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Figure 1.
Random-Effects Meta-analysis of Fluid Overload (Categorical Exposure) and Mortality Stratified by Case Mix
Random-Effects Meta-analysis of Fluid Overload (Categorical Exposure) and Mortality Stratified by Case Mix

Included were 17 studies.5,6,24,26-28,31,35,38,40,42-44,49-52 CRRT indicates continuous renal replacement therapy; and OR, odds ratio.

Figure 2.
Random-Effects Meta-analysis of Fluid Overload (Categorical Exposure) and Mortality Stratified by Fluid Overload Definition
Random-Effects Meta-analysis of Fluid Overload (Categorical Exposure) and Mortality Stratified by Fluid Overload Definition

Included were 12 studies.6,24,27,31,35,38,40,43,44,49,51,52 CRRT indicates continuous renal replacement therapy; %FO, percentage fluid overload; OR, odds ratio; and PICU, pediatric intensive care unit.

Figure 3.
Percentage Fluid Overload (Continuous Variable)
Percentage Fluid Overload (Continuous Variable)

Shown is the association with mortality, stratified by case mix. Included were 22 studies.4,5,7,8,20,21,23-26,28-30,32,33,35,38-40,49,50,52 ALI indicates acute lung injury; CRRT, continuous renal replacement therapy; %FO, percentage fluid overload; and OR, odds ratio.

