Balanced crystalloids <i>versus</i> saline for critically ill patients: an overview of systematic reviews

Shin, Seok Woo; Ribeiro, Mayra Carvalho; Sansoni, Talita Magalhaes; Vergueiro Neto, Francisco; Falcao, Antonio Luis Eiras; Stamponi, Danilo da Silva

doi:10.62675/2965-2774.20260215

person Seok Woo Shin

conceptualization · methodology · formal analysis · investigation · data curation · writing - original draft · writing - review & editing · visualization · project administration

schoolDepartment of Intensive Care Medicine, Universidade Estadual de Campinas - Campinas (SP), Brazil.

0009-0007-3268-2818

person Mayra Carvalho Ribeiro

conceptualization · methodology · formal analysis · investigation · data curation · visualization

schoolClinical Hospital, Universidade Estadual de Campinas - Campinas (SP), Brazil.

0009-0007-9381-8627

person Talita Magalhaes Sansoni

methodology · validation · writing - review & editing · project administration

schoolDepartment of Intensive Care Medicine, Universidade Estadual de Campinas - Campinas (SP), Brazil.

0000-0003-0031-1442

person Francisco Vergueiro Neto

validation · writing - review & editing

schoolDepartment of Intensive Care Medicine, Universidade Estadual de Campinas - Campinas (SP), Brazil.

0009-0000-2940-0719

person Antonio Luis Eiras Falcao

validation · supervision

schoolDepartment of Intensive Care Medicine, Universidade Estadual de Campinas - Campinas (SP), Brazil.

0000-0002-1630-7889

person Danilo da Silva Stamponi

conceptualization · writing – review & editing · supervision · project administration

schoolDepartment of Intensive Care Medicine, Universidade Estadual de Campinas - Campinas (SP), Brazil.

0009-0009-3306-4442

personCorresponding author: Seok Woo Shin Departamento de Medicina Intensiva Universidade Estadual de Campinas Rua Tessália Vieira de Camargo, 126 Zip code: 13083-887 - Campinas (SP), Brazil E-mail:
seok@unicamp.br

Conflicts of interest:

None.

Responsible editor:

Alexandre Biasi Cavalcanti 0000-0003-2798-6263

Author	Design	Studies included	Population	Intervention	Comparator	Outcome measure	Subgroups
Hammond et al.(⁸)	Meta-analysis and systematic review of RCTs	13 RCTs	35,884 critically ill adults	Balanced crystalloids	Normal saline	Mortality, AKI, RRT, MV-free days, vasopressor-free days	Sepsis, trauma, traumatic brain injury, and patients admitted to the ICU after cardiac surgery
Zampieri et al.(⁹)	Meta-analysis and systematic review of RCTs	6 RCTs	34,685 critically ill adults	Balanced crystalloids	Normal saline	In-hospital mortality, survival at last follow-up, RRT, days alive and out of hospital, and out of ICU	Surgical, sepsis, traumatic brain injury
Liu et al.(¹⁸)	Network meta-analysis and systematic review	49 RCTs	40,910 critically ill patients	Balanced crystalloids	Normal saline	Mortality, AKI, RRT	Sepsis, trauma, hypovolemia, elderly
Tseng et al.(¹⁹)	Network meta-analysis and systematic review	58 RCTs	26,351 critically ill patients	Balanced crystalloids	Normal saline	Mortality, fluid resuscitation volume, AKI, and transfusion volume	Sepsis, surgical, trauma, traumatic brain injury
Hammond et al.(²⁰)	Meta-analysis of cohort studies and randomized trials	13 studies	30,950 critically ill patients	Balanced crystalloids	Normal saline	28-/30-days/ hospital mortality, ICU mortality, ICU length of stay, hospital length of stay, AKI, RRT, MV-free days, MAKE30, serum chloride concentration change	Sepsis
González-Castro et al.(²¹)	Meta-analysis of controlled, randomized clinical trials and prospective studies	8 studies	20,684 critically ill patients -adults (age 18 years or over) admitted to the ICU	Balanced crystalloids	Normal saline	Mortality in the ICU or hospital, AKI	No subgroups
Zayed et al.(²²)	Meta-analysis and systematic review of RCTs	6 RCTs	19,332 critically ill patients	Balanced crystalloids	Normal saline	AKI, in-hospital mortality, ICU mortality, RRT	No subgroups
Chua et al.(²³)	Meta-analysis and systematic review of RCTs	4 RCTs	19,105 critically ill patients	Balanced crystalloids	Normal saline	Mortality, AKI, RRT	No subgroups
Dong et al.(²⁴)	Meta-analysis and systematic review of RCTs	8 RCTs	35,456 critically ill patients	Balanced crystalloids	Normal saline	Mortality, AKI, RRT	Sepsis, non-sepsis, TBI, non-TBI
Jackson et al.(²⁵)	Meta-analysis and systematic review of RCTs	7 RCTs	20,171 critically ill patients	Balanced crystalloids	Normal saline	ICU and hospital mortality, MAKE30, AKI, RRT	No subgroups
Liu et al.(²⁶)	Meta-analysis and systematic review of RCTs	9 RCTs	20,526 critically ill patients (> 18 years old) requiring fluid resuscitation	Balanced crystalloids	Normal saline	Mortality, AKI, RRT	No subgroups
Xue et al.(²⁷)	Meta-analysis and systematic review of RCTs	8 RCTs	19,301 critically ill patients (acutely ill adult patients in the ICU or surgical adult patients transferred to the ICU in the perioperative period)	Balanced crystalloids	Normal saline	In-hospital mortality, AKI, RRT, RRT-free days, MAKE30, serum chloride concentration change, MV-free days, vasopressor-free days	Sepsis, non-sepsis, TBI, non-TBI
Zwager et al.(²⁸)	Meta-analysis and systematic review of RCTs	9 RCTs	32,777 critically ill adults (intensive care medicine and emergency medicine)	Balanced crystalloids	Normal saline	Mortality, AKI, RRT	Sepsis, TBI
Chen et al.(²⁹)	Meta-analysis and systematic review of RCTs	18 RCTs	36,224 critically ill adults	Balanced crystalloids	Normal saline	Composite mortality, AKI, RRT, hospital length of stay, MV-free days	Sepsis, trauma, TBI, admission to the ICU after surgery, diabetic ketoacidosis, and renal complications

