|Year : 2019 | Volume
| Issue : 3 | Page : 107-115
Effects of two dosing cohorts of dexmedetomidine as a primary sedative in critically ill infants with respiratory failure
Jehan A Sayed1, Mohamed A.F Riad2, Hala S Abdel-Ghaffar1
1 Department of Anesthesia and Intensive Care, Faculty of Medicine, Assiut University, Assiut, Egypt
2 Department of Pediatrics, Faculty of Medicine, Assiut University, Assiut, Egypt
|Date of Submission||23-Sep-2019|
|Date of Decision||10-Oct-2019|
|Date of Acceptance||10-Oct-2019|
|Date of Web Publication||27-Apr-2020|
Hala S Abdel-Ghaffar
Department of Anesthesia and Intensive Care, Faculty of Medicine, Assiut University, Assiut
Source of Support: None, Conflict of Interest: None
Background Despite being increasingly used, prospective randomized dose-finding studies on dexmedetomidine (DEX) sedation in infants are deficient. Aim The aim was to compare the efficacy of two fixed dosing cohorts of DEX as a primary sedative in the pediatric ICU.
Patients and methods Thirty-seven pediatric ICU mechanically ventilated infants (1–12 months) with acute respiratory failure were randomly allocated to receive DEX infusion without a loading dose: 0.5 µg/kg/h (group I, intermediate dose, n=18) or 0.35 µg/kg/h (group II, low dose, n=19) up to 72 h. The primary outcome was University of Michigan Sedation Scale (UMSS). Secondary outcomes were supplemental sedation or analgesia, hemodynamics, withdrawal adverse effects, withdrawal assessment tool-version 1, and ICU and length of hospital stay.
Results Duration of DEX infusion was (48.8±21.7 vs 37.8±21.3 h) in groups I and II (P=0.127). UMSS scores were significantly lower in group II. Supplemental sedation was needed in two patients in group II. Total ICU and hospital length of stay were 6.2±1.4 vs 3.6±1.9 days, P<0.000 and 9.9±2.2 vs 6.58±2.6 day, P=0.000, in groups I and II. Withdrawal effects in 12 h after DEX discontinuation were hypertension (1 vs1), tachycardia (1 vs 1), and agitation (1 vs 10) in groups I and II. The withdrawal assessment tool-version 1 score in 12th was (0.28±0.1 vs 0.89±0.2, P<0.02) and 24th (0.28±0.1 vs 0.79±0.2, P<0.02) in groups I and II.
Conclusion Two doses produced adequate sedation with comparable opioid sparing. The low dose was associated with lower UMSS scores, more agitation following DEX discontinuation, and lower ICU and length of hospital stay.
Keywords: dexmedetomidine, mechanical ventilation, pediatric critical care, sedation, α2 agonists
|How to cite this article:|
Sayed JA, Riad MA, Abdel-Ghaffar HS. Effects of two dosing cohorts of dexmedetomidine as a primary sedative in critically ill infants with respiratory failure. Alex J Pediatr 2019;32:107-15
|How to cite this URL:|
Sayed JA, Riad MA, Abdel-Ghaffar HS. Effects of two dosing cohorts of dexmedetomidine as a primary sedative in critically ill infants with respiratory failure. Alex J Pediatr [serial online] 2019 [cited 2020 Jun 2];32:107-15. Available from: http://www.ajp.eg.net/text.asp?2019/32/3/107/283323
| Introduction|| |
Critically ill children who are mechanically ventilated often require sedative and/or analgesic drugs to diminish anxiety or pain, facilitate synchronization with mechanical ventilation (MV), and enable invasive procedures to be performed . The importance of optimizing the levels of sedation in pediatric critical care has been increasingly recognized . This is because both undersedation and oversedation are undesirable, and may adversely affect patient’s outcomes ,.
Dexmedetomidine (DEX) is a sedative–anxiolytic α2-agonist administered off-label in pediatric intensive care unit (PICU) as a first-line sedative–analgesic agent (in an infusion dose of 0.2–0.7 μg/kg/h) and as an adjunct to other sedative–analgesic regimens . It has gained increasing popularity in PICU because it is short acting (half-life of 1.6–2.5 h in children), has inactive metabolites, causes minimal respiratory depression, and is associated with a shorter time to extubation in mechanically ventilated children, relative to those receiving benzodiazepine infusions for sedation .
