Chapter 44 Critical Care and Fluid Therapy for Horses
EQUINE FLUID PHYSIOLOGY
Physiologic fluid compartments consist of total body water (TBW), extracellular fluid volume (ECFV), and intracellular fluid volume (ICFV). TBW is the most clearly defined compartment because it represents the total amount of water comprising an individual. Values for TBW in adult horses have been reported to range from 0.623 to 0.677 L/kg.1-4 Values in foals are believed to be larger than in adult animals. In human neonates, TBW values up to 0.784 L/kg have been measured.5 Acute changes in TBW in clinical patients can be detected with serial body weight measurements, but this becomes less accurate over long periods of time.
ECFV represents the component of TBW that is not contained within the cells. This includes plasma volume, interstitial volume, and transcellular compartments (gastrointestinal tract, joint fluid, cerebrospinal fluid [CSF], body cavities, and so on). The ECFV has been measured using a number of techniques in horses; reported values in adult horses range from 0.214 ± 0.01 to 0.253 ± 0.01 L/kg.1,6 Estimations of ECFV in foals are significantly larger, including 0.400 L/kg in newborn foals and 0.290 L/kg in foals 24 weeks of age.7 Plasma volume has been determined to be 0.050 L/kg in healthy adult horses and 0.090 in foals at 2 days of age.7
ICFV is the volume of fluid contained within cells. It has been estimated as the difference between TBW and ECFV. Bioimpedance technology has also been used to estimate the volume of intracellular space in horses, whereas standard indicator dilution techniques cannot be easily applied to the ICFV.1,2 Reported values for ICFV in adult horses range between 0.356 ± 0.01 and 0.458 ± 0.06 L/kg.1,2
Rapid changes in fluid balance and compartment volumes can occur during disease states, especially critical illness. The next section discusses the physiologic relationships between these fluid volumes.
Plasma and Interstitial Balance
Although both are components of the ECFV, the plasma volume is separated from the interstitial space by blood vessel walls, with constant flow of fluid and proteins into the interstitial space. The plasma and interstitial volume therefore are in constant flux, and a single equation (the Starling hypothesis) describes the flow between these two spaces:
where Kf is the capillary filtration coefficient, being dependent on capillary surface area and hydraulic conductivity. The other five terms in the equation represent the primary determinants of fluid balance between plasma and the interstitium:
COP is determined by the concentration of plasma proteins, primarily albumin, and their ability to attract ions. Normal COP in adult horses is approximately 20 mm Hg (19 to 26 mm Hg) and in neonatal foals is 18.8 ± 1.9 (15 to 22.6) mm Hg.8,9 Hypoproteinemia with resultant decreased oncotic pressure can occur during a variety of diseases in horses but is most often a result of loss or decreased production. Losses most commonly occur through the diseased gastrointestinal tract in large animal species (protein-losing enteropathies); losses also may occur secondary to glomerular diseases or large accumulations of protein-rich effusions within body cavities or the interstitial space. Decreased production of protein (specifically albumin) occurs in response to systemic inflammation because albumin is a negative acute-phase protein.10 Hypoproteinemia also occurs uncommonly because of liver disease.11 Improvement of plasma COP is one of two primary means of manipulating Starling forces for fluid balance during treatment of clinical cases.
Interstitial COP is more difficult to measure than plasma COP, but estimates of this number include 12 to 15 mm Hg in other species under experimental conditions.12 Changes in total plasma protein concentration are likely to also affect the interstitial protein concentration and therefore alter both oncotic pressure components in Starling’s equation. This may explain why some horses with significant hypoproteinemia do not show clinical signs of interstitial fluid accumulation (i.e., edema). That is to say, the gradient between capillary and interstitial oncotic pressure is only minimally affected when both have decreased proportionally, especially with time. It has been speculated that acute changes in plasma total protein concentration, however, may lead to edema formation more often than chronic hypoproteinemia; this is because of a relatively larger decrease in plasma protein concentration as compared with that in the interstitium with acute disease. Conversely, administration of hyperoncotic intravenous fluids (fluids with a COP >20 cm H2O) can potentially shift the balance of oncotic pressure back to the vascular space by raising plasma COP. However, the colloid molecules from these fluids must remain within the vascular space to have this effect, which may be negated by significant alterations in capillary permeability.
Vascular hydrostatic pressure represents the pressure of plasma within the vessels pushing out toward the interstitium. A number of factors influence this pressure, including blood volume, vascular tone, and central venous pressure (CVP). This outward pressure on the vessel walls serves as the driving pressure for the continuous flux of fluid and protein out of the vessels into the interstitium. Pathologic increases in hydrostatic pressure can be caused by right-sided heart failure or other obstructive processes, such as venous thromboses, which can lead to edema formation. Pulmonary capillary hydrostatic pressure increases with left-sided heart failure and significant pulmonary vasoconstriction.
Administration of intravenous fluids can also increase capillary hydrostatic pressure; this is the second means by which therapeutic intervention can affect fluid balance between plasma and interstitial spaces in clinical patients (the first was altering plasma oncotic pressure). Fluid losses resulting from diuretic administration and acute blood loss are examples of decreased capillary hydrostatic pressure.
The hydrostatic pressure of the interstitium varies in different tissues but often has been overlooked as a significant contributor to fluid balance between the vascular and interstitial spaces. Newer understanding of interstitial fluid balance has recently been reviewed.12 This information suggests that degeneration of the interstitial collagen network may cause a decrease in interstitial hydrostatic pressure, resulting in a shift of fluid into the interstitium. Inflammatory cytokines have been implicated as a cause for these changes in interstitial hydrostatic pressure. Severe burn injury can also result in marked negative pressures within the interstitium, causing a draw of fluid into the interstitial space and subsequent edema formation. In the future there may be therapeutic options to manipulate interstitial hydrostatic pressure and alter fluid balance, but currently there are no practical measures to do so.
Changes in capillary permeability can dramatically increase the flux of fluid and protein from the intravascular space into the interstitium. If this increase in flow cannot be balanced by a corresponding increase in lymphatic return, edema results. Increased vascular permeability has been regarded as a major mechanism of edema formation; however, it may be only one component of the significant fluid shift that results from a systemic inflammatory response syndrome (SIRS). Adult horses and neonatal foals may have significant differences in interstitial composition and vascular permeability. It has also been proposed that foals have an increased capillary filtration coefficient as compared with adults.13 These hypotheses may explain the propensity of neonatal foals to form edema relatively easily in response to overzealous fluid administration. Because of this increased risk, careful monitoring and serial assessment of the balance between plasma volume and the interstitium is warranted when treating neonatal foals with fluid therapy.
Extracellular to Intracellular Fluid Volume Relationship
There are three main determinants of net movement of fluid between the ECFV and ICFV:
The tonicity (or effective osmolality) of the ECFV is estimated by the following equation14:
Under normal circumstances, sodium and chloride are the primary determinants of ECFV tonicity; the equation doubles the sodium concentration rather than including the concentration of specific anions, some of which may not be easily measured. It should be noted that BUN is not included in the tonicity formula, because BUN is an ineffective osmole.
Other effective osmoles can be added to the ECFV, thereby increasing tonicity and inducing a shift of water from the ICFV to the ECFV. The tonicity of the ECFV is primarily regulated by vasopressin (ADH). Administration of fluids with a tonicity greater than or less than ECFV tonicity is a means to manipulate the balance of fluid between the ECFV and ICFV. This explains why hypertonic saline causes a shift of water from the ICFV to the ECFV. Recent mathematic models have been used to predict the influence of tonicity on the absolute volumes of these fluid compartments.15 Similarly, fluid loss that has a tonicity different from the ECFV will also alter the ratio of fluid between the ECFV and the ICFV.
The tonicity of the ICFV is primarily determined by the intracellular concentration of potassium and its related anions. The tonicity of the ICFV and ECFV are the same at any given time point, a homeostatic mechanism meant as a safeguard to prevent acute changes in cell volume. Any imbalance in tonicity between the two fluid spaces will result in a rapid shift of fluid in order to maintain osmolar equality. The tonicity of the ICFV can be altered over time by the cells in response to changes in ECFV tonicity; an example of such a response is the production of idiogenic osmoles during hypernatremia.16 Significant changes to ICFV tonicity during disease (resulting from damaged cell membranes) can result in accumulation of intracellular potassium, calcium, or cellular debris.
Cell membranes are selectively permeable to water and ions. Changes in this permeability usually do not cause large alterations in global fluid balance during healthy states. However, cell membrane damage during disease states can result in significant fluid shifts. In fact, a shift of fluid from the ECFV to the ICFV is an indicator of cellular membrane damage.
Effects of Fluid Physiology on Clinical Fluid Therapy
Specific disease states dictate individualized fluid plans. However, with intravenous therapy the administered fluid enters the vascular space. From there, the characteristics of the administered fluid will determine its movement from the vascular space into the interstitium and from the ECFV to the ICFV. Hyperoncotic or hypertonic fluids result in the greatest relative expansion of plasma volume, with a corresponding reduction in ICFV. Hypotonic fluids result in the smallest increase in ECFV but add volume to the ICFV owing to a decrease in the tonicity of the ECFV. Estimates of the volumes of the different fluid spaces (whether based on clinical or laboratory values) before and during fluid therapy will allow for evaluation of the physiologic response in the clinical setting. The standard and universal administration of isotonic and hypooncotic fluids (such as lactated Ringer’s solution [LRS] or physiologic saline) to all patients regardless of disease condition ignores the available research and clinical insight to suggest otherwise.
GENERAL PRINCIPLES FOR FLUID THERAPY IN CRITICAL CARE
Current guidelines for fluid therapy in human critical care emphasize the “fluid challenge” method, believed to be more effective and safer than traditional estimates of percent dehydration.17 The author’s (KGM) protocol of fluid administration in horses follows this same algorithm. Considerations for the fluid challenge technique incorporate four primary decision phases: (1) type of fluid, (2) rate and volume, (3) goals or endpoints of fluid therapy, and (4) safety limits to fluid therapy.
The goals of replacement fluid therapy include rapid correction of hypovolemia by reversal of the signs of shock, including seven perfusion parameters: tachycardia (except in some neonatal foals), pale mucous membranes, prolonged capillary refill time, cold extremities, poor pulse quality, depressed mentation, and, in horses, reduced jugular fill. Urine production is another positive sign indicating correction of fluid deficits. Dehydration is corrected more slowly and is marked by reduced skin turgor (increased skin tent), dry mucous membranes, and dry corneal surface (reduced tear production).
Additional goals of volume replacement include correction of hypotension, tachycardia, oliguria, and blood lactate.17 A decrease in urine specific gravity (in the absence of renal failure), an increase in arterial blood pressure and CVP, and improvement in venous oxygen saturation are specific endpoints. The goals of maintenance fluid therapy are different; they are to maintain a normal degree of hydration by providing for ongoing losses, including insensible losses (respiratory, cutaneous evaporative losses) and any abnormal ongoing losses such as diarrhea. Maintenance fluid rates for horses vary with ambient temperature, use, diet, and metabolic status. In general, a reasonable starting point for maintenance fluid requirements includes 2 to 3 mL/kg/hr for adult horses and 4 to 6 mL/kg/hr for neonatal foals.18,19
The reader is referred to the section entitled Fluid Therapy for Horses with Gastrointestinal Diseases for side effects of fluid therapy and principles of oral fluid therapy.
CRITICAL CARE AND FLUID THERAPY MONITORING TECHNIQUES
Monitoring tools provide for advanced critical care in the large animal intensive care unit. Several of these tools are pertinent to fluid therapy and provide guidance, endpoints, and safety limits. Many of these allow for direct monitoring of fluid during administration of therapy, whereas others provide indirect information through hemodynamic data. Both of these are important to overall case management of the critically ill equine patient.