Table 1.  
Characteristics of the Included Studies
Characteristics of the Included Studies
Table 2.  
Fluid Overload Definitions
Fluid Overload Definitions
1.
Rhodes  A, Evans  LE, Alhazzani  W,  et al.  Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock: 2016.  Crit Care Med. 2017;45(3):486-552.PubMedGoogle ScholarCrossref
2.
Davis  AL, Carcillo  JA, Aneja  RK,  et al.  American College of Critical Care Medicine clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock.  Crit Care Med. 2017;45(6):1061-1093.PubMedGoogle ScholarCrossref
3.
Flori  HR, Church  G, Liu  KD, Gildengorin  G, Matthay  MA.  Positive fluid balance is associated with higher mortality and prolonged mechanical ventilation in pediatric patients with acute lung injury.  Crit Care Res Pract. 2011;2011:854142. PubMedGoogle Scholar
4.
Abulebda  K, Cvijanovich  NZ, Thomas  NJ,  et al.  Post–ICU admission fluid balance and pediatric septic shock outcomes: a risk-stratified analysis.  Crit Care Med. 2014;42(2):397-403.PubMedGoogle ScholarCrossref
5.
Bhaskar  P, Dhar  AV, Thompson  M, Quigley  R, Modem  V.  Early fluid accumulation in children with shock and ICU mortality: a matched case-control study.  Intensive Care Med. 2015;41(8):1445-1453.PubMedGoogle ScholarCrossref
6.
Li  Y, Wang  J, Bai  Z,  et al.  Early fluid overload is associated with acute kidney injury and PICU mortality in critically ill children.  Eur J Pediatr. 2016;175(1):39-48.PubMedGoogle ScholarCrossref
7.
Goldstein  SL, Currier  H, Graf JM, Cosio  CC, Brewer  ED, Sachdeva  R.  Outcome in children receiving continuous venovenous hemofiltration.  Pediatrics. 2001;107(6):1309-1312.PubMedGoogle ScholarCrossref
8.
Selewski  DT, Cornell  TT, Lombel  RM,  et al.  Weight-based determination of fluid overload status and mortality in pediatric intensive care unit patients requiring continuous renal replacement therapy.  Intensive Care Med. 2011;37(7):1166-1173.PubMedGoogle ScholarCrossref
9.
Lombel  RM, Kommareddi  M, Mottes  T,  et al.  Implications of different fluid overload definitions in pediatric stem cell transplant patients requiring continuous renal replacement therapy.  Intensive Care Med. 2012;38(4):663-669.PubMedGoogle ScholarCrossref
10.
Hazle  MA, Gajarski  RJ, Yu  S, Donohue  J, Blatt  NB.  Fluid overload in infants following congenital heart surgery.  Pediatr Crit Care Med. 2013;14(1):44-49.PubMedGoogle ScholarCrossref
11.
PROSPERO International Prospective Register of Systematic Reviews. Systematic Review of the Association Between Fluid Balance and Outcome in Critically Ill Children. CRD42016036209. https://www.crd.york.ac.uk/prospero/#searchadvanced. Accessed November 11, 2017.
12.
Alobaidi  R, Morgan  C, Basu  RK,  et al.  Associations between fluid balance and outcomes in critically ill children: a protocol for a systematic review and meta-analysis.  Can J Kidney Health Dis. 2017;4:2054358117692560.PubMedGoogle ScholarCrossref
13.
Higgins  JPT, Green  S, eds. Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0. http://handbook.cochrane.org. Updated March 2011. Accessed November 16, 2017.
14.
Moher  D, Shamseer  L, Clarke  M,  et al; PRISMA-P Group.  Preferred Reporting Items for Systematic Review and Meta-analysis protocols (PRISMA-P) 2015 statement.  Syst Rev. 2015;4:1.PubMedGoogle ScholarCrossref
15.
Sampson  M, McGowan  J, Cogo  E, Grimshaw  J, Moher  D, Lefebvre  C.  An evidence-based practice guideline for the peer review of electronic search strategies.  J Clin Epidemiol. 2009;62(9):944-952.PubMedGoogle ScholarCrossref
16.
Wells  GA, Shea B, O’Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed November 16, 2017.
17.
Wan  X, Wang  W, Liu  J, Tong  T.  Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range.  BMC Med Res Methodol. 2014;14:135.PubMedGoogle ScholarCrossref
18.
Review Manager (RevMan) [computer program]. Version 5.3. Copenhagen, Denmark: The Nordic Cochrane Centre, The Cochrane Collaboration; 2014.
19.
Egger  M, Davey Smith  G, Schneider  M, Minder  C.  Bias in meta-analysis detected by a simple, graphical test.  BMJ. 1997;315(7109):629-634.PubMedGoogle ScholarCrossref
20.
Arikan  AA, Zappitelli  M, Goldstein  SL, Naipaul  A, Jefferson  LS, Loftis  LL.  Fluid overload is associated with impaired oxygenation and morbidity in critically ill children.  Pediatr Crit Care Med. 2012;13(3):253-258.PubMedGoogle ScholarCrossref
21.
Askenazi  DJ, Goldstein  SL, Koralkar  R,  et al.  Continuous renal replacement therapy for children ≤10 kg: a report from the Prospective Pediatric Continuous Renal Replacement Therapy Registry.  J Pediatr. 2013;162(3):587-592.e3.PubMedGoogle ScholarCrossref
22.
Baird  JS, Wald  EL.  Long-duration (>4 weeks) continuous renal replacement therapy in critical illness.  Int J Artif Organs. 2010;33(10):716-720.PubMedGoogle Scholar
23.
Boschee  ED, Cave  DA, Garros  D,  et al.  Indications and outcomes in children receiving renal replacement therapy in pediatric intensive care.  J Crit Care. 2014;29(1):37-42.PubMedGoogle ScholarCrossref
24.
Chen  J, Li  X, Bai  Z,  et al.  Association of fluid accumulation with clinical outcomes in critically ill children with severe sepsis.  PLoS One. 2016;11(7):e0160093.PubMedGoogle ScholarCrossref
25.
Choi  SJ, Ha  EJ, Jhang  WK, Park  SJ.  Factors associated with mortality in continuous renal replacement therapy for pediatric patients with acute kidney injury.  Pediatr Crit Care Med. 2017;18(2):e56-e61.PubMedGoogle ScholarCrossref
26.
Diaz  F, Benfield  M, Brown  L, Hayes  L.  Fluid overload and outcomes in critically ill children: a single center prospective cohort study.  J Crit Care. 2017;39:209-213.PubMedGoogle ScholarCrossref
27.
de Galasso  L, Emma  F, Picca  S, Di Nardo  M, Rossetti  E, Guzzo  I.  Continuous renal replacement therapy in children: fluid overload does not always predict mortality.  Pediatr Nephrol. 2016;31(4):651-659.PubMedGoogle ScholarCrossref
28.
Elbahlawan  L, West  NK, Avent  Y,  et al.  Impact of continuous renal replacement therapy on oxygenation in children with acute lung injury after allogeneic hematopoietic stem cell transplantation.  Pediatr Blood Cancer. 2010;55(3):540-545.PubMedGoogle ScholarCrossref
29.
Flores  FX, Brophy  PD, Symons  JM,  et al.  Continuous renal replacement therapy (CRRT) after stem cell transplantation: a report from the Prospective Pediatric CRRT Registry Group.  Pediatr Nephrol. 2008;23(4):625-630.PubMedGoogle ScholarCrossref
30.
Foland  JA, Fortenberry  JD, Warshaw  BL,  et al.  Fluid overload before continuous hemofiltration and survival in critically ill children: a retrospective analysis.  Crit Care Med. 2004;32(8):1771-1776.PubMedGoogle ScholarCrossref
31.
Gillespie  RS, Seidel  K, Symons  JM.  Effect of fluid overload and dose of replacement fluid on survival in hemofiltration.  Pediatr Nephrol. 2004;19(12):1394-1399.PubMedGoogle ScholarCrossref
32.
Goldstein  SL, Somers  MJ, Baum  MA,  et al.  Pediatric patients with multi-organ dysfunction syndrome receiving continuous renal replacement therapy.  Kidney Int. 2005;67(2):653-658.PubMedGoogle ScholarCrossref
33.
Gulla  KM, Sachdev  A, Gupta  D, Gupta  N, Anand  K, Pruthi  PK.  Continuous renal replacement therapy in children with severe sepsis and multiorgan dysfunction: a pilot study on timing of initiation.  Indian J Crit Care Med. 2015;19(10):613-617.PubMedGoogle ScholarCrossref
34.
Hassinger  AB, Wald  EL, Goodman  DM.  Early postoperative fluid overload precedes acute kidney injury and is associated with higher morbidity in pediatric cardiac surgery patients.  Pediatr Crit Care Med. 2014;15(2):131-138.PubMedGoogle ScholarCrossref
35.
Hayes  LW, Oster  RA, Tofil  NM, Tolwani  AJ.  Outcomes of critically ill children requiring continuous renal replacement therapy.  J Crit Care. 2009;24(3):394-400.PubMedGoogle ScholarCrossref
36.
Hoover  NG, Heard  M, Reid  C,  et al.  Enhanced fluid management with continuous venovenous hemofiltration in pediatric respiratory failure patients receiving extracorporeal membrane oxygenation support.  Intensive Care Med. 2008;34(12):2241-2247.PubMedGoogle ScholarCrossref
37.
Ingelse  SA, Wiegers  HM, Calis  JC, van Woensel  JB, Bem  RA.  Early fluid overload prolongs mechanical ventilation in children with viral–lower respiratory tract disease.  Pediatr Crit Care Med. 2017;18(3):e106-e111.PubMedGoogle ScholarCrossref
38.
Jhang  WK, Kim  YA, Ha  EJ,  et al.  Extrarenal sequential organ failure assessment score as an outcome predictor of critically ill children on continuous renal replacement therapy.  Pediatr Nephrol. 2014;29(6):1089-1095.PubMedGoogle ScholarCrossref
39.
Kaempfen  S, Dutta-Kukreja  P, Mok  Q.  Continuous venovenous hemofiltration in children less than or equal to 10 kg: a single-center experience.  Pediatr Crit Care Med. 2017;18(2):e70-e76.PubMedGoogle ScholarCrossref
40.
Ketharanathan  N, McCulloch  M, Wilson  C,  et al.  Fluid overload in a South African pediatric intensive care unit.  J Trop Pediatr. 2014;60(6):428-433.PubMedGoogle ScholarCrossref
41.
Lex  DJ, Tóth  R, Czobor  NR,  et al.  Fluid overload is associated with higher mortality and morbidity in pediatric patients undergoing cardiac surgery.  Pediatr Crit Care Med. 2016;17(4):307-314.PubMedGoogle ScholarCrossref
42.
Michael  M, Kuehnle  I, Goldstein  SL.  Fluid overload and acute renal failure in pediatric stem cell transplant patients.  Pediatr Nephrol. 2004;19(1):91-95.PubMedGoogle ScholarCrossref
