The acute respiratory distress syndrome (ARDS) represents 10% of intensive care unit (ICU) admissions and a mortality rate approaching 50%.1,2 Although mechanical ventilation (MV) is the primary supportive therapy for patients with ARDS, it is associated with ventilator-associated lung injury.3 Lung-protective ventilation strategies, which deliver small tidal volumes and limit inspiratory pressures, may substantially reduce ARDS mortality.4,5 However, in patients with severe ARDS, it may not be possible to achieve oxygenation and ventilation goals within the confines of lung-protective ventilation. Venovenous extracorporeal membrane oxygenation (VV-ECMO) may be used in these cases to support gas exchange and potentially facilitate recovery from the underlying disease by permitting “lung rest” with minimal tidal volumes and pressures.6,7
Sedation management is an important consideration in the care of the ECMO patient, and no evidence-based guidelines exist for this population. For medical–surgical patients, there are strong recommendations for sedation minimization (i.e., daily interruption of sedation8 or protocols targeting light sedation9). These strategies have demonstrated improved outcomes including shorter durations of MV and ICU stay.10 Patients who are deeply sedated early in their critical illness spend more time on the ventilator and have higher hospital mortality and higher mortality at 0.5 and 2 year follow-up.11,12 Transitioning to minimal sedation early also permits mobilization. Mobilization within 48–72 hours of intubation is associated with improved functional status at hospital discharge, reduced delirium, and decreased ICU and hospital lengths of stay.13,14
Patients on ECMO have additional challenges that may encourage deep sedation and immobility, such as severe hypoxemia and fear of patient-initiated cannula removal.15 In addition, changes in patient position may compromise ECMO blood flow and worsen oxygenation. As with conventionally ventilated ARDS patients, ventilator dyssynchrony can lead to increased oxygen demands and potentially injurious tidal volumes and trans-pulmonary pressures.15,16
For patients with ARDS supported on VV-ECMO, the optimal sedation and analgesic strategy is not known, and data are sparse. In our study, we characterize the use of sedatives, analgesics, neuromuscular blocking agents (NMBA), and antipsychotics in an experienced ECMO center. We describe sedation depth, mobilization efforts, and the incidence of agitation and delirium throughout ECMO treatment in our cohort. These data allow for an appraisal of current practice in relation to clinical guidelines for other critically ill populations, serve as a comparator for other ECMO centers, and generate hypotheses about optimizing sedation management in this population.
Materials and Methods
Study Design and Patient Selection
In this retrospective study, we evaluated sedation and analgesia practice for patients with ARDS undergoing VV-ECMO at Toronto General Hospital (TGH). We conducted a comprehensive literature search on sedation and MV in patients with ARDS or in patients supported with ECMO, between January 1990 and December 2015 to determine the most important variables. The study was approved by the Research Ethics Board of the University Health Network, Toronto, Canada.
Data were extracted from the records of all consecutive patients >18 years who were treated with VV-ECMO for severe ARDS from January 2012 to October 2015. We excluded bridge to lung transplant patients, lung transplant patients with primary graft dysfunction, non-ARDS causes of respiratory failure (chronic thromboembolic pulmonary hypertension (CTEPH) and status asthmaticus), and post lung-reduction surgery patients with ARDS because their pre-existing lung pathology could influence their outcomes. Patients with severe ARDS (PaO2/FiO2 < 100) were selected as candidates for VV-ECMO at the discretion of the ECMO team with the aim to cannulate within the first week of MV. All off-site cannulations were in the jugular–femoral arrangement because of the lack of fluoroscopic equipment at outside hospitals. On-site cannulation techniques were also physician dependent and varied between double-lumen jugular and jugular–femoral arrangements. Sedation management of ECMO patients was not protocolized. There was a 1:1 or 2:1 nurse to patient ratio in the care of these patients. All patients were ventilated with a “lung rest” strategy (peak inspiratory pressure 20 cmH2O, positive end expiratory pressure 10 cmH2O, respiratory rate 10 breaths/minute, and FIO2 30%)17 as tolerated while on VV-ECMO.
