Physiological modelling of agitation-sedation dynamics.

Agitation-sedation cycling in critically ill patients, characterized by oscillations between states of agitation and over-sedation, damages patient health and increases length of stay and cost. A model that captures the essential dynamics of the agitation-sedation system and is physiologically representative is developed, and validated using data from 37 critical care patients. It is more physiologically representative than a previously published agitation-sedation model, and captures more realistic and complex dynamics. The median time in the 90% probability band is 90%, and the total drug dose, relative to recorded drug dose data, is a near ideal 101%. These statistical model validation metrics are 5-13% better than a previously validated model. Hence, this research provides a platform to develop and test semi-automated sedation management controllers that offer the significant clinical potential of improved agitation management and reduced length of stay in critical care.

[1]  Jörn Lötsch,et al.  Pharmacokinetic modeling to predict morphine and morphine‐6‐glucuronide plasma concentrations in healthy young volunteers , 2002, Clinical pharmacology and therapeutics.

[2]  Koch Sigmund Ed,et al.  Psychology: A Study of A Science , 1962 .

[3]  H. Schwilden,et al.  The effect of age on the pharmacokinetics and pharmacodynamics of midazolam , 1999, Clinical pharmacology and therapeutics.

[4]  D. Crippen.  The role of sedation in the ICU patient with pain and agitation. , 1990, Critical care clinics.

[5]  E. Anderson.  Hudson et al. , 1977 .

[6]  D. Fish.  Treatment of delirium in the critically ill patient. , 1991, Clinical pharmacy.

[7]  J. Foss,et al.  Are Peripheral Opioid Antagonists the Solution to Opioid Side Effects? , 2004, Anesthesia and analgesia.

[8]  L. Christrup,et al.  Relationships among morphine metabolism, pain and side effects during long-term treatment: an update. , 2003, Journal of pain and symptom management.

[9]  A. Shafer.  Complications of sedation with midazolam in the intensive care unit and a comparison with other sedative regimens. , 1998, Critical care medicine.

[10]  S L Shafer,et al.  Response Surface Model for Anesthetic Drug Interactions , 2000, Anesthesiology.

[11]  R. Waldhorn,et al.  Analgesia, sedation and paralysis in the intensive care unit. , 1995, American family physician.

[12]  G. Brattebø,et al.  Effect of a scoring system and protocol for sedation on duration of patients' need for ventilator support in a surgical intensive care unit , 2002, BMJ : British Medical Journal.

[13]  M Danhof,et al.  Characterization of the pharmacodynamic interaction between parent drug and active metabolite in vivo: midazolam and alpha-OH-midazolam. , 1999, The Journal of pharmacology and experimental therapeutics.

[14]  G. Guyatt,et al.  Adaptation to the Intensive Care Environment (ATICE): Development and validation of a new sedation assessment instrument , 2003, Critical care medicine.

[15]  A. Donner,et al.  Optimal intravenous dosing strategies for sedatives and analgesics in the intensive care unit. , 1995, Critical care clinics.

[16]  W. Haefeli,et al.  Prolonged sedation due to accumulation of conjugated metabolites of midazolam , 1995, The Lancet.

[17]  J. Reves,et al.  Sedation in the intensive care unit , 2000, Critical care medicine.

[18]  A. Dahan,et al.  Pharmacokinetic-Pharmacodynamic Modeling of Morphine-6-glucuronide-induced Analgesia in Healthy Volunteers: Absence of Sex Differences , 2004, Anesthesiology.

[19]  R. Boulieu,et al.  Evaluation of the estimation of midazolam concentrations and pharmacokinetic parameters in intensive care patients using a bayesian pharmacokinetic software (PKS) according to sparse sampling approach , 2003, The Journal of pharmacy and pharmacology.

[20]  Theodore Speroff,et al.  Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. , 2004, JAMA.

[21]  J. Chase,et al.  Physiologically-based minimal model of agitation-sedation dynamics , 2004, The 26th Annual International Conference of the IEEE Engineering in Medicine and Biology Society.

[22]  L. Smith,et al.  The Pharmacokinetics of Midazolam in Chronic Renal Failure Patients , 1983, Anesthesiology.

[23]  G Sherman,et al.  Effect of a nursing-implemented sedation protocol on the duration of mechanical ventilation. , 1999, Critical care medicine.

[24]  G C Wake,et al.  Rethinking sedation and agitation management in critical illness. , 2003, Critical care and resuscitation : journal of the Australasian Academy of Critical Care Medicine.

[25]  R. Levine.  Pharmacology of intravenous sedatives and opioids in critically ill patients. , 1994, Critical care clinics.

[26]  G. Fraser,et al.  Monitoring sedation, agitation, analgesia, and delirium in critically ill adult patients. , 2001, Critical care clinics.

[27]  G. Wake,et al.  Modelling and control of the agitation-sedation cycle , 2003 .

[28]  J. Vender,et al.  Anxiety, delirium, and pain in the intensive care unit. , 2001, Critical care clinics.

[29]  A. Somogyi,et al.  The disposition of morphine and its 3- and 6-glucuronide metabolites in humans and animals, and the importance of the metabolites to the pharmacological effects of morphine. , 1996, Drug metabolism reviews.

[30]  Christina Starfinger,et al.  Quantifying agitation in sedated ICU patients using heart rate and blood pressure. , 2004, Physiological measurement.

[31]  C. T. French,et al.  Effects of a multifaceted, multidisciplinary, hospital-wide quality improvement program on weaning from mechanical ventilation , 2002, Critical care medicine.

[32]  U. Hofmann,et al.  Pharmacokinetic modelling of morphine, morphine-3-glucuronide and morphine-6-glucuronide in plasma and cerebrospinal fluid of neurosurgical patients after short-term infusion of morphine. , 2002, British journal of clinical pharmacology.

[33]  C. Gross,et al.  Sedating critically ill patients: factors affecting nurses' delivery of sedative therapy. , 2001, American journal of critical care : an official publication, American Association of Critical-Care Nurses.

[34]  Dominic S. Lee,et al.  Modeling and control of the agitation-sedation cycle for critical care patients. , 2004, Medical engineering & physics.

[35]  W. Härdle.  Applied Nonparametric Regression , 1991 .

[36]  U. Klotz,et al.  Pharmacokinetics and the pharmacodynamic action of midazolam in young and elderly patients undergoing tooth extraction , 1998, Clinical pharmacology and therapeutics.

[37]  J. Geoffrey Chase,et al.  Quantifying agitation in sedated ICU patients using digital imaging , 2004, Comput. Methods Programs Biomed..

[38]  J. Kress,et al.  Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. , 2000, The New England journal of medicine.

[39]  D. O'Hara,et al.  Pharmacokinetics and Pharmacodynamics of Sedatives and Analgesics in the Treatment of Agitated Critically Ill Patients , 1997, Clinical pharmacokinetics.

[40]  Rob Janknegt,et al.  Clinical pharmacokinetics of midazolam in intensive care patients, a wide interpatient variability? , 1988, Clinical pharmacology and therapeutics.

[41]  P. Hartvig,et al.  Pharmacokinetics of midazolam in total i.v. anaesthesia. , 1987, British journal of anaesthesia.

[42]  R. Moore,et al.  Systematic review of factors affecting the ratios of morphine and its major metabolites , 1998, Pain.

[43]  Y. Skrobik,et al.  Intensive Care Delirium Screening Checklist: evaluation of a new screening tool , 2001, Intensive Care Medicine.

[44]  M Danhof,et al.  Pharmacokinetic‐pharmacodynamic modeling of midazolam effects on the human central nervous system , 1988, Clinical pharmacology and therapeutics.