Diagnosis of Acute Cholecystitis


Indication Overview

Acute cholecystitis is a sudden onset of inflammation of the gallbladder that causes severe abdominal pain. Abdominal pain is often accompanied by fever and abnormally high white blood cell count (leukocytes).1 Acute cholecystitis is usually caused by gallstones obstructing the cystic duct.2 This prevents the normal flow of bile in and out of the gallbladder into the bowel. Increased pressure in the gallbladder due to the obstruction results in inflammation and pain. Up to 14% of acute cholecystitis cases are acalculous.2 In these patients, there is an obstruction but gallstones are not the cause. Acute acalculous cholecystitis usually occurs in patients who are already critically ill from another medical condition. Mortality and morbidity is high in patients with acute acalculous cholecystitis.

The initial treatment for acute cholecystitis in the emergency room is usually intravenous antibiotics, hydration, and analgesia. If inflammation of the gallbladder continues, removal of the gallbladder (cholecystectomy) is usually required.3

Complications of acute cholecystitis include gangrenous cholecystitis (gangrene of the gallbladder wall), gallbladder perforation (hole or piercing of the wall of the gallbladder), and emphysematous cholecystitis (acute infection of the gallbladder caused by gas-forming organisms). These complications occur in up to 20% of people with cholecystitis, have high mortality associated with them, and therefore require emergency surgery.2

Population: Patients with suspected acute cholecystitis.

Intervention: Cholescintigraphy.

Cholescintigraphy, also known as a hepatobiliary iminodiacetic (HIDA) scan, is a nuclear medicine test used to diagnose intrahepatic or extrahepatic obstruction of the bile ducts, gallbladder disease, and bile leaks. Before cholescintigraphy, patients are injected with a radiopharmaceutical tracer (technetium-99m [99mTc]-iminodiacetic acid). Patients need to fast three to four hours before this injection to avoid gallbladder contraction.4 After injection, a gamma camera is used to detect gamma rays emitted by the patient from the injected radiopharmaceuticals. Images are created from the detected gamma rays. If there is no cystic duct blockage, the radiopharmaceutical will enter the gallbladder, which will be visualized in images created by the gamma camera. If a gallstone is obstructing a patient's cystic duct, the radiopharmaceutical will not enter the gallbladder and visualization of the gallbladder cannot occur. Non-visualization of the gallbladder is indicative of acute cholecystitis. If the gallbladder is not seen one hour after injection, images should be retaken three to four hours after injection.5 This delayed imaging increases the specificity of cholescintigraphy for the diagnosis of acute cholecystitis. An alternative to delayed imaging is to inject the patient with a small amount of morphine sulphate (0.02 mcg/kg). Administration of morphine sulphate facilitates the flow of bile toward the cystic duct by causing contraction of the sphincter of Oddi. The injection of morphine sulphate can reduce the time to confirm the diagnosis from three or four hours to 1.5 hours.4

Comparators: For this report, the following diagnostic tests are considered as alternatives to cholescintigraphy:

  • Computed Tomography (CT): In a CT scan, a rotating x-ray device moves around the patient and takes multiple detailed images of organs and body parts.6 Sometimes patients are injected with a contrast agent before images are taken, for better visualization of the body part being examined.6 CT findings consistent with acute cholecystitis include gallbladder wall thickening, gallbladder distention, pericholecystic fluid, and pericholecystic fat.
  • Magnetic Resonance Cholangiopancreatography (MRCP): An MRCP is a magnetic resonance imaging (MRI) test that produces detailed images of the hepatobiliary and pancreatic systems. Images are created using a magnetic field and radiofrequency pulses. Patients undergoing MRI are placed on to a table that is moved into the centre of the MRI machine. Some patients are given contrast material before the MRI. MRCP findings indicative of acute cholecystitis include gallbladder stones, wall thickening, and pericholecystic fluid.7
  • Ultrasound (U/S): During a U/S, a transducer is placed over the organ of interest. The transducer generates sound waves that pass through the body and produce echoes that are analyzed by a computer to produce images of the body part being analyzed.8 U/S findings consistent with acute cholecystitis include the visualization of gallstones, intraluminal sludge, thickening of the gallbladder wall, pericholecystic fluid, increased blood flow in the gallbladder wall, and sonographic Murphy's sign.9 Murphy's sign of cholecystitis refers to pain felt by the patient on taking a deep breath while pressure is placed in the right upper quadrant of the abdomen.10

Outcomes: Eleven outcomes (referred to as criteria) are considered in this report:

  • Criterion 1: Size of the affected population
  • Criterion 2: Timeliness and urgency of test results in planning patient management
  • Criterion 3: Impact of not performing a diagnostic imaging test on mortality related to the underlying condition
  • Criterion 4: Impact of not performing a diagnostic imaging test on morbidity or quality of life related to the underlying condition
  • Criterion 5: Relative impact on health disparities
  • Criterion 6: Relative acceptability of the test to patients
  • Criterion 7: Relative diagnostic accuracy of the test
  • Criterion 8: Relative risks associated with the test
  • Criterion 9: Relative availability of personnel with expertise and experience required for the test
  • Criterion 10: Accessibility of alternative tests (equipment and wait times)
  • Criterion 11: Relative cost of the test.

Definitions of the criteria are in Appendix 1.

Methods

The literature search was performed by an information specialist using a peer-reviewed search strategy.

Published literature was identified by searching the following bibliographic databases: MEDLINE with In-Process records and daily updates via Ovid; The Cochrane Library (2011, Issue 2) via Wiley; and PubMed. The search strategy consisted of both controlled vocabulary, such as the National Library of Medicine's MeSH (Medical Subject Headings), and keywords. The main search concepts were radionuclide imaging and cholecystitis.

Methodological filters were applied to limit retrieval to health technology assessments, systematic reviews, meta-analyses, randomized controlled trials, and non-randomized studies, including diagnostic accuracy studies. The search was limited to English language. No date limits were applied for the systematic review search. The primary studies search was limited to documents published between January 1, 1996, and March 2, 2011. Regular alerts were established to update the search until October 2011. Detailed search strategies are located in Appendix 2.

