Neuromuscular Signs Associated with Acute Hypophosphatemia in a Dog

Introduction

Hypophosphatemia is a potential complication in critically ill animals, particularly those who have either been anorexic and/or malnourished or are suffering from diseases such as diabetic ketoacidosis (DKA) and sepsis. Moderate hypophosphatemia is frequently observed in animals and humans, but clinical consequences directly associated with hypophosphatemia are rarely seen unless whole body phosphorous depletion exists.¹ Phosphate is the body's major intracellular anion, and movement into and out of the cells can rapidly change serum phosphorous concentrations.^1–6 Phosphate homeostasis is primarily maintained by intestinal absorption and renal reabsorption. Hypophosphatemia is caused by any or all of the following: decreased intestinal absorption, increased renal excretion, and/or redistribution of phosphorous from the extracellular to the intracellular compartment.^1–5,7–10

Most cases of hypophosphatemia are mild and subclinical; however, either severe acute or prolonged hypophosphatemia may occur and cause a variety of signs in virtually any body system. The most recognized clinical sign of hypophosphatemia in animals is hemolytic anemia.¹ Hypophosphatemia may also result in dysfunctions of the central nervous system (CNS) with signs such as seizures and ataxia and of the peripheral nervous system with signs including rhabdomyolysis and weakness.^{1–8,11–15} The objective of this case report is to describe successful recognition and management of neuromuscular abnormalities as a result of spontaneous, severe, acute hypophosphatemia in a dog.

Case Report

A 5 yr old castrated male Swiss Mountain dog weighing 42 kg with a body condition score of 5 out of 9 presented to an emergency service with a 2 day history of complete anorexia and persistent vomiting. He had a history of pica, although his owner was not aware of any recent ingestion of foreign material or other dietary indiscretion. The patient also had a 3 yr history of seizures, which was presumed to be due to idiopathic epilepsy based on age of onset of seizures, normal interictal behavior, and normal interictal neurologic exams. The owners reported a seizure frequency of 1 seizure q 3 mo, with the last seizure occurring 2 wk prior to presentation.

At presentation, he had a rectal temperature of 38.2°C with pink mucous membranes and a capillary refill time of 2 sec. He was tachycardic (150 beats/min); tachypneic (40 breaths/min); and he had strong, synchronous femoral pulses. The neurologic examination was normal. Abdominal pain was present based on a hunched posture and a mild painful response on cranial abdominal palpation.

Initial laboratory tests included a complete blood count (CBC), serum biochemical profile, and electrolytes. On CBC, all values were normal except for an elevated hemoglobin (188 g/L; reference range, 120–180 g/L) and monocytosis (2.51 × 10⁹/L; reference range, 0.3–2 × 10⁹/L ). The packed cell volume and total solids were at the high end of the reference ranges at 55% (reference range, 45–55%) and 7.8 units (6.0–7.8 g/dL). A serum biochemical profile was normal with the exception of an elevated blood urea nitrogen (11.42 mmol/L; reference range, 2.5–9.64 mmol/L) and alkaline phosphatase (16.03 μkat/L; reference range, 0.38–3.54 μkat/L). Electrolyte analysis results were as follows: sodium, 138 units (reference range, 144–160 mmol/L); potassium, 3.4 units (reference range, 3.5–5.8 mmol/L); chloride, 108 units (reference range, 109–122 mmol/L); phosphorous, 1.58 mmol/L (reference range, 0.81–2.2 mmol/L); and Ca, 2.6 mmol/L (reference range, 1.98–3 mmol/L).

Abdominal radiographs were obtained and interpreted by the admitting veterinarian and a board-certified radiologist. Radiographic findings included fluid and gas distention of the stomach and multiple, irregular, small mineral opacities within the gastrointestinal tract. An abnormal grouping of intestine was noted in the right cranial abdomen, as well as focal decrease in serosal detail. A mechanical obstruction was suspected, and an exploratory laparotomy was recommended.

Following the administration of a 20 mL/kg fluid bolus and 2 hr of aggressive fluid therapy^a, hydromorphone^b (0.1 mg/kg), and midazolam^c (0.25 mg/kg) were administered intramuscularly for anesthetic premedication. Propofol^d (4.7mg/kg) was administered IV for induction, and anesthesia was maintained with a fentanyl^e (10.9 µg/kg/hr), lidocaine^f (46 µg/kg/min), and ketamine^g (9.3 µg/kg/min) continuous rate infusion (CRI) and isofluorane^h gas in O₂. Fluids were administered at a rate of 9.5 mL/kg/hr during anesthesia, and no hypotensive episodes occurred.

