Dexmedetomidine is a highly selective central α2-agonist used as a sedative in pediatric intensive care unit (PICU). However, little is known about the relationship between dexmedetomidine dose and its plasma concentration during long-term infusion. We have previously demonstrated that the sedative plasma dexmedetomidine concentration is moderately correlated with the administered dose in adults (r = 0.653, P = 0.001). We hypothesized that there would be a similar relationship between the sedative dexmedetomidine concentration and administered dose in infants.
All patients admitted to the PICU at Nagoya City University Hospital, Japan, between November 2012 and March 2013 were eligible for inclusion in the study. Plasma dexmedetomidine concentration was measured by ultra-performance liquid chromatography coupled with tandem mass spectrometry.
We measured the plasma dexmedetomidine concentration in 203 samples from 45 patients. Of these, 96 samples collected from 27 patients < 2 years old were included in this study. All patients received dexmedetomidine at 0.12–1.40 µg/kg/h. The median administration duration was 87.6 hours (range: 6–540 hours). Plasma dexmedetomidine concentration ranged from 0.07 to 3.17 ng/ml. Plasma dexmedetomidine concentration was not correlated with the administered dose (r = 0.273, P = 0.007). The approximate linear equation was y = 0.690x + 0.423.
In infants, plasma dexmedetomidine concentration did not exhibit any correlation with administered dose, which is not a reliable means of obtaining optimal plasma concentration.
Dexmedetomidine is a highly selective central α2-agonist with anesthetic and analgesic properties used in critically ill pediatric patients [
The recommended dose of dexmedetomidine for children in the pediatric intensive care unit (PICU) is intravenous infusion of 0.12–1.4 µg/kg/h. There are no methods for simulating blood dexmedetomidine concentration. We have shown previously that a dexmedetomidine dose of 0.20–0.83 µg/kg/h achieved effective sedation in adults, with a plasma dexmedetomidine concentration of 0.22–2.50 ng/ml; dexmedetomidine concentration was moderately correlated with the administered dose (r = 0.653, P < 0.01) [
Our primary aim was to investigate whether the correlation coefficient between the sedative dose of dexmedetomidine and its plasma concentration in infants would exceed 0.5. We conducted a prospective observational cohort study of infants admitted to the PICU at our institution.
This study was conducted in the PICU of Nagoya City University Hospital, Japan. The name of the registry site was the University Hospital Medical Information Network Clinical Trials Registry (unique trial number: UMIN000009115). Ethical approval for the study was provided by the Ethics Committee of Nagoya City University Hospital, Nagoya, Japan, in July 2012 (chair Professor Y. Fujii, reference number 688). The requirement for written informed consent from participants' parents or caregivers was waived by the Ethics Committee, as we used blood samples < 0.5 ml that would otherwise have been discarded after routine blood gas analysis every morning. Nevertheless, we explained the study to the infants' parents or caregivers and recorded their agreement to participate in the medical records.
We recruited consecutive children < 2 years old admitted to the PICU of our institution between November 2012 and March 2013. We excluded infants in whom the dose of dexmedetomidine was changed within 6 hours. Dexmedetomidine was not administered to patients with a history of intolerance to dexmedetomidine, or with significant metabolic, hematological, or endocrine disease.
Patients received continuous intravenous infusion of dexmedetomidine (Precedex®; Hospira Japan, Osaka, Japan) at 0.12–1.4 µg/kg/h without a loading dose. Dexmedetomidine was administered based on clinical need, and all other standard PICU care needs were met. Standard care included intravenous administration of fentanyl or morphine as an analgesic, potentially supplemented by midazolam as a sedative. The oral sedative-hypnotic agents diazepam, triclofos, clonidine, and phenobarbital were also used in selected patients at the discretion of the supervising physician. Sedation was assessed using the Richmond Agitation-Sedation Scale (RASS) as follows: +4, combative; +3, very agitated; +2, agitated; +1, restless; 0, alert and calm; −1, drowsy; −2, light sedation; −3, moderate sedation; −4, deep sedation; −5, unarousable. Arterial blood gas analysis was routinely performed (once daily between 05:00 and 07:00). Blood that would otherwise have been discarded was collected immediately in EDTA tubes. Samples were stored at 4℃ and centrifuged. Plasma was frozen at −80℃ after separation and stored until analysis.
