Fluid Resuscitation

   Few topics in EMS generate as much debate as fluid resuscitation. Should relative hypotension be allowed? If so, in which patient population? Should you aggressively push fluids in blunt trauma or chest trauma? The debates and the data are endless. This article will not join the debate, but will provide information on different types of fluids commonly and not so commonly used for resuscitation, as well as options that may be forthcoming in the near future.

Evolution of the debate

   According to shock researcher Dr. Frederick Moore, et al, advances in shock resuscitation have occurred during military conflict as a result of concentrated experience with patients.¹ Shock resuscitation is an obligatory intervention that with refinement has changed the epidemiology of deaths from trauma. During World War I, as a result of the wound toxin hypothesis, no preoperative resuscitation was administered and many soldiers died. In World War II and the Korean conflict, due to the misconception over hemoconcentration, colloids were administered and eventually banked blood resuscitation became standard care. Early survival improved, but many casualties died later due to acute renal failure. During the Vietnam War, with the recognition that extracellular fluid space had to be repleted, large-volume isotonic crystalloid solutions replaced colloids for initial shock resuscitation. Mortality rates and the incidence of acute renal failure decreased, but adult respiratory distress syndrome emerged as a major source of morbidity and mortality.¹ Through the 1970s and early 1980s, intensive care units were developed, where advanced technology and improved care allowed patients with single organ failure to survive for long periods. Patients no longer died of acute renal failure or adult respiratory distress syndrome, but developed multiple organ failure, which, at that time, was usually fatal.

Fluid Resuscitation Options

Blood Products

   Blood is a composition of cells traveling in fluid. The cells are erythrocytes (red blood cells), leukocytes (white blood cells) and thrombocytes (platelets). The fluid is plasma. Also circulating in this fluid are proteins, hormones and other substances. A mature red blood cell consists of a membrane surrounding a liquid solution of hemoglobin, an iron-containing protein that gives blood its red color. The primary function of hemoglobin is to transport oxygen to the body tissues and remove carbon dioxide from them. White blood cells maintain immunity, and platelets form clots. Donated blood is typically broken down into the component parts for storage, namely packed red blood cells, plasma and platelets.

   Packed red blood cells (PRBC) are used in the emergency department for trauma resuscitation. While long held as the "gold standard" in fluid resuscitation, the infusion of packed red blood cells has several potential drawbacks: Blood transfusion incites an inflammatory response in the recipient; blood and blood products are not optimal prehospital therapies; and blood has the ability to be contaminated by viruses (hepatitis, HIV), must be kept cool, has a shelf life of approximately 42 days, and the supply is limited, depending on donors.

   Recent clinical trials and animal experiments have raised fundamental questions about the efficacy of stored or aged RBCs. A review article in 2006 cited a number of retrospective clinical studies examining association between prolonged storage times of red cells and adverse clinical outcomes, documenting an increase in mortality, pneumonia, serious infection, multiorgan failure and length of stay in hospital.² Changes accompanying the storage of red blood cells are known as the "storage lesion", which can be defined as a series of biochemical and biomechanical changes in the RBC and storage media that reduce RBC survival and function. In critically ill patients, clinical studies have reported an association between RBC transfusions and increased morbidity and mortality, an effect that may increase with the age of transfused RBCs.²

Crystalloids

   Crystalloids are solutions of mineral salts or other water-soluble molecules. For EMS purposes, we are talking about salt (saline) and sugar (dextrose). Intravenous fluids are divided into three categories based on the concentration of particles to fluid in their mixture as compared to human blood. Since isotonic fluids have the same concentration as the normal cells of the body and blood, when infused intravenously, they will remain in the intravascular space. "Normal" saline (0.9% NaCl) and lactated Ringer's solution are typical isotonic fluids used.

   Hypertonic fluids have a higher particle concentration than in normal cells of the body and the blood. These agents draw fluid into the intravascular space from cells. Hypertonic saline (3% NaCl) is a common hypertonic fluid.

   Hypotonic fluids (0.45 normal saline, 0.33 NaCl) are composed mostly of free water and will enter the cells rather than remain in the intravascular space. Normal saline and lactated Ringer's are the two balanced salt solutions most commonly used in current fluid resuscitation. No trials conducted in humans have demonstrated the superiority of one over the other for fluid resuscitation.

