Sample collection and analysis

A useful screening test for acid–base status in animals without evidence of respiratory disease is the total CO₂. Total CO₂ is defined as the amount of total carbon dioxide in plasma that can be liberated with a strong acid, and can be calculated from the results of routine blood gas analysis as: total CO₂ = [HCO₃⁻] + dissolved CO₂ + [H₂CO₃]. The [HCO₃⁻] is calculated using the Henderson–Hasselbalch equation, the dissolved CO₂ is equal to S × Pco₂, whereas [H₂CO₃] is negligible.

Many automatic serum biochemical analyzers directly measure total CO₂ (instead of calculating its value from the results of blood gas analysis) but for total CO₂ measurement it is important that blood collection tubes are completely filled before serum is harvested: failure to completely fill the blood tubes promotes escape of CO₂ from serum into the partial vacuum above, thus resulting in measured total CO₂ values that underestimate true serum total CO₂.¹ Because changes in total CO₂ reflect changes in actual [HCO₃⁻], total CO₂ can never provide an independent measure of the nonrespiratory component of an acid–base disturbance. Total CO₂ does, however, provide a useful screening test for the presence of acid– base disturbances in domestic animals without clinical evidence of respiratory disease. In the absence of respiratory disease, a decrease in total CO₂ indicates a metabolic acidosis, whereas an increase in total CO₂ indicates metabolic alkalosis. Total CO₂ has historically been measured using the Harleco apparatus,² although this methodology is no longer used due to the availability of point-of-care analyzers.

If the primary clinical interest is acid– base assessment, then a jugular venous blood sample should be anaerobically obtained in a 3 mL plastic syringe that has been previously coated internally with sodium heparin (by drawing sodium heparin into the syringe barrel and then expelling all heparin from the syringe into the barrel before blood collection). Three mL of air should then be drawn into the syringe and forcibly expelled; this process is repeated three times. Evacuating the syringe in this manner ensures that minimal heparin is retained to dilute the blood sample but a sufficient quantity is still present to prevent coagulation.³ After blood collection, the air bubbles should be removed from the blood in the syringe, the end should be corked to prevent loss of CO₂ and addition of O₂ to the blood sample and the syringe should be placed on ice (4°C) until analysis. This will minimize any time-related changes in pH, Pco₂ and base excess that occur when blood is held at room temperature (20°C), particularly in blood samples with high white blood cell concentrations. The change in pH, Pco₂ and base excess per hour at 22–24°C are –0.024, +2.5 and –0.5 respectively.³ A portable blood gas analyzer for equine venous blood is available and provides reproducible and acceptable analysis.⁴

If the primary interest is evaluation of the respiratory system, an arterial blood sample should be obtained in the same manner but the sample should be kept at body temperature (preferable) or room temperature before blood gas analysis, which should be performed as soon as possible. This is because keeping 3 mL plastic syringes on ice (4°C) facilitates oxygen diffusion through the plastic syringe barrel, causing an increased Po₂.⁵

Use of point-of-care clinical analyzing systems has greatly facilitated routine evaluation of acid–base status in domestic animals. Thorough assessment of acid– base status requires blood gas analysis and serum biochemical analysis, with blood samples being obtained from a major vein or any artery. If serum total protein, albumin and phosphate concentrations are approximately normal, then acid–base status should be evaluated using blood pH, Pco₂ and extracellular base excess concentration. This is the traditional Henderson–Hasselbalch approach. The presence of unidentified anions should be investigated by calculating the anion gap. If serum total protein, albumin, and phosphate concentrations are markedly abnormal, then acid–base status should be evaluated using blood pH, Pco₂, measured [SID⁺] and [A_TOT]. This is the simplified strong ion approach. The presence of unidentified strong ions should be investigated by calculating the SIG.

Blood pH and acid–base interpretation

Normal blood pH varies from 7.35 to 7.45 (venous blood). The degree of acidemia encountered includes moderate acidemia (pH 7.30–7.25), severe acidemia (pH 7.25–7.20), grave (and commonly fatal except in neonates) acidemia (pH 7.10–7.00). Horses with volvulus or strangulation of the intestines generally have blood lactate levels over 75 mg/dL (8.2 mmol/L) whereas cases of impaction have levels of 5–9 mg/dL (0.55–1.0 mmol/L). The normal value is 6.0 mg/dL (0.78 mmol/L) with a range of 4–12 mg/dL (0.44–1.33 mmol/L). The survival rate in a series fell from 85% to 0% as the lactate concentration increased from 75 to 155 mg/dL (8.3 to 17.2 mmol/L).

Strong ion gap

The strong ion gap represents the concentration of unmeasured strong ions in plasma and is more specific in detecting the presence of unmeasured strong ions in plasma than the anion gap. The SIG concept is a logical extension of the AG concept and was developed using the strong ion difference approach in order to express SIG in terms of other factors: SIG = A_TOT/(1 + 10^(pKa−pH)) – AG, where SIG represents the difference between unmeasured strong cation concentration and unmeasured strong anion concentration in plasma or serum.⁸ Calculation of the SIG requires species-specific values for the total plasma concentration of nonvolatile weak acids (A_TOT; i.e. the total concentration of plasma nonvolatile buffers; albumin, globulin and phosphate) and the negative logarithm to the base 10 (pK_a) of the effective dissociation constant (K_a) for plasma nonvolatile buffers. Values for A_TOT and pK_a have been determined for the plasma of horses (A_TOT, 15.0 mmol/L = 0.22 mmol/g of total protein or 0.47 mmol/g of albumin; pK_a, 6.66) and calves (A_TOT, 23.1 mmol/L = 0.41 mmol/g of total protein or 0.75 mmol/g of albumin; pK_a, 7.08).^9,10

The normal SIG value is –5 to +5 mEq/L. An increase in SIG to above 5 mEq/L (a rare occurrence) therefore reflects an increase in unmeasured strong cations or a decrease in unmeasured strong anions. A decrease in SIG to below –5 mEq/L (a common occurrence) reflects a decrease in unmeasured strong cations or, more likely, an increase in unmeasured strong anions.

