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Anesth Analg 2003;97:1595-1604
© 2003 International Anesthesia Research Society

CARDIOVASCULAR ANESTHESIA

New Light on Intravascular Volume Replacement Regimens: What Did We Learn from the Past Three Years?

Joachim Boldt, MD

Department of Anesthesiology and Intensive Care Medicine, Klinikum der Stadt Ludwigshafen, Ludwigshafen, Germany

Address correspondence and reprint requests to Joachim Boldt, MD, Department of Anesthesiology and Intensive Care Medicine, Klinikum der Stadt Ludwigshafen, Bremserstr. 79, D-67063 Ludwigshafen, Germany. Address e-mail to BoldtJ{at}gmx.net


   Abstract
Top
 Abstract
Introduction
 What Has Been Published...
 Conclusions
 References
 
Definition of the "ideal" intravascular fluid volume replacement strategy still remains a critical problem. This article analyzes studies on volume replacement by using a MEDLINE search of the past 3 years (from January 1, 2000, to December 12, 2002). Forty original studies in humans with a total of 2454 subjects were identified. Five studies were performed in volunteers (n = 113); the other 35 studies (n = 2341) were performed in a variety of patients (e.g., cardiac surgery, trauma patients, children, and intensive care unit patients). The influence of different volume replacement regimens on coagulation was one of the major topics of interest (16 studies with 1183 subjects), and other studies focused on metabolic state, alterations in macro- and microcirculation, volume distribution, and organ function (e.g., kidney function and splanchnic perfusion). Among all synthetic colloids, hydroxyethyl starch (HES) was the solution most often studied. Two new HES preparations have been approved (Hextend®, a balanced hetastarch solution, and a new third-generation HES [130/0.4]). Only two studies used albumin, and no superiority of albumin was found over less expensive synthetic colloids. In almost all studies, the outcome either was no end-point or was not reported. Volume replacement has often been hitherto based on dogma and personal beliefs. Future well performed studies in this area will hopefully help to shed new light on the ideal volume replacement strategy.

IMPLICATIONS: By using a MEDLINE search covering the last 3 yr, the present knowledge on volume replacement regimens was analyzed. Forty studies in humans were identified. New hydroxyethyl starch preparations have shed light on this topic, whereas no additional data supporting the use of albumin have been presented.


   Introduction
Top
 Abstract
 Introduction
What Has Been Published...
 Conclusions
 References
 
Hypovolemia is common among surgical, trauma, and intensive care unit (ICU) patients. It can occur in the absence of obvious fluid loss secondary to vasodilation or during generalized alterations of the endothelial barrier resulting in diffuse capillary leak. Thus, especially in the patient with inflammation, large fluid deficits become obvious. This situation is characterized by panendothelial injury with subsequent development of increased endothelial permeability, leading to a loss of proteins and a fluid shift from the intravascular to the interstitial compartment (1,2). A prospective study of patients who died in the hospital after admission for treatment of injuries showed that inadequate fluid resuscitation was the most common mismanagement (3). An adequate intravascular volume replacement therapy may help to improve organ function and reduce patient morbidity or even mortality. In approximately 50% of septic patients, adequate volume replacement alone can reverse hypotension and restore hemodynamics (4).

Although the importance of adequate volume replacement has been widely accepted, the "optimal" strategy is still the focus of debate (5). The continuing interest in this topic is reflected by the fact that in almost every anesthesia and intensive care journal, several articles on volume replacement have been published. In a systematic review from 1999 comparing crystalloids and colloids for fluid resuscitation, Choi et al. (6) identified 17 relevant primary studies out of 105 articles on this topic published from 1966 to 1996. We are living in times of very rapidly changing medical information. Thus, this study focuses on the present approach to intravascular volume therapy. Original human studies and meta-analyses on different volume replacement regimens that have been published during the past 3 yr (2000–2002) in the English literature were identified with a MEDLINE analysis. Key words entered were as follows: "volume," "volume replacement," "volume therapy," "fluid," "fluid replacement," "fluid therapy," "humans," "children," "hydroxyethylstarch," "dextran," "gelatin," and "crystalloids." Letters, case reports, and experimental (in vitro) or animal studies were not included because animal models of hypovolemia cannot mimic clinical conditions.


