State-of-the-art review
Journal of Veterinary Emergency and Critical Care 13(4) 2003, pp 201^213
Acute pancreatitis in dogs Jennifer L. Holm, DVM, Daniel L. Chan, DVM and Elizabeth A. Rozanski, DVM, DACVECC, DACVIM
Abstract Objective: To summarize current information regarding severity assessment, diagnostic imaging, and treatment of human and canine acute pancreatitis (AP). Human-based studies: In humans, scoring systems, advanced imaging methods, and serum markers are used to assess the severity of disease, which allows for optimization of patient management. The extent of pancreatic necrosis and the presence of infected pancreatic necrosis are the most important factors determining the development of multiple organ failure (MOF) and subsequent mortality. Considerable research efforts have focused on the development of inexpensive, easy, and reliable laboratory markers to assess disease severity as early as possible in the course of the disease. The use of prophylactic antibiotics, enteral nutrition, and surgery have been shown to be beneficial in certain patient populations. Veterinary-based studies: The majority of what is currently known about naturally occurring canine AP has been derived from retrospective evaluations. The identification and development of inexpensive and reliable detection kits of key laboratory markers in dogs with AP could dramatically improve our ability to prognosticate and identify patient populations likely to benefit from treatment interventions. Treatment remains largely supportive and future studies evaluating the efficacy of surgery, nutritional support and other treatment modalities are warranted. Data sources: Current human and veterinary literature. Conclusions: Pancreatitis can lead to a life-threatening severe systemic inflammatory condition, resulting in MOF and death in both humans and dogs. Given the similarities in the pathophysiology of AP in both humans and dogs, novel concepts used to assess severity and treat people with AP may be applicable to dogs. (J Vet Emerg Crit Care 2003; 13(4): 201–213)
Keywords: canine, diagnostic imaging, illness severity markers, scoring schemes, therapy
Introduction Acute pancreatitis (AP) is a mild, self-limiting disease in the majority of affected humans. However, 10–20% of human patients develop a more severe form of the disease characterized by sepsis and multiple organ failure (MOF), with mortality rates approaching 30%.1,2 In 1992, the International Symposium on Acute Pancreatitis proposed a consensus statement outlining From the Department of Clinical Sciences, Tufts University School of Veterinary Medicine, North Grafton, MA. Address correspondence and reprint requests to: Dr. Elizabeth A. Rozanski, Department of Clinical Sciences, Tufts University School of Veterinary Medicine, 200 Westboro Road, North Grafton, MA 01536. Fax: (508) 839-7922. E-mail: Elizabeth.rozanski@tufts.edu & Veterinary Emergency and Critical Care Society 2003
the criteria defining severe AP. Severe AP was defined as the development of systemic complications such as organ failure and/or local complications such as pancreatic necrosis, pseudocyst, or abscess.3 The extent of pancreatic necrosis and the presence of infected pancreatic necrosis are the most important factors determining the development of MOF and subsequent mortality.4,5 Considerable efforts have been directed toward early identification of patients at risk for developing severe AP. Several methods of severity determination have been developed in humans, and include clinical scoring systems, serum markers, and evaluation by contrast-enhanced computed tomography (CECT). The utility of objective criteria for patient stratification includes identification of subjects eligible for clinical trials and guides for treatment decisions, 201
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and enables monitoring of disease progression and response to treatment.5–11 AP is a common disease in dogs with reported mortality rates ranging from 27 to 42%, although most dogs that have mild disease recover within a few days.12,13 Although there are no studies evaluating the cause of death in dogs with AP, most dogs that develop systemic complications, such as respiratory distress, acute kidney failure, and disseminated intravascular coagulation, are considered to have a guarded to poor prognosis. An article reviewing the pathophysiology of systemic inflammatory response leading to MOF in dogs with AP has recently been published.14 Although pancreatic infection is rarely documented in dogs,15–21 the extent of pancreatic necrosis may be an important contributing prognostic factor of severity, similar to what has been shown in humans. A recent report documents histological evidence of acute pancreatic necrosis in 67/70 (96%) of dogs with fatal AP.22 The 2 most common causes of AP in humans are gallstones and alcohol abuse, together accounting for up to 80% of cases.23,24 Other less common causes include hyperlipidemia, hyperparathyroidism (or other causes of hypercalcemia), structural abnormalities, endoscopic retrograde cholangiopancreatography, drugs/ toxins, autoimmune, hereditary and idiopathic diseases, and trauma.24 The inciting cause in most cases of canine AP usually remains unidentified, but the above factors should be considered.12,25 Experimentally induced pancreatitis is more severe in dogs fed a high-fat diet as compared with a low-fat diet,26–28 but the exact mechanism by which hyperlipidemia causes pancreatitis is unknown. Despite etiological differences between human and canine AP, the pathophysiology of AP is similar. The initial event in AP is the intracellular activation of trypsinogen to trypsin, resulting in pancreatic cell destruction. Trypsin is also capable of activating all other pancreatic zymogens, causing further injury and autodigestion of the gland.29,30 Because of these similarities, novel concepts used in humans regarding severity assessment and therapy may be applicable to dogs.
