Number 10
"Association Between a Chloride-Liberal vs Chloride-Restrictive Intravenous Fluid Administration Strategy and Kidney Injury in Critically Ill Adults" (pubmed) [Yunos et al JAMA. 2012;308(15):1566-1572. doi:10.1001/jama.2012.13356]
The research question in this paper was whether administration of chloride rich intravenous fluids precipitates acute kidney injury (AKI).
The authors hypothesized that a chloride-restrictive intravenous fluids strategy in critically ill patients was associated with a decreased incidence and severity of AKI compared with a chloride-liberal intravenous strategy.
The rationale for the study was from some prior data: "supraphysiological concentrations of chloride induces or exacerbates hyperchloremia and metabolic acidosis, may cause renal vasoconstriction and decreased glomerular filtration rate (GFR), prolong time to first micturition, and decrease urine output in major surgery. Recently, in a double-blind randomized controlled trial, 2 L of saline decreased cortical perfusion in human study participants compared with Plasma-Lyte.
The authors performed a prospective, open-label, before-and-after pilot study in the 22-bed multidisciplinary intensive care unit (ICU) of the Austin Hospital, a tertiary care hospital affiliated with the University of Melbourne. [On ClinicalTrails.gov, the authors state that the intervention mode is a "cross-over assignment" and that 7000 patients would be enrolled.]
They did not obtain informed consent from patients arguing that treatment was considered "unit protocol–based and data collection required no direct patient contact. The study was approved by the human research ethics committee of the Austin Hospital with a waiver for informed consent because this was a practice change that applied to all admissions."
I disagree with the ethics committee regarding the need for patient consent. If this was not a clinical trial one could have said that patient consent was not needed. However, the investigators registered the study as a clinical trial [clinicaltrials.gov Identifier: NCT00885404].
The chloride rich fluids included, 0.9% saline (chloride concentration: 150 mmol/L), 4% succinylated gelatin solution (chloride concentration: 120 mmol/L), and 4% albumin in sodium chloride (chloride concentration: 128 mmol/L). The chloride restricted fluids were Hartmann's solution (chloride concentration 109 mmol/L), Plasma-Lyte (chloride concentration 98 mmol/L) and 20% albumin (chloride concentration 19 mmol/L).
The primary outcomes were: 1. increase in creatinine from baseline to peak ICU level and, 2. incidence of AKI according to the risk, injury, failure, loss, end-stage (RIFLE) system definitions. Secondary post hoc analysis outcomes included the need for RRT, length of stay in ICU and hospital, and survival.
The results
- Chloride administration decreased by 144 504 mmol (from 694 to 496 mmol/patient) from the control period to the intervention period.
- Comparing the control period with the intervention period, the mean serum creatinine level increase while in the ICU was 22.6 μmol/L (95% CI, 17.5-27.7 μmol/L) vs 14.8 μmol/L (95% CI, 9.8-19.9 μmol/L) (P = .03).
- The incidence of injury and failure class of RIFLE-defined AKI was 14% (95% CI, 11%-16%; n = 105) vs 8.4% (95% CI, 6.4%-10%; n = 65) (P <.001)
- The use of RRT was 10% (95% CI, 8.1%-12%; n = 78) vs 6.3% (95% CI, 4.6%-8.1%; n = 49) (P = .005).
- After adjustment for covariates, this association remained for incidence of injury and failure class of RIFLE-defined AKI (odds ratio, 0.52 [95% CI, 0.37-0.75]; P <.001) and use of RRT (odds ratio, 0.52 [95% CI, 0.33-0.81]; P = .004).
- There were no differences in hospital mortality, hospital or ICU length of stay, or need for RRT after hospital discharge.
The limitations
- This was not a randomized study. There were key imbalances in the two populations with respect to co-morbidities (even if they did not reach statistical significance they might have been important in the aggregate). These imbalances between the groups could have impacted on the findings. Surprisingly, the authors did not adjust for co-morbidities in their multivariate models. Here is what they say they did: " adjusting for the a priori–defined covariates of sex, APACHE III score, diagnosis, operative status, and admission type (elective or emergency). Because the magnitude of the increase in creatinine level was dependent on the starting level, baseline creatinine level was also included as a covariate for all outcomes."
- It was open label in design and outcomes did not appear to be independently adjudicated.
- The intervention was a bundle. The authors also used solutions in the "intervention phase' that were relatively low in sodium and rich in potassium - these could plausibly account for the differences in outcomes.
- The funding for the study and what role the funding source had in the study design, data collection and analysis are unclear. One source of support was from Baxter. This company makes Plasma Lyte and also Hartmann's.
The conclusions
The authors conclude: "We conducted a before-and-after study comparing a chloride-restrictive intravenous fluids strategy with a chloride-liberal intravenous fluids strategy in a multidisciplinary tertiary ICU. We found that restricting intravenous chloride intake was associated with a significant decrease in the incidence of AKI and the use of RRT."
My take: This is an interesting study - hypothesis generating. But, findings have great clinical relevance, the study is novel, and if confirmed could be very important in how we manage patients with AKI.
The main problem is the intervention. The authors claim that they are testing a chloride restrictive versus chloride-rich strategy for hydration and resuscitation. Rather, as they correctly point out in the discussion:
" This was a bundle-of-care study. The control bundle of care was based on the delivery of commonly used chloride-rich fluids, while the interventional bundle of care was based on the removal of such fluids and the exclusive administration of lower chloride fluids. Thus, we are not in a position to identify which component of our intervention (restricting chloride, using balanced solutions containing lactate, stopping a commercial 4% gelatin solution, using more 20% albumin and less 4% albumin, giving less sodium, delivering more potassium, or any combination of these) might have been responsible for the changes in outcomes observed."
Bottom-line is that I liked the study (thus, it makes my top 10) even though I don't agree with how they worded their conclusion: "The implementation of a chloride-restrictive strategy in a tertiary ICU was associated with a significant decrease in the incidence of AKI and use of RRT."
