Abstract
Objective
Care of critically-ill children includes sedation but current therapies are suboptimal. To describe dexmedetomidine (DEX) use in children supported on mechanical ventilation for acute respiratory failure.
Design
Secondary analysis of data from the RESTORE clinical trial.
Setting
Thirty-one pediatric ICUs.
Patients
Data from 2449 children; 2 weeks to 17 years old.
Interventions
Sedation practices were unrestrained in the usual care arm. Patients were categorized as receiving dexmedetomidine as a primary sedative (DEXp), secondary sedative (DEXs), periextubation agent (DEXe), or never prescribed. DEX exposure and sedation and clinical profiles are described.
Measurements and Main Results
Of 1224 usual care patients, 596 (49%) received DEX. DEXp patients (N=138; 11%) were less critically ill (PRISM III-12 score median 6 [IQR 3–11]) and when compared to all other cohorts, experienced more episodic agitation. In the intervention group, time in sedation target improved from 28% to 50% within one day of initiating DEXp. DEXs usual care patients (N=280; 23%) included more children with severe PARDS or organ failure. DEXs patients experienced more inadequate pain (22% vs 11%) and sedation (31% vs 16%) events. DEXe patients (N=178; 15%) were those known to not tolerate an awake, intubated state and experienced a shorter ventilator weaning process (2.1 vs 2.3 days).
Conclusions
Our data support the use of dexmedetomidine as a primary agent in low criticality patients offering the benefit of rapid achievement of targeted sedation levels. Dexmedetomidine as a secondary agent does not appear to add benefit. The use of dexmedetomidine to facilitate extubation in children intolerant of an awake, intubated state may abbreviate ventilator weaning. These data support a broader armamentarium of pediatric critical care sedation.
Keywords: Endotracheal intubation, extubation, analgesia, agitation, withdrawal, pediatric intensive care
Sedation management is fundamental to the care of critically-ill children supported on mechanical ventilation. Although practice variation exists, the most common sedation strategy in pediatric critical care includes the concomitant administration of an opioid and benzodiazepine.1–4 The use of these agents is associated with adverse effects contributing to intensive care morbidity, such as decreased spontaneous ventilation and prolonged mechanical ventilation. Further, gamma aminobutyric acid (GABA) agonists, such as benzodiazepines,3 demonstrate neurotoxic apoptotic effects, and when used to provide anesthesia at a young age, may impact neurocognitive development.5,6
Dexmedetomidine (DEX) is an alpha 2-adrenoceptor agonist principally acting centrally in the locus ceruleus to produce sedation, as well as in the spinal cord resulting in analgesia. Unlike most sedatives used in intensive care, DEX preserves respiratory drive, allowing for sedation with maintenance of spontaneous breathing. In critically-ill adults, sedation with DEX has been shown to provide adequate levels of sedation while reducing the duration of delirium and/or coma and shortening the duration of mechanical ventilation.7–9 Of particular interest to the pediatric population, animal models demonstrate a neuroprotective effect10–13 that requires further clinical investigation.
Although not approved for use in children by the Food and Drug Administration (FDA), DEX has gained popularity in pediatric critical care. To date, data describing DEX use are derived from single-center retrospective cohort studies or case reports.4,14–18 Most often, DEX has been used for short durations (<24 hours) and as an adjunct to other sedative agents. Here we describe DEX use in pediatric intensive care units (PICUs) over a 4-year period using data prospectively collected in a large multicenter study of sedation practices. In addition to describing the change in DEX use over time, we describe the sedation and clinical courses of patients receiving DEX as a primary agent, as a secondary agent, or to facilitate endotracheal extubation in a cohort of children supported on mechanical ventilation for acute respiratory failure.
METHODS
We performed a secondary analysis of the Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE) study dataset. RESTORE was a cluster randomized trial that compared usual care to a nurse-implemented goal-directed sedation algorithm in children with acute respiratory failure.19 Thirty-one PICUs participated and were randomized to continued usual care (14 sites, 1224 patients) or to the intervention (17 sites, 1225 patients). Prior to randomization, all PICUs implemented the same pain (FLACC,20 FACES,21 Individualized Numeric Rating Scale22), sedation (State Behavioral Scale [SBS]23), and withdrawal assessment (Withdrawal Assessment Tool-Version 1 [WAT-1]24) instruments.
RESTORE enrolled children, 2 weeks to 17 years of age, who were expected to require mechanical ventilation for at least 24 hours for acute airways or parenchymal disease, between 2009 and 2013. The database includes demographic and medical history data, baseline Pediatric Cerebral Performance Category (PCPC) and Pediatric Overall Performance Category (POPC),25 Pediatric Risk of Mortality (PRISM) III-12 scores,26 pediatric acute respiratory distress syndrome (PARDS)27 severity, daily clinical and organ function data, daily comfort assessments, and sedative dosing data from endotracheal intubation to 72 hours after the last opioid dose.
Most analyses focus on the usual care patients where DEX use was unrestrained. In the intervention group, DEX use per protocol was limited to the periextubation period in children assessed to be intolerant of an awake state. To facilitate data interpretation, patients were categorized into one of four DEX usage groups: 1) DEXe: DEX used as a periextubation agent, defined as DEX initiated on the day of, or day before, the first planned extubation, 2) DEXp: DEX used as a primary agent, defined as DEX initiated within the first 2 days of intubation and administered for ≥50% of intubated days and not used as a periextubation agent, 3) DEXs: DEX as a secondary agent, defined as DEX used but not as a periextubation or primary agent, and 4) DEX never prescribed.
Sedation profiles include opioid and benzodiazepine exposure, number of different sedative classes, measures of wakefulness, episodic pain and agitation, and sedation-related adverse events including inadequate pain management (2+ consecutive hours of pain scores ≥ 4), inadequate sedation management (2+ consecutive hours of SBS +1/+2), and clinically significant iatrogenic withdrawal (treatment of increased WAT-1 scores).28 For patients in the intervention group, we report the percentage of time spent within the prescribed SBS target range.
Statistical analysis
For the usual care arm, we describe the frequency of DEX usage groups by year. Site variability in DEX use was evaluated by calculating the percentage of patients managed with DEX by site and the intraclass correlation coefficient (ICC). The ICCs were derived from analysis of variance adjusting for age group, PRISM III-12 score, and baseline POPC>1 as performed in the primary trial publication, as well as study year to control for potential time trends in DEX use. Confidence intervals for the ICCs were constructed using Searle’s method to adjust for unequal sample sizes across sites.29,30 All usual care patients were used in calculating the DEXp ICC, all patients excluding DEXp patients were used in calculating the DEXs ICC, and DEXe and DEX never prescribed patients were used in calculating the DEXe ICC.
Baseline patient characteristics were compared across the four DEX usage groups using linear, logistic, multinomial logistic, and cumulative logit regression for continuous, binary, nominal, and ordinal variables, respectively. Analyses of sedation and clinical profile data used these methods as well as proportional hazards and Poisson regression for time-to-event and rate variables, respectively. Continuous variables except percentage of study days variables were log-transformed. For duration of mechanical ventilation, we adjusted for age group, PRISM III-12 score, and baseline POPC>1 as performed in the primary trial publication, as well as worst PARDS on days 0 to 1 to control for severity of lung injury.19 All regression analyses except for primary diagnosis accounted for PICU as a cluster variable using generalized estimating equations. To reflect how decisions are made in clinical practice, sedation and clinical profiles were also compared between 1) DEXp vs all other patients, 2) DEXs vs all other patients excluding DEXp patients, and 3) DEXe vs DEX never prescribed, when the overall P value comparing across the four DEX groups was <0.05. Due to multiple comparisons, P values <0.01 were considered to indicate statistically significant differences for the additional comparisons. All data analyses were performed using SAS (Version 9.4, SAS Institute, Cary, NC).
