Association Between the Use of Balanced Fluids and Outcomes in Critically Ill Children: A Before and After Study

doi:10.21203/rs.3.rs-357546/v1

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Association Between the Use of Balanced Fluids and Outcomes in Critically Ill Children: A Before and After Study

https://doi.org/10.21203/rs.3.rs-357546/v1

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published 29 Jul, 2021

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Background: Hyperchloremia and the administration of higher chloride loads have been associated with worse clinical outcomes in critically ill patients. We sought to evaluate the electrolyte profile and clinical outcomes associated with a unit-wide transition from saline to balanced fluids as standard care for resuscitation and maintenance fluid administration in a pediatric intensive care unit (PICU).

Methods: A before and after analysis of patients admitted to a PICU in a large, urban, academic hospital between May 2018 and March 2020. The transition from the use of saline as the main fluid of choice to the use of balanced fluids for both resuscitation and maintenance fluid as standard care occurred in June 2019. The primary outcome was acute kidney injury (AKI) and the secondary outcomes were mortality, ventilator free days (VFD), need for renal replacement therapy (RRT), hospital length of stay (LOS), and electrolyte abnormalities.

Results: Overall, 2863 patients (47% female) with an AKI rate of 8% (n=228) and a mortality rate of 2.8% (n=79) were included. The pre-intervention period (May 2018 to April 2019) included 1,380 patients and the post-intervention period (August 2019 to March 2020) included 1,483 patients. After adjusting for confounders (age, PRISM III, mechanical ventilation and immunocompromised state), there were no significant differences in the odds of AKI (Pre 8.1%, Post 8%; adjusted odds ratio [aOR] 1.0 95%CI 0.8-1.3, p=0.98). Additionally, there were no differences in the odds of mortality, VFD, need for RRT, nor hospital LOS. The post-intervention period had fewer patients with hyperchloremia (Pre 10.4% vs. Post 15.5%, p=<0.0001) and hyperkalemia (Pre 1.4% vs. Post 3.2%, p=0.02) and more patients with hypochloremia (Pre 9.5% vs. Post 14.4%, p=<0.0001) and hypokalemia (Pre 38.2% vs. Post 47.2%, p=<0.0001).

Conclusions: Following a unit-wide implementation of balanced fluids as standard care, there were no differences in rates of AKI or other clinical outcomes. However, there were changes in the electrolyte profile: lower rates of hyperkalemia and hyperchloremia and higher rates of hypokalemia and hypochloremia. Further evaluation of the effect of balanced fluids and the clinical significance of electrolyte abnormalities in critically ill children is needed.

Critical Care & Emergency Medicine

balanced fluids

acute kidney injury

mortality

pediatric critical care

The administration of higher chloride loads and hyperchloremia have been associated with worse clinical outcomes in critically ill patients, including higher rates of mortality and acute kidney injury (AKI) [1-8]. Saline (0.9% sodium chloride fluid), has a considerably larger than the normal concentration of chloride than blood (154 vs. ~100 mmol/L) and is one of the most commonly used fluids in the hospital setting [9]. Balanced fluids, like Lactated Ringers or Plasma-Lyte, have more physiologic levels of chloride, but while they have been gaining popularity in the last few years, they are still not as commonly used as saline.

In animal studies, elevated tubular chloride leads to afferent arteriolar vasoconstriction which in turn leads to decreased glomerular filtration rate (GFR) and impaired renal perfusion [10]. Chowdury et al. demonstrated that the administration of hyperchloremic fluid leads to decreased renal blood flow and decreased cortical tissue perfusion in healthy adults [11]. The presence and development of hyperchloremia has been independently associated with higher rates of AKI and mortality in both critically adults and children [4, 5, 8, 12]. Moreover, a recent randomized clinical trial of critically ill adults, Isotonic Solutions and Major Adverse Renal Events Trial, compared the effects of balanced fluids versus saline and found a 1% absolute reduction in the composite outcome of major acute kidney event at 30 days with the use of balanced fluids[6].

AKI occurs commonly in critically ill children, affecting up to 27% of all pediatric intensive care unit (PICU) admissions [13], and is associated with higher mortality, a greater duration of mechanical ventilation, and longer length of stay in both the pediatric and adult the intensive care units [13, 14]. The chloride content of resuscitation and maintenance fluids is a potential modifiable risk factor of AKI, which has led many practitioners to shift towards the use of balanced fluids. In fact, the recent pediatric Surviving Sepsis Campaign guidelines recommends the use of balanced fluids for resuscitation [15]. However, the impact of a change from a saline-based to a balance fluid-based management strategy on the electrolyte profile and outcomes of critically ill children remains unknown.