Clinical scoring systems Several scoring systems for AP have been evaluated in humans. The Ranson score, first introduced in 1974, consists of 11 criteria that were identified to be prognostically significant when 43 clinical and laboratory variables were analyzed. Five of the criteria can be obtained at the time of initial diagnosis, while the remaining 6 criteria are evaluated in the ensuing 48 hours after the diagnosis of AP. Using this scoring 202
scheme, a patient is considered to have severe AP if there are 3 Ranson criteria met, and mortality approaches 100% beyond a score of 6.3,6 Subsequently, a modified Glasgow score was proposed as a simplified alternative to the Ranson score.31,32 Despite the elimination of several parameters, the Glasgow criteria have been shown to be as effective as the Ranson score in predicting the severity of AP.7 However, the reliance of these scoring systems on evolving laboratory parameters, obtained as late as 48 hours after the diagnosis, are considered major disadvantages of these schemes. The Acute Physiology and Chronic Health Evaluation (APACHE) II system is widely accepted as a reliable measure of illness severity in a variety of diseases and is currently the scoring scheme of choice for severity determination of AP in humans.1 Briefly, this score is the sum of points assigned for abnormal values of several clinical and laboratory parameters, age category, and pre-existing chronic health issues.33 It has several advantages over other scoring systems. First, it can be assessed at the time of admission and at 24-hour intervals. Patients with severe disease show increasing scores over 48 hours, whereas decreasing scores are correlated with mild disease. In short, the APACHE II score can be used to monitor disease progression and response to treatment. An APACHE II score of 8 is consistent with severe AP.3,7,8,34 Because obesity has been shown to be an independent risk factor for the prediction of severity in AP,35–37 an APACHE-O system has been proposed, which incorporates a score for obesity. Initial studies suggest that the APACHE-O score may be more predictive of severity than APACHE II for AP, but further studies are warranted.38,39 In the veterinary literature, Ruaux and Atwell40 proposed a severity score for spontaneous canine AP that was intended for use in general practice. Severity was assessed by relating pancreatic enzyme concentration to an organ score that was based on the number of extrapancreatic organs showing compromise. The organ score ranged from 0 to 4 and was based on laboratory values obtained at initial presentation. Table 1 defines the organ systems evaluated and the criteria used in determining the organ score. Dogs with scores of 3 or greater had a 50% mortality rate. This study suggested that the organ score was better for determining the severity of disease than pancreatic enzyme elevations.40 While this study did not consider cardiovascular or respiratory parameters, it supports the hypothesis and clinical observations that development of MOF in dogs with AP is a poor prognostic indicator.14 The limitations of this study make the results difficult to interpret. Diagnosis of AP was based on elevated & Veterinary Emergency and Critical Care Society 2003
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Table 1: Severity score based on organ system compromise in spontaneous canine APn
System
Criterion
Reference range 9
Lymphoid
410% band neutrophils or WBC 4 24 10 /L
Renal
BUN414 mmol/L or creatinine (39 mg/dL) Concentration 40.3 mmol/L (3.4 mg/dL) ALP, AST, or ALT 43 reference range
Hepatic
Acid/base bufferingw Endocrine pancreasw
Bicarbonate o13 or 426 mmol/L and/or anion gap o15 or 438 mmol/L Blood glucose 413 mmol/L and/or b-OH (232 mg/dL) Butyrate41 mmol/L
0.0–0.2 109/L band neutrophils 4.5–17.0 109/L WBC 2.5–9.5 mmol/L BUN (7–21 mg/dL) 0.06–0.18 mmol/L creatinine (0.7–2.0 mg/dL) 0–140 IU/L ALP 15–80 IU/L AST 15–80 IU/L ALT 15–24 mmol/L bicarbonate 17–35 mmol/L anion gap 3.3–6.8 mmol/L blood glucose (59–121 mg/dL) 0–0.6 mmol/L b-OH butyrate
Reproduced with permission from: Ruaux CG, Atwell RB. A severity score for spontaneous canine acute pancreatitis. Aust Vet J 1998; 76(12):804–808. If hyperglycemia, increased butyrate and acidosis coexist, count as one system. AP, acute pancreatitis; WBC, white blood cell count; BUN, blood urea nitrogen; ALP, alkaline phosphatase; AST, aspartate aminotransferase; ALT, alanine aminotransferase. n
w
