• Richard D Collage, Gina M Howell, Xianghong Zhang, Jennifer L Stripay, Janet S Lee, Derek C Angus, and Matthew R Rosengart.
• 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.
• Crit. Care Med. 2013 Nov 1; 41 (11): e352-60.

BackgroundCalcium 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.ObjectiveWe 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.DesignProspective, randomized controlled experimental murine study and observational clinical cohort analysis.SettingUniversity research laboratory and eight ICUs at a tertiary care center.PatientsA cohort of 870 septic ICU patients.SubjectsC57Bl/6 and CaMKK mice.InterventionsMice underwent cecal ligation and puncture polymicrobial sepsis and were administered with calcium chloride (0.25 or 0.25 mg/kg) or normal saline.Measurements And Main ResultsAdministering 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).ConclusionsDerangements 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.

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