Intravenous Fluids and Renal Failure

Transcription

1 ) ( TATM 2003;5(4): Intravenous Fluids and Renal Failure S UMMARY Numerous intravenous fluid preparations are available for administration to patients in the clinical setting. These fluids have traditionally been described as either CATHERINE M.N. O MALLEY, FFARCSI DEPARTMENT OF ANAESTHESIA ST JAMES S HOSPITAL DUBLIN, IRELAND crystalloid or colloid but they may be further classified according to the nature of the solution itself, i.e. 0.9% NaCl (normal saline) or balanced salt-based fluids (e.g., lactated Ringer s solution). Until recently, little attention has been paid to the potential systemic effects of intravenous fluids that occur independently of their efficacy as agents for intravascular volume replacement.this article explores the available data regarding the impact of intravenous fluids on the kidney to determine whether there is any evidence linking intravenous fluid administration and the pathogenesis of renal dysfunction or renal Intravenous fluids Renal failure Renal function Hydroxyethyl starch Normal saline 0.9% NaCl Lactated Ringer s Dextran Gelatin failure. Particular reference is made to 0.9% NaCl and the hydroxyethylstarch solutions but other fluids such as gelatin and dextran are also considered. In addition, the metabolic effects of intravenous fluids are discussed as these may influence the choice of fluid type in patients with impaired renal function and renal failure. ( Page 416 )

2 Every day millions of liters of fluid are administered intravenously to patients in operating theaters, intensive care units, on hospital wards and in the emergency rooms. There are numerous preparations available for intravenous (IV) fluid therapy and the choice of fluid type is determined by multiple factors such as type of surgery, ongoing blood loss, the underlying disease process, and patient hemodynamic status. 1 Other variables may play a role including product availability and cost, and physician routine or institutional tradition. 1,2 Recently, additional factors have come into play, specifically the potential impact of intravenous fluid preparations on organ systems independent of their effects on intravascular volume. It is recognized that IV fluids may have drug like effects with influences on processes such as coagulation. An adverse effect of fluid preparations on renal function would have particular significance given the crucial role that intravenous fluid therapy plays in the prevention and treatment of renal impairment and renal failure. Which patient population might be particularly susceptible to a deleterious effect of fluids on kidney function? Normal individuals are unlikely to be vulnerable, while there are a number of factors that predispose to renal impairment and failure. For example, patients who are dehydrated, patients who have an abnormal glomerular filtration rate, and individuals who receive radiocontrast or undergo cardiovascular surgery are among the many who are at increased risk of renal failure. 3 The administration of certain colloids has been associated with the development of renal dysfunction in all of these clinical scenarios. 4-7 Given that certain patients may be more likely to develop renal dysfunction or renal failure, how is that outcome to be delineated? Unfortunately, this point is a controversial one and there is no consensus as to what clinical and/or biochemical criteria constitute renal impairment and failure. 3,8 There are numerous indices of renal function and definitions of kidney dysfunction and failure described in the literature. In many cases little more than urine output and/or serum creatinine are reported and the significance of such changes is unclear. Consequently, clinical research in the arena of renal function is mired by inconsistency. For the purposes of this review, therefore, there can reasonably be no single definition of renal failure or renal dysfunction. The results of the published studies are presented and readers are encouraged to arrive at their own interpretation of the significance of these findings and their impact, if any, on clinical practice. A discussion of the impact of IV fluids on renal function is further constrained by a number of other factors. First, there is a paucity of large, prospective, randomized, blinded clinical studies of IV fluids. Nevertheless, multiple outcomes, including various indices of renal function, have been examined in small investigations in numerous and diverse patient populations and in studies of healthy volunteers. The interpretation of the results of these investigations is also