Grey literature (literature that is not commercially published) was identified by searching relevant sections of the CADTH Grey Matters checklist. Google was used to search for additional web-based materials. The searches were supplemented by reviewing the bibliographies of key papers. See Appendix 2 for more information on the grey literature search strategy.

Targeted searches were done as required for the criteria, using the aforementioned databases and Internet search engines. When no literature was identified that addressed specific criteria, experts were consulted.

Search Results

Fourteen articles11-24 were identified through the MA/SR/HTA search; of those, eight13-18,21,24 underwent full text review. One systematic review15 was identified from the full text review that compared the diagnostic accuracy of cholescintigraphy with one of the alternative imaging modalities.

A review of primary studies was conducted to identify studies that directly compared the diagnostic accuracy of cholescintigraphy with one of its alternatives. Four primary studies25-28 were found that compared cholescintigraphy with U/S. No primary studies were identified that directly compared cholescintigraphy with CT, with MRCP, or with ERCP. Articles from the grey literature search were used to address criterion 1 (one article)29 and criterion 8 (one article).30 Articles from the primary study search were used to help address criterion 1 (one article),31 criterion 3 (one article),32 criterion 6 (four articles), and criterion 8 (two articles).

Literature from targeted searches was used to supplement the articles identified in the primary study search. When no literature was identified addressing specific criteria, experts were consulted.

Summary table

Table 1: Summary of Criterion Evidence

Domain 1: Criteria Related to the Underlying Health Condition
Criterion Synthesized Information
1 Size of the affected population No estimates of point prevalence of acute cholecystitis were found in the literature. An Ontario hospital-based study29 estimated the annual incidence of acute cholecystitis from 1992 to 2000 to be 0.88 people per 1,000 population.

The size of affected population is more than 1 in 10,000 (0.01%) and less than or equal 1 in 1,000 (0.1%)
2 Timeliness and urgency of test results in planning patient management Saskatchewan hospital guidelines indicate that cholescintigraphy for diagnosis of suspected acute cholecystitis should be conducted within 24 hours (Patrick Au, Acute and Emergency Services Branch, Saskatchewan Ministry of Health: unpublished data, 2011)

The target time frame for performing the test is in 24 hours or less and obtaining the 99mTc-based test results in the appropriate timely manner for the underlying condition has significant impact on the management of the condition or the effective use of health care resources.
3 Impact of not performing a diagnostic imaging test on mortality related to the underlying condition If a test for diagnosing acute cholecystitis is not available, treatment might be delayed and complications associated with high mortality rates might be more likely to develop. Complications from acute cholecystitis occur in around 20% of patients and complicated acute cholecystitis is associated with a mortality rate of around 25%.33 Perforation of the gallbladder, which occurs in 3% to 15% of patients with cholecystitis, has a 60% mortality rate.34 Acute acalculous cholecystitis has a mortality rate of around 30%.35

Diagnostic imaging test results can have minimal impact on mortality.
4 Impact of not performing a diagnostic imaging test on morbidity or quality of life related to the underlying condition If a test for diagnosing acute cholecystitis is not available, treatment might be delayed and patients may have to suffer symptoms of acute cholecystitis longer than necessary. Delayed treatment will make patients more susceptible to complications that could increase the global hospitalization length and have an impact on their survival or quality of life.

Diagnostic imaging test results can have moderate impact on morbidity or quality of life.

 

Domain 2: Criteria Comparing 99mTc with an Alternative or Comparing Between Clinical Uses
Criterion Synthesized Information
5 Relative impact on health disparities To be scored locally.
6 Relative acceptability of the test to patients Cholescintigraphy
Patients may have concerns about radiation exposure and the intravenous injection of a radiopharmaceutical agent.

CT
Patients undergoing CT scan may have concerns about radiation exposure and may also feel claustrophobic while in the scanner. This is less of a problem with new CT scanners (MIIMAC expert opinion). Patients may be required to hold their breath for a substantial period of time, which is seen as "uncomfortable" and "difficult," particularly for patients with severe abdominal pain.36

MRCP
MRCP is an MRI-based imaging test. Because of the closed space of an MRI, patients may experience feelings of claustrophobia as well as be bothered by the noise. This may be less of a problem with new MRI machines, if available (MIIMAC expert opinion). It has been reported that up to 30% of patients experience apprehension and 5% to 10% endure some severe psychological distress, panic, or claustrophobia.37,38 Some patients may have difficulty remaining still during the scan. Patients are not exposed to radiation during an MRI scan, which may be more acceptable to some.

U/S
Some discomforts associated with U/S include cold, unspecified pain, and tenderness. In a study comparing U/S with MRI in undiagnosed shoulder pain, 100% of the patients participating said that they would be willing to undergo the U/S exam again.39 This test may be preferred in pediatric patients as there is no exposure to ionizing radiation, and the test does not require sedation.

Overall, acceptability to patients of cholescintigraphy using 99mTc-radiolabelled isotopes is:
  • minimally more acceptable than CT
  • minimally less acceptable than MRCP,
  • minimally less acceptable than U/S.
7 Relative diagnostic accuracy of the test

Cholescintigraphy versus U/S
The table presents the sensitivity and specificity reported in one systematic review15 and three primary studies25,27,28 that compared the diagnostic accuracy of cholescintigraphy and U/S for acute cholecystitis. Diagnosis of acute cholecystitis was confirmed with pathological or surgical findings (gold standard).

Diagnostic Accuracy
Author, Year Cholescintigraphy U/S
N Sensitivity Specificity N Sensitivity Specificity
Shea et al. 199415 2466 0.97 0.90 532 0.88 0.80
Chatziioannou et al. 200027 107 0.88 0.93 107 0.50 0.88
Kalimi et al. 200128 28 0.86 NR 50 0.48 NR
Alobaidi et al. 200425 22 0.91 NR 100 0.62 NR

N = number of patients; U/S = ultrasound.

