Sedation Management in Children Supported on

Extracorporeal Membrane Oxygenation for Acute

Respiratory Failure
James B. Schneider, MD1; Todd Sweberg, MD1; Lisa A. Asaro, MS2; Aileen Kirby, MD3; David Wypij, PhD2,4,5;
Ravi R. Thiagarajan, MBBS, MPH2,5; Martha A. Q. Curley, RN, PhD6,7,8; for the Randomized Evaluation of
Sedation Titration for Respiratory Failure (RESTORE) Study Investigators

Objectives: To describe sedation management in children supported Interventions: Sedation managed per usual care or Randomized
on extracorporeal membrane oxygenation for acute respiratory failure. Evaluation of Sedation Titration for Respiratory Failure protocol.
Design: Secondary analysis of prospectively collected data from a Measurements and Main Results: Sixty-one Randomized Evalua-
multicenter randomized trial of sedation (Randomized Evaluation tion of Sedation Titration for Respiratory Failure patients (5%) with
of Sedation Titration for Respiratory Failure). moderate/severe pediatric acute respiratory distress syndrome were
Setting: Twenty-one U.S. PICUs. supported on extracorporeal membrane oxygenation, including 29
Patients: One thousand two hundred fifty-five children, 2 weeks managed per Randomized Evaluation of Sedation Titration for Respi-
to 17 years old, with moderate/severe pediatric acute respiratory ratory Failure protocol. Most extracorporeal membrane oxygenation
distress syndrome. patients received neuromuscular blockade (46%) or were heavily
sedated with State Behavioral Scale scores –3/–2 (34%) by extra-
1
Division of Pediatric Critical Care Medicine, Department of Pediatrics,
corporeal membrane oxygenation day 3. Median opioid and benzo-
Cohen Children’s Medical Center, Hofstra-Northwell School of Medicine,
New York, NY. diazepine doses on the day of cannulation, 0.15 mg/kg/hr (3.7 mg/
2
Department of Cardiology, Boston Children’s Hospital, Boston, MA. kg/d) and 0.11 mg/kg/hr (2.8 mg/kg/d), increased by 36% and 58%,
3
Division of Pediatric Critical Care Medicine, Oregon Health & Science respectively, by extracorporeal membrane oxygenation day 3. In the 41
University School of Medicine, Portland, OR. patients successfully decannulated prior to study discharge, patients
4
Department of Biostatistics, Harvard T.H. Chan School of Public Health, were receiving 0.40 mg/kg/hr opioids (9.7 mg/kg/d) and 0.39 mg/
Boston, MA.
kg/hr benzodiazepines (9.4 mg/kg/d) at decannulation, an increase
5
Department of Pediatrics, Harvard Medical School, Boston, MA.
from cannulation of 108% and 192%, respectively (both p < 0.001).
6
Department of Family and Community Health, School of Nursing, Univer-
Extracorporeal membrane oxygenation patients experienced more
sity of Pennsylvania, Philadelphia, PA.
clinically significant iatrogenic withdrawal than moderate/severe pedi-
7
Division of Anesthesia and Critical Care Medicine at the Perelman School
of Medicine, University of Pennsylvania, Philadelphia, PA. atric acute respiratory distress syndrome patients managed without
Critical Care and Cardiovascular Program, Boston Children’s Hospital,
8 extracorporeal membrane oxygenation support (p < 0.001). Com-
Boston, MA. pared to extracorporeal membrane oxygenation patients managed per
The Randomized Evaluation of Sedation Titration for Respiratory Failure Randomized Evaluation of Sedation Titration for Respiratory Failure
(RESTORE) study investigators are listed in Acknowledgment section.
protocol, usual care extracorporeal membrane oxygenation patients
Supported, in part, by grants from the National Heart, Lung, and Blood Insti-
received more opioids during the study period (mean cumulative dose
tute and the National Institute of Nursing Research, National Institutes of
Health (U01 HL086622 to Dr. Curley and U01 HL086649 to Dr. Wypij). of 183.0 vs 89.8 mg/kg; p = 0.02), over 6.5 greater exposure days
Drs. Schneider, Wypij, and Curley, and Ms. Asaro received support for (p = 0.002) with no differences in wakefulness or agitation.
article research from the National Institutes of Health (NIH). Dr. Schnei- Conclusions: In children, the initiation of extracorporeal membrane
der’s institution received funding from the National Heart, Lung, and Blood
oxygenation support is associated with deep sedation, substantial
Institute (NHLBI), the National Institute of Nursing Research, and the NIH
(U01 HL086622 to Dr. Curley and U01 HL086649 to Dr. Wypij). Ms. sedative exposure, and increased frequency of iatrogenic with-
Asaro’s institution received funding from the NIH/NHLBI. Dr. Wypij’s drawal syndrome. A standardized, goal-directed, nurse-driven
institution received funding from the NIH/NHLBI. Dr. Thiagarajan’s institu-
sedation protocol may help mitigate these effects. (Crit Care Med
tion received funding from Bristol Myers Squibb and Pfizer. Dr. Curley’s
institution received funding from the NHLBI. The remaining authors have 2017; XX:00–00)
disclosed that they do not have any potential conflicts of interest. Key Words: agitation; iatrogenic withdrawal syndrome; pediatric
For information regarding this article, E-mail: [email protected] intensive care; State Behavioral Scale; Withdrawal Assessment
Copyright © 2017 by the Society of Critical Care Medicine and Wolters Tool-Version 1
Kluwer Health, Inc. All Rights Reserved.
DOI: 10.1097/CCM.0000000000002540

