Best Practice & Research Clinical Anaesthesiology 28 (2014) 235e247
Contents lists available at ScienceDirect
Best Practice & Research Clinical Anaesthesiology journal homepage: www.elsevier.com/locate/bean
4
Balanced versus unbalanced salt solutions: What difference does it make? Sheldon Magder, MD Departments of Critical Care, Medicine and Physiology, McGill University Health Centre, 687 Pine Av W, Montreal, Quebec H3A 1A1, Canada
Keywords: electrolytes osmolality chloride sodium acidebase hyperchloremia
Background: The infusion of crystalloid solutions is a fundamental part of the management of critically ill patients. These solutions are used to maintain the balance of water and essential electrolytes and replace losses when patients have limited gastrointestinal intake. They also act as carriers for intravenous infusion of medication and red cells. The most commonly used solution, 0.9% saline, has equal concentrations of Naþ and Cl even though the plasma concentration of Naþ normally is 40 meq/L higher than that of Cl. The use of this fluid thus can produce a hyperchloremic acidosis in a dose-dependent manner, but it is not known whether this has clinical significance. Approach: The first part of this article deals with the significance of Naþ and Cl in normal physiology. This begins with examination of their roles in the regulation of osmolality, acidebase balance, and generation of electrochemical gradients and why the concentration of Cl normally is considerably lower than that of Naþ. The next part deals with how their concentrations are regulated by the gastrointestinal tract and kidney. Based on the physiology, it would seem that solutions in which the concentration of Naþ is “balanced” by a substance other than Cl would be advantageous. The final part examines the evidence to support that point. Conclusions: There are strong observational data that support the notion that avoiding an elevated Cl concentration or using fluids that reduce the rise in Cl reduces renal dysfunction, infections, and possibly even mortality. However, observational studies only can indicate an association and cannot indicate causality. Unfortunately, randomized trials to date are far too limited to address this crucial issue. What is clear is that appropriate randomized trials will require very large populations. It also is not known
E-mail addresses: [email protected], [email protected].
http://dx.doi.org/10.1016/j.bpa.2014.07.001 1521-6896/© 2014 Elsevier Ltd. All rights reserved.
236
S. Magder / Best Practice & Research Clinical Anaesthesiology 28 (2014) 235e247
whether the important variable is the concentration of Cl, the difference in concentrations of Naþ and Cl, or the total body mass of Cl. © 2014 Elsevier Ltd. All rights reserved.
Introduction Single-atom electrolytes such as sodium, potassium, and chloride play a unique role in biology [1e4]. Because they are not metabolized, their quantity in the body must be regulated through intake and excretion. They are primarily dissolved in water although there are exceptions, such as the formation of boney structures by calcium and the interaction of calcium ion with the many calciumbinding proteins. Sodium ion (Naþ), too, can be sequestered by glycosaminoglycans in the skin in a process that is tightly regulated by monocyte phagocytic cells and vascular endothelial growth factor C (VEGF-C) [5,6]. However, these bound ions do not contribute to the osmotic activity of solutions. Electrolytes in solutions play three crucial biological roles. They are major determinants of the osmolality of the extracellular and intracellular compartments, which is essential for the maintenance of constant cell volume relative to the external environment [4]. Second, gradients in strong electrolytes across cell membranes create a transmembrane potential energy that can be used to move charged substances across the walls of cells and to regulate intracellular processes [4]. Third, strong electrolytes are important regulators of hydrogen ion (Hþ) concentration, that is, pH [7]. I will first review the physiological significance of electrolytes in