Stewart's theory and acid-base changes induced by crystalloid infusion in humans: a randomized physiological trial

Background Stewart's acid-base theory states that, under isocapnic conditions, crystalloid infusion affects plasma pH due to changes in strong ion difference and total weak acid concentration: a comprehensive study also assessing renal response and hemodilution effects has not been conducted in humans. We aimed to evaluate Stewart's approach during crystalloid infusion in humans. Methods In this randomized trial, patients undergoing surgery with minimal blood losses were randomized to receive to normal saline (chloride content 154 mEq/L, strong ion difference 0 mEq/L), lactated Ringer's (chloride content 112 mEq/L, strong ion difference 29 mEq/L) or Crystalsol (chloride content 98 mEq/L, strong ion difference 50 mEq/L): patients received 10 ml/kg immediately after intubation, and 20 ml/kg after 2 h. Plasma/urinary acid-base and electrolytes were measured before study start and then at prespecified timepoints. The primary endpoint was pH one hour after the second fluid bolus: secondary outcomes included urinary/plasmatic electrolyte concentrations and strong ion difference during the study. Results Forty-five patients were enrolled (15 in each group). The extent of hemodilution achieved with the first (median [Interquartile range]: saline 9% [6-15], Ringer's 7% [4-9], Crystalsol 8% [5-12]) and the second fluid bolus (saline 13% [5-17], Ringer's 12% [9-15], Crystalsol 15% [10-20]) was not different between groups (p = 0.39 and p = 0.19, respectively). Patients in saline group received more chloride (449 mEq [383-495]) vs. Ringer's (358 mEq [297-419]) and Crystalsol groups (318 mEq [240-366]) (p = 0.001). One hour after the second bolus, pH was lower in saline group (7.34 [7.32-7.36]) vs. Ringer's (7.40 [7.35-7.43) and Crystalsol groups (7.42 [7.38-7.44]) (both p < 0.01), since plasma chloride increased significantly over time in saline group but not in Ringer's and Crystalsol groups. Overall chloride urinary excretion was not different between study groups (saline 36 mEq [28-64], Ringer's 42 mEq [29-68], Crystalsol 44 mEq [27-56], p = 0.60) but, at the end of experiments, urinary chloride concentration was higher and diuresis was lower in saline group vs. Ringer's and Crystalsol groups (p = 0.01, p = 0.04, respectively). Conclusions Consistent with Stewart's approach, crystalloid solutions with high chloride content lower pH due to reduced strong ion difference, progressive hemodilutional acidosis and limited renal response to chloride load. Trial Registration Registered on clinicaltrials.gov (NCT03507062) on April, 24th 2018.