Microvascular reactivity is altered early in patients with acute respiratory distress syndrome

This prospective, observational, non-invasive, physiological study was conducted in the 35-bed Department of Intensive Care of Erasme University Hospital (Brussels, Belgium). Institutional Ethical Committee approval was obtained, and all volunteers and patients (or their next of kin) provided written informed consent.

Twenty-seven healthy volunteers were recruited (mean age 30 [range 27–31] years; 15 male) and 32 patients with ARDS (mean age 63 [range 48–71], 21 male). The main demographic, clinical and biochemical characteristics of the volunteers and patients are presented in Table 1. The characteristics of ARDS survivors and non-survivors are shown in Additional file 1: Table S1.

NIRS derived parameters are shown in Table 2. ARDS patients had lower StO₂ values and Asc slope, but not Desc slope, than healthy volunteers. Patients with a poor evolution had a lower NIRS Asc slope than those with a good evolution (Fig. 2a), but StO₂ and Desc slope values were not significantly different (Table 2). Likewise, non-survivors had a lower NIRS Asc slope than survivors (Fig. 2b). There were no differences in the Asc slope values according to the cause of ARDS (including sepsis and its severity) (Additional file 1: Figure S1 and S2).

There were no significant differences in the PaO₂/FiO₂ ratio between patients with a good or poor evolution, or between survivors and non-survivors (Tables 1 and Additional file 1: Table S1). However, ARDS patients with a PaO₂/FiO₂ ratio < 100 had a lower NIRS Asc slope than those with a PaO₂/FiO₂ ratio between 201 and 300 (Fig. 3).

The NIRS Asc slope was a better predictor of poor evolution (and of mortality alone) than the PaO₂/FiO₂ ratio (Fig. 4). This was confirmed in the multivariate analysis in which the NIRS Asc slope was the most significant factor associated with a poor evolution during the ICU stay (Additional file 1: Tables S2 and S3).

The main finding of our study is that ARDS patients have altered peripheral microvascular reactivity as assessed using NIRS. This alteration is directly related to the severity of the disease characterized as death and/or prolonged need for mechanical ventilation.

The only published data on microcirculatory alterations in humans with acute respiratory failure assessed using non-invasive techniques were reported by our group in a small series of patients with acute lung injury due to Influenza AH1N1 [28]. These patients had diminished capillary density in the sublingual area, with a low proportion of perfused vessels and a reduced microvascular flow index. In the thenar muscle, post-occlusive reactive hyperemia was impaired, as manifest by low values of the Asc slope, similar to those found in septic patients in other studies [29‐31]. Our current study extends these data to a larger and more heterogeneous population of patients with ARDS.

Half of the patients in our study had sepsis, but microcirculatory alterations detected by NIRS are not pathognomonic of septic conditions. Numerous studies have shown alterations of the Asc slope in septic populations, especially in the presence of shock [20, 29, 30], but low values of the Asc slope have also been observed in other acute conditions (normal values of 288 and 323 %/min have been reported [20, 22]): Gomez et al. reported values of 172 ± 103 %/min in trauma patients [22]; Petroni et al. reported values of 77 ± 42 %/min in patients with severe acute heart failure requiring veno-arterial extracorporeal membrane oxygenation (ECMO) support [23]; Morel et al. reported values of 144 (126–228) %/min 6 h after cardiopulmonary bypass in patients who had undergone cardiac surgery [24]; Donadello et al. reported values of 68 ± 32 %/min in resuscitated cardiac arrest patients after cessation of therapeutic hypothermia [25]; and we previously reported values of 186 ± 89 %/min in patients with circulatory shock of different etiologies [31]. In the present study, patients with septic shock had similar Asc slope values to patients with ARDS of non-septic causes. Although the mechanisms involved in the control of post-occlusive reactive hyperemia (NIRS Asc slope) have not been completely identified and are sometimes controversial [32, 33], it is well known that multiple vasodilator pathways (e.g., nitric oxide and prostaglandins) are necessary to obtain the transient increase in local blood flow [32] and complex inflammatory alterations will have been present in all the populations studied above [20, 22‐25, 31]. Thus, the NIRS VOT is a functional test of the microcirculation, which measures its reserve (recruitability) under controlled ischemia, and involves multiple pathways.

Our findings suggest that microvascular endothelial dysfunction is present in the earliest stages of ARDS and is correlated with its severity. This concept fits well with the elevated concentrations of various pro-inflammatory molecules seen in patients with ARDS [8, 12, 34] and with autopsy findings revealing an initial pro-inflammatory and exudative phase [7, 35]. Dolinay and colleagues performed a series of experiments in mice and various cohorts of ARDS patients and showed that several inflammasome-regulated cytokines, including interleukin-18, play a major role in the development of ARDS [36]. Orfanos and colleagues demonstrated that severe ARDS was associated with decreased pulmonary capillary endothelium-bound angiotensin converting enzyme (ACE) function in vivo (an indirect marker of endothelial injury) [37]. More recently, Moussa et al. demonstrated that patients with ARDS in the context of sepsis had elevated numbers of circulating endothelial cells (a direct marker of endothelial injury), which were correlated with severity [10].

Early prognostication of outcome in ARDS is challenging. In large databases, the mortality rate is directly related to the severity of the alterations in gas exchange as expressed by the PaO₂/FiO₂ ratio, but the relationship is not very strong [38, 39], with an AUC of only 0.58 in a recent multicenter study [1]. We used a main combined outcome of death or need for prolonged mechanical ventilation which is essentially the opposite of ventilator-free days [40], but we also observed positive results when mortality was considered alone. Previous investigators have tried to predict similar combined outcomes, but they needed to use clinical data obtained during the first three days of hospitalization [41], rather than just on the first day as in the present study. Other groups have developed scores mixing various clinical and demographic data at admission, but these were not superior to the APACHE II score for predicting mortality [42]. We also observed that those patients who recovered rapidly had a similar Asc slope when compared with volunteers, despite the severe hypoxemia. Additionally, the NIRS Asc slope was the best predictor for death or more than 7 days on mechanical ventilation. Together these observations suggest that performing a NIRS VOT test on the first day of ARDS enables identification of patients at high-risk of poor outcome, potentially creating a target population for the testing of early interventions.

Our study has some limitations. First, it was a monocenter study and patient enrolment depended on researcher availability, although we included a heterogeneous sample of patients with different severities of ARDS. Second, we performed a single measurement and the time course of the Asc slope during subsequent days of treatment may provide additional information, as has been shown in septic patients [20]. Third, our control group was comprised of healthy younger individuals who may have different vascular reactivity to that of ARDS patients. However, we have previously reported that NIRS values are quite similar in control cohorts of patients and in healthy younger volunteers [20, 31]. Our comparison enables the whole spectrum from the normal values of health to those in severe ARDS patients to be considered. Finally, the sample size of our population was small, potentially explaining the non-significant differences in some variables, for example, the norepinephrine doses between patients with good and poor evolution (Table 1) or the NIRS Asc slope in the different groups of PaO₂/FiO₂ ratios, despite trends in the data. Nevertheless, the clinical relevance of the NIRS Asc slope was higher than that of other studied variables and this variable needs to be investigated further.

In ARDS patients, there is an early, marked alteration in microvascular reactivity, which is directly related to the severity of the disease as reflected by the duration of mechanical ventilation and mortality.