   What Has Been Published During the Past Three Years?
Top
 Abstract
 Introduction
 What Has Been Published...
Conclusions
 References
 
Forty studies including 2454 people were found (Tables 1–3) (7–46). Five studies were performed in volunteers (n = 113). The other 35 studies were performed in a variety of patients (e.g., cardiac surgery, trauma patients, children, and ICU patients) (n = 2341). Only one study used a retrospective study design (7). Two studies were retrospective questionnaires (41,44), and in one study, the study design was not clearly described (10). The other studies were prospective randomized studies or even used a double-blinded design (n = 8).


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  		Table 1. Studies on Volume Replacement Strategies and Coagulation/Bleeding
 

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  		Table 2. Studies on Volume Replacement Strategies
 

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  		Table 3. Studies on Volume Replacement Strategies
 
Coagulation
Coagulopathy associated with (cardiac) surgery, trauma, or intensive care is an intricate, multifactorial, and multicellular event. Hemostatic disorders are frequent complications in these patients. The appropriate therapy is a complex issue and must be adapted according to the individual situation. Hypercoagulability may be helpful in the severely bleeding trauma patient but disastrous for organ perfusion in the same patient in the ICU.

The choice of volume replacement strategy may also have an important effect on the coagulation process. An unaffected hemostasis by volume administration apart from the hemodilution seems to be an appropriate request when looking for the "ideal" volume replacement strategy.

Most of the identified studies of this analysis were studies on the use of different volume replacement regimens and coagulation (n = 16 with 1183 patients). Most studies used sophisticated measurement devices to identify alterations in coagulation, whereas, unfortunately, only a few studies focused on the amount of bleeding or the use of blood and blood products.

When compared with colloids, crystalloids are often preferred because they are inexpensive and appear to be almost free of significant side effects, especially with regard to hemostasis. There is convincing evidence that the use of crystalloids has a substantial influence on coagulation: hypercoagulability with the use of crystalloids has been demonstrated in four studies (14,18,20,22). The reason for the hypercoagulable state appears to be an imbalance between naturally occurring anticoagulants and activated procoagulants; a reduction of antithrombin III is probably the most important (47). This increase in coagulation seems to be independent of the type of crystalloid that has been used (20). Although negative data on crystalloids and coagulation are available, the clinical importance of this hypercoagulability after infusion of considerable amounts of crystalloids remains unclear. Only one early study reported that the increase in coagulation in patients to whom crystalloids were given during surgery was associated with an increased incidence of deep vein thrombosis (48). Thus, more information is necessary to assess whether crystalloids are still "good" with regard to the coagulation process.

The lack of acceptance of hydroxyethyl starch (HES) for volume replacement is most likely due to reports on abnormal coagulation with this plasma substitute. Reports on HES showing compromised blood coagulation and an increased bleeding tendency are mostly based on the use of the first-generation, high-molecular-weight (HMW) HES preparation (mean molecular weight [Mw], 450 kDa) with a high degree of substitution (DS; 0.7) (hetastarch) or HES preparations with a high DS (0.62). The known negative effect of hetastarch on hemostasis has been confirmed by a retrospective study in cardiac surgery patients (7) and a prospective randomized study in noncardiac surgery patients (22). Other highly substituted HES preparations (DS, 0.62) are also associated with considerable negative effects on blood clotting and subsequently may increase the postoperative bleeding tendency. This has been confirmed by a study in patients undergoing minor elective surgery in whom either saline solution 15 mL/kg (n = 15) or 15 mL/kg of a HES preparation with a medium Mw (200 kDa) but a high DS (0.62) was given (10). Only in the HES-treated group was reduced glycoprotein IIb/IIIa expression seen, indicating an impaired platelet-related coagulation process.

The weight average (Mw) of the HES preparation appears to play a certain role in the modification of coagulation: in a study in healthy volunteers, either 500 mL of HES with a Mw of 70 kDa or HES with a Mw of 200 kDa was infused over 30 min (9). von Willebrand factor, prothrombin time, and maximal clotting amplitude (indicating the strength of the thrombus), measured by thrombelastography (TEG®; Haemoscope Corp., Skokie, IL), were more altered by HES 200/0.5 than by HES 70/0.5.

