It’s another busy day in the ED when an elderly female comes in from triage with fever, cough, and new oxygen requirement. Even before the patient comes back you are concerned for pneumonia with sepsis. The patient is tachycardic and hypotensive with a shock index greater than one. You institute early antibiotics and fluids and systematically begin to aggressively resuscitate her. The patient requires nearly four liters of normal saline before her blood pressure stabilizes. Your attending suggests that your liberal use of normal saline will induce a hyperchloremic metabolic acidosis, and perhaps you should have used lower chloride containing fluid, like lactated ringers. You perform a brief literature review on the topic of balanced resuscitation using lower chloride containing fluids.
|Strong Ion Difference (Kishen et al)|
The main difference between normal saline and balanced fluids, such as lactated ringers, is the strong ions difference (SID), that is, the difference between cations (e.g. Na+) and anions (e.g. Cl-). Normal saline has a SID of zero (equal parts Na+ and Cl-) where as Lactated ringers has a SID of 28, which is due to the additional cations such as Ca+, K+, and lower anion (Cl-) content. Importantly, normal plasma SID content ranges from 38-44mmol/L, therefore balanced fluids more closely approximates physiologic SID. As the SID becomes narrower, as is the case with significant normal saline administration, a non-gap metabolic acidosis develops. 
The use of normal saline in large volumes has been shown to produce a reliable drop in serum pH as demonstrated by Scheinraber et al, in a study among patients undergoing elective surgery.  However, the development of a hyperchloremic acidosis is of unclear clinical significance. Early animal models in dog kidneys demonstrated that compared to non-chloride fluids, chloride containing solution led to renal vasoconstriction and decline in glomerular filtration rate. Similarly a randomized, double blind crossover study in healthy humans demonstrated a significant reduction in renal blood flow and renal tissue perfusion, after the administration of two liters of normal saline compared to low chloride (98 mEq/L) Plasma-Lyte solution.  However, the effect of isotonic saline in acutely ill patients is still not as clear. A prospective cohort study among 175 ICU patients demonstrated that higher chloride levels (109.4 vs 115.1mEq) was an independent factor for increased mortality, although a limitation of this study was they could not distinguish the cause of hyperchloremia (iatrogenic, renal dysfunction, or endogenous hyperchloremia) 
A large retrospective cohort study of critically ill adults with
vasopressor dependent sepsis showed lower in-hospital mortality in patients who
received balanced (lower chloride) fluids versus isotonic saline, 19.6% versus
22.8% (RR 0.86; 95% CI,0.78-0.94). A limitation of this study was that patients
receiving balanced solutions were younger, less likely to have chronic heart
and renal failure, and more likely to receive steroids, colloids and invasive
monitoring.  A 2014 retrospective study in 109,836 patients that met SIRS
criteria and received crystalloid fluid resuscitation, showed that low-chloride
loads were associated with lower in-hospital mortality. This mortality
difference remained even after adjustment for severity of illness and total
fluid volume administered. 
|Traditional and 'balanced' fluid content (crashingpatient.com)|
Similarly, a before and after study by Yunos et al involving 1644 ICU patients, reported the use of chloride-restricted fluids was associated with lower serum creatinine and decreased rates of renal replacement therapy (6 vs 10%) compared to controls. Like the study by Shaw et al, the difference was independent of severity of illness or total fluid volume administered. However, as mentioned by the authors, determining which component of lower-chloride fluid may have led to the observed effect is difficult, as there was simultaneous administration of lower sodium content, as well as increase in the administration of acetate, lactate, and gluconate. Importantly, this study showed no difference in mortality. 
Take home points: Administration of large volume of isotonic saline is associated with a metabolic acidosis. Animal models have demonstrated decreased renal perfusion with chloride containing fluids. Several retrospective studies indicate that chloride is an independent risk factor for mortality in acutely ill patients. More and more literature in humans seems to indicate that a ‘balanced resuscitation’ may decrease morbidity, and possibly mortality, in patients receiving large volumes of crystalloids as part of their resuscitation. A single nonrandomized study demonstrated a correlation between low chloride fluids and decreased use of renal replacement therapy. Blinded, randomized, prospective studies are needed to further elucidate this observed effect.