   Isotonic crystalloids primarily function by simply expanding the amount of intravascular fluid in an attempt to increase blood pressure and deliver the red blood cells and oxygen they carry to body tissues. Their net effect is between one-fourth to one-third of the fluid infused, meaning that after a liter of isotonic crystalloid, between 250-333 ml remains in the intravascular space. If used to replace blood loss, 3 to 4 times the volume lost must be administered, as only one-third to one-fourth remains intravascularly.³

   The advantages of crystalloid solutions are numerous. They are inexpensive, easy to store with long shelf life, readily available, have a very low incidence of adverse reactions, are effective for use as replacement fluids or maintenance fluids, no special compatibility testing is required, and there are no religious objections to their use.⁴

   There is significant interest in using hypertonic fluids in resuscitation, as, theoretically, one would need to administer less fluid because the administered fluid would draw more fluid from the body into the vascular space. From the late 1980s through the early 1990s, several trials individually found survival outcome to be inconsistently improved, but did document that a bolus of hypertonic saline was safe. Meta-analysis of these data suggests that hypertonic saline is no better than standard of care isotonic crystalloid fluids. Subgroup analysis showed that patients who presented with shock and severe closed head injury benefited most from hypertonic saline.¹ This finding has led some authorities to recommend that hypertonic saline should replace mannitol in the management of intracranial hypertension in patients with severe closed head injury.

Colloid

   Colloids are large molecular weight substances. In normal plasma, plasma proteins are the major colloids present. The general problem with colloid solutions for fluid resuscitation is that they cost much more than the crystalloids and, so far, have not demonstrated superior results in clinical testing. In addition, there is a small but significant incidence of adverse reactions (anaphylactoid reactions).⁵

   Colloids have a few potential advantages over crystalloids. Because of their higher molecular weights, colloids are confined to the intravascular space and their infusion results in more efficient plasma volume expansion. In severe hemorrhagic shock, however, the permeability of capillary membranes increases, allowing colloids to leave the intravascular space, which can then worsen edema and impair tissue oxygenation. Current available colloids include albumin, dextrans, hydroxyethyl starches and gelatins. Higher molecular weight agents (e.g., dextran 70) coat red blood cells, which can interfere with blood typing; the lower weight agents (such as dextran 40) coat platelets and can interfere with clotting.⁶

Albumin

   Albumin, one of the original plasma expanders, is a protein that maintains osmotic pressure in a cell and helps the cell maintain its internal fluid. When we read about protein in urine, especially in diabetics and those with kidney disease, we are talking about albumin.

   Just as there are different concentrations of saline (0.9%, 0.45%, 0.33% etc.), there are different concentrations of albumin for fluid resuscitation, most commonly 4%, 5%, 20% and 25% solutions. Currently, 4%-5% albumin solutions are employed for volume expansion. These solutions expand intravascular volume by approximately 80% of the administered volume (i.e., a 1000cc infusion increases intravascular fluid by 800cc). However, 20% albumin averages 210% and 25% albumin averages 260% of the administered volume. Consequently, these larger concentration solutions can accomplish the same volume expansion effect as 4%-5% albumin using roughly one-third of the administered volume, thus diminishing the time needed to attain the desired expansion of the intravascular space. The disproportion in administered volume is far greater than that of crystalloid. For example, the required volume of Ringer's lactate (RL) was fourfold that of 5% albumin to achieve the same hemodynamic endpoints in a randomized trial of patients with multiple trauma and shock. Furthermore, the effect of hyperoncotic albumin is relatively long-lasting, with at least two-thirds of the initial volume expansion effect persisting at 6-8 hours after infusion.⁷ While analyses of studies have not found a conclusive benefit of using albumin for resuscitation, it is noted that several of the studies used only 5% albumin and did not evaluate 20% or 25% albumin. Hyperoncotic 20% to 25% albumin solutions may be suitable for small-volume resuscitation.⁷

   Some drawbacks to using albumin are, as a naturally occurring protein, it has an expiration date, and it is more expensive than crystalloids. It should be noted that the infusion rate of albumin is as slow as 1 ml/min.

Hydroxyethyl starches

   Hydroxyethyl starch (HES) is a derivative of thin, boiling, waxy cornstarch, which mainly consists of a glucose polymer (amylopectin). These substances serve only to expand intravascular volume. They function as a 1:1 replacement, i.e., a 500 ml infusion remains in the intravascular space for prolonged periods and expands the volume by 500 ml. There is no standard HES, but rather a variety of different substances with different weights, sizes and chemical properties. They are all administered within 0.9% saline.

