Supplementary Table 1Cardiovascular procedures excluded from study

ICD9 Code / Description
35 / Operations on Valves and Septa of Heart
35.00 / Closed Heart Valvotomy, Unspecified Valve
35.0 / Closed Heart Valvotomy or Transcatheter Replacement of Heart Valve
35.01 / Closed Heart Valvotomy, Aortic Valve
35.02 / Closed Heart Valvotomy, Mitral Valve
35.03 / Closed Heart Valvotomy, Pulmonary Valve
35.04 / Closed Heart Valvotomy, Tricuspid Valve
35.05 / Endovascular Replacement of Aortic Valve
35.06 / Transapical Replacement of Aortic Valve
35.07 / Endovascular Replacement of Pulmonary Valve
35.08 / Transapical Replacement of Pulmonary Valve
35.09 / Endovascular Replacement of Unspecified Heart Valve
35.1 / Open Heart Valvuloplasty without Replacement
35.10 / Open Heart Valvuloplasty without Replacement, Unspecified Valve
35.11 / Open Heart Valvuloplasty of Aortic Valve without Replacement
35.12 / Open Heart Valvuloplasty of Mitral Valve without Replacement
35.13 / Open Heart Valvuloplasty of Pulmonary Valve without Replacement
35.14 / Open Heart Valvuloplasty of Tricuspid Valve without Replacement
35.2 / Open and Other Replacement of Heart Valve
35.20 / Open and Other Replacement of Unspecified Heart Valve
35.21 / Open and Other Replacement of Aortic Valve with Tissue Graft
35.22 / Open and Other Replacement of Aortic Valve
35.23 / Open and Other Replacement of Mitral Valve with Tissue Graft
35.24 / Open and Other Replacement of Mitral Valve
35.25 / Open and Other Replacement of Pulmonary Valve with Tissue Graft
35.26 / Open and Other Replacement of Pulmonary Valve
35.27 / Open and Other Replacement of Tricuspid Valve with Tissue Graft
35.28 / Open and Other Replacement of Tricuspid Valve
35.3 / Operations on Structures Adjacent to Heart Valves
35.31 / Operations on Papillary Muscle
35.32 / Operations on Chordae Tendineae
35.33 / Annuloplasty
35.34 / Infundibulectomy
35.35 / Operations on Trabeculae Carneae Cordis
35.39 / Operations on Other Structures Adjacent to Valves of Heart
35.4 / Production of Septal Defect in Heart
35.41 / Enlargement of Existing Atrial Septal Defect
35.42 / Creation of Septal Defect in Heart
35.5 / Repair of Atrial and Ventricular Septa with Prosthesis
35.50 / Repair of Unspecified Septal Defect of Heart with Prosthesis
35.51 / Repair of Atrial Septal Defect with Prosthesis, Open Technique
35.52 / Repair of Atrial Septal Defect with Prosthesis, Closed Technique
35.53 / Repair of Ventricular Septal Defect with Prosthesis, Open Technique
35.54 / Repair of Endocardial Cushion Defect with Prosthesis
35.55 / Repair of Ventricular Septal Defect with Prosthesis, Closed Technique
35.6 / Repair of Atrial and Ventricular Septa with Tissue Graft
35.60 / Repair of Unspecified Septal Defect of Heart with Tissue Graft
35.61 / Repair of Atrial Septal Defect with Tissue Graft
35.62 / Repair of Ventricular Septal Defect with Tissue Graft
35.63 / Repair of Endocardial Cushion Defect with Tissue Graft
35.7 / Other and Unspecified Repair of Atrial and Ventricular Septa
35.70 / Other and Unspecified Repair of Unspecified Septal Defect of Heart
35.71 / Other and Unspecified Repair of Atrial Septal Defect
35.72 / Other and Unspecified Repair of Ventricular Septal Defect
35.73 / Other and Unspecified Repair of Endocardial Cushion Defect
35.8 / Total Repair of Certain Congenital Cardiac Anomalies
35.81 / Total Repair of Tetralogy of Fallot
35.82 / Total Repair of Total Anomalous Pulmonary Venous Connection
