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Fluid choice for resuscitation of the trauma patient: a review of the physiological, pharmacological, and clinical evidence

[Le choix du liquide pour la réanimation du patient polytraumatisé : une revue des données physiologiques, pharmacologiques et cliniques]

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

Address correspondence to: Prof. Dr. Joachim Boldt, Department of Anesthesiology and Intensive Care Medicine, Klinikum der Stadt Ludwigshafen, Bremserstr. 79, D-67063 Ludwigshafen, Germany. Fax: 0621-503-3024; E-mail: BoldtJ{at}gmx.net

	Abstract

TOP Abstract Introduction Pathophysiology of shock in... Goals of volume replacement... Fluid choices in trauma... Colloids Clinical considerations of... Volume replacement in trauma... Analysis of the literature Conclusions References

 
Purpose: Volume replacement regimens are discussed very emotionally. Interpretation of the literature is difficult due to variations in study design, patient population, target for volume replacement, endpoints, and type of fluids. Meta-analyses may not be very helpful because all kinds of patients and very old studies are included. The principles and options for volume replacement were reviewed exclusively in trauma patients and studies from the literature focusing on this problem were analyzed.

Source: Using a MEDLINE search, volume replacement therapy in adult trauma patients published in the English language from 1985 to the end of 2002 were identified and analyzed. Studies on prehospital volume replacement, volume replacement in the emergency area or in the operating room, and volume therapy in trauma intensive care unit patients were included.

Principle findings: The age-old crystalloid/colloid controvery has still not been resolved but has been enlarged to a colloid/colloid debate. It is now widely accepted that human albumin could easily be replaced by synthetic colloids for volume replacement in trauma patients. No superiority of a specific volume replacement strategy with regard to outcome was found. However, in several studies outcome was not the major endpoint. Although showing some promising results, the importance of hypertonic solutions for volume replacement in the trauma patient is not yet defined.

Conclusion: The choice of fluid therapy in trauma patients engenders the most controversy and an examination of the body of literature on this subject results in confusion. It is imperative to continue the search for substances that are effective in avoiding the development of post-trauma multi-organ dysfunction syndrome without detrimental side-effects.

	Introduction

TOP Abstract Introduction Pathophysiology of shock in... Goals of volume replacement... Fluid choices in trauma... Colloids Clinical considerations of... Volume replacement in trauma... Analysis of the literature Conclusions References

 
TRAUMA is the fourth-leading cause of death in the USA.¹ Volume deficits are often present in trauma patients and may result in the development of post-trauma multiple organ failure on the intensive care unit (ICU). In addition to apparent blood loss, fluid deficits may also occur secondary to generalized alterations of the endothelial barrier resulting in diffuse capillary leakage and fluid shift from the intravascular to the interstitial compartment.

Adequate volume therapy appears to be a cornerstone of managing the trauma patient. In a prospective review of 111 consecutive patients who died in hospital after admission for treatment of injuries, the most common defects in patients’ management were related to inadequate fluid resuscitation.²

Besides (hypo-, iso-, and hypertonic) crystalloids, human albumin (HA) and various synthetic colloids [e.g., dextrans, gelatins, hydroxyethyl starch (HES) preparations] are available to treat trauma-related volume deficits. In recent years, the crystalloid/colloid dispute has been enlarged to a colloid/colloid debate because, aside from the natural colloid albumin, several synthetic colloids are increasingly used as plasma substitutes in the trauma patient.

Aggressive pre-hospital fluid administration (‘in the field’) has been common practice for more than 25 years in trauma patients. Some recent studies, however, have shown that early volume restoration before definite hemostasis has been performed may result in accelerated blood loss, hypothermia, and dilutional coagulopathy in certain types of trauma.³ Thus it has been recommended that volume replacement should not be started early (concept of "permissive hypotension;" "scoop and run" principle).⁴ This review is not designed to intensify the controversy between delayed fluid resuscitation and early (field) volume replacement, nor to suggest new guidelines for appropriate volume therapy in the trauma patient, but to recall the options for volume replacement and to analyze the literature according to different volume replacement regimens in trauma patients exclusively. Trauma patients are definitely different from cardiac surgery patients, patients with malignancies undergoing surgery or septic patients and thus volume replacement strategies should be reviewed separately for these patients.