In this study, we sought to evaluate the electrolyte profiles and clinical outcomes associated with a unit-wide transition from saline to balanced fluids as standard care for fluid administration in a PICU. We hypothesized that the transition would be associated with improved electrolyte profiles and clinical outcomes.

Study Design and Population

We performed a before and after study of all patients admitted to the PICU at Ann & Robert H. Lurie Children’s Hospital between May 2018 and March 2020. In June 2019, the pediatric intensive care unit (PICU) a transitioned from the use of saline as the main fluid of choice to the use of balanced fluids for both resuscitation and maintenance fluid as standard care. The standard resuscitation fluid was transitioned to a commercially available balanced crystalloid solution (PlasmaLyte-148) and the standard maintenance fluid became Lactated Ringers with or without dextrose. All care was subject to the preference of the attending physician and therefore patients continued to receive saline if there was concern for sodium management or an elevated intracranial pressure. Patients with a primary cardiac diagnosis or a history of congenital heart disease were excluded as they are admitted to a separate cardiac unit. All data were extracted from the electronic health records (EHRs) [16]. The Institutional Review Board at Ann & Robert H. Lurie Children’s Hospital approved the study with a waiver of informed consent.

Definitions

Patients from May 2018 – April 2019 prior to the clinical change (pre-intervention group) were compared with patients from August 2019 - March 2020 after the clinical change (post-intervention group). The SARS-CoV-2 pandemic occurred after the change to balanced fluids. We therefore limited our data collection to equivalent time periods prior to March 2020. We collected patient data for the first seven days of hospital stay following admission to the PICU admission. Each PICU day was defined by 24-hour periods from the time of admission to the PICU (e.g. day 1 was 0-24 hours after admission). Weight adjusted fluid volume was calculated as the total volume administered divided by the PICU admission weight. Resuscitation fluid was identified either by the clinical label recorded in the EHR, a single administration of crystalloid or colloid fluid ≥10 mL/kg, or was labeled as a “bolus” (e.g. “Normal Saline Bolus”, “Lactated Ringers Bolus”, etc.). Fluid given prior to the admission to the PICU was not included in this assessment. Severity of illness on admission was based on their Pediatric Risk of Mortality (PRISM) III score in the first 24 hours[17]. Immunocompromised state was defined as patients with a malignancy or a history of stem cell or solid organ transplantation[18].

AKI was defined using the Kidney Disease Improving Global Outcomes (KDIGO) serum creatinine criteria[19]. Baseline creatinine was defined as the lowest serum creatinine in the 3 months prior to admission. If no baseline creatinine was available, one was calculated using previously validated estimations based on age and sex[20, 21]. Septic Shock was defined as known or suspected infection and a receipt of a vasoactive medication.

Total chloride load was defined as the mmol of chloride per kilogram of weight. Fluid adjusted chloride load was calculated by the chloride load in mmol per kilogram divided by the fluid administered in liters per kilogram. This estimated the type of fluid given based on the fluid adjusted chloride load (mmol/L), ie. a patient receiving only saline would have a load of 154mmol/L, those receiving only PlasmaLyte-148 would have a load of 98mmoL/L and those receiving only Lactated Ringers would have a load of 109 mmoL/L.

Hypochloremia was defined as a mean chloride level <98mmol/L. Normochloremia was defined as a mean chloride level 98-109mmol/L. Hyperchloremia was defined as a mean chloride level >109mmol/L. Hyponatremia was defined as a mean sodium level <136mmol/L. Normonatremia was defined as a mean sodium level 136-149mmol/L. Hypernatremia was defined as a mean sodium level >149mmol/L. Hypokalemia was defined as a mean potassium level <3.9mmol/L. Normokalemia was defined as a mean potassium level 3.9-5.7mmol/L. Hyperkalemia was defined as a mean potassium level >5.7mmol/L. Acidemia was defined as a mean bicarbonate level <20mmol/L. Alkalemia was defined as a mean bicarbonate level >30 mmol/L.

Outcomes

The primary outcome was AKI during the first 7 days of admission to the PICU. The secondary outcomes were in hospital mortality, need for renal replacement therapy (RRT), hospital length of stay, ventilator-free days at 28 days, and frequency of electrolyte abnormalities including hyperchloremia, hypochloremia, hypernatremia, hyponatremia, hyperkalemia, hypokalemia, acidemia and alkalemia.

