Science > A suitable crystalloids for the fluid resuscitation to prevent ‘pre-renal’ AKI

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The high chloride content of 0.9% saline leads to adverse pathophysiological effects in both animals and healthy human volunteers, changes not seen after balanced crystalloids. Small randomized trials confirm that the hyperchloremic acidosis induced by saline also occurs in patients, but no clinical outcome benefit was demonstrable when compared with balanced crystalloids, perhaps due to a type II error. A strong signal is emerging from recent large propensity-matched and cohort studies for the adverse effects that 0.9% saline has on the clinical outcome in surgical and critically ill patients when compared with balanced crystalloids. Major complications are the increased incidence of acute kidney injury and the need for renal replacement therapy, and that pathological hyperchloremia may increase postoperative mortality. However, there are no large-scale randomized trials comparing 0.9% saline with balanced crystalloids. Some balanced crystalloids are hypo-osmolar and may not be suitable for neurosurgical patients because of their propensity to cause brain edema. Saline may be the solution of choice used for the resuscitation of patients with alkalosis and hypochloremia. Nevertheless, there is evidence to suggest that balanced crystalloids cause less detriment to renal function than 0.9% saline, with perhaps better clinical outcome. Hence, it is argued that chloride-rich crystalloids such as 0.9% saline should be replaced with balanced crystalloids as the mainstay of fluid resuscitation to prevent ‘pre-renal’ acute kidney injury.


Any rational approach to fluid and electrolyte therapy and volume resuscitation must take into account the evolved mammalian responses to stress, starvation, injury, or infection. These responses preserve the blood supply to essential organs, allowing time for the individual to recover, and activate the host defense and repair pathways.

In addition to the evolutionary response to conserve salt and water, the patient’s ability to excrete administered salt and water is also limited by renal compromise and reduced ability to concentrate urine. As a consequence, it requires 2–4 times the normal volume of urine to excrete the sodium and chloride load administered.

Although Evans1 commented on the dangers of the reckless way in which salt solutions were prescribed as early as 1911, the clinical effects of salt and water excess have largely been ignored till relatively recently, with continued inappropriate and excessive use of chloride-rich crystalloid infusions, such as 0.9% saline, both within the settings of resuscitation and maintenance. The development of balanced crystalloids highlights the need to reappraise the continued use of 0.9% saline, especially considering the detrimental effects the latter has on renal function.


From the renal perspective, the aim of fluid resuscitation of the hypovolemic patient is to improve renal blood flow, increase glomerular filtration rate (GFR), and reduce the incidence of acute kidney injury. However, the ability of fluid therapy to achieve this aim is dependent on a number of other factors including the type of fluid used and the effects of acute illness, chronic disease, and drugs that may alter determinants of fluid responsiveness. Teleologically, the kidney is better adapted to conservation of salt and water than to excreting an excess of either.3 In addition, factors such as hypotension, pain, and injury activate the sympathetic nervous system and the renin–angiotensin–aldosterone system. Subsequent release of the antidiuretic hormone overrides normal homeostatic mechanisms and leads to further sodium and water retention. Even in the absence of renal impairment, the relationship between fluid input and natriuresis is weak, and the administration of intravenous fluid may lead to salt and water accumulation rather than a diuresis,2,4,5 effects that are exaggerated with 0.9% saline when compared with balanced crystalloids, which bear a closer resemblance to the constituents of plasma (Table 1).