	Pathophysiology of shock in the trauma patient

TOP Abstract Introduction Pathophysiology of shock in... Goals of volume replacement... Fluid choices in trauma... Colloids Clinical considerations of... Volume replacement in trauma... Analysis of the literature Conclusions References

 
Trauma is often associated with blood loss. Hemorrhage-related hypovolemic shock after trauma can be divided into three phases:⁵

-phase I is the period from injury to operation for control of bleeding (pre-definitive care);

-phase II is the period during and immediately after the operation;

-phase III is the period in the ICU (post-defini- tive care).

Trauma-related hypovolemia may be associated with flow alterations which are inadequate to fulfill the nutritive role of the circulation. Many of the manifestations of organ failure after successful primary resuscitation after trauma may result from peripheral (micro-) circulatory derangements. In spite of achieving "normal" systemic hemodynamics it is not guaranteed that perfusion in all organs and tissues is maintained as well. During low output syndrome the organism tries to compensate perfusion deficits by redistribution of flow to vital organs (e.g., heart, brain) resulting in an underperfusion of other organs (splanchnic bed, kidney). Various inflammatory mediators and vasopressors are released in this situation and are of particular importance for the development of impaired perfusion.

Recent evidence suggests that the endothelium is not only a passive barrier between the circulating blood and the tissues, but may also be markedly involved in the regulation of microcirculatory blood flow by producing important regulators of the vascular tone (e.g., prostaglandins, nitric oxide, endothelins, angiotensin II).⁶ The regional regulation of blood flow is likely due to a balance between systemic mechanisms (e.g., the autonomous nervous system) and other more locally active blood flow regulators. One important approach to improve perfusion in this situation appears to be the use of adequate volume. Our pathophysiologic knowledge on the importance of the endothelium in modulating microcirculation and inflammation has increased, however, the influence of different volume replacement strategies on endothelial function has still to be elucidated.

	Goals of volume replacement in the trauma patient

TOP Abstract Introduction Pathophysiology of shock in... Goals of volume replacement... Fluid choices in trauma... Colloids Clinical considerations of... Volume replacement in trauma... Analysis of the literature Conclusions References

 
The primary goal of volume administration is to guarantee stable systemic hemodynamics and microcirculation by rapidly restoring circulating plasma volume. Excessive fluid accumulation, particularly in the interstitial tissue should be avoided. Blood or blood products should be avoided as far as possible due to unwanted risks.^7–9

The infused fluid may stay in the intravascular compartment or equilibrate with the interstitial/intracellular fluid compartments. Different mechanisms are involved in the control of volume and composition of each compartment including the antidiuretic-hormone (ADH) system and the renin-angiotensin systems (RAS). The principal action of these systems is to retain water in order to restore water or intravascular volume deficits, to retain sodium in order to restore the intravascular volume, and to increase hydrostatic perfusion pressure by vasoconstriction. Enhanced activity of these systems is known to occur in stress situations, e.g., in trauma. If water or intravascular volume deficits and the stress-related stimuli are additive, volume therapy may inhibit this process through counter-regulatory mechanisms. ADH production is dependent on the maintenance of the extracellular volume and, particularly, the intravascular compartment. Administration of a restricted amount of crystalloids could replace a previous water deficit, but the replacement of an intravascular volume deficit would require much more volume to inhibit the activation of this system. Thus it can be expected that replacement of only water will not inhibit the normal response of ADH and RAS, whereas administering a combination of crystalloids and colloids (replacement of the water deficit and simultaneous guarantee of a sufficient intravascular volume) may achieve this goal.

One important aspect of fluid therapy in the traumatized patient is the risk of inducing interstitial edema. Tissue edema is related to an imbalance in the sum of the Starling forces across capillary membranes or an increase in protein permeability, by which an increase in fluid flux to the interstitial space is promoted. A decrease in membrane integrity, an increase in hydrostatic pressure, and a decrease in intravascular colloid oncotic pressure (COP) will induce fluid movement across the microvascular membrane and may produce interstitial tissue fluid accumulation (e.g., pulmonary edema). Moreover, endothelial swelling may occur by which organ perfusion is further disturbed.

