Effects of Extracorporeal Membrane Oxygenation Initiation on Oxygenation and Pulmonary Opacities

The use of extracorporeal membrane oxygenation (ECMO) as a strategy to support adult patients with refractory hypoxemia or hypercapnia as well as for hemo-dynamic support, continues to increase [1]. Given the temporary nature of the ECMO support for pulmonary indications, it is considered a ‘bridge to destination’ therapy. ECMO may aid in the decision-making process, though ultimately, patients were bridged to either recovery or lung transplantation (LT) surgery.

Despite significant advancements in the pump and circuitry equipment used for ECMO, which allowed patients to be supported for more extended periods, it is not a benign intervention, and the clinical course among patients on ECMO can be precarious with the potential for complications to follow [2]. Several research studies, mostly conducted in paediatric populations, have demonstrated that the initiation of ECMO, almost immediately activates an inflammatory cascade, similar to the systemic inflammatory response syndrome (SIRS) [3, 4, 5, 6, 7, 8, 9, 10]. This cascade leads to the release of several pro-inflammatory cytokines that causes organ dysfunction.

Despite pre-clinical studies demonstrating the pro-inflammatory effects of ECMO initiation, there remains a lack of data regarding the frequency of these complications and their impact on outcomes among adult patients on ECMO.

Specifically, data are lacking regarding the pulmonary effects of ECMO related SIRS, which can be hard to differentiate from the background lung disease necessitating ECMO support.

The current study aimed to evaluate the progressive changes in oxygenation and pulmonary opacities after the initiation of ECMO, correlate these changes with non-pulmonary organ functions and evaluate its association with hospitalisation durations.

The Institutional Review Board of the University of Texas Southwestern Medical Centre in Dallas, Texas, USA, provided approval for the study with the waiver that written patient consent be obtained before the commencement of the study (IRB# STU 072015-001).

The institutional ECMO database of the centre was searched. Patients with advanced lung disease who needed VV or VA ECMO during three years between 1st January 2013 and 31st December 2015 were eligible for inclusion (n=37). Among these, patients who did not survive at least 96 hours after ECMO initiation were excluded (n=4).

The current study was conducted to assess the changes in functional pulmonary characteristics and radiologic changes after the initiation of ECMO support.

Routinely captured variables, namely, chest radiographs and the PF ratio were used to investigate these characteristics. The key benefit of using these two variables was their easy availability and consistent use in the routine daily care and clinical decision making among these patients. These characteristics should allow the results from the current analysis to be readily generalisable to other clinical settings.

A primary consideration during the study planning was the inherent challenge in evaluating the impact of ECMO on the functional and radiologic characteristics of lungs that are significantly abnormal in the first instance. Irrespective of whether the goals of ECMO was as a bridge to LT or bridge to recovery, patients needing ECMO support had profound background pulmonary impairment. To circumvent these issues, each patient was used as their own ‘control’ and utilised pre-ECMO characteristics as the baseline for comparisons.

While the PF ratio is widely used as a marker of functional assessment, no validated measure for objective assessment of chest opacities was available. It was necessary to quantify the extent and severity of new opacities that may have developed in the background of pre-existing lung disease necessitating ECMO support.

To this end, a dedicated scoring system to quantify the extent and severity of opacities on serial radiographs, was tested. Since this was a novel scoring system, two different thoracic radiologists independently scored the radiographs. Apart from the instrument having an excellent inter-observer agreement, a highly significant inverse association with the functional measure (PF ratio) supports the construct validity of the tool.

Based on the knowledge from earlier studies [3, 4, 5, 6, 7, 8, 9, 10], mostly among paediatric populations, demonstrating an almost immediate increase in the pro-inflammatory cytokines with the initiation of ECMO, some degree of worsening of pulmonary status was anticipated.

A statistically significant increase in the opacity score for the entire study group confirmed that radiological worsening does indeed occur with ECMO initiation. In contrast, the functional assessment, as reflected by the oxygenation trends, was not statistically significant (Figure 1). It is noteworthy that the initiation of ECMO would be expected to improve the PF ratio given that a significant proportion of cardiac output is oxygenated by the circuit leading to higher PaO₂, which in turn should permit a reduction in the FiO₂. While this seemed to occur transiently in the immediate post-ECMO period (Figure 1), it was not sustained, and the PF ratio began to decline from post-ECMO Day 1. In this context, a lack of improvement in the PF ratio may indicate a functional worsening after starting ECMO. Besides, other variables such as haemoglobin, cardiac output, size of the cannula, ECMO flows, recirculation with VV-ECMO, and fibrin or thrombus build-up in the oxygenator may impact systemic oxygenation and confound the association between PF ratio and pulmonary status.