Two new HES preparations have been developed to avoid negative effects on coagulation: a modified HMW HES (Hextend®; Abbott Laboratories, North Chicago, IL) and a third-generation, low-molecular-weight/low-substituted HES (Mw, 130 kDa; DS, 0.4). Hextend® is a modified, physiologically "balanced" first-generation HMW HES preparation (molar substitution, 0.7; weight average molecular weight, approximately 670 kDa; Mw, 550 kDa) containing balanced electrolytes (Na+, 143 mmol/L; Cl-, 124 mmol/L; lactate, 28 mmol/L; Ca2+, 2.5 mmol/L; K+, 3 mmol/L; Mg2+, 0.45 mmol/L; glucose, 5 mmol/L) (49). By using TEG®, this specific HES preparation was reported to impair coagulation significantly less than standard HMW HES (hetastarch) (22). Others, however, could not verify that this modification of an HMW (Mw, 550 kDa), highly substituted (DS, 0.7) HES preparation eliminated the known negative effects on coagulation of such an HES preparation (19).

A third-generation HES preparation with a low Mw (130 kDa) and the smallest available DS (0.4) shows favorable physicochemical properties compared with other HES solutions (50). In six studies (8,12,13,16,17,19), the beneficial effects on coagulation have been shown. In healthy patients undergoing minor elective surgery, 10 mL/kg of saline or of four different HES preparations, including the new HES 130/0.4, was given (13). After infusion of HES 130/0.4, platelet function (measured by a platelet function analyzer: PFA-100TM; Dade-Behring, Marburg, Germany) remained unaffected, whereas the other HES preparations (HES 70/0.5, HES 200/0.5, and HES 450/0.7) resulted in significant alterations in platelet function. Whether the platelet function analyzer is of clinical value with regard to bleeding is unclear because large prospective studies with this tool are missing. With TEG®, infusion of approximately 2500 mL of HES 130/0.4 in patients undergoing major abdominal surgery was associated with no negative effect on hemostasis (17,19). This HES preparation did not show a negative influence in cardiac surgery patients on coagulation time, clot formation, or maximum clot firmness as measured by the TEG® technique (16). HES 130/0.4 also seems to have beneficial effects on bleeding tendency: in vivo studies using HES 130/0.4 in cardiac surgical (8) and orthopedic (12) patients showed a trend toward less bleeding and less use of blood or blood products with HES 130/0.4 than volume therapy with a conventional HES 200/0.5 preparation.

Renal Function
The negative effects of dextran on renal function have been described (51) (Table 2). The pathogenesis of acute renal failure (ARF) after dextran infusion appears to be multifactorial, including "hyperoncotic ARF," tubular obstruction, and direct toxicity.

Negative effects with the use of HES on kidney function have been published in two case reports (52,53). Only three studies published over the past 3 years focused on kidney function (23–25). In a randomized, multicenter study in 129 ICU patients with sepsis or septic shock, the effects of HES infusion were assessed (23). The patients received either gelatin (n = 64) or a highly substituted HES preparation (Mw, 200 kDa; DS, 0.62; n = 65) for volume therapy ("to treat hypotension/hypoperfusion"). The median cumulative volume replacement was 31 mL/kg with HES and 43 mL/kg with gelatin. ARF (defined as a twofold increase in serum creatinine concentration or the need for renal replacement therapy) developed in 27 (42%) of the HES-treated patients and in 15 (23%) of the gelatin-infused patients (P < 0.028). Differences in creatinine concentrations became significant 6 days after first use of HES. Unfortunately, the two volume groups already showed different creatinine levels before the start of volume therapy: median serum creatinine concentrations were 143 µmol/L in the HES-treated and 114 µmol/L in the gelatin-treated patients. With a multivariate analysis, the administration of a slow degradable HES preparation (HES 200/0.62) was identified as a risk factor for the occurrence of ARF. Despite a more frequent incidence of ARF in the HES-treated patients, mortality was not significantly different between the two groups.

In another clinical study in patients without altered renal function undergoing middle ear surgery, small doses (15 mL/kg) of different HES preparations (6% HES 450/0.7, 6% HES 200/0.62, or 6% HES 200/0.5) did not result in impaired kidney function as assessed by sensitive markers of altered renal integrity (e.g., {alpha}1-microglobulin, D-acetyl-ß-glucosamidase, Tamm-Horsfall protein, and inulin clearance) (24).

Unfortunately, extensive information concerning volume replacement in patients with altered kidney function before volume administration is still lacking. Thus, all HES preparations cannot be recommended in patients with impaired kidney function. The "critical" creatinine level when HES should be avoided is not known. There has been new light shed on this problem by a new HES preparation: in volunteers, the new third-generation HES (HES 130/0.4) was used in patients who showed mild to severe renal dysfunction (mean creatinine clearance, 50.6 mL/min per 1.73 m2) (25). After 500 mL of HES 130/0.4, kidney function was not affected (creatinine clearance was even slightly increased by 7.5 mL/min per 1.73 m2), indicating no negative effects of this new preparation with regard to kidney function.