Central Venous Pressure
CVP is the pressure within the vena cava; the term most commonly refers to that within the cranial vena cava. It is determined by blood volume as well as venous tone and cardiac contractility. With serial measurements CVP provides a limit to the administered volume of fluid. Normal CVP is approximately 2 to 12 cm H2O in foals and 5 to 15 cm H2O in adults.21-24 Subnormal to negative CVP values signify hypovolemia; however, normal values do not necessarily imply euvolemia. This is because CVP is affected by compensatory responses such as venoconstriction.
CVP is easily measured in neonatal foals through the use of 20-cm central venous catheters, such as long-term single- to triple-lumen polyurethane catheters. Measurements can be obtained in adult horses with the use of 55-cm commercial CVP catheters. CVP can also be measured by passing a smaller gauge polyurethane catheter or polyethylene tubing through a 14-gauge, 5¼-inch standard intravenous catheter. CVP can be measured with a disposable water manometer (for spot readings) or using a pressure transducer for continuous waveforms. Interpretation of CVP waveforms requires knowledge of component waves and descents, including the a, c, and v waves and x and y descents. The a wave represents atrial contraction. The mean of the a wave is the appropriate point at which to measure CVP (at expiration). The c wave is associated with tricuspid valve closure and a bulging of the valve into the right atrium, and the v wave is caused by atrial filling from venous return. The x descent occurs after the a wave and represents the fall in pressure associated with atrial relaxation. The y descent occurs after the v wave, representing a drop in CVP caused by ventricular relaxation and reopening of the atrioventricular valves.
High CVP readings also occur with pericardial tamponade, pleural effusion, or pneumothorax, as well as false increases from catheter occlusion and air within the lines. For accurate and consistent serial results a zero reference point should be selected and used for each measurement. The top of the sternal manubrium is a good reference point for the level of the pressure transducer or water manometer. The pressure transducer or water manometer can be taped to a fluid pole, providing a fixed zero point for repeated measurements in standing horses.
It should be noted that adequacy of intravascular volume cannot be guided by any one CVP level. Precision and reliability are limited by variable zero reference points, the effects of afterload and ventricular compliance, and alterations in intrathoracic pressure.17 There is no linear relationship between intravascular volume and filling pressures, and CVP should be regarded as only an indirect estimate of volume. Serial measurements and trends over time are more useful than single numbers. The way CVP can be used on a clinical level for monitoring fluid therapy is as follows: if the patient responds to fluid boluses without increases or with only minor increases (2 to 3 cm H2O) in CVP, then it is appropriate to continue infusions until signs of hypoperfusion are reversed.17 Additional guidelines used in human patients are as follows: if the CVP increases to 3 to 7 cm H2O (2 to 5 mm Hg), the infusion should be paused and perfusion reevaluated after a 10-minute wait. If the change in CVP was an increase ≥7 cm H2O (>5 mm Hg) after the fluid bolus, the infusion is stopped.17
Arterial Blood Pressure
Arterial blood pressure measurements provide some insight into perfusion status, particularly when used in conjunction with clinical signs and labwork, such as blood lactate. It can be measured either directly through the use of arterial catheters or indirectly with a blood pressure cuff on the tail head. Arterial lines can be placed in the great metatarsal artery of recumbent foals and the transverse facial artery in standing adult animals for direct measurements. Indirect measurements are best performed with oscillometric blood pressure monitors that provide systolic, diastolic, and mean arterial pressure (MAP). Cuffs are provided by the manufacturer and vary in width and length with size of the patient.
Arterial blood pressure in healthy neonatal foals is highly variable and depends on breed, gestational age, and size of foal. In general, normal mean arterial blood pressure (direct) is 84.4 ± 3.7 mm Hg at 1 day of age and up to 101.3 ± 4.4 mm Hg at 14 days of age.22 Indirect blood pressure readings in thoroughbred foals has been reported as 144 ± 15, 74 ± 9, and 95 ± 13 mm Hg for systolic, diastolic, and mean pressures, respectively.25 Direct blood pressure has been reported for adult horses: 126 to 168 (systolic)/85 to 116 (diastolic) with a range for the mean arterial pressure of 110 to 133 mm Hg.26-29 Indirect blood pressure in adult horses is 111.8 ± 13.3 mm Hg for systolic pressure and 67.7 ± 13.8 mm Hg for diastolic pressure.30
Blood pressure values should not be regarded as the sole criteria for intervention. Rather, they should be used in conjunction with perfusion parameters, blood lactate concentration, and urine output in deciding whether there is need for further fluid administration or inotrope and vasopressor support.
Blood or Plasma Lactate
Blood or plasma lactate concentrations are very useful in monitoring fluid support as well as perfusion and metabolic status. Increased blood lactate may be a result of hypoperfusion and reduced oxygen delivery (hypovolemia, hypotension, anemia, hypoxemia, heart failure). Other considerations for hyperlactatemia should include SIRS, sepsis, catecholamine surges, liver or renal failure, thiamine deficiency, alkalosis, hyperglycemia, exercise, seizure activity, and the action of drugs such as salicylates and theophylline.31-34 SIRS may increase circulating lactate concentrations independent of perfusion status; inflammatory mediators and cytokines activate pyruvate dehydrogenase kinase, an inactivator of pyruvate dehydrogenase, resulting in reduced activity of the citric acid cycle. Normal lactate concentrations in horses are <2 mmol/L, with most horses having levels <1 mmol/L.35-37 Neonatal foals have decremental values after birth, with reported concentrations of 4.9 ± 1.02, 2.25 ± 0.6, and 0.89 mmol/L at birth, 12 hours of age, and 24 hours of age, respectively.37-39 In a study I performed, foals had values of 2.3 ± 0.9, 1.2 ± 0.3, 1.1 ± 0.3 at 0 to 2, 24, and 48 hours of age, respectively, compared with 0.6 ± 0.2 mmol/L in adult horses.40
Cardiac Output
Advanced monitoring in equine critical care includes cardiac output measurement. A number of methods of cardiac output monitoring have bee described in horses, including the Fick principle, indicator dilution methods (such as lithium dilution), Doppler and volumetric echocardiography, pulse contour analysis, and partial carbon dioxide rebreathing. The most practical of these include lithium dilution and echocardiographic techniques.41-46
Lithium dilution precludes the need for placement of cardiac catheters. A small bolus of lithium chloride is injected into a peripheral vein or the cranial vena cava (via central line). Arterial blood is sampled using an arterial catheter at a constant rate and passes through a lithium electrode to generate a lithium concentration-time curve. Cardiac output is calculated from the area under the curve for lithium over time. Advantages of lithium dilution include only moderate invasiveness, good accuracy, and requirements for only small volumes of injectate. Disadvantages include the need for continuous arterial blood and limitations on repetitive measurements owing to lithium accumulation.44-46
Noninvasive cardiac output measurements can be made using the Bullet method through volumetric echocardiography.43 Giguere and colleagues reported that the Bullet method provided an accurate estimate of cardiac output in anesthetized foals.43 Cardiac output is calculated using heart rate and stroke volume (SV) as follows:
where LVAd = left ventricular area in diastole (short axis view); LVLd = left ventricular length in diastole (long axis view); LVAs = left ventricular area in systole (short axis view); and LVLs = left ventricular length in systole (long axis view).
Cardiac output in healthy adult horses (400 to 500 kg) is 32 to 40 L/min.41 Normal cardiac index, which is cardiac output expressed per unit of body weight, is 72 to 88 mL/kg/min. In the neonatal foal cardiac output has been reported to be 7.1 ± 0.4 L/min (cardiac index = 155.3 ± 8.1 mL/kg/min) in 2-hour-old foals.22 At 24 hours of age cardiac output was determined to be 9.0 ± 0.5 L/min (cardiac index = 197.3 ± 12.0 mL/kg/min). This increased to 15.7 ± 1.5 L/min (cardiac index = 222.1 ± 21.6 mL/kg/min) at 14 days of age.22 A general guideline for normal cardiac index is 100 to 300 mL/kg/min.43
Blood Glucose
Blood glucose concentration has been the focus of much study in human critical care in recent years. A number of studies have demonstrated improved survival and reduced complications with tight glucose control using intensive insulin therapy in critically ill humans.47,48 Maintenance of euglycemia (80 to 110 mg/dL) resulted in reduced mortality in surgical intensive care unit patients as compared with hyperglycemia (180 to 200 mg/dL). Hyperglycemia may be associated with detrimental effects in pediatric intensive care patients as well.49 How these findings relate to critically ill horses is unknown, but prevention of hyperglycemia is likely warranted and its effects in the equine intensive care unit require further study.
Monitoring Urine Analytes
Urine indices are useful for monitoring responses to fluid therapy. Successful production of urine output is a primary goal of fluid therapy, and measurement of urine production allows determination of “fluid balance” (input – output). Another important means of assessing the response to fluid loading is measurement of urine specific gravity and/or osmolarity. In the absence of renal failure, progressively dilute urine is a positive response to fluid administration. Urinalysis should be performed, and fractional excretion of electrolytes, particularly sodium, provides information regarding tubular function and can aid in differentiation of prerenal from renal azotemia. Normal fractional excretion is <1% in adult horses and 0.31 ± 0.18% in neonatal foals.50-53
FLUID THERAPY FOR SPECIFIC DISEASES AND DISORDERS
Fluid Therapy for Liver Dysfunction and Failure (Box 44-1)
Acute liver disease may result in hypovolemia owing to lack of water intake, third space losses into the gut and peritoneal cavity, and possibly pooling of blood in the portal circulation. Portal hypertension may result in gut edema with subsequent fluid loss. Considerations of fluid therapy in cases with hepatic dysfunction include reduced metabolic capacity as well as compromised synthetic ability of the liver. Because lactate clearance primarily occurs in the liver, fluids containing lactate should be avoided. Isotonic replacement fluids, such as Normosol-R (Abbott Laboratories, North Chicago, Ill.) and Plasma-Lyte 148 (Baxter Healthcare Corporation, Deerfield, Ill.), and acetated Ringer’s are preferred over LRS. One millimole of acetate yields 1 mmol of bicarbonate during metabolism and is therefore alkalinizing.54 These balanced, polyionic fluids are optimal as compared with physiologic saline because of the propensity of the latter to produce a mild, strong ion (hyperchloremic) acidosis, and many horses with liver dysfunction have a propensity toward acidemia.55
Provision of dextrose, even in the face of normoglycemia, should be considered unless enteral nutrition is adequate. The addition of dextrose to fluids will minimize gluconeogenesis demands on the liver, as well as catabolism of endogenous tissues with subsequent increases in nitrogen turnover (and increased ammoniagenesis). Risk of hypoglycemia from liver dysfunction is also minimized, as patients may have insufficient liver and muscle glycogen reserves and impaired hepatic gluconeogenesis to maintain normal blood glucose concentrations. A dextrose supplementation rate for adult horses is 1 to 2 mg/kg/min. This equates to 3% to 6% dextrose in fluids if 1 L of crystalloid per hour is administered to a 500-kg horse. The addition of B vitamins can be helpful for anorectic horses because they are required cofactors for oxidative metabolism. Horses that remain anorectic for longer than 24 to 72 hours should be considered candidates for parenteral nutrition.