43.
Modem  V, Thompson  M, Gollhofer  D, Dhar  AV, Quigley  R.  Timing of continuous renal replacement therapy and mortality in critically ill children.  Crit Care Med. 2014;42(4):943-953.PubMedGoogle ScholarCrossref
44.
Naveda  OE, Naveda  AF.  Positive fluid balance and high mortality in paediatric patients with severe sepsis and septic shock  [in Spanish].  Pediatria. 2016;49(3):71-77.Google ScholarCrossref
45.
Park  SK, Hur  M, Kim  E,  et al.  Risk factors for acute kidney injury after congenital cardiac surgery in infants and children: a retrospective observational study.  PLoS One. 2016;11(11):e0166328.PubMedGoogle ScholarCrossref
46.
Randolph  AG, Forbes  PW, Gedeit  RG,  et al; Pediatric Acute Lung Injury & Sepsis Investigators (PALISI) Network.  Cumulative fluid intake minus output is not associated with ventilator weaning duration or extubation outcomes in children.  Pediatr Crit Care Med. 2005;6(6):642-647.PubMedGoogle ScholarCrossref
47.
Sampaio  TZ, O’Hearn  K, Reddy  D, Menon  K.  The influence of fluid overload on the length of mechanical ventilation in pediatric congenital heart surgery.  Pediatr Cardiol. 2015;36(8):1692-1699.PubMedGoogle ScholarCrossref
48.
Seguin  J, Albright  B, Vertullo  L,  et al.  Extent, risk factors, and outcome of fluid overload after pediatric heart surgery.  Crit Care Med. 2014;42(12):2591-2599.PubMedGoogle ScholarCrossref
49.
Selewski  DT, Cornell  TT, Blatt  NB,  et al.  Fluid overload and fluid removal in pediatric patients on extracorporeal membrane oxygenation requiring continuous renal replacement therapy.  Crit Care Med. 2012;40(9):2694-2699.PubMedGoogle ScholarCrossref
50.
Sinitsky  L, Walls  D, Nadel  S, Inwald  DP.  Fluid overload at 48 hours is associated with respiratory morbidity but not mortality in a general PICU: retrospective cohort study.  Pediatr Crit Care Med. 2015;16(3):205-209.PubMedGoogle ScholarCrossref
51.
Sutherland  SM, Zappitelli  M, Alexander  SR,  et al.  Fluid overload and mortality in children receiving continuous renal replacement therapy: the Prospective Pediatric Continuous Renal Replacement Therapy Registry.  Am J Kidney Dis. 2010;55(2):316-325.PubMedGoogle ScholarCrossref
52.
Sutawan  IB, Wati  DK, Suparyatha  IB.  Association of fluid overload with mortality in pediatric intensive care unit.  Crit Care Shock. 2016;19(1):8-13.Google Scholar
53.
Valentine  SL, Sapru  A, Higgerson  RA,  et al; Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network; Acute Respiratory Distress Syndrome Clinical Research Network (ARDSNet).  Fluid balance in critically ill children with acute lung injury.  Crit Care Med. 2012;40(10):2883-2889.PubMedGoogle ScholarCrossref
54.
Vidal  S, Pérez  A, Eulmesekian  P.  Fluid balance and length of mechanical ventilation in children admitted to a single pediatric intensive care unit [in Spanish].  Arch Argent Pediatr. 2016;114(4):313-318.PubMedGoogle Scholar
55.
Willson  DF, Thomas  NJ, Tamburro  R,  et al; Pediatric Acute Lung and Sepsis Investigators Network.  The relationship of fluid administration to outcome in the pediatric Calfactant in Acute Respiratory Distress Syndrome trial.  Pediatr Crit Care Med. 2013;14(7):666-672.PubMedGoogle ScholarCrossref
56.
Sakr  Y, Vincent  JL, Reinhart  K,  et al; Sepsis Occurrence in Acutely Ill Patients Investigators.  High tidal volume and positive fluid balance are associated with worse outcome in acute lung injury.  Chest. 2005;128(5):3098-3108.PubMedGoogle ScholarCrossref
57.
Wiedemann  HP, Wheeler  AP, Bernard  GR,  et al; National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network.  Comparison of two fluid-management strategies in acute lung injury.  N Engl J Med. 2006;354(24):2564-2575.PubMedGoogle ScholarCrossref
58.
Rosenberg  AL, Dechert  RE, Park  PK, Bartlett  RH; NIH NHLBI ARDS Network.  Review of a large clinical series: association of cumulative fluid balance on outcome in acute lung injury: a retrospective review of the ARDSNet tidal volume study cohort.  J Intensive Care Med. 2009;24(1):35-46.PubMedGoogle ScholarCrossref
59.
Boyd  JH, Forbes  J, Nakada  TA, Walley  KR, Russell  JA.  Fluid resuscitation in septic shock: a positive fluid balance and elevated central venous pressure are associated with increased mortality.  Crit Care Med. 2011;39(2):259-265.PubMedGoogle ScholarCrossref
60.
Acheampong  A, Vincent  JL.  A positive fluid balance is an independent prognostic factor in patients with sepsis.  Crit Care. 2015;19:251.PubMedGoogle ScholarCrossref
61.
Kelm  DJ, Perrin  JT, Cartin-Ceba  R, Gajic  O, Schenck  L, Kennedy  CC.  Fluid overload in patients with severe sepsis and septic shock treated with early goal-directed therapy is associated with increased acute need for fluid-related medical interventions and hospital death.  Shock. 2015;43(1):68-73.PubMedGoogle ScholarCrossref
62.
Payen  D, de Pont  AC, Sakr  Y, Spies  C, Reinhart  K, Vincent  JL; Sepsis Occurrence in Acutely Ill Patients (SOAP) Investigators.  A positive fluid balance is associated with a worse outcome in patients with acute renal failure.  Crit Care. 2008;12(3):R74.PubMedGoogle ScholarCrossref
63.
Bouchard  J, Soroko  SB, Chertow  GM,  et al; Program to Improve Care in Acute Renal Disease (PICARD) Study Group.  Fluid accumulation, survival and recovery of kidney function in critically ill patients with acute kidney injury.  Kidney Int. 2009;76(4):422-427.PubMedGoogle ScholarCrossref
64.
Grams  ME, Estrella  MM, Coresh  J, Brower  RG, Liu  KD; National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome Network.  Fluid balance, diuretic use, and mortality in acute kidney injury.  Clin J Am Soc Nephrol. 2011;6(5):966-973.PubMedGoogle ScholarCrossref
65.
Vaara  ST, Korhonen  AM, Kaukonen  KM,  et al; FINNAKI Study Group.  Fluid overload is associated with an increased risk for 90-day mortality in critically ill patients with renal replacement therapy: data from the prospective FINNAKI study.  Crit Care. 2012;16(5):R197.PubMedGoogle ScholarCrossref
66.
Brandstrup  B, Tønnesen  H, Beier-Holgersen  R,  et al; Danish Study Group on Perioperative Fluid Therapy.  Effects of intravenous fluid restriction on postoperative complications: comparison of two perioperative fluid regimens: a randomized assessor-blinded multicenter trial.  Ann Surg. 2003;238(5):641-648.PubMedGoogle ScholarCrossref
67.
Stewart  RM, Park  PK, Hunt  JP,  et al; National Institutes of Health/National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome Clinical Trials Network.  Less is more: improved outcomes in surgical patients with conservative fluid administration and central venous catheter monitoring.  J Am Coll Surg. 2009;208(5):725-735.PubMedGoogle ScholarCrossref
68.
Lobo  SM, Ronchi  LS, Oliveira  NE,  et al.  Restrictive strategy of intraoperative fluid maintenance during optimization of oxygen delivery decreases major complications after high-risk surgery.  Crit Care. 2011;15(5):R226.PubMedGoogle ScholarCrossref
69.
Stein  A, de Souza  LV, Belettini  CR,  et al.  Fluid overload and changes in serum creatinine after cardiac surgery: predictors of mortality and longer intensive care stay: a prospective cohort study.  Crit Care. 2012;16(3):R99.PubMedGoogle ScholarCrossref
70.
Mikkelsen  ME, Christie  JD, Lanken  PN,  et al.  The Adult Respiratory Distress Syndrome Cognitive Outcomes Study: long-term neuropsychological function in survivors of acute lung injury.  Am J Respir Crit Care Med. 2012;185(12):1307-1315.PubMedGoogle ScholarCrossref
71.
Maitland  K, Kiguli  S, Opoka  RO,  et al; FEAST Trial Group.  Mortality after fluid bolus in African children with severe infection.  N Engl J Med. 2011;364(26):2483-2495.PubMedGoogle ScholarCrossref
72.
Maitland  K, George  EC, Evans  JA,  et al; FEAST Trial Group.  Exploring mechanisms of excess mortality with early fluid resuscitation: insights from the FEAST trial.  BMC Med. 2013;11:68.PubMedGoogle ScholarCrossref
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Chen  C, Kollef  MH.  Targeted fluid minimization following initial resuscitation in septic shock: a pilot study.  Chest. 2015;148(6):1462-1469.PubMedGoogle ScholarCrossref
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Hjortrup  PB, Haase  N, Bundgaard  H,  et al; CLASSIC Trial Group; Scandinavian Critical Care Trials Group.  Restricting volumes of resuscitation fluid in adults with septic shock after initial management: the CLASSIC randomised, parallel-group, multicentre feasibility trial.  Intensive Care Med. 2016;42(11):1695-1705.PubMedGoogle ScholarCrossref
75.
Parker  MJ, Thabane  L, Fox-Robichaud  A, Liaw  P, Choong  K; Canadian Critical Care Trials Group; Canadian Critical Care Translational Biology Group.  A trial to determine whether septic shock–reversal is quicker in pediatric patients randomized to an early goal-directed fluid-sparing strategy versus usual care (SQUEEZE): study protocol for a pilot randomized controlled trial.  Trials. 2016;17(1):556.PubMedGoogle ScholarCrossref
76.
Goldstein  S, Bagshaw  S, Cecconi  M,  et al; ADQI XII Investigators Group.  Pharmacological management of fluid overload.  Br J Anaesth. 2014;113(5):756-763.PubMedGoogle ScholarCrossref
77.
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Original Investigation
March 2018