	Fluid choices in trauma resuscitation

TOP Abstract Introduction Pathophysiology of shock in... Goals of volume replacement... Fluid choices in trauma... Colloids Clinical considerations of... Volume replacement in trauma... Analysis of the literature Conclusions References

 
Crystalloids
Hypotonic (e.g., dextrose in water), isotonic (e.g., Ringer’s solution) and hypertonic crystalloids (e.g., 7.5% saline solution) have to be distinguished when crystalloids are used for volume replacement. Crystalloids are freely permeable to the vascular membrane and are therefore distributed mainly in the interstitial and/or intercellular compartment. Only 25% of the infused crystalloid solution remains in the intravascular space, whereas 75% extravasates into the interstitium.¹⁰ Dilution of plasma protein concentration may also be accompanied by a reduction in plasma COP subsequently leading to tissue edema. It has been shown in animal experiments that even a massive crystalloid resuscitation is less likely to achieve adequate restoration of microcirculatory blood flow compared to a colloid-based volume replacement strategy.¹¹ In a study in patients who underwent major abdominal surgery and in whom crystalloids (RL) or colloids were used for volume replacement, Prien et al.¹² demonstrated a significantly larger intestinal edema with the use of RL than with colloids. In an experimental trauma-hemorrhage model either colloids (dextran) or crystalloids (Ringer’s acetate) were used to replace blood loss after surgical trauma.¹³ The crystalloid group showed significantly larger amounts of tissue water in muscle and jejunum than the colloid-treated group of animals.

	Colloids

TOP Abstract Introduction Pathophysiology of shock in... Goals of volume replacement... Fluid choices in trauma... Colloids Clinical considerations of... Volume replacement in trauma... Analysis of the literature Conclusions References

 
Albumin
Albumin is a naturally occurring plasma protein. The molecular weight of albumin is approximately 69 kD. Albumin is derived from pooled human plasma, heated and sterilized by ultrafiltration. Thus albumin is generally accepted to be safe in terms of transmission of infectious diseases. Albumin may have some additional specific effects aside from its volume replacing properties. The importance of albumin may be related to its transport function for various drugs and endogenous substances, e.g., bilirubin, free fatty acids.¹⁴ Albumin has also been reported to possess beneficial effects on membrane permeability secondary to free radical scavenging.¹⁵ These effects, however, were shown only experimentally and no clinical study has demonstrated any of these beneficial effects in comparison with synthetic plasma substitutes.

Dextran (Table I)
Dextran is a glucose polymer that is available in two preparations of different molecular weights and concentrations [6% dextran 70 (average molecular weight 70 kD); 10% dextran 40 (average molecular weight 40 kD)]. Increase of plasma volume after infusion of 1,000 mL of dextran 70 ranged from 600 to 800 mL. Some negative side-effects of dextrans have been well described including coagulation abnormalities resulting in increased bleeding tendency and severe life-threatening hypersensitivity reactions.

Gelatins (Table II)

HES (Table III)

Hypertonic solution (HS; Table IV)
Enthusiasm has been expressed for HS or hypertonic-hyperoncotic solutions in the treatment of hypovolemic shock in trauma patients. The concentration of sodium ranges from 3% to 7.5% and HS appear to improve cardiovascular function on multiple levels:

-displacement of tissue fluid into the blood com- partment;

-direct vasodilatory effects in the systemic and pulmonary circulations;

-reduction in venous capacitance;

-and positive inotropic effects through direct actions on myocardial cells.

The main mechanism of action of HS is the rapid mobilization of endogenous fluid and subsequent plasma volume expansion. Due to the hypertonicity of the solutions, only a small volume of fluid (approximately 4 mL•kg^–1) is necessary to effectively restore cardiovascular function (‘small volume resuscitation’). The initial improvement in cardiovascular function (e.g., increase in cardiac output) seems to be mediated by the hypertonicity of the solution, whereas the solute composition does not seem to be important. Beneficial effects of hypertonic saline solution were reported to be rather transient. Thus, HS are often mixed with colloids (dextran or HES), and these solutions show a significant prolongation of efficacy. The use of extreme HS (up to 2,400 mosmol•L^–1) has been studied in a limited number of clinical trials, mostly in trauma patients with severe hypovolemia and burns.

	Clinical considerations of volume replacement in the trauma patient

TOP Abstract Introduction Pathophysiology of shock in... Goals of volume replacement... Fluid choices in trauma... Colloids Clinical considerations of... Volume replacement in trauma... Analysis of the literature Conclusions References

 
All fluids used for volume replacement in the trauma patient have merits and demerits. The most alarming problems that have to be considered when using a specific fluid are anaphylactoid reactions, increased bleeding tendency, development of tissue edema, renal dysfunction, and possible alterations of the immune function.