Horses with liver dysfunction should be monitored closely for hyperammonemia as a marker of hepatic encephalopathy. Fluids can be tailored to minimize the risks of hyperammonemia. Provision of potassium provides for an electrolyte draw of hydrogen atoms from intracellular stores, thereby lowering pH and promoting ionization of ammonia to its less diffusible form, ammonium ion, which is not able to cross the blood-brain barrier.56 Hypokalemia also promotes metabolic alkalosis and may compound hepatoencephalopathy owing to increased urinary losses of hydrogen ion (H+) and increased tubular absorption of ammonia. For similar reasons, sodium bicarbonate should be used judiciously and with caution in horses with a propensity toward hepatic encephalopathy. Increases in the pH of plasma will result in conversion of ammonium ion to ammonia; this facilitates the brain uptake of ammonia with subsequent intracerebral trapping of ammonium.
The rate of fluid administration for horses with liver dysfunction will vary with the volume and hydration status of the individual. In general, rates should exceed maintenance requirements to account for hypoperfusion and produce diuresis of ammonium and other toxins such as conjugated (direct) bilirubin that would otherwise have been metabolized or eliminated by the liver. Volume of fluid administration should be monitored closely in horses with ascites or portal hypertension resulting from severe liver disease because of the propensity of these patients for third space fluid accumulation. Other considerations for horses with liver disease include hypoalbuminemia, hyponatremia, hypokalemia, coagulopathies, and hyperlactatemia. Monitoring CVP will aid in preventing rises in hydrostatic pressure that would contribute to transudates or ascites.
Fluid support should be modified in horses with preexisting ascites or edema to reduce the administered sodium load. Commercially available solutions with restricted sodium concentrations (maintenance crystalloids), such as Plasma-Lyte 56 or Normosol-M, can be used in foals. Because of their availability in only small volumes (1-L bags), combinations of isotonic crystalloids and sterile water or 5% dextrose in water can be used as maintenance fluids in larger patients. If sterile water is selected, it should be allowed to mix with the isotonic fluid before entering the patient; administered alone, water could cause osmotic hemolysis. Another option in such horses is to restrict the volume of crystalloid administered through concurrent administration with colloids. Colloids expand the intravascular volume, limit the requirement for crystalloids, and may reduce the propensity of edema formation by raising oncotic pressure.
Colloids are indicated in horses with significant hypoalbuminemia (<1.5 g/dL). Hetastarch can be used at a dose of 10 mL/kg/day unless coagulopathies are present. Liver failure may result in decreased production of clotting factors or antithrombin and can initiate disseminated intravascular coagulation (DIC). Because hetastarch can induce decreased activity of von Willebrand’s factor and factor VIII, as well as interfere with platelet function, it is contraindicated in horses with bleeding tendencies (after consumption of factors).57 Plasma is an alternative colloid that has additional benefits for horses with hepatic failure. Coagulopathies associated with liver disease can be addressed through provision of exogenous antithrombin and clotting factors in plasma products. Plasma should probably not be administered to horses with serum hepatitis (Theiler’s disease), as this disease is poorly understood and associated with prior administration of equine-origin biologics. Replacement of albumin is beneficial not only for oncotic pressure support but also for drug and toxin binding and as an endogenous buffer. If hypoalbuminemia is a result of hepatic dysfunction, and not urinary or gastrointestinal losses, colloids will have a longer retention time in the circulation.
Fluid Therapy for Diarrhea and Colitis (Box 44-2)
Horses with acute colitis are often presented in a state of severe SIRS with endotoxemia, hypovolemia, and malperfusion of tissues. Fluid therapy is the cornerstone of hemodynamic and therapeutic support for these horses. Not only is circulating volume an indication for fluids, but acid-base and electrolyte derangements also warrant their use in these cases. Specifically, horses with colitis often exhibit hypovolemia, both organic and inorganic acidoses, and hyponatremia. Organic acidosis primarily is a result of hyperlactatemia, whereas inorganic acidosis is often a result of relative hyperchloremia (or hyponatremia).
Because of the poor sensitivity of physical examination in detecting hypovolemia, estimates of percent dehydration and water deficit are not very accurate.17 A more objective means of providing fluids is through the “fluid challenge method” described in the previous sections.17 In this protocol a bolus dose of 10 to 20 mL of isotonic crystalloid per kilogram is administered, with subsequent reassessment of perfusion parameters. Perfusion parameters consist of mentation, peripheral pulse quality, heart rate, mucous membrane color, capillary refill time, and extremity temperature. Lactate, arterial blood pressure, and central venous oxygen saturation are perfusion monitoring tools that should be evaluated serially in patients undergoing fluid administration and can provide endpoints to fluid therapy. Urine output is another clinical indicator of improvement in perfusion in response to fluid loading. Fluid challenge should continue as repeat boluses until perfusion parameters normalize or plateau in terms of improvement. No further improvement of perfusion parameters in response to boluses of fluids suggests that inotrope or vasopressor support may be required and that further fluid therapy will not be of aid. A safety limit to fluid loading includes measurement of a high CVP value.
Crystalloid fluid choices for horses with colitis include replacement fluids, such as Normosol-R, LRS, and Plasma-Lyte 148. Normosol-R and Plasma-Lyte 148 are slightly advantageous over LRS from the stand point of providing a wider strong ion difference (sodium-chloride difference). In contrast, LRS has a chloride concentration greater than that of equine plasma (109 vs. approximately 100 mEq/L) and can compound an inorganic acidosis. Physiologic saline (0.9%) is even greater in its chloride concentration and produces a mild strong ion acidosis on administration of large volumes.55
Colloids are an important adjunct to crystalloid therapy, particularly for horses with hypoproteinemia such as those with acute colitis. In human critical care medicine there is no consensus as to whether crystalloids or colloids provide more successful fluid resuscitation.17 A combination of both is likely optimal.17 Colloids are particularly important for horses with hypoproteinemia, such as those with colitis. Concurrent hypovolemia and hypoproteinemia warrant administration of colloids in the resuscitative period, because the use of crystalloids alone could result in dilutional hypoproteinemia.57
Hypertonic saline (7% to 7.5%) is a rapid plasma volume expander that can be used in the early volume replacement period. Hypertonic saline increases plasma volume by three to four times the volume administered. In comparison, crystalloids increase plasma volume by only 0.25 to 0.33 mL for each milliliter administered. Hypertonic saline has additional advantages beyond volume expansion, particularly for the horse with endotoxemia. These include immunomodulatory, antiinflammatory, antiedema (particularly of the endothelium and erythrocytes), and inotropic effects.58-60 Microvasculature effects enhance microcirculatory perfusion, which is often disturbed during sepsis and endotoxemia. Reduction of endothelial and erythrocyte edema, two processes that contribute to multiple organ dysfunction during sepsis, results in reduced vascular resistance and blood viscosity.59,60 The hypertonicity created by hypertonic saline evokes vasodilation, which also contributes to microperfusion when coupled with an increase in cardiac output caused by contractility-enhancing effects of hypertonic saline. The antiinflammatory and immunomodulatory effects include antiapoptosis, free-radical scavenging properties, inhibition of leukoactivation, and prevention of immunosuppression after sepsis.58-60 In an experimental model of hemorrhagic shock in horses, hypertonic saline resulted in improved cardiac output, stroke volume, cardiac contractility and blood pressure as compared with isotonic saline.61 Hypertonic saline has demonstrated attenuation of cardiovascular derangements in equine endotoxemia models as compared with isotonic saline.62
The dose for hypertonic saline is 4 mL/kg, and it should be followed with isotonic crystalloids or water to replace the “borrowed” water from the intracellular space. Hypertonic saline is generally safe but should be avoided in horses with uncontrolled hemorrhage when hypotensive resuscitation is indicated. In addition, horses with marked sodium derangements should not be administered hypertonic saline.
Fluid Therapy for Sepsis (Peritonitis, Pleuritis, Pneumonia, Internal Abscess) (Box 44-3)
Box 44-3 Fluid Considerations for Horses with Sepsis
The optimal fluid for resuscitation of patients with sepsis is unknown.63-65 Despite this controversy, a rational approach to fluid therapy in patients with sepsis is to optimize hemodynamics (increase blood pressure and urine output) while attempting to limit edema formation.17,63,66 There is no evidence to support the use of either colloids or crystalloids over the other. Metaanalysis of clinical studies comparing crystalloids and colloids in human patient populations showed no outcome difference.64-68 Regardless of the lack of consensus recommendations for fluid choices, fluid therapy is a keystone in the management of severe sepsis and septic shock. This is because septic shock is associated with both absolute and relative hypovolemia. Relative hypovolemia is the result of vasodilation and peripheral blood pooling in the face of cytokinemia. Volume repletion allows for increases in cardiac output and subsequently in systemic oxygen delivery.67
Fluid therapy in horses with sepsis is similar to that recommended for horses with acute enterocolitis; both conditions are examples of a state of SIRS. In fact, enterocolitis can be thought of as a form of sepsis. Sepsis incites a host of hemodynamic derangements that challenge fluid therapy. It causes myriad microperfusion abnormalities; these include hypovolemia, myocardial depression, vascular permeability derangements, vasodilation, DIC, and cellular changes resulting in abnormal membrane potential and membrane pump or channel function.69 These pathophysiologic processes must be considered when a fluid plan for horses with sepsis is designed.
Sepsis is defined as concurrent SIRS and documented or suspected infection.70 Many equine cases fall into this category, including horses with peritonitis, pneumonia, pleuritis, enterocolitis, meningitis, and metritis. Sepsis and SIRS are states of cytokine milieu, in which cytokines and inflammatory mediators predominate. Aside from antimicrobials, the fundamental therapy is hemodynamic support, consisting of fluid and vasopressor therapy.
Initial fluid resuscitation is centered on isotonic (or near isotonic) replacement type fluids, colloids and hypertonic saline. Horses with sepsis often are presented with negative fluid balance resulting from both hypovolemia and dehydration. Fluid choices are the same as for horses with enterocolitis, and a combination of crystalloids and colloids may have advantages in sepsis.17 Such a combination would address both blood volume and interstitial deficits, with colloids expanding the vascular space and crystalloids addressing both fluid spaces. Hypertonic saline may have some additional advantages for sepsis, including immunomodulatory, antiinflammatory, antiedema, vascular, and inotropic effects.58-60 A dose of 2 to 4 mL of hypertonic saline per kilogram may be added to the combination of crystalloids and colloids.
Colloids are intriguing fluids for horses with sepsis. Colloids may attenuate capillary leak associated with sepsis and SIRS.71 The exact physiology behind this colloid effect is not exactly worked out; however, theories include reduction in endotoxin-induced leukocyte-endothelial cell interactions.72 Interactions with endothelial glycocalyx are also hypothesized in the ability of both synthetic colloids and albumin to reduce capillary leakiness.73 Hetastarch exhibits antiinflammatory properties by reducing neutrophil adhesion and accumulation in tissues.74 In addition, hetastarch has been suggested to be beneficial for tempering DIC in that it exerts dose-dependent effects on coagulation.57 Hetastarch lowers concentrations of von Willebrand’s factor and factor VIII:C and reduces platelet aggregability, which may aid during hypercoagulable states such as DIC.57,75-79 Both of these properties warrant further investigation in horses with sepsis because vascular derangements and coagulopathies are quite common. It should be kept in mind, however, that bleeding may be potentiated by the administration of hetastarch to the hemorrhaging patient.80 In a trial comparing concentrated albumin with crystalloids in human patients, there was a trend toward improved survival with albumin in patients with sepsis.81 Concentrated equine albumin is not currently available; however, one study showed that a human albumin product could be used safely in horses.82
Care should be taken to avoid overexpansion of the extracellular fluid compartment with excessive fluid administration. Horses with sepsis have a predilection for edema because of the presence of concurrent hypoalbuminemia and increased vascular permeability. Therefore careful monitoring of fluid balance is warranted. Fluid balance refers to input and output of fluids, and it can be monitored with urinary collection systems. CVP is also useful in monitoring for safety limits in this group of patients; maximal normal CVP (10 cm H2O in foals; 15 cm H2O in adults) should not be exceeded. Serial ultrasonography and arterial blood gas analysis can be used to detect pulmonary edema from relative or absolute fluid overload, before the development of gross signs (froth, crackles, tachypnea) of edema.
