Acute pancreatitis accounts for more than 220,000 hospital admissions in the United States annually.1 In the following review, we outline the etiology of acute pancreatitis, discuss its complications, and provide an updated review on its management for the hospitalized patient.

Etiology

Gallstone disease and excess alcohol ingestion are the most common causes of acute pancreatitis in the United States. Gallstones account for roughly 45% of all cases, and the pathogenesis is due to transient obstruction of the pancreatic duct orifice to the flow of pancreatic exocrine secretions.2 Excess alcohol ingestion accounts for approximately 35% of all cases, yet the pathogenesis here is less understood.3 Most theories suggest a direct toxic effect of the ethanol upon the pancreatic parenchyma or its neurovascular supply.4

There are many other less common causes of acute pancreatitis including toxins, drugs, infections, trauma, vascular insults, anatomic abnormalities, and metabolic derangements. Hypertriglyceridemia and hypercalcemia are both implicated in acute pancreatitis. Serum triglyceride levels >1000 mg/dL can precipitate an attack of acute pancreatitis though the pathogenesis is not clearly understood.5 Hypercalcemia is also an uncommon cause of acute pancreatitis, and is thought to result from deposition of calcium in the pancreatic duct and calcium activation of trypsinogen.6

Idiopathic pancreatitis occurs in up to 20% of patients with acute pancreatitis, and by definition, the cause is not established by history, physical examination, routine laboratory tests, or imaging. The majority of idiopathic cases of pancreatitis are thought to have a biliary source. In patients with gallbladder in situ, it is estimated that up to 75% acquire pancreatitis from microlithiasis, or biliary sludge and stone debris, that causes obstruction of the distal common bile and main pancreatic ducts. Conversely, sphincter of Oddi dysfunction (SOD) resulting in transient pancreatic ductal obstruction is felt to be the most common cause in those patients who have undergone a previous cholecystectomy.7

An emerging entity, autoimmune pancreatitis (AIP), is more commonly associated with chronic pancreatitis but may cause episodes of acute pancreatitis or mimic pancreatic carcinoma. Typically, the diagnosis is based on elevated levels of serum gammaglobulin subgroup 4 (IgG4) populations, along with characteristic findings on computed tomography (CT) scan (eg, narrowed or wispy main pancreatic duct and an enlarged pancreatic parenchyma). Core‐needle biopsy may confirm the diagnosis of AIP with lymphoplasmacytic infiltration and dense fibrosis.8 Since AIP can mimic pancreatic cancer, the diagnosis may not be made until the time of surgical resection.

Diagnosis

Along with characteristic symptoms, the diagnosis of acute pancreatitis is often based on elevated serum levels of pancreatic enzymes that are at least twice the normal level. Amylase and lipase are the most frequently used serum markers for acute pancreatitis, though their elevation is not pathognomonic for the presence of disease. These enzymes may not always be significantly elevated during times of acute inflammation, and elevation of the enzymes can come from nonpancreatic origins as well (Table 1). Although there is no gold standard for the diagnosis of acute pancreatitis, using serum lipase (>250 IU/L) in conjunction with amylase (>160 IU/L) improves the overall diagnostic sensitivity from 81% to 94%.9 Isoamylase levels can be used to distinguish among pancreatic, salivary, and macroamylasemia though this is not often used if pancreatitis is suspected clinically. Similarly, serum isolipase can be measured, though this is not readily available.

In order to improve the sensitivity and specificity of diagnosis, other tests have been studied to help predict disease presence and severity. Previously, serum tests for trypsin, elastase, phospholipase A2, and carboxylester lipase have all been evaluated but shown to have no significant improvement in diagnostic capability.1014 More recently, trypsinogen (a pancreatic proteinase) has proven to be a useful aid in the accurate diagnosis of acute disease. Trypsinogen undergoes activation into trypsin during acute pancreatic inflammation.3 It is comprised of 2 main isoenzymes (trypsinogen‐1 and trypsinogen‐2) that are secreted into the pancreatic fluid with a small proportion escaping into the circulation.15 Higher concentrations of trypsinogen‐1 are seen in healthy people, while higher concentrations of trypsinogen‐2 are seen in those with acute pancreatitis.16 Urinary trypsinogen‐2 dipstick tests detect acute pancreatitis more accurately than quantitative serum or urinary amylase, with a sensitivity as high as 94%, and a specificity of 95%.17 Studies have shown that in post‐endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis, serum trypsinogen‐2 levels begin to rise as early as 1 hour and peak at 6 hours.17 The Actim Pancreatitis (Medix Biomedica, Kauniainen, Finland) urine test strips measure concentrations of trypsinogen‐2 as low as 50 g/L, but is not a quantitative test and, thus, it does not predict severity. Some studies have advocated the use of urinary trypsinogen‐2 as a screening tool, with a positive result indicating a need for further evaluation of acute pancreatitis.1820 Urinary trypsinogen‐2 is less costly than serum tests, plus may result in additional cost savings with earlier patient discharge. Unfortunately, this test is not widely available for clinical use. Urinary trypsinogen activation peptide (TAP) is another test that has been studied in the diagnosis of acute pancreatitis, but may signify disease severity rather than the presence or absence of disease.21 Currently urinary assays for TAP are not widely available in the United States.

Choosing the Appropriate Imaging Modality

Along with the measurement of pancreatic release enzymes, abdominal imaging is often used, though not always necessary to confirm the diagnosis of acute pancreatitis. Imaging techniques such as CT, magnetic resonance imaging (MRI), and transabdominal ultrasonography may be used to rule out other causes of abdominal pain or elucidate the cause of the pancreatitis itself. Ultrasound may show pancreatic enlargement, diminished echogenicity, and possible adjacent fluid collections.22 In searching for evidence of gallstone pancreatitis, transabdominal ultrasound has a sensitivity of 67% and a specificity of 100%.23 However, it may be insensitive for detecting stones in the distal common bile duct near the ampulla due to acoustic interference from gas within the small bowel.24 Furthermore, ultrasound itself is operator‐dependent.

Contrast‐enhanced CT is the standard mode of imaging for diagnosing acute pancreatitis and provides superior imaging of the pancreas. Unfortunately it is more costly than ultrasound, involves radiation exposure, and requires intravenous contrast medium.25 Findings of acute pancreatitis frequently seen on CT include diffuse or segmental enlargement of the gland, irregular pancreatic contour, obliteration of peripancreatic fat planes, parenchymal heterogeneity, and ill‐defined fluid collections within the pancreas or in the lesser sac and pararenal spaces.26 CT scan may also be used to detect pancreatic necrosis, an important finding for the management and prognosis of this disease.27 Despite this, normal CT findings have been reported in patients with acute pancreatitis, and certain CT findings may be related to disease severity.25

Although MRI is less commonly used in the diagnosis of acute pancreatitis, it may provide a useful alternative to CT, especially in cases of renal failure or intravenous contrast hypersensitivity. When combined with magnetic resonance cholangiopancreatography (MRCP) imaging, MRI may even be able to detect a local area of pancreatic duct disruption.27 MRCP allows for a noninvasive cholangiogram and is frequently used to stratify patients who may benefit from ERCP. It can accurately identify common bile duct stones, with a higher sensitivity for choledocholithiasis than ultrasound or CT.2830 MRCP can also assist in the diagnosis of other disorders of the intrahepatic and extrahepatic biliary tree that may be related to the cause of pancreatitis. Overall, unless a patient has a contraindication, or the goal of the study is to diagnose choledocholithiasis, a contrast‐enhanced CT scan remains the imaging procedure of choice due to improved accessibility, lower cost, ease of performance, and increased sensitivity in the detection of gas bubbles (potentially indicating pancreatic infection).3133 Ordering a CT scan or other imaging at admission is not necessary in the diagnosis of acute pancreatitis if the patient's presentation is classic. At admission, however, a CT scan may be reasonable to exclude other serious causes of abdominal pain, such as a perforated ulcer. Imaging may also be ordered to define the cause of the episode of pancreatitis and to exclude occult malignancy. In addition, CT scan should be strongly considered in patients who do not improve within 2 to 3 days to assess for complications such as pancreatic necrosis, pseudocysts, or other complications.34

Most recently, endoscopic ultrasound (EUS) has risen to the forefront as a leader in accurate imaging of the pancreas and biliary tree. EUS is more sensitive than transabdominal ultrasound in detecting biliary stones,35 and it has been shown to have equivalent, and in some cases superior, sensitivity to ERCP and MRCP. Because EUS is able to detect smaller stones or sludge, it may have a role in those patients diagnosed with idiopathic pancreatitis.36 Like MRCP, EUS can also help stratify patients into those that are likely to benefit most from ERCP.37 Figure 1 reviews the evaluation of acute pancreatitis.

Figure 1

Prognosis

For the majority of patients with acute pancreatitis, the clinical course is mild and self‐limiting. In approximately 20% to 25% of patients, however, it is severe and associated with organ failure and significant morbidity and mortality.38, 39 Determining the severity of acute pancreatitis is critical, as patients at high‐risk for severe disease require closer monitoring and possible intervention. Several validated scoring systems are available that aim to predict the severity of acute pancreatitis including Ranson's criteria, the Imrie scoring system, the Acute Physiology and Chronic Health Evaluation (APACHE II) scale, and the CT Severity Index (CTSI) (Table 2).4043

In 1992, the Atlanta Classification of acute pancreatitis was developed to provide a rational approach in predicting disease severity, thus allowing for comparison between clinical trials. It defines severe acute pancreatitis (SAP) on the basis of standard clinical manifestations, a Ranson's score 3, an APACHE II score 8, and evidence of organ failure and intrapancreatic pathological findings.44 Serum markers such as C‐reactive protein (CRP), interleukin‐6, and phospholipase A2 have all been studied to predict severity; however, only CRP is widely available. A cutoff level of 150 mg/L at 48 hours distinguishes mild disease from SAP.45 Clinical findings such as thirst, poor urine output, progressive tachycardia, tachypnea, hypoxemia, confusion, and a lack of improvement in symptoms within the first 48 hours are warning signs of impending severe disease, and thus warrant consideration of admission to an intensive care unit (ICU).34

Natural History and Complications

Despite initial aggressive intensive care treatment, 30% to 50% of patients with SAP do not respond promptly to ICU treatment and develop persistent multisystem organ failure.39 Severe organ failure in the first week of onset of acute pancreatitis is closely linked to the development of pancreatic infection occurring within 2 weeks of the initiation of symptoms.46 Early multiorgan dysfunction triggers additional mechanisms that render bacterial translocation into clinically manifested sepsis and septic shock.39 In most studied series, infection (including bacteremia, fungemia, and pancreatic abscess) remains the leading cause of death in patients with acute pancreatitis, accounting for up to 80% of fatal cases.4749 While sepsis is the more frequent cause of death in patients surviving beyond 7 days, death occurring early in the course of disease is more likely to be from respiratory complications such as pulmonary edema.50

In the spectrum of acute pancreatitis, ongoing pancreatic injury can lead to pancreatic necrosis, fluid collections, pseudocyst formation, and pancreatic duct disruption (Figures 24).51 In patients hospitalized with acute pancreatitis, up to 57% will have peripancreatic fluid collections that are initially ill‐defined.44, 52 Typically, these fluid collections may be managed conservatively; however, if they continue to enlarge, cause persistent abdominal pain, become infected, or compress adjacent organs, they may require further intervention.53 Ductal disruption may be diagnosed when fluid collections have high levels of pancreatic amylase, and their presence may lead to the formation of pseudocysts, persistent ascites, or pleural effusions.54 Pancreatic pseudocysts usually require 4 weeks for complete formation, and they classically contain fluid only without significant solid debris.55 Formation typically occurs as a result of limited pancreatic necrosis causing a pancreatic duct leak with subsequent organization, or from areas of necrosis that liquefy over time.56 Both pancreatic pseudocysts and necrotic pancreatic tissue may become infected leading to abscess formation.51

Figure 2

Figure 3

Figure 4

Pancreatic necrosis is defined as diffuse or focal areas of nonviable pancreatic parenchyma, and it is seen in approximately 20% of patients with acute pancreatitis.44, 57 While pseudocyst formation takes approximately 1 month to occur, pancreatic necrosis can occur within the first few days of initial symptoms and is associated with an increase in complications leading to an increased risk of morbidity and mortality.58 More than 80% of deaths in acute pancreatitis are associated with the presence of pancreatic necrosis.39 Patients at highest risk for complications are those with necrosis involving more than 50% of the gland based on MRI or contrast‐enhanced CT scan.59, 60

Patients with pancreatic infection may have infected necrosis, pancreatic abscess, and/or infected pseudocysts.39 The microbes most frequently involved are gram‐negative organisms including Escherichia coli, Enterococcus, and Klebsiella.61 Recently, gram‐positive bacteria have been implicated in pancreatic infection.62 Fungal infection with Candida species is seen in up to 15% of patients with infected necrosis and is associated with more serious systemic complications.63 The use of prophylactic antibiotics may increase the risk of fungal infection. It may be challenging to distinguish between infected and sterile pancreatic necrosis; hence, needle aspiration under EUS or radiologic guidance may be required.61, 64

Management

Management of Pancreatic Necrosis

Sterile pancreatic necrosis is typically managed conservatively without drainage. Generally, CT scans are repeated every 7 to 10 days to assess the necrosis and to evaluate for further complications.32 Patients who are clinically unstable with fever, tachycardia, leukocytosis, or organ failure may require percutaneous sampling to evaluate for infected necrosis.33 If the pancreatic tissue is sterile, the patient is determined to have sterile necrosis. If the patient with sterile necrosis is clinically unstable then prophylactic antibiotics may be indicated. If the pancreatic tissue is infected, the patient is deemed to have infected necrosis and treatment with antibiotics and necrosectomy is often indicated, especially in those with a poor clinical state. The antibiotic chosen should have adequate penetration into the necrotic material, such as imipenem, meropenem, or a combination of quinolone and metronidazole.99

It may be challenging to distinguish between sterile and infected pancreatic necrosis. A CT scan is unable to differentiate them with certainty; though, intrapancreatic, retroperitoneal, or lesser sac gas may indicate infection.31 In addition, inducing infection within a previously sterile collection is a potential risk of percutaneous sampling. As a result, sampling should not be performed unless completely indicated.31

In patients with sterile pancreatic necrosis who are symptomatic with refractory abdominal pain, gastric outlet obstruction, or failure to thrive at 4 or more weeks following the onset of acute pancreatitis, drainage and/or debridement is usually indicated. Pancreatic necrosectomy for sterile pancreatic necrosis may be accomplished endoscopically, or more traditionally by a surgical approach.55 Although endoscopic drainage is less invasive, it is technically difficult and has a higher rate of complication in the hands of inexperienced operators.100 Careful selection and evaluation of patients undergoing endoscopic drainage procedures is necessary. Bleeding, perforation, infection, pancreatitis, aspiration, stent migration, and pancreatic ductal damage are all possible complications during the drainage of necrotic pancreatic fluid collections.55 If pancreatic necrosis is infected, surgical necrosectomy should be performed as this is the gold standard for infected necrosis when debridement is necessary.55 Figure 5 reviews the management of acute pancreatitis.

