Fluid Therapy in Acute Neurologic Injury (Box 44.6)

Darien J. Feary

The approach to fluid therapy in horses and ruminants with acute brain or spinal cord injury is aimed at maintaining oxygen delivery, cerebral perfusion, and energy supply to meet the

■ BOX 44.6

Fluid Guidelines for Horses With Acute Neurologic Injury

1.

2. Isotonic crystalloid solutions appear to be the most appropri­ate fluids for resuscitation in acute neurologic injury, followed by careful administration of hyperosmolar therapy with mannitol or hypertonic saline if evidence of cerebral edema is present.

3. Diligent monitoring of clinical and laboratory measures of perfusion, osmolarity, and electrolyte concentrations is important for optimizing patient care and the likelihood of recovery in these patients. 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 or prompt recognition and treatment of hypovolemia and hypotension, intracranial hypertension (or cerebral edema), and glucose and electrolyte abnormalities. There is a large body of evidence in the human critical care literature that indicates hypoxemia (PaO₂ may be impaired, often with concurrent traumatic shock and hypotension, and CBF becomes directly dependent on CPP. Therefore it becomes critical to prevent hypotension by maintaining MAP above 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.

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. The author suggests the following goal- directed approach:

• Goal 1: Treat hypovolemia and hypotension with adequate fluid replacement therapy to attain a normovolemic and normotensive state.

• Goal 2: Treat signs of cerebral edema or intracranial hyperten­sion with hyperosmolar therapy.

• 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 TBI under the premise that intravenous fluids increase cerebral edema formation, this recommendation has been replaced by prompt restoration of adequate intravascular volume using the fluid challenge approach, with the goal of achieving and maintaining euvolemia, normal blood pressure, and tissue oxygenation.⁸ This is best achieved and controlled through the intravenous route in injured horses. Overhydration should be avoided, particularly in neonates, which are more susceptible to volume overload than adult horses.

Balanced isotonic crystalloid fluids are traditionally used for volume resuscitation, although there may be a role for hypertonic saline during resuscitation, as well as for specific treatment of intracranial hypertension (see later).⁸ Selection of the appropriate fluid for replacement therapy requires an understanding of the role of the blood-brain barrier.

Hypotonic crystalloids, such as 5% dextrose in water or 0.45% saline solutions, are contraindicated in patients with TBI. 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 LRS, Plasma-Lyte 148 or Plasma-Lyte A, 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 patients with brain and spinal cord injury. 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.

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; 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.¹³ 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. Furthermore, findings from the saline versus albumin fluid evaluation (SAFE) study showed an increased mortality in a subgroup analysis of human patients with TBI who were treated with albumin.¹⁴

HYPEROSMOLAR THERAPY IN BRAIN AND SPINAL CORD INJURY. Hyperosmolar therapy is the pharmacologic induction of supraphysiologic serum osmolality with either hypertonic saline or mannitol and is the mainstay of medical management of patients with intracranial hypertension (ICP >20 mm Hg) associated with TBI and intracranial hemorrhage.¹³ If clinical evaluation of the equine patient with TBI suggests that the patient has or is at risk for developing intracranial hypertension, then osmotherapy may be indicated.

The two most commonly used and available hyperosmolar solutions for use in large animals are mannitol (20%) and hypertonic (3% to 23.4%) saline. Both agents have been shown to be effective in lowering ICP in human patients with TBI, although some studies suggest greater efficacy and fewer side effects with the use of hypertonic saline,^15,16 whereas other comparative studies have shown no benefit of hypertonic saline over mannitol in controlling ICP when multiple doses are administered over 5 days.¹⁷ A proposed reason for this lack of benefit is an increased urinary loss of sodium with hypertonic saline and consequent inability to achieve higher serum sodium concentrations and osmolarity.

Although it is widely established that both mannitol and hypertonic saline are effective in acutely lowering ICP when it is increased, the recent Brain Trauma Foundation guidelines failed to find any evidence meeting current standards on which to base recommendations regarding osmotherapy.¹²

It is challenging to relate outcomes from research in human medicine to large animal patients because the etiology, type of brain injuries, and frequency of surgical intervention in human patients with TBI make them a very different patient population. Until ICP can be measured in the clinical setting, large animal veterinarians must use their frequent neurologic assessments, blood analysis (including osmolarity), judicious use of osmotherapy when indicated (neurologic evidence of increased ICP), and response to therapy.

