Electrolyte Derangements, Hyperlactatemia, and Cardiac Abnormalities Secondary to Refeeding in Three Dogs: Case Report
ABSTRACT
Three dogs that presented to the emergency service in severely emaciated body conditions were admitted to the hospital for monitoring and refeeding. During their hospitalization, all three dogs developed electrolyte derangements or required supplementation to prevent hypophosphatemia and hypomagnesemia. Additionally, all dogs developed hyperlactatemia, which was suspected to be secondary to thiamine deficiency. Two dogs were reported to have cardiac abnormalities, including cardiac arrhythmias, systolic dysfunction, and spontaneous echogenic contrast. These cases highlight the complexity of refeeding syndrome and its associated complications that extend beyond electrolyte deficiencies.
Introduction
Malnutrition and subsequent starvation are caused by imbalances between metabolic demands and nutrient intake. Simple starvation occurs when a healthy individual has reduced caloric intake prompting emaciation, organ dysfunction, and eventually death, whereas stressed starvation arises when decreased caloric intake occurs in the face of a hypermetabolism caused by critical illness.1 In simple starvation, exogenous glucose sources are used within 4–5 hr, after which glycogen stores are rapidly depleted.2 The predominant energy source becomes ketones, sparing skeletal muscle amino acids.3 There is reduced gluconeogenesis, insulin secretion, and basal metabolic rate.3,4 The musculoskeletal, cardiovascular, and neurologic systems are adversely affected.5
When energy sources are reintroduced, the body switches from a catabolic to an anabolic state leading to hyperlactatemia, thiamine depletion, and cardiac arrhythmias.6,7 The body transitions from fat use to carbohydrate metabolism.6 Glucose surges cause increased insulin and decreased glucagon secretion; glucose, phosphorus, potassium, and magnesium are translocated intracellularly.4,6,7 These changes are recognized as refeeding syndrome (RFS).
There is no universal definition of RFS. A variety of clinical and diagnostic findings have been published in human studies and case reports in cats, with limited reports in dogs.8–10 This case report describes RFS in three emaciated dogs and reviews approaches to minimize its occurrence and adverse effects. Table 1 summarizes the data from each case.
Case Report
Case One
A 6 mo old intact female Pit bull terrier (2.44 kg) was presented to the emergency service (ES) after being found with an unknown history. On examination, the patient was comatose, hypothermic (below the detectable level), mildly tachycardic (140 beats per minute [BPM]), and 10% dehydrated, with a blood pressure (BP) below the detectable level with both oscillometric and Doppler methodologies. She had a body condition score (BCS) of 1/9 and a muscle condition score (MCS) of 1/3. On rectal exam, melena was present. Blood work revealed hypoglycemia (below detectable limit), normokalemia (4.3 mEq/L), normolactatemia (17.3 mg/dL), hypoalbuminemia (1.5 g/dL), low-normal phosphorus (2.8 mg/dL), nonregenerative anemia (hematocrit 12%, reticulocyte count 7 K/μL), and neutropenia (2.0 K/μL). Thoracic radiographs revealed a mild bronchointerstitial pattern. Echocardiogram was normal. Fecal ova, parasite, and giardiaa, tick-borne diseaseb, and parvovirusc tests were negative.
The dog was resuscitated with IV crystalloid fluidd (20 mL/kg), dextrosee (6 mL of 25% solution) boluses, and 20 mL/kg of packed red blood cells. The packed cell volume (PCV) and systolic BP after transfusion were 24% and 100mm Hg (obtained via Doppler), respectively. Rehydration fluids (120 mL/kg/day crystalloid), vitamin B complexf (0.5 mL/250 mL), dextrose (5%), maropitantg (1 mg/kg IV q 24 hr), pantoprazoleh (1 mg/kg IV q 12 hr), metronidazolei (10 mg/kg IV q 12 hr), sucralfatej (0.5 g per os [PO] q 8 hr), and ampicillin/sulbactamk (30 mg/kg IV q 8 hr) were started. The patient’s mentation and vitals normalized. Oral feeding with a growth dietl at one-eighth of resting energy requirement (RER; in kcal, RER = 70 × [body weight (kg)]0.75) was well tolerated.
Approximately 20 hr following feeding, phosphorus (2.7 mg/dL) and total serum magnesium (1.97 mg/dL) were low-normal. A potassium phosphatem constant rate infusion (CRI; providing 0.03 mEq/kg/hr phosphorus and 0.05 mEq/kg/hr potassium) and a magnesium sulfaten CRI (0.5 mEq/kg/day) were started. After 12 hr of supplementation, blood work revealed mild hyperlactatemia (26.3 mg/dL), improved phosphorus (3.8 mg/dL) and magnesium (2.16 mg/dL), and static potassium (3.85 mEq/L). Electrolyte supplementation was discontinued. Feedings were increased to 30% RER.