The SIG offers a more accurate approach to identifying unmeasured strong ions in plasma than does the AG. The critical difference between the AG and SIG is that the SIG provides an estimate of the difference between unmeasured strong cations and strong anions, whereas AG provides an estimate of the difference between unmeasured cations and anions (including strong ions and nonvolatile buffer ions such as albumin, globulins, and phosphate). A change in SIG therefore provides a more specific method for detecting a change in unmeasured strong ions (such as lactate) than a change in AG.

Osmolal gap

Evaluation of the osmolal gap is a means of detecting an increased amount of abnormal osmotically active solute in the blood. The osmolal gap is the difference between the measured plasma osmolality and the osmolality calculated from the plasma concentration of normally measured solutes. Sodium and potassium and their associated anions, along with glucose and urea, constitute the majority of normal osmotically active solutes. The following formula is recommended, although many clinicians disregard the contribution of serum urea nitrogen (SUN) because it is an ineffective osmole that easily crosses cell membranes:

1.86 × ([Na⁺] + [K⁺]) + (glucose/18) + (SUN/2.8) + 8.6.

Examination of the triad of calculated osmolality, measured osmolality and the osmolal gap is beneficial in the diagnosis and prognosis of a number of diseases.

The effects of acidemia on the anion gap and electrolytes can vary depending on the cause of the acidosis and the species involved. Experimentally in horses, the infusion of l-lactic acid and d- and l-lactic acid results in acidosis with a high anion gap.¹¹ An infusion of hydrochloric acid causes metabolic acidosis with a decreased anion gap. Saline infusions cause mild acidosis with no significant change in anion gap. The plasma potassium was decreased by the infusions of the organic acids but not by hydrochloric acid. Hypophosphatemia occurred with the saline and hydrochloric acid infusions but not with the organic acids. These results indicate that large changes in plasma potassium and serum inorganic phosphate can occur in acidosis in the horse and are probably not the direct result of acidemia. High-intensity exercise in the horse results in a progressive rise in plasma potassium and lactate.¹²

Crystalloid solutions

A crystalloid is a substance that forms a true solution and is capable of being crystallized. Examples of crystalloid solutions are Ringer’s solution, lactated Ringer’s solution, acetated Ringer’s solution, 0.9% NaCl, 7.2% NaCl (hypertonic saline), 1.3% NaHCO₃, 8% NaHCO₃, calcium gluconate and 50% dextrose. Sodium chloride is the classic crystalloid solution, as table salt (NaCl) exists as a crystal but dissolves completely when placed in water. Because crystalloids dissolve completely in water, crystalloid solutions containing sodium distribute throughout the entire extracellular fluid space and are therefore not confined to the intravascular space. Sodium-containing crystalloid solutions are always indicated in hypovolemia (circuit problem) but are contraindicated in congestive heart failure (pump problem) because they provide an additional sodium load, and animals with heart failure have already retained too much sodium. Sodium-containing crystalloid solutions are also contraindicated in the presence of severe hypoalbuminemia because sodium-containing crystalloids will further decrease plasma albumin concentration and oncotic pressure, resulting in movement of fluid into the interstitial spaces and exacerbating tissue edema.

Crystalloid solutions are characterized in terms of the number of molecules (numerator) per volume of solution (denominator). The number of molecules is expressed in moles (abbreviated as mol), where 1 mol of compound is equivalent to the molecular weight of the compound in grams (formula weights for NaCl, NaHCO₃ and KCl are 58.5 g, 85 g and 74 g respectively). Because body fluids are dilute, we express moles as millimoles (mmol = mol/1000) to facilitate readability.

Crystalloid solutions are commonly expressed in terms of the number of charged components (numerator) per volume of solution (denominator). The number of charged components is expressed in equivalents (abbreviated as Eq), where 1 Eq is the number of each charged component that combines with or replaces 1 mol of hydrogen ion (this means that Eq is always a positive number). Because body fluids are dilute, equivalents are expressed as milliequivalents (mEq = Eq/1000). To calculate the number of mEq from mmol, we simply multiply the number of millimoles by the valence (charge), whereby: mEq/L = (mmol/L) × valence. For instance, 1 mmol of NaCl in solution provides 2 mEq: 1 mEq of Na⁺ (1 × 1) and 1 mEq of Cl⁻ (1 × 1), assuming that NaCl acts as a strong electrolyte in water (i.e. it completely dissociates into Na⁺ and Cl⁻ in water). In comparison, 1 mmol of CaCl₂ in solution provides 4 mEq: 2 mEq of Ca²⁺ (1 × 2) and 2 mEq of Cl⁻ (2 × 1), and 1 mmol of dextrose provides 0 mEq, because dextrose does not dissociate into charged components in water.

The principal reason we define constituents of plasma in terms of mEq instead of mmol is because electroneutrality must be preserved at all times; the difference between the charge assigned to all strong cations (Na⁺, K⁺, Ca²⁺, Mg²⁺) and strong anions (Cl⁻, lactate, sulfate, ketoacids, non-esterified fatty acids, etc.) in plasma is called the strong ion difference and this factor independently and directly alters blood pH and therefore acid–base status. The normal SID of plasma is approximately 40 mEq/L, although there are species differences in the actual value. Electrolyte solutions with an effective SID of more than 40 mEq/L are therefore alkalinizing because they create a strong ion alkalosis. Electrolyte solutions with an effective SID = 0 are acidifying because they create a strong ion acidosis. Electrolyte solutions of intermediate SID may be alkalinizing or acidifying, depending upon the change in plasma SID relative to the decrease in plasma protein concentration (which is alkalinizing) (Table 2.3).

Table 2.3 Summary of effective strong ion difference (SID) and osmolarity of parenterally administered crystalloid solutions.

The effective SID is the difference between the strong cation and strong anion concentration after metabolizable anions (such as lactate or acetate) have been completely metabolized to produce bicarbonate. Electrolyte solutions with an effective SID of more than 27 mEq/L are alkalinizing because they create a strong ion alkalosis. Electrolyte solutions with an effective SID = 0 are acidifying because they create a strong ion acidosis.

