June 15, 2017

The LICRA Trial 

Article Review

Observational studies have consistently identified an association for both chloride-rich IV fluid administration and hyperchloraemia with adverse clinical outcomes among critically ill patients [1, 2]. However, high quality evidence of the effect of hyperchloraemia  in high risk surgical patients is lacking [3]. Patients undergoing cardiac surgery are at high risk of AKI and receive large volumes of fluids perioperatively [4]. 

The “Limiting I.V. Chloride to Reduce AKI” (LICRA) study was a prospective clinical trial investigating the effect of a chloride-limited IV fluid compared to a chloride-rich in reducing the incidence of AKI in adults undergoing cardiac surgery [5]. The primary endpoints were peak delta serum creatinine (ΔSCr) within 5 postoperative days and the proportion of patients meeting stage 2 or 3 Kidney Disease within the first 5 postoperative days. 

Adult patients undergoing cardiac surgery within a single Australian academic medical center were enrolled to receive either a chloride-rich fluid strategy (n=569) or a chloride-limited strategy (n=567).

Intervention and comparison
The LICRA study was a prospective, open label, four-period sequential study. Each period was conducted over 5 consecutive calendar months: 
1.    The first period involved the application of a chloride-rich perioperative fluids included 0.9% saline (chloride concentration 150mmol/L) and 4% albumin (chloride concentration 128mmol/L) as the default IV crystalloid and colloid solutions, respectively. 
2.    The second period involved chloride-limited fluids including Hartmann’s solution (chloride concentration 109mmol/L) and 20% albumin (chloride concentration 19mmol/L) as the default intravenous crystalloid and colloid solutions respectively.
3.    A third period involved a strategy of chloride-limited solution included the administration of Plasmalyte-148 (chloride concentration 98mmol/L) and 20% albumin as the default intravenous crystalloid and colloid solutions respectively. 
4.    The fourth period involved a return to the same chloride-rich strategy used in Period 1

During chloride-limited periods the cardiopulmonary bypass (CPB) circuit was primed with the low-chloride crystalloid of the corresponding period, together with 20% albumin. During chloride-rich periods Hartmann’s solution and 4% albumin were use to prime the CPB circuit
without constituting a protocol violation, as 0.9% saline was not used for this purpose in clinical practice within Australia.

•    The protocol compliance rate of 95% and did not differ between chloride-rich and chloride-limited groups or individual study periods.
•    Patients assigned to a chloride-rich fluid strategy received a greater total fluid volume intraoperatively (3300 vs. 3200ml; p=0.01), but less total fluid volume on postoperative days 0 and 1 combined (1435 (vs. 1750ml; p <0.001) compared to patients assigned to a chloride-limited fluid strategy. 
•    Intraoperatively, peak SCl−  was higher in patients assigned to a chloride-rich strategy than in those assigned to a chloride-limited strategy (115 vs. 111mmol/L; p  < 0.001) and was accompanied by a greater degree of metabolic acidosis.
•    Peak ΔSCr  within 5 days postoperatively did not differ between patients assigned to a chloride-rich fluid strategy and those assigned to a chloride-limited fluid strategy (13 vs. 13 μmol/L; p =  0.320).
•    The incidence of stage 2 or 3 AKI did not differ between patients assigned to a chloride-rich fluid strategy (10.8%) and those assigned to a chloride-limited strategy (10.5%), even on adjusting for pre-specified covariates.
•    There was no difference in the incidence of postoperative RRT, hospital mortality or ICU length of stay between chloride-rich and chloride-limited groups

LICRA was a pragmatic study with high compliance to study protocol in a well-defined population. However, the authors acknowledged that the non-normal distribution in peak ΔSCr reduced the statistical power of the study by an uncertain amount, possibly leading to an under-powered study. This observation needs to be factored into the design of future studies exploring chloride-rich fluids. Another interesting observation was that two-thirds of the chloride-limited group developed hyperchloraemia. The authors suggest that factors other than administered chloride load may be important in the development of hyperchloraemia, although this mechanism has not been elucidated. This may have confounded the results and there was no post-hoc analysis to study the association between patients that actually developed hyperchloraemia and renal outcomes.

In summary, a perioperative fluid strategy designed to restrict IV chloride administration was not associated with a difference in the incidence of AKI or other metrics of renal injury in adult patients undergoing cardiac surgery.

Article review prepared and submitted by EJRC member Nish Arulkumaran, MD (Centre for Intensive Care Medicine, University College London, London, UK).


1. Shaw AD, Schermer CR, Lobo DN, et al. Impact of intravenous fluid composition on outcomes in patients with systemic inflammatory response syndrome. Crit Care 2015; 19: 334
2. Yunos NM, Bellomo R, Hegarty C, et al. Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. JAMA 2012; 308: 1566-72
3. Burdett E, Dushianthan A, Bennett-Guerrero E, et al. Perioperative buffered versus non-buffered fluid administration for surgery in adults. Cochrane Database Syst Rev 2012; 12: CD004089
4. Parke RL, McGuinness SP, Gilder E, McCarthy LW, Cowdrey KA. A randomised feasibility study to assess a novel strategy to rationalise fluid in patients after cardiac surgery. Br J Anaesth 2015; 115: 45-52
5. McIlroy D, Murphy D, Kasza J, et al. Effects of restricting perioperative use of intravenous chloride on kidney injury in patients undergoing cardiac surgery: the LICRA pragmatic controlled clinical trial. Intensive Care Med 2017

Comment on this news