Raisin Ingestion and Pancreatitis in a 10-Year-Old Cocker Spaniel

Emily Viani
Advisors: Dr. Julie Menard and Dr. Sarah Robbins
Senior Seminar Paper
Cornell University College of Veterinary Medicine
May 17, 2017
















Key Words: raisins, acute renal failure, acute renal injury, pancreatitis

Abstract:
	A ten-year-old female spayed cocker spaniel presented to Cornell Emergency Service on April 1, 2017 for acute ingestion of a 20 oz container of raisins. On presentation, physical examination was unremarkable, aside from the fact that the dog was nervous and panting. Initial point of care blood work and urinalysis were within normal limits. Treatment included induction of emesis with apomorphine, and administration of activated charcoal. She was admitted to the intensive care unit for further monitoring, and fluid therapy to promote diuresis and prevent acute renal failure caused by raisins. The following day, the patient had two episodes of vomiting, and a concern for aspiration was raised; however, thoracic radiographs showed no evidence of aspiration at the time. Two days post-ingestion, vomiting subsided, but she was painful upon abdominal palpation, and inappetent. After notification from the owner of the possible ingestion of a foreign body, an abdominal ultrasound was performed, which showed no signs of a foreign body, but revealed pancreatitis. The patient improved with supportive care and was discharged with no evidence of acute renal failure, and continued medical management of the pancreatitis. 
	The objective of this case report is to present the management of raisin ingestion toxicity, and the diagnosis and treatment of acute pancreatitis in dogs.






Introduction:
	One of the most common causes of acute renal failure in dogs is toxicity, including medications, plants, and ethylene glycol.1 Evidence of raisin or grape ingestion leading to acute renal failure began in 1999, when the Animal Poison Control Center received an increasing amount of reports of healthy dogs developing renal failure after ingestion of grapes or raisins.2 Since then, studies have failed to identify the specific toxicant in grapes and raisins that cause acute renal injury/failure in dogs. A common sequela to raisin ingestion is gastrointestinal irritation or inflammation.1 In the case reported, a secondary complication of raisin ingestion was acute pancreatitis.

Signalment and Case History:
	The patient, a 10-year-old female spayed Cocker Spaniel, presented to the Cornell Emergency and Critical Care Service for acute ingestion of a 20 oz container of raisins. Prior to ingestion, the patient had been overall healthy, and had no other medical concerns at the time of presentation.

Clinical Findings:
	On presentation to Cornell Emergency Service, the patient was bright, alert, responsive, and anxious. She weighed 10.5 kg (23.1 lb) with a Purina body condition score of 6 out of 9. Her vital parameters were within normal limits (temperature: 100.4 F, HR: 120 bpm, RR: 32 bpm). Her abdomen was soft and non painful on palpation. The remainder of her physical examination was unremarkable.
	To assess overall internal organ health, and status of the patient’s baseline kidney function, initial point of care blood work was performed. Blood gas results were within normal limits. All blood values were within normal limits with packed cell volume 48% (41-58%), total solids 6.8 g/dL (5.9-7.8 g/dL), Azo Stick 5-15 mg/dL, phosphorous 3.7 mg/dL (2.9-5.2 mg/dL), and creatinine 0.7 mg/dL (0.6-1.4 mg/dL). A urine sample was collected, which revealed a urine specific gravity of 1.024. The urine specific gravity (USG) was not within the isosthenuric range (1.008-1.012), which would be indicative of renal dysfunction or failure; however, the lower concentration is suspicious for a USG that was trending toward that range.

Problem List/Differential Diagnosis
	The most concerning problem is raisin ingestion leading to acute renal failure. There was also the possibility that the patient ingested part or all of the container of the raisins, which led to the speculation of a foreign body obstruction.