   In December 2007, the FDA approved the HES Voluven (6% hydroxyethyl starch 130/0.4 in 0.9% sodium chloride injection) for the treatment of perioperative blood volume loss, but there are no reports of prehospital use to date.

Dextrans

   Dextrans produce plasma volume expansion by a mechanism similar to albumin and are administered in a 0.9% (normal) saline solution. In adults, infusion rates are 500-1000 mL at a rate of 20-40 mL/minute. Dextran 40 is known as low molecular weight dextran (LMD). Maximum plasma volume expansion is reached approximately one hour post-infusion.

   Both clinical grade dextran 40 and dextran 70 have been marketed in the U.S. for several years and are approved by the FDA for plasma volume expansion in the treatment of hypovolemic shock and as a component of the pump prime for cardiopulmonary bypass. The dextrans offer a much briefer volume expansion effect compared with starches and gelatins, and have one of the highest risks of anaphylaxis of all the colloids. Dextran can also interfere with blood typing (cross-matching and grouping).⁷

   Most publications have concluded that there is no clear benefit from hypertonic saline solutions in terms of survival or reduced morbidity. However, reanalysis of individual data from previous studies of a combination of hypertonic saline and dextran found improved survival in both hypotensive patients with head injury, where it acts to increase cerebral perfusion pressure, and in those with penetrating injuries needing immediate surgery.⁸

Perfluorocarbon emulsions

   Perfluorocarbons (PFCs) are chemically inert molecules containing primarily, as the name suggests, fluorine and carbon atoms. They are capable of dissolving large amounts of many gases, including oxygen. PFC particles are about 40 times smaller than the diameter of a red blood cell, which enables them to go through capillaries where no RBCs are flowing. In theory, this can benefit damaged, blood-starved tissue that conventional red cells cannot reach. In addition to hypovolemia, this may be beneficial for MI, CVA and sickle-cell crises, among other similar obstructive ischemic conditions.

   Perfluorochemical solutions carry oxygen so well that mammals and humans can survive breathing liquid PFC solution, called liquid breathing, which has been used in ICU settings. The ability of liquid perfluorochemicals (PFCs) to support liquid breathing was first demonstrated in the early 1960s by immersing a mouse in a glass beaker filled with an oxygenated PFC. Although it was completely submerged in liquid, the mouse was able to breathe, which proved that the PFC was able to facilitate the exchange of oxygen and carbon dioxide. PFCs are entirely man-made, thus eliminating the risk of transmitting viruses and infection from donor material. They are also compatible with all blood types and have a shelf life of approximately 2 years.

   After intravenous administration, the droplets of this emulsion are taken up by the lymphatic system and slowly broken down. They are then transported to blood, where they are bound to lipids and move to the lungs. PFCs are typically removed from the body by exhalation.

   The first PFC to be marketed was withdrawn from the market due to adverse effects and other problems. Even Oxygent, the most recent PFC to be studied, has showed an increased incidence of stroke in recipients, and trials have been halted.⁹

Hemoglobin-Based Blood Substitutes

   HBBS, sometimes referred to as hemoglobin-based oxygen carriers (HBOCs), use purified human, animal or recombinant hemoglobin. A solution containing hemoglobin not contained within a red blood cell has many advantages over red blood cells, including the ability to withstand sterilization and a shelf life of approximately 2 years at room temperature. Many products have been on the market or in production for years, including HemAssist, Hemopure, Hemolink, PolyHeme and Hemospan.

   Hemopure is also known as hemoglobin glutamer-250 (bovine) or HBOC 201. Hemopure is made of chemically stabilized cow hemoglobin situated in a salt solution. It is smaller in size (up to 1,000 times smaller than a typical red blood cell) and has less viscosity than human red blood cells. This means it can carry more oxygen at a lower blood pressure than red blood cells. Also, because of its smaller size, it can carry oxygen through partially obstructed or restricted blood vessels where red blood cells cannot reach. Its advantages over blood include the ability to be stored at room temperature, it is ready to use quickly and has a 3-year shelf life.