Cholescintigraphy versus CT
No studies comparing the diagnostic accuracy of cholescintigraphy and CT for acute cholecystitis were identified.

Cholescintigraphy versus MRCP
No studies comparing the diagnostic accuracy of cholescintigraphy and MRCP for acute cholecystitis were identified.

Based on limited evidence and expert opinion, the diagnostic accuracy of cholescintigraphy using 99mTc-radiolabelled isotopes is:

  • moderately better than CT
  • similar to MRCP,
  • minimally better than U/S.
8 Relative risks associated with the test

Non–radiation-related Risks

Cholescintigraphy
Risks associated with a cholescintigraphy include allergy to HIDA and pain during CCK injection (causes gallbladder contraction), chills, nausea, and rash.40

CT
Some patients may experience an allergic reaction to the contrast agent (if required).41 In addition, patients may experience mild side effects from the contrast agent, such as nausea, vomiting, or hives. A 2009 retrospective review of 456,930 intravascular doses of low-osmolar iodinated and Gd contrast materials administered between 2002 and 2006 found 0.15% of patients experienced side effects, most of which were mild. According to the American College of Radiology Manual on Contrast Media,42 the frequency of severe, life-threatening reactions with Gd is extremely rare (0.001% to 0.01%).

MRCP
MRCP is an MRI-based test and is contraindicated in patients with metallic implants, including pacemakers.43 MRI is often used in conjunction with the contrast agent Gd. Some patients may experience an allergic reaction to the contrast agent (if required).41 Gd is contraindicated in patients with renal failure or end-stage renal disease, as they are at risk of nephrogenic systemic fibrosis. The frequency of severe, life-threatening reactions with Gd is extremely rare (0.001% to 0.01%).42

U/S
There are no reported risks associated with U/S in the literature that was reviewed.

Radiation-related Risks

Some tests expose patients to radiation. The following table presents the effective radiation dose to which patients are exposed during the various diagnostic tests.

Radiation doses
Test Effective Radiation Dose (mSv)
Cholescintigraphy 3.144
Abdominal CT 8.044
MRCP (MRI) 030
Abdominal U/S 030
Annual natural radiation exposure 1 to 3.044-46

Overall, the risks associated with cholescintigraphy using 99mTc-radiolabelled isotopes is:

  • minimally safer than CT
  • minimally less safe than MRCP,
  • minimally less safe than U/S.
9 Relative availability of personnel with expertise and experience required for the test

As of 2006 in Canada, there were 2,034 diagnostic radiologists, 221 nuclear medicine physicians, 12,255 radiological technologists, 1,781 nuclear medicine technologists, and 2,900 sonographers available across Canada. Yukon, Northwest Territories, and Nunavut do not have the available personnel to perform and interpret tests to detect bile leak. Other jurisdictions (e.g., Prince Edward Island) may offer limited nuclear medicine services.

Assuming the necessary equipment is available, if cholescintigraphy using 99mTc-radiolabelled isotopes is not available, it is estimated that:

  • more than 95% of the procedures can be performed in a timely manner using CT
  • 25-74% of the procedures can be performed in a timely manner using MRCP
  • more than 95% of the procedures can be performed in a timely manner using U/S.
10 Accessibility of alternative tests (equipment and wait times) Cholescintigraphy
For the diagnosis of acute cholecystitis, nuclear medicine facilities with gamma cameras (including SPECT) are required. As of January 1, 2007, there was an average of 18.4 nuclear medicine cameras per million people, with none available in the Yukon, Northwest Territories, or Nunavut.47

MRCP
No MRI scanners are available in the Yukon, Northwest Territories, or Nunavut.48 According to CIHI's National Survey of Selected Medical Imaging Equipment database, the average number of hours of operation per week for MRI scanners in 2006-2007 ranged from 40 hours in Prince Edward Island to 99 hours in Ontario with a national average of 71 hours.47 In 2010, the average wait time for MR imaging in Canada was 9.8 weeks.49

CT
No CT scanners are available in Nunavut.48 For CT scanners, the average weekly use ranged from 40 hours in Prince Edward Island to 69 hours in Ontario, with a national average of 60 hours.47

U/S
The median wait time for a U/S in Canada was estimated to be 4.5 weeks in 2010.49 No information was found on the number of U/S machines available in Canada.

Assuming the necessary expertise is available, if cholescintigraphy using 99mTc-radiolabelled isotopes is not available, it is estimated that:
  • more than 95% of the procedures can be performed in a timely manner using CT
  • 25-74% of the procedure can be performed in a timely manner using MRCP,
  • more than 95% of the procedures can be performed in a timely manner using U/S.
11 Relative cost of the test

According to our estimates, the cost of cholescintigraphy with 99mTc-based radioisotopes is $298.38. CT is minimally more costly and MRCP is moderately more costly. U/S is minimally less costly.

Relative costs
Test Total costs ($) Cost of test relative to 99mTc-based test ($)
Cholescintigraphy 298.38 Reference
CT 383.85 +85.47
MRCP 595.15 +296.77
U/S 88.25 -210.13

 

CCK = cholecystokinin; CIHI = Canadian Institute for Health Information; CT = computed tomography; Gd = Gadolinium; HIDA = hepatobiliary iminodiacetic acid; MRCP = magnetic resonance cholangiopancreatography; MRI = magnetic resonance imaging; mSv = millisievert; NR = not reported; SPECT = single-photon emission computed tomography; 99mTc = technetium-99m; U/S = ultrasound.

Criterion 1: Size of affected population (link to definition)

No estimates of point prevalence of acute cholecystitis were found in the literature. An Ontario study that estimated the annual incidence of acute cholecystitis was identified.29 Urbach and Stukel29 sought to find out whether the observed increased rate of elective cholecystectomy resulted in changes in the incidence of severe complications of gallbladder disease, including acute cholecystitis. Cases of severe gallbladder complications occurring from 1988 through 2000 in persons aged 18 years and older in Ontario were identified from hospital admission data from the Canadian Institute of Health Information (CIHI) and the Ontario Health Insurance Plan. Hospital admissions for acute cholecystitis were identified using specific ICD-9-CM codes. The authors estimated the average annual incidence rate of acute cholecystitis in Ontario during the years 1992-2000 to be 88.1 per 100,000 people. This is equivalent to 0.88 people per 1,000 people.