RESULTS
In total, 596 of 1224 (49%) usual care patients ever received DEX. DEXp and DEXs use increased each year; specifically, from 6% to 17% for DEXp and 17% to 32% for DEXs. DEXe use remained consistent throughout the 4-year enrollment period ranging from 13% to 17%. The percentage of patients managed with DEX varied by site: DEXp 8% (median; range, 0–37%), DEXs 23% (9–32%), and DEXe 12% (4–20%). The ICC indicated moderate variability by site: DEXp 0.081 (95% CI, 0.043–0.173), DEXs 0.050 (0.024–0.117), and DEXe 0.035 (0.012–0.092).
DEX as a primary agent
Baseline characteristics of usual care patients by DEX usage group are presented in Table 1. The DEXp cohort (N=138; 11%) included children with lower median PRISM III-12 scores and more children with asthma or reactive airway disease. When used as DEXp, the mean daily DEX dose was 0.6 mcg/kg/hr (median; IQR, 0.4–0.8), the peak daily DEX dose was 0.9 mcg/kg/hr (0.6–1.3), and the cumulative DEX dose was 77.0 mcg/kg (37.6–167.0). The median duration of DEXp exposure was 6 days (IQR, 4–10) with 28% (N=39) receiving DEX postextubation for a median of 2 days (IQR, 1–3). Table 2 illustrates DEXp sedation profiles on the day DEX was initiated followed by two subsequent days. Most DEXp patients were awake and calm with modal SBS scores −1/0. Table 3 compares the sedation profiles by DEX usage group. Compared to all other patients, children receiving DEXp were exposed to significantly less opioids (median cumulative dose 12.4 vs 18.5 mg/kg) but more sedative classes (median 4 vs 3), propofol (18% vs 10%), and ketamine (38% vs 29%). Children receiving DEXp experienced significantly more study days with any episode of agitation (median 50% vs 38%). Table 4 compares the clinical profiles by DEX usage group. The duration of mechanical ventilation was significantly shorter in the DEXp group compared to all other patients (median 5.0 vs 6.8 days).
Table 1.
Baseline Characteristics of Usual Care Patients by DEX Usage Group
| Characteristics | DEXp (N=138) | DEXs (N=280) | DEXe (N=178) | DEX Never Prescribed (N=628) | P Value Across All Groupsa |
|---|---|---|---|---|---|
| Age at PICU admission, median (IQR), y | 2.5 (1.1–9.0) | 2.6 (0.7–8.7) | 3.1 (0.9–8.1) | 2.6 (0.4–9.8) | 0.26 |
| Female sex, No. (%) | 44 (32) | 138 (49) | 78 (44) | 283 (45) | 0.01 |
| Non-Hispanic white, No./total no. (%) | 61/136 (45) | 152/279 (54) | 87/176 (49) | 302/619 (49) | 0.045 |
| Cognitive impairment (baseline PCPC score >1), No. (%)b | 26 (19) | 71 (25) | 43 (24) | 161 (26) | 0.38 |
| Functional impairment (baseline POPC score >1), No. (%)b | 35 (25) | 94 (34) | 50 (28) | 183 (29) | 0.37 |
| PRISM III-12 score, median (IQR) | 6 (3–11) | 9 (5–13) | 8 (4–13) | 9 (5–15) | <0.001 |
| Percent risk of mortality based on PRISM III-12 score, median (IQR) | 2.9 (1.0–7.7) | 5.9 (1.7–15.0) | 3.8 (1.7–11.7) | 5.8 (1.7–20.8) | <0.001 |
| Primary diagnosis, No. (%) | <0.001 | ||||
| Pneumonia | 49 (36) | 99 (35) | 58 (33) | 227 (36) | |
| Bronchiolitis | 23 (17) | 54 (19) | 34 (19) | 117 (19) | |
| Acute respiratory failure related to sepsis | 13 (9) | 40 (14) | 18 (10) | 141 (22) | |
| Asthma or reactive airway disease | 26 (19) | 29 (10) | 28 (16) | 37 (6) | |
| Aspiration pneumonia | 9 (7) | 19 (7) | 14 (8) | 37 (6) | |
| Otherc | 18 (13) | 39 (14) | 26 (15) | 69 (11) | |
| PARDS based on worst OI or OSI on Days 0 to 1, No. (%)d | <0.001 | ||||
| At risk (OI <4.0 or OSI <5.0) | 24 (17) | 21 (8) | 26 (15) | 117 (19) | |
| Mild (OI 4.0–7.9 or OSI 5.0–7.4) | 36 (26) | 57 (20) | 44 (25) | 127 (20) | |
| Moderate (OI 8.0–15.9 or OSI 7.5–12.2) | 40 (29) | 89 (32) | 55 (31) | 174 (28) | |
| Severe (OI≥16.0 or OSI≥12.3) | 38 (28) | 113 (40) | 53 (30) | 210 (33) | |
| Any past medical history, No. (%) | |||||
| Prematurity (<36 weeks post-menstrual age) | 19 (14) | 47 (17) | 27 (15) | 82 (13) | 0.29 |
| Asthma (prescribed bronchodilators or steroids) | 34 (25) | 53 (19) | 43 (24) | 80 (13) | <0.001 |
| Seizure disorder (prescribed anticonvulsants) | 7 (5) | 26 (9) | 11 (6) | 68 (11) | 0.03 |
| Cancer (current or past diagnosis) | 13 (9) | 26 (9) | 10 (6) | 60 (10) | 0.02 |
| Trisomy 21 | 3 (2) | 10 (4) | 7 (4) | 13 (2) | 0.27 |
| Number of organ dysfunctions on Days 0 to 1, median (IQR)e | 2 (1–2) | 2 (2–3) | 2 (1–3) | 2 (1–3) | <0.001 |
Abbreviations: DEX, dexmedetomidine; DEXe, DEX used as a periextubation agent; DEXp, DEX used as a primary agent; DEXs, DEX used as a secondary agent; IQR, interquartile range; OI, oxygenation index; OSI, oxygen saturation index; PARDS, pediatric acute respiratory distress syndrome; PCPC, Pediatric Cerebral Performance Category; POPC, Pediatric Overall Performance Category; PICU, pediatric intensive care unit; PRISM III-12, Pediatric Risk of Mortality score from first 12 hours in the PICU.
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.
PCPC and POPC scores range from 1 to 6, with higher categories indicating greater impairment.
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 other.
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.
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 non-reactive). 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 ALT thresholds or total bilirubin thresholds.
Table 2.