35.83 / Total Repair of Truncus Arteriosus
35.84 / Total Correction of Transposition of Great Vessels, Not Elsewhere Classified
35.9 / Other Operations on Valves and Septa of Heart
35.91 / Interatrial Transposition of Venous Return
35.92 / Creation of Conduit Between Right Ventricle and Pulmonary Artery
35.93 / Creation of Conduit Between Left Ventricle and Aorta
35.94 / Creation of Conduit Between Atrium and Pulmonary Artery
35.95 / Revision of Corrective Procedure on Heart
35.96 / Percutaneous Balloon Valvuloplasty
35.97 / Percutaneous Mitral Valve Repair with Implant
35.98 / Other Operations on Septa of Heart
35.99 / Other Operations on Valves of Heart
36 / Operations on Vessels of Heart
36.0 / Removal of Coronary Artery Obstruction
36.01 / Single Vessel Percutaneous Transluminal Coronary Angioplasty [Ptca] Or Coronary Atherectomy Without Mention Of Thrombolytic Agent
36.02 / Single Vessel Percutaneous Transluminal Coronary Angioplasty [Ptca] Or Coronary Atherectomy With Mention Of Thrombolytic Agent
36.03 / Open Chest Coronary Artery Angioplasty
36.04 / Intracoronary Artery Thrombolytic Infusion
36.05 / Multiple Vessel Percutaneous Transluminal Coronary Angioplasty [Ptca] Or Coronary Atherectomy Performed During The Same Operation, With Or Without Mention Of Thrombolytic Agent
36.06 / Insertion of Non-Drug-Eluting Coronary Artery Stent(s)
36.07 / Insertion of Drug-Eluting Coronary Artery Stent(s)
36.09 / Other Specified Removal of Coronary Artery Obstruction
36.1 / Bypass Anastomosis for Heart Revascularization
36.10 / Aortocoronary Bypass for Heart Revascularization, Not Otherwise Specified
36.11 / (Aorto)coronary Bypass of One Coronary Artery
36.12 / (Aorto)coronary Bypass of Two Coronary Arteries
36.13 / (Aorto)coronary Bypass of Three Coronary Arteries
36.14 / (Aorto)coronary Bypass of Four or More Coronary Arteries
36.15 / Single Internal Mammary-Coronary Artery Bypass
36.16 / Double Internal Mammary-Coronary Artery Bypass
36.17 / Abdominal - Coronary Artery Bypass
36.19 / Other Bypass Anastomosis for Heart Revascularization
36.2 / Heart Revascularization by Arterial Implant
36.3 / Other Heart Revascularization
36.31 / Open Chest Transmyocardial Revascularization
36.32 / Other Transmyocardial Revascularization
36.33 / Endoscopic Transmyocardial Revascularization
36.34 / Percutaneous Transmyocardial Revascularization
36.39 / Other Heart Revascularization
36.9 / Other Operations on Vessels of Heart
36.91 / Repair of Aneurysm of Coronary Vessel
36.99 / Other Operations on Vessels of Heart
37 / Other Operations on Heart and Pericardium
37.0 / Pericardiocentesis
37.1 / Cardiotomy and Pericardiotomy
37.10 / Incision of Heart, Not Otherwise Specified
37.11 / Cardiotomy
37.12 / Pericardiotomy
37.2 / Diagnostic Procedures on Heart and Pericardium
37.20 / Noninvasive Programmed Electrical Stimulation [NIPS]
37.23 / Combined Right and Left Heart Cardiac Catheterization
37.24 / Biopsy of Pericardium
37.25 / Biopsy of Heart
37.26 / Catheter Based Invasive Electrophysiologic Testing
37.27 / Cardiac Mapping
37.28 / Intracardiac Echocardiography
37.29 / Other Diagnostic Procedures on Heart and Pericardium
37.3 / Pericardiectomy and Excision of Lesion of Heart
37.31 / Pericardiectomy
37.32 / Excision of Aneurysm of Heart
37.34 / Excision or Destruction of Other Lesion or Tissue of Heart, Endovascular Approach
37.35 / Partial Ventriculectomy
37.36 / Excision, Destruction, or Exclusion of Left Atrial Appendage (LAA)