Hypertonic crystalloid solutions

Fifty percent dextrose is 2500 mosmol/L (approximately eight times normal osmolarity). Fifty percent dextrose solutions are commonly administered to ruminants with ketosis or hypoglycemia and produce a transient increase in cardiac contractility.²² Some commercially available formulations in Europe contain an equimolar mix of dextrose and fructose, although the addition of fructose does not appear to produce a more sustained increase in plasma glucose concentration than that produced by glucose alone.²³

The necessity for glucose in fluid therapy has been controversial. Hypoglycemia occurs commonly in septicemic neonates and calves with diarrhea but is uncommon in most other common diseases in which there is an acute fluid and electrolyte disturbance. Dextrose will promote the movement of extracellular potassium into the cell, will provide metabolic water and is a source of carbohydrate. If glucose is indicated, large quantities of parenteral glucose are necessary to meet the maintenance energy requirements and every effort must be made to restore the animal’s appetite and to provide the necessary requirements through dietary intake. The energy requirements for maintenance are calculated on the basis of metabolic body size, kg^0.73, which is a measure of the fasting metabolism in an animal not eating and not doing any muscular work. If 1 g of dextrose given intravenously will provide 5 kcal (2.1 kJ) of energy, the approximate amounts of dextrose solution needed to meet the energy needs for maintenance in cattle are shown in Table 2.4. Table 2.4 comprises a rough estimate of the requirements and should be used as a general guideline only. Every effort should be made to supply the energy needs through oral intake of energy-containing foods.

Table 2.4 Estimated daily energy requirements of fasting cattle.

NaCl 7.2% (Hypertonic saline) is 2460 mosmol/L (approximately eight times normal osmolarity) and is used for the rapid resuscitation of animals with hypovolemia. Hypertonic saline should be administered at 4–5 mL/kg BW intravenously over 4–5 min (1 (ml/kg BW)/min). Faster rates of administration lead to hemodynamic collapse due to vasodilation and decreased cardiac contractility, whereas slower rates of administration provide no advantages over isotonic crystalloid solutions. Like high-volume 0.9% NaCl, small-volume hypertonic saline consistently induces a mild strong ion acidosis as its effective SID = 0 mEq/L. In general, the decrease in pH following hypertonic saline administration is less than 0.08 pH units and rapidly dissipates with time.²³ The effect of hypertonic saline on acid–base balance is therefore clinically inconsequential.

The use of small volumes (4–5 mL/kg BW) of hypertonic saline solution, ranging in concentration from 7.0% to 7.5%, has been extensively evaluated for the treatment of various forms of hemorrhagic, septic and endotoxic shock.²⁴ Plasma volume is increased by the movement of free water from the intracellular space, thereby increasing cardiac output, mean arterial blood pressure, systemic oxygen delivery and glomerular filtration rate. Total peripheral vascular resistance and pulmonary vascular resistance decrease, and mean circulatory filling pressure increases. Urine output is restored and acid–base equilibrium returns towards normal in conjunction with improved tissue perfusion.

Hypertonic saline solution is widely used for the treatment of dairy cattle with endotoxic shock and endotoxemia associated with coliform mastitis. Affected cows are given 2 L of hypertonic saline (4–5 mL/kg BW) intravenously, followed by immediate access to drinking water and other supportive therapy. The small volume of hypertonic saline followed by the oral water load increases circulatory volume rapidly, induces slight metabolic acidosis, increases renal perfusion and glomerular filtration rate, and induces homeostatic changes in serum calcium and phosphorus.²⁵ In experimental endotoxin-induced mastitis of cattle, small volumes of hypertonic saline given intravenously (7.5%, 5 mL/kg BW) resulted in expanded plasma volume and increased the cows’ voluntary water intake by about 12 times compared to cows treated with isotonic saline.²⁶ The rapid intravenous administration of hypertonic saline can successfully, but only transiently, resuscitate calves in experimental endotoxic shock.²⁷ Hypertonic saline (7.2%NaCl, 2400 mosmol/L), 4 mL/kg BW intravenously over 4 min can be safely administered to endotoxic calves.²⁸ On a comparative basis, the rapid infusion of large-volume isotonic saline is superior to small-volume hypertonic saline for initial resuscitation of experimentally induced acutely endotoxemic calves.²⁷

Hypertonic saline has been associated with greater and more prolonged improvement in cardiopulmonary function and survival in horses with experimentally induced hemorrhagic and endotoxemic shock and in halothane-induced hypotension in horses.²⁹ When given intravenously to normal conscious horses at 5 mL/kg BW, there are increases in plasma osmolality and serum sodium and chloride but clinically normal horses rapidly regulate variable sodium loads.³⁰

Sodium bicarbonate 8.4% is 2000 mosmol/L (approximately seven times normal osmolarity). This solution is used for rapid alkalinization, particularly in the presence of severe acidemia (pH < 7.20). The solution osmolarity was selected because it provides 1 mEq of HCO₃⁻/mL of solution, which facilitates calculation of the volume to be administered. The speed of intravenous administration of 8.4% sodium bicarbonate should not exceed 1 (ml/kg BW)/min. There is one report of the intravenous administration of 8.4% sodium bicarbonate to normovolumic calves with experimentally induced mixed respiratory and metabolic acidosis; the study found that rapid administration of NaHCO₃ (5 mL/kg intravenously over 5 min) rapidly corrected the metabolic acidosis, increased blood pH and improved cardiovascular status without inducing paradoxical cerebrospinal fluid acidosis,³¹ suggesting that this treatment may be of value in treating dehydrated diarrheic calves. Efficacy studies in calves with naturally acquired diarrhea appear indicated. Hypertonic solutions of sodium bicarbonate are highly effective for the initial treatment of acidosis associated with d-lactic acidosis in calves, acute diarrhea in calves³¹ and strong ion (metabolic) acidosis in newborn calves.³²

Sodium bicarbonate 5% is 1190 mosmol/L (approximately four times normal osmolarity). This solution is also used for rapid alkalinization in the presence of severe acidemia (pH < 7.20). The speed of intravenous administration of 5.0% sodium bicarbonate should not exceed 2 (ml/kg)/min. Three to five L of 5% sodium bicarbonate may be necessary as initial therapy to correct the severe hyponatremia and strong ion (metabolic) acidosis that occurs in the horse with acute diarrhea. Following this initial treatment, hypokalemia characterized by muscular weakness commonly occurs, which can be treated using a high sodium, high potassium, alkalinizing solution.

