The quest for suitable intravenous fluids began with the cholera pandemic of the 1830s. The deadly disease was characterized by repeated evacuation of large volumes of a rice-water-like fluid leading to severe dehydration among those afflicted. It spread from India to South East Asia and the Middle East, then towards Russia and the rest of Europe killing thousands of people along the way. Latta, a Scottish physician, concerned by the loss of huge volumes of fluid from the body, suggested replenishment with a “salt” solution. This solution was administered rectally first, and later, intravenously, with a profound effect on those affected. Several decades later, a Dutch scientist, Hamburger, suggested that the concentration of salt in the human body was 0.9%. He proposed that an identical concentration of salt would be “normal” and physiologically appropriate. From this early, humble beginning, “normal” saline percolated down generations of physicians and became deeply entrenched into contemporary clinical practice. Yes, normal saline has been, by far, the most commonly prescribed intravenous fluid for nearly two centuries.
Is normal saline really physiological as Hamburger believed?
The sodium and chloride levels of normal saline are markedly different from serum levels. Normal saline is acidic (pH: 5.4) and contains 154 mmol/L each of sodium and chloride. Compared to serum levels, the Na+level in normal saline is approximately 10% higher, and even more importantly, the chloride level is almost 50% higher.
Does normal saline cause acidosis? According to Stewart’s hypothesis, the pH of any fluid is dependent only on three factors, including the PCO2 level, the content of non-volatile acid (albumin and phosphate), and most importantly, the strong ion difference (SID). SID is the difference between the fully dissociated cations and anions. Thus, SID = Strong cations (Na+, K+, Ca++, and Mg++) – Strong anions (Cl–, lactate, ketoacids, and organic anions). The normal SID is 40 mmol/L; a lower SID which may occur with a relative increase in the strong anions, leading to a lower pH (acidosis). The pH increases when the SID is higher (alkalosis). When normal saline is infused, both Na+and the Cl–levels rise. However, the increase in Cl–is much higher than the increase in Na+. This is because the Cl–level in normal saline is almost 50% higher than the serum level, compared to the minimal difference in Na+levels. Hence, the infusion of normal saline results in a relative increase in the Cl–levels with a reduction in the SID, leading to acidosis.
Normal saline and the kidneys
The excessive Cl–content of the fluid filtered through the glomeruli is sensed by the macula densa, a group of specialized cells located at the junction of the ascending limb of the loop of Henle and the distal convoluted tubule. The Cl–signal is transmitted to the afferent arteriole, which is in close contact with the macula densa. This leads to vasoconstriction of the afferent arteriole, a drop in the perfusion pressure in the glomeruli, and reduced glomerular filtration (Fig. 1).
Fig. 1: The macula densa senses a high concentration of chloride in the filtered fluid and signals vasoconstriction in the afferent arteriole, thus reducing the glomerular filtration rate (From: Li, Heng, Shi-ren Sun, John Q. Yap, Jiang-hua Chen, and Qi Qian. 2016. 0.9% Saline Is Neither Normal nor Physiological. Journal of Zhejiang University-SCIENCE B 17(3): 181–187)
Normal saline and potassium levels
Many clinicians believe that it may be safer to infuse normal saline compared to Ringer Lactate in patients with high potassium levels. This is based on the assumption that, Ringer Lactate, with a K+ concentration of 4.0 mmol/L, may exacerbate hyperkalemia. However, this assumption is largely incorrect; the acidosis arising from normal saline infusion leads to a shift of K+ from the intracellular to the extracellular compartment with an increase in the serum K+ levels. Several clinical studies have confirmed higher potassium levels with the infusion of normal saline compared to Ringer’s lactate (Weinberg et al. 2017).
Does the use of normal saline as a resuscitation fluid lead to clinical harm?
It is somewhat bewildering that the ubiquitous use of normal saline remained unquestioned for more than a century. Beginning from the 1980s, concerns were raised regarding the high Cl– content in normal saline and the possibility of consequent renal injury. Clinical investigation into possible harm commenced much later, with several observational studies suggesting a detrimental effect (Raghunathan et al. 2015; Shaw et al. 2012).
