Acute Cholecystitis: A Review PDF | JAMA, 2022

Clinical Review & Education JAMA | Review Acute Cholecystitis A Review Jared R. Gallaher, MD, MPH; Anthony Charles, MD, MPH Multimedia IMPORTANCE Gallbladder disease affects approx...

Clinical Review & Education JAMA | Review Acute Cholecystitis A Review Jared R. Gallaher, MD, MPH; Anthony Charles, MD, MPH Multimedia IMPORTANCE Gallbladder disease affects approximately 20 million people in the US. Acute cholecystitis is diagnosed in approximately 200 000 people in the US each year. OBSERVATIONS Gallstone-associated cystic duct obstruction is responsible for 90% to 95% of the cases of acute cholecystitis. Approximately 5% to 10% of patients with acute cholecystitis have acalculous cholecystitis, defined as acute inflammation of the gallbladder without gallstones, typically in the setting of severe critical illness. The typical presentation of acute cholecystitis consists of acute right upper quadrant pain, fever, and nausea that may be associated with eating and physical examination findings of right upper quadrant tenderness. Ultrasonography of the right upper quadrant has a sensitivity of approximately 81% and a specificity of approximately 83% for the diagnosis of acute cholecystitis. When an ultrasound result does not provide a definitive diagnosis, hepatobiliary scintigraphy (a nuclear medicine study that includes the intravenous injection of a radiotracer excreted in the bile) is the gold standard diagnostic test. Following diagnosis, early (performed within 1-3 days) vs late (performed after 3 days) laparoscopic cholecystectomy is associated with improved patient outcomes, including fewer composite postoperative complications (11.8% for early vs 34.4% for late), a shorter length of hospital stay (5.4 days vs 10.0 days), and lower hospital costs. During pregnancy, early laparoscopic cholecystectomy, compared with delayed operative management, is associated with a lower risk of maternal-fetal complications (1.6% for early vs 18.4% for delayed) and is recommended during all trimesters. In people older than 65 years of age, laparoscopic cholecystectomy is associated with lower mortality at 2-year follow-up (15.2%) compared with nonoperative management (29.3%). A percutaneous cholecystostomy tube, in which a drainage catheter is placed in the gallbladder lumen under image guidance, is an effective therapy for patients with an exceptionally high perioperative risk. However, percutaneous cholecystostomy tube placement in a randomized trial was associated with higher rates of postprocedural complications (65%) compared with laparoscopic cholecystectomy (12%). For patients with acalculous acute cholecystitis, Author Affiliations: Department of percutaneous cholecystostomy tube should be reserved for patients who are severely ill at Surgery, School of Medicine, the time of diagnosis; all others should undergo a laparoscopic cholecystectomy. University of North Carolina, Chapel Hill. CONCLUSIONS AND RELEVANCE Acute cholecystitis, typically due to gallstone obstruction of Corresponding Author: Anthony the cystic duct, affects approximately 200 000 people in the US annually. In most patient Charles, MD, MPH, Department of populations, laparoscopic cholecystectomy, performed within 3 days of diagnosis, is the Surgery, University of North Carolina, 4008 Burnett Womack Bldg, first-line therapy for acute cholecystitis. CB 7228, Chapel Hill, NC 27599 ([email protected]). JAMA. 2022;327(10):965-975. doi:10.1001/jama.2022.2350 Section Editor: Mary McGrae McDermott, MD, Deputy Editor. A cute cholecystitis is an acute inflammatory disease of the 80% are asymptomatic.5 Twenty percent of patients with gall- gallbladder that is caused by gallstone obstruction of stones will eventually develop gallstone-related complications at the cystic duct in approximately 90% to 95% of people di- an incidence rate of 1% to 4% annually, with calculous acute chole- agnosed with this condition.1 Less commonly, acalculous cholecys- cystitis as the first clinical presentation in 10% to 15% of all patients titis, in which acute inflammation of the gallbladder develops with- with gallstones.6 out gallstones, is present in approximately 5% to 10% of people In contrast, the etiology of acalculous acute cholecystitis, diagnosed with acute cholecystitis. defined as an acute inflammatory disease of the gallbladder in Gallbladder disease affects approximately 20 million individu- the absence of cholelithiasis, is multifactorial. Factors associated als in the US and results in estimated direct annual costs of more with acalculous acute cholecystitis include critical illness, diabetes, than $6.3 billion, with more than 200 000 people diagnosed HIV infection, atherosclerosis, and total parenteral nutrition.7,8 with acute cholecystitis each year.2-4 Of the 10% to 15% of adults Acalculous acute cholecystitis is present in approximately 5% to in the US general population with cholelithiasis, approximately 10% of patients presenting with acute cholecystitis. Acalculous jama.com (Reprinted) JAMA March 8, 2022 Volume 327, Number 10 965 © 2022 American Medical Association. All rights reserved.  