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Department of Anesthesia and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, Illinois
Address correspondence to Michael F. O’Connor, MD, Department of Anesthesia and Critical Care, Box MC 4028, University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637.
Well controlled, carefully conducted blinded clinical studies are powerful tools for answering important clinical questions. Interval analysis of data is sometimes necessary as a safeguard to ensure the protection of research subjects from unnecessary risk. If the interval analysis includes end points of unknown importance, a potentially important clinical study may be stopped over a finding of questionable significance.
Anesthesiologists, surgeons, and intensivists routinely administer large volume infusions to patients. Crystalloid and colloid solutions remain among the most important pharmaceuticals administered to patients, as they are used to support the circulation during periods of large fluid shifts. Clinical interest in improving practice has spawned a large number of trials over the past three decades. The state of the art has advanced from early, less than optimally controlled trials (1), to more carefully controlled, thoughtfully executed studies (2,3). Several metaanalyses have been performed and published in prominent medical journals (4,5). Strongly worded reviews and special articles remain of broad interest in these communities and have both advocated colloid solutions (5) and strongly discouraged their use (6). The enormous diversity of practice observable in the real world reflects the lack of consensus about what this vast clinical literature means.
Hyperchloremic acidosis is a consequence of the infusion of large quantities of solutions containing a large concentration of chloride (0.9% normal saline in the clinical setting). Hyperchloremic acidosis was first discussed in the anesthesia literature in a randomized study of 30 patients reported by McFarlane and Lee in 1994 (7), who clearly demonstrated an association between the infusion of large quantities of normal saline and the evolution of a metabolic acidosis. Subsequent studies have confirmed their observations (8) and have generated interest in electrolyte solutions designed to avoid this problem. Hyperchloremic acidosis by itself is of no known pathologic or physiologic consequence. The greatest danger associated with it appears to be either the reaction of clinicians who may not recognize or appreciate its presence, or that it may worsen or confuse an acidosis caused by some other process. Our insight into the adverse effects of hyperchloremic acidosis is limited by the meager clinical literature and even smaller basic science literature about the subject. This lack of information reflects the minimal resources that have been allocated to understanding this problem at any level. If relevant basic science studies were to suggest greater harm associated with this syndrome, then its evolution in patients would be regarded far more seriously.
In this issue of Anesthesia & Analgesia, Wilkes et al. (9) report a randomized blinded comparison of 6% hetastarch formulated in either 0.9% saline (Hespan) or a balanced salt solution very similar in composition to lactated Ringer’s solution (Hextend). Although there are other differences in the fluids compared (potassium, glucose, calcium, magnesium), the study is ultimately a careful comparison of lactate versus chloride as anions. Patients in both groups received approximately 2,500 mL of colloid solution, 1,400 mL of crystalloid solution, and comparable quantities of blood products. This represents a larger volume of 6% hetastarch than many had previously believed to be safe and also represents a different ratio of colloid to crystalloid than most clinicians use. Of course, most of the previous studies comparing crystalloid and colloid solutions involved comparisons of albumin, not hetastarch, and hence may not apply. Regardless, the study was stopped after an interim analysis revealed that patients in the saline group were developing a hyperchloremic acidosis, which should hardly have been surprising, given the prior studies by McFarlane and Lee (7) and Scheingraber et al. (8). The premature termination of the study may have prevented the authors from demonstrating an association between the different anions and perioperative incidence of nausea, vomiting, and use of antiemetics. There certainly does appear to be a qualitative difference in these variables between the two groups. The difference in urinary volumes between the two groups, although not statistically significant, is intriguing, as it is consistent with what is presently believed about the physiology of tubular glomerular feedback. It seems that the safety committee charged with the oversight of this study stopped it because of concern about a syndrome of unknown importance and thereby prevented it from providing insight into major problems whose importance are widely accepted. We the readers are left with appetites whetted but unsatisfied, and the authors are left with a study that replicates the findings of earlier comparisons of saline and balanced salt solutions.
Those interested in further optimizing their fluid management of patients may find the present study by Wilkes et al. (9) to be yet another step closer to optimal fluid management for their patients. Others may view it as an extraordinarily careful comparision of chloride as an anion to lactate as an anion. Only time and further investigation will reveal which is the truth.
References
This article has been cited by other articles:
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  D. A. Story, H. Morimatsu, and R. Bellomo Strong ions, weak acids and base excess: a simplified Fencl-Stewart approach to clinical acid-base disorders{dagger} Br. J. Anaesth., January 1, 2004; 92(1): 54 - 60. [Abstract] [Full Text] [PDF]
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 S. M. Jakob Splanchnic Blood Flow in Low-Flow States Anesth. Analg., April 1, 2003; 96(4): 1129 - 1138. [Abstract] [Full Text] [PDF]
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M. Rehm and U. Finsterer Treating Intraoperative Hyperchloremic Acidosis with Sodium Bicarbonate or Tris-Hydroxymethyl Aminomethane: A Randomized Prospective Study Anesth. Analg., April 1, 2003; 96(4): 1201 - 1208. [Abstract] [Full Text] [PDF]
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N. Parekh, N. J. Wilkes, S. V. Mallett, and M. G. Mythen Hyperchloremic Acidosis * Response Anesth. Analg., December 1, 2002; 95(6): 1821 - 1822. [Full Text] [PDF]
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