Figure 5

Conclusion

Acute pancreatitis is a common disease frequently caused by choledocholithiasis or excess alcohol ingestion. In idiopathic acute pancreatitis, microlithiasis and SOD should be considered. Though CT scan remains the imaging modality of choice, newer methods such as MRCP and EUS may help to provide additional and improved diagnostic information.

The management of acute pancreatitis is frequently challenging, and severity scales help to predict the likelihood of complications, determine necessary interventions, and guide the appropriate level of care. Nutrition is critical in patients with SAP, and enteral feeding is clearly preferred over TPN. Currently, prophylactic antibiotics do not appear to have a role in SAP. Finally, though not always straightforward, recommendations do exist to guide the management of many of the complications of acute pancreatitis, such as pseudocyst formation and necrotizing disease. A multidisciplinary approach should be used in managing patients with severe disease, and the primary inpatient physician should not hesitate to involve specialists, including gastroenterologists, radiologists, and surgeons.

Acute pancreatitis accounts for more than 220,000 hospital admissions in the United States annually.1 In the following review, we outline the etiology of acute pancreatitis, discuss its complications, and provide an updated review on its management for the hospitalized patient.

Etiology

Gallstone disease and excess alcohol ingestion are the most common causes of acute pancreatitis in the United States. Gallstones account for roughly 45% of all cases, and the pathogenesis is due to transient obstruction of the pancreatic duct orifice to the flow of pancreatic exocrine secretions.2 Excess alcohol ingestion accounts for approximately 35% of all cases, yet the pathogenesis here is less understood.3 Most theories suggest a direct toxic effect of the ethanol upon the pancreatic parenchyma or its neurovascular supply.4

There are many other less common causes of acute pancreatitis including toxins, drugs, infections, trauma, vascular insults, anatomic abnormalities, and metabolic derangements. Hypertriglyceridemia and hypercalcemia are both implicated in acute pancreatitis. Serum triglyceride levels >1000 mg/dL can precipitate an attack of acute pancreatitis though the pathogenesis is not clearly understood.5 Hypercalcemia is also an uncommon cause of acute pancreatitis, and is thought to result from deposition of calcium in the pancreatic duct and calcium activation of trypsinogen.6

Idiopathic pancreatitis occurs in up to 20% of patients with acute pancreatitis, and by definition, the cause is not established by history, physical examination, routine laboratory tests, or imaging. The majority of idiopathic cases of pancreatitis are thought to have a biliary source. In patients with gallbladder in situ, it is estimated that up to 75% acquire pancreatitis from microlithiasis, or biliary sludge and stone debris, that causes obstruction of the distal common bile and main pancreatic ducts. Conversely, sphincter of Oddi dysfunction (SOD) resulting in transient pancreatic ductal obstruction is felt to be the most common cause in those patients who have undergone a previous cholecystectomy.7

An emerging entity, autoimmune pancreatitis (AIP), is more commonly associated with chronic pancreatitis but may cause episodes of acute pancreatitis or mimic pancreatic carcinoma. Typically, the diagnosis is based on elevated levels of serum gammaglobulin subgroup 4 (IgG4) populations, along with characteristic findings on computed tomography (CT) scan (eg, narrowed or wispy main pancreatic duct and an enlarged pancreatic parenchyma). Core‐needle biopsy may confirm the diagnosis of AIP with lymphoplasmacytic infiltration and dense fibrosis.8 Since AIP can mimic pancreatic cancer, the diagnosis may not be made until the time of surgical resection.

Diagnosis

Along with characteristic symptoms, the diagnosis of acute pancreatitis is often based on elevated serum levels of pancreatic enzymes that are at least twice the normal level. Amylase and lipase are the most frequently used serum markers for acute pancreatitis, though their elevation is not pathognomonic for the presence of disease. These enzymes may not always be significantly elevated during times of acute inflammation, and elevation of the enzymes can come from nonpancreatic origins as well (Table 1). Although there is no gold standard for the diagnosis of acute pancreatitis, using serum lipase (>250 IU/L) in conjunction with amylase (>160 IU/L) improves the overall diagnostic sensitivity from 81% to 94%.9 Isoamylase levels can be used to distinguish among pancreatic, salivary, and macroamylasemia though this is not often used if pancreatitis is suspected clinically. Similarly, serum isolipase can be measured, though this is not readily available.

In order to improve the sensitivity and specificity of diagnosis, other tests have been studied to help predict disease presence and severity. Previously, serum tests for trypsin, elastase, phospholipase A2, and carboxylester lipase have all been evaluated but shown to have no significant improvement in diagnostic capability.1014 More recently, trypsinogen (a pancreatic proteinase) has proven to be a useful aid in the accurate diagnosis of acute disease. Trypsinogen undergoes activation into trypsin during acute pancreatic inflammation.3 It is comprised of 2 main isoenzymes (trypsinogen‐1 and trypsinogen‐2) that are secreted into the pancreatic fluid with a small proportion escaping into the circulation.15 Higher concentrations of trypsinogen‐1 are seen in healthy people, while higher concentrations of trypsinogen‐2 are seen in those with acute pancreatitis.16 Urinary trypsinogen‐2 dipstick tests detect acute pancreatitis more accurately than quantitative serum or urinary amylase, with a sensitivity as high as 94%, and a specificity of 95%.17 Studies have shown that in post‐endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis, serum trypsinogen‐2 levels begin to rise as early as 1 hour and peak at 6 hours.17 The Actim Pancreatitis (Medix Biomedica, Kauniainen, Finland) urine test strips measure concentrations of trypsinogen‐2 as low as 50 g/L, but is not a quantitative test and, thus, it does not predict severity. Some studies have advocated the use of urinary trypsinogen‐2 as a screening tool, with a positive result indicating a need for further evaluation of acute pancreatitis.1820 Urinary trypsinogen‐2 is less costly than serum tests, plus may result in additional cost savings with earlier patient discharge. Unfortunately, this test is not widely available for clinical use. Urinary trypsinogen activation peptide (TAP) is another test that has been studied in the diagnosis of acute pancreatitis, but may signify disease severity rather than the presence or absence of disease.21 Currently urinary assays for TAP are not widely available in the United States.

Choosing the Appropriate Imaging Modality

Along with the measurement of pancreatic release enzymes, abdominal imaging is often used, though not always necessary to confirm the diagnosis of acute pancreatitis. Imaging techniques such as CT, magnetic resonance imaging (MRI), and transabdominal ultrasonography may be used to rule out other causes of abdominal pain or elucidate the cause of the pancreatitis itself. Ultrasound may show pancreatic enlargement, diminished echogenicity, and possible adjacent fluid collections.22 In searching for evidence of gallstone pancreatitis, transabdominal ultrasound has a sensitivity of 67% and a specificity of 100%.23 However, it may be insensitive for detecting stones in the distal common bile duct near the ampulla due to acoustic interference from gas within the small bowel.24 Furthermore, ultrasound itself is operator‐dependent.

Contrast‐enhanced CT is the standard mode of imaging for diagnosing acute pancreatitis and provides superior imaging of the pancreas. Unfortunately it is more costly than ultrasound, involves radiation exposure, and requires intravenous contrast medium.25 Findings of acute pancreatitis frequently seen on CT include diffuse or segmental enlargement of the gland, irregular pancreatic contour, obliteration of peripancreatic fat planes, parenchymal heterogeneity, and ill‐defined fluid collections within the pancreas or in the lesser sac and pararenal spaces.26 CT scan may also be used to detect pancreatic necrosis, an important finding for the management and prognosis of this disease.27 Despite this, normal CT findings have been reported in patients with acute pancreatitis, and certain CT findings may be related to disease severity.25

Although MRI is less commonly used in the diagnosis of acute pancreatitis, it may provide a useful alternative to CT, especially in cases of renal failure or intravenous contrast hypersensitivity. When combined with magnetic resonance cholangiopancreatography (MRCP) imaging, MRI may even be able to detect a local area of pancreatic duct disruption.27 MRCP allows for a noninvasive cholangiogram and is frequently used to stratify patients who may benefit from ERCP. It can accurately identify common bile duct stones, with a higher sensitivity for choledocholithiasis than ultrasound or CT.2830 MRCP can also assist in the diagnosis of other disorders of the intrahepatic and extrahepatic biliary tree that may be related to the cause of pancreatitis. Overall, unless a patient has a contraindication, or the goal of the study is to diagnose choledocholithiasis, a contrast‐enhanced CT scan remains the imaging procedure of choice due to improved accessibility, lower cost, ease of performance, and increased sensitivity in the detection of gas bubbles (potentially indicating pancreatic infection).3133 Ordering a CT scan or other imaging at admission is not necessary in the diagnosis of acute pancreatitis if the patient's presentation is classic. At admission, however, a CT scan may be reasonable to exclude other serious causes of abdominal pain, such as a perforated ulcer. Imaging may also be ordered to define the cause of the episode of pancreatitis and to exclude occult malignancy. In addition, CT scan should be strongly considered in patients who do not improve within 2 to 3 days to assess for complications such as pancreatic necrosis, pseudocysts, or other complications.34

Most recently, endoscopic ultrasound (EUS) has risen to the forefront as a leader in accurate imaging of the pancreas and biliary tree. EUS is more sensitive than transabdominal ultrasound in detecting biliary stones,35 and it has been shown to have equivalent, and in some cases superior, sensitivity to ERCP and MRCP. Because EUS is able to detect smaller stones or sludge, it may have a role in those patients diagnosed with idiopathic pancreatitis.36 Like MRCP, EUS can also help stratify patients into those that are likely to benefit most from ERCP.37 Figure 1 reviews the evaluation of acute pancreatitis.

Figure 1

Prognosis

For the majority of patients with acute pancreatitis, the clinical course is mild and self‐limiting. In approximately 20% to 25% of patients, however, it is severe and associated with organ failure and significant morbidity and mortality.38, 39 Determining the severity of acute pancreatitis is critical, as patients at high‐risk for severe disease require closer monitoring and possible intervention. Several validated scoring systems are available that aim to predict the severity of acute pancreatitis including Ranson's criteria, the Imrie scoring system, the Acute Physiology and Chronic Health Evaluation (APACHE II) scale, and the CT Severity Index (CTSI) (Table 2).4043

In 1992, the Atlanta Classification of acute pancreatitis was developed to provide a rational approach in predicting disease severity, thus allowing for comparison between clinical trials. It defines severe acute pancreatitis (SAP) on the basis of standard clinical manifestations, a Ranson's score 3, an APACHE II score 8, and evidence of organ failure and intrapancreatic pathological findings.44 Serum markers such as C‐reactive protein (CRP), interleukin‐6, and phospholipase A2 have all been studied to predict severity; however, only CRP is widely available. A cutoff level of 150 mg/L at 48 hours distinguishes mild disease from SAP.45 Clinical findings such as thirst, poor urine output, progressive tachycardia, tachypnea, hypoxemia, confusion, and a lack of improvement in symptoms within the first 48 hours are warning signs of impending severe disease, and thus warrant consideration of admission to an intensive care unit (ICU).34

Natural History and Complications

Despite initial aggressive intensive care treatment, 30% to 50% of patients with SAP do not respond promptly to ICU treatment and develop persistent multisystem organ failure.39 Severe organ failure in the first week of onset of acute pancreatitis is closely linked to the development of pancreatic infection occurring within 2 weeks of the initiation of symptoms.46 Early multiorgan dysfunction triggers additional mechanisms that render bacterial translocation into clinically manifested sepsis and septic shock.39 In most studied series, infection (including bacteremia, fungemia, and pancreatic abscess) remains the leading cause of death in patients with acute pancreatitis, accounting for up to 80% of fatal cases.4749 While sepsis is the more frequent cause of death in patients surviving beyond 7 days, death occurring early in the course of disease is more likely to be from respiratory complications such as pulmonary edema.50

In the spectrum of acute pancreatitis, ongoing pancreatic injury can lead to pancreatic necrosis, fluid collections, pseudocyst formation, and pancreatic duct disruption (Figures 24).51 In patients hospitalized with acute pancreatitis, up to 57% will have peripancreatic fluid collections that are initially ill‐defined.44, 52 Typically, these fluid collections may be managed conservatively; however, if they continue to enlarge, cause persistent abdominal pain, become infected, or compress adjacent organs, they may require further intervention.53 Ductal disruption may be diagnosed when fluid collections have high levels of pancreatic amylase, and their presence may lead to the formation of pseudocysts, persistent ascites, or pleural effusions.54 Pancreatic pseudocysts usually require 4 weeks for complete formation, and they classically contain fluid only without significant solid debris.55 Formation typically occurs as a result of limited pancreatic necrosis causing a pancreatic duct leak with subsequent organization, or from areas of necrosis that liquefy over time.56 Both pancreatic pseudocysts and necrotic pancreatic tissue may become infected leading to abscess formation.51