Clinical Review & Education Review Acute Cholecystitis—A Review Figure. Progression of Acute Cholecystitis A Gallbladder and surrounding anatomy B Development and progression of acute cholecystitis Cystic duct obstruction leads to intraluminal pressure, cholesterol supersaturated bile, and subsequent inflammatory response. Cystic duct obstruction LIVER Increased intraluminal STOMACH pressure Hemorrhage due Inflammation to endothelial damage Advanced Edema necrosis D U O DE Gallbladder NUM Early necrosis Pancreas Gallstones Perforation is uncommon but may occur in up to 10% of cases. Right hepatic artery C Progression of acalculous acute cholecystitis Cystic artery Decreased gallbladder emptying leads to bile stasis, epithelial injury, and subsequent inflammatory response. ER D D A Bile stasis BL LL Cystic GA Vascular duct Epithelial occlusion injury Common Inflammation Ischemia bile duct Advanced Early necrosis necrosis Edema Increased Perforation may occur in 10%-20% of cases. intraluminal The combined complication rate of gangrene, pressure empyema, and perforation is up to 50%. acute cholecystitis occurs in about 0.2% to 0.4% of all critically ill in Mapuche Indian individuals and 27% in Hispanic individuals.13 patients, usually in patients aged 50 years or older, and is at least 3 In contrast, the prevalence of cholelithiasis among individuals times more common in men than women.9-11 from sub-Saharan Africa is approximately 5% and the prevalence is approximately 3.2% to 15.6% in Asia.14,15 In the US, the age-standardized prevalence of gallbladder dis- ease was estimated based on a sample of more than 14 000 per- Methods sons aged 20 to 74 years in whom gallstones were detected by The PubMed and Cochrane databases were used to search for ultrasonography or after cholecystectomy. The gallbladder dis- English-language reports related to acute cholecystitis, including ease prevalence was 8.6% among non-Hispanic White men and studies focused on risk factors, pathogenesis, diagnosis, and 16.6% among non-Hispanic White women, 8.9% among Mexican treatment that were published between January 1, 2000, and American men and 26.7% among Mexican American women, and December 31, 2021. Seminal studies published before 2000 were 5.3% among non-Hispanic Black men and 13.9% among non- included when relevant to the review and when more recent data Hispanic Black women.2 Risk factors for gallbladder disease, such were unavailable. as obesity, weight loss, pregnancy, and drinking less than 1 or 2 A total of 4802 studies were identified. We prioritized random- alcoholic drinks per day (7-14 g/d), do not explain the differences ized clinical trials, meta-analyses, systematic reviews, national or in- in the racial or ethnic prevalence of cholelithiasis.16 ternational guidelines, population-based studies, and observa- Genetic markers have not been shown to explain the differ- tional studies. A total of 102 studies were included, consisting of 4 ences in risk among racial and ethnic groups. Other factors, such randomized clinical trials, 6 meta-analyses, 5 systematic reviews, as a diet high in fat or low in fiber, may explain a more significant 7 national or international guidelines, 30 population-based stud- fraction of the attributable risk associated with cholelithiasis.17 ies, and 50 observational (cross-sectional) studies. Although gallstones are 2 to 3 times more common in women, this difference tends to diminish with older age, and the risk of developing cholelithiasis increases with age.6 The pathophysi- ological basis for the increasing prevalence of gallstone disease in Risk Factors older people is unclear. Cholelithiasis is the most common risk factor for acute cholecysti- Congenital hemolytic anemias, especially thalassemia and tis. People from Central and South America who have Hispanic sickle cell disease, are a common cause of gallstones, particularly