No other estimates of the prevalence or incidence of acute cholecystitis were found in the literature search. However, estimates of the prevalence of gallstones, the primary cause of acute cholecystitis, were found. It has been estimated that up to 10% to 20% of residents of the United States have gallstones and that one-third of these patients will suffer from acute cholecystitis at some point in their lives.31

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Criterion 2: Timeliness and urgency of test results in planning patient management (link to definition)

Saskatchewan hospital guidelines indicate that cholescintigraphy for diagnosis of suspected acute cholecystitis should be conducted within 24 hours (Patrick Au, Acute and Emergency Services Branch, Saskatchewan Ministry of Health: unpublished data, 2011).

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Criterion 3: Impact of not performing a diagnostic imaging test on mortality related to the underlying condition (link to definition)

If a test for diagnosing acute cholecystitis is not available, treatment might be delayed and complications with associated high mortality rates might be more likely to develop. Complications from acute cholecystitis occur in around 20% of patients. Complicated acute cholecystitis is associated with a mortality rate of around 25%.33 Perforation of the gallbladder, which occurs in 3% to 15% of patients with cholecystitis, has a 60% mortality rate.34 Acute acalculous cholecystitis has a mortality rate of around 30%.35

In an analysis of more than 29,000 elderly Medicare beneficiaries who presented with acute cholecystitis, those who were immediately treated with cholecystectomy had a lower mortality rate than patients not immediately treated with cholecystectomy.34,50 Patients given immediate cholecystectomy had mortality rates of 2.0%, 9.5%, and 15.2% at 30 days, one year, and two years, respectively. Patients not immediately treated with cholecystectomy had mortality rates of 5.0%, 19.4%, and 29.3% at 30 days, one year, and two years, respectively.

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Criterion 4: Impact of not performing a diagnostic imaging test on morbidity or quality of life related to the underlying condition (link to definition)

If a test for diagnosing acute cholecystitis is not available, treatment might be delayed and patients may have to suffer symptoms of acute cholecystitis longer than necessary. Additionally, delayed treatment may make patients more susceptible to complications that could affect their survival or their quality of life.

Two studies were identified that evaluated the quality of life impact of acute cholecystitis. A 2005 Norwegian study by Vetrhus et al.51 compared the quality of life over a five-year period of 64 patients presenting at their institution with acute cholecystitis. Patients were randomized to one of two treatment groups (all patients treated conservatively with antibiotics): observation, or cholecystectomy. Quality of life was assessed using the Psychological General Well-Being index (PGWB) and the Nottingham Health Profile (NHP) part II. Pain was evaluated using a pain score and a visual analogue pain scale (VAPS). No statistically significant differences between the two treatment groups over time were found in any of the instruments. However, the differences in mean scores in the quality of life and pain instruments at randomization and at five years reflect the morbidity impact of the acute cholecystitis episode. Table 2 presents selected findings of the study.

Table 2: Selected Results Reported in Vetrhus et al. 200551

Instrument Mean Score Interpretation
Randomization 5 years
PGWB Higher scores reflect better quality of life
  Observation 94.2 112.0
  Cholecystectomy 88.1 102.5
NHP Higher scores reflect worse quality of life
  Observation 2.0 0.7
  Cholecystectomy 2.2 1.4
Pain Score Higher scores reflect worse pain
  Observation 6.6 1.3
  Cholecystectomy 8.1 2.6
VAPS Higher scores reflect worse pain
  Observation 57.1 6.2
  Cholecystectomy 57.7 11.3

NHP = Nottingham Health Profile part II; PGWB = Psychological General Well-Being index; VAPS = visual analogue pain scale.

Bass et al.52 estimated the quality of life impact of different types and treatments of gallbladder disease. After being presented with descriptions of different diseases and procedures, 40 subjects (without gallstones) provided preference scores by means of either a simple 0 to 100 rating scale (n = 22; score of 0 = immediate death and 100 = perfect health) or standard gamble (n = 18). The relative mean rating score — rated relative to other related conditions — for an episode of acute cholecystitis was 0.36 and 0.77 by standard gamble.

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Criterion 5: Relative impact on health disparities (link to definition)

To be scored locally.

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Criterion 6: Relative acceptability of the test to patients (link to definition)

Cholescintigraphy
Patients may have concerns about radiation exposure and the intravenous injection of a radiopharmaceutical agent.

CT
Patients undergoing CT scan may have concerns about radiation exposure and may also feel claustrophobic while in the scanner. This is less of a problem with new CT scanners (MIIMAC expert opinion). Patients may be required to hold their breath for a substantial period of time, which is seen as "uncomfortable" and "difficult," particularly for patients with severe abdominal pain.36

MRCP
MRCP is an MRI-based imaging test. Because of the closed space of an MRI, patients may experience feelings of claustrophobia, as well as be bothered by the noise. This may be less of a problem with new MRI machines, if available (MIIMAC expert opinion). It has been reported that up to 30% of patients experience apprehension and 5% to 10% endure some severe psychological distress, panic, or claustrophobia.37,38 Some patients may have difficulty remaining still during the scan. Patients are not exposed to radiation during an MRI scan, which may be more acceptable to some.

U/S
Some discomforts associated with U/S include cold, unspecified pain, and tenderness. In a study comparing U/S with MRI in undiagnosed shoulder pain, 100% of the patients participating said that they would be willing to undergo the U/S exam again.39 This test may be preferred in pediatric patients as there is no exposure to ionizing radiation, and the test does not require sedation.