Allergic reactions
The use of crystalloids is not associated with anaphylactic reactions. Dextran-associated anaphylactic reactions are widely known for their frequency and severity.¹⁹ Gelatins are at risk of producing a larger number of anaphylactic reactions compared with starch preparations as shown in a large trial including approximately 20,000 patients.²⁰ Gelatins were associated more often with severe, life-threatening anaphylactic reactions, whereas this was very rare after the infusion of HES.²⁰

Influence on coagulation and increased bleeding tendency
Coagulopathy is a common complication of hemorrhagic shock. Additionally, resuscitation-associated hemodilution may alter hemostasis by lowering the concentration of clotting proteins. Use of crystalloids has been thought to be without negative influence on coagulation except for that attributable to hemodilution, although recent studies have demonstrated an increased coagulability during hemodilution with saline.²¹ Albumin is considered to be the colloid with the least negative influence on coagulation, although procoagulatory or anticoagulatory effects (e.g., inhibiting platelet aggregation, enhancing the inhibition of factor Xa by antithrombin III) have been described with albumin.²² Dextrans are the plasma substitutes with the most widely accepted negative effects on hemostasis i.e., increasing bleeding tendency. Using dextran both VIIIR:Ag and VIIIR:RCo levels decrease significantly.²³ With reduced VIIIR:RCo there is a reduced binding to platelet membrane receptor proteins GPIb and GPIIb/IIIa that results in decreased platelet adhesion.²³ Gelatins have been thought to possess no negative effect on coagulation. However in a study in which healthy humans received either 1,000 mL of gelatin or saline solution, de Jonge et al.²⁴ found that the infusion of gelatin resulted in a significant impairment of primary hemostasis and thrombin generation. Changes in coagulation have most often been reported with the use of HES.²⁵ However, the different HES preparations have to be distinguished concerning their influence on the hemostatic process.^26,27 HMW-HES (hetastarch) diminishes concentrations of VIIIR:Ag and VIIIR:RCo more than a LMW-HES.²³ Platelet aggregation abnormalities have also been observed after the infusion of HMW-HES, whereas infusion of HES with a LMW did not change platelet aggregation induced by adenosine diphosphate.²⁸ A substantial body of evidence supports the concept that HES with MMW-HES: 130 kD, 200 kD and especially low MS (0.4; 0.5) have significantly less negative effects on coagulation and can be safely used with regard to hemostasis in humans.^27,28

Tissue edema
Factors contributing to tissue edema formation are venous congestion, reduced COP, arteriolar vasodilation/venous vasoconstriction, disorganization of the interstitial matrix, increased endothelial permeability, and lymphatic dysfunction. COP appears to be an important aspect in determining fluid shifts between the intravascular and interstitial compartments. Manipulation of COP appears to be promising to ensure adequate intravascular volume. Controversy still exists whether the choice of fluid for restoration of circulating volume is able to limit development of tissue edema. Dilution of serum proteins by the massive administration of crystalloids lowers COP with the risk of progressive expansion of the interstitial space. In a non-trauma experimental peritonitis model, crystalloid infusion resulted in more pronounced endothelial cell swelling and decreased systemic capillary cross-sectional area compared with volume therapy with colloids.²⁹

Maintenance of COP by the administration of albumin has been postulated to be a desirable goal. The oncotic force of concentrated albumin (e.g., HA 20%) has been shown to reduce tissue edema (e.g., pulmonary edema).³⁰ In patients with impaired vascular endothelial integrity (e.g., in trauma patients), albumin may pass into the interstitial compartment and fluid will subsequently shift from the intravascular to the interstitial space. A rapid and profound increase in the transcapillary escape rate of radio-labelled albumin has been described within six hours of surgery.³¹ The endothelium may also swell and, subsequently, microcirculatory perfusion is altered. In severely ill patients it was shown that the addition of albumin resulted in more signs of respiratory failure, compared to patients who did not receive albumin. This appears to be, most likely, due to increased leakage into the interstitial space.³²

In inflammatory-related capillary leaks, HES has been reported to have ‘occlusive’ effects on damaged capillaries, subsequently limiting the extravasation of fluid.³³ LMW-HES may exert beneficial effects on endothelial function, e.g., by O₂ free radical scavenging, by stabilization of fragile cell membranes, or by avoiding endothelial swelling. This may be of benefit, particularly in those trauma patients suffering from severe endothelial leakage syndrome.³⁴

