Article Identification

• Article title: Midazolam and propofol used alone or sequentially for long-term sedation in critically ill, mechanically ventilated patients: a prospective, randomized study
• Citation: Zhou Y, Jin X, Kang Y, Liang G, Liu T, Deng N. Midazolam and propofol used alone or sequentially for long-term sedation in critically ill, mechanically ventilated patients: a prospective, randomized study. Critical Care. 2014;18:R122. doi:10.1186/cc13922
• DOI/PMID: DOI: 10.1186/cc13922

Quick Reference Summary

• The sequential use of midazolam and propofol (group M-P) significantly reduced the incidence of agitation after cessation of sedation compared to midazolam alone (19.4% vs. 48.7%, P=0.01).
• Additionally, group M-P demonstrated shorter recovery time (1.0 vs. 58.0 hours, P<0.01), extubation time (2.0 vs. 45.0 hours, P<0.01), and mechanical ventilation time (114.8 vs. 192.0 hours, P<0.01) compared to midazolam alone, while also incurring lower pharmaceutical and ICU costs.

Core Clinical Question

Does the sequential administration of midazolam and propofol for long-term sedation in critically ill mechanically ventilated patients reduce adverse effects, enhance recovery times, and lower associated ICU costs compared to using midazolam or propofol alone?

Background

• Disease/Condition Overview:
  • Critically ill patients often require mechanical ventilation and sedation to alleviate anxiety, facilitate procedures, and reduce complications.
• Prior Data:
  • Midazolam and propofol are the predominant sedatives used in ICUs, each effective for short-term sedation but associated with adverse effects during long-term use.
  • Previous studies indicated that midazolam may lead to withdrawal syndromes and prolonged recovery, whereas propofol is linked to hypertriglyceridemia and cardiovascular depression.
• Current Standard of Care:
  • Light to moderate sedation using benzodiazepines (e.g., midazolam) or propofol, with an emphasis on minimizing delirium and facilitating weaning from mechanical ventilation.
• Knowledge Gaps Addressed by the Study:
  • Limited evidence on the benefits of sequential sedation protocols using midazolam and propofol for long-term sedation.
  • Unclear impact of sequential sedation on adverse effects, recovery times, and ICU costs.
• Study Rationale:
  • Combining midazolam and propofol sequentially may mitigate individual drug adverse effects, enhance sedation quality, and improve clinical and economic outcomes.

Methods Summary (Concise)

• Study design: Prospective, randomized, open-label trial
• Setting and time period: West China Hospital of Sichuan University, Sichuan, China; March 2010 to September 2011
• Population characteristics: 135 critically ill, mechanically ventilated adults (>18 years) expected to require mechanical ventilation for ≥72 hours
• Inclusion criteria: Intubated patients admitted to ICU within 1 hour, requiring long-term mechanical ventilation
• Exclusion criteria: Allergy to sedatives, pregnancy, gross obesity, hyperlipemia, moribund state, history of alcoholism, chronic renal failure, coma due to trauma or neurosurgery, unwillingness to consent
• Intervention details:
  • Group M: Midazolam infusion adjusted to achieve desired sedation
  • Group P: Propofol infusion adjusted similarly
  • Group M-P: Start with midazolam, switch to propofol upon passing the spontaneous breathing trial (SBT) safety screen
• Control/comparison group details: Groups M and P serve as controls against the sequential Group M-P
• Primary and secondary outcomes:
  • Primary: Recovery time, extubation time, mechanical ventilation time
  • Secondary: Pharmaceutical cost, total ICU cost, recollection of mechanical ventilation-related events
• Basic statistical analysis approach: Intention-to-treat and treatment-received analyses; significance set at P<0.05
• Sample size calculations: Powered to detect a 15% relative reduction in recovery time with 90% power
• Ethics and funding information: Approved by ethics committee; no competing interests declared

