) ( TATM 2003;5(4):424-430 Hyperchloremic Acidosis: Pathophysiology and Clinical Impact S UMMARY Hyperchloremic acidosis is a predictable consequence of normal EDWARD BURDETT, MA, MB BS, MRCP, 1 ANTONY M. ROCHE, MB ChB, FRCA, MMed (Anaes), 1 MICHAEL G. MYTHEN, MB BS, FRCA, MD 2 1 RESEARCH FELLOW UCL CENTRE FOR ANAESTHESIA MIDDLESEX HOSPITAL 2 PORTEX PROFESSOR OF ANAESTHESIA AND CRITICAL CARE UNIVERSITY COLLEGE LONDON HEAD OF THE PORTEX ANAESTHESIA INTENSIVE CARE AND RESPIRATORY UNIT INSTITUTE OF CHILD HEALTH UCL CENTRE FOR ANAESTHESIA MIDDLESEX HOSPITAL LONDON, UNITED KINGDOM saline-based fluid administration.the theoretical basis for this is easily understood using Stewart s model of acid-base homeostasis. Data are emerging which describe the consequences of hyperchloremic acidosis in the surgical population. Hyperchloremic acidosis Fluid resuscitation Colloids Crystalloids Volume replacement ( Page 424 )
Hyperchloremic acidosis is a well-recognized entity, pertinent to many areas of clinical practice. It is observed in diabetic ketoacidosis, and in some forms of renal tubular acidosis; 1 it is also an important consequence of large-volume administration of some intravenous fluids. 2 Most hospital clinicians routinely administer large volumes of intravenous fluids, to support the circulation during significant fluid shifts. Normal saline (0.9% sodium chloride solution), and colloids suspended in normal saline, are often infused because they are easily available, and are isotonic with plasma. Their nonphysiological levels of chloride and lack of buffer cause metabolic acidosis. 2 The term dilutional acidosis has been used to describe this effect; the term implying that plasma expansion and dilutional reduction of plasma bicarbonate are the underlying mechanisms. This is not the whole story. More elegant, the Stewart model emphasizes the importance of hyperchloremia in reducing the strong-ion difference, with the consequent impairment of homeostatic mechanisms, including coagulation abnormalities and renal hypoperfusion. Pathophysiology Debate continues about the exact mechanism for acid-base homeostasis in humans. The two main camps in the dispute follow either the original Henderson-Hasselbalch and Siggaard-Andersen line of thinking, or the more recent Stewart approach to acid-base physiology. Below, a brief overview of the original approach will be covered, followed by a more in depth view of the Stewart theory and its modifications. ph is a logarithmic scale of the reciprocal of H + ion concentration. Both respiratory (e.g., CO 2 tension) and metabolic factors (e.g., lactic acid) affect H +. 3 Classically, decisions based on blood gas analysis are based on the apparent ph, in relation to the pco 2 (carbon dioxide tension), further assisted by the bicarbonate concentration (HCO 3- ) and base excess variables, can assess whether derangements are likely to be metabolic or respiratory in origin. The first principle applied to acid-base physiology is as follows: if the pco 2 rises, so too does the eventual H + ion concentration. This is due to the formation of carbonic acid by the combination of water and carbon dioxide. Carbonic acid then dissociates to form H + and HCO 3-. It is a cornerstone to understanding the way in which the body creates and handles acid. H 2 0 + CO 2 < > H 2 CO 2 < > H + - + HCO 3 This was modified, originally by Henderson, then further by Hasselbalch, into: The Henderson-Hasselbalch Equation ph = pk + log (HCO 3- /pco 2 x 0.225) Note units of measurement: HCO 3- = mmol/l pco 2 = kpa From this, one can observe that any increase in pco 2 or decrease in bicarbonate would lead to a reduction in the ph, likely to be respiratory and metabolic acidosis respectively (depending on the primary disturbance and compensation). Conversely, when these variables display a rise in bicarbonate or a reduction in pco 2, one would find metabolic and respiratory alkaloses, respectively. Base Excess The use of base excess was introduced to assist the quantification of the metabolic components of acid-base disturbances. The most notable developments in quantifying these were by Siggaard- Andersen and Severinghaus. 3,4 Base excess quantifies the severity of metabolic acidosis or alkalosis, and is defined as the amount of base (or acid) that must be added to a sample of whole blood in vitro in order to restore the ph of the sample to 7.40 (keeping the pco 2 constant at 5.3 kpa). 