Hyperlactatemia affects the association of hyperglycemia with mortality in nondiabetic adults with sepsis.

Sepsis is a significant cause of death and morbidity in the United States, resulting in more than one million annual hospitalizations and over 200,000 deaths.1 Early identification of patients at high risk for sepsis-related morbidity leads to improved clinical outcomes via targeted, empiric, broad-spectrum antibiotics and rapid resuscitation.2–4 For nondiabetic patients, hyperglycemia has been associated with an increased mortality risk in sepsis.5–7 Whether hyperglycemia has a causal role in the pathologic process of sepsis has been disputed, but the possibility has led to investigations of intensive insulin therapy to improve outcomes.8 Unfortunately, recent evidence indicates that such efforts may not decrease, and may rather increase, mortality risk.9 This discrepancy prompted our new look at the relationship of hyperglycemia with mortality risk in nondiabetic sepsis. Sepsis is a hypermetabolic pathophysiologic state. The inflammatory cascade leads to a catecholamine surge, relative insulin resistance, and hyperglycemia.10 Recent studies demonstrate that a single episode of hyperglycemia (serum glucose > 200 mg/dL) on initial patient presentation may be associated with increased mortality risk in nondiabetic sepsis.5,7 However, these analyses did not account for possible simultaneous hyperlactatemia. Previous research has shown that glucose and lactate levels may correlate in sepsis and that abnormal glucose accumulation could be in part a direct result of hyperlactatemia.11 Accumulated lactate in sepsis can be cleared by oxidation to pyruvate or transformed into glucose by gluconeogenesis or into glycogen via the Cori cycle.12 Subsequent glycogenolysis can lead to further glucose accumulation, a pathway known to have increased activity in sepsis.12 Consequently, hyperglycemia in nondiabetic sepsis could be directly linked to lactate metabolism. As hyperlactatemia has a known significant association with mortality risk in sepsis, the association of glucose with lactate levels must be determined prior to assessing the correlation of hyperglycemia with mortality. If hyperglycemia’s association with mortality risk were a direct result of coexisting hyperlactatemia, we would expect several findings. First, hyperglycemia would be significantly correlated with hyperlactatemia in sepsis, even after adjustment for illness severity and comorbidities. Second, hyperlactatemia would be associated with increased mortality risk, regardless of the presence of simultaneous hyperglycemia. Finally, isolated hyperglycemia (in the absence of coexisting hyperlactatemia) would not correlate with increased mortality risk in nondiabetic sepsis. To determine whether hyperglycemia’s association with mortality in sepsis was dependent on simultaneous hyperlactatemia, we analyzed a previously identified cohort of nondiabetic, adult ED patients hospitalized for suspected sepsis. The objective of this study was to first determine whether admission hyperglycemia correlated with simultaneous hyperlactatemia after adjustment for demographics and coexisting illness severity. Additionally, we sought to determine whether hyperglycemia on initial ED presentation was associated with an increased 28-day mortality risk in sepsis after adjusting for concurrent hyperlactatemia and other markers of illness severity.