Sensitivity Analyses:

Sensitivity analyses were performed evaluating the effect modification of each of the following on our outcomes of interest: septic shock, PRISM III, volume of resuscitation fluid (mL/kg) during the first week, and chloride load (mmol/kg) during the first week.

Post hoc analyses were performed based on the significant electrolyte abnormalities identified. We evaluated the association of each significantly different electrolyte abnormality (hyperchloremia, hypochloremia, hyperkalemia, hypokalemia) with the outcomes of interest. These was performed because prior literature has demonstrated the association of hyperchloremia with mortality and AKI in critically ill children [7, 8, 12], and the known clinical risks of hyperkalemia and hypokalemia.

Statistical Analysis

Data analysis was performed using STATA 14 (StataCorp LP, Texas, USA). Clinical, demographic, and fluid data were summarized and compared between groups. Non-normally distributed continuous variables were compared using Wilcoxon Rank Sum and Kruskal-Wallis tests and categorical variables were compared using the Chi-square test. Following a statistically significant omnibus test, a pairwise comparison using a Bonferroni correction was done as appropriate. Statistical significance level was set at a two-sided alpha <0.05.

To evaluate the association of the intervention time period with the outcomes of interest, multivariable logistic regression analyses were performed adjusting for confounders: age, PRISM III score, need for mechanical ventilation, and immunocompromised state. The confounding variables were chosen a priori, based on known confounders of mortality.

For the sensitivity analyses, the regression analyses previously described were repeated evaluating the effect modification of each of the following on the outcomes of interest: septic shock, PRISM3, volume of resuscitation fluid (mL/kg) during the first week, and chloride load (mmol/kg) during the first week. For the post hoc analyses, logistic regression analyses were performed. These analyses evaluated hypochloremia, normochloremia, and hyperchloremia (using normochloremia as the reference) with our outcomes of interest, both in the entire cohort and in the subpopulations of each time period adjusting for the previously discussed confounding variables. The regression analyses were repeated evaluating hypokalemia, normokalemia, and hyperkalemia (using normokalemia as the reference) with our outcomes of interest similarly to the chloride analyses.

A total of 2863 patients (47% female, n=1,345) were included in the study. The patients had a median age of 3.3 years (IQR 1.1-10.4), a median weight of 14.2kg (IQR 9.2-29.9). Table 1 presents the clinical characteristics of the study years dichotomized by study time period (Pre vs. Post Intervention). There was a significantly greater proportion of patients requiring mechanical ventilation in the post-intervention time period. Additionally, there was significantly greater volume of resuscitation fluid administered in the post-intervention time period. The total chloride load, chloride load from resuscitation fluid, and chloride load from maintenance fluid were all significantly lower in the post-intervention period. The chloride load from maintenance fluid represented nearly the entire difference in total chloride load. The resuscitation fluid choice demonstrated a significant change in the types of fluid used for both resuscitation as well as maintenance fluid following the intervention.

The total cohort had an AKI rate of 8% (n=228), a severe AKI rate of 3.5% (n=99), a median hospital length of stay 5.1 days (IQR 2.9-10.5), and a mortality rate of 2.8% (n=79). Table 2 summarizes the outcomes between study periods. There was no difference in the primary outcome of AKI between the two time periods, pre-intervention 8.1% (n=119), post-intervention 8% (n=109). There was a significantly longer length of stay and fewer ventilator free days during the post-intervention fluid time period. Mortality rate was similar in the pre-intervention period 2.6% (n=39) vs. the post-intervention 2.9% (n=40).

In the multivariable outcome analyses to evaluate the association of the intervention with our outcomes of interest, there was no significant difference in AKI between the pre and post intervention time periods: OR 0.98 (95%CI 0.8-1.3, p=0.9), aOR 1.0 (95%CI 0.8-1.3, p=0.98). Similarly, there was no significant difference in any of the secondary outcomes in the pre and post intervention time periods.

In the sensitivity analyses, there were no significant differences between the study time periods regarding any outcomes (AKI, mortality or VFD) following evaluation of the effect modification of the presence of septic shock, PRISM III score, volume of resuscitation (mL/kg), total chloride load (mmol/kg).

Table 3 summarizes the plasma electrolyte values. There were statistically significant differences between the median sodium, potassium, chloride and bicarbonate levels. There were significantly lower rates of hyperkalemia and hyperchloremia and higher rates of hypokalemia and hypochloremia during the post-intervention period.

