• Canadian Critical Care Trials Group
    The Canadian Critical Care Trials Group (CCCTG) is a highly collegial group that is dedicated to the pursuit of excellence and advancement of critical care research in Canada.
  • Canadian Critical Care Trials Group
    The CCCTG has are more than 30 research programs underway and over 100 peer-reviewed publications to its credit, with direct impact on clinical practice in critical care.
  • Canadian Critical Care Trials Group
    The Canadian Critical Care Trials Group (CCCTG) is a national organization of more than 300 individuals with research interests in the management of the critically ill patient.
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Principal Investigator(s)

Yoanna Skrobik



SPICE - Adverse drug reactions in the critically ill

Adverse drug reactions in the critically ill (SPICE)

Patient safety (PS) determines outcomes and costs. PS includes several areas such as Adverse Events, Adverse Drug Reactions (ADRs), iatrogenic complications and nosocomial infections. Every study reviewed systematically in the 2011 ‘Economics of Patient Safety in Acute Care’ recently published by the CPSI (Canadian Patient Safety Institute) suggests it is cost-effective to address prevention in safety issues.

ADRs can be defined in several ways:
1. Pharmacologically (e.g. by knowing the interaction mechanism behind Dilantin and Coumadin co-administration[1])
2. Related to clinical or biological outcomes (e.g. torsade may be more likely with simultaneous IV amiodarone, haloperidol and ciprofloxacin)
3. Biochemically (serum level 50% higher than ‘therapeutic range’

ADRs are expensive[2, 3], morbid[3, 4],  and are believed to rank between the fourth and the sixth cause of death in hospitalized patients[5]. ADRs have been reported to occur in twice as many (15%) ICU patients than on the ward (6.7%) yet are almost never conveyed (6% of the time) in routine quality assurance reports [6]; a more recent systematic review and meta-analysis  suggests a higher overall incidence still (17.8%)[7] . Direct prospective observations reflect practice more accurately than do data-based or retrospective studies[8].  Errors resulting in preventable adverse drug events or reactions occur most often when ordering (56%) or administering (34%) pharmacological interventions in critical care [9]. Errors are actionable (i.e. much more likely to be intercepted) if the error occurs earlier in the pharmacological intervention delivery process (e.g.48% interception is possible at the ordering stage [9]). Patients in critical care units receive more medications than most hospitalized patients, and this factor is believed to account for the high prevalence of ADRs [4, 10, 11].  Nursing workload has also been invoked as an associated ADR feature[12]

Sedatives and opiate analgesics are routinely administered in severely ill and mechanically ventilated patients [13], and rank as the most likely among medication categories to be responsible for ADRs in critical care[14]. The clinical manifestation of iatrogenic coma is morbid, associated with mortality [15, 16], and directly associated with drug-drug interactions[17].

  • Iatrogenic coma is associated with supratherapeutic drug levels of both parent drug and active metabolites, and is thus defined as an ADR by all 3 definitions listed above
  • Some of these will be predictable (drug-drug interaction)
  • Some will be biological factor dependent (e.g. renal failure)
  • Some will be pharmacogenomically determined[18], although the evidence for this in excess sedation, albeit biologically plausible, is currently unclear[19]
  • All of the patients identified as sedative-associated ADRs will cost more than patients without this iatrogenic complication
Study design:
This study is being done in 200 patients consented to the ANZICs SPICE-III RCT, in which patients are sedated with dexmedetomidine or the sedative agent of the treating physician’s choice; outcomes are 90 day mortality.
This sub-study is an observational cohort at 4 academic multidisciplinary intensive care units; these centers provide a representative sample of Canadian ICUs. Target population: mechanically ventilated ICU patients without stroke, TBI or major neurological injury, receiving intravenous sedatives, opiates or both (continuously or in bolus form). This study will 1) collect clinical (pain, target sedation, and delirium) and 2) pharmacological data; 3) dailyx3 then q 2 day blood samples for drug& metabolite levels; 4) estimate costs including a 6 month trajectory (IQCODE, caregiver burden and health.