Available studies of DEX pharmacology in children have provided conflicting information, while some suggest that infants need a higher dosage; others conclude that current dosing ranges are adequate . Theoretically, children younger than 2 years have a larger volume of distribution compared with older children and adults. Thereby, to reach a certain plasma concentration they need larger initial doses of DEX than older children and adults, with comparable maintenance infusion rates . In adults, sedative plasma DEX concentration is moderately correlated with the administered dose . However, it was recently found that in infants, plasma DEX concentration did not exhibit any correlation with the administered dose, which is not a reliable means of obtaining optimal plasma concentration signifying the importance of clinical dose-finding studies on DEX sedation in infants ,.
Prospective, randomized clinical dose-finding studies on DEX sedation in infants are scarce. Moreover, data on the quality of sedation and safety of long-term use of DEX in infants for more than 24 h are limited and data on withdrawal adverse effects are deficient..
| Aim|| |
We aimed to compare the efficacy and safety of two fixed dosing schedules of DEX (0.35 and 0.5 μg/kg/h maintenance infusions without a loading dose) as a primary sedative for up to 72 h in critically ill mechanically ventilated infants with respiratory failure as their primary pathology.
| Patients and methods|| |
Ethical approval for this study was provided by the Medical Ethics Committee, Faculty of Medicine, Assiut University, Assiut, Egypt. The study started in December 2016 and completed in July 2018. It was prospectively registered in https://clinicaltrials.gov (identifier: NCT02996058) and strictly followed the regulations and amendments of Helsinki Declaration. A written informed consent was obtained from the parental or guardian-authorized representative before participation in the study.
This prospective, randomized, double-blind comparative clinical study was carried out in the PICU in Children’s Hospital, Faculty of Medicine, Assiut University, Assiut, Egypt. Infants (1–12 months) with acute respiratory failure as a single-organ failure who were admitted in the PICU and requiring endotracheal intubation and MV with light to moderate sedation of an estimated duration of up to 72 h were included in the study. Exclusion criteria included patients with sustained hypotension or bradycardia for 1 h preceding DEX initiation (defined as any value outside the normal range for the patient’s age), second-degree, or third-degree heart block and patients with significant renal, hepatic, endocrine, metabolic, or neurological disease.
Patients were randomly assigned to two groups to receive DEX infusion dose of either 0.5 µg/kg/h (group I, intermediate dose group, n=18) or 0.35 µg/kg/h (group II, low-dose group, n=19), without a loading bolus dose.
Randomization was done at the time of study drug administration according to a computer-generated randomized number table. Study drug concentrations were diluted and prepared on color-coded basis by an investigator not involved in patients’ management. Patients’ guardians and all study personnel were blinded to the treatment group assignment.
Study drug administration
In PICU, pediatric patients (1–12 months) supported on MV for acute respiratory failure were candidates to receive continuous infusion of DEX for sedation either 0.5 or 0.35 µg/kg/h according to group assignment for no longer than 72 h. Dosage adjustments were not permitted. The quality of sedation was assessed using the University of Michigan Sedation Scale (UMSS) .
Based on UMSS and the physicians’ subjective assessments, patients not adequately sedated by DEX received supplemental sedation and analgesia administered as weight-based unit doses. One-unit dose of additional sedation was defined as: midazolam 0.1 mg/kg and one-unit dose of additional analgesics were defined as fentanyl 1 μg/kg. Supplemental sedation and analgesia were analyzed for each patient as the total number of unit doses administered during the study period. If a patient was deemed oversedated, the DEX infusion was discontinued and not restarted, and the patient was excluded from the study.
Study drug infusion was gradually stopped at extubation or if the investigator felt it was in the best interest of the patient. The duration of the study was 72 h. If sedation was required beyond 72 h, an alternative sedation regimen was initiated.
Patients’ demographic and baseline characteristics included age, weight, sex, primary diagnosis, associated comorbidities, and pediatric risk of mortality score on PICU admission .
Efficacy evaluation parameters
- The primary efficacy outcome was the quality of sedation assessed by the UMSS , assessed before initiation of DEX sedation and at 1, 10, 20, 30, 60 min, 2, 4, 6, 12, 18, 24, 36, 48, 60, and 72 h after study drug administration.
- Total number of unit doses of supplemental sedatives and analgesics.
- Patients’ outcome at the end of the study; extubated and successfully weaned, continued on MV or died.
- Duration of intubation, duration of MV and PICU and length of hospital stay.
- 30-day mortality.
