Intravenous Fluid Administration: Picking the Right Solution
Intravenous Fluid Administration: Picking the Right Solution
Authors: Ronald M. Perkin, MD, MA, Professor and Chairman, Department of Pediatrics, The Brody School of Medicine, East Carolina University, Greenville, NC; James D. Swift, MD, Assistant Professor of Pediatrics, University of Nevada School of Medicine; Medical Director of Pediatric Care Medicine and Pediatric Emergency Medicine, Sunrise Children’s Hospital, Las Vegas, NV.
Peer Reviewer: Jane F. Knapp, MD, FAAP, FACEP, Professor of Pediatrics, Children’s Mercy Hospital, University of Missouri-Kansas City School of Medicine, Kansas City, MO.
Infections, hemorrhage, endocrine diseases, and a wide variety of disease processes may result in a major alteration of the physiologic distribution of fluids within the body, particularly in patients who are critically ill. Emergency department (ED) physicians frequently provide initial stabilization and on-going management for critically ill or injured children who require fluid resuscitation and stabilization. Fluid management, therefore, is an integral component of the overall care of critically ill patients, and it is a key factor for the survival of patients who have severe, acute hypovolemia. Volume replacement and restoration of capillary perfusion are essential for reversal of the ischemic changes that can lead to multiple organ failure and death.
Because the pathophysiologic mechanisms causing acute hypovolemia depend, to a large degree, on the nature and severity of the underlying condition, approaches to fluid management and the choice of fluid used for volume restoration may vary considerably from patient to patient. The number of replacement fluids available and various institutional protocols for their use further complicate the issue of fluid replacement in the critical care setting.
In addition, ED physicians may have to provide on-going management for patients who are critical and must be transferred to tertiary care centers. This may involve a change from the initial fluid chosen for resuscitation to a more definitive solution (i.e., blood products). It is important to recognize the limits of the fluid selected for resuscitation, and consider alternative intravenous solutions that may enhance the outcome of the child, depending on the disease process. Finally, concerns recently have been expressed about the efficacy and safety of some replacement fluids.1-6 This article reviews the recent literature on fluid resuscitation in critically ill or injured children which may help guide physicians in their choice of intravenous fluids for these children.
— The Editor
Physiology
The total body water is distributed across three fluid spaces. Intracellular fluid (ICF) is separated from extracellular fluid (ECF) by a cell membrane that is highly permeable to water but not to most electrolytes. The intracellular volume is maintained by the membrane sodium-potassium pump, which moves sodium out of the cell (carrying water with it) in exchange for potassium. Thus, there are significant differences in the electrolytic composition of intracellular and extracellular fluid.7 The capillary membrane separates the two main ECF compartments: the interstitial fluid and the plasma. The pores of the capillary membrane are highly permeable to almost all solutes in the extracellular fluid except the proteins. Thus, the ionic composition of plasma and interstitial fluid are similar but the former contains a higher concentration of protein.
The total osmolarity of each of the three fluid compartments is approximately 280 mOsm/L. The osmotic pressure of a solution is related to the number of osmotically active particles it contains. Thus, about 80% of the total osmolarity of interstitial fluid and plasma is due to sodium and chloride ions. An isotonic solution (e.g., 0.9% sodium chloride) will have an osmolarity of approximately 280 mOsm/L, and cells placed in it will neither shrink nor swell. A cell placed in a hypotonic solution (< 280 mOsm/L) will swell, and those placed in a hypertonic solution (> 280 mOsm/L) will shrink. An isotonic saline solution given intravenously will distribute quickly across most of the ECF space. Although capillary pores are highly permeable to sodium and chloride, the cell membrane behaves as if it were impermeable to these ions, thus keeping the saline solution out of the intracellular space.
In health, albumin accounts for 80% of the total plasma oncotic pressure of 28 mmHg. The relatively low number of proteins in comparison with other particles results in only a small contribution to the total osmotic pressure at the cell membrane. Starling has described the factors determining fluid movement through the capillary membrane.7,8 The forces that usually move fluid outward are the mean capillary pressure, a negative interstitial fluid pressure, and the interstitial fluid colloid osmotic pressure. The plasma oncotic pressure tends to move fluid inward. Under normal conditions, there is a net outward force which, in the presence of a normal filtration coefficient (Kf, flow of fluid across the microvascular membrane per unit time per unit pressure per 100 g of tissue), results in a net rate of fluid filtration in the entire body. This fluid is carried away by the lymphatic system and is returned to the blood. Higher capillary pressures will increase the rate of fluid filtration, but the lymphatic system can cope with 20-fold increases in flow. In inflammatory conditions, the capillary pores may be considerably larger and the reflection coefficient will be low. The increased loss of protein molecules through these "leaky" capillaries may make it difficult to extrapolate fluid therapy data derived from healthy subjects to those with inflammatory disorders (e.g., the systemic inflammatory response syndrome [SIRS] associated with illness and injury).
The principal contributor to plasma colloid osmotic pressure (COP) and retention of fluid in the plasma compartment is albumin.8 Normal COP in the ambulating human is approximately 25 mmHg and is lower in the supine position. Hypoalbuminemia also decreases plasma COP. Decreases in plasma COP promote the escape of fluids into the interstitial compartment, which can result in pulmonary edema. If plasma COP and pulmonary capillary wedge pressure are measured simultaneously, the COP-pulmonary capillary wedge pressure gradient can be determined. The normal gradient range is 9-15 mmHg; a gradient of less than 4 mmHg is associated with the development of pulmonary edema.8
Pharmacology
Crystalloids. A crystalloid is a solution of small non-ionic or ionic particles. The contents of commonly used crystalloids are listed in Table 1. Most crystalloid intravenous fluids are isotonic with plasma. Their precise distribution will be determined by their sodium concentration. Solutions containing approximately isotonic concentrations of sodium (e.g., 0.9% saline, lactated Ringer’s solution) will distribute across most of the extracellular space. The volume kinetics of crystalloids is very complicated and differs between normovolemic and hypovolemic subjects.7 Simplistically, about three-fourths of an intravenous infusion of this solution will pass into the interstitial space and one-fourth initially will remain in the intravascular space. Thus, 1500-2000 mL fluid is needed to replace an acute blood loss of 450 mL.