confounded by their size and design. Most studies are small, few are blinded and follow-up is often limited. Furthermore, only a small number of investigations have set out to specifically determine the effect of intravenous fluids on the kidney with indices of renal function as the primary outcome measure(s). Additionally, few studies of IV fluids and renal function have concentrated attention on the likely mechanisms for any effects of intravenous fluids on the kidney by, for example, the analysis of sensitive markers of renal function or potential mediators of IV fluid induced effects on the kidney. In this review, the relationship between IV fluids and renal dysfunction and renal failure will be approached from several perspectives. Necessarily, not all fluid types and preparations can be exhaustively discussed in this format. After a brief review of the solutions that are available to the clinician, two particular IV fluid types will be discussed the hydroxyethyl starch solutions and normal saline-based fluids. The evidence presented has generally been limited to randomized clinical trials of intravenous fluid preparations rather than experimental investigations. Additionally, studies that have considered the effects of relatively large volumes of fluid (i.e., more than one liter) are included. It seems reasonable to suppose that small volumes of an intravenous solution are unlikely to have a clinically relevant impact on the kidney and that if an effect is seen it will also be apparent when larger volumes of fluid are administered. In addition, the effect of IV fluids on some of the metabolic derangements associated with renal failure will be explored. Lastly, the associations between dextran and gelatin and renal function and renal failure will be briefly examined. Intravenous Fluid Preparations Conventionally, intravenous fluids have been classified according to whether they are crystalloid or colloid in nature. Crystalloid fluids comprise electrolyte solutions with or without a bicarbonate precursor such as acetate or lactate. The colloids contain a complex sugar or protein suspended in an electrolyte solution. A further distinction between intravenous fluid types may be based on the nature of the solution. 0.9% NaCl (normal saline) based preparations (crystalloid or colloid) contain no electrolytes other than sodium and chloride. In contrast, balanced salt-based fluids such as lactated Ringer s solution (Hartman s solution, compound sodium lactate) contain other electrolytes with or without a bicarbonate precursor. Several types of colloid are available but three are most commonly used hydroxyethyl starch, gelatin and albumin. Dextran solutions are no longer widely utilized for their volume expansion properties, 1,2 although they may still occasionally be utilized in some surgical patients for their anticoagulant properties. They are referred to for the purposes of this review as they have been implicated in the pathogenesis of renal dysfunction and failure. The hydroxyethyl starch (HES) preparations differ from one another according to their concentration, molecular weight and extent of hydroxyethylation or substitution with resultant varying ( Page 417 )

3 physiochemical properties. HES solutions may be described according to concentration (3%, 6%, 10%), weight-averaged mean molecular weight in kilodaltons (kda): high-molecular weight (450 kda), middle-molecular weight (200 kda, 270 kda), low-molecular weight (130 kda, 70 kda) and the molar substitution ( ). HES 450/0.7 is available in a normal saline solution and in a lactated electrolyte solution. The gelatins are derived from bovine collagen. Commercially available solutions include succinylated and urea-linked formulations. The principal differences between the gelatin preparations lie in the electrolyte concentrations of the fluids. There are two dextran solutions available, dextran 40 (molecular weight 40 kda) and dextran 70 (molecular weight 70 kda). While all of these colloid solutions are used in Europe, gelatins are not available in the United States (US) and the only hydroxyethyl starch preparations approved for use in the US are the 6% HES 450/0.7 formulations. Normal Saline and Renal Failure As mentioned above, IV fluids may be classified according to the nature of the solution itself. Broadly speaking, fluids can be divided into normal saline-based solutions (e.g., 0.9% NaCl, albumin, most HES preparations) or balanced-salt based solutions (e.g., lactated Ringer s, HES 450/0.7 in lactated electrolyte injection). In light of this classification, there are some data from prospective, randomized