Measurement of dexmedetomidine concentration was performed by a single blind method. Arterial blood samples were numbered and no clinical information, including on whether dexmedetomidine had been administered, was provided to the investigators performing the assays. We have established a method to measure dexmedetomidine concentration using only 10 µl of plasma [
Power analysis was calculated for the primary endpoint, the correlation coefficient between dexmedetomidine dose and plasma dexmedetomidine concentration. Our preliminary data (sample number = 43) estimated the correlation coefficient to be 0.42. A total sample size of 48–82 was judged to be necessary to obtain a correlation coefficient of 0.35–0.45 and detect the primary outcome with statistical significance, assuming a two-tailed type I error of 5% and type II error of 10%. The Kolmogorov–Smirnov test was used to assess the distribution of data. Data are presented as means ± SD for normally distributed variables, the median [interquartile range, IQR] for non-normally distributed variables, or S the number (proportion, %), as appropriate. The relationship between dexmedetomidine dose and its plasma concentration was determined by linear regression. The correlation coefficient was calculated with Pearson's r or Spearman's ρ, according to the type of distribution. All P values are two-tailed. In all analyses, P < 0.05 was taken to indicate statistical significance.
We also assessed the relationship between dexmedetomidine dose and its plasma concentration in a variety of subgroups: patients undergoing single- or two-ventricle cardiac surgery; patients stratified according to Risk Adjustment in Congenital Heart Surgery (RACHS-1) score (comparing those with RACHS scores of 1–3 to those with scores of 4–6); and patents grouped according to the curative or palliative surgical strategy and age. Finally, we measured the correlation coefficient in patients from whom more than five samples were obtained.
All statistical analyses were performed using SPSS software (ver. 19.0; SPSS Inc., Chicago, IL, USA).
After exclusions, we collected 96 samples from 27 patients; plasma dexmedetomidine concentration was measured after assay failure in four specimens (
The dexmedetomidine dose had not been changed for at least 6 hours before all samples were collected. The median (range) duration of administration was 60.0 (6-276) hours. Dexmedetomidine concentration ranged from 0.07 to 3.17 ng/ml. Dexmedetomidine concentration was not correlated with the administered dose (r = 0.273, P = 0.007). The approximate linear equation was y = 0.690x + 0.423 (
Subgroup analyses indicated that neither single- or two-ventricle repair, RACHS-1 score, nor surgical strategy influenced the relationship between dexmedetomidine dose and plasma concentration (
The median [IQR] doses of co-administered drugs were as follows: fentanyl, 1.35 [0.66–2.56] µg/kg/h; morphine, 9.80 [6.00–15.39] µg/kg/h; midazolam, 0.16 [0.10–0.33] mg/kg/h; diazepam, 0.41 [0.38–0.48] mg/kg/day; triclofos, 42.6 [11.0–64.1] mg/kg/day; clonidine, 13.2 [9.90–16.0] µg/kg/day; and phenobarbital, 2.94 [2.94–2.94] mg/kg/day.
We found that plasma dexmedetomidine concentration ranged from 0.07 to 3.17 ng/ml in critically ill children under 2 years old administered a dose of 0.2–1.40 µg/kg/h. There was no relationship between plasma dexmedetomidine concentration and the administered dose, even in specific subgroups, in contrast to our previous study in adults that identified a moderate correlation [
Although the sedative concentration of dexmedetomidine in infants is not known, the concentrations that we identified were judged to be sufficient to achieve sedation in our cohort. The range in our cohort corresponded closely to the sedative concentration reported in adults (0.2–3.2 ng/ml) [
There may be several explanations for the absence of a relationship between dexmedetomidine dose and its plasma concentration in the present study compared to our previous finding of a moderate correlation in adults, some of which may be a consequence of the study's limitations. First, dosing regimens were based on body weight, a greater proportion of which may change during critical illness in infants compared with adults (all participants in our cohort weighed < 10 kg). Furthermore, body weight was measured before surgery or the onset of critical illness. Changes in body weight, and concomitant changes in blood volume, may be responsible for the variation in plasma dexmedetomidine concentration found here. Second, the pharmacokinetics and pharmacodynamics of dexmedetomidine are poorly understood and unpredictable in this population, particularly in infants with organ failure [
Our study had several other limitations. First, as its design was observational, strategies for the administration of dexmedetomidine and other sedative and analgesic drugs were tailored to each infant at the discretion of the supervising physician and other clinical staff. In future studies, consideration should be given to administering other sedatives and analgesics according to a protocol, titrated by sedation and pain scores. Second, multiple samples were obtained from some patients, so we cannot exclude the possibility that these may have influenced our findings for all participants. Finally, we defined an infant as a child under 2 years old, when typically the term is used to refer to children under 1 year old. Unlike some institutions where the youngest children are admitted to a neonatal intensive care unit, we admit all critically ill children to our PICU from birth onward. Consequently, including patients up to the age of 2 years more closely represents our routine clinical practice; furthermore, we found that age did not influence the correlation coefficient.
