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Pulmonary Vascular Dysfunction and Cor Pulmonale During Acute Respiratory Distress Syndrome in Sicklers

Cecchini, Jérôme; Boissier, Florence; Gibelin, Aude; de Prost, Nicolas; Razazi, Keyvan; Carteaux, Guillaume; Galacteros, Frederic; Maitre, Bernard; Brun-Buisson, Christian; Mekontso Dessap, Armand

Author Information
doi: 10.1097/SHK.0000000000000640

Abstract

INTRODUCTION

Sickle cell disease (SCD) is an inherited hemoglobinopathy that manifests by chronic hemolysis and acute vaso-occlusive events. Acute chest syndrome (ACS) is the most common cause for intensive care unit (ICU) admission and death among adult sicklers (1, 2). Severe forms of ACS lead to acute respiratory distress syndrome (ARDS) with a high mortality rate (1, 3, 4).

During ARDS, pulmonary vascular dysfunction (PVD) is common and may lead to right ventricle (RV) dysfunction with a poor prognosis (5–7). The prevalence and prognostic role of PVD may be even more important during ARDS complicating ACS (1, 3). In addition to the many pathophysiologic changes of lung vasculature observed during all forms of ARDS, ACS is specifically associated with vasoconstriction (due to hemolysis and the scavenging of nitric oxide) and vaso-occlusion (due to fat embolism and/or in situ thrombosis) (8, 9). An increase in pulmonary pressures has been demonstrated during severe ACS, and acute cor pulmonale (ACP) is associated with a higher risk of death in this setting (1, 3). The aim of the present study was to evaluate the prevalence and prognosis of PVD and ACP during ARDS related to ACS (ACS-ARDS). This study includes some patients previously described in reports focusing on RV function during ARDS or ACS (3, 5).

PATIENTS AND METHODS

Patients

This was a retrospective analysis of data prospectively collected between June 2004 and June 2014 in the medical ICU of a French university hospital hosting a national reference center for SCD patients. Although many patients were included before 2011, all actually met the Berlin definition criteria for moderate-to-severe ARDS: they had acute respiratory failure requiring invasive mechanical ventilation within 1 week of a known clinical insult or new or worsening respiratory symptoms, bilateral chest opacities not fully explained by effusions or lobar/lung collapse or nodules or by cardiac failure or fluid overload, and a PaO2/FiO2 ratio at most 200 mmHg with positive end-expiratory pressure (PEEP) at least 5 cmH2O (10). All patients were routinely assessed using transthoracic or transesophageal echocardiography within the first 3 days after the diagnosis of ARDS. ARDS episodes were assigned to one of two groups according to whether the clinical insult was ACS in an SCD patient (ACS-ARDS group) or not (nonACS-ARDS group). The diagnosis of ACS was defined as an acute illness characterized by fever and/or respiratory symptoms, accompanied by a new pulmonary infiltrate on a chest x-ray in a patient with genetically proven SCD (11). Exclusion criteria included chronic pulmonary disease requiring long-term oxygen therapy or home mechanical ventilation, chronic pulmonary hypertension (defined by a mean pulmonary arterial pressure ≥25 mmHg on right heart catheterization), and chronic cor pulmonale. In all patients, a protective mechanical ventilation strategy was applied with a target tidal volume of 6 mL/kg of predicted body weight and an inspiratory plateau pressure not exceeding 30 cmH2O. Patients with ACS-ARDS received a uniform standardized treatment protocol for ACS including red blood cell transfusion therapy (12). Follow-up for the study was until ICU discharge or at least 28 days. The study was approved by the institutional ethics committee of the French Society of Intensive Care (Société de Réanimation de Langue Française). Because we routinely use echocardiography to assess the circulatory status of mechanically ventilated patients with ARDS in our ICU, this technique was considered as a component of standard care and patient's consent was waived.

Echocardiography

Transthoracic and/or transesophageal echocardiography were performed using a Sonos 5500, Envisor or a IE 33 system (Philips Ultrasound, Bothell, Wash) by trained intensivists qualified in advanced critical care echocardiography, using a standardized procedure (13). Left ventricle (LV) systolic dysfunction was defined as LV ejection fraction less than 50%. ACP was defined as a dilated RV (end-diastolic RV/LV area ratio >0.6) associated with septal dyskinesia on the short-axis view (14). Septal dyskinesia was particularly sought during end-systole (13, 14) while analyzing images in slow motion. Pulmonary artery systolic pressure (PASP) was assessed using the tricuspid regurgitation continuous-wave Doppler technique; undetectable values of tricuspid regurgitation were assigned a PASP value lower than any actually measured during the study (20 mmHg) (3, 15). Patients were stratified into three groups based on the degree of PVD, as follows: no dysfunction (PASP ≤40 mmHg with normal RV size and normal interventricular septum kinetics), moderate dysfunction (PASP >40 mmHg or a dilated RV but without ACP), and severe dysfunction (i.e., ACP) (14).