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Schneider et al

S
edation management is a ubiquitous and important score per patient’s phase of illness, and nurses used an algo-
aspect of pediatric critical care. The goals of sedation rithm to titrate sedatives to achieve the prescribed goal. Primary
include maintenance of comfort, avoidance of agitation, sedatives were morphine and midazolam. Per algorithm,
and patient safety (1). Therapeutic sedation risks hemody- patients supported on ECMO were considered to be in their
namic and respiratory depression in the short term and tol- acute phase of illness where the sedation goal is to maintain
erance, physical dependence, iatrogenic withdrawal syndrome the status quo with an SBS of –1 (responsive to gentle touch or
(IWS), and potential for neurotoxicity in the long term (2, 3). voice) or lower if deemed appropriate by the care team.
Recent focus has centered on identifying novel approaches that The RESTORE database includes demographic information,
provide adequate sedation while minimizing these untoward medical history data, baseline Pediatric Cerebral Performance
effects (4). Category and Pediatric Overall Performance Category (21),
Sedation goals may be more difficult to achieve in pediatric Pediatric Risk of Mortality III-12 scores (22), daily organ func-
patients undergoing extracorporeal membrane oxygenation tion scores, comfort assessments, and sedative dosing data from
(ECMO). Previous studies have shown that ECMO circuits endotracheal intubation to study discharge (72 hr after the last
alter the pharmacokinetics and pharmacodynamics of seda- opioid dose, day 28, or hospital discharge). Sedation profiles
tive medications (5–9), although these effects with contempo- include total sedative exposure, use of neuromuscular block-
rary ECMO circuits are not well understood. These alterations ade (NMB), sedation-related adverse events, and measures of
are related to medication absorption by components of the wakefulness, pain, and agitation. ECMO data include mode of
ECMO circuit, where up to 40% of lorazepam and 50% of cannulation, equipment type, and center volume. Centers with
morphine doses can be extracted (10, 11). In addition, ECMO- greater than 10 ECMO cases in a calendar year were defined as
related physiologic and metabolic alterations raise concern for high-volume centers for that year.
variations in sedative requirements in ECMO patients (12).
Escalating sedative requirements, as well as development of Statistical Analysis
IWS, have been well described in the neonatal ECMO popula- Baseline patient characteristics were compared between
tion (13, 14). ECMO patients and those not supported on ECMO. To facili-
Although ECMO circuit-related pharmacokinetic alterations tate appropriate comparisons, we excluded all data from sites
in opioid and benzodiazepine concentrations are well known, not contributing at least one ECMO study patient and from
little knowledge exists on the clinical effects of these issues all lower acuity patients unlikely to be supported on ECMO;
outside the neonatal population, and an optimal approach to specifically, patients with an oxygenation index less than 8.0 or
patient sedation on ECMO has not been achieved (15). The oxygenation saturation index less than 7.5 (23) on the first 2
purpose of this article is to describe sedation management in days after intubation.
pediatric patients supported on ECMO for severe respiratory For patients supported on ECMO, sedatives, sedation-
failure and to contrast sedation management using a nurse- related adverse events, and SBS scores are presented by day
implemented goal-directed sedation strategy to usual care. preceding, during, and subsequent to cannulation and decan-
nulation (± 3 d), and sedative dose changes over time were
evaluated. Clinical variables and outcomes surrounding can-
MATERIALS AND METHODS nulation and decannulation were considered separately to
We performed a secondary analysis of prospectively collected more clearly describe these clinically independent events dur-
data from the Randomized Evaluation of Sedation Titration for ing the course of ECMO. For cannulation, we included data
Respiratory Failure (RESTORE) clinical trial. RESTORE was a from all ECMO patients. For decannulation, we only included
multicenter cluster randomized trial that compared a nurse- data from ECMO patients successfully decannulated during
implemented goal-directed sedation strategy to usual care in the study period. In this subset of patients, we compared seda-
children 2 weeks to 17 years old with acute respiratory failure sec- tive dosing during ECMO and NMB use at decannulation by
ondary to airways or parenchymal lung disease. The study pro- mode of ECMO support (veno-venous vs veno-arterial), cir-
tocol and findings have been described elsewhere (4). Essential cuit configuration (polymethylpentene vs polypropylene oxy-
elements included daily team discussion of the patient’s trajectory genator, roller vs centrifugal pump), age (< 2 vs ≥ 2 yr), and
of illness (acute, titration, or weaning phase); prescribing a State high- versus low-volume centers. We also compared sedative
Behavioral Scale (SBS) (16) target per phase of illness; arousal dosing during ECMO for patients who were comanaged with
assessments if the patient was oversedated in the titration/wean- NMB for at least half of their ECMO course versus those who
ing phases; daily extubation readiness testing; titrating sedatives were not and those requiring renal replacement therapy (RRT)
at least every 8 hours; and either discontinuing or weaning seda- versus no RRT.
tives per target Withdrawal Assessment Tool-Version 1 (17) based To assess the clinical impact of the RESTORE sedation
on length of exposure. This study was reviewed and approved by protocol, sedative profiles were compared between ECMO
the institutional review board of each participating site. patients in the usual care and intervention groups. We com-
Assessments of pain (18–20), sedation (16), and IWS (17) pared sedation requirements between ECMO and non-ECMO
were standardized in all participating PICUs. Bedside care intervention group patients during their acute phase of illness.
teams at intervention PICUs assigned a daily target sedation In addition, the frequency of IWS was compared between the