ethnicity and individuals with American Indian ancestry have in children.18 A university-based study in Brazil of 107 patients the highest prevalence of cholelithiasis.2,12 The age- and sex- that evaluated cholelithiasis in patients with sickle cell disease adjusted global prevalence of cholelithiasis is approximately 35% showed a prevalence of 4.4% in patients younger than 10 years, 966 JAMA March 8, 2022 Volume 327, Number 10 (Reprinted) jama.com © 2022 American Medical Association. All rights reserved. Acute Cholecystitis—A Review Review Clinical Review & Education 35.4% in patients aged 11 to 29 years, and 18.2% in patients aged 30 years or older.19 Box. Diagnostic Criteria for Acute Cholecystitis Pregnancy increases stone and sludge formation. Sludge con- Based on 2018 Tokyo Guidelines sists of a suspension of mucus, cholesterol, and calcium salts formed within the gallbladder and affects 5.1% of pregnant people during Local Signs of Inflammation Murphy sign the second trimester, 7.9% during the third trimester, and 10.2% at Right upper quadrant mass, pain, or tenderness 4 weeks’ to 6 weeks’ postpartum.20,21 Obesity is also a risk factor for cholelithiasis. In a US study of Systemic Signs of Inflammation 13 962 participants in the third National Health and Nutrition Ex- Fever Elevated C-reactive protein level amination Survey, women who had gallstones had a higher mean Elevated white blood cell count body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) compared with those without gallstones Imaging Findings Characteristic of Acute Cholecystitis (29.7 vs 25.9, respectively), whereas men with gallstones had a mean Suspected diagnosis: 1 local sign plus 1 systemic sign Definite diagnosis: 1 local sign plus 1 systemic sign plus 1 image BMI of 28.3 vs 26.5 those without gallstones.22 Substantial weight finding characteristic of acute cholecystitis loss, particularly after bariatric surgery, is associated with the de- velopment of gallstones.23 A retrospective analysis of 586 patients Adapted from Yokoe et al.42 (75.7% female) who underwent bariatric surgery showed that among patients who developed symptomatic gallstones postoperatively, 91.3% had lost greater than 25% of their body weight.24 tom onset). The third phase, the chronic or purulent phase, is char- Some medications, such as octreotide (incidence rate of 5%- acterized by leukocyte infiltration, necrotic tissue, and suppuration 66% after long-term use [>1 month]) and ceftriaxone (incidence rate along with intraluminal pus and gross infection (occurs on day 6 or of 8.8% after 10 doses), are associated with an increased rate of gall- later after symptom onset) (Figure). stone formation.25,26 Calculous acute cholecystitis is also more com- After this acute phase, intraluminal purulence is replaced with mon in people with diabetes.27 The incidence rate per 10 000 per- granulation tissue and progresses to subacute cholecystitis and even- son-years for people with type 2 diabetes was 51.6 vs 35.5 for those tually chronic cholecystitis.37 In contrast, the pathogenesis of acal- without type 2 diabetes.28 In a population-based study of 71 369 par- culous acute cholecystitis is multifactorial and likely results from bile ticipants, the use of glucagon-like peptide analogues to treat type stasis or ischemia of the gallbladder wall. Bile stasis can be caused 2 diabetes (such as exenatide or liraglutide) was associated with an by fasting or ileus, leading to bile inspissation that is directly toxic increased risk of bile duct and gallbladder disease vs the concur- to the gallbladder epithelium.38 Microvascular occlusion of the gall- rent use of at least 2 oral antidiabetes drugs (6.1 vs 3.3 per 1000 per- bladder vasculature occurs secondary to endothelial injury, leading son-years, respectively).29 to gallbladder ischemia in the setting of hypoperfusion, which may In studies of specific patient populations, risk factors for acal- occur in critically ill patients.1 Acalculous acute cholecystitis can also culous acute cholecystitis included critical illness (0.2%-0.4%), se- progress to gangrene, gallbladder empyema, and perforation in up vere trauma (10%), burns (0.4%-3.5%), cardiac surgery with car- to 50% of patients.10 diopulmonary bypass (0.08%), and total parenteral nutrition (16%). In patients undergoing bone marrow transplant, the incidence of acalculous acute cholecystitis was as high as 4%.30-34 Diagnosis Acute cholecystitis should be suspected in patients presenting with constant right upper