Patient-Specific Factors Associated with Dexmedetomidine Dose Requirements in Critically Ill Children

Karryn R. Crisamore; Philip E. Empey; Jonathan H. Pelletier; Robert S. B. Clark; Christopher M. Horvat

doi:10.1055/s-0042-1753537

Journal of Pediatric Intensive Care, Table of Contents

J Pediatr Intensive Care
DOI: 10.1055/s-0042-1753537

Original Article

Patient-Specific Factors Associated with Dexmedetomidine Dose Requirements in Critically Ill Children

Karryn R. Crisamore

¹Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania, United States

,

Philip E. Empey

³Department of Pharmacy and Therapeutics, University of Pittsburgh School of Pharmacy, Pittsburgh, PA

,

Jonathan H. Pelletier

²Division of Pediatric Critical Care Medicine, Department of Critical Care Medicine, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania, United States

,

Robert S. B. Clark

²Division of Pediatric Critical Care Medicine, Department of Critical Care Medicine, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania, United States

,

Christopher M. Horvat

²Division of Pediatric Critical Care Medicine, Department of Critical Care Medicine, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania, United States

› Author Affiliations

Abstract

The objective of this study was to evaluate patient-specific factors associated with dexmedetomidine dose requirements during continuous infusion. A retrospective cross-sectional analysis of electronic health record-derived data spanning 10 years for patients admitted with a primary respiratory diagnosis at a quaternary children's hospital and who received a dexmedetomidine continuous infusion (n = 346 patients) was conducted. Penalized regression was used to select demographic, clinical, and medication characteristics associated with a median daily dexmedetomidine dose. Identified characteristics were included in multivariable linear regression models and sensitivity analyses. Critically ill children had a median hourly dexmedetomidine dose of 0.5 mcg/kg/h (range: 0.1–1.8), median daily dose of 6.7 mcg/kg/d (range: 0.9–38.4), and median infusion duration of 1.6 days (range: 0.25–5.0). Of 26 variables tested, 15 were selected in the final model with days of dexmedetomidine infusion (β: 1.9; 95% confidence interval [CI]: 1.6, 2.3), median daily morphine milligram equivalents dosing (mg/kg/d) (β: 0.3; 95% CI: 0.1, 0.5), median daily ketamine dosing (mg/kg/d) (β: 0.2; 95% CI: 0.1, 0.3), male sex (β: −1.1; 95% CI: −2.0, −0.2), and non-Black reported race (β: −1.2; 95% CI: −2.3, −0.08) significantly associated with median daily dexmedetomidine dose. Approximately 56% of dose variability was explained by the model. Readily obtainable information such as demographics, concomitant medications, and duration of infusion accounts for over half the variability in dexmedetomidine dosing. Identified factors, as well as additional environmental and genetic factors, warrant investigation in future studies to inform precision dosing strategies.

