- Email: [email protected]
Hyperkalemia in diarrheic calves: Implications for diagnosis and treatment
The Veterinary Journal 195 (2013) 271–272
Contents lists available at SciVerse ScienceDirect
The Veterinary Journal journal homepage: www.elsevier.com/locate/tvjl
Guest Editorial
Hyperkalemia in diarrheic calves: Implications for diagnosis and treatment Hyperkalemia is frequently associated with acidemia, with a mean value for D[K]/DpH of 0.3 to 0.5 mEq/L per 0.1 pH unit (Simmons and Avedon, 1959). The long held mechanism for the inverse relationship between plasma [K] and pH posits that hyperkalemia results from the direct electrochemical exchange of potassium for protons across the cell membrane. Although widely accepted, this purported mechanism has never had a sound physicochemical basis in that a decrease in plasma pH from 7.4 to 7.0 (equivalent to an increase in plasma hydrogen ion activity from 40 nEq/L to 100 nEq/L) would decrease plasma [K] from 7.0 mEq/L to 6.99994 mEq/L on the basis of electrochemical exchange of cations; obviously such a decrease is not only physiologically irrelevant but is also undetectable with current laboratory equipment. Interestingly, hyperkalemia can be induced experimentally by intravenous (IV) infusion with inorganic acids such as HCl but not by infusion of organic acids such as lactic acid, ketoacids or ammonium chloride, and metabolic acidosis is associated with more pronounced hyperkalemia than respiratory acidosis. These observations warrant consideration of alternative mechanisms for the association of hyperkalemia with acidemia. An attractive hypothesis for the development of hyperkalemia is that the low intracellular pH due to acidemia slows Na–K-ATPase activity causing potassium ions to leak down a concentration gradient from the intracellular to the extracellular space; however, there are no experimental data indicating Na–K-ATPase activity is directly influenced by pH within the physiological range (Sweadner, 1985). Low intracellular pH does exert a marked effect on phosphofructokinase activity in the glycolytic pathway (Trivedi and Danforth, 1966). With Na–K-ATPase activity being dependent on ATP availability, decreased phosphofructokinase activity presents another potential pathway for acidemia-induced hyperkalemia. Hampered insulin-dependent cellular potassium uptake in states of acidemia presents another potential mechanism explaining the association between hyperkalemia and acidemia, in that mild declines in blood pH can induce insulin resistance. Because insulin triggers a transcellular shift of glucose and potassium, tissue resistance to insulin has the potential to contribute to hyperkalemia. An equally viable mechanism for acidemia-induced hyperkalemia is activation of a cell membrane potassium channel called TREK-1 by low intracellular pH, resulting in potassium efflux from the cell (Maingret et al., 1999). In this issue of The Veterinary Journal, Dr. Florian Trefz of the Centre for Clinical Veterinary Medicine at LMU Munich, and his colleagues, report on an investigation using 124 calves with diarrhea (Trefz et al., 2013) in which the authors raise two questions of interest, namely, (1) what clinical signs are predictive of hyperkalemia in diarrheic calves? and (2) what is the most practical and effective treatment protocol for hyperkalemia in diarrheic calves? 1090-0233/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tvjl.2012.11.002
The clinical signs of hyperkalemia in humans are usually vague, with the exceptions being weakness progressing to a flaccid paralysis (typically sparing the diaphragm), minimal depression of cranial nerve reflexes, and the presence of specific electrocardiographic manifestations such as peaked T waves, widening of the QRS complex, diminution of P wave amplitude, and terminal ventricular fibrillation (Weisberg, 2008). Because an ECG is rarely available when examining diarrheic calves, the clinical detection of hyperkalemia has focused on the presence of muscle weakness and bradycardia or bradyarrhythmias. Two preliminary studies in diarrheic calves failed to demonstrate that determination of heart rate or the presence of rhythm disturbances had clinical utility in predicting serum [K] (Klee, 1980; Constable et al., 1999). The findings reported in the study by Trefz et al. (2013) are consistent with these two studies in that hyperkalemic calves tend to have higher heart rates; however, their new findings were that muscle weakness accompanied