amylase and/or lipase concentrations, and clinical signs consistent with AP (abdominal pain, vomiting, collapse, or lethargy). There was no medical imaging or histopathologic criteria considered for diagnosis. Also, the criteria used for determination of the organ score were not specific for or sensitive to organ failure as elevations in kidney enzymes, liver enzymes, and white blood cell count can be seen in many diseases without concurrent organ failure.40 Further studies are needed to validate this scoring system and its utility in canine AP. Risk factors that have been identified in a recent retrospective evaluation to be associated with fatal AP in dogs include obesity, diabetes mellitus, hyperadrenocorticism, hypothyroidism, prior gastrointestinal tract disease, and epilepsy.25 As such, consideration of these factors in a scoring system for AP in dogs might improve the assessment of severity. As the use of scoring systems is relatively new in veterinary medicine, further studies are warranted to determine their utility in AP. However, it is important to keep in mind that scoring systems are not necessarily intended to determine individual prognosis, but rather to stratify patients into categories based on severity of illness.33
Laboratory markers Elevations in the concentration of serum biochemical substances such as cytokines and proteins relatively specific to AP are considered potential markers of disease severity.11,41,42 Ideally, a severity marker should reliably parallel severity of disease, be relatively simple and inexpensive to perform, widely available, and most importantly, accurate within the first 48 hours of diagnosis.1 As the success of novel therapies for AP & Veterinary Emergency and Critical Care Society 2003
may hinge upon usage in particular patient populations, the identification and stratification of patients based on disease severity have become integral in clinical trial design.43,44 As such, considerable research emphasis has centered on the development of laboratory assays designed to assess disease severity before the occurrence of MOF.11,45–49 Greater understanding of the pathophysiology of MOF in AP has led to the identification of many possible candidates that can be used as severity markers. During the initial phase of AP, intracellular activation of trypsin causes pancreatic acinar cell destruction and subsequent activation of the complement system, leading to the production of potent chemokines such as C3a and C5a. In addition, pancreatic acinar cell damage leads to the release of several cytokines such as tumor necrosis factor alpha (TNF-a), interleukin-1 (IL-1), and platelet activating factor (PAF). This proinflammatory state causes neutrophil and macrophage migration to the area, which consequently leads to further release of TNF-a, IL-1, nitric oxide, and PAF into pancreatic tissue and serum. Trypsin then activates the other pancreatic enzymes, causing further pancreatic cell damage. Thus, local damage to pancreatic acinar cells induces a systemic inflammatory reaction typified by increased capillary permeability, fever, tachycardia, and hypotension, and ultimately leads to MOF.14,50 Currently, the most useful types of serum markers for AP have been divided into 2 categories: markers of trypsinogen activation and markers of inflammation.51,52 Markers of trypsinogen activation Typically, markers of trypsinogen activation have a rapid increase very early in the disease, peak within 1–2 days and then are rapidly degraded. These markers can 203
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be measured in serum and urine, and generally are more reliable than serum amylase for the diagnosis of AP.51,54,58 While the utility of markers of trypsinogen activation are questionable after 3–4 days after the onset of clinical signs, the rapid rise following the initiation of AP may prove to be the earliest indicators of severity.55
of elevated levels of trypsinogen activation. Its stability in serum and urine, in addition to its high specificity and sensitivity, enhances its potential use as a marker of severity in AP.62 While initial studies can attest to its specificity and sensitivity within the first 48–72 hours from the onset of clinical signs, further studies are warranted to confirm its use in earlier phases of AP.61,62
Trypsinogen activation peptide: Trypsinogen activation peptide (TAP) is produced when trypsinogen is cleaved to form the active protease, trypsin. Normally, TAP is produced in the small intestine, where trypsinogen is activated by the brush-border enzyme enterokinase. However, the initiation phase of AP is characterized by the inappropriate activation of trypsinogen within the gland, resulting in TAP release into the abdominal cavity, plasma, and urine.29,56 In experimental rodent models, TAP concentrations are elevated within 15 minutes after the induction of AP.30 The close relationship between the release of TAP and AP has prompted the evaluation of TAP as a diagnostic and prognostic tool in human AP. Several studies have shown that it is more sensitive and specific than amylase levels in the diagnosis of AP.45,46,53,54,57 In addition, a dipstick test for the detection of urinary trypsinogen has been shown to be a specific and accurate screening test, with a negative result ruling out AP with a high degree of certainty.58 Measurements of urinary TAP