Results

• Participant flow and demographics:
  • 135 enrolled; 11 excluded due to rapid deterioration
  • 124 included in intention-to-treat analysis: 43 (M), 42 (P), 39 (M-P)
  • No significant differences in demographics or baseline parameters among groups
• Primary outcome results:
  • Agitation incidence: Group M-P (19.4%) vs. Group M (48.7%), P=0.01
  • Recovery time: Group M-P (1.0 hours) vs. Group M (58.0 hours), P<0.01
  • Extubation time: Group M-P (2.0 hours) vs. Group M (45.0 hours), P<0.01
  • Mechanical ventilation time: Group M-P (114.8 hours) vs. Group M (192.0 hours), P<0.01
• Secondary outcome results:
  • Pharmaceutical cost: Group M-P significantly lower than Group P (P<0.01)
  • Total ICU cost: Group M-P significantly lower than Group M (P=0.016)
  • Recollection of uncomfortable events: Group M-P had fewer unbearable memories than Group M (11.7% vs. 25.0%, P<0.01)
• Subgroup analyses:
  • No significant differences between Group P and Group M-P in primary outcomes
• Adverse events/safety data:
  • Hypotension: Group M-P (20.5%) lower than Group P (52.4%), P=0.01
  • No significant differences in ICU or hospital mortality, acute kidney injury, or continuous renal replacement therapy among groups

Outcome	Intervention Group	Control Group	Difference (95% CI)	P-value
Primary Outcome: Recovery Time	1.0 hours	58.0 hours	-57.0 hours (P<0.01)	<0.01
Primary Outcome: Extubation Time	2.0 hours	45.0 hours	-43.0 hours (P<0.01)	<0.01
Primary Outcome: MV Time	114.8 hours	192.0 hours	-77.2 hours (P<0.01)	<0.01
Agitation Incidence	19.4%	48.7%	-29.3% (P=0.01)	0.01
Pharmaceutical Cost (yuan)	1,969	3,744	-1,775 yuan (P<0.01)	<0.01
Total ICU Cost (yuan)	57,634	81,123	-23,489 yuan (P=0.016)	0.016
Unbearable Memories	11.7%	25.0%	-13.3% (P=0.01)	<0.01
Hypotension Incidence	20.5%	52.4%	-31.9% (P=0.01)	0.01

Authors' Conclusions

• The sequential use of midazolam and propofol constitutes a safe and effective sedation protocol for long-term sedation in critically ill mechanically ventilated patients.
• This approach resulted in a lower incidence of agitation, faster recovery and extubation, shorter mechanical ventilation duration, and reduced ICU costs compared to using midazolam or propofol alone.
• The study advocates for the adoption of sequential sedation protocols to enhance clinical outcomes and cost-efficiency in ICU settings.
• Future research is recommended to further validate these findings and explore the broader clinical applications of sequential sedation.

Critical Analysis

A. Strengths

• Randomized Design: The prospective, randomized nature of the study enhances the internal validity by minimizing selection bias.
• Adequate Sample Size: The study was adequately powered to detect significant differences in recovery time, ensuring reliability of primary outcomes.
• Comprehensive Outcome Measures: Inclusion of both clinical outcomes (recovery time, extubation time) and economic measures (pharmaceutical and ICU costs) provides a holistic view of the intervention's impact.
• Cost Analysis: Detailed assessment of pharmaceutical and total ICU costs offers valuable insights into the economic benefits of sequential sedation.
• Use of Intention-to-Treat and Treatment-Received Analyses: These analyses bolster the study’s validity by accounting for all participants and treatment adherence respectively.

B. Limitations

• Open-Label Design: Lack of blinding may introduce performance and detection bias, as clinicians and patients were aware of the sedation protocol being administered.
• Single-Center Study: Conducted in a single hospital in China, which may limit the generalizability of the findings to other settings and populations.
• Potential Confounders: Although randomized, unmeasured confounders such as variations in ICU protocols or patient management could influence outcomes.
• Short-Term Follow-Up: The study primarily focused on immediate ICU outcomes without assessing long-term patient recovery or neurological outcomes post-ICU.
• Withdrawal and Missing Data: Exclusions and withdrawals (e.g., patients who died or were transferred) may affect the intention-to-treat analysis, potentially introducing attrition bias.