Keywords

sedation - precision medicine - dexmedetomidine

Full Text

References

References
1 Walker T, Kudchadkar SR. Pain and sedation management: 2018 update for the Rogers' textbook of pediatric intensive care. Pediatr Crit Care Med 2019; 20 (01) 54-61
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 (07) 1592-1600
3 Chiu JA, Shergill M, Dhingra V. et al. Variation in the management of pain, agitation, and delirium in intensive care units in British Columbia. Am J Crit Care 2020; 29 (02) 122-129
4 Vet NJ, Ista E, de Wildt SN, van Dijk M, Tibboel D, de Hoog M. Optimal sedation in pediatric intensive care patients: a systematic review. Intensive Care Med 2013; 39 (09) 1524-1534
5 Silver G, Traube C, Gerber LM. et al. Pediatric delirium and associated risk factors: a single-center prospective observational study. Pediatr Crit Care Med 2015; 16 (04) 303-309
6 Ista E, van Dijk M, Gamel C, Tibboel D, de Hoog M. Withdrawal symptoms in children after long-term administration of sedatives and/or analgesics: a literature review. “Assessment remains troublesome”. Intensive Care Med 2007; 33 (08) 1396-1406
7 Shehabi Y, Bellomo R, Kadiman S. et al; Sedation Practice in Intensive Care Evaluation (SPICE) Study Investigators and the Australian and New Zealand Intensive Care Society Clinical Trials Group. Sedation intensity in the first 48 hours of mechanical ventilation and 180-day mortality: a multinational prospective longitudinal cohort study. Crit Care Med 2018; 46 (06) 850-859
8 Belleville JP, Ward DS, Bloor BC, Maze M. Effects of intravenous dexmedetomidine in humans. I. Sedation, ventilation, and metabolic rate. Anesthesiology 1992; 77 (06) 1125-1133
9 Weerink MAS, Struys MMRF, Hannivoort LN, Barends CRM, Absalom AR, Colin P. Clinical pharmacokinetics and pharmacodynamics of dexmedetomidine. Clin Pharmacokinet 2017; 56 (08) 893-913
10 Hospira, Inc.. Precedex (dexmedetomidine hydrochloride) [package insert]. U.S. Food and Drug Administration website. Revised April 2016. Accessed April 18, 2021 at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/021038s027lbl.pdf
11 Smith HAB, Besunder JB, Betters KA. et al. 2022 Society of Critical Care Medicine Clinical Practice Guidelines on Prevention and Management of Pain, Agitation, Neuromuscular Blockade, and Delirium in Critically Ill Pediatric Patients With Consideration of the ICU Environment and Early Mobility. Pediatr Crit Care Med 2022; 23 (02) e74-e110
12 Riker RR, Shehabi Y, Bokesch PM. et al; SEDCOM (Safety and Efficacy of Dexmedetomidine Compared With Midazolam) Study Group. Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. JAMA 2009; 301 (05) 489-499
13 Jakob SM, Ruokonen E, Grounds RM. et al; Dexmedetomidine for Long-Term Sedation Investigators. Dexmedetomidine vs midazolam or propofol for sedation during prolonged mechanical ventilation: two randomized controlled trials. JAMA 2012; 307 (11) 1151-1160
14 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
15 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 (02) 126-131
16 Venkatraman R, Hungerford JL, Hall MW, Moore-Clingenpeel M, Tobias JD. Dexmedetomidine for sedation during noninvasive ventilation in pediatric patients. Pediatr Crit Care Med 2017; 18 (09) 831-837
17 Grof TM, Bledsoe KA. Evaluating the use of dexmedetomidine in neurocritical care patients. Neurocrit Care 2010; 12 (03) 356-361
18 Sperotto F, Mondardini MC, Dell'Oste C. et al; Pediatric Neurological Protection and Drugs (PeNPAD) Study Group of the Italian Society of Neonatal and Pediatric Anesthesia and Intensive Care (SARNePI). Efficacy and safety of dexmedetomidine for prolonged sedation in the PICU: a prospective multicenter study (PROSDEX). Pediatr Crit Care Med 2020; 21 (07) 625-636
19 Haenecour AS, Seto W, Urbain CM, Stephens D, Laussen PC, Balit CR. Prolonged dexmedetomidine infusion and drug withdrawal in critically ill children. J Pediatr Pharmacol Ther 2017; 22 (06) 453-460
