altitude area experience more severe hypoxaemia than those in the plains. In addition, some populations living in high-altitude areas have been suggested to express genes whose products are likely involved in high-altitude adaptation,6–8 which is also different from patients living in the plains.

    Qinghai Province is located in northwest China, and the whole province has an average altitude of 3000 m. Due to the characteristics of low atmospheric pressure and hypoxaemia in high-altitude areas, according to previous studies,9 patients with ARDS in high-altitude areas may have different pathophysiological characteristics from those of the patients in the plains. The purpose of this study was to explore the influencing factors and clinical characteristics of patients with a risk of pulmonary hypertension secondary to ARDS in a high-altitude area.

    Methods

    Study design

    This was a prospective observational study conducted in the affiliated Hospital of Qinghai University, where the altitude is 2260 m.

    Inclusion and exclusion criteria

    All patients were admitted to the Department of Critical Care Medicine from 25 November 2021 to 30 June 2022. The inclusion criteria were (1) meeting the Berlin Definition of ARDS and (2) mechanical ventilation within 48 hours.

    The exclusion criteria were (1) history of pulmonary hypertension; (2) pregnancy; (3) younger than 18 years or older than 80 years; and (4) intensive care unit (ICU) time <2 days; and (5) unclear image. The protocol was approved by the Institutional Ethics Committee of the affiliated Hospital of Qinghai University (P-SL-2022-096) and registered on clinicaltrials.gov (NCT05166759).

    Study protocol

    Two investigators independently assessed the pulmonary artery pressure (PAP) and RV function of the patients who met the criteria; when the results provided by investigators were similar, the mean value was used. In addition, patients were evaluated within 48 hours of admission into the ICU. Central venous pressure (CVP) was measured by a central venous catheter. Right heart function, including tricuspid annular plane systolic excursion (TAPSE), FAC, S′ and Tei, were measured according to the guidelines endorsed by the European Association of Echocardiography. TAPSE, FAC and S′ could reflect the systolic function of the right ventricle, and Tei could reflect both systolic and diastolic function of the right ventricle.10 Philips cx50 made by Royal Philips of the Netherlands was employed in this study. To ensure the accuracy of the data, if the researchers could not obtain a clear picture, the patient was excluded. Then, baseline characteristics and clinical characteristics of the patient were collected, and researchers followed up over 28 days with those patients who were included in this study.

    Definition

    The diagnostic criterion of PAH in the high-altitude area was systolic pulmonary artery pressure (sPAP) >50 mm Hg according to the Consensus statement on chronic and subacute high-altitude diseases.11 If the altitude of the place where patients live is less than 2500 m, the diagnostic criterion for PAH is sPAP >40 mm Hg.12 sPAP was the sum of the CVP and the peak pressure gradient between the peak right ventricle and the right atrium.10

    Echocardiography

    All parameters were measured in the apical four-chamber cardiac view. When measuring tricuspid regurgitation velocity, the sampling line should be parallel to the regurgitation beam. The M-mode cursor was placed on the lateral tricuspid annulus to measure the displacement of the tricuspid annulus from end diastole to end systole, with TAPSE <1.6 cm indicating impaired RV systolic function (RVSF). When the right ventricle area was measured, trabeculation, tricuspid leaflets and chords should be included. Fractional area change (FAC) is the ratio of the difference between end-diastolic area and end-systolic area to end-diastolic area. The RV myocardial performance index (TEI) and S′ were measured by colour-coded tissue Doppler. FAC <35% and S′ <10 cm/s indicate impaired RVSF. In addition, we measured some parameters of left cardiac structure and function, including left atrial diameter, left ventricular end-diastolic diameter, ejection fraction, fractional shortening, interventricular septal thickness and left ventricular posterior wall thickness, according to guidelines.

    Date collection

    Baseline characteristics of patients who met the inclusion criteria, such as sex, age, altitude of residence, ethnicity, Sequential Organ Failure Assessment (SOFA) Score and complication were collected at study enrolment. In addition, ventilator settings, respiratory mechanics, blood gases, RV function and haemodynamics were also recorded during the time of estimating PAP.