A ventral midline incision was made from the xiphoid to the pubis. Surgical findings included foreign material in the stomach, proximal jejunum (with plication), and colon. There was no gross contamination upon initial inspection of the peritoneum; however, multiple areas of perforation on the mesenteric border of the proximal jejunum were discovered upon release of plications resulting in mild, focal peritoneal contamination. A resection and anastomosis was performed, removing approximately 30 cm of compromised intestine including the distal duodenum and proximal jejunum. A gastrotomy was also performed to remove foreign material that was not connected to the intestinal foreign material. The abdomen was lavaged copiously, and a standard three-layer abdominal closure was performed. No culture was obtained, presumably due to the surgeon's assessment of minimal contamination. Cefazolin was administered intraoperatively IV q 90 min and was continued postoperatively until the dog was switched to oral cephalexin on the day of discharge. The patient recovered uneventfully from anesthesia. Postoperative analgesia was provided as a CRI of fentanyl, lidocaine, and ketamine for 24 hr.

Small, frequent meals were offered beginning 10 hr after surgery, and the patient began eating small meals 24 hr postsurgically with no vomiting. On his second postoperative day, approximately 12 hr after he began eating (36 hr after recovering from surgery), generalized muscle tremors were noted as he was resting in the cage. At that time, his rectal temperature was 39.8°C. Less than 1 hr previously, the temperature had been 38.4°C when tremors had not been apparent. The tremors continued when he attempted to walk out of the cage. The dog was ambulatory, but generally weak and ataxic, and only took a few steps before lying down while the generalized tremors continued. He was mentally appropriate, although anxious while tremulous. A venous blood sample was obtained immediately for a CBC, serum biochemical analysis, electrolyte panel, and a blood gas analysis. The only significant change from the presurgical panel was a severe hypophosphatemia of 0.26 mmol/L (reference range, 0.81–2.2 mmol/L). Unfortunately, that test was not repeated for verification of low value. Sodium (150 mmol/L), potassium (4.2 mmol/L), and chloride (122 mmol/L) were all normal, as was the partial pressure of CO₂ (39 units; reference range, 32–49 mm Hg). Potassium phosphate supplementationⁱ (0.022 mmol/kg/hr) commenced immediately. After 6 hr of supplementation, signs of neuromuscular dysfunction had resolved and his phosphorous returned to normal (3.1 mg/dL). Neither hemolysis nor anemia was noted at any time. No further neurologic deficits or neuromuscular signs were observed for the remainder of his hospitalization.

Twelve hours after severe hypophosphatemia was documented and neurologic signs developed, the dog's phosphate supplementation was decreased. Serum phosphorous concentration was repeated and was maintained in the normal range (1.39 mmol/L). The patient was discharged 3 days following surgery without residual signs of neuromuscular weakness.

Discussion

Phosphorous is a nonmetallic substance that does not occur in a free state in nature.² Phosphorous may be compounded with Ca, Na, and potassium to form phosphate salts. Phosphoric acid and the salt of Phosphoric acid are some of the most important biological chemical compounds.³ Phosphate is distributed throughout the body in the following proportions: 85% as hydroxyapatite in bone (a complex of Ca, phosphate, and hydroxyl ions), 15% in the intracellular compartment, and <1% in the extracellular compartment.^1,2,5,7,8

Dietary phosphate is absorbed in the duodenum and jejunum via active and passive transport under the influence of vitamin D₃.^1–5,7 Excretion is predominately renal (90%) with phosphate being freely filtered at the glomerulus, 80–95% reabsorbed at the proximal tubule, and a lesser portion absorbed at the distal convoluted tubule.^1–4,16

Phosphate is a vital component of the lipid bilayer of cell membranes and plays an important role in cellular structure and function.^1,2,4,5,7,8 It is essential for many important biologic processes, including those requiring adenosine triphosphate (ATP), guanosine triphosphate, cyclic adenosine monophosphate, and phosphocreatinine.^1,2,4,5,7,17 Hypophosphatemia can affect virtually all organ systems, causing a wide variety of detrimental effects because phosphorous is required for the formation of intracellular ATP.^{1–6,8,9,18,19} ATP is required for essential metabolic processes including muscle contraction, neuronal impulse conduction, and maintaining electrochemical membrane gradients.^1–4,7

