A 2-year-old 14.9-kg (32.8-lb) neutered female Shetland Sheepdog was admitted to the University of Liverpool Small Animal Teaching Hospital for evaluation of acute collapse. The dog had collapsed 2 hours prior to admission after a short period of exercise in the proximity of derelict buildings in rural Wales. The dog had vomited once during transport to the hospital. The owners reported that the vomitus appeared to consist only of water and food. Prior to collapse, the dog had no history of relevant medical problems and was not receiving any medications.
Physical examination revealed that the dog was nonambulatory but was responsive and able to maintain sternal recumbency. Ventroflexion of the neck was evident. The dog was in good body condition (body condition score of 5; scale of 1 to 9). Respiratory rate was 80 breaths/min, and heart rate was 100 beats/min. No adventitious lung sounds or murmurs were evident during auscultation of the thorax. Peripheral pulse quality was good, and no pulse deficits were detected. Abdominal palpation did not reveal any abnormalities.
Neurologic examination did not reveal abnormalities of the cranial nerves, panniculus reflex, or withdrawal reflexes. Forelimb and hind limb reflexes were reduced, and muscle tone was diminished. Findings of the neurologic examination were consistent with diffuse lower motor neuron dysfunction.
Blood samples were obtained for hematologic and biochemical analyses and blood gas analysis. Hematologic evaluationa revealed neutrophilia (neutrophil count, 20.5 × 109 cells/L; reference range, 3.5 × 109 cells/L to 12.5 × 109 cells/L) and monocytosis (monocyte count, 3.51 × 109 cells/L; reference range, 0.3 × 109 cells/L to 2 × 109 cells/L), which were considered consistent with a stress leukogram. Changes consistent with hemoconcentration (hemoglobin concentration, 20.1 g/L; reference range, 12 to 18 g/L; Hct, 57.6%; reference range, 37% to 55%) were also evident. The only abnormality detected during biochemical analysisb,c was severe hypokalemia (1.7 mEq/L; reference range, 3.5 to 5.8 mEq/L). Blood gas analysisd of a sample of venous blood collected at the time of admission revealed no acid-base abnormalities.
Urinalysis of a sample obtained via cystocentesis revealed an increase in specific gravity (1.055), which was compatible with the suspected hemoconcentration. Other results of the urinalysis were unremarkable. Examination of an ECG revealed a prolonged QT interval (0.35 seconds; reference range, 0.15 to 0.25 seconds). Abdominal ultrasonography did not reveal any abnormalities.
Intravenous administration of lactated Ringer's solution was initiated; the solution was supplemented with potassium chloridee (0.5 mEq/kg/h [0.23 mEq/lb/h]). Despite this treatment, the clinical status of the dog continued to deteriorate. One hour after admission, muscle twitching was evident. The dog remained tachypneic (80 breaths/min). Muscle weakness progressed, and 3 hours after admission, the dog was unable to maintain sternal recumbency. Respiratory rate slowed to 28 to 36 breaths/min. The gag reflex was no longer detected; thus, the dog was moved into a head-down position to prevent aspiration of saliva.
Clinical deterioration was accompanied by marked irregularities on the ECG. Large numbers of ventricular premature complexes were seen, followed by the appearance of ventricular couplets and triplets and then runs of ventricular tachycardia. Antiarrhythmic medications were not administered because the pulse quality and capillary refill time of the dog remained adequate.
Blood gas analysis of a venous sample obtained at that time revealed the development of acidemia (pH, 7.18; reference range, 7.35 to 7.45) and consequent ionized hypercalcemia (0.39 mg/dL; reference range, 0.28 to 0.35 mg/dL). The hypokalemia worsened (1.4 mEq/L). The Pco2, which was not abnormal at the time of admission (reference range, 35 to 38 mm Hg), increased to 50 mm Hg. The increase in Pco2 was associated with a reduction in respiratory rate and depth of respiration. Muscle paralysis was generalized, and the onset of ventilatory failure as a result of respiratory muscle weakness was suspected.
At 3.5 hours after admission, the dog had signs of clinical improvement (muscle strength, mentation, and a more physiologically appropriate tachypnea). By 4.5 hours after admission, the dog was able to attain a sitting position and appeared bright and alert. The potassium concentration and acid-base status had correspondingly returned to within the respective reference ranges.
The dog remained hospitalized for 52 additional hours. During that time, blood gas analysis and hematologic and biochemical analyses were repeated 3 times. The results were within the respective reference ranges for all analyses at these 3 times.
