CHOLECYSTITIS

ntroduction
Background

Cholecystitis is defined as inflammation of the gallbladder that occurs most commonly because of an obstruction of the cystic duct from cholelithiasis. Ninety percent of cases involve stones in the cystic duct (ie, calculous cholecystitis), with the other 10% of cases representing acalculous cholecystitis.1 Although bile cultures are positive for bacteria in 50-75% of cases, bacterial proliferation may be a result of cholecystitis and not the precipitating factor. Risk factors for cholecystitis mirror those for cholelithiasis and include increasing age, female sex, certain ethnic groups, obesity or rapid weight loss, drugs, and pregnancy.

Acalculous cholecystitis is related to conditions associated with biliary stasis, including debilitation, major surgery, severe trauma, sepsis, long-term total parenteral nutrition (TPN), and prolonged fasting. Other causes of acalculous cholecystitis include cardiac events; sickle cell disease; Salmonella infections; diabetes mellitus; and cytomegalovirus, cryptosporidiosis, or microsporidiosis infections in patients with AIDS.
Pathophysiology

Acute calculous cholecystitis is caused by obstruction of the cystic duct, leading to distention of the gallbladder. As the gallbladder becomes distended, blood flow and lymphatic drainage are compromised, leading to mucosal ischemia and necrosis. A study by Cullen et al demonstrated the ability of endotoxin to cause necrosis, hemorrhage, areas of fibrin deposition, and extensive mucosal loss, consistent with an acute ischemic insult.2 Endotoxin also abolished the contractile response to cholecystokinin (CCK), leading to gallbladder stasis.

Although the exact mechanism of acalculous cholecystitis is unclear, a couple of theories exist. Injury may be the result of retained concentrated bile, an extremely noxious substance. In the presence of prolonged fasting, the gallbladder never receives a CCK stimulus to empty; thus, the concentrated bile remains stagnant in the lumen.
Frequency
United States

An estimated 10-20% of Americans have gallstones, and as many as one third of these people develop acute cholecystitis. Cholecystectomy for either recurrent biliary colic or acute cholecystitis is the most common major surgical procedure performed by general surgeons, resulting in approximately 500,000 operations annually.
International

Cholelithiasis, the major risk factor for cholecystitis, has an increased prevalence among people of Scandinavian descent, Pima Indians, and Hispanic populations, whereas cholelithiasis is less common among individuals from sub-Saharan Africa and Asia.3,4
Mortality/Morbidity

* Most patients with acute cholecystitis have a complete remission within 1-4 days. However, 25-30% of patients either require surgery or develop some complication.
* Patients with acalculous cholecystitis have a mortality rate ranging from 10-50%, which far exceeds the expected 4% mortality rate observed in patients with calculous cholecystitis. Emphysematous cholecystitis has a mortality rate approaching 15%.
* Perforation occurs in 10-15% of cases.

Race

* Pima Indian and Scandinavian people have the highest prevalence of cholelithiasis and, consequently, cholecystitis.
* Populations at the lowest risk reside in sub-Saharan Africa and Asia.
* In the United States, white people have a higher prevalence than black people.

Sex

* Gallstones are 2-3 times more frequent in females than in males, resulting in a higher incidence of calculous cholecystitis in females.
* Elevated progesterone levels during pregnancy may cause biliary stasis, resulting in higher rates of gallbladder disease in pregnant females.
* Acalculous cholecystitis is observed more often in elderly men.

Age

The incidence of cholecystitis increases with age. The physiologic explanation for the increasing incidence of gallstone disease in the elderly population is unclear. The increased incidence in elderly men has been linked to changing androgen-to-estrogen ratios.
Clinical
History

* The most common presenting symptom of acute cholecystitis is upper abdominal pain, often radiating to the tip of the right scapula.
o Most patients with acute cholecystitis describe a history of biliary pain. Some patients may have documented gallstones. Acalculous biliary colic also occurs, most commonly in young–to–middle-aged females. The presentation is almost identical to calculous biliary colic with the exception of reference range laboratory values and no findings of cholelithiasis on ultrasound.
o Frequently, the pain begins in the epigastric region and then localizes to the right upper quadrant (RUQ). Although the pain may initially be described as colicky, it becomes constant in virtually all cases.
o Signs of peritoneal irritation may be present, and, in some patients, the pain may radiate to the right shoulder or scapula.
* Nausea and vomiting are generally present, and patients may report fever.
* In elderly patients, pain and fever may be absent, and localized tenderness may be the only presenting sign. Patients with acalculous cholecystitis may present similarly to patients with calculous cholecystitis, but acalculous cholecystitis frequently occurs suddenly in severely ill patients without a prior history of biliary colic. Often, patients with acalculous cholecystitis may present with fever and sepsis alone, without history or physical examination findings consistent with acute cholecystitis.
* Cholecystitis is differentiated from biliary colic by the persistence of constant severe pain for more than 6 hours.