Literature Review

A. Positioning the Current Study in Existing Evidence

The use of sedatives in the ICU, particularly midazolam and propofol, has been extensively studied, yet optimal sedation strategies remain debated. Zhou et al. (2014) contribute to this discourse by investigating the sequential use of midazolam and propofol for long-term sedation, aiming to mitigate the adverse effects associated with prolonged use of each agent alone.

Previous Studies and Meta-Analyses:

• Smuszkiewicz et al. (2016) characterized the pharmacokinetics of propofol in ICU patients, establishing a robust PK model that underscores consistent propofol clearance despite patient heterogeneity. This foundational understanding supports the feasibility of propofol-based sedation protocols.
• Tang et al. (2022) conducted a pilot study comparing remimazolam and propofol, indicating that remimazolam is effective and safe for long-term sedation, offering an alternative to traditional agents like midazolam and propofol.
• Riker et al. (2009) demonstrated that dexmedetomidine reduces the duration of mechanical ventilation and the incidence of delirium compared to midazolam and propofol, aligning with Zhou et al.’s findings on improved clinical outcomes with alternative sedation strategies.
• Zhou et al. (2022) explored the sequential use of midazolam and dexmedetomidine, finding it effective and safe, which parallels the current study's focus on sequential sedation protocols to enhance patient outcomes.

Contrasting Methodological Quality:

Earlier sedation studies often exhibited variability in design, sample sizes, and outcome measures, leading to inconsistent conclusions. In contrast, Zhou et al. (2014) employed a robust randomized controlled design with adequate power to detect meaningful clinical differences, enhancing the reliability and applicability of their findings.

Comparisons with Guidelines:

Current ICU sedation guidelines, such as those from the American College of Critical Care Medicine (ACCM), advocate for light sedation levels to minimize ICU delirium and facilitate weaning from mechanical ventilation. The Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium in Adult Patients in the ICU (Barr et al., 2013) emphasize the importance of sedation protocols that balance patient comfort with the minimization of adverse effects.

This Trial’s Contribution:

Zhou et al. (2014) offer evidence that sequential sedation using midazolam and propofol can achieve clinical benefits—such as reduced agitation and faster extubation—while also lowering ICU costs. This aligns with guideline recommendations for sedation practices that prioritize patient outcomes and resource efficiency. By demonstrating both clinical and economic advantages, the study reinforces the potential of sequential sedation protocols as a viable strategy in intensive care.

B. Comprehensive Synthesis of Findings

Alignment with Other Studies:

The findings of Zhou et al. (2014) are consistent with Riker et al. (2009) and Tang et al. (2022), who also reported that alternative or sequential sedation strategies can lead to improved clinical outcomes, including shorter mechanical ventilation durations and reduced delirium incidence. The sequential use of midazolam and propofol in Zhou’s study mirrors the benefits observed with dexmedetomidine in other research, suggesting that tapering or switching sedatives can mitigate adverse effects and enhance patient recovery.

Contradictions and Conflicts:

While most studies support the benefits of alternative sedation strategies, some, like Smuszkiewicz et al. (2016), focus primarily on pharmacokinetics without directly addressing clinical outcomes. Additionally, Ruokonen et al. (2012) found no significant difference in ICU length of stay when comparing dexmedetomidine to midazolam or propofol, which slightly contradicts Zhou et al.’s findings of reduced ICU costs with sequential sedation.

Methodological Strengths and Weaknesses:

Zhou et al. (2014) utilized a randomized controlled design with clearly defined primary and secondary outcomes, enhancing the study’s credibility. However, the lack of blinding and single-center nature may limit the generalizability of the results. In contrast, larger multicenter trials like Riker et al. (2009) offer broader applicability but may sacrifice depth in specific protocol evaluations.

