This study assessed cognitive and neuropsychological long-term outcomes in severe ARDS survivors comparing patients treated or not treated with VV-ECMO through the use of an in-person interview using a well-established and validated highly specific measurement instrument. The results of the present study suggest that VV-ECMO treatment does not worsen long-term cognitive and neuropsychological outcomes in severe ARDS survivors.
External validity
The main concern in comparing neurocognitive outcome studies is the great variability of the measurement instruments used and the lack of validated thresholds to define cognitive impairment. Only two non-comparative ECMO cognitive outcome studies used the WAIS-IV as in the present study. Von Bahr et al. [
34] found results similar to our cohort with a median full-scale intelligence index of 97, but the follow-up time was much longer with a mean of 9 years post discharge. Holzgraefe et al. [
35] found also similar results at a median of 3.2 years post ICU discharge but with a cohort of only seven patients. However, in these two studies, there was no control group without ECMO.
Moreover, previous similar studies have frequently combined venovenous and venoarterial ECMO [
21,
34], whereas the risk of cerebral injury—and hence cognitive outcome—is much greater with venoarterial than venovenous ECMO.
Risnes et al. [
21] found an incidence of 33% of cognitive impairment predominant on attention and verbal memory, 5 years after discharge, as well as a correlation between cognitive impairment and neuroradiologic findings. However, they used a composite impairment score in a pediatric and adult population with various indications of ECMO [
21].
In the present study, few patients had a cerebral imaging during or after ICU stay; however, this is acceptable since the incidence of cerebrovascular lesion in VV-ECMO patients has declined from 17 to 26% in some reports [
21,
34] to 2% in the recent EOLIA trial [
7]. Moreover, as there was no difference among the 2 groups, the need for cerebral imaging in highly questionable.
Luyt et al. [
36] did the only comparative study and found similar outcomes in terms of health-related quality of life, incidence of anxiety, depression and PTSD in H1N1-ARDS survivors treated with ECMO or conventional ventilation 1 year after their discharge. However, cognitive function was not assessed in this cohort.
Hodgson et al. [
37] reported that long-term ARDS survivors treated with ECMO had low general health, mental health, vitality and social function SF-36 subscores, but unlike our study this study was not comparative.
Even though ECMO patients were more subjected to severe hypoxemia in the present report, it was not associated with more cognitive dysfunction, which is consistent with other similar studies [
34,
35].
In our cohort, very few patients had returned to work 2 years after their discharge which is inconsistent with other studies. In Luyt’s cohort, 83% of ECMO patients and 64% of non-ECMO patients had returned to work 1 year post discharge from the ICU [
36] whereas 53% of patients had returned to work at 8 months in Hodgson’s cohort [
37]. This may be explained by the fact that patients were younger in both cohorts [
36,
37] as compared with ours.
Cognitive and neuropsychological outcomes of the non-ECMO control group from the present study are consistent with other reports of long-term outcome in ARDS survivors [
11,
14,
16,
18,
38]. Health-related quality of life is also comparable to previous studies except for the physical and emotional dimension [
12,
14,
39]. It should be noted that we did not compare these results to the SF-36 scores of the healthy French population. However, we believe that these results are consistent with the low proportion of patients who returned to work because physical and emotional aspects reflect the extent to which physical health and emotional problems interfere with work and may limit activity.
Strengths and limitations
One of the main strengths of the present study is the comprehensive in-person evaluation of cognitive function assessed by an expert. We used validated outcome measurement instruments to assess cognitive and psychological function in ARDS patients. Few ECMO long-term outcomes studies have a control group; the comparative design of this study is another strength.
There are several limitations to this study. The first is the small sample size and the absence of randomization due to the study’s nature as a single-center study. Moderate associations were possibly missed because of low statistical power due to the sample size, which was arguably too small. A larger sample will allow the confirmation of these findings. As the differences were very small, it is highly probable that a larger sample would confirm the present results. The reason why some patients with very profound hypoxemia were treated with VV-ECMO and others were not is related to the admission procedure of the patients. Indeed, our ICU is the regional (a 31,400-km
2 region with approximately five million inhabitants) VV-ECMO referral center for the treatment of severe respiratory failure. For patients referred to our center, VV-ECMO was implemented in the referring center by our mobile team before transfer. In our own center, as VV-ECMO can be very rapidly applied, we are able to wait until lower PaO
2 levels. This is confirmed by the information provided in Table
1 showing that 8 of 18 patients from the non-ECMO group were initially hospitalized in our own ICU as compared with only 5 of 22 from the ECMO group. Families play an important role in the outcome of ICU patients, and we did not evaluate between groups differences regarding family support. Moreover, even though psychological symptoms like anxiety and PTSD in patients may affect willingness to participate in such follow-up research and lead to an under estimation of the prevalence of such neuropsychological impairments, follow-up rates in this cohort were rather good with more than 45% of the eligible patients included. Second, although patients with prior neurocognitive or psychological impairment were excluded, we did not have patient’s baseline cognitive data, which is a common limitation of cognitive function ICU studies. We tried to address this by adjusting on the education level. Although ECMO patients had a higher educational level, no significant difference was found between the two groups after multivariate analysis. Also, because working memory and verbal comprehension indexes can be influenced by the level of education, we performed an adjustment on this parameter and found no significant differences between ECMO and non-ECMO groups.
The WAIS-IV is exploring only some aspects of neurocognition. Neurocognitive function also included psychomotor speed, spatial reasoning, verbal memoring, visual memoring which are partially assessed by the WAIS-IV. However, cognitive exploration takes time and is not easy to insert in a prolonged interview. The evaluation proposed in the present study was face-to-face, lasting approximately 3 h, which is already noteworthy in a post-ICU follow-up study. Finally, it is extremely difficult to distinguish normal variations in test performances from true cognitive impairment. In fact, for the WAIS-IV, 68% of the healthy French population scores vary between ± 1 SD of the mean and 95% between ± 2 SD [
24]. We performed the statistical analysis with three different thresholds and found no significant differences between the two groups regardless of the cutoff. We finally chose to use a cutoff of at least one WAIS-IV index below one SD to define cognitive impairment even though by doing so we may have overestimated the incidence of cognitive impairment.
Prevention
This study emphasizes the need to prevent long-term cognitive and neuropsychological sequelae in ARDS patients. ICU-based interventions like ICU diaries written by clinicians and family members to critically ill patients [
40], in-ICU psychological and cognitive interventions [
41], social support [
38], rehabilitation psychologists, post-ICU coping skills training [
42] and rehabilitation clinics could be helpful in reducing long-term cognitive and neuropsychological disorders. However, they need a more extensive evaluation.
Follow-up and rehabilitation programs in order to screen, prevent and treat these impairments need to be developed to improve long-term outcomes in severe ARDS survivors.
In conclusion, we reported that VV-ECMO treatment for severe ARDS does not seem to be associated with worse long-term cognitive and neuropsychological outcomes compared to patients not undergoing VV-ECMO. Nevertheless, the incidence of cognitive impairment and neuropsychological sequalae in severe ARDS patients remains high with consequences regarding quality of life and social health. Development of strategies for prevention and treatment is of major concern.