Calcium gluconate 23% or calcium borogluconate are 1069 mosmol/L (approximately three and a half times normal osmolarity). Calcium borogluconate is the standard treatment for milk fever (hypocalcemia) in cattle. d-gluconate is an aldose sugar produced by oxidation of d-glucose and is the preferred salt for calcium-containing parenteral solutions because it does not cause tissue necrosis as severe as does CaCl₂. Calcium gluconate should not be added to sodium bicarbonate solutions because a white precipitate (CaCO₃) forms immediately that interferes with normal fluid administration. Likewise, calcium gluconate should not be administered with tetracycline antibiotics because a yellow precipitate forms.

Colloid solutions

A colloid is a substance that is too large to pass through a semipermeable membrane. Examples of colloid solutions administered to ruminants are whole blood, stroma-free hemoglobin, plasma, dextrans, hydroxyethyl starches and gelatins. As a group, colloid solutions are excellent for sustained expansion of plasma volume, which is in marked contrast to the effect of crystalloid solutions. Colloid solutions are contraindicated in congestive heart failure because these animals have increased plasma volume. Colloid solutions are also contraindicated in the presence of oliguric or anuric renal failure because the sustained volume overload may lead to pulmonary edema.

Whole blood is the perfect balanced colloid/crystalloid solution, with great O₂-carrying capacity. It has a short shelf life (< 24 h at 4°C) and is expensive to obtain. Whole blood administration runs the risk of disease transmission and allergic reactions; the latter are extremely rare in ruminants with the first blood transfusion but common enough in horses for blood typing or cross-matching to be required. Excellent descriptions for collecting, storing and administering blood are available elsewhere (Chapter 9).³³

Stroma-free hemoglobin is a blood substitute containing a purified hemoglobin glutamer-200 solution (13 g hemoglobin/dL) derived from cattle blood. A commercially available solution has a 2-year shelf life at 20°C, an osmolarity of 300 mosmol/L and an oncotic pressure of 43 mmHg; the solution is therefore isotonic but hyperoncotic. Stroma-free hemoglobin solutions are excellent at increasing oxygen delivery and carrying capacity, while providing similar plasma volume expansion to dextrans and hydroxyethyl starches. The major theoretical concerns regarding administration of stroma-free hemoglobin solutions are potent vasoconstriction³⁴ and hemoglobinuric nephrosis. Some of the original experimental studies examining the effects of stroma-free hemoglobin administration were completed in sheep^35,36 and there are occasional reports of its successful administration to critically ill horses in a clinical situation. It is likely that the high cost of this product will minimize its administration to large animals.

Plasma (fresh or frozen) is an excellent balanced colloid/crystalloid solution. Compared with blood, plasma has a much longer shelf life (at least 1 year at −20°C) but is more expensive to obtain. Details for collection, harvesting, storing and administering plasma are available elsewhere,³³ and bovine, equine and New World camelid plasma is commercially available. Like blood, administration of plasma runs the risk of disease transmission and allergic reactions, although these risks are less than with blood transfusion.

Plasma is routinely administered to foals with inadequate transfer of passive immunity. Hyperimmune plasma is occasionally administered to neonatal foals and adult horses with Gram-negative septicemia and endotoxemia. There appears to be only one report documenting the efficacy of plasma administered to neonatal calves with diarrhea, and these calves were probably colostrum-deprived. The 14-day survival rate in diarrheic calves that received 600–800 mL of bovine plasma (5 g protein/dL) and electrolytes intravenously was 93% (37/40), which was significantly greater than the survival rate of calves receiving intravenous electrolytes alone (54%, 7/13).³⁷ Another study failed to identify a beneficial effect of blood transfusion in treating diarrheic calves.³⁸ Because blood is cheaper to obtain than plasma, whole blood transfusions are usually administered when a neonatal ruminant needs plasma.

Dextran preparations (such as Dextran-70) are high-molecular-weight glucose polymers obtained by bacterial fermentation of sucrose; the fermentation metabolites then undergo acid hydrolysis and fractionation. The molecular weight of dextran can therefore be ‘selected’, and two dextran products, Dextran-70 (mean molecular weight 70 000) and Dextran-40 (mean molecular weight 40 000) are commercially available. Because the molecular weight of Dextran-70 is similar to albumin (molecular weight 65 000), there is limited diffusion of dextran into the interstitial space and Dextran-70 therefore acts clinically as a plasma volume expander; this is in contrast to isotonic crystalloid solutions, which act as extracellular fluid volume expanders. Dextran-70 has been the most widely used dextran formulation in large animals and is therefore the recommended product for administration. Dextran-70 is supplied as a 6% concentration in 0.9% NaCl; this provides a hyperoncotic but isotonic solution. Reported administration rates of Dextran-70 are 5–40 (mL/kg)/h, but it is safer to administer Dextran-70 at less than 20 (mL/kg)/h. One mL of Dextran-70 expands the plasma volume by 0.8–1.2 mL, but 50% of the administered dose is gone by 24 hours. Dextran administration runs the risk of exacerbating pre-existing coagulopathies, although the clinical significance of dextran-induced prolongation of activated partial thromboplastin time (APTT) by decreasing factor VIII:C is probably minimal. The risk of coagulopathy is dependent upon the administration rate, total dose administered (20 mL/kg is maximum 24 h dose in humans) and the molecular weight of dextran. The deleterious effects of dextrans are usually associated with large doses or prolonged administration.

