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1 Supplementary Online Content Yunos NM, Bellomo R, Hegarty C, Story D, Ho L, Bailey M. Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. JAMA. 2012;308(15):doi: /jama etable 1. Baseline characteristics of the nested cohort of patients etable 2. Detailed data on fluid intake of the nested cohort of patients etable 3. Secular trends in the study ICU for patient characteristics and use of renal replacement therapy etable 4. Subgroup analysis according to markers of likely fluid intake efigure 1. Relationship between log-chloride intake and change in serum creatinine efigure 2. Changes in serum creatinine [geometric mean (95% CI)] in the control and intervention group during the first 4 days (75% of cohort) efigure 3. Subgroup analysis esupplement. Key finding after exclusion of patients without baseline serum creatinine levels This supplementary material has been provided by the authors to give readers additional information about their work.

2 etable 1. Baseline characteristics of the nested cohort of patients Characteristic Control (n=99)* Intervention (n=100) P value Age (years) 61.2 (16.7) 60.1 (19.2) 0.67 Male Gender 61 (62%) 64 (64%) 0.73 APACHE II score 15.8 (7.1) 15.9 (7.9) 0.96 APACHE III score 56.8 (25.7) 56.7 (27.6) 0.98 SAPS II score 32.5 (14.3) 32.4 (16.3) 0.95 Mechanical ventilation 62 (63%) 71 (71%) 0.21 Admission after elective surgery 31 (31%) 34 (34%) 0.69 Post operative admission 54 (55%) 54 (54%) 0.94 Admission from ER 16 (16%) 28 (28%) 0.04

3 Characteristic Control (n=99)* Intervention (n=100) P value Admission from ward 20 (20%) 7 (7%) 0.01 Admission for other ICU 9 (9%) 11 (11%) 0.65 Cardiovascular diagnosis 41 (41%) 43 (43%) 0.12 Gastrointestinal diagnosis 21 (21%) 13 (13%) 0.88 Metabolic diagnosis 4(4%) 9 (9%) 0.16 Neurological diagnosis 9 (9%) 13 (13%) Renal/Genitourinary diagnosis 4 (4%) 1 (1%) 0.21 Respiratory diagnosis 9 (9%) 13 (13%) 0.38 Severe sepsis/septic shock 6 (6%) 12 (12%) 0.14 Baseline creatinine (µmol/l) 88 (69 120) 88 (70 141) 1.00

4 Characteristic Control (n=99)* Intervention (n=100) P value Chronic lung disease 3 (3%) 1 (1.0%) 0.37 Chronic cardiovascular disease 2 (2%) 8 (8%) 0.05 Chronic liver disease 50 (6.6%) ( ) 37 (4.8%) ( ) 0.13 Chronic renal failure 34 (4.5%) ( ) 29 (3.8%) ( ) 0.48 Immunosuppression 29 (3.8%) ( ) 26 (3.4%) ( ) 0.63 Lymphoma 5 (0.7%) ( ) 5 (0.7%) ( ) 0.98 Metastatic cancer 19 (2.55) ( ) 22 (2.8%) ( ) 0.67 Luekemia/Myeloma 7 (0.9%) ( ) 14 (1.8%) ( ) 0.13 * one patient was readmission

5 etable 2. Detailed data on fluid intake of the nested cohort of patients Type of fluid Control Period (n=99)* Intervention Period (n=100) Saline 720 ( ) ml 0 (0 0) ml Gelofusine 100 (0 900) ml 0 (0 0) ml 4% Albumin 0 (0 300) ml 0 (0 0) ml 20% Albumin 0 (0 100) ml 200 (0 300) ml Hartmann s 0 (0 0) ml 1840 ( ) ml Plasma lyte 0 (0 0) ml 0 (0 0) ml Values as medians with interquartile intervals *One patient was a readmission

6 etable 3. Secular trends in the study ICU for patient characteristics and use of renal replacement therapy Year Admissions Age APACHE II APACHE III RRT (n) % RRT % % % INTERVENTION % % % Age in years (mean age) APACHE (acute physiologic and chronic health evaluation score) version II and version III (mean value) RRT: renal replacement therapy (actual number of patients treated) %RRT: percentage of patients admitted who received RRT

