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Balanced crystalloids versus normal saline for fluid resuscitation in critically ill patients: A systematic review and meta-analysis with trial sequential analysis

  • Author Footnotes
    1 Chao Liu, Guangming Lu and Dong Wang contributed equally to this work.
    Chao Liu
    Footnotes
    1 Chao Liu, Guangming Lu and Dong Wang contributed equally to this work.
    Affiliations
    Department of Critical Care Medicine, Chinese People's Liberation Army General Hospital, Beijing, People's Republic of China
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  • Author Footnotes
    1 Chao Liu, Guangming Lu and Dong Wang contributed equally to this work.
    Guangming Lu
    Footnotes
    1 Chao Liu, Guangming Lu and Dong Wang contributed equally to this work.
    Affiliations
    Department of Health Management Institute, Chinese People's Liberation Army General Hospital, Beijing, People's Republic of China

    Department of National Clinical Research Center for Geriatric Diseases, Chinese People's Liberation Army General Hospital, Beijing, People's Republic of China
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  • Author Footnotes
    1 Chao Liu, Guangming Lu and Dong Wang contributed equally to this work.
    Dong Wang
    Footnotes
    1 Chao Liu, Guangming Lu and Dong Wang contributed equally to this work.
    Affiliations
    Scientific Research Division of the Medical Administration Department, Chinese People's Liberation Army General Hospital, Beijing, People's Republic of China
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  • Yi Lei
    Affiliations
    Department of Anesthesiology, Military General Hospital of Xinjiang People's Liberation Army, Urumqi, People's Republic of China
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  • Zhi Mao
    Affiliations
    Department of Critical Care Medicine, Chinese People's Liberation Army General Hospital, Beijing, People's Republic of China
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  • Pan Hu
    Affiliations
    Department of Critical Care Medicine, Chinese People's Liberation Army General Hospital, Beijing, People's Republic of China
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  • Jie Hu
    Affiliations
    Department of Critical Care Medicine, Chinese People's Liberation Army General Hospital, Beijing, People's Republic of China
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  • Rui Liu
    Affiliations
    Department of Critical Care Medicine, Tangdu Hospital, Forth Military Medical University, Xian, People's Republic of China
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  • Dong Han
    Affiliations
    Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, People's Republic of China
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  • Feihu Zhou
    Correspondence
    Corresponding author at: Critical Care Medicine, Chinese People's Liberation Army General Hospital, 28 Fu-Xing Road, Beijing 100853, People's Republic of China.
    Affiliations
    Department of Critical Care Medicine, Chinese People's Liberation Army General Hospital, Beijing, People's Republic of China

    National Clinical Research Center for Kidney Diseases, Chinese People's Liberation Army General Hospital, Beijing, People's Republic of China
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  • Author Footnotes
    1 Chao Liu, Guangming Lu and Dong Wang contributed equally to this work.
Open AccessPublished:March 01, 2019DOI:https://doi.org/10.1016/j.ajem.2019.02.045

      Abstract

      Introduction

      Fluid resuscitation is a fundamental component of the management of critically ill patients, but whether choice of crystalloid affects patient outcomes remains controversial. Therefore, we performed this meta-analysis to compare the efficacy and safety of balanced crystalloids with normal saline.

      Methods

      We searched the MEDLINE, Cochrane Central and EMBASE up to October 2018 to identify randomized controlled trials (RCTs) that compared balanced crystalloids versus normal saline in critically ill patients. The primary outcome was mortality. The secondary results were the incidence of acute kidney injury (AKI) and risk of receiving renal replacement therapy (RRT). Two authors independently screened articles based on the inclusion and exclusion criteria. The meta-analysis was conducted using Revman 5.3, trial sequential analysis (TSA) 0.9 and STATA 12.0.

      Results

      Nine RCTs were identified. The pooled analyses showed that there were no significant differences in mortality (relative risk (RR) = 0.93, 95% confidence interval (CI) = 0.86, 1.01, P = 0.08), incidence of AKI (RR 0.94, 95% CI 0.88, 1.00, P = 0.06) or RRT use rate (RR 0.94, 95% CI 0.69, 1.27, P = 0.67) between balanced crystalloids and normal saline groups. However, TSA did not provide conclusive evidence.

      Conclusions

      Among critically ill patients receiving crystalloid fluid therapy, use of a balanced crystalloid compared with normal saline did not reduce the mortality, risk of severe AKI or RRT use rate. Further large randomized clinical trials are needed to confirm or refute this finding.

      Trial registration

      A protocol of this meta-analysis has been registered on PROSPERO (registration number: CRD42018094857).