The use of hypertonic saline–dextran solution (4 mL/kg, 2400 mosmol/L sodium chloride in 6% Dextran-70 administered intravenously once over 4 min) combined with an isotonic oral alkalinizing solution containing sodium chloride (3.22 g/L), potassium chloride (1.12 g/L), sodium acetate trihydrate (4.76 g/L) and glucose anhydrous (16.22 g/L), providing 300 mosmol/kg of water and administered at 55 mL/kg BW, was superior to either solution alone for the treatment of experimentally induced hypovolemic diarrhea in calves.³⁹ The combined treatment resulted in immediate and sustained increases in plasma volume, cardiac output and stroke volume, thereby improving tissue perfusion. Rapid and sustained rehydration after the combined treatment was indicated by improvement in hydration and clinical depression scores and decreases in hematocrit, blood lactate concentration and serum creatinine, albumin and phosphate concentrations. Resuscitation with oral electrolyte solution alone was slower but was complete within 24 hours. Resuscitation with the hypertonic saline–dextran solution alone resulted in only transient benefit.

The administration of hypertonic saline–dextran solution (7.2% NaCl solution with 6% dextran at the rate of 4 mL/kg BW, intravenously during a 4 min period, combined with oral administration of isotonic electrolyte solution at the rate of 50–60 mL/kg BW) provided a rapid and effective method for resuscitating severely dehydrated calves with experimentally induced diarrhea⁴⁰ or with naturally acquired diarrhea.⁴¹

Hydroxyethyl starch preparations (hetastarch, pentastarch) Two hydroxyethyl starch preparations are currently commercially available; hetastarch and pentastarch. Hetastarch is a high-molecular-weight glucose polymer (mean molecular weight 450 000) that is chemically synthesized from amylopectin, producing a highly branched glucose polymer with a structure similar to that of glycogen. Because the molecular weight of hetastarch is much greater than that of albumin, hetastarch decreases endothelial permeability by sealing separations of endothelial cells. Hetastarch is hydrolyzed in blood by α-amylase, and the addition of hydroxyethyl groups slows hydrolysis and therefore prolongs the duration of plasma volume expansion. Hetastarch is supplied as a 6% concentration in 0.9% NaCl; this provides a hyperoncotic but approximately isotonic solution. Reported administration rates are 5–40 (mL/kg BW)/h but, like Dextran-70, it is safer to administer hetastarch at less than 20 (mL/kg BW)/h. Like Dextran-70, hetastarch administration also runs the risk of exacerbating pre-existing coagulopathies. The risk of coagulopathy is dependent upon the administration rate and total dose administered (20 mL/kg BW is the maximum 24 h dose in humans).

Pentastarch has a mean molecular weight of 280 000 and is available as a 10% solution. Pentastarch has two important advantages over hetastarch: it has less exacerbating effect on pre-existing coagulopathies and the rate of elimination is faster. Pentastarch has rarely been administered to large animals.

Gelatins (modified bovine collagens) are available for veterinary use. The formulation uses gelatin with a mean molecular weight of 30 000 and is a 5.6% suspension in NaCl. Compared to dextrans and hydroxyethyl starches, gelatins have a shorter plasma half-life but appear to have less effect on coagulation. In general, gelatins have not been evaluated as completely as dextrans and hydroxyethyl starches and, on this basis, are not currently preferred.

Parenteral fluid therapy

The total amount of the estimated necessary hydration therapy should be given intravenously using indwelling intravenous catheters in the first 4–6 hours in order to expand and maintain circulating blood volume. If acidemia or alkalemia is present, it also should be treated immediately. Thus the most important abnormalities – decreased circulating blood volume and acid–base imbalance – are treated first. Restoring circulating blood volume will restore renal function, which will assist in correcting acid–base and electrolyte balance. The immediate correction of acidemia will return the tissues to their normal physiological activity. The intravenous route is preferred for hydration therapy and for the correction of severe acid–base and electrolyte imbalances. All other routes (intraperitoneal, subcutaneous and oral) are unsatisfactory in the presence of decreased circulating blood volume.

During the intravenous administration, the animal must be monitored for clinical and laboratory evidence of improvement or deleterious effects. A favorable response is indicated by urination within 30–60 minutes, an improvement in mental attitude and some evidence of hydration. Unfavorable responses include dyspnea because of pre-existing pneumonia or pulmonary edema because of too rapid administration, failure to urinate because of renal failure or paralysis of the bladder, and tetany because of the excessive administration of alkali. Unusual responses such as sweating, trembling and depression within several hours following the intravenous administration of electrolytes or other substances such as commercial amino-acids may occur if the infusion is contaminated during administration.⁴⁷ If a laboratory is available, the determination of PCV, bicarbonate and blood pH will provide an excellent monitoring system during the administration of the fluids.

Intravenous catheters and complications

The administration of large quantities of fluids intravenously to farm animals is best done with an indwelling jugular vein flexible catheter (10–14-gauge) that is appropriately secured to the animal’s neck to prevent withdrawal from the vein. Standard aseptic technique must be used. A plastic, spring-like, coiled tube and suitable rubber tubing are used to deliver the fluids from large 20–25 L plastic containers. The coiled plastic tubing allows the animal to lie down or stand up without disrupting the catheter and tubing.⁴⁸ The use of a drip chamber in the rubber tubing system assists in determining the flow rate, which can be adjusted with a clamp. With a 12-gauge catheter, 25–30 L of fluids can be delivered as hydration therapy to a mature horse or cow.

Oral fluid therapy in calves and adult cattle

For diarrheic calves, the total 24-hour maintenance requirement is calculated and given orally in divided doses every 2–4 hours. Compared to parenteral therapy, there is less danger from overhydration and electrolyte toxicity, and in acute diarrhea the maintenance of oral fluid and electrolyte intakes will replace continuous losses that are occurring during the diarrhea. Livestock owners should be informed of the value of providing newborn animals affected with diarrhea associated with dehydration, depression, inactivity or failure to suck with oral fluids and electrolytes as soon as possible and of the value of continuing this treatment until the animal has returned to normal. Oral electrolyte solutions and water should be made available at all times to animals affected with diarrhea and other diseases in which there are continuous losses of fluid and electrolytes. The exception is cattle affected with carbohydrate engorgement, in which the water supply should be restricted to one-half or less until the animals begin to eat.