   Made by the same company as Hemopure, Oxyglobin solution is the first and only oxygen therapeutic to be both U.S. FDA- and European Commission-approved for veterinary use. In 2004, cyclist Jesus Manzano admitted to using Oxyglobin during a Spanish national time trial championship and during the Tour de France, where he became sick and crashed.⁹

   PolyHeme, which utilizes human hemoglobin as the oxygen-carrying molecule in solution, originally began as a military project following the Vietnam War and has since shown great potential for both military and civilian use.⁹

   Hemospan is produced in powder form, allowing it to be stored for years, according to scientists. The powder can be mixed into liquid form and transfused immediately, regardless of a patient's blood type. The starting material for Hemospan is unmodified hemoglobin from outdated human red blood cells; however, the source could be any form of hemoglobin--human, animal or recombinant.⁹

   While each of these products had initially positive reviews, a scathing review of clinical trials in JAMA in 2008 altered the attractive landscape.¹⁰ The article identified these products as increasing the risk of myocardial infarction and death, outweighing their potential benefit. Hemoglobin molecules used to manufacture these products are not contained by a red cell membrane, and when released into the vasculature, they rapidly scavenge nitric oxide. This can result in systemic vasoconstriction, decreased blood flow, increased release of proinflammatory mediators and potent vasoconstrictors, and loss of platelet inactivation, creating conditions that may lead to vascular thrombosis of the heart or other organs. The JAMA article cited data from randomized controlled trials of five different HBBSs conducted over the last decade in elective surgery, trauma and stroke patients, noting there was an overall 30% statistically significant increase in mortality risk. There was also a statistically significant 2.7-fold increase in MI risk associated with these products. Seven trials examined the ability of HBBSs to limit blood transfusions. Two of these trials reported that HBBSs acutely prevented the need for blood transfusions, but this was completely offset by increased blood requirements later. Two trials were stopped early for safety concerns, and the other three trials reported decreases in transfusion requirements--one statistically significant and the other two not significant.¹⁰

Gelatins

   Gelatin is the name given to proteins formed when the connective tissues of animals are boiled. They have the properties of dissolving in hot water and forming a jelly when cooled. Gelatin solutions were first used as colloids in humans in 1915. Currently, the gelatin plasma expanders Haemaccel and Gelofusine are approved and have been used in resuscitation for some time in the United Kingdom and Europe, but not in the U.S.

   Following intravenous administration, Haemaccel is distributed between intravascular and extravascular compartments. Fluid is not drawn from the extravascular compartment. The intravascular half life of Haemaccel has been established to be 4-6 hours.

Conclusion

As the debate rages on regarding the timing and amount of fluid resuscitation for different categories of patients, so too does the debate about which fluids are best for each patient subgroup. Prehospital providers should be aware of the effects of different resuscitation fluids, and their indications and contraindications.

References

1. Moore FA, McKinley B, Moore E. The next generation in shock resuscitation. Lancet 363(9425):1988-1996, Jun 12, 2004.

2. Tinmouth A, Fergusson D, Yee IC, Hébert PC, ABLE Investigators, Canadian Critical Care Trials Group. Clinical consequences of red cell storage in the critically ill. Transfusion 46(11):2014-2027, Nov 2006.

3. Stevens WJ. Fluid balance and resuscitation critical aspects of ICU care. Nursing Care 2008 3(2):12-21, 2008.

4. www.anaesthesiamcq.com/FluidBook/fl7_2.php.

5. Jacob M, Chappell D, Conzen P, et al. Small-volume resuscitation with hyperoncotic albumin: A systematic review of randomized clinical trials. Crit Care 12(2), 2008.

6. Williams DA, Lemke TL, Foye WO. Foye's Principles of Medicinal Chemistry, 5th ed. Lippincott Williams & Wilkins, 2002.

7. Riback W. Plasma Expanders: Expanding the options. www.traumasa.co.za accessed on December 15, 2008.

8. Søreide E, Deakin C. Prehospital fluid therapy in the critically injured patient: A clinical update. Injury 36(9):1001-1010, 2005.

9. Winslow RH. Current status of oxygen carriers ('blood substitutes'). Vox Sang 91(2):102-110, Aug 2006.

10. Natanson C, Kern SJ, Lurie P, et al. Cell-free, hemoglobin-based blood substitutes and risk of myocardial infarction and death: A meta-analysis. JAMA 299(19):2304-2312, May 21, 2008.

Rob Curran has been an EMT in New York City for over 15 years. He instructs undergraduate and graduate pathophysiology at SUNY-Downstate and Human Anatomy and Physiology at CUNY-Brooklyn College.