      Keywords

      1. Introduction

      Fluid resuscitation is a fundamental component of the management of critically ill patients, but whether choice of crystalloid affects patient outcomes remains controversial [
      • Young P.
      Saline is the solution for crystalloid resuscitation.
      ,
      • Myburgh J.A.
      • Mythen M.G.
      Resuscitation fluids.
      ]. Currently, normal saline is the most commonly used resuscitation fluid. However, concern has focused on the hypothesis that the high chloride content of saline contributes to the development of acute kidney injury (AKI) [
      • Yunos N.M.
      • 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.
      ,
      • Yunos N.M.
      • Bellomo R.
      • Glassford N.
      • Sutcliffe H.
      • Lam Q.
      • Bailey M.
      Chloride-liberal vs. chloride-restrictive intravenous fluid administration and acute kidney injury: an extended analysis.
      ]. Alternatives to normal saline include crystalloids with electrolyte compositions that more close resemble that of plasma, such as Lactated Ringer's solution, Hartmann solution, or Plasma-Lyte [
      • Semler M.W.
      • Rice T.W.
      Saline is not the first choice for crystalloid resuscitation fluids.
      ,
      • Young P.
      • Bailey M.
      • Beasley R.
      • Henderson S.
      • Mackle D.
      • McArthur C.
      • et al.
      Effect of a buffered crystalloid solution vs saline on acute kidney injury among patients in the intensive care unit: the SPLIT randomized clinical trial.
      ]. Although observational data suggest that those balanced crystalloids may be associated with a decreased risk of severe AKI, this advantage of balanced crystalloids was not found in a recent RCT of critically ill patients [
      • Young P.
      • Bailey M.
      • Beasley R.
      • Henderson S.
      • Mackle D.
      • McArthur C.
      • et al.
      Effect of a buffered crystalloid solution vs saline on acute kidney injury among patients in the intensive care unit: the SPLIT randomized clinical trial.
      ].
      Our previous network meta-analysis [
      • Liu C.
      • Mao Z.
      • Hu P.
      • Hu X.
      • Kang H.
      • Hu J.
      • et al.
      Fluid resuscitation in critically ill patients: a systematic review and network meta-analysis.
      ], which focused on fluid resuscitation in critically ill patients, found that balanced crystalloids, especially Plasma-Lyte, are presumably the best choice for most critically ill patients who need fluid resuscitation. However, the evidence was not conclusive.
      Recently, three RCTs [
      • Semler M.W.
      • Wanderer J.P.
      • Ehrenfeld J.M.
      • Stollings J.L.
      • Self W.H.
      • Siew E.D.
      • et al.
      Investigators S, the pragmatic critical care research G: balanced crystalloids versus saline in the intensive care unit: the SALT randomized trial.
      ,
      • Verma B.
      • Luethi N.
      • Cioccari L.
      • Lloyd-Donald P.
      • Crisman M.
      • Eastwood G.
      • et al.
      A multicentre randomised controlled pilot study of fluid resuscitation with saline or Plasma-Lyte 148 in critically ill patients.
      ,
      • Semler M.W.
      • Self W.H.
      • Wanderer J.P.
      • Ehrenfeld J.M.
      • Wang L.
      • Byrne D.W.
      • et al.
      Investigators S, the pragmatic critical care research G: balanced crystalloids versus saline in critically ill adults.
      ] have been published that provide new evidence on this topic, but the findings are not entirely consistent with each other. To provide the most recent available evidence, we conducted this meta-analysis to evaluate the efficacy and safety of balanced crystalloids versus normal saline for fluid resuscitation in critically ill patients, and we further used trial sequential analysis (TSA) to determine whether the current evidence was robust and conclusive.

      2. Methods

      The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMAs) were used to perform this meta-analysis [
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      • Group P
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      ].

      2.1 Search strategy

      A literature search of MEDLINE, Cochrane Central and EMBASE databases from database inception to October 2018 was performed. The search terms used were “normal saline” or “isotonic saline” or “sodium chloride” compared with “lactated ringer” or “Hartmann” or “Plasma-Lyte” or “buffered crystalloid” or “balanced crystalloids” and “randomized” or “randomized”. The searches were limited to published studies in human subjects. There were no language restrictions. We also hand-searched conference proceedings and the reference lists of review articles (Appendix A).

      2.2 Eligibly criteria

      The inclusion criteria were as follows: 1) population: critically ill patients (≥18 years old) requiring fluid resuscitation, the length of follow up was according to the included studies; 2) intervention: balanced crystalloids (contains Lactated Ringer's, Hartmann and Plasma-Lyte); 3) comparison: normal saline; 4) outcome measure: the primary outcome was mortality. The secondary outcomes were incidences requiring RRT and the incidence of AKI (AKI of stage 2 or higher (according to the Kidney Disease: Improving Global Outcomes plasma creatinine criteria) and injury or higher (according to the RIFLE categories)); 5) study design: RCT.
      The exclusion criteria were as follows: 1) patients with pre-existing chronic renal failure; 2) patients younger than 18 years old; 3) repeated data; 4) fluids used as maintenance rather than resuscitation.

      2.3 Study selection

      Two independent investigators performed the study selection. Disagreements between two investigators were resolved in meetings or adjudicated by a third reviewer.

      2.4 Data extraction

      Two independent reviewers (CL and GML) performed the data extraction using a standardized form. The following data on study characteristics were collected: first author, publication year, study design, number of patients, mean age of patients, patient characteristics, and balanced crystalloids type. The other two independent reviewers (DW and JH) checked the data to make sure it was correct. The methodological quality of included trials was assessed by two reviewers according to the Cochrane Risk of Bias Tool.