Figure 2

Figure 3

Figure 4

Pancreatic necrosis is defined as diffuse or focal areas of nonviable pancreatic parenchyma, and it is seen in approximately 20% of patients with acute pancreatitis.44, 57 While pseudocyst formation takes approximately 1 month to occur, pancreatic necrosis can occur within the first few days of initial symptoms and is associated with an increase in complications leading to an increased risk of morbidity and mortality.58 More than 80% of deaths in acute pancreatitis are associated with the presence of pancreatic necrosis.39 Patients at highest risk for complications are those with necrosis involving more than 50% of the gland based on MRI or contrast‐enhanced CT scan.59, 60

Patients with pancreatic infection may have infected necrosis, pancreatic abscess, and/or infected pseudocysts.39 The microbes most frequently involved are gram‐negative organisms including Escherichia coli, Enterococcus, and Klebsiella.61 Recently, gram‐positive bacteria have been implicated in pancreatic infection.62 Fungal infection with Candida species is seen in up to 15% of patients with infected necrosis and is associated with more serious systemic complications.63 The use of prophylactic antibiotics may increase the risk of fungal infection. It may be challenging to distinguish between infected and sterile pancreatic necrosis; hence, needle aspiration under EUS or radiologic guidance may be required.61, 64

Management

Management of Pancreatic Necrosis

Sterile pancreatic necrosis is typically managed conservatively without drainage. Generally, CT scans are repeated every 7 to 10 days to assess the necrosis and to evaluate for further complications.32 Patients who are clinically unstable with fever, tachycardia, leukocytosis, or organ failure may require percutaneous sampling to evaluate for infected necrosis.33 If the pancreatic tissue is sterile, the patient is determined to have sterile necrosis. If the patient with sterile necrosis is clinically unstable then prophylactic antibiotics may be indicated. If the pancreatic tissue is infected, the patient is deemed to have infected necrosis and treatment with antibiotics and necrosectomy is often indicated, especially in those with a poor clinical state. The antibiotic chosen should have adequate penetration into the necrotic material, such as imipenem, meropenem, or a combination of quinolone and metronidazole.99

It may be challenging to distinguish between sterile and infected pancreatic necrosis. A CT scan is unable to differentiate them with certainty; though, intrapancreatic, retroperitoneal, or lesser sac gas may indicate infection.31 In addition, inducing infection within a previously sterile collection is a potential risk of percutaneous sampling. As a result, sampling should not be performed unless completely indicated.31

In patients with sterile pancreatic necrosis who are symptomatic with refractory abdominal pain, gastric outlet obstruction, or failure to thrive at 4 or more weeks following the onset of acute pancreatitis, drainage and/or debridement is usually indicated. Pancreatic necrosectomy for sterile pancreatic necrosis may be accomplished endoscopically, or more traditionally by a surgical approach.55 Although endoscopic drainage is less invasive, it is technically difficult and has a higher rate of complication in the hands of inexperienced operators.100 Careful selection and evaluation of patients undergoing endoscopic drainage procedures is necessary. Bleeding, perforation, infection, pancreatitis, aspiration, stent migration, and pancreatic ductal damage are all possible complications during the drainage of necrotic pancreatic fluid collections.55 If pancreatic necrosis is infected, surgical necrosectomy should be performed as this is the gold standard for infected necrosis when debridement is necessary.55 Figure 5 reviews the management of acute pancreatitis.

Figure 5

Conclusion

Acute pancreatitis is a common disease frequently caused by choledocholithiasis or excess alcohol ingestion. In idiopathic acute pancreatitis, microlithiasis and SOD should be considered. Though CT scan remains the imaging modality of choice, newer methods such as MRCP and EUS may help to provide additional and improved diagnostic information.

The management of acute pancreatitis is frequently challenging, and severity scales help to predict the likelihood of complications, determine necessary interventions, and guide the appropriate level of care. Nutrition is critical in patients with SAP, and enteral feeding is clearly preferred over TPN. Currently, prophylactic antibiotics do not appear to have a role in SAP. Finally, though not always straightforward, recommendations do exist to guide the management of many of the complications of acute pancreatitis, such as pseudocyst formation and necrotizing disease. A multidisciplinary approach should be used in managing patients with severe disease, and the primary inpatient physician should not hesitate to involve specialists, including gastroenterologists, radiologists, and surgeons.

Acute pancreatitis accounts for more than 220,000 hospital admissions in the United States annually.1 In the following review, we outline the etiology of acute pancreatitis, discuss its complications, and provide an updated review on its management for the hospitalized patient.

Etiology

Gallstone disease and excess alcohol ingestion are the most common causes of acute pancreatitis in the United States. Gallstones account for roughly 45% of all cases, and the pathogenesis is due to transient obstruction of the pancreatic duct orifice to the flow of pancreatic exocrine secretions.2 Excess alcohol ingestion accounts for approximately 35% of all cases, yet the pathogenesis here is less understood.3 Most theories suggest a direct toxic effect of the ethanol upon the pancreatic parenchyma or its neurovascular supply.4

There are many other less common causes of acute pancreatitis including toxins, drugs, infections, trauma, vascular insults, anatomic abnormalities, and metabolic derangements. Hypertriglyceridemia and hypercalcemia are both implicated in acute pancreatitis. Serum triglyceride levels >1000 mg/dL can precipitate an attack of acute pancreatitis though the pathogenesis is not clearly understood.5 Hypercalcemia is also an uncommon cause of acute pancreatitis, and is thought to result from deposition of calcium in the pancreatic duct and calcium activation of trypsinogen.6

Idiopathic pancreatitis occurs in up to 20% of patients with acute pancreatitis, and by definition, the cause is not established by history, physical examination, routine laboratory tests, or imaging. The majority of idiopathic cases of pancreatitis are thought to have a biliary source. In patients with gallbladder in situ, it is estimated that up to 75% acquire pancreatitis from microlithiasis, or biliary sludge and stone debris, that causes obstruction of the distal common bile and main pancreatic ducts. Conversely, sphincter of Oddi dysfunction (SOD) resulting in transient pancreatic ductal obstruction is felt to be the most common cause in those patients who have undergone a previous cholecystectomy.7

An emerging entity, autoimmune pancreatitis (AIP), is more commonly associated with chronic pancreatitis but may cause episodes of acute pancreatitis or mimic pancreatic carcinoma. Typically, the diagnosis is based on elevated levels of serum gammaglobulin subgroup 4 (IgG4) populations, along with characteristic findings on computed tomography (CT) scan (eg, narrowed or wispy main pancreatic duct and an enlarged pancreatic parenchyma). Core‐needle biopsy may confirm the diagnosis of AIP with lymphoplasmacytic infiltration and dense fibrosis.8 Since AIP can mimic pancreatic cancer, the diagnosis may not be made until the time of surgical resection.

Diagnosis

Along with characteristic symptoms, the diagnosis of acute pancreatitis is often based on elevated serum levels of pancreatic enzymes that are at least twice the normal level. Amylase and lipase are the most frequently used serum markers for acute pancreatitis, though their elevation is not pathognomonic for the presence of disease. These enzymes may not always be significantly elevated during times of acute inflammation, and elevation of the enzymes can come from nonpancreatic origins as well (Table 1). Although there is no gold standard for the diagnosis of acute pancreatitis, using serum lipase (>250 IU/L) in conjunction with amylase (>160 IU/L) improves the overall diagnostic sensitivity from 81% to 94%.9 Isoamylase levels can be used to distinguish among pancreatic, salivary, and macroamylasemia though this is not often used if pancreatitis is suspected clinically. Similarly, serum isolipase can be measured, though this is not readily available.

In order to improve the sensitivity and specificity of diagnosis, other tests have been studied to help predict disease presence and severity. Previously, serum tests for trypsin, elastase, phospholipase A2, and carboxylester lipase have all been evaluated but shown to have no significant improvement in diagnostic capability.1014 More recently, trypsinogen (a pancreatic proteinase) has proven to be a useful aid in the accurate diagnosis of acute disease. Trypsinogen undergoes activation into trypsin during acute pancreatic inflammation.3 It is comprised of 2 main isoenzymes (trypsinogen‐1 and trypsinogen‐2) that are secreted into the pancreatic fluid with a small proportion escaping into the circulation.15 Higher concentrations of trypsinogen‐1 are seen in healthy people, while higher concentrations of trypsinogen‐2 are seen in those with acute pancreatitis.16 Urinary trypsinogen‐2 dipstick tests detect acute pancreatitis more accurately than quantitative serum or urinary amylase, with a sensitivity as high as 94%, and a specificity of 95%.17 Studies have shown that in post‐endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis, serum trypsinogen‐2 levels begin to rise as early as 1 hour and peak at 6 hours.17 The Actim Pancreatitis (Medix Biomedica, Kauniainen, Finland) urine test strips measure concentrations of trypsinogen‐2 as low as 50 g/L, but is not a quantitative test and, thus, it does not predict severity. Some studies have advocated the use of urinary trypsinogen‐2 as a screening tool, with a positive result indicating a need for further evaluation of acute pancreatitis.1820 Urinary trypsinogen‐2 is less costly than serum tests, plus may result in additional cost savings with earlier patient discharge. Unfortunately, this test is not widely available for clinical use. Urinary trypsinogen activation peptide (TAP) is another test that has been studied in the diagnosis of acute pancreatitis, but may signify disease severity rather than the presence or absence of disease.21 Currently urinary assays for TAP are not widely available in the United States.

Choosing the Appropriate Imaging Modality

Along with the measurement of pancreatic release enzymes, abdominal imaging is often used, though not always necessary to confirm the diagnosis of acute pancreatitis. Imaging techniques such as CT, magnetic resonance imaging (MRI), and transabdominal ultrasonography may be used to rule out other causes of abdominal pain or elucidate the cause of the pancreatitis itself. Ultrasound may show pancreatic enlargement, diminished echogenicity, and possible adjacent fluid collections.22 In searching for evidence of gallstone pancreatitis, transabdominal ultrasound has a sensitivity of 67% and a specificity of 100%.23 However, it may be insensitive for detecting stones in the distal common bile duct near the ampulla due to acoustic interference from gas within the small bowel.24 Furthermore, ultrasound itself is operator‐dependent.

Contrast‐enhanced CT is the standard mode of imaging for diagnosing acute pancreatitis and provides superior imaging of the pancreas. Unfortunately it is more costly than ultrasound, involves radiation exposure, and requires intravenous contrast medium.25 Findings of acute pancreatitis frequently seen on CT include diffuse or segmental enlargement of the gland, irregular pancreatic contour, obliteration of peripancreatic fat planes, parenchymal heterogeneity, and ill‐defined fluid collections within the pancreas or in the lesser sac and pararenal spaces.26 CT scan may also be used to detect pancreatic necrosis, an important finding for the management and prognosis of this disease.27 Despite this, normal CT findings have been reported in patients with acute pancreatitis, and certain CT findings may be related to disease severity.25

Although MRI is less commonly used in the diagnosis of acute pancreatitis, it may provide a useful alternative to CT, especially in cases of renal failure or intravenous contrast hypersensitivity. When combined with magnetic resonance cholangiopancreatography (MRCP) imaging, MRI may even be able to detect a local area of pancreatic duct disruption.27 MRCP allows for a noninvasive cholangiogram and is frequently used to stratify patients who may benefit from ERCP. It can accurately identify common bile duct stones, with a higher sensitivity for choledocholithiasis than ultrasound or CT.2830 MRCP can also assist in the diagnosis of other disorders of the intrahepatic and extrahepatic biliary tree that may be related to the cause of pancreatitis. Overall, unless a patient has a contraindication, or the goal of the study is to diagnose choledocholithiasis, a contrast‐enhanced CT scan remains the imaging procedure of choice due to improved accessibility, lower cost, ease of performance, and increased sensitivity in the detection of gas bubbles (potentially indicating pancreatic infection).3133 Ordering a CT scan or other imaging at admission is not necessary in the diagnosis of acute pancreatitis if the patient's presentation is classic. At admission, however, a CT scan may be reasonable to exclude other serious causes of abdominal pain, such as a perforated ulcer. Imaging may also be ordered to define the cause of the episode of pancreatitis and to exclude occult malignancy. In addition, CT scan should be strongly considered in patients who do not improve within 2 to 3 days to assess for complications such as pancreatic necrosis, pseudocysts, or other complications.34

Most recently, endoscopic ultrasound (EUS) has risen to the forefront as a leader in accurate imaging of the pancreas and biliary tree. EUS is more sensitive than transabdominal ultrasound in detecting biliary stones,35 and it has been shown to have equivalent, and in some cases superior, sensitivity to ERCP and MRCP. Because EUS is able to detect smaller stones or sludge, it may have a role in those patients diagnosed with idiopathic pancreatitis.36 Like MRCP, EUS can also help stratify patients into those that are likely to benefit most from ERCP.37 Figure 1 reviews the evaluation of acute pancreatitis.