In the post hoc analyses of the electrolyte abnormalities, the post-intervention time period was found to have a lower odds of hyperchloremia after adjusting for confounding variables, aOR 0.63 (95% CI: 0.46-0.86, p=0.003), higher odds of hypochloremia, aOR 1.6 (95% CI: 1.2-2.2, p=0.004), lower odds of hyperkalemia aOR 0.41 (95% CI: 0.2-0.83, p=0.01), and higher odds of hypokalemia, aOR 1.5 (95% CI: 1.2-1.8, p<0.001). Table 4 summarizes the association of the stratified chloride levels (hypochloremia, hyperchloremia in reference to normochloremia) with the unadjusted and adjusted outcomes of interest categorized by the time periods. In the full cohort after adjustment for confounders, hypochloremia was associated with higher odds of AKI, and a decreased likelihood of having a ventilator free day, but was not associated with a higher odds of mortality. The same associations were consistent in both the pre and post intervention time periods. In the full cohort after adjustment for confounders, hyperchloremia was associated with higher odds of AKI, higher odds of mortality, and a decreased likelihood of having a ventilator free day. The same associations were consistent in both the pre and post intervention time periods. The evaluation of the association of potassium levels with the outcomes of interest indicated that after adjustment for confounders neither hypokalemia nor hyperkalemia was associated with AKI, mortality, or the likelihood of having a ventilator free day regardless of the time period.

In this before and after study, we evaluated the clinical outcomes following a change from saline to balanced fluids as standard care for resuscitation and maintenance for patients admitted to a large urban tertiary care PICU. To our knowledge, this study represents the first evaluation of balanced fluids as a standard care in a PICU. The volume adjusted chloride load demonstrated that the transition from saline to balanced fluids occurred, and there was a greater use of balanced fluids for both resuscitation and maintenance fluid. This increased use of balanced fluids was associated with a lower chloride load administered to patients. Most of this decreased load was attributable to the change of maintenance fluid. Despite the change in fluid type and chloride loads, there were no significant differences in most of the primary and secondary outcomes between the study time periods, including AKI, in-hospital morality, need for RRT, hospital length of stay, or ventilator-free days. There was however a significant change in the profile of electrolyte abnormalities, with lower rates of hyperchloremia and hyperkalemia and higher rates of hypochloremia and hypokalemia in the post-intervention period. Furthermore, the chloride abnormalities were independently associated with poor outcomes, both in the pre and post-intervention periods.

Several randomized control trials of balanced fluids vs. saline in adult patients have also shown no difference in outcomes. The Saline vs. Plasma-Lyte for ICU fluid Therapy trial was a randomized control trial that evaluated critically ill adults and compared the use of saline vs. Plasma-Lyte 148. The authors demonstrated no significant difference in outcomes between the two study groups[22]. The Saline vs. Lactated Ringers randomized control trial evaluated adults receiving non-emergent abdominal surgery and compared the two crystalloid fluid types during the operation. The investigators found no differences in clinical outcomes. In contrast to these findings, the Isotonic Solutions and Major Adverse Renal Events Trial showed improvements in the composite outcome of mortality, new need for RRT, and persistent reduction in renal function among patients receiving balanced fluids[6]. There are important differences between each of these studies notably the severity of illness of each population, and the administration of saline to patients prior to initiation of the studies. These factors likely also affect our findings.

Our findings as they relate to the patient electrolyte abnormality profiles are notable. In the post intervention time period, there were lower rates of hyperchloremia and hyperkalemia as well as higher rates of hypochloremia and hypokalemia. This was likely due to the common use of D5 saline with 20mEq of potassium chloride for maintenance fluid in the pre-intervention period. The decrease in both chloride and potassium likely was the driver of these changes. Importantly, there were no differences in the sodium or bicarbonate abnormalities. In the post hoc analyses of these electrolyte abnormalities, hyperchloremia was associated with a higher rate of AKI, a higher rate mortality, and a lower likelihood of having a ventilator free day after adjusting for confounders and hypochloremia was associated with a higher rate of AKI and lower likelihood of having a ventilator free day. These associations occurred whether we evaluated the full cohort or either of the time periods. This association of serum chloride levels and poor clinical outcomes is consistent with prior literature in critically ill adults and children[2, 7, 8, 12, 23, 24]. However, our findings are notable for the significant change in the electrolyte abnormality profiles between the two time periods, and the transition to balanced fluids did not necessarily lead to better electrolyte homeostasis. The clinical relevance of these electrolyte changes is undetermined. Further study will be needed to elucidate the impact that chloride load has on patients who develop hyperchloremia and hypochloremia and the associated outcomes.