37.37 / Excision or Destruction of Other Lesion or Tissue of Heart, Thoracoscopic Approach
37.4 / Repair of Heart and Pericardium
37.41 / Implantation of Prosthetic Cardiac Support Device Around the Heart
37.49 / Other Repair of Heart and Pericardium
37.5 / Heart Replacement Procedures
37.51 / Heart Transplantation
37.52 / Implantation of Total Internal Biventricular Heart Replacement System
37.53 / Replacement or Repair of Thoracic Unit of (Total) Replacement Heart System
37.54 / Replacement or Repair of Other Implantable Component of (Total) Replacement Heart System
37.55 / Removal of Internal Biventricular Heart Replacement System
37.6 / Implantation of Heart and Circulatory Assist System(s)
37.60 / Implantation or Insertion of Biventricular External Heart Assist System
37.61 / Implant of Pulsation Balloon
37.63 / Repair of Heart Assist System
37.64 / Removal of External Heart Assist System(s) or Device(s)
37.65 / Implant of Single Ventricular (Extracorporeal) External Heart Assist System
37.67 / Implantation of Cardiomyostimulation System
37.7 / Insertion, Revision, Replacement and Removal of Leads; Insertion of Temporary Pacemaker System; or Revision of Cardiac Device Pocket
37.70 / Initial Insertion of Pacemaker Lead [electrode], Not Otherwise Specified
37.71 / Initial Insertion of Transvenous Lead [electrode] Into Ventricle
37.72 / Initial Insertion of Transvenous Leads [electrodes] Into Atrium and Ventricle
37.73 / Initial Insertion of Transvenous Lead [electrode] Into Atrium
37.74 / Insertion or Replacement of Epicardial Lead [electrode] Into Epicardium
37.75 / Revision of Pacemaker Lead [electrode]
37.76 / Replacement of Transvenous Atrial and/or Ventricular Lead(s) [electrode]
37.77 / Removal of Pacemaker Lead(s) [electrode] without Replacement
37.78 / Insertion of Temporary Transvenous Pacemaker System
37.79 / Revision or Relocation of Cardiac Device Pocket
37.8 / Insertion, Replacement, Removal, and Revision of Pacemaker Device
37.80 / Insertion of Permanent Pacemaker, Initial or Replacement, Type of Device Not Specified
37.81 / Initial Insertion of Single-Chamber Device, Not Specified as Rate Responsive
37.82 / Initial Insertion of Single-Chamber Device, Rate Responsive
37.83 / Initial Insertion of Dual-Chamber Device
37.85 / Replacement of Any Type Pacemaker Device with Single-Chamber Device, Not Specified as Rate Responsive
37.86 / Replacement of Any Type of Pacemaker Device with Single-Chamber Device, Rate Responsive
37.87 / Replacement of Any Type Pacemaker Device with Dual-Chamber Device
37.89 / Revision or Removal of Pacemaker Device
37.9 / Other Operations on Heart and Pericardium
37.90 / Insertion of Left Atrial Appendage Device
37.91 / Open Chest Cardiac Massage
37.92 / Injection of Therapeutic Substance Into Heart
37.93 / Injection of Therapeutic Substance Into Pericardium
37.95 / Implantation of Automatic Cardioverter/Defibrillator Lead(s) Only
37.96 / Implantation of Automatic Cardioverter/Defibrillator Pulse Generator Only
37.97 / Replacement of Automatic Cardioverter/Defibrillator Lead(s) Only
37.98 / Replacement of Automatic Cardioverter/Defibrillator Pulse Generator Only
37.99 / Other Operations on Heart and Pericardium
38.34 / Resection of Aorta with Anastomosis
38.36 / Resection of Abdominal Arteries with Anastomosis
38.44 / Resection of Abdominal Aorta with Replacement
38.64 / Other Excision of Aorta
39.25 / Aorta-Iliac-Femoral Bypass
39.52 / Other Repair of Aneurysm