Renal function
Renal dysfunction in trauma patients may develop for several reasons including insufficiently treated hypovolemia. Crystalloids have no specific negative effects on renal function except that they may not restore blood volume adequately. The effects of the different colloids are controversial. In patients with excessive fluid deficits, the glomerular filtration of hyperoncotic colloids (dextrans, 10% HES, 20% or 25% albumin) causes a hyperviscous urine and stasis of the tubular flow resulting in obstruction of tubular lumen.³⁵ Certain commercially available albumins are known to contain remarkable quantities of ions from the preparation process resulting in toxic concentrations of aluminium in patients with acute renal failure.³⁶ HES molecules and gelatin molecules are eliminated by glomerular filtration. Gelatins appear to be almost devoid of significant damaging effects on the kidneys. In a retrospective analysis of patients undergoing kidney transplantation and in whom HES with a high DS (0.62) was infused, "osmotic-nephrosis-like lesions" were documented.³⁷ This phenomenon, however, did not have negative effects on graft function three and six months after transplantation. Use of 6% HES 200/0.62 (2,100 ± 660 mL) in brain-dead donors resulted in impaired renal function in kidney transplant recipients.³⁸ Patients treated with this HES preparation with a high MS showed higher serum creatinine concentrations and a more frequent need for hemodialysis compared to a gelatin-treated group of patients. In a multicentre study in intensive care patients, HES (200/0.62) resulted in a significantly higher incidence of renal failure compared to a comparable group of patients who received a gelatin preparation.³⁹ Fortunately, the authors distinguished between different types of starches, and state that the results of the study may not be applicable to more rapidly degradable HES preparations (e.g., HES 200/0.5). Use of HES 200/0.5 over five days in a study of critically ill ICU patients was without negative effects on renal function compared to a control group in whom albumin was administered.⁴⁰ In a study in elderly patients (> 75 yr) administration of 6% HES 200/0.5 undergoing major abdominal surgery was not associated with relevant changes of markers of renal function (e.g., alpha-1-microglobulin, N-acetyl-beta-D-glucosaminidase).⁴¹

Accumulation and dose limitations
Storing, accumulation, and dose limitations have to be considered only when using synthetic colloids. Gelatin and dextrans are naturally occurring substances and both are fully metabolized in man. Nevertheless, a dose-limitation exists for dextrans (approximately 2,500 mL•day^–1) most likely because higher doses are associated with severe bleeding complications. All available HES preparations are stored and may accumulate depending on the preparation. The smaller molecules are rapidly eliminated by glomerular filtration. A varying proportion of the HES administered leaves the vascular space and is taken up by the reticuloendothelial system (RES). RES storage, however, appears to be without detrimental consequences.⁴² Nevertheless, a dose limitation exists for all HES preparations ranging from 20 mL•kg^–1 to 50 mL•kg^–1.

Immune function
Traumatic injury is known to induce intense alterations in circulatory hemostasis and cell-mediated or humoral immunity.⁴³ These sequelae of trauma predispose to the development of post-trauma sepsis or systemic inflammatory response syndrome (SIRS). The mediators of immunosuppression secondary to trauma are not definitely elucidated. Endotoxin, tissue metabolic products resulting from cellular hypoxia, shock proteins, hormonal mediators (e.g., catecholamines) are suspected to take part in this process. Polymorphonuclear cells are supposed to be key mediators of tissue injury and organ failure. While neutrophils are essential for bacterial killing, they paradoxically have the capacity to injure host tissue. The interactions of neutrophils with endothelial cells are regulated by complementary adhesion molecules, which are present on these cells (e.g., the immunoglobulin superfamily [e.g., vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1)]; the integrin family [e.g., lymphocyte function-associated antigen (e.g., LFA-1 = CD11a/CD18)]; the selectins [E-selectin = endothelial leukocyte adhesion molecule (ELAM-1)]; L-selectin = e.g., leukocyte endothelial cell adhesion molecule; P-selectin = granule membrane protein 140 (= GMP-140). The soluble forms of some of these adhesion molecules appear to be excellent markers of inflammation and endothelial activation or damage.⁴⁴ The influence of HES on endothelial cell activation was studied experimentally by Collis et al.⁴⁵ using endothelial cell cultures (human umbilical vein endothelial cells). E-selectin expression on lipopolysaccharide-stimulated endothelial cells was not influenced by HES. The authors, however, suggested a possible beneficial role of HES by inhibiting endothelial activation. Thrombin-stimulated von Willebrand factor (vWF) release was significantly more reduced in the presence of HES than in the presence of HA. The authors concluded from their data that HES may be able to inhibit endothelial activation with subsequent damage of endothelial integrity and that, by this mechanism, HES may be able to ameliorate capillary leak secondary to inflammation. The effects of 10% HES 200/0.5 or 20% albumin for volume replacement over five days in severely (non-septic) traumatized patients on plasma levels of circulating adhesion molecules were assessed in a prospective randomized study.⁴⁶ Soluble ELAM-1, soluble ICAM-1, and soluble VCAM-1 plasma levels did not differ between HES- and HA-treated patients indicating no negative effect of the synthetic colloid HES on endothelial function.