by normal cranial nerve reflexes, or the presence of cardiac arrhythmias (test Sp = 0.96), could be suitable to predict the presence of hyperkalemia. Strongest associations were reported between plasma [K] and indices of dehydration, emphasizing the importance of decreased glomerular filtration rate for the development of hyperkalemia. Current recommendations for treating hyperkalemia in humans focus on (1) antagonizing the effect of K on excitable cell membranes, (2) redistributing extracellular K into cells, and (3) enhancing elimination of K from the body (Weisberg, 2008). These treatment objectives can be readily achieved in dehydrated diarrheic and hyperkalemic calves by rapid IV administration of hypertonic sodium salt solutions such as NaCl or NaHCO3 (7.2% NaCl; 4–5 mL/kg BW over 4–5 min, or 8.4% NaHCO3; 10 mL/kg over 10 min), which not only enhance the redistribution of extracellular K into cells but also produce sustained extracellular volume expansion and a sustained increased in glomerular filtration rate. An intracellular shift of K can also be triggered by IV administration of 50% dextrose (0.3–1.0 g/kg BW over 4–5 min) but this may require the concomitant treatment of acidemia as this insulin-dependent effect is likely to be hampered in states of acidemia. Conventional IV infusion with isotonic crystalloid solutions may not directly stimulate cellular K uptake but produces sustained extracellular volume expansion enhancing renal K excretion. Hypertonic sodium solutions such as NaCl or NaHCO3 have a sound physiological basis in the initial treatment of hyperkalemic calves with diarrhea in that hyponatremia is common in diarrheic calves and plays an important role in the development and maintenance of acidemia and strong ion acidosis (Constable et al., 2005; Koch and Kaske, 2008). Moreover, the electrocardiographic effects of hyperkalemia are exacerbated by the presence
272
Guest Editorial / The Veterinary Journal 195 (2013) 271–272
of hyponatremia and acidemia (Garcia-Palmieri, 1962). IV administration of hypertonic saline to hyperkalemic humans, dogs, and a diarrheic calf rapidly reversed the electrocardiographic abnormalities of hyperkalemia and decreased the serum [K] (Garcia-Palmieri, 1962; Constable, 1999; Kaplan et al., 2000). Treatment efficacy is most likely due to increased plasma [Na] to [K] ratio, increased cardiac conduction, as well as expansion of plasma volume and extracellular fluid volume and therefore volume dilution of potassium in the extracellular space (Constable, 1999; Grünberg et al., 2011). Hypertonic NaHCO3 may be more efficacious than hypertonic saline in the treatment of hyperkalemia in diarrheic calves because it is also an effective alkalinizing agent but requires larger infusion volumes since 8.4% NaHCO3 solution contain less Na and has a lower osmolarity than 7.2% NaCl solution. Although IV administration of 50% dextrose should be sufficient to induce sufficient endogenous insulin release for insulin-mediated translocation of potassium, studies documenting this effect in acidemic patients have not been conducted (Grünberg et al., 2006). IV 50% dextrose also increases cardiac contractility and causes plasma volume expansion (Constable et al., 1994). Insulin administration without supplemental glucose is not recommended because hypoglycemia is common in diarrheic calves. Finally, re-establishment of renal blood flow and glomerular filtration rate is required to eliminate excess potassium from the body. Peter D. Constable Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, IN, USA E-mail address: [email protected] Walter Grünberg Department of Farm Animal Health, Universiteit Utrecht, Utrecht, The Netherlands E-mail address: [email protected]
References Constable, P.D., 1999. Hypertonic saline. Veterinary Clinics of North America, Food Animal Practice 15, 559–585. Constable, P.D., Berchtold, J.F., Walker, P.G., Gohar, H.M., Morin, D.E., 1999. Effect of serum potassium concentration on heart rate in dehydrated calves with diarrhea. Journal of Veterinary Internal Medicine 13, 233. Constable, P.D., Muir, W.W., Binkley, P.F., 1994. Hypertonic saline is a negative inotropic agent in normovolumic dogs. American Journal of Physiology 267, H667–H677. Constable, P.D., Stämpfli, H.R., Navetat, H., Berchtold, J., Schelcher, F., 2005. Use of a quantitative strong ion approach to determine the mechanisms for acid–base abnormalities in sick calves with or without diarrhea. Journal of Veterinary