Return to Summary Table

Criterion 7: Relative diagnostic accuracy of the test (link to definition)

One systematic review15 was identified that evaluated the diagnostic accuracy of cholescintigraphy with U/S in patients suspected to have acute cholecystitis. This review was somewhat dated (1994) and the majority of studies included were not head-to-head comparisons of cholescintigraphy and U/S. No systematic reviews were identified that compared cholescintigraphy with CT or MRCP. Therefore, a search for primary diagnostic accuracy studies comparing cholescintigraphy with any of the alternatives (U/S, CT, and MRCP) was conducted. Four primary studies were identifed that compared the diagnostic accuracy of cholescintigraphy to U/S.25-28 Three of the studies reported sensitivity, specificity, or both sensitivity and specificity of the diagnostic test.25,27,28 The other study reported only the correlation of findings between cholescintigraphy and U/S. No primary studies were found that compared cholescintigraphy with CT or MRCP.

Cholescintigraphy versus U/S
Table 3 presents the sensitivity and specificity reported in one systematic review15 and three primary studies25,27,28 that compared the diagnostic accuracy of cholescintigraphy and U/S for acute cholecystitis. In their systematic review, Shea et al.15 estimated the sensitivity of cholescintigraphy and U/S to be 0.97 (95% confidence interval [CI], 0.96 to 0.98) and 0.88 (95% CI, 0.74 to 1.0), respectively. They estimated the specificity of cholescintigraphy to be 0.90 (95% CI, 0.86 to 0.95) and the specificity of U/S to be 0.80 (95% CI, 0.62 to 0.98). The sensitivity and specificity estimates incorporated an adjustment to account for verification bias.

The three primary retrospective studies all found cholescintigraphy to have higher sensitivity than U/S for the diagnosis of acute cholecystitis. Chatziioannou et al.27 found the sensitivity of cholescintigraphy and U/S to be 0.88 and 0.50, respectively. Kalimi et al.28 reported the sensitivity of cholescintigraphy and U/S to be 0.86 and 0.48, respectively, while Alobaidi et al.25 reported the sensitivity of cholescintigraphy and U/S to be 0.91 and 0.62, respectively. In their study, Chatziioannou et al.27 found the specificity of cholescintigraphy to be 0.93 compared with 0.88 for U/S. In all three of these primary studies, findings from the imaging tests were compared with histopathological findings of the same patients suspected of acute cholecystitis. In Chatziioannou et al.,27 all 107 patients in the study underwent both cholescintigraphy and U/S.

Tables 3 and 4 present other diagnostic findings from primary studies. Chatziioannou et al.27 found the overall accuracy of cholescintigraphy and U/S to be 0.92 and 0.77, respectively. Blaivas et al.26 found the correlation between the diagnosis of acute cholecystitis with cholescintigraphy and U/S to be 0.74.

Table 3: Sensitivity and Specificity of Cholescintigraphy and Ultrasonography

Author Year Cholescintigraphy Ultrasonography
N Sensitivity (95% CI) Specificity (95% CI) N Sensitivity (95% CI) Specificity (95% CI)
Meta-analyses
Shea et al.15 1994 22 0.97 (0.96 to 0.98) 0.90 (0.86 to 0.95) 5 0.88 (0.74 to 1.0) 0.80 (0.62 to 0.98)
Primary Retrospective Studies
Chatziioannou et al.27 2000 107 0.88 0.93 107 0.50 0.88
Kalimi et al.28 2001 28 0.86 (0.67 to 0.96) NR 50 0.48 (0.34 to 0.63) NR
Alobaidi et al.25 2004 22 0.91 NR 100 0.62 NR

CI = confidence interval; N = number of patients; NR = not reported.

Table 4: Other Measures of Diagnostic Accuracy for Cholescintigraphy and Ultrasonography

Author Year Cholescintigraphy Ultrasonography
N PPV NPV Acc Cor N PPV NPV Acc Cor
Chatziioannou et al.27 2001 107 0.85 0.95 0.92 NR 107 0.64 0.80 0.77 NR
Blaivas et al.26 2007 102 NR NR NR 0.74 102 NR NR NR 0.74

Acc = accuracy; cor = correlation; N = number of patients; NR = not reported; NVP = negative predictive value; PPV = positive predictive value.

Cholescintigraphy versus CT
No studies were identified that compared the diagnostic accuracy of cholescintigraphy and CT scan.

Cholescintigraphy versus MRCP
No studies were identified that compared the diagnostic accuracy of cholescintigraphy and MRCP.

Details of the diagnostic accuracy studies can be found in Appendix 3.

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Criterion 8: Relative risks associated with the test (link to definition)

Non–radiation-related Risks

Cholescintigraphy
Risks associated with cholescintigraphy include allergy to HIDA, pain during cholecystokinin (CCK) injection (causes gallbladder contraction), chills, nausea, and rash. In susceptible subjects, CCK has induced panic attacks.40 Rapid administration of CCK has been associated with deterioration in blood gases and respiratory function in infants. In a study of 18 subjects, slow infusion of CCK resulted in no adverse reactions, specifically abdominal pain, which was present in the group that had a bolus injection. Slow infusion of CCK is now a well-recognized practice (MIIMAC expert opinion).

CT
Some patients may experience an allergic reaction to the contrast agent (if required), which may worsen with repeated exposure.41 In addition, patients may experience mild side effects from the contrast agent such as nausea, vomiting, or hives. A 2009 retrospective review of all intravascular doses of low-osmolar iodinated and Gd contrast materials administered at the Mayo Clinic between 2002 and 2006 (456,930 doses) found that 0.15% of patients given CT contrast material experienced side effects, most of which were mild. A serious side effect was experienced by 0.005% of patients.53 CT is contraindicated in patients with elevated heart rate, hypercalcemia, and impaired renal function. 42

MRI
MRI is contraindicated in patients with metallic implants, including pacemakers.43 MRI is often used in conjunction with the contrast agent Gd. Some patients may experience an allergic reaction to the contrast agent (if required), which may worsen with repeated exposure.41 Side effects of Gd include headaches, nausea, and metallic taste. Gd is contraindicated in patients with renal failure or end-stage renal disease, as they are at risk of nephrogenic systemic fibrosis. According to the American College of Radiology Manual on Contrast Media,42 the frequency of severe, life-threatening reactions with Gd is extremely rare (0.001% to 0.01%). Moderate reactions resembling an allergic response (i.e., rash, hives, urticaria) are also very unusual and range in frequency from 0.004% to 0.7%.42

U/S
There are no reported risks associated with U/S in the literature that was reviewed.