| Table 1. Composition and Properties of Crystalloid Solutions | |||||||||
| Composition (mEq/L) Tonicity Relative | |||||||||
| Osmolarity Solution (mOsm/L) | Sodium | Chloride | Potassium | Calcium | Magnesium | Lactate | pH | To Plasma | |
| 5% Dextrose | 0 | 0 | 0 | 0 | 0 | 0 | 5.0 | Isotonic 253 | |
| 0.9% Sodium chloride | 154 | 154 | 0 | 0 | 0 | 0 | 5.7 | Isotonic 308 | |
| Normosol-R (Abbott) | 140 | 98 | 5 | 0 | 3 | 0 | 7.4 | Isotonic 295 | |
| Plasmalyte R (Baxter) | 140 | 103 | 10 | 5 | 3 | 8 | 5.5 | Isotonic 312 | |
| Lactated Ringer’s | 130 | 109 | 4 | 3 | 0 | 28 | 6.7 | Isotonic 273 | |
| 3% Sodium chloride | 513 | 513 | 0 | 0 | 0 | 0 | 5.8 | Hypertonic 1026 | |
| 7.5% Sodium chloride | 1283 | 1283 | 0 | 0 | 0 | 0 | 5.7 | Hypertonic | 2567 |
Crystalloid solutions are less expensive than other plasma volume expanders; are sterile; and if the container is unopened, do not serve as potential sources of nosocomial infection.
Hypotonic Saline Solutions. Crystalloid solutions containing less than isotonic concentrations of sodium will be distributed to the intracellular space. Dextrose 5%, although isotonic, has no sodium, is distributed throughout the total body water, and is ineffective for replacing intravascular fluid.
Dextrose solutions (i.e., 5% dextrose in water) should not be used for the initial fluid resuscitation of children because large volumes of glucose-containing intravenous solutions do not effectively expand the intravascular compartment and may result in hyperglycemia and a secondary osmotic diuresis. In addition, hyperglycemia before cerebral ischemia worsens neurological outcome,9,10 and if detected after traumatic or nontraumatic cardiac arrest, is associated with a worse neurological outcome. Although these data suggest that the presence of postarrest or postresuscitation hyperglycemia may reflect multiorgan system injury with impaired use of glucose (i.e., postischemic hyperglycemia may be an epiphenomenon and not a cause of the poor neurological outcome), hyperglycemia should be avoided, especially in the clinical setting of head injury. Every child with a critical illness or injury should have his or her glucose monitored; if hypoglycemia is suspected or confirmed, it should be treated with intravenous glucose. The notions that 5% dextrose in water is somehow safer for pediatric patients, or that hypotonic "maintenance" fluids may be used in bolus therapy, need to be abandoned.11,12 Isotonic saline is recommended as the initial resuscitation fluid of choice.11
The use of diluted solutions not only is ineffective for plasma volume expansion but also may be harmful by reducing serum sodium concentration abruptly. Clinical manifestations of hyponatremia are more severe when the serum sodium concentration rapidly falls. Bolus therapy with hypotonic fluids creates this clinical condition.11,13,14 A decline in serum sodium produces a reduction in plasma osmolality. The osmotic gradient across the blood-brain barrier causes water to move into the brain parenchyma. The neurological manifestations of hyponatremia result from cerebral edema. Symptoms of cerebral edema include apathy, nausea, vomiting, agitation, headache, seizures, coma, and herniation. The mortality rate after acute, severe hyponatremia has been reported to be as high as 50%.11,13 Based on these considerations, there is simply no role for hypotonic saline solutions in the volume resuscitation of pediatric patients.
Hyperchloremic Acidosis Following 0.9% Saline Fluid Resuscitation: Chasing the Base Deficit. Base deficit (BD) traditionally is used as a marker for metabolic acidosis and as such has gained a wide variety of clinical uses, including prognostication and assessment of significant blunt trauma, shock, and regional hypoperfusion.5,15,16
It is, therefore, reasonable to assume that appropriate fluid resuscitation that attempts to improve metabolic "well being" by restoring tissue oxygenation and perfusion should decrease the BD. As the magnitude of the BD may be correlated with mortality, an important yet overlooked issue concerning the crystalloid-colloid controversy is that the type of fluid used for resuscitation may influence acid-base status directly.15 Chloride rich solutions, such as 0.9% saline, used in large volumes can potentiate metabolic acidosis regardless of the underlying disease process.17-19
Stewart’s theory states that three independent variables determine pH in plasma by changing the degree of water dissociation into hydrogen ions.15,17 These three variables are the strong ion difference (SID), pCO2, and charge from weak acids (ATOT). For example, a decrease in the SID and increase in the pCO2 or ATOT all have an acidifying effect on plasma.
The effect that plasma chloride has on pH can be assessed by analyzing the SID, which is calculated as the charge difference between the sum of measured strong cations (Na+, K+, Ca+2, and Mg+2) and measured strong anions (Cl-, lactate).
An increase in the plasma Cl- relative to Na+ decreases the plasma SID (normal values 38-43 mmol/L), thereby increasing the dissociation of water into hydrogen ions. In other words, the smaller the SID, the lower the pH.15,17
One of the most important implications of the Stewart analysis is the role of chloride in acid-base homeostasis. If the body is to alter the SID, its primary tools are Na+ and Cl-. Na+ concentration is tightly regulated by the body to control tonicity, Cl- emerges as the body’s foremost tool for adjusting the SID and hence the plasma pH. Furthermore, acid-base abnormalities frequently are the result of disorders in chloride homeostasis.17
Using the above principles, normal saline 0.9% has equimolar concentrations of Na+ and Cl- (154 mEq/L) and therefore has an SID of 0. The administration of large quantities of normal saline progressively will lower the plasma SID, producing a hyperchloremic metabolic acidosis.18-20 A solution of Ringer’s lactate, which has an SID of 28 mmol/L, would decrease the pH to a lesser extent.