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 Online Clinical Investigation

ECMO and non-ECMO groups, and between ECMO patients respectively, from the day of cannulation for the 58 patients
in the usual care and intervention groups. still on ECMO support. On this day, almost half of the patients
All group comparisons were performed using linear, logis- were receiving NMB, approximately one third had modal SBS
tic, multinomial logistic, cumulative logit, and proportional scores of –3/–2, and the remaining were more awake.
hazards regression accounting for PICU as a cluster vari- Table 3 shows daily sedation profiles around decannulation
able using generalized estimating equations for continuous, of the 41 ECMO patients successfully decannulated by the end
binary, nominal, ordinal, and time-to-event variables, respec- of the study period. On the day of decannulation, patients were
tively. Continuous variables except percentage of study days’ receiving 0.40 mg/kg/hr opioids (9.7 mg/kg/d) and 0.39 mg/kg/hr
variables were log-transformed. The statistical significance of benzodiazepines (9.4 mg/kg/d). Opioid and benzodiazepine
sedative dose changes over time was evaluated using intercept- doses increased significantly from cannulation to decannula-
only linear regression. All data analyses were performed using tion day (p < 0.001 for each). Median daily opioid and benzodi-
SAS (Version 9.4, SAS Institute, Cary, NC). azepine doses increased 108% and 192%, respectively, over this
time period for the 41 patients successfully decannulated prior
to study discharge. Contrary to the time after cannulation, opi-
RESULTS oid and benzodiazepine doses significantly decreased for the
Of 2,449 RESTORE patients from 31 PICUs, we excluded 482 3 days postdecannulation (all p < 0.05). For the 40 patients
patients from 10 PICUs that did not enroll an ECMO patient still on study, by the third day postdecannulation, median daily
as well as 712 patients with at-risk/mild pediatric acute respi- opioid and benzodiazepine doses decreased by 35% and 24%,
ratory distress syndrome (PARDS) from the remaining 21 respectively, and modal SBS scores shifted to an awake state.
PICUs (nine usual care, 12 intervention). The 21 PICUs sup- Restricting to the 41 patients successfully decannulated
ported a median of 25 patients annually on ECMO (range, prior to study discharge, there were no differences in sedation
2–77). Most centers (n = 18) supported more than 10 patients dosing during ECMO or the percentage of patients receiving
per year on ECMO during the course of the study. Sixty-one NMB on the day of decannulation by ECMO mode, center
of the remaining 1,255 study patients (5%) were supported volume, or age group. Those supported on polymethylpen-
with ECMO, specifically veno-venous ECMO (n = 38, 62%) tene versus polypropylene oxygenators and/or roller versus
or veno-arterial ECMO (n = 23, 38%). ECMO equipment var- centrifugal pumps received higher mean daily benzodiazepine
ied, with polymethylpentene oxygenators used for 34 patients doses during ECMO (median, 0.33 vs 0.19 mg/kg/hr, p < 0.001;
(56%), polypropylene for 23 (38%), and silicone for four (7%). 0.34 vs 0.21 mg/kg/hr, p = 0.001, respectively), but similar opi-
Centrifugal pumps were more commonly used (n = 35, 57%) oid doses and NMB use at decannulation. There were no dif-
than roller pumps. ferences in sedation dosing during ECMO between patients
Table 1 describes the baseline characteristics of the 61 comanaged with NMB and those who were not. RRT patients
patients supported on ECMO compared to the 1,194 patients (n = 16) had more study days on ECMO (median, 11.5 vs 6
with moderate/severe PARDS not supported on ECMO. ECMO d; p < 0.001) and were exposed to more opioids compared
patients had more severe PARDS and exhibited more organ with non-RRT patients: median mean daily dose 0.38 versus
dysfunction on days 0–1. Over half of the 61 ECMO patients 0.24 mg/kg/hr (p = 0.050) and median cumulative dose 88.6
were cannulated by day 3 (median: interquartile range [IQR], versus 36.6 mg/kg (p = 0.004).
1–6) postintubation. Patients remained on ECMO support We compared sedation profiles of ECMO patients by
for a median of 9 study days prior to study discharge (IQR, RESTORE treatment group (32 usual care, 29 intervention).
6–14). Twenty-eight ECMO patients (46%) were successfully There were no treatment group differences in either opioid
decannulated and extubated by the end of the study period, or benzodiazepine daily doses during 3 days precannulation
with a median length of intubation postdecannulation of 4 through 3 days postcannulation (Fig. 1). Restricting to the 41
days (IQR, 3–8.5). In addition, 13 (21%) were decannulated patients successfully decannulated prior to study discharge (23
but remained intubated and 20 (33%) were not decannulated usual care, 18 intervention), usual care patients received more
prior to study discharge. Of the 20 patients not decannulated, opioids during the entire study period compared with interven-
10 died while on ECMO support, eight were still on ECMO on tion patients: median mean daily dose 0.26 versus 0.15 mg/kg/
day 28, and two were still on ECMO upon transfer to a non- hr (p = 0.03), median cumulative dose 183.0 versus 89.8 mg/kg
participating PICU. (p = 0.02), and median length of exposure 29 versus 22.5
Table 2 shows daily sedation profiles around cannulation of days (p = 0.002). Usual care and intervention group patients
all 61 ECMO patients. On the day of cannulation, median doses received similar mean daily doses of benzodiazepines (median,
of opioid and benzodiazepines received were 0.15 mg/kg/hr 0.23 vs 0.16 mg/kg/hr; p = 0.72). Patients in both groups spent
(3.7 mg/kg/d) and 0.11 mg/kg/hr (2.8 mg/kg/d), respectively. similar amounts of time awake and calm (median, 70% vs
With little change in sedative dosing in the 3 days prior to can- 66% intubated days; p = 0.86) and days to first awake and calm
nulation, significant increases in opioid and benzodiazepine state (9 vs 4 d; p = 0.20). Modal pain scores were rarely greater
doses were identified on each of the 3 days postcannulation than 4 in either group. Patients in the usual care arm experi-
(all p < 0.05). By the third day postcannulation, median daily enced fewer study days with any episode of pain (30% vs 50%;
opioid and benzodiazepine dose increased by 36% and 58%, p = 0.004); percentage of days with any episode of agitation