7 etable 4. Subgroup analysis according to markers of likely fluid intake Subgroup n Events (95%CI) Raw OR (95%CI) Raw P-value Adj. OR (95%CI) Adj. P-value a) Sepsis [14% (7.7 20%)] 0.25 ( ) ( ) 0.03 b) High Apache 2 (>14) [4.4% ( %)] 0.40 ( ) ( ) 0.02 c) High Risk of death (>5%) [16% (13 19%)] 0.53 ( ) ( ) d) Long ICU stay (>43hrs) [18% (15 21%)] 0.51 ( ) ( ) e) Low Apache2 (<=14) [18% (15 21%)] 0.61 ( ) ( ) f) Low Risk of Death (<5%) [13% (9 16%)] 0.63 ( ) ( ) 0.16 g) Cardiac Surgery [6.2% ( %)] 0.61 ( ) ( ) 0.24 h) Short ICU stay (<=43 hrs) [4.1% ( %)] 0.81 ( ) ( ) 0.39 OR = odds ratio; Adj = adjusted for covariates (gender, APACHE III score, diagnosis, operative status, admission type (elective/emergency) and baseline creatinine)

8 efigure 1. Relationship between log chloride intake and change in serum creatinine There is a signifciant relationship (p=0.02) between log chloride and delta creatinine in two nested cohort of 100 patients each where detailed chloride intake was available

9 efigure 2. Changes in serum creatinine [geometric mean (95% CI)] in the control and intervention group during the first 4 days (75% of cohort) Y axis: serum creatinine level in micromol/l X axis: days from ICU admissions Overall difference between groups (p=0.001)

10 Day 0 = patients with baseline values, day 1 admission day (as incomplete day, not all patients have morning ICU creatinine value), numbers decrease from the first complete days (day 2) over the next 48 hrs. Creatinine levels during ICU stay Creatinine was well approximated by a log normal distribution, so was log transformed prior to analysis with results reported as geometric means (95%CI). A repeat measures analysis of variance was performed using mixed linear modeling with each individual patient treated as a random effect. Main effects were fitted for treatment, day and an interaction between treatment and day to determine if creatinine levels behaved differently over time. Main effects were also fitted for an a priori defined list of covariates (gender, APACHE III score, diagnosis, operative status, admission type (elective/emergency) as well as baseline creatinine. To ensure the marker of patient severity was independent of creatinine, the creatinine component was removed from the APACHEIII score. No adjustment has been made for multiple comparisons. As only 25% of patients had creatinine measurements beyond day 4, this analysis was restricted to the first four days of ICU stay. A two sided p value of 0.01 was considered to be statistically significant.

11 efigure 3. Subgroup analysis Patients were divided according to the presence of cardiac surgery, sepsis or an APACHE II score or estimated risk of death or ICU stay above or below the median value. The outcome of interest is the development of combined RIFLE I or F class AKI with odds ratios presented as Intervention vs. Control The above analysis shows a progressive decrease in risk of AKI during chloride restricive therapy compared with chloride liberal therapy.

12 esupplement. Key finding after exclusion of patients without baseline serum creatinine levels After exclusion of patients for whom there was no baseline creatinine value, during the study period, there were 1320 ICU admissions in 1304 patients (649 during the control period and 655 during the intervention period). There were no significant differences with regard to age, sex, baseline creatinine, APACHE scores, SAPS II scores, co-morbidities, diagnostic groups and types of admission. The incidence of class I and F of RIFLE was significantly lower during the intravenous chloride-restrictive strategy ]period [47(7.2%( %)) vs. 81(12.5%(10-15%)); p=0.001]. RRT use also significantly decreased from 60 [9.2% ( %)] patients in the control group to 38 [5.8% ( %)] patients in the intervention group (p =0.02). This decrease was a deviation from secular trends for the study ICU and consistent with changes in serum creatinine over time (see electronic appendix). After adjusting for gender, APACHE III score, diagnosis, operative status, baseline serum creatinine and admission type (elective/emergency), the overall incidence of RIFLE class I and F (OR, 0.48; 95% CI, ; P = ) and the incidence of RRT (OR: 0.52; 95% CI ; p=0.01) remained significantly lower in the intervention group.

13 There were also significant differences in the hazard ratios for these events after the Cox proportional hazards model adjustment for the same covariates with a hazards ratio of 0.49 (95% CI: ; p=0.001) for the development of RIFLE class I and F combined and a hazards ratio of 0.58 (95% CI, ; P =0.01) for receiving RRT.