    Date analysis

    All statistical analyses were performed using SPSS V.25.0. Normally distributed data are described by the mean±SD, and differences between two groups were analysed by t-tests. If the data were non-normally distributed, they were presented as medians (P25 and P75), and differences between two groups were analysed by the Mann-Whitney test. Categorical variables and count data are expressed as frequencies and percentages, and comparisons between two groups were performed by the Mann-Whitney test and χ2 test (continuously corrected χ2 test or Fisher’s exact probability test), respectively. Variables were selected for univariate and multivariable logistic regression analyses according to the statistical results and clinical knowledge of the investigators. The receiver operating characteristic (ROC) curve was generated by GraphPad Prism for Windows V.8.3.0, and the cut-off value of factors associated with PAH secondary to ARDS in the high-altitude area was the corresponding value of the maximum Youden index. p<0.05 was considered statistically significant.

    Patients and public involvement

    The patients and the public were not involved in the design of the study.

    Results

    Baseline characteristics

    As of 30 June 2022, 43 subjects were enrolled in this study, with 19 patients diagnosed with PAH (figure 1). Pneumonia was the most common cause of ARDS, followed by aspiration and trauma-induced lung injury. As ARDS worsened, the incidence of pulmonary hypertension increased. The altitude of the residents in the PAH group was lower than that in the normal PAP group (altitude of residents: 2261.00 (2173.00–2680.00) m vs 2711.00 (2388.00–3033.75) m, p=0.007). The baseline characteristics, including age, sex, ethnicity, cause of ARDS, pre-existing diseases and SOFA, did not differ between the two groups. More details are shown in table 1.

    Figure 1
    Figure 1

    Flow diagram of patient screening and enrolment. ARDS, acute respiratory distress syndrome; PH, pulmonary hypertension; ICU, intensive care unit.

    View this table:
    Table 1

    Baseline characteristics of the patients

    The median PAP within the first 48 hours following the diagnosis of ARDS was statistically significant between the two groups (54.00 mm Hg (IQR: 52.00–56.00) versus 29.00 mm Hg (IQR: 22.25–37.25), p<0.001). The mean blood pressure, CVP, heart rate and numbers of patients with vasopressors between the two groups were similar. The difference in the ventilator settings between the two groups was not statistically significant. The plateau pressure (Pplat) and driving pressure in the PAH group were higher than the normal PAP group (Pplat: 21.02±4.05 vs 17.40±2.84 cmH2O, p=0.001; driving pressure: 13.00 (11.00–17.00) vs 10.50 (9.00–12.00 cmH2O), p=0.004); however, Crs and partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FiO2) in the PAH group was significantly lower than the normal PAP group (Crs: 33.00 (28.00–41.00) vs 42.50 (34.16–51.50) mL/cmH2O, p=0.012; PaO2/FiO2: 126.55±42.33 vs 166.58±39.89 mm Hg, p=0.003). PaCO2 and PAH were not significantly different between the two groups. The left ventricular structure between the two groups was not different. Compared with the normal PAP group, RV TAPSE was lower in the PAH group (1.82±0.40 vs 2.09±0.32 cm, p=0.021); however, RV S′ and RV FAC, which showed a similar trend, were not significantly different between the two groups. RV Tei between the two groups was also not statistically significant. TAPSE/sPAP was significantly smaller in the PAH group (TAPSE/sPAP: 0.03±0.01 vs 0.08±0.03 cm/mmHg, p<0.001). The RV basal dimensions were significantly larger in the PAH group (RVD1: 45.47±2.60 vs 40.67±6.12 mm, p=0.019). More details are shown in table 2.

    View this table:
    Table 2

    Haemodynamics, ventilator settings, respiratory system mechanics, blood gases, right ventricular function and left ventricular structure

    Outcomes

    The 28-day all-cause mortality of ARDS in this research was 44.19%, with 57.89% mortality in the PAH group and 33.33% mortality in the normal PAP group. The 28-day mortality, ICU stay, hospital stay and duration of invasive ventilator use in the two groups were not statistically significant. More details are shown in table 3.

    View this table:
    Table 3

    Outcomes in the two groups

    Factors associated with PAH secondary to ARDS in the high-altitude area

    The area under the ROC of the Pplat, driving pressure, PaO2/FiO2, compliance, tidal volume, altitude of resident were 0.7675 (95% CI Power: 0.6171 to 0.9180, p<0.01), 0.7544 (95% CI Power: 0.6091 to 0.8997, p<0.01), 0.7500 (95% CI Power: 0.6037 to 0.8963, p<0.01), 0.7259 (95% CI Power: 0.5667 to 0.8850, p=0.01), 0.6491 (95% CI Power: 0.4835 to 0.8148, p=0.10), 0.7401 (95% CI Power: 0.5886 to 0.8916, p<0.01). Our study revealed that PaO2/FiO2 <165.13 mm Hg was an independent risk factor for PAH secondary to ARDS in a high-altitude area. More details are shown in figure 2 and table 4.

