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Study Overview
Objective. To evaluate balanced crystalloids in comparison with normal saline in the intensive care unit (ICU) population.
Design. Pragmatic, un-blinded, cluster-randomized, multiple-crossover clinical trial (the SMART study).
Setting and participants. The study evaluated critically ill adults > 18 years of age, admitted and readmitted into 5 ICUs, both medical and surgical, from June 2015 to April 2017. 15,802 patients were enrolled, powered to detect a 1.9% percentage point difference in primary outcome. ICUs were randomized to use either balanced crystalloids (lactated Ringer’s [LR] or Plasma-Lyte A, depending on the provider’s preference) or normal saline during alternate calendar months. Relative contraindications to use of balanced crystalloids included traumatic brain injury and hyperkalemia. The admitting emergency rooms and operating rooms coordinated intravenous fluid (IVF) choice with their respective ICUs. An intention-to-treat analysis was conducted. In addition to primary and secondary outcome analyses, subgroup analyses based on factors including total IVF volume to day 30, vasopressor use, predicted in-hospital mortality, sepsis or traumatic brain injury diagnoses, ICU type, source of admission, and kidney function at baseline were also done. Furthermore, sensitivity analyses taking into account the total volume of crystalloid, crossover and excluding readmissions were performed.
Main outcome measures. The primary outcome was the proportion of patients that met at least 1 of the 3 criteria for a Major Adverse Kidney Event at day 30 (MAKE30) or discharge, whichever occurred earlier. MAKE30 is a composite measure consisting of death, persistent renal dysfunction (creatinine ≥ 200% baseline), or new renal replacement therapy (RRT). Patients previously on RRT were included for mortality analysis alone. In addition, secondary clinical outcomes including in-hospital mortality (prior to ICU discharge, at day 30 and day 60), ventilator-free days, vasopressor-free days, ICU-free days, days alive and RRT-free days in the first 28 days were assessed. Secondary renal outcomes such as persistent renal dysfunction, acute kidney injury (AKI) ≥ stage 2 (per Kidney Disease: Improving Global Outcomes Criteria {KDIGO}) criteria, new RRT, highest creatinine during hospitalization, creatinine at discharge and highest change in creatinine during hospitalization were also evaluated.
Results. 7942 patients were randomized to the balanced crystalloid group and 7860 to the saline group. Median age for both groups was 58 years and 57.6% patients were male. In terms of patient acuity, approximately 34% patients were on mechanical ventilation, 26% were on vasopressors, and around 14% carried a diagnosis of sepsis. At time of presentation, 17% had chronic kidney disease (CKD) ≥ stage 3 and approximately 5% were on RRT. Around 8% came in with AKI ≥ stage 2. Baseline creatinine in the both groups was 0.89 (interquartile range [IQR] 0.74–1.1). Median volumes of balanced crystalloid and saline administered was 1L (IQR 0–3.2L) and 1.02L (IQR 0–3.5L) respectively. Less than 5% in both groups received unassigned fluids. Predicted risk of in-hospital death for both groups was approximately 9%.
Significantly higher number of patients had plasma chloride ≥ 110 mmol/L and bicarbonate ≤ 20 mmol/L in the saline group (P < 0.001). In terms of primary outcome, MAKE30 rates in the balanced crystalloid vs saline groups were 14.3 vs 15.4 (marginal odds ratio {OR} 0.91, 95% confidence interval {CI} 0.84–0.99, P = 0.04) with similar results in the pre-specified sensitivity analyses. This difference was more prominent with larger volumes of infused fluids. All 3 components of composite primary outcome were improved in the crystalloid group, although none of the 3 individually achieved statistical significance.
Overall, mortality before discharge and within 30 days of admission in the balanced crystalloid group was 10.3% compared to 11.1% in the saline group (OR 0.9, CI 0.8–1.01, P = 0.06). In-hospital death before ICU discharge and at 60 days also mirrored this trend, although they did not achieve statistical significance either. Of note, in septic patients, 30-day mortality rates were 25.2 vs 29.4 in the balanced crystalloid and saline groups respectively (OR 0.8, 95% CI 0.67–0.97, P = 0.02).