We recorded patient demographics, MV, and respiratory parameters before ECMO initiation. Sedative and analgesic data (mode of administration, medications, and median daily dose) were recorded at 3 time points: 48 hours after ECMO initiation, 24 hours before ECMO discontinuation, and 48 hours after ECMO discontinuation. Benzodiazepine and opioid doses were presented as midazolam (1 mg midazolam = 0.5 mg clonazepam) and fentanyl (0.1 mg fentanyl = 2 mg hydromorphone = 10 mg morphine) equivalents, respectively.18 For patients paralyzed on ECMO, we recorded NMBA medication, duration of infusion, and Train-of-Four monitoring (number of daily assessments, twitches per score). Incidence of delirium (Intensive Care Delirium Screening Checklist10 for 2012–2013 patients and Confusion Assessment Method for ICU [CAM-ICU]10 for 2014–2015 patients) and agitation (Sedation Agitation Scale [SAS] score ≥ 6), antipsychotic administration (drug, median daily dose), and physical restraint use were recorded. Mobilization efforts (time until first physiotherapy session and maximum mobility/exercise achieved) were also described. Other parameters included the incidence of patient-initiated device removal and use of cointerventions (blood products, vasopressors, inotropes, renal replacement therapy, and ventilator/oxygenation therapies).
Daily SAS scores were recorded from ECMO initiation to 72 hours after ECMO discontinuation for each patient. The SAS score ranges from unarousable (SAS score = 1) to dangerous agitation (SAS score = 7) and is a valid and reliable sedation assessment tool for measuring quality and depth of sedation in adult ICU patients (high degree of inter-rater reliability and discriminates different sedation levels in various clinical situations).10 On a given day, sedation depth for each patient was defined as “deep” (SAS score < 3), “intermediate” (SAS score = 3), or “light” (SAS score > 3).19 Because patients received multiple SAS scores throughout the day, we treated these scores as continuous variables and defined sedation depth by the proportion of intermediate or light scores a patient received on a given day. A patient was categorized as light on a given day if >33% of daily SAS scores were > 3,11,19 as intermediate on a given day if >33% of daily SAS scores were = 3 but did not exceed 3, and as deep if they met neither of these criteria.
Mortality on ECMO and duration of MV, ICU, and hospital stay were recorded. Outcome data were only available while patients were admitted to TGH. Once transferred to another hospital, data regarding outcomes was unavailable unless reported in a note from a follow-up visit at TGH.
Data were summarized using medians and interquartile ranges (IQR) for continuous data and proportions for categorical data. Wilcoxon signed-rank tests were used to compare oxygenation (PaO2/FiO2) and MV parameters (tidal volumes and peak inspiratory pressure) across different time points. For all analyses, a p value < 0.05 was considered statistically significant. All analyses were conducted with SAS version 9.3 (SAS Institute, Cary, NC).
Of the 151 patients treated with ECMO (56 cardiac cases and 95 respiratory cases) during the study period, 45 (30%) were ARDS patients supported on VV-ECMO and were included in the study (Table 1). The remaining respiratory cases on ECMO support were bridge to transplant (n = 34), non-ARDS respiratory failure (n = 12; secondary to chronic thromboembolic pulmonary hypertension, status asthmaticus, etc.), and postoperative ARDS after lung-reduction surgery (n = 4). The majority of patients were male (73%), and the median age was 47 years (IQR, 35–56). The median Charlson comorbidity index at admission was 1 (IQR, 0–2), and respiratory infection was a contributing ARDS etiology in 91%. Use of NMBA (93%), recruitment maneuvers (51%), and prone positioning (42%) were the most common therapies attempted before ECMO. Within 24 hours before ECMO initiation, median PaO2/FiO2 was 71 (IQR, 59–83), and median peak inspiratory pressures were 34 cmH2O (IQR, 21–28). Most patients (73%) had jugular–femoral vein cannulation, and 27% had dual-lumen jugular vein cannulation. The median ECMO duration was 11 days (IQR, 8–17) from cannulation to decannulations or death.