Internal Medicine 19, 581–589. Garcia-Palmieri, M.R., 1962. Reversal of hyperkalemic cardiotoxicity with hypertonic saline. American Heart Journal 64, 483–488. Grünberg, W., Hartmann, H., Burfeind, O., Heuwieser, W., Staufenbiel, R., 2011. Plasma potassium-lowering effect of oral glucose, sodium bicarbonate, and the combination thereof in healthy neonatal dairy calves. Journal of Dairy Science 94, 5646–5655. Grünberg, W., Morin, D.E., Drackley, J.K., Constable, P.D., 2006. Effect of rapid intravenous administration of 50% dextrose solution on phosphorus homeostasis in postparturient dairy cows. Journal of Veterinary Internal Medicine 20, 1471–1478. Kaplan, J.L., Eynon, C.A., Dalsey, W.C., Braitman, L.E., Clas, D., Garavilla, L., 2000. Hypertonic saline treatment of severe hyperkalemia in nonnephrectomized dogs. Academic Emergency Medicine 7, 965–973. Klee, W., 1980. Retrospective study of the correlation of serum potassium concentrations and the findings of heart auscultation in calves with neonatal diarrhea. In: Proceedings of the 3rd International Symposium on Neonatal Diarrhea, Saskatoon, Saskatchewan, Canada, 6–8 October 1980, pp. 375–381. Koch, A., Kaske, M., 2008. Clinical efficacy of intravenous hypertonic saline solution or hypertonic bicarbonate solution in the treatment of inappetant calves with neonatal diarrhea. Journal of Veterinary Internal Medicine 22, 202–211. Maingret, F., Patel, A.J., Lesage, F., Lazdunski, M., Honoré, E., 1999. Mechano- or acid stimulation, two interactive modes of activation of the TREK-1 potassium channel. The Journal of Biological Chemistry 274, 26691–26696. Simmons, D.H., Avedon, M., 1959. Acid–base alterations and plasma potassium concentration. American Journal of Physiology 197, 319–326. Sweadner, K.J., 1985. Enzymatic properties of separated isozymes of the Na, KATPase. Journal of Biological Chemistry 260, 11508–11513. Trefz, M.F., Lorch, A., Feist, M., Sauter-Louis, C., Lorenz, I., 2013. The prevalence and clinical relevance of hyperkalemia in calves with neonatal diarrhea. The Veterinary Journal 195, 350–356. Trivedi, B., Danforth, W.H., 1966. Effect of pH on the kinetics of frog muscle phosphofructokinase. Journal of Biological Chemistry 241, 4110–4112. Weisberg, L.S., 2008. Management of severe hyperkalemia. Critical Care Medicine 36, 3246–3251.
Contents lists available at SciVerse ScienceDirect
The Veterinary Journal journal homepage: www.elsevier.com/locate/tvjl
Guest Editorial
Hyperkalemia in diarrheic calves: Implications for diagnosis and treatment Hyperkalemia is frequently associated with acidemia, with a mean value for D[K]/DpH of 0.3 to 0.5 mEq/L per 0.1 pH unit (Simmons and Avedon, 1959). The long held mechanism for the inverse relationship between plasma [K] and pH posits that hyperkalemia results from the direct electrochemical exchange of potassium for protons across the cell membrane. Although widely accepted, this purported mechanism has never had a sound physicochemical basis in that a decrease in plasma pH from 7.4 to 7.0 (equivalent to an increase in plasma hydrogen ion activity from 40 nEq/L to 100 nEq/L) would decrease plasma [K] from 7.0 mEq/L to 6.99994 mEq/L on the basis of electrochemical exchange of cations; obviously such a decrease is not only physiologically irrelevant but is also undetectable with current laboratory equipment. Interestingly, hyperkalemia can be induced experimentally by intravenous (IV) infusion with inorganic acids such as HCl but not by infusion of organic acids such as lactic acid, ketoacids or ammonium chloride, and metabolic acidosis is associated with more pronounced hyperkalemia than respiratory acidosis. These observations warrant consideration of alternative mechanisms for the association of hyperkalemia with acidemia. An attractive hypothesis for the development of hyperkalemia is that the low intracellular pH due to acidemia slows Na–K-ATPase activity causing potassium ions to leak down a concentration gradient from the intracellular to the extracellular space; however, there are no experimental data indicating Na–K-ATPase activity is directly influenced by pH within the physiological range (Sweadner, 1985). Low intracellular pH does exert a marked effect on phosphofructokinase activity in the glycolytic pathway (Trivedi and Danforth, 1966). With Na–K-ATPase activity being dependent on ATP availability, decreased phosphofructokinase activity presents another potential pathway for acidemia-induced hyperkalemia. Hampered insulin-dependent