Figure 1

Prognosis

For the majority of patients with acute pancreatitis, the clinical course is mild and self‐limiting. In approximately 20% to 25% of patients, however, it is severe and associated with organ failure and significant morbidity and mortality.38, 39 Determining the severity of acute pancreatitis is critical, as patients at high‐risk for severe disease require closer monitoring and possible intervention. Several validated scoring systems are available that aim to predict the severity of acute pancreatitis including Ranson's criteria, the Imrie scoring system, the Acute Physiology and Chronic Health Evaluation (APACHE II) scale, and the CT Severity Index (CTSI) (Table 2).4043

In 1992, the Atlanta Classification of acute pancreatitis was developed to provide a rational approach in predicting disease severity, thus allowing for comparison between clinical trials. It defines severe acute pancreatitis (SAP) on the basis of standard clinical manifestations, a Ranson's score 3, an APACHE II score 8, and evidence of organ failure and intrapancreatic pathological findings.44 Serum markers such as C‐reactive protein (CRP), interleukin‐6, and phospholipase A2 have all been studied to predict severity; however, only CRP is widely available. A cutoff level of 150 mg/L at 48 hours distinguishes mild disease from SAP.45 Clinical findings such as thirst, poor urine output, progressive tachycardia, tachypnea, hypoxemia, confusion, and a lack of improvement in symptoms within the first 48 hours are warning signs of impending severe disease, and thus warrant consideration of admission to an intensive care unit (ICU).34

Natural History and Complications

Despite initial aggressive intensive care treatment, 30% to 50% of patients with SAP do not respond promptly to ICU treatment and develop persistent multisystem organ failure.39 Severe organ failure in the first week of onset of acute pancreatitis is closely linked to the development of pancreatic infection occurring within 2 weeks of the initiation of symptoms.46 Early multiorgan dysfunction triggers additional mechanisms that render bacterial translocation into clinically manifested sepsis and septic shock.39 In most studied series, infection (including bacteremia, fungemia, and pancreatic abscess) remains the leading cause of death in patients with acute pancreatitis, accounting for up to 80% of fatal cases.4749 While sepsis is the more frequent cause of death in patients surviving beyond 7 days, death occurring early in the course of disease is more likely to be from respiratory complications such as pulmonary edema.50

In the spectrum of acute pancreatitis, ongoing pancreatic injury can lead to pancreatic necrosis, fluid collections, pseudocyst formation, and pancreatic duct disruption (Figures 24).51 In patients hospitalized with acute pancreatitis, up to 57% will have peripancreatic fluid collections that are initially ill‐defined.44, 52 Typically, these fluid collections may be managed conservatively; however, if they continue to enlarge, cause persistent abdominal pain, become infected, or compress adjacent organs, they may require further intervention.53 Ductal disruption may be diagnosed when fluid collections have high levels of pancreatic amylase, and their presence may lead to the formation of pseudocysts, persistent ascites, or pleural effusions.54 Pancreatic pseudocysts usually require 4 weeks for complete formation, and they classically contain fluid only without significant solid debris.55 Formation typically occurs as a result of limited pancreatic necrosis causing a pancreatic duct leak with subsequent organization, or from areas of necrosis that liquefy over time.56 Both pancreatic pseudocysts and necrotic pancreatic tissue may become infected leading to abscess formation.51

Figure 2

Figure 3

Figure 4

Pancreatic necrosis is defined as diffuse or focal areas of nonviable pancreatic parenchyma, and it is seen in approximately 20% of patients with acute pancreatitis.44, 57 While pseudocyst formation takes approximately 1 month to occur, pancreatic necrosis can occur within the first few days of initial symptoms and is associated with an increase in complications leading to an increased risk of morbidity and mortality.58 More than 80% of deaths in acute pancreatitis are associated with the presence of pancreatic necrosis.39 Patients at highest risk for complications are those with necrosis involving more than 50% of the gland based on MRI or contrast‐enhanced CT scan.59, 60

Patients with pancreatic infection may have infected necrosis, pancreatic abscess, and/or infected pseudocysts.39 The microbes most frequently involved are gram‐negative organisms including Escherichia coli, Enterococcus, and Klebsiella.61 Recently, gram‐positive bacteria have been implicated in pancreatic infection.62 Fungal infection with Candida species is seen in up to 15% of patients with infected necrosis and is associated with more serious systemic complications.63 The use of prophylactic antibiotics may increase the risk of fungal infection. It may be challenging to distinguish between infected and sterile pancreatic necrosis; hence, needle aspiration under EUS or radiologic guidance may be required.61, 64

Management

Management of Pancreatic Necrosis

Sterile pancreatic necrosis is typically managed conservatively without drainage. Generally, CT scans are repeated every 7 to 10 days to assess the necrosis and to evaluate for further complications.32 Patients who are clinically unstable with fever, tachycardia, leukocytosis, or organ failure may require percutaneous sampling to evaluate for infected necrosis.33 If the pancreatic tissue is sterile, the patient is determined to have sterile necrosis. If the patient with sterile necrosis is clinically unstable then prophylactic antibiotics may be indicated. If the pancreatic tissue is infected, the patient is deemed to have infected necrosis and treatment with antibiotics and necrosectomy is often indicated, especially in those with a poor clinical state. The antibiotic chosen should have adequate penetration into the necrotic material, such as imipenem, meropenem, or a combination of quinolone and metronidazole.99

It may be challenging to distinguish between sterile and infected pancreatic necrosis. A CT scan is unable to differentiate them with certainty; though, intrapancreatic, retroperitoneal, or lesser sac gas may indicate infection.31 In addition, inducing infection within a previously sterile collection is a potential risk of percutaneous sampling. As a result, sampling should not be performed unless completely indicated.31

In patients with sterile pancreatic necrosis who are symptomatic with refractory abdominal pain, gastric outlet obstruction, or failure to thrive at 4 or more weeks following the onset of acute pancreatitis, drainage and/or debridement is usually indicated. Pancreatic necrosectomy for sterile pancreatic necrosis may be accomplished endoscopically, or more traditionally by a surgical approach.55 Although endoscopic drainage is less invasive, it is technically difficult and has a higher rate of complication in the hands of inexperienced operators.100 Careful selection and evaluation of patients undergoing endoscopic drainage procedures is necessary. Bleeding, perforation, infection, pancreatitis, aspiration, stent migration, and pancreatic ductal damage are all possible complications during the drainage of necrotic pancreatic fluid collections.55 If pancreatic necrosis is infected, surgical necrosectomy should be performed as this is the gold standard for infected necrosis when debridement is necessary.55 Figure 5 reviews the management of acute pancreatitis.

Figure 5

Conclusion

Acute pancreatitis is a common disease frequently caused by choledocholithiasis or excess alcohol ingestion. In idiopathic acute pancreatitis, microlithiasis and SOD should be considered. Though CT scan remains the imaging modality of choice, newer methods such as MRCP and EUS may help to provide additional and improved diagnostic information.

The management of acute pancreatitis is frequently challenging, and severity scales help to predict the likelihood of complications, determine necessary interventions, and guide the appropriate level of care. Nutrition is critical in patients with SAP, and enteral feeding is clearly preferred over TPN. Currently, prophylactic antibiotics do not appear to have a role in SAP. Finally, though not always straightforward, recommendations do exist to guide the management of many of the complications of acute pancreatitis, such as pseudocyst formation and necrotizing disease. A multidisciplinary approach should be used in managing patients with severe disease, and the primary inpatient physician should not hesitate to involve specialists, including gastroenterologists, radiologists, and surgeons.

A 65‐year‐old man with chronic obstructive pulmonary disease and right lung nodule presented with dyspnea. Physical examination revealed a pulse of 130 beats per minute, respiratory rate of 28 times per minute, blood pressure of 100/60 mm Hg, estimated jugular venous pressure of greater than 15 cm above the right atrium at a 45‐degree semirecumbent position, and distant heart sounds. He subsequently developed hypotension and an arterial line was placed. A single‐channel electrocardiogram (Figure 1A; upper tracing) demonstrated electrical alternans. Simultaneous arterial line (Figure 1A; lower tracing) showed decreased systolic blood pressure from 136 mm Hg (Figure 1A; arrow) to 96 mm Hg (Figure 1A; arrowhead) with inspiration, consistent with exaggerated pulsus paradoxus. A transthoracic echocardiogram confirmed a large pericardial effusion with the heart oscillating from side (Figure 1B) to side (Figure 1C) within the pericardial sac. Pericardiocentesis was performed and 1100 mL of bloody pericardial fluid was removed with prompt resolution of hypotension, tachycardia, electrical alternans, and abnormal pulsus paradoxus. Pericardial effusion (PE), right ventricle (RV), and left ventricle (LV) are depicted in Figure 1B, C.

Figure 1

The etiology of this patient's pericardial effusion was felt to be due to metastatic pericardial disease from lung cancer. The mechanism of electrical alternans is felt to be due to motion as the heart oscillates back and forth within the pericardial sac.1 The exaggerated pulsus paradoxus reflects decreased LV filling during inspiration as RV filling increases and compresses the LV, referred to as ventricular interdependence.

A 65‐year‐old man with chronic obstructive pulmonary disease and right lung nodule presented with dyspnea. Physical examination revealed a pulse of 130 beats per minute, respiratory rate of 28 times per minute, blood pressure of 100/60 mm Hg, estimated jugular venous pressure of greater than 15 cm above the right atrium at a 45‐degree semirecumbent position, and distant heart sounds. He subsequently developed hypotension and an arterial line was placed. A single‐channel electrocardiogram (Figure 1A; upper tracing) demonstrated electrical alternans. Simultaneous arterial line (Figure 1A; lower tracing) showed decreased systolic blood pressure from 136 mm Hg (Figure 1A; arrow) to 96 mm Hg (Figure 1A; arrowhead) with inspiration, consistent with exaggerated pulsus paradoxus. A transthoracic echocardiogram confirmed a large pericardial effusion with the heart oscillating from side (Figure 1B) to side (Figure 1C) within the pericardial sac. Pericardiocentesis was performed and 1100 mL of bloody pericardial fluid was removed with prompt resolution of hypotension, tachycardia, electrical alternans, and abnormal pulsus paradoxus. Pericardial effusion (PE), right ventricle (RV), and left ventricle (LV) are depicted in Figure 1B, C.

Figure 1

The etiology of this patient's pericardial effusion was felt to be due to metastatic pericardial disease from lung cancer. The mechanism of electrical alternans is felt to be due to motion as the heart oscillates back and forth within the pericardial sac.1 The exaggerated pulsus paradoxus reflects decreased LV filling during inspiration as RV filling increases and compresses the LV, referred to as ventricular interdependence.

A 65‐year‐old man with chronic obstructive pulmonary disease and right lung nodule presented with dyspnea. Physical examination revealed a pulse of 130 beats per minute, respiratory rate of 28 times per minute, blood pressure of 100/60 mm Hg, estimated jugular venous pressure of greater than 15 cm above the right atrium at a 45‐degree semirecumbent position, and distant heart sounds. He subsequently developed hypotension and an arterial line was placed. A single‐channel electrocardiogram (Figure 1A; upper tracing) demonstrated electrical alternans. Simultaneous arterial line (Figure 1A; lower tracing) showed decreased systolic blood pressure from 136 mm Hg (Figure 1A; arrow) to 96 mm Hg (Figure 1A; arrowhead) with inspiration, consistent with exaggerated pulsus paradoxus. A transthoracic echocardiogram confirmed a large pericardial effusion with the heart oscillating from side (Figure 1B) to side (Figure 1C) within the pericardial sac. Pericardiocentesis was performed and 1100 mL of bloody pericardial fluid was removed with prompt resolution of hypotension, tachycardia, electrical alternans, and abnormal pulsus paradoxus. Pericardial effusion (PE), right ventricle (RV), and left ventricle (LV) are depicted in Figure 1B, C.

Figure 1

The etiology of this patient's pericardial effusion was felt to be due to metastatic pericardial disease from lung cancer. The mechanism of electrical alternans is felt to be due to motion as the heart oscillates back and forth within the pericardial sac.1 The exaggerated pulsus paradoxus reflects decreased LV filling during inspiration as RV filling increases and compresses the LV, referred to as ventricular interdependence.

Staphylococcus aureus (SA) infection can cause a wide range of clinical syndromes, from folliculitis to life‐threatening endocarditis. Further, SA is second only to S. epidermidis as a cause of bacteremia in hospitalized patients.1, 2 Recent single‐institution studies suggests that SA could be the most frequent cause of nosocomial bacteremia,3, 4 but this needs to be validated in multicenter studies. SA bacteremia (SAB) is often complicated by hematogenous seeding into deep tissues or prosthetic material. The association of future hardware infection following SAB is well documented.5, 6 One study showed that SAB can precede and be associated with prosthetic joint infections in up to 34% of cases.6 Intravascular cardiac devices can also be infected by SAB, with rates from 28% to 75% depending on how early the bacteremia occurred in relation to the implantation of the device.5 Risk stratification for these complications is a clinical challenge. Fowler et al.7 postulated some clinical identifiers of complicated SAB; however, predicting which patients will develop a complication from SAB remains very difficult. Muder et al.8 demonstrated that the presence of SA bacteriuria (SABU) correlates with subsequent SAB, but a possible association of SABU with complicated bacteremia was not examined. A more recent study from Huggan et al.9 has suggested a possible association between SABU and poor clinical outcomes in adults with SAB.

We hypothesized that the presence of SABU would identify those patients at increased risk of complications from SAB. SABU may be a practical, economical, and readily available predictor of complicated SAB. Those patients at higher risk for complications may require a more aggressive diagnostic and therapeutic approach.

Methods

We conducted a retrospective cohort study of SAB patients with and without SA in the urine to investigate the association between SABU and the outcomes of the complications and mortality.

The study was conducted at Miami Valley Hospital (MVH, Dayton, OH), an 848‐bed, level 1 trauma center with 69 intensive care unit (ICU) beds. MVH is a community teaching hospital affiliated with Wright State University Boonshoft School of Medicine and averages 35,000 admissions per year. The same microbiology laboratory (Compunet Clinical Laboratories) processed all the blood and urine culture specimens of the patients in this study.

The inclusion criteria were as follows: 1) admission to MVH between January 1, 2004 and December 31, 2007 with a documented episode of SAB (at least 1 positive blood culture); and 2) a documented urine culture within 7 days of the episode of SAB. Patients without a documented urine culture or with inadequate/emncomplete treatment for SAB were excluded. A total of 118 patients were included based on the presence of a positive blood culture for SA and the presence of a documented urine culture. Patient electronic and paper records were reviewed by 3 of the investigators (E.V.P.‐J., S.D.B., and W.B.B.). Patients subsequently admitted to MVH and to MVH's companion medical center in Dayton, Good Samaritan Hospital, were followed through the electronic medical record common to both institutions.

Study patients were divided into 2 cohorts. One cohort included the patients with a urine culture that grew SA, either methicillin‐resistant SA (MRSA) or methicillin‐susceptible SA (MSSA). The other cohort included patients who had either a negative urine culture or a positive urine culture with organisms other than SA. The age, sex, date of admission, length of stay, and duration of follow‐up were recorded for each patient. Clinical variables included blood culture and urine culture results, presence of intravenous catheters, antibiotic therapy and duration, presence of comorbidities, and clinical outcomes (complications and death).