Differential diagnoses for hypokalemia included reduced dietary intake, increased renal losses (attributable to renal pathological conditions, diuretics, or chronic lithium exposure1), increased gastrointestinal losses (attributable to gastrointestinal pathological conditions or exposure to laxatives2), or intracellular sequestration of potassium. Intracellular sequestration of potassium may result from alkalosis, hypoglycemia-inducing medications (insulin, orally administered hypoglycemics, or xylitol), β-receptor agonists and other sympathomimetics,2 thyroxicosis,3 barium toxicosis, and breed-specific hypokalemic periodic paralysis.
The dog did not have a history of a reduced dietary intake or gastrointestinal or renal abnormalities to support these as the cause of the hypokalemia. Although the dog had no known access to toxicants or pharmaceuticals commonly associated with hypokalemia, toxicant exposure was suspected given the acute onset and subsequent rapid response to treatment. Unfortunately, the vomitus produced by the dog during transportation to the hospital was not available for toxicological analysis. Urine and plasma (lithium heparin) samples acquired during the period of collapse were submitted to the SAS Unit for Trace Elements of Southampton General Hospital for barium analysis because barium toxicosis reportedly causes similar clinical signs in humans.3–6 Barium analysis was performed by use of ICP-MS,f with rhodium as an internal standard. Detection limit was 0.06 μg/dL for plasma and 0.027 μg/dL for urine. Within-batch CV for lithium heparin plasma was 2.4% for a concentration of 2.4 μg/dL and 3.3% for a concentration of 13.7 μg/dL. Within-batch CV for urine was 4.6% for a concentration of 2.7 μg/dL and 8.6% for a concentration of 1.2 μg/dL.
High barium concentrations were detected in plasma samples obtained 1 (47.4 μg/dL), 3 (45.1 μg/dL), and 5.5 (41.9 μg/dL) hours after admission, and a high barium concentration was detected in a urine sample (14.7 μg/dL) collected 1 hour after admission. The urinary barium-tocreatinine ratio was 24.5 for the sample obtained 1 hour after admission. Given the infrequency with which this assay is performed on samples obtained from dogs, no reference range has been established for barium content in plasma or urine obtained from healthy dogs. Reference ranges for barium concentration in the plasma7 and urine8 of humans have been calculated as < 0.1 μg/dL and 0.01 to 0.85 μg/dL, respectively, and the reference range for the urinary barium-to-creatinine ratio in humans is 0.2 to 7.1. The concentrations detected in the dog reported here were comparable with those detected in humans with confirmed barium intoxication.9 No substantial increases in 30 other potentially toxic trace elements (including arsenic, lead, and molybdenum) were detected in the initial urine and plasma samples when screened semiquantitatively via ICP-MS by use of a multiple-element scanning program.
Paired urine and plasma (lithium heparin) samples were obtained from 5 randomly selected control dogs admitted to our small animal teaching hospital for various non–toxin-related reasons. The 5 control dogs were a 12-year-old neutered female Jack Russell Terrier with chronic bronchitis, a 2-year-old sexually intact male German Shepherd Dog with a fractured tibia as a result of being struck by a car, a 10-year-old sexually intact male Rhodesian Ridgeback with a parathyroid gland adenoma, a 10-year-old neutered male German Shepherd Dog with a cutaneous hemangiosarcoma, and a 3-year-old neutered female Saluki with hepatopathy.
Samples were submitted for analysis to assess the range of barium concentrations in plasma and urine samples of the control dogs. Barium concentrations ranged from 0.07 to 0.19 μg/dL for the plasma samples and from 0.21 to 3.15 μg/dL for the urine samples, and the urinary barium-to-creatinine ratio ranged from 1.9 to 14.4. These results further strengthened the diagnosis of barium toxicosis in the dog reported here.
A plasma sample was obtained for electrolyte analysis 10 days after the dog collapsed (7 days after discharge from our facility); the results were unremarkable. Electrolyte concentrations of the dog were analyzed again on day 56 after collapse, and these results also were within the respective reference ranges. On day 56, urine and plasma (lithium heparin) samples were submitted for barium analysis. The results revealed a decrease in the barium concentration in the plasma (0.3 μg/dL) and urine (1.7 μg/dL); however, the urinary barium-to-creatinine ratio was 34.4 and was still elevated. Ninety days after collapse, the dog remained clinically normal.