Clinical data

Baseline characteristics recorded included the type of hemoglobinopathy, the steady-state hemoglobin value, and the history and long-term treatment of SCD. Severity of illness at admission was evaluated by the SAPS II score, which was also computed without using age because of the typically young age of SCD patients admitted in ICU (1). Respiratory and hemodynamic variables were collected at the time of echocardiography and included vital parameters, ventilator settings, and arterial blood gases (last available value on the day of echocardiography). Driving pressure was calculated as the difference between plateau pressure and PEEP. Severe hypoxemia was defined as a PaO2/FiO2 ratio less than 150 mmHg and/or the need for inhaled nitric oxide or prone position to achieve a PaO2/FiO2 ratio at least 150 mmHg (16). Shock was defined as the need for catecholamine infusion to maintain adequate arterial pressure (17). Pneumonia, aspiration, and sepsis were diagnosed as previously described (17, 18).

We computed the ACP risk score, which is based on four variables (pneumonia as cause of ARDS, driving pressure, PaO2/FiO2 ratio, and PaCO2) ranging from 0 to 4 and which has been found to predict the probability of ACP (see e-Table 1 in Supplemental Digital Content 1, https://links.lww.com/SHK/A394) (7). Patients with ACS were considered as having pneumonia only in case of microbiologically documented lower respiratory tract infection (infective pneumonia).

Statistical analysis

The data were analyzed using the SPSS Base 20.0 statistical software package (SPSS Inc, Chicago, Ill) and Stata 13.1 (StataCorp LP, College Station, Tex). Continuous data were expressed as mean ± SD unless otherwise specified and were compared using the Student t test or Mann-Whitney U test for independent samples, as appropriate. Categorical variables, expressed as percentages, were evaluated using the chi-square test or Fisher exact test, as appropriate. To evaluate independent factors associated with ACP, significant univariable risk factors were examined using backward stepwise logistic regression analysis. A goodness-of-fit test (Hosmer-Lemeshow) and the area under the receiver-operating characteristic curve were used to assess calibration and discrimination of the models, respectively. Among related significant univariable ventilatory factors, only those with the highest absolute standardized difference were entered into the regression model to minimize the effect of colinearity. Because ACP is likely to cause hemodynamic compromise, hemodynamic variables were not included into this predictive model (5). To analyze the association between ACS-ARDS and ACP while taking into account the ACP risk score (7), we stratified ACS-ARDS and nonACS-ARDS patients into the five groups of ACP risk score, used the Tarone test for homogeneity of odds ratio [OR], and estimated a common OR by using the Mantel-Haenszel test. We also used propensity score analyses to better scrutinize the association of ACS-ARDS with the occurrence of ACP. The rationale and methods underlying the use of propensity scores for proposed causal exposure variables have been previously described (19). The selection of covariates included in the multivariable logistic regression model used to estimate the propensity score for having ACS-ARDS was guided by clinical significance and imbalances between ACS-ARDS and nonACS-ARDS groups (excluding age which could not be matched), as estimated by an absolute standardized difference above 15%. The final propensity score model included the following covariates: sex, infective pneumonia, driving pressure, PEEP, respiratory system compliance, severe hypoxemia, PaCO2, SAPS II score, and shock. We matched patients with ACS-ARDS to those with nonACS-ARDS, using a greedy nearest neighbor matching algorithm with a caliper width of 0.15 SD of the log odds of the estimated propensity score and sampling without replacement. We used a graphical representation with standardized differences to check the balance of covariates in the matched sample. Two-tailed P values less than 0.05 were considered statistically significant.

RESULTS

During the study period, 629 patients were hospitalized for moderate-to-severe ARDS. Among them, 307 were excluded because echocardiography was not performed during the first 3 days after the diagnosis of ARDS (n = 258, including no SCD patient) or because of chronic pulmonary hypertension (n = 4, including 3 SCD patients) or chronic cor pulmonale (n = 5, including no SCD patient). Thus, the present study includes a total of 362 patients.

ACS

Twenty-four SCD patients with ACS were assigned to the ACS-ARDS group. The baseline characteristics and medical history of these patients are shown in Table 1. Identified causes of ACS included medullary necrosis (n = 3, 13%), delayed hemolytic transfusion reaction (n = 3, 13%), and infective pneumonia (n = 6, 25%). A vaso-occlusive pain crisis preceded or accompanied ACS in 20 cases (83%). A pulmonary artery thrombosis was found in 3 of 17 patients (18%) in whom a chest computed tomography was performed. All episodes of ACS were treated with antibiotics and transfusion therapy, which included single transfusions (n = 8, 33%) or exchange transfusion (n = 16, 67%) with a median (25th–75th centiles) total of packed red blood cells of 4.5 (4.0–8.0).