general and chloride (Cl) in particular and then discuss the empiric evidence for the clinical use of intravenous solutions in which the concentration of Cl is less than that of Naþ. Some of these issues have been well discussed in two recent reviews, one especially focused on specific issues related to Cl [8] and the other on the nature of substitutes for Cl [9]. Osmolality Water is the essential solvent of living organisms and the volume of water in cells needs to be regulated to maintain normal cell function. Water does not flow freely, but rather follows along concentration gradients. Accordingly, water volume is regulated by regulating the concentrations of solutes. Since single-atom electrolytes are not metabolized, they provide ideal substances for regulating water distribution. Life evolved out of the sea in which the two most common elements (not including oxygen and hydrogen ion) are Cl and Naþ. Thus, it is not surprising that these two electrolytes which dominated the extracellular environment of early organisms still dominate the extracellular environment of multicellular organisms. Typical NaCl concentration of seawater is in the range of 3%, whereas that of extracellular space is 110 mmol/L based on the maximum [Cl] on postoperative days 1e5, versus those without hyperchloremia. Hyperchloremia was present in 22% of patients and thus common. Patients with hyperchloremia had an increased risk of mortality at 30 days (3.0% vs. 1.9%), longer hospital stay, and more renal dysfunction. In a retrospective study, it cannot be ruled out that hyperchloremia was just a marker of a greater severity of illness. For example, the longer hospital stay could have been a consequence of giving more Cl, but also because the risk of becoming hyperchloremic was greater because there was more time to develop it. The study also did not address the all-important question as to why [Cl] was increased in one group since by design they had the same propensity for an elevated [Cl]. Was this due to the type of fluid given or due to greater use of fluid which could have been a risk in and of itself? However, this study, too, supports the argument that there is a need for further investigation of the clinical impact of hyperchloremia and, importantly, whether it increases morbidity and mortality. The third observational study was by Shaw et al. who used a large US automated hospital claims database to perform a retrospective cohort study of almost 500,000 patients who had undergone abdominal surgery [40]. The primary hypothesis was that in comparison to a balanced crystalloid solution, 0.9% saline use in major abdominal surgery increased major morbidity, which included respiratory failure, cardiac decompensation, major gastrointestinal dysfunction, infectious complications, and acute renal failure. They only included patients who were at a risk of potential need for blood transfusion, with the exception of traumatic injuries, for they wanted to exclude calcium-containing solutions. The balanced crystalloid solution was either Plasma-Lyte A or Plasma-Lyte 148. Out of the large number of patients in the database, 30,994 received 0.9% saline and 926 received a balanced salt solution. Importantly, balanced salt solution recipients were less likely to be minorities, to be admitted via the emergency department, to be in a major teaching hospital, to have Medicare as the primary payer, and were more likely to have commercial insurance indicating that they were a more advantaged population. These differences were adjusted with use of a propensity score. Overall, the odds of developing major infection were significantly lower in patients receiving the balanced salt solutions. There was no difference in mortality between the groups but the baseline mortality was low. Directional changes in the use of dialysis, use of blood transfusions, respiratory failure, major hemorrhage, and resource utilization favored the balanced salt solution. Thus, this study, too, supports an outcome benefit for use of balanced salt solutions. However, only 2.7% of patients received the balanced solution and only 0.3% met