|Year : 2022 | Volume
| Issue : 2 | Page : 36-42
0.9% sodium chloride versus dextrose 5% in water safety as medication's diluents in critically ill patients: Meta-analysis of observational studies
Samiah Alsohimi1, Alaa Ghazi Almagthali2, Khalid Eljaaly3, Ghazwa B Korayem4, Khalid Al Sulaiman5, Ohoud Aljuhani6
1 Department of Pharmaceutical Care, King Abdulaziz University Hospital; Department of Pharmaceutical Care, King Fahad Armed Forces Hospital, Jeddah, Saudi Arabia
2 Department of Pharmaceutical Care, King Abdulaziz University Hospital, Jeddah, Saudi Arabia
3 Department of Pharmacy Practice, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia; College of Pharmacy, University of Arizona, Tucson, AZ, United States
4 Department of Pharmacy Practice, College of Pharmacy, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
5 Department of Pharmacy Practice, College of Pharmacy, Princess Nourah bint Abdulrahman University; Department of Pharmaceutical Care, King Abdulaziz Medical City; King Abdullah International Medical Research Center; College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences; Saudi Critical Care Pharmacy Research (SCAPE) Platform, Riyadh, Saudi Arabia
6 Department of Pharmacy Practice, Faculty of Pharmacy, King Abdulaziz University, Jeddah; Saudi Critical Care Pharmacy Research (SCAPE) Platform, Riyadh, Saudi Arabia
|Date of Submission||29-Apr-2022|
|Date of Acceptance||16-Jun-2022|
|Date of Web Publication||30-Sep-2022|
Pharmaceutical Care Department , King Abdulaziz University Hospital; Pharmaceutical Care Department, King fahad Armed Forces Hospital, Jeddah
Source of Support: None, Conflict of Interest: None
Adverse drug effects such as electrolyte abnormalities and acid-base disturbances are commonly associated with intravenous (IV) fluids administered in the intensive care units (ICUs). Although several studies have addressed the risk associated with resuscitative fluids in ICU patients, limited data evaluating the safety of IV medications diluents and their association with clinical outcomes in critical care settings. We conducted a systematic review and meta-analysis to compare the safety of 0.9% sodium chloride (0.9% NaCl) and dextrose 5% in water (D5W) as drug diluents in ICU settings. We searched PubMed, MEDLINE, Cochrane Library bibliographic databases, and conference abstracts for studies comparing medication diluents in adult critically ill patients. Our primary outcome was the risk of hypernatremia. The secondary outcomes included hyperchloremia, acute kidney injury (AKI) rate, ICU length of stay (LOS), ICU mortality, and hospital mortality. Three observational studies were included (1549 patients), all received 0.9% NaCl as standard diluents and D5W was the comparison. Our results shows that hypernatremia and hyperchloremia were significantly higher in 0.9% NaCl group (risk ratio [RR], 1.84; 95% confidence interval [CI], 1.38–2.47; P ≤ 0.001; I = 0%), (RR, 1.78; 95% CI, 1.38–2.31; P < 0.001, I2 = 0%), respectively. There was no significant difference in AKI risk, hyperglycemia, and hospital mortality between the groups. However, the 0.9% NaCl group has a longer ICU LOS (mean difference 0·407, 0·062–0·752; P = 0.021). The utilization of D5W as medication diluent in critical care settings was associated with a lower incidence of hypernatremia and hyperchloremia, In addition, may be associated with shorter ICU LOS.