      2.5 Grading the quality of evidence

      Two reviewers evaluated the quality of evidence according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. Based on risk of bias, indirectness, imprecision, inconsistency and publication bias, the quality of the evidence was classified as high, moderate, low or very low. The software of GRADE Pro version 3.6 was used for this analysis.

      2.6 Statistical analysis

      Dichotomous outcomes were expressed as relative risks (RRs) with 95% confidence intervals (CI), and continuous outcomes were expressed as the mean difference (MD) with 95% CI. Statistical heterogeneity across studies was analyzed by using the I2 statistic. An I2 > 50% indicated significant heterogeneity [
      • Higgins J.P.
      • Thompson S.G.
      • Deeks J.J.
      • Altman D.G.
      Measuring inconsistency in meta-analyses.
      ]. The fixed-effect model was used to analyze results with acceptable or no heterogeneity, and the random-effect model was used to analyze results with significant heterogeneity. Subgroup and sensitivity analyses were performed to investigate potential between-study heterogeneities and estimate other potentially confounding factors. Statistical analyses were performed using Review Manager, version 5.3 (RevMan, The Cochrane Collaboration, Oxford, UK). The Begg and Egger tests were employed using STATA 12.0 (Stata Corporation, College Station, TX, USA). A P value <0.05 was considered a statistically significant.

      2.7 Trial sequential analysis

      To determine whether the evidence from a meta-analysis is reliable and conclusive and to reduce the risk of reaching a false-positive or false-negative conclusion, the trial sequential analysis (TSA) was used [
      • Liu C.
      • Mao Z.
      • Kang H.
      • Hu J.
      • Zhou F.
      Regional citrate versus heparin anticoagulation for continuous renal replacement therapy in critically ill patients: a meta-analysis with trial sequential analysis of randomized controlled trials.
      ]. This method, which combines an a priori information size calculation with the adaptation of monitoring boundaries, can be used to control the P value and widen the confidence intervals [
      • Wetterslev J.
      • Thorlund K.
      • Brok J.
      • Gluud C.
      Estimating required information size by quantifying diversity in random-effects model meta-analyses.
      ]. When the cumulative z-curve enters the futility area or crosses the trial sequential monitoring boundary, the anticipated intervention effect may reach a sufficient level of evidence. If the z-curve does not cross any of the boundaries and the required information size has not been reached, the evidence is inadequate to reach a conclusion [
      • Mao Z.
      • Gao L.
      • Wang G.
      • Liu C.
      • Zhao Y.
      • Gu W.
      • et al.
      Subglottic secretion suction for preventing ventilator-associated pneumonia: an updated meta-analysis and trial sequential analysis.
      ]. We calculated the required information size based on a relative risk reduction of 10%. The type I error (α) and power (1–β) were set as 0.05 and 0.90, respectively. The control event rates were calculated from the normal saline group. The TSA was conducted with the use of TSA version 0.9 beta software (http://www.ctu.dk/tsa).

      3. Results

      3.1 Search results and study characteristics

      The process of study selection is outlined in Fig. 1. In total, nine studies [
      • Young P.
      • Bailey M.
      • Beasley R.
      • Henderson S.
      • Mackle D.
      • McArthur C.
      • et al.
      Effect of a buffered crystalloid solution vs saline on acute kidney injury among patients in the intensive care unit: the SPLIT randomized clinical trial.
      ,
      • Semler M.W.
      • Wanderer J.P.
      • Ehrenfeld J.M.
      • Stollings J.L.
      • Self W.H.
      • Siew E.D.
      • et al.
      Investigators S, the pragmatic critical care research G: balanced crystalloids versus saline in the intensive care unit: the SALT randomized trial.
      ,
      • Verma B.
      • Luethi N.
      • Cioccari L.
      • Lloyd-Donald P.
      • Crisman M.
      • Eastwood G.
      • et al.
      A multicentre randomised controlled pilot study of fluid resuscitation with saline or Plasma-Lyte 148 in critically ill patients.
      ,
      • Semler M.W.
      • Self W.H.
      • Wanderer J.P.
      • Ehrenfeld J.M.
      • Wang L.
      • Byrne D.W.
      • et al.
      Investigators S, the pragmatic critical care research G: balanced crystalloids versus saline in critically ill adults.
      ,
      • Young J.B.
      • Utter G.H.
      • Schermer C.R.
      • Galante J.M.
      • Phan H.H.
      • Yang Y.
      • et al.
      Saline versus Plasma-Lyte A in initial resuscitation of trauma patients: a randomized trial.
      ,
      • Annane D.
      • Siami S.
      • Jaber S.
      • Martin C.
      • Elatrous S.
      • Declere A.D.
      • et al.
      Effects of fluid resuscitation with colloids vs crystalloids on mortality in critically ill patients presenting with hypovolemic shock: the CRISTAL randomized trial.
      ,
      • Choosakul S.
      • Harinwan K.
      • Chirapongsathorn S.
      • Opuchar K.
      • Sanpajit T.
      • Piyanirun W.
      • et al.
      Comparison of normal saline versus lactated Ringer's solution for fluid resuscitation in patients with mild acute pancreatitis.
      ,
      • Wu B.U.
      • Hwang J.Q.
      • Gardner T.H.
      • Repas K.
      • Delee R.
      • Yu S.
      • et al.
      Lactated Ringer's solution reduces systemic inflammation compared with saline in patients with acute pancreatitis.
      ,

      Ratanarat R; Sanguanwit PCA: The effects of normal saline versus balanced crystalloid solution as a resuscitation fluid on acute kidney injury in shock patients: a randomized opened label-controlled trial.23–27, 2017. 30th Annu Congr Eur Soc intensive care Med ESICM 2017 2017.

