What is the evidence for using lactated Ringer's in diabetes ketoacidosis (DKA) patients over normal saline for maintenance IV fluids?

Comment by InpharmD Researcher

Limited data is available on the use of lactated Ringer’s solution over sodium chloride in DKA patients for IV fluid maintenance. While some evidence suggests potential benefits of balanced crystalloids (such as LR or Plasmalyte) over saline in terms of shorter time to DKA resolution and faster discontinuation of continuous insulin infusion (Table 1), another study failed to indicate benefit from using Ringer’s lactate regarding time to normalization of pH compared to normal saline (Table 2). A recent meta-analysis demonstrated that balanced crystalloids may help prevent hyperchloremic metabolic acidosis associated with saline, due to a reduction in post-resuscitation chloride concentration. However, more high-quality trials are needed to confirm the benefits of crystalloids over sodium chloride among DKA patients.

Background

A recently published meta-analysis aimed to compare the clinical effects between balanced electrolyte solutions (BESs) and normal saline in managing diabetes ketoacidosis (DKA). BESs, such as lactated Ringer’s, serve as an alternative to normal saline and can replace some of the chloride content with rapidly metabolized and excreted organic anions such as lactate; they also achieve a higher physiological bicarbonate concentration. As a result, BESs are expected to have a minimal impact on acid-base balance, unlike the often-reported hyperchloremic metabolic acidosis associated with normal saline. This type of metabolic acidosis has been linked to adverse clinical outcomes, including increased renal injury and prolonged resolution of DKA. [1]

A total of eight trials involving 595 participants were included in the analysis. The duration of DKA resolution did not exhibit any significant difference (mean difference [MD] −4.73; 95% confidence interval [CI] −2.72 to 4.92; I2 = 92%; p = 0.180). However, there was a notable decrease in post-resuscitation chloride concentration in the BES (MD 2.96; 95% CI − 4.86 to − 1.06; I2 = 59%; p = 0.002). There was also a significant decrease in the time needed for bicarbonate levels to return to normal in the BES group (MD 3.11; 95% CI − 3.98 to 2.23; I2 = 5%; p = 0.0004). There were no significant differences between groups in terms of the time needed for pH recovery, admission to the intensive care unit, or the occurrence of adverse events (mortality and acute renal failure). The use of BES during resuscitation was linked to a decrease in chloride levels and an increase in bicarbonate values in DKA patients. This suggests that BES helps prevent hyperchloremic metabolic acidosis in DKA patients. However, high-quality trials with a larger sample size are required to assess if the use of BESs compared with normal saline is associated with better clinical outcomes in managing DKA. It is also important to interpret the results with caution, as they are not exclusive to lactated Ringer’s and also include other BESs such as Plasmalyte and Hartmann's solution. [1]

Another meta-analysis conducted in 2022 assessed if the use of BES in fluid resuscitation leads to faster resolution of DKA compared to isotonic saline. A total of three studies with a population of 316 subjects were included in the final analysis. The meta-analysis revealed that the combined hazard ratio (HR) for DKA resolution was 1.46 (95% CI 1.10 to 1.94; p= 0.009), indicating a significant result, with low 12% heterogeneity in favor of BES. Additionally, the combined MD for the time (in hours) required for DKA resolution was calculated, demonstrating a nonsignificant difference of 3.02 (95% CI -6.78 to 0.74; p= 0.12), with a significant heterogeneity of 85%. Considering the evidence from pooled small randomized trials with moderate overall certainty of evidence, the use of BES in DKA was associated with faster rates of DKA resolution compared to isotonic saline. [2]

References:

[1] Tamzil R, Yaacob N, Noor NM, Baharuddin KA. Comparing the clinical effects of balanced electrolyte solutions versus normal saline in managing diabetic ketoacidosis: A systematic review and meta-analyses. Turk J Emerg Med. 2023;23(3):131-138. Published 2023 Jun 26. doi:10.4103/tjem.tjem_355_22
[2] Catahay JA, Polintan ET, Casimiro M, et al. Balanced electrolyte solutions versus isotonic saline in adult patients with diabetic ketoacidosis: A systematic review and meta-analysis. Heart Lung. 2022;54:74-79. doi:10.1016/j.hrtlng.2022.03.014
Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

What is the evidence for using lactated Ringer's in diabetes ketoacidosis (DKA) patients over normal saline for maintenance IV fluids?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-2 for your response.