studies to suggest that nature of a solution rather than, for example, the type of colloid, may have an impact on renal function. Several clinical trials have compared the effects of normal salinebased and balanced salt-based fluids and observed that normal saline or normal saline-based fluids may have adverse effects on the kidney These clinical studies, carried out in elderly surgical patients, 9 women undergoing major gynecological surgery 10 and in patients undergoing major surgery 11,12 observed greater urinary output in patients who had received balanced salt type fluids rather than normal saline-based fluids during surgery. Additionally, Moretti and colleagues observed a rise in serum creatinine in 4/30 patients treated with HES 450/0.7 in normal saline, but in only 1/30 treated with lactated Ringer s, and in 0/30 patients treated with HES 450/0.7 in a balanced salt solution. 12 Although these differences did not reach statistical significance, more compelling evidence has emerged that normal saline may indeed be detrimental to renal function. In a double-blind cross over study in healthy volunteers, Williams and colleagues compared the effects of infusion of large volumes of lactated Ringer s with normal saline. 13 Time to first urination was longer after infusion of normal saline than after infusion of lactated Ringer s implying that urine flow rate may be lower after administration of normal saline. In a study of similar design comparing the effect of normal saline and lactated Ringer s, urine volume was greater and the time to first micturition was shorter in healthy volunteers who received lactated Ringer s rather than normal saline. 14 Although interesting, data from healthy volunteers cannot always be extrapolated to patients undergoing major surgery or in the intensive care unit who may be at risk of the development of renal impairment and renal failure. Accordingly, a number of studies in surgical patients also indicate that normal saline may have adverse effects on renal function in patients. In a prospective, randomized, double-blinded study 200 cardiac surgical patients were randomized to receive one of four fluids for intraoperative fluid therapy lactated Ringer s, HES 450/0.7 in normal saline (HES 450/NS), HES 450/0.7 in a balanced salt solution (HES 450/BS) or 5% albumin in normal saline (5% albumin/ns). 15 Measures of renal function were urine flow rate, postoperative serum creatinine, creatinine clearance, and the requirement for postoperative renal replacement therapy. Patients who received normal saline based-fluids, i.e. HES 450/NS or 5% albumin/ns, had worse renal function, reflected by all measured parameters, than patients who were treated with the balanced salt based-fluids (HES 450/BS, lactated Ringer s). Furthermore, the differences in renal function persisted until the end of the first week after surgery. Although patients in the lactated Ringer s group received greater volumes of fluid than patients in the three other groups, this does not explain the observed differences in renal function since the outcomes were similar in the lactated Ringer s and the HES 450/BS groups. In a subsequent clinical trial, patients undergoing genitourinary surgery were randomized to receive either HES 450/BS or 5% albumin/ns by Gan and colleagues. 16 Although this study was not designed to examine the effects of these fluids on renal function, the observed urine output was less in the 5% albumin/ns group than in the patients who received HES 450/BS. Lang and colleagues compared the effect of volume replacement therapy with lactated Ringer s and HES 130/0.4 in normal saline on muscle tissue oxygen tension in patients undergoing major surgery. No other measures of renal function were reported but urine output was greater in the patients who received the balanced salt fluid. 17 It should be noted that the patients in the lactated Ringer s group did receive more fluid than those who were on the HES 130/0.4 regime. What might be the explanation for a normal saline induced renal dysfunction? One explanation may lie in the occurrence of the hyperchloraemia that is seen with the administration of substantial volumes of normal saline and normal saline-based fluids. Wilcox, in an experimental model, observed that hyperchloremia produces a progressive renal vasoconstriction and a fall in glomerular filtration rate with changes in renal blood flow correlating with plasma chloride. This vasoconstriction was only seen in the renal vasculature and not in vascular regions such as the femoral artery. 18 Therefore, a chloride load may explain, in part, the mechanism for the putative normal saline induced renal dysfunction. Alternatively, the metabolic acidosis that is associated with the administration of large volumes of normal saline may induce vasoconstriction and redistribution of intrarenal blood flow with ( Page 418 )