5 The value ranges from 30 to +30 mmol/l, with the normal range being 2 to +2 mmol/l. Its measurement requires only a small venous or arterial blood sample, and it is widely used in clinical practice. It has been established as an accurate indicator of the metabolic component to any acid-base disturbance. Indeed, base excess derangement is an independent predictor of mortality in critically ill patients. 6 Traditionally, it was suggested that ph is kept within a tight range by the body s ability to buffer acid, using bicarbonate, plasma proteins and hemoglobin. Physicochemical Theory How does a change in chloride concentration bring about such profound alteration in acid-base equilibrium? The answer is not obvious when analyzed using the Henderson-Hasselbalch equation. However, it can be explained by Stewart's method of analysis of quantitative acid and base chemistry. Stewart turned the whole world of acid-base homeostasis upside down in the late 1970s and early 1980s, when he published his mathematical theory of the body s ability to regulate acid and base content. 7,8 Stewart's approach shows the way to understanding plasma as a physico-chemical system, and provides a basis for quantitative analysis and rational manipulation of acid-base state, in vivo and in vitro. 9 The Stewart theory rests on two important physicochemical principles, which describe the behavior of ions in fluids. Firstly, all positively charged and all negatively charged ions in a solution must always be equal, the law of electro-neutrality. What this implies is that the sum of all positively and all negatively charged ions in a solution must equal zero. The second principle is the conservation of mass, which means that the total amount of a substance remains constant, unless it is added to or generated, or ( Page 425 )
Table 1. Electrolyte Hartmann s Solution 0.9% NaCl Plasma Concentration Sodium 131 154 135-146 Chloride 111 154 98-102 Potassium 5 0 3.5-5.0 Calcium 2 0 2.20-2.67 Magnesium 0 0 0.7-1.1 Phosphate 0 0 0.8-1.5 Bicarbonate/lactate 27 0 22-30 All values quoted are electrolyte concentration in mmol/l. removed or destroyed. Furthermore, the body is composed of 65-70% water, thereby providing an inexhaustible amount of H + and OH - for bodily functions and processes. 7-8,10 According to Stewart, three main factors determine H + ion concentration, namely carbon dioxide, weak acids in the body, and the strong ion difference. As examined above, carbon dioxide directly affects H + concentration by the mechanism of increasing or reducing carbonic acid production, and thereby its dissociation into H + and HCO 3-. Complicating one s understanding slightly is the body s inexhaustible supply of H + and OH -. Due to its dynamic nature, the dissociation of water into these ions is also largely dictated by CO 2 and the strong ions. This plays a further role in reactions observed in maintaining the acid-base and more importantly electrochemical neutrality. Stewart s second principle is that of weak acids (or weak electrolytes), which are acids or electrolytes in the body that are only partially ionized at ph levels encountered physiologically, such as plasma proteins like albumin, and phosphates. These play a role in the mathematical model Stewart originally described, along with CO 2 and the Strong Ion Difference (SID, described below), and hence the final H + ion concentration. As the total weak acid drops, in isolation, an increase can be expected in the ph. Even though weak acids are important in acid-base regulation, and noted in certain units, they are not commonly used for clinical interpretations of acid-base derangements. The observation that the only clinically relevant weak acids are inorganic phosphate and albumin was later confirmed by Fencl s group, noting that a charge of approximately 12 meq/l can be attributed to these acids, and that globulins play a negligible role. 11 Probably the most interesting discovery in Stewart s theory was that of the Strong Ion Difference (SID). This principle rests on the chemistry of strong ions in the body (or aqueous solutions). Strong ions (or electrolytes) are almost completely ionized in aqueous solutions. The most notable of the strong ions are Na+, K +, Ca 2+, Mg 2+, Cl -, and Lactate. 