20 Carroll CL, Krieger D, Campbell M, Fisher DG, Comeau LL, Zucker AR. Use of dexmedetomidine for sedation of children hospitalized in the intensive care unit. J Hosp Med 2008; 3 (02) 142-147
21 Holliday SF, Kane-Gill SL, Empey PE, Buckley MS, Smithburger PL. Interpatient variability in dexmedetomidine response: a survey of the literature. ScientificWorldJournal 2014; 2014: 805013
22 von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP. STROBE Initiative. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Ann Intern Med 2007; 147 (08) 573-577
23 Children's Hospital Association. PHIS. Accessed September 16, 2021 at: https://www.childrenshospitals.org/Programs-and-Services/Data-Analytics-and-Research/Pediatric-Analytic-Solutions/Pediatric-Health-Information-System
24 Feudtner C, Feinstein JA, Zhong W, Hall M, Dai D. Pediatric complex chronic conditions classification system version 2: updated for ICD-10 and complex medical technology dependence and transplantation. BMC Pediatr 2014; 14: 199
25 LexiComp Online, Pediatric and Neonatal Lexi-Drugs Online. Hudson, OH: UpToDate Inc.; 2020
26 Zuppa AF, Curley MAQ. Sedation analgesia and neuromuscular blockade in pediatric critical care: overview and current landscape. Pediatr Clin North Am 2017; 64 (05) 1103-1116
27 Horvat CM, Ogoe H, Kantawala S. et al. Development and performance of electronic pediatric risk of mortality and pediatric logistic organ dysfunction-2 automated acuity scores. Pediatr Crit Care Med 2019; 20 (08) e372-e379
28 Leteurtre S, Duhamel A, Salleron J, Grandbastien B, Lacroix J, Leclerc F. Groupe Francophone de Réanimation et d'Urgences Pédiatriques (GFRUP). PELOD-2: an update of the PEdiatric logistic organ dysfunction score. Crit Care Med 2013; 41 (07) 1761-1773
29 Wagner D, Pasko D, Phillips K, Waldvogel J, Annich G. In vitro clearance of dexmedetomidine in extracorporeal membrane oxygenation. Perfusion 2013; 28 (01) 40-46
30 Grant MJ, Schneider JB, Asaro LA. et al; Randomized Evaluation of Sedation Titration for Respiratory Failure Study Investigators. Dexmedetomidine use in critically ill children with acute respiratory failure. Pediatr Crit Care Med 2016; 17 (12) 1131-1141
31 Riley RD, Snell KIE, Ensor J. et al. Minimum sample size for developing a multivariable prediction model: part I—continuous outcomes. Stat Med 2019; 38 (07) 1262-1275
32 van Buuren S, Groothuis-Oudshoorn K. mice: Multivariate Imputation by Chained Equations in R. J Stat Softw 2011; 1 (03) 2011
33 White IR, Royston P, Wood AM. Multiple imputation using chained equations: Issues and guidance for practice. Stat Med 2011; 30 (04) 377-399
34 Steif J, Brant R, Sreepada RS. et al. Prediction model performance with different imputation strategies: a simulation study using a North American ICU Registry. Pediatr Crit Care Med 2022; 23 (01) e29-e44
35 Friedman J, Hastie T, Tibshirani R. Regularization paths for generalized linear models via coordinate descent. J Stat Softw 2010; 33 (01) 1-22
36 Leisman DE, Harhay MO, Lederer DJ. et al. Development and reporting of prediction models: guidance for authors from editors of respiratory, sleep, and critical care journals. Crit Care Med 2020; 48 (05) 623-633
37 Hastie T, Tibshirani R, Wainwright M. Statistical learning with sparsity: the lasso and generalizations. Boca Raton: CRC Press; 2015
38 Thao LTP, Geskus R. A comparison of model selection methods for prediction in the presence of multiply imputed data. Biom J 2019; 61 (02) 343-356
39 Fleming S, Thompson M, Stevens R. et al. Normal ranges of heart rate and respiratory rate in children from birth to 18 years of age: a systematic review of observational studies. Lancet 2011; 377 (9770): 1011-1018
40 R Core Team. . (2021). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. Accessed June 21, 2022 at: https://www.R-project.org/
