Hypokalemia Syndrome i n Cattle Nicolas Sattlera, Gilles Fecteaub,* KEYWORDS  Bovine  Hypokalemia  Recumbency  Electrolytes  Anorexia  Potassium KEY POINTS  Risk factors for hypokalemia syndrome include the early lactation period, anorexia, and repeated administration of isoflupredone.  Treatment includes basic supportive care for recumbent animals and aggressive potassium replacement therapy.  Prognosis is guarded for recumbent cattle and worsens if hypokalemic myopathy or complications of recumbency occur. INTRODUCTION Total body potassium depletion leads to muscle weakness and may or may not be associated with low plasma potassium concentration (hypokalemia). More often, hypokalemia is observed on a serum biochemistry profile in animals without potassium depletion (potassium redistribution). The clinical significance of hypokalemia cannot be ascertained without considering the other electrolytes as well as the acid-base status. Moreover, the physical examination and complete history dictate whether intervention is necessary. NORMAL POTASSIUM BALANCE Potassium is mostly intracellular. Serum potassium concentration is a poor indicator of the potassium status of the animal. Determination of intracellular potassium concentration in erythrocytes or muscle cells is a more accurate way to assess potassium depletion, but with current technology it is not clinically feasible in most cases.1,2 The concentration of potassium in plasma depends on external potassium balance and internal potassium balance. External potassium balance refers to potassium The authors have nothing to disclose. a Service Vétérinaire Saint-Vallier, 400 montée de la station, Saint-Vallier, Québec, G0R3J0 Canada; b Clinical Sciences Department, Faculté de Médecine Vétérinaire, Université de Montréal, Saint-Hyacinthe, Québec J2S 7C6, Canada * Corresponding author. E-mail address: gilles.fecteau@umontreal.ca Vet Clin Food Anim 30 (2014) 351–357 http://dx.doi.org/10.1016/j.cvfa.2014.04.004 vetfood.theclinics.com 0749-0720/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved. 352 Sattler & Fecteau intake and absorption from the gastrointestinal (GI) tract, and potassium excretion by the kidneys. The primary source of potassium is the forage portion of the normal ruminant diet. An animal with a normal appetite usually has a normal serum potassium concentration. Almost all ingested potassium (more than 300 g per day for a 600-kg cow) is absorbed and reaches the intracellular fluid compartment. Because they have a forage-based diet, lactating dairy cows may eat more than 10 times their daily potassium requirement. For this reason, cattle have renal excretory mechanisms that are well developed to eliminate the excess potassium load from the body. When intake is interrupted, the excretory mechanisms may not respond rapidly enough to avoid potassium depletion. Cows with partial and/or total anorexia frequently have moderate hypokalemia. This hypokalemia is not coupled with clinical signs of weakness. Other abnormalities such as diarrhea, third space loss, and alkalosis can exacerbate potassium loss from the intracellular and extracellular fluid compartments. Some corticosteroids with mineralocorticoid effects are known to lead to hypokalemia (eg, isoflupredone acetate) by increasing potassium excretion in the kidneys. Diuretic drugs (eg, furosemide) may also contribute to renal potassium loss. Following relief of a urinary obstruction, a diuretic phase occurs and may lead to significant potassium loss. Internal potassium balance refers to the distribution of potassium between the intracellular fluid (ICF) compartment and extracellular fluid (ECF) compartment. Acid-base balance has a significant effect on the distribution of potassium between these compartments, with acidosis causing the movement of potassium from the ICF to the ECF and resulting in hyperkalemia, and alkalosis causing potassium movement in the other direction resulting in hypokalemia. Insulin also facilitates the movement of potassium from the ECF to the ICF. Therefore, the administration of dextrose or insulin may result in hypokalemia or an amelioration of hyperkalemia if it exists. THE CLINICAL SYNDROME Introduction Hypokalemia syndrome has been reported.3–6 Lactating dairy cows as well as younger animals may develop the disease. At present, except for animals treated with repeated isoflupredone acetate administrations, the exact determinants causing hypokalemia syndrome remain uncertain. Risk Factors Lactating dairy cows less than 60 days in milk seem to be at greatest risk. Systemic illness causing anorexia of several days’ duration is a risk factor.4 Repeated systemic or intramammary administration of isoflupredone acetate can cause the syndrome. The mineralocorticoid activity of isoflupredone acetate disturbs both the internal and external potassium balance.7 Repeated doses can reduce serum potassium concentration by 70%.8 Food-restricted dairy cattle receiving repeated doses of isoflupredone acetate developed the syndrome in an experimental model.9 Following the label directions concerning dose and duration seems to be important. Although it is a less potent mineralocorticoid, use