The most severe effects are via cellular damage when phosphate stores are depleted.^1,3,4 Hypophosphatemia decreases erythrocyte concentrations of ATP and leads to red blood cell fragility and, eventually, hemolysis.^{1–7,11,12,19} This is not typically seen until plasma levels reach <0.32 mmol/L.^1,4,7 Hypophosphatemia reduces 2,3-diphosphoglycerate concentrations within erythrocytes and decreases the affinity of hemoglobin for O₂, resulting in a decrease in O₂ delivered to tissues.^1–8,11 Leukocytes are also affected via impaired chemotaxis, phagocytosis, and bactericidal ability, particularly in ill patients receiving parenteral nutrition.^{1–5,7,8,10–12,19} Platelets may also be affected via shorted life span, impaired clot retraction, and thrombocytopenia.^{1–5,7,12,19}

Normal serum phosphorous concentrations are between 0.97 and 1.94 mmol/L in adult dogs and cats, with some variation between laboratories.^1,4,7 Hypophosphatemia is defined as a serum phosphorous concentration, which is below the normal range; however, that value does not necessarily reflect total body phosphate or correlate with clinical signs.^1,3,7–9,11 Hypophosphatemia is not typically considered clinically significant until the concentration falls <0.32 mmol/L.^1,2,7 Hypophosphatemia is considered to be moderate at 0.32–0.65 mmol/L and severe at <0.32 mmol/L.^2,5,9,12

Gradual changes in total body phosphorous can be accommodated without noticeable changes in serum phosphorous due to compartment shifting and redistribution.^1,2,4,7 Therefore, many animals may appear clinically normal with significant hypophosphatemia. Hypophosphatemia can occur with normal, low, or high total body phosphate.^1–5,7,9,12 Phosphate depletion may occur as a result of decreased intestinal absorption, urinary wasting, and/or shifts from the extracellular fluid compartment into the intracellular compartment.^{1,3–5,7–9,12,20}

Intracellular shifting of phosphorous is the most common cause of hypophosphatemia in the human intensive care unit setting and may be associated with sepsis, trauma (such as head injury), burns, DKA, alcoholism, chronic obstructive pulmonary disease, and refeeding syndrome.^{1–5,8–10,12,15,19} Diseases of veterinary patients that are most likely to lead to significant hypophosphatemia with life threatening consequences include DKA, sepsis, respiratory disease, metabolic and respiratory alkalosis, and the initiation of parenteral nutrition and fluid therapy.^2,7,9

Refeeding syndrome is a potential complication when reintroducing nutrition via either enteral or parenteral routes to a malnourished or starving patient because they may have whole body phosphate depletion.^{1,4,6–8,11,12} Electrolyte derangements associated with refeeding syndrome include hypophosphatemia, hypokalemia, hypomagnesemia, and hyperglycemia.^{1,4,6,7,11,12} Refeeding syndrome is seen particularly with the administration of carbohydrates as insulin is released and facilitates movement of glucose and phosphorous into the cells.^{1–4,6–8,11,12} Severe hypophosphatemia in malnourished patients receiving parenteral nutrition is due to the accelerated rate of tissue repair during which phosphate is incorporated into new cells and cell membranes, as well as the need for phosphate utilization in glycolysis when there is a sudden shift back to glucose as the primary fuel source.^2–4,7,11 Refeeding syndrome will typically occur and become clinically evident approximately 3 days after the initiation of enteral or parenteral nutrition.¹¹

Postsurgical hypophosphatemia is a common complication in humans and has been widely documented as a morbidity after major hepatic surgery (such as living donor hepatectomies) and cardiac surgeries (such as cardiac bypass and/or valve replacement).^4,9,19 In general, it is theorized that postoperative hypophosphatemia is multifactorial and may be influenced by preoperative phosphate, increased renal loss, compartmental shifting (due to respiratory alkalosis, hormones, proinflammatory cytokines, parenteral nutrition), and hemodilution.^16,17 One theory regarding intracellular shifting of phosphate is that it may be related to tissue ischemia, which depletes intracellular phosphate stores.¹⁷ In the reperfusion state, creatinine and phosphate are consumed to form more ATP and creatine phosphate. The hypophosphatemia could potentially be severe, depending on the degree of ischemia.¹⁶