Prognosis:
	The prognosis of raisin ingestion is variable based on the individual variability of patients’ compensatory mechanisms. The unknown toxin of raisins/grapes causes an initial insult to kidney function. Based on the individual patient, the body is either able to compensate for the injury, and the kidneys recover, or if the body is unable to maintain perfusion, the injury may lead to acute kidney failure, and carry a more guarded prognosis. The response of affected dogs is considered idiosyncratic, due to the lack of apparent dose-response relationship; however, the more raisins ingested, the higher the probability of toxicity. This in turn can also lessen the likelihood of recovery.2

Treatment and Further Diagnoses:
	Initial treatment was comprised of decontamination and aggressive intravenous fluid therapy. Emesis was induced with apomorphine (0.03 mg/kg IV), and was successful, as a large amount of whole raisins was recovered. Cerenia (1mg/kg) was administered intravenously after inducing emesis to decrease side effects of nausea and prevent aspiration pneumonia. Further decontamination included the administration of activated charcoal with sorbitol (5 ml/kg by mouth once). The patient was then placed on twice maintenance rate of intravenous Normosol fluids. The patient was admitted into the Intensive Care Unit (ICU) for continued treatment and monitoring.
	On the day following admission, she was continued on a high rate of fluids, while serially checking her kidney values for signs of acute renal failure. Intact raisins with activated charcoal were recovered in her stool during her morning walk. The patient did well throughout the day; however, in the afternoon she had three episodes of emesis, and became dull and inappetent. Due to her decreased mentation following emesis, as well as evidence of B lines on T-FAST, aspiration pneumonia was suspected. Pneumonia was sequentially ruled out by thoracic radiographs, which revealed no signs of pulmonary or mediastinal disease. She was continued on Cerenia every 24 hours, as well as pantoprazole for gastrointestinal protection from dietary indiscretion. 
	On the second day of hospitalization, she was maintained on a higher intravenous fluid rate. She continued to have episodes of vomiting and inappetence; and was painful on abdominal palpation. After sharing this information with the owners, they reported that the top of the container of raisins was never found. 
	Blood was collected for a complete blood count and chemistry panel. The hematology revealed a leukocytosis [18.4 thou/uL (5.7-14.2 thou/uL)] characterized by a neutrophilia [15.1 thou/uL (2.7-9.4 thou/uL)]. This was indicative of inflammation. The chemistry panel revealed normal renal values compared to baseline values with BUN 6 mg/dL (10-32 mg/dL), creatinine 0.4 mg/dL (0.6-1.4 mg/dL), calcium 7.9 mg/dL (9.3-11.4 mg/dL), phosphate 3.0 mg/dL (2.9-5.2 mg/dL). In addition, her albumin was decreased at 1.4 g/dL (3.1-4.2 g/dL), with a low total protein [3.5 g/dL (5.3-7.0 g/dL)] and anion gap [0.7 (0.9-2.1)]. Her alkaline phosphatase, amylase, and magnesium were out of the reference range, but these abnormalities were not clinically relevant. 
	An abdominal ultrasound was performed to investigate the cause of the emesis and abdominal pain. The ultrasound revealed no signs of foreign body, but an enlarged, lobulated, hypoechoic pancreas was observed, with surrounding hyperechoic mesentery, and a small amount of anechoic peritoneal fluid. These ultrasonic findings are characteristic of pancreatitis.6 Due to this new finding, the patient was placed on methadone 0.2 mg/kg intravenous every 4-8 hours as needed to control pain associated with pancreatitis.
	On the third day of hospitalization, the patient was bright, alert, and responsive, and had a good appetite, with no episodes of emesis or nausea. Her fluids were reduced to a maintenance rate. She was continued on intravenous pain control. Blood was collected for a renal panel, as well as a blood smear to assess platelet, red blood cell, and total solid values. Packed cell volume was 40% (41-58%), total solids 5.3 g/dL (5.9-7.8 g/dL), and there was adequate amount of platelets on blood smear. These values were pertinent to assess due to the risk of systemic complications from pancreatitis, such as disseminated intravascular coagulation (DIC). There was no continued evidence of renal injury, despite reducing the rate of fluids. The renal panel revealed a BUN 7 mg/dL (10-32 mg/dL), creatinine 0.4 mg/dL (0.6-1.4 mg/dL), calcium 8.4 mg/dL (9.3-11.4 mg/dL), phosphate 4.4 mg/dL (2.9-5.2 mg/dL), total protein 4.1 g/dL (5.3-7.0 g/dL), albumin 1.6 g/dL (3.1-4.2 g/dL), and an anion gap ratio 0.6 (0.9-2.1).
	On the fourth and final day of hospitalization, the patient continued to be bright and alert, eating well with no nausea, and no pain on abdominal palpation. Given her clinical appearance, the patient was transferred onto oral pain medication (tramadol) and an oral gastrointestinal protectant (omeprazole). Blood was collected to assess platelets, packed cell volume, and total solids. The packed cell volume was unchanged from the previous day’s value. The total solids was 5.6 g/dL (5.9-7.8 g/dL), and blood smear revealed adequate platelets. She was discharged to the owner’s care with these medications, and instructions to feed a bland diet. 