Physical

* Physical examination may reveal fever, tachycardia, and tenderness in the RUQ or epigastric region, often with guarding or rebound.
* A palpable gallbladder or fullness of the RUQ is present in 30-40% of cases.
* Jaundice may be noted in approximately 15% of patients.
* The absence of physical findings does not rule out the diagnosis of cholecystitis. Many patients present with diffuse epigastric pain without localization to the RUQ. Patients with chronic cholecystitis frequently do not have a palpable RUQ mass secondary to fibrosis involving the gallbladder.
* Elderly patients and patients with diabetes frequently have atypical presentations, including absence of fever and localized tenderness with only vague symptoms.
* Murphy sign, which is specific but not sensitive for cholecystitis, is described as tenderness and an inspiratory pause elicited during palpation of the RUQ.

Causes

* Risk factors for calculous cholecystitis mirror those for cholelithiasis and include the following:
o Female sex
o Certain ethnic groups (see Race)
o Obesity or rapid weight loss
o Drugs (especially hormonal therapy in women)
o Pregnancy
o Increasing age
* Acalculous cholecystitis is related to conditions associated with biliary stasis, to include the following:
o Critical illness
o Major surgery or severe trauma/burns
o Sepsis
o Long-term TPN
o Prolonged fasting
* Other causes of acalculous cholecystitis include the following:
o Cardiac events, including myocardial infarction
o Sickle cell disease
o Salmonella infections
o Diabetes mellitus
o Patients with AIDS with cytomegalovirus, cryptosporidiosis, or microsporidiosis
* Idiopathic cases exist.Differential Diagnoses
Abdominal Aortic Aneurysm
Gastritis, Acute
Acute Mesenteric Ischemia
Gastroesophageal Reflux Disease
Amebic Hepatic Abscesses
Hepatitis, Viral
Appendicitis
Myocardial Infarction
Biliary Colic
Nephrolithiasis
Biliary Disease
Pancreatitis, Acute
Cholangiocarcinoma
Peptic Ulcer Disease
Cholangitis
Pneumonia, Bacterial
Choledocholithiasis
Pregnancy and Urolithiasis
Cholelithiasis
Pyelonephritis, Acute
Gallbladder Cancer
Renal Disease and Pregnancy
Gallbladder Mucocele
Renal Vein Thrombosis
Gallbladder Tumors

Gastric Ulcers

Workup
Laboratory Studies

* A retrospective study by Singer attempted to determine a set of clinical and laboratory parameters that could be used to predict the outcome of hepatobiliary scintigraphy (HBS) in all patients with suspected acute cholecystitis.5
o The results of the study showed that, in 40 patients with pathologically confirmed acute cholecystitis, fever and leukocytosis were absent at the time of presentation in 36 (90%) and 16 (40%) of the patients, respectively.
o The study also found that no combination of laboratory or clinical values was useful in identifying patients at high risk for a positive HBS finding.
* Although laboratory criteria are not reliable in identifying all patients with cholecystitis, the following findings may be useful in arriving at the diagnosis:
o Leukocytosis with a left shift may be observed in cholecystitis.
o Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels are used to evaluate the presence of hepatitis and may be elevated in cholecystitis or with common bile duct obstruction.
o Bilirubin and alkaline phosphatase assays are used to evaluate evidence of common duct obstruction.
o Amylase/lipase assays are used to evaluate the presence of pancreatitis. Amylase may also be elevated mildly in cholecystitis.
o An elevated alkaline phosphatase level is observed in 25% of patients with cholecystitis.
o Urinalysis is used to rule out pyelonephritis and renal calculi.
o All females of childbearing age should have pregnancy testing.