Sedation Profiles of Usual Care Patients in Primary DEX Usage Group By Day
| Variables | Day First Received DEXp (N=138) | 1 Day Later (N=138) | 2 Days Later (N=137) |
|---|---|---|---|
| Opioid dose, median (IQR), mg/kga | 1.5 (0.4–2.9) | 2.4 (0.7–3.8) | 1.9 (0.5–3.6) |
| Benzodiazepine dose, median (IQR), mg/kgb | 1.0 (0.4–2.3) | 1.8 (0.5–2.9) | 1.5 (0.4–3.3) |
| Secondary sedatives, No. (%) | |||
| Propofol | 8 (6) | 2 (1) | 3 (2) |
| Barbiturates | 1 (<1) | 3 (2) | 8 (6) |
| Ketamine | 29 (21) | 17 (12) | 18 (13) |
| Clonidine | 1 (<1) | 2 (1) | 3 (2) |
| Methadone | 3 (2) | 3 (2) | 4 (3) |
| Chloral hydrate | 7 (5) | 12 (9) | 13 (9) |
| No. of different sedative classes received, median (IQR)c | 3 (3–3) | 3 (3–3) | 3 (3–3) |
| Modal pain score, No. (%) | |||
| 0–3 | 119 (86) | 123 (89) | 119 (87) |
| ≥4 | 2 (1) | 1 (<1) | 1 (<1) |
| N/A patient chemically paralyzed entire day | 16 (12) | 12 (9) | 14 (10) |
| Not assessed | 1 (<1) | 2 (1) | 3 (2) |
| Modal SBS score, No. (%) | |||
| −3/−2 | 27 (20) | 26 (19) | 22 (16) |
| −1/0 | 61 (44) | 82 (59) | 86 (63) |
| +1/+2 | 12 (9) | 10 (7) | 9 (7) |
| N/A patient chemically paralyzed entire day | 16 (12) | 12 (9) | 14 (10) |
| N/A not intubated | 0 | 1 (<1) | 1 (<1) |
| Not assessed | 22 (16) | 7 (5) | 5 (4) |
Abbreviations: DEX, dexmedetomidine; DEXp, DEX used as a primary agent; IQR, interquartile range; SBS, State Behavioral Scale.
Opioid doses were calculated as morphine equivalents in mg/kg. Opioids (morphine equivalents) include morphine (1), fentanyl (0.015), methadone (0.3), enteral codeine (20), hydromorphone (0.15), enteral oxycodone (3), and remifentanil (0.015).
Benzodiazepine doses were calculated as midazolam equivalents in mg/kg. Benzodiazepines (midazolam equivalents) include midazolam (1), clonazepam (0.2), lorazepam (0.3), and diazepam (2).
Different sedative classes include opioids, benzodiazepines, α2-adrenergic agonists, ketamine, chloral hydrate, propofol, and barbiturates.
Table 3.
Sedation Profiles of Usual Care Patients by DEX Usage Group
| Variables | DEXp (N=138) | DEXs (N=280) | DEXe (N=178) | DEX Never Prescribed (N=628) | P Value Across All Groupsa | P Value DEXp vs All Other Patientsa | P Value DEXs vs DEXe or Never Prescribeda | P Value DEXe vs Never Prescribeda |
|---|---|---|---|---|---|---|---|---|
| Sedatives administered | ||||||||
| Opioid exposure, median (IQR)b | ||||||||
| Cumulative dose, mg/kg | 12.4 (4.9–38.6) | 53.2 (23.3–111.4) | 12.8 (4.8–39.6) | 13.3 (3.9–36.6) | <0.001 | 0.003 | <0.001 | 0.24 |
| No. of exposure days | 7.5 (4–18) | 19 (12–29) | 7 (4–15) | 7 (4–18) | <0.001 | 0.34 | <0.001 | 0.33 |
| Benzodiazepines exposure, median (IQR)c | ||||||||
| Cumulative dose, mg/kg | 13.1 (4.1–33.7) | 42.3 (17.7–86.2) | 9.7 (3.7–27.3) | 9.3 (2.8–26.3) | <0.001 | 0.17 | <0.001 | 0.16 |
| Secondary sedatives, No. (%) | ||||||||
| Propofol | 25 (18) | 51 (18) | 15 (8) | 46 (7) | <0.001 | <0.001 | <0.001 | 0.07 |
| Barbiturates | 25 (18) | 104 (37) | 29 (16) | 68 (11) | <0.001 | 0.70 | <0.001 | 0.01 |
| Ketamine | 53 (38) | 116 (41) | 51 (29) | 148 (24) | <0.001 | 0.009 | <0.001 | <0.001 |
| Clonidine | 22 (16) | 82 (29) | 23 (13) | 36 (6) | <0.001 | 0.25 | <0.001 | 0.07 |
| Methadone | 49 (36) | 135 (48) | 38 (21) | 146 (23) | <0.001 | 0.08 | <0.001 | 0.98 |
| Chloral hydrate | 29 (21) | 61 (22) | 28 (16) | 63 (10) | <0.001 | 0.97 | 0.01 | 0.07 |
| No. of different sedative classes received, Median (IQR)d | 4 (3–5) | 4 (3–5) | 4 (3–4) | 2 (2–3) | <0.001 | <0.001 | <0.001 | <0.001 |
| Antidelirium medications, No. (%) | 4 (3) | 10 (4) | 7 (4) | 5 (<1) | 0.005 | 0.50 | <0.001 | 0.007 |
| Measures of wakefulness, pain, and agitation, median (IQR) | ||||||||
| Study days awake and calm (modal SBS score −1 or 0), % | 75 (56–100) | 71 (50–88) | 68 (40–100) | 75 (50–100) | 0.002 | 0.049 | 0.82 | 0.02 |
| Days to first awake/calm state | 2 (1–3) | 2 (1–5) | 2 (1–3) | 2 (1–5) | <0.001 | 0.03 | 0.89 | <0.001 |
| Study days with an episode of pain (highest pain score ≥ 4), % | 29 (7–55) | 30 (16–50) | 25 (0–50) | 17 (0–40) | <0.001 | 0.02 | 0.001 | <0.001 |
| Study days with an episode of agitation (highest SBS score +1 or +2), % | 50 (33–73) | 52 (29–75) | 50 (20–67) | 25 (0–51) | <0.001 | <0.001 | <0.001 | <0.001 |
| Sedation-related adverse events | ||||||||
| Inadequate pain management, No. (%) | 22 (16) | 61 (22) | 27 (15) | 64 (10) | <0.001 | 0.22 | <0.001 | 0.02 |
| Inadequate sedation management, No. (%) | 33 (24) | 87 (31) | 34 (19) | 92 (15) | <0.001 | 0.03 | <0.001 | 0.003 |
| Clinically significant iatrogenic withdrawal, No. (%) | 14 (10) | 41 (15) | 14 (8) | 45 (7) | <0.001 | 0.64 | <0.001 | 0.21 |
| Extubation failure (reintubation within 24 h), No. (%) | 13 (9) | 37 (13) | 17 (10) | 37 (6) | 0.02 | 0.72 | 0.01 | 0.15 |
| Unplanned endotracheal tube extubation, No. of events/100 ventilator days | 1.07 | 0.56 | 0.45 | 0.33 | 0.28 | - | - | - |
| Unplanned removal of any invasive tube, No. of events/100 device days | 0.12 | 0.11 | 0.12 | 0.13 | 0.86 | - | - | - |
Abbreviations: DEX, dexmedetomidine; DEXe, DEX as a periextubation agent; DEXp, DEX as a primary agent; DEXs, DEX as a secondary agent; IQR, interquartile range; SBS, State Behavioral Scale.
P values for the comparison between groups were calculated using linear, proportional hazards, logistic, and Poisson regression for log-transformed continuous variables (except percentage of study days variables), time-to-event variables, binary variables, and rate variables, respectively. All regression analyses accounted for PICU as a cluster variable using generalized estimating equations.
Opioid doses were calculated as morphine equivalents in mg/kg. Opioids (morphine equivalents) include morphine (1), fentanyl (0.015), methadone (0.3), enteral codeine (20), hydromorphone (0.15), enteral oxycodone (3), and remifentanil (0.015).