Radiation-related Risks

Among the modalities to diagnose acute cholecystitis, cholescintigraphy, CT, and ERCP expose the patient to ionizing radiation. The average effective dose of radiation delivered with each of these procedures can be found in Table 5.

Table 5: Effective Radiation Doses for Various Imaging Tests

Test Effective Radiation Dose (mSv) Pediatric Effective Dose Estimate Range (mSv)
99mTc-disofenin 3.154 NR
99mTc-mebrofenin 3.154 NR
CT 8.044 8.044
ERCP* 1 to 1055 0.3 to 355
MRCP (MRI) 0 0
U/S 0 0
Average background dose of radiation per year 1-3.044-46 1-3.044-46

CT = computed tomography; ERCP = endoscopic retrograde cholangiopancreatography; GI = gastrointestinal; MRCP = magnetic resonance cholangiopancreatography; NR = not reported; 99mTc-disofenin = technetium-99m disofenin; 99mTc-mebrofenin = technetium-99m mebrofenin; U/S = ultrasound.
*Based on x-ray of abdomen and upper GI series with bowel follow-through.55

Return to Summary Table

Criterion 9: Relative availability of personnel with expertise and experience required for the test (link to definition)

Cholescintigraphy
In Canada, physicians involved in the performance, supervision, and interpretation ofcholescintigraphy should be nuclear medicine physicians or diagnostic radiologists with training or expertise in nuclear imaging.56 Physicians should have a Fellowship of Certification in Nuclear Medicine or Diagnostic Radiology with the Royal College of Physicians and Surgeons of Canada and/or the Collège des médecins du Québec. Nuclear medicine technologists are required to conduct hepatobiliary scans. Technologists must be certified by the Canadian Association of Medical Radiation Technologists (CAMRT) or an equivalent licensing body.

All alternative imaging modalities
In Canada, physicians involved in the performance, supervision, and interpretation of diagnostic CT scans, MRI, and U/S should be diagnostic radiologists47 and must have a Fellowship or Certification in Diagnostic Radiology with the Royal College of Physicians and Surgeons of Canada and/or the Collège des médecins du Québec. Foreign-trained radiologists also are qualified if they are certified by a recognized certifying body and hold a valid provincial license.56

Service engineers are needed for system installation, calibration, and preventive maintenance of the imaging equipment at regularly scheduled intervals. The service engineer's qualification will be ensured by the corporation responsible for service and the manufacturer of the equipment used at the site.

Qualified medical physicists (on-site or contracted part-time) should be available for the installation, testing, and ongoing quality control of CT scanners, MR scanners, and nuclear medicine equipment.56

CT
For the performance of CT scan, medical radiation technologists who are certified by CAMRT, or an equivalent licensing body recognized by CAMRT, are required. The training of technologists specifically engaged in CT should meet with the applicable and valid national and provincial specialty qualifications.

MRCP
Medical technologists must have CAMRT certification in magnetic resonance or be certified by an equivalent licensing body recognized by CAMRT.

U/S
Sonographers (or ultrasonographers) should be graduates of an accredited school of sonography or have obtained certification by the Canadian Association of Registered Diagnostic Ultrasound Professionals. They should be members of their national or provincial professional organization. Sonography specialties include general sonography, vascular sonography, and cardiac sonography.47 In Quebec, sonographers and medical radiation technologists are grouped together; in the rest of Canada, sonographers are considered a distinct professional group.47

The availability of expertise to diagnose acute cholecystitis varies across the jurisdictions. Table 6 reports the number of medical imaging professionals nationally and highlights those provinces and territories that lack a specific expertise. Gastroenterologists are not included in this list; however, the number of gastroenterologists in Canada available to perform the procedure is reported to be 1.83 per 100,000 persons.57

Table 6: Medical Imaging Professionals in Canada47

Jurisdiction Diagnostic Radiology Physician Nuclear Medicine Physician Medical Radiation Technologists Nuclear Medicine Technologists Sonographers Medical Physicist
NL 46 3 263 15 NR NR
NS 71 5 403 71 NR NR
NB 47 3 387 55 NR NR
PEI 7 0 57 3 NR 0
QC 522 90 3,342 460 NR NR
ON 754 69 4,336 693 NR NR
MB 58 8 501 42 NR NR
SK 61 4 359 36 NR NR
AB 227 18 1,229 193 NR NR
BC 241 21 1,352 212 NR NR
YT 0 0 0 0 NR 0
NT 0 0 26 1 NR 0
NU 0 0 0 0 NR 0
Total 2,034 221 12,255 1,781 2,900* 322*

AB = Alberta; BC = British Columbia; MB = Manitoba; NB = New Brunswick; NL = Newfoundland and Labrador; NR = not reported for jurisdictions; NS = Nova Scotia; NT= Northwest Territories; NU = Nunavut; ON = Ontario; PEI = Prince Edward Island; QC = Quebec; YT = Yukon.
*This represents a total for all of the jurisdictions

Return to Summary Table

Criterion 10: Accessibility of alternative tests (equipment and wait times) (link to definition)

There are notable variations in the availability of medical imaging technologies across Canada. Table 7 provides an overview of the availability of equipment required to diagnose acute cholecystitis. Data for nuclear medicine cameras (including SPECT) are current to January 1, 2007. The number of CT, MRI, and SPECT/CT scanners is current to January 1, 2010. Data were not available for U/S.