quadrant pain with or without an association Pathogenesis with eating. Fever, nausea, and vomiting are the typical presenting Acute cholecystitis due to gallstones occurs after a cystic duct ob- symptoms. In a 2017 systematic review that included 3 observa- struction caused by gallstones or sludge or lithogenic bile.35 The de- tional studies, the sensitivity for fever was 31% to 62%.39 On physi- gree and duration of the cystic duct obstruction determine the rate cal examination, right upper quadrant tenderness associated with of progression to acute cholecystitis and the severity of gallbladder localized peritonitis was present in 95.7% of patients.40 Murphy sign inflammation. Cystic duct obstruction increases intraluminal pres- (arrest of inspiration during palpation of the right upper quadrant sure within the gallbladder and, together with cholesterol- due to pain) is pathognomonic of acute cholecystitis. Murphy supersaturated bile, initiates an acute inflammatory response. Sec- sign has a sensitivity of 62% and a specificity of 96% for acute ondary bacterial infections with enteric organisms (most commonly cholecystitis.39 Patients typically have leukocytosis with left shift and Escherichia coli, Klebsiella, and Streptococcus faecalis) occur in about immature bands. 20% of patients with acute cholecystitis.36 In severe acute cholecystitis, mild jaundice (serum concentra- Acute cholecystitis progresses in 3 distinct phases after a cys- tions of bilirubin 3 mm) for concurrent Gallbladder wall edema choledocholithiasis Gallbladder distention (>40 mm) Pericholecystic fluid Fluid around the liver count and serum chemistry panel, including a liver function test, bil- Computed Tomography irubin level, and serum lipase level (to rule out acute pancreatitis in The computed tomographic (CT) scan characteristics associated with the differential diagnosis), in addition to chest radiography and uncomplicated acute cholecystitis include distension of the gall- electrocardiography. bladder, mural thickening, pericholecystic fat stranding, and peri- The diagnostic criteria for acute cholecystitis according to the cholecystic fluid.50 Gallstone detection with a CT scan is depen- Tokyo guidelines42,43 are outlined in the Box. In small studies in- dent on the composition of the gallstones and the thickness of CT cluding fewer than 200 patients, the sensitivity of these criteria was slices. At least 20% of gallstones have similar attenuation as bile and estimated to be between 83% and 85% with the specificity esti- are not detectable with CT.47 A 2012 meta-analysis of 5859 pa- mated between 37% and 50%.44,45 tients reported an estimated sensitivity of 94% and a specificity of 59% for CT in the diagnosis of acute cholecystitis.46 Hepatobiliary Scintigraphy (Hepatic Iminodiacetic Acid Scan) Diagnostic Studies Hepatobiliary scintigraphy, also known as the hepatic iminodiacetic Right Upper Quadrant Ultrasonography acid scan, is a nuclear medicine diagnostic test in which technetium- Ultrasonography is the initial imaging modality of choice for evalu- labeled analogue iminodiacetic acid (radiotracer) is intravenously in- ating suspected acute cholecystitis due to its relatively low cost, easy jected. The radiotracer is excreted into the bile.51,52 Patients should accessibility, short examination duration, and absence of ionizing ra- fast for at least 4 hours to 6 hours before radiotracer injection. Ad- diation (Table 1). Sonograms typically show pericholecystic fluid ministration of a subanalgesic dose of morphine causes sphincter of (fluid around the gallbladder), gallbladder distention, an edema- Oddi contraction, thus diverting incoming bile to the gallbladder. In tous gallbladder wall, and gallstones or sludge if present. A 2012 patients with a patent cystic duct, gallbladder filling will be visible meta-analysis of 5859 patients with acute cholecystitis reported that within 30 minutes of morphine administration. ultrasonography was associated with a sensitivity of 81% and a speci- Continued nonvisualization of the gallbladder after delayed im- ficity of 80% for acute cholecystitis.46 ages or morphine augmentation confirms cystic duct obstruction. In a study of 189 patients with suspected calculous acute cho- Hepatobiliary scintigraphy has a sensitivity of 96% and a specific- lecystitis, the presence of gallstones and a positive ultrasono- ity of 90% for acute cholecystitis.46 Ultrasonography is preferred graphic Murphy sign (maximal abdominal tenderness when the as the initial