 

Clinical Effects of Balanced Crystalloids vs Saline in Adults With Diabetic Ketoacidosis: A Subgroup Analysis of Cluster Randomized Clinical Trials

Design

Post-hoc, subgroup analysis of 2 randomized, controlled trials

N= 172

Objective

 To compare the clinical effects of balanced crystalloids with the clinical effects of saline for the acute treatment of adults with diabetic ketoacidosis (DKA)

Study Groups

Balanced crystalloids (n= 94)

Normal saline (n= 78)

Inclusion Criteria

Adults who presented to the emergency department (ED) with DKA and enrolled in the SALT-ED or SMART trials; plasma glucose > 250 mg/dL; plasma bicarbonate ≤ 18 mmol/L; anion gap > 10 mmol/L

Exclusion Criteria

 Transferred from an outside hospital to the study ED; admission to the cardiac or neurologic intensive care unit (ICU); presented to the ED within 24 hours prior to a planned crossover in the trial (experienced a crossover during the first 24 hours of DKA treatment)

Methods

This was a pooled subgroup analysis of patients with diagnosed DKA who were enrolled into the SALT-ED or SMART randomized controlled trials. These trials evaluated the use of balanced crystalloids (Lactated Ringer's or Plasmalyte A) versus normal saline for volume expansion. The choice of Lactated Ringer's or Plasmalyte A in the crystalloid group was made by the treating clinicians.

All other aspects of clinical management, including the volume of fluid administered, selection of other fluids, and insulin dosing, were chosen by the treating clinicians.

Duration

January 1, 2016 to March 31, 2017

Follow-up: up to 28 days

Outcome Measures

Primary: time to DKA resolution (time between ED presentation and resolution of ketoacidosis)

Secondary: time to discontinuation of insulin infusion; in-hospital mortality; acute kidney injury (AKI) incidence

Baseline Characteristics

  

Balanced crystalloids (n= 94)

Normal saline (n= 78)

  

Age, years (IQR)

 28 (23-39) 30 (25-49)  

Female

57.4% 46.2%  

White

 70.2% 74.4%  

Type 1 diabetes

 87.2% 76.9%  

Hemoglobin A1c, %

 10.8 (9.2-12.6) 11.3 (9.2-13.3)  

Severity based on bicarbonate

Mild (15-18 mmol/L)

Moderate (10-14 mmol/L)

Severe (<10 mmol/L)

 

26.6%

33%

40.4%

 

32.1%

30.8%

37.2%

  

Laboratory values

Creatinine, mg/dL (IQR)

Glucose, mg/dL (IQR)

Anion gab, mEq/L (IQR)

 

1.5 (1.2-2.0)

557 (415-761)

22 (19-28)

 

1.5 (1.2-2.0)

518 (373-750)

24 (19-29)

  
IQR: interquartile range

Results

Endpoint

Balanced crystalloids (n= 94)

Normal saline (n= 78)

p-value
Time to DKA resolution, hours (IQR)

13.0 (9.5-18.8)

 16.9 (11.9-34.5) 0.004

Time to insulin discontinuation, hours (IQR)

 9.8 (5.1-17.0) 13.4 (11.0-17.9) 0.03

In-hospital death

 0 1% N/A

ICU admission

 82% 83% 0.26

Stage ≥2 AKI after ED discharge

 8% 8% 0.98

New-onset hyperkalemia (K > 6 mmol/L)

New-onset hypokalemia (K < 3.0 mmol/L)

12%

10%

23%

19%

0.19

0.03

Adverse Events

 Seizure (1% vs 3%; p= 0.46)

Study Author Conclusions

 In this secondary analysis of 2 cluster randomized clinical trials, compared with saline, treatment with balanced crystalloids resulted in more rapid resolution of DKA, suggesting that balanced crystalloids may be preferred over saline for acute management of adults with DKA.

InpharmD Researcher Critique

Strengths of this study include the assignment of crystalloids or saline upon presentation to the ED with little room for accidental crossover. Study sites were only allowed to use balanced crystalloids (choice of Lactated Ringer's or Plasmalyte A) or normal saline during certain months (based on randomization). The two trials from which the data was drawn were well-designed, pragmatic, clinical trials.

Limitations include the post-hoc, pooled, subgroup design. This can lead to retrospective bias, confounding, and smaller sample sizes; power was not calculated for this analysis. The primary endpoint of DKA resolution was not always the American Diabetes Association (ADA) definition, but a clinical definition that met criteria for discharge.