Table 7: Diagnostic Imaging Equipment in Canada47,48

  Nuclear Medicine Cameras CT Scanners MRI Scanners SPECT/CT Scanners
Number of devices 60347 46048 21848 9648
Average number of hours of operation per week (2006-2007)47 40 60 71 n/a
Provinces and Territories with no devices available YT, NT, NU NU YT, NT, NU PE, YT, NT, NU

NT = Northwest Territories; NU = Nunavut; PE = Prince Edward Island; YT = Yukon

Cholescintigraphy
To perform cholescintigraphy, nuclear medicine facilities with gamma cameras (including SPECT) are required. Three jurisdictions, the Yukon, the Northwest Territories, and Nunavut, do not have any nuclear medicine equipment.47

CT
No CT scanners are available in Nunavut.48 The average weekly use of CT scanners ranged from 40 hours in PEI to 69 hours in Ontario, with a national average of 60 hours.47 In 2010, the average wait time for a CT scan in Canada is 4.2 weeks.49

ERCP
ERCP is an x-ray–based test. X-ray machines are widely available across the country.

MRCP
MRCP is an MRI based test. No MRI scanners available in the Yukon, Northwest Territories, or Nunavut.48 According to CIHI's National Survey of Selected Medical Imaging Equipment database, the average number of hours of operation per week for MRI scanners in 2006–2007 ranged from 40 hours in PEI to 99 hours in Ontario with a national average of 71 hours.47 In 2010, the average wait time for MR imaging in Canada was 9.8 weeks.49

U/S
U/S machines are widely available across the country. According to the Fraser Institute, the average wait time for U/S in 2010 was 4.5 weeks.

Return to Summary Table

Criterion 11: Relative cost of the test (link to definition)

Fee codes from the Ontario Schedule of Benefits were used to estimate the relative costs of cholescintigraphy and its alternatives. Technical fees are intended to cover costs incurred by the hospital (i.e., radiopharmaceutical costs, medical/surgical supplies, and non-physician salaries). Maintenance fees are not billed to OHIP — estimates here were provided by St. Michael's Hospital in Toronto. Certain procedures (i.e., PET scan, CT scan, MRI scan) are paid for, in part, out of the hospital's global budget — these estimates were provided by The Ottawa Hospital. It is understood that the relative costs of imaging will vary from one institution to the next.

According to our estimates (Table 8), the cost of cholescintigraphy with 99mTc-based radioisotopes is $298.38. CT is minimally more costly, MRCP is moderately more costly, and U/S is minimally less costly. An estimate for ERCP could not be obtained; however, actual costs (i.e., excluding professional fees) obtained from one Ontario hospital were reported to be approximately $1900. Therefore, ERCP is a significantly more costly alternative.

Table 8: Cost Estimates Based on the Ontario Schedule of Benefits for Physician Services Under the Health Insurance Act (September 2011)58

Fee Code Description Tech. Fees ($) Prof. Fees ($) Total Costs ($)
Cholescintigraphy
J804 First transit — without blood pool images 16.50 20.95 37.45
Y831 Biliary scintigraphy 152.69 66.24 168.40
Maintenance fees — from global budget 42.00   42.00
TOTAL 211.19 87.19 298.38
CT
X410 Abdominal CT — with IV contrast   102.65 102.65
X232 Pelvic CT — with IV contrast   102.65 102.65
Technical cost — from global budget 150.00   150.00
Maintenance fees — from global budget 28.55   28.55
TOTAL 178.55 205.30 383.85
MRCP
X451C MRI – cannulation abdomen — multislice sequence   77.20 77.20
X455C (×3) Repeat (another plane, different pulse sequence), to a maximum of 3 repeats   38.65 (×3) = 115.95 115.95
X499C 3-D MRI acquisition sequence, including post-processing (minimum of 60 slices; maximum 1 per patient per day)   65.50 65.40
Technical cost — from global budget 300.00   300.00
Maintenance fees — from global budget 36.50   36.50
TOTAL 336.50 258.65 595.15
U/S
J135 Complete abdominal scan 50.00 34.95 84.95
Maintenance fees — from global budget 3.30   3.30
TOTAL 53.30 34.95 88.25

3-D = three-dimensional; anes = anesthetic; CT = computed tomography; ERCP = endoscopic retrograde cholangiopancreatography; MRCP = magnetic resonance cholangiopancreatography; MRI = magnetic resonance imaging; RNA = radionuclide angiogram; spec = specialist; SPECT = single-photon emission computed tomography; U/S = ultrasound.

Return to Summary Table

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Appendix 1: Multi-Criteria Decision Analysis Definitions

Domain 1: Criteria Related to the Underlying Health Condition
Criterion Definition
1. Size of the affected population The estimated size of the patient population that is affected by the underlying health condition and which may potentially undergo the test. The ideal measure is point prevalence, or information on how rare or common the health condition is.
2. Timeliness and urgency of test results in planning patient management The timeliness and urgency of obtaining the test results in terms of their impact on the management of the condition and the effective use of health care resources.
3. Impact of not performing a diagnostic imaging test on mortality related to the underlying condition Impact of not performing the test, in whatever way, on the expected mortality of the underlying condition. Measures could include survival curves showing survival over time, and/or survival at specific time intervals with and without the test.
4. Impact of not performing a diagnostic imaging test on morbidity or quality of life related to the underlying condition Impact of not performing the test, in whatever way, on the expected morbidity or on the quality of life reduction of the underlying condition. Measures of impact may include natural morbidity outcome measures such as events or disease severity, or might be expressed using generic or disease-specific quality of life rating scales with and without the test.
Domain 2: Criteria Comparing 99mTc with an Alternative, or Comparing between Clinical Uses
Criterion Definition
5. Relative impact on health disparities Health disparities are defined as situations where there is a disproportionate burden (e.g., incidence, prevalence, morbidity, or mortality) amongst particular population groups (e.g., gender, age, ethnicity, geography, disability, sexual orientation, socioeconomic status, and special health care needs).

Impact on health disparities is assessed by estimating the proportion of current clients of the 99mTc-based test that are in population groups with disproportionate burdens.