4 subsequent effects on function. This may occur on a systemic level in association with vasoconstriction in other vascular beds such as the splanchnic circulation. 9 A third possibility is that the development of acidosis stimulates the production of a local or paracrine vasoconstrictor by the kidney with subsequent decreases in renal blood flow, glomerular filtration rate and urinary output. Other investigators have not noted superior renal function following the administration of balanced salt fluids. In a prospective, randomized study of patients undergoing major spine surgery, patients who received normal saline for intraoperative fluid therapy had a higher urine output than patients who were treated with lactated Ringer s. 19 This difference did not reach statistical significance. Waters and colleagues observed that intraoperative urine output was greater in patients who received normal saline than in patients who were given lactated Ringer s solution during abdominal aortic aneurysm repair. 20 Of note, normal saline treated patients received a larger volume of fluid than patients in the lactated Ringer s group. In patients undergoing major abdominal surgery, cumulative urine output measured on the second postoperative day was slightly greater in normal saline treated patients than in lactated Ringer s treated patients. 21 In both of these studies, normal saline treated patients received significant quantities of sodium bicarbonate intraoperatively for treatment of hyperchloremic metabolic acidosis. This suggests that the prevention and/or treatment of the metabolic acidosis may have negated the negative impact of normal saline on renal function in some way. If indeed bicarbonate therapy has this positive effect, it would appear that, at least in the surgical patient, metabolic acidosis (either directly or through some other mediator) rather than hyperchloremia alone may have an impact on the kidney. unrecognized. The choice of balanced-salt based fluids rather than normal saline-based fluids for intravenous fluid therapy averts the risk of hyperchloremic metabolic acidosis. Clinicians may be reluctant to administer lactated Ringer s and other potassium containing fluids such as urea-linked gelatins to patients with renal failure and dysfunction. This is in keeping with the long held belief that the administration of potassium containing fluids to patients with severe renal dysfunction or renal failure may be associated with the development of hyperkalemia So, despite the lack of evidence to support this practice, potassium free fluids are commonly administered to patients with renal failure in an attempt to avoid the theoretical risk of hyperkalemia. 29 However, the development of hyperkalemia as a consequence of the administration of potassium containing, balanced-salt fluids seems unlikely for several reasons. The concentration of potassium in intravenous fluids such as lactated Ringer s is 4 mmol/l which represents a minute amount of potassium when compared with the total body potassium stores. Furthermore, balanced-salt fluids contain potassium in a dilute form which is usually administered in large volumes over a period of hours. This is not the same as the rapid administration of a small volume of concentrated potassium, which is more likely to increase serum potassium levels. There is little or no published evidence to suggest that the administration of potassium containing fluids causes hyperkalemia in patients with renal failure. In contrast, a prospective, randomized, double-blinded trial of intraoperative administration of normal saline and lactated Ringer s solution in patients undergoing living-donor renal transplantation found that treatment for hyperkalemia was more common in patients who received normal saline rather than lactated Ringer s. 30 Intravenous fluids, Metabolic Acidosis and Serum Potassium Levels in Renal Failure The administration of large volumes of normal saline is associated with development of hyperchloremic metabolic acidosis. 9,10,17,20,22,23 The mechanism by which this occurs has been attributed to the dilution of bicarbonate by the administration of large volumes of buffer free fluid. 24 An alternate explanation is that the hyperchloremia caused by the administration of normal saline causes a decrease in the strong ion difference of the blood with consequent development of metabolic acidosis. 