      ] met the inclusion criteria. The main characteristics of the included studies are summarized in Table 1. These studies were published between 2011 and 2018. Six studies [
      • Young P.
      • Bailey M.
      • Beasley R.
      • Henderson S.
      • Mackle D.
      • McArthur C.
      • et al.
      Effect of a buffered crystalloid solution vs saline on acute kidney injury among patients in the intensive care unit: the SPLIT randomized clinical trial.
      ,
      • Semler M.W.
      • Wanderer J.P.
      • Ehrenfeld J.M.
      • Stollings J.L.
      • Self W.H.
      • Siew E.D.
      • et al.
      Investigators S, the pragmatic critical care research G: balanced crystalloids versus saline in the intensive care unit: the SALT randomized trial.
      ,
      • Verma B.
      • Luethi N.
      • Cioccari L.
      • Lloyd-Donald P.
      • Crisman M.
      • Eastwood G.
      • et al.
      A multicentre randomised controlled pilot study of fluid resuscitation with saline or Plasma-Lyte 148 in critically ill patients.
      ,
      • Semler M.W.
      • Self W.H.
      • Wanderer J.P.
      • Ehrenfeld J.M.
      • Wang L.
      • Byrne D.W.
      • et al.
      Investigators S, the pragmatic critical care research G: balanced crystalloids versus saline in critically ill adults.
      ,
      • Annane D.
      • Siami S.
      • Jaber S.
      • Martin C.
      • Elatrous S.
      • Declere A.D.
      • et al.
      Effects of fluid resuscitation with colloids vs crystalloids on mortality in critically ill patients presenting with hypovolemic shock: the CRISTAL randomized trial.
      ,

      Ratanarat R; Sanguanwit PCA: The effects of normal saline versus balanced crystalloid solution as a resuscitation fluid on acute kidney injury in shock patients: a randomized opened label-controlled trial.23–27, 2017. 30th Annu Congr Eur Soc intensive care Med ESICM 2017 2017.

      ] focused on patients in ICU, two studies [
      • Choosakul S.
      • Harinwan K.
      • Chirapongsathorn S.
      • Opuchar K.
      • Sanpajit T.
      • Piyanirun W.
      • et al.
      Comparison of normal saline versus lactated Ringer's solution for fluid resuscitation in patients with mild acute pancreatitis.
      ,
      • Wu B.U.
      • Hwang J.Q.
      • Gardner T.H.
      • Repas K.
      • Delee R.
      • Yu S.
      • et al.
      Lactated Ringer's solution reduces systemic inflammation compared with saline in patients with acute pancreatitis.
      ] focused on patients with acute pancreatitis and one study [
      • Young J.B.
      • Utter G.H.
      • Schermer C.R.
      • Galante J.M.
      • Phan H.H.
      • Yang Y.
      • et al.
      Saline versus Plasma-Lyte A in initial resuscitation of trauma patients: a randomized trial.
      ] included trauma patients.
      Table 1Characteristics of included studies.
      StudySettingPopulationNo. of patients (M/F)Mean age (years)SeverityBalanced crystalloids typeFluid volume (24 h)
      Annane D [
      • Annane D.
      • Siami S.
      • Jaber S.
      • Martin C.
      • Elatrous S.
      • Declere A.D.
      • et al.
      Effects of fluid resuscitation with colloids vs crystalloids on mortality in critically ill patients presenting with hypovolemic shock: the CRISTAL randomized trial.
      ] (2013; multi-country)
      57 participating ICUsSepsis, trauma, or hypovolemic shock without sepsis or traumaBC: 72 (NR)

      NS: 1035 (NR)
      63 (50–75)SAPSII: 50 (36–65)
      Median (interquartile range).
      Lactated ringer'sNR
      Young JB [
      • Young J.B.
      • Utter G.H.
      • Schermer C.R.
      • Galante J.M.
      • Phan H.H.
      • Yang Y.
      • et al.
      Saline versus Plasma-Lyte A in initial resuscitation of trauma patients: a randomized trial.
      ] (2014; United States)
      Level 1 trauma centerAdult trauma patients (≥18 years) requiring blood transfusion, intubation, or operation within 60 minBC: 22 (16/6)

      NS: 24 (19/5)
      BC: 38 ± 19
      Mean ± standard error.


      NS: 39 ± 14
      Mean ± standard error.
      BC: 24 ± 18 (ISS)
      Mean ± standard error.


      NS: 22 ± 14 (ISS)
      Mean ± standard error.
      Plasma-Lyte ABC: 9000 ± 5500
      Mean ± standard error.