Keywords: Dextrose 5%, Normal saline, 0.9% NaCl, Diluent, Hypernatremia, Hyperchloremia, Intensive care unit, Critically ill
|How to cite this article:|
Alsohimi S, Almagthali AG, Eljaaly K, Korayem GB, Sulaiman KA, Aljuhani O. 0.9% sodium chloride versus dextrose 5% in water safety as medication's diluents in critically ill patients: Meta-analysis of observational studies. Saudi Crit Care J 2022;6:36-42
|How to cite this URL:|
Alsohimi S, Almagthali AG, Eljaaly K, Korayem GB, Sulaiman KA, Aljuhani O. 0.9% sodium chloride versus dextrose 5% in water safety as medication's diluents in critically ill patients: Meta-analysis of observational studies. Saudi Crit Care J [serial online] 2022 [cited 2023 Jun 4];6:36-42. Available from: https://www.sccj-sa.org/text.asp?2022/6/2/36/357642
| Introduction|| |
The isotonic saline (0.9% sodium chloride [NaCl]) also called “normal saline” is commonly used during hospital admissions for resuscitation, maintenance fluid therapy, and parenteral medication diluent as it contains sodium and chloride in supraphysiological concentrations.,,, The 0.9% NaCl contains 154 mEq/L of sodium and chlorides. It is usually preferred over other fluids, particularly in critically ill patients, despite the lack of evidence supporting its superiority., In critically ill patients admitted to the intensive care unit (ICU), the frequent use of 0.9% NaCl may be associated with patients' electrolyte and acid-base disturbances. Furthermore, acute kidney injury (AKI) is usually seen in ICU patients and is associated with a disturbance in serum electrolytes and glucose levels, both of which are independent predictors of mortality.,,,
The administration of 0.9% NaCl in critically ill patients may cause hyperchloremia, leading to reduced renal perfusion and raising the risk of AKI. This risk is driven by the abnormal chloride concentration of 154 mEq/L, which is 40%–50% higher than plasma chloride concentration.,, The medication diluents may have an important effect on the clinical outcomes among critically ill patients, especially most of them required several parenteral medications such as vasopressors, inotropes, analgesics, sedatives, and antibiotics. Furthermore, the drawback of using 0.9% NaCl is that the high sodium content required to dilute medications and keep the catheter open contributes to the common occurrence of ICU acquired hypernatremia, which can be avoided by diluting the drug in dextrose 5% in water (D5W) rather than 0.9% NaCl.
D5W can be used as an alternate diluent to dissolve several medications in most critically ill patients, potentially overcoming the significant drawbacks of 0.9% NaCl, such as hyperchloremia and hypernatremia., In critically ill patients, using D5W as a diluent for medications did not affect blood glucose control. At the same time, there are limited resources to support the use of either 0.9% NaCl or D5W as a medication diluent in the ICUs settings. Therefore, this meta-analysis is conducted to compare the safety of 0.9% NaCl and D5W as medication diluents in critically ill patients.
| Methods|| |
We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guideline during the design of this meta-analysis.
Strategy and selection criteria
The following databases have been used to search for studies comparing medication diluents in critically ill patients without restricting the date and the study design: PubMed, MEDLINE, Cochrane Library bibliographic databases, and unpublished manuscripts on ClinicalTrails.Gov, and conference abstracts. Studies that evaluate the use of 0.9% NaCl or D5W for resuscitation purposes were excluded. Two authors independently searched the databases until the end of January 2021 [see search strategy in Appendix A]. Articles were restricted to the English language and adult patients aged ≥16 years old admitted to ICUs. Any identified disagreement in the literature screening and reviewing of extracted data has been resolved by consensus or consultation with a third independent researcher.
Outcomes, data analysis, and risk of bias
The primary outcome of the study was the risk of hypernatremia. The secondary outcomes included hyperchloremia, AKI risk, ICU length of stay (LOS), ICU mortality, and in-hospital mortality. The definition of hypernatremia, hyperchloremia, and AKI used in studies are presented in [Table 1]. Mantel–Haenszel risk ratio (RR) for categorical variables and mean difference (MD) for continuous variables with the 95% confidence interval (CIs) were estimated using a random-effects model. Heterogenicity (I2) was assessed using Cochran's Chi-squared test. Comprehensive Meta-Analysis v. 3 software (Biostat Inc., Englewood, NJ, USA) was used for all analyses.
|Table 1: Definition of hypernatremia, hyperchloremia and acute kidney injury in each study|
Click here to view
| Results|| |
Results and study characteristics
The search initially retrieved 4520 studies, and 17 articles were identified for full-text review after excluding the remaining articles by title and abstract. Only three articles were included [Figure 1] and 14 articles were excluded after a full-text review according to the exclusion criteria.,,
All included studies were observational design. The total number of included patients from all studies is 1549 patients. The characteristics of included studies are listed in [Table 2]. Included studies were from the United Kingdom (n = 1), Japan (n = 1), and Australia (n = 1). All studies included adult patients with a mean age of 62.6 years. There were two prospective studies and one retrospective study.,,
All three studies used 0.9% NaCl and D5W as a diluent for parenteral medication infusions and boluses. Bihari et al. also used 4% glucose with 0.18% NS as a diluent for parenteral medication. The total amount of fluid was significantly different in Magee et al., the total volume of 0.9% NaCl received from medication diluents was significantly greater in the saline group compared with the D5W group (2941 mL [1288–4855] vs. 951 mL [375–2001]; P < 0.001). However, the total amount of diluents administered in Aoyagi et al. was not significantly different in the D5W group compared with the saline group (4697 mL [3475–6502] vs. 4883 mL [3381–6988]; P = 0.541). Bihari et al. study did not report the differences in the total amount of fluid.