of dexamethasone was also reported as a potential cause in some cases.4,6 Multiple treatments of dextrose and insulin are also reported to be associated with the syndrome.3–6 In young animals, the repeated administration of isoflupredone acetate to treat pneumonia and intravenous (IV) fluid administration have been reported to initiate the syndrome.4 Hypokalemia Syndrome in Cattle Clinical Signs In most cases, a primary disease was diagnosed and treated by either the owner or a veterinarian before the generalized weakness or recumbency developed. The identification of the concomitant disease is essential and should not be overlooked because it influences the recovery and prognosis. Some patients are presented with an obscure GI problem: anorexia, little to no feces, reluctance to move, and rapid return to recumbency after stimulation to get up, mimicking colic. In most cases, the animal rapidly becomes incapable of getting up and severe paresis develops. This constellation of signs creates some confusion in the management of the case; specifically, whether surgery is indicated. After the initial phase of stiffness and tendency to lie down, most animals develop the following clinical signs:  Severe apparent depression (generalized weakness with little resistance to any manipulations)  Lack of tone of most muscle groups (tail tone to tongue tone are reduced)  Tachycardia  Abnormal neck posture (S-shaped neck) (Fig. 1)  Recumbency  GI stasis (forestomach and intestine) so no ruminal motility and little if any feces Fig. 1. Typical (or classic) S-shape position of the neck of a cow with hypokalemia. The neck muscle tone is so weak that the head cannot be held straight. 353 354 Sattler & Fecteau In our experience, 2 types of recumbent animals may be observed. Some are weak to the point of being unable to rise but do not have severe generalized rhabdomyolysis, whereas others have severe rhabdomyolysis even in the non–weight-bearing muscle groups. The patients with severe rhabdomyolysis recuperate slower, even after the serum potassium value returns to normal. The increase in creatine kinase and aspartate aminotransferase are more pronounced in the second group. The generalized weakness often prevents the animal from reaching for food or water, and it is common to observe a cow eating her grain if her head is placed in the feed bucket. Perhaps an apparent lack of appetite can be explained by the inability to reach the feed rather than anorexia. The position of the head is worth describing in more detail. There is a complete inability to keep the head in a straight position. The neck is carried in an S-shaped posture. Lack of muscle tone allows easy movement of the head. Sometimes it is possible to position the head and neck in their normal straight position, but inevitably the head eventually falls to one side or the other. The first few cases of hypokalemia syndrome diagnosed by the authors were initially suspected to have cervical subluxation because of this awkward positioning of the neck. This condition may be observed in the standing animal immediately before recumbency occurs or in the recumbent patient. Cardiac dysrhythmias may also be noted (ventricular tachycardia, accelerated escape ventricular rhythm, or atrial fibrillation).4 Pathophysiology Because most of the total body potassium is intracellular,10 plasma concentration is not as important as the gradient between the potassium concentrations of the ICF and ECF compartments, which is the determinant of the resting cellular membrane potential and plays a role in the formation and transmission of action potentials.11 This gradient explains why animals may be observed with weakness in the absence of severe rhabdomyolysis. However, structural damage associated with potassium depletion has also been reported in cattle.3–5,12 This structural damage most likely occurs in the group of patients observed with severe rhabdomyolysis. As far as the authors know and according to other investigators, there is no clear explanation for the distribution of animals into one category or the other.3,4 The changes in cardiac electrical activity associated with hypokalemia could be explained by one or more of the following phenomena: hyperpolarization of the cardiac cell resulting in spontaneous automatic activity, slow conduction caused by the increased difference between resting membrane potential and threshold potential, increased action potential duration as a result of slow repolarization, depressed fast responses because of higher membrane potential when a slow repolarizing cell is stimulated, slow responses in fibers normally showing fast responses, and conduction block.13 In addition to electrical abnormalities, if muscle cell necrosis occurs, cardiac dysrhythmia could become even more likely. However, muscle lesions compatible with hypokalemic myopathy (muscular necrosis) have not been consistently documented in the reported hypokalemia syndrome of cattle.3–6 Differential Diagnosis In the early stages of the condition, hypokalemia syndrome could be confused with GI problems such as acute abdomen: intestinal ileus and intussusception or musculoskeletal/neurologic