Although restoration of intravascular volume remains a crucial and necessary goal of fluid resuscitation, failure to recognize the contribution of hyperchloremia could lead to the BD becoming unreliable as a marker for effective resuscitation when large volumes of normal saline are used.
Hyperchloremic acidosis is observed in every patient who receives moderate to large volumes of normal saline (0.9% NaCl).21 A recent study demonstrated a mean fall of 0.04 pH units after a 50 mL/kg infusion of 0.9% saline in healthy volunteers.20 In acutely ill or injured patients, the rate and extent of acidification after saline infusion will depend on the rate and amount of saline administered, the renal handling of sodium and chloride, transmembrane movement of strong ions, and associated blood loss.
If the hyperchloremic acidosis is misinterpreted to represent hypovolemia, tissue hypoperfusion, and lactic acidosis, the common practice of chasing the acidosis with more fluid may worsen, rather than correct, the acidosis.21
The problem of hyperchloremic acidosis raises an interesting angle to the debate concerning the ideal resuscitation fluid. Neither normal saline nor colloid preparations are physiological in the sense that both have an acidifying effect on the plasma.15,22
Although a persisting BD has been associated with increased mortality,5,23 to what degree a chloride-driven acidosis influences mortality remains an open question.15,22
What one can conclude at present is that the use of large volumes of "non-physiological" chloride-rich solutions, such as normal saline or albumin, may potentiate metabolic acidosis, making BD interpretation misleading. Clinicians should be aware of the concept of a chloride-driven acidosis and when faced with a persisting BD, once hypotension or hypoxia has been corrected, think twice before giving another fluid bolus of normal saline or albumin solution to "chase" the base deficit.15,24
Solutions with Multicarbon Anions
The clinical implication for patient management is that when large volumes of fluid are used for resuscitation, they should be more physiologic than normal saline. Recent studies have established that the use of solutions containing multicarbon anions results in less acidosis when compared to normal saline.18,25,26 Commercially available solutions include Ringer’s lactate and plasmalyte. (See Table 1.) Lactated Ringer’s solution contains a more physiologic difference between Na+ and Cl- thus, the SID is closer to normal. Of course this assumes that the lactate is metabolized, which may take several minutes.
The clinical importance of the attenuation of post infusion acidosis by electrolyte solutions containing multicarbon anions is unclear. An experimental swine model examined mortality after life-threatening hemorrhage and subsequent resuscitation using different crystalloid solutions.27 Some of the clinically important differences in acid-base change and survival were not statistically significant. The largest percentage of 24-hour survival occurred in the Ringer’s lactate group (67%), followed by the 0.9% saline group (50%). Plasmalyte had the lowest survival (30%).
Some clinicians are concerned that brain injury may be aggravated by the hypo-osmolality of Ringer’s lactate solution.9,28 One group demonstrated that osmolality fell by a mean of 4 mOsm/L after 50 mL/kg lactated Ringer’s infusion in healthy volunteers.20 Normal saline was administered to a second group of healthy volunteers and resulted in no change in osmolality.
Treatment of Metabolic Acidosis
Once metabolic acidosis has occurred, it often is necessary to provide supportive treatment. Although the suggestion to "treat the underlying cause" may seem obvious, it cannot be overemphasized. In patients with traumatic injuries, as in other types of critically ill patients, acid-base disorders frequently are important for what they tell the clinician about the underlying pathophysiology of the patient. Nonetheless, even when the underlying condition is addressed, the patient still may require corrective therapy. Here again, this physical-chemical approach also provides a more logical basis for treatment of metabolic acid-base disorders.29,30 In metabolic acidosis, the SID is narrowed and there is either an increased strong ion such as lactate, or the normal difference between Na+ concentration and Cl- concentration is reduced. The anion gap is a reasonable screening test to distinguish these, provided that the patient’s albumin concentration and phosphate concentration are near normal. The distinction is very important because non-anion gap metabolic acidoses are the result of the body’s inability to maintain the normal Na+ concentration and Cl- concentration.
If the metabolic acidosis is associated with a normal anion gap and a normal Na+ concentration, administration of NaHCO3 can prove effective. Creation of a "normotonic" crystalloid fluid utilizing variable amounts of sodium bicarbonate can help offset the expected rise in Cl- in the massively volume resuscitated patient. A recent study documented that sodium bicarbonate delivered in small boluses (and by extension, continuous infusion) did not result in significant paradoxical intracellular acidosis.31
Only by increasing the Na+ concentration relative to the Cl- concentration can NaHCO3- repair a metabolic acidosis. By contrast, when the acidosis is due to an anion that can be metabolized (e.g., lactate, ketones), the goal of therapy should be to augment metabolic removal and reduce production. In the case of lactate, hypoperfusion should be reversed when present. It has been suggested that, in rare cases, partial treatment is necessary to improve metabolic removal of the anions or to stabilize the patient until metabolic removal can occur. Severe acidemia impairs normal hepatic lactate metabolism, for example, and therapy to increase the pH may be useful.30 However, it is noted that there is no evidence supporting the use of bicarbonate administration for patients with lactic acidosis, regardless of the degree of acidemia.32
Hypertonic Saline
Hypertonic solutions of saline continue to be investigated as resuscitation fluids.7,8,33 The highly hypertonic 7.5% sodium chloride has an osmolality of approximately 2500 mOsm/L and produces a transient increase in intravascular volume of many times the volume infused.7 This may be an advantage when storage volume and/or weight are limited (e.g., prehospital). The effects of hypertonic saline on the cardiovascular system are not confined to volume expansion; heart rate and contractility are increased and peripheral vascular resistance is reduced.33 The intravascular persistence of hypertonic saline can be extended by mixing it with a colloid. The most common of these hypertonic-hyperoncotic solutions is hypertonic saline dextran (HSD, typically NaCl 7.5% and dextran 70 6%).