The primary outcome was complications during hospital admission. The 8 complications investigated were as follows: endocarditis, osteomyelitis, septic arthritis, thrombophlebitis, septic shock, septic embolism/abscess, persistent SAB (lasting more than 5 days after starting adequate SA treatment), and recurrent SAB. In addition, the 2 groups were compared on: 1) any complication, 2) average complications, 3) early complications (ie, within the current hospital admission), and 4) delayed complications (ie, complications diagnosed on subsequent admissions).

Results

Of the 118 patients, 58 were female (49.2%) and 60 male (50.8%). The age of the patients was 63.3 16.7 years (mean SD). The length of hospital stay was 19.3 17.0 days, and the duration of follow up was 8.3 5.7 months. MRSA was isolated in 75 patients (63.6%) and MSSA in 43 patients (36.4%). In the 28 patients with SA in urine cultures, MRSA was found more frequently than MSSA (20 vs. 8 patients). The acquisition of SAB was equally divided among outpatient (35.6%), healthcare‐associated (30.5%), and hospital‐acquired (33.9%) settings.

Table 1 shows that the group with SABU did not differ from the group without SABU in age (66 years vs. 62 years; P = 0.29), sex (43% male vs. 53% male; P = 0.33), length of hospital stay (18 days vs. 20 days; P = 0.59), and duration of follow‐up (6.6 months vs. 8.8 months; P = 0.064). The 2 cohorts also did not differ on the proportion with MRSA bacteremia (71% vs. 61%; P = 0.32), origin of SAB (P = 0.12), and the presence of comorbidities (diabetes mellitus, cardiomyopathy/congestive heart failure, malignancy, renal disease, and immunosuppression) (all P values > 0.30).

Table 2 shows that patients in the SABU group were nearly twice as likely to have a complication as the group without SABU (64% vs. 33%; P = 0.004) and had a higher mean number of complications (0.89 vs. 0.48; P = 0.016). Patients in the SABU group also were more likely to have early complications (64% vs. 23%; P < 0.001) but no more likely to have a delayed complication (14% vs. 12%; P = 0.75). Of the 8 specific complications evaluated, the 2 groups differed only on the presence of septic shock, with the SABU group having 3 times more patients with this complication (21% vs. 7%; P = 0.035). Also, a higher proportion of patients died in the SABU group (32.1% vs. 14.4%; P = 0.036).

Patients with MRSA (n = 75) and those with MSSA (n = 43) did not differ on any complication, average complications, early or late complications, or 7 of the specific complications (data not shown). Only with thrombophlebitis did the 2 groups differ; the MSSA group had 4 (9.3%) patients with this complication while none in the MRSA group were affected (P = 0.016).

Discussion

In our retrospective analysis, SAB with concomitant SABU was associated with more severe disease, complications, and death. Compared to SAB patients without SA in the urine, those with SAB and SA in the urine had more total complications and more early complications, especially septic shock. Further, the proportion of deaths in the SABU cohort was more than twice as high (32% vs. 14%). Therefore, the presence of SABU in patients with SAB could potentially be a useful predictor of complicated SAB and death.

The relationship between SABU and early complications and death remained after excluding the complication of septic shock/need for vasopressors from the analysis (data not shown). The lack of relationship between SABU and delayed complications might have been due to the adequacy of treatment for SAB. Appropriateness of therapy, a criterion for patient inclusion, may have lessened the likelihood of an insufficient treatment plan causing complications. Those patients with MRSA did not differ from those with MSSA on the mean number of complications or early and delayed complications. A greater proportion of MSSA patients had thrombophlebitis than MRSA patients.

Other investigations have identified predictors of mortality or complications from SAB,7, 912 but SABU was not included as a variable in most of these studies. Fowler et al.7 proposed a prognostic model of complicated SAB using the predictors from their study; community acquisition of organisms, persistent bacteremia, persistent fever over 72 hours, and skin examination suggestive of an acute systemic infection. Muder et al.8 reported a relationship between SABU and subsequent SAB, but they did not examine the association between SABU and the risk of complicated SAB. Huggan et al.9 found that concomitant SABU is associated with ICU admission and increased in‐hospital mortality in patients with SAB.

SAB patients with SABU may be at risk for early complications. Consequently, such patients may warrant more aggressive evaluation and treatment. Further, SABU in patients with SAB may be indicative of an endocarditis‐like condition. SA is rarely isolated from the urinary tract as a uropathogen, although it may colonize indwelling catheters and may cause catheter‐related urinary tract infections.13, 14 Thus, when present in urine, SA could be a marker of deep tissue dissemination with the potential to cause complications. Guidelines for the management of intravascular device‐associated bacteremia have been published by the Infectious Diseases Society of America (IDSA) and other organizations,15, 16 and recent studies have demonstrated the effectiveness of newer agents for the management of SAB.17 Nevertheless, there is still controversy regarding some aspects of the management of SAB (eg, duration of therapy, criteria for echocardiographic evaluation, role of combination therapy). The presence of SABU, the marker evaluated in our study, may be an additional factor to consider when deciding upon duration of therapy and whether to obtain echocardiography or other imaging.

Our study was limited by its retrospective nature. Patient records were not always complete. For example, not all patients had echocardiography to evaluate for endocarditis or venous ultrasound to evaluate for septic thrombophlebitis. Also, the presence (or proper removal) of intravascular or urinary catheters could not be documented reliably in all patients. In addition, the 7‐day cutoff for obtaining urine cultures may have been too lenient, leading to underdiagnosis of bacteriuria. Finally, while 13 patients were lost to follow‐up, the 2 groups (SABU and No SABU) did not differ in the proportion lost.

In conclusion, our study found that SABU may be a useful predictor of complicated SAB and death. SAB patients with SABU may be at risk for more and earlier complications. These patients may need closer monitoring due to the higher risk of septic shock and death. Additional therapeutic and management recommendations might include: 1) longer duration of therapy even if a removable source of the bacteremia is identified; 2) more frequent and better supervised follow‐up; and 3) imaging studies including either computed tomography (CT) scans or ultrasound for thorough evaluation of complications. Prospective studies including randomized controlled trials are required before implementing these suggested diagnostic and therapeutic recommendations.

Staphylococcus aureus (SA) infection can cause a wide range of clinical syndromes, from folliculitis to life‐threatening endocarditis. Further, SA is second only to S. epidermidis as a cause of bacteremia in hospitalized patients.1, 2 Recent single‐institution studies suggests that SA could be the most frequent cause of nosocomial bacteremia,3, 4 but this needs to be validated in multicenter studies. SA bacteremia (SAB) is often complicated by hematogenous seeding into deep tissues or prosthetic material. The association of future hardware infection following SAB is well documented.5, 6 One study showed that SAB can precede and be associated with prosthetic joint infections in up to 34% of cases.6 Intravascular cardiac devices can also be infected by SAB, with rates from 28% to 75% depending on how early the bacteremia occurred in relation to the implantation of the device.5 Risk stratification for these complications is a clinical challenge. Fowler et al.7 postulated some clinical identifiers of complicated SAB; however, predicting which patients will develop a complication from SAB remains very difficult. Muder et al.8 demonstrated that the presence of SA bacteriuria (SABU) correlates with subsequent SAB, but a possible association of SABU with complicated bacteremia was not examined. A more recent study from Huggan et al.9 has suggested a possible association between SABU and poor clinical outcomes in adults with SAB.

We hypothesized that the presence of SABU would identify those patients at increased risk of complications from SAB. SABU may be a practical, economical, and readily available predictor of complicated SAB. Those patients at higher risk for complications may require a more aggressive diagnostic and therapeutic approach.

Methods

We conducted a retrospective cohort study of SAB patients with and without SA in the urine to investigate the association between SABU and the outcomes of the complications and mortality.

The study was conducted at Miami Valley Hospital (MVH, Dayton, OH), an 848‐bed, level 1 trauma center with 69 intensive care unit (ICU) beds. MVH is a community teaching hospital affiliated with Wright State University Boonshoft School of Medicine and averages 35,000 admissions per year. The same microbiology laboratory (Compunet Clinical Laboratories) processed all the blood and urine culture specimens of the patients in this study.

The inclusion criteria were as follows: 1) admission to MVH between January 1, 2004 and December 31, 2007 with a documented episode of SAB (at least 1 positive blood culture); and 2) a documented urine culture within 7 days of the episode of SAB. Patients without a documented urine culture or with inadequate/emncomplete treatment for SAB were excluded. A total of 118 patients were included based on the presence of a positive blood culture for SA and the presence of a documented urine culture. Patient electronic and paper records were reviewed by 3 of the investigators (E.V.P.‐J., S.D.B., and W.B.B.). Patients subsequently admitted to MVH and to MVH's companion medical center in Dayton, Good Samaritan Hospital, were followed through the electronic medical record common to both institutions.

Study patients were divided into 2 cohorts. One cohort included the patients with a urine culture that grew SA, either methicillin‐resistant SA (MRSA) or methicillin‐susceptible SA (MSSA). The other cohort included patients who had either a negative urine culture or a positive urine culture with organisms other than SA. The age, sex, date of admission, length of stay, and duration of follow‐up were recorded for each patient. Clinical variables included blood culture and urine culture results, presence of intravenous catheters, antibiotic therapy and duration, presence of comorbidities, and clinical outcomes (complications and death).

The primary outcome was complications during hospital admission. The 8 complications investigated were as follows: endocarditis, osteomyelitis, septic arthritis, thrombophlebitis, septic shock, septic embolism/abscess, persistent SAB (lasting more than 5 days after starting adequate SA treatment), and recurrent SAB. In addition, the 2 groups were compared on: 1) any complication, 2) average complications, 3) early complications (ie, within the current hospital admission), and 4) delayed complications (ie, complications diagnosed on subsequent admissions).

Results

Of the 118 patients, 58 were female (49.2%) and 60 male (50.8%). The age of the patients was 63.3 16.7 years (mean SD). The length of hospital stay was 19.3 17.0 days, and the duration of follow up was 8.3 5.7 months. MRSA was isolated in 75 patients (63.6%) and MSSA in 43 patients (36.4%). In the 28 patients with SA in urine cultures, MRSA was found more frequently than MSSA (20 vs. 8 patients). The acquisition of SAB was equally divided among outpatient (35.6%), healthcare‐associated (30.5%), and hospital‐acquired (33.9%) settings.

Table 1 shows that the group with SABU did not differ from the group without SABU in age (66 years vs. 62 years; P = 0.29), sex (43% male vs. 53% male; P = 0.33), length of hospital stay (18 days vs. 20 days; P = 0.59), and duration of follow‐up (6.6 months vs. 8.8 months; P = 0.064). The 2 cohorts also did not differ on the proportion with MRSA bacteremia (71% vs. 61%; P = 0.32), origin of SAB (P = 0.12), and the presence of comorbidities (diabetes mellitus, cardiomyopathy/congestive heart failure, malignancy, renal disease, and immunosuppression) (all P values > 0.30).

Table 2 shows that patients in the SABU group were nearly twice as likely to have a complication as the group without SABU (64% vs. 33%; P = 0.004) and had a higher mean number of complications (0.89 vs. 0.48; P = 0.016). Patients in the SABU group also were more likely to have early complications (64% vs. 23%; P < 0.001) but no more likely to have a delayed complication (14% vs. 12%; P = 0.75). Of the 8 specific complications evaluated, the 2 groups differed only on the presence of septic shock, with the SABU group having 3 times more patients with this complication (21% vs. 7%; P = 0.035). Also, a higher proportion of patients died in the SABU group (32.1% vs. 14.4%; P = 0.036).

Patients with MRSA (n = 75) and those with MSSA (n = 43) did not differ on any complication, average complications, early or late complications, or 7 of the specific complications (data not shown). Only with thrombophlebitis did the 2 groups differ; the MSSA group had 4 (9.3%) patients with this complication while none in the MRSA group were affected (P = 0.016).

Discussion

In our retrospective analysis, SAB with concomitant SABU was associated with more severe disease, complications, and death. Compared to SAB patients without SA in the urine, those with SAB and SA in the urine had more total complications and more early complications, especially septic shock. Further, the proportion of deaths in the SABU cohort was more than twice as high (32% vs. 14%). Therefore, the presence of SABU in patients with SAB could potentially be a useful predictor of complicated SAB and death.

The relationship between SABU and early complications and death remained after excluding the complication of septic shock/need for vasopressors from the analysis (data not shown). The lack of relationship between SABU and delayed complications might have been due to the adequacy of treatment for SAB. Appropriateness of therapy, a criterion for patient inclusion, may have lessened the likelihood of an insufficient treatment plan causing complications. Those patients with MRSA did not differ from those with MSSA on the mean number of complications or early and delayed complications. A greater proportion of MSSA patients had thrombophlebitis than MRSA patients.

Other investigations have identified predictors of mortality or complications from SAB,7, 912 but SABU was not included as a variable in most of these studies. Fowler et al.7 proposed a prognostic model of complicated SAB using the predictors from their study; community acquisition of organisms, persistent bacteremia, persistent fever over 72 hours, and skin examination suggestive of an acute systemic infection. Muder et al.8 reported a relationship between SABU and subsequent SAB, but they did not examine the association between SABU and the risk of complicated SAB. Huggan et al.9 found that concomitant SABU is associated with ICU admission and increased in‐hospital mortality in patients with SAB.

SAB patients with SABU may be at risk for early complications. Consequently, such patients may warrant more aggressive evaluation and treatment. Further, SABU in patients with SAB may be indicative of an endocarditis‐like condition. SA is rarely isolated from the urinary tract as a uropathogen, although it may colonize indwelling catheters and may cause catheter‐related urinary tract infections.13, 14 Thus, when present in urine, SA could be a marker of deep tissue dissemination with the potential to cause complications. Guidelines for the management of intravascular device‐associated bacteremia have been published by the Infectious Diseases Society of America (IDSA) and other organizations,15, 16 and recent studies have demonstrated the effectiveness of newer agents for the management of SAB.17 Nevertheless, there is still controversy regarding some aspects of the management of SAB (eg, duration of therapy, criteria for echocardiographic evaluation, role of combination therapy). The presence of SABU, the marker evaluated in our study, may be an additional factor to consider when deciding upon duration of therapy and whether to obtain echocardiography or other imaging.