Because of thrombotic risks associated with sepsis-induced coagulopathies, these patients should be instrumented with minimally thrombogenic catheters, such as long-term polyurethane catheters. Attention to asepsis and cleanliness are paramount.
In human critical care “early goal-directed therapy” has been advocated by some clinical trials.83 These studies have used goal-oriented therapeutic adjustments of preload, afterload, and contractility to achieve a balance between oxygen delivery and demand. Endpoints have included normalization of central venous oxygen saturation, blood lactate, CVP, and MAP. The therapy consisted of crystalloids and colloids for correction of CVP, vasopressors and vasodilators for MAP, and dobutamine and red cell transfusions for central venous oxygen saturation. Patients receiving this early goal-directed therapy received a greater volume of fluids early (first 6 hours of treatment) and less later, as compared with patients in the conventional group. The treatment group had a lower mortality rate and less severe organ dysfunction, highlighting the importance of early identification of patients with insidious or occult malperfusion, consisting of patients with global hypoxia yet stable vital signs.83 There has been considerable debate over what the optimal fluid choices are for human patients with sepsis: crystalloids or colloids. The ideal fluid for volume replacement remains equivocal because concrete evidence implicating one over the other is lacking.64,84 A current philosophy is to recognize the advantages of both fluids, with concurrent or sequential administration of both. Because crystalloids distribute approximately 75% of administered volume to the interstitium, they allow for greater interstitial expansion compared with colloids. This property is advantageous when dehydration is also present, but a disadvantage when edema is a risk. In fact, crystalloid administration further dilutes total protein and albumin concentrations, thereby lowering COP and predisposing to edema. Colloids, on the other hand, are restricted to the intravascular space and are particularly indicated in hypovolemic shock; they replace intravascular losses more rapidly than do crystalloids.85 Colloids are associated with a plasma volume expansion between 100% and 200% of the infused volume.86-88 In humans and anesthetized horses with colic, cardiac output is better maintained with lower volumes of fluid administration when colloids are used rather than crystalloids.89
Marked alterations of the reflection coefficient, as are associated with severe capillary leak and acute respiratory distress syndrome (ARDS), warrant careful consideration and monitoring of patient status when colloids are administered; because of a theoretic potential for extravascular leakage of colloids with marked endothelial alterations, patients with ARDS should be monitored closely for clinical deterioration. Despite these theoretic concerns, a new form of hydroxyethyl starch (130/0.4) has demonstrated protective effects in a model of acute lung injury (ALI).90 The numbers after the colloid in the preceding sentence refer to the average molecular weight and degree of substitution of starch molecules with a hydroxyethyl group, respectively. This hydroxyethyl starch resulted in the best oxygenation and a reduced inflammatory response as compared with a modified gelatin colloid or Ringer’s acetate crystalloid in a rabbit model of ALI.90 Standard hetastarch has an average molecular weight of 450 kDa and a degree of substitution of 0.7; the newer hydroxyethyl starch (Voluven; 130/0.4) has been modified to have more complete renal elimination and less tissue storage than the standard product, with fewer side effects such as coagulopathies. The use of different colloids in patients with ARDS needs further study. Except for situations that may call into question the use of colloids, the concurrent use of crystalloids and colloids obviates the need for large volumes of crystalloids; this approach minimizes the risk of interstitial edema and may restore blood volume more rapidly than crystalloids alone. A “blending” of crystalloids and colloids should therefore be considered for patients with sepsis whenever colloids are not contraindicated.
Tight glucose control has been one of the very few therapeutic modalities to affect outcome in patients with sepsis. Through the use of intensive insulin infusions, glucose is regulated in the range of 80 to 110 mg/dL as compared with traditional approaches that allow for slight hyperglycemia. This direction has led to a reduction in mortality, organ failure, and septic complications in human patients.91 Whether this approach will have similar results in horses remains to be seen. The author (KGM) uses regular insulin as a continuous rate infusion (CRI) at a rate of 0.01 to 0.1 IU/kg/hr.
Fluid Therapy for Renal Failure (Box 44-4)
Box 44-4 Fluid Considerations for Horses with Acute Renal Failure
Fluid therapy is the major component of therapy of renal failure in horses, regardless of cause. Hemodialysis has been reported in horses; however, it is not widely available, further highlighting the importance of fluid diuresis. Peritoneal dialysis is an option to complement fluid therapy, particularly if unresponsive anuria is present.92,93 Development of a fluid plan for horses with renal failure begins with classification of the disease into polyuric, anuric, or oliguric renal failure. Polyuria and anuria are self-explanatory; oliguric renal failure in this section refers to a normally hydrated animal with concurrent azotemia and urine production <0.5 mL/kg/hr.
For both oliguric or anuric and polyuric renal failure, there are two primary considerations when beginning fluid therapy: fluid type and rate. The total amount of fluid administered is usually determined by the response to treatment and does not necessarily need to be identified at initiation of therapy.
POLYURIC RENAL FAILURE
The goal of fluid therapy in these patients is to induce diuresis, with removal of uremic toxins and maintenance of fluid, acid-base, and electrolyte balance.94,95 The degree of renal failure that is reversible is often unknown at the onset; this is evaluated over time, particularly with response to fluid therapy. It should be noted that azotemia may not improve for up to 72 hours after initiation of fluid therapy when acute renal failure is severe. A lack of initial improvement in plasma creatinine or BUN during the first day or two of therapy should not necessarily prompt a poor prognosis or discontinuation of therapy.
The rate of fluid administration should facilitate diuresis.95 A rate of two to three times maintenance fluid rate (4 to 6 mL/kg/hr, where maintenance rate is 2 to 3 mL/kg/hr) is a reasonable starting point; however, there is a paucity of literature to recommend evidence-based rates of fluid administration for treatment of acute renal failure or other disorders. Similar fluid rates have been suggested in small animal patients with renal failure.95 It is unknown whether increases in the fluid rate beyond this point are beneficial. Certainly, if urine output is greater than this rate, it should be matched with fluid input. Measurement of CVP has become more practical in equine patients and can be used to ensure that fluid administration is not excessive.96,97 Reference ranges of <15 cm H2O have been reported for adult horses; values exceeding 20 cm H2O indicate a need to decrease the rate of fluid administration to avoid development of edema.97
A balanced isotonic crystalloid is suitable for diuresis while preventing significant electrolyte alterations.95 Horses should be allowed free access to water whenever possible while intravenous fluids are administered. This allows for some degree of self-regulation of water balance and can provide free water for renal excretion of the large sodium load provided by isotonic crystalloids.
Hyperkalemia is a relatively common feature of acute renal failure.98,99 This is often corrected when renal perfusion is optimized and diuresis is instituted. When hyperkalemia is present, anuria should be ruled out. Cardiac dysrhythmias can develop during hyperkalemia; potassium free fluids (0.9% saline or isotonic sodium bicarbonate) should be administered to patients with dangerous hyperkalemia (>6 mmol/L), along with calcium, dextrose, and possibly insulin.
LRS has the benefit of containing a minor amount of free water (osmolarity 273 mOsm/L) and slightly less sodium than other fluids (130 mEq/L). A potential disadvantage, however, is that it contains more chloride (109 mEq/L) than equine plasma. Horses with renal insufficiency may be unable to excrete excess chloride provided by LRS diuresis. Mild hyperchloremia may result, causing a minor strong ion acidosis. LRS also contains potassium (4 mEq/L), which is a consideration in the hyperkalemic patient. However, studies in human renal transplant patients failed to demonstrate development of hyperkalemia as a result of LRS administration.100
Isotonic saline (0.9%) solution has an even higher chloride content (154 mEq/L) than LRS. In fact, neither the sodium nor the chloride concentration in this fluid is similar to those of equine plasma. Isotonic saline solution has been shown to cause hyperchloremia and a mild acidosis during prolonged administration; for these reasons it is not the ideal fluid for long-term management of acute renal failure.101,102 Saline does not contain potassium and therefore may be warranted in horses with hyperkalemia. However, creation of a metabolic acidosis because of hyperchloremia may also pose a risk for hyperkalemia by causing an extracellular shift of potassium; this shift occurs as a result of acute changes in blood hydrogen concentration, which occur in association with hyperchloremic metabolic acidosis.100 The effects of saline on potassium balance in horses warrant further study. Metabolic alkalosis, caused by hypochloremia or relative hypernatremia, is an indication for saline administration.
Normosol-R (Abbott Laboratories, North Chicago, Ill.) and Plasma-Lyte 148 (Baxter Healthcare Corporation, Deerfield, Ill.) have a sodium and chloride concentration most similar to equine plasma among the commercial isotonic or nearly isotonic fluids and are excellent fluids for diuresis of acute renal failure cases. It should be noted that these contain the highest potassium concentration (5 mEq/L) of all of the commercial fluids described; however, this potassium content is unlikely to contribute to clinically significant hyperkalemia in polyuric animals because of urinary excretion of excessive potassium (possible exceptions: uroperitoneum, anuria).
Isotonic sodium bicarbonate solution can be made by mixing sterile water and sodium bicarbonate to create a solution with a sodium concentration of 150 mmol/L. Isotonic sodium bicarbonate does not contain potassium or chloride and can be modified to contain an increased amount of free water as needed by lowering the sodium concentration. It exerts an alkalinizing effect by increasing strong cation (Na+) concentrations without a corresponding increase in strong anions (i.e., strong ion alkalosis).
Blending of fluids with different compositions is also an option in order to correct or maintain electrolyte and free water balance. Over time, horses often develop a plasma electrolyte profile similar to that of the administered fluid, especially when large volumes are administered for prolonged periods; therefore combining or changing fluids may be necessary if derangements develop. It is also clear that monitoring of electrolytes (one to four times per day) is particularly important in renal patients.
ANURIC OR OLIGURIC RENAL FAILURE
Anuria and oliguria should be considered emergency medical conditions; the longer the duration of little to no urine production, the lower the chances of correcting it. Urine output in healthy horses is approximately 1 mL/kg/hr, but this may decrease by 80% (to 0.2 mL/kg/hr) in horses deprived of water.103,104 In humans without significant fluid deficits, a urine flow <0.5 mL/kg/hr is one criterion used to define acute renal injury, whereas acute renal failure is associated with a urine flow <0.3 mL/kg/hr.105 Oliguric renal failure should be suspected in azotemic horses with urine production <0.5 mL/kg/hr despite the administration of intravenous fluids. Once anuria or oliguria is suspected, a methodic approach to fluid administration and monitoring should be instituted immediately because of the associated high mortality rate. A delay in instituting treatment makes reversal of anuria less likely.
Treatment of Anuria or Oliguria
Hyperkalemia and metabolic acid-base disorders are common in horses with anuric or oliguric renal failure.98 As noted earlier, hyperkalemia can be associated with life-threatening dysrhythmias. Rapid initiation of diuresis and administration of sodium bicarbonate, dextrose, and insulin are therapeutic interventions for hyperkalemia. If dysrhythmias are present, calcium should be administered to raise membrane threshold potential thereby reducing the likelihood of abnormal rhythms.
As mentioned previously, hemodialysis has been reported infrequently in horses.92 More recently, peritoneal dialysis has been described as a cost-effective and practical approach for horses with acute renal failure.93 These are therapeutic options in horses that do not respond to conventional fluid therapy and medical treatments of anuria described earlier.