Over the next 2 days, fluids were tapered, and dextrose supplementation was discontinued. On day three, blood work revealed improved anemia and neutropenia, with static hypoalbuminemia. Hyperlactatemia was progressive (66.6 mg/dL) despitenormal perfusion. Phosphorus (3.4 mg/dL), magnesium (1.8 mg/dL), and potassium (3.98 mEq/dL) were low-normal. Potassium phosphate and magnesium sulfate supplementation were re-initiated at their previous doses, and thiamineo supplementation was initiated (100 mg subcutaneously [SC] q 12 hr).
On day four, fluids and electrolyte supplementation were discontinued. Oral medications (amoxicillin-clavulanic acidp 13.75 mg/kg PO q 12 hr, omeprazoleq 1 mg/kg PO q 12 hr, and metronidazoler 10 mg/kg PO q 12 hr) were initiated and feeding was increased to 100% RER. The patient was transferred to a long-term care facility weighing 2.97 kg (21% increase from presentation).
Case Two
A 5 mo old intact female Pit bull terrier (4.55 kg) was presented to the ES for lethargy. Before declining, her daily diet provided 50% RERs. On examination, the patient was dull and recumbent, hypothermic (32.3°C) with a normal heart rate (120 BPM), and 10% dehydrated, with a marginally low BP, oscillometric measurement of 92/63 (75) mm Hg. She had a BCS of 1/9, an MCS of 1/3, and melena on rectal exam. A grade III/VI left systolic heart murmur was auscultated.
Blood work revealed marginal hypoglycemia (65 mg/dL), normokalemia (4.3 mEq/L), hyperlactatemia (26.1 mg/dL), mild nonregenerative anemia (hematocrit 31.4%, reticulocyte count 10 K/μL), hyperphosphatemia (6.2 mg/dL), normomagnesemia (2.3 mg/dL), and hypoalbuminemia (1.6 g/dL). Thoracic and abdominal radiographs were unremarkable. Fecal ova, parasite, giardia, tick-borne disease, and parvovirus tests were negative. Echocardiogram showed mild mitral valve regurgitation and left ventricular dilation with no left atrial enlargement.
The patient received a crystalloid bolus (25 mL/kg IV) and was started on rehydration fluids (120 mL/kg/day), with dextrose (2.5%), potassium chloridet (0.1 mEq/kg/hr), and B vitamin complex (0.5 mL/250 mL), along with ampicillin/sulbactam (30 mg/kg IV q 8 hr), maropitant (1 mg/kg IV q 8 hr), pantoprazole (1 mg/kg IV q 12 hr), thiamine (50 mg SC q 12 hr), and fenbendazoleu (50 mg/kg PO q 24 hr). Feeding was started at one-eighth RER with a growth diet and was well tolerated.
Twelve hours later, the patient’s temperature had improved (36.5 °C), and lactate was 6.4 mg/dL. The PCV was 15%, which was suspected to be from hemodilution and/or gastrointestinal bleeding. Packed red blood cells (10 mL/kg) were administered, bringing the PCV to 30%. Sucralfate (500 mg PO q 6 hr) was added. Inadvertently, thiamine was discontinued. Feedings were increased to 25% RER.
Thirty-six hours after admission, blood work showed normal potassium (4.27 mEq/L) and lactate (6.58 mg/dL); phosphorus was 3.2 mg/dL, and magnesium was 1.95 mg/dL, both normal but decreased. CRIs of magnesium sulfate (0.5 mEq/kg/day) and potassium phosphate (0.03 mEq/kg/hr) were started. Feeding was increased to one-third RER.
Over the next 3 days, the dog’s strength and mentation improved. She was euhydrated and well perfused, and no heart murmur was auscultated. Blood work remained static, aside from a progressive, marked hyperlactatemia (50.4 mg/dL, then 90.8 mg/dL). Thiamine was restarted at a higher dose in response (100 mg SC q 12 hr). Electrolyte and dextrose supplementation were discontinued. Feeding was progressively increased to 200% RER, in an attempt to compensate for the higher metabolic needs of a juvenile patient.
