Table 1.

Lack of evidence for the 'traditional' mechanisms explaining sepsis-associated hyperlactatemia

Tissue hypoxia
Boekstegers et al. [43]	Muscle PO2 in septic patients	No evidence of muscle hypoxia
Sair et al. [44]
Levy et al. [45]
VanderMeer et al. [46]	Intestinal and bladder mucosal PO2 in septic animals	No evidence of mucosal hypoxia
Rosser et al. [47]
Hotchkiss and Karl [48]	Cellular oxygenation by using hypoxic marker ([18 F] fluoromisonidazole) in septic animals	No cellular hypoxia in muscle, heart, lung and brain
Regueira et al. [49]	Measurements of HIF-1α in septic patients/animals	No relation between HIF-1α and lactate levels
Textoris et al. [50]
Opdam and Bellomo [51]	Lactate production by the lung in septic shock patients	Substantial lactate release by the lung
Mitochondrial dysfunction
Hotchkiss and Karl [48]	Measurements of ATP and PCr in muscle samples of septic animals/patients	No decrease in any of the indicators of mitochondrial function
Alamdari et al. [53]
Brealey et al. [54]
Pyruvate dehydrogenase
Alamdari et al. [53]	Mitochondrial PDH activity in septic animals/patients	No association between PDH deficit/dysfunction and lactate increase
Jahoor et al. [55]
Stacpoole et al. [56]
		Dichloroacetate lowers lactate levels by stimulating the PDH complex
DO2 – VO2 mismatch
Ronco et al. [57,58]	Critical DO2 in septic patients as they approached death	No association between hyperlactatemia and decreased DO2 or impaired O2ER
Mira et al. [59]	Relationship between DO2/SvO2 and SAHL	No relationship between DO2/SvO2 was found
Astiz et al. [60]
Marik and Sibbald [65]		Increases in DO2 did not decrease lactate concentration in SAHL

DO₂, oxygen delivery; HIF, hypoxia-inducible factor; O₂ER, oxygen extraction ratio; PCr, phosphocreatine; PDH, pyruvate dehydrogenase; PO_2, partial pressure of oxygen; SAHL, sepsis-associated hyperlactatemia; SvO₂, mixed venous oxygen saturation.