The infusion of hypertonic saline solutions significantly increases plasma sodium concentrations and osmolality for 6-24 hours.8 Therefore, compared with isotonic solutions, smaller quantities of hypertonic saline solutions initially are required for adequate fluid resuscitation.
A number of prospective, double-blinded, randomized trials evaluating hypertonic saline with or without dextran have been conducted, primarily in trauma patients.33,34 These trials have been predominantly favorable without clear statistical significance, although subgroup analyses suggest benefits in the severely head injured or in hypotensive patients requiring surgery.6,34-37
In addition, there are other possible benefits of hypertonic saline. Hypertonic saline may provide an element of immunologic protection compared with lactated Ringer’s solution and artificial colloids.38-43 In vitro studies have shown that hypertonic saline reverses hemorrhage-induced T-cell suppression after experimental hemorrhage.39 Conversely, lactated Ringer’s solution may have an inherently proinflammatory effect.42,43
Some concerns exist about the possible adverse effects of hypertonic saline resuscitation, especially adverse neurologic sequelae.9,44 Although it has been inherently difficult to prove statistical superiority in divergent populations of trauma patients, as an aggregate the controlled studies have certainly shown no overall harm.34
Colloids
A colloid is a fluid that contains particles large enough to exert an oncotic pressure across the microvascular membrane. In comparison with crystalloids, colloids have greater intravascular persistence. Albumin, dextran, and blood are naturally occurring colloids. Semisynthetic colloids include modified gelatins, hydroxyethyl starch, and hemoglobin solutions. An appropriate colloid choice will take into account cost, intravascular half-life, and side effects, such as coagulopathy and anaphylactoid reactions. The molecular weights and ionic composition of various colloids are shown in Table 2.
| Table 2. Compositions and Properties of Colloidal Solutions | ||||||||
| Composition (mEq/L) | ||||||||
| Solution | Volume(s) (mL) | Sodium | Chloride | Calcium | pH | Tonicity Relative to Plasma | Osmolarity (mOsm/L) | |
| 5% Albumin | 250, 500 | 130-160 | 130-160 | 0 | 6.9 | Isotonic | ~ 330 | |
| 25% Albumin | 20, 50, 100 | 130-160 | 130-160 | 0 | 6.9 | Hypertonic | ~ 330 | |
| 6% Hetastarch | 500 | 154 | 154 | 0 | 5.5 | Isotonic | 310 | |
| 10% Pentastarch | 500 | 154 | 154 | 0 | 5.0 | Isotonic | 326 | |
| 10% Dextran 40 | 500 | 0/154* | 0/154* | 0 | 4.5 | Isotonic | 300 | |
| 6% Dextran 70 | 500 | 0/154 | 0/154 | 0 | 4.5 | Isotonic | 300 | |
| Modified fluid gelatin | 500 | 154 | 125 | 0 | 7.4 | Isotonic | 279 | |
| Polygeline | 500 | 145 | 145 | 12 | 7.3 | Isotonic | 370 | |
| Oxypolygelatin | 250, 500 | 154 | 130 | 1 | 7.0 | Isotonic | 300 | |
| *Dextrans are available both in 0.9% sodium chloride injection and in 5% dextrose injection. | ||||||||
Colloidal solutions increase plasma oncotic pressure and effectively move fluid from the interstitial compartment to the deficient plasma compartment. These solutions are made from natural products such as proteins (albumin, plasma protein fraction, fresh frozen plasma), carbohydrates (dextrans, starches), and animal collagen (gelatin). Colloidal solutions should: 1) have the ability to maintain effective colloid osmotic pressure for several hours; 2) be stable during storage over a wide range of temperatures; 3) be free of pyrogens, antigens, and microorganisms; and 4) be metabolized and eliminated in such a way as not to adversely affect the patient; and 5) not cause hemolysis.
Dextrans
Modern dextrans are produced by the action of the enzyme dextran sucrase during the growth of the bacteria Leuconostoc mesenteroides on a sucrose medium.7 The resulting polysaccharide is hydrolyzed to produce dextrans of various molecular weights. Currently available dextran solutions are 6% dextran 70 and 10% dextran 40. Both dextran 40 and dextran 70 are available in 0.9% saline and in 5% dextrose solutions. Dextran 40 is hyperoncotic and initially will expand the intravascular volume by more than that infused.8 However, dextran 40 is more rapidly excreted than dextran 70. Approximately 70% of dextran is excreted through the kidneys and the remainder is broken down by endogenous dextranase. Dextran reduces blood viscosity, reduces platelet adhesiveness, and enhances fibrinolysis. These properties make dextran useful for prophylaxis against thromboembolism; however, doses greater than 1.5 g/kg body weight will increase bleeding. Dextran 40 has been associated with renal failure, particularly in the presence of hypovolemia and pre-existing renal dysfunction. Roleaux formation and interference with blood cross-matching was a feature of the very high molecular weight dextrans that were first used in the 1940s.7,45 Modern dextran solutions do not interfere with the cross-matching of blood. Dextrans can cause mild anaphylactoid reactions. The more severe anaphylactic reactions are relatively uncommon and are caused by naturally occurring dextran reactive antibodies (DRAs) of the IgG class.7 These reactions are caused by immune complex (type III) anaphylaxis. The reactive sites of the antibodies can be blocked by giving an injection of 20 mL of dextran 1 (monovalent hapten dextran). This prevents the formation of immune complexes when an infusion of dextran 40 or 70 is given, and has dramatically reduced the incidence of serious reactions to dextran.45
Hydroxyethyl Starch
Hydroxyethyl starch (HES) solutions are synthetic polymers derived from amylopectin.7,8 They are broken down by amylase. HES solutions can be divided into high, medium, and low molecular weights.46,47 Intravascular persistence will depend on the molecular weight, the substitution ratio, and the C2/C6 ratio. High molecular weight HES (e.g., 480/0.7) has a prolonged intravascular persistence, with 38% of the initial dose remaining in the intravascular space for 24 hours.8,47 High molecular weight HES reduces factor VIII and von Willebrand factor and will cause coagulopathy.46 For these reasons, the maximum dose of high molecular weight HES is restricted to approximately 20 mL/kg/d and isn’t recommended for trauma patient resuscitation.7,47 Medium molecular weight starch (e.g., 200/0.5) has significantly less effect on coagulation.48 On a rather empirical basis, the maximum daily volume of HES (200/0.5) is restricted to 33 mL/kg/d. This solution has an intravascular persistence of about 4-6 hours. Low molecular weight HES may have minimal effect on coagulation.47
Animal studies suggest that fractionated HES solutions may be capable of plugging leaky capillaries in inflammatory states.49 Hydroxyethyl starch encourages the restoration of macrophage function after hemorrhagic shock.50 A recent study of trauma and sepsis patients showed that 10% HES (200/0.5) resulted in significantly better systemic hemodynamics and splanchnic perfusion than volume replacement with 20% human albumin.51 Although the incidence of significant anaphylactoid reactions associated with HES appears to be low, a number of anaphylactic reactions have been reported.