With regard to renal outcomes in the balanced crystalloid vs normal saline groups, results were as follows: new RRT {2.5 vs 2.9%, P = 0.08}, new AKI development 10.7% vs 11.5% (OR 0.9, P = 0.09). In patients with a history of previous RRT or presenting with an AKI, crystalloids appeared to provide better MAKE30 outcomes, although not achieving statistical significance.
Conclusion. In the critically ill population, balanced crystalloids provide a beneficial effect over normal saline on the composite outcome of persistent renal dysfunction, new RRT and mortality at day 30.
Commentary
Unbalanced crystalloids, especially normal saline, are the most commonly used IVF for resuscitation in the critically ill. Given the data suggesting risk of kidney injury, acidosis, and effect on mortality with the use of normal saline, this study aimed to evaluate balanced crystalloids in comparison with normal saline in the ICU population.
Interest in the consequences of hyperchloremia and metabolic acidosis from supra-physiologic chloride concentrations in normal saline first stemmed from data in preclinical models, which demonstrated that chloride-induced renal inflammation adversely impacted renal function and mortality [1,2]. While in theory “balanced” solutions carry dual benefits of both an electrolyte composition that closely mirrors plasma and the presence of buffers which improve acid-base milieu, the exact repercussions on patient-centered outcomes with use of one over the other remain unknown.
An exploratory randomized control trial (RCT) evaluating biochemistry up to day 4 in normal saline vs Plasma-Lyte groups in 70 critically ill adults showed significantly higher hyperchloremia with normal saline but no difference in AKI rates between the two groups [3]. A pilot study evaluating “chloride-restrictive vs chloride liberal” strategies in 760 ICU patients involved use of Hartmann’s solution and Plasma-Lyte in place of saline for a 6-month period except in case of specific contraindications such as traumatic brain injury. Results indicated that incidence of AKI and use of RRT significantly reduced by limiting chloride. No changes in mortality, ICU length of stay or RRT on discharge were noted [4].A large retrospective study in over 53,000 ICU patients admitted with sepsis and on vasopressors across 360 US hospitals showed that balanced fluids were associated with lower in-hospital mortality especially when higher volume of IVFs were infused. While no differences were seen in terms of AKI rates, lower risk of CKD was noted in balanced fluid groups [5].
In post-surgical populations, an observational study analyzing saline vs balanced fluids over 30,000 patients showed significantly lower mortality, renal failure, acidosis investigation/intervention rates with balanced fluids [6].Additionally, a meta-analysis assessing outcomes in peri-operative and ICU patients based on whether they received high or low chloride containing fluids was performed on over 6000 patients across 21 studies. No association with mortality was found. However, statistically significant correlations were noted between high chloride fluids and hyperchloremia, metabolic acidosis, AKI, mechanical ventilation times and blood transfusion volumes [7].
In 2015, a large RCT involving ICUs in New Zealand evaluated balanced crystalloids vs normal saline and rates of AKI in a double-blind, cluster-randomized, double-crossover trial (the SPLIT study). 2278 patients from medical and surgical ICUs were enrolled. Patients already receiving RRT were excluded. No significant difference in incidence of AKI (defined as a two-fold rise or a 0.5mg/dL increase in creatinine), new RRT or mortality was detected between the two groups [8].
Given the ambiguity and lack of consensus on outcomes, the current SMART study addresses an important gap in knowledge. Its large sample size makes it well powered, geared to detect small signals in outcomes. Inclusion of medical, surgical, and neurologic ICUs helps diversify applicability. Being a pragmatic, intention-to-treat RCT, the study design mirrors real-world clinical practice.
In terms of patient acuity, less than a third of the patients were intubated or on vasopressors. Predicted mortality rates were 9%. In addition, median volume infused was around 1 L. Given the investigators’ conclusions that the MAKE30 outcome signals were more pronounced with larger volumes of infusions, this brings into question whether more dramatic signals could have been appreciated in each of the 3 components of the primary outcome had the study population been a higher acuity group requiring larger infusion volumes.
While the composite MAKE30 outcome reflects a sense of an overarching benefit with balanced crystalloids, there was no statistically significant improvement noted in each primary component. This questions the rationale for combining the components of the MAKE30 outcome as well as how generalizable the results are. Overall, as is the case with many studies that evaluate a composite outcome, this raises concern about overestimation of the intervention’s true impact.
