Criteria abstracted from The Users' Guide to Medical Literature, from the Health Information Research Unit and Clinical Epidemiology and Biostatistics, McMaster University

Highlighted lines and questions below provide links to the pertinent description of criteria in The EBM User's Guide, now available at the Canadian Centres for Health Evidence

Article Reviewed:

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Daily Interruption of Sedative Infusions in Critically Ill Patients Undergoing Mechanical Ventilation.

Kress JP, Pohlman AS, O'Connor MF, Hall JB.

N Engl J Med 2000;342:1471-1477. [abstract]

Reviewed by Al Torres, MD, MS, University of Illinois College of Medicine at Peoria

Review posted September 1, 2000

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I. What is being studied?:

The study objective:

To determine whether daily interruption of sedative infusions to critically ill adult patients receiving mechanical ventilation would decrease the duration of mechanical ventilation and the length of stay in the ICU and hospital.

The study design:

A randomized, controlled unblinded trial.

The patients included:

128 adult patients admitted in the medical ICU who were intubated and receiving mechanical ventilation and who were deemed to require sedation by continuous intravenous infusion.

The patients excluded:

Exclusion criteria included pregnancy, transfer from an outside institution with sedative already being administered, and admission after resuscitation from a cardiac arrest.

The interventions compared:

Daily interruption of the infusion of sedatives (midazolam or propofol and morphine) beginning 48 hours of enrollment (the intervention group) or continuous infusion of sedatives with interruption only at the discretion of the ICU team (the control group).

The outcomes evaluated:

The primary outcomes were the duration of mechanical ventilation, the length of stay in the ICU, and the length of stay in the hospital. The total dose of sedatives administered, use of neurologic tests, number of patients requiring paralytic drugs, reintubation, noninvasive ventilation, or tracheostomy were also recorded and evaluated. Adverse events (removal of endotracheal tube by the patient), transfer to a facility equipped to provide long-term ventilation, withdrawal of care, and death in the hospital were also recorded.

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes. Besides being randomly assigned to the intervention or the control group, the subjects were randomly assigned to receive either midazolam or propofol. Randomization was generated using a computer and concealed in sealed envelopes. Characteristics of the subjects including severity of illness were not significantly different between the two groups which confirms adequate randomization.

2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?

Was followup complete?

Yes. All of the 128 patients that did not die or were not extubated prior to the institution of the study protocol were included in the analysis. Seven patients in the intervention group and 15 in the control group were excluded because either the endotracheal tube was removed or they died on the first or second day in the ICU.

Were patients analyzed in the groups to which they were randomized?

Yes. The 68 subjects remaining in the intervention group (75 enrolled in each group) and the 60 subjects in the control group underwent an intention-to-treat analysis despite 30% of the control group having their sedative infusions interrupted temporarily during the study. The investigators would have provided further evidence supporting the intervention if they had included the 22 subjects dropped from the analyses in the comparison of group characteristics and still demonstrated no difference between the groups.

Secondary questions:

3. Were patients, health workers, and study personnel "blind" to treatment?

No. Although an investigator not directly involved with patient care interrupted the sedative infusions in the intervention group, the clinicians caring for the patients were not blinded to study group assignment.

4. Were the groups similar at the start of the trial?

Maybe. Since the investigators do not specify whether the subjects dropped died, i.e., were sicker, or were extubated on the first or second day, i.e, were less sick, it is impossible to know whether the groups were truly similar at the start. The characteristics of the study patients the investigators provide showed that there was no difference between the groups in terms of age, APACHE score, diagnosis, etc.

5. Aside from the experimental intervention, were the groups treated equally?

Unknown. The investigators do not state the method(s) used to assess for readiness to extubate. Tolerance of weaning modes, e.g., CPAP, T-piece, etc., may have been better appreciated in the intervention group since they were awakened daily. The investigators could have strengthened their support for the intervention if the subjects in both groups were assessed daily for readiness to extubate.

III. What were the results?

1. How large was the treatment effect?

The median duration of ventilation and ICU length of stay in the intervention group was shortened by 2.4 days and 3.5 days, respectively. The length of stay in the hospital did not differ between the two groups.

The total dose of morphine and midazolam was lower in the intervention group compared to controls (p < 0.01 and p = 0.05, respectively) but in those that received propofol, there was no difference in total propofol or morphine dose.

Significantly fewer diagnostic tests to assess changes in mental status were ordered in the intervention group than in the control group. This finding suggests the control patients didn't wake up as well and therefore were evaluated more often than the intervention group.

There were no significant differences in adverse events, paralytic agents, rate of reintubation, transfer to long-term ventilation facility, withdrawal of care, in-hospital mortality, or rate of discharge to home between groups. In the intervention group, the average number of hours per day that patients received the sedative infusion was 22.8 among those given propofol, as compared with 18.7 among those given midazolam (p = 0.05).

2. How precise was the estimate of the treatment effect?

The investigators provided a relative risk of extubation of 1.9 for the intervention group with 95% confidence intervals of 1.3 to 2.7, p < 0.001. The investigators also provided relative risk of discharge of 1.6 for the intervention group with 95% confidence intervals of 1.1 to 2.3, p = 0.02. These results suggest the intervention group were more likely to be discharged or extubated early compared to the control group (after controlling for demographic, severity, and disease type differences). The investigators reported interquarter ranges with the median values for the duration of extubation or length of ICU stay rather than 95% confidence intervals making these results less interpretable.

IV. Will the results help me in caring for my patients?

1. Can the results be applied to my patient care?

Maybe. Although the intervention group was ventilated less time and spent less time in the ICU, the investigators conclude that this was due to a reduction in accumulation of drug and reduction in the accompanying delay in improvement in mental status. It is possible that clinicians were more apt to assess or could more easily assess tolerance to weaning ventilation during their wakeful state during sedative interruption. The rate of adverse events, e.g., inadvertant extubation, are more likely to occur in the uncooperative preschool-aged child than the adult. Tolerance to infusions of sedatives and analgesics occurs frequently in children resulting in greater dosages to obtain the same level of sedation. Interruption of infusions in these children may result in the abrupt onset of consciousness, undesirable motor activity, or seizures.

2. Were all clinically important outcomes considered?

No. The emotional and physical stress associated with daily interruption of sedatives were not evaluated.

3. Are the likely treatment benefits worth the potential harms and costs?

Maybe. If a randomized controlled trial of daily interruption of sedatives in mechanically ventilated children that also assessed all children daily for readiness to extubate demonstrated a reduction in duration of ventilation and length of ICU stay without an increase in adverse events, the benefits would obviously exceed the risks.

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