Discussion
Barium toxicosis is a rare condition and is reported infrequently in the human medical literature.4–6,10–14 To the authors' knowledge, barium toxicosis has not been reported in domestic animals. Barium salts are used in industry (glass, textiles, welding fluxes, and ceramic glazes) and as pesticides, depilatories, firework colorants, and radiographic contrast agents.9 Toxicosis results after exposure to barium salts including carbonate, acetate, chloride, sulfide, oxide, nitrate, and peroxide salts. Barium sulfate, which is used in radiography, is an insoluble salt and has a robust safety record.15 Barium toxicosis in humans has been reported after both inhalation11 and ingestion.6,10,12 The source of barium for the dog reported here is unknown, but it was suspected that the dog ingested the toxicant while exercising and scavenging in derelict buildings prior to the acute collapse. The derelict buildings were not an industrial property; therefore, it was considered unlikely that many of the possible soluble barium salts would have been present in the buildings. Barium carbonate has been used as a rodenticide in the past, and it was hypothesized as the most likely source of exposure. To our knowledge, there have been no other published case reports of barium intoxication in the geographic area of this report.
Oral absorption of barium is reportedly in the range of 7% to 20% and varies with the barium salt, species and age of animal, dietary composition, and feeding status (ie, not fed vs fed state).16 Measurements of serum barium concentrations in dogs indicate that there is peak absorption within 1 hour after ingestion.17 The acute oral LD50 of barium varies considerably with compound and the species and age of animal. Unfortunately, the source and dose of barium for the dog reported here were unknown; however, we hypothesized that barium carbonate in the form of a rodenticide preparation may have been the source of exposure. The estimated fatal dose of barium carbonate for a human is 20 to 30 mg/kg (9.1 to 13.6 mg/lb).18 In controlled experiments, the LD50 of barium chloride was found to be significantly higher in dogs than in humans,19 which suggests that dogs are comparatively resistant to barium toxicosis; therefore, the LD50 of barium carbonate may be higher in dogs than in humans. The range of barium concentrations in urine and plasma samples obtained from the 5 control dogs was higher than the reference range for humans but well below the barium concentrations for the dog reported here.
In acute intoxication in humans as a result of oral ingestion of barium, plasma barium concentrations decrease quickly, with an elimination half-life of 3 hours to 3.6 days.16,20 Following IV injection of 133barium in 1 healthy adult human in 1 study,16 20% of the dose was excreted in the feces and urine within 24 hours, 70% was excreted after 3 days, and 85% was excreted after 10 days, with a fecal-to-urine ratio of 9:1 after 8 days. Barium is incorporated into bone, especially in young growing animals, but without evident detrimental effects.16 The half-life in bone has been estimated as 460 days.16 Barium concentrations in plasma and urine obtained from the dog of the present report at 56 days after admission (0.3 and 1.7 μg/dL, respectively) remained higher than those of the control dogs (0.07 to 0.19 μg/dL and 0.21 to 3.15 μg/dL, respectively), which likely reflected sequestration of barium within bone.
Clinical signs of toxicosis in humans include nausea, vomiting, diarrhea, and abdominal pain during the initial 10 to 60 minutes after intoxication, which are followed by cardiac arrhythmias, hyporeflexia, skeletal muscle paralysis, muscle twitching, salivation, and hypertension, which become evident within 2 to 3 hours following intoxication.21 Intoxication in humans reportedly results in death attributable to fatal ventricular arrhythmias, respiratory failure, and renal damage.22 The dog of the present report had skeletal muscle weakness, muscle twitching, and hyporeflexia. No evidence of abdominal pain or nausea was detected at the time of admission; however, the dog had vomited during transport to the hospital. The temporal progression of clinical signs in the dog of our report appeared comparable to that in humans with barium toxicosis.6,10,21
Most of the clinical signs for barium intoxication relate to the severe hypokalemia that is induced. It has been suggested22 that hypokalemia in dogs results from a shift of extracellular potassium into the intracellular space (notably muscle and RBCs). It is widely postulated that barium competitively blocks the passive potassium channels that typically permit efflux of potassium ions from a cell18,23; in frogs, passive permeability of muscle to potassium ions in the presence of barium is reduced to < 20% of the value for untreated muscle.24 Resting membrane potential of a cell initially remains stable because of the hyperpolarizing effect of pump electrogenesis by Na+-K+-ATPase pumps.18,24 Intracellular sequestration of potassium develops and hypokalemia results. The activity of Na+-K+-ATPase pumps appears to be greatly reduced in hypokalemic environments; therefore, their activity is decreased as hypokalemia develops, and the resting cell membrane potential subsequently approaches the resting ionic diffusion potential.24 At this degree of depolarization, muscle fibers are nonexcitable; thus, flaccid paralysis results.10,24
The mainstay of treatment for barium toxicosis is IV administration of supplemental potassium5; however, controversy exists regarding whether the clinical signs of barium intoxication relate solely to hypokalemia or whether a direct effect of barium may be partially responsible. Several authors have reported12,25 that muscle strength correlates better with barium concentration than it does with the plasma potassium concentration; however, others have reported26 that plasma potassium concentrations correlate well with paresis. Clinical signs that conflict with a solely hypokalemia-mediated etiology of barium intoxication include hypertension and muscle twitching, which are reported in dogs during experimental conditions22 and in human patients with barium intoxication.11 Muscle twitching is considered a direct effect of barium on skeletal muscle.20 The hypertension is not responsive to administration of supplemental potassium and is therefore unlikely to be mediated by hypokalemia. The hypertension is also unaffected by α-receptor antagonists or bilateral nephrectomy; thus, catecholamine activity or activation of the renin-angiotensin-aldosterone system is an unlikely cause. It is speculated that hypertension is a direct effect of barium on vascular smooth muscle.22,26 Lactic acidemia, oliguria, and rhabdomyolysis20 have been reported and are also postulated to be a result of severe vasoconstriction.6,10,11 Blood pressure was not monitored in the dog reported here; therefore, no comment can be made on hypertension. Subjectively, urine production was extremely limited despite high rates of fluids administered IV.