The study was un-blinded, raising concern for bias, and it was a single-center trial, which raises questions regarding generalizability. Un-blinding may have played a role in influencing decisions to initiate RRT earlier in the saline group. The extent to which this impacted RRT rates (one of the MAKE30 outcomes), remains unclear. Furthermore, approximately 5% of the participants received unassigned fluids, and while this is in line with the pragmatic/intention-to-treat design, the clinical repercussions remain unclear. Hyperkalemia is an exclusion criterion for balanced fluids and it is unclear whether a proportion of patients presenting with AKI-associated hyperkalemia were restricted from receiving balanced fluids. In addition, very few patients received Plasma-Lyte, confining the study’s conclusions to lactated Ringer’s alone.
Despite these pitfalls, the study addresses an extremely relevant clinical question. It urges clinicians to tailor fluid choices on a case-by-case basis and pay attention to the long-term implications of daily biochemical changes on renal outcomes, particularly in large volume resuscitation scenarios. There is a negligible cost difference between lactated Ringer’s and saline, making use of a balanced fluid economically feasible. The number needed to treat for MAKE30 based on this study is 94 patients, and changes in clinical practice extrapolated to ICUs nationwide could have an impact on renal outcomes from an epidemiologic point of view without risking financial burden at an institution level.
Applications for Clinical Practice
Overall, this trial clarifies an important gap in knowledge regarding fluid choice in the care of critically ill adults. The composite outcome of death, persistent renal dysfunction, and new RRT was significantly lower when a balanced fluid was used in comparison with saline. The ease of implementation, low financial impact, and epidemiologically significant renal outcomes supports a consideration for change in practice. However, clinicians should evaluate implementation on a case-by-case basis. More studies evaluating MAKE30 outcomes individually in specific diagnoses and clinical contexts are necessary. Moreover, data on long-term MAKE outcomes would help characterize long-term public health implications of 30-day effects.
—Divya Padmanabhan Menon, MD, Christopher L. Trautman, MD, and Neal M. Patel, MD, Mayo Clinic, Jacksonville, FL
1. Zhou F, Peng ZY, Bishop JV, et al. Effects of fluid resuscitation with 0.9% saline versus a balanced electrolyte solution on acute kidney injury in a rat model of sepsis. Crit Care Med 2014;42:e270–8.
2.
3. Verma B, Luethi N, Cioccari L, et al. A multicentre randomised controlled pilot study of fluid resuscitation with saline or Plasma-Lyte 148 in critically ill patients. Crit Care Resusc 2016;18:205–12.
4. Yunos NM, Bellomo R, Hegarty C, et al. Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. JAMA 2012;308:1566–72.
5. Raghunathan K, Shaw A, Nathanson B, et al. Association between the choice of IV crystalloid and in-hospital mortality among critically ill adults with sepsis. Crit Care Med 2014;42:1585–91.
6. Shaw AD, Bagshaw SM, Goldstein SL, et al. Major complications, mortality, and resource utilization after open abdominal surgery: 0.9% saline compared to Plasma-Lyte. Ann Surg 2012;255:821–9.
7. Krajewski ML, Raghunathan K, Paluszkiewicz SM, et al. Meta-analysis of high- versus low-chloride content in perioperative and critical care fluid resuscitation. Br J Surg 2015 102:24–36.
8. Young P, Bailey M, Beasley R, 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;314:1701–10.
Study Overview
Objective. To evaluate balanced crystalloids in comparison with normal saline in the intensive care unit (ICU) population.
Design. Pragmatic, un-blinded, cluster-randomized, multiple-crossover clinical trial (the SMART study).
Setting and participants. The study evaluated critically ill adults > 18 years of age, admitted and readmitted into 5 ICUs, both medical and surgical, from June 2015 to April 2017. 15,802 patients were enrolled, powered to detect a 1.9% percentage point difference in primary outcome. ICUs were randomized to use either balanced crystalloids (lactated Ringer’s [LR] or Plasma-Lyte A, depending on the provider’s preference) or normal saline during alternate calendar months. Relative contraindications to use of balanced crystalloids included traumatic brain injury and hyperkalemia. The admitting emergency rooms and operating rooms coordinated intravenous fluid (IVF) choice with their respective ICUs. An intention-to-treat analysis was conducted. In addition to primary and secondary outcome analyses, subgroup analyses based on factors including total IVF volume to day 30, vasopressor use, predicted in-hospital mortality, sepsis or traumatic brain injury diagnoses, ICU type, source of admission, and kidney function at baseline were also done. Furthermore, sensitivity analyses taking into account the total volume of crystalloid, crossover and excluding readmissions were performed.