Calves with dehydration and diarrhea absorb electrolyte solutions almost as effectively as healthy calves. The important principle underlying the efficacy of oral fluid therapy is the use of low concentrations of glucose (about 2%) to promote sodium absorption from the intestine.⁵⁶ Water follows passively and, because sodium is the osmotic skeleton of the extracellular fluid, fluid is held predominantly where it is needed in the extracellular space, including plasma. Amino acids, such as glycine, also act like glucose to promote sodium absorption. In enterotoxigenic colibacillosis in calves, the glucose and amino acid cotransport mechanisms for sodium transport into epithelial cells are intact.⁵⁷ Thus, water and salt, together with glucose and glycine, facilitate the absorption of sodium and water in calves with diarrhea.

A high-calorie hypertonic oral rehydration solution containing glutamine was more effective in correcting plasma, extracellular fluid and blood volume than conventional solutions with a lower calorie content and without glutamine.⁵⁸ Glutamine also promotes enteric sodium uptake and may be important in sustaining villus form and function. The higher-calorie solution (7.5% glucose) also sustains blood glucose levels at a higher level than conventional solutions. An effective oral fluid should also contain or yield sufficient bicarbonate to correct metabolic acidosis.

A variety of oral and parenteral electrolyte replacement solutions are available commercially.⁵⁹ Most preparations are in the form of powders to be mixed with water. They contain sodium, chloride, potassium, glucose, glycine and bicarbonate or its precursors (acetate or propionate).

The sodium bicarbonate included in oral fluids for the acidosis in calf diarrhea is usually effective directly and quickly. There is speculation that sodium bicarbonate may interfere with milk clotting in the abomasum, which requires an acidic environment for the action of rennin.⁶⁰ There is no direct evidence that oral fluids containing sodium bicarbonate interfere significantly with clotting of milk in the abomasum. Nevertheless, some oral electrolyte solutions for diarrheic calves contain acetate, propionate or citrate, which, when absorbed, act as bicarbonate precursors;⁵⁷ it should be noted that gluconate is not metabolized in calves and probably not in other large animals. Because of their acidic pH, it is claimed that these fluids do not interfere with abomasal clotting of milk but, as already stated, there is no direct evidence to support the claim and no evidence that the final outcome in naturally occurring cases of diarrhea in calves is superior when oral fluids containing metabolizable bases (rather than bicarbonate) are used. Furthermore, the oral fluids containing the base precursors are most effective in diarrheic calves with a blood pH over 7.2 (see Colibacillosis of calves, Ch. 18).

The alkalinizing effects of commercial oral electrolyte solutions have been compared in healthy calves.^61,62 A sodium bicarbonate-rich solution induced the best alkalinization effect. The preparation should not be mixed with milk but given one hour before or after feeding milk because any fluid substance added to milk changes the physicochemical characteristics of milk and may interfere with optimum clotting of milk by rennin in the abomasum, although the clinical significance of this effect remains uncertain. Bicarbonate-containing oral electrolyte solutions will restore acid–base imbalance in calves with viral-induced diarrhea much more effectively than solutions without bicarbonate.

The continued feeding of milk to diarrheic calves while they are receiving oral fluids and electrolytes is controversial.⁶¹ It has been conventional to withhold milk from diarrheic calves for 1–2 days and gradually reintroduce milk over the next few days when there is evidence of recovery. An extreme practice was to totally deprive the calf of milk until the diarrhea ceased. The rationale was that the ability of the calf’s intestine to digest milk was impaired. It is known that lactose digestion is impaired in the rotavirus and coronavirus diarrheas of young calves. It was also thought that the presence of milk in the intestine would provide a substrate for continued growth of enteric pathogens.

Another different practice was to continue feeding milk to diarrheic calves because it resulted in more rapid recovery from diarrhea, less debilitation, continued weight gain and improved circulating plasma volume. This is based on the premise that continuous feeding provides the intestinal mucosa with nutrients.

In experimentally induced diarrhea in calves, the continued feeding of milk during the course of the diarrhea sustained growth, resulted in greater fat stores, facilitated regeneration of the intestinal mucosa and resulted in less thymic atrophy than calves deprived of milk.⁶¹ However, the number of calves in the experiment was small and extrapolation of the results to the naturally occurring disease is not yet warranted. Whole milk and an acidic oral fluid therapy given to calves with naturally occurring diarrhea did not adversely affect the calves or prolong or worsen the diarrhea, and promoted body weight gain.⁶³ However, none of the calves was severely dehydrated or acidemic and treatment was begun very early in the stage of diarrhea (see also E. coli in Ch. 18).

Oral fluid therapy in horses

Intravenous fluid and electrolyte therapy has been used extensively for the treatment of dehydration and electrolyte disturbances in the horse with diarrhea. However, oral fluid therapy, as used in calves, has not been employed to the same extent. It may be an effective, practical and economical method of rehydration of horses with diarrhea that has not yet been fully explored.^64,65

In the horse with acute diarrhea, several factors contribute to the nature of the fluid and electrolyte losses. There are increases in fecal sodium and water loss but the fecal potassium excretion may remain unchanged.⁶⁴ Experimentally induced diarrhea (castor oil) in adult horses results in dehydration, metabolic acidosis and large fecal losses of sodium and urinary losses of potassium.⁶⁶ Plasma volume decreased while horses were clinically dehydrated. The lack of feed intake, which affects primarily the potassium intake, can result in losses of 2500–3000 mmol of potassium per day. Although urinary water and potassium losses are reduced, potassium depletion continues; thus potassium losses are very high and need to be replaced, especially in the anorexic horse. The large potassium deficit in diarrheic horses should also be considered when formulating the composition of oral fluids. Administration of 30–40 g potassium chloride or, if chloride administration is inappropriate, 30–40 g potassium bicarbonate in 2–4 L of water given by nasogastric tube several times daily to an inappetent horse with diarrhea can complement intravenous fluid therapy and replace the potassium deficit.