In the United States, only one type of HES (480/0.7) is approved for plasma volume expansion (6% Hespan).47 Most available data have demonstrated that 500 mL of 6% HES (480/0.7) administered over 60 minutes expands plasma volume by 720 mL in hypovolemic patients.47 It has the advantage of a relatively prolonged volume effect but has been associated with hemorrhagic complications. For this reason, many U.S. physicians in intensive care and anesthesia prefer to use albumin. From a fiscal point of view, HES is an attractive alternative to albumin.47
Albumin
Human albumin is a single polypeptide with a molecular weight of 65-69 kDa and a strong negative charge of minus 17.7,57 It has transport functions, free radical scavenging and anticoagulant properties, and may have a role in preserving microvascular integrity.53 In health, it contributes about 80% of oncotic pressure; however, in critically ill patients, serum albumin concentration correlates poorly with colloid osmotic pressure.54 It is relatively expensive and its use in critically ill patients does not appear to improve outcome.7,53 As a result of the manufacturing process, human albumin solution generally is considered to be free from any risk of transmitting infection.
Albumin is distributed between the intravascular (40%) and interstitial (60%) compartments. Albumin synthesis is stimulated by cortisol and thyroid hormone and decreased by elevated plasma oncotic pressure.8 The normal serum albumin concentration is 3.5-5.0 g/dL and is correlated with nutritional status. After depletion of the intravascular compartment, interstitial albumin is mobilized and moved to the intravascular compartment through lymphatic channels or by transcapillary refill.8
The water-binding capacity of albumin is related to the amount of albumin given and the plasma volume deficit. One gram of albumin increases plasma volume by approximately 18 mL, and 100 mL of 25% albumin solution increases plasma volume by 465 + 47 mL (mean + SD), compared with 194 + 18 mL for 1 L of lactated Ringer’s injection.53 Infused albumin is distributed completely within the intravascular compartment in two minutes and has an initial plasma half-life of 16 hours. Ninety percent of an albumin dose remains in the plasma for two hours after administration. After initial distribution into the plasma compartment, albumin equilibrates between the intravascular and extravascular compartments over a 7- to 10-day period, with 75% of the albumin being gone from the plasma in two days.8 However, studies have shown that albumin significantly increases plasma osmotic pressure for at least two days after resuscitation in patients with shock. The retention of infused albumin in the intravascular compartment varies greatly with regard to the patient’s disease.53
Commercially available human albumin is supplied as 5% and 25% solutions in physiological saline stabilized with sodium acetyltryptophanate and sodium caprylate. The contents and physiological properties of albumin solutions and the other colloidal solutions are listed in Table 2. Albumin solutions manufactured in the United States must contain at least 96% albumin.8
Albumin solutions are sterilized by pasteurization for 10 hours, which effectively kills the human immunodeficiency virus, the hepatitis B virus, and the hepatitis C virus. However, albumin solutions have been found to contain pyrogens, and bacterial infections have been caused by contaminated albumin solutions. Pasteurization can cause albumin to polymerize, resulting in an antigenic macromolecule. The frequency of anaphylactoid reactions to albumin is less than 0.015%.8,53
Albumin solutions, which also contain citrate, may bind serum calcium. One group observed decreases in left ventricular function in trauma patients after albumin infusions that were correlated with decreases in free serum calcium concentrations.55 Resuscitation with colloidal solutions also may cause bleeding secondary to decreased aggregation of platelets and dilution of coagulation factors and platelets. Albumin infusions cause minor changes in prothrombin time (PT), partial thromboplastin time (PTT), and activated clotting time (ACT), with platelet counts decreasing in critically ill patients.8
Potential Anti-Inflammatory Effects of Albumin. The initial circulatory effects of acute hypovolemia and shock rapidly lead to a cascade of immune mediators, which in turn contribute to the systemic inflammatory response syndrome, organ failure, and death that characterize sepsis.56
In addition to its role in maintaining plasma oncotic pressure, contribution to plasma antioxidant defenses, and ability to decrease transendothelial permeability to macromolecules, albumin may possess direct anti-inflammatory properties independent of its antioxidant effects.57 Such anti-inflammatory properties might be beneficial when albumin is given to patients with sepsis.
More recently, another group studied a number of resuscitation fluids to determine their effect on human neutrophil activation and adhesion.42 Whole blood from healthy volunteers was serially diluted with saline, lactated Ringer’s solution, dextran, HES, and human albumin, and neutrophil activation (intracellular oxidative burst activity) and adhesion were measured by flow cytometry. A dose-related increase in neutrophil oxidative burst activity was observed following dilution with crystalloid fluids, dextran, and HES, with activity 12- to 18-fold greater at the 75% dilution than at baseline. The increase from baseline was only 2.2-fold greater with 5% albumin, and 25% albumin did not produce any increased neutrophil activity. A similar significant increase in the neutrophil adhesion expression occurred with dextran and HES (P < 0.05) and to a lesser extent with crystalloids, but not with albumin.