Main outcome measures. The primary outcome was the proportion of patients that met at least 1 of the 3 criteria for a Major Adverse Kidney Event at day 30 (MAKE30) or discharge, whichever occurred earlier. MAKE30 is a composite measure consisting of death, persistent renal dysfunction (creatinine ≥ 200% baseline), or new renal replacement therapy (RRT). Patients previously on RRT were included for mortality analysis alone. In addition, secondary clinical outcomes including in-hospital mortality (prior to ICU discharge, at day 30 and day 60), ventilator-free days, vasopressor-free days, ICU-free days, days alive and RRT-free days in the first 28 days were assessed. Secondary renal outcomes such as persistent renal dysfunction, acute kidney injury (AKI) ≥ stage 2 (per Kidney Disease: Improving Global Outcomes Criteria {KDIGO}) criteria, new RRT, highest creatinine during hospitalization, creatinine at discharge and highest change in creatinine during hospitalization were also evaluated.
Results. 7942 patients were randomized to the balanced crystalloid group and 7860 to the saline group. Median age for both groups was 58 years and 57.6% patients were male. In terms of patient acuity, approximately 34% patients were on mechanical ventilation, 26% were on vasopressors, and around 14% carried a diagnosis of sepsis. At time of presentation, 17% had chronic kidney disease (CKD) ≥ stage 3 and approximately 5% were on RRT. Around 8% came in with AKI ≥ stage 2. Baseline creatinine in the both groups was 0.89 (interquartile range [IQR] 0.74–1.1). Median volumes of balanced crystalloid and saline administered was 1L (IQR 0–3.2L) and 1.02L (IQR 0–3.5L) respectively. Less than 5% in both groups received unassigned fluids. Predicted risk of in-hospital death for both groups was approximately 9%.
Significantly higher number of patients had plasma chloride ≥ 110 mmol/L and bicarbonate ≤ 20 mmol/L in the saline group (P < 0.001). In terms of primary outcome, MAKE30 rates in the balanced crystalloid vs saline groups were 14.3 vs 15.4 (marginal odds ratio {OR} 0.91, 95% confidence interval {CI} 0.84–0.99, P = 0.04) with similar results in the pre-specified sensitivity analyses. This difference was more prominent with larger volumes of infused fluids. All 3 components of composite primary outcome were improved in the crystalloid group, although none of the 3 individually achieved statistical significance.
Overall, mortality before discharge and within 30 days of admission in the balanced crystalloid group was 10.3% compared to 11.1% in the saline group (OR 0.9, CI 0.8–1.01, P = 0.06). In-hospital death before ICU discharge and at 60 days also mirrored this trend, although they did not achieve statistical significance either. Of note, in septic patients, 30-day mortality rates were 25.2 vs 29.4 in the balanced crystalloid and saline groups respectively (OR 0.8, 95% CI 0.67–0.97, P = 0.02).
With regard to renal outcomes in the balanced crystalloid vs normal saline groups, results were as follows: new RRT {2.5 vs 2.9%, P = 0.08}, new AKI development 10.7% vs 11.5% (OR 0.9, P = 0.09). In patients with a history of previous RRT or presenting with an AKI, crystalloids appeared to provide better MAKE30 outcomes, although not achieving statistical significance.
Conclusion. In the critically ill population, balanced crystalloids provide a beneficial effect over normal saline on the composite outcome of persistent renal dysfunction, new RRT and mortality at day 30.
Commentary
Unbalanced crystalloids, especially normal saline, are the most commonly used IVF for resuscitation in the critically ill. Given the data suggesting risk of kidney injury, acidosis, and effect on mortality with the use of normal saline, this study aimed to evaluate balanced crystalloids in comparison with normal saline in the ICU population.
Interest in the consequences of hyperchloremia and metabolic acidosis from supra-physiologic chloride concentrations in normal saline first stemmed from data in preclinical models, which demonstrated that chloride-induced renal inflammation adversely impacted renal function and mortality [1,2]. While in theory “balanced” solutions carry dual benefits of both an electrolyte composition that closely mirrors plasma and the presence of buffers which improve acid-base milieu, the exact repercussions on patient-centered outcomes with use of one over the other remain unknown.