Muscle twitches are seen before the onset of flaccid paralysis26 and may be explained by the intermittent potentiation of membrane depolarization and automaticity as a result of intracellular sequestration of potassium27; however, the resting membrane potential reached in barium toxicosis is generally considered likely to render muscle fibers inexcitable.22,24 Several authors have reported12,22,28 that muscle twitching is a direct effect of barium intoxication.
The rational treatment of barium-induced hypokalemic paralysis is aggressive IV administration of supplemental potassium (0.5 mEq/kg/h), which reverses the hypokalemia. It also facilitates the excretion of barium because the blockade of passive potassium efflux channels by barium is a competitive phenomenon.10,13 Oral administration of magnesium or sodium sulfate limits enteral absorption through the formation of insoluble barium sulfate.12,29 Activated charcoal does not bind barium and therefore cannot be recommended for use.4,5 Intravenous administration of sulfate solutions has been used; however, renal failure attributable to precipitation of barium sulfate has been reported.30 The use of hemodialysis has been associated with rapid clinical improvement through enhanced elimination of barium and rapid correction of electrolyte and acid-base abnormalities.4,5,10,13 Thus, hemodialysis has been recommended as a safe and effective adjuvant to traditional treatment regimens.4,13 Additional supportive treatments, including ventilatory support, may be required if profound muscle weakness causes respiratory failure.
Barium toxicosis is an extremely rare event in domestic animals, but it remains an important differential diagnosis for severe hypokalemia in the absence of suspected underlying disease. Clinical signs largely relate to profound hypokalemia and include gastrointestinal signs followed by cardiac arrhythmias and flaccid paralysis. Hypertension and muscle twitching are also frequently evident. Treatment, if instituted rapidly, can lead to a rewarding outcome; the long-term prognosis after recovery from an acute event would be expected to be good in domestic animals on the basis of favorable long-term outcomes in humans with barium toxicosis.
ABBREVIATIONS
| CV | Coefficient of variation |
| ICP-MS | Inductively coupled plasma mass spectrometry |
LaserCyte hematology analyzer, Idexx Laboratories, Chalfont St Peter, Buckinghamshire, England.
VetTest biochemistry analyzer, Idexx Laboratories, Chalfont St Peter, Buckinghamshire, England.
Vetlyte analyzer, Idexx Laboratories, Chalfont St Peter, Buckinghamshire, England.
iSTAT, Abbott, Birmingham, West Midlands, England.
Potassium chloride concentrate BP 20% wt/vol, Martindale Pharmaceuticals, Brentwood, Essex, England.
Elan 6100DRC plus, SCIEX Perkin Elmer, Beaconsfield, Buckinghamshire, England.
References
1. Marples D, Christensen S, Christensen EI, et al. Lithium-induced downregulation of aquaporin-2 water channel expression in rat kidney medulla. J Clin Invest 1995; 95:1838-1845.
2. Hoffman R. Fluid, electrolyte, and acid-base principles. In: Goldfrank L, Flomenbaum N, Lewin N, et al, eds. Goldfrank's toxicologic emergencies. 7th ed. New York: McGraw-Hill Co, 2002;364–380.
3. Ahlawat SK, Sachdev A. Hypokalaemic paralysis. Postgrad Med J 1999; 75:193-197.
4. Wells JA, Wood KE. Acute barium poisoning treated with hemodialysis. Am J Emerg Med 2001; 19:175-177.
5. Bahlmann H, Lindwall R, Persson H. Acute barium nitrate intoxication treated by haemodialysis. Acta Anaesthesiol Scand 2005; 49:110-112.