This study has several strengths. The study cohort is large and heterogenous. In addition, the comparison groups are from similar time periods and represent similar populations. The study also has several limitations. First, the data were retrospective and observational, and the study design can only establish associations and not causality. Second, these results could be subject to a selection bias due to the types of patients admitted to a large urban pediatric hospital. Third, the SARS-CoV-2 pandemic impacted our hospital starting in March 2020 and limited the ability to compare a larger number of patients and likely limited the power to detect possible differences between the study periods. Fourth, though the only major change that occurred in the PICU during the study period was the increased use of balanced fluids; other unmeasured changes may have influenced the outcomes. Fifth, due to the concurrent timing of the AKI and electrolyte abnormalities it is impossible to assess the directionality of effect. Sixth, patients may have received fluids of potentially large volumes prior to coming to the PICU. The composition of fluids prior to admission was not calculated and may have influenced the outcomes. Anecdotally, the most used fluid in other parts of the hospital was and remains saline.

Following a practice change in a PICU from the use of saline to the use of balanced fluids as standard care for both maintenance fluids and resuscitation, there were no significant differences in clinical outcomes including AKI and mortality. However, the intervention was associated with a significant change in the profile of electrolyte abnormalities in the critically ill children. The balanced fluid time period was associated with significantly lower rates of hyperkalemia and hyperchloremia, but with higher rates of hypokalemia and hypochloremia. Both hyper- and hypochloremia were independently associated with increased rates of AKI, decreased ventilator-free days after adjustment for confounders, both in the full cohort as well as in each of the two periods. Hyperchloremia was also independently associated with higher in-hospital mortality. The direct impact of the use of balanced fluids on the profiles of electrolyte abnormalities and its association with outcomes in critically ill children requires further evaluation.

AKI: acute kidney injury; PICU: pediatric intensive care unit; EHR: electronic health record; GFR: glomerular filtration rate; OR: odds ratio; VFD: ventilator free days; RRT: renal replacement therapy; PRISM: pediatric risk of mortality

Ethical Approval and Consent to participate: The Institutional Review Board at Ann & Robert H. Lurie Children’s Hospital approved the study with a waiver of informed consent.

Consent for publication: Not applicable

Availability of supporting data: The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests: The authors declare that they have no competing interests.

Funding: No financial support was used for this study.

Authors Contributions: The authors did the following contributions:

MFB [Study design, analysis, first draft of the manuscript]

DN/TM/JC [study design, review of the manuscript]

LNS [Study design, analysis, review of the manuscript]