Imaging Studies

* Radiography (without contrast)
o Gallstones may be visualized in 10-15% of cases. This finding only indicates cholelithiasis, with or without active cholecystitis.
o Subdiaphragmatic free air cannot originate in the biliary tract, and, if present, it indicates another disease process.
o Gas limited to the gallbladder wall or lumen represents emphysematous cholecystitis, usually because of gas-forming bacteria, such as Escherichia coli and clostridial and anaerobic streptococci species. Emphysematous cholecystitis is associated with an increased mortality rate and occurs most commonly in males with diabetes and with acalculous cholecystitis.
o A diffusely calcified gallbladder (ie, porcelainized) most commonly is associated with carcinoma, although one retrospective study by Towfigh found no association between partial calcification of the gallbladder and carcinoma.6
o Other findings may include renal calculi, intestinal obstruction, or pneumonia.
* Ultrasonography
o Ultrasonography provides greater than 95% sensitivity and specificity for the diagnosis of gallstones more than 2 mm in diameter. Ultrasonography is 90-95% sensitive for cholecystitis and is 78-80% specific. Studies indicate that emergency clinicians require minimal training in order to use right upper quadrant ultrasonography in their practice.
o Ultrasonographic findings that are suggestive of acute cholecystitis include the following: pericholecystic fluid, gallbladder wall thickening greater than 4 mm, and sonographic Murphy sign. The presence of gallstones also helps to confirm the diagnosis.
o Ultrasonography is performed best following a fast of at least 8 hours because gallstones are visualized best in a distended bile-filled gallbladder.
* Hepatobiliary scintigraphy (hepatoiminodiacetic acid [HIDA]/diisopropyl iminodiacetic acid [DISIDA])
o HBS has been found to be up to 95% accurate in diagnosing acute cholecystitis. The reported sensitivities and specificities of biliary scintigraphy are in the range of 90-100% and 85-95%. (See the following 2 images.)
o

Cholecystitis. Normal finding on hepatoiminodiace...
Cholecystitis. Normal finding on hepatoiminodiacetic acid (HIDA) scan.

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Cholecystitis. Normal finding on hepatoiminodiace...

Cholecystitis. Normal finding on hepatoiminodiacetic acid (HIDA) scan.
o

Cholecystitis. Abnormal finding on hepatoiminodia...
Cholecystitis. Abnormal finding on hepatoiminodiacetic acid (HIDA) scan.

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Cholecystitis. Abnormal finding on hepatoiminodia...

Cholecystitis. Abnormal finding on hepatoiminodiacetic acid (HIDA) scan.
o In a typical study, the gallbladder, common bile duct, and small bowel fill within 30-45 minutes.
o If the gallbladder is not visualized, intravenous morphine administration can improve the accuracy of HBS by increasing resistance to flow through the sphincter of Oddi, resulting in filling of the gallbladder if the cystic duct is patent. The addition of morphine also reduces the number of false-positive scan results observed in patients who are critically ill and immobilized with viscous bile.
* CT scan and MRI
o The sensitivity and specificity of CT scan and MRI for predicting acute cholecystitis have been reported to be greater than 95%.7 Spiral CT scan and MRI (unlike endoscopic retrograde cholangiopancreatography [ERCP]) have the advantage of being noninvasive, but they have no therapeutic potential and are most appropriate in cases where stones are unlikely.
o Findings suggestive of cholecystitis include wall thickening (>4 mm), pericholecystic fluid, subserosal edema (in the absence of ascites), intramural gas, and sloughed mucosa.
o CT scan and MRI are also useful for viewing surrounding structures if the diagnosis is uncertain.

Procedures

* Endoscopic retrograde cholangiopancreatography
o ERCP may be useful in patients at high risk for common duct gallstones if signs of common bile duct obstruction are present.
o A study performed by Sahai et al found that ERCP was preferred over endoscopic ultrasound and intraoperative cholangiography for patients at high risk for common duct stones undergoing laparoscopic cholecystectomy.8
o ERCP allows visualization of the anatomy and may be therapeutic by removing stones from the common bile duct.
o Disadvantages include the need for a skilled operator, high cost, and complications such as pancreatitis, which occurs in 3-5% of cases.
* Endoscopic ultrasound-guided transmural cholecystostomy: Studies indicate that this procedure may be safe as initial, interim, or definitive treatment of patients with severe acute cholecystitis who are at high operative risk for immediate cholecystectomy.9
* Mutignani et al investigated the efficacy of endoscopic gallbladder drainage as a treatment for acute cholecystitis.10 The authors, who conducted the study on 35 patients with the condition and with no residual common bile duct obstruction, found that endoscopic gallbladder drainage was technically successful in 29 patients and, after a median period of 3 days, clinically successful in 24 of them. Four patients died within 3 days after the procedure as a result of septic complications, while a fifth patient accidentally removed a nasocholecystic drain 24 hours after the operation. At follow-up (on 21 patients, after a median period of 17 months), the investigators found that 4 patients had suffered a relapse of either acute cholecystitis (2 patients) or biliary pain (2 patients). Mutignani et al concluded that endoscopic gallbladder drainage appears to be an effective, but temporary, means of resolving acute cholecystitis.