    Figure 2
    Figure 2

    The receiver operating characteristic curve of factors associated with pulmonary hypertension secondary to acute respiratory distress syndrome in the high-altitude area.

    View this table:
    Table 4

    Factors associated with PAH secondary to ARDS in the high-altitude area

    Discussion

    This study found a 44.19% prevalence of PAH in patients with ARDS in the high-altitude area during the first 48 hours. Hypoxaemia was associated with PAH secondary to ARDS in the high-altitude area. PAH secondary to ARDS in the high-altitude area could cause RV dysfunction.

    The following mechanisms contribute to PAH secondary to ARDS. (1) Hypercapnia and hypoxaemia cause pulmonary vasoconstriction. (2) Endothelial cell damage and abnormal coagulation function result in the formation of thrombosis, which increases pulmonary vascular resistance in the form of mechanical obstruction and is clearly shown in COVID-19 ARDS. (3) Inappropriate mechanical ventilation can also lead to increased pulmonary vascular resistance. Lung volumes, whether greater or less than functional residual volume, lead to elevated PAP; pulmonary vascular resistance was lowest only when lung volume was equal to functional residual capacity.13 (4) The inflammatory response is involved in the development of pulmonary hypertension, but the specific mechanism is still unclear.14 (5) Pulmonary vessels are squeezed by swollen alveoli, resulting in increased pulmonary vascular resistance.

    Hypoxaemia in high-altitude areas makes patients with ARDS more likely to develop pulmonary hypertension. High-altitude hypoxaemia can induce an inflammatory response,15 16 which can further aggravate vascular endothelial injury in patients with ARDS and promote the development of pulmonary hypertension. Furthermore, some inflammatory factors could be directly involved in vascular muscularisation and vascular remodelling.15 17 Hypoxaemia in the high-altitude area can also reduce the production and effect of vasodilator substances, and the hypoxaemia-inducible factor induced by hypoxemia can promote vascular remodelling.18 19

    Hypoxaemic pulmonary vasoconstriction is an important cause of PAH secondary to ARDS in high-altitude areas. Fifty years ago, researchers found that the mean PAP of natives was higher than that of newcomers in high-altitude areas.20 A systematic review and meta-analysis with 1544 enrolled patients also revealed that sPAP in high-altitude areas was higher than that in low-altitude areas.21 We attribute the difference in sPAP between different altitudes to hypoxic pulmonary vasoconstriction and pulmonary vascular remodelling. However, the altitude of most patients was between 2260 and 3000 m in our study, and the role of vascular remodelling was not considered. In our study, the difference in the altitude of the residents between the two groups (450 m) was statistically significant. According to a previous study, as the altitude decreases by 300 m, the equivalent oxygen concentration increases by 1%.22 Our study was conducted at 2260 m, and every subject travelled from place of residence to 2260 m before enrolment. In the process of migration, the inhaled oxygen concentration increased by 1% –2% for the patients in the normal PAP group, which improved hypoxic pulmonary vasoconstriction. PaO2/FiO2 is a parameter that can reflect the degree of hypoxaemia to a certain extent. Mekontso et al found that one of the independent risk factors associated with ACP was a PaO2/FiO2 ratio <150 mm Hg.5 Similar to Mekontso et al’s findings, our study revealed that a PaO2/FiO2 ratio <165.13 mm Hg was associated with PAH secondary to ARDS in a high-altitude area, and as ARDS worsened, the incidence of PAH increased. Although the cut-off value in our study was different from previous findings, which was attributed to the different subjects, our results also clarify the necessity of improving oxygenation for ARDS with PAH.

