It’s 2 AM during a busy ED shift on a Saturday night and you’ve identified a septic patient with pneumonia whose most recent blood pressure reading is 70/30 with a heart rate of 130. The nurse turns to you and asks, “Should I start a one liter normal saline bolus?” The answer in your mind has always been “yes” in this situation throughout your career, is there any reason to doubt that now?
While the debate rages on over crystalloid versus colloid, the new discussion over the past few years examining which crystalloid solution is best for resuscitation has drawn many people’s attention. Concerns related to normal saline leading to worse clinical outcomes such as acute kidney injury have led some to switch over to more balanced solutions like lactated Ringer’s or Plasma-Lyte for volume resuscitation. This practice pattern may not be cost effective or soundly evidence based.
Normal saline likely had its origin in the late 19th or early 20th century when it was being used to treat patients for cholera.1
Despite historical references reporting a more balanced composition of the “original” normal saline, the current version that is ubiquitous today as 0.9% saline has been used for over a century, saving countless lives as a resuscitation fluid. Normal saline does, however, provide a supraphysiologic chloride load and causes a non-gap metabolic acidosis utilizing the strong ion approach.2
There are several associations noted in the literature between normal saline and decreased renal perfusion leading to acute kidney injury (AKI), coagulopathy, immune dysfunction as well as other perceived negative consequences.. However, a direct causality has not been proven definitively.
Animal studies are among the most commonly cited head-to-head comparisons between normal saline and balanced solutions. In rat models of sepsis, infusing chloride-rich solutions suggests an increase in inflammatory cytokines and a decrease in renal blood flow.3-4
Zhou et al studied more clinically related variables in a rat model of sepsis looking at acute kidney injury and classifying it according to the RIFLE criteria.5
Plasma-Lyte compared to normal saline had less acute kidney injury and improved survival. Although thought-provoking, much of the literature supporting the use of balanced solutions involves animal models. Translating these outcomes into clinically relevant and definitive human trials has yet to be accomplished.
Human studies have been challenging to conduct in a randomized controlled fashion while eliminating crossover of different crystalloid solutions to properly study their effects. Most studies have been observational or retrospective and conducted in non-emergency department settings. Waters et al randomized patients undergoing abdominal aortic aneurysm repair to normal saline (n=33) or lactated Ringer’s (n=33) and found no differences in post-operative complications related to AKI, death, ICU length of stay, and time on the ventilator.6
There was a statistically significant difference in metabolic acidosis, which is not unexpected, and the normal saline group required more platelet transfusions. However, estimated blood loss and total packed red cells transfused were the same, which questions the clinical significance of this finding. A retrospective cohort study by Shaw et al examining patients treated with normal saline or Plasma-Lyte after undergoing major open abdominal surgery showed similar results.7
Despite using propensity matching due to significant differences in the cohorts (normal saline group being more sick, more emergent cases), there were no statistically significant differences between the groups in mortality, renal dysfunction, and other predefined endpoints. There were differences in infectious complications, bleeding, and electrolyte derangements, but this should be interpreted with caution given the nature of the study design.
One particular study that has received a lot of attention is the study by Yunos et al in JAMA from 2012.8
This was a prospective, open label before and after trial looking at AKI outcomes using a chloride-restrictive strategy in an ICU in Australia. They found a decreased incidence of AKI by RIFLE criteria as well as decreased need for renal replacement therapy (RRT) in the chloride-restrictive group. Despite these results, there are factors to consider with this trial. First, you cannot prove direct causality based on the trial design—one can only show association. Given that it was a bundled trial with fluids other than normal saline being restricted (including 4% albumin, and a gelatin solution) it is challenging to discern which change in fluid led to these results. Secondly, there is no data on the amount or which type of IV fluids the patients received prior to ICU arrival. If the quantity of IV fluids was not small this could certainly affect the results. Furthermore, even though the chloride-restrictive group required less RRT, long-term follow-up did not show any statistical differences in need for dialysis, and the trial was not designed to look for differences in mortality. In addition, before and after trials cannot take into account ICU practice changes and quality improvement that occur over time.