Supplementary Table 2Summary of patient demographics by resuscitation fluid volume received

Resuscitation fluid volume received (72 h following SIRS qualification)
Patient characteristic / <1500 mL
(n=49,210) / 1500-3000 mL
(n=33,054) / 3000-4500 mL
(n=18,791) / 4500-6000 mL
(n=4,621) / 6000-7500 mL
(n=2,538) / ≥7500 mL
(n=1,622)
Age
Mean (SD) / 60.4 (18.7) / 59.2 (18.9) / 56.0 (18.9) / 56.1 (18.8) / 54.7 (18) / 54.2 (17.7)
Median (range) / 62 (18-90) / 60 (18-90) / 57 (18-90) / 57 (18-90) / 56 (18-90) / 55 (18-90)
18-35 years, n (%) / 5,881 (12%) / 4,495 (13.6%) / 3,294 (17.5%) / 776 (16.8%) / 448 (17.7%) / 272 (16.8%)
36-50 years, n (%) / 8,662 (17.6%) / 6,029 (18.2%) / 3,872 (20.6%) / 994 (21.5%) / 524 (20.6%) / 388 (23.9%)
51-64 years, n (%) / 12,691 (25.8%) / 8,566 (25.9%) / 4,979 (26.5%) / 1213 (26.2%) / 759 (29.9%) / 465 (28.7%)
≥65 years, n (%) / 21,976 (44.7%) / 13,964 (42.2%) / 6,646 (35.4%) / 1638 (35.4%) / 807 (31.8%) / 497 (30.6%)
Gender a
Female, n (%) / 27,292 (55.5%) / 18,168 (55%) / 10,116 (53.8%) / 2,421 (52.4%) / 1,314 (51.8%) / 813 (50.1%)
Male, n (%) / 21,894 (44.5%) / 14,873 (45%) / 8,663 (46.1%) / 2,196 (47.5%) / 1,223 (48.2%) / 809 (49.9%)
Race
White, n (%) / 32,067 (65.2%) / 21,977 (66.5%) / 12,203 (64.9%) / 3,013 (65.2%) / 1,600 (63%) / 1,020 (62.9%)
Black, n (%) / 12,831 (26.1%) / 8,642 (26.1%) / 5,209 (27.7%) / 1,213 (26.2%) / 760 (29.9%) / 488 (30.1%)
Asian/Pacific, n (%) / 549 (1.1%) / 407 (1.2%) / 247 (1.3%) / 64 (1.4%) / 37 (1.5%) / 21 (1.3%)
Hispanic, n (%) / 983 (2%) / 467 (1.4%) / 319 (1.7%) / 79 (1.7%) / 37 (1.5%) / 26 (1.6%)
Other, n (%) / 2,113 (4.3%) / 1,170 (3.5%) / 622 (3.3%) / 199 (4.3%) / 89 (3.5%) / 57 (3.5%)
APS
Mean (SD) / 6 (5) / 7 (5) / 8 (6) / 9 (6) / 10 (7) / 12 (8)
Median (range) / 6 (0-39) / 6 (0-45) / 6 (0-45) / 7 (0-42) / 8 (0-41) / 10 (0-43)
Elixhauser comorbidity score
Mean (SD) / 4 (7) / 4 (7) / 4 (7) / 5 (7) / 5 (7) / 5 (7)
Median (range) / 3 (-16-54) / 3 (-16-46) / 3 (-16-43) / 3 (-18-45) / 5 (-14-46) / 3 (-13-35)

APS = acute physiology score

a Gender not specified for 54 patients

Supplementary Table 3Summary of patient diagnoses and surgical procedures by resuscitation fluid volume received

Resuscitation fluid volume received (72 h following SIRS qualification)
Patient characteristic / <1500 mL
(n=49,210) / 1500-3000 mL
(n=33,054) / 3000-4500 mL
(n=18,791) / 4500-6000 mL
(n=4,621) / 6000-7500 mL
(n=2,538) / ≥7500 mL
(n=1,622)
Most common diagnoses, n (%) / Pneumonia
5,067 (10.3%) / Pneumonia
2,979 (9.0%) / Septicemia
1.581 (8.4%) / Septicemia
623 (13.5%) / Septicemia
447 (17.6%) / Septicemia
366 (22.6%)
Symptoms involving respiratory system and other chest symptoms
3,977 (8.1%) / General symptoms
2,155 (6.5%) / Pneumonia
1,521 (8.1%) / Diabetes mellitus
390 (8.4%) / Diabetes mellitus
314 (12.4%) / Diabetes mellitus
171 (10.5%)
General symptoms
3,444 (7.0%) / Septicemia
2,145 (6.5%) / Diabetes mellitus
1,410 (7.5%) / Pneumonia
292 (6.3%) / Other symptoms involving abdomen and pelvis
162 (6.4%) / General symptoms
99 (6.1%)
Chronic bronchitis
2,451 (5.0%) / Symptoms involving respiratory system and other chest symptoms
1,846 (5.6%) / General symptoms
1,217 (6.5%) / General symptoms
260 (5.6%) / Pneumonia
147 (5.8%) / Other symptoms involving abdomen and pelvis
94 (5.8%)
Septicemia
2,292 (4.7%) / Other symptoms involving abdomen and pelvis
1,777 (5.4%) / Other symptoms involving abdomen and pelvis
1,195 (6.4%) / Other symptoms involving abdomen and pelvis
244 (5.3%) / General symptoms
120 (4.7%) / Acute kidney failure
79 (4.9%)
Patients undergoing surgical procedure prior to SIRS qualification / 895 (1.8%) / 420 (1.3%) / 179 (1.0%) / 32 (0.7%) / 24 (0.9%) / 12 (0.7%)