diagnostic test and hepatobiliary scintigraphy is re- ultrasound probe is applied over the gallbladder) had a sensitivity served for the 20% of patients with equivocal ultrasonography test of 48% for acute cholecystitis. The specificity for acute cholecysti- results. Hepatobiliary scintigraphy is the most reliable imaging study tis in patients with a negative Murphy sign was 96%. Bedside ultra- for patients with suspected acalculous acute cholecystitis.30 sonography by nonradiologists, particularly among clinicians in the emergency department for the diagnosis of acute cholecystitis, is Magnetic Resonance Imaging and Magnetic Resonance increasingly used as a diagnostic test. In a study of 1690 patients, Cholangiopancreatography bedside ultrasonography performed by emergency department Magnetic resonance imaging findings of acute uncomplicated cho- physicians had a sensitivity of 88% (95% CI, 84%-91%) and a lecystitis include (1) gallstones (often impacted in the gallbladder neck specificity of 87% (95% CI, 82%-91%) using radiological interpreta- or cystic duct), (2) gallbladder wall thickening (>3 mm), (3) gallblad- tion as the criterion reference.49 der wall edema, (4) gallbladder distention (diameter >40 mm), 968 JAMA March 8, 2022 Volume 327, Number 10 (Reprinted) jama.com © 2022 American Medical Association. All rights reserved. Acute Cholecystitis—A Review Review Clinical Review & Education Table 2. Summary of Treatment Options for Acute Cholecystitis Disease process Disease process definition Treatment options Additional information Adverse events associated with treatment Uncomplicated Acute inflammation of Laparoscopic Should be performed early (1-3 d) after Common bile duct injury: 0.4%-0.6% calculous acute the gallbladder due to cholecystectomy diagnosis of cases56,57 cholecystitis cystic duct obstruction Available for pregnant patients Infectious or bleeding complications: 1%-2% by a gallstone without (during any trimester) of cases56 abscess, perforation, Older patients have better clinical or gangrene outcomes with laparoscopic cholecystectomy vs nonoperative management Should be offered to patients with mild to moderate liver cirrhosis Combination Antibiotics should be used before and ampicillin and at the time of surgery sulbactam or Not indicated postoperatively combination piperacillin and tazobactam Complicated Acute inflammation of Laparoscopic vs open Should be performed early to obtain Common bile duct injury: 0.4%-0.6% calculous acute the gallbladder due to cholecystectomy source control of cases56,57 cholecystitis cystic duct obstruction Infectious or bleeding complications: 1%-2% by a gallstone with of cases56 abscess, perforation, Subtotal Available when the gallbladder cannot Cystic duct leak: 18% of cases58,59 or gangrene cholecystectomy be safely removed Postoperative abscess: 5%-6% of cases58 A gallbladder fossa drain should be left Recurrent biliary event: 9%-18% of cases60 postoperatively Combination Antibiotics should be used before and ampicillin and at the time of surgery sulbactam or Continue a 4- to 7-d course combination postoperatively in patients without piperacillin and adequate source control or signs tazobactam of sepsis Acalculous acute Acute inflammation of Laparoscopic vs open In patients with acceptable In critically ill patients, higher composite cholecystitis the gallbladder cholecystectomy perioperative risk, should proceed with postoperative complications vs percutaneous without gallstones early cholecystectomy cholecystostomy tube (8% vs 5%)61 Percutaneous Reserved for patients with Mortality: 4.7% vs 1.2% for cholecystectomy cholecystostomy tube exceptionally high perioperative risk Bleeding: 17.1% vs 9.5% for cholecystectomy or severe critical illness Infection:13.3% vs 4.5% for Uncommonly used for patients with cholecystectomy62 calculous cholecystitis (5) pericholecystic fluid, and (6) fluid around the liver.53 The pres- hepatic and extrahepatic biliary ducts. Other diagnoses to con- ence of 1 or more of these 6 findings indicates acute cholecystitis, sider in a patient presenting with symptoms of acute cholecystitis yielding a sensitivity of 88% and a specificity of 89%.48 Magnetic include acute gastritis, peptic ulcer disease, hiatal hernia, acute resonance imaging can also be used to evaluate potential complica- pancreatitis, acute viral hepatitis, acute appendicitis, and myocar- tions of acute cholecystitis such as gangrenous, emphysematous, dial infarction. and perforated cholecystitis. Furthermore, magnetic