      NS: 10300 ± 6500
      Mean ± standard error.
      Young P [
      • Young P.
      • Bailey M.
      • Beasley R.
      • Henderson S.
      • Mackle D.
      • McArthur C.
      • et al.
      Effect of a buffered crystalloid solution vs saline on acute kidney injury among patients in the intensive care unit: the SPLIT randomized clinical trial.
      ] (2015; Australian and New Zealand)
      Four tertiary ICUsICU patients receiving crystalloid fluid therapy as clinically indicatedBC: 1152 (739/413)

      NS: 1110 (746/364)
      BC: 60.1 ± 16.8
      Mean ± standard error.


      NS: 61.0 ± 16.3
      Mean ± standard error.
      BC: 14.1 ± 6.9 (APACHEII)
      Mean ± standard error.


      NS: 14.1 ± 6.7 (APACHEII)
      Mean ± standard error.
      Plasma-Lyte 148NR
      Verma B [
      • Verma B.
      • Luethi N.
      • Cioccari L.
      • Lloyd-Donald P.
      • Crisman M.
      • Eastwood G.
      • et al.
      A multicentre randomised controlled pilot study of fluid resuscitation with saline or Plasma-Lyte 148 in critically ill patients.
      ] (2016; Australia)
      Three multidisciplinary ICUsICU patients (≥18 years) receiving crystalloid fluid resuscitationBC: 33 (21/12)

      NS: 34 (21/13)
      BC: 62 (45–70)
      Median (interquartile range).


      NS: 64 (46–72)
      Median (interquartile range).
      BC: 55 (44–81) (APACHEIII)
      Median (interquartile range).


      NS: 64 (48–73) (APACHEIII)
      Median (interquartile range).
      Plasma-Lyte 148BC: 1090 (620–2500)
      Median (interquartile range).


      NS: 1275 (435–2243)
      Median (interquartile range).
      Semler MW [
      • Semler M.W.
      • Wanderer J.P.
      • Ehrenfeld J.M.
      • Stollings J.L.
      • Self W.H.
      • Siew E.D.
      • et al.
      Investigators S, the pragmatic critical care research G: balanced crystalloids versus saline in the intensive care unit: the SALT randomized trial.
      ] (2016; United States)
      A tertiary medical ICUICU patients receiving crystalloid fluid therapyBC: 520 (268/252)

      NS: 454 (246/208)
      BC: 57 (44–68)
      Median (interquartile range).


      NS: 58 (46–70)
      Median (interquartile range).
      NRLactated ringer's solution and Plasma-Lyte ABC: 1424 (500–3377)
      Median (interquartile range).


      NS: 1617 (500–3628)
      Median (interquartile range).
      Semler MW [
      • Semler M.W.
      • Self W.H.
      • Wanderer J.P.
      • Ehrenfeld J.M.
      • Wang L.
      • Byrne D.W.
      • et al.
      Investigators S, the pragmatic critical care research G: balanced crystalloids versus saline in critically ill adults.
      ] (2018; United States)
      Five ICU at an academic centerPatients (≥18 years) who were admitted to a participating ICUBC: 7942 (4540/3402)

      NS: 7860 (4557/3303)
      BC: 58 (44–69)
      Median (interquartile range).


      NS: 58 (44–69)
      Median (interquartile range).
      NRLactated ringer's solution and Plasma-Lyte ABC: 1000 (0−3210)
      Median (interquartile range).


      NS: 1020 (0–3500)
      Median (interquartile range).
      Ratanarat R [

      Ratanarat R; Sanguanwit PCA: The effects of normal saline versus balanced crystalloid solution as a resuscitation fluid on acute kidney injury in shock patients: a randomized opened label-controlled trial.23–27, 2017. 30th Annu Congr Eur Soc intensive care Med ESICM 2017 2017.

      ] (2017; Thailand)
      ICUNRBC: 88 (NR)

      NS: 93 (NR)
      NRNRNRNR
      Wu BU [
      • Wu B.U.
      • Hwang J.Q.
      • Gardner T.H.
      • Repas K.
      • Delee R.
      • Yu S.
      • et al.
      Lactated Ringer's solution reduces systemic inflammation compared with saline in patients with acute pancreatitis.
      ] 2011;
      A 777-bed tertiary care centerPatients (≥18 years) with acute pancreatitisBC: 19 (8/11)

      NS: 21 (14/7)
      BC: 50 (40–73)
      Median (interquartile range).


      NS: 54 (40–60)
      Median (interquartile range).
      BC: 3 (0–6) (APACHEIII)
      Median (interquartile range).


      NS: 3 (1–5) (APACHEIII)
      Median (interquartile range).
      Lactated ringer'sNR
      Choosakul S [
      • Choosakul S.
      • Harinwan K.
      • Chirapongsathorn S.
      • Opuchar K.
      • Sanpajit T.
      • Piyanirun W.
      • et al.
      Comparison of normal saline versus lactated Ringer's solution for fluid resuscitation in patients with mild acute pancreatitis.
      ] 2018;
      A 1200-bed tertiary care center and pancreatic centerPatients (18–80 years old) with acute pancreatitisBC: 23 (12/11)

      NS: 24 (17/7)
      BC: 54.8 ± 20.4
      Mean ± standard error.


      NS: 48.3 ± 13.6
      Mean ± standard error.
      BC: 1 (0–2) (SIRS)
      Median (interquartile range).