T1-4
Table 1:
Baseline characteristics of the 24 sicklers with acute respiratory distress syndrome

Clinical and respiratory variables

Patients with ACS-ARDS mostly differed from those with nonACS-ARDS by a younger age (which accounted for the difference in SAPS II score), more female sexes, higher values of driving pressure, and lower values of respiratory system compliance, tidal volume, and PEEP (Table 2).

T2-4
Table 2:
Patient characteristics, treatment, and outcome of acute respiratory distress syndrome in sicklers (ACS-ARDS) and nonsicklers (nonACS-ARDS)

Hemodynamic and echocardiographic variables

Patients with ACS-ARDS had a higher heart rate as compared with those with nonACS-ARDS, with no significant difference in terms of occurrence of shock (Table 2). PVD was present in all patients (n = 24/24) in the ACS-ARDS group as compared with 60% (n = 204/338) in the nonACS-ARDS group; ACP was also more frequent in the former group: (83% vs. 20 %; Table 2). The difference in PVD rate persisted after stratification according to the ACP risk score (Fig. 1; OR 15.7, 95% confidence interval [CI] 4.9–50.1, P < 0.001).

F1-4
Fig. 1:
Prevalence of pulmonary vascular dysfunction during acute respiratory distress syndrome in sicklers (ACS-ARDS) and nonsicklers (nonACS-ARDS) stratified according to the acute cor pulmonale (ACP) risk score (7).White, gray, and black bars denote absent, moderate, and severe pulmonary vascular dysfunction, respectively. Odds ratio (OR) values of the association between ACP and ACS-ARDS were homogeneous within each ACP risk score strata [χ2 (3 df) = 1.5, P = 0.7] with a global OR of 15.7, 95% confidence interval 4.9–50.1 (P < 0.001).

Factors associated with ACP

In univariable analysis, risk factors for ACP included the following: ACS-ARDS; younger age, severe hypoxemia; lower values of tidal volume and respiratory system compliance; and higher values of plateau pressure, driving pressure, and PaCO2 (see e-Table 2 in Supplemental Digital Content 1, https://links.lww.com/SHK/A394). In multivariable analysis, ACS-ARDS, severe hypoxemia, and PaCO2 were independently associated with ACP (Table 3).

T3-4
Table 3:
Factors associated with acute cor pulmonale in patients with acute respiratory distress syndrome

Of the 24 patients with ACS-ARDS, 21 (88%) were matched using the propensity score to a similar patient with nonACS-ARDS. The covariate balance between the ACS-ARDS and nonACS-ARDS groups improved substantially through propensity score matching (see e-Figure 1 in Supplemental Digital Content 1, https://links.lww.com/SHK/A394), except for age that could not be matched. In the propensity-matched cohort, age and ACS-ARDS were the two factors associated with ACP in univariable analysis, whereas no association was found between the covariates included into the propensity score and ACP. After multivariable analysis, only ACS-ARDS remained associated with ACP (OR 11.7, 95% CI 1.2–110.8, P = 0.03). Figure 2 shows the significant association of ACS-ARDS with ACP using various logistic regression models.

F2-4
Fig. 2:
Odds ratio with 95% confidence intervals for the association between acute respiratory distress syndrome secondary to acute chest syndrome and acute cor pulmonale in logistic regression models with crude analysis [19.9 (6.6–60), P < 0.0001], multivariable adjustment [27.4 (8.2–91.5), P < 0.001], and propensity matching [11.7 (1.2–110.8), P = 0.03].

Outcome

Patients with ACS-ARDS required more adjunctive therapies for ARDS during the ICU course than those with nonACS-ARDS (Table 2). The in-ICU and 28-day mortality did not differ between ACS-ARDS and nonACS-ARDS patients (Table 2). As compared with patients without ACP, those with ACP had a higher 28-day mortality but similar in-ICU mortality (see e-Table 2 in supplementary appendix, Supplemental Digital Content 1, https://links.lww.com/SHK/A394).

DISCUSSION

We herein show that patients with ACS-ARDS are extremely prone to PVD. These results suggest that ACS-ARDS is a distinctive form of ARDS, where PVD might play a critical role.

Acute pulmonary hypertension and ACP have been previously documented in 60% and 13% of patients with severe ACS, a majority of whom were not mechanically ventilated (3). Our study focused on more severe patients requiring invasive mechanical ventilation with ARDS criteria. This might explain the very high prevalence of PVD and ACP in the ACS-ARDS group (100% and 83%, respectively), which is in line with previous studies suggesting that ACP is a severity marker during ACS (1, 3, 20). The high mortality rate of ACS-ARDS is also consistent with previous studies of SCD patients requiring mechanical ventilation for acute complications (1, 4). The lower mechanical ventilation duration in ACS-ARDS patients as compared with their counterparts may reflect a better general condition related to their younger age.