Association Between Fluid Balance and Outcomes in Critically Ill Children: A Systematic Review and Meta-analysis

Author Affiliations
  • 1Division of Pediatric Critical Care, Department of Pediatrics, Stollery Children’s Hospital, Edmonton, Alberta, Canada
  • 2Division of Nephrology, Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada
  • 3Division of Critical Care Medicine, Department of Pediatrics, Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Georgia
  • 4Division of Critical Care Medicine, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
  • 5Alberta Strategy for Patient-Oriented Research (SPOR) SUPPORT Unit Knowledge Translation Platform, Alberta Research Center for Health Evidence (ARCHE), Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada
  • 6Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada
  • 7Department of Critical Care Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada
JAMA Pediatr. 2018;172(3):257-268. doi:10.1001/jamapediatrics.2017.4540
Key Points

Question  Is there an association between fluid balance and outcomes in critically ill children admitted to pediatric intensive care?

Findings  This systematic review and meta-analysis of 44 studies including 7507 children showed strong and consistent evidence of an association between fluid overload and poor outcomes in critically ill children, including worsening respiratory function, development of acute kidney injury, longer pediatric intensive care stay, and death.

Meaning  Fluid overload appears to be an important modifier of outcome in critically ill children, implying that additional research is needed focused on strategies for preventing or mitigating this risk.

Abstract

Importance  After initial resuscitation, critically ill children may accumulate fluid and develop fluid overload. Accruing evidence suggests that fluid overload contributes to greater complexity of care and worse outcomes.

Objective  To describe the methods to measure fluid balance, define fluid overload, and evaluate the association between fluid balance and outcomes in critically ill children.

Data Sources  Systematic search of MEDLINE, EMBASE, Cochrane Library, trial registries, and selected gray literature from inception to March 2017.

Study Selection  Studies of children admitted to pediatric intensive care units that described fluid balance or fluid overload and reported outcomes of interest were included. No language restrictions were applied.

Data Extraction and Synthesis  All stages were conducted independently by 2 reviewers. Data extracted included study characteristics, population, fluid metrics, and outcomes. Risk of bias was assessed using the Newcastle-Ottawa Scale. Narrative description of fluid assessment methods and fluid overload definitions was done. When feasible, pooled analyses were performed using random-effects models.