Adverse effects of hypophosphatemia on myocardial function and respiratory function have been noted clinically and studied.^{1–3,5,6,8–10,15,20} Respiratory failure may result from impaired diaphragm contractility secondary to hypophosphatemic-induced muscle weakness.^{2,3,5,6,8,9,11,16,20} Hypophosphatemia may also lead to difficulty in weaning patients from mechanical ventilation and prolonged recovery.^8,19,20 Zazzo et al. (1995) performed a prospective study in a surgical intensive care unit and demonstrated that in hypophosphatemic patients, cardiac performance was improved with phosphorous supplementation, as shown by increased cardiac index, systolic index, and left ventricular stroke volume index.¹⁹ Their results confirm the previous observations of high incidences of hypophosphatemia (28.8%) and its association with increased mortality.^10,19

Hypophosphatemia has long been associated with the early stages of sepsis, particularly when associated with gram-negative infections.^1,10,18,21 As many as 80% of septic human intensive care unit patients are hypophosphatemic.^5,10,18,21 Hypophosphatemia has been related to the severity of illness and outcome.^10,17 Death is more common, with one study reporting an eightfold increase in septic patients with severe hypophosphatemia compared to septic patients with normal phosphorus values.^9,10 The mechanism for hypophosphatemia in sepsis is not fully understood but is likely multifactorial, and involving intracellular redistribution of phosphate.¹⁰ Respiratory alkalosis, which may be associated with sepsis, draws phosphate from the extracellular space secondary to an intracellular increase in pH.^1,4,10,21 Another contributing factor is the release of, or infusions of, hormones such as insulin, catecholamines, glucagon, and cortisol.^16,17 One area that has been studied more in recent years is the role of cytokines and acute phase proteins in sepsis-associated hypophosphatemia.²¹ Endotoxemia and bacteremia initiate an exaggerated cascade of proinflammatory cytokines that may not be down regulated in septic patients.^10,17,18,21 Those proinflammatory cytokines stimulate hepatocytes to release the acute phase protein, C-reactive protein.²¹ Studies have shown that high levels of interleukin-6, tumor necrosis factor-α, and C-reactive protein are all statistically associated with low concentrations of serum phosphate.^9,18,21

Hypophosphatemia has also been associated with at least three potential deleterious effects in patients that have progressed to septic shock: decreased cardiac contractility, impaired response to vasopressors, and decreased O₂ delivery to tissues, all of which may contribute to an increased mortality rate in hypophosphatemic septic patients.^2,9,10,15 That finding is of particular interest in critical care, and hypophosphatemic myocardial depression should be considered as a compounding factor with septic patients.^10,15,19

Clinical signs of hypophosphatemia are often manifested as dysfunction of the CNS or neuromuscular systems in human medicine but are seldom considered as an etiology in dogs presenting with neuromuscular signs.^1,6,12,17 Signs of hypophosphatemia-induced neuromuscular dysfunction include weakness and pain associated with rhabdomyolysis as well as anorexia, vomiting, and pain associated with ileus.^{1,4,7–9,11,19} Low phosphorous may also impair CNS glucose utilization and ATP production, the cause of which may be tissue hypoxia and ATP depletion secondary to a decrease in 2,3-diphosphoglycerate.^1,3,4,11 Effects of the metabolic encephalopathy include a variety of signs in people, such as confusion, irritability, seizures, and coma.^1,3,4,7 In humans, myalgia, muscle weakness, and anorexia are typical early signs of moderate to severe hypophosphatemia (phosphorous <0.48 mmol/L). When phosphorous reaches 0.26 mmol/L, neurologic signs such as paresthesia, tremors, confusion, decreased reflexes, seizures, and coma may develop.^5,6

Neuromuscular weakness, neurologic dysfunction, and rhabdomyolysis have been experimentally induced and evaluated in animal models. Animals were malnourished and starved to 25–40% of their original body weight and developed hypophosphatemia (severe in some cases) and neuromuscular signs when challenged with nutrition.^13,14 Although the patient presented here was clearly not starved to that extent, neuromuscular signs developed naturally after 48 hr of anorexia and gastrointestinal losses.