7 At this stage, it is prudent to remember the basis of the physicochemical approach, which is firstly that of electrochemical neutrality being maintained at all times, and secondly the conservation of mass. In plasma, when all the strong ions mentioned above, both anions and cations, are added together, the result does not end up as zero. This accounts for what is known as the strong ion difference. Weak acids, for example, have not been taken into account in the equation. Stewart originally described the equation as follows: (Na + + K + ) (Cl - + Lactate) = SID The SID is determined by the charge of the ions as well as the quantity; in healthy volunteers it usually equals approximately 40-49 milliequivalents per liter, and can therefore be affected by changes in plasma electrolyte concentrations. This SID, which is an independent mechanism of acid-base regulation, determines (along with CO 2 and weak acids), what the plasma hydrogen ion concentration will be. The electrochemical forces generated by this SID determine water dissociation, hence H + ion concentration required to balance plasma ionic charges. The net result always has to be a plasma ionic charge equal to zero (electrochemical neutrality). As one can see, H + is not the driving force of the reaction; it is the dependent variable, along with OH - to a much lesser degree. To continually balance these electrochemical forces, a decrease in H + concentration is observed with increases in the SID, and H + concentration increases as the SID decreases. 8,12 An increased plasma chloride ion concentration relative to sodium and potassium concentrations will produce a smaller plasma strong ion difference, leading to an increased hydrogen ion concentration, and therefore acidosis. Stewart's approach relates to how sodium bicarbonate corrects the metabolic acidosis. The metabolic acidosis may be corrected not so much by its bicarbonate content but by its sodium content. The increased sodium concentration resulting from bicarbonate therapy corrects the reduced SID toward normal, thereby correcting the acidosis. According to Stewart, bicarbonate is a dependent variable and therefore cannot bring about a change in another dependent variable like hydrogen ion concentration. More recently, the SID equation was expanded to include Ca 2 + and Mg 2+, to account for further plasma ions. 10,13 (Na + + K + + Ca 2+ + Mg 2+ ) (Cl - + Lactate) = SID apparent Many approaches to the management of critical care acid-base derangements use modified Stewart approaches. Below, we comment on the role of this technique in explaining ph derangements commonly observed with intravenous fluid resuscitation. 0 ( Page 426 )
Fluid Therapy Understanding the role of intravenous fluid electrolyte content in affecting acid-base balance in vivo, one must first take note of normal plasma electrolyte content in healthy individuals. To recapitulate on the concentrations of the plasma ions, see Table 1. Crystalloid intravenous fluids can be divided into resuscitation fluids (e.g., 0.9% Sodium Chloride, Hartmann s Solution) and non-resuscitation fluids (e.g., 5% Dextrose, 4% Dextrose with 0.18% Sodium Chloride). The main distinction between the two groups can be described by the electrolytic component (versus dextrose) providing the osmolar load. Although not identical to human plasma, intravenous solutions with a balanced electrolyte formulation (such as Hartmann s solution) match the biochemical composition of human plasma more closely than saline-based fluids. Saline-based fluids are non-physiological in three ways. Firstly, the level of chloride is significantly above that of plasma (154 mmol, as compared to 98-102 mmol); secondly they lack several electrolytes present in normal plasma, including potassium, calcium, glucose, and magnesium. Thirdly, they lack the bicarbonate or bicarbonate precursor buffer necessary to maintain plasma ph within normal limits. Each of these may be responsible for homeostatic disruption, and in particular the metabolic acidosis produced by normal-saline infusion. 14 As can be seen in Table 1, there are significant differences in the electrolyte content of 0.9% Sodium Chloride (Saline, and saline based fluids, e.g. most colloid preparations) and balanced electrolyte fluid preparations (e.g., Hartmann s, Lactated Ringers). Saline has a supra-physiological concentration of both sodium and chloride. This is of less importance for longer term maintenance infusions, but very important in fluid resuscitation scenarios. 