In a sequential pilot study that compared 6 months each of a chloride-liberal vs. chloride-restricted intravenous fluid, the incidence of acute kidney injury (AKI) and the need for renal replacement therapy were significantly lower during the chloride-restricted period (Yunos et al. 2012). The SPLIT study was a double-blind, cluster-randomized, crossover study that compared 0.9% saline with Plasma-Lyte 148 (Young et al. 2015). There was no significant difference in the incidence of AKI, the need for renal replacement therapy, and in-hospital mortality between groups. However, this study was aimed primarily to evaluate the feasibility and assess sample size for future studies. The study was meant to be conducted over a specific period of time with no fixed sample size. No power calculation was made considering the lack of previous randomized controlled trials.
Two large randomized controlled trials were conducted at the Vanderbilt University Medical Centre comparing normal saline Vs balanced crystalloids (Ringer’s solution or Plasma Lyte A) and published earlier this year (Self et al. 2018; Semler et al. 2018). The SMART study was carried out in five intensive care units. Patients were randomly assigned to receive one of the two types of fluid on alternate months. The primary composite outcome was one or more major kidney events during 30 days (MAKE-30) of follow-up. The MAKE-30 criteria included mortality, the requirement for renal replacement therapy, and a rise in creatinine to twice the baseline or more in 30 days. The composite outcome was significantly less with balanced crystalloids compared to normal saline (14.3 vs 15.4%; p = 0.04). The SALT-ED study was conducted on non-critically ill patients presenting to the emergency department and admitted to the wards. Using a similar design, this study also revealed a more favorable composite outcome (4.7 vs. 5.6%; p = 0.01). Subgroup analysis suggested that the impact of using balanced crystalloids was more pronounced in patients who received larger volumes of fluid and those with sepsis.
The question of whether balanced crystalloids is preferable to normal saline may be far from unequivocally answered as yet. However, we know today that the centuries-old practice of unrestricted use of normal saline may lead to unfavorable clinical outcomes. Balanced crystalloids, including Ringer’s lactate and Plasma Lyte, offer possible safer alternatives, especially if large volume resuscitation is required. It is also pertinent to point out that a perceptible outcome difference based on the choice of fluid may be largely confined to the most severely ill patients. An 8800-patient randomized controlled trial comparing normal saline vs. Plasma Lyte 148 (the PLUS study) is currently in progress across multiple ICUs in Australia and New Zealand and may add substantially to our body of knowledge. In our practice, we confine to Ringer Lactate for most of our patients who need fluid resuscitation. The findings of SMART and SALT-ED have only strengthened our bias.
Raghunathan, Karthik, Anthony Bonavia, Brian H. Nathanson, et al. 2015.Association between Initial Fluid Choice and Subsequent In-Hospital Mortality during the Resuscitation of Adults with Septic Shock. Anesthesiology 123(6): 1385–1393.
Self, Wesley H., Matthew W. Semler, Jonathan P. Wanderer, et al. 2018. Balanced Crystalloids versus Saline in Noncritically Ill Adults. The New England Journal of Medicine 378(9): 819–828.
Semler, Matthew W., Wesley H. Self, Jonathan P. Wanderer, et al. 2018. Balanced Crystalloids versus Saline in Critically Ill Adults. The New England Journal of Medicine 378(9): 829–839.
Shaw, Andrew D., Sean M. Bagshaw, Stuart L. Goldstein, et al. 2012. Major Complications, Mortality, and Resource Utilization after Open Abdominal Surgery: 0.9% Saline Compared to Plasma-Lyte. Annals of Surgery 255(5): 821–829.
Weinberg, L., L. Harris, R. Bellomo, et al. 2017. Effects of Intraoperative and Early Postoperative Normal Saline or Plasma-Lyte 148® on Hyperkalaemia in Deceased Donor Renal Transplantation: A Double-Blind Randomized Trial. British Journal of Anaesthesia 119(4): 606–615.
Young, Paul, Michael Bailey, Richard Beasley, et al. 2015.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 314(16): 1701–1710.
Yunos, Nor’azim Mohd, Rinaldo Bellomo, Colin Hegarty, et al. 2012. Association between a Chloride-Liberal vs Chloride-Restrictive Intravenous Fluid Administration Strategy and Kidney Injury in Critically Ill Adults. JAMA 308(15): 1566–1572.