within 48 hours have also been shown to be significantly higher in patients with severe versus mild AP. In a recent multicenter study by Neoptolemos et al.,57 urinary TAP measurements provided accurate severity prediction 24 hours after symptom onset. Despite promising results, the detection kits available for serum and urine samples are costly and have not been widely used.59 Currently, there is a single veterinary study evaluating TAP concentrations in naturally occurring canine AP as compared with healthy dog and dogs with other systemic diseases.60 After validating the test for canine use, no significant differences in urinary TAP concentrations were detected between groups. While plasma TAP concentrations were significantly higher in the AP group when compared with the healthy dogs and dogs with other systemic diseases, no difference was detected between the AP group and dogs with renal disease. Dogs with severe and fatal AP, however, did have significantly higher concentrations of plasma TAP than dogs with mild disease.60 This study suggests that although plasma TAP may be a good prognostic indicator in AP, its utility as a diagnostic tool is limited by the failure to detect appreciable levels in dogs with mild pancreatitis. Another candidate for a marker of disease severity in human AP is carboxypeptidase B activation peptide (CAPAP). Several studies have identified its elevation in plasma and urine in people with AP.61–63 CAPAP is the largest activation peptide produced by the cleavage of any pancreatic proenzyme and is an indirect measure
Markers of inflammation C-reactive protein: C-reactive protein (CRP) is an acute-phase reactant produced by the liver in response to inflammation, infection, or tissue destruction. CRP synthesis is mediated by IL-1 and IL-6, which are hallmarks of systemic inflammation.11,47 The low cost and ease of performing CRP assays has led to widespread use.64,65 CRP is currently the gold standard serum marker for predicting severity in AP.1 The sensitivity and specificity of CRP in predicting pancreatic necrosis have also been reported to be greater than 80%.66,67 Extensive evaluation of CRP has resulted in a cutoff value of 150 mg/L as the standard differentiating mild versus severe AP. The major disadvantage is that elevations of CRP concentration are most reliably detected 48 hours after the onset of symptoms and may not reach prognostically useful cutoff values until 98 hours after the onset of clinical symptoms.1 CRP has been shown to be elevated in dogs with infection, trauma, inflammation, and experimentally induced AP.68–72 While there are no published studies evaluating CRP concentrations in dogs with naturally occurring AP, a recently published abstract supports the notion that CRP concentrations may have prognostic value as they were found to be significantly different between dogs with mild (interstitial) AP and dogs with severe pancreatic necrosis.a Further evaluation of CRP in dogs is warranted to clarify its potential use in prognosticating for AP.
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Cytokines: TNF-a, IL-6, and IL-8 have been shown to be consistently elevated in humans with systemic inflammatory conditions, including AP, and reliably reflect the severity of disease. Because these markers are found to be elevated very early (within 12–24 hours) in the course of the disease, they may prove to be among the best tests for early assessment of severity.11 Their routine use is limited by lack of easy and rapid testing methodology. However, clinical assays of these markers are currently being developed.41,42,47–49 TNF-a concentrations have been studied in 60 dogs with spontaneous AP.73 The dogs were grouped according to severity using the previously described scoring system based on laboratory samples taken at presentation.40 TNF activity was evaluated using bioassays, and total TNF protein levels were evaluated using a dot-blot immunoassay. TNF activity was elevated in the most severely affected dogs (score 4/4) in 4/6 dogs. However, total TNF protein levels were not significantly different among dogs with varying & Veterinary Emergency and Critical Care Society 2003
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degrees of AP, and between dogs with AP and controls. The lack of a detectable difference in total TNF protein between groups precludes its use in the assessment of AP. However, other factors, such as soluble TNF receptors, may help elucidate the role of TNF in the pathophysiology of spontaneous canine AP and potentially serve as a reliable marker of severity.73 Soluble TNF receptors have been shown to rise early in human patients with AP and may help predict severity in preliminary studies.42,74,75 As clinical assays are developed, critical evaluation of these markers (e.g. TNF-a, IL-6, IL-8, and soluble TNF receptors) is necessary to determine their potential role for prognosticating AP.