Main Outcomes and Measures  Mortality was the primary outcome. Secondary outcomes included treatment intensity, organ failure, and resource use.

Results  A total of 44 studies (7507 children) were included in this systematic review and meta-analysis. Of those, 27 (61%) were retrospective cohort studies, 13 (30%) were prospective cohort studies, 3 (7%) were case-control studies, and 1 study (2%) was a secondary analysis of a randomized trial. The proportion of children with fluid overload varied by case mix and fluid overload definition (median, 33%; range, 10%-83%). Fluid overload, however defined, was associated with increased in-hospital mortality (17 studies [n = 2853]; odds ratio [OR], 4.34 [95% CI, 3.01-6.26]; I2 = 61%). Survivors had lower percentage fluid overload than nonsurvivors (22 studies [n = 2848]; mean difference, −5.62 [95% CI, −7.28 to −3.97]; I2 = 76%). After adjustment for illness severity, there was a 6% increase in odds of mortality for every 1% increase in percentage fluid overload (11 studies [n = 3200]; adjusted OR, 1.06 [95% CI, 1.03-1.10]; I2 = 66%). Fluid overload was associated with increased risk for prolonged mechanical ventilation (>48 hours) (3 studies [n = 631]; OR, 2.14 [95% CI, 1.25-3.66]; I2 = 0%) and acute kidney injury (7 studies [n = 1833]; OR, 2.36 [95% CI, 1.27-4.38]; I2 = 78%).

Conclusions and Relevance  Fluid overload is common and is associated with substantial morbidity and mortality in critically ill children. Additional research should now ideally focus on interventions aimed to mitigate the potential for harm associated with fluid overload.

Introduction

Fluid therapy is the cornerstone of resuscitation in critically ill children. Reestablishment of adequate intravascular volume using early aggressive fluid administration can be lifesaving.1,2 However, beyond fluid therapy directed at resuscitation, critically ill children often receive variable amounts of “obligatory” fluid intake as part of their management (ie, nutrition, medications, and maintenance fluid). This cumulative fluid delivery frequently exceeds fluid loss, leading to a net positive fluid balance. A growing body of circumstantial evidence suggests that fluid accumulation after initial resuscitation may exert hazard for major morbidity and mortality.3-6 These observations highlight the importance of monitoring fluid status and daily evaluation of critically ill children for avoidable fluid accumulation.

The concept of “fluid overload” has been described in the literature using various definitions.7-10 Although some of the proposed definitions have shown strong correlation with outcomes, it is unclear how generalizable these findings are considering limitations in study design, size and methods, and variation in case mix. There are concerns about the potential discrepancy in fluid overload estimation contingent on the definition applied.9 Moreover, there is no clear consensus on how to precisely and reliably define fluid overload.

Our aim was to describe the methods used to assess fluid balance, discuss the definitions for fluid overload, and evaluate the association between fluid balance and outcomes in critically ill children. We contend that a rigorous synthesis of available evidence is needed to harmonize the definitions of fluid metrics and aid in the development of management strategies to prevent or mitigate avoidable fluid overload.

Methods

This systematic review and meta-analysis followed an a priori protocol that was registered with the PROSPERO International Prospective Register of Systematic Reviews11 (CRD42016036209) and previously published.12 We followed the formats recommended by the Cochrane13 Centre for Reviews and Dissemination and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.14

Data Sources and Searches

The search strategy15 was developed and executed in consultation with an experienced research librarian (R.F.) and was independently peer reviewed by a nonauthor second librarian. We executed our original search in June 2016 and completed an updated search in March 2017. No language or publication date restrictions were applied (eTable 1 in the Supplement).

We searched Ovid MEDLINE (1946 to present), Ovid EMBASE (1974 to present), Cochrane Library via Wiley (inception to present), ProQuest Dissertations & Theses Global (1861 to present), and selected gray literature. In addition, clinicaltrials.gov (http://www.clinicaltrials.gov) and the World Health Organization International Clinical Trials Registry Platform (http://www.who.int/ictrp/en/) were searched for ongoing and completed clinical trials. Proceedings of selected relevant pediatric, critical care, and nephrology conferences in the last 3 years were manually searched (eTable 2 in the Supplement). A manual search using reference lists of retrieved citations was conducted for other relevant studies.

Study Selection

Potentially relevant citations were identified through independent screening of search result titles and abstracts by 2 of us (R.A. and E.S.). The selected studies were then retrieved and subjected to a second screening phase for eligibility using standard, predefined eligibility criteria. Disagreements were resolved through discussion, with input from another of us (S.M.B). Eligible studies had the following criteria: (1) investigated a population that was limited to patients younger than 25 years who were admitted to a pediatric intensive care unit (PICU) setting; (2) presented original data from interventional (randomized controlled trials or quasi-randomized controlled trials), cohort, or case-control studies; (3) described a measure of fluid balance, fluid accumulation, or fluid overload; and (4) contained at least one outcome of interest. Studies were excluded if they had one of the following characteristics: (1) included patients 25 years or older; (2) comprised primary neonatal studies inclusive of premature infants or infants younger than 4 weeks; (3) were case reports, case series, review articles, or observational studies without a control or comparator; or (4) represented studies conducted in a non–critical care setting.

Outcome Measures

The primary outcome was all-cause mortality, as defined by the included studies. Secondary outcomes included respiratory outcomes, acute kidney injury (AKI), PICU length of stay, and other reported measures of treatment intensity, organ failure, and health resource use.

Data Extraction

A structured data extraction form was piloted and then used to extract data from the reports of all included studies in duplicate and independently by 2 of us (R.A. and E.S.). Discrepancies in extracted data were resolved through discussion. Both crude and adjusted statistics were collected. Where relevant, attempts were made to contact authors for missing data.

Quality Assessment

Two of us (R.A. and E.S.) independently assessed the risk of bias using the Newcastle-Ottawa Scale,16 and any discordant assessments were resolved via discussion. We considered a study to be of good quality if its total score was at least 8, of fair quality if the score was 5 to 7, and of poor quality if the score was 4 or lower.