Hemodynamics, Microcirculation, Volume Distribution, and Inflammation
During hypovolemia, systemic hemodynamics and microcirculation are impaired, subsequently triggering a vicious cycle of progressive tissue damage that finally may lead to development of multiple organ failure (Table 2). By adequately restoring intravascular volume, organ perfusion may be guaranteed, nutritive microcirculatory flow may be improved, and activation of a complex series of damaging cascades may be avoided. Whether the kind of fluid therapy might influence the vicious cycle induced by hypovolemia has not yet been definitely decided. In some (older) experimental studies, it has been demonstrated that compared with colloids, even a massive crystalloid resuscitation alone is less likely to achieve adequate restoration of (microcirculatory) blood flow (54). Microcirculation, organ perfusion, and tissue oxygenation are difficult to assess in humans. Most often, unspecific and indirect indicators are used (e.g., gastric intramucosal pH [pHi]). Whether these variables reflect tissue perfusion is still unclear. Also, the link to patient morbidity or mortality remains to be elucidated.

Only three studies (26,28,32) in humans were identified that focused on organ perfusion, microcirculation, and tissue oxygenation with different types of plasma substitutes.

  1. In a study in septic hypovolemic patients, 500 mL of gelatin or 500 mL of HES 200/0.62 was used, and the effects on splanchnic perfusion measured by tonometry were assessed (26). Only gelatin infusion increased pHi slightly (from 7.27 ± 0.08 to 7.31 ± 0.07), whereas pHi decreased in the HES-treated patients (from 7.26 ± 0.11 to 7.22 ± 0.08).
  2. In critically ill hypovolemic patients who had sepsis syndrome, volume expansion with a 10% Mw HES preparation (Mw, 250 kDa; pentastarch) did not change abnormal intramucosal CO2 tension, gastric-atrial PCO2 gradient, or pHi, despite increasing cardiac index, oxygen delivery, and filling pressures (28).
  3. In patients undergoing major abdominal surgery, the influence of a new third-generation HES (HES 130/0.4) on tissue PO2 was compared with only saline solution (n = 21) for volume replacement (32). By using flexible minimally invasive microsensoric PO2 catheters, tissue PO2 was monitored for 24 h after surgery. Although systemic hemodynamics and systemic oxygenation data were unchanged from baseline and were similar in both groups, tissue PO2 increased significantly in the HES-treated patients (maximum, +59%), whereas it decreased in the Ringer’s lactate solution (RL) group (maximum, -23%). It was concluded that intravascular volume replacement with HES 130/0.4 may improve tissue oxygenation during and after major surgical procedures, most likely because of improved microcirculation.

The effects of an albumin-based versus a normal saline (NS)-based volume therapy on volume distribution were compared in a study in cardiac surgery ICU patients (29). Intravascular volume was given to achieve a specific pulmonary artery occlusion pressure that was determined by the attending clinician. Albumin 5% (8 ± 3 mL/kg) as a plasma volume substitute was five times as efficient as NS (16 ± 6 mL/kg). No differences were seen with regard to interstitial fluid volume and oxygen delivery.

Whether the choice of volume affects the inflammatory process is still not clear. Jaeger et al. (27) used three different kinds of HES preparation and gelatin in patients undergoing urological procedures. Only gelatin significantly decreased the phagocytic activity of polymorphonuclear neutrophils.

Metabolic Status
Significant alterations in acid-base balance developed in patients in whom considerable amounts of 0.9% saline solution were infused ("hyperchloremic acidosis") (55) (Table 3). One recent study in patients undergoing major spine surgery showed that this phenomenon occurs only when considerable amounts of NS solution are infused. The use of RL was not associated with hyperchloremic acidosis (37).