Diagnostic imaging CECT is currently the method of choice for the diagnosis, severity determination, and identification of complications of AP in humans.1 Diagnostic findings of CECT have a sensitivity and positive predictive value approaching 100% for detecting pancreatic necrosis between 4 and 10 days after the onset of symptoms.76 Severity is correlated with a CT severity index (CTSI). This scoring scheme incorporates a point system, accounting for morphologic characteristics of the pancreas and peripancreatic tissues along with the degree of necrosis. The degree of pancreatic necrosis is inferred by the lack of enhancement within the gland after contrast injection and is further classified into 3 categories: approximating 30%, between 30 and 50%, and encompassing greater than 50% of the gland. Morbidity and mortality are strongly correlated with increasing degrees of necrosis.9,76 In addition, definitions of local complications associated with AP such as acute fluid collection, necrosis, abscess, and pseudocyst include CT criteria.77 Another important use of CT includes guidance for fine-needle aspiration of necrotic areas to determine if infection is present.78 More recently, CT-guided percutaneous drainage of peripancreatic fluid has been evaluated as a possible alternative or a means to delay the need for surgery.79 Diagnostic imaging techniques commonly used for diagnosis of AP in dogs include abdominal radiographs and ultrasonography. Common radiographic findings reported in AP include loss of organ detail or increased granularity in the right cranial abdomen, loss of gastric symmetry by displacement of the pyloric antrum to the left, displacement of the duodenum to the right, and a thickening of the descending duodenal wall.80 However, radiographic findings supportive of AP are not always present and a recent study demonstrated that radiographic changes were only present in 24% of dogs with fatal AP.22 Abdominal ultrasound (AUS) is currently the most widely used technique for evaluation of the canine pancreas. The characteristic changes & Veterinary Emergency and Critical Care Society 2003
seen with AP include an enlarged, hypoechoic pancreas with a bright peripancreatic mesentery. These changes are produced by edema, hemorrhage, and necrosis of the gland.81–83 In addition, AUS is used to identify focal abnormalities consistent with areas of pancreatic necrosis, pseudocyst, and abscesses formation.15–18 Abdominal ultrasound was reported to have a 68% detection rate for fatal AP in dogs.22 While AUS remains the modality of choice for evaluation of the canine pancreas, poor visualization of the pancreas due to gas interference from the gastrointestinal tract can hamper proper diagnosis.84 Until recently, the only reported CT description of the canine pancreas was of normal dogs.85 Litzlbauer et al. 86 were the first to describe the CT appearance of 28 dogs with inflammatory, degenerative, or neoplastic diseases of the pancreas. The routine use of CT in veterinary patients is limited by low availability, high cost, high degree of expertise required for appropriate interpretation, and the need for anesthesia.87 However, despite these limitations, CT scans may one day prove to be more useful than AUS for evaluation of the canine pancreas, especially in severe or complicated cases. The potential use of CECT imaging in dogs with AP is illustrated in Figure 1. The utility of MRI pancreatography has also been evaluated in humans. While MRI certainly provides
Figure 1: Contrast-enhanced computed tomography image of a dog with severe acute pancreatitis. The pancreas is located medial to the duodenum (white arrowhead) and ventral to the portal vein (black arrowhead). Following intravenous injection of iodinated contrast material, perfused areas of the pancreatic parenchyma will exhibit enhancement compared with areas of diminished or no blood flow, which represent areas of pancreatic necrosis. The black arrow represents perfused areas of the pancreas, while the white arrow represents an area of necrosis.
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more detailed images of the pancreas, it was found to be comparable to CT in detecting the presence and extent of necrosis and fluid collections. Although CT is less expensive and more widely available, the possible advantages of MRI are the avoidance of repeated radiation doses and the contrast medium used may be safer and better tolerated.77,88 To date, there are no reports of MRI use in evaluating dogs with AP.
Therapy Treatment of AP in dogs remains largely supportive. Parenteral fluid and electrolyte replacement, analgesia, and nothing per os are the mainstays of therapy. Other therapeutic strategies such as supplemental nutritional support, fresh frozen plasma (FFP) administration, antibiotic therapy, peritoneal dialysis, and surgery have also been reported.89 Although certain aspects of AP therapy remain controversial, evidenced-based recommendations have been published to provide guidelines for the treatment of humans with varying degrees of AP.1,90 While patients with mild disease will not typically require any additional treatment beyond general support and parenteral fluid administration, several treatment modalities have been devised for the treatment of individuals with moderate to severe disease.91 Nutritional support The need for nutritional support is well documented in people with severe AP. In fact, nutritional support is one of the few treatment modalities definitively shown to improve outcome. Perhaps less clear is the route by which nutrition should be administered.92–95 Total parenteral nutrition (TPN) has been the standard of therapy for many years because it accomplished ‘pancreatic rest,’ a concept eluding to the reduction of pancreatic secretions, and thereby limiting peripancreatic release of digestive enzymes. Some studies also suggested that early oral feeding or nasogastric feeding may increase risk of pancreatic infection and worsening the disease.93 However, complications such as catheterrelated sepsis associated with TPN administration have been shown to increase morbidity.96 Additionally, the avoidance of enteral feedings has been correlated to increased gut permeability, bacterial translocation, and immunosuppression. The culmination of these detrimental effects has been associated with a greater risk for septic complications and adds significant expense.92–95 With the potential pitfalls of parenteral nutrition (PN), several randomized clinical trials have shown that enteral nutrition (EN) can be safely administered via nasojejunal feeding tubes in patients with AP with 206