To say that normal saline should not be routinely used in the emergency department for volume resuscitation would be a significant change, and one that at least as of now requires further investigation before implementing. There are many instances in which normal saline should be the fluid of choice including in traumatic brain injury and for patients with metabolic alkalosis or hyponatremia. The debate parallels that of crystalloid versus colloid in terms of cost and truly relevant clinical outcomes, with the final answer still to be determined. In the emergency department, our true focus should be correcting life-threatening hypoperfusion, a much more significant acute problem than the chloride load received. Therefore, in the meantime, when the nurse asks me for a one liter bolus of normal saline for my patient in septic shock, I will respond, “Better make that two.”References
- Awad S, Allison SP, Lobo DN. The history of 0.9% saline. Clin Nutr. 2008;27:179–188. doi: 10.1016/j.clnu.2008.01.008.
- Madhusudan P, Vajayaraghavan BKT, Cove ME. Fluid resuscitation in sepsis: reexamining the paradigm. BioMed Res Int. 2014;20. Article ID 984082.
- Wilcox CS. Regulation of renal blood flow by plasma chloride, J Clin Invest. 1983;71(3):726–735.
- Kellum A, Song M, and Almasri E. Hyperchloremic acidosis increases circulating inflammatory molecules in experimental sepsis. Chest. 2006;130)(4):962–967.
- 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(4):e270-e278.
- Waters JH, Gottlieb A, Schoenwald P, Popovich MJ, Sprung J, Nelson DR. Normal saline versus lactated Ringer’s solution for intraoperative fluid management in patients undergoing abdominal aortic aneurysm repair: an outcome study. Anesth Analg. 2001;93:817–822.
- 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. 2014;255(5):821–829.
- Yunos NM, Bellomo R, Hegarty C, Story D, Ho L, Bailey M. Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. JAMA. 2012;308(15):1566-1572.
Since 1832, when Dr. Thomas Latta administered “two drachms of muriate and two scruples of carbonate, of soda, in sixty ounces of water” to a patient in hypovolemic shock from cholera, the administration of intravenous fluids has been the cornerstone of resuscitation of critically ill patients. Intravenous fluids are often given to critically ill patients to augment cardiac output and improve tissue perfusion and oxygenation. It is clear that the timing and dosing of their administration are critical to patient outcomes. In fact, indiscriminate and excessive volume administration (“salt water drowning”) is associated with increases in patient morbidity and mortality rates.1
Emerging evidence suggests that the specific type of intravenous fluid also could affect patient outcomes. The adage “There’s very little damage you can do with a few liters of normal saline” no longer holds water.
Quite simply, normal saline never has been, and never will be, a true physiologic solution. It contains 154 mEq/L of sodium and 154 mEq/L of chloride, with an osmolarity of 308 mOsm/L.2
With a strong ion difference of zero (Na2
+ – Cl-
), normal saline reliably produces, or worsens, metabolic acidosis. In addition, the chloride concentration of normal saline is approximately 40% higher than the chloride concentration of plasma. This supraphysiologic amount increases systemic inflammation and can cause renal vasoconstriction and decrease the glomerular filtration rate.3-7
In a prospective, open-label study of more than 1,500 patients at a single center in Australia, Yunos et al demonstrated a lower increase in creatinine and a lower rate of kidney injury by restricting the use of normal saline and other high-chloride-containing intravenous fluids. In a large, observational study of patients undergoing major abdominal surgery, Shaw et al demonstrated that those who received normal saline had a greater need for renal replacement therapy than did patients who received PlasmaLyte solution.8
In addition to its negative effects on the kidney, hyperchloremia can adversely affect the pulmonary, splanchnic, circulatory, and coagulation systems. Perhaps most importantly, hyperchloremia from fluid resuscitation could worsen patient outcome. In a recent retrospective review of more than 109,000 patients, Shaw et al demonstrated a lower in-hospital mortality rate among patients who received intravenous fluids with lower chloride loads.9