study criteria. Thus, despite the use of the propensity score there were likely still unobserved covariates. The higher rate of major hemorrhage observed by Shaw et al. [40]. is supported by a small but detailed comparison of the coagulation profile with the use of thromboelastography in a randomized trial of lactated Ringer's, 6% Hetastarch in a balanced salt solution, and 6% Hetastarch in 0.9% saline [41]. The 6% starch in the 0.9% saline group had a hypocoagulative profile, the lactated Ringer's group a hypercoagulative profile, and the 6% starch group in a balanced salt solution was in the middle. Synthesis From an evolutionary and physiological perspective, there is little doubt that serum chloride concentrations much above 100 are abnormal. The question remains, do they have a significant impact? Animal studies indicate harm under septic conditions but it is less clear that there is a problem in nonseptic animals [42e44]. Three large observational studies indicate greater morbidity and even mortality in one study, but this only indicates an association and not causality. Unfortunately, the randomized trials are far too insufficient to make any statement of causality, even with a meta-analysis. A further fundamental question arises as to whether it is the total burden of Cl that is important or is it the concentration in the serum and interstitial space that counts. This has important implications for
S. Magder / Best Practice & Research Clinical Anaesthesiology 28 (2014) 235e247
245
therapy. If it is the total burden of excess Cl and overall fluid balance that is important then this can be dealt with by more restrictive fluid policies. It is apparent that a lot more Naþ is being given than is often appreciated [45], and it is likely that the bulk of this Naþ is accompanied by an equal amount of Cl. If the issue is the bulk of Cl, then the use of hypotonic saline solutions (i.e., 0.45%) might also be helpful. However, this will inevitably result in some lowering of serum [Naþ] and some argue that even small decreases in [Naþ] worsen outcome [46e49]. Only large randomized trials will be able to answer these questions. It is unlikely that mortality will be a useful end point for standard clinical practice because these fluids most often are used in patients with low mortalities. From the observational studies, renal failure, infections, and perhaps functional status after surgery might be appropriate end points. A large randomized cluster pilot trial is currently under way and will hopefully soon provide some important information on how to move forward on this central issue in the management of perioperative and critically ill patients (https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id¼365460). Conflict of interest The author has no conflicts of interest to report related to this manuscript. There were no outside funding sources or sponsor. Practice points When administering electrolyte solutions, consideration should be given to total body accumulation and not just concentration. Solutions with a high chloride concentration add a stress to excretory systems. Solutions with high chloride should be expected to produce a metabolic acidosis and increase base excess; one must be careful not to overreact to this frequent cause of acidemia by thinking that it is due to inadequate tissue perfusion. Observational data suggest that hyperchloremia is dose-dependently associated with renal dysfunction, bowel dysfunction, and increased risk of bleeding. One study even showed a relationship with mortality. Current randomized trials are inadequate to determine whether hyperchloremia caused morbidity and mortality or are simply associated.