Fresh Frozen Plasma
Fresh frozen plasma is obtained after the cellular elements have been removed from whole blood by centrifugation. The plasma is frozen within six hours of separation. Although the use of fresh frozen plasma for routine fluid resuscitation is not recommended, it may be used as an adjunct to massive blood transfusions in patients with underlying coagulation disorders.8 Five hundred milliliters of fresh frozen plasma expands the plasma compartment as efficiently as dextran or polygeline but less than hetastarch.8 The risk of transmission of pathogens by fresh frozen plasma is the same as for whole blood. However, chemical inactivation processes are being developed that may decrease the risk of viral transmission by plasma products.
Oncotic Pressure and Tissue Edema: The Crystalloid-Colloid Controversy
In the case of the acutely hypovolemic patient, debate persists regarding the relative merits of crystalloids or colloids. Crystalloid solutions have been promoted as ideal for replacement of the intravascular fluid deficit that occurs with hemorrhage. However, these balanced salt solutions freely cross intact capillary membranes, resulting in a reduced duration of plasma expansion. Colloids are large, oncotically active molecules that do not cross intact capillary membranes and can replace fluid deficits faster than crystalloids, with 2-4 times less volume infused.
A large number of clinical trials have been published over the years that have compared crystalloid with colloid. The groups studied have included patients with trauma; postsurgical patients; and patients with burns, shock, or albumin infusions for augmentation of plasma albumin levels in critically ill hypoalbuminemic patients. Most of these are small studies with physiologically diverse end points, and none have been sufficiently powered to demonstrate an outcome difference. The debate has been rekindled by the recent publication of several systematic reviews of the randomized human trials of colloid and crystalloid. Two that gained a great deal of attention, not only in critical care circles but also in the media, were systematic reviews of randomized controlled trials (RCTs) that compared crystalloid and colloids in critically ill patients.1,2 In Schierhout and Roberts, they performed a meta-analysis of 26 RCTs that compared any colloid with any crystalloid, either isotonic or hypertonic, in critically ill patients with burns, trauma, or sepsis or postsurgery patients. The researchers then analyzed the mortality data from 19 trials, studying a total of 1315 patients. Based on this, their conclusion was that there were four extra deaths per every 100 patients who received colloid.1
One of the chief weaknesses of the systematic review by Schierhout and Roberts was that it failed to take into account significant differences between one colloid and another. The wide-ranging pharmacological and pharmacodynamic properties of the colloids emphasize the significant differences between these fluids. The oncotic pressure exerted at the capillary membrane will depend not just on the specific colloid but also on the porosity of the capillary endothelium. Thus, on the basis of in vitro measurements of oncotic pressure only, it may be very difficult to predict what effect a specific colloid will have on the intravascular oncotic pressure of a severely injured patient. While smaller molecular weight colloids (e.g., gelatins) may pass easily through leaky capillaries, colloids of larger molecular size (e.g., HES) will have better intravascular retention.7
A second meta-analysis performed by the Cochrane Group Reviewers evaluated RCTs that compared albumin with crystalloid, analyzed under categories for which human albumin is approved, namely hypovolemia, burns, and hypoalbuminemia.2 Thirty studies met the criteria for inclusion in the albumin meta-analysis and included 1419 patients. Twenty studies had one or more deaths in either arm of the study and were analyzed for relative risk of death. There were five studies of children, four of which were of neonates, the other being a study of albumin supplementation in children with burns. The researchers’ conclusion was that the use of albumin was associated with an extra six deaths per 100 patients treated.
The publication of these two articles caused a great deal of controversy in the critical care community, especially for those clinicians involved in pediatric care where albumin is frequently used for the treatment of hypovolemia. If colloids were not available, human and animal studies would suggest that approximately 2-3 times the amount of crystalloid as colloid would have to be infused to achieve an equal volume expansion.
The reviewers were widely criticized for, among other things, grouping together multiple, different studies in diverse disease processes; the lack of a content expert among the reviewers; and the use of meta-analysis as a tool for guiding the practice of evidence-based medicine.4 It also was pointed out that most of the studies involved small numbers of patients (n < 50) and were not powered for a mortality end point; indeed, many of these studies did not actually report it. It should be emphasized that meta-analyses with such limitations can be viewed as useful for generating hypotheses rather than supporting evidence-based, clinical recommendations.58 The reviewers’ most important conclusion was that the use of albumin should be tested in properly designed RCTs.4 Subsequent systematic reviews of albumin and crystalloid have found no difference in mortality.3,58,59 Although the Cochrane report suggested the possibility of increased mortality risk in albumin recipients and thus called into question the safety of albumin, the preponderance of available evidence continues to support the safety of albumin.59
The reality is that we do need properly designed clinical trials to evaluate the clinical utility of colloids, such as albumin. These may demonstrate that there are some important niche areas for which some of the unique properties of albumin, such as its important anti-inflammatory and anti-oxidant properties in sepsis and ischemia-reperfusion injury, may make it superior to synthetic colloids and crystalloid.57 An example of such a study is a recent multi-center, randomized, controlled trial that showed that the administration of albumin improved survival and reduced the incidence of renal failure in patients with cirrhosis and peritonitis.60
Fluid resuscitation is vital for the treatment of hypovolemic shock. Shifts in paradigm have suggested that the majority of cellular injuries occur during resuscitation and not during the ischemic period.61-63 This injury is the result of reperfusing ischemic tissues and results in resuscitation injury. Recent data have suggested that the type of resuscitation fluid used to treat hemorrhagic shock may affect the physiologic response, including the systemic inflammatory state. Not all fluids seem to be innocuous, particularly in the reperfused state. Lactated Ringer’s solution has been demonstrated to activate neutrophils and up-regulate cell adhesion molecules.43,64 More recently, it has been demonstrated that increased apoptosis occurs in liver, small intestine, and the lung of hemorrhaged animals treated with lactated Ringer’s in comparison to whole blood or plasma resuscitation.61,65
Although these experiments provide interesting data, the clinical usefulness is unclear presently. What is clear is that the overwhelming majority of ill and injured patients benefit from resuscitation programs based on electrolyte solutions. Recent questioning of the pace and volume of fluid infusion has targeted resuscitation practice and not the solutions per se.5,66
Oxygen-Carrying Resuscitation Fluids
The major problem with crystalloid and colloidal plasma volume expanders is their inability to carry oxygen. Especially during hemorrhagic shock, the arterial blood oxygen content is greatly reduced and must be restored. Oxygen-carrying volume expanders, therefore, are the most desirable resuscitation agents, because they not only increase plasma volume but also improve tissue oxygenation.