Histologic Findings

Edema and venous congestion are early acute changes. Acute cholecystitis is usually superimposed on a histologic picture of chronic cholecystitis. Specific findings include fibrosis, flattening of the mucosa, and chronic inflammatory cells. Mucosal herniations known as Rokitansky-Aschoff sinuses are related to increased hydrostatic pressure and are present in 56% of cases. Focal necrosis and an influx of neutrophils may also be present. Advanced cases may show gangrene or perforation.Treatment
Medical Care

For acute cholecystitis, initial treatment includes bowel rest, intravenous hydration, analgesia, and intravenous antibiotics. For mild cases of acute cholecystitis, antibiotic therapy with a single broad-spectrum antibiotic is adequate. Some options include the following:

* The current Sanford guide recommendations include piperacillin/tazobactam (Zosyn, 3.375 g IV q6h or 4.5 g IV q8h), ampicillin/sulbactam (Unasyn, 3 g IV q6h), or meropenem (Merrem, 1 g IV q8h). In severe life-threatening cases, the Sanford Guide recommends imipenem (500 mg IV q6h).
* Alternative regimens include a third-generation cephalosporin plus Flagyl (1 g IV loading dose followed by 500 mg IV q6h).
* Bacteria that are commonly associated with cholecystitis include E coli and Bacteroides fragilis and Klebsiella, Enterococcus, and Pseudomonas species.
* Emesis can be treated with antiemetics and nasogastric suction.
* Because of the rapid progression of acute acalculous cholecystitis to gangrene and perforation, early recognition and intervention are required.
* Supportive medical care should include restoration of hemodynamic stability and antibiotic coverage for gram-negative enteric flora and anaerobes if biliary tract infection is suspected.
* Daily stimulation of gallbladder contraction with intravenous CCK has been shown by some to effectively prevent the formation of gallbladder sludge in patients receiving TPN.

Surgical Care

Laparoscopic cholecystectomy is the standard of care for the surgical treatment of cholecystitis. Studies have indicated that early laparoscopic cholecystectomy resulted in shorter total hospital stays with no significant difference in conversion rates or complications.11 Wilson et al used decision tree analytic modeling to compare the cost-effectiveness and quality-adjusted life years (QALYs) of early laparoscopic cholecystectomy (ELC) and delayed laparoscopic cholecystectomy (DLC) and found that, on average, ELC is less expensive and results in better quality of life (+0.05 QALYs per patient) than DLC.12

For elective laparoscopic cholecystectomy, the rate of conversion from a laparoscopic procedure to an open surgical procedure is approximately 5%. The conversion rate for emergency cholecystectomy where perforation or gangrene is present may be as high as 30%.

Some considerations regarding cholecystectomy include the following:

* Immediate cholecystectomy or cholecystotomy is usually reserved for complicated cases in which the patient has gangrene or perforation.
* Early operation within 72 hours of admission has both medical and socioeconomic benefits and is the preferred approach for patients treated by surgeons with adequate experience in laparoscopic cholecystectomy.13
* For patients at high surgical risk, placement of a sonographically guided, percutaneous, transhepatic cholecystostomy drainage tube coupled with the administration of antibiotics may provide definitive therapy.14
* Results of studies suggest that most patients with acute acalculous cholecystitis can be treated with percutaneous drainage alone.10
* Contraindications for laparoscopic cholecystectomy include the following:
o High risk for general anesthesia
o Morbid obesity
o Signs of gallbladder perforation, such as abscess, peritonitis, or fistula
o Giant gallstones or suspected malignancy
o End-stage liver disease with portal hypertension and severe coagulopathy

Consultations

* Definitive therapy involves cholecystectomy or placement of a drainage device; therefore, consultation with a surgeon is warranted.
* Consultation with a gastroenterologist for consideration of ERCP may also be appropriate if concern exists of choledocholithiasis.

Diet

Patients admitted for cholecystitis should receive nothing by mouth (NPO) because of expectant surgery. However, in uncomplicated cholecystitis, a liquid or low-fat diet may be appropriate until the time of surgery.
Medication

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.
Antiemetics

Patients with cholecystitis frequently experience associated nausea and vomiting. Antiemetics can help to make the patient more comfortable and can prevent fluid and electrolyte abnormalities.

