Acute respiratory distress syndrome (ARDS), which is characterized by life-threatening impairment in gas exchange, resulting in hypoxia or hypercapnia with respiratory acidosis, is still an unsolved problem in the intensive care unit (ICU).1 Conventional treatment with lung protective ventilation is often insufficient to overcome life-threatening hypoxemia in patients with the most severe acute respiratory failure, and additional strategies are necessary to prevent further ventilator-induced lung injuries.2
Extracorporeal membrane oxygenation (ECMO) was first used in adults with respiratory failure in the 1970s,3 and multiple studies have evaluated the effect of ECMO on mortality in patients with severe acute respiratory failure.4–11 Although venovenous (VV)-ECMO provides no direct cardiac support, applying ECMO allows ventilator settings to be reduced to “lung resting” levels, which resolves many of the ventilator-induced lung injuries and hemodynamic instability associated with respiratory failure.10, 12 Recent studies11, 13 have demonstrated that referral to an ECMO center significantly improves recovery from, and survival after, severe ARDS.
In recent years, the use of ECMO in the ICU (particularly for severe acute respiratory failure) has increased dramatically.14 However, few reports have investigated the relationship between patients being successfully weaned from ECMO and their clinical findings. Therefore, we conducted this study to identify clinical parameters associated with successful ECMO weaning.
Methods
This study included patients who visited Seoul National University Bundang Hospital from March 2011 through March 2014. The patients underwent VV-ECMO support because of respiratory failure (n = 53) in a 16 bed medical ICU. We excluded patients who were converted to venoarterial ECMO support (n = 3) and those who were temporarily assisted with ECMO during an operation (n = 5) from analysis (Figure 1). The remaining 45 patients were divided into two groups according to ECMO weaning. Successful weaning was defined as weaning from ECMO support followed by survival more than 48 hours.8 We examined the differences in clinical parameters between the ECMO weaned and nonweaned groups to identify candidate predictors of ECMO weaning.
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Figure 1: Patients received VV-ECMO for 3 years. VV-ECMO, venovenous extracorporeal membrane oxygenation.
The following retrospective data were obtained: demographic data, primary diagnosis for ECMO implementation, whether the patient was currently being weaned off ECMO support, Acute Physiology and Chronic Health Evaluation II score, Sequential Organ Failure Assessment (SOFA) score, duration of hospitalization, and outcome.
Data collection was approved by the Institutional Review Board of Seoul National University Bundang Hospital (IRB No: B-1404-248-115) and was performed in accordance with the Declaration of Helsinki.
The Statistical Package for the Social Sciences (SPSS) ver. 17.0 (SPSS Inc., Chicago, IL) was used for the statistical analysis. The patients’ clinical variables were analyzed using common descriptive statistics. Results are expressed as median and range. We compared the clinical variables between the weaned and nonweaned groups. Nonparametric two independent samples test and the χ2 test were used to analyze continuous and categorical variables, respectively. Logistic regression was used for the multivariate analysis.
Results
The study population included 45 patients who were supported with VV-ECMO for severe acute respiratory failure in a medical ICU between March 2011 and March 2014. Table 1 lists the patients’ demographic data and the primary reason for ECMO support. The median age of the patients was 64 years, and 29 (64.4%) patients were male. The most common reason for ECMO support was pneumonia (42.2%), followed by ARDS related to interstitial lung disease (24.4%). Patients with postoperative ARDS were all successfully weaned.
Table 1: Patients’ Baseline Characteristics and Primary Diagnosis for ECMO Support
Successful weaning from ECMO was achieved in 21 cases (46.7%). Table 2 presents the differences in clinical parameters between the ECMO weaned and nonweaned groups. Respiratory rate before ECMO insertion (prerespiratory rate) and platelet (PLT) count were significantly different in two groups. Initial PLT count (at the time of ICU admission) and pre-PLT count (lowest value within 24 hours before initiating ECMO) were significantly higher in the ECMO-weaned group than those in the nonweaned group. A higher PLT count tended to be observed on day 1 (24 hours after initiating ECMO; p = 0.096). However, there was no significant difference in the amount of transfused PLT during peri-ECMO insertion period (the day before ECMO insertion, insertion day, and the day after ECMO insertion between weaned group and nonweaned group; Table 2).
Table 2: Comparison of Variables Between ECMO Weaned Group and Nonweaned Group at ICU Admission, Pre-ECMO and Post-ECMO Era
In a multivariate analysis of factors affecting ECMO weaning (Table 3), PLT level of 70 × 109/L, the odds ratio (OR) for successful ECMO weaning was 11.0 (95% confidence interval [CI] 1.34–87.16; p = 0.023). The appropriate cutoff of the pre-PLT count for successful ECMO weaning was found using the receiver operating characteristic curve (C statistic = 0.67 [95% CI 0.51–0.81; p = 0.030]).
Table 3: Multivariate Logistic Regression of Factors Affecting ECMO Weaning
Overall survival rate was 17.8%, and it was significantly related to ECMO weaning (Table 4). Median ECMO duration was 10.2 days, and maximal duration of long-run ECMO was 71.8 days. Of the 21 patients successfully weaned from ECMO, 13 died in hospital. Two patients’ deaths were considered due to reprogression of the original problems. The major cause of death was severe sepsis caused by multidrug-resistant bacteria (imipenem-resistant Acinetobacter baumanni, methicillin-resistant Staphylococcus aureus, and extended spectrum beta-lactamase-positive Klebsiella pneumoniae) and fungemia. The infection foci were as follows: newly developed ventilator-associated pneumonia (n = 5); catheter-related bloodstream infection (n = 3); intra-abdominal infection (n = 2); neutropenic fever and septic thrombophlebitis (n = 1).