Supplementary Table 4. Summary of multivariate regression analysis. A multivariate regression model accounting for patient demographics, hospital characteristics, Elixhauser comorbidities, APS, and volume-adjusted chloride load was constructed to assess mortality OR, and modeled the change in in-hospital mortality OR associated with a 10 mmol/L incremental increase in volume-adjusted chloride load

Volume-adjusted Cl- <105 mmol/L / Volume-adjusted Cl-≥105 mmol/L
c-statistic / Mortality OR [confidence limits] / c-statistic / Mortality OR [confidence limits]
Unadjusted / 0.814 / 0.875 [0.810; 0.948] / 0.781 / 1.011 [0.982; 1.042]
APS-adjusted / 0.862 / 0.916 [0.844; 0.997] / 0.843 / 1.046 [1.013; 1.079]

Supplementary Table 5. Summary of mortality ORs associated with a 1 mmol/L incremental increase in volume-adjusted chloride load across three defined ranges. Analysis was carried out using continuous data. The 98-110 mmol/L range was defined as the normal range based on mean normal serum chloride ranges reported by hospitals in the EHR database. ORs overlapping with the null value (OR=1) suggest the absence of a meaningful association between mortality odds and increasing volume-adjusted chloride load. The multivariate regression model accounted for patient demographics, hospital characteristics, Elixhauser comorbidities, APS, and volume-adjusted chloride load

Mortality OR [confidence limits] / Mortality OR [confidence limits] (multivariate model)
Volume-adjusted Cl- < 98 mmol/L / Volume-adjusted Cl- 98-110 mmol/L / Volume-adjusted Cl- >110 mmol/L / Volume-adjusted Cl- < 98 mmol/L / Volume-adjusted Cl- 98-110 mmol/L / Volume-adjusted Cl- >110 mmol/L
Unadjusted / 0.988
[0.963; 1.104] / 1.037
[0.986; 1.091] / 1.011
[1.008; 1.014] / 1.011
[0.980; 1.044] / 1.030
[0.969; 1.095] / 1.002
[0.999; 1.006]
APS-adjusted / 1.000
[0.973; 1.027] / 1.027
[0.970; 1.086] / 1.011
[1.008; 1.014] / 1.014
[0.981; 1.048] / 1.016
[0.951; 1.084] / 1.006
[1.003; 1.009]

Supplementary Fig.1 Flow chart summarizing patients meeting study inclusion criteria. Among patients meeting SIRS criteria and receiving fluid resuscitation, 19,092 were excluded as a result of having <2 serum chloride measurements

Supplementary Fig. 2Relationship between baseline serum chloride concentration and in-hospital mortality (a) and peak serum chloride concentration and in-hospital mortality (b) in patients meeting SIRS criteria and receiving >500 mL intravenous crystalloid within two days of SIRS qualification. Data in both panels are fitted with a cubic polynomial function. Fit lines (solid lines) are weighted based on the number of patients with given baseline or peak chloride concentrations. Dashed lines represent 95% confidence interval

Supplementary Fig. 3 Relationship between sodium load received via IV resuscitation fluids within 72 h following SIRS qualification and in-hospital mortality, stratified by total resuscitation fluid volume received. In the <1500 mL group, there was a weak association between increasing sodium load and reduced mortality (weighted linear fit; slope=-0.012, R2=0.99). For the 1500-3000 mL group, weighted regression analysis showed a minimal association between the two variables (slope=-0.001; R2=0.01). For the 3000-4500 through 6000-7500 mL groups, there was an increasingly positive association (increased mortality with increasing sodium load) for each incremental volume increase (3000-4500 mL: slope=0.006, R2=0.81; 4500-6000 mL: slope=0.016, R2=0.61; 6000-7500 mL: slope=0.028, R2=0.85; >7500 mL: slope=0.007, R2=0.34)

Supplementary Fig. 4 Relationship between volume-adjusted sodium load received within 72 h following SIRS qualification and in-hospital mortality. The majority of patients (87%) received either 135-145 or 145-155 mmol/L sodium. Mortality was lowest (2.7%) for patients receiving 135-145 mmol/L sodium, while volume-adjusted sodium loads <115mmol/L were associated with >5% mortality. Regression line (solid line) represents a cubic polynomial fit and is weighted based on the number of patients receiving each given amount of volume-adjusted sodium. Dashed lines represent 95% confidence interval