Our study was limited by its retrospective nature. Patient records were not always complete. For example, not all patients had echocardiography to evaluate for endocarditis or venous ultrasound to evaluate for septic thrombophlebitis. Also, the presence (or proper removal) of intravascular or urinary catheters could not be documented reliably in all patients. In addition, the 7‐day cutoff for obtaining urine cultures may have been too lenient, leading to underdiagnosis of bacteriuria. Finally, while 13 patients were lost to follow‐up, the 2 groups (SABU and No SABU) did not differ in the proportion lost.

In conclusion, our study found that SABU may be a useful predictor of complicated SAB and death. SAB patients with SABU may be at risk for more and earlier complications. These patients may need closer monitoring due to the higher risk of septic shock and death. Additional therapeutic and management recommendations might include: 1) longer duration of therapy even if a removable source of the bacteremia is identified; 2) more frequent and better supervised follow‐up; and 3) imaging studies including either computed tomography (CT) scans or ultrasound for thorough evaluation of complications. Prospective studies including randomized controlled trials are required before implementing these suggested diagnostic and therapeutic recommendations.

Staphylococcus aureus (SA) infection can cause a wide range of clinical syndromes, from folliculitis to life‐threatening endocarditis. Further, SA is second only to S. epidermidis as a cause of bacteremia in hospitalized patients.1, 2 Recent single‐institution studies suggests that SA could be the most frequent cause of nosocomial bacteremia,3, 4 but this needs to be validated in multicenter studies. SA bacteremia (SAB) is often complicated by hematogenous seeding into deep tissues or prosthetic material. The association of future hardware infection following SAB is well documented.5, 6 One study showed that SAB can precede and be associated with prosthetic joint infections in up to 34% of cases.6 Intravascular cardiac devices can also be infected by SAB, with rates from 28% to 75% depending on how early the bacteremia occurred in relation to the implantation of the device.5 Risk stratification for these complications is a clinical challenge. Fowler et al.7 postulated some clinical identifiers of complicated SAB; however, predicting which patients will develop a complication from SAB remains very difficult. Muder et al.8 demonstrated that the presence of SA bacteriuria (SABU) correlates with subsequent SAB, but a possible association of SABU with complicated bacteremia was not examined. A more recent study from Huggan et al.9 has suggested a possible association between SABU and poor clinical outcomes in adults with SAB.

We hypothesized that the presence of SABU would identify those patients at increased risk of complications from SAB. SABU may be a practical, economical, and readily available predictor of complicated SAB. Those patients at higher risk for complications may require a more aggressive diagnostic and therapeutic approach.

Methods

We conducted a retrospective cohort study of SAB patients with and without SA in the urine to investigate the association between SABU and the outcomes of the complications and mortality.

The study was conducted at Miami Valley Hospital (MVH, Dayton, OH), an 848‐bed, level 1 trauma center with 69 intensive care unit (ICU) beds. MVH is a community teaching hospital affiliated with Wright State University Boonshoft School of Medicine and averages 35,000 admissions per year. The same microbiology laboratory (Compunet Clinical Laboratories) processed all the blood and urine culture specimens of the patients in this study.

The inclusion criteria were as follows: 1) admission to MVH between January 1, 2004 and December 31, 2007 with a documented episode of SAB (at least 1 positive blood culture); and 2) a documented urine culture within 7 days of the episode of SAB. Patients without a documented urine culture or with inadequate/emncomplete treatment for SAB were excluded. A total of 118 patients were included based on the presence of a positive blood culture for SA and the presence of a documented urine culture. Patient electronic and paper records were reviewed by 3 of the investigators (E.V.P.‐J., S.D.B., and W.B.B.). Patients subsequently admitted to MVH and to MVH's companion medical center in Dayton, Good Samaritan Hospital, were followed through the electronic medical record common to both institutions.

Study patients were divided into 2 cohorts. One cohort included the patients with a urine culture that grew SA, either methicillin‐resistant SA (MRSA) or methicillin‐susceptible SA (MSSA). The other cohort included patients who had either a negative urine culture or a positive urine culture with organisms other than SA. The age, sex, date of admission, length of stay, and duration of follow‐up were recorded for each patient. Clinical variables included blood culture and urine culture results, presence of intravenous catheters, antibiotic therapy and duration, presence of comorbidities, and clinical outcomes (complications and death).

The primary outcome was complications during hospital admission. The 8 complications investigated were as follows: endocarditis, osteomyelitis, septic arthritis, thrombophlebitis, septic shock, septic embolism/abscess, persistent SAB (lasting more than 5 days after starting adequate SA treatment), and recurrent SAB. In addition, the 2 groups were compared on: 1) any complication, 2) average complications, 3) early complications (ie, within the current hospital admission), and 4) delayed complications (ie, complications diagnosed on subsequent admissions).

Results

Of the 118 patients, 58 were female (49.2%) and 60 male (50.8%). The age of the patients was 63.3 16.7 years (mean SD). The length of hospital stay was 19.3 17.0 days, and the duration of follow up was 8.3 5.7 months. MRSA was isolated in 75 patients (63.6%) and MSSA in 43 patients (36.4%). In the 28 patients with SA in urine cultures, MRSA was found more frequently than MSSA (20 vs. 8 patients). The acquisition of SAB was equally divided among outpatient (35.6%), healthcare‐associated (30.5%), and hospital‐acquired (33.9%) settings.

Table 1 shows that the group with SABU did not differ from the group without SABU in age (66 years vs. 62 years; P = 0.29), sex (43% male vs. 53% male; P = 0.33), length of hospital stay (18 days vs. 20 days; P = 0.59), and duration of follow‐up (6.6 months vs. 8.8 months; P = 0.064). The 2 cohorts also did not differ on the proportion with MRSA bacteremia (71% vs. 61%; P = 0.32), origin of SAB (P = 0.12), and the presence of comorbidities (diabetes mellitus, cardiomyopathy/congestive heart failure, malignancy, renal disease, and immunosuppression) (all P values > 0.30).

Table 2 shows that patients in the SABU group were nearly twice as likely to have a complication as the group without SABU (64% vs. 33%; P = 0.004) and had a higher mean number of complications (0.89 vs. 0.48; P = 0.016). Patients in the SABU group also were more likely to have early complications (64% vs. 23%; P < 0.001) but no more likely to have a delayed complication (14% vs. 12%; P = 0.75). Of the 8 specific complications evaluated, the 2 groups differed only on the presence of septic shock, with the SABU group having 3 times more patients with this complication (21% vs. 7%; P = 0.035). Also, a higher proportion of patients died in the SABU group (32.1% vs. 14.4%; P = 0.036).

Patients with MRSA (n = 75) and those with MSSA (n = 43) did not differ on any complication, average complications, early or late complications, or 7 of the specific complications (data not shown). Only with thrombophlebitis did the 2 groups differ; the MSSA group had 4 (9.3%) patients with this complication while none in the MRSA group were affected (P = 0.016).

Discussion

In our retrospective analysis, SAB with concomitant SABU was associated with more severe disease, complications, and death. Compared to SAB patients without SA in the urine, those with SAB and SA in the urine had more total complications and more early complications, especially septic shock. Further, the proportion of deaths in the SABU cohort was more than twice as high (32% vs. 14%). Therefore, the presence of SABU in patients with SAB could potentially be a useful predictor of complicated SAB and death.

The relationship between SABU and early complications and death remained after excluding the complication of septic shock/need for vasopressors from the analysis (data not shown). The lack of relationship between SABU and delayed complications might have been due to the adequacy of treatment for SAB. Appropriateness of therapy, a criterion for patient inclusion, may have lessened the likelihood of an insufficient treatment plan causing complications. Those patients with MRSA did not differ from those with MSSA on the mean number of complications or early and delayed complications. A greater proportion of MSSA patients had thrombophlebitis than MRSA patients.

Other investigations have identified predictors of mortality or complications from SAB,7, 912 but SABU was not included as a variable in most of these studies. Fowler et al.7 proposed a prognostic model of complicated SAB using the predictors from their study; community acquisition of organisms, persistent bacteremia, persistent fever over 72 hours, and skin examination suggestive of an acute systemic infection. Muder et al.8 reported a relationship between SABU and subsequent SAB, but they did not examine the association between SABU and the risk of complicated SAB. Huggan et al.9 found that concomitant SABU is associated with ICU admission and increased in‐hospital mortality in patients with SAB.

SAB patients with SABU may be at risk for early complications. Consequently, such patients may warrant more aggressive evaluation and treatment. Further, SABU in patients with SAB may be indicative of an endocarditis‐like condition. SA is rarely isolated from the urinary tract as a uropathogen, although it may colonize indwelling catheters and may cause catheter‐related urinary tract infections.13, 14 Thus, when present in urine, SA could be a marker of deep tissue dissemination with the potential to cause complications. Guidelines for the management of intravascular device‐associated bacteremia have been published by the Infectious Diseases Society of America (IDSA) and other organizations,15, 16 and recent studies have demonstrated the effectiveness of newer agents for the management of SAB.17 Nevertheless, there is still controversy regarding some aspects of the management of SAB (eg, duration of therapy, criteria for echocardiographic evaluation, role of combination therapy). The presence of SABU, the marker evaluated in our study, may be an additional factor to consider when deciding upon duration of therapy and whether to obtain echocardiography or other imaging.

Our study was limited by its retrospective nature. Patient records were not always complete. For example, not all patients had echocardiography to evaluate for endocarditis or venous ultrasound to evaluate for septic thrombophlebitis. Also, the presence (or proper removal) of intravascular or urinary catheters could not be documented reliably in all patients. In addition, the 7‐day cutoff for obtaining urine cultures may have been too lenient, leading to underdiagnosis of bacteriuria. Finally, while 13 patients were lost to follow‐up, the 2 groups (SABU and No SABU) did not differ in the proportion lost.

In conclusion, our study found that SABU may be a useful predictor of complicated SAB and death. SAB patients with SABU may be at risk for more and earlier complications. These patients may need closer monitoring due to the higher risk of septic shock and death. Additional therapeutic and management recommendations might include: 1) longer duration of therapy even if a removable source of the bacteremia is identified; 2) more frequent and better supervised follow‐up; and 3) imaging studies including either computed tomography (CT) scans or ultrasound for thorough evaluation of complications. Prospective studies including randomized controlled trials are required before implementing these suggested diagnostic and therapeutic recommendations.

Hospitals have important legal and ethical responsibilities for human participant research conducted within their facilities, such as ensuring that research complies with federal regulations and presents minimal risks to patients. Many hospitals accept as sufficient the federal requirement that human participant research studies have Institutional Review Board (IRB) review and approval. IRBs must review proposed research according to numerous criteria, such as scientific soundness, alignment with accepted ethics principles and weighing of benefit vs. risk to study participants.1, 2 The legally required aspects of IRB review do not, however, include considering practical matters in implementing and operating an interventional clinical trial in the complex environment of the modern acute care hospital.

Our hospital system established a broad policy requiring internal review and formal approval of any human participant research conducted within any of its hospitals, including studies that enroll hospital patients or hospital employees, utilize hospital medical records, or request hospital‐provided services for research tests or procedures. The purpose of this paper is to describe this formal hospital system review and approval process, the reasons for implementing it, and the types of issues considered prior to our hospital system granting a principal investigator permission to conduct a study.

Background

Surprisingly little healthcare or medical literature exists regarding hospital responsibilities toward human subject research conducted on its premises. Much of the literature focuses on ethics issues, the nature of informed consent, and study design. As critical as these discussions are, they seldom address the numerous complex operational issues and challenges that implementation of a clinical trial can create in a hospital setting.

Flanders et al.3 make the case for hospitalists and specialists to work together to support research that includes inpatients as study participants. Moore and Goldberg4 discuss the ingredients of successfully developing a research program in a community hospital and mention the need to involve all affected hospital departments in the initial hospital review of a study, evaluating study impact on hospital workflow, and establishing processes related to budgeting and billing. Jamerson5 also makes the case for hospital departmental review and involvement, assessment of the ability to integrate study activities into the hospital structure, assessment of the resources needed to support the research, determination of whether the hospital will contribute financially to the research, and explicit decision making regarding the assumption of institutional risk.

Despite the recognition that US patients increasingly live with multiple chronic conditions6 and that clinical trial protocols have become more procedure and resource intensive and costly,79 there has not been a corollary recognition of the increasing need for hospitals to understand and manage research activities occurring within their facilities.

Our organization is a hospital system with 9 acute care hospitals, including an academic teaching hospital (affiliated with a university medical school) with a Level 1 Trauma Center, 1 specialty rehabilitation hospital, numerous specialized clinics, and a LifeFlight Program with a 6‐helicopter fleet (Geisinger, Danville, PA). This system of hospitals serves the fourth largest metropolitan community in the US (Houston and Harris County in southeastern TX), with a population of nearly four million and a geographic spread of 1778 square miles.10, 11 The hospital system has approximately 140,700 inpatient admissions per year and 586,000 outpatient visits.

Eight years ago, our hospital system adopted a corporate policy requiring that any activity associated with human participant research receive prior hospital system review and approval. Our organization considers this review process vital to: (1) maintaining our commitment to our Federalwide Assurance with the Office for Human Research Protections, (2) abiding by the Joint Commission requirements related to research,12 (3) protecting the safety and confidentiality of patients and employees who are potential or actual research participants, (4) protecting the confidentiality of participants' medical information, (5) assuring that legal fundamentals and good clinical practice (GCH)13 are a part of study plans, (6) assuring that studies are operationally feasible, and (7) evaluating and minimizing risks to patients and risks to the organization.

Review and Approval Process

Overview

An investigator triggers a formal hospital system review by submitting study documents to 1 of the IRBs listed on the system's Federalwide Assurance through the electronic IRB system and completing the required hospital system's Research Application Form. The hospital system review occurs in parallel with the IRB review, not duplicating it but rather focusing separately on patient safety, operational and financial issues, and hospital risk issues.