25 Regardless of the mechanism by which it occurs, the acidosis that is associated with the infusion of normal saline may be of particular significance in patients with renal failure or renal dysfunction. These individuals often have preexisting abnormalities of acid-base balance. Therefore, the administration of large volumes of normal saline or normal saline-based fluid may cause worsening of acidosis, complicate interpretation of acid-base data and, at worst, result in unnecessary interventions, particularly if the etiology goes Hydroxyethyl Starch Solutions and Renal Failure Not only may IV fluids have an impact on renal function but renal dysfunction and failure may affect the disposition of those fluids that are metabolized and/or excreted by the kidney in a manner similar to the altered drug handling that occurs in renal failure. The clinical relevance of this may lie in the potentiation of the adverse effects of IV fluids as their elimination is inhibited. The kidney excretes HES and thus its pharmacokinetic disposition is altered by the presence of renal dysfunction. In normal individuals up to 64% of an injected dose is eliminated by the kidney within the first 24 hours of injection. 31 HES molecules of less than 50 kda are eliminated unchanged in the urine while larger HES molecules are cleaved in plasma by amylase and subsequently excreted or temporarily taken up by the reticuloendothelial system prior to cleavage and excretion. The degree to which elimination of HES is affected by kidney function is influenced the mean molecular weight, the degree of molar substitution and the ratio of C2/C6 hydroxylation. The older ( Page 419 )

5 Table 1. The Impact of Commonly Used Intravenous Fluids on Renal Function in Surgical Patients Author Fluids Studied Type of Surgery Findings Bennett-Guerrero et al. 15 HES 450/BS (n = 47), Cardiac Lower urine output & creatinine clearance, LR (n = 53), 5% albumin (n = 52), in 5% albumin and HES 450/NS groups HES 450/NS (n = 48) Beyer et al. 42 HES 200 (n = 19), Orthopedic No difference in urine output, serum creatinine Gelatin (n = 22) Boldt et al. 21 LR (n = 21), Abdominal No difference in urine output 0.9% NaCl (n = 21) Boldt et al. 46 HES 130 (n = 20), Cardiac No difference in urine output, serum creatinine, Gelatin (n = 20) Gallandat Huet et al. 40 HES 130 (n = 30), Cardiac No difference in urine output, serum creatinine HES 200 (n = 29) Gan et al. 16 HES 450/BS (n = 14), Urological Lower urine output in 5% albumin group 5% albumin (n = 11) Gan et al. 11 HES 450/BS (n = 60), General, Urological No difference in urine output HES 450/NS (n = 60) Gynecological, Orthopedic, Haisch et al. 44 HES 130 (n = 21), Cardiac No difference in urine output Gelatin (n = 21) Haisch et al. 43 HES 130 (n = 21), Abdominal No difference in urine output Gelatin (n = 21) Kumle et al. 39 HES 70(n = 20), Abdominal No difference in urine output, serum creatinine, HES 200(n = 20), Gelatin (n = 20) Lang et al. 17 HES 130 (n = 21), Abdominal Lower urine output in HES 130 group LR (n = 21) Langeron et al. 41 HES 130 (n = 52), Orthopaedic No difference in urine output HES 200(n = 48) Moretti et al. 12 HES 450/NS (n = 30), General, Urological, No difference in urine output, serum creatinine starches such as HES 450/0.7 may accumulate after multiple infusions even in individuals with normal renal function. Clearly, this may be a concern as patients may be at risk of unwanted side effects without ongoing clinical benefit. The development of newer, lower molecular weight HES formulations has occurred, at least in part, in an attempt to maximize the rate of elimination while maintaining intravascular volume expanding effects. Jungheinrich and colleagues concluded that although the pharmacokinetics of HES 130/0.4 are altered by renal ( Page 420 ) dysfunction, the residual plasma concentrations in subjects with mild-severe renal impairment are smaller than the reported concentrations higher serum creatinine, more patients dialysed observed in healthy volunteers who received HES 450/0.7 or HES 200/ No worsening of renal dysfunction has been observed in small pharmacokinetic studies of creatinine clearance, fractional excretion of sodium patients with stable renal impairment but it cannot be inferred that HES preparations do not worsen renal function. 32,33 Pharmacokinetic studies use small volumes of fluid in individuals with stable disease, making a clinically discernable effect on kidney function unlikely. creatinine clearance, fractional excretion of sodium However, in patients with renal failure, liver biopsies have demonstrated significant accumulation of HES in hepatocytes. While no causative relationship has been established, it was suggested that this HES accumulation after large dose infusion could be a possible cause of hepatomegaly in the context of renal failure. 