The hypernatremia and hyperchloremia risk were significantly higher in the 0.9% NaCl group compared to D5W group (RR 1.84, 95% CI 1.38–2.47, P < 0.001, I2 = 0%; RR 1.78, 95% CI 1.38–2.31, P < 0.001, I2 = 0%, respectively) [Figure 2] and [Figure 3]. There were no significant differences between the groups in the risk of AKI (RR 1.16, 95% CI 0.85–1.57, P = 0.355, I2 = 0%), and hospital mortality (RR 0.96, 95% CI 0.87–1.06, P = 0.428, I2 = 0%). Utilizing 0.9% NaCl as diluents was associated with longer ICU LOS (MD 0.407, 95% CI 0.062–0.752, P = 0.021) [Figure 4]. There were no statistically significant differences in hyperglycemia (RR 0.96, 95% CI 0.89–1.05, P = 0.405), hyponatremia (RR 0.93, 95% CI 0.69–1.26, P = 0.65), and ICU mortality (RR 0.82, 95% CI 0.62–1.08, P = 0.164) for all comparison groups.
|Figure 2: Forest plot showing the Mantel-Haenszel risk ratios of hypernatremia using random-effects models in patients receiving 0.9% NaCl versus D5W, Central vertical line, “no difference” point between the 2 Groups; horizontal line, 95% confidence interval; squares, risk ratios; diamonds, pooled risk ratios. NaCl: Sodium Chloride, D5W: Dextrose 5% in Water|
Click here to view
|Figure 3: Forest plot showing the Mantel-Haenszel risk ratios of hyperchloremia using random-effects models in patients receiving 0.9% NaCl versus D5W, Central vertical line, “no difference” point between the 2 Groups; horizontal line, 95% confidence interval; squares, risk ratios; diamonds, pooled risk ratios. NaCl: Sodium Chloride, D5W: Dextrose 5% in Water|
Click here to view
|Figure 4: Forest plot showing mean difference in length of intensive care unit stay, central vertical line, “no difference” point between the 2 Groups; horizontal line, 95% confidence interval; squares, differences in mean; diamonds, pooled differences in mean|
Click here to view
| Discussion|| |
This meta-analysis compares the safety of utilizing D5W versus 0.9% NaCl as medication diluents in critically ill patients. The main finding of this study shows that the rate of hypernatremia and hyperchloremia is significantly higher in the 0.9% NaCl group compared to the D5W group, these results are mostly driven by the findings in Aoyagi et al., and Magee et al., observational studies.,
NaCl (0.9%) is the most used intravenous (IV) resuscitative fluid and parenteral medications' diluent in patients with critical illnesses., Excess use of IV 0.9% NaCl in critically ill patients as maintenance fluid or diluent is associated with developing hypernatremia, hyperchloremia, metabolic acidosis, and AKI due to the inadvertent administration of high content of sodium and chloride.,, Due to lacking randomized controlled trials (RCTs) that assess D5W safety as drug diluents in ICU settings, it is important to evaluate D5W utilization as an alternative d iluent in critically ill patients. This is the first systematic review and meta-analysis to compare the safety of D5W versus 0.9% NaCl as medication diluent in critically ill patients.
Hypernatremia is a common electrolyte disturbance in critically ill patients; it was an independent risk factor for increased mortality among ICU patients. One of the serious adverse effects of 0.9% NaCl is the association between the elevation of serum sodium and hyperosmolality that might be disturb neurological function due to free water shift from intracellular to extracellular space. This shift can lead to brain cell shrinkage, vascular rupture, and in severe cases, permanent neurological damage. In addition, in critically ill patients, hyperchloremia may have an additional significant impact on mortality along with other contributing factors such as persistent renal dysfunction that led to patient death. Hypernatremia and hyperchloremia are major drawbacks of 0.9% NaCl that could be prevented when choosing an appropriate drug diluent.