An exploratory randomized control trial (RCT) evaluating biochemistry up to day 4 in normal saline vs Plasma-Lyte groups in 70 critically ill adults showed significantly higher hyperchloremia with normal saline but no difference in AKI rates between the two groups [3]. A pilot study evaluating “chloride-restrictive vs chloride liberal” strategies in 760 ICU patients involved use of Hartmann’s solution and Plasma-Lyte in place of saline for a 6-month period except in case of specific contraindications such as traumatic brain injury. Results indicated that incidence of AKI and use of RRT significantly reduced by limiting chloride. No changes in mortality, ICU length of stay or RRT on discharge were noted [4].A large retrospective study in over 53,000 ICU patients admitted with sepsis and on vasopressors across 360 US hospitals showed that balanced fluids were associated with lower in-hospital mortality especially when higher volume of IVFs were infused. While no differences were seen in terms of AKI rates, lower risk of CKD was noted in balanced fluid groups [5].
In post-surgical populations, an observational study analyzing saline vs balanced fluids over 30,000 patients showed significantly lower mortality, renal failure, acidosis investigation/intervention rates with balanced fluids [6].Additionally, a meta-analysis assessing outcomes in peri-operative and ICU patients based on whether they received high or low chloride containing fluids was performed on over 6000 patients across 21 studies. No association with mortality was found. However, statistically significant correlations were noted between high chloride fluids and hyperchloremia, metabolic acidosis, AKI, mechanical ventilation times and blood transfusion volumes [7].
In 2015, a large RCT involving ICUs in New Zealand evaluated balanced crystalloids vs normal saline and rates of AKI in a double-blind, cluster-randomized, double-crossover trial (the SPLIT study). 2278 patients from medical and surgical ICUs were enrolled. Patients already receiving RRT were excluded. No significant difference in incidence of AKI (defined as a two-fold rise or a 0.5mg/dL increase in creatinine), new RRT or mortality was detected between the two groups [8].
Given the ambiguity and lack of consensus on outcomes, the current SMART study addresses an important gap in knowledge. Its large sample size makes it well powered, geared to detect small signals in outcomes. Inclusion of medical, surgical, and neurologic ICUs helps diversify applicability. Being a pragmatic, intention-to-treat RCT, the study design mirrors real-world clinical practice.
In terms of patient acuity, less than a third of the patients were intubated or on vasopressors. Predicted mortality rates were 9%. In addition, median volume infused was around 1 L. Given the investigators’ conclusions that the MAKE30 outcome signals were more pronounced with larger volumes of infusions, this brings into question whether more dramatic signals could have been appreciated in each of the 3 components of the primary outcome had the study population been a higher acuity group requiring larger infusion volumes.
While the composite MAKE30 outcome reflects a sense of an overarching benefit with balanced crystalloids, there was no statistically significant improvement noted in each primary component. This questions the rationale for combining the components of the MAKE30 outcome as well as how generalizable the results are. Overall, as is the case with many studies that evaluate a composite outcome, this raises concern about overestimation of the intervention’s true impact.
The study was un-blinded, raising concern for bias, and it was a single-center trial, which raises questions regarding generalizability. Un-blinding may have played a role in influencing decisions to initiate RRT earlier in the saline group. The extent to which this impacted RRT rates (one of the MAKE30 outcomes), remains unclear. Furthermore, approximately 5% of the participants received unassigned fluids, and while this is in line with the pragmatic/intention-to-treat design, the clinical repercussions remain unclear. Hyperkalemia is an exclusion criterion for balanced fluids and it is unclear whether a proportion of patients presenting with AKI-associated hyperkalemia were restricted from receiving balanced fluids. In addition, very few patients received Plasma-Lyte, confining the study’s conclusions to lactated Ringer’s alone.
Despite these pitfalls, the study addresses an extremely relevant clinical question. It urges clinicians to tailor fluid choices on a case-by-case basis and pay attention to the long-term implications of daily biochemical changes on renal outcomes, particularly in large volume resuscitation scenarios. There is a negligible cost difference between lactated Ringer’s and saline, making use of a balanced fluid economically feasible. The number needed to treat for MAKE30 based on this study is 94 patients, and changes in clinical practice extrapolated to ICUs nationwide could have an impact on renal outcomes from an epidemiologic point of view without risking financial burden at an institution level.