8,15-17 Illustration of this concept with a simplified mathematical model will demonstrate the effect of fluid resuscitation with a salinebased fluid versus a balanced electrolyte fluid (Hartmann s). Let s consider an adult patient, with plasma electrolyte contents as follows (amongst others): Na + 140 mmol/l K + 4 mmol/l Ca 2+ 2 mmol/l Cl - 100 mmol/l If we calculate the total electrolyte content of the entire extracellular fluid space (electrolyte concentrations roughly constant across the space), by multiplying the respective concentrations by 15 L (an average for a 70 kg male), we would obtain the following results: Na + 2100 mmol K + 60 mmol Ca 2+ 30 mmol Cl - 1500 mmol If the patient lost 5 L of the plasma due to hemorrhage, the concentration of the various ions would be the same, but the total content would be as follows (concentration multiplied by 10 L): Na + 1400 mmol K + 40 mmol Ca 2+ 20 mmol Cl - 1000 mmol If we chose to replace this lost volume of plasma with 5 L Saline, the electrolyte load would be 770 mmol of sodium and chloride each (5 L x 154 mmol/l). This would take the total plasma ionic content to the following: Na + 1400 mmol + 770 mmol = 2170 mmol K + 40 mmol Ca 2+ 20 mmol Cl - 1000 mmol + 770 mmol = 1770 mmol This would equate into the following concentrations: Na + 145 mmol/l K + 2.7 mmol/l Ca 2+ 1.3 mmol/l Cl - 118 mmol/l In calculating the SID however, charge balance demands milliequivalents per liter, not millimol. The normal SID in healthy volunteers is 40-49 meq/l. Bivalent ions such as calcium and magnesium, therefore, count double. When these variables are examined using the SID, we would find the following: (Na + + K + + Ca 2+ + Mg 2+ ) (Cl - + Lactate) = (140 + 4 + 4 + 2) (100 + 1) = 151 101 = 49 meq/l (before hemorrhage and transfusion) and = (145 + 2.7 + 2.6 + 2) (118 + 1) = 151.7 119 = 32.7 meq/l (after saline resuscitation) The net result would be increased water dissociation, hence the H+ concentration would increase with saline resuscitation to maintain electrochemical neutrality. A fall in the ph would result. This is commonly observed clinically as a hyperchloremic metabolic acidosis associated with saline fluid resuscitation. If we resuscitated the same patient, but this time using Hartmann s solution, the SID after resuscitation would be 42.7 meq/l (146.7-104), assuming the lactate would be normally metabolised. Remember that these are only simplified examples of the role of SID in acid-base management, to help with the understanding of the principle involved. Clinical Implications The physiological risks of hyperchloremic metabolic acidosis are not clear. It is fair to question whether hyperchloremic metabolic acidosis is benign and self-limiting, or whether it is ( Page 427 )
Table 2. Summary of Clinical Trials Showing Intraoperative Estimated Blood Loss (EBL) With Balance Saline Based Fluid Administration Trial author Fluids used Number in Patient group / op type Outcome (Balanced each arm compared to non-balanced) Scheingraber 16 NS/LR 12 Gynecologic Non-significant reduction McFarlane 22 NS/ 15 General surgery No significant difference plasmalyte148 Waters 18 NS/LR 33 Open AAA repair Non-significant reduction Wilkes 17 Hextend / Hespan 23 Surgical patients age > 60 Non-significant increase Martin 21 Hextend / Surgical patients with Significant reduction 30 Hespan / LR EBL > 500 ml Gan 20 Hextend / Hespan 60 Surgical patients Significant reduction with EBL > 500 ml Boldt 24 NS/LR 21 Abdominal cancer Non-significant reduction surgery Takil 25 NS/LR 15 Scoliosis repair Non-significant reduction LR = Lactated Ringers solution; NS = Normal Saline; Hextend is a hetastarch suspended in a balanced electrolyte formulation. Hespan is a hetastarch suspended in normal saline. Table 3. Summary of Perioperative Clinical Trials Comparing Estimated Intraoperative Urine Output (UO) With Balanced Saline Based Fluid Administration Trial author Fluids used Number in Patient group / op type Outcome (Balanced each arm compared to non-balanced) Scheingraber 16 NS / LR 12 Gynecologic Non-significant increase in UO Waters 18 NS / LR 33 Open AAA repair Non-significant increase in UO Wilkes 17 Hextend / Hespan 23 Surgical patients age > 60 Significant improvement in UO and post-op creatinine Guerrero 30 and post-op creatinine Bennett- Hextend / Hespan 50 Cardiac surgery Significant improvement in UO Gan 20 Hextend / Hespan 60 Surgical patients No difference with EBL > 500 ml Boldt 24 NS / LR 21 Abdominal cancer Non-significant surgery decrease in UO Takil 25 NS / LR 15 Scoliosis repair Non-significant reduction decrease in UO LR = Lactated Ringers solution; NS = Normal Saline; Hextend is a hetastarch suspended in a balanced electrolyte formulation. Hespan is a hetastarch suspended in normal saline. clinically relevant. Metabolic acidosis, whatever the etiology, can depress myocardial function, reduce cardiac output, and reduce renal and intestinal perfusion. Acidemia can inactivate membrane calcium channels, and inhibit the release of norepinephrine from sympathetic nerve fibers. This may result in the redistribution of cardiac output away from internal organs. 