Sedation and Analgesia
Table 2 shows sedative and analgesic drugs administered; mode of administration; and the median daily dose at 48 hours after ECMO initiation, 24 hours before ECMO discontinuation, and 48 hours after discontinuation. After ECMO initiation (48 hours), 96% patients were deeply sedated (Figure 1) primarily with infusions (96%) of midazolam (49%), propofol (18%), or both (29%). Analgesia was provided by infusions (98%) of fentanyl (93%) or morphine (4%). Sedative and analgesic doses were generally highest within the first week of ECMO; peak midazolam dose (307 mg/day; IQR, 240–480) was on day 5 (IQR 3–6), peak propofol dose (4,600 mg/day; IQR, 2,915–5,275) was on day 3 (IQR, 3–7), and peak fentanyl dose (5,880 mg/day; IQR, 4,800–8,680) was on day 5 (IQR, 3–9). At 24 hours before ECMO discontinuation, 23% of patients who survived ECMO were still deeply sedated (Figure 1); however, 20% of ECMO survivors were receiving no sedation, and 9% were receiving no opioids. By 48 hours after ECMO discontinuation (n = 30), 97% achieved light or intermediate levels of sedation. At this time point, 27% and 40% were receiving continuous infusions of sedatives and opioids, respectively.
Sedatives administered during ECMO were midazolam in 87% (n = 39), clonazepam in 44% (n = 20), propofol in 76% (n = 34), clonidine in 36% (n = 16), dexmedetomidine in 7% (n = 3), and ketamine in 2% (n = 1). After ECMO initiation, patients spent a median of 6 days (IQR, 3–10) deeply sedated before their first light or intermediate day of sedation (Figure 2). Only 78% of patients achieved ≥1 day of light or intermediate sedation while supported by ECMO. Per patient, 64% of ECMO days were spent deeply sedated. Of the 654 days on ECMO recorded in our cohort, 29% (190 days) were spent in light sedation, 17% (108 days) in intermediate sedation, and 54% (356 days) in deep sedation. Paralysis (n = 36, 80%) often accompanied deep sedation, particularly after ECMO initiation (64% patients within 48 hours). Patients were paralyzed with cisatracurium infusions (56%), rocuronium boluses (13%), or both (11%) while on ECMO, and median infusion duration was 24 hours (IQR, 12–98; see Table 2, Supplemental Digital Content, https://links.lww.com/ASAIO/A193). Cointerventions and other supportive therapies used while on VV-ECMO are displayed in Table 1, Supplemental Digital Content 2 (https://links.lww.com/ASAIO/A192).
Agitation, Delirium, and Complications
Patients were assessed for delirium while on ECMO using the intensive care delirium screening checklist (ICDSC) (33% patients) or CAM-ICU score (67% patients; Table 3). All patients were assessed for delirium while on ECMO support, but only 33 patients (73%) had delirium assessments when SAS score ≥ 3 (cannot diagnose delirium if patient’s SAS score < 3). Of these patients, 26 (58%) had at least one positive ICDSC or CAM-ICU score for delirium while on ECMO. One quarter of patients in our cohort had at least 1 SAS score ≥ 6 (very agitated or dangerous agitation). Haloperidol (49%) and quetiapine (76%) were the only antipsychotics administered throughout ECMO. The median daily dose was 15 mg (IQR, 5–25) for haloperidol and 150 mg (IQR, 50–300 mg) for quetiapine. Physical restraints were used in 40% of patients for a median of 3 days (IQR 2–7). Four patient-initiated device removals occurred in three patients (7%): one self-extubation and three removals of a peripheral intravenous catheter.
Seventy-one percent of patients underwent physical therapy (PT) at least once while on ECMO (see Table 3, Supplemental Digital Content, https://links.lww.com/ASAIO/A194). Median time until the first physiotherapy exercise was 7 days (IQR, 4–12) after ECMO initiation. Most patients only achieved passive range of motion (42%) while on ECMO, but others were able to achieve active range of motion (n = 9, 20%), few dangled their feet or sat up in bed (n = 3, 7%), and only one patient stood.