Balanced solutions such as Plasma-Lyte, lactated Ringer’s, and Hartmann’s solution have less of an adverse effect on acid‒base equilibrium than does normal saline. Through the addition of organic anions (eg, lactate, acetate, gluconate, citrate), balanced solutions contain significantly lower concentrations of chloride than does normal saline. Trials comparing balanced solutions with normal saline have demonstrated lower chloride concentrations, higher bicarbonate concentrations, and faster resolution of base deficit and correction of arterial pH.10-12
In fact, recent data suggest that balanced solutions might be superior to normal saline for fluid resuscitation. In a retrospective cohort from a large database, Raghunathan et al evaluated the association of balanced solutions versus higher chloride solutions on the in-hospital mortality rate among patients with sepsis.13
Almost 3,400 patients in this study received a balanced solution (most commonly lactated Ringer’s) as a component of their overall fluid volume. The in-hospital mortality rate was lower among patients who received a balanced solution than among those who received only saline. Based on a systematic review and network meta-analysis, Rochwerg et al reported that balanced solutions might be superior to saline for fluid resuscitation in sepsis.14
Admittedly, no large, randomized, double-blind study has compared normal saline with any of the balanced solutions. Furthermore, much of the literature on intravenous fluid administration and the harms of normal saline do not directly evaluate emergency department patients. Regardless, we know that interventions in the early stages of critical illness often have profound effects on patient morbidity and mortality. Critically ill patients deserve the same level and focus of care regardless of their location within the hospital. The signal from the literature regarding the negative physiologic and potential outcome effects of normal saline is becoming stronger. In short, there is nothing normal about normal saline. Stop using this fluid on a routine basis for volume resuscitation of critically ill patients in the emergency department.The authors would like to acknowledge Linda Kesselring for editorial assistance.References
- Marik PE. Iatrogenic salt water drowning and the hazards of a high central venous pressure. Ann Intensive Care. 2014;4:21.
- Awad S, Allison SP, Lobo DN. The history of 0.9% saline. Clin Nutr. 2008;27:179-188.
- Bullivant EM, Wilcox CS, Welch WJ. Intrarenal vasoconstriction during hyperchloremia: role of thromboxane. Am J Physiol. 1989;256:F152-F157.
- Kellum JA, Song M, Almasri E. Hyperchloremic acidosis increases circulating inflammatory molecules in experimental sepsis. Chest. 2006; 130:962-967.
- Hadimioglu N, Saadawy I, Saglam T, Ertug Z, Dinckan A. The effect of different crystalloid solutions on acid-base balance and early kidney function after kidney transplantation. Anesth Analg. 2008;107:264-269.
- Chowdhury AH, Cox EF, Francis ST, Lobo DN. A randomized, 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;256:18-24.
- 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.
- Shaw AD, Bagshaw SM, Goldstein SL, Scherer LA, Duan M, Schermer CR, et al. Major complications, mortality, and resource utilization after open abdominal surgery: 0.9% saline compared to Plasma-Lyte. Ann Surg. 2012;255:821-829.
- Shaw AD, Raghunathan K, Peyerl FW, Munson SH, Paluszkiewicz SM, Schermer CR. Association between intravenous chloride load during resuscitation and in-hospital mortality among patients with SIRS. Intensive Care Med. 2014;40:1897-1905
- McFarlane C, Lee A. A comparison of Plasmalyte 148 and 0.9% saline for intra-operative fluid replacement. Anaesthesia. 1994;49:779-781.
- Mahler SA, Conrad SA, Wang H, Arnold TC. Resuscitation with balanced electrolyte solution prevents hyperchloremic metabolic acidosis in patients with diabetic ketoacidosis. Am J Emerg Med. 2011;29:670-674.
- Young JB, Utter GH, Schermer CR, Galante JM, Phan HH, Yang Y, et al. Saline versus Plasma-Lyte A in initial resuscitation of trauma patients: a randomized trial. Ann Surg. 2014;259:255-262.
- Raghunathan K, Shaw A, Nathanson B, Sturmer T, Brookhart A, Stefan MS, et al. Association between the choice of IV crystalloid and in-hospital mortality among critically ill adults with sepsis. Crit Care Med. 2014;42:1585-1591.
- Rochwerg B, Alhazzani W, Sindi A, Heels-Ansdell D, Thabane L, Fox-Robichaud A, et al. Fluid resuscitation in sepsis: a systematic review and meta-analysis. Ann Intern Med. 2014;161:347-355.