Critical Care Alert: Vasopressor Utilization in Septic Shock Patients Receiving Propofol Versus Midazolam

ARTICLE: Weger BR, Carabetta SM, Gignac L, Hayes S, Johnson JT. Vasopressor utilization in septic shock patients receiving propofol versus midazolam. J Crit Care. 2025;85:154935.

OBJECTIVE: To evaluate the effect of propofol vs. midazolam on vasopressor requirements in patients with septic shock to better guide sedative selection

BACKGROUND

Appropriate selection of sedative agents in critically ill and mechanically ventilated patients is crucial in reducing the length of ICU stay, duration of mechanical ventilation, and occurrence of delirium.¹ The 2018 Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Duration (PADIS) guidelines recommend non-benzodiazepine sedation over benzodiazepines.² One popular agent used for both induction and maintenance is propofol, which is thought to enhance the inhibitory effect of GABA on receptors.³ Its use is often thought to be limited by the development of hypotension, which may prompt physicians to turn to midazolam as an alternative. Midazolam is a short-acting benzodiazepine that works as a GABA-receptor agonist and has historically been a popular sedative choice in the ICU.⁴ Despite its advantage of causing less hemodynamic instability, it is associated with increased incidence of delirium and longer time spent in the ICU and on ventilation.² Thus, the choice between propofol and midazolam poses a great dilemma in patients who present with or are at risk for hemodynamic instability (eg, sepsis). 

Clear guideline choice of sedative agents in patients requiring vasopressors is limited. Previous studies have compared propofol to a placebo or were underpowered to detect a significant difference in the septic shock population.⁵ This study is a retrospective observational study investigating how propofol vs. midazolam affects the requirement of vasopressor agents in patients with septic shock. 

DESIGN 

This is a multicenter, retrospective, observational, IRB-approved, non-inferiority cohort study that evaluated the effect of propofol versus midazolam on vasopressor requirements in patients with septic shock. The study was conducted across medical intensive care units in 4 community hospitals in Florida. The study reviewed records of patients treated with norepinephrine and propofol or midazolam between Jan. 1, 2013, and Sept. 17, 2023. Demographic and clinical data were extracted from electronic medical records and reviewed by a single reviewer after patients were determined to meet the inclusion criteria. If a patient transitioned between sedative agents, information was collected only from the first sole administration if it was for at least 12 hours. After initial data collection, a second reviewer screened the information for consistency and replicability. 

The study's primary outcome was to compare maximum increases in vasopressor requirements, standardized to norepinephrine equivalents (NEE), within the first 12 hours after sedative initiation. Furthermore, a superiority analysis was conducted using the primary outcome results. To assess NEE the study used an equation derived from a scoping review in 2021 that standardized equipotent doses of common vasopressors: 

“Norepinephrine dose (μg/kg/min) + epinephrine dose (μg/kg/min) +1/10 * phenylephrine dose(μg/kg/min) + 1/100 * dopamine dose (μg/kg/min) + 1/8 * metaraminol (μg/kg/min) + 2.5 * vasopressin dose (U/min) + 10 * angiotensin II dose (μg/kg/min)”⁶

A sample size of 246 patients was calculated to provide sufficient power for a non-inferiority margin of 0.1 μg/kg/min in NEE changes. To obtain their primary and secondary outcomes the study developed multivariable linear regression models to adjust for potential confounding variables. All primary and secondary analyses were completed with R software. 

INCLUSION CRITERIA 

• Patients ≥18 years old
• Diagnosed with septic shock defined as having a lactic acid level >2 mmol/L, organ dysfunction, and hypotension requiring vasopressors within the first 12 hours of sedative initiation
• Exclusive use of continuous intravenous propofol or midazolam for sedation lasting at least 12 hours

EXCLUSION CRITERIA

• Sedation <12 hours
• Concomitant sedatives
• No vasopressors within 12 hours
• Shock due to other causes (eg, hypovolemic, cardiogenic, neurogenic)
• Use of midodrine, ketamine, or a propofol bolus
• Patients with COVID-19, pregnancy, incarceration, or transferred from another facility

PRIMARY OUTCOME

• The maximum increase in vasopressor requirements (measured as norepinephrine equivalents) within the first 12 hours after sedative initiation.