Ten patients(22%) died while receiving ECMO (see Table 4, Supplemental Digital Content, https://links.lww.com/ASAIO/A195):two deaths were because of intracranial hemorrhage and eight because of multiorgan failure. Complete follow-up data was available for 10 ECMO survivors: median duration of MV was 22 days (IQR, 16–37), median ICU length of stay 30 days (IQR, 22–46), and median hospital length of stay 49 days (IQR, 38–76).
This is the first detailed study on sedation practice in ARDS patients treated with VV-ECMO at an experienced center. The main findings from our retrospective cohort are as follows. First, after ECMO initiation, patients were deeply sedated with continuous sedative and opioid infusions, periods of paralysis, and limited or no mobilization. Second, midazolam and propofol were the most commonly infused sedatives, and fentanyl was the most commonly infused opioid. Third, during ECMO, the majority of patients achieved a responsive state of intermediate or light sedation, and a minority were managed without sedatives or opioids around the time ECMO was discontinued. Fourth, during periods of intermediate and light sedation, some patients participated in active mobilization. Fifth, delirium while on ECMO was very prevalent, with a high incidence of antipsychotic and physical restraint use.
With increasing use of ECMO, it is important to evaluate the use of supportive therapies that may impact patient outcome, including sedation and analgesia management, delirium, and mobilization. In critically ill non-ECMO patients, these areas have been well studied and have resulted in evidence-based guidelines.10 For example, oversedation, particularly early in the critical illness (within 48 hours of MV initiation or ICU admission), is clearly associated with worse outcomes, including longer duration of MV and higher mortality.11,12 Delirium is associated with longer ICU and hospital stay and higher ICU and hospital mortality.20 Early mobilization may improve outcomes including better functional status at discharge, reduction in delirium, and more ventilator-free days in mechanically ventilated patients.13
The literature on sedation management in ECMO patients is very limited,19,21–28 and no guidelines exist in this population. In an international survey of 102 ECMO practitioners, 51% perceived that they achieve a responsive and cooperative level of sedation during ECMO, although there was heterogeneity in the use of sedation strategies (e.g., sedation score targets or daily sedation interruption) between centers.21 Although patients in our cohort experienced periods of wakefulness throughout the day (Figure 1), they spent the majority (64%) of their days on ECMO deeply sedated—especially after ECMO initiation. Similarly, in an observational study of 16 ARDS patients treated with VA- or VV-ECMO, patients were sedated and often paralyzed at ECMO initiation but were “awake and able to communicate with staff and their family, watch television, etc.” by the end of ECMO treatment (mean 15 days; range, 3–52 days).22
Potential explanations for prolonged deep sedation after ECMO initiation in our cohort include profound hypoxemia, paralysis, patient-ventilator dyssynchrony and spontaneous breathing, hemodynamic instability, fear of cannula dislodgement, or patient agitation and clinician comfort.15,16 Although it appears that deep sedation may be necessary immediately after cannulation, it is feasible and safe for patients to be awake and interactive during ECMO given that 78% of our patients achieved at least 1 day of intermediate or light sedation while on ECMO, and 20% of surviving patients were not receiving any sedatives 24 hours before ECMO discontinuation. These observations underscore the need to assess sedation requirements on a daily basis and, in the absence of barriers to light sedation, continually attempt to lighten sedation. It is conceivable that stable VV-ECMO patients may be weaned to light levels of sedation after cannulation and even progress to periods of no sedation. However, prospective studies are required to further define whether this transition can safely occur early in the ECMO course.