Applications for Clinical Practice
Overall, this trial clarifies an important gap in knowledge regarding fluid choice in the care of critically ill adults. The composite outcome of death, persistent renal dysfunction, and new RRT was significantly lower when a balanced fluid was used in comparison with saline. The ease of implementation, low financial impact, and epidemiologically significant renal outcomes supports a consideration for change in practice. However, clinicians should evaluate implementation on a case-by-case basis. More studies evaluating MAKE30 outcomes individually in specific diagnoses and clinical contexts are necessary. Moreover, data on long-term MAKE outcomes would help characterize long-term public health implications of 30-day effects.
—Divya Padmanabhan Menon, MD, Christopher L. Trautman, MD, and Neal M. Patel, MD, Mayo Clinic, Jacksonville, FL
Study Overview
Objective. To evaluate balanced crystalloids in comparison with normal saline in the intensive care unit (ICU) population.
Design. Pragmatic, un-blinded, cluster-randomized, multiple-crossover clinical trial (the SMART study).
Setting and participants. The study evaluated critically ill adults > 18 years of age, admitted and readmitted into 5 ICUs, both medical and surgical, from June 2015 to April 2017. 15,802 patients were enrolled, powered to detect a 1.9% percentage point difference in primary outcome. ICUs were randomized to use either balanced crystalloids (lactated Ringer’s [LR] or Plasma-Lyte A, depending on the provider’s preference) or normal saline during alternate calendar months. Relative contraindications to use of balanced crystalloids included traumatic brain injury and hyperkalemia. The admitting emergency rooms and operating rooms coordinated intravenous fluid (IVF) choice with their respective ICUs. An intention-to-treat analysis was conducted. In addition to primary and secondary outcome analyses, subgroup analyses based on factors including total IVF volume to day 30, vasopressor use, predicted in-hospital mortality, sepsis or traumatic brain injury diagnoses, ICU type, source of admission, and kidney function at baseline were also done. Furthermore, sensitivity analyses taking into account the total volume of crystalloid, crossover and excluding readmissions were performed.
Main outcome measures. The primary outcome was the proportion of patients that met at least 1 of the 3 criteria for a Major Adverse Kidney Event at day 30 (MAKE30) or discharge, whichever occurred earlier. MAKE30 is a composite measure consisting of death, persistent renal dysfunction (creatinine ≥ 200% baseline), or new renal replacement therapy (RRT). Patients previously on RRT were included for mortality analysis alone. In addition, secondary clinical outcomes including in-hospital mortality (prior to ICU discharge, at day 30 and day 60), ventilator-free days, vasopressor-free days, ICU-free days, days alive and RRT-free days in the first 28 days were assessed. Secondary renal outcomes such as persistent renal dysfunction, acute kidney injury (AKI) ≥ stage 2 (per Kidney Disease: Improving Global Outcomes Criteria {KDIGO}) criteria, new RRT, highest creatinine during hospitalization, creatinine at discharge and highest change in creatinine during hospitalization were also evaluated.
Results. 7942 patients were randomized to the balanced crystalloid group and 7860 to the saline group. Median age for both groups was 58 years and 57.6% patients were male. In terms of patient acuity, approximately 34% patients were on mechanical ventilation, 26% were on vasopressors, and around 14% carried a diagnosis of sepsis. At time of presentation, 17% had chronic kidney disease (CKD) ≥ stage 3 and approximately 5% were on RRT. Around 8% came in with AKI ≥ stage 2. Baseline creatinine in the both groups was 0.89 (interquartile range [IQR] 0.74–1.1). Median volumes of balanced crystalloid and saline administered was 1L (IQR 0–3.2L) and 1.02L (IQR 0–3.5L) respectively. Less than 5% in both groups received unassigned fluids. Predicted risk of in-hospital death for both groups was approximately 9%.