Discussion:
	Raisins and grapes both serve as toxins causing acute renal failure; however, the specific toxicant has not been identified. Studies have shown that cranberries and currants have similar effects as well.3 Contamination, such as from insecticides, pesticides, heavy metals, or mycotoxins, has been proposed as a possible cause of acute renal failure, but these theories have not been proven.1 In general, acute renal failure is due to an ischemic event causing lack of blood supply to the kidneys, or due to a toxic chemical directly effecting renal function. In the case of raisins/grapes, some unidentified chemical is causing direct renal tubular damage or is causing renal ischemia. One retrospective study has demonstrated a lack of a dose-response relationship, whereby acute renal failure was seen in dogs with a toxicity dose range of 2.8 g/kg to 19.6 g/kg. The toxic effect is considered an idiosyncratic reaction; however, the more raisins/grapes ingested, the higher the probability that a reaction will take place.2
	This idiosyncratic reaction is based on the individual variability of patients’ compensatory mechanisms. The ingestion of raisins causes a toxic insult to the kidneys, which results in acute renal injury caused by a decrease in perfusion, leading to a loss of function. In some cases, the kidney is able to regenerate, and recover allowing patients to maintain renal function post-ingestion. Patients that experience acute kidney injury will demonstrate clinical signs associated with loss of nephron function, such as vomiting, lethargy, abdominal pain, diarrhea, and anorexia.1  Concomitant changes in blood work and urinalysis are also present shortly following ingestion. Injury to the nephron leads to a loss of ability to concentrate urine, which is seen in a USG between 1.008-1.012. The kidney is no longer functioning to either concentrate or dilute urine. An increase in creatinine (0.3 mg/dL compared to baseline value) occurs over the next 24 hours despite fluid therapy. Hyperphosphatemia is also seen, which leads to an increase in the Ca x P product, typically seen in end stage kidney failure, and mineralization. These changes in blood work are also progressively seen in patients whose kidneys are unable to regenerate/recover, leading to acute kidney failure, which can be seen within 24-72 hours. Clinical signs of oliguria or anuria are diagnostic of acute kidney failure.
	Initial treatment for raisin/grape ingestion is as described for the patient. Decontamination and aggressive fluid therapy are main stay treatments to prevent acute renal failure in dogs. Decontamination includes inducing emesis and administering activated charcoal, to eliminate the toxins from the body and bind toxins, respectively.1,2,3 The actual benefit of giving activated charcoal is unknown due to the lack of understanding of the etiology of this toxicity; however, the potential benefit outweighs the inherent risks of the therapy. Due to this, multiple doses of activated charcoal are not indicated at this time.2  Gastrointestinal protectants and/or antiemetics, such as Cerenia and pantoprazole, are important in decreasing nausea (from induction of emesis and the administration of activated charcoal) and gastrointestinal irritation from dietary indiscretion, and preventing aspiration pneumonia. Sorbitol is often administered with activated charcoal, which acts as a cathartic.2
	An aggressive rate of intravenous fluid therapy is essential in maintaining glomerular filtration rate (GFR), and preventing injury to the kidneys. As the diagnosis of acute kidney injury (AKI) relies on a small increase in creatinine compared to baseline value, it is recommended to obtain baseline laboratory values prior to initiating treatment.2
	Should initial supportive care fail to curtail the development of AKI, other medical interventions have been recommended in the past; however, these options are now considered either controversial or are currently not recommended. Furosemide, mannitol, and fenoldopam have excellent diuretic properties, but they have provided no change in renal function and no change in the clinical course.2,4 A low-dose dopamine was previously recommended in acute renal failure, however, this medication is no longer recommended as a treatment option because it has no effect on the outcome of the clinical disease.5
	Hemodialysis and peritoneal dialysis would be recommended for patients that develop azotemia in the face of aggressive supportive care.2,3 There is no strict consensus as to what triggers the initiation of hemodialysis, and this relies on the overall patient’s clinical state as well as discussion with owners, given the invasive and expensive nature of treatment. Hemodialysis is a method of treatment that removes uremic toxins, and possible nephrotoxicants, and corrects electrolyte, hydrogen ion, and fluid imbalances via a diffusion across a semipermeable membrane that takes place during extracorporeal circulation of the patient’s blood through a hemodialyzer. One of the limitation of this therapy is its limited availability throughout the country. 2,3 
	A secondary option, is peritoneal dialysis, which has a similar mechanism compared to hemodialysis. A dialysate is infused into the abdomen of the patient, whereby the peritoneum serves as a filter within the body cavity of the dog. The dialysate absorbs waste and fluid from the blood, and is then removed from the body.1,2,3 This method is less efficient and has a potentially higher complication rate than hemodialysis.7 