no significant detrimental effects.97–99 Jejunal feeding was demonstrated not to increase pancreatic secretions, as nutrient delivery occurs in areas devoid of cholecystokinin (CCK)-releasing cells. The proposed advantages of EN include reduction of bacterial translocation, and thus, limiting septic complications by protecting intestinal mucosal integrity, improving immune function, and an overall decrease in cost and mortality.97–99 Two studies comparing EN and TPN demonstrated that patients receiving EN had significantly fewer total complications and were at a decreased risk of septic complications as compared with patients receiving TPN.97,99 Another study comparing the effect of EN versus TPN on the disease progression and the acutephase protein response demonstrated that disease severity scores and CRP levels decreased in the EN group.98 Because these studies involved small numbers of patients, large, multicenter, randomized studies are required for definitive conclusions; however, most sources agree that EN is preferable to TPN in the treatment of AP.100 The current recommendation is to begin a trial of EN delivered via a nasojejunal tube as early as possible in patients with moderate to severe AP. TPN is only to be initiated in patients who do not tolerate EN.1,90,91 The use of nutritional support in dogs with AP has been extensively reported.101–106 The most frequently cited complications of PN include metabolic disturbances such as hyperglycemia and mechanical issues related to technical aspects of administration. Catheterrelated sepsis is infrequently reported in studies evaluating PN support in dogs with various diseases.102,104,106 While there are reports of dogs with pancreatitis that developed catheter-related sepsis while receiving PN, the impact of this complication on outcome could not be determined.101 In the single veterinary study that specifically evaluated nutritional support in dogs with AP, no septic complications were identified.102 The use of jejunostomy feeding tubes has also been described and recommended in veterinary patients with AP.103,105 Mild complications such as focal cellulitis, tube dislodgement, and tube occlusion were reported in up to 34% of animals.105 Severe complications associated with breakdown of the surgical site were seen in only 3/47 (6%) of patients in the study by Crowe et al.,105 while Swann et al.103 found no such complication in a similar population of dogs. Although some of the dogs who received EN via jejunostomy tubes were diagnosed with AP,103,105 there are currently no studies specifically evaluating the utility and safety of jejunostomy tube feedings in dogs with AP. Furthermore, there are no studies comparing EN versus PN for dogs with AP. As jejunostomy feeding tube placement is only indicated in patients who require & Veterinary Emergency and Critical Care Society 2003
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surgical laparotomy,105,107 this may be reflective of a more severely afflicted population, precluding comparisons with medically managed AP. While not exclusively evaluating patients with pancreatitis, Chan et al.106 documented that animals receiving supplemental EN survived more often than animals who received PN alone. Until studies evaluating the efficacy of EN and PN use in dogs with AP conclusively show a benefit of one technique versus another, the optimal mode of nutritional support remains speculative. Advancements in nonsurgical placement of jejunal feeding tubes hold much promise for future nutritional support options in patients with AP.108 Current recommendations include the use of PN in dogs with severe AP, with particular consideration for the placement of jejunostomy tubes in patients requiring surgical intervention.105 Surgical intervention Clear indications for surgical intervention in humans with AP include pancreatic infection (infected necrosis or pancreatic abscess), persistent biliary pancreatitis, and cases in which the diagnosis is in question.1,90 Considerable controversy exists regarding the decision to explore patients with sterile pancreatic necrosis surgically.1 The theoretical benefit of necrosectomy arises from the fact that pancreatic parenchymal and/or extrapancreatic necrosis are one of the major predictors of MOF development.1,4 In addition, infection of pancreatic necrosis is more likely to occur in patients with necrosis of more than 50% of the pancreas.78,109 Because infection of pancreatic necrosis is also one of the major determinants of MOF in humans,4 some authors believe that surgery should be strongly considered in patients with 450% pancreatic necrosis.90,110 However, most studies show no benefit to surgery in cases of sterile necrosis,111–114 and there is recent evidence that prophylactic antibiotic administration in patients with CECT-documented pancreatic necrosis demonstrates improved outcomes and allows for conservative management.112,115–117 Despite this, surgery should be considered in certain patient populations with sterile pancreatic necrosis.1 Patient populations identified to potentially benefit from surgical intervention include those patients with rapid progression of MOF and patients who fail to respond to maximal intensive care.1,90,111 Surgical treatment of AP has also been reported in dogs.15,16 Edwards et al.16 describe 7 dogs with necrotic, inflammatory pancreatic masses. Six of the 7 dogs were treated surgically and died within 9 days postoperatively. The remaining dog was treated medically and survived. Salisbury et al.15 describe 6 dogs with pancreatic abscess diagnosed by exploratory celiotomy. Two dogs were euthanized at the time of diagnosis, and & Veterinary Emergency and Critical Care Society 2003