Author	AMSTAR-2 item																	Overall
Author	1	2*	3	4*	5	6	7*	8	9*	10	11*	12	13*	14	15*	16	Number of critical domains not met	Overall
Chen et al.(⁸)	Y	N	Y	N	Y	Y	N	PY	Y	N	Y	Y	Y	Y	Y	Y	3	Critically low
Zampieri et al.(⁹)	Y	Y	Y	PY	Y	Y	N	Y	Y	N	Y	Y	Y	Y	Y	Y	1	Low
Liu et al.(¹⁸)	Y	Y	Y	Y	Y	Y	N	PY	Y	N	Y	Y	Y	Y	Y	Y	1	Low
Tseng et al.(¹⁹)	Y	Y	Y	PY	Y	Y	Y	Y	Y	N	Y	Y	Y	Y	Y	Y	0	High
Hammond et al.(²⁰)	Y	Y	Y	Y	Y	Y	N	Y	Y	N	Y	Y	Y	Y	Y	Y	1	Low
González-Castro et al.(²¹)	Y	N	Y	Y	Y	Y	N	PY	Y	N	Y	Y	Y	Y	Y	Y	2	Critically low
Zayed et al.(²²)	Y	N	Y	Y	N	Y	N	PY	Y	N	Y	Y	Y	Y	N	Y	3	Critically low
Chua et al.(²³)	Y	N	Y	Y	N	N	N	PY	Y	N	Y	Y	Y	Y	N	Y	3	Critically low
Dong et al.(²⁴)	Y	Y	Y	PY	Y	Y	N	Y	Y	N	Y	Y	Y	Y	Y	Y	1	Low
Jackson et al.(²⁵)	Y	N	Y	Y	Y	Y	N	PY	Y	N	Y	Y	Y	Y	Y	Y	2	Critically low
Liu et al.(²⁶)	Y	Y	Y	Y	Y	Y	N	PY	Y	N	Y	Y	Y	Y	Y	Y	1	Low
Xue et al.(²⁷)	Y	Y	Y	PY	Y	Y	N	Y	Y	N	Y	Y	Y	Y	Y	Y	1	Low
Zwager et al.(²⁸)	Y	Y	Y	Y	Y	Y	N	Y	Y	N	Y	Y	Y	Y	Y	Y	1	Low