	Dogs with any ingestion of foreign material should be monitored for complications such as pancreatitis.2 Pancreatitis is inflammation of the pancreas. Common causes reported include dietary indiscretion, hyperlipidemia, drugs, toxins, hypercalcemia, duct obstruction, duodenal/biliary reflux, trauma, ischemia/reperfusion, and idiopathic. In general, dogs present with anorexia, depression, abdominal pain, and vomiting. Dogs with more severe forms of acute pancreatitis can have signs of hypovolemia and shock, including tachycardia, tachypnea,  prolonged capillary refill time, and dry mucous membranes.6
	Diagnosis of pancreatitis in dogs and cats is challenging. Laboratory abnormalities can suggest evidence of inflammation, but are not specific for pancreatitis. Hence, changes conducive with hypovolemia and inflammation, are common. Our patient developed a low albumin, which could be secondary to negative acute phase protein in the phase of inflammation. Pancreatic specific enzymes such as lipase and amylase are sometimes elevated in relation to inflammation; however, they originate from the gastrointestinal mucosa, are excreted by the kidneys and are affected by azotemia. They also can be within reference range even in the face of pancreatitis.6
	Canine trypsin-like immunoreactivity (cTLI) is a specific indicator of pancreatic function, but rapidly decreases, and will most likely be normal by the time a sample is collected in the patient. Canine pancreatic lipase immunoreactivity (cPLI) is the most specific blood test to help diagnose pancreatitis.6 It measures only pancreatic lipase, and increases solely in response to pancreatic inflammation. Additionally, abdominal ultrasound may contribute to the diagnosis of pancreatitis. Common findings on abdominal ultrasound include changes in pancreatic echogenicity, with enlarged, hypoechoic pancreas with hyperechoic surrounding mesentery. Peritoneal fluid may or may not been seen as well. Focal lesions on the pancreas may or may not also be presented. Radiographs commonly demonstrate a lack of detail in the cranial abdomen, and may or may not include a widened pyloric-duodenal angle and shift in the descending duodenum toward the body wall. Ultrasound is highly user dependent and experienced radiologists are more likely to recognize subtle changes within the pancreas.6 Radiographs are not sensitive, and are often used to rule out a foreign body due to similar clinical signs.6
	Treatment of pancreatitis is mainly supportive therapy, and can be very extensive in the case of acute necrotizing pancreatitis. The four main therapies are analgesia, nutrition, fluids, and gastro-intestinal medication. Abdominal pain is commonly associated with pancreatitis, and providing analgesia is very beneficial for patient comfort. Nutrition is important in maintaining sufficient luminal nutrients to the gastrointestinal tract and prevent bacterial translocation. Antiemetics and gastrointestinal protectants are also vital to decrease nausea, to increase likelihood that the patient will continue to eat on their own, while also decreasing chances of gastric ulcers. Lastly, fluids have been shown to prevent progression of mild pancreatitis to severe necrotizing pancreatitis by maintaining adequate circulation to the pancreas, and decreasing vascular permeability.6 If pancreatitis does progress, systemic complications should be treated in addition to the main treatments described.
	The severity of pancreatitis directly effects the prognosis of pancreatitis. A mild pancreatitis has a good prognosis with proper treatment, whereas a severe necrotizing pancreatitis carries a guarded prognosis leading to a wide range of mortality rates (27-58%). A retrospective study found a survival rate of 63% in dogs that underwent surgical intervention; however, pancreatic abscessation leads a more guarded prognosis.8 The high mortality rate in severe necrotizing pancreatitis is due to the presence of systemic inflammatory response syndrome (SIRS), sepsis, and multiple organ dysfunction or failure.
	The mild pancreatitis experience by the patient in this case was a minor complication to raisin ingestion, that was successfully managed by intravenous fluids, pain control, and a low fat diet. Despite initial suspicion of kidney injury based on a lower USG, the patient responded well to initial decontamination, and continued fluid and gastrointestinal protective therapy. Throughout her hospitalization, the patient’s blood work did not show signs of acute kidney failure, and she discharged to the care of her owners.
	The patient returned to Cornell Critical Care Service one week later for re-evaluation and blood work. The owners reported that the patient was doing well at home, and was showing no clinical signs of renal failure or pancreatitis. On physical examination, no abnormalities were found. Blood was collected for a renal panel, which revealed a BUN 8 mg/dL (10-32 mg/dL), creatinine 0.5 mg/dL (0.6-1.4 mg/dL), calcium 9.1 mg/dL (9.3-11.4 mg/dL), and phosphate 3.7 mg/dL (2.9-5.2 mg/dL). This demonstrated that the patient’s kidneys continued to have no signs of failure, and she was again discharged to her owners in good health.





