Promethazine (Phenergan, Prorex, Anergan)

For symptomatic treatment of nausea in vestibular dysfunction. Antidopaminergic agent effective in treating emesis. Blocks postsynaptic mesolimbic dopaminergic receptors in brain and reduces stimuli to brainstem reticular system.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

12.5-25 mg PO/IV/IM/PR q4h prn
Pediatric

<2 years: Contraindicated >2 years: 0.25-1 mg/kg PO/IV/IM/PR q4-6h prn

* Dosing
* Interactions
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May have additive effects when used concurrently with other CNS depressants or anticonvulsants; coadministration with epinephrine may cause hypotension

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Documented hypersensitivity; <2 years (incidences of death due to respiratory depression) * Dosing * Interactions * Contraindications * Precautions Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus Precautions Caution in patients with cardiovascular disease, impaired liver function, seizures, sleep apnea, and asthma Prochlorperazine (Compazine) May relieve nausea and vomiting by blocking postsynaptic mesolimbic dopamine receptors through anticholinergic effects and depressing reticular activating system. In addition to antiemetic effects, it has the advantage of augmenting hypoxic ventilatory response, acting as a respiratory stimulant at high altitude. * Dosing * Interactions * Contraindications * Precautions Adult 5-10 mg PO/IM tid/qid; not to exceed 40 mg/d 2.5-10 mg IV q3-4h prn; not to exceed 10 mg/dose or 40 mg/d 25 mg PR bid Pediatric 2.5 mg PO/PR q8h or 5 mg q12h prn; not to exceed 15 mg/d IV dosing is not recommended for children 0.1-0.15 mg/kg/dose IM; change to PO as soon as possible * Dosing * Interactions * Contraindications * Precautions Coadministration with other CNS depressants or anticonvulsants may cause additive effects; coadministration with epinephrine may cause hypotension * Dosing * Interactions * Contraindications * Precautions Documented hypersensitivity; bone marrow suppression; narrow-angle glaucoma; severe liver or cardiac disease * Dosing * Interactions * Contraindications * Precautions Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus Precautions Drug-induced Parkinson syndrome or pseudoparkinsonism occurs frequently; akathisia is the most common extrapyramidal reaction in elderly persons; lowers seizure threshold; caution in patients with history of seizures Analgesics Pain is a prominent feature of cholecystitis. Classic teaching is that morphine is not the agent of choice because of the possibility of increasing tone at the sphincter of Oddi. Meperidine has been shown to provide adequate analgesia without affecting the sphincter of Oddi and, therefore, is the DOC. Meperidine (Demerol) DOC. Analgesic with multiple actions similar to those of morphine. May produce less constipation, smooth muscle spasm, and depression of cough reflex than similar analgesic doses of morphine. * Dosing * Interactions * Contraindications * Precautions Adult 50-150 mg PO/IV/IM/SC q3-4h prn Pediatric 1-1.8 mg/kg (0.5-0.8 mg/lb) PO/IV/IM/SC q3-4h prn; not to exceed adult dose * Dosing * Interactions * Contraindications * Precautions Monitor for increased respiratory and CNS depression with coadministration of cimetidine; hydantoins may decrease effects; avoid with protease inhibitors * Dosing * Interactions * Contraindications * Precautions Documented hypersensitivity; MAOIs; upper airway obstruction or significant respiratory depression; during labor when delivery of premature infant is anticipated * Dosing * Interactions * Contraindications * Precautions Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus Precautions Category D in prolonged use or high doses at term; caution in patients with head injuries because may increase respiratory depression and CSF pressure (use only if absolutely necessary); use caution postoperatively and in patients with history of pulmonary disease (suppresses cough reflex); increased dosing levels, because of tolerance, may aggravate or cause seizures (even without prior history); adjust dose in patients with renal insufficiency (do not use in patients severe renal dysfunction); normeperidine metabolite accumulation may induce CNS toxicity; monitor closely for morphine-induced seizure activity if prior seizure history Hydrocodone and acetaminophen (Vicodin, Lortab 5/500, Lorcet-HD) Drug combination indicated for moderate to severe pain. Each tab/cap contains 5 mg hydrocodone and 500 mg acetaminophen. * Dosing * Interactions * Contraindications * Precautions Adult 1-2 tab/cap PO q4-6h prn Pediatric <12 years: 10-15 mg/kg/dose acetaminophen PO q4-6h prn; not to exceed 2.6 g/d acetaminophen >12 years: 750 mg acetaminophen PO q4h; not to exceed 10 mg hydrocodone bitartrate/dose or 5 doses/24 h