6. Sigue G, Gamble L, Pelitere M, et al. From profound hypokalemia to life-threatening hyperkalemia: a case of barium sulfide poisoning. Arch Intern Med 2000; 160:548-551.
7. Mauras Y, Allain P. Dosage du baryum dans l'eau et les liquides biologiques par spectrometrie d'emission avec source plasma haute frequence. Anal Chim Acta 1979; 110:271-277.
8. Sutton A, Shepherd H. Urinary barium excretion in man and its reduction by alginate. Health Phys 1973; 25:182-184.
9. Baselt RC, Cravey RH. Barium. In: Baselt RC, Cravey RH, eds. Disposition of toxic drugs and chemicals in man. 3rd ed. Chicago: Year Book Medical Publishers, 1989;75–77.
10. Schorn TF, Olbricht C, Schuler A, et al. Barium carbonate intoxication. Intensive Care Med 1991; 17:60-62.
11. Jacobs IA, Taddeo J, Kelly K, et al. Poisoning as a result of barium styphnate explosion. Am J Ind Med 2002; 41:285-288.
12. Phelan DM, Hagley SR, Guerin MD. Is hypokalaemia the cause of paralysis in barium poisoning? Br Med J (Clin Res Ed) 1984; 289:882.
13. Koch M, Appoloni O, Haufroid V, et al. Acute barium intoxication and hemodiafiltration. J Toxicol Clin Toxicol 2003; 41:363-367.
14. Kakar A, Anand I, Sethi P. Barium carbonate intoxication: an electrophysiological study. J Neurol Neurosurg Psychiatry 1998; 65:606-607.
15. Ramanathan R. Barium and barium salts. In: Committee on Spacecreft Exposure Guidelines, ed. Spacecraft water exposure guidelines for selected contaminants. Washington, DC: National Academies Press, 2007;52–95.
16. World Health Organization. Barium: environmental health criteria series No 107. New York: World Health Organization, 1990.
17. Chou C, Chin YC. The absorption, fate and concentration in serum of barium in acute experimental poisoning. Chin Med J (Engl) 1943; 61:313-322.
18. Dawson A. Barium. In: Flomenbaum N, Goldfrank L, Hoffman R, et al, eds. Goldfrank's toxicologic emergencies. 8th ed. Norwalk, Conn: Appleton and Lange, 2006;1480–1483.
19. Sax NI. Barium chloride. In: Lewis RJ, eds. Dangerous properties of industrial materials. Vol 2. 6th ed. New York: Van Nostrand Reinhold, 1984;340.
20. Johnson CH, VanTassel V. Acute barium poisoning with respiratory failure and rhabdomyolysis. Ann Emerg Med 1991; 20:1138-1142.
21. Ellenhorn MJ, Schonwald S, Orgdog G, et al. Barium. In: Ellenhorn MJ, ed. Ellenhorn's medical toxicology: diagnosis and treatment of human poisoning. 2nd ed. Baltimore: Williams & Wilkins, 1997;1363–1395.
22. Roza O, Berman LB. The pathophysiology of barium: hypokalemic and cardiovascular effects. J Pharmacol Exp Ther 1971; 177:433-439.
23. Bradberry SM, Vale JA. Disturbances of potassium homeostasis in poisoning. J Toxicol Clin Toxicol 1995; 33:295-310.
24. Layzer RB. Periodic paralysis and the sodium-potassium pump. Ann Neurol 1982; 11:547-552.
25. Thomas M, Bowie D, Walker R. Acute barium intoxication following ingestion of ceramic glaze. Postgrad Med J 1998; 74:545-546.
26. Smith RP, Gosselin RE. Current concepts about the treatment of selected poisonings: nitrite, cyanide, sulfide, barium, and quinidine. Annu Rev Pharmacol Toxicol 1976; 16:189-199.
27. Sjodin RA, Ortiz O. Resolution of the potassium ion pump in muscle fibers using barium ions. J Gen Physiol 1975; 66:269-286.
28. Bryson P. Miscellaneous metals. In: Bryson P, ed. Comprehensive review in toxicology for emergency clinicians. 3rd ed. London: Taylor and Francis, 1996;633–640.
29. Chaudhary SC, Aggarwal A, Avasthi R. Acute severe poisoning by barium carbonate (rat poison). J Indian Acad Clin Med 2008; 9:133-135.
30. Wetherill SF, Guarino MJ, Cox RW. Acute renal failure associated with barium chloride poisoning. Ann Intern Med 1981; 95:187-188.