resonance imaging and, specifically, magnetic resonance cholangiopancrea- tography allow the exclusion of concurrent choledocholithiasis in Treatment the setting of cholecystitis, which can assist in the planning of the therapeutic approach.54,55 The standard treatment for calculous acute cholecystitis is chole- cystectomy (Table 2). In the US, laparoscopic cholecystectomy is the Differential Diagnosis standard of care.63-65 Acute cholecystitis must be differentiated from other diseases that cause right upper quadrant abdominal pain and nausea or Early vs Delayed Cholecystectomy vomiting, such as biliary colic and acute cholangitis. The term A 2013 open-label randomized clinical trial (n = 618) compared pa- biliary colic, consisting of abdominal pain due to a blocked cystic tients with acute cholecystitis undergoing surgery within 24 hours duct is a misnomer. Biliary colic presents with intense, constant of admission vs patients first treated with antibiotics before under- right upper quadrant pain in the absence of fever and leukocyto- going cholecystectomy between 7 and 45 days after initial admis- sis. This pain is not intermittent or colicky as is often assumed, sion. The study found a much lower prevalence of postoperative but relatively constant due to the cystic ductal obstruction, and complications within the first 75 days in the group treated with early the pain only dissipates after the gallstones fall back into the cholecystectomy (11.8% for patients treated within 24 hours of ad- gallbladder.5 Biliary colic typically appears within a couple of hours mission vs 34.4% for those treated 7-45 days after initial admis- after eating a meal and improves within a few hours. The gallblad- sion; P <.001). Early cholecystectomy was also associated with a der wall is within normal limits on the ultrasound without any evi- shorter mean hospital length of stay (5.4 days for patients treated dence of pericholecystic fluid. within 24 hours of admission vs 10.0 days for those treated 7-45 days Acute cholangitis is defined by fever, jaundice, and right after initial admission; P <.001) and lower total hospital costs (€2919 upper quadrant pain with the ultrasound revealing dilated intra- vs €4262, respectively; P <.001).66 jama.com (Reprinted) JAMA March 8, 2022 Volume 327, Number 10 969 © 2022 American Medical Association. All rights reserved.  Clinical Review & Education Review Acute Cholecystitis—A Review A review of 15 760 Swedish patients with acute cholecystitis Biliary duct injury during surgery typically manifests with jaun- showed that bile duct injury after surgery was lower for patients who dice and fever postoperatively and is typically diagnosed intraop- underwent cholecystectomy within 4 days of admission (0.17% vs eratively or within a few days postoperatively. Even though the sur- 0.53% for those who underwent cholecystectomy after >4 days; geon can manage most bleeding or infectious complications, concern P =.008) and that patients also had a lower rate of death within 30 for a biliary injury requires prompt diagnosis and management by a days when patients underwent cholecystectomy within 2 days of surgeon with expertise in hepatobiliary reconstruction. The evalu- admission compared with more than 2 days after admission (0.39% ation for postoperative jaundice should include liver function tests. vs 1.33%, respectively; P =.004).67 A 2015 observational study of Ultrasonography is a practical first test to assess fluid collection or 45 452 patients from France showed that intensive care admis- enlarged biliary ducts. When evaluating for bile duct injury postop- sion, reoperation, and postoperative sepsis were lower for pa- eratively, magnetic resonance cholangiopancreatography is more in- tients who underwent surgery between 1 and 3 days after admis- formative compared with CT and should be obtained in the setting sion than patients who underwent surgery later. Mortality was also of abnormal bilirubin levels or abnormal ultrasound findings.74 lower for patients who underwent cholecystectomy between days 1 and 3 than for patients who underwent cholecystectomy on day 5 Acute Cholecystitis in Older Patients (1.0% vs 1.9%, respectively; P <.001).68 Initial nonoperative management with delayed cholecystectomy In 2020, a review of more than 100 000 cholecystectomies has been evaluated as an alternative strategy to immediate chole- in New York State found that patients who underwent cholecys- cystectomy for older patients (aged >65 years).75 However, data