Benzodiazepine doses were calculated as midazolam equivalents in mg/kg. Benzodiazepines (midazolam equivalents) include midazolam (1), clonazepam (0.2), lorazepam (0.3), and diazepam (2).
Different sedative classes include opioids, benzodiazepines, α2-adrenergic agonists, ketamine, chloral hydrate, propofol, and barbiturates.
Table 4.
Clinical Profiles of Usual Care Patients by DEX Usage Group
| Variables | DEXp (N=138) | DEXs (N=280) | DEXe (N=178) | DEX Never Prescribed (N=628) | P Value Across All Groupsa | P Value DEXp vs All Other Patientsa | P Value DEXs vs DEXe or Never Prescribeda | P Value DEXe vs Never Prescribeda |
|---|---|---|---|---|---|---|---|---|
| Duration of mechanical ventilation, median (IQR), db | 5.0 (3.1–8.6) | 9.9 (6.4–16.5) | 4.4 (2.5–7.0) | 6.0 (3.5–12.1) | <0.001 | 0.005 | <0.001 | <0.001 |
| Adjusted for age group, PRISM III-12 score, POPC score >1, and worst PARDS on days 0 to 1 | <0.001 | 0.01 | <0.001 | <0.001 | ||||
| Time to recovery from acute respiratory failure, median (IQR), dc | 1.7 (1.0–4.0) | 4.7 (1.7–9.0) | 1.9 (1.0–4.1) | 2.3 (1.0–4.6) | <0.001 | 0.07 | <0.001 | 0.13 |
| Duration of weaning from mechanical ventilation, median (IQR), dd | 3.0 (1.2–5.3) | 4.1 (2.0–7.0) | 2.1 (0.7–3.4) | 2.3 (1.1–4.5) | <0.001 | 0.74 | <0.001 | 0.006 |
| Neurological testing, No. (%) | 20 (14) | 66 (24) | 21 (12) | 123 (20) | <0.001 | 0.18 | 0.06 | <0.001 |
| Length of stay, median (IQR), de | ||||||||
| PICU | 8.6 (5.5–14.1) | 14.6 (9.4–22.7) | 7.1 (4.5–12.4) | 8.7 (5.1–15.3) | <0.001 | 0.16 | <0.001 | 0.002 |
| Hospital | 13 (8–24) | 23 (14–37) | 12 (7–21) | 15 (9–27) | <0.001 | 0.09 | <0.001 | <0.001 |
| In-hospital mortality, No. (%) | ||||||||
| At 28 d | 2 (1) | 12 (4) | 1 (<1) | 48 (8) | 0.002 | 0.03 | 0.33 | 0.007 |
| At 90 d | 4 (3) | 21 (8) | 1 (<1) | 62 (10) | <0.001 | 0.02 | 0.90 | 0.003 |
Abbreviations: DEX, dexmedetomidine; DEXe, DEX as a periextubation agent; DEXp, DEX as a primary agent; DEXs, DEX as a secondary agent; IQR, interquartile range; PARDS, pediatric acute respiratory distress syndrome; PICU, pediatric intensive care unit; POPC, Pediatric Overall Performance Category; PICU, pediatric intensive care unit; PRISM III-12, Pediatric Risk of Mortality score from first 12 hours in the PICU.
P values for the comparison between groups were calculated using proportional hazards and logistic regression accounting for PICU as a cluster variable using generalized estimating equations for time-to-event and binary variables, respectively.
Patients were assigned 28 days of mechanical ventilation if they remained intubated or were transferred or died prior to day 28 without remaining extubated for 24 hours, therefore making the outcome equivalent to ventilator-free days.
Time to recovery from acute respiratory failure was defined as the duration from day 0 start (endotracheal intubation, initiation of assisted breathing for chronically trached patients, or PICU admission for patients intubated at an outside hospital) to the time that the patient first met criteria to be tested for extubation readiness (spontaneously breathing and oxygenation index ≤6). Excludes nonsurvivors who did not meet criteria prior to death. For survivors who never met criteria, the duration of recovery was set equal to the duration of mechanical ventilation if the patient was successfully extubated or to 28 days if the patient was still intubated on day 28 or transferred to another PICU still intubated. Calculated for 135 DEXp, 267 DEXs, 177 DEXe, and 577 DEX never prescribed patients.
Duration of weaning from mechanical ventilation was defined as the duration from the time that the patient first met criteria to be tested for extubation readiness to successful endotracheal extubation (remained extubated for >24 hours) or successful removal of assisted breathing for trached patients. Excludes nonsurvivors who were not extubated for >24 hours prior to death. Also excludes survivors who never met criteria or were still intubated on day 28. Calculated for 111 DEXp, 212 DEXs, 159 DEXe, and 478 DEX never prescribed.
PICU and hospital length of stay exclude all nonsurvivors. Patients still in the PICU or hospital on day 90 were censored at day 90.
DEX as a secondary agent
The DEXs cohort (N=280; 23%) included more children with severe PARDS and children with a greater number of organ dysfunctions on admission. When used as DEXs, the mean daily DEX dose was 0.5 mcg/kg/hr (median; IQR, 0.3–0.7), the peak daily DEX dose was 0.7 mcg/kg/hr (0.5–1.1), and the cumulative DEX dose was 49.8 mcg/kg (19.8–133.5). DEXs was initiated on Day 4 (median; IQR, 2–8) postintubation. The median duration of DEXs exposure was 4 days (IQR, 3–9) with 27% (N=75) receiving DEX postextubation for a median of 2 days (IQR, 1–3). Table 5 illustrates DEXs sedation profiles on the day DEX was initiated and up to two days before and after initiation. Most DEXs patients were awake and calm with modal SBS scores −1/0; on the first day of receiving DEX, 18% were agitated with modal SBS scores +1/+2. The percentage of patients receiving neuromuscular blockade was higher on the days before DEX was initiated. Compared to all other patients excluding DEXp patients, children receiving DEXs were exposed to significantly more opioids (median cumulative dose 53.2 vs 13.2 mg/kg), benzodiazepines (42.3 vs 9.5 mg/kg), and sedative classes (median 4 vs 3). DEXs patients experienced significantly more study days with any episode of pain (median 30% vs 20%) and agitation (52% vs 33%) compared to all other patients excluding DEXp patients. The DEXs group also experienced significantly more sedation-related adverse events, specifically, inadequate pain management (22% vs 11%), inadequate sedation management (31% vs 16%), and clinically significant iatrogenic withdrawal (15% vs 7%). The duration of mechanical ventilation was significantly longer in the DEXs group compared to all other patients excluding DEXp patients (9.9 vs 5.6 days). The DEXs group also experienced a significantly longer recovery from acute respiratory failure (median 4.7 vs 2.2 days), longer duration of weaning from mechanical ventilation (4.1 vs 2.2 days), and longer lengths of PICU and hospital stay (14.6 vs 8.3 days and 23 vs 14 days, respectively).
Table 5.
