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Table 1 Intervention stopping rules and protocol deviation

From: Adjunct low-dose ketamine infusion vs standard of care in mechanically ventilated critically ill patients at a Tertiary Saudi Hospital (ATTAINMENT Trial): study protocol for a randomized, prospective, pilot, feasibility trial

EventsAction regarding the intervention (ketamine)Action regarding the study procedure (data collection and data analysis)
Completed 48 hKetamine will be discontinued (intended duration for this trial is 48 h). Continuation of ketamine or other analgesics and sedatives for more than 48 h will be left to the treating physicians, but will not be related to the research purposeSubject will be included in the data analysis
Positive CAM-ICU score for delirium and hallucination within the first 48 hKetamine will be continued, and delirium treatment (non-pharmacological and antipsychotic use) will be left to the treating physicians.
In cases of uncontrolled agitation (removal of tubes and lines and combative behavior) within the first 48 h, ketamine will be discontinued (refer to protocol deviation below)
Subject will be included in the data analysis (safety outcome data)
Use of physical restraint within the first 48 hKetamine will be continued unless uncontrolled agitation (removal of tubes and lines and combative behavior) within the first 48 h, in which case ketamine will be discontinued (refer to protocol deviation below)Subject will be included in the data analysis (safety outcome data)
Hypersalivation and frequent suctioning within the first 48 hKetamine will be continued and management of hypersalivation will be left to the treating physiciansSubject will be included in the data analysis
Protocol deviation (patient did not complete the intended duration of the trial (i.e., 48 h)
 Patient or proxies withdraw consentKetamine will be discontinuedAll information will be removed and not included in the analysis (modified intention-to-treat principle)
 Patient extubated and sedation weaned off within the first 48 hKetamine will be discontinuedSubject will be included in the data analysis
 If the ICU team believed the patient is not in target for RASS within the first 48 hWhen the patient is deemed to be excessively sedated after receiving ketamine and other sedatives (propofol and/or fentanyl and/or midazolam), the other sedatives will be held first (or decreased) and ketamine will be continued until the subject reaches the team’s desired RASS goal. In situations where excessive sedation persisted and the patient is not yet in target RASS, then ketamine will be discontinued
When the patient is deemed to be agitated after receiving ketamine and other sedatives (propofol and/or fentanyl and/or midazolam), the other sedatives will be increased, use as needed boluses, or add dexmedetomidine. The decision to continue or discontinue ketamine infusion will be left to the discretion of the treating physicians
Subject will be included in the data analysis
 Persistent tachycardia with HR > 150 for > 3 h within the first 48 hIf the ICU treating physicians believes that ketamine is the primary causative factor, ketamine will be discontinued and patient will be followed up for 24 h. Detailed documentation will be carried out in the medical record for adverse event, severity of event, recovery from event, group allocation, and relation to study protocolSubject will be included in the data analysis
 Hypertension with SBP > 180 for > 3 h within the first 48 hSubject will be included in the data analysis
 Uncontrolled agitation (pulling off tubes and lines) within the first 48 hSubject will be included in the data analysis
 Combative behavior within the first 48 hSubject will be included in the data analysis
 Patient dieda or goal of care changed to comfort care within the first 48 hKetamine will be discontinuedSubject will be included in the data analysis (safety outcome data)
 Physician decline after randomizationKetamine will be discontinuedSubject will be included in the data analysis
  1. aIn cases of death (either within the first 48 h, until ICU or hospital discharge, or 28 days after randomization, whichever comes first), detailed documentation will be carried out in the medical record for the cause of death, group allocation, and relation to study protocol