cellular potassium uptake in states of acidemia presents another potential mechanism explaining the association between hyperkalemia and acidemia, in that mild declines in blood pH can induce insulin resistance. Because insulin triggers a transcellular shift of glucose and potassium, tissue resistance to insulin has the potential to contribute to hyperkalemia. An equally viable mechanism for acidemia-induced hyperkalemia is activation of a cell membrane potassium channel called TREK-1 by low intracellular pH, resulting in potassium efflux from the cell (Maingret et al., 1999). In this issue of The Veterinary Journal, Dr. Florian Trefz of the Centre for Clinical Veterinary Medicine at LMU Munich, and his colleagues, report on an investigation using 124 calves with diarrhea (Trefz et al., 2013) in which the authors raise two questions of interest, namely, (1) what clinical signs are predictive of hyperkalemia in diarrheic calves? and (2) what is the most practical and effective treatment protocol for hyperkalemia in diarrheic calves? 1090-0233/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tvjl.2012.11.002
The clinical signs of hyperkalemia in humans are usually vague, with the exceptions being weakness progressing to a flaccid paralysis (typically sparing the diaphragm), minimal depression of cranial nerve reflexes, and the presence of specific electrocardiographic manifestations such as peaked T waves, widening of the QRS complex, diminution of P wave amplitude, and terminal ventricular fibrillation (Weisberg, 2008). Because an ECG is rarely available when examining diarrheic calves, the clinical detection of hyperkalemia has focused on the presence of muscle weakness and bradycardia or bradyarrhythmias. Two preliminary studies in diarrheic calves failed to demonstrate that determination of heart rate or the presence of rhythm disturbances had clinical utility in predicting serum [K] (Klee, 1980; Constable et al., 1999). The findings reported in the study by Trefz et al. (2013) are consistent with these two studies in that hyperkalemic calves tend to have higher heart rates; however, their new findings were that muscle weakness accompanied by normal cranial nerve reflexes, or the presence of cardiac arrhythmias (test Sp = 0.96), could be suitable to predict the presence of hyperkalemia. Strongest associations were reported between plasma [K] and indices of dehydration, emphasizing the importance of decreased glomerular filtration rate for the development of hyperkalemia. Current recommendations for treating hyperkalemia in humans focus on (1) antagonizing the effect of K on excitable cell membranes, (2) redistributing extracellular K into cells, and (3) enhancing elimination of K from the body (Weisberg, 2008). These treatment objectives can be readily achieved in dehydrated diarrheic and hyperkalemic calves by rapid IV administration of hypertonic sodium salt solutions such as NaCl or NaHCO3 (7.2% NaCl; 4–5 mL/kg BW over 4–5 min, or 8.4% NaHCO3; 10 mL/kg over 10 min), which not only enhance the redistribution of extracellular K into cells but also produce sustained extracellular volume expansion and a sustained increased in glomerular filtration rate. An intracellular shift of K can also be triggered by IV administration of 50% dextrose (0.3–1.0 g/kg BW over 4–5 min) but this may require the concomitant treatment of acidemia as this insulin-dependent effect is likely to be hampered in states of acidemia. Conventional IV infusion with isotonic crystalloid solutions may not directly stimulate cellular K uptake but produces sustained extracellular volume expansion enhancing renal K excretion. Hypertonic sodium solutions such as NaCl or NaHCO3 have a sound physiological basis in the initial treatment of hyperkalemic calves with diarrhea in that hyponatremia is common in diarrheic calves and plays an important role in the development and maintenance of acidemia and strong ion acidosis (Constable et al., 2005; Koch and Kaske, 2008). Moreover, the electrocardiographic effects of hyperkalemia are exacerbated by the presence
272
Guest Editorial / The Veterinary Journal 195 (2013) 271–272