Dr. Schwarz, an Assistant Professor here at Wash U, and both an Emergency Physician and Toxicologist has provided some of his own thoughts on the topic.
First, I’d like to thank Louis for picking a great topic and generating discussion about a very important subject. I initially became interested in this topic a few years ago. Originally, I was much more interested in the mechanism by which normal saline (NS) caused a non-anion gap metabolic acidosis, and that’s when I learned about the strong ion difference and a ‘balanced resuscitation.’ As a full disclosure while I found the pathophysiology really interesting, I initially didn’t think it had much clinical relevance. However as more investigators have studied this, I’ve come to believe that my initial impressions were incorrect and changed my practice.
The last time I reviewed the literature, I didn’t see a randomized, controlled trial comparing resuscitation with NS and lactated ringers in the ED. However I do believe that there are studies out there that are applicable to the ED. A retrospective study compared patients undergoing elective or emergent general surgery that received either NS or a ‘balanced fluid.’1 Unadjusted mortality and the number of patients developing major complications were higher in the group that received NS; after adjusting with propensity scoring, the mortality was no longer significantly different between the 2 groups. However, patients that received NS were 4.8 times more likely to require dialysis. In a meta-analysis of patients with sepsis, patients that received a ‘balanced resuscitation’ had a lower mortality than patients receiving NS.2 The trend, however, was not significant.
In a promise to keep this short, I won’t review all the other literature that has been published on this topic and kept the discussion on the 2 articles that I did include short. I’ll also concede that the literature is not perfect, and as I mentioned earlier, I’m also still waiting for that perfect ED-based study to be completed. However the cost of NS or a ‘balanced solution’ such as lactated ringers is nearly equivalent. I’m also not aware of significant complications from administering lactated ringers in most patients. So when the risks, costs, and benefits of implementing a ‘balanced resuscitation’ verses a standard resuscitation with NS are viewed together, I think there is enough evidence to consider changing your resuscitation strategy.
Now like many EDs, lactated ringers is not kept in our department. It is on shortage but so is NS. Neither of those are reasons not to use it. So what do I do? Since I haven’t been able to convince pharmacy to keep lactated ringers in the ED yet, I do my best to guess early on which patients are going to need large-volume resuscitations. If I think they are going to likely need more than 2-3 liters of fluid, I order additional lactated ringers from the pharmacy when I place their initial orders. In an hour after the patient has received the first few liters of NS, the lactated ringers should be there from the pharmacy. If they need further resuscitation I can use it or return if they no longer need it. For those that are interested to read more about this topic, I’d direct you to the upcoming May 2015 edition of Emergency Physicians Monthly. From my understanding, it’s brilliantly written! (Sorry for my shameless plug)
 Kishen R, Honoré PM, Jacobs R, et al. Facing acid–base disorders in the third millennium – the Stewart approach revisited. International Journal of Nephrology and Renovascular Disease. 2014;7:209-217. doi:10.2147/IJNRD.S62126.
 Scheingraber et al. Rapid Saline infusions produces hyperchloremic acidosis in patients undergoing gynecologic surgery. Anesthesiology 1999;90;1265
 Chowdhury A et al. . 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
 Boniatti MM et al. Is hyperchloremia associated with mortality in critically ill patients? A prospective cohort study. J Crit Care. 2011;26:175–179. doi: 10.1016/j.jcrc.2010.04.013
 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
 Shaw A et al. Association between intravenous chloride load during resuscitation and in-hospital mortality among patients with SIRS. Intensive Care Medicine. 2014;40(12):1897-1905. doi:10.1007/s00134-014-3505-3.
 Waikar SS, Saving the Kidneys by Sparing Intravenous Chloride?.JAMA. 2012;308(15):1583-1585. doi:10.1001/jama.2012.14076.
 Yunos N 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.
1. Shaw 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.
2. Rochwerg et al. Fluid Resuscitation in Sepsis. A Systematic Review and Network Meta Analysis. Ann Intern Med 2014;161:347-355.
Faculty Reviewed by Evan Schwarz @