3/4 dogs that had surgical treatment survived to discharge. Clinical deterioration despite medical management prompted surgical intervention in these cases.15,16 Direct comparison between these studies is confounded by differing terminology, diagnostic testing, surgical procedures, and post-operative management. In addition, these case series only included a small number of dogs, precluding definitive conclusions. In the absence of a large and conclusive study evaluating the utility and efficacy of surgical intervention in dogs with AP, the current recommended indications for surgery in AP include documented infection, failure to respond favorably to medical management, and cases where diagnostic confirmation is essential.15,16 Further studies are warranted to identify more objective criteria for surgical intervention in dogs as the decision to intervene solely based on failure to respond to medical treatment is fraught with subjective impression. Antiprotease therapy The initiating phase of AP involves the inappropriate activation of trypsin and other proteolytic enzymes within the pancreatic acinar cell, resulting in cellular injury. Once acinar cell damage occurs, there is systemic release of activated proteolytic enzymes.50 Endogenous antiproteases serve to defend host tissue against damage by local and systemic release of activated protease enzymes by the pancreas. These include a-macroglobulins and a-antitrypsins, which are found in plasma. a-Macroglobulin undergoes a conformational change that allows it to bind 2 free trypsin molecules and the resulting complex is cleared from circulation within minutes to hours. As free activated proteolytic enzyme molecules are neutralized by scavenging antiproteases, there is a depletion of these endogenous cellular defenses.118 a-macroglobulin is the most studied antiprotease, and its concentration has been demonstrated to be markedly decreased in humans with severe AP.119 Antiprotease concentrations are shown to be decreased in dogs with both naturally occurring and experimental AP.120,121 Thus, it has been hypothesized that replenishment of depleted antiprotease concentrations may serve to bind activated proteolytic enzymes and enhance their clearance from systemic circulation. While there were some preliminary studies suggesting that antiprotease supplementation may be beneficial in the treatment of AP in some patients,122–124 subsequent studies have failed to substantiate these earlier findings.125,126 Aprotinin and gabexate mesilate, both protease inhibitors, have not been found to improve outcome in double-blinded, randomized clinical trials.1,31,127 fresh frozen plasma (FFP) transfusions, 207
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intended to replace antiproteases, have also failed to improve outcome in randomized clinical trials.125,126 The possible explanation for failure of antiprotease therapy is that the systemic inflammatory response related to AP is primarily mediated by cytokine release rather than systemic proteolytic enzyme release. While the release of activated proteolytic enzymes may be important in the initiating event of AP, it is the systemic inflammatory response that ensues which is believed to lead to MOF.50,118 Based on the results of several clinical trials, antiprotease therapy is currently not recommended for the treatment of AP in humans.1,90 To date, there are no clinical trials with antiprotease therapy in dogs. Without clear evidence that replenishment of antiproteases via FFP administration is beneficial in dogs with AP, recommendations for FFP use in dogs with AP should be limited to cases in which there is documented coagulopathy.85
Antibiotic therapy Infection of pancreatic necrosis is the primary determinant of mortality in severe AP in humans.4,78 In light of this, prophylactic antibiotic treatment of patients with pancreatic necrosis has been the focus of several studies. Recently, 2 meta-analyses documented a reduction in incidence of infected pancreatic necrosis and mortality of patients treated with antibiotics.116,117 Appropriate choice of antibiotic therapy is based on drug activity against bacteria known to cause pancreatic infection and the ability of the drug to penetrate the pancreas. Pancreatic infections are most commonly caused by gram-negative enteric pathogens and are believed to be secondary to bacterial translocation.1,78 In humans, antibiotics such as clindamycin, fluoroquinolones, imipenem, and metronidazole are deemed to have good penetration into the pancreas.90,115,128 Patients with documented pancreatic necrosis should be treated with prophylactic antibiotics for 2 weeks.1,78,90 While prophylactic antibiotic therapy has been shown to decrease the overall rate of gram-negative bacterial infections, there are recent reports of other microorganisms causing pancreatic infection despite prophylactic antibiotics.78,112 The isolation of methicillin-resistant Staphylococcus aureus and Candida spp. in these cases may represent a shift in the spectrum of microorganisms involved in infections of necrotic pancreas.91 In contrast to what has been demonstrated in humans with AP, pancreatic infection has only been rarely documented in dogs with naturally occurring AP.15–21 While reasons for this difference are unknown, there are several possible explanations. While there are many similarities in the pathogenesis of AP in dogs and humans,14,29,30,50 etiological differences12,23,24 could 208