On day six, the patient developed regurgitation with gastric hypomotility and became tachycardic (148 BPM) and febrile (39.2°C). A grade III/VI systolic heart murmur was again auscultated. Blood work showed a static PCV (28%), neutropenia (2.02 K/μL, 208 bands/μL), improved lactate (20.4 mg/dL), mild hypokalemia (3.9 mEq/L), normophosphatemia (5.4 mg/dL), and hypomagnesemia (1.63 mg/dL). Thoracic radiographs and abdominal ultrasound remained unremarkable. Repeat echocardiogram showed a marked increase in mitral regurgitation and a suspect vegetative lesion on the mitral valve, as well as chord rupture, consistent with endocarditis. A bacterial blood culture grew a Salmonella sp. Ampicillin/sulbactam was discontinued. Clindamycinv (25 mg/kg IV q 12 hr), ceftazidimew (30 mg/kg IV q 12 hr), metoclopramidex CRI (2 mg/kg/day), ondansetrony (0.5 mg/kg IV q 8 hr), and erythromycinz (1 mg/kg IV q 8 hr) were started, along with magnesium supplementation at the previous amount. A nasogastric tube was placed. Feeding was increased to 400% RER because of concerns for a negative energy balance and failure to maintain weight in a growing dog.
By day eight, the tachycardia, fever, and regurgitation had resolved. Blood work showed normal lactate (6.94 mg/dL), resolution of neutropenia (3.9 K/μL), and normal electrolytes. Magnesium supplementation was discontinued, and the nasogastric tube was removed.
Over the following three days, the patient’s vitals and appetite remained normal. IV fluids and medications were discontinued. Oral cefpodoximeaa (10 mg/kg PO q 24 hr) and clindamycinbb (11 mg/kg PO q 12 hr) were started, and the dog was discharged to a long-term care facility on day 13, weighing 5.92 kg (30% weight gain from presentation).
Case Three
A 2 yr old intact male Pit bull terrier (12 kg) was presented to the ES after being found in a trash bag with vomitus. On examination, the patient was dull, recumbent, normothermic (38 °C) with a normal heart rate (100 BPM), and 10% dehydrated, with an oscillometric BP of 99/80 (85) mm Hg after a crystalloid bolus (20 mL/kg IV). He had a BCS of 1/9, an MCS of 1/3, and diarrhea on rectal exam. A grade II/VI left systolic heart murmur was auscultated. Blood work revealed mild hyperglycemia (115 mg/dL), normolactatemia (17.5 mg/dL), normokalemia (4.14 mEq/L), normal hematocrit (42%), mild neutrophilia with a left shift (13.23 K/μL, 189 bands/μL), normophosphatemia (4.8 mg/dL), low-normal magnesium (1.8 mg/dL), and hypoalbuminemia (1.7 g/dL). Thoracic radiographs and echocardiogram were consistent with hypovolemia; spontaneous echogenic contrast (SEC) and left ventricular systolic dysfunction were noted. Fecal ova, parasite, giardia, and parvovirus tests were negative.
The dog was started on rehydration fluids (120 mL/kg/day crystalloid) with potassium chloride (0.1 mEq/kg/hr) and B vitamin complex (0.5 mL/250 mL fluid), metronidazole (10 mg/kg IV q 12 hr), ampicillin/sulbactam (30 mg/kg IV q 8 hr), maropitant (1 mg/kg IV q 24 hr), pantoprazole (1 mg/kg IV q 12 hr), fenbendazole (50 mg/kg PO q 24 hr), pimobendancc (5 mg PO q 12 hr), and thiamine (100 mg SC q 12 hr). Oral feeding was started at 25% RER with a gastrointestinal dietdd.
Twelve hours after feeding, blood work showed a mild hypokalemia (3.82 mEq/L), progressive hypomagnesemia (1.3 mg/dL), and low-normal phosphorus (2.6 mg/dL). Supplementation of potassium phosphate (CRI of 0.06 mEq/kg/day) and magnesium sulfate (CRI of 0.5 mEq/kg/day) were started, increasing total potassium supplementation to 0.15 mEq/kg/hr. Feeding was increased to 50% RER. A short period of a ventricular tachyarrhythmia resolved without intervention.
On day two of hospitalization, blood work revealed normal lactate (13.8 mg/dL), normokalemia (4.2 mEq/L), normal phosphorus (3.9 mg/dL), and persistently low-normal magnesium (1.8 mg/dL). Magnesium supplementation was doubled (1 mEq/kg/day), and feeding was increased to two-thirds RER. Repeat echocardiogram showed progressive systolic dysfunction (decreased fractional shortening, increased end systolic dimension, and increased diastolic dimension) and persistent spontaneous echogenicity; clopidogrelee (18.75 mg PO q 24 hr) was started.