problems such as cervical trauma, luxations, osteomyelitis or neoplasia, vertebral malformations, fractures, and torticollis. A complete history and thorough physical examination help rule out the other possibilities mentioned earlier. Other conditions to rule out when the animal is presented recumbent are Hypokalemia Syndrome in Cattle hypocalcemia, botulism, and tick paralysis. It is important to consider hypokalemia syndrome as a differential diagnosis in recumbent postpartum cows because administration of calcium solution intravenously to normocalcemic cows carries a substantial risk. Clinical Pathology and Ancillary Tests Serum biochemistry profile is helpful in the management of hypokalemic cattle. However, there is no consensus on the lower threshold for potassium below which the diagnosis is confirmed. The lower threshold limit is usually stated to be 2.2 to 2.5 mmol/L. The degree of increase of creatine phosphokinase and other muscle enzymes suggests whether the muscle damage is related to the primary problem (hypokalemia) or to secondary (recumbency-associated) muscle damage. Concomitant acid-base derangements vary from severe metabolic hypochloremic alkalosis to metabolic acidosis in severe advanced cases.3 Hypophosphatemia has been observed in 25% to 40% of cases but the significance of this finding remains to be shown.3–5 Lumbar muscle biopsy (between L2 and L5) on a living patient or sampling during postmortem examination helps to differentiate primary hypokalemic myopathy from secondary myopathy caused by recumbency. Fractional urinary excretion of potassium (FEk) has been used to provide insight into the pathophysiology of hypokalemia syndrome. In one study, FEk remained in the normal to high range despite a documented severe hypokalemia 12 to 24 hours before clinical signs appeared. FEk from 55% to 128% have been reported in 5 hypokalemia cases.5 The normal range of FEk for early lactating cattle has been reported to be 26.9% to 120%.14 A method of determining both the internal and external potassium balances simultaneously in dairy cows has been presented.3 Treatment Nonspecific treatment Any concomitant or preexisting problems should be addressed appropriately. Good nursing care appropriate for any down cow should be in place and emphasized. Of particular importance is keeping feed and water easily accessible to the cow at all times. Dairy cows should be milked regularly and turned from one side to the other. Any device helping the animal to get up is useful, but the timing is important. Premature attempts may aggravate or cause a musculoskeletal problem because weak animals are prone to injury (lack of muscle tone). Use of a flotation tank (Aquacow Rise System) is of great value once the serum potassium concentration has returned to the normal range. Specific treatment If serious complications arise during the animal’s recumbency, even if normal potassium status is restored, the complicating problem may result in the death of the animal. Good nursing care is critical to the recovery of hypokalemic patients. Specific treatment is intended to address potassium depletion. Potassium chloride supplementation administered orally is the preferred method. The optimal total amount to administer daily remains to be defined, but the authors have used 60 to 100 g/100 kg of body weight per day. However, most investigators recommend a lower dose (250 g per cow per day). When IV potassium chloride is administered, the rate should not exceed 0.5 mEq of K1/kg/h. Serum potassium should be monitored daily to allow adjustment of 355 356 Sattler & Fecteau the treatment regimen. Treatment is usually necessary for 3 to 5 days.3–5 It is probably safe to continue some supplementation until the appetite has returned to 100%. Prevention Prevention is oriented toward supplementation of animals considered to be at risk. Dairy cattle that are chronically anorectic and treated with isoflupredone acetate and/or IV dextrose and insulin should received oral potassium supplementation. The optimal dosage regimen to administer to a normal patient considered at risk is empiric, but 100 g twice a day seems safe. Prognosis In 3 reports, the survival rates were 2 of 8,3 7 of 17,5 and 11 of 14.4 The survival rate in retrospective studies is inconsistent because so many variables accounted for death and/or euthanasia (duration of recumbency, severity of concomitant disease, presence of hypokalemic myopathy, and treatments received, as well as cost of treatment in a particular hospital).1 Prevention of any complications associated with recumbency is probably a major determinant in the outcome. The complexity of the disease and the duration of the recovery phase warrant a guarded prognosis at best. The availability of a flotation tank seems to be a significant positive prognostic factor.3–5 UNANSWERED QUESTIONS A few important questions remain unanswered. The precise relationship between the perturbations of internal versus external potassium balance in affected cattle is not clear. The precipitating factor for some cattle to develop the severe rhabdomyolysis is still not understood. 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