Table 4: Overall Outcomes
The complications related to ECMO support are listed in Table 5. The rate of overall complication related to ECMO tended to be higher in nonweaned group (47.6% vs. 75.0%; p = 0.059). A bleeding complication was the most prevalent (51.1%), and seven (15.6%) patients showed more than two bleeding foci. The cases of abdominal bleeding (hematochezia) and airway bleeding (epistaxis) required embolization. Among eight patients with cannulation problem, cardiopulmonary arrest was developed in five cases during or just after cannulation. One case was not resuscitated because of esophageal rupture during cannulation process, and other four cases were successfully resuscitated but all dead during their hospital stay.
Table 5: Complication During ECMO Support
Discussion
This study describes a retrospective analysis of our clinical experience with VV-ECMO in patients with severe acute respiratory failure who were unresponsive to conventional treatment. Among the 45 patients, 21 (46.7%) were successfully weaned off VV-ECMO, and 8 patients survived (hospital survival 17.8%). Interestingly, PLT count at ICU admission and during the peri-ECMO period (within 24 hours) was consistently related to successful ECMO weaning.
The significance of this association remains uncertain. Blood is exposed not only to oxidative stress during ECMO but also to a large artificial surface area that can cause PLT dysfunction.15–17 In a multicenter database, factors that increase the risk of death while on ECMO include cerebral infarction or hemorrhage such as pulmonary or gastrointestinal origin.10 Therefore, thrombocytopenia in patients on VV-ECMO could be related to either coagulopathy problems that occur during ECMO or the severity of illness itself.18
The overall complication rate in our study was 62.2% and bleeding complications were the most common (51.1%). There was one case with fatal intracranial hemorrhage resulting death. Bleeding is one of the most common complications of ECMO,17 and the PLT count is closely related to the bleeding tendency. In practice, we have a policy of maintaining a PLT count of at least 100 × 109/L to prevent bleeding complications. In this study, a pre-ECMO PLT cutoff of 70 × 109/L was significantly associated with successful ECMO weaning (OR = 11.0; 95% CI 1.34–87.16; p = 0.023). In addition, the intra-abdominal bleeding rate was significantly higher in the group with PLT < 70 × 109/L (0% vs. 20%; p = 0.036; data not shown in Results). Larger studies examining the optimal PLT count and its relationship to successful weaning are needed.
Thrombocytopenia is a well-known independent predictor of mortality in critically ill patients.19, 20 However, there is a lack of data on the PLT count and prognosis in patients on ECMO, especially those on VV-ECMO. Previous studies18, 21 reported that bleeding complications after ECMO were associated with hospital mortality in patients with ECMO support, and these studies analyzed venoarterial (VA)-ECMO cases only, or mixed cases of VA with VV. Although, Arbon et al.18 reported that the volume of PLTs transfused was associated with mortality in patients on VV-ECMO, there were no data on the PLT count itself. Therefore, considering the limitations of our small retrospective study, it is worth clarifying the effects of anticoagulation and the proper target PLT level in the management of VV-ECMO in respiratory failure.
In practice, we attempted to maintain the PLT count at approximately 100 × 109/L to prevent bleeding complications. However, there was no significant difference in the amount of transfused PLT during the peri-ECMO insertion period (the day before ECMO insertion, insertion day, and the day after ECMO insertion) in our study between the weaned and nonweaned groups. This suggests that the important factor related to successful weaning is the PLT count itself, rather than the amount of transfused PLT. Although thrombocytopenia itself is a well-known prognostic factor in critically ill patients, the clinical benefits of prophylactic PLT transfusions in avoiding bleeding and mortality in thrombocytopenic critically ill patients remain unknown.19, 21 In addition, despite transfusions with PLT concentrates, the circulating PLT showed impaired aggregatory function,16 and the mean PLT count decreased by 47% ± 7% from the pre-ECMO values within 1 hour after initiating ECMO.19 Therefore, it is difficult to guide PLT transfusion in thrombocytopenic patients being prepared for ECMO. Nevertheless, we still recommend transfusion before ECMO insertion to maintain a PLT count of at least 70 × 109/L according to our results.
Our results were disappointing compared to those of the recent studies that reported more than 65–70% of weaning rates and overall mortality of 37.7–50% for VV-ECMO.4, 11, 18 Possible explanations include an initial learning curve effect and a difference in patient selection. VV-ECMO managed by an intensivist at the medical ICU was initiated in 2011 at our hospital, so there may have been some trial and error. In addition, relatively liberal patient selection could have affected the outcomes. In the CEASAR trial,11 patients with high pressure (>30 cm H2O of peak airway pressure) or high FiO2 (0.8) ventilation more than 7 days were excluded. In our study, seven patients were on a ventilator for more than 7 days, but no high pressure or high FiO2 was observed before initiating ECMO. Better outcomes are expected with additional accumulated experience and an established protocol for ECMO support.
This was a retrospective study from a single center and sample size was relatively small. In addition, some laboratory variables to explore the presence of hemolysis, coagulopathy, or the anticoagulation characteristics could not be included in the analysis because of incomplete data. In spite of these limitations, our study is one of the few which reported the importance of PLT count as a weaning outcome of patients after VV-ECMO support.
Conclusion
A high PLT count at ICU admission and on the day before initiating ECMO might play a role in successful weaning from VV-ECMO in patients suffering from severe acute respiratory failure. Further studies are needed to evaluate the PLT target level that will enhance ECMO outcomes.
Acknowledgement
This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI14C0746).
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