Acknowledgements: Not applicable

Lee JY, Hong TH, Lee KW, Jung MJ, Lee JG, Lee SH: Hyperchloremia is associated with 30-day mortality in major trauma patients: a retrospective observational study. Scand J Trauma Resusc Emerg Med 2016, 24(1):117.
Zhang Z, Xu X, Fan H, Li D, Deng H: Higher serum chloride concentrations are associated with acute kidney injury in unselected critically ill patients. BMC Nephrol 2013, 14:235.
Toyonaga Y, Kikura M: Hyperchloremic acidosis is associated with acute kidney injury after abdominal surgery. Nephrology (Carlton) 2017, 22(9):720-727.
Suetrong B, Pisitsak C, Boyd JH, Russell JA, Walley KR: Hyperchloremia and moderate increase in serum chloride are associated with acute kidney injury in severe sepsis and septic shock patients. Crit Care 2016, 20(1):315.
Neyra JA, Canepa-Escaro F, Li X, Manllo J, Adams-Huet B, Yee J, Yessayan L, Group AKIiCIS: Association of Hyperchloremia With Hospital Mortality in Critically Ill Septic Patients. Crit Care Med 2015, 43(9):1938-1944.
Semler MW, Self WH, Wanderer JP, Ehrenfeld JM, Wang L, Byrne DW, Stollings JL, Kumar AB, Hughes CG, Hernandez A et al: Balanced Crystalloids versus Saline in Critically Ill Adults. N Engl J Med 2018, 378(9):829-839.
Barhight MF, Lusk J, Brinton J, Stidham T, Soranno DE, Faubel S, Goebel J, Mourani PM, Gist KM: Hyperchloremia is independently associated with mortality in critically ill children who ultimately require continuous renal replacement therapy. Pediatr Nephrol 2018.
Barhight MF, Brinton J, Stidham T, Soranno DE, Faubel S, Griffin BR, Goebel J, Mourani PM, Gist KM: Increase in chloride from baseline is independently associated with mortality in critically ill children. Intensive Care Med 2018, 44(12):2183-2191.
Kellum JA: Fluid resuscitation and hyperchloremic acidosis in experimental sepsis: improved short-term survival and acid-base balance with Hextend compared with saline. Crit Care Med 2002, 30(2):300-305.
Wilcox CS: Regulation of renal blood flow by plasma chloride. J Clin Invest 1983, 71(3):726-735.
Chowdhury AH, Cox EF, Francis ST, Lobo DN: A randomized, controlled, double-blind crossover study on the effects of 2-L infusions of 0.9% saline and plasma-lyte® 148 on renal blood flow velocity and renal cortical tissue perfusion in healthy volunteers. Ann Surg 2012, 256(1):18-24.
Stenson EK, Cvijanovich NZ, Anas N, Allen GL, Thomas NJ, Bigham MT, Weiss SL, Fitzgerald JC, Checchia PA, Meyer K et al: Hyperchloremia Is Associated With Complicated Course and Mortality in Pediatric Patients With Septic Shock. Pediatr Crit Care Med 2018, 19(2):155-160.
Kaddourah A, Basu RK, Bagshaw SM, Goldstein SL, Investigators A: Epidemiology of Acute Kidney Injury in Critically Ill Children and Young Adults. N Engl J Med 2016, 376(1):11-20.
Hoste EA, Bagshaw SM, Bellomo R, Cely CM, Colman R, Cruz DN, Edipidis K, Forni LG, Gomersall CD, Govil D et al: Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study. Intensive Care Med 2015, 41(8):1411-1423.
Weiss SL, Peters MJ, Alhazzani W, Agus MSD, Flori HR, Inwald DP, Nadel S, Schlapbach LJ, Tasker RC, Argent AC et al: Executive summary: surviving sepsis campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children. Intensive Care Med 2020, 46(Suppl 1):1-9.
Kahn MG, Callahan TJ, Barnard J, Bauck AE, Brown J, Davidson BN, Estiri H, Goerg C, Holve E, Johnson SG et al: A Harmonized Data Quality Assessment Terminology and Framework for the Secondary Use of Electronic Health Record Data. EGEMS (Wash DC) 2016, 4(1):1244.
Pollack MM, Patel KM, Ruttimann UE: PRISM III: an updated Pediatric Risk of Mortality score. Crit Care Med 1996, 24(5):743-752.
Feudtner C, Feinstein JA, Zhong W, Hall M, Dai D: Pediatric complex chronic conditions classification system version 2: updated for ICD-10 and complex medical technology dependence and transplantation. BMC Pediatr 2014, 14:199.
Khwaja A: KDIGO clinical practice guidelines for acute kidney injury. Nephron Clin Pract 2012, 120(4):c179-184.
Hessey E, Ali R, Dorais M, Morissette G, Pizzi M, Rink N, Jouvet P, Lacroix J, Phan V, Zappitelli M: Evaluation of height-dependent and height-independent methods of estimating baseline serum creatinine in critically ill children. Pediatr Nephrol 2017, 32(10):1953-1962.
Hoste L, Dubourg L, Selistre L, De Souza VC, Ranchin B, Hadj-Aissa A, Cochat P, Martens F, Pottel H: A new equation to estimate the glomerular filtration rate in children, adolescents and young adults. Nephrol Dial Transplant 2014, 29(5):1082-1091.
Young P, Bailey M, Beasley R, Henderson S, Mackle D, McArthur C, McGuinness S, Mehrtens J, Myburgh J, Psirides A 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. JAMA 2015, 314(16):1701-1710.
de Vasconcellos K, Skinner DL: Hyperchloraemia is associated with acute kidney injury and mortality in the critically ill: A retrospective observational study in a multidisciplinary intensive care unit. J Crit Care 2018, 45:45-51.
Neyra JA, Canepa-Escaro F, Li X, Manllo J, Adams-Huet B, Yee J, Yessayan L, Acute Kidney Injury in Critical Illness Study G: Association of Hyperchloremia With Hospital Mortality in Critically Ill Septic Patients. Crit Care Med 2015, 43(9):1938-1944.

Table 1: Demographic, clinical characteristics, and fluid use in the study periods.