Fluid Therapy for Horses with Vasculitis
Horses with vasculitis present a unique challenge to fluid therapy in that they have increased vascular permeability and are therefore at increased risk for developing edema. Examples of such patients that may require restoration of fluid volume include horses with purpura hemorrhagica, type I hypersensitivity reactions (such as anaphylaxis or anaphylactoid reactions), and Anaplasma phagocytophila infections. Often horses with systemic vasculitis have edema, particularly in the distal limbs and ventrum, in the face of concurrent hypovolemia.
Correction of hypovolemia in these horses is challenging, as increasing the extracellular fluid compartment with crystalloid fluids may compound edema and lose efficiency in terms of blood volume expansion. Such cases may benefit from colloid administration. Depending on the degree of vasculitis and the molecular weight of the colloid, a portion of the administered colloid may also extravasate into the interstitium or third space area, compounding edema. Therefore horses receiving colloid fluids should be monitored for progression of their overall status, including increasing edema in response to fluid administration.
Colloids with a molecular weight of 100 to 300 kDa and those with narrower ranges, such as pentastarch (average molecular weight of 268 kDa) and the newer (third-generation) hydroxyethyl starches (molecular weight of 130), may have reduced extravasation compared with those with smaller molecular weights and wider molecular weight ranges. Colloids with this size molecule may reduce endothelial-leukocyte responses and are thought to interact with the endothelial glycocalyx in reducing capillary leakiness.72,73 However, these are not yet available in the United States. Commercial hetastarch is heterogeneous in terms of particle size (range, 15 to 3400 kDa), and those molecules below 100 kDa could extravasate more readily.
The total amount of colloid administered needs to be considered, as doses above 10 mL/kg/day of hetastarch lead to coagulopathies.57 The safe total cumulative dose of hetastarch over time (over days) is unknown. Plasma can be administered instead; however, albumin is relatively small (68 kDa), and much of it can redistribute extravascularly because of the altered reflection coefficient.
Fluid Therapy for Horses with Hypoproteinemia
Similar to horses with systemic vasculitis, those with hypoproteinemia are at increased risk for edema formation with fluid therapy, making them among the most challenging to manage. The presence of concurrent hypovolemia and hypoproteinemia is a potential indication for colloids rather than crystalloids. Administration of crystalloids alone may result in compounding of the hypoproteinemia through hemodilution.111 With altered Starling’s forces, crystalloids distribute to the extracellular fluid to a relative greater extent than they would otherwise, because of a lack of plasma oncotic force for retention. Currently available colloids include hetastarch, dextrans, plasma, and concentrated human albumin.112 Because of the increased potential for side effects associated with dextrans, there is no clear indication to use them over hetastarch. Side effects of dextrans reported in horses include muscle fasciculations, swaying of the hindquarters, tachycardia, and collapse in 8 of 64 horses.113
Numerous commercial equine plasma products are also currently available. Many include antibodies to salmonella, endotoxin, and clostridial organisms; these are unlabelled claims and are largely unstudied in terms of efficacy. Other advantages of plasma, especially for the hypoproteinemic horse, include provision of albumin, antithrombin, and additional clotting factors. Because albumin has multiple functions, including as a carrier protein (drugs, toxins) and physiologic buffer, plasma cannot be entirely replaced with synthetic colloids. Concentrated albumin has been used in neonatal foals, but its use in adult horses may be limited by cost.112 The potential side effects of human plasma products in horses are largely unknown and require further study.
In one study evaluating the response of hypoproteinemic horses with gastrointestinal disease to hetastarch, it was determined that the oncotic benefit lasted 24 hours; in contrast, hetastarch raised the oncotic pressure of healthy horses for up to 5 days.57,111 Nevertheless, even a short-term benefit in oncotic pressure may be preferable to the dilutional effects of crystalloids.
Fluid Therapy for Hemorrhagic Shock (Box 44-5)
Box 44-5 Fluid Considerations for Horses with Acute Hemorrhage
With the exception of prompt hemorrhage control, the key component to early trauma care is adequate fluid resuscitation. Traditionally, replacement with isotonic crystalloids of three times the volume of shed blood has been the approach in human trauma patients. Up to eight times the blood loss volume has been administered in severe shock states.
Despite its importance, high-volume resuscitation is not innocuous; ARDS has been described in patients that received massive crystalloid resuscitation after trauma.114 Severe trauma patients enter a phase of SIRS, with some patients developing multiple organ failure and others entering a compensatory antiinflammatory response syndrome (CARS). This latter syndrome causes immune suppression and increased susceptibility to infections. Both commercial LRS, which is a racemic mixture of L- and D-lactate, and artificial colloids, namely dextrans and some hydroxyethyl starches, have proinflammatory effects.115 It appears that the D-lactate (nonmammalian form) is largely responsible for the inflammatory reaction to LRS, because removing it from the solution eliminates this effect.116 These fluids, both artificial crystalloids and colloids, can also cause neutrophil activation and upregulation of adhesion molecules.117 There is currently an L-isomer form of LRS available commercially (Baxter Healthcare Corp., Deerfield, IL). Hypertonic saline, on the other hand, has been shown to be immunomodulatory and causes suppression of neutrophil oxidative burst activity and neutrophil-endothelial adhesions.118-121 Hypertonic saline counteracts the inflammatory effects of dextrans when used in combination.122 Therefore hypertonic saline has potential advantages for early fluid resuscitation of patients with significant blood loss, after the source of hemorrhage has been controlled. This should be followed with isotonic crystalloids, perhaps acetate-containing fluids, such as Normosol-R, or physiologic saline rather than racemic lactate. Plasma similarly does not result in inflammatory cell activation. If hetastarch is used, hemorrhage must be controlled before its administration because of its rapid volume expansion as well as dose-dependent induction of coagulopathies.57,75-79
Aggressive fluid resuscitation in the face of uncontrolled hemorrhage cannot be justified. Such fluid protocols can exacerbate bleeding as a result of increases in blood pressure, disruption of clots, and hemodilution of clotting factors. Instead, a protocol of hypotensive resuscitation should be followed when bleeding cannot be stopped directly.123 With hypotensive resuscitation, low volumes of crystalloids or whole blood should be administered to maintain organ vitality without normalizing pressures. A goal of maintaining a MAP of 60 mm Hg will still allow end organ perfusion while allowing for hemostasis.
Fluid Therapy in Acute Neurologic Injury (Box 44-6)
Box 44-6 Fluid Guidelines for Horses with Acute Neurologic Injury
The approach to fluid therapy in horses and ruminants with acute brain or spinal cord injury is aimed at maintaining oxygen delivery and energy supply to meet the metabolic demands of the neuronal tissue, and fluid therapy is a fundamental part of preventing or minimizing secondary neuronal injury, ischemia, and irreversible damage.
The primary goals of fluid therapy for both brain and spinal cord injury follow similar principles and include prevention and/or prompt recognition and treatment of hypovolemia and hypotension, intracranial hypertension (or cerebral edema), and glucose and electrolyte abnormalities.
Although both brain and spinal cord injuries are potentially life-threatening in large animals, acute brain injury is likely to be the most influenced, either negatively or positively, by the particular fluid therapy plan that is instituted. This is mainly because the cranial vault is a closed space, composed of brain (approximately 80%), blood (approximately 10%) and CSF (approximately 10%). An increase in one component has to result in a compensatory decrease in another. The presence of the blood-brain barrier, intact or not, is another important factor in the selection of the most appropriate fluid for management of acute brain injury.
The most important consideration in the management of cerebral injury is the maintenance of cerebral blood flow (CBF), which is often reduced postinjury. The major determinant of CBF is cerebral perfusion pressure (CPP), which is the difference between MAP and intracranial pressure (ICP) as defined by the following equation: CPP = MAP − ICP. In the normal brain, cerebral autoregulation maintains a relatively constant CBF despite wide variations in perfusion pressure, within the range of 50 to 150 mm Hg (in humans). In the injured brain autoregulation may be impaired, often with concurrent traumatic shock and hypotension, and CBF becomes directly dependant on CPP. Therefore it becomes critical to prevent hypotension by maintaining MAP >80 mm Hg and to avoid increases in ICP that result from cerebral edema or hemorrhage. ICP is not routinely measured in large animal patients, limiting its use in guiding fluid therapy. However, neurologic signs suggestive of elevated ICP (such as obtunded mentation, mydriasis) indicate the need for specific treatment to reduce ICP, with frequent reassessment of neurologic status being important in determining response to treatment.
Fluid management in large animal patients with acute neurologic injury is essentially based on the principles and guidelines established in human medicine from extensive laboratory and clinical studies. The ideal fluid for these human patients remains controversial and is a topic of ongoing research. When presented with a large animal patient with central nervous system injury, the clinician should formulate a fluid therapy plan tailored to the individual animal, based on findings of thorough physical and neurologic examinations and assessment of laboratory data. I suggest the following goal-directed approach:
Goal 1—Treat hypovolemia and hypotension with adequate fluid replacement therapy to attain a normovolemic and normotensive state. Goal 3—Use fluid additives to normalize glucose and electrolyte values, and provide thiamine supplementation.REPLACEMENT FLUID THERAPY FOR NEUROLOGIC TRAUMA CASES
Although fluid restriction historically has been advocated for patients with traumatic brain injury (TBI) under the premise that intravenous fluids increase cerebral edema formation, this practice is no longer recommended, in humans or horses, for two main reasons. First, inadequate data support the theory that fluid restriction decreases cerebral edema formation, and second, systemic hypotension has been associated with increased mortality and poor neurologic outcome in human patients with TBI.124-126
Therefore prompt restoration of adequate intravascular volume with the goal of achieving and maintaining euvolemia and normal blood pressure should be the primary goal of fluid management in patients with neurologic injury. This is best achieved and controlled via the intravenous route in injured horses. Overhydration should be avoided, particularly in neonates, which are more susceptible to volume overload than adult horses.
Selection of the appropriate fluid for replacement therapy requires an understanding of the role of the blood-brain barrier. Because of its unique properties, the development of cerebral edema is fundamentally different from edema formation in other organs or tissues.127 Briefly, the normal blood-brain barrier functions as a semipermeable membrane, separating the brain from the intravascular space. In the normal animal the blood-brain barrier is impermeable to large molecules (plasma proteins) but is only minimally permeable to most ions. It is freely permeable to water, however. The tonicity of the intravascular fluid, determined by its sodium concentration, influences the movement of free water across the blood-brain barrier by creating an osmotic pressure gradient between the brain interstitium and the intravascular space. In TBI the blood-brain barrier may be damaged, often producing heterogeneous regions of varying degrees of blood-brain barrier integrity and permeability. Unfortunately, demonstrating and predicting the extent of such injury in clinical patients is very difficult; the clinician often likely has to assume the presence of normal brain and functional blood-brain barrier regions for certain principles of fluid management, such as osmotherapy, to be effective.128
Hypotonic crystalloids, such as 5% dextrose in water or 0.45% saline solutions, are contraindicated in TBI patients. They lower plasma osmolarity and result in excess free water diffusion into the brain, with subsequent cerebral edema formation. Hypotonic fluids should be avoided for rapid volume replacement in patients with brain injury.
Isotonic crystalloids, such as 0.9% saline, LRS, and Normosol-R, create a minimal to no osmotic gradient across the blood-brain barrier, are readily available and inexpensive, and are therefore the current fluids of choice for replacement and maintenance therapy in brain and spinal cord injury patients.
Hypertonic crystalloids, such as 7.5% saline, create an osmotic gradient across the blood-brain barrier in favor of free water movement out of the brain, thereby reducing ICP. Hypertonic fluids are indicated only after adequate provision of intravascular fluid volume in horses with signs of elevated ICP or deteriorating neurologic status and are discussed in more detail in the following section on hyperosmolar therapy.