18 Whilst this may have little effect on fit patients undergoing minor elective surgery, the concern is the effect of severe hyperchloremic acidosis from aggressive fluid resuscitation in acutely ill patients during major surgery, in particular vascular surgery, and organ transplantation; or following trauma or burns. After tourniquet release, or in vascular surgery, lactate and carbonic acid load may be superimposed on the iatrogenic hyperchloremic acidosis towards the end of the procedure. If an intraoperative metabolic acidosis becomes apparent during fluid replacement, the clinician may be misled into believing that the patient is hypovolemic, or has a surgical cause for their acidosis. This may lead to inappropriate management, reports of which have been described in the clinical setting. 19 Further administration of saline-based fluids will exacerbate rather than relieve the problem. In this setting, a hyperchloremic metabolic acidosis may not be differentiated from lactic acidosis by the inexperienced anesthetist. Below, we detail some specific physiological mechanisms that become disrupted in the presence of hyperchloremia. Coagulation Coagulation, as any other physiologic system, has optimal ph and electrolyte levels at which ( Page 428 )
it functions most effectively. What is less known in vivo, is the extent of minor to moderate acid-base and electrolyte disturbances on overall coagulation and hemostasis. One can assess clinical outcomes of coagulation or hemostatic function from a number of well-conducted clinical trials of in vivo fluid therapy or resuscitation, where balanced electrolyte formulations have been compared with saline-based fluids. Studies comparing saline-based versus balanced electrolyte crystalloids or colloids have shown differences in bleeding and coagulation, favoring reduced bleeding and less derangement of coagulation function in the balanced electrolyte formulations. 20,21 Waters et al. showed a deleterious effect on hemostasis from infusion of normal saline based fluids, when compared to balanced electrolyte solutions, in patients undergoing abdominal aortic aneurysm repair. Overall, the patients in the balanced fluid group were exposed to significantly less blood products. 18 Other studies (see Table 2), underpowered for blood loss or assessment of coagulation variables (where these have not been primary outcome variables), have shown no difference. 16,17,22 Systematic review and meta-analysis of the available data of all randomized controlled trials investigating buffered versus nonbuffered fluid therapy (cf. balanced electrolyte versus saline-based fluids) has recently shown a significant reduction in blood loss in the pooled data of buffered fluids. 23 Questions may be asked on why this should occur. Calcium may well play a role, albeit limited. Even when calcium has been controlled for with hemodilution with fluids in these two groups, a difference still exists in blood coagulation as assessed by thrombelastograph analysis (TEG, Haemoscope Corp). 26 Calcium does not have any further beneficial effects in enhancing blood coagulation above ionized concentrations of 0.6 mmol/l. 27 Further research will help in understanding the role of other electrolytes in the coagulation process. Renal Effects Animal studies suggest that hyperchloremia causes renal vasoconstriction: Wilcox, in a canine model, has shown that renal blood flow and glomerular filtration rate are regulated by plasma chloride. 28 He demonstrated that hyperchloremia produces a progressive renal vasoconstriction by inhibiting the intrarenal release of renin and angiotensin II; and a decrease in glomerular filtration rate and renal blood flow that was independent of renal innervation, enhanced by prior salt depletion, and related to a tubular reabsorption mechanism involving chloride. He went on to show that chloride-induced vasoconstriction appears specific for the renal vessels. Renal afferent arterioles are major regulatory sites of renal vascular resistance. Hansen showed that plasma chloride levels directly affect renal afferent arteriolar tone through calcium activated chloride channels in the afferent arteriolar smooth muscle in rabbits. He demonstrated a total occlusion of rabbit renal afferent arterioles at a chloride level of 110 mmol per liter, only slightly above normal plasma level. 