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, http://links.lww.com/ASAIO/A193). Cointerventions and other supportive therapies used while on VV-ECMO are displayed in Table 1, Supplemental Digital Content 2 (http://links.lww.com/ASAIO/A192).
Agitation, Delirium, and Complications
Patients were assessed for delirium while on ECMO using the intensive care delirium screening checklist (ICSDC) (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 ICSDC 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, http://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, http://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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acute respiratory distress syndrome; extracorporeal membrane oxygenation; sedation depth; delirium; mobilization
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