Author	Mortality in-hospital	ICU mortality	Acute kidney injury	New renal replacement therapy	RRT-free days	MAKE30	Hospital length of stay	ICU length of stay	MV-free days	Vasopressor-free days	Serum chloride concentration changes
Hammond et al.(⁸)	Low risk of bias: RR 0.96; 95%CI 0.91 - 1.01; p = 0.13; I² = 12.1%; 6 RCTs; 34,450 patients Overall: RR 0.93; 95%CI 0.76 - 1.15; p = 0.52; I² = 88.4%; 11 RCTs	Not assessed	Low risk of bias: RR 0.96; 95%CI 0.89 - 1.02; p = 0.20; I² = 8.6%; 5 RCTs; 25,224 patients Overall: RR 0.96; 95%CI 0.83 - 1.11; p = 0.54; I² = 72.6%; 10 RCTs	Low risk of bias: RR 0.95; 95%CI 0.81 - 1.11; p = 0.53; I²= 59.5%; 5 RCTs; 33,554 patients Overall: RR 0.91; 95%CI 0.66 - 1.24; p = 0.54; I² = 86.5%; 9 RCTs	Not assessed	Not assessed	Not assessed	Not assessed	MD 0.18; 95%CI -0.45 - 0.81; p = 0.58; I² = 79.5%; 5 RCTs; 32,191 patients	MD 0.19; 95%CI -0.13 - 0.51]; p = 0.25; I² = 24.1%; 3 RCTs; 21,62 2 patients	Not assessed
Zampieri et al.(⁹)	OR 0.96; 95%CI 0.91 - 1.02; 6 RCTs; 34,479 patients	Not assessed	Not assessed	OR 0.93; 95%CI 0.85 - 1.02; 6 RCTs; 33,431 patients	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed
Liu et al.(¹⁸)	OR 0.91; 95%CI 0.83 - 0.99; I² = 8%	Not assessed	OR 0.98; 95%CI 0.81 - 1.15; I² = 7%	OR 0.96; 95%CI 0.74 - 1.45; I² = 15%	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed
Tseng et al.(¹⁹)	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed
Hammond et al.(²⁰)	RR 0.86; 95%CI 0.75 - 0.99; p = 0.04; I² = 63%; 6 RCTs + 4 observational studies; 31,116 patients	RR 0.90; 95%CI 0.82 - 0.98; p = 0.02; I² = 0%; 5 RCTs; 1,759 patients	RR 0.91; 95%CI 0.85 - 0.98; p = 0.007; I² = 0%; 5 RCTs + 3 observational studies; 29,255 patients	RR 0.93; 95%CI 074-1.17; p = 0.55; I² = 38%; 3 RCTs + 3 observational studies; 24,566 patients	Not assessed	Not assessed	MD 0.27 days; 95% CI [-0.47, 0.70]; p = 0.57; I² = 52%; 3 RCTs + 2 observational studies	MD 0.00 days; 95% CI [-0.11, 0.12]; p = 0.98; I² = 0%; 3 RCTs + 2 observational studies	MD 0.31 days; 95% CI [0.04, 0.57]; p = 0.02; I² = 0%; 3 RCTs	Not assessed	MD -7.40; 95%CI -11.78 - -3.01; p = 0.0009; I² = 82%; 1 RCT + 2 observational studies
González-Castro et al.(²¹) (adjusted OR)	OR 0.92; 95%CI 0.85 - 0.99; I² = 0%; 8 RCTs; 20,684 patients	Not assessed	OR 1.00; 95%CI 0.99 - 1.01; I² = 0%; 7 RCTs	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed
Zayed et al.(²²)	OR 0.92; 95%CI 0.85 - 1.01; p = 0.09; I² = 0%; 5 RCTs	OR 0.90; 95%CI 0.81 -1.01; p = 0.08; I² = 0%; 4 RCTs	OR 0.92; 95%CI 0.84 - 1.01; p = 0.1; I² = 0%; 5 RCTs	OR 0.92; 95%CI 0.67 - 1.28; p = 0.65; I² = 38%; 5 RCTs	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed
Chua et al.(²³)	RR 0.91; 95%CI 0.82 -1.01; p = 0.09; I² = 0%; 4 RCTs; 19,105 patients	Not assessed	RR 0.94; 95%CI 0.87 - 1.02; p = 0.17; I² = 0%; 4 RCTs; 18,147 patients	RR 0.91; 95%CI 0.77 - 1.07; p = 0.26; I² = 19%; 4 RCTs; 18,319 patients	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed
Dong et al.(²⁴)	RR 0.96; 95%CI 0.92 - 1.01; p = 0.09; I² = 0%; 7 RCTs; 34,517 patients	Not assessed	RR 0.95; 95%CI 0.90 - 1.01; p = 0.08; I² = 0%; 7 RCTs; 24,593 patients	RR 0.93; 95%CI 0.86 - 1.02; p = 0.11; I² = 19%; 7 RCTs; 33,830 patients	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed
Jackson et al.(²⁵)	RR 0.92; 95%CI 0.85 - 1.00; p = 0.05; I² = 0%; 6 RCTs; 20,105 patients	RR 0.91; 95%CI 0.82 - 1.00; p = 0.06; 6 RCTs; 20,125 patients	RR 0.94; 95%CI 0.86 - 1.02; p = 0.11; I² = 0%; 3 RCTs; 18,082 patients	RR 0.91; 95%CI 0.77 - 1.027; p = 0.26; I² = 19%; 4 RCTs; 18,319 patients	Not assessed	RR 0.95; 95%CI 0.88 - 1.01; p = 0.11; I² = 0%; 4 RCTs; 18,933 patients	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed
Liu et al.(²⁶)	RR 0.93; 95%CI 0.86 - 1.01; p = 0.08; I² = 0%; 8 RCTs; 20,345 patients	Not assessed	RR 0.94; 95%CI 0.88 - 1.00; p = 0.06; I² = 0%; 7 RCTs; 19,203 patients	RR 0.94; 95%CI 0.69 - 1.27; p = 0.67; I² = 39%; 5 RCTs	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed
Xue et al.(²⁷)	RR 0.92; 95%CI 0.85 - 1.00; p = 0.06; I² = 0%; 8 RCTs; 19,301 patients	Not assessed	RR 0.93; 95%CI 0.86 - 1.01; p = 0.09; I² = 0%; 6 RCTs; 18,261 patients	RR 0.91; 95%CI 0.77 - 1.07; p = 0.24; I² = 20%; 5 RCTs; 18,379 patients	SMD 0.09; 95%CI 0.06 - 0.12; p < 0.00001; I² = 0%; 2 RCTs	RR 0.93; 95%CI 0.88 - 1.00; p = 0.04; I² = 0%; 2 RCTs; 16,696 patients	Not assessed	Not assessed	SMD 0.08, 95%CI 0.05 - 0.11; p < 0.001; I² = 0%; 3 RCTs; 16,822 patients	SMD 0.04, 95%CI 0.00 - 0.07; p = 0.02; I² = 0%; 2 RCTs; 16,776 patients	SMD -1,23; 95%CI -1.59 - -0.87; p < 0.00001; I² = 0%; 3 RCTs
Zwager et al.(²⁸)	RR 0.94; 95%CI 0.82 - 1.07; p = 0.36; I² = 0%; 5 RCTs; 6,350 patients	Not assessed	RR 0.95; 95%CI 0.86 - 1.06; p = 0.40; I² = 0%; 6 RCTs; 6,417 patients	RR 0.87; 95%CI 0.63 - 1.20; p = 0.41; I² = 9%; 5 RCTs; 6,401 patients	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed
Chen et al.(²⁹)	RR 0.96; 95%CI 0.93 - 1.00; p = 0.03; I² = 0%; 18 RCTs; 36,244 patients	RR 0.97; 95%CI 0.87 - 1.08; p = 0.57; 6 RCTs; 23,992 patients	RR 0.93; 95%CI 0.87 - 0.99; p = 0.03; I² = 0%; 8 RCTs; 28,918 patients	RR 0.95; 95%CI 0.83 - 1.08; p = 0.34; I² = 0%; 7 RCTs; 23,294 patients	Not assessed	Not assessed	SMD -0.07; 95% CI [-0.41, 0.27]; p = 0.64; I² = 39%; 7 RCTs; 357 patients	Not assessed	SMD 0.03; 95%CI -0.01 - 0.07; p = 0.10; I² = 0%; 3 RCTs; 21,363 patients	Not assessed	Not assessed