29 He suggested that a raised plasma chloride could increase renal sensitivity to angiotensin 2, and modulate the release of renin. Although the message is not as strong as with the coagulation data, a number of clinical studies (Table 3) now suggest that renal indices are perturbed by normal saline infusion in the perioperative setting. Bennett-Guerrero et al. showed a significant improvement in urine output, serum creatinine, creatinine clearance in perioperative patients given balanced salt solution, when compared to a saline-based product. 30 Similarly, Wilkes et al., in their elderly surgical patient population, demonstrated a doubling of urine output in their balanced fluid group, and a significant reduction in post-operative creatinine. 17 Williams et al. in their healthy volunteer study 31 noted a significantly prolonged time to first urination in the group infused with 50ml per kg of normal saline as compared to the Ringer s lactate group. These trials are small, and not powered for patient outcome, and the overall data in this area are unclear. A recent systematic review reveals a non-significant difference in intraoperative urine output. 32 Other Clinical Implications Wilkes et al studied gastric tonometry in their trial, and noted a significant increase in the CO2 gap in their unbalanced group. This implies gastric hypoperfusion, and indeed there was a trend toward increased post-operative nausea and vomiting in the same group. These data tie-in well with the healthy volunteer study by Williams et al. where normal saline infusion caused abdominal discomfort in significantly more volunteers than the same volume of Ringer s lactate. The mechanism for this is unclear, but it might be hypothesized that metabolic acidosis itself causes gut hypoperfusion, or that chloride acts on the splanchnic vasculature in the same vasoconstricive in the same way as on the renal arterioles. The respiratory response to perioperative intravenous fluid administration was noted by Takil et al. 25 in their study of ASA 1 and 2 patients undergoing scoliosis repair. They discovered a significantly increased post-operative hypercarbia in their Ringer s lactate group (44 mmhg) as compared to their normal saline group (40 mmhg). They concluded that this hypercarbia may lead to reduced opiate administration, and inadequate pain control. It is fair to hypothesize that the metabolic acidosis found in their normal saline group caused these patients to overbreathe in compensation post-operatively. The clinical effects of this are unclear. Conclusion In the field of anesthesia and perioperative medicine, it has now firmly been established that hyperchloremic metabolic acidosis is a predictable consequence of saline-based, non-balanced ( Page 429 )
intravenous fluid administration. Current evidence suggests that it is a clinically relevant and easily avoidable condition. Clearly, further studies are needed to better understand the pathophysiology and effects of hyperchloremic metabolic acidosis in acutely ill patients. We think that until such data are available, the logical approach should be to avoid iatrogenic hyperchloremia. This is more easily achieved if a fluid that is more normal than normal saline is utilized. We advocate the use of intravenous fluids that have a more balanced composition. Conflicts of Interest The authors have received unrestricted educational grants from the following: Abbott Laboratories USA; Biotime, Inc. USA; Fresenius UK; B Braun UK. Acknowledgements The authors wish to thank Dr. Mark Hamilton for his help and background research, and Dr. Marika Davies for her patience and inspiration. R E F E R E N C E S 1. Brivet F, Bernardin M, Dormont J. [Hyperchloremic acidosis in metabolic acidosis with anion gap excess. Comparison with diabetic ketoacidosis]. Presse Med 1991;20:413-7. 2. Burdett E, Roche T, Donnelly T, Moulding R, Mythen M. Saline-based fluid resuscitation is associated with metabolic acidosis in surgical patients. Eur J Anaesthesiology 2003; in press. 3. Astrup P, Jorgensen K, Siggaard-Andersen O, et al. Acidbase metabolism: a new approach. Lancet 1960;1:1035-9. 4. Severinghaus JW. Acid-base balance nomogram--a Boston- Copenhagen detente. Anesthesiology 1976;45:539-41. 5. Siggaard-Andersen O. The ph-log pco2 blood acid-base nomogram revisited. Scand J Lab Invest 1962;14:598-604. 6. Neugebauer E, Zander R. Clinical relevance of base excess and lactate concentration. Anasthesiol Intensivmed Notfallmed Schmerzther 2002;37:341-2. 