The Myth of 0.9% Saline Neither Normal nor Physiological

Crit Care Nurs Q

Vol. 38, No. 4, pp. 385–389

Copyright Qc  2015 Wolters Kluwer Health, Inc. All rights reserved.


Normal saline is the crystalloid of choice for fluid resuscitation with its utility born out of the cholera epidemic of 1832. However, its ubiquitous usage is being challenged because of a growing body of evidence suggesting that a large volume infusion of normal saline does in fact have deleterious effects on multiple body systems. Careful considerations should be given to the physiological effects of using large amounts of normal saline as one would with another pharmacological agents. Key  words:  crystalloidsfluid  resuscitationnormal  salinephysiological   effects

I at length resolved to throw the fluid immediately into the circulation. In this, having no precedent to direct me, I proceeded with much caution . . . ounce after ounce was injected . . . when six pints had been injected, she expressed in a firm voice that she was free from all uneasiness.

FLUID RESUSCITATION using 0.9%  normal saline (NS), now the mainstay therapy for many conditions, was born out of  the cholera epidemic of the 1800s. In 1831, Dr O’Shaughnessy analyzed the blood of patients with cholera and noted the loss of large amount of water and neutral salt components. On the basis of his findings, he hypothesized that replacing the lost salt contents with tepid water and highly oxygenized salt—such as nitrate or the chlorate of potash (based on animal studies)—would be effective in  treating patients with cholera in extremis.1 In 1832, Dr Thomas Latta documented his treatment of an elderly patient with cholera using what is now recognized as intravenous fluid resuscitation. Then, with a silver syringe connected to a flexible injection tube, he injected saline into the basilica vein of the patient and noted the return of the patient’s color and alleviation of symptoms.2 Ultimately, however, the patient’s condition relapsed and died after the responsibility of her care was transferred to the hospital surgeon, who no doubt venosected the patient as that was the favored remedy for patients with cholera at the time.

Although the practice of intravenous saline solutions was first described during the cholera epidemic, the salt contents used in those days were very different from the 0.9% solution that we are familiar with currently. The idea of 0.9% saline as physiological was based on the experiments of Dr Hamburger, a Dutch physiological chemist who, in 1896, published a study in which he noted that mammalian red blood cells did not swell when the NaCl concentration of solutions was titrated to 0.92%. On the basis of his findings, he concluded that 0.9% NaCl is isotonic with the mammalian blood of most animals including humans, and thus physiological.3 Since then, 0.9% “normal saline” has become the standard intravenous solution used in clinical practice.

Although termed “normal saline,” 0.9% NS is  in  fact  supraphysiological  because  of its

abnormally high chloride content.4 Each liter of NS contains 154 meq of chloride, which exceeds the normal physiological range of 96 to 106 meq/L by approximately 1.5 times. With large volume infusion of NS, the large chloride load has been shown to have negative effects on blood pH, immune system, coagulation function, and renal perfusion.4,


In both animal and human studies, the infu- sion of a large amount of NS has been noted to decrease the pH of the subjects, the effect of which could last for several hours and the resultant acidosis could lead to coagulopathy and negative hemodynamics.4-7 There are 2 schools of thought behind the acidosis caused by NS: the dilutional acidosis hypothesis and the Stewart physiochemical hypothesis. The dilutional acidosis theory posits that with a large volume of NS infusion, there is dilution of serum bicarbonate concentration leading to acidosis.5 The Stewart hypothesis is based on Peter Stewart’s physiochemical findings that a strong ion difference (SID) is an inde- pendent factor for altering serum pH. Stew- art’s hypothesis emphasizes electroneurtrality and when differences are present in between the cations and anions, the body converts water (H2O) into hydrogen ion and bicarb accordingly to maintain electroneutrality.8-10 In the original equation, strong ions include sodium, chloride, and other electrolytes such as potassium and magnesium; these other electrolytes are much less in concentration, therefore not enough to cause a physiologi- cal effect. In terms of acid–base physiology in Peter Stewart’s approach, the SID is usu- ally effectively the difference between sodium and chloride. (Although hyperphosphatemia is one condition where phosphate increases so much that it can alter the SID.)8-10 When the SID increases, the serum pH becomes alkalinized and when the difference decreases, the opposite effect occurs. NS’s Na:Cl ratio is 1:1 with an SID of 0; therefore, when large volumes are infused, serum acidosis results.8-10 More balanced solutions with less chloride including lactate Ringer and Normosol/Plasma- Lyte have SIDs ranging from 21 to 42 and have less of an acidotic effect when infused in large volumes8-10 (see the Table).


In animal studies, hyperchloremic acido- sis has been linked with increased release of inflammatory markers and cytokines.11 This pro-inflammatory response seems to be dose dependent.11 Although a clear association has been made between chloride and cytokines, the clinical implication for this phenomenon is unknown because no large study on hu- mans has yet been conducted.11,12 It makes physiological sense; however, in conditions such as severe sepsis when there is already  an overwhelming inflammatory cascade, we do not infuse NS, which further increases cytokine release. However, large-scale human study would be needed to explore its clinical impact.


Large volume of NS infusion has been associated with increased blood loss and increased blood products needed in surgery and trauma literature. This association may be due to NS’s effect on lowering the pH, which is detrimental to coagulation cascade.13 The effect  of acidosis on coagulation cascade is thought to be through its inhibitory effect on thrombin and fibrinogen, which results in prolonged bleeding.14,15 Therefore, using large volume of NS to supplement for blood loss has the detrimental effect of increased bleeding and more blood product need.13-15


The infusion of NS has been associated with greater interstitial edema and longer time to micturation.4,5,16 This effect was first seen in animal studies, and later confirmed in human studies where subjects were infused with NS and was compared with those infused    with

lactated Ringer. This effect on renal perfusion is likely due to the vasoconstrictive effect of chloride on the renal afferent arteries.4,5   A high chloride concentration in the renal tubules causes a depolarization effect in the macula densa and leads to activation of A1 receptors in the renal arteries, inducing a decrease in glomerular filtration rate. This vasoconstrictive effect also causes greater interstitial edema in the renal capsules, leading to compression on the tubules, which further affects urine output and tissue perfusion. These effects have not been noted when the subjects are infused with balanced solutions.4,5




Studies of both surgical patients and critically ill medical patients all have demonstrated an association of chloride-rich solutions, with worse clinical outcomes such as increased incidence of acute kidney injury, increased needs for renal replacement therapy, higher need for fluid/blood product, and most importantly, increased mortality.13,16-20 Although there is a concern with using balanced fluids in potential hyperkalemic patients, small-scale studies have demonstrated

their safety because of the limited amount of potassium contained in the balanced fluids (no more than 5 mmol/L).21,22 Rather than resuscitating patients in shock with NS only, careful consideration should be given to fluid selection much like one would with medications. The clinician should have understanding of the physiological changes NS infusion brings and be cognizant of its ill effects. Given the available literatures suggesting deleterious effects associated with large volume NS infusion, we should give more considerations to balanced crystalloid solutions as the primary resuscitation fluid


Although the resuscitation fluid of choice, NS’s high chloride content makes it neither “normal” nor physiological.” Its chloride-rich content has been associated with adverse ef- fects in pH, coagulation, renal function, and patient outcomes. Although the evidences against the use of NS are mostly animal studies or associative by nature, it is reasonable for clinicians of all discipline to understand the potential deleterious effects of large volume infusion of NS.


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