While the current analysis substantiates the link between ECMO initiation and the worsening of opacities, it is unable to elucidate the putative mechanisms behind the association. The lack of difference in the need or quantity of transfusions before or after ECMO initiation between the two groups argues against transfusion-associated acute lung injury as the aetiology. Similarly, the median fluid balance was also similar among the two groups, which excludes volume overload as the culprit. While an inflammatory aetiology akin to acute lung injury as part of the ECMO associated SIRS [3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13] was considered, the lack of association with any of the other non-pulmonary organ dysfunction (Table 3) argues against this possibility. This is especially pertinent as the development of non-pulmonary organ dysfunction appeared to be correlated amongst each other. For example, patients with acute renal failure (ARF, 30.3% of the study group), had significantly higher risk of hematologic dysfunction (100% of patients with ARF vs 69.5% among those without ARF, p=0.049), hepatic dysfunction (60% vs 8.7%, p=0.002) and shock (90% vs 56.5%, p=0.06). Regardless, the lack of association of worsening pulmonary opacities with other organ dysfunctions does not completely exclude an inflammatory aetiology as the timing and severity of the impact of cytokines on the pulmonary parenchyma may differ among organs. Physiologically, lungs are disadvantaged by way of being exposed to the full complement of the cardiac output as against the other organs, whereby their exposure to cytokines may be much higher. Additionally, lungs are the first organ to be exposed to the blood returning from the circuit, especially among patients on VV-ECMO, where these cytokines may initiate an inflammatory reaction. The almost ubiquitous (>93% of the study group) worsening of pulmonary opacities after ECMO initiation may indicate the same. In contrast, the SIRS response may be attenuated among other organs as they receive a fraction of the cardiac output, which has already passed through the pulmonary capillary bed. Furthermore, the immunoregulatory pathways in the pulmonary capillaries may attenuate the ongoing cytokine storm and reduce the risk of non-pulmonary organ dysfunction [14, 15, 16, 17].

The comparative analysis among patients with and without a significant worsening of opacities did not reveal any difference in their presenting characteristics or outcomes. While the comparative analysis may have been underpowered given the small sample size, patients with significant worsening of opacities tended to have a higher proportion of interstitial lung disease (ILD) patients. It is indeed plausible that patients with background fibrotic lung diseases may be vulnerable to acute lung injury related to ECMO initiation. Patients with significantly worse opacities seemed to spend less time on the ECMO, although the eventual hospital survival was not different. The duration of ECMO support may be impacted by its goal as patients being bridged to LT often need to be supported for a shorter period as recovery usually takes longer. The goal for ECMO in the current study group was LT among the majority, which confounds the association of worsening pulmonary opacities with survival. Regardless of their pulmonary status, the high lung allocation score (usually the top one percentile of the waitlisted patients) among waitlisted ECMO patients ensures that they get prioritised for lung offers. It appears that ECMO associated pulmonary dysfunction may be more consequential among patients with a goal of recovery rather than those awaiting LT.

The current analysis has some limitations. The retrospective study design that does not allow causality assessment with an inability to account for unmeasured confounding variables. The pulmonary opacity score used to assess the serial radiologic changes has not been studied before, although we used two blinded readers to ensure the objectivity and reproducibility of the instrument. Also, the concurrent PF ratio assessments supported the construct validity of the instrument. While the sample size in the current analysis provided adequate information regarding serial changes in the daily assessments, comparative analysis of the two groups formed based on significant worsening of pulmonary opacities, seemed underpowered. More extensive studies are needed to elucidate predictors of worsening of pulmonary status and its impact among patients bridged to recovery. Finally, the current analysis is unable to evaluate the impact of management strategies for worsening oxygenation and pulmonary opacities and how they could have impacted the outcomes.

ECMO may be associated with a worsening of pulmonary status that starts early and tends to peak around 48 hours after initiation. The progression of opacities on radiographs seems to precede worsening in oxygenation that is typically seen beyond the 24 hours after ECMO initiation. Both the oxygenation and radiographic opacities tend to stabilise by the third post-ECMO day. Future research is needed to understand better the mechanistic pathways behind the worsening of pulmonary opacities, identify clinical, laboratory, and radiological variables that predict its development and evaluate its association with outcomes.