  Human plasma 0.9% Sodium chloride Hartmann's  Ringers lactate Ringers acetate Plasma Lyte 148 Plasma Lyte A pH 7.4

Sterofundin/ Ringerfundin

Osmolarity(mOsm/l) 275-295 308 278 273 276 295 295 309
pH 7.35-7.45 4.5-7.0 5.0-7.0 6.0-7.5 6.0-8.0 4.0-8.0 7.4 5.1-5.9
Sodium (mmol/l) 135-145 154 131 130 130 140 140 145
Chloride (mmol/l) 94-111 154 111 109 112 98 98 127
Potassium (mmol/l) 3.5-5.3 0 5 4 5 5 5 4
Calcium (mmol/l) 2.2-2.6 0 2 1.4 1 0 0 2.5
Magnesium (mmol/l) 0.8-1.0 0 0 0 1 1.5 1.5 1
Bicarbonate(mmol/l) 24-23              
Acetate (mmol/l) 1 0 0 0 27 27 27 24
Lactate (mmol/l) 1-2 0 29 28 0 0 0 0
Gluconate (mmol/l) 0 0 0 0 0 23 23 0
Maleate (mmol/l) 0 0   0   0 0 5
strong>Na:Cl ratio 1.21:1 to 1.54:1 1:1 1.18:1 1.19:1 1.16:1 1.43:1 1.43:1 1.14:1


Large volume infusions (50 ml/kg over 1 h) of 0.9% saline in healthy volunteers have been shown to be associated with a persistent acidosis and delayed micturition, and to produce

abdominal discomfort and pain, nausea, drowsiness, and decreased mental capacity to perform complex tasks, but these changes were not noted after infusion of identical volumes of Hartmann’s solution.8

The hyperchloremic acidosis caused by infusion of moderate-to-large quantities of 0.9% saline can last for several hours after the end of the infusion even in healthy volunteers 2,4,5,8,9 and may reflect the lower [Naþ]:[Cl_] ratio in saline (1:1) than in balanced crystalloids (1.18–1.43:1) or in plasma (1.38:1).10 Two theories have been proposed to explain this phenomenon: dilutional acidosis 11,12  and the Stewart hypothesis.13

Dilutional acidosis

It has been proposed that infusion of large volumes of saline causes a decrease in serum bicarbonate concentration due to a dilutional effect, resulting in acidosis.11,12

Stewart hypothesis

The mechanism of acidosis after infusions of 0.9% saline may be better explained by the Stewart hypothesis.33 This describes a mathematical approach to acid–base balance based on the apparent strong ion difference (SIDa, [Naþ]þ[Kþ]—[Cl_]) being the major determinant of

Hþ ion concentration. A decrease in SIDa is associated with metabolic acidosis and an increase with metabolic alkalosis. Hyperchloremia consequent on saline infusions decreases the SIDa, and is the process that results in a metabolic acidosis.12,14,16,17 Canine experiments on resuscitation from septic shock have shown that 0.9% saline accounted for 42% of the acidosis observed, whereas lactate was responsible for only 10%.6


Healthy human volunteer studies have shown that retention of fluid in the interstitial space is greater after infusions of 0.9% saline, than after those of balanced crystalloids or 5% dextrose, and that this fluid retention is associated with reduced urine volume. The data show that humans require approximately 2 days to restore normal sodium and water balance after an acute saline infusion and that urodilation and the renin–angiotensin–aldosterone system may participate in the long-term renal response to such infusions. Veech10 had emphasized that, when large amounts of saline are infused, the kidney is slow to excrete the excess chloride load.

Studies on young adult men have shown that plasma renin activity was suppressed 30 and 60 min after infusion of sodium chloride, but not after infusion of sodium bicarbonate, suggesting that both the renin and blood pressure responses to sodium chloride are dependent on chloride.18 A recent healthy volunteer study using magnetic resonance imaging has shown, for the first time in humans, that acute infusions of 2 liters of 0.9% saline can cause a reduction in renal artery flow velocity and renal cortical tissue perfusion when compared with a balanced crystalloid, and that this may be associated with the hyperchloremia caused by saline.4

Saline infusions have been shown to cause a greater increase in interstitial fluid volume (and, hence, edema) than balanced crystalloids and this may lead to a relatively greater increase in renal volume.4 Even small increases in the volume of an organ enclosed by a relatively non-expansible capsule may lead to intracapsular hypertension, which may further compromise tissue perfusion, reduce microvascular blood flow, and impair organ function.7