Author	Mortality (sepsis)	AKI (sepsis)	RRT (sepsis)	MAKE30 (sepsis)	Mortality (non-sepsis)	Mortality (TBI)	Mortality (non-TBI)
Hammond et al.(⁸)	Low risk of bias: RR 0.93; 95%CI 0.86 - 1.01; p = 0.10; I² = 22.3%; 5 RCTs; 6,754 patients Overall: RR 0.93; 95%CI 0.85 - 1.01; p = 0.07; I² = 19.3%; 6 RCTs	Not assessed	Not assessed	Not assessed	Not assessed	RR 1.26; 95%CI 0.98 - 1.60; p = 0.07; I² = 20.2%; 3 RCTs; 1,896 patients	Not assessed
Zampieri et al.(⁹)	OR 0.95; 95%CI 0.88 - 1.03; 6 RCTs; 6,753 patients	Not assessed	OR 0.88; 95%CI 0.77 - 1.00; 6 RCTs; 6,686 patients	Not assessed	OR 0.98; 95%CI 0.92 - 1.05; 6 RCTs; 27,707 patients	OR 1.36; 95%CI 1.09 - 1.70; 6 RCTs; 1,961 patients	OR 0.95; 95%CI 0.90 - 1.00; 6 RCTs; 32,502 patients
Liu et al.(¹⁸)	OR 1.01; 95%CI 0.46 - 2.10; I² = 20%	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed
Tseng et al.(¹⁹)	OR 0.84; 95%CI 0.74 - 0.95; p < 0.01; moderate confidence rating	OR 0.98; 95%CI 0.82 - 1.17; low confidence rating	Not assessed	Not assessed	Not assessed	OR 1.29; 95%CI 0.33 - 5.03; very low confidence rating	Not assessed
Hammond et al.(²⁰)	OR 0.98; 95%CI 0.80 - 1.20; p = 0.86; I² = 0%; 1 RCT + 2 observational studies; 7,292 patients	Not assessed	Not assessed	OR 0.78; 95%CI 0.66 - 0.91; p = 0.002; I² = 42%; 2 RCTs; 939 patients	Not assessed	Not assessed	Not assessed
González-Castro et al.(²¹)	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed
Zayed et al.(²²)	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed
Chua et al.(²³)	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed
Dong et al.(²⁴)	RR 0.94; 95%CI 0.87 - 1.00; p = 0.04; I² = 0%; 4 RCTs; 6,501 patients	Not assessed	Not assessed	Not assessed	RR 0.98; 95%CI 0.92 - 1.04; p = 0.46; I² = 0%; 4 RCTs; 26,925 patients	RR 1.24; 95%CI 1.02 - 1.50; p = 0.03; I² = 7%; 3 RCTs; 1,906 patients	RR 0.94; 95%CI 0.90 - 0.99; p = 0.02; I² = 0%; 4 RCTs; 31,534 patients
Jackson et al.(²⁵)	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed
Liu et al.(²⁶)	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed
Xue et al.(²⁷)	RR 0.86; 95%CI 0.75 - 0.98; p = 0.02; I² = 0%; 2 RCTs; 2,420 patients	Not assessed	Not assessed	RR 0.81; 95%CI 0.66 - 1.01; p = 0.21; I² = 61%; 2 RCTs; 2,596 patients	RR 0.96; 95%CI 0.86 - 1.07; p = 0.48; I² = 0%; 5 RCTs; 15,794 patients	RR 1.11; 95%CI 0.86 - 1.43; p = 0.43; I² = 0%; 2 RCTs; 1,420 patients	RR 0.90; 95%CI 0.82 - 0.99; p = 0.02; I² = 0%; 5 RCTs; 16,794 patients
Zwager et al.(²⁸)	RR 0.87; 95%CI 0.77 - 0.98; p = 0.02; I² = 0%; 2 RCTs; 1,873 patients	Not assessed	Not assessed	Not assessed	RR 0.96; 95%CI 0.82 - 1.11; p = 0.59; I² = 0%;2 RCTs; 5,692 patients	Not assessed	Not assessed
Chen et al.(²⁹)	RR 0.91; 95%CI 0.85 - 0.99; p = 0.02; 6 RCTs; 6,914 patients	Not assessed	Not assessed	Not assessed	Not assessed	RR 1.26; 95%CI 0.93 - 1.70; p = 0.13; 4 RCTs; 1,927 patients	Not assessed