Data Synthesis and Analysis

The included studies were arranged based on exposure (ie, the main measure used to describe fluid balance) and outcomes of interest. Within each group, studies were further clustered based on whether the exposure was dichotomous or continuous. For dichotomous outcomes, odds ratios (ORs) were used as the common measure of an association, with their 95% CIs. Continuous outcomes were reported as weighted mean differences (WMDs), with their 95% CIs. Where necessary, means (SDs) were estimated from the median and interquartile range using a standard approach.17 We used random-effects models for pooled analyses because of anticipated heterogeneity. Statistical analyses were performed using Review Manager software (RevMan, version 5.3; The Cochrane Collaboration).18 When statistical pooling was not possible due to exposure-outcome heterogeneity or an insufficient number of studies for an outcome or exposure, the findings were described in narrative form.

Assessment of Heterogeneity and Reporting Bias

Clinical heterogeneity was addressed by performing subgroup analyses based on populations, exposures, and outcome measurements in all included studies. Statistical heterogeneity was evaluated using I2 statistics, with estimates of 50% or higher considered as significant heterogeneity.13 Visual assessment of funnel plots was used to evaluate reporting bias in analyses with a sufficient number of studies (>10).19 Statistical significance was set at 2-sided P < .05.

Results

The literature search identified 7211 potentially relevant studies. Forty-four studies, including 7507 children, fulfilled all eligibility criteria (eFigure 1 in the Supplement). Of those, 27 (61%) were retrospective cohort studies, 13 (30%) were prospective cohort studies, 3 (7%) were case-control studies, and 1 study (2%) was a secondary analysis of a randomized trial. Of the included studies, 15 (34%) were performed in cohorts of patients receiving renal replacement therapy (RRT), 9 (20%) in multisystem PICUs, 6 (14%) after cardiac surgery, 5 (11%) in children with sepsis, 4 (9%) in stem cell transplantation, 3 (7%) in children with acute lung injury, and 2 (5%) in children supported by extracorporeal membrane oxygenation (ECMO) (Table 1).3-10,20-55

The median risk-of-bias score was 8 (range, 6-9). Fourteen studies (32%) were labeled as being of fair quality, while the remaining 30 studies (68%) were of good quality. The main potential sources of bias were “representativeness of the cohort” and “comparability,” which required adjustment for the confounders of age and severity of illness in the analysis (eTable 3 in the Supplement).

Fluid Balance Assessment

Four different fluid metrics were used to describe fluid balance. These metrics included cumulative or peak percentage fluid overload (37 studies), cumulative or peak percentage weight change (4 studies), net fluid balance in relation to weight (5 studies), and net fluid balance in relation to body surface area (1 study) (eTable 4 in the Supplement).

Percentage fluid overload was calculated using the following formula: [(Total Fluid Intake in Liters − Total Fluid Output in Liters) / Admission Weight in Kilograms] × 100. This equation was based on the literature.4-10,20-35,38-45,47,48,50-52,54

Percentage weight change was calculated as follows: [(Current Weight − Admission Weight) / Admission Weight] × 100. This equation was taken from relevant studies.8-10,49

The PICU admission weight was used as the denominator “admission weight” in 22 studies, hospital admission weight was used in 7 studies, outpatient weight was used in 2 studies, and dry or ideal body weight was used in 2 studies. In 13 studies, the weight used was not specified. These results are summarized in eTable 5 in the Supplement.

Three studies compared the fluid intake-output and weight-based methods. In a small cohort of patients undergoing stem cell transplant, Lombel et al9 described significant variability in fluid balance calculations, with the fluid intake-output method showing the greatest correlation and effect on outcomes in adjusted analysis. The weight-based method was significantly associated with outcomes only when PICU admission weight was used instead of hospital admission weight or estimated dry weight. Hazle et al10 reported significant correlation between the 2 methods (r = 0.65, P < .0001) in infants after cardiac surgery, although percentage fluid overload was an independent predictor of poor outcome in adjusted analysis only when calculated by the weight-based method. Alternatively, in a cohort of patients receiving continuous RRT (CRRT), Selewski et al8 reported significant correlation and comparable predictive values between these 2 methods.

Fluid Overload Definitions

Twenty-six studies identified the following specific threshold values to define fluid overload: greater than 5% (n = 4), greater than 7% (n = 1), greater than 10% (n = 15), greater than 13% (n = 1), greater than 15% (n = 1), and greater than 20% (n = 10). The assessment period varied from 24 hours after PICU admission to the entire PICU stay (Table 2). Depending on the population and fluid overload definition used, the proportion of children identified as having fluid overload (dichotomous exposure) ranged between 10% (in patients after cardiac surgery) and 83% (in ECMO patients receiving RRT), with a pooled median of 32.7%. Three studies described the time to maximum percentage fluid overload (continuous exposure). Arikan et al20 reported that maximum percentage fluid overload was achieved on mean (SD) day 5.7 (4.2) after PICU admission in a cohort of general PICU patients receiving mechanical ventilation. In 2 studies47,48 of patients after cardiac surgery, percentage fluid overload peaked within the first 24 to 48 hours after surgery.

Outcomes
Mortality

Seventeen studies evaluated mortality using fluid overload as a dichotomous exposure. Fluid overload, however defined across studies, was associated with increased in-hospital mortality (OR, 4.34 [95% CI, 3.01-6.26]; I2 = 61%; n = 2835) (Figure 1). This association between fluid overload and mortality was robust in sensitivity analysis that included data from only 6 studies that adjusted for illness severity (adjusted OR, 4.38 [95% CI, 2.64-7.28]; I2 = 14%; n = 782) (eFigure 2 in the Supplement). Similarly, sensitivity analysis that included non-RRT studies only showed significant association with mortality (OR, 6.20 [95% CI, 2.89-13.28]; I2 = 80%; n = 1868) (eFigure 3 in the Supplement).

We pooled studies that used similar fluid overload threshold and duration of assessment. This process resulted in 4 different fluid overload definitions, all of which showed significant association with mortality and low statistical heterogeneity (Figure 2). Definition 1 was cumulative percentage fluid overload exceeding 5% during the first 24 hours of admission (OR, 9.35 [95% CI, 5.05-17.29]; I2 = 0%; n = 572). Definition 2 was peak percentage fluid overload exceeding 10% at any point during the entire PICU admission (OR, 15.02 [95% CI, 7.09-31.82]; I2 = 0%; n = 322). Definition 3 was cumulative percentage fluid overload exceeding 10% at CRRT initiation (OR, 2.82 [95% CI, 1.95-4.10]; I2 = 0%; n = 451). Definition 4 was cumulative percentage fluid overload exceeding 20% at CRRT initiation (OR, 4.29 [95% CI, 2.78-6.62]; I2 = 0%; n = 460).