SECONDARY OUTCOME

• Maximum increases in vasopressor requirements at 3, 6, and 24 hours following sedative initiation
• Maximum number of vasopressors used during sedation
• Incidence of sustained bradycardia and delirium
• Duration of vasopressor use, sedation, and mechanical ventilation
• ICU and hospital length of stay, 28-day ventilator-free days, and in-hospital mortality

KEY RESULTS

A total of 3,640 patients were screened, with the final cohort consisting of 246 patients. They were categorized into propofol vs. midazolam groups at a 1:1 ratio. Those assigned to the midazolam group were older, had worse baseline hypertension, higher baseline temperature, and received more frequent doses of stress steroids, while the propofol group had a higher baseline MAP and lower baseline NEE. Other baseline characteristics were similar. 

Primary Outcome  

• The maximum increase in NEE within the first 12 hours of sedation was non-inferior between propofol vs. midazolam group (0.09 vs. 0.129 μg/kg/min, p =0.002), even after adjusting for possible confounding variables including BMI, baseline serum creatinine and baseline lactate level. 
• Propofol was not found to be superior to midazolam within the first 12 hours of the sedation window (p = 0.074).                                           

Secondary Outcome 

• The maximum increase in NEE was significantly lower in the propofol group compared to the midazolam group within the first 6 hours (0.06 vs. 0.086 μg/kg/min, p =0.043) and 24 hours (0.11 vs. 0.25 μg/kg/min, p =0.013) 
• There was no significant difference between the maximum NEE increase between the two groups within the first 3 hours of sedation (0.02 vs. 0.04 μg/kg/min, p =0.208) 
• Duration (1.49 vs. 2.25 days, p <0.001) and number of vasopressors needed (1 vs 2 vasopressors, p =0.001) were significantly lower in the propofol group
• More patients in the propofol group experienced delirium (26.83 vs. 11.38 %, p =0.002)
• No significant difference in the incidence of sustained bradycardia (7 vs. 5; p  = 0.605)
• No significant difference existed between the propofol and midazolam groups for sedation duration (1.59 vs. 1.9 days, p =0.122), mechanical ventilation duration (3.6 vs 4.8 days, p =0.094), and mortality (44.72 vs. 54.47 %, p =0.126). 

LIMITATIONS

• The study was a retrospective study, which can contribute to selection bias.
• Some patients were not receiving vasopressors prior to sedation, which limits the ability to assess the true change in NEE based on sedation agents alone. 
• Patients may have received benzodiazepine pushes prior to propofol initiation or may have switched from propofol to midazolam after the initial 12-hour study period. This could have affected the outcomes on delirium.
• The study was conducted in ICUs only. Results may not be generalizable in the ED environment with variable nursing-to-patient ratios and experience.   

EM TAKE-AWAYS 

In EM, we are often the first to diagnose and manage septic shock, making critical decisions that significantly impact a patient's hospital course. This large cohort study directly compares the effects of midazolam and propofol on vasopressor requirements in patients with septic shock. The study’s findings demonstrate that vasopressor requirement increases with propofol were non-inferior to those observed with midazolam within the first 12 hours of sedation initiation. This supports the use of propofol as a first-line sedative agent in septic shock.

REFERENCES

1. Grap MJ, Munro CL, Wetzel PA, et al. Sedation in adults receiving mechanical ventilation: physiological and comfort outcomes. Am J Crit Care. 2012;21(3):e53-e64. 
2. Devlin JW, Skrobik Y, G´elinas C, et al. Clinical practice guidelines for the prevention and Management of Pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU. Crit Care Med. 2018;46(9):e825–73.
3. Diprivan®. Propofol Injectable Emulsion [FDA Label]. Lake Zurich, IL: Fresenius Kabi; 2022.
4. Midazolam in Sodium Chloride Injection [FDA Label]. Paramus, NJ: WG Critical Care; 2021.
5. Shibahashi K, Hifumi T, Sugiyama K, Inoue A, Sakamoto T, Yasuhiro K, for the SAVE-J II study group. Comparison of sedation using propofol vs. midazolam in patients admitted to the intensive care unit after extracorporeal cardiopulmonary resuscitation for out-of-hospital cardiac arrest: a multicentre observational study. Eur Heart J Acute Cardiovasc Care. 2023;12(4):246-256.
6. Goradia S, Sardaneh AA, Narayan SW, Penm J, Patanwala AE. Vasopressor dose equivalence: a scoping review and suggested formula. J Crit Care. 2021;61:233-240.