title: Calcium supplementation during sepsis exacerbates organ failure and mortality via calcium/calmodulin-dependent protein kinase kinase signaling.
abstract: BACKGROUND
  Calcium plays an essential role in nearly all cellular processes. As such, cellular and systemic calcium concentrations are tightly regulated. During sepsis, derangements in such tight regulation frequently occur, and treating hypocalcemia with parenteral calcium administration remains the current practice guideline.
  
  
  OBJECTIVE
  We investigated whether calcium administration worsens mortality and organ dysfunction using an experimental murine model of sepsis and explored the mechanistic role of the family of calcium/calmodulin-dependent protein kinases in mediating these physiological effects. To highlight the biological relevance of these observations, we conducted a translational study of the association between calcium administration, organ dysfunction, and mortality among a cohort of critically ill septic ICU patients.
  
  
  METHODS
  Prospective, randomized controlled experimental murine study and observational clinical cohort analysis.
  
  
  METHODS
  University research laboratory and eight ICUs at a tertiary care center.
  
  
  METHODS
  A cohort of 870 septic ICU patients.
  
  
  METHODS
  C57Bl/6 and CaMKK mice.
  
  
  METHODS
  Mice underwent cecal ligation and puncture polymicrobial sepsis and were administered with calcium chloride (0.25 or 0.25 mg/kg) or normal saline.
  
  
  RESULTS
  Administering calcium chloride to septic C57Bl/6 mice heightened systemic inflammation and vascular leak, exacerbated hepatic and renal dysfunction, and increased mortality. These events were significantly attenuated in CaMKK mice. In a risk-adjusted analysis of septic patients, calcium administration was associated with an increased risk of death, odds ratio 1.92 (95% CI, 1.00-3.68; p = 0.049), a significant increase in the risk of renal dysfunction, odds ratio 4.74 (95% CI, 2.48-9.08; p < 0.001), and a significant reduction in ventilator-free days, mean decrease 3.29 days (0.50-6.08 days; p = 0.02).
  
  
  CONCLUSIONS
  Derangements in calcium homeostasis occur during sepsis that is sensitive to calcium administration. This altered calcium signaling, transduced by the calmodulin-dependent protein kinase kinase cascade, mediates heightened inflammation and vascular leak that culminates in elevated organ dysfunction and mortality. In the clinical management of septic patients, calcium supplementation provides no benefit and may impose harm.
authors.affiliation: 1Department of Surgery, University of PittsburghPittsburgh, PA. 2Division of Pulmonary, Allergy, and Critical Care Medicine, University of PittsburghPittsburgh, PA. 3Department of Critical Care Medicine, University of PittsburghPittsburgh, PA.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Collage
authors.forename: Gina M
authors.initials: GM
authors.lastname: Howell
authors.forename: Xianghong
authors.initials: X
authors.lastname: Zhang
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Stripay
authors.forename: Janet S
authors.initials: JS
authors.lastname: Lee
authors.forename: Derek C
authors.initials: DC
authors.lastname: Angus
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Rosengart
mesh_terms: D018806:APACHE; D000818:Animals; D002122:Calcium Chloride / Q000009:adverse effects*; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007362:Intensive Care Units; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009102:Multiple Organ Failure / Q000209:etiology / Q000401:mortality / Q000503:physiopathology*; D009195:Peroxidase / Q000378:metabolism; D011897:Random Allocation; D012189:Retrospective Studies; D018805:Sepsis / Q000150:complications / Q000401:mortality / Q000503:physiopathology*
chemical_list: D009195:Peroxidase; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D002122:Calcium Chloride