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Coadministration with phenothiazines may decrease analgesic effects; toxicity increases with CNS depressants or tricyclic antidepressants

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Documented hypersensitivity; high-altitude cerebral edema (HACE); elevated intracranial pressure (ICP)

* Dosing
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Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions

Tab contains metabisulfite, which may cause hypersensitivity; caution in patients dependent on opiates because this substitution may result in acute opiate withdrawal symptoms; caution in severe renal or hepatic dysfunction

Oxycodone and acetaminophen (Percocet, Tylox, Roxicet)

Drug combination indicated for relief of moderate to severe pain.
Each tab/cap contains 5 mg oxycodone and 325 mg acetaminophen.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

1-2 tab/cap PO q4-6h prn
Pediatric

0.05-0.15 mg/kg/dose oxycodone PO; not to exceed 5 mg/dose of oxycodone PO q4-6h prn

* Dosing
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* Precautions

Phenothiazines may decrease analgesic effects; toxicity increases with coadministration of CNS depressants or tricyclic antidepressants

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Documented hypersensitivity

* Dosing
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Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions

Duration of action may increase in elderly persons; be aware of total daily dose of acetaminophen patient is receiving; not to exceed 4000 mg/24h of acetaminophen; higher doses may cause liver toxicity
Antibiotics

Treatment of cholecystitis with antibiotics should provide coverage against the most common organisms, including E coli, B fragilis, and Klebsiella, Pseudomonas, and Enterococcus species. Current Sanford guide recommendations for the treatment of cholecystitis include Unasyn, Zosyn for non–life-threatening cases of cholecystitis. In life-threatening cases, Sanford recommends Primaxin or meropenem. Alternatives include metronidazole plus a third-generation cephalosporin or Cipro or Aztreonam.

Ciprofloxacin (Cipro)

Fluoroquinolone that inhibits bacterial DNA synthesis and, consequently, growth, by inhibiting DNA gyrase and topoisomerases, which are required for replication, transcription, and translation of genetic material. Quinolones have broad activity against gram-positive and gram-negative aerobic organisms. Has no activity against anaerobes. Continue treatment for at least 2 d (7-14 d typical) after signs and symptoms have disappeared.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

400 mg IV q12h
Pediatric

<18 years: Not recommended >18 years: Administer as in adults

* Dosing
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* Precautions

Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2-4 h before or after taking fluoroquinolones; cimetidine may interfere with metabolism of fluoroquinolones; ciprofloxacin reduces therapeutic effects of phenytoin; probenecid may increase ciprofloxacin serum concentrations
May increase toxicity of theophylline, caffeine, cyclosporine, and digoxin (monitor digoxin levels); may increase effects of anticoagulants (monitor PT)

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Documented hypersensitivity

* Dosing
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Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions

Dosage adjustments (adult adjustments)
CrCl (mL/min) <10: 50% of PO or IV dose q12h HD: 0.25-0.5 g PO or 0.2-0.4 g IV q12h During peritoneal dialysis: 0.25-0.5 g PO or 0.2-0.4 g IV q8h In prolonged therapy, perform periodic evaluations of organ system functions (eg, renal, hepatic, hematopoietic); adjust dose in renal function impairment; superinfections may occur with prolonged or repeated antibiotic therapy Not drug of first choice in pediatrics due to increased incidence of adverse events compared to controls, including arthropathy; no data exist for dose for pediatric patients with renal impairment (ie, CrCl <50 mL/min) Meropenem (Merrem) Bactericidal broad-spectrum carbapenem antibiotic that inhibits cell-wall synthesis. Effective against most gram-positive and gram-negative bacteria. Has slightly increased activity against gram-negatives and slightly decreased activity against staphylococci and streptococci compared to imipenem. * Dosing * Interactions * Contraindications * Precautions Adult 1 g IV q8h Pediatric 60 mg/kg/d IV divided q8h * Dosing * Interactions * Contraindications * Precautions Probenecid may inhibit renal excretion of meropenem, increasing meropenem levels * Dosing * Interactions * Contraindications * Precautions Documented hypersensitivity * Dosing * Interactions * Contraindications * Precautions Pregnancy B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals Precautions Dosage adjustments (adult adjustments): CrCl (mL/min) 10-50: 0.5-1 g q12h CrCl <10: 0.5 g/d HD: As for CrCl <10, with an extra 0.5 g after HD Pseudomembranous colitis and thrombocytopenia may occur, requiring immediate discontinuation of medication Imipenem and cilastatin (Primaxin) For treatment of multiple organism infections in which other agents do not have wide spectrum coverage or are contraindicated due to potential for toxicity. * Dosing * Interactions * Contraindications * Precautions Adult Base initial dose on severity of infection, and administer in equally divided doses; dose may range from 250 to 500 mg q6h IV for a maximum of 3-4 g/d Alternatively, 500-750 mg IM q12h or intra-abdominally Pediatric Infants >3 months and children <12 years: 15-25 mg/kg/dose IV q6h Fully susceptible organisms: Not to exceed 2 g/d Infections with moderately susceptible organisms: Not to exceed 4 g/d >12 years: Administer as in adults

