The effect of sedatives on innate immunity in the lung and the development of viral or bacterial pneumonia and sepsis
Lead Research Organisation:
Imperial College London
Department Name: Surgery and Cancer
Abstract
Following development of a new sedative drug, dexmedetomidine, by Prof Maze we conducted a randomised controlled trial of its use in patients in the intensive care unit. The results of this trial showed increased survival in patients with severe infections. Another trial of critically ill patients has shown reduced infectious complications in patients sedated with dexmedetomidine. In a series of experiments we will evaluate the ability of dexmedetomidine or the standard intensive care sedative, midazolam, on both viral and bacterial infectious disease. In these experiments we will build the scientific foundations for future clinical trials to extend the use of dexmedetomidine so more patients may benefit. Finally with the potential for a viral pandemic such as ‘Bird Flu‘ ahead we will analyse the ability of these sedative agents to change outcome from infection with viruses or with a viral followed by bacterial superinfection as frequently occurs in the community or in hospital. These developments will allow better preparation for any future viral pandemic.
Technical Summary
Following the discovery of the anaesthetic properties of dexmedetomidine (a highly-selective alpha-2 adrenoceptor agonist [a2 agonist]) by my supervisor, this compound underwent clinical development and received FDA approval for use as a sedative in mechanically ventilated patients in the intensive care unit. Our randomised clinical trial (RCT) showed reduced brain dysfunction (delirium/coma) in critically ill patients who received an a2 agonist compared to those that received sedation with a benzodiazepine (BDZ). In further analysis of these clinical trial data we uncovered a life-sparing effect of dexmedetomidine in septic patients in whom 28-day mortality was reduced from 50% (BDZ cohort) to 21% (hazard ratio of 0.3 [0.1-0.9]); p=0.036). Our finding regarding brain dysfunction was corroborated in a recently-reported RCT which also established that the rate of infection (mostly lung) in BDZ-sedated patients (20%) was double that seen in patients sedated with dexmedetomidine (10%; p=0.015).
As dexmedetomidine sedation appears more analogous to endogenous slow-wave sleep than benzodiazepine sedation a reduction in sleep deprivation could account for the reduction in immune dysfunction observed in the dexmedetomidine group. Furthermore a2 agonists are cytoprotective (including anti-apoptotic action), anti-inflammatory and improve macrophage function and therefore the anti-infective properties that we have discovered appear plausible. In this proposal, I plan to study the putative mechanisms for the infection-reducing and sepsis life-sparing properties of a2 agonists in animal models developed by my supervisors. The lung microenvironment in separate cohorts of mice will be examined after periods of sedation with dexmedetomidine or midazolam for macrophage and T cell number and function. In a subsequent experiment we will test the ability of the lungs of sedated mice to contain an infection induced by nasal inoculation with either influenza virus or Streptococcus pneumoniae. The end-points will be viral and bacterial load, immune function, and number of mice achieving 30% weight loss. In the last series of experiments, I will simulate the clinical scenario of community acquired viral pneumonia complicated by bacterial superinfection; mice will be inoculated with both influenza virus and Streptococcus pneumoniae, with a period of sedation either between the two inoculations or after both inoculations after which I will assess the above-mentioned endpoints. Data from these experiments will provide mechanistic insights into the putative protective properties of dexmedetomidine and lay the foundations for further clinical trials. Ultimately, we expect that patients who require mechanical ventilation will receive more appropriate sedation to withstand their critical illness.
As dexmedetomidine sedation appears more analogous to endogenous slow-wave sleep than benzodiazepine sedation a reduction in sleep deprivation could account for the reduction in immune dysfunction observed in the dexmedetomidine group. Furthermore a2 agonists are cytoprotective (including anti-apoptotic action), anti-inflammatory and improve macrophage function and therefore the anti-infective properties that we have discovered appear plausible. In this proposal, I plan to study the putative mechanisms for the infection-reducing and sepsis life-sparing properties of a2 agonists in animal models developed by my supervisors. The lung microenvironment in separate cohorts of mice will be examined after periods of sedation with dexmedetomidine or midazolam for macrophage and T cell number and function. In a subsequent experiment we will test the ability of the lungs of sedated mice to contain an infection induced by nasal inoculation with either influenza virus or Streptococcus pneumoniae. The end-points will be viral and bacterial load, immune function, and number of mice achieving 30% weight loss. In the last series of experiments, I will simulate the clinical scenario of community acquired viral pneumonia complicated by bacterial superinfection; mice will be inoculated with both influenza virus and Streptococcus pneumoniae, with a period of sedation either between the two inoculations or after both inoculations after which I will assess the above-mentioned endpoints. Data from these experiments will provide mechanistic insights into the putative protective properties of dexmedetomidine and lay the foundations for further clinical trials. Ultimately, we expect that patients who require mechanical ventilation will receive more appropriate sedation to withstand their critical illness.