When fluid overload was evaluated as a continuous exposure (22 studies), survivors had lower percentage fluid overload compared with nonsurvivors (WMD, −5.62 [95% CI, −7.28 to −3.97]; I2 = 76%; n = 2848) (Figure 3). There was marked variation in the periods during which percentage fluid overload was assessed (eFigure 4 in the Supplement). Among 11 studies that adjusted for illness severity, pooled analysis found a 6% increased odds of mortality for every 1% increase in percentage fluid overload (adjusted OR, 1.06 [95% CI, 1.03-1.10]; I2 = 66%; n = 3200) (eFigure 5 in the Supplement). Funnel plots of fluid overload percentage (as a categorical and continuous variable) association with mortality are shown in eFigure 6 and eFigure 7 in the Supplement.

Respiratory Outcomes

Respiratory dysfunction and outcomes, including change in oxygenation index, ventilation-free days, or length of mechanical ventilation, were evaluated in 19 studies. Of these, 15 studies (79%) reported that positive fluid balance or fluid overload was associated with negative outcomes (eTable 6 in the Supplement). Six studies20,40,47,48,50,55 reported significant correlation between increasing fluid overload and worsening oxygenation index. In addition, 3 studies20,48,50 showed that greater percentage fluid overload was an independent predictor of worsened oxygenation index. In 3 studies3,53,55 of children with acute lung injury, positive fluid balance was associated with fewer ventilation-free days. Pooled data from 3 studies6,34,54 demonstrated that fluid overload was associated with prolonged mechanical ventilation (>48 hours) (OR, 2.14 [95% CI, 1.25-3.66]; I2 = 0%; n = 631) (eFigure 8 in the Supplement). Pooled analyses of the remaining data were not feasible due to marked clinical and statistical heterogeneity in exposure-outcome combinations.

Acute Kidney Injury

Data from 7 studies demonstrated that fluid overload was associated with increased risk of AKI (OR, 2.36 [95% CI, 1.27-4.38]; I2 = 78%; n = 1833) compared with those without fluid overload (eFigure 9 in the Supplement). In one study,35 fluid overload was significantly associated with longer time to kidney recovery in a cohort of children receiving CRRT.

PICU Length of Stay

Pooled data from 6 studies showed that fluid overload was associated with longer PICU stay compared with no fluid overload (WMD, −2.51 [95% CI, −4.99 to −0.03]; I2 = 88%; n = 1001) (eFigure 10 in the Supplement). Three additional studies20,26,47 reported significant association between fluid overload and increased PICU length of stay; however, data could not be pooled statistically.

Additional Outcomes

Additional outcomes in association with fluid overload are summarized in eTable 7 in the Supplement. These data include the use of RRT, ECMO, and composite outcomes.

Discussion

In this rigorous and comprehensive systematic review and meta-analysis, we synthesized the evidence from 44 studies, including 7507 children, to describe the methods used to assess fluid balance, define fluid overload, and describe the association between fluid balance and outcomes in critically ill children. We found the current evidence to be largely composed of small observational studies applying heterogeneous metrics to assess fluid balance and define fluid overload. This variation was particularly evident in the following 3 areas: (1) the methods used to measure fluid balance, (2) the methods used to quantify fluid overload, and (3) the thresholds and duration of fluid overload assessment in relation to outcome assessment. Nevertheless, our findings were robust and consistent in suggesting that fluid overload was common and portended greater risk for death, worsened respiratory physiology that included prolonged mechanical ventilation, and additional outcomes implying greater intensification of support. These findings align with growing evidence describing the negative association between fluid accumulation and outcomes in adult critically ill populations, including acute respiratory distress syndrome,56-58 sepsis,59-61 and AKI,62-65 and in perioperative settings.66-69

Despite accumulating observational data showing the harmful effect of fluid overload on outcomes, there is currently no consensus on how best to define it. The current definitions of fluid overload include 3 components. First are the methods of fluid balance assessment: accurate monitoring of fluid balance is an imperative first step to recognize fluid overload. We identified 2 main methods of assessing fluid balance based on either recorded daily intake-output or serial weight measurements. Recording daily intake and output can be time-consuming to track and prone to error. Serial weight measurements offer some theoretical advantages, including presumed integration of insensible fluid losses. However, frequent weight measurements might not be feasible in the PICU environment due to the unstable condition of many PICU patients. More objective tools, such as electrical bioimpedence and point-of-care ultrasound, have shown promise in providing more objective assessment of fluid status. However, none of the studies identified in this systematic review and meta-analysis evaluated their clinical utility.

Second are the methods used to quantify fluid overload. The calculation of percentage fluid overload proposed by Goldstein and colleagues7 was the most frequently used method to quantify fluid overload. Some studies used percentage weight change as an alternative. Two studies8,10 of the 3 that compared both methods showed that they were highly correlated. Based on that observation and until further evidence suggests otherwise, it seems reasonable to consider both methods to be clinically useful.

Third are threshold and duration of fluid overload assessment. While various combinations of thresholds and durations were used, we identified the following 4 common definitions that showed significant association with outcomes: (1) early fluid overload, with cumulative percentage fluid overload exceeding 5% in the first 24 hours; (2) peak percentage fluid overload exceeding 10% during PICU admission; (3) cumulative percentage fluid overload exceeding 10% at CRRT initiation; and (4) cumulative percentage fluid overload exceeding 20% at CRRT initiation. These definitions align with a similar threshold of 10% that has been used in some adult studies63,65 and showed association with worse outcomes.