Safety evaluation parameters
- Vital signs were recorded at the same time points mentioned above and at the time of intervention for any adverse events and included heart rate, mean arterial blood pressure, and respiratory rate. Normal values for these parameters were determined on the basis of patients’ age.
- Treatment-related adverse events such as hypotension, bradycardia, hypertension respiratory depression or arrhythmia were treated and recorded. For all variables, an adverse event was defined as any value outside the normal range for the patient’s age . The probability of an adverse event to be a consequence of DEX sedation assessed by the Naranjo score . It categorizes adverse events to have a probable or definite correlation with DEX as being definite (≥9), probable (5–8), possible (1–4), or doubtful (0).
- Withdrawal-related adverse events: patients were strictly followed for 12 h after end of study drug infusion by recording postinfusion vitals (the mean arterial blood pressure, heart rate, and respiratory rate), the UMSS, and adverse effects. For the next 72 h following discontinuation of DEX infusion, the occurrence of any potential signs and symptoms of withdrawal such as agitation, tachycardia, hypertension, tremors, anxiety, vomiting, diarrhea, or abdominal cramps were recorded and treated, accordingly. Withdrawal assessment score was determined with the withdrawal assessment tool-version 1 (WAT-1) performed twice daily for 72 h after discontinuation of DEX infusion. The total score is 0–12 and clinically significant withdrawal was diagnosed as WAT-1 score greater than or equal to 3 .
Power of the study
Our primary end point was the quality of sedation as assessed by UMSS. Secondary outcomes were use of additional sedatives or analgesics, hemodynamics, withdrawal adverse effects, and patients’ outcome. On the basis of previous studies ,,, a target sample size was calculated. A power analysis estimated that a sample size of 17 patients in each group would have an 80% power and at 0.05 level of significance to detect a significant difference between the two groups in the primary endpoint.
Data were presented as mean (SD), median (range), number, and percentages. Distribution of continuous variables was assessed by Shapiro–Wilk tests. Normally distributed continuous variables were analyzed using the two‑sample (unpaired) t‑test. Categorical data were analyzed using the χ2-test or Fisher’s exact test as appropriate. Nonparametric data were analyzed using the Mann–Whitney U test. A P less than 0.05 was considered statistically significant. All statistical analyses were performed using IBM SPSS statistics version 20 (SPSS Inc., Chicago, Illinois, USA).
| Results|| |
Among 45 pediatric patients admitted to the PICU with acute respiratory failure supported on MV, 40 patients were successfully consented, enrolled, and received the allocated drug intervention. Three patients were lost during follow-up. Finally, 37 patients were subjected to statistical analysis (18 vs 19 patients in group I and group II, respectively) ([Figure 1]). Patients’ demographic and clinical characteristics were similar in the two groups ([Table 1]).
Efficacy evaluation parameters
The mean duration of DEX infusion was 48.8±21.7 h in group I vs 37.8±21.3 h in group II (P=0.127). From the 10th minute after administration of DEX infusion till 48th h, the mean UMSS scores were significantly lower in group II, with no significant differences between the two groups in other time points ([Figure 2]).
|Figure 2 The University of Michigan Sedation Scale (UMSS) during dexmedetomidine infusion: group I: intermediate dose cohort: 0.5 μg/kg/h and group II: low-dose cohort: 0.35 μg/kg/h). From the 10th minute after administration of dexmedetomidine infusion till the 48th hour, the mean UMSS scores were significantly lower in group II.|
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In group I, no patient needed additional sedative or analgesic drugs during DEX sedation. In group II, additional sedation drugs were required in two patients (mean unit dose 2.0±1.0) and additional analgesics were also required in two patients (mean unit dose 1.0±0.0) ([Table 1]).
At the end of the study, 16 versus 15 patients were successfully extubated and weaned from MV in group I and group II, respectively (P=0.281). The mean duration of intubation was 51.3±21.6 vs 40.9±21.3 h in group I and group II, respectively (P=0.152). The mean duration of MV was 51.3±21.6 vs 40.9±21.5 h in group I and group II, respectively (P=0.152). One patient continued on mechanical ventilation in group II and was shifted to midazolam sedation ([Table 1]).
The mean total ICU and length of hospital stay were (6.2±1.4 vs 3.6±1.9 day, P<0.000) and (9.9±2.3 vs 6.6±2.6 day, P<0.000), in group I and group II, respectively. During the study, two patients died in group I vs two in group II and the cause of death was probably not related to DEX sedation ([Table 1]).