tectomy less than 72 hours from admission had a lower conver- have consistently shown that outcomes following early laparo- sion to an open procedure (7.5% vs 13.8% who underwent chole- scopic cholecystectomy in octogenarians are comparable with cystectomy >72 hours after admission; P <.001).69 However, younger patients.76 A 2010 study using Medicare data examined these results may have been influenced by confounding if 29 818 patients older than 65 years of age and reported that healthier patients were more likely to undergo an earlier opera- among patients who did not undergo initial cholecystectomy, 38% tion. In addition, evidence from 243 536 patients in the US were readmitted for gallbladder-related complications, whereas Nationwide Inpatient Sample database showed that non-White the readmission rate was only 4% for those who underwent an ini- patients had higher rates of emergent admission compared with tial cholecystectomy. White patients (84% vs 78%, respectively; P <.001), suggesting The absence of cholecystectomy during the initial hospitaliza- there are disparities in health care access for non-White patients tion was associated with higher mortality at 2 years (29.3%) com- who have acute cholecystitis.70 In summary, early cholecystec- pared with patients who underwent a cholecystectomy during the tomy was associated with significantly better outcomes than initial hospitalization (15.2%) (P <.001).77 A similar study from delayed cholecystectomy.66-69 England analyzed 47 500 patients aged 80 years or older from a Approximately 2% to 15% of patients undergoing laparoscopic national hospital database. Although the study demonstrated high cholecystectomy must be converted to open cholecystectomy. 30-day mortality in the early cholecystectomy cohort compared This phenomenon occurs when a safe surgical dissection is not pos- with the delayed cholecystectomy cohort (11.6% vs 9.9%, respec- sible during the laparoscopic procedure. 71 A 2017 systematic tively), there was a more substantial increase in mortality at 1 year review of 30 observational and mostly retrospective studies found for patients who underwent delayed cholecystectomy (20.8 vs that while the data quality was poor with a high probability of bias, 27.1%; P <.001).78 However, these observational studies are likely most studies showed that male sex, older age, high BMI, and the influenced by confounding, in which healthier patients were presence of acute cholecystitis were associated with higher rates of selected for early cholecystectomy. conversion to an open procedure.72 One single-center, longitudinal observational study of 732 patients reported several variables with Acute Cholecystitis During Pregnancy a significant association with conversion from laparoscopic to open Nongynecological surgery occurs in 1% to 2% of pregnant patients, cholecystectomy: previous upper abdominal surgery (11% vs 0.8% and abdominal surgery, including cholecystectomy, comprises 45% in those undergoing laparoscopic cholecystectomy), BMI greater of these surgeries.79 Current guidelines from the American College than 30 (55% vs 18%), impacted gallstone at the gallbladder neck of Obstetricians and Gynecologists and the Society of American (51% vs 16%), and gallbladder wall thickness greater than 3 mm Gastrointestinal and Endoscopic Surgeons recommend that laparo- (38% vs 0.4%).73 scopic cholecystectomy be performed for acute cholecystitis dur- ing any trimester in the presence of acute cholecystitis. 80,81 Postoperative Complications After Cholecystectomy Despite these recommendations, national data from the US A 2011 analysis of a Swiss national database of 4113 patients showed that approximately 60% of pregnant women with acute (median age, 59.8 years; 52.8% female) who underwent laparo- cholecystitis were managed nonoperatively.82 scopic cholecystectomy for acute cholecystitis reported that 6.1% Recent data suggested that the risk associated with cholecys- of patients had a postoperative complication.56 The most common tectomy was lower than the risk associated with nonoperative complications were abdominal wall or intra-abdominal bleeding management of acute cholecystitis during pregnancy. A 2017 study (1.8%) and superficial wound infection (1.0%). Extrahepatic bile of a national database in England included 47 628 pregnant duct injury occurred in 17 patients (0.4%). In a 2021 analysis of patients undergoing nonobstetric surgery.83 The estimated risk of the US National Readmissions Database, including 1 768 725 