7. Stewart PA. Independent and dependent variables of acidbase control. Respir Physiol 1978;33:9-26. 8. Stewart PA. How to Understand Acid-Base. New York: Elsevier, 1981. 9. Fencl V, Leith DE. Stewart's quantitative acid-base chemistry: applications in biology and medicine. Respiration Physiol 1993;91:1-16. 10. Stewart PA. Modern quantitative acid-base chemistry. Can J Physiol Pharmacol 1983;61:1444-61. 11. Figge J, Rossing TH, Fencl V. The role of serum proteins in acid-base equilibria. J Lab Clin Med 1991;117:453-67. 12. Kellum JA. Determinants of blood ph in health and disease. Crit Care 2000;4:6-14. 13. Figge J, Mydosh T, Fencl V. Serum proteins and acid-base equilibria: a follow-up. J Lab Clin Med 1992;120:713-9. 14. O'Connor MF, Roizen MF. Lactate versus chloride: which is better? Anesth Analg 2001;93:809-10. 15. Kellum JA. Saline-induced hyperchloraemic metabolic acidosis. Crit Care Med 2002;30:259-61. 16. Scheingraber S, Rehm M, Sehmisch C, Finsterer U. Rapid saline infusion produces hyperchloraemic acidosis in patients undergoing gynecologic surgery. Anesthesiology 1999;90:1265-70. 17. Wilkes NJ, Woolf R, Mutch M, et al. The effects of balanced versus saline-based hetastarch and crystalloid solutions on acid-base and electrolyte status and gastric mucosal perfusion in elderly surgical patients. Anesth Analg 2001;93:811-16. 18. Waters JH, Gottlieb A, Schoenwald P, Popovich MJ, Sprung J, Nelson DR. Normal saline versus lactated Ringer's solution for intraoperative fluid management in patients undergoing abdominal aortic aneurysm repair: an outcome study. Anesth Analg 2001;93:817-22. 19. Parekh N. Hyperchloremic acidosis. Anesth Analg 2002;95:1821. 20. Gan TJ, Bennett-Guerrero E, Phillips-Bute B, et al. Hextend, a physiologically balanced plasma expander for large volume use in major surgery: a randomized phase III clinical trial. Hextend Study Group. Anesth Analg 1999;88:992-8. 21. Martin G, Bennett-Guerrero E, Wakeling H, et al. A prospective, randomized comparison of thromboelastographic coagulation profile in patients receiving lactated Ringer's solution, 6% hetastarch in a balanced-saline vehicle, or 6% hetastarch in saline during major surgery. J Cardiothorac Vasc Anesth 2002;16:441-6. 22. McFarlane C, Lee A. A comparison of Plasmalyte 148 and 0.9% saline for intra-operative fluid replacement. Anaesthesia 1994;49:779-81. 23. Fong K, Roche AM, Burdett E, Mythen MG. Meta-analysis of estimated peri-operative blood loss for buffered versus non-buffered IV fluid Resuscitation. Anesthesiology 2002;96:A197. 24. Boldt J, Haisch G, Suttner S, Kumle B, Schellhase F. Are lactated Ringer's solution and normal saline solution equal with regard to coagulation? Anesth Analg 2002;94:378-84. 25. Takil A, Eti Z, Irmak P, Yilmaz Gogus F. Early postoperative respiratory acidosis after large intravascular volume infusion of lactated ringer's solution during major spine surgery. Anesth Analg 2002;95:294-8. 26. Roche AM, James MF, Mythen MG. In vitro addition of calcium to saline-based intravenous fluids only partially compensates for TEG pictures observed during haemodilution. Anesth Analg 2002;94:S73. 27. James MF, Roche AM. Dose-response relationship between calcium and thrombelastography. Anesthesiology 2001;95:A185. 28. Wilcox CS. Regulation of renal blood flow by plasma chloride. J Clin Invest 1983;71:726-35. 29. Hansen PB, Jensen BL, Skott O. Chloride regulates afferent arteriolar contraction in response to depolarization. Hypertension 1998;32:1066-70. 30. Bennett-Guerrero E, Frumento RJ, Mets B, Manspeizer HE, Hirsh AL. Impact of normal saline based versus balanced-salt intravenous fluid replacement on clinical outcomes: a randomized blinded clinical trial. Anesthesiology 2001;95:A147. 31. Williams EL, Hildebrand KL, McCormick SA, Bedel MJ. 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. 32. Burdett E, Roche AM, Fong K, Grocott M, Mythen MG. A systematic review of buffered versus non-buffered perioperative fluid resuscitation and urine output. Anesthesiology 2002;96:A201. Transfusion Alternatives in Transfusion Medicine is published bimonthly by LMS Group, 70/86, avenue de la République 92325 Châtillon Cedex FRANCE S.A.R.L. au capital de 50,000 FF. Phone: + 33 1 42 53 03 03 Fax: + 33 1 42 53 03 02 Printed in France, De Chabrol, 189 rue d Aubervilliers, 75886 Paris Cedex 18 FRANCE Numéro ISSN: 1295-9022 All rights reserved Copyright LMS Group Advertising: For details on media opportunities within this journal, please contact the advertising sales department (phone: + 33 1 42 53 03 03) Dépôt légal 3 e trimestre 2003. ( Page 430 )