	Volume replacement in trauma patient: analysis of the literature

TOP Abstract Introduction Pathophysiology of shock in... Goals of volume replacement... Fluid choices in trauma... Colloids Clinical considerations of... Volume replacement in trauma... Analysis of the literature Conclusions References

 
In the Advanced Trauma Life Support guidelines Ringer’s lactate is recommended as part of the emergency resuscitation of the trauma patient, proceeding to blood products as required.⁴⁷ The American College of Surgeons Classes of Acute Hemorrhages specify four classes of acute hemorrhage using a blood loss ranging from up to 750 mL to > 2,000 mL.⁴⁸ Fluid replacement should be performed with crystalloids exclusively (3:1 rule) - there is no place for infusing (synthetic) colloids in their recommendations.

	Analysis of the literature

TOP Abstract Introduction Pathophysiology of shock in... Goals of volume replacement... Fluid choices in trauma... Colloids Clinical considerations of... Volume replacement in trauma... Analysis of the literature Conclusions References

 
Crystalloids vs colloids in trauma patients
PUBLISHED META-ANALYSES
We are living in times of meta-analyses and evidence based medicine (EBM). Different volume replacement regimens have been examined with the help of these popular instruments:

-In a meta-analysis from 1989, a possible reduction in mortality was documented when crystalloids were used in traumatized patients.⁴⁹ In this analysis, five trauma studies were included, two were from 1981, one from 1979, one from 1978, and one from 1977.

-In a meta-analysis by Schierhout and Robertson in 1998,⁵⁰ the use of colloids was associated with an increased incidence of death. Seven trauma studies were included in this meta-analysis - three of them used hypertonic/colloidal solutions, two albumin, one dextran, and another gelatin. Summarizing all 37 analyzed studies, resuscitation with colloids was associated with an increased absolute risk of mortality of 4% (or four extra deaths for every 100 patients resuscitated).

-In the Cochrane EBM analysis on volume replacement in 1998, four trauma studies were included - one was from 1977, two were from 1978, and one was from 1983.⁵¹ The message of this EBM analysis was that albumin "kills our patients" (for every 17 patients treated with albumin there was one additional death).

-Only one meta-analysis distinguished between trauma patients and other kinds of patients (e.g., cardiac surgery, critical care patients).⁵² In this analysis from 1999 four trauma studies were included; all of them were more than 17 years old. All kinds of colloids were compared to crystalloid-based resuscitation. There were no differences between the two volume replacement strategies.

-The influence of an albumin-based volume therapy on mortality compared to other less expensive volume replacement strategies was compared in a meta-analysis of randomized controlled trials in 2001.⁵³ No study more recent than 2000 was included. In one subgroup, studies involving surgery and trauma (27 studies) were included. None of the analyzed factors (outcome, mortality) were significantly influenced by either volume replacement regimens. There was, overall, no beneficial effect of (expensive) albumin in comparison to other (cheaper) plasma substitutes on mortality.

Meta-analyses have two fundamental problems:⁵⁴

1. There may be a selection bias of included trials; and
   
2. the results of the analyses may be similar, but they can be interpreted quite differently. Specific objections to all meta-analyses on volume therapy are:
   

   -The mixing of patients with different diseases;
   

   -The use of different kinds of fluids that have been infused;
   

   
   

-The physicochemical properties of the various synthetic colloids have been neglected in all meta-analyses. Because of the important differences between individual colloids, it is not appropriate to summarize all colloids in a "colloid group."

-Most meta-analyses include studies more than 15 years old. Important innovative strategies have been developed in managing the trauma patient in the last 15 years including improved monitoring techniques, ventilation strategies, feeding, and others that may also influence outcomes.

