Article Identification

• Article Title: Midazolam versus propofol for long-term sedation in the ICU: a randomized prospective comparison
• Citation: Weinbroum AA, Halpern P, Rudick V, Sorkine P, Freedman M, Geller E. Midazolam versus propofol for long-term sedation in the ICU: a randomized prospective comparison. Intensive Care Med. 1997;23:1258-1263.
• DOI/PMID: PMID: Not provided

Quick Reference Summary

• The randomized study compared midazolam and propofol for prolonged ICU sedation in 67 mechanically ventilated patients, finding no significant difference in sedation duration (141 hours for midazolam vs. 99 hours for propofol, p=NS).
• Midazolam was associated with higher sedation quality (8.2 vs. 7.3 on a 10-cmVAS, p<0.001), fewer significant blood pressure drops (31% vs. 68%, p<0.001), and lower costs compared to propofol.

Core Clinical Question

Does midazolam provide more effective, safer, and more cost-efficient long-term sedation compared to propofol in mechanically ventilated ICU patients? (P: Critically ill, mechanically ventilated ICU patients; I: Midazolam; C: Propofol; O: Sedation efficacy, safety, and cost-effectiveness)

Background

• Disease/Condition Overview:
  • Critically ill patients often require prolonged mechanical ventilation and sedation to ensure comfort, tolerance of invasive devices, and synchronization with ventilatory support.
• Prior Data:
  • Midazolam is favored for its anxiolytic, hypnotic, anticonvulsant properties, short half-life, and lack of active metabolite accumulation.
  • Propofol is a rapidly acting anesthetic with quick recovery profiles but concerns regarding hemodynamic stability.
• Current Standard of Care:
  • Benzodiazepines like midazolam and non-benzodiazepines like propofol are commonly used for ICU sedation, with choice often based on patient-specific factors and institutional protocols.
• Knowledge Gaps Addressed by the Study:
  • Comparative efficacy and safety of midazolam versus propofol for prolonged sedation beyond 24 hours.
  • Cost-effectiveness of using midazolam over propofol in the ICU setting.
• Study Rationale:
  • To provide evidence on the optimal sedative agent balancing efficacy, safety, and cost for long-term ICU sedation.

Methods Summary

• Study Design: Randomized, prospective comparison.
• Setting and Time Period: 100-bed teaching hospital general ICU, conducted in 1997.
• Population Characteristics: 67 critically ill, mechanically ventilated patients.
• Inclusion/Exclusion Criteria: Included patients requiring prolonged sedation; exclusion criteria not specified.
• Intervention Details:
  • Midazolam: Loading dose of 0.11 mg/kg followed by continuous infusion titrated to sedation score.
  • Propofol: Loading dose of 1.3 mg/kg followed by continuous infusion titrated similarly.
• Control/Comparison Group Details: Patients randomized to receive either midazolam or propofol.
• Primary and Secondary Outcomes:
  • Primary: Duration of sedation, sedation quality, hemodynamic stability.
  • Secondary: Amnesia incidence, recovery time, agitation levels, cost.
• Basic Statistical Analysis Approach: Chi-square for nonparametric data, repeated measures ANOVA for parametric variables; p<0.05 significant.
• Sample Size Calculations: Not specified.
• Ethics and Funding Information: Approved by Institutional Human Studies Review Committee; partially supported by Hoffmann La Roche, Basel, Switzerland.

Detailed Results

• Participant Flow and Demographics:
  • Midazolam: 36 patients; Propofol: 31 patients.
  • No significant differences in age, weight, sex, APACHE II scores, or admission diagnoses.
• Primary Outcome Results:
  • Duration of sedation: Midazolam 141 ± 27 hours vs. Propofol 99 ± 15 hours (p=NS).
  • Sedation quality: Midazolam 8.2 ± 0.1 vs. Propofol 7.3 ± 0.1 (p<0.001).
  • Hemodynamic stability: >20% SBP decrease in 31% (midazolam) vs. 68% (propofol) (p<0.001).
• Secondary Outcome Results:
  • Amnesia: 100% midazolam vs. ~33% propofol patients (p<0.001).
  • Recovery time: Propofol faster (1.8 vs. 2.8 hours, p<0.02).
  • Agitation post-sedation: More in propofol group.
  • Cost: Midazolam $164 ± 37 vs. Propofol $662 ± 150 per patient (p<0.001).
• Subgroup Analyses:
  • Not extensively reported; general comparisons made between groups.
• Adverse Events/Safety Data:
  • Propofol associated with significant hypotension and required more volume loading.
  • Both drugs caused respiratory depression; midazolam had more prolonged effects beneficial for ventilated patients.

Authors' Conclusions

• Primary Conclusions:
  • Both midazolam and propofol provided reliable, safe, and controllable long-term sedation in ICU patients.
  • Midazolam offered better sedation quality, complete amnesia, and was more cost-effective.
  • Propofol was associated with more significant cardiovascular depression and higher agitation post-sedation.
• Clinical Implications Stated by Authors:
  • Midazolam may be preferred for long-term ICU sedation due to its advantages in sedation quality, safety, and cost.
• Future Research Recommendations:
  • Further studies to explore the long-term cognitive effects and optimal dosing strategies for both sedatives.