Sedation Profiles of Usual Care Patients in Secondary DEX Usage Group By Day
| Variables | 2 Days Earlier (N=244) | 1 Day Earlier (N=257) | Day First Received DEXs (N=280) | 1 Day Later (N=278) | 2 Days Later (N=276) |
|---|---|---|---|---|---|
| Opioid dose, median (IQR), mg/kga | 3.2 (1.5–6.0) | 3.9 (2.4–6.4) | 4.3 (2.0–6.9) | 4.2 (1.6–6.7) | 3.8 (1.3–6.5) |
| Benzodiazepine dose, median (IQR), mg/kgb | 2.5 (1.1–5.2) | 3.2 (1.5–6.1) | 3.2 (1.3–6.7) | 3.0 (1.4–6.3) | 2.8 (1.0–5.8) |
| Secondary sedatives, No. (%) | |||||
| Propofol | 6 (2) | 7 (3) | 8 (3) | 3 (1) | 6 (2) |
| Barbiturates | 27 (11) | 42 (16) | 50 (18) | 50 (18) | 49 (18) |
| Ketamine | 43 (18) | 45 (18) | 46 (16) | 26 (9) | 26 (9) |
| Clonidine | 10 (4) | 12 (5) | 17 (6) | 21 (8) | 24 (9) |
| Methadone | 24 (10) | 29 (11) | 35 (13) | 46 (17) | 52 (19) |
| Chloral hydrate | 14 (6) | 23 (9) | 31 (11) | 32 (12) | 29 (11) |
| No. of different sedative classes received, median (IQR)c | 2 (2–3) | 2 (2–3) | 3 (3–4) | 3 (3–4) | 3 (3–4) |
| Modal pain score, No. (%) | |||||
| 0–3 | 187 (77) | 207 (81) | 244 (87) | 236 (85) | 236 (86) |
| ≥4 | 5 (2) | 6 (2) | 6 (2) | 4 (1) | 5 (2) |
| N/A patient chemically paralyzed entire day | 46 (19) | 41 (16) | 22 (8) | 30 (11) | 32 (12) |
| Not assessed | 6 (2) | 3 (1) | 7 (3) | 7 (3) | 2 (<1) |
| Modal SBS score, No. (%) | |||||
| −3/−2 | 45 (18) | 43 (17) | 45 (16) | 35 (13) | 30 (11) |
| −1/0 | 110 (45) | 126 (49) | 152 (54) | 162 (58) | 151 (55) |
| +1/+2 | 19 (8) | 32 (12) | 50 (18) | 40 (14) | 43 (16) |
| N/A patient chemically paralyzed entire day | 46 (19) | 41 (16) | 22 (8) | 30 (11) | 32 (12) |
| N/A not intubated | 4 (2) | 5 (2) | 2 (<1) | 4 (1) | 13 (5) |
| Not assessed | 20 (8) | 10 (4) | 8 (3) | 6 (2) | 6 (2) |
Abbreviations: DEX, dexmedetomidine; DEXs, DEX used as a secondary agent; IQR, interquartile range; SBS, State Behavioral Scale.
Opioid doses were calculated as morphine equivalents in mg/kg. Opioids (morphine equivalents) include morphine (1), fentanyl (0.015), methadone (0.3), enteral codeine (20), hydromorphone (0.15), enteral oxycodone (3), and remifentanil (0.015).
Benzodiazepine doses were calculated as midazolam equivalents in mg/kg. Benzodiazepines (midazolam equivalents) include midazolam (1), clonazepam (0.2), lorazepam (0.3), and diazepam (2).
Different sedative classes include opioids, benzodiazepines, α2-adrenergic agonists, ketamine, chloral hydrate, propofol, and barbiturates.
DEX as a periextubation agent
The DEXe cohort (N=178; 15%) included fewer children with acute respiratory failure related to sepsis and more with asthma or reactive airways disease, patients known to not tolerate an awake, intubated state. When used as DEXe, the mean daily DEX dose was 0.3 mcg/kg/hr (median; IQR, 0.1–0.4), the peak daily DEX dose was 0.3 mcg/kg/hr (0.2–0.5), and the cumulative DEX dose was 11.2 mcg/kg (4.9–19.4). The median duration of DEXe exposure was 2 days (IQR, 1–2) with 22% (N=40) receiving DEX postextubation for a median of 1 day (IQR, 1–2). Children receiving DEXe were exposed to significantly more sedative classes (median 4 vs 2), ketamine (29% vs 24%), and anti-delirium medications (4% vs <1%) compared to the DEX never prescribed group. The DEXe group experienced significantly more days with episodic pain (median 25% vs 17%) and agitation (median 50% vs 25%) and more inadequate sedation management events (19% vs 15% of patients). Patients prescribed DEXe experienced significantly shorter weaning from mechanical ventilation (2.1 vs 2.3 days).
DEX use in the intervention group
As expected, DEX use was much lower in the intervention group, with 287 of 1225 (23%) intervention patients ever receiving DEX. When DEXp was prescribed as a protocol deviation (N=80; 7%), time in sedation target improved from 28% to 50% within one day of initiating DEX. No such improvements were noted when DEXs was prescribed as a protocol deviation (N=152; 12%). When compared to the DEX never prescribed cohort (N=938, 77%), patients in the intervention group who were prescribed DEXe per protocol (N=55; 4%) experienced a shorter duration of mechanical ventilation (median [IQR] 6.1 [3.6–9.7] vs 6.2 [4.0–10.5] days; P=0.002). In addition, no DEX-related adverse events were reported in either arm of the RESTORE clinical trial.
DISCUSSION
We present the sedation and clinical profiles of mechanically ventilated children receiving dexmedetomidine over a four-year period within a large multicenter clinical trial. Our data indicate that dexmedetomidine use is increasing as both a primary and secondary agent in pediatric critical care. We report that clinicians are prescribing DEXp more often in children who are less critically ill, and, in the intervention group, DEXp resulted in more time within the prescribed sedation target. Adding DEXs into an existing sedative regime does not appear to add benefit. Dexmedetomidine as a periextubation agent is prescribed more often in patients who experienced a difficult sedation course (more episodic pain and agitation and inadequate sedation management) or in those known not to tolerate an awake, intubated state; specifically, patients with reactive airways disease or asthma. When prescribed, DEXe shortened the ventilator weaning process.
The ideal sedation agent in pediatric critical care would effectively produce anxiolysis in a wide range of patient age and developmental levels, preserve spontaneous ventilation, and exhibit a short half-life. In addition, the ideal sedation agent would not be associated with physiological tolerance with continued use or produce adverse effects including the potential for long-term neurocognitive dysfunction. While the pharmacologic and pharmacodynamics properties of DEX meet most of these criteria, symptoms characteristic of sympathetic over-activity including tachycardia, hypertension, emesis, agitation and seizures have been reported in children upon DEX discontinuation and warrant further study.18,31–34
Data supporting the use of DEXp in pediatrics are limited.35 In adult critical care, multiple large randomized controlled clinical trials support DEXp as an effective sedation agent that shortens the duration of mechanical ventilation and length of intensive care unit stay.7,8 Here we report a large cohort of critically-ill children who were adequately sedated with DEXp for a median of 6 days. In our cohort, children prescribed DEXp were less critically ill with a short anticipated length of mechanical ventilation, such as children with asthma but without multisystem organ failure.
DEXp was opioid-sparing but was associated with the use of more sedative classes. With light levels of sedation, it is not surprising that those receiving DEXp experienced more intermittent episodes of agitation. Importantly, despite an increase in episodic agitation, we did not identify an increase in unplanned removal of medical devices. Of note, when prescribed in the intervention group as a protocol deviation, DEXp was associated with a rapid achievement of targeted sedation scores.
Even after adjusting for severity of illness, DEXp was associated with a shorter duration of mechanical ventilation, possibly due to the more awake state and use of less opioids known to depress spontaneous respiration. Literature describing the use of DEX in children after cardiac surgery also suggests that DEX is effective as a primary agent and may facilitate earlier extubation.36,37 Pending further investigation, data may support the use of DEXp as a superior sedative agent in pediatric populations where the duration of mechanical ventilation is expected to be short.