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Coadministration with cyclosporine may increase CNS side effects of both agents; coadministration with ganciclovir may result in generalized seizures

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* Contraindications
* Precautions

Documented hypersensitivity; known hypersensitivity to amide local anesthetics; children with CNS infections (increased seizure risk); children <30 kg with renal impairment (lack of data) * Dosing * Interactions * Contraindications * Precautions Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus Precautions Adjust dose in renal insufficiency (adult adjustments): CrCl (mL/min) 80-50: 0.5 g q6-8h CrCl 50-10: 0.5 g q8-12h Hemodialysis (HD): 0.25-0.5 g after HD, then q12h Adjust dose in renal insufficiency; avoid use in children <12 y with CNS infections Caution with history of seizures, hypersensitivity to penicillins, cephalosporins, or other beta lactam antibiotics Piperacillin and tazobactam (Zosyn) Antipseudomonal penicillin plus beta-lactamase inhibitor. Inhibits biosynthesis of cell wall mucopeptide and is effective during stage of active multiplication. * Dosing * Interactions * Contraindications * Precautions Adult 3/0.375 g (piperacillin 3 g and tazobactam 0.375 g) IV q6h Pediatric 75 mg/kg of piperacillin component IV q6h * Dosing * Interactions * Contraindications * Precautions Tetracyclines may decrease effects of piperacillin; high concentrations of piperacillin may physically inactivate aminoglycosides if administered in same IV line; effects when administered concurrently with aminoglycosides are synergistic; probenecid may increase penicillin levels; high-dose parenteral penicillins may cause increased risk of bleeding * Dosing * Interactions * Contraindications * Precautions Documented hypersensitivity; treating severe pneumonia, bacteremia, pericarditis, emphysema, meningitis, and purulent or septic arthritis with a PO penicillin during acute stage * Dosing * Interactions * Contraindications * Precautions Pregnancy B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals Precautions Perform CBC counts before initiation of therapy and at least weekly during therapy; monitor for liver function abnormalities by measuring AST and ALT levels during therapy; caution in hepatic insufficiencies; perform urinalysis and BUN and creatinine determinations during therapy and adjust dose if values become elevated; monitor blood levels to avoid possible neurotoxic reactions Ampicillin and sulbactam (Unasyn) Drug combination of beta-lactamase inhibitor with ampicillin. Covers epidermal and enteric flora and anaerobes. Not ideal for nosocomial pathogens. * Dosing * Interactions * Contraindications * Precautions Adult 1.5 g (1 g ampicillin plus 0.5 g sulbactam) to 3 g (2 g ampicillin plus 1 g sulbactam) IV/IM q6-8h; not to exceed 4 g/d sulbactam or 8 g/d ampicillin Pediatric <3 months: Not established 3 months to 12 years: 100-200 mg ampicillin/kg/d (150-300 mg Unasyn) IV divided q6h >12 years: Administer as in adults

* Dosing
* Interactions
* Contraindications
* Precautions

Probenecid and disulfiram elevate ampicillin levels; allopurinol decreases ampicillin effects and has additive effects on ampicillin rash; may decrease effects of PO contraceptives

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions

Adjust dose in renal failure; evaluate rash and differentiate from hypersensitivity reaction

Metronidazole (Flagyl)

Imidazole ring-based antibiotic active against various anaerobic bacteria and protozoa. Used in combination with other antimicrobial agents (except Clostridium difficile enterocolitis).