The choice of sedative agents may be an important consideration for ECMO patients given the long ICU stay, high dose requirements, and pharmacokinetic alterations caused by the ECMO circuit (drug sequestration, increased volume of distribution, and decreased elimination).21,24,29 For example, current sedation guidelines suggest avoidance of benzodiazepines, as they are associated with longer durations of MV,30,31 ICU length of stay,10 and higher hospital mortality.31 Yet, as with our cohort, midazolam was reported as the most common sedative among 18 expert ECMO centers surveyed,21 a prospective cohort of 32 adults,25 and a retrospective cohort of 160 pediatric patients28 requiring ECMO. Physician familiarity, cost, and expected duration of sedation may underlie the frequent use of benzodiazepines in our cohort. Similar to our study, after midazolam, propofol was the most commonly used sedative in adult ECMO patients, followed by ketamine or dexmedetomidine.21,25 Previous studies examining coadministration of ketamine in ECMO patients have contrasting results with respect to reducing opioid and benzodiazepine consumption,23,26 and further research is needed to demonstrate the utility of these agents in this population.
Patient agitation and device removal are potential consequences of prematurely minimizing sedation. A study by Fraser et al. reported agitation in 44% of ICU patients which was significantly associated with patient-initiated device removal (i.e., nasogastric tubes, endotracheal tubes, vascular catheters).32 The rate of device removal in non-ECMO patients ranges from 22 to 211 episodes per 1,000 patient days.32,33 In the ECMO population, accidental decannulation may have devastating consequences, although no patient in our cohort experienced this complication. Our cohort’s lower rate of agitation (24%) and device (endotracheal tube (ETT) or peripheral intravenous (IV)) removal (6.6 events per 1,000 patient days) may in part be explained by the high proportion of deeply sedated patients, the use of antipsychotics, and the high nurse to patient ratio. The incidence of delirium in our cohort was 58% while on ECMO, similar to that reported by Ely et al.34 in critically ill patients. Withdrawal from large doses of benzodiazepines and opioids administered over many days may play a role in the high incidence of delirium in our cohort20,35 and warrants more investigation. If sedation minimization is achieved early after ECMO initiation, delirium and withdrawal syndromes may be reduced, thus allowing earlier and more aggressive mobilization. For example, in addition to achieving “awake” sedation, a recent meta-analysis found that dexmedetomidine was also associated with a reduction in ICU length of stay, MV duration, and delirium occurrence.36
Early mobilization (within 72 hours) and the implementation of mobility protocols improve outcomes in mechanically ventilated patients including better functional status at discharge, reduction in delirium, more ventilator-free days,13 and shorter ICU and hospital lengths of stay,13,14 although the latter association remains controversial.37 In our cohort, PT was initiated after a median of 7 days after ECMO cannulation, and only one patient achieved standing at the bedside. In contrast, in a retrospective study of 100 ECMO patients, the first PT treatment occurred within 2 days (IQR, 1–4.5), 18% of patients were ambulating, and 23% of patients were extubated while receiving ECMO.38 Deep sedation, lack of a mobility protocol, limited PT resources, a high incidence of femoral cannulation,39 and physician comfort may underlie the delayed introduction of PT and low incidence active mobilization achieved in our cohort while on ECMO.
Our study is the first to provide a detailed description of sedation management in ARDS patients treated with VV-ECMO, and our results may also serve as a comparator for other ECMO centers internationally. Our evaluation of sedation depth in this cohort not only helps graphically explain the fluctuations in a patient’s level of sedation throughout ECMO treatment but also illustrates the limitations in categorizing patients as lightly or deeply sedated over a specified time period.8,11,12 For instance, patients may have episodes with SAS score ≥ 3 throughout the day (i.e., daily awakening) and still be classified as deeply sedated on that day. Our definition of sedation depth was adapted from Shehabi et al.,11 but other thresholds for defining light and deep sedation12 may generate different conclusions. Furthermore, the retrospective design, single-center data, small sample size, and incomplete preadmission and follow-up data for ECMO survivors limit our conclusions, and our findings may not represent practice at other hospitals.
In our cohort of ARDS patients on VV-ECMO support, light levels of sedation and active mobilization were feasible and safe. Outcomes related to sedation management and mobilization in the ECMO population remain unclear and require further exploration.
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