On day three, repeat blood work showed a hyperlactatemia (22.4 mg/dL) and normal electrolytes. Metronidazole and thiamine were discontinued. Magnesium, phosphorus, and potassium supplementation were tapered to 0.5 mEq/kg/day, 0.03 mEq/kg/hr, and 0.1 mEq/kg/hr, respectively.
Over the next 2 days, feeding was gradually increased to 200% RER. Hypomagnesemia (1.29 mg/dL) recurred; potassium and phosphorus remained normal. Progressive hyperlactatemia (45.4 mg/dL) was noted. Potassium and phosphorus supplementation were discontinued. Thiamine supplementation was restarted. On day six, lactate normalized (17.1 mg/dL), and magnesium improved (1.46 mg/dL).
Over the following 4 days, electrolytes normalized. Echocardiogram on day 10 showed normalized systolic function with resolution of spontaneous echogenicity. IV fluids, magnesium, and clopidogrel were discontinued, and feedings were increased to 300% RER. The patient was discharged to a long-term management facility on day 12, weighing 14.2 kg (18% increase from presentation). Feedings were at 300% RER, and pimobendan and thiamine supplementation were continued.
Discussion
RFS is most notably associated with complications from electrolyte depletion. In this case series, other systemic effects of RFS are highlighted, including suspected thiamine depletion with resultant type B hyperlactatemia and cardiovascular abnormalities.
Hypophosphatemia is considered the dominant characteristic of RFS in people.3 Reintroduction of nutrition increases insulin production, forcing already depleted phosphorus intracellularly.6,11 An accompanying surge in oxygen consumption amplifies cellular demand for phosphorus to generate adenosine triphosphate and 2,3-diphosphoglyceric acid.3,6 Severe hypophosphatemia can trigger rhabdomyolysis, cardiomyopathy, neurologic changes, osteopenia, renal tubular impairment, and hemolysis.6,11 All three dogs in this series developed hypophosphatemia, or phosphate supplementation is suspected to have maintained normophosphatemia.
Hypomagnesemia and hypokalemia are also documented with RFS, with similar mechanisms as hypophosphatemia.3,12 Magnesium is an important cofactor for adenosine triphosphate use throughout the body, and both magnesium and potassium maintain integrity of intracellular proteins and membrane potentials.4 Severe hypomagnesemia and hypokalemia instigate cardiac arrhythmias, muscle weakness, tetany, seizures, hypoventilation, and rhabdomyolysis.6 Hypomagnesemia, or normomagnesemia maintained with supplementation, was identified in all cases. Hypomagnesemia is also associated with ileus and gastroparesis; this may have contributed to the regurgitation and gastric distention noted in case two. Hypokalemia was documented infrequently; the clinical significance of this is unknown.
Decreased thiamine (Vitamin B1) is reported during RFS in people.13 Thiamine is a cofactor for pyruvate dehydrogenase and essential for aerobic metabolism.14 Thiamine has a short half-life and limited body stores, becoming depleted after 20 days of malnutrition in humans.14 With refeeding in a starved patient, use of thiamine for glycolysis is rapidly increased, and stores are quickly drained.13,14 Without thiamine, anaerobic metabolism predominates, and pyruvate is converted to lactate with ensuing hyperlactatemia.14 The brain and the kidney exhibit clinical signs including Wernicke’s encephalopathy and acute tubular necrosis.14 In people, Wernicke’s encephalopathy leads to ataxia, vestibular dysfunction, vision loss, and mentation changes.6,14 Renal tubular dysfunction causes increased urinary excretion of phosphorus, potassium, and magnesium.13 Diagnosis of thiamine depletion is often made based on clinical signs and response to therapy because the gold standard of testing via high-performance liquid chromatography is not readily available.
Hyperlactatemia is commonly identified in RFS.13 Type A hyperlactatemia is caused by relative or absolute tissue oxygen deficiency.15 Type B hyperlactatemia is seen with certain underlying diseases (e.g., thiamine deficiency), various drugs and toxins, or heritable conditions.15 All three dogs developed hyperlactatemia 3–5 days into hospitalization associated with an increase in feeding, without evidence of shock. In each case, thiamine was not being supplemented at the time of peak hyperlactatemia, and hyperlactatemia resolved with supplementation. This combined with consistent electrolyte derangements suggests that thiamine deficiency was a contributing cause of hyperlactatemia.