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Schneider et al

TABLE 1. Patient Characteristics According to Group

Characteristics ECMO (n = 61) No ECMO (n = 1,194) pa

Age at PICU admission, median (IQR), yr 4.2 (0.8–12.0) 2.6 (0.5–9.3) 0.04
Female sex, n (%) 39 (64) 563 (47) < 0.001
Non-Hispanic white, n/total (%) 30/57 (53) 620/1,183 (52) 0.80
Cognitive impairment (baseline Pediatric Cerebral Performance 6 (10) 301 (25)
Category score > 1), n (%) 0.002
Functional impairment (baseline Pediatric Overall Performance 9 (15) 363 (30)
Category score > 1), n (%) 0.006
PRISM III-12 score, median (IQR) 12 (4–21) 8 (3–14) 0.09
Percent risk of mortality based on PRISM III-12 score, median (IQR) 13.1 (1.7–42.6) 4.6 (1.3–15.0) 0.02
Primary diagnosis, n (%) 0.09
 Pneumonia 28 (46) 411 (34)
 Bronchiolitis 8 (13) 292 (24)
  Acute respiratory failure related to sepsis 14 (23) 197 (17)
  Asthma or reactive airway disease 6 (10) 87 (7)
  Aspiration pneumonia 1 (2) 71 (6)
 Other b
4 (7) 136 (11)
Past medical history, n (%)
  Prematurity (< 36 wk postmenstrual age) 8 (13) 188 (16) 0.58
  Asthma (prescribed bronchodilators or steroids) 7 (11) 180 (15) 0.43
  Seizure disorder (prescribed anticonvulsants) 3 (5) 108 (9) 0.22
  Cancer (current or previous diagnosis) 8 (13) 123 (10) 0.47
  Known chromosomal abnormality 2 (3) 60 (5) 0.48
Intervention group, n (%) 29 (48) 582 (49) 0.92
Pediatric acute respiratory distress syndrome based on worst
OI or OSI on days 0–1, n (%)c < 0.001
  Moderate (OI, 8.0–15.9 or OSI, 7.5–12.2) 4 (7) 576 (48)
  Severe (OI ≥ 16.0 or OSI ≥ 12.3) 57 (93) 618 (52)
Organ dysfunctions on days 0–1, median (IQR)d 3 (2–4) 2 (1–3) < 0.001
Neuromuscular blockade for the entire duration of days 0–2, n (%) 15 (25) 115 (10) 0.009
ECMO = extracorporeal membrane oxygenation, IQR = interquartile range, OI = oxygenation index, OSI = oxygen saturation index, PRISM III-12 = Pediatric
Risk of Mortality III score from first 12 hours in the PICU.
a
p values for the comparison between groups were calculated using linear, logistic, multinomial logistic, and cumulative logit regression for log-transformed
continuous, binary, nominal, and ordinal variables, respectively. All regression analyses except for primary diagnosis accounted for PICU as a cluster variable
using generalized estimating equations.
b
Other primary diagnoses include pulmonary edema, thoracic trauma, pulmonary hemorrhage, laryngotracheobronchitis, acute respiratory failure after bone
marrow transplantation, acute chest syndrome/sickle cell disease, pertussis, pneumothorax (nontrauma), acute exacerbation lung disease (cystic fibrosis or
bronchopulmonary dysplasia), acute respiratory failure related to multiple blood transfusions, pulmonary hypertension (not primary), and pulmonary embolus.
c
Oxygenation index was calculated as ([Fio2 × mean airway pressure]/Pao2 × 100). When an arterial blood gas measurement was not available, Spo2 was used
to estimate Pao2 in order to calculate OSI ([Fio2 × mean airway pressure]/Spo2 × 100). Lower scores reflect better oxygenation.
d 
Number of organ dysfunctions ranges from 1 to 6. All patients had respiratory dysfunction. Cardiovascular dysfunction based on vasoactive medication use
(single or multiple). Neurologic dysfunction based on worst level of consciousness (stupor or coma) or pupillary response (one or both pupils nonreactive).
Hematologic dysfunction based on platelet threshold (< 80 K/µL). Renal dysfunction based on age-specific creatinine thresholds. Hepatic dysfunction based on
age- and gender-specific alanine transaminase thresholds or total bilirubin thresholds.