Clinical Applicability in Light of Guidelines:

Zhou et al.’s findings support guideline recommendations for minimizing deep sedation and reducing delirium by offering a practical sedation protocol that balances efficacy and safety. The reduction in agitation and faster extubation times align with goals to enhance patient comfort and expedite recovery, integral aspects of current ICU sedation guidelines.

Integration of Systematic Reviews and Meta-Analyses:

Systematic reviews, such as Walder et al. (2001), highlight the lack of clear superiority between propofol and midazolam, but Zhou et al.’s study introduces the concept of sequential use, which may bridge gaps identified in meta-analyses by leveraging the strengths of both agents while mitigating their weaknesses. This innovative approach warrants further investigation in larger, diverse populations to validate its effectiveness and cost benefits.

Cost-Effectiveness Considerations:

The economic analysis presented by Zhou et al. (2014) underscores the potential for cost savings with sequential sedation protocols. This is particularly relevant in resource-constrained settings where ICU costs are a significant concern. Comparing these findings with Manley et al. (1997), which also demonstrated cost benefits with alternative sedation strategies, reinforces the economic viability of optimizing sedation protocols.

Ongoing Trials:

Emerging studies, such as pilot trials comparing remimazolam and propofol (Tang et al., 2022) and sequential use of midazolam and dexmedetomidine (Zhou et al., 2022), continue to expand the evidence base for alternative sedation strategies. These studies build upon Zhou et al.’s (2014) findings, exploring additional sedative combinations and their impact on patient outcomes and ICU resource utilization.

C. Gaps and Future Directions

Despite the promising results, several gaps remain:

• Long-Term Outcomes: There is a need to assess the long-term neurological and cognitive outcomes of patients subjected to sequential sedation protocols.
• Diverse Populations: Future studies should include multicenter trials across different geographic regions and healthcare settings to enhance generalizability.
• Blinded Studies: Implementing blinded study designs could reduce potential biases and strengthen evidence.
• Comparison with Emerging Sedatives: With the introduction of newer agents like remimazolam, comparative studies are necessary to position sequential protocols relative to these alternatives.
• Mechanistic Insights: Understanding the pharmacodynamic interactions between midazolam and propofol in sequential use could optimize dosing strategies and further reduce adverse effects.
• Cost-Benefit Analyses in Different Healthcare Systems: Evaluating the economic impact of sequential sedation in various healthcare infrastructures can inform global best practices.

Clinical Application

• The findings from Zhou et al. (2014) suggest that implementing a sequential sedation protocol using midazolam followed by propofol can enhance patient outcomes by reducing agitation and accelerating recovery and extubation times.
• This approach is particularly beneficial for critically ill, mechanically ventilated patients who require long-term sedation, as it also offers cost savings for ICU resources.

Implementation Considerations:

• Feasibility: Sequential sedation protocols can be integrated into existing ICU sedation practices with appropriate training and protocol adjustments.
• Cost-Effectiveness: By lowering pharmaceutical and total ICU costs, sequential sedation supports sustainable healthcare practices, especially in resource-limited settings.
• Patient Selection: This protocol is most applicable to patients who are stable enough to transition from midazolam to propofol and can safely undergo spontaneous breathing trials.

Integration with Existing Guidelines:

Sequential sedation aligns with current guidelines advocating for light sedation and minimizing delirium. It reinforces the importance of individualized sedation strategies that consider both clinical effectiveness and economic factors, thereby adhering to evidence-based practices recommended by bodies such as the ACCM.

How To Use This Info In Practice

Clinicians should consider adopting sequential sedation protocols involving midazolam and propofol for long-term sedation in mechanically ventilated ICU patients, integrating these findings with current guidelines to optimize sedation management and enhance patient outcomes. This approach is supported by recent evidence and can be tailored to align with institutional protocols and patient-specific factors.