Our Clinical Innovation and Research Institute manages the hospital system review. Upon electronic notification of a new study submission, an Institute Clinical Research Associate examines all study‐related documents, including the completed Research Application Form and other submitted documents, such as the study protocol, the investigational product's Investigator's Brochure, consent forms, Food and Drug Administration (FDA) letters, survey questions, and diary and other data collection forms. The Associate may spend considerable time communicating with the investigator's research team, collecting missing information and building a complete study file, including identifying the affected hospitals and hospital departments. The Institute then provides study documents to the individuals responsible for hospital‐level research review, and each affected hospital conducts its own internal review and approval process.

The hospital‐level review process varies depending on the hospitals involved. The academic teaching hospital has the most detailed review process, due to the complexities and risks associated with the full spectrum of human participant research which occurs there (Hospital A in Figure 1). If a study affects this hospital, the Institute provides study documents to each affected Department Manager, the affected Service Line Chief, the Chief Medical Officer or Medical Director of each Intensive Care Unit within which the study will recruit and enroll patients, and the Infection Control Officer and Radiation Safety Officer, as appropriate.

Figure 1

The specialty rehabilitation hospital has a long‐standing national reputation for its research programs; its Director of Research knows each investigator, reviews each study, and provides that hospital's administrative review (Hospital B). Seven of the system's community hospitals have either a Chief Executive Officer, Chief Nursing Officer, or Chief Financial Officer serve as the hospital's executive administrator responsible for research review, and this person distributes the study documents to the Chief Medical Officer, if deemed necessary, and to each affected department (Hospitals C‐I). One of the smaller community hospitals participates in relatively few studies; the Chief Nursing Officer reviews and provides hospital‐level approval (Hospital J). For retrospective studies requesting a clinical data set, the Institute provides the study documents to the Director of the Information Systems Department. All studies accessing patient data are provided to the system Privacy Officer for review and approval.

Studies may involve 1 or more hospitals; some have involved as many as 7 at once.

All reviewers also receive a standardized Research Study Evaluation Form for their written comments and recommendations (Approve, Disapprove, or Defer) regarding whether the hospital system should approve the study.

If a study requests hospital‐provided research services, the Institute's Research Financial Coordinator develops a research budget listing the hospital charges that the researcher will incur for these tests and procedures.

Once reviewers return completed Evaluation Forms, the Institute Clinical Research Associate makes an initial determination whether the review process has satisfactorily answered all questions and resolved all outstanding issues. The Manager of Clinical Research Operations then examines the study file to ensure a satisfactory review. Finally, the system Executive Director for Clinical Research provides a Letter of Approval to the Principal Investigator, which serves as the agreement of terms for conducting the study within the hospital system. The letter contains standard stipulations, such as requiring the Principal Investigator to abide by federal law and International Conference on Harmonization (ICH) GCPs and the budget for the hospital‐provided research tests and procedures. Additionally, it includes any stipulations unique to the studyfor example, that the Principal Investigator will provide training to hospital personnel who will be operating nonhospital equipment. The Institute provides affected hospital departments with copies of the approval letter. Upon signing and returning the letter, the Principal Investigator may begin the study in the designated hospitals.

Some details about the hospital system review are discussed in sections below.

Discussion

Our hospital research review and approval process is critical to ensuring that only safe and regulatory‐compliant research activities occur within our hospital system, but the review and approval process, with its many steps and numerous reviewers, can be cumbersome. There is no substitute for human beings reading and understanding the protocol, consent forms for patient involvement in a study, the proposed use of protected health information, Investigator's Brochure, Research Application Form, and other study documents and then identifying pertinent issues and resolving them, and this process does require significant staff time.

We have improved (continuously) the Research Application Form to help in the crucial initial gathering of information about studies' operational needs. We have also converted from a predominantly paper‐based review process to the widespread use of electronic documents, but we have not automated the distribution process for these electronic documents and a staff person must still do this through email.

Despite our efforts to improve the review process, investigators are sometimes frustrated with it, particularly if someone identifies a new issue late in the process, or if the hospital system's approval for the study lags behind the IRB approval by more than a few days.

Currently, the hospital system provides the majority of study approvals to the Principal Investigator within 2 weeks of IRB approval, with some approvals provided within 1 day of IRB approval and others as long as 3 months afterward. Delays in hospital approval can be due to a study lacking required approval from a Department of Defense IRB, the FDA not providing permission to proceed with a study, the absence of an executed contract with a vendor to pick up and dispose of radioactive waste from the investigational product and many other factors. Of course, when the research team can respond in timely fashion to inquiries or issues that we have raised, that assists all of us in completing the review and approval process as quickly as possible.

The review and approval process benefits hospital patients, hospital personnel who will be supporting studies, and hospitals as institutions. Thinking through, planning, and preparing for study operations, particularly for studies taking place in an ICU, benefits the research team, hospital personnel, and the patients. Overall, the hospital system's research review and approval process affords many protections to our patients and reduces risks to the hospital system while permitting research studies to be conducted within its varied healthcare facilities.

We encourage researchers not to view today's modern hospital as bricks and mortar, but as an institution with deep responsibility for safety on hospital premises. Hospitals must meet over a thousand Joint Commission standards, set goals for patient outcomes, measure and report on quality indicators, protect patient confidentiality, maintain the safety an ever‐expanding array of simple and complex equipment, maintain, check and document contents of adult and pediatric crash carts, have 24‐7 code teams at‐the‐ready, create, maintain and store patient medical records securely, transport patients, and much more.

Conclusion

Our hospital system, in accordance with a system‐wide policy, engages in a comprehensive review and approval process for any human participant research that has been proposed to be conducted within one or more of our facilities. The process focuses primarily on patient safety within the hospital premises, operational study issues, financial issues and hospital risk issues. This process decreases risks to the patients, researchers, and hospital facilities engaging in human participant research.

Hospitals have important legal and ethical responsibilities for human participant research conducted within their facilities, such as ensuring that research complies with federal regulations and presents minimal risks to patients. Many hospitals accept as sufficient the federal requirement that human participant research studies have Institutional Review Board (IRB) review and approval. IRBs must review proposed research according to numerous criteria, such as scientific soundness, alignment with accepted ethics principles and weighing of benefit vs. risk to study participants.1, 2 The legally required aspects of IRB review do not, however, include considering practical matters in implementing and operating an interventional clinical trial in the complex environment of the modern acute care hospital.

Our hospital system established a broad policy requiring internal review and formal approval of any human participant research conducted within any of its hospitals, including studies that enroll hospital patients or hospital employees, utilize hospital medical records, or request hospital‐provided services for research tests or procedures. The purpose of this paper is to describe this formal hospital system review and approval process, the reasons for implementing it, and the types of issues considered prior to our hospital system granting a principal investigator permission to conduct a study.

Background

Surprisingly little healthcare or medical literature exists regarding hospital responsibilities toward human subject research conducted on its premises. Much of the literature focuses on ethics issues, the nature of informed consent, and study design. As critical as these discussions are, they seldom address the numerous complex operational issues and challenges that implementation of a clinical trial can create in a hospital setting.

Flanders et al.3 make the case for hospitalists and specialists to work together to support research that includes inpatients as study participants. Moore and Goldberg4 discuss the ingredients of successfully developing a research program in a community hospital and mention the need to involve all affected hospital departments in the initial hospital review of a study, evaluating study impact on hospital workflow, and establishing processes related to budgeting and billing. Jamerson5 also makes the case for hospital departmental review and involvement, assessment of the ability to integrate study activities into the hospital structure, assessment of the resources needed to support the research, determination of whether the hospital will contribute financially to the research, and explicit decision making regarding the assumption of institutional risk.

Despite the recognition that US patients increasingly live with multiple chronic conditions6 and that clinical trial protocols have become more procedure and resource intensive and costly,79 there has not been a corollary recognition of the increasing need for hospitals to understand and manage research activities occurring within their facilities.

Our organization is a hospital system with 9 acute care hospitals, including an academic teaching hospital (affiliated with a university medical school) with a Level 1 Trauma Center, 1 specialty rehabilitation hospital, numerous specialized clinics, and a LifeFlight Program with a 6‐helicopter fleet (Geisinger, Danville, PA). This system of hospitals serves the fourth largest metropolitan community in the US (Houston and Harris County in southeastern TX), with a population of nearly four million and a geographic spread of 1778 square miles.10, 11 The hospital system has approximately 140,700 inpatient admissions per year and 586,000 outpatient visits.

Eight years ago, our hospital system adopted a corporate policy requiring that any activity associated with human participant research receive prior hospital system review and approval. Our organization considers this review process vital to: (1) maintaining our commitment to our Federalwide Assurance with the Office for Human Research Protections, (2) abiding by the Joint Commission requirements related to research,12 (3) protecting the safety and confidentiality of patients and employees who are potential or actual research participants, (4) protecting the confidentiality of participants' medical information, (5) assuring that legal fundamentals and good clinical practice (GCH)13 are a part of study plans, (6) assuring that studies are operationally feasible, and (7) evaluating and minimizing risks to patients and risks to the organization.

Review and Approval Process

Overview

An investigator triggers a formal hospital system review by submitting study documents to 1 of the IRBs listed on the system's Federalwide Assurance through the electronic IRB system and completing the required hospital system's Research Application Form. The hospital system review occurs in parallel with the IRB review, not duplicating it but rather focusing separately on patient safety, operational and financial issues, and hospital risk issues.

Our Clinical Innovation and Research Institute manages the hospital system review. Upon electronic notification of a new study submission, an Institute Clinical Research Associate examines all study‐related documents, including the completed Research Application Form and other submitted documents, such as the study protocol, the investigational product's Investigator's Brochure, consent forms, Food and Drug Administration (FDA) letters, survey questions, and diary and other data collection forms. The Associate may spend considerable time communicating with the investigator's research team, collecting missing information and building a complete study file, including identifying the affected hospitals and hospital departments. The Institute then provides study documents to the individuals responsible for hospital‐level research review, and each affected hospital conducts its own internal review and approval process.

The hospital‐level review process varies depending on the hospitals involved. The academic teaching hospital has the most detailed review process, due to the complexities and risks associated with the full spectrum of human participant research which occurs there (Hospital A in Figure 1). If a study affects this hospital, the Institute provides study documents to each affected Department Manager, the affected Service Line Chief, the Chief Medical Officer or Medical Director of each Intensive Care Unit within which the study will recruit and enroll patients, and the Infection Control Officer and Radiation Safety Officer, as appropriate.

Figure 1

The specialty rehabilitation hospital has a long‐standing national reputation for its research programs; its Director of Research knows each investigator, reviews each study, and provides that hospital's administrative review (Hospital B). Seven of the system's community hospitals have either a Chief Executive Officer, Chief Nursing Officer, or Chief Financial Officer serve as the hospital's executive administrator responsible for research review, and this person distributes the study documents to the Chief Medical Officer, if deemed necessary, and to each affected department (Hospitals C‐I). One of the smaller community hospitals participates in relatively few studies; the Chief Nursing Officer reviews and provides hospital‐level approval (Hospital J). For retrospective studies requesting a clinical data set, the Institute provides the study documents to the Director of the Information Systems Department. All studies accessing patient data are provided to the system Privacy Officer for review and approval.

Studies may involve 1 or more hospitals; some have involved as many as 7 at once.

All reviewers also receive a standardized Research Study Evaluation Form for their written comments and recommendations (Approve, Disapprove, or Defer) regarding whether the hospital system should approve the study.

If a study requests hospital‐provided research services, the Institute's Research Financial Coordinator develops a research budget listing the hospital charges that the researcher will incur for these tests and procedures.

Once reviewers return completed Evaluation Forms, the Institute Clinical Research Associate makes an initial determination whether the review process has satisfactorily answered all questions and resolved all outstanding issues. The Manager of Clinical Research Operations then examines the study file to ensure a satisfactory review. Finally, the system Executive Director for Clinical Research provides a Letter of Approval to the Principal Investigator, which serves as the agreement of terms for conducting the study within the hospital system. The letter contains standard stipulations, such as requiring the Principal Investigator to abide by federal law and International Conference on Harmonization (ICH) GCPs and the budget for the hospital‐provided research tests and procedures. Additionally, it includes any stipulations unique to the studyfor example, that the Principal Investigator will provide training to hospital personnel who will be operating nonhospital equipment. The Institute provides affected hospital departments with copies of the approval letter. Upon signing and returning the letter, the Principal Investigator may begin the study in the designated hospitals.

Some details about the hospital system review are discussed in sections below.

Discussion

Our hospital research review and approval process is critical to ensuring that only safe and regulatory‐compliant research activities occur within our hospital system, but the review and approval process, with its many steps and numerous reviewers, can be cumbersome. There is no substitute for human beings reading and understanding the protocol, consent forms for patient involvement in a study, the proposed use of protected health information, Investigator's Brochure, Research Application Form, and other study documents and then identifying pertinent issues and resolving them, and this process does require significant staff time.

We have improved (continuously) the Research Application Form to help in the crucial initial gathering of information about studies' operational needs. We have also converted from a predominantly paper‐based review process to the widespread use of electronic documents, but we have not automated the distribution process for these electronic documents and a staff person must still do this through email.

Despite our efforts to improve the review process, investigators are sometimes frustrated with it, particularly if someone identifies a new issue late in the process, or if the hospital system's approval for the study lags behind the IRB approval by more than a few days.

Currently, the hospital system provides the majority of study approvals to the Principal Investigator within 2 weeks of IRB approval, with some approvals provided within 1 day of IRB approval and others as long as 3 months afterward. Delays in hospital approval can be due to a study lacking required approval from a Department of Defense IRB, the FDA not providing permission to proceed with a study, the absence of an executed contract with a vendor to pick up and dispose of radioactive waste from the investigational product and many other factors. Of course, when the research team can respond in timely fashion to inquiries or issues that we have raised, that assists all of us in completing the review and approval process as quickly as possible.