was not significantly different between groups. Two days post- During RESTORE’s acute phase of illness, intervention group
decannulation, the usual care group received more opioids patients supported on ECMO (n = 29) received higher mean
(0.32 vs 0.26 mg/kg/hr; p = 0.03) and more sedative classes (3 daily doses of both opioids (median, 0.23 vs 0.10 mg/kg/hr;
vs 2; p = 0.02) than the intervention group. p < 0.001) and benzodiazepines (0.28 vs 0.09 mg/kg/hr; p < 0.001)

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 Online Clinical Investigation

TABLE 2. Sedation Profiles of Extracorporeal Membrane Oxygenation Patients By Day

around Cannulation
Day of
3 D Earlier 2 D Earlier 1 D Earlier ­Cannulation 1 D Later 2 D Later 3 D Later
Variables (n = 31) (n = 35) (n = 52) (n = 61) (n = 61) (n = 61) (n = 58)

Sedatives administered
  Opioid dose, median 3.2 (1.5–6.5) 3.5 (1.8–6.8) 3.7 (1.4–6.2) 3.7 (2.4–5.6) 4.9 (2.8–6.9) 4.6 (2.8–8.1) 5.2 (3.4–9.8)
(IQR), mg/kga
  No. of opioid bolus doses, 3 (1–6) 4 (1–6) 4 (2–6.5) 4 (2–6) 4 (1–7) 4 (2–7) 6 (1–9)
median (IQR)
Benzodiazepine dose, median 3.0 (1.3–7.3) 3.4 (2.0–7.4) 2.9 (0.9–6.3) 2.8 (1.2–6.5) 3.8 (2.2–7.8) 3.7 (2.2–9.6) 5.2 (3.4–11.2)
(IQR), mg/kgb
No. of benzodiazepine bolus 3 (1–5) 3 (1–6) 3 (1–7) 2 (1–5) 3 (1–6) 3 (1–8) 4 (1–8)
doses, median (IQR)
Secondary sedatives, n (%)
 Dexmedetomidine 6 (19) 7 (20) 8 (15) 8 (13) 11 (18) 13 (21) 10 (17)
 Propofol 0 0 0 2 (3) 0 1 (2) 0
 Barbiturates 2 (6) 1 (3) 3 (6) 4 (7) 5 (8) 8 (13) 7 (12)
 Ketamine 3 (10) 2 (6) 6 (12) 10 (16) 3 (5) 5 (8) 6 (10)
 Clonidine 2 (6) 3 (9) 3 (6) 4 (7) 3 (5) 3 (5) 4 (7)
  Chloral hydrate 0 0 0 0 1 (2) 1 (2) 1 (2)
No. of different sedative 2 (2–3) 2 (2–3) 2 (2–3) 2 (2–3) 2 (2–3) 2 (2–3) 2 (2–3)
classes received, median
(IQR)c
Sedation-related adverse
eventsd
  Inadequate pain 0 0 2 (4) 0 0 3 (5) 1 (2)
management, n (%)
  Inadequate sedation 0 1 (3) 3 (6) 0 2 (3) 3 (5) 2 (3)
management, n (%)
Sedation scorese n = 27 n = 35 n = 47 n = 59 n = 56 n = 58 n = 56
  Modal SBS score, n (%)
  +1/+2 0 0 1 (2) 0 0 2 (3) 2 (4)
  –1/0 6 (22) 5 (14) 4 (9) 4 (7) 6 (11) 6 (10) 9 (16)
  –3/–2 7 (26) 12 (34) 9 (19) 15 (25) 20 (36) 23 (40) 19 (34)
   NMB entire day 14 (52) 18 (51) 33 (70) 40 (68) 30 (54) 27 (47) 26 (46)
  Highest SBS score, n (%)
  +1/+2 3 (11) 3 (9) 4 (9) 4 (7) 7 (13) 7 (12) 10 (18)
  –1/0 8 (30) 7 (20) 2 (4) 3 (5) 9 (16) 13 (22) 10 (18)
  –3/–2 2 (7) 7 (20) 8 (17) 12 (20) 10 (18) 11 (19) 10 (18)
   NMB entire day 14 (52) 18 (51) 33 (70) 40 (68) 30 (54) 27 (47) 26 (46)
IQR = interquartile range, NMB = neuromuscular blockade, SBS = State Behavioral Scale.
a
Opioid doses were calculated as morphine equivalents in mg/kg, including morphine (1), fentanyl (0.015), methadone (0.3), enteral codeine (20),
hydromorphone (0.15), enteral oxycodone (3), and remifentanil (0.015).
b
Benzodiazepine doses were calculated as midazolam equivalents in mg/kg, including midazolam (1), clonazepam (0.2), lorazepam (0.3), and diazepam (2).
c
Different sedatives classes include opioids, benzodiazepines, α2-adrenergic agonists, propofol, barbiturates, ketamine, and chloral hydrate.
d 
Inadequate pain management: pain score > 4 (or pain assumed present if receiving NMB) for 2 consecutive hours; inadequate sedation management: SBS
score > 0 (or agitation assumed present if receiving NMB) for 2 consecutive hours.
e
The SBS scores range from –3 (unresponsive) to +2 (agitated).