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Stanley, Skye W., and Cathy E. Langston. “Hemodialysis in a Dog with Acute Renal Failure from Currant Toxicity.” The Canadian Veterinary Journal 49.1 (2008): 63–66.
Ho, K. M., and B. M. Power. "Benefits and Risks of Furosemide in Acute Kidney Injury." Anaesthesia 65.3 (2010): 283-93.
Bekes, C.e. "‘Low-dose’ Dopamine Worsens Renal Perfusion in Patients with Acute Renal Failure." Yearbook of Critical Care Medicine 2007 (2007): 239-40.
Mansfield, Caroline. "Acute Pancreatitis in Dogs: Advances in Understanding, Diagnostics, and Treatment." Topics in Companion Animal Medicine 27: (2012): 123-132.
Forster, Vincent, Rea Deborah Signorell, Maurizio Roveri, and Jean-Christophe Leroux. "Liposome-supported Peritoneal Dialysis for Detoxification of Drugs and Endogenous Metabolites." Science Translational Medicine. American Association for the Advancement of Science 6: (2014): 258-141.
Thompson, Lisa J., Ravi Seshadri, and Marc R. Raffe. "Characteristics and Outcomes in Surgical Management of Severe Acute Pancreatitis: 37 dogs (2001-2007)." Journal of Veterinary Emergency and Critical Care 19.2 (2009): 165-73.
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