Author	Mortality (trauma)	AKI (trauma)	Mortality (surgical)	AKI (surgical)	Mortality (after cardiac surgery)	Mortality (hypovolemia)	Mortality (elderly)	Mortality (AKI)	Mortality (DKA)
Hammond et al.(⁸)	Low risk of bias: RR 0.93; 95%CI 0.86 - 1.01; p = 0.10; I² = 22.3%; 5 RCTs; 6,754 patients Overall: RR 0.93; 95%CI 0.85 - 1.01; p = 0.07; I² = 19.3%; 6 RCTs	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed
Zampieri et al.(⁹)	OR 0.95; 95%CI 0.88 - 1.03; 6 RCTs; 6,753 patients	Not assessed	OR 0.88; 95%CI 0.77-1.00; 6 RCTs; 6,686 patients	Not assessed	OR 0.98; 95%CI 0.92 - 1.05; 6 RCTs; 27,707 patients	Not assessed	Not assessed	Not assessed	Not assessed
Liu et al.(¹⁸)	OR 0.45; 95%CI 0.07 - 2.15; I² = 20%	Not assessed	Not assessed	Not assessed	Not assessed	OR 0.90; 95%CI 0.32 - 2.52; I² = 22%	OR 1.00; 95%CI 0.03 - 28.55; I² = 89%	Not assessed	Not assessed
Tseng et al.(¹⁹)	OR 0.84; 95%CI 0.74 - 0.95; p < 0.01; moderate confidence rating	OR 0.98; 95% CI 0.82 - 1.17; low confidence rating	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed
Hammond et al.(²⁰)	OR 0.98; 95%CI 0.80 - 1.20; p = 0.86; I² = 0%; 1 RCT + 2 observational studies; 7,292 patients	Not assessed	Not assessed	OR 0.78; 95%CI 0.66-0.91; p = 0.002; I² = 42%; 2 RCTs; 939 patients	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed
González-Castro et al.(²¹)	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed
Zayed et al.(²²)	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed
Chua et al.(²³)	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed
Dong et al.(²⁴)	RR 0.94; 95%CI 0.87 - 1.00; p = 0.04; I² = 0%; 4 RCTs; 6,501 patients	Not assessed	Not assessed	Not assessed	RR 0.98; 95%CI 0.92-1.04; p = 0.46; I² = 0%; 4 RCTs; 26,925 patients	Not assessed	Not assessed	Not assessed	Not assessed
Jackson et al.(²⁵)	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed
Liu et al.(²⁶)	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed
Xue et al.(²⁷)	RR 0.86; 95%CI 0.75 - 0.98; p = 0.02; I² = 0%; 2 RCTs; 2,420 patients	Not assessed	Not assessed	RR 0.81; 95%CI 0.66 - 1.01; p = 0.21; I² = 61%; 2 RCTs; 2,596 patients	RR 0.96; 95%CI 0.86 - 1.07; p = 0.48; I² = 0%; 5 RCTs; 15,794 patients	Not assessed	Not assessed	Not assessed	Not assessed
Zwager et al.(²⁸)	RR 0.87; 95%CI 0.77 - 0.98; p = 0.02; I² = 0%; 2 RCTs; 1,873 patients	Not assessed	Not assessed	Not assessed	RR 0.96; 95%CI 0.82 - 1.11; p = 0.59; I² = 0%; 2 RCTs; 5,692 patients	Not assessed	Not assessed	Not assessed	Not assessed
Chen et al.(²⁹)	RR 0.91; 95%CI 0.85 - 0.99; p = 0.02; 6 RCTs; 6,914 patients	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	Not assessed	RR 0.98; 95%CI 0.92 - 1.04; p = 0.46; 4 RCTs; 5,607 patients	RR 0.78; 95%CI 0.24 - 2.49; p = 0.67; 3 RCTs; 149 patients

Outcome	No. of systematic reviews	Approx. total patients	Direction of effect	Consistency across reviews	Certainty of evidence (if reported)
Mortality	13	~6,000 - 35,000	↓ ↔ Small reduction or neutral	High consistency	Low–moderate
Mortality in sepsis	9	~2,000 - 7,000	↓ ↔ Small reduction or neutral	Moderate consistency	Low
Mortality in TBI	6	~1,400 - 2,000	↑↔ Small increase or neutral	Moderate consistency	Very low
Mortality in non-TBI	3	~16,000 - 32,000	↓ ↔ Small reduction or neutral	High consistency	Very low
Acute kidney injury	12	~6,000 - 30,000	↔	High consistency	Low–moderate
Renal replacement therapy	13	~6,000 - 34,000	↔	Low–moderate consistency	Very low–low

[TFN1] RCT - randomized clinical trial; AKI - acute kidney injury; RRT - renal replacement therapy; MV - mechanical ventilation; ICU - intensive care unit; TBI - traumatic brain injury; MAKE30: composite outcome assessing major adverse kidney events within 30 days, including mortality, initiation of renal replacement therapy, and persistent renal dysfunction.

Balanced crystalloids versus saline for critically ill patients: an overview of systematic reviews