Research agenda There is a great need for large randomized trials to determine the clinical significance of the use of fluids with a chloride concentration similar to that of normal plasma. In initial studies, an important end point that is feasible to achieve is potential reduction in the development of renal dysfunction with use of a reduced chloride solution compared to 0.9% saline. Determining that reduced chloride solutions reduce mortality compared to 0.9% saline will require very large trials, perhaps >20,000 subjects. It will be essential in future trials to account for the use of each type of fluid during the whole hospital stay and not just the immediate perioperative period. Trials should try to differentiate the total accumulation of sodium and chloride as well as the change in serum concentrations of these elements. Patients with inflammatory conditions should be studied separately for the animal data suggest that the impact of excess chloride is greater in septic animals than controls.
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S. Magder / Best Practice & Research Clinical Anaesthesiology 28 (2014) 235e247
References [1] Else PL, Turner N, Hulbert AJ. The evolution of endothermy: role for membranes and molecular activity. Physiol Biochem Zool 2004 Nov;77(6):950e8. [2] Wilson TH, Maloney PC. Speculations on the evolution of ion transport mechanisms. Fed Proc 1976 Aug;35(10):2174e9. [3] Wilson TH, Lin EC. Evolution of membrane bioenergetics. J Supramol Struct 1980;13(4):421e46. [4] Brett CL, Donowitz M, Rao R. Evolutionary origins of eukaryotic sodium/proton exchangers. Am J Physiol Cell Physiol 2005 Feb;288(2):C223e39. [5] Titze J, Muller DN, Luft FC. Taking another “look” at sodium. Can J Cardiol 2014 May;30(5):473e5. [6] Titze J, Dahlmann A, Lerchl K, et al. Spooky sodium balance. Kidney Int 2014 Apr;85(4):759e67. [7] Stewart PA. How to understand acidebase. A quantitative acid-base primer for biology and medicine. New York: Elsevier North Holland; 1981. *[8] Yunos NM, Bellomo R, Story D, et al. Bench-to-bedside review: chloride in critical illness. Crit Care 2010;14(4):226. *[9] Morgan TJ. The ideal crystalloid e what is 'balanced'? Curr Opin Crit Care 2013 Aug;19(4):299e307. [10] Pitts RF. Mechanisms of reabsorption and excretion of ions and water. Physiology of the kidney and body fluids: an introductory text. 2nd ed. Chicago: Year Book Medical Publishers Incorporated; 1968. p. 94e128. [11] Patrick ML, Wood CM. Ion and acid-base regulaton in the freshwater mummichog (Fundulus heteroclitus): a departure from the standard model for freshwater teleosts. Comp Biochem Physiol Part A 1999;122:445e56. [12] Parks SK, Tresguerres M, Goss GG. Theoretical considerations underlying Na(þ) uptake mechanisms in freshwater fishes. Comp Biochem Physiol C Toxicol Pharmacol 2008 Nov;148(4):411e8. [13] Wood CM, Laurent P. Naþ versus Cl transport in the intact killifish after rapid salinity transfer. Biochim Biophys Acta 2003 Dec 30;1618(2):106e19. [14] Stewart PA. Modern quantitative acid-base chemistry. Can J Physiol Pharmacol 1983 Dec;61(12):1444e61. *[15] Kellum JA, Elbers PW. Peter Stewart's textbook of acidebase. 2nd ed. 2009. www.acidbase.org. [16] Kellum JA, Kramer DJ, Pinsky MR. Strong ion gap: a methodology for exploring unexplained anions. J Crit Care 1995 Jan 1; 10(2):51e5. [17] Gilfix BM, Bique M, Magder SA. A physiological approach to the analysis of acid-base balance in the clinical setting. J Crit Care 1993;8:187e97. [18] Jones NL. A quantitative physiochemical approach to acid-base physiology. Clin Biochem 1990;23:189e95. [19] Roos A, Boron WF. Intracellular pH. Physiol Rev 1981 Jan 1;61(2):296e434. [20] Magder S. Intracellular [Hþ]. In: Kellum JA, Elbers PW, editors. Stewart's textbook of acid-base; 2009. p. 247e65. [21] Uchida S. Physiological role of CLCeK1 chloride channel in the kidney. Nephrol Dial Transpl 2000;15(Suppl. 6):14e5. [22] Uchida S. In vivo role of CLC chloride channels in the kidney. Am J Physiol Ren Physiol 2000 Nov;279(5):F802e8. *[23] Barrett KE, Keely SJ. Chloride secretion by the intestinal epithelium: molecular basis and regulatory aspects. Annu Rev Physiol 2000;62:535e72. [24] Kato A, Romero MF. Regulation of electroneutral NaCl absorption by the small intestine. Annu Rev Physiol 2011;73: 261e81. *[25] Yunos NM, Bellomo R, Hegarty C, et al. Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. JAMA 2012 Oct 17;308(15):1566e72. [26] Keely SJ, Barrett KE. Regulation of chloride secretion. Novel pathways and messengers. Ann N Y Acad Sci 2000;915:67e76. [27] Hamilton DL, Roe WE. Electrolyte levels and net fluid and electrolyte movements in the gastrointestinal tract of weanling swine. Can J Comp Med 1977 Jul;41(3):241e50. *[28] Edwards JC. Chloride transport. Compr Physiol 2012 Apr;2(2):1061e92. [29] Ring T, Frische S, Nielsen S. Clinical review: renal tubular acidosisea physicochemical approach. Crit Care 2005;9(6): 573e80. [30] Pitts RF. Renal regulation of acid-base balance. In: F.Pitts Robert, editor. Physiology of the kidney and body fluids. 2nd ed. Chicago: Year Book Medical Publishers Incorporated; 1968. p. 179e212. [31] Sartorius OW, Roemmelt JC, Pitts RF. The renal regulation of acid-base balance in man; the nature of the renal compensations in ammonium chloride acidosis. J Clin Invest 1949 May;28(3):423e39. [32] Burdett E, Dushianthan A, nett-Guerrero E, et al. Perioperative buffered versus non-buffered fluid administration for surgery in adults. Cochrane Database Syst Rev 2012;12. CD004089. [33] Base EM, Standl T, Lassnigg A, et al. Efficacy and safety of hydroxyethyl starch 6% 130/0.4 in a balanced electrolyte solution (volulyte) during cardiac surgery. J Cardiothorac Vasc Anesth 2011 Jun;25(3):407e14. [34] Pagano PJ, Chanock SJ, Siwik DA, et al. Angiotensin II induces p67phox mRNA expression and NADPH oxidase superoxide generation in rabbit aortic adventitial fibroblasts. Hypertension 1998 Jan 1;32:331e7. [35] Waters JH, Gottlieb A, Schoenwald P, et al. Normal saline versus lactated Ringer's solution for intraoperative fluid management in patients undergoing abdominal aortic aneurysm repair: an outcome study. Anesth Analg 2001 Oct;93(4): 817e22. [36] O'Malley CM, Frumento RJ, Hardy MA, et al. A randomized, double-blind comparison of lactated Ringer's solution and 0. 9% NaCl during renal transplantation. Anesth Analg 2005 May;100(5):1518e24 [table]. [37] Hadimioglu N, Saadawy I, Saglam T, et al. The effect of different crystalloid solutions on acid-base balance and early kidney function after kidney transplantation. Anesth Analg 2008 Jul;107(1):264e9. [38] Waikar SS, Winkelmayer WC. Saving the kidneys by sparing intravenous chloride? JAMA 2012 Oct 17;308(15):1583e5. *[39] McCluskey SA, Karkouti K, Wijeysundera D, et al. Hyperchloremia after noncardiac surgery is independently associated with increased morbidity and mortality: a propensity-matched cohort study. Anesth Analg 2013 Aug;117(2):412e21. *[40] 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 2012 May;255(5):821e9. [41] Martin G, Bennett-Guerrero E, Wakeline H, et al. A prospective, randomized comparison of thromboelastographic coagulation profile in patients receiving tactated Ringer's solution, 6% hetastarch in a balanced-saline vehicle, or 6% hetastarch in saline during major surgery. Cardiothorac Vasc Anesth 2002 Jan 1;16(4):441e6.
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*[42] 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 Apr;42(4):e270e8. *[43] Kellum JA. Fluid resuscitation and hyperchloremic acidosis in experimental sepsis: improved short-term survival and acid-base balance with hextend compared with saline. Crit Care Med 2002 Jan 1;30(2):300e5. [44] Noritomi DT, Pereira AJ, Bugano DD, et al. Impact of plasma-lyte pH 7.4 on acid-base status and hemodynamics in a model of controlled hemorrhagic shock. Clin Sao Paulo 2011;66(11):1969e74. [45] Bihari S, Ou J, Holt AW, et al. Inadvertent sodium loading in critically ill patients. Crit Care Resusc 2012 Mar;14(1):33e7. [46] Stelfox HT, Ahmed SB, Zygun D, et al. Characterization of intensive care unit acquired hyponatremia and hypernatremia following cardiac surgery. Can J Anaesth 2010 Jul;57(7):650e8. [47] Stelfox HT, Ahmed SB, Khandwala F, et al. The epidemiology of intensive care unit-acquired hyponatraemia and hypernatraemia in medical-surgical intensive care units. Crit Care 2008;12(6):R162. [48] Funk GC, Lindner G, Druml W, et al. Incidence and prognosis of dysnatremias present on ICU admission. Intensive Care Med 2010 Feb;36(2):304e11. [49] Padhi R, Panda BN, Jagati S, et al. Hyponatremia in critically ill patients. Indian J Crit Care Med 2014 Feb;18(2):83e7.