Safety evaluation parameters
Patients in group I showed significantly lower mean heart rates in 2nd, 4th, 18th, 24th, 36th, and 48th hours after the administration of DEX infusion (P<0.05), (data not presented). Lower mean arterial blood pressure values were recorded in group I at 20 min after start of DEX infusion (P<0.01), with no significant differences between groups in other time points (data not presented). The incidence of adverse effects that were deemed ‘probably’ be attributable to DEX (with Naranjo score of ≥9) was hypotension (1 vs 2), bradycardia (1 vs 1), both hypotension and bradycardia (0 vs 1) in group I and group II, respectively ([Table 1]).
Withdrawal-related adverse events
- In the first 12 h after discontinuation of DEX infusion: since discontinuation of DEX infusion till 11th h afterwards, patients in group II showed significantly lower mean UMSS ([Figure 3]). The MAP was significantly lower in group I in the first and second hour after discontinuation of DEX infusion with no significant differences between groups in other time points ([Figure 4]). There were no significant differences between groups in the mean HR either in the RR at any time point (data not presented). Sedative drugs were required in two patients in group II (mean unit dose 2.0±1.4) vs zero in group I. Analgesics were required in 13 patients in group II (mean unit dose 2.9±1.7) vs six patients in group I (mean unit dose 1.5±0.8, P=0.072), ([Table 1]). The relative distribution of withdrawal adverse effects was hypertension (1 vs 1), tachycardia (1 vs 1), and agitation (1 vs 10) in group I and group II, respectively ([Table 1]).
|Figure 3 The University of Michigan Sedation Scale (UMSS) in the first 12 h after discontinuation of dexmedetomidine infusion: group I, intermediate dose cohort: 0.5 μg/kg/h and group II, low-dose cohort: 0.35 μg/kg/h. Since the discontinuation of dexmedetomidine infusion till the 11th hour afterwards, patients in group II showed significantly lower mean UMSS.|
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|Figure 4 Mean arterial pressure (MAP) in the first 12 h after discontinuation of dexmedetomidine infusion: group I, intermediate dose cohort: 0.5 μg/kg/h; group II, low-dose cohort: 0.35 μg/kg/h). MAP was significantly lower in group I in the first (P<0.02) and second hour (P<0.04) after discontinuation of dexmedetomidine infusion.|
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- 12–72 h after discontinuation of DEX infusion.
Significant differences between groups in the mean WAT-1 score were recorded in the 12th hour (0.28±0.1 vs 0.89±0.2, P<0.02) and 24th hour (0.28±0.1 vs 0.79±0.2, P<0.02) after discontinuation of DEX infusion in group I and group II, respectively ([Figure 5]). Except for one patient in group II who had a WAT-1 score of 3 (significant withdrawal) in the 12th hour, no patient in this study was considered to have a WAT-1 score indicative of withdrawal syndrome.
|Figure 5 Withdrawal assessment tool-version 1 mean score in the first 12 h after discontinuation of dexmedetomidine infusion (group I: intermediate dose cohort: 0.5 μg/kg/h; group II: low-dose cohort; 0.35 μg/kg/h). Significant differences between groups in the mean withdrawal assessment tool-version 1 score were recorded in the 12th hour (P<0.02) and 24th hour (P<0.02) after discontinuation of dexmedetomidine infusion.|
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| Discussion|| |
In this study, we compared the sedative effects of two fixed dosing schedules of DEX sedation (0.35 and 0.5 μg/kg/h maintenance infusions without a loading dose) as a primary sedative for up to 72 h in critically ill, mechanically ventilated infants with respiratory failure. Our results demonstrated that most patients had adequate sedation while receiving DEX and did not need further sedative or analgesic supplementation. However, infants receiving the lower dose of DEX showed lower UMSS scores, increased incidence of agitation in the first 12 h following DEX discontinuation, and lower ICU and length of hospital stay.
Compared with dosing schedules described in the literature ,,,, the two doses used in this study are relatively low. Our goal was to keep our infants awake and comfortable with MV, while other studies investigated DEX sedation in surgical patients who needed more sedative and analgesic requirements.
Su et al.  in their prospective pharmacokinetic and pharmacodynamics dose–response study found that, despite dose escalation, there were no statistically significant differences in UMSS scores between three fixed dosing cohorts of DEX sedation in infants following open heart surgery. In contrast, in this study, we recorded significantly lower UMSS in the low-dose schedule. Su et al.  study was of a small sample size (n=12 per group) and was powered for pharmacokinetic assessments. Further prospective dose-finding studies are needed.