Furthermore, just as the increased interstitial fluid overload caused by large volumes of saline infusions can result in peripheral edema, it may also cause splanchnic edema, intestinal stretch increased abdominal pressure, ascites,19 and even the abdominal compartment syndrome,20 which can further compromise renal and gastrointestinal function. 21-22


Although human studies 2,4,5,8,9,10,14,23-24 have confirmed that 0.9% saline infusions lead to a hyperchloremic metabolic acidosis, which causes detriment to renal function, until recently there was no firm evidence that the use of saline led to adverse patient outcomes. Studies in the perioperative14,15 and resuscitation25 settings have shown that 0.9% saline causes a hyperchloremic acidosis when compared with balanced crystalloids. Over the past few years a few studies have suggested that 0.9% saline leads to more adverse events than balanced crystalloids, and, hence, worse patient outcomes.


As balanced crystalloids contain potassium, they were traditionally considered to be contraindicated in the presence of hyperkalemia or situations with a potential for hyperkalemia,

such as diabetic ketoacidosis or rhabdomyolysis. However, the maximum concentration of potassium in balanced crystalloids is 5mmol/l, which gets rapidly diluted in extracellular fluid after infusion. This is unlikely to cause an appreciable increase in serum potassium concentrations.


This comprehensive review of literature has shown that 0.9% saline is neither ‘normal’ nor ‘physiological’ and that its high chloride content leads to many pathophysiological changes,

especially with regard to renal function, in both animals and healthy human volunteers. These changes are not seen after infusions with balanced crystalloids. Small randomized clinical trials have shown that the hyperchloremic acidosis induced by saline is also seen in patients, but this did not translate into being a detriment to clinical outcomes when compared with balanced crystalloids, perhaps because of a type II error.

A strong signal is emerging from recent large propensity matched and cohort studies for the adverse effects that large volumes of 0.9% saline have no clinical outcome in surgical and in critically ill patients when compared with balanced crystalloids. The major adverse events are the increased incidence of acute kidney injury and the need for renal replacement therapy caused by 0.9% saline and the resultant hyperchloremia. There is also an increase in other side effects

and resource utilization and pathological hyperchloremia has been associated with increased postoperative mortality.

Balanced crystalloids are not suitable for the resuscitation of patients with alkalosis and hypochloremia (e.g., profound vomiting) and in this situation 0.9% saline may be the solution of choice.

Nevertheless, on the basis of current literature there is adequate evidence to suggest that balanced crystalloids are more physiological than 0.9% saline and cause less detriment to renal

function, with perhaps better clinical outcome. Hence, the article suggests that the article have presented a coherent argument to recommend that chloride-rich crystalloids such as 0.9% saline should be replaced with balanced crystalloids as the mainstays of fluid resuscitation to prevent ‘pre-renal’ acute kidney injury.


1. Evans GH. The abuse of normal salt solution. JAMA 1911; 57: 2126–2127.

2. Reid F, Lobo DN, Williams RN et al. (Ab)normal saline and physiological Hartmann’s solution: a randomized double-blind crossover study. Clin Sci(Lond)     2003; 104: 17–24.

3. Lobo DN. Sir David Cuthbertson medal lecture. Fluid, electrolytes and nutrition: physiological and clinical aspects. Proc Nutr Soc 2004; 63:453–466.

4. Chowdhury AH, Cox EF, Francis ST et al. A randomized, controlled, double-blind crossover study on the effects of 2-L infusions of 0.9% saline and plasma-lyte(R) 148 on renal blood flow velocity and renal cortical tissue perfusion in healthy volunteers. Ann Surg 2012; 256: 18–24.

5. Lobo DN, Stanga Z, Aloysius MM et al. Effect of volume loading with 1 liter intravenous infusions of 0.9% saline, 4% succinylated gelatin (Gelofusine) and 6% hydroxyethyl starch (Voluven) on blood volume and endocrine responses: a randomized, three-way crossover study in healthy volunteers. Crit Care Med 2010; 38: 464–470.