Significantly higher number of patients had plasma chloride ≥ 110 mmol/L and bicarbonate ≤ 20 mmol/L in the saline group (P < 0.001). In terms of primary outcome, MAKE30 rates in the balanced crystalloid vs saline groups were 14.3 vs 15.4 (marginal odds ratio {OR} 0.91, 95% confidence interval {CI} 0.84–0.99, P = 0.04) with similar results in the pre-specified sensitivity analyses. This difference was more prominent with larger volumes of infused fluids. All 3 components of composite primary outcome were improved in the crystalloid group, although none of the 3 individually achieved statistical significance.
Overall, mortality before discharge and within 30 days of admission in the balanced crystalloid group was 10.3% compared to 11.1% in the saline group (OR 0.9, CI 0.8–1.01, P = 0.06). In-hospital death before ICU discharge and at 60 days also mirrored this trend, although they did not achieve statistical significance either. Of note, in septic patients, 30-day mortality rates were 25.2 vs 29.4 in the balanced crystalloid and saline groups respectively (OR 0.8, 95% CI 0.67–0.97, P = 0.02).
With regard to renal outcomes in the balanced crystalloid vs normal saline groups, results were as follows: new RRT {2.5 vs 2.9%, P = 0.08}, new AKI development 10.7% vs 11.5% (OR 0.9, P = 0.09). In patients with a history of previous RRT or presenting with an AKI, crystalloids appeared to provide better MAKE30 outcomes, although not achieving statistical significance.
Conclusion. In the critically ill population, balanced crystalloids provide a beneficial effect over normal saline on the composite outcome of persistent renal dysfunction, new RRT and mortality at day 30.
Commentary
Unbalanced crystalloids, especially normal saline, are the most commonly used IVF for resuscitation in the critically ill. Given the data suggesting risk of kidney injury, acidosis, and effect on mortality with the use of normal saline, this study aimed to evaluate balanced crystalloids in comparison with normal saline in the ICU population.
Interest in the consequences of hyperchloremia and metabolic acidosis from supra-physiologic chloride concentrations in normal saline first stemmed from data in preclinical models, which demonstrated that chloride-induced renal inflammation adversely impacted renal function and mortality [1,2]. While in theory “balanced” solutions carry dual benefits of both an electrolyte composition that closely mirrors plasma and the presence of buffers which improve acid-base milieu, the exact repercussions on patient-centered outcomes with use of one over the other remain unknown.
An exploratory randomized control trial (RCT) evaluating biochemistry up to day 4 in normal saline vs Plasma-Lyte groups in 70 critically ill adults showed significantly higher hyperchloremia with normal saline but no difference in AKI rates between the two groups [3]. A pilot study evaluating “chloride-restrictive vs chloride liberal” strategies in 760 ICU patients involved use of Hartmann’s solution and Plasma-Lyte in place of saline for a 6-month period except in case of specific contraindications such as traumatic brain injury. Results indicated that incidence of AKI and use of RRT significantly reduced by limiting chloride. No changes in mortality, ICU length of stay or RRT on discharge were noted [4].A large retrospective study in over 53,000 ICU patients admitted with sepsis and on vasopressors across 360 US hospitals showed that balanced fluids were associated with lower in-hospital mortality especially when higher volume of IVFs were infused. While no differences were seen in terms of AKI rates, lower risk of CKD was noted in balanced fluid groups [5].
In post-surgical populations, an observational study analyzing saline vs balanced fluids over 30,000 patients showed significantly lower mortality, renal failure, acidosis investigation/intervention rates with balanced fluids [6].Additionally, a meta-analysis assessing outcomes in peri-operative and ICU patients based on whether they received high or low chloride containing fluids was performed on over 6000 patients across 21 studies. No association with mortality was found. However, statistically significant correlations were noted between high chloride fluids and hyperchloremia, metabolic acidosis, AKI, mechanical ventilation times and blood transfusion volumes [7].
In 2015, a large RCT involving ICUs in New Zealand evaluated balanced crystalloids vs normal saline and rates of AKI in a double-blind, cluster-randomized, double-crossover trial (the SPLIT study). 2278 patients from medical and surgical ICUs were enrolled. Patients already receiving RRT were excluded. No significant difference in incidence of AKI (defined as a two-fold rise or a 0.5mg/dL increase in creatinine), new RRT or mortality was detected between the two groups [8].