34 Renal dysfunction and renal failure are associated with a prolongation of the rise in serum amylase concentrations that is routinely seen after infusion of HES solutions. Although the magnitude of the increase in serum amylase concentration is not affected, elevated levels may persist beyond 72 hours after infusion of 500 ml of HES 450/0.7 in individuals with severe renal dysfunction. 33 This increase in amylase concentration is apparently of no clinical significance unless the clinical picture is complicated by the suggestion of pancreatic disease. The serum amylase level associated with HES administration is rarely of a magnitude that would mislead clinicians to suspect significant pancreatic dysfunction. Much controversy surrounds the debate about the effects of HES preparations on renal function. Cittanova and colleagues demonstrated that serum creatinine was higher and the need for renal replacement therapy was greater in patients who were HES 450/BS (n = 30), Gynecological LR (n = 30) Mortelmans et al. 45 HES 200 (n = 21), Orthopedic No difference in urine output Gelatin (n = 21) Scheingraber et al. 10 LR (n = 12), Gynecological No difference in urine output 0.9% NaCl (n = 12) Takil et al. 19 NS (n = 15), LR (n = 15) Spine surgery No difference in urine output Virgilio et al. 58 LR (n = 14), Abdominal Greater urine output in LR group 5% albumin/bs (n = 15) aortic surgery on postoperative day 2 Vogt et al. 23 HES 200 (n = 20), Orthopedic No difference in urine output, creatinine clearance 5% albumin (n = 21). Greater serum creatinine in 5% albumin group 6 hours postoperatively Vogt et al. 48 HES 200 (n = 25), Urological No difference in urine output, serum creatinine 5% albumin (n = 25) Waters et al % NaCl (n = 33), Abdominal Aortic Greater urine output in 0.9% NaCl LR (n = 33) Aneurysm group, no difference in serum creatinine Wilkes et al. 9 HES 450/NS & NS (n = 23), Abdominal, orthopedic, No difference in urine output HES 450/BS & LR (n = 24) genitourinary, plastic surgery HES = hydroxyethylstarch, NS = 0.9% NaCl or normal saline-like solution, BS = balanced salt-based solution, LR = lactated Ringer s

6 transplanted with kidneys from cadaveric donors who received a HES 200/0.6 and gelatin combination rather than gelatin alone for volume replacement therapy prior to organ donation. 35 Subsequently, a prospective multicenter study of patients with severe sepsis or septic shock and normal to mild renal dysfunction, demonstrated that the administration of HES 200/0.6 but not 3% modified gelatin was independently associated with development of acute renal failure (a doubling of serum creatinine level from baseline or need for renal replacement therapy). However, there was no difference between groups in the requirement for dialysis or in mortality. 36 Suggested mechanisms for the findings of renal failure and dysfunction are several. The presence of osmotic-nephrosis like lesions in the renal tubules has been associated with treatment with HES. 35,37 However, these histological findings are not specific and have been demonstrated after the administration of other drugs and solutions. A further possible explanation is that renal dysfunction or failure after the adminstration of large volumes of HES is caused by an imbalance between hydrostatic forces and oncotic forces at the glomerular membrane. 38 An accumulation of unfilterable, osmotically active molecules in plasma results in an increase in colloid osmotic pressure which, when associated with low renal perfusion pressure results in a decrease in glomerular filtration. Lastly, the unfilterable molecules may accumulate and precipitate, causing obstruction of the renal tubules. Clinical studies which compare different HES solutions and other colloid preparations in surgical patients with normal renal function have not found that HES is detrimental to renal function (Table 1). Investigations have compared the clinical impact of different HES preparations, HES with gelatin, HES with lactated Ringer s, 47 and HES with 5% albumin. 23,48 Unfortunately, few of these studies were designed to explore the effects of the fluids studied on renal function. 