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Schneider et al

TABLE 3. Sedation Profiles of Extracorporeal Membrane Oxygenation Patients By Day

around Decannulationa
Day of
3 D Earlier 2 D Earlier 1 D Earlier ­Decannulation 1 D Later 2 D Later 3 D Later
Variables (n = 39) (n = 41) (n = 41) (n = 41) (n = 41) (n = 41) (n = 40)

Sedatives administered
  Opioid dose, median 7.3 7.7 7.8 9.7 8.1 7.1 5.1
(IQR), mg/kgb (3.7–11.2) (4.3–11.5) (4.9–12.5) (5.2–14.5) (4.8–13.2) (4.4–11.3) (3.0–12.3)
  No. of opioid bolus doses, 5 (2–7) 5 (2–8) 5 (3–8) 5 (3–8) 3 (1–6) 4 (1–7) 1.5 (0–5)
median (IQR)
Benzodiazepine dose, median 6.2 7.3 7.7 9.4 8.7 7.5 6.5
(IQR), mg/kgc (3.6–12.6) (4.3–11.7) (5.1–12.6) (6.2–13.0) (4.8–12.6) (4.8–13.3) (3.6–12.5)
No. of benzodiazepine bolus doses, 4 (2–7) 4 (1–9) 5 (2–7) 5 (1–8) 4 (1–6) 3 (1–6) 1.5 (0–5.5)
median (IQR)
Secondary sedatives, n (%)
 Dexmedetomidine 10 (26) 12 (29) 11 (27) 11 (27) 14 (34) 13 (32) 14 (35)
 Propofol 0 1 (2) 2 (5) 2 (5) 0 0 1 (3)
 Barbiturates 7 (18) 10 (24) 12 (29) 13 (32) 12 (29) 9 (22) 8 (20)
 Ketamine 5 (13) 4 (10) 5 (12) 7 (17) 5 (12) 2 (5) 3 (8)
 Clonidine 3 (8) 4 (10) 4 (10) 4 (10) 4 (10) 5 (12) 5 (13)
 Methadone 1 (3) 1 (2) 1 (2) 1 (2) 6 (15) 10 (24) 15 (38)
  Chloral hydrate 1 (3) 1 (2) 1 (2) 1 (2) 3 (7) 3 (7) 2 (5)
No. of different sedative classes 2 (2–3) 2 (2–3) 3 (2–3) 3 (2–3) 3 (2–3) 3 (2–3) 2.5 (2–3)
received, median (IQR)d
Sedation-related adverse eventse
  Inadequate pain management, 3 (8) 1 (2) 2 (5) 0 2 (5) 3 (7) 2 (5)
n (%)
  Inadequate sedation 2 (5) 2 (5) 2 (5) 2 (5) 4 (10) 6 (15) 3 (8)
management, n (%)
  Clinically significant iatrogenic 0 0 0 0 0 1 (2) 2 (5)
withdrawal, n (%)
Sedation scoresf n = 38 n = 39 n = 38 n = 40 n = 40 n = 37 n = 39
  Modal SBS score, n (%)
  +1/+2 0 0 0 0 3 (8) 1 (3) 3 (8)
  –1/0 8 (21) 13 (33) 10 (26) 12 (30) 22 (55) 27 (73) 24 (62)
  –3/–2 11 (29) 6 (15) 8 (21) 9 (23) 6 (15) 3 (8) 3 (8)
   NMB entire day 19 (50) 20 (51) 20 (53) 19 (48) 9 (23) 6 (16) 3 (8)
   No longer intubated 0 0 0 0 0 0 6 (15)
  Lowest SBS score, n (%)
  +1/+2 0 0 0 0 1 (3) 0 0
  –1/0 3 (8) 6 (15) 5 (13) 8 (20) 14 (35) 22 (59) 23 (59)
  –3/–2 16 (42) 13 (33) 13 (34) 13 (33) 16 (40) 9 (24) 7 (18)
   NMB entire day 19 (50) 20 (51) 20 (53) 19 (48) 9 (23) 6 (16) 3 (8)
   No longer intubated 0 0 0 0 0 0 6 (15)
(Continued )

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 Online Clinical Investigation

TABLE 3. (Continued). Sedation Profiles of Extracorporeal Membrane Oxygenation

Patients By Day around Decannulationa
Day of
3 D Earlier 2 D Earlier 1 D Earlier ­Decannulation 1 D Later 2 D Later 3 D Later
Variables (n = 39) (n = 41) (n = 41) (n = 41) (n = 41) (n = 41) (n = 40)

  Highest SBS score, n (%)