Given the ambiguity and lack of consensus on outcomes, the current SMART study addresses an important gap in knowledge. Its large sample size makes it well powered, geared to detect small signals in outcomes. Inclusion of medical, surgical, and neurologic ICUs helps diversify applicability. Being a pragmatic, intention-to-treat RCT, the study design mirrors real-world clinical practice.
In terms of patient acuity, less than a third of the patients were intubated or on vasopressors. Predicted mortality rates were 9%. In addition, median volume infused was around 1 L. Given the investigators’ conclusions that the MAKE30 outcome signals were more pronounced with larger volumes of infusions, this brings into question whether more dramatic signals could have been appreciated in each of the 3 components of the primary outcome had the study population been a higher acuity group requiring larger infusion volumes.
While the composite MAKE30 outcome reflects a sense of an overarching benefit with balanced crystalloids, there was no statistically significant improvement noted in each primary component. This questions the rationale for combining the components of the MAKE30 outcome as well as how generalizable the results are. Overall, as is the case with many studies that evaluate a composite outcome, this raises concern about overestimation of the intervention’s true impact.
The study was un-blinded, raising concern for bias, and it was a single-center trial, which raises questions regarding generalizability. Un-blinding may have played a role in influencing decisions to initiate RRT earlier in the saline group. The extent to which this impacted RRT rates (one of the MAKE30 outcomes), remains unclear. Furthermore, approximately 5% of the participants received unassigned fluids, and while this is in line with the pragmatic/intention-to-treat design, the clinical repercussions remain unclear. Hyperkalemia is an exclusion criterion for balanced fluids and it is unclear whether a proportion of patients presenting with AKI-associated hyperkalemia were restricted from receiving balanced fluids. In addition, very few patients received Plasma-Lyte, confining the study’s conclusions to lactated Ringer’s alone.
Despite these pitfalls, the study addresses an extremely relevant clinical question. It urges clinicians to tailor fluid choices on a case-by-case basis and pay attention to the long-term implications of daily biochemical changes on renal outcomes, particularly in large volume resuscitation scenarios. There is a negligible cost difference between lactated Ringer’s and saline, making use of a balanced fluid economically feasible. The number needed to treat for MAKE30 based on this study is 94 patients, and changes in clinical practice extrapolated to ICUs nationwide could have an impact on renal outcomes from an epidemiologic point of view without risking financial burden at an institution level.
Applications for Clinical Practice
Overall, this trial clarifies an important gap in knowledge regarding fluid choice in the care of critically ill adults. The composite outcome of death, persistent renal dysfunction, and new RRT was significantly lower when a balanced fluid was used in comparison with saline. The ease of implementation, low financial impact, and epidemiologically significant renal outcomes supports a consideration for change in practice. However, clinicians should evaluate implementation on a case-by-case basis. More studies evaluating MAKE30 outcomes individually in specific diagnoses and clinical contexts are necessary. Moreover, data on long-term MAKE outcomes would help characterize long-term public health implications of 30-day effects.
—Divya Padmanabhan Menon, MD, Christopher L. Trautman, MD, and Neal M. Patel, MD, Mayo Clinic, Jacksonville, FL
1. Zhou F, Peng ZY, Bishop JV, et al. Effects of fluid resuscitation with 0.9% saline versus a balanced electrolyte solution on acute kidney injury in a rat model of sepsis. Crit Care Med 2014;42:e270–8.
2.
3. Verma B, Luethi N, Cioccari L, et al. A multicentre randomised controlled pilot study of fluid resuscitation with saline or Plasma-Lyte 148 in critically ill patients. Crit Care Resusc 2016;18:205–12.
4. Yunos NM, Bellomo R, Hegarty C, et al. Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. JAMA 2012;308:1566–72.
5. Raghunathan K, Shaw A, Nathanson B, et al. Association between the choice of IV crystalloid and in-hospital mortality among critically ill adults with sepsis. Crit Care Med 2014;42:1585–91.
6. Shaw AD, Bagshaw SM, Goldstein SL, et al. Major complications, mortality, and resource utilization after open abdominal surgery: 0.9% saline compared to Plasma-Lyte. Ann Surg 2012;255:821–9.
7. Krajewski ML, Raghunathan K, Paluszkiewicz SM, et al. Meta-analysis of high- versus low-chloride content in perioperative and critical care fluid resuscitation. Br J Surg 2015 102:24–36.
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