The MENDSII Study, Maximizing the Efficacy of Sedation and Reducing Neurological Dysfunction and Mortality in Septic Patients With Acute Respiratory Failure

• Delirium/Coma Free Days (DCFDs) [ Time Frame: 14 days ] [ Designated as safety issue: No ]
  The analysis of DCFDs will be conducted using Intention-to-Treat (ITT) population, defined as all patients who were randomized to study drug. We chose a 14 day evaluation period for delirium, because it represents the best balance of gaining valuable clinical information, while maximizing resource utilization, given the average study drug infusion to be 7 days and maximum duration to be 14 days. Thus our follow-up period will cover 7 additional days of delirium monitoring after the study drug is stopped in the majority of our patients.
  
  

• Ventilator-free days (VFDs) [ Time Frame: 28 Days ] [ Designated as safety issue: No ]
  Ventilator-free days (VFDs), i.e., days alive and free of MV at 28 days. This endpoint has been used by the NHLBI's ARDSNet in numerous critical care trials examining ICU populations.
  
  
• 90-day Survival [ Time Frame: 1 through 90 days ] [ Designated as safety issue: No ]
  That sedation of mechanically ventilated severely septic patients with an alpha2 agonist (dexmedetomidine) rather than a GABAergic agent (propofol) will improve 90-day survival of ICU patients.
  
  
• Decrease incidence and severity of long-term cognitive impairment [ Time Frame: 6 months after randomization ] [ Designated as safety issue: No ]
  Neuropsychological function, Activities of Daily Living (ADL) and Instrumental ADLs will be assessed 6 months after randomization using a validated and reliable telephone battery for post-ICU patients, to measure incidence, duration, and severity of dysfunction in memory, attention, reasoning, and executive function domains as well as assess independence and quality of life.
  
  
• Markers of Inflammation [ Time Frame: Days, 1, 3, 5, 7, and 14 ] [ Designated as safety issue: No ]

  Plasma will be obtained on days 1, 3, 5, 7 and 14. About 30 mL of blood will be collected at each time point (150 mL max during the study). These samples will be batched analysed for the following:

  1. Genetic predictors of delirium duration, including, but not limited to, the apolipoprotein E4 polymorphism
  2. Inflammatory/coagulopathic biomarkers, (e.g., IL-1, IL-6, IL-10, CRP, sTNFR1, and HMGB1) based on their importance in sepsis and kinetic responses. Furthermore, combination of pro- and anti-inflammatory cytokine markers improves the predictive quality of these biomarkers for mortality.
  3. Other biomarkers to be determined by ongoing and future studies.
  
  
• Secondary Infections [ Time Frame: 48 Hours ] [ Designated as safety issue: No ]
  Secondary infections will be considered as any new sites of infection detected 48 hours after the original source of infection noted at enrollment. The site of infection and organism will be tracked until conclusion of the interventional trial phase.
  
  
• Organ Dysfunction [ Time Frame: 14 Days ] [ Designated as safety issue: No ]
  Organ dysfunctions will be tracked until conclusion of the interventional trial phase using daily SOFA scores and continuous as well as established predefined cut offs for each organ failure: Kidney, Cr > 2 mg/dL or urine < 400 cc/day; Lung, PaO2/FiO2 <300 or SaO2/FiO2 <315; Liver, total bilirubin > 2 mg/dL; Coagulation, Platelet count < 100,000/mm3; and Hemodynamic, need for vasopressor, consistent with definitions utilized in published studies of organ dysfunction in critically ill patients.
  
  
• Acute Respiratory Distress Syndrome [ Time Frame: 14 Days ] [ Designated as safety issue: No ]
  Acute Respiratory Distress Syndrome - we will monitor a patient's oxygenation status by tracking daily SaO2/FiO2 ratios or PaO2/FiO2 ratios. Chest X-rays that are ordered as part of routine clinical care will be followed daily in patients who meet ARDS oxygenation threshold and patients with bilateral infiltrates confirmed by the medical team, will be considered to have ARDS. Time to onset of ARDS and duration of ARDS will be tracked until conclusion of the interventional trial phase.
  
  

The need for mechanical ventilation (MV) secondary to sepsis is the leading cause of admission to the intensive care unit, often necessitating sedation for patient safety and comfort. Recently, we have learned that these sedative medications contribute to iatrogenic injury, such as prolonging ventilator time and ICU length of stay and exacerbating acute brain dysfunction. This acute brain dysfunction, manifested as delirium and coma, occurs in 50%-70% of MV septic patients and is a significant contributor not only to death but also to functional and cognitive decline, which can persist for years after recovery of lung and other organ function, levying significant costs to patients and society. Despite advances in the management of acute respiratory failure and sepsis, few clinical trials have examined the effects that supportive therapies, like sedation, may have on both short- and long-term outcomes in this vulnerable population. The gamma-aminobutyric acid (GABA)-ergic benzodiazepines, in particular, have been shown to increase brain dysfunction, promote infection, and prolong MV. Therefore, the short-acting GABA-ergic sedative propofol and the alpha2 agonist dexmedetomidine are becoming widely used to sedate septic MV patients. There are only a few randomized trials, however, to guide clinicians when selecting between these and other sedatives, and none have explored the mechanisms underlying the differences in outcomes, though some data indicate that GABA-ergic and alpha2 agonist agents have very different effects on innate immunity, apoptosis, arousability, and respiratory drive. In early animal and human studies, dexmedetomidine had more anti-inflammatory effects than the GABA-ergic agents; dexmedetomidine improved bacterial clearance, whereas propofol impaired it. In addition, sedation with dexmedetomidine instead of benzodiazepines reduces delirium by 20%-30% and improves arousability, cognition, and attentiveness in ventilated patients. Alpha2 agonists induce unconsciousness at the brainstem—more akin to natural sleep—which may improve autonomic function and immunity. All these factors converge to suggest that sedation with an alpha2 agonist rather than a GABAergic agent may improve outcomes, including brain function, MV, and survival, for septic MV patients. We therefore propose the MENDS II (Maximizing the Efficacy of Sedation and Reducing Neurological Dysfunction and Mortality in Septic Patients with Acute Respiratory Failure) study, in which we will test the hypotheses that sedation of MV severely septic patients with an alpha2 agonist (dexmedetomidine) rather than a GABAergic agent (propofol) will (Aim 1A) increase days alive without delirium or coma, (Aim 1B) increase ventilator-free days, (Aim 2A) improve 90-day survival, (Aim 2B) decrease long-term cognitive impairment, and (Aim 3) reduce the pro-inflammatory cytokine cascade following sepsis. We will randomize 530 ventilated, severely septic patients requiring goal-directed sedation with dexmedetomidine or propofol, giving the study 90% power to detect a difference of 1.5 delirium/coma-free days and an absolute difference in mortality of 10% between the two groups.