  +1/+2 6 (16) 9 (23) 7 (18) 10 (25) 14 (35) 20 (54) 22 (56)
  –1/0 9 (24) 9 (23) 10 (26) 8 (20) 15 (38) 11 (30) 7 (18)
  –3/–2 4 (11) 1 (3) 1 (3) 3 (8) 2 (5) 0 1 (3)
  Neuromuscular blockade 19 (50) 20 (51) 20 (53) 19 (48) 9 (23) 6 (16) 3 (8)
entire day
   No longer intubated 0 0 0 0 0 0 6 (15)
IQR = interquartile range, NMB = neuromuscular blockade, SBS = State Behavioral Scale.
a
Excluded 20 patients who were not decannulated prior to study discharge (10 patients died on extracorporeal membrane oxygenation (ECMO) support, eight
patients still on ECMO on day 28, and two patients still on ECMO on day of transfer to nonparticipating PICU).
b
Opioid doses were calculated as morphine equivalents in mg/kg, including morphine (1), fentanyl (0.015), methadone (0.3), enteral codeine (20),
hydromorphone (0.15), enteral oxycodone (3), and remifentanil (0.015).
c
Benzodiazepine doses were calculated as midazolam equivalents in mg/kg, including midazolam (1), clonazepam (0.2), lorazepam (0.3), and diazepam (2).
d
Different sedatives classes include opioids, benzodiazepines, α2-adrenergic agonists, propofol, barbiturates, ketamine, and chloral hydrate.
e
Inadequate pain management: pain score > 4 (or pain assumed present if receiving NMB) for 2 consecutive hours; inadequate sedation management: SBS
score > 0 (or agitation assumed present if receiving NMB) for 2 consecutive hours; clinically significant iatrogenic withdrawal in patients weaning from 5 or
more days of opioids: rescue therapy to manage an increase in Withdrawal Assessment Tool-1 symptoms.
The SBS scores range from –3 (unresponsive) to +2 (agitated).
f

and received more classes of sedatives (3 vs 2; p < 0.001) than In young children, the large ECMO cannulas and their
intervention group patients not on ECMO (n = 462). Further, precise positioning require a calm patient. Although this may
during the acute phase, intervention ECMO patients more com- require the use of large doses of sedatives, the mechanism for
monly received NMB for at least 1 entire day than intervention increased sedative requirements during ECMO is likely mul-
non-ECMO patients (83% vs 45%; p < 0.001). tifactorial. Although extraction of medications by the ECMO
Clinically significant iatrogenic withdrawal occurred more circuit is well described (8, 10–12), additional factors including
frequently in ECMO than in non-ECMO patients (27% vs expanded volume of distribution and blood administration
10%; p < 0.001) (Table 4), and no age-based differences in clin- can alter medication clearance and bioavailability. Patient-
ically significant IWS were noted. No differences were found in specific alterations in organ function resulting from increased
median PICU (27.9 vs 28.8 d; p = 0.62) or hospital length of perfusion may affect pharmacokinetics and pharmacodynam-
stay (36 vs 38 d; p = 0.73) between ECMO survivors with and ics of sedatives. The use of RRT during ECMO may also con-
without IWS. tribute to increased medication requirements.
Our findings support previous data, including the need for
a rapid increase in sedative dosing following ECMO cannu-
DISCUSSION lation to achieve sedation targets (12, 24). In the first 3 days
Here, we describe sedation management in children supported postcannulation, most ECMO patients in our study received
on ECMO for acute respiratory failure. Our data demonstrate NMB and/or were heavily sedated. We found that opioid and
the unique, dynamic, and challenging clinical paradigm pre- benzodiazepine doses increased by 36% and 58%, respectively.
sented by pediatric patients with moderate or severe PARDS By the time of decannulation, ECMO patients were receiving
supported on ECMO. We quantify the trajectory of ECMO more than double their pre-ECMO doses of these medications
sedation management and report a significant increase in opi- for a lighter level of sedation.
oid and benzodiazepine dosing postcannulation, continued Recent data on ECMO management have challenged the use
dose escalation throughout the duration of ECMO support, of deep sedation and NMB and emphasize need for early reha-
and development of IWS postdecannulation. Although 30% bilitation especially in those bridging to lung transplantation
of ECMO patients are awake and calm on the day of decan- on ECMO (25). However, we demonstrate that deep sedation
nulation, the vast majority of ECMO patients remained deeply and NMB remain common in patients with acute hypoxemic
sedated and/or received NMB throughout their ECMO run. respiratory failure receiving ECMO. This finding was unrelated
Postdecannulation, nearly 90% of ECMO patients exhib- to center ECMO volume, suggesting that it may be related to
ited symptoms of iatrogenic withdrawal and over a quarter severity of illness of the patients in our cohort.
required rescue treatment of IWS. Our data also show that a We demonstrate the effect of discontinuing ECMO on seda-
nurse-managed sedation protocol may help limit total sedative tion requirements and levels of sedation. Discontinuation of
exposure in these patients. the ECMO circuit and NMB, and reduced sedation levels’ goals

Critical Care Medicine www.ccmjournal.org 7

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Schneider et al

Figure 1. Sedative doses (A) and State Behavioral Scale (SBS) scores (B) by day around cannulation by treatment group, and sedative doses (C) and
SBS scores (D) by day around decannulation by treatment group. I = intervention group, NMB = neuromuscular blockade entire day, U = usual care
group.

postdecannulation decreased sedative use (5, 6, 8, 9). Within 3 days that tolerance occurs more frequently than previously appreci-
of decannulation, patients had shifted to a more awake state, and ated (13, 14). Specifically, the ECMO circuit is not protecting
by the fourth day, half of the patients were successfully extubated. the patient from increased sedative exposure during ECMO
The diagnosis of physiologic tolerance, defined as a decreas- support, a situation that places them at high risk for IWS post-
ing clinical effect of a sedative after prolonged exposure, is dif- decannulation. In our cohort, patients on ECMO experienced
ficult to operationalize in patients supported on ECMO (26). IWS more frequently than comparable patients not supported
However, the continued escalation of doses following cannu- on ECMO. Both increased exposure to sedatives and the result-
lation and the prevalence of IWS postdecannulation suggests ing increase in withdrawal are of concern, as data suggest