To the authors' knowledge, there has not been a documented veterinary case of neuromuscular dysfunction secondary to spontaneous, severe, acute hypophosphatemia. The authors believe that a combination of events in this dog led to the neuromuscular signs associated with his severe hypophosphatemia. He was malnourished, having been completely anorexic and vomiting for 2 days prior to surgery. He was then fasted for another 12 hr after surgery, for an approximate total of 72 hr without food. Both vomiting and anorexia led to decreased intestinal absorption of phosphorous and likely total body depletion. He was clinically dehydrated on presentation and was placed on a high rate of fluids prior to, during, and for a short time after surgery. Fluid diuresis may have contributed to the hypophosphatemia by increasing renal losses.⁷ There may have also been cellular redistribution of phosphorous as presumed preoperative acid-base abnormalities secondary to his gastrointestinal signs were corrected, though an initial blood gas was not performed. This patient met the criteria for systemic inflammatory response syndrome at presentation, and surgical findings made it evident that he was in the early stages of sepsis.⁷ Unfortunately, there were no cultures obtained to document a bacterial infection. Sepsis likely contributed to the progression and severity of this patient's hypophosphatemia.

Surgery resulted in removal of a significant portion of his duodenum and proximal jejunum, which are important for absorption of dietary phosphorous. It is unclear from the literature if removal of just those segments would affect phosphorous dramatically. It is possible, however, that surgical ischemia, as described above, may have contributed to his hypophosphatemia. Refeeding syndrome was not considered to be a likely contributor in this patient because his neuromuscular signs occurred just 12 hr after reintroduction of enteral nutrition, and refeeding effects are not typically seen until 3 days after nutrition is reintroduced.¹¹ The authors also feel that respiratory alkalosis was not a significant contributor to the development of hypophosphatemia because, at the time of blood gas collection, his respiratory rate and effort were normal. Finally, the authors feel that a spurious laboratory error was unlikely, given his predisposing factors and response to therapies; however, the value was not verified with a second sample.

Treatment for hypophosphatemia is aimed at correcting the underlying cause and providing appropriate phosphorous supplementation.^1,4–8 When hypophosphatemia occurs, recommendations are to start supplementing phosphorous when serum values are <0.48 mmol/L or if the patient becomes symptomatic. There are no agreed upon guidelines to aide in the treatment approach because studies evaluating supplementation in critically ill patients are lacking in both the human and veterinary literature.^5,6,8,9 The patient in this report had a unexpectedly positive response to a conservative rate of phosphorous supplementation. Why this occurred is unknown, but the authors suspect it was secondary to redistribution of phosphorous because large shifts can occur very quickly. Although oral supplementation is available and may be chosen in mild and moderate, nonsymptomatic cases, its effect is slow.^3,6 Moreover, it is an unacceptable dosing route in most symptomatic patients due to the presence of vomiting and/or anorexia; therefore, most patients require parenteral administration.^1,4,6,7

Supplementation is typically initiated as a CRI at a rate of 0.01–0.06 mmol/kg/hr in dogs and cats, although higher doses (0.16–0.64 mmol/kg over 4–12 hr) are administered to human patients.^1,4,5,7,11 Calcium-containing fluids should be avoided because Ca phosphate may precipitate.^1,2,4–7,9 Serum phosphorous should be monitored q 4–8 hr during supplementation.^1,4–8 Oversupplementation may result in hyperphosphatemia, hypomagnesemia, hypocalcemia, and hypotension.^1,4,5,7,9

Conclusion

Hypophosphatemia is a potential complication in critically ill animals and may present as any of a wide variety of signs. Most cases of hypophosphatemia are mild and subclinical; however, cases may be severe, acute, or prolonged hypophosphatemia that can affect virtually any body system. Although the most commonly recognized and discussed clinical sign of hypophosphatemia in animals is hemolytic anemia, there are a number of other signs that may go unrecognized.¹ Experimentally induced hypophosphatemia in animals have demonstrated signs similar to those recognized as neuromuscular signs in humans. It stands to reason that neuromuscular signs with spontaneous hypophosphatemia can occur in small animal patients as well. Hypophosphatemia should be an early differential diagnosis to rule out when presented with a patient suffering from neuromuscular dysfunction. The patient described in this report had a number of predisposing events that the authors believe led to his severe acute hypophosphatemia, including surgery to resect portions of duodenum and jejunum, fluid diuresis, 72 hr of anorexia, vomiting, and presumed intracellular shifting of phosphorous. To the authors' knowledge, this is the first reported case of neuromuscular dysfunction due to spontaneous, severe hypophosphatemia in a dog.