  1. Harder, S. and P. Thurmann, Clinically important drug interactions with anticoagulants. An update. Clin Pharmacokinet, 1996. 30(6): p. 416-44.
  2. Bates, D.W., et al., The costs of adverse drug events in hospitalized patients. Adverse Drug Events Prevention Study Group. Jama, 1997. 277(4): p. 307-11.
  3. Classen, D.C., et al., Adverse drug events in hospitalized patients. Excess length of stay, extra costs, and attributable mortality. Jama, 1997. 277(4): p. 301-6.
  4. Cullen, D.J., et al., Preventable adverse drug events in hospitalized patients: a comparative study of intensive care and general care units. Crit Care Med, 1997. 25(8): p. 1289-97.
  5. Lazarou, J., B.H. Pomeranz, and P.N. Corey, Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. Jama, 1998. 279(15): p. 1200-5.
  6. Cullen, D.J., et al., The incident reporting system does not detect adverse drug events: a problem for quality improvement. Jt Comm J Qual Improv, 1995. 21(10): p. 541-8.
  7. Miguel, A., et al., Frequency of adverse drug reactions in hospitalized patients: a systematic review and meta-analysis. Pharmacoepidemiol Drug Saf, 2012. 21(11): p. 1139-54.
  8. Kopp, B.J., et al., Medication errors and adverse drug events in an intensive care unit: direct observation approach for detection. Crit Care Med, 2006. 34(2): p. 415-25.
  9. Bates, D.W., et al., Incidence of adverse drug events and potential adverse drug events. Implications for prevention. ADE Prevention Study Group. Jama, 1995. 274(1): p. 29-34.
  10. Reis, A.M. and S.H. Cassiani, Adverse drug events in an intensive care unit of a university hospital. Eur J Clin Pharmacol, 2011. 67(6): p. 625-32.
  11. Grenouillet-Delacre, M., et al., Life-threatening adverse drug reactions at admission to medical intensive care: a prospective study in a teaching hospital. Intensive Care Med, 2007. 33(12): p. 2150-7.
  12. Seynaeve, S., et al., Adverse drug events in intensive care units: a cross-sectional study of prevalence and risk factors. Am J Crit Care, 2011. 20(6): p. e131-40.
  13. Devlin, J.W., S. Mallow-Corbett, and R.R. Riker, Adverse drug events associated with the use of analgesics, sedatives, and antipsychotics in the intensive care unit. Crit Care Med, 2010. 38(6 Suppl): p. S231-43.
  14. Kane-Gill, S.L., et al., Analysis of risk factors for adverse drug events in critically ill patients*. Crit Care Med, 2012. 40(3): p. 823-8.
  15. Shehabi, Y., et al., Sedation depth and long-term mortality in mechanically ventilated critically ill adults: a prospective longitudinal multicentre cohort study. Intensive Care Med, 2013. 39(5): p. 910-8.
  16. Shehabi, Y., et al., Early intensive care sedation predicts long-term mortality in ventilated critically ill patients. Am J Respir Crit Care Med, 2012. 186(8): p. 724-31.
  17. Skrobik, Y., et al., Factors predisposing to coma and delirium: fentanyl and midazolam exposure; CYP3A5, ABCB1, and ABCG2 genetic polymorphisms; and inflammatory factors. Crit Care Med, 2013. 41(4): p. 999-1008.
  18. Empey, P.E., Genetic predisposition to adverse drug reactions in the intensive care unit. Crit Care Med, 2010. 38(6 Suppl): p. S106-16.
  19. Manolopoulos, V.G., Pharmacogenomics and adverse drug reactions in diagnostic and clinical practice. Clin Chem Lab Med, 2007. 45(7): p. 801-14.


Jacques Turgeon, Janusz Kaczorowski, R.O. Hopkins, Rick Hall, Ute Schwartz, Richard Kim