Mannitol (20%) is a six-carbon sugar with an osmolarity of 1098 mOsm/L. The recommended dose is a 0.5 to 1 g/kg IV bolus administered over 20 to 30 minutes, every 6 to 8 hours. It is important to avoid rapid mannitol infusion (2 to 3 days). Side effects include hypovolemia and hypotension caused by excessive diuresis, electrolyte disturbances (e.g., hyponatremia, hypochloremia, hypokalemia, hypocalcemia), acidosis, 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 a damaged blood-brain barrier.¹⁸ A threshold level of serum osmolarity of 320 mOsm/L is often used as an indicator for decrease or withdrawal of mannitol therapy. However, serum osmolarity is not a sensitive indicator of mannitol-induced renal failure, and the osmolar gap (the difference between calculated and measured serum osmolarity) is more reflective of serum mannitol accumulation. Based on this, an osmolar gap threshold of 55 mOsm/kg has been suggested for monitor­ing mannitol therapy in TBI.¹⁵ 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, similar to mannitol, effectively reduces ICP primarily through an immediate hemodynamic effect, followed by a delayed osmotic effect. Hypertonic saline (7.5%) can be administered as an intravenous bolus dose (4 mL/kg) or as a CRI. There are no clear guidelines as to the optimal concentra­tion (3% to 23.4%) or dose of hypertonic saline in human patients with TBI. However, effective CRI dosing has been achieved in human patients using 3% hypertonic saline at 0.1 to 2.0 mL/kg/h, titrating to serum sodium concentrations of 145 to 155 mmol/L, and not exceeding serum osmolarity of 360 mOsm/L.¹⁵ Hypertonic saline may have additional 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 sodium-related stabilization of cell membrane electrochemical gradients and modulation of the inflammatory response.¹⁹

Laboratory studies investigating the effects 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.²⁰ Further clinical studies are needed.

Complications of hypertonic saline are uncommon and include hypernatremia and theoretical development of central pontine myelinolysis.¹⁵ Hypokalemia can occur because of kaliuresis in response to reabsorption of large amounts of sodium 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 could occur as a result of dilutional effects but are of greater concern in the actively bleeding patient. Risks 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.¹⁵

Osmotherapy is likely to be most effective if initiated early following significant TBI in cases with clinical evidence of increased ICP, and with duration determined by response to therapy, limited to 24 to 48 hours, with close observation and monitoring of neurologic status, serum electrolytes, acid-base status, osmolarity, and renal function, to minimize development of side effects. Because measurement of ICP is not practical to perform routinely in equine patients with TBI at this time (it has been measured in a research setting), the efficacy of and optimal recommendations for hyperosmolar therapy in equine patients with TBI remain unknown and are based on the human medical literature.

FLUID ADDITIVES IN NEUROLOGIC INJURY

Glucose. It has been widely recognized that hyperglycemia is a common occurrence in acute brain injury in humans.²¹ Hyperglycemia is believed to worsen neuronal injury and is associated with increased mortality and neurologic outcomes after TBI.^21,22 Consequently, glucose supplementation during large-volume fluid replacement should be avoided unless the patient is hypoglycemic. As noted below, hypoglycemia should be avoided in patients with TBI.