Colloids, such as plasma, human albumin, and the synthetic agents hetastarch, pentastarch and dextran, exert variable oncotic pressures and are very effective for intravascular volume expansion and maintenance. The use of colloid solutions in neurologic injury is debatable, mainly because the major determinant of fluid flux across the blood-brain barrier is plasma osmolarity, and because colloids contribute only a small number of particles in plasma, even large changes in plasma colloid oncotic pressure only minimally influence water movement across the normal blood-brain barrier. This is in contrast to the effectiveness of even small changes in plasma osmolarity.129 In addition, the relatively higher cost of colloid solutions and the greater risk of development of hemostatic abnormalities and allergic reactions suggest little benefit of colloid solutions over crystalloids in cases of TBI. The exception is when they are used in combination with crystalloids for fluid volume expansion, provided hydrostatic pressures are not increased excessively as a result of the colloid infusion.127
HYPEROSMOLAR THERAPY IN BRAIN AND SPINAL CORD INJURY
If clinical evaluation of the equine patient with TBI suggests the patient has, or is at risk for developing, intracranial hypertension, then osmotherapy may be indicated. Clinical signs such as obtunded mentation, progressive mydriasis, or any deterioration of neurologic status may indicate increased intracranial hypertension. Hyperosmolar solutions exert their effect of reducing ICP by creating an osmotic gradient across the blood-brain barrier of at least a 10 mOsm/L. Studies in humans suggest that the goal of increasing plasma osmolarity without exceeding 320 mOsm/L is probably a safe and effective approach.130 It is advisable to measure plasma osmolarity in large animal patients, at least before administration of hyperosmolar solutions, to avoid excessive increases in plasma osmotic pressure. Osmotherapy should be instituted only after restoration of adequate intravascular volume and blood pressure if CPP is to be optimized.
The two most commonly used and available hyperosmolar solutions for use in large animals are mannitol (20%) and hypertonic (3% to 7.5%) saline. Both agents have been shown to be effective in lowering ICP in human TBI patients, and although there has been recent renewed interest in hypertonic saline, studies comparing the effectiveness of the two agents have not yet demonstrated a consistent benefit of one solution over the other.
Mannitol (20%) is a six-carbon sugar with an osmolarity of 1098 mOsm/L. The recommended dose is a 0.25- to 1-g/kg intravenous bolus administered over 20 to 30 minutes, every 6 to 8 hours. The ICP-reducing effects of hyperosmolar solutions are believed to be biphasic in nature. After bolus dose administration, there is an initial plasma-expanding effect that reduces blood viscosity and hematocrit and improves rheologic properties of red blood cells, resulting in reduced ICP and improved CBF. After this immediate hemodynamic effect is a delayed osmotic diuretic effect resulting from the decreased reabsorption of sodium and water by the renal tubules, which also contributes to ICP reduction. Onset of effect of mannitol therapy is 15 to 30 minutes after bolus administration. Mannitol should not be administered as a continuous infusion for the purpose of treating cerebral edema, as it loses its plasma-expanding effects and increases the likelihood of development of side effects.131
The detrimental effects of mannitol are more likely to develop and become clinically significant with excessive or prolonged (>2 to 3 days) use. Side effects include hypovolemia and hypotension caused by excessive diuresis, electrolyte disturbances (hyponatremia, hypochloremia, hypokalemia, hypocalcemia), acute renal failure, and a rebound increase in ICP associated with reversal of the osmotic gradient, a phenomenon most likely explained by accumulation of the osmotic agent in brain tissue after movement across regions of damaged blood-brain barrier.131 There is insufficient evidence to support the dogma that mannitol is contraindicated in the presence of intracranial hemorrhage.
Hypertonic (7.5%) saline has an osmolarity of 2400 mOsm/L and, similarly to mannitol, effectively reduces ICP primarily through an immediate hemodynamic effect, followed by a delayed osmotic effect. Hypertonic saline can be administered as an intravenous bolus dose (4 mL/kg) or as a CRI. Hypertonic saline may have addition beneficial effects over mannitol in TBI because of rapid augmentation of cardiac output, contractility, and MAP with administration of smaller volumes. In addition, hypertonic saline is theoretically less likely to cross the blood-brain barrier than mannitol because the reflection coefficient of NaCl is 1 (not permeable), compared with 0.9 for mannitol (more permeable). Additional benefits of hypertonic saline on the injured brain include Na-related stabilization of cell membrane electrochemical gradients and modulation of the inflammatory response.132
Laboratory studies investigating the effect of hypertonic saline in resuscitation after spinal cord injury have also shown promising results, with increased spinal cord blood flow, downregulation of the inflammatory response, and attenuation of spinal cord injury.133 Further clinical studies are needed.
Complications of hypertonic saline are uncommon and include hypernatremia and development of central pontine myelinolysis (theoretic, as it has not been reported to occur when used in cases of TBI).130 Hypokalemia can occur because of kaliuresis in response to reabsorption of large amounts of Na in the distal tubule, as well as hyperchloremic acidosis, emphasizing the importance of regular assessment of hemodynamic and plasma electrolyte and acid-base status. Coagulopathy and bleeding complications can occur as a result of dilutional effects but are of more concern in the actively bleeding patient. Risk of hypovolemia and acute renal failure are not reported for hypertonic saline in TBI, although renal insufficiency is a relative contraindication to all hyperosmolar therapy. Rebound elevations in ICP can occur with withdrawal of therapy; therefore slow, gradual weaning of hypertonic saline infusions is recommended.130
Osmotherapy is likely to be most effective if initiated early (after isotonic fluid replacement) and with duration determined by response to therapy, with close observation and monitoring to minimize development of side effects.
FLUID ADDITIVES IN NEUROLOGIC INJURY
Glucose
It has been widely recognized that hyperglycemia is a common occurrence in acute brain injury in humans.134 Hyperglycemia is believed to worsen neuronal injury and is associated with increased mortality and neurologic outcomes after TBI.134,135 Consequently, glucose supplementation during large-volume fluid replacement should be avoided, unless the patient is hypoglycemic.
It has not been determined whether hyperglycemia after TBI is a physiologic reflection of the response and severity of injury, or if it contributes to the progression of secondary brain injury. Nevertheless, in ischemic brain tissue aerobic metabolism is impaired and excess glucose leads to lactate accumulation and intracellular acidosis via anaerobic metabolism; this can contribute to a proinflammatory and prooxidant state, thereby potentially worsening neurologic injury and increasing cell death.130 A beneficial effect of reducing blood glucose with insulin therapy in human patients with TBI has been suggested but has not been clinically proven at this time.136
It is prudent to avoid hypoglycemia as well as hyperglycemia in neurologic injury. The brain is dependant on a constant supply of glucose for aerobic energy production, and glucose use may be increased after TBI, thereby increasing energy demands. These factors should be considered in the monitoring and fluid therapy plan for any large animal with neurologic injury, particularly neonates, as they are more susceptible to hypoglycemia.
Thiamine
Thiamine (vitamin B1) is a water-soluble B vitamin synthesized only by plants and microorganisms. Most animals have a nutritional requirement for this vitamin, although adult ruminants and horses normally can obtain adequate quantities produced by bacteria in the rumen or cecum.
Thiamine, in its active form (thiamine pyrophosphate), plays a very important role in glucose metabolism and energy production, where it functions as a required cofactor for certain enzymes (pyruvate dehydrogenase, α-ketoglutarate dehydrogenase, branched-chain ketoacid dehydrogenase, transketolase) involved in glycolysis, the citric acid cycle, and the pentose phosphate pathway. Thiamine is also important in nerve and muscle function, where it plays a role in neurotransmission and excitation.
Thiamine deficiency is known to be associated with neurologic disease in humans and in ruminants (polioencephalomalacia). Determination of thiamine status of an animal requires measurement of red blood cell transketolase activity; therefore measurement and documentation of thiamine deficiency in clinical cases is not routinely reported. Whether or not supplementation of thiamine in acute traumatic neurologic injury is indicated is not currently supported by published evidence. However, given the increased susceptibility of damaged neuronal tissue to inadequate energy production and supply, the practice of thiamine supplementation in neurologic injury in large animals appears justified. In addition, recent experimental investigation suggests a potential neuroprotective role of thiamine in reactive oxygen species—induced neuronal injury.137 The author (DJF) has used a dose of 5 to 10 mg of thiamine per kilogram diluted in crystalloids.
Electrolytes
Sodium disturbances can have serious consequences in brain injury and should be corrected promptly if they are acute (<24 hours’ duration). Isotonic fluid administration is appropriate in the majority of cases. Glucose and mannitol cause translocation of water into the extracellular fluid, and excessive amounts can lead to a clinically significant reduction in sodium concentration, as can free water administration with hypotonic fluids. If hyponatremia (Na+ <125 mEq/L) is believed to have been present for >24 hours, then slower correction (0.5 mEq/L/hr) is needed to avoid development of central pontine myelinolysis.
Calcium is essential in maintaining cell membrane potentials and promoting neurotransmitter release. Excessive intracellular calcium accumulation is also well recognized as one of the most important pathways of secondary neuronal damage. During conditions of cerebral or spinal cord ischemia, inadequate energy supply in the form of adenosine triphosphate (ATP) leads to widespread neuronal depolarization and alterations in ion channel permeability, ultimately resulting in excessive intracellular calcium concentrations and cell death.
Serum total and ionized calcium concentrations are measures of extracellular calcium, and so the goal of targeting intracellular calcium homeostasis is limited to maintaining normal extracellular fluid concentrations at this time. Because of the known toxic effects of excessive calcium in neuronal injury, a conservative approach to calcium supplementation may be justified in the acute fluid management of large animal patients. In order to prevent the detrimental effects of hypocalcemia, one approach may be to avoid the addition of calcium to the intravenous fluids over the initial 24 to 48 hours unless the ionized calcium concentration is <1.0 mmol/L or clinical signs of hypocalcemia are present.
Magnesium is an important cofactor in many enzymatic reactions and for the regulation of sodium and potassium transport across cell membranes through activation of the Na-K ATPase pump. Magnesium is essential for central nervous system cellular energy metabolism, modulation of excitatory amino acid transmission, and calcium channel antagonism. After neurologic injury, disruptions in the blood-brain barrier may impair regulation of CSF magnesium concentrations, and hypomagnesemia is commonly recognized in human patients with brain injury.138 Experimental and clinical evidence suggests that a depletion of CSF magnesium concentrations is associated with the risk of secondary neurologic injury.130 Studies also suggest a neuroprotective effect of intravenous magnesium administration after traumatic brain injury,139 although results of other studies are conflicting.130 Currently the dose of intravenous magnesium needed to achieve adequate CSF concentrations for neuroprotective benefits is unknown.
In large animal patients it would seem important to monitor serum total and ionized magnesium concentrations to prevent and treat hypomagnesemia after neurologic injury. Selection of intravenous fluids containing magnesium, such as Normosol-R (Mg2+ = 5 mmol/L) may be beneficial.
Other electrolyte disturbances identified commonly in patients with neurologic injury include hypokalemia and hypophosphatemia. A combination of decreased dietary intake and increased renal loss as a result of diuretic therapy is a likely explanation. Because of the important role of potassium in establishing normal resting membrane potential and nerve conduction, among other functions, regular monitoring and intravenous fluid supplementation if serum potassium concentration decreases to <3.0 to 3.2 mEq/L is indicated in large animal patients with neurologic injury.