Contents lists available at ScienceDirect
Best Practice & Research Clinical Anaesthesiology journal homepage: www.elsevier.com/locate/bean
4
Balanced versus unbalanced salt solutions: What difference does it make? Sheldon Magder, MD Departments of Critical Care, Medicine and Physiology, McGill University Health Centre, 687 Pine Av W, Montreal, Quebec H3A 1A1, Canada
Keywords: electrolytes osmolality chloride sodium acidebase hyperchloremia
Background: The infusion of crystalloid solutions is a fundamental part of the management of critically ill patients. These solutions are used to maintain the balance of water and essential electrolytes and replace losses when patients have limited gastrointestinal intake. They also act as carriers for intravenous infusion of medication and red cells. The most commonly used solution, 0.9% saline, has equal concentrations of Naþ and Cl even though the plasma concentration of Naþ normally is 40 meq/L higher than that of Cl. The use of this fluid thus can produce a hyperchloremic acidosis in a dose-dependent manner, but it is not known whether this has clinical significance. Approach: The first part of this article deals with the significance of Naþ and Cl in normal physiology. This begins with examination of their roles in the regulation of osmolality, acidebase balance, and generation of electrochemical gradients and why the concentration of Cl normally is considerably lower than that of Naþ. The next part deals with how their concentrations are regulated by the gastrointestinal tract and kidney. Based on the physiology, it would seem that solutions in which the concentration of Naþ is “balanced” by a substance other than Cl would be advantageous. The final part examines the evidence to support that point. Conclusions: There are strong observational data that support the notion that avoiding an elevated Cl concentration or using fluids that reduce the rise in Cl reduces renal dysfunction, infections, and possibly even mortality. However, observational studies only can indicate an association and cannot indicate causality. Unfortunately, randomized trials to date are far too limited to address this crucial issue. What is clear is that appropriate randomized trials will require very large populations. It also is not known
E-mail addresses: [email protected], [email protected].
http://dx.doi.org/10.1016/j.bpa.2014.07.001 1521-6896/© 2014 Elsevier Ltd. All rights reserved.
236
S. Magder / Best Practice & Research Clinical Anaesthesiology 28 (2014) 235e247
whether the important variable is the concentration of Cl, the difference in concentrations of Naþ and Cl, or the total body mass of Cl. © 2014 Elsevier Ltd. All rights reserved.
Introduction Single-atom electrolytes such as sodium, potassium, and chloride play a unique role in biology [1e4]. Because they are not metabolized, their quantity in the body must be regulated through intake and excretion. They are primarily dissolved in water although there are exceptions, such as the formation of boney structures by calcium and the interaction of calcium ion with the many calciumbinding proteins. Sodium ion (Naþ), too, can be sequestered by glycosaminoglycans in the skin in a process that is tightly regulated by monocyte phagocytic cells and vascular endothelial growth factor C (VEGF-C) [5,6]. However, these bound ions do not contribute to the osmotic activity of solutions. Electrolytes in solutions play three crucial biological roles. They are major determinants of the osmolality of the extracellular and intracellular compartments, which is essential for the maintenance of constant cell volume relative to the external environment [4]. Second, gradients in strong electrolytes across cell membranes create a transmembrane potential energy that can be used to move charged substances across the walls of cells and to regulate intracellular processes [4]. Third, strong electrolytes are important regulators of hydrogen ion (Hþ) concentration, that is, pH [7]. I will first review the physiological significance of electrolytes in general and chloride (Cl) in particular and then discuss the empiric evidence for the clinical use of intravenous solutions in which the concentration of Cl is less than that of Naþ. Some of these issues have been well discussed in two recent reviews, one especially focused on specific issues related to Cl [8] and the other on the nature of substitutes for Cl [9]. Osmolality Water is the essential solvent of living organisms and the volume of water in cells needs to be regulated to maintain normal cell function. Water does not flow freely, but rather follows along concentration