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

Loading dose: 15 mg/kg or 1 g for 70-kg adult IV over 1 h
Maintenance dose: 6 h following loading dose, infuse 7.5 mg/kg or 500 mg for 70-kg adult over 1 h q6-8h; not to exceed 4 g/d
Pediatric

Administer as in adults.Follow-up
Further Inpatient Care

* Objectives during inpatient stay include the following:
o Correction of fluid and electrolyte abnormalities
o Antibiotics for complicating infections
o Performing imaging studies as appropriate (eg, ultrasound, HBS)
o Cholecystectomy once the patient is stable or percutaneous transhepatic cholecystostomy drainage in unstable high-risk surgical patients

Further Outpatient Care

* In cases of uncomplicated cholecystitis, outpatient treatment may be appropriate. If a patient can be treated as an outpatient, discharge with antibiotics, appropriate analgesics, and definitive follow-up care. Criteria for outpatient treatment include the following:
o Afebrile with stable vital signs
o No evidence of obstruction by laboratory values
o No evidence of common bile duct obstruction on ultrasound
o No underlying medical problems, advanced age, pregnancy, or immunocompromised condition
o Adequate analgesia
o Reliable patient with transportation and easy access to a medical facility
o Prompt follow-up care

Inpatient & Outpatient Medications

* For outpatient treatment of uncomplicated cholecystitis, the following medicines may be appropriate:
o Prophylactic antibiotic coverage with Levaquin (500 mg PO qd) and Flagyl (500 mg PO bid), which should provide coverage against the most common organisms
o Antiemetics, such as oral/rectal Phenergan or Compazine, to control nausea and to prevent fluid and electrolyte disorders
o Analgesics, such as oral Percocet or Vicodin

Transfer

* Consider patient transfer if the following conditions apply:
o Appropriate diagnostic resources are not available.
o Higher level of care is required.
o Surgeons and/or specialists are unavailable.

Deterrence/Prevention

* Prevention of cholecystitis requires cholecystectomy.
* In patients who are unstable, percutaneous transhepatic cholecystostomy drainage may be appropriate.
* Some studies have shown that daily CCK administration may help prevent acalculous cholecystitis in patients at risk.

Complications

* Bacterial proliferation within the obstructed gallbladder results in empyema of the organ. Patients with empyema may have a toxic reaction and may have more marked fever and leukocytosis. The presence of empyema frequently requires conversion from laparoscopic to open cholecystectomy.
* In rare instances, a large gallstone may erode through the gallbladder wall into an adjacent viscus, usually the duodenum. Subsequently, the stone may become impacted in the terminal ileum or in the duodenal bulb and/or pylorus, causing a gallstone ileus.
* Emphysematous cholecystitis occurs in approximately 1% of cases and is noted by the presence of gas in the gallbladder wall from the invasion of gas-producing organisms, such as E coli, Clostridia perfringens, and Klebsiella species. This complication is more common in patients with diabetes, has a male predominance, and is acalculous in 28% of cases. Because of a high incidence of gangrene and perforation, emergency cholecystectomy is recommended.
* Sepsis
* Pancreatitis
* Perforation occurs in up to 15% of patients.

Prognosis

* For uncomplicated cholecystitis, the prognosis is excellent, with a very low mortality rate.
* In patients who are critically ill with cholecystitis, the mortality rate approaches 50-60%, especially in the setting of gangrene or empyema.
* Once complications such as perforation/gangrene develop, the prognosis becomes less favorable. In patients who are critically ill with acalculous cholecystitis and perforation or gangrene, the mortality rate can be as high as 50-60%.

Patient Education

* Patients diagnosed with cholecystitis must be educated regarding causes of their disease, complications if left untreated, and medical/surgical options to treat cholecystitis.
* For excellent patient education resources, visit eMedicine's Liver, Gallbladder, and Pancreas Center. Also, see eMedicine's patient education articles Gallstones and Pancreatitis.

Miscellaneous
Medicolegal Pitfalls

* Delays in making the diagnosis of acute cholecystitis result in a higher incidence of morbidity and mortality. This is especially true for ICU patients who develop acalculous cholecystitis. The diagnosis should be considered and investigated promptly in order to prevent poor outcomes.

Special Concerns

* Pregnancy
o RUQ pain in pregnancy can be related to a number of different diagnoses, including preeclampsia, appendicitis, and cholelithiasis.
o These patients must have a thorough examination because complications can arise quickly and can be life threatening to both the mother and the unborn child.
o Although laparoscopic cholecystectomy is considered safest during the second trimester, it has been performed successfully during all trimesters.
* Elderly patients (especially patients with diabetes) may present with vague symptoms and without many key historical and physical findings. Elderly patients may also progress to complicated cholecystitis rapidly and without warning.
* The pediatric population may also present without many of the classic findings. Children who are at higher risk for developing cholecystitis include patients with sickle cell disease, seriously ill children, those on prolonged TPN, those with hemolytic conditions, and those with congenital and biliary anomalies.
* Patients who are immunocompromised are at increased risk of developing cholecystitis from a number of different infectious sources.