account for the much lower rate of pancreatic infection in dogs. Another possibility is that the actual infection rate in dogs with AP may be higher than what has been reported because of failure to document infection of the pancreas. Possible factors that could interfere with the successful culture of microorganisms include concurrent antibiotic administration15 and poor culture handling techniques. Additionally, attempts to culture pancreatic samples are generally limited to dogs undergoing surgical intervention for AP15,16 and to dogs in which a cystic or mass lesion is identified via AUS.17–21 As fine-needle aspiration of the pancreas is not routinely performed in dogs with severe AP, this can further contribute to the under-diagnosis of pancreatic infection. Given the lack of evidence that pancreatic infection plays a major role in the pathogenesis of canine AP, the routine use of prophylactic antibiotics in canine AP cannot be recommended. However, in dogs with documented pancreatic infection and in protracted cases of AP failing to respond to supportive measures, antibiotic use is justified.15,16 Experimental studies have shown that clindamycin, metronidazole, chloramphenicol, and ciprofloxacin achieve therapeutic tissue levels in canine models of AP.129,130 Peritoneal lavage Theoretical benefits of peritoneal lavage for the treatment of AP include the removal of harmful substances released into the peritoneal cavity such as trypsin and kinins. Peritoneal lavage has been evaluated as a therapeutic modality in humans with AP in several clinical trials with varying results.131–133 A recent metaanalysis of 8 prospective, randomized clinical trials evaluating the use of continuous peritoneal lavage found no significant improvement in morbidity and mortality in patients with AP.134 Given the lack of efficacy of this treatment, the procedure is no longer recommended for use in humans with AP.91 The use of peritoneal lavage or dialysis as an adjunct therapy for naturally occurring canine AP may have been based on positive results in an experimental study of canine AP.135 This early study documented a significant improvement in survival with peritoneal dialysis (PD) in dogs with AP. However, to date there are no studies specifically evaluating the use of PD as a therapy for dogs with naturally occurring AP. Until controlled clinical studies are performed in dogs, the potential benefit of PD therapy remains unknown for dogs with AP. Given the potential risks (e.g. peritonitis, hypoalbuminemia, hypovolemia), increased costs, and increased level of intensive care associated with PD,136 the utility of this procedure for AP must be carefully considered. & Veterinary Emergency and Critical Care Society 2003
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Novel approaches As the intricacies of pathogenesis of AP are further unraveled, new therapies are considered. The considerable healthcare costs associated with AP in humans have prompted researchers to develop and test numerous novel approaches targeting key events in the pathogenesis of AP. Unfortunately, most of these novel approaches have resulted in disappointing results. Therapies aimed at minimizing pancreatic secretion (e.g. glucagon, somatastatin, octreotide) have shown no benefit in large, randomized clinical trials after encouraging preliminary data.1,43,90 More recently, specific cytokine blockade has been extensively investigated in a variety of diseases, including experimental and naturally occurring AP.137 Of the most promising, the PAF antagonist, lexipafant, showed a significant reduction in mortality in patients treated.138 However, a subsequent larger study could not confirm any significant benefit of this approach, resulting in the discontinuation of further evaluation.139 Nevertheless, continued efforts and new breakthroughs may yet show cytokine blockade to be beneficial in certain patient populations.
Conclusions The recognition that canine AP has serious sequelae (e.g. systemic inflammatory response syndrome, multiple organ dysfunction, death), which may parallel the clinical course in humans, has prompted investigators to seek and evaluate new prognostic markers and treatment modalities for possible use in dogs.a,14,73,102–106,121 A key development in human clinical trial design has been the identification and stratification of different patient populations undergoing treatment in order to determine those individuals most likely to benefit from specific therapies. To this end, scoring schemes that are indispensable in determining disease severity in humans have been proposed for use in dogs.40 However, until there is validation of a scoring system for AP in dogs as well as a consensus statement clearly defining severe AP, future studies of canine AP may be limited. The identification and development of inexpensive and reliable detection kits of key laboratory markers in dogs with AP could dramatically improve our ability to prognosticate and identify patient populations likely to benefit from treatment interventions. Evaluations of one such marker, i.e., CRP in dogs with AP, are currently underway and may prove useful in our understanding of canine AP. Advances in diagnostic imaging modalities are also likely to aid in the assessment of canine AP. As ultrasonographic, CT, and MRI capabilities become more widely used and our & Veterinary Emergency and Critical Care Society 2003
ability to correlate abnormalities detected with specific pathological changes improve, diagnostic imaging may play a greater role in the management of AP in dogs. Studies evaluating the efficacy and feasibility of therapeutic modalities such as enteral nutritional support, surgical intervention, and specific cytokine blockade are also warranted. Despite disappointing results with some of these therapies in humans with AP, future studies may identify possible applications of these therapies in dogs with AP. While there are many similarities between human and canine AP, there may be important differences in the pathophysiology that could result in new breakthroughs in the management of canine AP.
Footnotes a
Spillmann T, Korrell J, Wittker A, et al. Serum canine pancreatic elastase and canine C-reactive protein for the diagnosis and prognosis of acute pancreatitis in dogs. J Vet Intern Med 2002; 16(5):635.
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