Cardiac dysfunction is of great concern in RFS. Cardiac myocytes are depleted as part of general muscle loss in starvation, exemplified in people with anorexia nervosa, in which one-third of deaths are cardiovascular in nature.16,17 Echocardiogram in these patients shows a reduced cardiac output, along with reduced left ventricular dimensions. This creates a relatively large mitral valve annulus prone to prolapse, seen in 30% of anorexic humans.16–18 Eighty percent exhibit arrhythmias or ventricular repolarization abnormalities including QT interval prolongation, which can predict onset of fatal arrhythmias.17 Bradycardia, the most common arrhythmia observed, likely develops secondary to the histologic changes induced by cardiac atrophy and increased vagal tone.16 The increase in metabolic rate and electrolyte derangements seen in RFS lead to increased risk of congestive heart failure, cardiac arrhythmias, pericardial effusion, fluid overload, and cardiac arrest.16
Two cases in this series demonstrated cardiac abnormalities similar to findings in humans with RFS. Case two had mild mitral regurgitation and ventricular dilation. This patient had few risk factors for Salmonella, aside from antibiotic therapy.19 Instead, the patient’s cardiac changes, along with immunosuppression from starvation, likely put this patient at risk for endocarditis. Endocarditis, though rare, has been reported in human patients with anorexia nervosa.20 In case three, serial echocardiograms documented progressive worsening, then resolution of, systolic dysfunction. This patient also had a period of self-limiting ventricular arrhythmias coinciding with exacerbation of hypophosphatemia and hypomagnesemia. SEC on echocardiogram was also observed. This is caused by red blood cell aggregation, arising from interactions between red blood cells and plasma proteins, such as fibrinogen.21 A case series in dogs with SEC found a temporal association with hyperfibrinogenemia, and in humans SEC can be a marker of a hypercoagulable state.21,22 Magnesium plays a role in endothelial health and platelet function; hypomagnesemia has been associated with a hypercoagulable state, which is a theoretical cause for the presence of SEC in RFS.22 Spontaneous echogenic contrast is not regularly witnessed in humans suffering from starvation or RFS. This finding may reflect a unique response in dogs, as the authors have observed this in similar canine starvation cases.
Conclusion
RFS has become increasingly recognized in human medicine yet remains rare in veterinary medicine. There are few case reports of RFS in the veterinary literature, with most involving cats. Cats may be at greater risk than dogs because of low hepatic glycogen stores, accelerated gluconeogenesis, and obligate carnivore status.3 During refeeding, an emaciated cat developed seizures, cardiac arrhythmias, and electrolyte derangements.8 Another cat developed severe hypophosphatemia, hemolysis, hypoglycemia, and hypokalemia.9 A single case report highlighted a dog starved for 27 days that developed hypophosphatemia and hypomagnesemia upon refeeding.10 None of these cases serially evaluated lactate or cardiac function.
Appropriate medical management of RFS in veterinary patients is extrapolated from human data. Key points include initially feeding a small percentage of RER (20–25% based on current weight) using a high protein, low-carbohydrate diet.3 Electrolytes are monitored carefully as feeding is gradually increased, often to 200–300% RER over days to weeks.3,5 It is not currently recommended to delay feeding in the face of electrolyte imbalances but to initiate or continue feeding and supplement electrolytes simultaneously.11 Empiric supplementation of phosphorus, magnesium, and potassium is recommended for the first 24 hr in all high-risk patients, along with thiamine and other B vitamins for 10 days.3
All dogs in this case series were slowly fed orally. Electrolyte supplementation prevented severe abnormalities. Provision of thiamine supplementation was associated with the resolution of hyperlactatemia in all three dogs. Contrary to current recommendations, our patients received high-carbohydrate and low-protein diets, possibly contributing to the severity of RFS. Given the cardiac complications documented, electrocardiography and (serial) echocardiography early during treatment of starvation in dogs appears warranted.
This review of complications associated with simple starvation and subsequent refeeding suggests that characterization of RFS in dogs be expanded beyond electrolyte derangements to include cardiovascular changes, thiamine deficiency, and hyperlactatemia. In the authors’ hospital, previous shortcomings in recognition of these facets of RFS prompted implementation of an RFS treatment protocol (Figure 1), which addresses them.
Citation: Journal of the American Animal Hospital Association 57, 6; 10.5326/JAAHA-MS-7132
A copy of the in-hospital protocol created to guide therapy of patients at risk of RFS. BID, q 12 hr; BW, body weight; CBC, complete blood count; ECG, electrocardiogram; RER, resting energy requirement; RFS, refeeding syndrome; SC, subcutaneously; SEC, spontaneous echogenic contrast.
Contributor Notes
From the Emergency and Critical Care Department, Animal Medical Center, New York, New York