nonobstetric surgery during pregnancy was relatively low, with 1 patients who underwent laparoscopic cholecystectomy, 0.46% of stillbirth occurring in 1 of every 287 surgical operations and 1 pre- patients required a bile duct injury repair. term delivery occurring in 1 of every 31 operations. Even though this 970 JAMA March 8, 2022 Volume 327, Number 10 (Reprinted) jama.com © 2022 American Medical Association. All rights reserved. Acute Cholecystitis—A Review Review Clinical Review & Education study was observational and may not have accounted for signifi- In most patients with complicated cholecystitis, laparoscopic cant confounding, it suggested that the rate of obstetric complica- cholecystectomy is a reasonable initial approach, but conversion to tions associated with surgery is low. open cholecystectomy may be required. Inability to achieve a safe A 2021 study examined the US National Inpatient Sample and gallbladder dissection during laparoscopic or open cholecystec- identified nearly 24 000 pregnant women diagnosed with acute cho- tomy should prompt subtotal cholecystectomy, which consists of lecystitis. Among these patients, early laparoscopic cholecystec- removing most of the gallbladder wall, gallstones, and closing the tomy for acute cholecystitis was associated with lower preterm de- cystic duct orifice by fenestration.90 An analysis of 290 855 pa- livery, preterm labor, or spontaneous abortion when performed tients from the Nationwide Inpatient Sample identified that among within 1 day of presentation compared with a delay of 7 days or lon- those who underwent subtotal cholecystectomy compared with ger (1.6% vs 18.4%, respectively; P <.001).84 In summary, laparo- total cholecystectomy there was an increased prevalence in use of scopic cholecystectomy should be recommended to pregnant subtotal cholecystectomy in men (68.2% vs 48.3% women; women with acute cholecystitis regardless of trimester. P <.001), in Asian patients (5.4% vs 2.4% for non–Asian patients; P =.013), and in patients with alcohol use disorder (4.9% vs 2.4% Acute Cholecystitis in Patients With Cirrhosis for patients without alcohol use disorder; P <.018).91 In retrospective studies, the Child-Pugh score and the Model for Few data are available regarding the appropriate management End-stage Liver Disease (MELD) score are associated with out- of cholecystoenteric fistula and potential gallstone ileus (a gall- comes prior to cholecystectomy in patients with acute cholecysti- stone passed into the intestinal tract causing bowel obstruction). tis. A 2010 retrospective study of 220 patients in Greece with cir- A 2020 case series of 15 patients with cholecystoenteric fistula re- rhosis and acute cholecystitis reported higher perioperative ported high variability in the treatment strategy in that 5 patients complications for patients with a Child-Pugh score of 10 to 15 underwent laparotomy and stone removal without repair of their (class C; decompensated disease) or a MELD score greater than 13 fistula, 8 patients underwent an open cholecystectomy and repair compared with more favorable scores (MELD score range, 6-40).85 after laparoscopic conversion, and 2 patients underwent a laparo- A more recent analysis of the American College of Surgeons scopic repair.92 National Surgical Quality Improvement database showed similar Few studies have reported complication rates after open and results and reported that higher MELD scores were associated with laparoscopic subtotal cholecystectomy. A 2015 meta-analysis of higher rates of postoperative complications (wound, infectious, or 1228 patients from 30 studies that included both randomized and respiratory) and mortality. Among patients with MELD scores observational data showed a higher prevalence of bile leak (defined greater than 15, mortality rates were 3.2%.86 The presence of asci- as a leak from the gallbladder remnant or cystic duct stump) after tes and a MELD score greater than 20 were associated with an subtotal cholecystectomy in patients who did not have their cystic even higher risk of postoperative complication after laparoscopic duct or gallbladder stump closed compared with those who did cholecystectomy (66.7%) or death (33.3%). (42.0% vs 16.5%, respectively).58 This review also reported that A 2021 study of 349 patients with cirrhosis who were US vet- postoperative procedures were common in patients who under- erans reported lower postoperative complications (9.5% vs 31.5%; went endoscopic retrograde cholangiopancreatography, which P