Large amounts of colloids may also be associated with metabolic acidosis: acute normovolemic hemodilution (aim: hematocrit 22%) in patients undergoing gynecologic surgery with either 5% albumin or 6% HES 200/0.5 resulted in metabolic acidosis in both groups (34). A dilution of extracellular bicarbonate or changes in strong ion differences and albumin concentration may be explanations for this type of acidosis. Others found decreased base excess only after use of standard HMW HES and not with albumin (33). However, there is little information as to the clinical relevance of this type of acidosis. Negative consequences of hyperchloremic acidosis on organ function have been elucidated by some studies: in patients undergoing abdominal aortic aneurysm repair, either RL total dose—6800 mL—or NS total dose—7000 mL—was used for volume replacement in a double-blinded fashion (42). Only the NS-treated patients developed hyperchloremic acidosis. They needed significantly more blood products than the RL patients. There is also some evidence that hyperchloremic acidosis may impair end-organ perfusion. In elderly patients undergoing elective surgery, either conventional HMW HES (hetastarch) or hetastarch in a balanced electrolyte and glucose formulation (Hextend®) was used (36). Only patients treated with the conventional hetastarch developed hyperchloremic acidosis (postoperative base excess, -0.2 vs -3.8 mmol/L). From their tonometric data, the authors suggested improved gastric mucosal perfusion in the group treated with the balanced hetastarch solution (Hextend®) when compared with a saline-dissolved hetastarch. However, differences in pHi between the two group may be attributable simply to changes in bicarbonate, because volume expansion occurred with solutions with different diluents.

Children
Volume therapy in children still remains an unsolved issue. In the past 3 yr, only two studies were performed in children (38,39), reflecting the difficulties in performing research in children. One randomized, prospective, double-blinded study was focused on children with Dengue shock syndrome. They achieved an initial fixed dose of RL, NS, gelatin, or dextran 70 (20 mL/kg). When additional volume was needed, dextran 70 was given to all patients at the "discretion of the doctors." Additional dextran boluses were given in the two crystalloid groups. The administration of colloids (gelatin and dextran) resulted in more beneficial effects with regard to hemodynamics than use of crystalloids. Outcome was not different among the four groups.

Another study in children compared an albumin-added priming with a pure crystalloid priming in children undergoing cardiac surgery with cardiopulmonary bypass (CPB) (39). The albumin patients had a negative post-CPB fluid balance and gained less weight after surgery. There were no differences with regard to length of ventilation, ICU or hospital stay, or mortality.

Safety, Costs, and Outcome
Three studies were safety studies that used new products [two used third-generation HES (40,45), and one used Hextend® (46)]. Two studies were questionnaires showing that large amounts of specific HES products may be associated with an increased risk of itching (41,44). Only one study focused on costs and showed that no big savings can be reached with use of crystalloids instead of one of the synthetic colloids (43).

There is still no large prospective study that shows the superiority of a specific volume replacement strategy with regard to outcome. One study with 66 patients undergoing abdominal aortic aneurysm repair was specifically focused on outcome, using two crystalloid-based volume replacement regimens (RL versus NS) (42): no differences in outcome between the two groups were seen in patients. This study was definitely underpowered to draw any conclusion concerning outcome. Well performed, adequately powered studies on volume replacement strategies and outcome are still missing.

Volume Therapy in the Light of Recent Meta-analyses
In a Cochrane Review from 2002, a systematic review was made of colloids versus crystalloids for fluid resuscitation in critically ill patients (56). No study more recent than 2000 was included in this analysis comparing the mortality of colloids versus crystalloids for fluid resuscitation in humans. Twenty-six trials comparing crystalloids with different kinds of colloids, nine trials comparing colloids prepared in hypertonic crystalloids with isotonic crystalloids, and three trials comparing hypertonic crystalloids with colloids were included. There was no evidence that resuscitation with colloids reduced the risk of death in patients after surgery or in those with trauma or burns.

In another systematic review from the Cochrane Group from 2002, a hypertonic-based volume replacement regimen was compared with crystalloid-based volume replacement in critically ill patients (57). Although many studies have been published on this topic, only 12 studies were included in the analysis. The authors concluded that there is no evidence that one strategy of volume therapy is superior to another for patients with trauma (five studies included) or burns (three studies included) or for those undergoing surgery (four studies included). The results concerning trauma patients are in contrast to another meta-analysis on hypertonic volume replacement from 1997, which included 12 studies that compared hypertonic saline-based volume therapy with dextran-based volume replacement (58). This meta-analysis suggests a favorable survival benefit for hypertonic saline treatment of traumatic hypotension.

The influence of an expensive albumin-based volume therapy on mortality compared with other less expensive volume replacement strategies was compared in a meta-analysis of randomized, controlled trials from 2001 (59). No study more recent than 2000 was included. Trials involving surgery and trauma (27 studies), burns (4 studies), hypoalbuminemia (5 studies), high-risk neonates (6 studies), ascites (5 studies), and other indications (8 studies) were included. None of the analyzed factors (outcome or mortality) was significantly influenced by either of the volume replacement regimens. There was overall no beneficial effect of albumin on mortality in these 55 studies (including 3504 patients) in comparison to other plasma substitutes. This analysis found only two studies (31,34) in patients comparing albumin with a synthetic colloid. There was no information on outcome in these two studies.