23,39,47,48 Kumle and colleagues analyzed serum creatinine and creatinine clearance as well as more sensitive markers of renal function such as urinary N-acetyl-β-glucosaminidase (NAG) and α-1 microglobulin concentrations and fractional excretion of sodium in an elaborate study to compare renal function in elderly and younger patients treated with HES 70/0.5, HES 200/0.5, or a modified gelatin. There were no discernable differences in renal function in these patients. 39 In a study comparing lactated Ringer s with three HES solutions (HES 200/0.5, HES 200/0.62, HES 450/0.7) in ASA I and ASA II patients with normal renal function undergoing middle ear surgery, no differences in kidney function were seen between groups, even when assessed by sensitive markers such as NAG and α-1 microglobulin. 47 In a prospective, randomized trial, Boldt and colleagues compared the effects of gelatin and HES 130/0.4 on renal function administered during and after cardiac surgery to elderly patients. 46 Sensitive markers of renal function including urinary NAG, α-1 microglobulin and glutathione transferase along with creatinine clearance and fractional excretion of sodium were measured. There were no differences observed between groups. In two further investigations, one in patients undergoing major urological surgery and another in patients undergoing total hip arthroplasty, Vogt and colleagues studied the effect of large doses of HES 200/0.5 on renal function. A single postoperative measurement of serum creatinine was higher in the albumin treated orthopedic patients than in the HES group. However, the patients in the HES group had received more adjunct therapy with lactated Ringer s than those in the albumin group. 23 Therefore, this difference in serum creatinine may be explained by hemodilution in the HES group. Other Intravenous Fluids and Renal Failure There is a long association between the administration of dextran solutions and the development of acute renal failure. 49 Therefore, dextran is no longer used for intravenous fluid therapy intraoperatively or in the ICU but may still be used for antithrombotic prophylaxis in surgical patients. In this context, there have been recent reports of renal failure occurring postoperatively in dextran treated patients who had no other apparent risk factors for kidney dysfunction. 50,51 Renal impairment is more likely to occur in individuals who are at underlying risk of renal failure. Patients with preexisting renal dysfunction or hypovolemia or patients who receive concomitant nephrotoxic agents (e.g., radio contrast agents) are among those vulnerable to the nephrotoxic effects of dextran solutions. 4-6 Hyperoncotic renal failure is the classical explanation for dextran induced kidney dysfunction in a manner similar to that described earlier for HES. The large molecular weight fraction of dextran solutions causes an increase in plasma oncotic pressure with a decrease in filtration pressure and thus glomerular filtration rate. Anuric renal failure may ensue but this is usually reversible and treatment is with temporary renal replacement therapy along with plasmapharesis to remove accumulated dextran from the blood. Osmotic nephrosis lesions, similar to those seen with HES administration are observed in biopsy specimens from dextran treated patients with renal failure. 52 As with the lesions seen after HES administration, their significance is unknown and whether or not they actually contribute to renal dysfunction is controversial. Another possible contributing factor to the development of acute renal failure after dextran administration may be the obstruction of renal tubules by precipitation of dextran. The gelatins have generally been regarded as safe fluids with respect to renal function. However, a case of acute renal failure has been reported after gelatin infusion. 53 In addition, microalbuminuria and microglobulinuria have been observed in association with gelatin administration. The significance of these findings is not clear. Microalbuminuria after trauma resuscitation with gelatin has been presumed to be due to post-trauma capillary leak rather than a renal effect per se. 54 On the other hand, Jones and colleagues, in a study of healthy volunteers, suggested that gelatin associated low ( Page 421 )