Available evidence describing the negative effect of fluid overload highlights the potential for evaluation of strategies to prevent, mitigate, and manage fluid accumulation in critically ill children. Clinical trials have suggested that conservative fluid management strategies are feasible and may be associated with improved outcomes. The Fluid and Catheter Treatment Trial (FACTT) reported that a conservative fluid management strategy during the first 7 days of intensive care unit admission among adults with acute lung injury portended shorter duration of mechanical ventilation and intensive care unit stay compared with a liberal fluid management strategy.57 However, in a planned secondary analysis, those allocated to the conservative strategy showed greater risk of cognitive impairment compared with those in the liberal management group, a finding that demands consideration in the context of critically ill children.70 The Fluid Expansion as Supportive Therapy (FEAST) study71 was a randomized controlled trial of 3141 African children with severe febrile illness and clinical evidence of organ hypoperfusion. Children were randomized to receive fluid boluses with 20 to 40 mL/kg (0.9% saline or 5% albumin) or no fluid bolus therapy. Children receiving fluid boluses had significantly greater mortality within 48 hours largely due to cardiovascular collapse.72 While FEAST has limited generalizability to modern PICU care, it raises concerns about our primitive understanding of the context and volume of fluid administered to critically ill children both acutely and during their PICU course and its association with outcomes. Two pilot studies73,74 have shown that a restrictive fluid management strategy after initial resuscitation is safe in septic adults. Currently under way is a similar study in children known as SQUEEZE75 to determine whether septic shock reversal is quicker in pediatric patients randomized to an early goal-directed fluid-sparing strategy vs usual care.

Our findings also suggest that fluid balance may represent an identifiable and modifiable target for intervention. The concept of “active deresuscitation” after initial stabilization using pharmacological or extracorporeal interventions has been introduced in the literature.76 A post hoc analysis of the FACTT showed that diuretic-induced negative fluid balance was associated with improved survival in adults with AKI.64 In a recent randomized clinical trial involving 73 infants after cardiac surgery, prophylactic peritoneal dialysis was more effective than furosemide in mitigating the development of fluid overload (>10%) and was associated with shorter duration of mechanical ventilation and inotrope use.77 However, it currently remains uncertain whether the earlier initiation of RRT in critical illness, particularly when confronted with AKI and fluid accumulation, can improve outcomes.78,79 The data summarized in our systematic review and meta-analysis would appear to support the evaluation of active strategies to prevent and mitigate fluid overload in critically ill children and should be tested in rigorous clinical trials.

Strengths and Limitations

Our systematic review and meta-analysis is strengthened by the use of a comprehensive search strategy, by rigorous screening and eligibility criteria, and by transparent reporting of our findings.13,14 We also found that our primary and secondary outcome findings were robust in sensitivity analyses considering prespecified case-mix subgroups, variable fluid overload definitions, and after including only studies in which illness severity adjustment was possible. However, the studies included in our systematic review and meta-analysis have important limitations. First, almost all studies were observational and mostly retrospective, with many having limited capacity for adjustment, and thus are at risk of selection bias and residual confounding. Second, as such, we cannot definitively confirm the causal link between fluid overload and adverse outcomes given the paucity of rigorous experimental trials evaluating fluid management strategies in critically ill children. Third, studies included had wide variation in case mix and in operational definitions for fluid balance and fluid overload, as well as significant heterogeneity in outcomes, which limited our capacity for pooled analyses in selected circumstances. Moreover, some selected studies reported fluid overload as a continuous exposure using the median and range, necessitating transformation of the data to the mean (SD) using previously described formulas. This process may have contributed to imprecise effect estimates.17 Some PICU subpopulations, such as trauma and burn patients, were underrepresented in the included studies, which could limit the generalizability of the findings. Few studies evaluated the temporal changes in fluid balance during the PICU course. Fourth, few studies considered the potential fluid deficit state of children or accounted for fluid administration and accumulation before PICU admission. This factor may have contributed to misclassification of fluid overload considering that many PICU patients receive fluid resuscitation in the emergency department, operating theater, or on general wards before transfer to the PICU.

Conclusions

Fluid overload is common among critically ill children and exerts a strong negative association with outcomes. The findings of our systematic review and meta-analysis support the hypothesis that a threshold may exist beyond which fluid accumulation becomes unhelpful or frankly harmful. Clinicians should monitor fluid balance and consider the hazard associated with avoidable fluid accumulation and overload. We believe that our work further provides a foundation for the development of optimal strategies for fluid management among critically ill children, specifically in the form of rigorous clinical trials aimed at avoiding and mitigating iatrogenic or avoidable fluid overload.

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Article Information

Accepted for Publication: October 11, 2017.

Corresponding Author: Sean M. Bagshaw, MD, MSc, Department of Critical Care Medicine, Faculty of Medicine and Dentistry, University of Alberta, Room 2-124E, Clinical Sciences Bldg, 8440 112th St NW, Edmonton, AB T6G 2B7, Canada (bagshaw@ualberta.ca).

Published Online: January 22, 2018. doi:10.1001/jamapediatrics.2017.4540

Author Contributions: Drs Alobaidi and Bagshaw had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Alobaidi, Morgan, Basu, Majumdar, Bagshaw.

Acquisition, analysis, or interpretation of data: Alobaidi, Stenson, Featherstone, Majumdar, Bagshaw.

Drafting of the manuscript: Alobaidi, Basu, Stenson, Featherstone, Bagshaw.

Critical revision of the manuscript for important intellectual content: Alobaidi, Morgan, Basu, Featherstone, Majumdar, Bagshaw.

Statistical analysis: Alobaidi, Basu, Stenson, Majumdar, Bagshaw.

Obtained funding: Majumdar, Bagshaw.

Administrative, technical, or material support: Featherstone.

Study supervision: Morgan, Basu, Majumdar, Bagshaw.

Conflict of Interest Disclosures: None reported.

Funding/Support: Dr Majumdar holds the endowed Research Chair in Patient Health Management, supported by the Faculty of Medicine and Dentistry and the Faculty of Pharmacy and Pharmaceutical Sciences at the University of Alberta. Dr Bagshaw is supported by a Canada Research Chair in Critical Care Nephrology. Research support for this project was received from the Alberta Strategies for Patient-Oriented Research (SPOR) SUPPORT Unit Knowledge Translation Platform.

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: Tara Landry, MLIS (Montreal General Hospital Medical Library, Montreal, Quebec, Canada), reviewed the search strategy and received a stipend for peer reviewing the search strategy from the Alberta Strategies for Patient-Oriented Research (SPOR) SUPPORT Unit Knowledge Translation Platform.

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