As a secondary agent, however, DEX did not improve the patient’s sedation profile. Adding DEXs into the sedative regime of complex PARDS patients with a median of two or more organ dysfunctions did not result in an appreciable improvement in patient comfort nor did DEXs reduce other sedative dosing. This finding is in contrast to that of others who report a reduction4 or plateau18 in opioid and benzodiazepine dosing after starting a DEX infusion. The profile and characteristics of the pediatric patient most likely to have either a comfort or reduced sedative burden benefit remain unclear, but this analysis suggests it is not useful as a secondary agent in complex pediatric patients.
The use of DEXe was stable over our 4-year enrollment. We found that patients receiving DEXe were weaned from mechanical ventilation earlier but, again, did not experience less opioid or benzodiazepine exposure as previously reported in pediatric cohort studies14,37–40 and case reports.41–45 Similar to difficult-to-extubate adult patients,46 DEXe improves the rate of successful extubation
Our analyses are vulnerable to design flaws and bias. Unmeasured factors may have impacted a clinician’s decision to prescribe DEX. Without patient-level randomization one cannot evaluate the impact of DEX on clinical outcomes. In addition, delirium was not systematically assessed in the parent trial and its presence may have impacted both the dose and number of sedative classes administered. Also, non-pharmacologic interventions which may impact sedation were not captured. Since DEX use was not the objective of the parent study there may have been an underreporting of DEX side effects. Evaluation of DEX safety, as well as the potential benefit of DEX in facilitating restorative sleep, requires prospective study.47–49 Finally, we studied pediatric patients with acute respiratory failure. These data may not apply to other critically-ill pediatric cohorts.
CONCLUSIONS
Our data support the use of dexmedetomidine as a primary sedative agent in low criticality children because it offers the benefit of rapid achievement of targeted sedation scores and awake patients whose comfort levels can be better assessed and rapidly managed. Prescribing dexmedetomidine as a secondary sedative agent in a cohort of high criticality children did not appear to add clinical benefit. Finally, using dexmedetomidine to facilitate extubation in children who are intolerant of an awake, intubated state may abbreviate ventilator weaning. These data allow us to broaden our armamentarium of pediatric critical care sedation and inform the design of future randomized controlled clinical trials investigating how dexmedetomidine can be best used in pediatric critical care.
Acknowledgments
The RESTORE study investigators include: Martha A.Q. Curley (Principal Investigator; School of Nursing and the Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Critical Care and Cardiovascular Program, Boston Children’s Hospital, Boston, MA); David Wypij, (Principal Investigator – Data Coordinating Center; Department of Biostatistics, Harvard T.H. Chan School of Public Health; Department of Pediatrics, Harvard Medical School; Department of Cardiology, Boston Children’s Hospital, Boston, MA); Geoffrey L. Allen (Children’s Mercy Hospital, Kansas City, MO); Derek C. Angus (Clinical Research, Investigation, and Systems Modeling of Acute Illness Center, Pittsburgh, PA); Lisa A. Asaro (Department of Cardiology, Boston Children’s Hospital, Boston, MA); Judy A. Ascenzi (The Johns Hopkins Hospital, Baltimore, MD); Scot T. Bateman (University of Massachusetts Memorial Children’s Medical Center, Worcester, MA); Santiago Borasino (Children’s Hospital of Alabama, Birmingham, AL); Cindy Darnell Bowens (Children’s Medical Center of Dallas, Dallas, TX); G. Kris Bysani (Medical City Children’s Hospital, Dallas, TX); Ira M. Cheifetz (Duke Children’s Hospital, Durham, NC); Allison S. Cowl (Connecticut Children’s Medical Center, Hartford, CT); Brenda L. Dodson (Department of Pharmacy, Boston Children’s Hospital, Boston, MA); E. Vincent S. Faustino (Yale-New Haven Children’s Hospital, New Haven, CT); Lori D. Fineman (University of California San Francisco Benioff Children’s Hospital at San Francisco, San Francisco, CA); Heidi R. Flori (University of California at San Francisco Benioff Children’s Hospital at Oakland, Oakland, CA); Linda S. Franck (University of California at San Francisco School of Nursing, San Francisco, CA); Rainer G. Gedeit (Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI); Mary Jo C. Grant (Primary Children’s Hospital, Salt Lake City, UT); Andrea L. Harabin (National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD); Catherine Haskins-Kiefer (Florida Hospital for Children, Orlando, FL); James H. Hertzog (Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE); Larissa Hutchins (The Children’s Hospital of Philadelphia, Philadelphia, PA); Aileen L. Kirby (Oregon Health & Science University Doernbecher Children’s Hospital, Portland, OR); Ruth M. Lebet (School of Nursing, University of Pennsylvania, Philadelphia, PA); Michael A. Matthay (University of California at San Francisco School of Medicine, San Francisco, CA); Gwenn E. McLaughlin (Holtz Children’s Hospital, Jackson Health System, Miami, FL); JoAnne E. Natale (University of California Davis Children’s Hospital, Sacramento, CA); Phineas P. Oren (St. Louis Children’s Hospital, St. Louis, MO); Nagendra Polavarapu (Advocate Children’s Hospital-Oak Lawn, Oak Lawn, IL); James B. Schneider (Cohen Children’s Medical Center of New York, Hyde Park, NY); Adam J. Schwarz (Children’s Hospital of Orange County, Orange, CA); Thomas P. Shanley (C. S. Mott Children’s Hospital at the University of Michigan, Ann Arbor, MI); Shari Simone (University of Maryland Medical Center, Baltimore, MD); Lewis P. Singer (The Children’s Hospital at Montefiore, Bronx, NY); Lauren R. Sorce (Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL); Edward J. Truemper (Children’s Hospital and Medical Center, Omaha, NE); Michele A. Vander Heyden (Children’s Hospital at Dartmouth, Dartmouth, NH); R. Scott Watson (Center for Child Health, Behavior, and Development, Seattle Children’s Research Institute, Seattle, WA); Claire R. Wells (University of Arizona Medical Center, Tucson, AZ).
Footnotes
Conflicts of Interest: No conflicts of interest.
Copyright form disclosures:
Dr. Grant received support for article research from the National Institutes of Health (NIH). Her institution received funding from National Heart, Lung, and Blood Institute (NHLBI), NIH and from the National Institute of Nursing Research, NIH. Dr. Schneider disclosed off-label product use (Dexmedetomidine in children). .0Dr. Asaro received support for article research from the NIH and disclosed off-label product use (Off-label use of dexmedetomidine [pediatric patients]). Her institution received support from the NIH/NHLBI. Dr. Dodson disclosed off-label product use (Dexmedetomidine used for non-procedural pediatric sedation). Dr. Hall disclosed off-label product use (Procedural pediatric sedation Dexmedetomidine/Pediatric Sedation for Acute Respiratory Failure). Dr. Simone disclosed off-label product use (Off label use of Dexmedetomidine). Dr. Cowl disclosed off-label product use (Dexmedetomidine for prolonged use in pediatric patients). Dr. Munkwitz disclosed off-label product use (Use of Dexmetetomidine in Pediatric Patients). Dr. Wypij received support for article research from the NIH and disclosed off-label product use (Dexmedetomidine). His institution received funding from NIH/NHLBI and National Institute of Nursing Research. Dr. Curley received support for article research from the NIH, disclosed off-label product use (Dex not FDA approved for children), and received funding from Hospira (Subject Matter Expert on the State Behavioral Scale [SBS]). Her institution received funding from NHLBI.