    The RV function of patients with PAH secondary to ARDS in high-altitude areas should not be ignored. ARDS is always complicated by right heart dysfunction and right heart enlargement.23 With the implementation of a lung protective ventilation strategy, 22%–25% of patients with ARDS are still diagnosed with ACP.4 5 Compared with patients with ARDS in the plains, the RV function of patients with ARDS in high-attitude areas should be given more attention because a high altitude could lead to slight alterations in right heart function.24 Our results revealed that the RV basal dimensions were larger and TAPSE was lower in the PAH group, which meant that PAH secondary to ARDS in high-altitude areas led to RV systolic dysfunction and RV enlargement. The right heart also has a reserve function, and organic lesions do not occur immediately. When PAP increases, the right heart can maintain right cardiac output through Frank-Starling mechanisms. If the right heart afterload does not decrease, the right heart will change from hypertrophic to dilatated over time.25 A systematic review and meta-analysis revealed that RV injury was significantly associated with increased overall and short-term mortality in patients with ARDS.26 RV dilation with systolic impairment has also been suggested to be independently associated with mortality in COVID-19 ARDS.27 In addition, the TAPSE/sPAP ratio could represent RV–PA coupling, and a TAPSE/sPAP <0.031 cm/mm Hg was associated with a worse prognosis.28 In our study, TAPSE/sPAP was lower in the PAH group (0.03±0.01 vs 0.08±0.03 cm/mm Hg, p<0.001), which meant worse RV–PA coupling in the PAH group. Although 28-day mortality between the two groups was not significantly different in our study, there were similar trends with previous studies.

    The right ventricle protective ventilation strategy in high-altitude areas still needs to be considered by clinicians. Previous studies found that reduced cardiac output in patients with ARDS was related to elevated pulmonary vascular resistance.29 With further understanding of cardiopulmonary interaction, people gradually realised that inappropriate mechanical ventilation could increase pulmonary vascular resistance and the afterload of the right heart. Therefore, a right ventricle protective ventilation strategy is necessary for patients with ARDS. In 2001, Vieillard-Baron et al recommended carrying out prone position ventilation when ACP was present.4 Subsequent research found that keeping the Pplat below 27 cmH2O in patients with ARDS could reduce the incidence of ACP, and driving pressure ≥18 cmH2O was an independent risk factor associated with ACP.5 30 31 Unfortunately, respiratory mechanics were not associated with PAH secondary to ARDS at high altitudes in our study. We attribute the result to the small sample. Notably, univariate logistic regression revealed that a tidal volume <6.56 mL/kg was associated with PAH secondary to ARDS at high altitudes, which is contrary to a previous study. Obviously, ARDS was more severe in the PAH group with low compliance, low PaO2/FiO2 and high Pplat. Clinicians tend to titrate to a lower tidal volume for severe ARDS, and in the multivariate logistic regression model, we did not find that the tidal volume could influence the incidence of PAH of ARDS. There is no difference in outcomes, and the numbers are small; hence, it is difficult to suggest management strategies based on the results.

    The results of our study need to be confirmed by a large sample study. There are some limitations in our study. (1) This is a small sample study, with 43 patients included in all, which is not enough for an epidemiological investigation. (2) Although we used strict inclusion and exclusion criteria, there may be some diseases ignored by us that could have an effect on pulmonary arterial pressure, which would result in a higher incidence of PAH than the true value. (3) In this study, cardiac ultrasonography was employed to assess pulmonary arterial pressure, which was less reliable than other methods, such as direct PAP monitoring by a Swan-Ganz catheter, but we invited two experienced investigators to independently assess PAP, which could reduce the bias of PAP. (4) We only assessed PAP and right heart function twice within the first 48 hours following the diagnosis of ARDS and lacked real-time evaluation.

    Conclusion

    Due to the hypoxic characteristics of high-altitude, the incidence of PAH in patients with ARDS in our study is higher than previous studies. PaO2/FiO2 were associated with PAH secondary to ARDS in a high-altitude area. Most noteworthy, PAH secondary to ARDS in high-altitude areas could cause RV dysfunction.

    Data availability statement

    Data are available upon reasonable request. No data are available.

    Ethics statements

    Patient consent for publication

    Ethics approval

    This study involves human participants and was approved by the Institutional Ethics Committee of the affiliated Hospital of Qinghai University (P-SL-2022-096). Participants gave informed consent to participate in the study before taking part.

    Acknowledgments

    We thank all the patients who participated in this study in the affiliated hospital of Qinghai University.

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    Footnotes

    • PZ and JZ are joint first authors.

    • Contributors PZ and JZ contributed equally to this paper. CP designed the study and is the guarantor, accepts full responsibility for the work. PZ, JZ and ST were responsible for collecting and analysing data. PZ and JZ wrote the manuscript. XS, ZQ and QX assisted in data collection. ZS, LS, MH and GG supported this study. All authors contributed to and approved the final manuscript.

    • Funding This work was funded by Key Project of Medical Scientific Research Project of Jiangsu Provincial Health Commission (ZD2021057), the Science and Technology Development Plan of Suzhou City, China (SYS2020136).

    • Competing interests None declared.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting or dissemination plans of this research.

    • Provenance and peer review Not commissioned; externally peer reviewed.