The optimum electrolyte composition of oral fluids and the amount to be used have not yet been determined for the horse. The amount given depends on the degree of dehydration. Dehydration in horses becomes clinically apparent when about 5% of body weight has been lost. In a 500 kg horse, assuming 90% water loss, the fluid deficit is about 23 L.⁶⁴ Abdominal discomfort may occur following the nasogastric tube administration of a series of 8–10 L doses of oral rehydration fluid.⁶⁷ The administration of large amounts may result in rapid transit through the stomach and intestines and decreased absorption. A slower rate of administration, such as 8–10 L every few hours, may be tolerated more effectively and the transit time in the intestine may be decreased, enhancing absorption. Volumes of 6–8 L can be given by nasogastric tube as often as every 15–20 minutes by funnel; as much as 20–30 L is possible during the first hour and 40 L is possible during a 2-hour period.⁶⁸ Oral fluids may also be administered through a small-diameter indwelling nasogastric tube, as is used for prolonged enteral nutrition of horses with dysphagia.⁶⁵

Commercially available oral electrolyte solutions are inadequate for horses because the concentrations of sodium and potassium are too low to adequately replace losses. When treating horses with acute diarrhea, the ratio of sodium to chloride ions in the oral solution should be approximately 1.4:1, and the need for glucose in an oral rehydration solution for adult horses has not been clearly demonstrated. One formulation contained 5.27 g of NaCl, 0.37 g of KCl and 3.78 g NaHCO₃ per liter of tap water; this produced a suitable electrolyte composition for oral administration (Na 135 mmol/L; K 5 mmol/L; Cl 95 mmol/L; HCO₃ 45 mmol/L).⁶⁹

Oral administration of bicarbonate will result in a pronounced alkalemia within 3–6 hours, with the maximum change in pH occurring at a sodium bicarbonate dose of 1 g/kg BW (which represents 40% of normal extracellular sodium). Doses above this level do not induce additional alkalinization, presumably because of limited absorption of bicarbonate from the intestinal tract. The oral administration of sodium bicarbonate to normal mature resting horses without ad libitum access to water induces metabolic alkalosis, hypernatremia, hypokalemia and hyperosmolality for at least 8 hours.⁷⁰ The oral doses were 0.25, 1 and 1.5 g/kg BW in 3 L water; the intravenous dose was 0.25 g/kg BW in 3 L water. The effects were dose-dependent: in the horses given the 1 and 1.5 g/kg BW oral doses, the hypercapnia persisted for 12 hours, whereas hypercapnia lasted 2 hours in horses given the 0.25 g/kg BW dose orally or intravenously. The effects of these large doses of sodium bicarbonate on the renal function of horses indicated increases in urine flow, fractional clearance of electrolytes and bicarbonate, electrolyte-free water reabsorption, urine concentrations of sodium and bicarbonate, urine excretion, clearance of sodium and bicarbonate, urine pH and anion gap.⁷⁰

The temperature or glucose concentration of the fluid does not appear to be important, as the rate of fluid absorption was similar in dehydrated horses administered an oral rehydration solution at 5°C, 21°C or 37°C or containing glucose at 0%, 2.5% or 3.5%.⁷¹ The tonicity of the oral rehydration solution is of minor clinical importance; however, oral administration of hypertonic solutions (628 mosmol/kg BW) to dehydrated horses caused a transient increase in plasma protein concentration that was attributed to movement of water into the bowel lumen.⁷¹ A practical limitation of oral rehydration solutions in horses is that they should be ingested voluntarily rather than by nasogastric intubation. This limitation has led to recent interest in the oral administration of pastes.

The oral administration of an electrolyte paste has been shown to be effective in correcting mild to moderate dehydration in horses, provided animals are monitored to ensure that they drink water.⁷² Oral electrolyte pastes may be formulated as follows: 30 g of 1:1 mixture of sodium chloride and potassium chloride, potassium chloride and sodium bicarbonate, or potassium chloride and potassium carbonate, and administered every 6 hours; 120 g of the latter mixture provides 1400 mmol or more of potassium in a 24-hour period.⁶⁵ Administration of higher doses of oral pastes (0.5 g of NaCl/kg BW, 0.5 g of KCl/kg BW or a mixture of 0.25 g of NaCl/kg BW and 0.25 g of KCl/kg BW) to dehydrated horses induced a transient period of hyperhydration and apparent plasma volume expansion that lasted 12 hours.⁷² Although the absorbed electrolytes from an oral paste are subsequently eliminated via the urine, this treatment is potentially of benefit in horses with disease processes associated with ongoing fluid losses, such as diarrhea.

There is no published information on the use of oral fluid therapy in horses that are diarrheic as a result of disease of the small intestine such as enteritis, or proximal enteritis (duodenitis). It would seem unlikely that oral fluid therapy would be indicated or effective for anterior duodenitis. In horses with colitis, the small intestinal absorptive capacity is probably intact and oral fluid therapy prior to transport of the horse to a clinical center for intensive fluid therapy may delay the onset of more serious complications. Horses with mild dehydration can be rehydrated effectively with oral fluid therapy. Horses treated with oral fluid therapy must be monitored clinically, and the hematocrit, total plasma protein concentration and serum electrolytes should be measured.

Oral fluid therapy in horses with impaction of the large colon provides an effective and inexpensive treatment and should be regarded as the initial treatment of choice. In general, 6–8 L of water can be administered by nasogastric tube and funnel (gravity flow) every 15–20 minutes;⁶⁸ the administered fluid is rapidly transported to the large intestine. It is generally recommended that the osmolality of the fluids should be isotonic, ranging from 280–360 mosmol/L; the upper range of tonicity which is safe to administer is unknown. Oral administration of 60 L of lactated Ringer’s solution or an isotonic solution over 12 hours was superior in hydrating the contents of the right dorsal colon when compared to intravenous administration of an equivalent volume of lactated Ringer’s solution or enteral administration of 1 g/kg BW of MgSO₄.7H₂O (Epsom’s salts) or anhydrous Na₂SO₄as a 1 L solution.^69,73 Moreover, enteral administration of Epsom’s salts has been associated with hypermagnesemia, and anhydrous Na₂SO₄ has been associated with hypocalcemia.⁷³

Fluid and electrolyte therapy in newborn piglets and lambs

The most common cause of fluid and electrolyte imbalance in newborn piglets and lambs is acute neonatal diarrhea. There is severe dehydration, acidemia, hyponatremia and, in some cases, hyperkalemia due to the acidosis. Balanced electrolyte solutions or isotonic saline and sodium bicarbonate initially followed by balanced electrolytes are indicated and successful. These are given subcutaneously or intraperitoneally at the rate of 15 mL per piglet every 2 hours plus the same amount orally. The safe amount of sterilized porcine serum or saline and 5% dextrose that can be given to piglets is equivalent to about 8% BW intraperitoneally, in two divided doses given 8 hours apart. Lambs are also treated subcutaneously (30–40 mL) and orally (50–100 mL) every 2 hours.