References
- 1.Jenkins IA, Playfor SD, Bevan C, Davies G, Wolf AR. Current United Kingdom sedation practice in pediatric intensive care. Paediatr Anaesth. 2007;17(7):675–683. doi: 10.1111/j.1460-9592.2006.02180.x. [DOI] [PubMed] [Google Scholar]
- 2.Kudchadkar SR, Yaster M, Punjabi NM. Sedation, sleep promotion, and delirium screening practices in the care of mechanically ventilated children: a wake-up call for the pediatric critical care community. Crit Care Med. 2014;42(7):1592–1600. doi: 10.1097/CCM.0000000000000326. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Twite MD, Rashid A, Zuk J, Friesen RH. Sedation, analgesia, and neuromuscular blockade in the pediatric intensive care unit: survey of fellowship training programs. Pediatr Crit Care Med. 2004;5(6):521–532. doi: 10.1097/01.PCC.0000144710.13710.2E. [DOI] [PubMed] [Google Scholar]
- 4.Czaja AS, Zimmerman JJ. The use of dexmedetomidine in critically ill children. Pediatr Crit Care Med. 2009;10(3):381–386. doi: 10.1097/PCC.0b013e3181a3191f. [DOI] [PubMed] [Google Scholar]
- 5.Ing C, DiMaggio C, Whitehouse A, et al. Long-term differences in language and cognitive function after childhood exposure to anesthesia. Pediatrics. 2012;130(3):e476–485. doi: 10.1542/peds.2011-3822. [DOI] [PubMed] [Google Scholar]
- 6.DiMaggio C, Sun LS, Li G. Early childhood exposure to anesthesia and risk of developmental and behavioral disorders in a sibling birth cohort. Anesth Analg. 2011;113(5):1143–1151. doi: 10.1213/ANE.0b013e3182147f42. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Riker RR, Shehabi Y, Bokesch PM, et al. Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. Jama. 2009;301(5):489–499. doi: 10.1001/jama.2009.56. [DOI] [PubMed] [Google Scholar]
- 8.Pandharipande PP, Pun BT, Herr DL, et al. Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: the MENDS randomized controlled trial. Jama. 2007;298(22):2644–2653. doi: 10.1001/jama.298.22.2644. [DOI] [PubMed] [Google Scholar]
- 9.Jakob SM, Ruokonen E, Grounds RM, et al. Dexmedetomidine vs midazolam or propofol for sedation during prolonged mechanical ventilation: two randomized controlled trials. Jama. 2012;307(11):1151–1160. doi: 10.1001/jama.2012.304. [DOI] [PubMed] [Google Scholar]
- 10.Koo E, Oshodi T, Meschter C, Ebrahimnejad A, Dong G. Neurotoxic effects of dexmedetomidine in fetal cynomolgus monkey brains. J Toxicol Sci. 2014;39(2):251–262. doi: 10.2131/jts.39.251. [DOI] [PubMed] [Google Scholar]
- 11.Maier C, Steinberg GK, Sun GH, Zhi GT, Maze M. Neuroprotection by the alpha 2-adrenoreceptor agonist dexmedetomidine in a focal model of cerebral ischemia. Anesthesiology. 1993;79(2):306–312. doi: 10.1097/00000542-199308000-00016. [DOI] [PubMed] [Google Scholar]
- 12.Kuhmonen J, Pokorny J, Miettinen R, et al. Neuroprotective effects of dexmedetomidine in the gerbil hippocampus after transient global ischemia. Anesthesiology. 1997;87(2):371–377. doi: 10.1097/00000542-199708000-00025. [DOI] [PubMed] [Google Scholar]
- 13.Sanders RD, Sun P, Patel S, Li M, Maze M, Ma D. Dexmedetomidine provides cortical neuroprotection: impact on anaesthetic-induced neuroapoptosis in the rat developing brain. Acta Anaesthesiol Scand. 2010;54(6):710–716. doi: 10.1111/j.1399-6576.2009.02177.x. [DOI] [PubMed] [Google Scholar]
- 14.Bejian S, Valasek C, Nigro JJ, Cleveland DC, Willis BC. Prolonged use of dexmedetomidine in the paediatric cardiothoracic intensive care unit. Cardiol Young. 2009;19(1):98–104. doi: 10.1017/S1047951109003515. [DOI] [PubMed] [Google Scholar]
- 15.Tobias JD, Berkenbosch JW. Sedation during mechanical ventilation in infants and children: dexmedetomidine versus midazolam. South Med J. 2004;97(5):451–455. doi: 10.1097/00007611-200405000-00007. [DOI] [PubMed] [Google Scholar]
- 16.Gupta P, Whiteside W, Sabati A, et al. Safety and efficacy of prolonged dexmedetomidine use in critically ill children with heart disease*. Pediatr Crit Care Med. 2012;13(6):660–666. doi: 10.1097/PCC.0b013e318253c7f1. [DOI] [PubMed] [Google Scholar]
- 17.Hasegawa T, Oshima Y, Maruo A, et al. Dexmedetomidine in combination with midazolam after pediatric cardiac surgery. Asian Cardiovasc Thorac Ann. 2015;23(7):802–808. doi: 10.1177/0218492315585644. [DOI] [PubMed] [Google Scholar]
- 18.Whalen LD, Di Gennaro JL, Irby GA, Yanay O, Zimmerman JJ. Long-term dexmedetomidine use and safety profile among critically ill children and neonates. Pediatr Crit Care Med. 2014;15(8):706–714. doi: 10.1097/PCC.0000000000000200. [DOI] [PubMed] [Google Scholar]
- 19.Curley MA, Wypij D, Watson RS, et al. Protocolized sedation vs usual care in pediatric patients mechanically ventilated for acute respiratory failure: a randomized clinical trial. Jama. 2015;313(4):379–389. doi: 10.1001/jama.2014.18399. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Merkel SI, Voepel-Lewis T, Shayevitz JR, Malviya S. The FLACC: a behavioral scale for scoring postoperative pain in young children. Pediatr Nurs. 1997;23(3):293–297. [PubMed] [Google Scholar]
- 21.Wong DL, Baker CM. Pain in children: comparison of assessment scales. Pediatr Nurs. 1988;14(1):9–17. [PubMed] [Google Scholar]
- 22.Solodiuk J, Curley MA. Pain assessment in nonverbal children with severe cognitive impairments: the Individualized Numeric Rating Scale (INRS) J Pediatr Nurs. 2003;18(4):295–299. doi: 10.1016/s0882-5963(03)00090-3. [DOI] [PubMed] [Google Scholar]
- 23.Curley MA, Harris SK, Fraser KA, Johnson RA, Arnold JH. State Behavioral Scale: a sedation assessment instrument for infants and young children supported on mechanical ventilation. Pediatr Crit Care Med. 2006;7(2):107–114. doi: 10.1097/01.PCC.0000200955.40962.38. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Franck LS, Harris SK, Soetenga DJ, Amling JK, Curley MA. The Withdrawal Assessment Tool-1 (WAT-1): an assessment instrument for monitoring opioid and benzodiazepine withdrawal symptoms in pediatric patients. Pediatr Crit Care Med. 2008;9(6):573–580. doi: 10.1097/PCC.0b013e31818c8328. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Fiser DH. Assessing the outcome of pediatric intensive care. J Pediatr. 1992;121(1):68–74. doi: 10.1016/s0022-3476(05)82544-2. [DOI] [PubMed] [Google Scholar]