Moreover, this meta-analysis showed no significant difference in AKI rate between the two diluents. These findings are mostly driven by the results found by Magee et al., and Aoyagal et al., where the number of patients who suffered from AKI was higher in the 0.9% NaCl group, but the difference was not statistically significant (P = 0.310 vs. 0.808), respectively., Several hypotheses explain the association between 0.9% NaCl and AKI; mainly, the high chloride content of 0.9% NaCl decreases the glomerular filtration rate and decreases the renal blood flow, but the clinical significance of this hypothesis is still controversial., Two large RCTs including critically ill patients evaluate the risk of renal adverse effects using crystalloid IV fluid, mainly 0.9% NaCl. The first trial was SPLIT, the investigators did not demonstrate a reduced risk of AKI, renal replacement therapy (RRT) or in-hospital mortality with balanced solutions compared with 0.9% NaCl. In contrast, the SMART trial has found that the major adverse kidney events (new RRT, or persistent renal dysfunction death) were reduced within 30 days among critically ill patients who received balanced solutions.
Elevated blood glucose levels risk might be limiting D5W utilization as alternative diluents. Nonetheless, we have found no significant difference in the hyperglycemia rate when using D5W instead of 0.9% NaCl. This endpoint was driven heavily by Aoyagi et al. study and showed no statistical significance in the incidences of hyperglycemia in the saline group compared to the D5W group. Aoyagi et al. and Magee et al. evaluated hyperglycemia risk with D5W versus 0.9% NaCl. The authors found no difference in hyperglycemia events between groups (P = 0.811 and P = 0.126, respectively).
All included studies demonstrated no significant difference between D5W versus 0.9% NaCl utilization on ICU and hospital mortality.,, Aoyagi et al. found that 0.9% NaCl not significantly lowered ICU mortality or hospital mortality (P = 0.557 and 0.769, respectively). Similar findings have been reported in Bihari et al. mortality rate was not significantly different between groups (alive at ICU discharge P = 0.97 and alive at hospital discharge P = 0.45). Likewise, Magee et al. found no difference between 0.9% NaCl or D5W and ICU mortality rate between groups (P = 0.19). However, one study ineligible for this meta-analysis has found a significant association between mortality and hyperchloremia and the 0.9% NaCl solution was the main cause of hyperchloremia among critically ill patients.
Our findings showed longer ICU LOS by utilizing 0.9% NaCl as a medication diluent. However, in the individually included studies, ICU and Hospital LOS were almost the same between 0.9% NaCl and D5W groups with a P > 0.2.,, Failure to detect differences may be related to a limited number of studies that evaluated LOS and a small sample size.
Severe limitations should be considered in this meta-analysis. First, the included studies were observational studies which might increase the risk of bias. Second, the meta-analysis was based only on a small number of studies. The confounding factors contributing to adverse effects other than the diluents in the included studies were not considered. Another limitation is that the two groups were not identical in the included studies; some patients received an additional type of IV fluids concomitantly with standard diluents which could affect the outcomes. However, in Aoyagal et al. and Magee et al., they adjust the difference by multivariable logistic regression.
| Conclusion|| |
The utilization of D5W as a medication diluent in critical care settings was associated with a lower incidence of hypernatremia and hyperchloremia. In addition, the use of D5W as a diluent may be associated with shorter ICU LOS. However, a large RCT needs to be conducted to evaluate the impact of medication diluents on critically ill patients' clinical outcomes.
We would like to acknowledge the investigators in the Saudi critical care pharmacy research (SCAPE) platform who participated in this project.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| Appendix A: Search Terms|| |
PubMed/MEDLINE (Searched until January 2021)
- Dextrose 5% OR Normal saline AND Hypernatremia AND ICU
- Dextrose 5% OR Normal saline AND Hypernatremia
- Dextrose 5% AND Normal saline AND Hypernatremia
- Medication diluent AND ICU.
Cochrane Library (Searched until January, 2021)
- Dextrose 5%
- Normal saline
- Hypernatremia AND ICU
Clinical trial registries (Searched until January, 2021)
- Condition: Critically ill other name: Normal saline
- Condition: Critically ill other name: Dextrose 5%
- Condition: Critically ill other name: Dextrose 5% OR Normal saline
- Condition: Hypernatremia other name: Dextrose 5% OR Normal saline
- Condition: Critically ill other name: diluent.
| References|| |
Finfer S, Liu B, Taylor C, Bellomo R, Billot L, Cook D, et al.
Resuscitation fluid use in critically ill adults: An international cross-sectional study in 391 Intensive Care Units. Crit Care 2010;14:R185.
Van Regenmortel N, Verbrugghe W, Roelant E, Van den Wyngaert T, Jorens PG. Maintenance fluid therapy and fluid creep impose more significant fluid, sodium, and chloride burdens than resuscitation fluids in critically ill patients: A retrospective study in a tertiary mixed ICU population. Intensive Care Med 2018;44:409-17.