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 Online Clinical Investigation

TABLE 4. Iatrogenic Withdrawal Syndrome According to Group

All Patients Usual Care Group Intervention Group

ECMOa No ECMOa ECMO No ECMO ECMO No ECMO

Variables (n = 41) (n = 1,194) pb (n = 23) (n = 612) pb (n = 18) (n = 582) pb

Withdrawal 31/35 (89) 596/840 (71) 0.007 18/20 (90) 300/409 (73) 0.02 13/15 (87) 296/431 (69) 0.14
Assessment
Tool-Version 1
score ever ≥3,
n/total (%)c
Clinically 11 (27) 124 (10) < 0.001 8 (35) 43 (7) < 0.001 3 (17) 81 (14) 0.66
significant
iatrogenic
withdrawal
syndrome,
n (%)d
ECMO = extracorporeal membrane oxygenation.
a
The ECMO group excludes 20 ECMO patients who were not decannulated prior to study discharge. For the ECMO group, Withdrawal Assessment Tool-
Version 1 (WAT-1) assessments and clinically significant iatrogenic withdrawal events postdecannulation were considered. For the no ECMO group, WAT-1
assessments and events on any study days were considered.
b
p values for the comparison between groups were calculated using logistic regression accounting for PICU as a cluster variable using generalized estimating
equations.
c
WAT-1 scores ≥ 3 are associated with clinically significant withdrawal symptoms; calculated for 875 survivors who completed weaning from ≥ 5 days of opioids
and had at least one WAT-1 assessment.
d
Rescue therapy to manage increasing WAT-1 scores.

exposure to sedatives and IWS impairs long-term neurodevel- with the use of ECMO and the development of IWS. Lastly,
opmental outcomes (3, 27). our data demonstrate the potential benefit of a nurse-managed
When comparing patients supported on ECMO in the protocolized approach to sedation for ECMO patients which
RESTORE intervention group to those in the usual care group, deserves future prospective investigation.
patients in the intervention group were exposed to less opioids
during the study period, despite similar sedative exposure prior
CONCLUSIONS
to cannulation. Further, intervention patients experienced 6.5
The provision of ECMO in children is associated with deep
fewer total sedative exposure days. These data suggest that the
sedation, substantial sedative exposure, and an increased fre-
exposure to opioids and benzodiazepines on ECMO can be
quency of IWS. It is incumbent upon the pediatric ECMO
mitigated with the use of a standardized, goal-directed, nurse-
community to evaluate sedation practices that may be poten-
driven sedation protocol. This must be weighed against the
tially harmful. Standardized, goal-directed, nurse-driven seda-
finding that the usual care ECMO patients experienced fewer
tion protocols may help mitigate these effects.
days with episodic pain compared with intervention patients.
There are several limitations to this study. First, unmea-
sured variables may have influenced clinical decision-making. ACKNOWLEDGMENT
Second, as a subset of a larger study, this analysis was not suf- The Randomized Evaluation of Sedation Titration for Respi-
ficiently powered to answer all questions of interest. Third, we ratory Failure (RESTORE) study investigators include Martha
attempted to compare ECMO patients to patients not requir- A. Q. Curley (Principal Investigator; School of Nursing and the
ing ECMO who had similar severity of lung disease. Although Perelman School of Medicine, University of Pennsylvania, Phil-
both groups consisted of patients with moderate or severe adelphia, PA; Critical Care and Cardiovascular Program, Bos-
PARDS, there may have been unmeasured physiologic or ton Children’s Hospital, Boston, MA); David Wypij, (Principal
metabolic alterations in patients that contributed to the differ- Investigator—Data Coordinating Center; Department of Biosta-
ences identified. Fourth, we were unable to characterize the full tistics, Harvard T.H. Chan School of Public Health; Department
ECMO course for 10 patients who were still on ECMO support of Pediatrics, Harvard Medical School; Department of Cardiol-
at the end of the study period. Nonetheless, the rapid increase ogy, Boston Children’s Hospital, Boston, MA); Geoffrey L. Allen
in sedative dosing following cannulation and decrease in the (Children’s Mercy Hospital, Kansas City, MO); Derek C. Angus
days following decannulation suggest that interaction between (Clinical Research, Investigation, and Systems Modeling of Acute
the ECMO circuit and drug pharmacokinetics plays a clinically Illness Center, Pittsburgh, PA); Lisa A. Asaro (Department of Car-
significant role in patients supported by ECMO. diology, Boston Children’s Hospital, Boston, MA); Judy A. Ascenzi
Despite these limitations, our findings build on existing (The Johns Hopkins Hospital, Baltimore, MD); Scot T. Bateman
research (9, 12, 24) and provide granular data that explore the (University of Massachusetts Memorial Children’s Medical Cen-
dynamic patient-ECMO-sedation interactions experienced ter, Worcester, MA); Santiago Borasino (Children’s Hospital of
during ECMO. Further, we demonstrate a clear association Alabama, Birmingham, AL); Cindy Darnell Bowens (Children’s

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Schneider et al

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