Randomization in clinical trials of titrated therapies: Unintended consequences of using fixed treatment protocols

Katherine J. Deans, Peter C. Minneci, Anthony F. Suffredini, Robert L. Danner, William D. Hoffman, Xizhong Ciu, Harvey G. Klein, Alan N. Schechter, Steven M. Banks, Peter Q. Eichacker, Charles Natanson

Research output: Contribution to journalArticlepeer-review

118 Scopus citations


OBJECTIVE: Clinical trial designs that randomize patients to fixed treatment regimens may disrupt preexisting relationships between illness severity and level of therapy. The practice misalignments created by such designs may have unintended effects on trial results and safety. METHODS: To illustrate this problem, the Transfusion Requirements in Critical Care (TRICC) trial and the Acute Respiratory Distress Syndrome Network low tidal volume (ARMA) trial were analyzed. RESULTS: Publications before TRICC indicated that clinicians used higher transfusion thresholds in patients with ischemic heart disease compared with younger, healthier patients (p = .001). The trial, however, randomized patients (n = 838) to liberal (10 g/dL hemoglobin) or restrictive (7 g/dL) transfusion thresholds. Thirty-day mortality was different and opposite in the liberal compared with the restrictive arm depending on presence (21 vs. 26%) or absence (25 vs. 16%) of ischemic heart disease (p = .03). At baseline in ARMA, consistent with prior publications, physicians set ventilator volumes lower in patients with high airway pressures and poor compliance (8.4-10.6 mL/kg interquartile range) than patients with less severe abnormalities (9.6-12 mL/kg) (p = .0001). In the trial, however, patients (n = 861) were randomized to low (6 mL/kg) or high (12 mL/kg) tidal volumes. In patients with low compliance (

Original languageEnglish (US)
Pages (from-to)1509-1516
Number of pages8
JournalCritical Care Medicine
Issue number6
StatePublished - Jun 2007
Externally publishedYes


  • Practice misalignment
  • Randomization
  • Treatment dose

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine


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