As previously described, the overall prevalence of ACP during the first days of ARDS was 24% and risk factors for ACP included severe hypoxemia and hypercapnia (5–7). ACS-ARDS was associated with ACP irrespective of classical ACP risk factors. Indeed, both the crude, adjusted, and propensity-matched analyses found a significant association between ACS-ARDS and ACP. Various specific alterations may impede right ventricular afterload during ACS-ARDS. First, pulmonary vasoreactivity related to hemolysis may induce an imbalance of vasoactive factors favoring vasoconstriction (21–23). Second, the biological properties of sickle hemoglobin may enhance hypoxic pulmonary vasoconstriction (24). Third, fat embolism (8) and in situ pulmonary thrombosis (9) may aggravate pulmonary vaso-occlusion. Our study does not enable to infer about the causal relation that links ACS-ARDS to PVD and future studies are needed to scrutinize the relative contribution of each of these factors. However, the strong association that we observed raises the question whether PVD is not only a consequence but also a causal factor contributing to the genesis of ACS-ARDS. Interestingly, high altitude pulmonary edema (HAPE), a peculiar form of noncardiogenic pulmonary edema, shares similar features with ACS-ARDS, supporting the hypothesis that ACS-ARDS might be primarily vascular pressure-driven. During HAPE, hypobaric hypoxia induces in susceptible subjects a sharp increase of pulmonary artery pressure via an exaggerated and uneven hypoxic pulmonary vasoconstriction, leading to regional overperfusion, stress failure of pulmonary capillaries, and finally to pulmonary edema (25–28). This pulmonary hypertension is related to defective nitric oxide synthesis and associated high endothelin-1 synthesis (29, 30), an imbalance also observed during vaso-occlusive crisis (21, 22). Moreover, during vaso-occlusive crisis, a condition commonly preceding the occurrence of ACS (1, 31), acute elevation in pulmonary arterial pressures has been observed (32). Finally, analyses of fluid edema suggested HAPE to be of high-permeability type because of a particularly high protein concentration exceeding that usually seen during ARDS (33–35); similarly high protein contents have been observed in bronchoalveolar lavage fluid during ACS (8, 36).

Our results have potentially important implications for both the recognition and clinical management of PVD during ACS-ARDS (3). Our data strongly suggest routinely assessing pulmonary pressures and RV function in patients with ACS-ARDS with the use of echocardiography. Measures aimed at mitigating PVD during ACS-ARDS may involve both the ventilatory management and pharmacologic interventions. Ventilator settings aimed at limiting plateau and driving pressures while controlling hypoxemia and hypercapnia have been recently proposed (RV protective approach) (37). Prone positioning, which is a key element in this approach, may be used liberally during ACS-ARDS to unload the RV (38). To date, there is no specific pharmacologic treatment for ACS or ARDS. Despite a strong physiological rationale, a recent trial on the use of inhaled nitric oxide did not show improvement of ACS course but suggested a benefit for the most hypoxemic patients (39). Inhaled nitric oxide neither improved the prognosis of unselected patients with ARDS (40), but future studies should assess its usefulness during ACS-ARDS. Whether the use of other pulmonary vasodilators (like epoprostenol) or anticoagulants to mitigate pulmonary vasoconstriction and in situ thrombosis (9) may alter the outcome of ACS-ARDS also warrants future trials. In case of shock with RV failure, noradrenaline can improve systemic hemodynamics and coronary perfusion without change in pulmonary vascular resistance (41). The use of inotropes like dobutamine (or levosimendan) can improve RV inotropy (and favor pulmonary vasodilatation), but they may trigger or aggravate systemic hypotension (41).

Our study has several limitations. First, its retrospective and monocentric design precludes the generalizability of our findings. However, the overall prevalence of ACP in our cohort was consistent with previous studies (5–7). Second, despite the large number of ARDS patients included in this study, the ACS-ARDS group had a limited size. Third, the propensity score model used to match ACS-ARDS to nonACS-ARDS could not include age as a covariate and ACS-ARDS patients were younger than nonACS-ARDS in the matched cohort. Despite this between-group imbalance, age was not retained by the multivariable model in the propensity-matched sample and no available data suggests that younger age might promote the occurrence of PVD.

In conclusion, all SCD patients presenting with moderate-to-severe ARDS as a consequence of ACS experienced PVD and more than 80% of them exhibited ACP. These results suggest a predominant role for PVD in the pathogenesis of severe ACS.

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Keywords:

Acute chest syndrome; adult/complications/ultrasonography; anemia; pulmonary heart disease; respiratory distress syndrome; sickle cell/complications

Supplemental Digital Content

© 2016 by the Shock Society