Serum phosphate concentrations are not as routinely monitored as other electrolytes in large animal patients, and so deficiency is rarely reported. Clinical signs of hypophosphatemia usually do not manifest until serum concentrations fall below 1 mg/dL in humans and animals. It is important to recognize phosphate deficiency in patients with recent neurologic injury because it can cause or contribute to altered mental status, muscle weakness, seizures, respiratory insufficiency, and ventricular dysrhythmias. Because clinical manifestations of hypophosphatemia have not been reported in horses, it is difficult to make recommendations for supplementation. I have used a dose of 0.01 mmol/kg/hr of sodium phosphate when marked hypophosphatemia has been present in horses.
Fluid Therapy for Horses with Rhabdomyolysis (Box 44-7)
Box 44-7 Fluid Considerations for Horses with Rhabdomyolysis
Horses with severe rhabdomyolysis are at risk for renal failure from myoglobinuria and hypovolemia. In addition, they may develop marked electrolyte derangements from cell lysis, including hyponatremia, hypochloremia, hyperkalemia, and hyperphosphatemia.140,141 In one study evaluating the electrolyte changes in horses with acute rhabdomyolysis, the most consistent abnormality was hypochloremia.140 These changes have been reported in foals with rhabdomyolysis as a consequence of selenium deficiency with or without vitamin E deficiency, possibly combined with increased oxidant stress resulting from sepsis or hypoxia and reperfusion injury after parturition.141 Three of four foals developed cardiac arrhythmias characterized by spiked T wave and decreased P wave amplitude on electrocardiographic analysis. Destruction of the major intracellular fluid compartment through extensive myonecrosis, combined with myoglobinuric renal insufficiency, produces major fluid shifts and electrolyte derangements. In this report foals with hyperkalemia caused y rhabdomyolysis were effectively treated with mineralocorticoids, loop diuretics, and ion exchange resins to enhance elimination of potassium. Intravenous calcium, glucose, insulin, and sodium bicarbonate were also administered to help redistribute potassium back to the intracellular fluid.141
Metabolic acidosis is not common in horses with acute rhabdomyolysis, and alkalosis associated with hypochloremia may be more of a concern.140 Therefore the use of sodium bicarbonate may not be indicated in the treatment of all such patients. In fact, fluids with relatively higher chloride concentration as compared with horse plasma may be optimal when hypochloremia is present. These include LRS (chloride, 109 mEq/L) and 0.9% saline (chloride, 154 mEq/L). If LRS is used, attention should be paid to serum potassium concentrations, because LRS contains potassium chloride in the amount of 4 mEq/L (see Table 44-1). LRS might be preferable over acetate-containing fluids such as Normosol-R or Plasma-Lyte 148 because the liver is the primary organ of lactate metabolism, whereas the muscle tissue plays a larger role in metabolism of acetate. In addition, the chloride concentration of these acetated fluids is lower than that of LRS. Lactate in LRS does not preclude its use in hyperlactatemic horses with muscle disorders, because hepatic metabolism of lactate occurs rapidly once plasma volume is expanded. In addition, lactate is not necessarily markedly elevated in horses with rhabdomyolysis.142
Hereditary causes of rhabdomyolysis in horses include polysaccharide storage myopathy, glycogen branching enzyme deficiency, and recurrent exertional rhabdomyolysis (RER).143-145 Because an alteration in muscle cell calcium regulation is a primary feature in the pathophysiology of RER, calcium supplementation of fluids administered to affected horses should be avoided.146 Serum potassium concentrations should be monitored frequently in horses with rhabdomyolysis, because of risks associated with hyperkalemia.
Because horses with acute rhabdomyolysis are at risk for renal failure, rates of fluid administration should exceed maintenance requirements. Affected horses are usually hypovolemic and dehydrated, and in severe cases horses are myoglobinuric. Myoglobin is nephrotoxic directly, as well as indirectly causing renal arteriolar vasoconstriction and hypoperfusion. Rates of fluid administration vary with individual fluid balance and renal function, but 1.5 to 2 times maintenance requirement is a reasonable starting point. The rate can be adjusted based on the rate of creatine kinase (CK) decline and resolution of myoglobinuria.
Fluid Therapy for Hyperkalemic Periodic Paralysis (Box 44-8)
Hyperkalemic periodic paralysis (HYPP) is caused by a genetic defect in the sodium channel on the sarcolemma, resulting in intermittent signs of sweating, muscle fasciculations, stridor, and weakness.147 Stressors such as anorexia, anesthesia, concurrent illness, trailering, and cold environmental temperatures can precipitate hyperkalemia and onset of clinical signs. Fluid therapy for horses with hyperkalemia should be low or free of potassium. Physiologic (0.9%) saline and isotonic sodium bicarbonate (1.3%) are options. Of note is that these two fluid types have potential effects on acid-base physiology, with saline producing a mild strong ion acidosis and sodium bicarbonate a metabolic alkalosis. Another option for horses without acid-base disturbances is to combine commercial balanced polyionic fluids, such as LRS or Normosol-R, with one of these fluids. This would dilute the potassium administered from the LRS or Normosol and would minimize the effects of saline or sodium bicarbonate on acid-base balance.
Fluid therapy for horses experiencing stressors such as forced withholding of feed before surgery or off feed because of concurrent illness should be administered fluids with dextrose and/or calcium supplementation prophylactically at a maintenance rate. These additives may minimize the development of hyperkalemia and subsequent HYPP episodes. Calcium does not decrease serum potassium concentrations but rather protects the heart from its adverse effects by raising threshold potential. Horses experiencing an active episode of hyperkalemia or showing clinical signs of HYPP should be administered 0.9% saline, sodium bicarbonate (1 mEq/kg empirically), dextrose (2.5% to 5% for provision of 0.5 to 2 mg of dextrose per kilogram per minute), and calcium (0.2 to 0.5 mEq of 23% calcium gluconate per kilogram). Calcium and sodium bicarbonate should not be administered concurrently in the same fluid administration set because of a potential for precipitation. LRS also contains calcium, and therefore sodium bicarbonate should not be added directly to it. Administration of two 5-L bags of saline with 2.5% to 5% dextrose, with one bag containing calcium (250 mL of 23% calcium gluconate total) and the other containing sodium bicarbonate (1 mEq/kg) given sequentially, is a reasonable approach to treating an acute episode. Some horses may not require this volume of crystalloid and can be treated with less; if less volume is desired, 4 to 6 mL of saline per kilogram can be administered. Dextrose, calcium, and sodium bicarbonate can be added to 1-L bags; the sodium bicarbonate and calcium must be kept separate. In this case 5% dextrose, 0.2 mL of 23% calcium gluconate per kilogram, and 0.5 to 1 mEq of sodium bicarbonate can be used.148
Long-term management of horses with HYPP consists of a low-potassium diet, regular exercise, attempts to minimize stressors, and medications such as acetazolamide and phenytoin.149 Horses undergoing chronic acetazolamide therapy could theoretically develop hyperchloremia and a tendency toward metabolic acidosis because of the effects of long-term inhibition of carbonic anhydrase. Administration of large volumes of 0.9% saline can compound hyperchloremia62; to minimize acidemia, it can be coadministered with isotonic sodium bicarbonate or other alkalinizing crystalloid when such horses require long-term fluid therapy devoid of or low in potassium. Phenytoin can mask the clinical signs of HYPP, even when hyperkalemia is present; it must be emphasized that phenytoin should not be the sole prophylactic medication in these horses, because hyperkalemia may be left unchecked.149
Fluid Therapy for Competitive Endurance Horses
Endurance horses are disqualified from rides for a variety of metabolic or lameness problems. Veterinarians are responsible for the emergency treatment of horses with metabolic derangements, but there is a paucity of research available for guidance. Fluid therapy is an essential component of the therapeutic management of critically ill endurance horses.
GENERAL APPROACH TO FLUID MANAGEMENT OF ENDURANCE HORSES
Endurance horses experience significant fluid losses during competition; even horses successfully completing rides lose approximately 5% of body weight in water.150,151 Horses presented for treatment of metabolic problems often exhibit clinical signs of hypoperfusion. In evaluating sick endurance horses the seven clinical perfusion parameters should be evaluated:
Urine production, when apparent, can be used as an additional perfusion parameter. In the absence of polyuric renal failure, urine output signifies renal perfusion, which is one means of assessing organ perfusion. Horses with altered mentation, persistent tachycardia (>60 bpm), poor peripheral pulse quality, pale mucous membranes, capillary refill time >2 seconds, cool extremities, or lack of urine production should be considered candidates for fluid therapy.
The rapid administration of large volumes of crystalloids is the basis of treatment at many ride events. Volume loading increases preload, thereby enhancing stroke volume, cardiac output, and subsequent oxygen delivery. One suggested protocol for fluid resuscitation of hypovolemic endurance horses is the fluid challenge method described earlier; this consists of a bolus dose of 20 mL of isotonic crystalloid per kilogram (10 L for an average, 500-kg horse) followed by reassessment of the seven perfusion parameters. If the parameters have not improved in response to the initial bolus, then another 20-mL/kg bolus should be administered and followed by clinical reassessment. Approximately 1 hour is required to administer a 10-L bolus through a 14-gauge intravenous catheter and standard administration set; multiple catheters or those with large bores (10 gauge) can be used for more rapid administration. Affected horses may require up to 40 to 60 L of crystalloids to address hypovolemia.
Several types of intravenous crystalloids are available for administration to endurance horses. LRS and Normosol-R are balanced polyionic crystalloids commonly administered to treat hypovolemia in these horses. Specific electrolyte abnormalities may dictate the use of isotonic saline (when hypochloremic alkalosis is present) or fluid additives (potassium chloride or calcium gluconate when hypokalemia or hypocalcemia is identified, respectively). The electrolyte and serum biochemistry profiles of endurance horses that fail to finish a race are not necessarily markedly abnormal and allow the use of commercial fluids such as LRS.151 Electrolyte monitoring identified hypokalemia as a common derangement in a small group of horses treated for metabolic disorders during a 100-mile endurance ride.(Fielding CL, unpublished data from the Western States 100-mile endurance ride, 2005 and 2006).
Calcium supplementation is common during fluid therapy of pulled endurance horses. However, results of studies examining the concentration of total and ionized serum calcium in horses during endurance rides have been equivocal as to calcium status.150-152 If calcium is used, it can be added to fluids through the use of calcium gluconate (1 mL of 23% calcium gluconate per kilogram at a rate of 50 mL of crystalloid per liter). Calcium supplementation is required in horses with synchronous diaphragmatic flutter and should be administered until clinical signs resolve.153 Excessive use of calcium in endurance horses may not be warranted, as it plays a role in cell death and apoptosis, particularly with reperfusion injury; supplementation of calcium in humans with rhabdomyolysis is controversial.154
Endurance horses with prolonged ileus or anorexia may benefit from dextrose supplementation of fluids. A dose of 1 mg of dextrose per kilogram per minute is well tolerated by adult horses and is equivalent to 3% dextrose in fluids administered at a rate of 1 L/hr for a 500-kg horse. Ideally, blood glucose concentrations should be monitored in horses administered dextrose to avoid hyperglycemia.
Medications commonly used in the treatment of endurance horses with metabolic derangements may affect fluid balance and should be considered in horses receiving fluid therapy. Sedatives and tranquilizers such as α2-agonists (xylazine, detomidine, romifidine) and phenothiazines (acepromazine) have deleterious effects on cardiac output and/or blood pressure.155,156 Drugs such as dimethyl sulfoxide (DMSO) and α2-agonist sedatives also affect urine output and can therefore alter fluid balance.157,158
The following metabolic conditions are common metabolic disorders of endurance horses.