      NS: 1 (0–2) (SIRS)
      Median (interquartile range).
      Lactated ringer'sBC: 4929.6 ± 1265.6
      Mean ± standard error.


      NS: 5374.2 ± 768.8
      Mean ± standard error.
      Abbreviations: APACHE, Acute Physiology and Chronic Health Evaluation; BC: Balanced crystalloids; NR, not report; NS: Normal saline; SAPS, Simplified Acute Physiology II score.
      a Mean ± standard error.
      b Median (interquartile range).

      3.2 Risk of bias and grades of evidence

      The risk of bias is summarized in Fig. 2. Randomized sequence generation and allocation concealment were reported adequately in most studies. Three studies were high-quality studies with low risk of bias in all items. The GRADE Working Group grade of evidence was moderate for mortality, incidence of AKI and incidence of RRT use.

      3.3 Primary outcome: mortality

      Eight studies reported mortality, and no statistically significant difference was found between the balanced crystalloids and normal saline groups (RR = 0.93, 95% CI = 0.86, 1.01, P = 0.08, I2 = 0%; Fig. 3a ). The fixed effects model was used to conduct TSA, and the cumulative Z-curve did not enter the futility area and did not cross the conventional boundary (Fig. 3b). Sensitivity analyses were performed to compare Plasma-Lyte with normal saline and compare Lactated Ringer's with normal saline. Similarly, no differences were found (Table 2).
      Fig. 3
      Fig. 3Effect of balanced crystalloids versus normal saline on mortality. a. Forest plot of mortality. b. Trial sequential analysis of mortality. A diversity-adjusted information size of 26,456 participants calculated on the basis of a mortality rate of 13.2% in the normal saline group, relative risk reduction 10%, α = 5% (two sided), β = 10%, and I2 = 0%. The solid blue line represents the cumulative Z-curve, which did not cross the trial sequential monitoring boundary and did not reach the futility area. BC, balanced crystalloids; NS, normal saline; M-H, Mantel-Haenszel. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
      Table 2Other outcomes.
      OutcomesComparisonNumber of studiesRisk ratio (95%CI)Test for effect (P value)Heterogeneity I2 (P value)
      MortalityPL vs NS3 (6,9,16)0,91 (0.69, 1.19)0.480% (0.41)
      LR vs NS3 (17,18,19)1.07 (0,78, 1.47)0.690% (0.48)
      AKI morbidityPL vs NS2 (6, 9)1.08 (0.83, 1.39)0.580% (0.42)
      LR vs NS3 (18,19,20)0.94 (0.54, 1.62)0.820% (0.73)
      RRT use rateBC vs NS5 (6,8,9,10,20)0.94 (0.69, 1.27)0.6739% (0.16)
      PL vs NS2 (6, 9)1.02 (0.67, 1.55)0.930% (0.42)
      LR vs NS1 (20)0.35 (0.12, 1.05)0.06NA
      ICU length of stayBC vs NS6 (6,8,9,16,18,19)−0.31 (−1.60,0.97)0.47100% (<0.01)
      Abbreviations: AKI, Acute kidney injury; BC, Balanced crystalloids; ICU, Intensive care medicine; LR, Lactated ringer's; NA, Not applicable; NS, Normal saline; PL, Plasma-Lyte; RRT, Renal replacement therapy.

      3.4 Secondary outcomes

      3.4.1 Incidence of AKI

      Seven studies reported the incidence of AKI. There was no significant difference between the two groups (RR 0.94, 95% CI 0.88, 1.00, P = 0.06, I2 = 0%; Fig. 4a ). Due to the low heterogeneity, the fixed-effect model was used for TSA, and the results showed that the cumulative Z-curve did not enter the futility area and did not cross the conventional boundary (Fig. 4b). Sensitivity analyses were performed to compare Plasma-Lyte with normal saline and compare Lactated Ringer's with normal saline. Similarly, no differences were found (Table 2).
      Fig. 4
      Fig. 4Effect of balanced crystalloids versus normal saline on AKI incident. a. Forest plot of severe AKI incident. b. Trial sequential analysis of AKI incident. A diversity-adjusted information size of 22,135 participants calculated on the basis of a mortality rate of 15.4% in the normal saline group, relative risk reduction 10%, α = 5% (two sided), β = 10%, I2 = 0%. The solid blue line represents cumulative Z-curve, which did not cross the trial sequential monitoring boundary and did not reach the futility area. AKI, acute kidney injury; BC, balanced crystalloids; M-H, Mantel-Haenszel; NS, normal saline. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

      3.4.2 RRT use rate

      Only five studies reported the RRT use rate, and no significant difference was found between the two groups (RR 0.94, 95% CI 0.69, 1.27, P = 0.67, I2 = 39%; Table 2). Sensitivity analyses were performed to compare the Plasma-Lyte and normal saline. Similarly, no differences were found (Table 2).

      3.4.3 ICU length of stays

      Six studies reported the results for ICU length of stay, and no significant difference was found between the two groups (RR -0.31 95% CI -1.60,0.97, P = 0.47, I2 = 100%; Table 2).