7 molecular weight proteinuria was due to competitive inhibition of tubular protein reabsorption. 55 Interestingly, an additional effect of gelatin administration and its renal excretion is interference with certain protein assays. In particular, protein assays that depend on dye binding are affected. The results of the more common turbidometric protein assays, are not influenced by gelatin. 56,57 The limited available evidence from prospective clinical studies, which have generally compared the effects of gelatins with other colloids, provide no evidence that gelatin solutions are associated with renal dysfunction or failure. 21,35,36,42-45 Conclusion It is clear from this review that the evidence regarding the impact of IV fluids on renal function and failure is limited and far from conclusive. It must be reiterated that there is no conclusive data from prospective clinical trials to support any absolute recommendations with regard to IV fluid therapy and renal failure. The primary constraint is the small number of published studies large enough to detect significant differences in clinically relevant measures of renal function. Moreover, in the absence of a universal definition of renal impairment and renal failure, it is difficult to determine whether an effect is indeed clinically relevant. There is an obvious need to conduct large, prospective, randomized, blinded clinical trials to further delineate any effect of intravenous fluid therapy on renal function. Crucially, the impact of an IV fluid on renal function may be dependent on the type of surgery and the clinical condition of the patient. The administration of 500 ml of any fluid to a healthy, young patient undergoing ambulatory surgery is, not surprisingly, unlikely to have a significant impact on renal function. It also seems unlikely, in light of the available evidence, that the administration of small volumes of fluid causes a significant clinical renal effect. Conversely, the administration of dextran to a dehydrated patient undergoing major vascular surgery may induce acute renal dysfunction. Indeed, on the basis of many reports of acute renal failure associated with dextran administration, they should not be administered for the restoration of blood volume. Their use as antithrombotic agents should also be avoided in patients who are dehydrated or have any risk factors for renal impairment or failure. It is apparent that the traditional classification of fluids into crystalloid and colloid may be too simplistic. The preparation of the same colloid in two different solutions may result in two fluids with distinct clinical impacts. Therefore, all colloids are not the same and the nature of a solution should also be referred to when categorizing an IV solution. Additionally, HES solutions with different molecular weights and degrees of substitution (and hence pharmacokinetic properties) may have varying effects. Two of the largest and best conducted of the clinical trials of HES and renal function demonstrated a negative impact on renal function with HES 200/0.6 adminstration 35,36 and HES 450/0.7 use has also been implicated in perioperative renal dysfunction in at risk patients. 11,15 There is, however, no suggestion in the literature that the lower molecular weight starches are deleterious to renal function. The administration of large volumes of HES, in particular high concentration and higher molecular weight preparations, might reasonably be avoided in patients who are at risk of renal dysfunction and failure. It may be prudent to avoid the infusion of large volumes of normal saline, normal saline-based fluids where balanced saltbased fluid preparations are available in individuals who are vulnerable. It is true that the evidence regarding the effect of 0.9% NaCl on the kidney is far from irrefutable. However, the administration of balanced salt-based fluids, at the very least, averts the hyperchloremic metabolic acidosis associated with normal saline. Furthermore, the fear of causing hyperkalemia with potassium containing balanced salt fluids in patients with renal failure may be unfounded. Intriguing questions are raised as to the potential mechanisms by which renal function may be influenced by intravenous fluid administration. Is the putative normal saline-induced renal dysfunction observed in cardiac surgical patients 15 mediated by a similar mechanism, possibly vasoconstriction, as the decrease in splanchnic perfusion observed in elderly surgical patients treated with normal saline-based fluids? 9 Might hyperchloremia or metabolic acidosis stimulate the release of some intrarenal vasoconstrictor? And what is the precise mechanism whereby some higher molecular weight colloids cause kidney dysfunction? Despite the limitations of the body of evidence that has been accumulated to date, there are some well designed studies which suggest that the choice of fluid type may indeed have an influence on renal function. Furthermore, the studies performed thus far raise several interesting questions and present possibilities for future clinical research. ( Page 422 )

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