gradients. Accordingly, water volume is regulated by regulating the concentrations of solutes. Since single-atom electrolytes are not metabolized, they provide ideal substances for regulating water distribution. Life evolved out of the sea in which the two most common elements (not including oxygen and hydrogen ion) are Cl and Naþ. Thus, it is not surprising that these two electrolytes which dominated the extracellular environment of early organisms still dominate the extracellular environment of multicellular organisms. Typical NaCl concentration of seawater is in the range of 3%, whereas that of extracellular space is 110 mmol/L based on the maximum [Cl] on postoperative days 1e5, versus those without hyperchloremia. Hyperchloremia was present in 22% of patients and thus common. Patients with hyperchloremia had an increased risk of mortality at 30 days (3.0% vs. 1.9%), longer hospital stay, and more renal dysfunction. In a retrospective study, it cannot be ruled out that hyperchloremia was just a marker of a greater severity of illness. For example, the longer hospital stay could have been a consequence of giving more Cl, but also because the risk of becoming hyperchloremic was greater because there was more time to develop it. The study also did not address the all-important question as to why [Cl] was increased in one group since by design they had the same propensity for an elevated [Cl]. Was this due to the type of fluid given or due to greater use of fluid which could have been a risk in and of itself? However, this study, too, supports the argument that there is a need for further investigation of the clinical impact of hyperchloremia and, importantly, whether it increases morbidity and mortality. The third observational study was by Shaw et al. who used a large US automated hospital claims database to perform a retrospective cohort study of almost 500,000 patients who had undergone abdominal surgery [40]. The primary hypothesis was that in comparison to a balanced crystalloid solution, 0.9% saline use in major abdominal surgery increased major morbidity, which included respiratory failure, cardiac decompensation, major gastrointestinal dysfunction, infectious complications, and acute renal failure. They only included patients who were at a risk of potential need for blood transfusion, with the exception of traumatic injuries, for they wanted to exclude calcium-containing solutions. The balanced crystalloid solution was either Plasma-Lyte A or Plasma-Lyte 148. Out of the large number of patients in the database, 30,994 received 0.9% saline and 926 received a balanced salt solution. Importantly, balanced salt solution recipients were less likely to be minorities, to be admitted via the emergency department, to be in a major teaching hospital, to have Medicare as the primary payer, and were more likely to have commercial insurance indicating that they were a more advantaged population. These differences were adjusted with use of a propensity score. Overall, the odds of developing major infection were significantly lower in patients receiving the balanced salt solutions. There was no difference in mortality between the groups but the baseline mortality was low. Directional changes in the use of dialysis, use of blood transfusions, respiratory failure, major hemorrhage, and resource utilization favored the balanced salt solution. Thus, this study, too, supports an outcome benefit for use of balanced salt solutions. However, only 2.7% of patients received the balanced solution and only 0.3% met study criteria. Thus, despite the use of the propensity score there were likely still unobserved covariates. The higher rate of major hemorrhage observed by Shaw et al. [40]. is supported by a small but detailed comparison of the coagulation profile with the use of thromboelastography in a randomized trial of lactated Ringer's, 6% Hetastarch in a balanced salt solution, and 6% Hetastarch in 0.9% saline [41]. The 6% starch in the 0.9% saline group had a hypocoagulative profile, the lactated Ringer's group a hypercoagulative profile, and the 6% starch group in a balanced salt solution was in the middle. Synthesis From an evolutionary and physiological perspective, there is little doubt that serum chloride concentrations much above 100 are abnormal. The question remains, do they have a significant impact? Animal studies indicate harm under septic conditions but it is less clear that there is a problem in nonseptic animals [42e44]. Three large observational studies indicate greater morbidity and even mortality in one study, but this only indicates an association and not causality. Unfortunately, the randomized trials are far too insufficient to make any statement of causality, even with a meta-analysis. A further fundamental question arises as to whether it is the total burden of Cl that is important or is it the concentration in the serum and interstitial space that counts. This has important implications for