6. Kellum JA, Bellomo R, Kramer DJ et al. Etiology of metabolic acidosis during saline resuscitation in endotoxemia. Shock 1998; 9: 364–368.

7. Stone HH, Fulenwider JT. Renal decapsulation in the prevention of postischemic oliguria. Ann Surg 1977; 186: 343–355.

8. Williams EL, Hildebrand KL, McCormick SA et al. The effect of intravenous lactated Ringer’s solution versus 0.9% sodium chloride solution on serum osmolality in human volunteers. Anesth Analg 1999; 88: 999–1003.

9. Lobo DN, Stanga Z, Simpson JAD et al. Dilution and redistribution effects of rapid 2-litre infusions of 0.9% (w/v) saline and 5% (w/v) dextrose on haematological parameters and serum biochemistry in normal subjects: a double-blind crossover study. Clin Sci (Lond) 2001; 101: 173–179.

10.  Veech RL. The toxic impact of parenteral solutions on the metabolism of cells: a hypothesis for physiological parenteral therapy. Am J Clin Nutr 1986; 44: 519–551.

11.  Goodkin DA, Raja RM, Saven A. Dilutional acidosis. South Med J 1990; 83: 354–355.

12.  Prough DS, Bidani A. Hyperchloremic metabolic acidosis is a predictable consequence of intraoperative infusion of 0.9% saline. Anesthesiology 1999; 90: 1247–1249.

13.  Stewart PA. Modern quantitative acid-base chemistry. Can J Physiol Pharmacol 1983; 61: 1444–1461.

14. Scheingraber S, Rehm M, Sehmisch C et al. Rapid saline infusion produces hyperchloremic acidosis in patients undergoing gynecologic surgery. Anesthesiology 1999; 90: 1265–1270.

15.  McFarlane C, Lee A. A comparison of Plasmalyte 148 and 0.9% saline for intra-operative fluid replacement. Anaesthesia 1994; 49: 779–781.

16.  Miller LR, Waters JH, Provost C. Mechanism of hyperchloremic metabolic acidosis. Anesthesiology 1996; 84: 482–483.

17.  Dorje P, Adhikary G, McLaren ID et al. Dilutional acidosis or altered strong ion difference. Anesthesiology 1997; 87: 1011–1012.

18.  Kotchen TA, Luke RG, Ott et al. Effect of chloride on renin and blood pressure responses to sodium chloride. Ann Intern Med 1983;98:817-822.

19.  Mayberry JC, Welker KJ, Goldman RK et al. Mechanism of acute ascites formation after trauma resuscitation. Arch Surg 2003; 138: 773–776.

20.  Balogh Z, McKinley BA, Cocanour CS et al. Supranormal trauma resuscitation causes more cases of abdominal compartment syndrome. Arch Surg 2003; 138: 637–642.

21.  Schnuriger B, Inaba K, Wu T et al. Crystalloids after primary colon resection and anastomosis at initial trauma laparotomy: excessive volumes are associated with anastomotic leakage. J Trauma 2011; 70: 603–610.

22.  Uray KS, Shah SK, Radhakrishnan RS et al. Sodium hydrogen exchanger as a mediator of hydrostatic edema-induced intestinal contractile dysfunction. Surgery 2011; 149: 114–125.

23.  Ho AM, Karmakar MK, Contardi LH et al. Excessive use of normal saline in managing traumatized patients in shock: a preventable contributor to acidosis. J Trauma 2001; 51: 173–177.

24Guidet B, Soni N, Della Rocca G et al. A balanced view of balanced solutions. Crit Care 2010; 14: 325.

25.  Young JB, Utter GH, Schermer CR et al. Saline versus Plasma-Lyte A in initial resuscitation of trauma patients: a randomized trial. Ann Surg 2014;259:255-     262.