- 26.Pollack MM, Patel KM, Ruttimann UE. PRISM III: an updated Pediatric Risk of Mortality score. Crit Care Med. 1996;24(5):743–752. doi: 10.1097/00003246-199605000-00004. [DOI] [PubMed] [Google Scholar]
- 27.Khemani RG, Smith LS, Zimmerman JJ, Erickson S. Pediatric acute respiratory distress syndrome: definition, incidence, and epidemiology: proceedings from the Pediatric Acute Lung Injury Consensus Conference. Pediatr Crit Care Med. 2015;16(5 Suppl 1):S23–40. doi: 10.1097/PCC.0000000000000432. [DOI] [PubMed] [Google Scholar]
- 28.Grant MJ, Scoppettuolo LA, Wypij D, Curley MA. Prospective evaluation of sedation-related adverse events in pediatric patients ventilated for acute respiratory failure. Crit Care Med. 2012;40(4):1317–1323. doi: 10.1097/CCM.0b013e31823c8ae3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Ridout MS, Demetrio CG, Firth D. Estimating intraclass correlation for binary data. Biometrics. 1999;55(1):137–148. doi: 10.1111/j.0006-341x.1999.00137.x. [DOI] [PubMed] [Google Scholar]
- 30.Ukoumunne OC. A comparison of confidence interval methods for the intraclass correlation coefficient in cluster randomized trials. Stat Med. 2002;21(24):3757–3774. doi: 10.1002/sim.1330. [DOI] [PubMed] [Google Scholar]
- 31.Carney L, Kendrick J, Carr R. Safety and Effectiveness of Dexmedetomidine in the Pediatric Intensive Care Unit (SAD-PICU) Can J Hosp Pharm. 2013;66(1):21–27. doi: 10.4212/cjhp.v66i1.1208. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Lardieri AB, Fusco NM, Simone S, Walker LK, Morgan JA, Parbuoni KA. Effects of Clonidine on Withdrawal From Long-term Dexmedetomidine in the Pediatric Patient. J Pediatr Pharmacol Ther. 2015;20(1):45–53. doi: 10.5863/1551-6776-20.1.45. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Kukoyi A, Coker S, Lewis L, Nierenberg D. Two cases of acute dexmedetomidine withdrawal syndrome following prolonged infusion in the intensive care unit: Report of cases and review of the literature. Hum Exp Toxicol. 2013;32(1):107–110. doi: 10.1177/0960327112454896. [DOI] [PubMed] [Google Scholar]
- 34.Takahashi Y, Ueno K, Ninomiya Y, Eguchi T, Nomura Y, Kawano Y. Potential risk factors for dexmedetomidine withdrawal seizures in infants after surgery for congenital heart disease. Brain Dev. 2016;38(7):648–653. doi: 10.1016/j.braindev.2016.02.003. [DOI] [PubMed] [Google Scholar]
- 35.Berkenbosch JW. Long-term dexmedetomidine use for pediatric critical care sedation: no need to sleep on it. Pediatr Crit Care Med. 2014;15(8):771–773. doi: 10.1097/PCC.0000000000000208. [DOI] [PubMed] [Google Scholar]
- 36.Chrysostomou C, Di Filippo S, Manrique AM, et al. Use of dexmedetomidine in children after cardiac and thoracic surgery. Pediatr Crit Care Med. 2006;7(2):126–131. doi: 10.1097/01.PCC.0000200967.76996.07. [DOI] [PubMed] [Google Scholar]
- 37.Hosokawa K, Shime N, Kato Y, et al. Dexmedetomidine sedation in children after cardiac surgery. Pediatr Crit Care Med. 2010;11(1):39–43. doi: 10.1097/PCC.0b013e3181b062d7. [DOI] [PubMed] [Google Scholar]
- 38.Su F, Nicolson SC, Zuppa AF. A dose-response study of dexmedetomidine administered as the primary sedative in infants following open heart surgery. Pediatr Crit Care Med. 2013;14(5):499–507. doi: 10.1097/PCC.0b013e31828a8800. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Burbano NH, Otero AV, Berry DE, Orr RA, Munoz RA. Discontinuation of prolonged infusions of dexmedetomidine in critically ill children with heart disease. Intensive Care Med. 2012;38(2):300–307. doi: 10.1007/s00134-011-2441-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Buck ML, Willson DF. Use of dexmedetomidine in the pediatric intensive care unit. Pharmacotherapy. 2008;28(1):51–57. doi: 10.1592/phco.28.1.51. [DOI] [PubMed] [Google Scholar]
- 41.Darnell C, Steiner J, Szmuk P, Sheeran P. Withdrawal from multiple sedative agent therapy in an infant: is dexmedetomidine the cause or the cure? Pediatr Crit Care Med. 2010;11(1):e1–3. doi: 10.1097/PCC.0b013e3181a66131. [DOI] [PubMed] [Google Scholar]
- 42.Enomoto Y, Kudo T, Saito T, et al. Prolonged use of dexmedetomidine in an infant with respiratory failure following living donor liver transplantation. Paediatr Anaesth. 2006;16(12):1285–1288. doi: 10.1111/j.1460-9592.2006.02008.x. [DOI] [PubMed] [Google Scholar]
- 43.Chrysostomou C, Zeballos T. Use of dexmedetomidine in a pediatric heart transplant patient. Pediatr Cardiol. 2005;26(5):651–654. doi: 10.1007/s00246-005-0683-3. [DOI] [PubMed] [Google Scholar]
- 44.Finkel JC, Johnson YJ, Quezado ZM. The use of dexmedetomidine to facilitate acute discontinuation of opioids after cardiac transplantation in children. Crit Care Med. 2005;33(9):2110–2112. doi: 10.1097/01.ccm.0000178183.21883.23. [DOI] [PubMed] [Google Scholar]
- 45.Finkel JC, Elrefai A. The use of dexmedetomidine to facilitate opioid and benzodiazepine detoxification in an infant. Anesth Analg. 2004;98(6):1658–1659. doi: 10.1213/01.ANE.0000113547.34160.A5. table of contents. [DOI] [PubMed] [Google Scholar]
- 46.Arpino PA, Kalafatas K, Thompson BT. Feasibility of dexmedetomidine in facilitating extubation in the intensive care unit. J Clin Pharm Ther. 2008;33(1):25–30. doi: 10.1111/j.1365-2710.2008.00883.x. [DOI] [PubMed] [Google Scholar]
- 47.Nelson LE, Lu J, Guo T, Saper CB, Franks NP, Maze M. The alpha2-adrenoceptor agonist dexmedetomidine converges on an endogenous sleep-promoting pathway to exert its sedative effects. Anesthesiology. 2003;98(2):428–436. doi: 10.1097/00000542-200302000-00024. [DOI] [PubMed] [Google Scholar]
- 48.Mason KP, O’Mahony E, Zurakowski D, Libenson MH. Effects of dexmedetomidine sedation on the EEG in children. Paediatr Anaesth. 2009;19(12):1175–1183. doi: 10.1111/j.1460-9592.2009.03160.x. [DOI] [PubMed] [Google Scholar]
- 49.Huupponen E, Maksimow A, Lapinlampi P, et al. Electroencephalogram spindle activity during dexmedetomidine sedation and physiological sleep. Acta Anaesthesiol Scand. 2008;52(2):289–294. doi: 10.1111/j.1399-6576.2007.01537.x. [DOI] [PubMed] [Google Scholar]