Two reviews and meta-analyses (60,61) focused only on the effects of plasma substitutes on blood coagulation. de Jonge and Levi (60) selected articles that provided data on the effects of all colloids on hemostasis and postoperative blood loss in humans. They concluded that all artifical colloids are potentially associated with an increased bleeding tendency after infusion of very large volumes; however, they concluded that rapidly degradable HES preparations (e.g., HES 200/0.5) and gelatin did not appear to impair the coagulation process significantly. New HES products were not included in this analysis.

Wilkes et al. (61) performed a meta-analysis on postoperative bleeding in cardiac surgery patients in whom either albumin or different HES preparations had been given. Both solutions had been used either before or after CPB or as an addition to the priming. When HMW HES (hetastarch) was compared with albumin (9 studies with 354 patients), postoperative bleeding was significantly more frequent in the HMW HES patients than in the albumin-treated patients. When HES with a lower Mw (200 kDa) was compared with albumin (8 studies with 299 patients), there was no more statistical difference in postoperative bleeding tendency. The differences in mean bleeding volume in the included studies comparing albumin with HES 200 ranged from a 40-mL larger bleeding volume in the albumin patients up to a 209-mL larger bleeding volume in the HES patients. Aside from lacking statistical significance, this difference in bleeding volume in cardiac surgery is without relevance. Use of blood and blood products was not systematically analyzed.


   Conclusions
Top
 Abstract
 Introduction
 What Has Been Published...
 Conclusions
References
 
Adequate management of the underlying insult is a prerequisite of treating trauma, surgical, and critically ill ICU patients—supportive therapy, including sufficient volume therapy, however, also appears to be highly important. What did we learn from the information that has been published on volume replacement strategies during the past 3 yr?

  1. Although the quality of studies has improved (prospective, randomized rather than retrospective studies), standardized protocols for volume replacement are unfortunately often still missing. Criteria for volume infusion such as "determined by the attending clinician" are inappropriate for assessing the effects of a certain substance.
  2. Although several studies are available assessing the different volume replacement strategies, there are still no convincing guidelines regarding the choice of fluid for volume replacement.
  3. Crystalloids may have a negative influence on coagulation (hypercoagulability) and on the metabolic state (acidosis). They appear to have no beneficial effect on microcirculation and organ perfusion.
  4. Although the albumin manufacturers put considerable pressure on the market by means of a US$2.2 million support program (62), recently published data do not support the use of albumin over synthetic colloids to treat hypovolemia.
  5. No new information on dextrans is available. The little interest concerning dextrans indicates that they are not the first choice for volume replacement.
  6. Gelatin was used in several recent studies without showing any severe negative effects.
  7. HES is the plasma substitute that has been studied most often. Conflicting results on the effects of HES on renal function, coagulation, organ perfusion, and side effects are due to the use of different HES preparations, varying clinical protocols, selection of patients, and different criteria for volume administration.
  8. Considerable effort has been devoted to developing new HES preparations without negative side effects (e.g., coagulation and kidney function). Two modifications have reached the market in the past years: Hextend®, a modified, physiologically "balanced" first-generation HMW HES, and a new third-generation HES preparation with a lower Mw (130 kDa) and smaller DS (0.4) than conventional HES preparations. Although these present some promising results, the final conclusions concerning these two new solutions are still open.
  9. One important lesson from the recent studies over the past years is not to become addicted to the myths of meta-analyses. It has been questioned whether they are appropriate instruments for examining the value of different volume replacement regimens (63), because outcome (mortality) was not the end-point of most of the studies. Outcome may also be defined as time spent on ventilator support, organ dysfunction, improved efficiency, decreased cost, or decreased days in the hospital or ICU. We do not need more meta-analyses that pool "old-to-very old" data, but we do need well controlled studies in well defined groups of patients (trauma, burns, sepsis, general surgery, and cardiac surgery) comparing different types of volume replacement strategies (crystalloids, albumin, gelatins, dextrans, and different HES preparations), using clear criteria for volume therapy, and using well defined end points aside from outcome. Original research on this topic may be more helpful in improving our therapy than will more meta-analyses (64).


   Footnotes
 
This study was not supported by a pharmaceutical company.


   References
Top
 Abstract
 Introduction
 What Has Been Published...
 Conclusions
 References
 

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Accepted for publication July 10, 2003.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press