In this study, the use of DEX as a primary sedative significantly reduced the need for additional sedatives and/or analgesics. In accordance, Czaja and Zimmerman  in their retrospective study in PICU reported a decrease in supplemental opioid and benzodiazepine consumption by 36–42% compared with the 24 h preceding DEX administration using every patient as his/her control. Su et al.  reported 53% reduction in analgesic and sedative medications during DEX sedation in infants after open-heart surgery.
In accordance with previous studies ,,,,, adverse events recorded during DEX infusion were mainly hemodynamic (hypotension and bradycardia). Cummings et al.  in their prospective pilot study (n=17) concluded that a continuous infusion of 0.7 µg/kg/h of DEX without a loading dose for up to 24 h in critically ill children had tolerable effects on heart rate and blood pressure. In accordance, adverse events recorded were mild and were successfully managed without the need to discontinue DEX infusion.
In this study, using DEX as a primary sedative confirms that withdrawal signs were recorded in group II (low dose group) were due to DEX discontinuation only. Despite the presence of withdrawal signs and symptoms (hypertension, tachycardia, and agitation) in low-dose group, the WAT-1 scores we recorded were consistent with withdrawal (WAT-1 ≥3) in one patient only. The occurrence of withdrawal signs and symptoms in the low-dose group may be attributed to insufficient sedation after DEX discontinuation rather than being an actual withdrawal.
Burbano et al.  in their study reported hypertension (35%), tachycardia (27%), and agitation (27%) in their patients in the first 12 h after DEX withdrawal. However, data on concomitant use of other sedatives were lacking raising the possibility that these adverse effects may be also in part be due to withdrawal of other sedatives. Haenecour et al.  in their retrospective chart review reported that most common symptoms were agitation, fever, vomiting/retching, loose stools, and decreased sleep. These symptoms occurred during the latter part of the weaning or after discontinuation of DEX. Shutes et al.  in their retrospective chart review on DEX as a primary sedative in PICU reported that 19 (5%) of his patients (n=382) experienced withdrawal syndrome attributed to DEX only. They concluded that although withdrawal was associated with higher cumulative dose, these symptoms were managed with short-term enteral clonidine. In accordance, the withdrawal of adverse effects recorded were short term and were effectively controlled.
In this study, no patient showed gastrointestinal manifestation claimed to be due to DEX withdrawal. Manifestations of withdrawal syndrome listed in many literatures were originally described for opioid and benzodiazepine abrupt withdrawal especially with longer duration of administration and high doses . In addition, the WAT-1 tool has been validated for use in assessing opioid and benzodiazepine withdrawal, which limits its applicability in assessing and quantifying the severity of DEX withdrawal . The development of pediatric scoring tools for withdrawal syndrome such as WAT-1 and the Sophia Observation Withdrawal Symptoms-scale (SOS) is a great achievement ,. Future development of a scoring tool specifically formulated for DEX withdrawal is needed.
In this study, patients in group II (the low-dose group) showed lower ICU and length of hospital stay. Chen et al.  in their meta-analysis concluded that DEX long-term sedation in critically ill adults reduced the duration of MV and length of ICU stay. Ahmed and Murugan  in their multicenter study in PICUs have concluded that the length of ICU and hospital stays, and mortality rates were similar among DEX, midazolam, and propofol. Further studies are needed to confirm or to declare our results. A limitation to this study is the small sample size. Further prospective dose-finding studies of larger sample size on DEX sedation in PICU are needed. In addition, lack of serum levels of DEX show the pharmacokinetic–pharmacodynamic relationship between the two selected doses.
| Conclusion|| |
In conclusion, this study showed that the two fixed dosing schedules of DEX produced adequate sedation with comparable opioid sparing. Infants receiving the low dose showed lower UMSS scores, increased the incidence of agitation in the first 12 h following DEX discontinuation and lower ICU and length of hospital stay.
The authors are grateful to the colleagues and staff of the PICU for their cooperation in data collection.
Jehan A. Sayed contributed to conduct of the study, data collection, and analysis and manuscript revision; Mohamed A.F. Riad contributed to conduct of study, data collection, and analysis and manuscript revision; Hala S. Abdel-Ghaffar contributed to study design, conduct of study, data collection, data analysis, and writing and editing of the manuscript.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]