Analgesic agents

There are five main types of analgesic agent administered parenterally or topically to large animals: 1) local anesthetic agents such as lidocaine, mepivacaine and bupivacaine; 2) nonsteroidal anti-inflammatory drugs (NSAIDs) such as flunixin meglumine, ketoprofen, phenylbutazone and meloxicam; 3) α₂-agonists such as xylazine and detomidine; 4) opioids such as morphine, fentanyl, butorphanol and buprenorphine; and 5) vanilloids such as capsaicin. In general, local anesthetic agents, α₂-agonists and opioids are used to provide short-term analgesia (hours), and parenteral NSAIDs and topical vanilloids are used to provide long-term analgesia (days to months). Standard anesthesiology texts should be consulted regarding techniques for local analgesia using regional or peripheral nerve blocks and local anesthetic agents, or for general analgesia using α₂-agonists and opioids.

Local anesthetic agents

Lidocaine, mepivacaine and bupivacaine exert their analgesic effect by addressing both the first pain and second pain after injury by blocking the voltage-gated sodium channels in peripheral nerves, thereby preventing propagation of depolarization. Type IAδ, type IIAδ and C-fibers are blocked before other sensory and motor fibers, meaning that it is possible (but sometimes a clinical challenge) to selectively block pain while leaving the animal able to maintain normal motor function. The main advantages of local anesthetic agents are their cost and predictable and local effect, the main disadvantage is short duration of action. Topical formulations of lidocaine (2.5%) and prilocaine (2.5%) are available that appear to be useful for transdermal administration of a local anesthetic in large animals prior to intravenous catheter placement, venipuncture, arthrocentesis or collection of cerebrospinal fluid.⁹

Nonsteroidal anti-inflammatory drugs

These drugs appear to exert most of their analgesic effect by addressing the second pain (slow pain) due to sensitization of C-fibers by eicosanoids; NSAIDs are not currently believed to exert a central analgesic effect. Animals receiving NSAIDs should be normally hydrated in order to minimize potential renal effects such as tubular nephrosis and papillary necrosis (see diseases of the kidney).

Xylazine

Xylazine was shown to be the most effective analgesic for the relief of experimentally induced superficial, deep and visceral pain in ponies when it was compared to fentanyl, meperidine (pethidine), methadone, oxymorphone and pentazocine.²⁴ However, its short duration of action and the accompanying sedation and decreased gastrointestinal motility and increased urine formation limit its use to short-term analgesia.

Narcotic analgesics

Meperidine (Demerol, pethidine) is extensively used as an analgesic for visceral pain in the horse. Methadone hydrochloride and pentazocine are also used, to a limited extent, and their use is detailed in the treatment of colic in the horse. Butorphanol, a synthetic narcotic used alone²⁵ or in combination with xylazine,²⁶ provides highly effective analgesia in horses. In general, narcotic analgesics are not as effective in ruminants because they have a different distribution of mu and kappa receptors to monogastric animals.

Narcotic agents are used in somatic pain in humans and may have wider applicability in animals. A recent clinical application has been transdermal delivery of fentanyl, which is a potent mu and kappa agonist opioid analgesic drug that is highly lipid-soluble. Fentanyl patches have been applied to the skin of horses, pigs, sheep, goats and llamas. The rate and magnitude of uptake is dependent on core temperature and environmental temperature (and therefore blood flow to the skin at the site of the patch), thickness of the skin at the site of the patch and adherence of the patch to the skin.²⁷ A significant limitation to the use of opioids is their addictive nature in humans, necessitating storage under strict control with written records of their usage required in most countries.

Vanilloids

Capsaicin is derived from hot chili peppers (Capsicum annum) and is the main vanilloid used in horses; these agents are characterized by their ability to activate a subpopulation of nociceptor primary afferent neurons. Capsaicin induces a transient primary hyperalgesia that is followed by a sustained period of desensitization that is species-, age-, dose- and route-of-administration-dependent. The sustained densensitization is responsible for capsaicin’s efficacy as an analgesic agent. Capsaicin therefore has dual effects: initial transient primary hyperalgesia (manifest as a burning sensation) and long-term desensitization. Topical application of capsaicin ointment over the site of the palmar digital nerves has been used in horses as an adjunctive method of analgesia in equine laminitis, with demonstrated efficacy.²⁸ The major clinical disadvantage of using capsaicin is the initial transient primary hyperalgesia.

Balanced analgesia

Because multiple mechanisms for pain modulation all act together, the concept of balanced analgesia has been proposed, similar to the way in which the use of different combinations of sedative and anesthetic agents results in the best aspects of each agent producing balanced anesthesia.² Among horses receiving NSAIDs at the end of an anesthetic, those that received butorphanol during surgery required less additional analgesia compared to those that did not receive any opioid. Thus, combinations of drugs can be used to produce sequential blocks in nociceptive pathways.

Administration routes

The main routes used for administration of analgesics have been local infiltration, subcutaneous, intramuscular and intravenous. Other routes, including the oral, epidural, intra-articular and topical, are now being explored.²

Xylazine and lidocaine given as epidural analgesia abolished pain and tenesmus in cows with acute tail-head trauma which was characterized by acute, intense pain and discomfort, severe tenesmus and a limp tail.²⁹ Extended pain relief was required for up to 3 weeks. Xylazine in the epidural space has also been used to provide analgesia for the castration of bulls.³⁰ In the horse epidural analgesia using a combination of butorphanol and local anesthetics has been used to provide perineal analgesia.²