Demographics	Pre-Intervention (n= 1,483)	Post-Intervention (n=1,380)	p value
Female n(%)	791 (47%)	727 (47%)	0.7
Age (years)	3.2 (1.2-10.4)	3.3 (1-10.4)	0.2
Weight (kg)	14.5 (9.5-30)	14 (8.7-29.9)	0.3
PRISM III	3 (0-7)	3 (0-7)	0.7
Immunocompromised n(%)	170 (11%)	147 (11%)	0.5
Mechanical ventilation n(%)	32% (474)	37% (510)	0.005
Septic Shock n(%)	7% (104)	7% (92)	0.7
Total Fluid Administered (mL/kg)	393.7 ± 294.1	423.7 ± 329.9	0.006
Resuscitation Volume (mL/kg)	6.3 ± 23.3	7 ± 16	<0.0001
Maintenance Volume (mL/kg)	151 ± 145.1	150.4 ± 130.6	0.2
Blood Products (mL/kg)	0.1 ± 1.4	0.05 ± 0.4	0.3
Total Chloride Load (mEq/kg)	28.1 ± 201	18.8 ± 16.9	<0.0001
Chloride Load from Resuscitation (mEq/kg)	0.8 ± 3.1	0.7 ± 1.8	0.002
Chloride Load from Maintenance (mEq/kg)	27.2 ± 200	17.8 ± 16.2	<0.0001
Resuscitation Fluid Type by Patient 0.9% Saline Plasma-Lyte Lactated Ringers Combination/Other	n=220 110 (50%) 0 (0%) 88 (40%) 22 (10%)	n=309 25 (8%) 271 (88%) 4 (1%) 9 (3%)	<0.0001
Maintenance Fluid Type per Patient 0.45% Saline 0.675% Saline 0.9% Saline 0.9% + 20mEq KCl Plasma-Lyte Lactated Ringers Lactated Ringers + 20mEq KCl Combination/Other	n=1253 26 (2%) 3 (0.2%) 83 (7%) 633 (51%) 6 (0.5%) 8 (0.6%) 4 (0.3%) 490 (39%)	n=1255 19 (1.5%) 35 (3%) 69 (6%) 62 (5%) 13 (1%) 478 (38%) 8 (0.6%) 571 (46%)	<0.0001

Table 2: Outcomes

Outcomes	Pre-intervention (n= 1,483)	Post-intervention (n=1,380)	p value	Post-intervention Unadjusted OR	Post-intervention Adjusted OR
Acute Kidney Injury	119 (8%)	109 (8%)	0.9	0.98 (95%CI: 0.8-1.3)	1.00 (95%CI: 0.8-1.3)
Mortality	39 (2.6%)	40 (2.9%)	0.7	1.1 (95%CI: 0.7-1.7)	1.3 (95%CI: 0.8-2.3)
Need for RRT	15 (1.1%)	24 (1.8%)	0.13	1.6 (95%CI: 0.9-3.2)	1.9 (95%CI: 0.9-3.7)
Length of Stay (days)	4.9 (2.9-9.7)	5.5 (3-11.3)	0.01	1.03 (95%CI: 1.01-1.05)	1.00 (95%CI: 0.98-1.02)
Ventilator Free Days	28 (26-28)	28 (25-28)	0.006	0.99 (95%CI: 0.97-1.00)	0.99 (95%CI: 0.98-1.01)

Legend: The transition from standard fluid practice to the suggested use of PlasmaLyte as the standard resuscitation fluid and Lactated Ringers as the standard maintenance fluid occurred in June 2019. The Pre-intervention time period era took place from May 2018-April 2019 and the Post-intervention time period took place from August 2019-March 2020. Acute Kidney Injury based on KDIGO creatinine definitions. RRT is Renal Replacement Therapy. Logistic regression analyses were used to evaluate the intervention periods and acute kidney injury, mortality and need for renal replacement therapy adjusting for age, PRISM III score, need for mechanical ventilation, and immunocompromised state. Poisson regression analyses were used to evaluate the intervention periods and length of stay and ventilator free days adjusting for the same confounding variables.

Table 3: Electrolyte profiles and abnormalities in the first 7 days after admission.

Electrolytes	Pre-intervention	Post-intervention	p value
Chloride
Hyperchloremia	119 (15.5%)	81 (10.4%)	<0.0001
Normochloremia	575 (75%)	587 (75%)
Hypochloremia	73 (9.5%)	112 (14.4%)
Potassium
Hyperkalemia	25 (3.2%)	11 (1.4%)	<0.0001
Normokalemia	453 (58.5%)	407 (51.5%)
Hypokalemia	296 (38.2%)	373 (47.2%)
Sodium
Hypernatremia	37 (4.7%)	36 (4.5%)	0.27
Normonatremia	697 (88.6%)	689 (86.6%)
Hyponatremia	53 (6.7%)	71 (8.9%)
Bicarbonate
Low/Acidosis	144 (18%)	144 (18.2%)	0.96
Normal	553 (71.3%)	565 (71.5%)
High/Alkalosis	83 (10.7%)	164 (10.5%)