Lactated Ringer's was the primary crystalloid used in both studies, but there was not enough information to differentiate between the use of Ringer's and Plasmalyte. While this study was open-label, it is unlikely that blinding would have affected outcomes.



References:

Self WH, Evans CS, Jenkins CA, et al. Clinical Effects of Balanced Crystalloids vs Saline in Adults With Diabetic Ketoacidosis: A Subgroup Analysis of Cluster Randomized Clinical Trials. JAMA Netw Open. 2020;3(11):e2024596. doi:10.1001/jamanetworkopen.2020.24596

 

Fluid management in diabetic-acidosis—Ringer’s lactate versus normal saline: a randomized controlled trial

Design

Randomized, double-blind, parallel-group, controlled trial

N= 54

Objective

To determine if Ringer’s lactate is superior to 0.9% sodium chloride solution for resolution of acidosis in the management of diabetic ketoacidosis (DKA)

Study Groups

Lactated Ringer's (n= 27)

Normal saline (n= 27)

Inclusion Criteria

Diagnosed with type 1 or 2 diabetes mellitus; age ≥18 years; venous blood pH between 6.9-7.2 at presentation; at least 2+ ketones on urine dipstick test at presentation; capillary blood glucose of >13 mmol/L

Exclusion Criteria

 Patients with another etiology of acidosis; severely ill patients requiring ionotropic or ventilatory support; patients who received >1 L of resuscitation fluid prior to enrollment

Methods

Eligible patients were treated according to the same DKA protocol at two hospitals in South Africa. Patients received 1 L of either lactated Ringer's or normal saline (0.9% sodium chloride) as initial resuscitation fluid until blood glucose was ​<14 mmol/L. Subsequently, the attending clinician could continue any dextrose- or glucose-containing fluid according to preference.

Duration

 February 2008 to November 2009

Outcome Measures

Primary: resolution of DKA (defined as venous pH >7.32, bicarbonate ≥18 mmol/L, and glucose < 11.1 mmol/L)

Secondary: time to reach venous pH of 7.32, time to reach glucose of 14 mmol/L

Baseline Characteristics

  

Lactated Ringer's (n= 27)

Normal saline (n= 27)

  

Age, years (interquartile range)

 36.1 (24.1-46.6) 36.6 (25.5-42.2)  

Male

 66.7% 48.1%  

Type 1 diabetes

 44.4% 55.6%  

Laboratory values

pH

Bicarbonate, mmol/L

Potassium, mmol/L

Glucose, mmol/L

Ketones, mmol/L

 

7.10 ± 0.105

6.47 ± 3.36

4.87 ± 1.01

25.01 ± 5.9

4.47 ± 1.41

 

7.12 ± 0.099

7.66 ± 3.71

4.93 ± 1.09

27.66 ± 10.02

4.27 ± 1.40

  

Results

 

Lactated Ringer's (n= 27)

Normal saline (n= 27)

p-value

Time to DKA resolution, minutes

 1,710 1,621 0.934

Time to reach pH of 7.32, minutes 

 540 (95% CI 184-896) 683 (95% CI 378-988) 0.251

Time to glucose of 14 mmol/L, minutes (IQR)

 410 (240-540) 300 (235-420) 0.044

Median duration of hospital stay, days

 7 7 0.547

At the end of follow-up, only 21 of the 54 patients (39%) achieved DKA resolution; the incidence between the groups was not reported. There was no significant difference in adjusted time to DKA resolution (hazard ratio 1.78; 95% CI 0.415 to 3.342; p= 0.758).

Adverse Events

 No deaths occurred in any of the two groups.

Study Author Conclusions

 This study failed to indicate benefit from using Ringer’s lactate solution compared to 0.9% sodium chloride solution regarding time to normalization of pH in patients with DKA. The time to reach a blood glucose level of 14 mmol/l took significantly longer with the Ringer’s lactate solution.

InpharmD Researcher Critique

 This study was limited by the sample size included, which did not achieve the calculated power. Anion gap was not measured and was not included in the results. The DKA protocol, outside of resuscitation fluid, used was not described, as this may differ from modern protocols or similar interventions used in the United States. Similarly, the rate of IV fluid administration was not reported.



References:

Van Zyl DG, Rheeder P, Delport E. Fluid management in diabetic-acidosis--Ringer's lactate versus normal saline: a randomized controlled trial. QJM. 2012;105(4):337-343. doi:10.1093/qjmed/hcr226