-Mortality was used as the endpoint for volume replacement in all meta-analyses. However, mortality was not the endpoint of most of the volume replacement studies. None of the studies found a statistically significant effect that favoured colloids. It is still unclear whether mortality is helpful to determine the ‘optimal’ volume resuscitation strategy.⁵⁵

Description of primary studies
With the help of a MEDLINE search, recent studies dealing with volume therapy in trauma patients were identified. Only studies published in English in adult patients on pre-hospital volume replacement, volume replacement in the emergency area or in the operating room (OR), and volume therapy in the trauma ICU published in the period from January 1^st 1985 to December 31^st 2002 were included. Studies in head trauma patients, in traumatized children, and in burned trauma patients were not included. Only original studies comparing different solutions for volume therapy were analyzed. Published abstracts, reviews, and letters were not included. Animal or experimental studies were excluded because animal models cannot completely mimic the human trauma situation.

A total of 13 studies were found and analyzed: six of them compared a crystalloid- vs a colloid-based volume replacement regimen^56–61 (Table V) and seven compared different colloids for volume resuscitation^{28,40,46,62–65} (Table VI). In none of the studies were different volume regimens during primary resuscitation (‘in the field’) studied. In six studies different volumes were administered in the emergency department (E) or in the OR,^57–61,65 and another seven studies looked at different volume therapies in the post-surgery period in the ICU.^{28,40,46,56,62–64} The study population in each volume group of the different studies differed widely, ranging from five to 75 patients. The amount of volume administered also differed widely (from 500 to > 3,500 mL) or was not mentioned.

ENDPOINTS TO ASSESS THE EFFICACY OF VOLUME THERAPY
Most studies were not focused primarily on outcome and outcome was not reported in some studies. Thus the influence of different volume replacement regimens on outcome in trauma patients cannot be determined by the studies examined.

Some studies focused only on possible adverse events (e.g., hemostasis, kidney/pulmonary function, inflammation). Because coagulation abnormalities have been reported, especially after the administration of HES, some studies looked especially at alterations of hemostasis after infusion of HES.^28,56,57,62 The general result from these studies was that the use of modern HES preparations is not associated with impaired hemostasis or an increased bleeding tendency.

One study focused on capillary leakage.⁶⁵ In 45 patients suffering from blunt trauma either HES [Mw 250 kD (Pentaspan^TM, Bristol-Myers Squibb, Montreal, Qc, Canada)] or gelatin were given for the first 24 hr. Resuscitation with HES resulted in significantly less post-trauma capillary leak (measured by microalbuminuria) than resuscitation with gelatin.

DURATION OF VOLUME THERAPY
Unfortunately, some trials only compared rather short-term effects of different volume replacement strategies. At the end of the study period, no further strict infusion protocols were implemented. A definitive evaluation of the efficacy of different volume replacement regimens is not possible with such a design. In a prospective randomized study, long-term volume therapy using either 20% HA or 6% HES 200/0.5 in the ICU was studied in trauma patients with an Injury Severity Score > 15 points.⁶³ HA or HES exclusively were infused over five days to keep PCWP between 10 and 15 mmHg. Besides hemodynamic monitoring, liver function was assessed using the monoethylglycinexylidide test. Gastric intramucosal pH was monitored by tonometry to evaluate splanchnic perfusion. Additionally, important regulators of circulation were measured from arterial blood samples. Mean arterial pressure, heart rate, and PCWP did not differ between the two groups, whereas confidence interval increased significantly more in the HES than in the HA group. Liver function and splanchnic perfusion were also similar between HA- and HES-treated trauma patients. Concentrations of all vasoactive regulators showed an almost similar course in both groups. Thus, in trauma patients, long-term volume therapy with HA did not show any advantages over a modern HES solution.

Volume replacement with HS
Treatment of trauma-related hypovolemia using hypertonic (and hyperoncotic) solutions should be assessed separately from the ‘classic’ colloid/crystalloid or colloid/colloid debate because this represents a special issue. This strategy is mostly used in the early (field) resuscitation of hemorrhagic hypovolemia.

PUBLISHED META-ANALYSES
-In a meta-analysis of the efficacy of a hypertonic 7.5% saline/6% dextran solution in trauma patients from 1997, nine (original) studies were analyzed.⁶⁶ The analysis revealed no significant improvement in outcome after the infusion of hypertonic saline solution, whereas the use of hypertonic saline plus dextran (HSD) "may" be superior compared to isotonic fluid resuscitation.