of hyponatremia and acidemia (Garcia-Palmieri, 1962). IV administration of hypertonic saline to hyperkalemic humans, dogs, and a diarrheic calf rapidly reversed the electrocardiographic abnormalities of hyperkalemia and decreased the serum [K] (Garcia-Palmieri, 1962; Constable, 1999; Kaplan et al., 2000). Treatment efficacy is most likely due to increased plasma [Na] to [K] ratio, increased cardiac conduction, as well as expansion of plasma volume and extracellular fluid volume and therefore volume dilution of potassium in the extracellular space (Constable, 1999; Grünberg et al., 2011). Hypertonic NaHCO3 may be more efficacious than hypertonic saline in the treatment of hyperkalemia in diarrheic calves because it is also an effective alkalinizing agent but requires larger infusion volumes since 8.4% NaHCO3 solution contain less Na and has a lower osmolarity than 7.2% NaCl solution. Although IV administration of 50% dextrose should be sufficient to induce sufficient endogenous insulin release for insulin-mediated translocation of potassium, studies documenting this effect in acidemic patients have not been conducted (Grünberg et al., 2006). IV 50% dextrose also increases cardiac contractility and causes plasma volume expansion (Constable et al., 1994). Insulin administration without supplemental glucose is not recommended because hypoglycemia is common in diarrheic calves. Finally, re-establishment of renal blood flow and glomerular filtration rate is required to eliminate excess potassium from the body. Peter D. Constable Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, IN, USA E-mail address: [email protected] Walter Grünberg Department of Farm Animal Health, Universiteit Utrecht, Utrecht, The Netherlands E-mail address: [email protected]
References Constable, P.D., 1999. Hypertonic saline. Veterinary Clinics of North America, Food Animal Practice 15, 559–585. Constable, P.D., Berchtold, J.F., Walker, P.G., Gohar, H.M., Morin, D.E., 1999. Effect of serum potassium concentration on heart rate in dehydrated calves with diarrhea. Journal of Veterinary Internal Medicine 13, 233. Constable, P.D., Muir, W.W., Binkley, P.F., 1994. Hypertonic saline is a negative inotropic agent in normovolumic dogs. American Journal of Physiology 267, H667–H677. Constable, P.D., Stämpfli, H.R., Navetat, H., Berchtold, J., Schelcher, F., 2005. Use of a quantitative strong ion approach to determine the mechanisms for acid–base abnormalities in sick calves with or without diarrhea. Journal of Veterinary Internal Medicine 19, 581–589. Garcia-Palmieri, M.R., 1962. Reversal of hyperkalemic cardiotoxicity with hypertonic saline. American Heart Journal 64, 483–488. Grünberg, W., Hartmann, H., Burfeind, O., Heuwieser, W., Staufenbiel, R., 2011. Plasma potassium-lowering effect of oral glucose, sodium bicarbonate, and the combination thereof in healthy neonatal dairy calves. Journal of Dairy Science 94, 5646–5655. Grünberg, W., Morin, D.E., Drackley, J.K., Constable, P.D., 2006. Effect of rapid intravenous administration of 50% dextrose solution on phosphorus homeostasis in postparturient dairy cows. Journal of Veterinary Internal Medicine 20, 1471–1478. Kaplan, J.L., Eynon, C.A., Dalsey, W.C., Braitman, L.E., Clas, D., Garavilla, L., 2000. Hypertonic saline treatment of severe hyperkalemia in nonnephrectomized dogs. Academic Emergency Medicine 7, 965–973. Klee, W., 1980. Retrospective study of the correlation of serum potassium concentrations and the findings of heart auscultation in calves with neonatal diarrhea. In: Proceedings of the 3rd International Symposium on Neonatal Diarrhea, Saskatoon, Saskatchewan, Canada, 6–8 October 1980, pp. 375–381. Koch, A., Kaske, M., 2008. Clinical efficacy of intravenous hypertonic saline solution or hypertonic bicarbonate solution in the treatment of inappetant calves with neonatal diarrhea. Journal of Veterinary Internal Medicine 22, 202–211. Maingret, F., Patel, A.J., Lesage, F., Lazdunski, M., Honoré, E., 1999. Mechano- or acid stimulation, two interactive modes of activation of the TREK-1 potassium channel. The Journal of Biological Chemistry 274, 26691–26696. Simmons, D.H., Avedon, M., 1959. Acid–base alterations and plasma potassium concentration. American Journal of Physiology 197, 319–326. Sweadner, K.J., 1985. Enzymatic properties of separated isozymes of the Na, KATPase. Journal of Biological Chemistry 260, 11508–11513. Trefz, M.F., Lorch, A., Feist, M., Sauter-Louis, C., Lorenz, I., 2013. The prevalence and clinical relevance of hyperkalemia in calves with neonatal diarrhea. The Veterinary Journal 195, 350–356. Trivedi, B., Danforth, W.H., 1966. Effect of pH on the kinetics of frog muscle phosphofructokinase. Journal of Biological Chemistry 241, 4110–4112. Weisberg, L.S., 2008. Management of severe hyperkalemia. Critical Care Medicine 36, 3246–3251.