Recommendations regarding glucose control in the critically ill patient have varied significantly in the last decade. Tight glycemic control (80 to 110 mg/dL) with the use of insulin was suggested for critically ill human patients, but these recom­mendations have been relaxed more recently because of associ­ated incidences of hypoglycemia when centers resort to such tight glycemic control.²³ In addition, the human critical care literature suggests that hypoglycemia may be particularly detrimental to an acutely injured brain. The brain has limited ability to compensate for low glucose concentrations, and the addition of impaired cerebral autoregulation with fluctuations in cerebral blood flow after TBI may cause increased susceptibil­ity to hypoglycemia.²⁴ Although there are no studies in horses with TBi to enable recommendations regarding the best management of blood glucose, recent human medical studies have shown that tight glycemic control after TBI is potentially detrimental due to increased regional glucose metabolism in the brain, leading to enhanced metabolic crisis, and increased markers of cellular distress (elevated lactate/pyruvate ratios and glutamate).²⁵ Therefore limiting the brain's glucose supply during a period of high metabolic demand after TBI may actually contribute to secondary injury. It is currently suggested that delivery of more glucose through mild hyperglycemia (120 to 150 mg/dL) may be necessary following TBI.²6

These factors should be considered in the monitoring and fluid therapy plan for any large animal with neurologic injury, particularly neonates, since 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 (polioencephaloma- lacia). 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.²⁷ The author has used a dose of 5 to 10 mg/kg of thia­mine diluted in crystalloid fluids. Thiamine should be protected from light.

Electrolytes. Sodium disturbances can have serious consequences in brain injury and should be corrected promptly if they are acute (abnormality was hypochloremia. These changes have been reported in foals with rhabdomyolysis as a consequence of selenium deficiency, possibly combined with increased oxidant stress resulting from sepsis or hypoxia and reperfusion injury after parturition. 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 that report, foals with hyperkalemia caused by 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.²

Metabolic acidosis is not common in horses with acute rhabdomyolysis, and alkalosis associated with hypochloremia may be more of a concern.¹ In fact, fluids with relatively higher chloride concentration as compared with horse plasma may be optimal when hypochloremia is present. These include LRS

■ BOX 44.7

Fluid Considerations for Horses With Rhabdomyolysis

(chloride, 109 mEq/L) or Hartmann’s solution (111 mEq/L). If LRS is used, attention should be paid to serum or plasma potassium concentrations because LRS contains potassium chloride in the amount of 4 mEq/L of potassium (see Table 44.1). LRS or Hartmann’s solution might be preferable over acetate-containing fluids such as Normosol-R or Plasma-Lyte 148 or Plasma-Lyte A in acute rhabdomyolysis cases, 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, which may be a slight disadvantage if horses have metabolic alkalosis resulting from hypochloremia. 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 increased in horses with rhabdomyolysis.

LRS is preferred over normal saline for treatment of humans with rhabdomyolysis. In a randomized blinded study of humans with rhabdomyolysis, urine and plasma pH was higher in the LRS group, whereas serum sodium and chloride concentrations were higher in the saline group.⁴ Unlike the saline group, the LRS group needed little supplemental sodium bicarbonate and did not develop metabolic acidosis. Acidic urine favors formation of myoglobin-induced tubular casts and tubular obstruction. Therefore LRS is considered by many to be the fluid of choice to maintain adequate urine flow in patients with rhabdomyolysis. One potential disadvantage of LRS in treatment of rhabdomyolysis is the presence of a low concentra­tion (3 mEq/L) of calcium. Calcium influx plays a role in cell lysis after lipoperoxidation of muscle cells. How these data apply to adult horses, which generally have alkaline urine at baseline, requires further study. Because 0.9% saline is mildly acidifying in horses as well, it likely is not the optimal fluid choice for horses with rhabdomyolysis either. Because foals often have acidic urine, LRS may be a good fluid choice for foals with rhabdomyolysis as well.

In addition to crystalloid support, sodium bicarbonate is recommended for human rhabdomyolysis only if necessary to correct a systemic metabolic acidosis. Mannitol is administered to maintain urine output (300 mL/h or greater urine output in adult humans).⁵

Hereditary causes of rhabdomyolysis in horses include polysaccharide storage myopathy, glycogen branching enzyme deficiency, and recurrent exertional rhabdomyolysis (KER).^6-8 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.⁹ 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 to provide diuresis and dilution of urine myoglobin concentration. In adult human patients with rhabdomyolysis, the goal of urine production is greater than 300 mL/h.⁵ Myoglobin is nephrotoxic directly to renal tubular epithelium; as well, it indirectly causes renal arteriolar vasoconstriction and secondary 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.