41 Tillman EM, Ipe J, Weaver KJ, Skaar TC, Rowan CM, Slaven JE. Variability of dosing and number of medications needed to achieve adequate sedation in mechanically ventilated pediatric intensive care patients. Clin Transl Sci 2021; 14 (01) 310-316
42 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 (08) 706-714
43 Banasch HL, Dersch-Mills DA, Boulter LL, Gilfoyle E. Dexmedetomidine use in a pediatric intensive care unit: a retrospective cohort study. Ann Pharmacother 2018; 52 (02) 133-139
44 Shutes BL, Gee SW, Sargel CL, Fink KA, Tobias JD. Dexmedetomidine as single continuous sedative during noninvasive ventilation: typical usage, hemodynamic effects, and withdrawal. Pediatr Crit Care Med 2018; 19 (04) 287-297
45 Curley MA, Wypij D, Watson RS. et al; RESTORE Study Investigators and the Pediatric Acute Lung Injury and Sepsis Investigators Network. Protocolized sedation vs usual care in pediatric patients mechanically ventilated for acute respiratory failure: a randomized clinical trial. JAMA 2015; 313 (04) 379-389
46 Tellor BR, Arnold HM, Micek ST, Kollef MH. Occurrence and predictors of dexmedetomidine infusion intolerance and failure. Hosp Pract (1995) 2012; 40 (01) 186-192
47 Smithburger PL, Smith RB, Kane-Gill SL, Empey PE. Patient predictors of dexmedetomidine effectiveness for sedation in intensive care units. Am J Crit Care 2014; 23 (02) 160-165
48 Kurnik D, Muszkat M, Sofowora GG. et al. Ethnic and genetic determinants of cardiovascular response to the selective alpha 2-adrenoceptor agonist dexmedetomidine. Hypertension 2008; 51 (02) 406-411
49 Klinger EV, Carlini SV, Gonzalez I. et al. Accuracy of race, ethnicity, and language preference in an electronic health record. J Gen Intern Med 2015; 30 (06) 719-723
50 Zhu AZ, Renner CC, Hatsukami DK. et al. The ability of plasma cotinine to predict nicotine and carcinogen exposure is altered by differences in CYP2A6: the influence of genetics, race, and sex. Cancer Epidemiol Biomarkers Prev 2013; 22 (04) 708-718
51 Kurnik D, Muszkat M, Li C. et al. Variations in the alpha2A-adrenergic receptor gene and their functional effects. Clin Pharmacol Ther 2006; 79 (03) 173-185
52 Thomas SS, Li SS, Lampe JW, Potter JD, Bigler J. Genetic variability, haplotypes, and htSNPs for exons 1 at the human UGT1A locus. Hum Mutat 2006; 27 (07) 717
53 Wassenaar CA, Conti DV, Das S. et al. UGT1A and UGT2B genetic variation alters nicotine and nitrosamine glucuronidation in European and African American smokers. Cancer Epidemiol Biomarkers Prev 2015; 24 (01) 94-104
54 Petroz GC, Sikich N, James M. et al. A phase I, two-center study of the pharmacokinetics and pharmacodynamics of dexmedetomidine in children. Anesthesiology 2006; 105 (06) 1098-1110
55 Ostchega Y, Porter KS, Hughes J, Dillon CF, Nwankwo T. Resting pulse rate reference data for children, adolescents, and adults: United States, 1999-2008. Natl Health Stat Rep 2011; Aug 24 (41) 1-16
56 Potts AL, Anderson BJ, Warman GR, Lerman J, Diaz SM, Vilo S. Dexmedetomidine pharmacokinetics in pediatric intensive care—a pooled analysis. Paediatr Anaesth 2009; 19 (11) 1119-1129
57 Wiczling P, Bartkowska-Śniatkowska A, Szerkus O. et al. The pharmacokinetics of dexmedetomidine during long-term infusion in critically ill pediatric patients. A Bayesian approach with informative priors. J Pharmacokinet Pharmacodyn 2016; 43 (03) 315-324
58 James NT, Breeyear JH, Caprioli R. et al. Population pharmacokinetic analysis of dexmedetomidine in children using real-world data from electronic health records and remnant specimens. Br J Clin Pharmacol 2021
59 Iirola T, Ihmsen H, Laitio R. et al. Population pharmacokinetics of dexmedetomidine during long-term sedation in intensive care patients. Br J Anaesth 2012; 108 (03) 460-468
60 Välitalo PA, Ahtola-Sätilä T, Wighton A, Sarapohja T, Pohjanjousi P, Garratt C. Population pharmacokinetics of dexmedetomidine in critically ill patients. Clin Drug Investig 2013; 33 (08) 579-587

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