      3.4.4 Publication bias

      Assessment of publication bias using Egger and Begg tests showed that there was no potential publication bias among the included trials (Egger's test, P = 0.25; Begg's test, P = 0.06).

      4. Discussion

      This systematic review and meta-analysis of nine RCTs evaluated the efficacy and safety of balanced crystalloids versus normal saline for fluid resuscitation in critically ill patients. The present meta-analysis suggests that there is no difference in mortality, AKI morbidity and RRT use rate. However, the subsequent TSA did not reach a definitive conclusion. Therefore, further high quality RCTs are needed to confirm or refute this finding.
      An earlier study focused on this topic, which included six RCTs with 19,332 patients, showed no difference on various clinical outcomes including in-hospital mortality, AKI, overall ICU mortality, and new RRT between balanced crystalloids and isotonic saline [
      • Zayed Y.Z.M.
      • Aburahma A.M.Y.
      • Barbarawi M.O.
      • Hamid K.
      • Banifadel M.R.N.
      • Rashdan L.
      • et al.
      Balanced crystalloids versus isotonic saline in critically ill patients: systematic review and meta-analysis.
      ]. Our study included more studies and we further used the TSA analysis to determine whether the evidence from this meta-analysis is reliable and conclusive and to reduce the risk of reaching a false-positive or false-negative conclusion.
      The different fluid types have difference effects on different diseases, populations and genders. For example, patients with sepsis may more sensitive to metabolic acidosis and may suffer more AKI or increased mortality [
      • Suetrong B.
      • Pisitsak C.
      • Boyd J.H.
      • Russell J.A.
      • Walley K.R.
      Hyperchloremia and moderate increase in serum chloride are associated with acute kidney injury in severe sepsis and septic shock patients.
      ,
      • Bonanno L.S.
      Early administration of intravenous fluids in sepsis: pros and cons.
      ]. The patients included in this analysis come from different sources, but with the limited studies included in this meta-analysis, we could not perform more subgroup or sensitivity analyses. Therefore, more studies are needed to evaluate the effect of different fluids on different patients and diseases. Meanwhile, individualized treatments are necessary for each critically ill patient.
      Normal saline is still the most commonly used crystalloid worldwide [
      • Semler M.W.
      • Rice T.W.
      Saline is not the first choice for crystalloid resuscitation fluids.
      ,
      • Zhou F.H.
      • Liu C.
      • Mao Z.
      • Ma P.L.
      Normal saline for intravenous fluid therapy in critically ill patients.
      ]. Many observational studies have shown that the use of normal saline is most likely associated with an increased incidence of AKI, hyperchloremic acidosis, coagulation disturbances, hemodynamic instability and mortality [
      • Marttinen M.
      • Wilkman E.
      • Petaja L.
      • Suojaranta-Ylinen R.
      • Pettila V.
      • Vaara S.T.
      Association of plasma chloride values with acute kidney injury in the critically ill - a prospective observational study.
      ,
      • Shaw A.D.
      • Bagshaw S.M.
      • Goldstein S.L.
      • Scherer L.A.
      • Duan M.
      • Schermer C.R.
      • et al.
      Major complications, mortality, and resource utilization after open abdominal surgery: 0.9% saline compared to Plasma-Lyte.
      ,
      • Pfortmueller C.A.
      • Kabon B.
      • Schefold J.C.
      • Fleischmann E.
      Crystalloid fluid choice in the critically ill: current knowledge and critical appraisal.
      ]. The balanced crystalloids in this meta-analysis contain Lactated Ringer's and Plasma-Lyte. Lactated Ringer's solution is a hypotonic solution (sodium concentration, 130 mmol/L) [
      • Moritz M.L.
      • Ayus J.C.
      Balanced crystalloids versus saline in critically ill adults.
      ] and may lead to hyponatremia when use for resuscitation in critically ill patients [
      • Moritz M.L.
      • Ayus J.C.
      Maintenance intravenous fluids in acutely ill patients.
      ]. Hyponatremia is also an independent predictor for hospital mortality [
      • Holland-Bill L.
      • Christiansen C.F.
      • Heide-Jorgensen U.
      • Ulrichsen S.P.
      • Ring T.
      • Jorgensen J.O.
      • et al.
      Hyponatremia and mortality risk: a Danish cohort study of 279 508 acutely hospitalized patients.
      ]. The electrolyte composition of Plasma-Lyte closely mimics human plasma in its content of electrolytes, osmolality, and pH [
      • Pfortmueller C.A.
      • Fleischmann E.
      Acetate-buffered crystalloid fluids: current knowledge, a systematic review.
      ]. Therefore, we performed sensitivity analysis to compare Plasma-Lyte with normal saline and compare Lactated Ringer's with normal saline. However, no significant differences were found.
      In this meta-analysis we only evaluated mortality, AKI morbidity, RRT use rate and ICU length of stay. However, we did not find any difference between the two groups. Therefore, whether the Plasma-Lyte is more effective than normal saline or Lactated Ringer's needs to be further evaluated. Further studies should also examine other outcomes, such as the incidence of hyponatremia or hospitalization cost.
      Fluid overload frequently occurs in critically ill patients and many studies report its significant association with higher mortality and more RRT [

      Zhang L, Chen Z, Diao Y, Yang Y, Fu P: Associations of fluid overload with mortality and kidney recovery in patients with acute kidney injury: a systematic review and meta-analysis. J Crit Care 2015, 30(4):860 e867–813.