Legend: The transition from standard fluid practice to the suggested use of PlasmaLyte as the standard resuscitation fluid and Lactated Ringers as the standard maintenance fluid occurred in June 2019. The Pre-intervention time period era took place from May 2018-April 2019 and the Post-intervention time period took place from August 2019-March 2020. The electrolyte calculations are based on fewer patients than the entire cohort as many patients did not have labs drawn. The Pre-intervention time period had 774 encounters (52% of total) with laboratory results and the Post-intervention time period had 790 encounters (57% of total) with laboratory results. Hypochloremia was defined as <98mmol/L. Normochloremia was defined as 98-109mmol/L. Hyperchloremia was defined as >109mmol/L. Hyponatremia was defined as <136mmol/L. Normonatremia was defined as 136-149mmol/L. Hypernatremia was defined as >149mmol/L. Hypokalemia was defined as <3.9mmol/L. Normokalemia was defined as 3.9-5.7mmol/L. Hyperkalemia was defined as >5.7mmol/L. Acidemia was defined as <20mmol/L of bicarbonate. Alkalemia was defined as >30 mmol/L of bicarbonate.

Table 4: Association between chloride abnormalities and outcomes stratified by time period.

Outcomes	Unadjusted analyses	Adjusted analyses
Acute Kidney Injury	Unadjusted OR (95%CI)	Adjusted OR (95%CI)
Entire study period
Hypochloremia	2.2 (1.5-3.3)	2.3 (1.5-3.6)
Normochloremia	Ref.	Ref.
Hyperchloremia	3.5 (2.4-4.9)	3.1 (2.1-2.6)
Pre-intervention
Hypochloremia	2.0 (1.1-3.7)	2.5 (1.3-4.9)
Normochloremia	Ref.	Ref.
Hyperchloremia	2.8 (1.7-4.4)	2.8 (1.6-4.7)
Post-intervention
Hypochloremia	2.5 (1.5-4.2)	2.5 (1.4-4.4)
Normochloremia	Ref.	Ref.
Hyperchloremia	4.6 (2.7-7.8)	3.6 (2.0-6.5)
In-Hospital Mortality	Unadjusted OR (95%CI)	Adjusted OR (95%CI)
Entire study period
Hypochloremia	2.4 (1.2-4.8)	1.3 (0.6-3)
Normochloremia	Ref.	Ref.
Hyperchloremia	5.4 (3.1-9.4)	2.8 (1.4-5.3)
Pre-intervention
Hypochloremia	1.7 (0.5-6.1)	0.8 (0.2-3.8)
Normochloremia	Ref.	Ref.
Hyperchloremia	4.1 (1.8-9.2)	2.5 (0.9-7.2)
Post-intervention
Hypochloremia	2.7 (1.1-6.6)	1.5 (0.6-3.9)
Normochloremia	Ref.	Ref.
Hyperchloremia	7.5 (3.5-16)	3.0 (1.2-7.2)
Ventilator-Free Days	Unadjusted IRR (95%CI)	Adjusted IRR (95%CI)
Entire study period
Hypochloremia	0.77 (0.74-0.8)	0.89 (0.86-0.92)
Normochloremia	Ref.	Ref.
Hyperchloremia	0.84 (0.81-0.86)	0.93 (0.9-0.96)
Pre-intervention
Hypochloremia	0.76 (0.72-0.81)	0.86 (0.81-0.91)
Normochloremia	Ref.	Ref.
Hyperchloremia	0.88 (0.84-0.91)	0.95 (0.91-0.99)
Post-intervention
Hypochloremia	0.78 (0.74-0.81)	0.91 (0.87-0.96)
Normochloremia	Ref.	Ref.
Hyperchloremia	0.78 (0.74-0.82)	0.90 (0.85-0.95)

Legend: The Balanced era took place from August 2019-February 2020 following the suggested use of PlasmaLyte as the standard resuscitation fluid and Lactated Ringers as the standard maintenance fluid. The Saline era took place from August 2018-February 2019 and reflected the practices in the unit prior to the change. Hypochloremia was defined as <98mmol/L. Normochloremia was defined as 98-109mmol/L. Hyperchloremia was defined as >109mmol/L. Logistic regression analyses were used to evaluate hyperchloremia and hypochloremia in reference to normochloremia with acute kidney injury and mortality adjusting for age, PRISM III score, need for mechanical ventilation, and immunocompromised state. Poisson regression analysis was used to evaluate hyperchloremia and hypochloremia in reference to normochloremia with ventilator free days adjusting for the same confounding variables.

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Association Between the Use of Balanced Fluids and Outcomes in Critically Ill Children: A Before and After Study

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