title: Propofol increases morbidity and mortality in a rat model of sepsis.
abstract: BACKGROUND
  Severe sepsis is associated with approximately 50% mortality and accounts for tremendous healthcare costs. Most patients require ventilatory support and propofol is commonly used to sedate mechanically ventilated patients. Volatile anesthetics have been shown to attenuate inflammation in a variety of different settings. We therefore hypothesized that volatile anesthetic agents may offer beneficial immunomodulatory effects during the course of long-term intra-abdominal sepsis in rats under continuous sedation and ventilation for up to 24 hours.
  
  
  METHODS
  Sham operation or cecal ligation and puncture (CLP) was performed in adult male Wistar rats followed by mechanical ventilation. Animals were sedated for 24 hours with propofol (7 to 20 mg/kg/h), sevoflurane, desflurane or isoflurane (0.7 minimal alveolar concentration each).
  
  
  RESULTS
  Septic animals sedated with propofol showed a mean survival time of 12 hours, whereas >56% of all animals in the volatile groups survived 24 hours (P <0.001). After 18 hours, base excess in propofol + CLP animals (-20.6 ± 2.0) was lower than in the volatile groups (isoflurane + CLP: -11.7 ± 4.2, sevoflurane + CLP: -11.8 ± 3.5, desflurane + CLP -14.2 ± 3.7; all P <0.03). Plasma endotoxin levels reached 2-fold higher levels in propofol + CLP compared to isoflurane + CLP animals at 12 hours (P <0.001). Also blood levels of inflammatory mediators (tumor necrosis factor-α, interleukin-1β, interleukin-10, CXCL-2, interferon-γ and high mobility group protein-1) were accentuated in propofol + CLP rats compared to the isoflurane + CLP group at the same time point (P <0.04).
  
  
  CONCLUSIONS
  This is the first study to assess prolonged effects of sepsis and long-term application of volatile sedatives compared to propofol on survival, cardiovascular, inflammatory and end organ parameters. Results indicate that volatile anesthetics dramatically improved survival and attenuate systemic inflammation as compared to propofol. The main mechanism responsible for adverse propofol effects could be an enhanced plasma endotoxin concentration, leading to profound hypotension, which was unresponsive to fluid resuscitation.
authors.affiliation: Department of Anesthesiology, University of Illinois at Chicago, 835 S Wolcott Ave (m/c 868), Chicago, IL, 60612, USA. martin.schlaepfer@uzh.ch.|Institute of Anesthesiology, University Hospital Zurich, Rämistrasse 100, CH-8091, Zurich, Switzerland. martin.schlaepfer@uzh.ch.|Institute of Physiology, Zurich Center for Integrative Human Physiology, University Zurich, Zurich, Switzerland. martin.schlaepfer@uzh.ch.
authors.forename: Martin
authors.initials: M
authors.lastname: Schläpfer
authors.affiliation: Department of Anesthesiology, University of Illinois at Chicago, 835 S Wolcott Ave (m/c 868), Chicago, IL, 60612, USA. tobias.piegeler@uzh.ch.|Institute of Anesthesiology, University Hospital Zurich, Rämistrasse 100, CH-8091, Zurich, Switzerland. tobias.piegeler@uzh.ch.
authors.forename: Tobias
authors.initials: T
authors.lastname: Piegeler
authors.affiliation: Department of Anesthesiology, University of Illinois at Chicago, 835 S Wolcott Ave (m/c 868), Chicago, IL, 60612, USA. rdull@uic.edu.|Department of Pharmacology, University of Illinois at Chicago, Chicago, IL, USA. rdull@uic.edu.|Department of Bioengineering, University of Illinois at Chicago, Chicago, IL, USA. rdull@uic.edu.
authors.forename: Randal O
authors.initials: RO
authors.lastname: Dull
authors.affiliation: Department of Anesthesiology, University of Illinois at Chicago, 835 S Wolcott Ave (m/c 868), Chicago, IL, 60612, USA. dschwarz@uic.edu.
authors.forename: David E
authors.initials: DE
authors.lastname: Schwartz
authors.affiliation: Department of Pharmacology, University of Illinois at Chicago, Chicago, IL, USA. zeuchmao@gmail.com.|Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA. zeuchmao@gmail.com.|Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA. zeuchmao@gmail.com.
authors.forename: Mao
authors.initials: M
authors.lastname: Mao
authors.affiliation: Department of Pharmacology, University of Illinois at Chicago, Chicago, IL, USA. mbonini@uic.edu.|Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA. mbonini@uic.edu.|Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA. mbonini@uic.edu.
authors.forename: Marcelo G
authors.initials: MG
authors.lastname: Bonini
authors.affiliation: Institute of Physiology, Zurich Center for Integrative Human Physiology, University Zurich, Zurich, Switzerland. birgit.roth@fgcz.uzh.ch.
authors.forename: Birgit Roth
authors.initials: BR
authors.lastname: Z'Graggen
authors.affiliation: Department of Anesthesiology, University of Illinois at Chicago, 835 S Wolcott Ave (m/c 868), Chicago, IL, 60612, USA. beatrice.beckschimmer@uzh.ch.|Institute of Anesthesiology, University Hospital Zurich, Rämistrasse 100, CH-8091, Zurich, Switzerland. beatrice.beckschimmer@uzh.ch.|Institute of Physiology, Zurich Center for Integrative Human Physiology, University Zurich, Zurich, Switzerland. beatrice.beckschimmer@uzh.ch.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Beck-Schimmer
authors.affiliation: Department of Anesthesiology, University of Illinois at Chicago, 835 S Wolcott Ave (m/c 868), Chicago, IL, 60612, USA. rminsh@uic.edu.|Department of Pharmacology, University of Illinois at Chicago, Chicago, IL, USA. rminsh@uic.edu.|Department of Bioengineering, University of Illinois at Chicago, Chicago, IL, USA. rminsh@uic.edu.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Minshall
mesh_terms: D018686:Anesthetics, Intravenous / Q000009:adverse effects*; D000818:Animals; D004195:Disease Models, Animal; D008297:Male; D015742:Propofol / Q000009:adverse effects*; D051381:Rats; D017208:Rats, Wistar; D012121:Respiration, Artificial; D018805:Sepsis / Q000150:complications / Q000401:mortality*
chemical_list: D018686:Anesthetics, Intravenous; D015742:Propofol