In conclusion, a dexmedetomidine dose of 0.12–1.40 µg/kg/h achieved a sedative plasma dexmedetomidine concentration of 0.07–3.17 ng/ml in critically ill infants under 2 years old. There was no relationship between dexmedetomidine dose and its plasma concentration. These observations suggest that administration of the recommended dose of dexmedetomidine did not reliably achieve the optimal plasma concentration in critically ill infants.
The authors thank Dr. Yoshiki Sento, Dr. Shinichiro Yoshimura, Dr. Yoshiyuki Nishizawa, Dr. Emi Sato, Dr. Miki Nakano, Dr. Kazuma Fujikake, Dr. Satoshi Aoki, Dr. Yukiko Mori, Dr. Taiki Kojima, Dr. Kentaro Miyake, and Dr. Toshihiro Yasui for their help collecting arterial samples and acquiring the data.
It was presented the Annual Congress of the European Society of Anaesthesiology, May 2015, CityCube Berlin, Berlin, Germany.
Infant | |
---|---|
Number | 27 |
Age (months) | 8.0 [0.5–23] |
M/F | 11/16 |
Weight (kg) | 5.9 ± 1.75 (2.6–9.4) |
Main reason for ICU admission, n (%) | |
Medical | 0 (0%) |
Surgical | 27 (100%) |
Cardiac disease | |
VSD | 7 (25.9%) |
DORV | 4 (14.8%) |
TAPVC | 4 (14.8%) |
TOF | 3 (11.1%) |
CAVSD | 3 (11.1%) |
TGA | 2 (7.4%) |
SRV | 2 (7.4%) |
SLV | 1 (3.7%) |
PDA | 1 (3.7%) |
Values are mean ± SD (range), median [interquartile range] or number (%).
ICU: intensive care unit, VSD: ventricular septal defect, DORV: double outlet right ventricle, TAPVC: total anomalous pulmonary venous connection, TOF: tetralogy of Fallot, cAVSD: complete atrioventricular septal defect, TGA: transposition of the great arteries, SRV: single right ventricle, SLV: single left ventricle, PDA: patent ductus arteriosus.
In 96 samples of 27 infants | |
---|---|
Drug treatment | |
Duration of infusion (h) | 60 [12, 108] |
Plasma concentrations (ng/ml) | 0.86 ± 0.65 |
Dosages (µg/kg/h) | 0.63 [0.40–0.71] |
Combined administration | |
No drug (only dexmedetomidine) | 11 (11.5%) |
1 drug (with fentanyl or morphine) | 22 (22.9%) |
2 drugs* | 49 (51.0%) |
3 or more drugs† | 14 (14.6%) |
Fentanyl | 71 (74.0%) |
Midazolam | 51 (57.3%) |
Management with artificial ventilation | 74 (77.1%) |
RASS | |
≥ 1 | 0 (0%) |
0 | 10 (10.4%) |
−1 | 12 (12.5%) |
−2 | 45 (46.9%) |
−3 | 20 (20.8%) |
−4 | 6 (6.3%) |
−5 | 3 (3.1%) |
Values are mean ± SD (range), median [interquartile range] (range) or number (%). Mechanical ventilation: respiratory management with mechanical ventilation when obtaining sample. *One sedative and one analgesic drug, †≥ 3 sedative and analgesic drugs. RASS: Richmond Agitation-Sedation Scale.
Subgroups | Sample (n = 96) | Patients (n = 27) | Correlation coefficient | P value |
---|---|---|---|---|
Single- or two-ventricle | ||||
Single ventricle | 8 | 4 | 0.643 | 0.085 |
Two ventricle | 88 | 23 | 0.082 | 0.450 |
RACHS-1 | ||||
1–3 | 81 | 23 | 0.162 | 0.149 |
4–6 | 15 | 4 | 0.149 | 0.597 |
Curative repair or palliative operation | ||||
Curative repair | 79 | 17 | 0.118 | 0.300 |
Palliative operation | 17 | 10 | 0.196 | 0.451 |
The same patient with several samples | ||||
A: VSD closure | 12 | 0.583 | 0.047 | |
B: curative repair for cAVSD | 11 | 0.844 | 0.001 | |
C: curative repair of TAPVC | 7 | 0.477 | 0.279 | |
D: curative repair of cAVSD | 7 | 0.612 | 0.144 | |
E: curative repair of cAVSD | 6 | 0.655 | 0.158 | |
F: VSD closure | 6 | 0.928 | 0.008 |
RACHS-1: Risk Adjustment in Congenital Heart Surgery, VSD: ventricular septal defect, cAVSD: complete atrioventricular septal defect, TAPVC: total anomalous pulmonary venous connection.