EXERTIONAL MYOPATHY
Intravenous fluid therapy is the most important feature of treatment for rhabdomyolysis. The reader is referred to the section on fluid therapy in rhabdomyolysis elsewhere in this chapter. Fluids should be administered in 10-L (20-mL/kg) boluses until urine output is achieved and the urine is grossly clear. Low doses of flunixin meglumine (0.5 mg/kg IV) are indicated for inflammation once hypovolemia is resolved and diuresis is achieved. Adequate fluid resuscitation is indicated before release of affected horses because exertional rhabdomyolysis has been associated with severe renal failure in both humans and horses.159,160 Horses with myopathies should be monitored closely and reevaluated within 48 hours for azotemia and progress of increased muscle enzymes.
FAILURE TO RECOVERY
Horses that are pulled from ride events because of persistent tachycardia warrant close monitoring. Such horses often require treatment at a later time. The seven clinical perfusion parameters should be evaluated thoroughly, and any animal with equivocal circulatory or hydration status should be reevaluated frequently to make sure that it is improving through voluntary eating and drinking, rather than deteriorating further. Those with clear hypovolemia or failure to improve with rest should be administered intravenous fluids as described earlier.
SYNCHRONOUS DIAPHRAGMATIC FLUTTER (THUMPS)
Synchronous diaphragmatic flutter is typically associated with hypocalcemia, and concurrent metabolic alkalosis, hypochloremia, and hypokalemia are often also present and have been implicated in its development.161 Many affected horses are otherwise stable hemodynamically and meet all the criteria for adequacy of perfusion. Despite these findings, horses with thumps often require treatment with intravenous fluids supplemented with calcium for resolution of hypocalcemia and clinical signs. Calcium gluconate can be added to 5-L bags of crystalloid (0.5 mL of 23% calcium gluconate per kilogram per 5-L bag), and fluids with dilute calcium can be administered as a bolus. Adverse effects of rapid calcium administration include bradycardia and warrant slow administration. Many mildly affected horses would likely resolve synchronous diaphragmatic flutter with oral electrolytes and/or the consumption of feed (particularly alfalfa).
Fluid Therapy for Burn (Thermal) Injury (Box 44-9)
Box 44-9 Fluid Guidelines for Burn Injury Patients
Horses with severe burn injuries develop hypovolemic shock and require large volumes of balanced electrolyte replacement fluids.162 Hypertonic saline and colloids may also be used but should be followed with isotonic crystalloids. In humans with burn injuries the guidelines for rate of administration of isotonic fluids is 2 to 4 mL/kg for each percentage of surface area burned (Parkland formula).163 Recently a retrospective study found that significantly larger volumes of fluid (5.58 mL/kg per percent total body surface area affected) were administered to patients during the first 24 hours of hospitalization than was predicted by the Parkland formula.164 If smoke inhalation has occurred, then the affected horse is at risk for pulmonary edema. In this case, fluid deficits should be corrected but not exceeded. Administration of excess crystalloids or high rates of fluids after resolution of hypovolemic shock will result in edema, which is detrimental to healing of burned tissues and potentially smoke-injured lungs. Once hydration is adequate, fluid therapy should be discontinued or administered at a rate necessary only to maintain hydration status. If maintenance rates of fluids are required, patients with severe burns may require more sodium than provided for by commercial maintenance fluids owing to the tremendous sodium losses through wounds.165 In these cases, isotonic to slightly hypertonic (1.8%) crystalloids may be required.166 Excess free water should be avoided in these patients, as it can promote intracellular tissue edema.166
An important component of fluid therapy of the thermal injury patient is the administration of plasma. Significant amounts of plasma proteins are lost through cutaneous burns.165 In addition, burn patients are at risk for coagulopathies, although this has been reported to be rare.167 Plasma transfusions are an effective source of albumin, as well as antithrombin III for coagulopathies. Horses with significant burns can require large volumes of plasma in the first 2 to 3 days. CRI of plasma can be provided for as long as required when ongoing losses are present.
Fluid Therapy for Acute Respiratory Distress Syndrome (Box 44-10)
Box 44-10 Fluid Guidelines for Acute Respiratory Distress Syndrome
ARDS presents a therapeutic challenge; because of altered Starling’s forces (increased vascular permeability), affected horses and foals often have significant pulmonary edema, with protein-rich fluid.168 Pulmonary capillary hydrostatic pressure becomes the main determinant of edema in these patients owing to the increased permeability of pulmonary capillaries.169 Despite this propensity toward edema formation, horses and foals with ARDS should not be allowed to develop dehydration. Maintenance of normal blood volume and hydration status is critical to tissue oxygenation, including the diseased pulmonary tissue. The goal in therapy of ARDS patients is to reduce extravascular lung water while still maintaining hemodynamic stability and perfusion. In a human clinical trial, conservative fluid management in patients with ALI improved lung function and shortened duration of mechanical ventilation and intensive care as compared with patients managed with a liberal fluid strategy, although there was no difference in mortality.170 The conservative management did not increase nonpulmonary-organ failures.170 It should be noted that the patients in this study were volume replete and relatively stable hemodynamically. Conservative fluid therapy therefore applies to the postresuscitation phase of these patients, when administration in excess of physiologic needs can be detrimental.
Large swings in pulmonary vascular pressures should be avoided to minimize increases in pulmonary hydrostatic pressure. To avoid these wide fluctuations, intravenous fluids should be provided as a continuous infusion rather than as intermittent boluses.171 The ideal type of fluid for volume replacement at the time of initial therapy of ARDS patients is unknown; however, colloids should be used judiciously owing to the theoretic risk of potentiating pulmonary edema through extravasation of colloids across the leaky pulmonary vasculature. This concern warrants further study; one study demonstrated no increase in net increase of transmicrovascular flux of radiolabelled colloids when COP was raised with albumin administration.172 Isotonic crystalloids, administered at a modest rate and only to effect in normoproteinemic patients, and replacement of plasma proteins in hypoproteinemic patients are probably the safest fluid guidelines for these patients with the current level of understanding.
Patients with ALI or ARDS should be monitored closely for hypoproteinemia. Correction of hypoproteinemia in human patients with ALI benefits from concurrent administration of albumin.173 Hypoproteinemic patients receiving both furosemide (as a CRI) and albumin had improved oxygenation, increased net fluid loss, and better maintenance of hemodynamic stability compared with those receiving only furosemide.173 In addition, 50% of patients in the treatment group achieved resolution of the ALI or respiratory distress syndrome, compared with only 11% of controls. Consideration should be given to correction of hypoproteinemia in foals and horses with ARDS or ALI. An additional benefit of albumin is its antioxidant properties. Albumin also can reduce microvascular permeability and endothelial cell apoptosis.174-176
Monitoring of fluid therapy in these patients is especially important in order to avoid marked increases in pulmonary hydrostatic pressure. This can be accomplished through measurement of pulmonary capillary wedge pressure; however, this requires placement of an intracardiac catheter. Alternatively, CVP can be measured directly. This is easily performed through central lines, those placed in the cranial vena cava. In a study comparing the use of pulmonary artery catheters with that of central venous catheters in guiding treatment of ALI in humans, it was found that pulmonary catheter—guided therapy did not improve survival or organ function and was associated with more complications than central venous catheter—guided therapy.177 The predominant catheter-related complication was development of arrhythmia. It was concluded that pulmonary catheters should not be routinely used for the management of ALI.177
Fluid Therapy for Horses with Metabolic Acidosis (Box 44-11)
Box 44-11 Fluid Guidelines for Metabolic Acidosis
Both organic and inorganic acidoses are found in horses with critical illness. A common cause of organic acidosis in horses is lactate (lactic acidosis). Hyperlactatemia occurs with hypovolemia, sepsis, and SIRSs such as endotoxemia, marked hypoxemia, heart failure, cytopathic hypoxia, and liver failure.31-34 Volume resuscitation can be performed with a combination of crystalloids and colloids, and possibly hypertonic saline. Acetated crystalloids (such as Normosol-R or Plasma-Lyte 148) do not contain lactate; however, even LRS will correct hyperlactatemia when it is caused by hypoperfusion. Hepatic perfusion will clear the lactate previously accumulated. The exception is liver failure, where fluids devoid of lactate should be administered. Other less common causes of organic (high anion gap) acidosis include ethylene glycol and salicylate toxicity and uremic acidosis. The treatment of lactic acidosis is correction of the underlying pathogenesis. If the cause is hypoperfusion, reversal of that state should be the goal of therapy; this is accomplished through restoring blood volume, cardiac output, and finally systemic vascular resistance through the administration of fluids, dobutamine, and vasopressors, respectively. Sodium bicarbonate is therefore not a part of the routine treatment of lactic acidosis. Its use in lactic acidosis is in fact controversial.178,179 In a canine model of lactic acidosis, the administration of sodium bicarbonate actually caused a decrease in pH and bicarbonate concentration and an increase in lactate.180 Similarly, in a model of endotoxemia in ponies, administration of sodium bicarbonate actually increased blood lactate concentration.181 Despite these controversies with sodium bicarbonate and lactic acidosis, when the pH of the patient’s blood is below 7.2, administration of sodium bicarbonate is justified to prevent the detrimental effects of severe acidemia, even when the acidosis is a result of lactate. Severe acidosis can lead to life-threatening cardiovascular complications such as impaired contractility, sensitization to ventricular arrhythmias, and impaired responses to pressors.182 Small doses of sodium bicarbonate should be administered slowly to increase the pH to 7.2, at which point increasing perfusion should be the goal.
Inorganic acidoses occur because of strong ion acidosis associated with electrolyte derangements. In horses these commonly result from hyperchloremia or hyponatremia, both of which decrease the strong ion difference. Common diseases associated with these metabolic abnormalities include enteritis, colitis, renal failure, and renal tubular acidosis (RTA). In these cases the acidosis is often caused by renal or gastrointestinal dysfunction of electrolyte homeostasis, and perfusion may be normal (i.e., normal lactate). Chronic administration of carbonic anhydrase inhibitors, such as acetazolamide, is another cause of hyperchloremia. The fluid of choice for patients with hyperchloremic metabolic acidosis is one containing only strong cations without strong ions. Because sodium bicarbonate contains only strong cations (sodium), it is an ideal choice for patients with normal anion gap (hyperchloremic) acidosis. Sodium bicarbonate should be administered slowly to allow time for distribution and evaluation of its effects. As a fluid choice, rather than as a supplement, isotonic (1.3%) sodium bicarbonate can be used; this formulation contains 150 mEq each of sodium and bicarbonate ion per liter. Potential side effects of sodium bicarbonate therapy include hypernatremia, hypokalemia, ionized hypocalcemia, vasodilation, metabolic alkalosis (if in excess), and an increased affinity of hemoglobin for oxygen (left shift of the oxygen dissociation curve).181
Fluid Therapy for Heart Failure (Box 44-12)
The cardiac patient represents a unique challenge to fluid therapy. Volume expansion poses significant risk to the horse with heart failure by raising venous pressures and potentiating sodium retention. Administration of sodium-containing fluids can lead to or compound edema and body cavity effusions. Despite these risks, patients with heart failure sometimes require fluid therapy, such as when they develop anorexia, renal failure, or diarrhea. Monitoring of CVP should be performed in these patients to aid in prevention of edema. Initial fluid therapy should consist of conservative rates, with frequent reassessment of the effects of fluids on the patient. Continuous, slow administration of fluids, rather than boluses, should be employed to avoid rapid swings in CVP. Any rise in CVP should be avoided in horses with heart failure.
The choice of fluid depends largely on concerns over sodium retention in the heart failure patient. Fluids with lower sodium content may be preferable, such as maintenance fluids (0.45% NaCl/2.5% dextrose, Plasma-Lyte 56, or combinations of replacement fluids mixed with sterile water).183 As soon as the patient is able to drink water the intravenous fluids should be discontinued.
Because of sodium retention in heart failure, these horses are often treated with diuretics such as furosemide, which aid in minimizing edema formation.183 A fine balance between fluid therapy and diuretics is required.
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