Massive transfusions of whole blood may cause bleeding abnormalities since stored blood is deficient in the labile coagulation factors V and VIII and in functional platelets. Thrombocytopenia is the most common disorder resulting from massive transfusion. The platelet count should be monitored in trauma patients requiring large volumes of blood transfusion, but the function of the platelets under such circumstances is unpredictable. Thus, while circulating platelet counts of 20,000/mm3 and less may be adequate in nonbleeding patients, platelet transfusion is indicated in the early postoperative period following trauma when the platelet count is below 100,000/mm3 and there is evidence of ongoing microvascular bleeding. In the face of proven, massive microvascular bleeding, the first dose of platelets may be given before the results of the platelet count are available. Additionally, if there is a history of pre-existing platelet dysfunction or the patient has taken aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) and hemostasis is inadequate despite local measure, the administration of platelet concentrate may be indicated regardless of platelet counts.
Allogeneic Blood Transfusions
The potential for adverse effects, high costs, and intermittent blood shortages mandate conservative use of allogeneic red blood cell (RBC) transfusions.67,68 Public concern for human immunodeficiency virus and hepatitis C infections and an increasing number of patients demanding treatment without allogeneic RBC transfusions represent additional reasons to develop effective alternatives.
Without any doubt, allogeneic RBC transfusions are crucial for the treatment of patients with trauma and major blood loss.67 In less extreme conditions, however, the efficacy of allogeneic RBC transfusions has been challenged.69 Two transfusion regimens (restrictive, aiming at a hemoglobin concentration of 7-9 g/dL vs, liberal, aiming at a hemoglobin concentration of 10-12 g/dL) were compared in a prospective, randomized study in 838 patients treated in an intensive care unit (ICU). In the restrictive transfusion group, a mean hemoglobin concentration of 8.5 + 0.7 g/dL was observed, less blood (2.6 + 4.1 U) was transfused, and a higher percentage of patients avoided any RBC transfusion (33%), as opposed to the liberal transfusion group, which had a mean hemoglobin concentration of 10.7 + 0.7 g/dL and 5.6 + 5.3 U transfused (avoidance: 0%). Thirty-day mortality was similar in the restrictive and liberal groups (18.7% vs 23.3%), but hospital mortality, adjusted multiorgan dysfunction score, and the incidence of pulmonary edema and myocardial infarction were significantly lower in the restrictive transfusion group.
The question of an acceptable hematocrit to be used as an end point in resuscitation with whole blood is controversial. Similarly, the difference between the minimal and the optimal hematocrit has not been defined. Patients with hemorrhagic shock have unpredictable changes in blood viscosity, since hypovolemia-induced decreases in viscosity are counteracted by increases in viscosity due to decreased flow. Stored whole blood and PRBCs may disproportionately increase blood viscosity and cause sludging, decreased venous return, and congestive heart failure after rapid transfusions.
The minimal hemoglobin level tolerated without organ dysfunction often is referred to as "critical hemoglobin." Such a value cannot be defined in a generally applicable way, but it is intriguing to learn that even extreme acute normovolemic hemodilution to a hemoglobin concentration of 5 g/dL was well tolerated in humans.70 No signs of compromised oxygen delivery, such as a decrease in oxygen consumption or an increase in lactate, were observed, not even after further compromising oxygen delivery by acute beta blockade, suggesting that a hemoglobin concentration of 5 g/dL was not yet critical.71 The critical hemoglobin level can, therefore, only be defined for certain organs, specific situations and disease states, and particular age groups.67,72
In spite of the many situations in which a physician may consider administering RBC transfusions to a child and the potentially serious complications associated with transfusion therapy, there is a remarkable paucity of controlled data on which to base decisions.73 Few studies address the most common pediatric problems for which transfusions are used, and most recommendations are extrapolated from adult data.
The characteristics of whole blood, PRBCs, and the other oxygen-containing resuscitation fluids are presented in Table 3.
| Table 3. Characteristics of Oxygen-Carrying Resuscitation Solutions | ||||||||
| Solution | Hemoglobin Concentration (g/dL) | P50 (mmHg) | Methemoglobin Content (%) | Colloid Oncotic Pressure (mmHg) | ||||
| Whole blood or PRBCs | 14-16 | 26 | < 2 | 25 | ||||
| Stroma-free hemoglobin | 6-9 | 12-14 | 2-5 | 20-25 | ||||
| Stabilized stroma-free bovine hemoglobin | 6-7 | 18-22 | 4-5 | 22-30 | ||||
| Pyridoxylated hemoglobin | 6-8 | 20-24 | 3-5 | 20-25 | ||||
| Polymerized, pyridoxylated hemoglobin | 14-15 | 14-16 | 4-5 | 20-25 | ||||
| Liposome-encapsulated hemoglobin | 16 | 20-28 | 3.6-15 | 0-37 | ||||
| Perfluorocarbon | 0 | 0 | 0 | 20-25 | ||||
| = Packed red blood cells (PRBCs) | ||||||||
| = Arterial oxygen tension required for 50% hemoglobin saturation. | ||||||||
Red-Cell Substitutes. For at least 50 years a major goal of resuscitation research has been the development of a safe RBCsubstitute that increases oxygen delivery to tissues.74 Red-cell substitutes fall into three general classes: perfluorochemicals, liposome-encapsulated hemoglobin, and hemoglobin-based oxygen carriers.75 However, every formulation should be considered a unique drug with its own physical characteristics, pattern of biologic activity, and profile of adverse reactions. Liposomal hemoglobin has yet to see the success that has been achieved with other liposome-encapsulated pharmaceuticals.