      ,
      • Frazee E.
      • Kashani K.
      Fluid management for critically ill patients: a review of the current state of fluid therapy in the intensive care unit.
      ,
      • Fulop T.
      • Zsom L.
      • Tapolyai M.B.
      • Molnar M.Z.
      • Rosivall L.
      Volume-related weight gain as an independent indication for renal replacement therapy in the intensive care units.
      ,
      • Jaffee W.
      • Hodgins S.
      • McGee W.T.
      Tissue edema, fluid balance, and patient outcomes in severe sepsis: an organ systems review.
      ]. Several studies have shown that normal saline (due to its high sodium content) may result in more fluid overload [
      • Pfortmueller C.A.
      • Kabon B.
      • Schefold J.C.
      • Fleischmann E.
      Crystalloid fluid choice in the critically ill: current knowledge and critical appraisal.
      ,
      • Bihari S.
      • Taylor S.
      • Bersten A.D.
      Inadvertent sodium loading with renal replacement therapy in critically ill patients.
      ]. In this meta-analysis, the fluid volume had a significant diversity between each study, but whether a patient's exposure to a positive or negative fluid balance is detrimental remains controversial. Therefore, when a patient needs fluid resuscitation, we should not only consider the fluid type but also consider the fluid responsiveness [
      • Orso D.
      • Paoli I.
      • Piani T.
      • Cilenti F.L.
      • Cristiani L.
      • Guglielmo N.
      Accuracy of ultrasonographic measurements of inferior vena cava to determine fluid responsiveness: a systematic review and meta-analysis.
      ].
      Our meta-analysis has several potential limitations. First, due to the limited data, it was difficult to perform more subgroup or sensitivity analyses. Second, patients included in this meta-analysis had varying degrees of severity (trauma, sepsis or acute pancreatitis), which will have caused heterogeneity and reduced the stability of the results. Third, the hyperchloremia, hyponatremia and fluid overload were all independent factors related to higher mortality. However, we could acquire sufficient evidence to perform comprehensive analyses; therefore, more studies focused on those issues are urgently needed. Fourth, there was the potential for incomplete retrieval of identified research studies, which could have introduced publication bias.

      5. Conclusions

      Among critically ill patients receiving crystalloid fluid therapy, use of a balanced crystalloid compared with normal saline did not reduce the mortality, the risk of AKI or the RRT use rate. Further large randomized clinical trials are needed to confirm or refute this finding.

      Abbreviations

      AKI
      acute kidney injury
      CI
      confidence interval
      GRADE
      Grading of Recommendations Assessment, Development, and Evaluation
      MD
      mean difference
      ICU
      intensive care unit
      PRISMA
      Preferred Reporting Items for Systematic Reviews and Meta-Analyses
      RCT
      randomized controlled trial
      RR
      relative risk
      RRT
      renal replacement therapy
      TSA
      trial sequential analysis

      Ethical approval and consent to participate

      Not applicable.

      Consent for publication

      Not applicable.

      Availability of supporting data

      The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files.

      Competing interests

      The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

      Funding

      The authors received no financial support for the research, authorship, and/or publication of this article.

      Authors' contribution

      CL,GML and DW contributed equally to this work. CL, GML and DW conceived the study, participated in the design, collected the data, performed statistical analyses and drafted the manuscript. YL, ZM and PH performed statistical analyses and helped to draft the manuscript. JH, RL and DH collected the data and revised the manuscript critically for important intellectual content. FHZ collected the data, performed statistical analyses and helped to revise the manuscript critically for important intellectual content. All authors read and approved the final manuscript.

      Acknowledgements

      Not applicable.

      Appendix A.

      Table 1Conferences searches.
      American Association for the Surgeons of Trauma (2008–2018)

      American College of Chest Physicians (2010–2018)

      American Society of Anaesthesiology (2009–2018)

      American Thoracic Society (2009–2018)

      Canadian Anesthesiologists' Society (2008–2018)

      European Society of Intensive Care Medicine (2008–2018)

      Society of Critical Care Medicine (2008–2018)
      Table 2Search strategy.
      n
      1Target terms for literature search:

       (“normal saline” OR “isotonic saline” OR “sodium chloride” OR “lactated ringer” OR “Hartmann” OR “Plasma-Lyte” OR “buffered crystalloid” OR “balanced crystalloids”) and (“sepsis” OR “infection” OR “septic shock” OR “severe sepsis” OR “shock” OR “systemic inflammatory response syndrome” OR “SIRS” OR “injury” OR “trauma” OR “hemorrhage” OR “toxic shock syndrome” OR “burns” OR “acute pancreatitis” OR “critical ill” OR “critical illness” OR “intensive care unit” OR “intensive care” OR “critical care” OR “ICU”)
      2245
      2Limit 1 to clinical trial

       Randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized [tiab] OR placebo [tiab] OR clinical trials as topic [mesh: noexp] OR randomly [tiab] OR trial [ti]
      788
      3Limit 2 to humans364

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