The review and approval process benefits hospital patients, hospital personnel who will be supporting studies, and hospitals as institutions. Thinking through, planning, and preparing for study operations, particularly for studies taking place in an ICU, benefits the research team, hospital personnel, and the patients. Overall, the hospital system's research review and approval process affords many protections to our patients and reduces risks to the hospital system while permitting research studies to be conducted within its varied healthcare facilities.

We encourage researchers not to view today's modern hospital as bricks and mortar, but as an institution with deep responsibility for safety on hospital premises. Hospitals must meet over a thousand Joint Commission standards, set goals for patient outcomes, measure and report on quality indicators, protect patient confidentiality, maintain the safety an ever‐expanding array of simple and complex equipment, maintain, check and document contents of adult and pediatric crash carts, have 24‐7 code teams at‐the‐ready, create, maintain and store patient medical records securely, transport patients, and much more.

Conclusion

Our hospital system, in accordance with a system‐wide policy, engages in a comprehensive review and approval process for any human participant research that has been proposed to be conducted within one or more of our facilities. The process focuses primarily on patient safety within the hospital premises, operational study issues, financial issues and hospital risk issues. This process decreases risks to the patients, researchers, and hospital facilities engaging in human participant research.

Hospitals have important legal and ethical responsibilities for human participant research conducted within their facilities, such as ensuring that research complies with federal regulations and presents minimal risks to patients. Many hospitals accept as sufficient the federal requirement that human participant research studies have Institutional Review Board (IRB) review and approval. IRBs must review proposed research according to numerous criteria, such as scientific soundness, alignment with accepted ethics principles and weighing of benefit vs. risk to study participants.1, 2 The legally required aspects of IRB review do not, however, include considering practical matters in implementing and operating an interventional clinical trial in the complex environment of the modern acute care hospital.

Our hospital system established a broad policy requiring internal review and formal approval of any human participant research conducted within any of its hospitals, including studies that enroll hospital patients or hospital employees, utilize hospital medical records, or request hospital‐provided services for research tests or procedures. The purpose of this paper is to describe this formal hospital system review and approval process, the reasons for implementing it, and the types of issues considered prior to our hospital system granting a principal investigator permission to conduct a study.

Background

Surprisingly little healthcare or medical literature exists regarding hospital responsibilities toward human subject research conducted on its premises. Much of the literature focuses on ethics issues, the nature of informed consent, and study design. As critical as these discussions are, they seldom address the numerous complex operational issues and challenges that implementation of a clinical trial can create in a hospital setting.

Flanders et al.3 make the case for hospitalists and specialists to work together to support research that includes inpatients as study participants. Moore and Goldberg4 discuss the ingredients of successfully developing a research program in a community hospital and mention the need to involve all affected hospital departments in the initial hospital review of a study, evaluating study impact on hospital workflow, and establishing processes related to budgeting and billing. Jamerson5 also makes the case for hospital departmental review and involvement, assessment of the ability to integrate study activities into the hospital structure, assessment of the resources needed to support the research, determination of whether the hospital will contribute financially to the research, and explicit decision making regarding the assumption of institutional risk.

Despite the recognition that US patients increasingly live with multiple chronic conditions6 and that clinical trial protocols have become more procedure and resource intensive and costly,79 there has not been a corollary recognition of the increasing need for hospitals to understand and manage research activities occurring within their facilities.

Our organization is a hospital system with 9 acute care hospitals, including an academic teaching hospital (affiliated with a university medical school) with a Level 1 Trauma Center, 1 specialty rehabilitation hospital, numerous specialized clinics, and a LifeFlight Program with a 6‐helicopter fleet (Geisinger, Danville, PA). This system of hospitals serves the fourth largest metropolitan community in the US (Houston and Harris County in southeastern TX), with a population of nearly four million and a geographic spread of 1778 square miles.10, 11 The hospital system has approximately 140,700 inpatient admissions per year and 586,000 outpatient visits.

Eight years ago, our hospital system adopted a corporate policy requiring that any activity associated with human participant research receive prior hospital system review and approval. Our organization considers this review process vital to: (1) maintaining our commitment to our Federalwide Assurance with the Office for Human Research Protections, (2) abiding by the Joint Commission requirements related to research,12 (3) protecting the safety and confidentiality of patients and employees who are potential or actual research participants, (4) protecting the confidentiality of participants' medical information, (5) assuring that legal fundamentals and good clinical practice (GCH)13 are a part of study plans, (6) assuring that studies are operationally feasible, and (7) evaluating and minimizing risks to patients and risks to the organization.

Review and Approval Process

Overview

An investigator triggers a formal hospital system review by submitting study documents to 1 of the IRBs listed on the system's Federalwide Assurance through the electronic IRB system and completing the required hospital system's Research Application Form. The hospital system review occurs in parallel with the IRB review, not duplicating it but rather focusing separately on patient safety, operational and financial issues, and hospital risk issues.

Our Clinical Innovation and Research Institute manages the hospital system review. Upon electronic notification of a new study submission, an Institute Clinical Research Associate examines all study‐related documents, including the completed Research Application Form and other submitted documents, such as the study protocol, the investigational product's Investigator's Brochure, consent forms, Food and Drug Administration (FDA) letters, survey questions, and diary and other data collection forms. The Associate may spend considerable time communicating with the investigator's research team, collecting missing information and building a complete study file, including identifying the affected hospitals and hospital departments. The Institute then provides study documents to the individuals responsible for hospital‐level research review, and each affected hospital conducts its own internal review and approval process.

The hospital‐level review process varies depending on the hospitals involved. The academic teaching hospital has the most detailed review process, due to the complexities and risks associated with the full spectrum of human participant research which occurs there (Hospital A in Figure 1). If a study affects this hospital, the Institute provides study documents to each affected Department Manager, the affected Service Line Chief, the Chief Medical Officer or Medical Director of each Intensive Care Unit within which the study will recruit and enroll patients, and the Infection Control Officer and Radiation Safety Officer, as appropriate.

Figure 1

The specialty rehabilitation hospital has a long‐standing national reputation for its research programs; its Director of Research knows each investigator, reviews each study, and provides that hospital's administrative review (Hospital B). Seven of the system's community hospitals have either a Chief Executive Officer, Chief Nursing Officer, or Chief Financial Officer serve as the hospital's executive administrator responsible for research review, and this person distributes the study documents to the Chief Medical Officer, if deemed necessary, and to each affected department (Hospitals C‐I). One of the smaller community hospitals participates in relatively few studies; the Chief Nursing Officer reviews and provides hospital‐level approval (Hospital J). For retrospective studies requesting a clinical data set, the Institute provides the study documents to the Director of the Information Systems Department. All studies accessing patient data are provided to the system Privacy Officer for review and approval.

Studies may involve 1 or more hospitals; some have involved as many as 7 at once.

All reviewers also receive a standardized Research Study Evaluation Form for their written comments and recommendations (Approve, Disapprove, or Defer) regarding whether the hospital system should approve the study.

If a study requests hospital‐provided research services, the Institute's Research Financial Coordinator develops a research budget listing the hospital charges that the researcher will incur for these tests and procedures.

Once reviewers return completed Evaluation Forms, the Institute Clinical Research Associate makes an initial determination whether the review process has satisfactorily answered all questions and resolved all outstanding issues. The Manager of Clinical Research Operations then examines the study file to ensure a satisfactory review. Finally, the system Executive Director for Clinical Research provides a Letter of Approval to the Principal Investigator, which serves as the agreement of terms for conducting the study within the hospital system. The letter contains standard stipulations, such as requiring the Principal Investigator to abide by federal law and International Conference on Harmonization (ICH) GCPs and the budget for the hospital‐provided research tests and procedures. Additionally, it includes any stipulations unique to the studyfor example, that the Principal Investigator will provide training to hospital personnel who will be operating nonhospital equipment. The Institute provides affected hospital departments with copies of the approval letter. Upon signing and returning the letter, the Principal Investigator may begin the study in the designated hospitals.

Some details about the hospital system review are discussed in sections below.

Discussion

Our hospital research review and approval process is critical to ensuring that only safe and regulatory‐compliant research activities occur within our hospital system, but the review and approval process, with its many steps and numerous reviewers, can be cumbersome. There is no substitute for human beings reading and understanding the protocol, consent forms for patient involvement in a study, the proposed use of protected health information, Investigator's Brochure, Research Application Form, and other study documents and then identifying pertinent issues and resolving them, and this process does require significant staff time.

We have improved (continuously) the Research Application Form to help in the crucial initial gathering of information about studies' operational needs. We have also converted from a predominantly paper‐based review process to the widespread use of electronic documents, but we have not automated the distribution process for these electronic documents and a staff person must still do this through email.

Despite our efforts to improve the review process, investigators are sometimes frustrated with it, particularly if someone identifies a new issue late in the process, or if the hospital system's approval for the study lags behind the IRB approval by more than a few days.

Currently, the hospital system provides the majority of study approvals to the Principal Investigator within 2 weeks of IRB approval, with some approvals provided within 1 day of IRB approval and others as long as 3 months afterward. Delays in hospital approval can be due to a study lacking required approval from a Department of Defense IRB, the FDA not providing permission to proceed with a study, the absence of an executed contract with a vendor to pick up and dispose of radioactive waste from the investigational product and many other factors. Of course, when the research team can respond in timely fashion to inquiries or issues that we have raised, that assists all of us in completing the review and approval process as quickly as possible.

The review and approval process benefits hospital patients, hospital personnel who will be supporting studies, and hospitals as institutions. Thinking through, planning, and preparing for study operations, particularly for studies taking place in an ICU, benefits the research team, hospital personnel, and the patients. Overall, the hospital system's research review and approval process affords many protections to our patients and reduces risks to the hospital system while permitting research studies to be conducted within its varied healthcare facilities.

We encourage researchers not to view today's modern hospital as bricks and mortar, but as an institution with deep responsibility for safety on hospital premises. Hospitals must meet over a thousand Joint Commission standards, set goals for patient outcomes, measure and report on quality indicators, protect patient confidentiality, maintain the safety an ever‐expanding array of simple and complex equipment, maintain, check and document contents of adult and pediatric crash carts, have 24‐7 code teams at‐the‐ready, create, maintain and store patient medical records securely, transport patients, and much more.

Conclusion

Our hospital system, in accordance with a system‐wide policy, engages in a comprehensive review and approval process for any human participant research that has been proposed to be conducted within one or more of our facilities. The process focuses primarily on patient safety within the hospital premises, operational study issues, financial issues and hospital risk issues. This process decreases risks to the patients, researchers, and hospital facilities engaging in human participant research.

Haloperidol is Food and Drug Administration (FDA)‐approved in the United States for the management of acute and chronic psychotic disorders and widely used in the management of delirium‐associated agitation in hospitalized patients.1 Delirium in the hospital is an acute confusional state that frequently arises from multiple complex factors and may affect up to 30% of hospitalized patients.2 Although the first step in the management of delirium involves identification and treatment of underlying causes and offering supportive behavioral care; medications may be needed to control severe agitation.2 Low dose intravenous (IV) haloperidol (ie, 0.250.5 mg every 4 hours) is a commonly used medication in this setting as recommended by expert‐groups including the Cochrane Collaboration and the American Psychiatric Association.2, 3

Although injectable haloperidol, a butyrophenone‐derived antipsychotic agent pharmacologically related to the piperazine phenothiazines,4 is approved for IV use in many countries (Table 1), parenteral use is approved only for intramuscular (IM) administration in the US. Thus, IV administration of the drug in the US is considered an off‐label use.5

Haloperidol is often preferred over other antipsychotics as a result of its effectiveness, low rate of anticholinergic side effects, familiarity with dosing and usage, and minimal respiratory or sedative properties.6 Use of the IV route in patients with acute delirium has several advantages over the IM or oral route,7 including rapid onset, immediate bioavailability, and ease and safety of administration.

Prior to September 2007, the package insert for haloperidol alerted healthcare professionals to the risk of cardiovascular side effects. Based on case reports of potentially fatal cardiac events, the FDA revised the label, warning that the QT prolongation (QTP) and risk of torsades de pointes (TdP) were increased with IV administration of haloperidol or administration of the drug at greater than recommended doses. Unfortunately, neither the typical dosing range nor the minimum dose associated with these cardiac side effects were specified in this recommendation.5

It is well‐established that haloperidol may prolong the QT interval by blocking the repolarizing potassium I_Kr current.8 Although drugs that block the I_Kr channel can produce arrhythmia in healthy individuals, additional risk factors, such as underlying heart conditions, electrolyte imbalances (ie, hypokalemia and hypomagnesemia), concomitant proarrhythmic drug use, and mechanical ventilation may increase this risk.9 Prolongation of the QT interval has been associated with subsequent malignant cardiac arrhythmias including ventricular fibrillation and TdP.10 Prolongation of the QT interval is considered the strongest risk factor for TdP, particularly with a baseline QTc > 450 msec.9

Based on the increased risk for QTP and TdP and the case reports of cardiac events, the FDA advisory recommended continuous electrocardiogram (ECG) monitoring in patients receiving IV haloperidol.5 However, such monitoring may be impractical and costly in hospitalized patients who require low doses of IV haloperidol to manage acute delirium and who are not in telemetry or intensive care units.

The aim of this review was to evaluate the case reports leading to the recent FDA warning for IV haloperidol, specifically focusing on the presence of risk factors for arrhythmias. Based upon the evidence, an additional aim was to provide an institutional response to this warning toward the optimal use of this agent.

Method

Two search pathways were used to evaluate reports of haloperidol‐associated TdP and/or QT prolongation:

Results

A total of 70 reported cases of IV haloperidol associated TdP and/or QTP were identified. Of these 70, 41 were identified through the PubMed/EMBASE/Scopus review, while an additional 29 cases were identified through the FDA database search.

Of the 29 cases in the FDA database, 21 were reported by health care professionals and 8 by manufacturers.

A total of 35 publications described cases originating from the US. Three cases took place in Japan and 1 case each in Canada, Germany and Spain. Several cases in the MedWatch database were reported outside the US: 1 case each originated from Austria, Canada, France, Japan, Spain, Switzerland and the United Kingdom. A summary of the published case reports is displayed in Table 2 and the FDA cases are summarized in Table 3.