Guidet B, Soni N, Della Rocca G, Kozek S, Vallet B, Annane D, et al.
A balanced view of balanced solutions. Crit Care 2010;14:325.
Bihari S, Peake SL, Seppelt I, Williams P, Bersten A. Sodium administration in critically ill patients in Australia and New Zealand: A multicentre point prevalence study. Crit Care Resusc 2013;15:294-300.
Walker HK, Hall WD, Hurst JW, editors. Clinical Methods: The History, Physical, and Laboratory Examinations. Boston: Butterworths Copyright © 1990, Butterworth Publishers, a Division of Reed Publishing; 1990.
Morgan M, Thrash WJ, Blanton PL, Glaser JJ. Incidence and extent of venous sequelae with intravenous diazepam utilizing a standardized conscious sedation technique. Part II: Effects of injection site. J Periodontol 1983;54:680-4.
Bihari S, Ou J, Holt AW, Bersten AD. Inadvertent sodium loading in critically ill patients. Crit Care Resusc 2012;14:33-7.
Hoste EA, Clermont G, Kersten A, Venkataraman R, Angus DC, De Bacquer D, et al
. RIFLE criteria for acute kidney injury are associated with hospital mortality in critically ill patients: A cohort analysis. Crit Care 2006;10:R73.
Singbartl K, Kellum JA. AKI in the ICU: Definition, epidemiology, risk stratification, and outcomes. Kidney Int 2012;81:819-25.
Hansen PB, Jensen BL, Skott O. Chloride regulates afferent arteriolar contraction in response to depolarization. Hypertension 1998;32:1066-70.
Krajewski ML, Raghunathan K, Paluszkiewicz SM, Schermer CR, Shaw AD. Meta-analysis of high- versus low-chloride content in perioperative and critical care fluid resuscitation. Br J Surg 2015;102:24-36.
Rein JL, Coca SG. “I don't get no respect”: The role of chloride in acute kidney injury. Am J Physiol Renal Physiol 2019;316:F587-605.
Choo WP, Groeneveld AB, Driessen RH, Swart EL. Normal saline to dilute parenteral drugs and to keep catheters open is a major and preventable source of hypernatremia acquired in the Intensive Care Unit. J Crit Care 2014;29:390-4.
Aoyagi Y, Yoshida T, Uchino S, Takinami M, Uezono S. Saline versus 5% dextrose in water as a drug diluent for critically ill patients: A retrospective cohort study. J Intensive Care 2020;8:69.
Magee CA, Bastin ML, Laine ME, Bissell BD, Howington GT, Moran PR, et al.
Insidious harm of medication diluents as a contributor to cumulative volume and hyperchloremia: A prospective, open-label, sequential period pilot study. Crit Care Med 2018;46:1217-23.
Bihari S, Prakash S, Potts S, Matheson E, Bersten AD. Addressing the inadvertent sodium and chloride burden in critically ill patients: A prospective before-and-after study in a tertiary mixed Intensive Care Unit population. Crit Care Resusc 2018;20:285-93.
Young P, Bailey M, Beasley R, Henderson S, Mackle D, McArthur C, et al.
Effect of a buffered crystalloid solution vs. saline on acute kidney injury among patients in the Intensive Care Unit: The SPLIT Randomized Clinical Trial. JAMA 2015;314:1701-10.
Myburgh JA, Mythen MG. Resuscitation fluids. N Engl J Med 2013;369:1243-51.
Semler MW, Self WH, Wanderer JP, Ehrenfeld JM, Wang L, Byrne DW, et al.
Balanced crystalloids versus saline in critically ill adults. N Engl J Med 2018;378:829-39.
Lindner G, Funk GC. Hypernatremia in critically ill patients. J Crit Care 2013;28:216.e11-20.
Shad ZS, Qureshi MSS, Qadeer A, Abdullah A, Munawar K, Khan MT, et al.
Hyperchloremia in Intensive Care Unit mortality: An underestimated fact. Cureus 2019;11:e4770.
Zhou F, Peng ZY, Bishop JV, Cove ME, Singbartl K, Kellum JA. 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.
Boniatti MM, Cardoso PR, Castilho RK, Vieira SR. Is hyperchloremia associated with mortality in critically ill patients? A prospective cohort study. J Crit Care 2011;26:175-9.
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2]