Hemoglobin-Based Oxygen Carriers (HBOCs). There is a continuous effort to develop a HBOC that is characterized by ease of storage and transport, freedom from serious side effects, a long shelf life, compatibility with all blood types, and freedom from infectious disease risk.74-83 Currently, no HBOCs are approved for marketing by the Food and Drug Administration.79 Most HBOCs are derived from human or bovine blood and have been chemically modified to provide molecules that differ in size, molecular weight, oxygen affinity, viscosity, and oncotic activity.75 Recombinant hemoglobin molecules with features not found in nature also have been prepared.
Artificial hemoglobin solutions combine the oxygen-carrying capacity of blood with the osmotic properties, long-term storage, and stability of colloidal preparations.8 Artificial hemoglobin solutions can be stored refrigerated for months to years and do not require typing or cross-matching. A stroma-free bovine preparation shows clinical promise because of its low antigenicity, good oxygen-carrying capabilities, and good supply. Solutions containing phospholipid-cholesterol-encapsulated or liposome-encapsulated hemoglobin and pyridoxylated polyhemoglobin offer a near-normal P50, adequate half-life, and normal oncotic pressure at physiological hemoglobin concentrations. Stroma-free hemoglobin is excreted by the kidneys, whereas liposome-encapsulated hemoglobin is eliminated by the reticulo-endothelial system. Artificial hemoglobin solutions do not alter coagulation test values.
HBOCs still face formidable hurdles. Freely diffusing oxygen bound to a red-cell substitute may be responsible for the gastrointestinal irritability, hypertension, and as recently publicized, unexpectedly high number of deaths among patients with trauma, which led to the termination of clinical trials and the withdrawal of two formulations of HBOCs from further development.81 Most formulations have a pressor effect, which is generally attributed to the ability of hemoglobin to scavenge the vasodilator nitric oxide.75 Economics also will influence the use of red-cell substitutes.
Perfluorochemicals
Perfluorocarbons are synthetic chemicals with very high oxygen-carrying capabilities.8 Fluosol, a 20% solution, contains perfluorodecalin 14 g/dL and perfluorotripropylamine 6 g/dL, which dissolve 45 mL and 48 mL of oxygen per 100 mL, respectively, under laboratory conditions. Fluosol must be administered as an emulsion with glycerol, emulsifiers, glucose, and an electrolyte solution because of poor water and plasma solubility. The emulsion is unstable and must be stored frozen and used immediately after thawing. After intravenous injection, perfluorocarbon particles are taken up by the RES, diffuse into the circulation over time, and are eliminated by the lungs. Fluosol has a plasma half-life of 4-6 hours in healthy volunteers.
Trials in severely anemic human subjects have shown that the oxygen-carrying capacity of perfluorocarbons is dependent on oxygenation and that a high inspired oxygen fraction (FiO2) (80-100%) is required for adequate oxygenation. The contribution of the additional oxygen-carrying capacity of perfluorocarbons to hemoglobin is minor and dependent on the amount of drug in the blood. However, perfluorocarbons unload oxygen more effectively than hemoglobin, and because of their smaller size (1 mm) may deliver oxygen more effectively at the tissue level.
Perfluorocarbons once held the promise of providing a substitute for oxygen-carrying capacity; however, multicenter trials failed to demonstrate differences in mortality and morbidity between groups given the perfluorocarbon Fluosol and controls treated with lactated Ringer’s solution. Fluosol has been withdrawn from the market as a blood substitute.84
Perflubron, a second-generation investigational perfluorocarbon, is associated with far fewer anaphylactoid reactions, delivers a much greater amount of oxygen, and is more convenient to handle.84 Like all oxygen-carrying colloids, Perflubron is only effective as a blood substitute for 24 hours following administration. Although perfluorocarbons will never replace RBCs in situations in which long-term oxygen-carrying capacity is needed, they will be useful for bridging periods of rapid blood loss.
Conclusions
The choice of resuscitation fluid should be based on a number of factors, including: 1) the cause of acute hypovolemia; 2) patient-specific clinical date; 3) careful monitoring of the patient’s physical examination and certain laboratory parameters; 4) previous experience with fluid replacement; 5) institutional guidelines if available; and 6) awareness of emerging trends in basic and clinical research. To achieve the optimal outcome, physicians must understand the relative merits of the various colloids and crystalloids and use the most appropriate replacement fluid according to each patient’s needs.
The crystalloid-colloid debate continues. Colloids vary substantially in their pharmacology and pharmokinetics, and the experimental findings based on one colloid cannot be extrapolated reliably to another.
In initial stages of patient resuscitation, the precise fluid used is not as important as providing the appropriate volume of fluid. Hypotonic solutions never should be utilized in the initial phases of resuscitation. Hypertonic saline solutions may have benefits in patients with head injuries.
Colloid solutions such as albumin and hydroxyethyl starch may prove useful for the treatment of patients with sepsis. Despite positive properties of albumin, it may not be appropriate for volume resuscitation of all hypovolemic patients.
A number of hemoglobin solutions are under development, but one of the most promising of these has been withdrawn recently. It is highly likely that at least one of these solutions eventually will become routine therapy for trauma patient resuscitation. In the meantime, contrary to traditional teaching, recent data suggest that a restrictive strategy of red cell transfusion may improve outcome in some critically ill patients.
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