S. Magder / Best Practice & Research Clinical Anaesthesiology 28 (2014) 235e247
245
therapy. If it is the total burden of excess Cl and overall fluid balance that is important then this can be dealt with by more restrictive fluid policies. It is apparent that a lot more Naþ is being given than is often appreciated [45], and it is likely that the bulk of this Naþ is accompanied by an equal amount of Cl. If the issue is the bulk of Cl, then the use of hypotonic saline solutions (i.e., 0.45%) might also be helpful. However, this will inevitably result in some lowering of serum [Naþ] and some argue that even small decreases in [Naþ] worsen outcome [46e49]. Only large randomized trials will be able to answer these questions. It is unlikely that mortality will be a useful end point for standard clinical practice because these fluids most often are used in patients with low mortalities. From the observational studies, renal failure, infections, and perhaps functional status after surgery might be appropriate end points. A large randomized cluster pilot trial is currently under way and will hopefully soon provide some important information on how to move forward on this central issue in the management of perioperative and critically ill patients (https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id¼365460). Conflict of interest The author has no conflicts of interest to report related to this manuscript. There were no outside funding sources or sponsor. Practice points When administering electrolyte solutions, consideration should be given to total body accumulation and not just concentration. Solutions with a high chloride concentration add a stress to excretory systems. Solutions with high chloride should be expected to produce a metabolic acidosis and increase base excess; one must be careful not to overreact to this frequent cause of acidemia by thinking that it is due to inadequate tissue perfusion. Observational data suggest that hyperchloremia is dose-dependently associated with renal dysfunction, bowel dysfunction, and increased risk of bleeding. One study even showed a relationship with mortality. Current randomized trials are inadequate to determine whether hyperchloremia caused morbidity and mortality or are simply associated.
Research agenda There is a great need for large randomized trials to determine the clinical significance of the use of fluids with a chloride concentration similar to that of normal plasma. In initial studies, an important end point that is feasible to achieve is potential reduction in the development of renal dysfunction with use of a reduced chloride solution compared to 0.9% saline. Determining that reduced chloride solutions reduce mortality compared to 0.9% saline will require very large trials, perhaps >20,000 subjects. It will be essential in future trials to account for the use of each type of fluid during the whole hospital stay and not just the immediate perioperative period. Trials should try to differentiate the total accumulation of sodium and chloride as well as the change in serum concentrations of these elements. Patients with inflammatory conditions should be studied separately for the animal data suggest that the impact of excess chloride is greater in septic animals than controls.
246
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References [1] Else PL, Turner N, Hulbert AJ. The evolution of endothermy: role for membranes and molecular activity. Physiol Biochem Zool 2004 Nov;77(6):950e8. [2] Wilson TH, Maloney PC. Speculations on the evolution of ion transport mechanisms. Fed Proc 1976 Aug;35(10):2174e9. [3] Wilson TH, Lin EC. Evolution of membrane bioenergetics. J Supramol Struct 1980;13(4):421e46. [4] Brett CL, Donowitz M, Rao R. Evolutionary origins of eukaryotic sodium/proton exchangers. Am J Physiol Cell Physiol 2005 Feb;288(2):C223e39. [5] Titze J, Muller DN, Luft FC. Taking another “look” at sodium. Can J Cardiol 2014 May;30(5):473e5. [6] Titze J, Dahlmann A, Lerchl K, et al. Spooky sodium balance. Kidney Int 2014 Apr;85(4):759e67. [7] Stewart PA. How to understand acidebase. A quantitative acid-base primer for biology and medicine. New York: Elsevier North Holland; 1981. *[8] Yunos NM, Bellomo R, Story D, et al. Bench-to-bedside review: chloride in critical illness. 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