-In a recently published meta-analysis (Cochrane review) from 2002, the use of crystalloids was compared with HS. Five studies in trauma patients were included. No beneficial influence of HS on outcome was found.⁶⁷

MEDLINE-ANALYSIS
In our MEDLINE analysis on HS, 12 studies were found and analyzed (Table VII, available as Additional Material at www.cja-jca.org).^68–77 Either hypertonic saline solution (HS; 7.5% NaCl) or a combination of HS with colloid (6% dextran 70; HSD) were used (Table IV). All studies used crystalloids [mostly normal saline solution (NS)] as a control group. The use of colloids was not compared. Six studies used HS in the field, five in the E, and one in the OR. Patient populations ranged from seven to 211 patients per group. The studies analyzed have several problems.

GOALS AND ENDPOINTS FOR VOLUME THERAPY
In most of the studies analyzed, a fixed volume of either fluid was given (250 mL). It is doubtful that 250 mL of an isotonic crystalloid (e.g., NS) was adequate to treat hypovolemia in trauma patients in the control groups. Systemic hemodynamics were either improved or without differences compared to the use of crystalloids. No negative influence on hemostasis, bleeding or use of packed red cells was documented. Outcome was not affected beneficially by the use of a hypertonic volume replacement strategy.

	Conclusions

TOP Abstract Introduction Pathophysiology of shock in... Goals of volume replacement... Fluid choices in trauma... Colloids Clinical considerations of... Volume replacement in trauma... Analysis of the literature Conclusions References

 
In the severely hypovolemic trauma patient adequate volume restoration appears to be essential to treat non-compensatory, irreversible shock. Lengthy uncorrected hypovolemia will jeopardize survival by the continuous stimulation of various vasopressive and immune cascades. Prolonged under-resuscitation of the hypovolemic trauma patient may have fatal consequences for organ function. Thus, vigorous optimization of the circulation - at least when surgical hemostasis has been achieved - is a prerequisite to avoid development of multiple organ dysfunction syndrome in the trauma patient.⁷⁸ This maneuver is aimed at assuring stable macro- and microhemodynamics while avoiding excessive fluid accumulation in the interstitial tissue. Blood volume is restored more rapidly with colloids than with crystalloids, colloids are more efficient resuscitative fluids than crystalloids,⁷⁹ and colloids are a more efficient regimen to ensure adequate microcirculatory flow than crystalloids.^11,80 Especially hypotonic solutions (e.g., Ringer’s lactate, hypotonic colloids) should be avoided due to the risk of (interstitial) fluid overload. Use of "balanced" colloids is a promising alternative to avoid electrolyte imbalances and overflow into the interstitial compartment in this situation.

What endpoints should be chosen to assess the ‘ideal’ volume replacement strategy? Although often used, "clinical signs" of hypovolemia are non-specific and insensitive. Most studies on volume replacement in trauma patients were not focused on outcome. It remains unclear whether mortality is an appropriate endpoint when comparing different volume replacement strategies.⁵⁵ New concepts on trauma, the development of SIRS, and post-trauma organ dysfunction (e.g., renal or pulmonary insufficiency) should change this point of view.

Very few studies are available comparing different volume replacement protocols exclusively in trauma patients. Based on these limited data, the publication of strict recommendations on the "best" volume replacement strategy in the hypovolemic trauma patient comes as a surprise. Further studies are necessary to distinguish different types (e.g., with/without head injury, blunt trauma, penetrating trauma) and severity of trauma. We should not only consider young, strong male victims but also - especially in highly industrialized countries - the > 70-yr-old trauma patient who presents with several comorbid states. It is time to leave emotions aside when discussing the most appropriate volume replacement strategy in trauma patients and to concentrate on the available scientific evidence. We need improved monitoring technologies that will help us guide volume therapy and better "point-of-care" markers that will help us assess when volume therapy is appropriate in the trauma patient.

	Footnotes

 
Manuscript assessed May 20, 2003. Accepted for publication September 16, 2003. Revision accepted February 13, 2004.

	References

TOP Abstract Introduction Pathophysiology of shock in... Goals of volume replacement... Fluid choices in trauma... Colloids Clinical considerations of... Volume replacement in trauma... Analysis of the literature Conclusions References

 
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