Critical Analysis

A. Strengths

• Methodological Strengths:
  • Randomized prospective design enhances internal validity.
  • Direct comparison of midazolam and propofol in a clinical setting.
• Internal Validity Considerations:
  • Randomization helped balance confounders between groups.
  • Use of standardized sedation scales and continuous monitoring.
• External Validity Considerations:
  • Conducted in a general 100-bed teaching hospital ICU, enhancing generalizability.
  • Inclusion of a diverse patient population (medical, posttrauma, surgical).

B. Limitations

• Study Design Limitations or Biases:
  • Lack of blinding could introduce observer bias, although multiple nurses were involved to mitigate this.
• Generalizability Issues:
  • Single-center study may limit applicability to other settings with different protocols or patient demographics.
• Statistical Limitations:
  • Small sample size (67 patients) may not detect all significant differences or rare adverse events.
• Missing Data Handling or Loss to Follow-Up:
  • No reported loss to follow-up; all enrolled patients completed the study.
• Additional Limitations:
  • Short follow-up period regarding long-term cognitive outcomes and delirium.
  • Did not assess patient-reported outcomes or quality of life post-ICU.

Literature Review

Introduction

The management of prolonged sedation in the intensive care unit (ICU) remains a critical aspect of care for mechanically ventilated patients. The 1997 randomized prospective study by Weinbroum et al. titled “Midazolam versus propofol for long-term sedation in the ICU” provides early comparative insights into the efficacy, safety, and cost-effectiveness of two commonly used sedatives: midazolam and propofol. This review contextualizes the study’s findings within the broader spectrum of evolving clinical evidence up to 2025, integrating recent trials, guidelines, and consensus statements to assess the current standing and applicability of these sedative agents.

A. Positioning the Current Study in Existing Evidence

• Earlier research, including Weinbroum et al. (1997), primarily focused on comparing midazolam and propofol regarding sedation quality, hemodynamic stability, and cost in ICU settings.
• Key Previous Studies:
  • Ronan KP et al. (1995) compared propofol and midazolam, finding similar sedation efficacy but greater hemodynamic instability with propofol.
  • Liou HL et al. (2008) conducted a randomized study showing comparable sedation quality and hemodynamic stability between protocol-directed propofol and midazolam by nurses.
  • Xu JY et al. (2008) explored the combination of midazolam and propofol, indicating enhanced amnesia and reduced adverse reactions.
• Guidelines and Consensus Statements:
  • The Society of Critical Care Medicine (SCCM) released guidelines in 2018 emphasizing evidence-based sedation practices aimed at minimizing delirium and optimizing sedation depth.
  • The European Society of Anaesthesiology (ESA) has similarly advocated for tailored sedation strategies, integrating newer agents like dexmedetomidine.

B. Comprehensive Synthesis of Findings

Alignment and Conflicts with Recent Data:

Weinbroum et al. (1997) found midazolam superior in sedation quality and cost, with fewer hemodynamic disturbances compared to propofol. These findings align with later studies:

• Liou HL et al. (2008) corroborated that midazolam and propofol provide similar sedation quality when protocols are followed but highlighted the importance of nurse-led sedation protocols in maintaining efficacy and stability.
• Xu JY et al. (2008) introduced a combination therapy approach, suggesting that combining midazolam with propofol could optimize sedation while mitigating adverse effects, presenting a nuanced perspective beyond the binary comparison.

However, more recent studies have introduced complexities:

• The Dexmedetomidine vs. Midazolam Trial demonstrated that dexmedetomidine may reduce delirium incidence and improve patient-ventilator synchrony, challenging the primacy of midazolam in sedation protocols.
• The Lorazepam and Delirium Study identified benzodiazepines, including midazolam, as independent risk factors for ICU delirium, prompting a reevaluation of their role in long-term sedation.

C. Gaps and Future Directions

• Delirium and Cognitive Outcomes: Long-term studies are needed to assess the cognitive sequelae of midazolam versus propofol sedation, particularly concerning delirium incidence and duration.
• Sedation Protocol Standardization: Uniform sedation protocols across studies would facilitate more direct comparisons and robust meta-analyses.
• Integration of New Sedatives: The role of newer agents like dexmedetomidine and volatile anesthetics in sedation protocols requires further exploration to establish optimal sedation strategies.
• Patient-Centered Outcomes: Future research should incorporate patient-reported outcomes and quality of life measures post-ICU to provide a holistic view of sedation impacts.

Conclusion

Weinbroum et al.’s (1997) study laid important groundwork in comparing midazolam and propofol for long-term ICU sedation, highlighting midazolam’s advantages in sedation quality and cost. However, evolving evidence introduces complexities regarding benzodiazepine use and cognitive outcomes, emphasizing the need for a multifaceted approach to sedation management.

Clinical Application

• Findings suggest prioritizing midazolam for cost-effective, high-quality sedation in selected ICU patients, while carefully monitoring for hemodynamic stability and potential delirium.
• Suitable for mechanically ventilated patients where cost constraints are significant and complete amnesia is desired.
• Establishing standardized sedation protocols incorporating midazolam, with guidelines for dose adjustments and monitoring to mitigate adverse effects.

How To Use This Info In Practice

Practitioners should consider midazolam as a viable option for long-term ICU sedation, particularly in settings where cost is a primary concern, while remaining vigilant about the latest guidelines and evidence regarding delirium and cognitive outcomes. Further evidence and patient-specific factors should guide the decision to optimize sedation strategies.