(Explanatory note: The implication of this definition is that, everything else being the same, it is preferable to prioritize those clinical uses that have the greatest proportion of clients in groups with disproportionate burdens.)
6. Relative acceptability of the test to patients Acceptability of the 99mTc-based test from the patient's perspective compared with alternatives. Patient acceptability considerations include discomfort associated with the administration of the test, out-of-pocket expenses or travel costs, factors that may cause great inconvenience to patients, as well as other burdens. This criterion does not include risks of adverse events but is about everything related to the experience of undergoing the test.
7. Relative diagnostic accuracy of the test Ability of the test to correctly diagnose the patients who have the condition (sensitivity) and patients who do not have the condition (specificity) compared with alternatives.
8. Relative risks associated with the test Risks associated with the test (e.g., radiation exposure, side effects, adverse events) compared with alternatives. Risks could include immediate safety concerns from a specific test or long-term cumulative safety concerns from repeat testing or exposure.
9. Relative availability of personnel with expertise and experience required for the test Availability of personnel with the appropriate expertise and experience required to proficiently conduct the test and/or interpret the test findings compared with alternatives.
10. Accessibility of alternatives (equipment and wait times) Availability (supply) of equipment and wait times for alternative tests within the geographic area. Includes consideration of the capacity of the system to accommodate increased demand for the alternatives. Excludes any limitation on accessibility related to human resources considerations.
11. Relative cost of the test Operating cost of test (e.g., consumables, heath care professional reimbursement) compared with alternatives.

 

Appendix 2: Literature Search Strategy

OVERVIEW

Databases:

Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) <1946 to March 2, 2011>

Date of Search:

March 2, 2011

Alerts:

Monthly search updates began March 2, 2011 and ran until October 2011.

Study Types:

Health technology assessments; systematic reviews; meta-analyses; randomized controlled trials; non-randomized studies; diagnostic accuracy studies

Limits:

English language

Publication years 1996-March 2, 2011 for primary studies search; no date limits for systematic review search.

SYNTAX GUIDE
/ At the end of a phrase, searches the phrase as a subject heading
MeSH Medical subject heading
.fs Floating subheading
exp Explode a subject heading
* Before a word, indicates that the marked subject heading is a primary topic; or, after a word, a truncation symbol (wildcard) to retrieve plurals or varying endings
ADJ Requires words are adjacent to each other (in any order)
ADJ# Adjacency within # number of words (in any order)
.ti Title
.ab Abstract
.hw Heading word; usually includes subject headings and controlled vocabulary 
.tw Text word: searches title, abstract, captions, and full text
.mp Keyword search; includes title, abstract, name of substance word, subject heading word and other text fields.
.pt Publication type
.rn CAS registry number
.nm Name of substance word: used to search portions of chemical names and includes words from the CAS Registry/EC Number/Name (RN) fields
.jw Journal words: searches words from journal names
/ri Radionuclide imaging subheading
/du Diagnostic use subheading

 

Multi-database Strategy
# Searches
1 exp Cholecystitis/ or exp Cholangitis/
2 *Gallbladder Diseases/ri or *Gallbladder/ri
3 Cholecystitis.ti,ab.
4 ((Gallbladder* or Gall Bladder*) adj3 (inflammation or Empyema)).ti,ab.
5 or/1-4
6 Technetium/
7 exp Technetium Compounds/
8 exp Organotechnetium Compounds/
9 exp Radiopharmaceuticals/
10 (Technetium* or Tc-99* or Tc99* or Tc-99m* or Tc99m* or 99mTc* or 99m-Tc* or 99mtechnetium* or 99m-technetium*).tw,nm.
11 Radionuclide Imaging/ or Perfusion Imaging/
12 radionuclide imaging.fs.
13 radioisotope*.mp.
14 ((radionucl* or nuclear or radiotracer* or hepatobiliary or hepato-biliary or sulfur colloid* or gall bladder* or gallbladder*) adj2 (imag* or scan* or test* or diagnos*)).ti,ab.
15 Tomography, Emission-Computed, Single-Photon/
16 (single-photon adj2 emission*).ti,ab.
17 (SPECT or scintigraph* or scintigram* or scintiphotograph* or Cholescintigraph*).ti,ab.
18 (lidofenin or gadolinium-HIDA or Gd-HIDA or iminodiacetic acid or HIDA or 99mTc-IDA).tw,nm.
19 (59160-29-1 or 73121-98-9).rn.
20 or/6-19
21 meta-analysis.pt.
22 meta-analysis/ or systematic review/ or meta-analysis as topic/ or exp technology assessment, biomedical/
23 ((systematic* adj3 (review* or overview*)) or (methodologic* adj3 (review* or overview*))).ti,ab.
24 ((quantitative adj3 (review* or overview* or synthes*)) or (research adj3 (integrati* or overview*))).ti,ab.
25 ((integrative adj3 (review* or overview*)) or (collaborative adj3 (review* or overview*)) or (pool* adj3 analy*)).ti,ab.
26 (data synthes* or data extraction* or data abstraction*).ti,ab.
27 (handsearch* or hand search*).ti,ab.
28 (mantel haenszel or peto or der simonian or dersimonian or fixed effect* or latin square*).ti,ab.
29 (met analy* or metanaly* or health technology assessment* or HTA or HTAs).ti,ab.
30 (meta regression* or metaregression* or mega regression*).ti,ab.
31 (meta-analy* or metaanaly* or systematic review* or biomedical technology assessment* or bio-medical technology assessment*).mp,hw.
32 (medline or Cochrane or pubmed or medlars).ti,ab,hw.
33 (cochrane or health technology assessment or evidence report).jw.
34 or/21-33
35 5 and 20 and 34
36 exp "Sensitivity and Specificity"/
37 False Positive Reactions/
38 False Negative Reactions/
39 du.fs.
40 sensitivit*.tw.
41 (distinguish* or differentiat* or enhancement or identif* or detect* or diagnos* or accura* or comparison*).ti,ab.
42 (predictive adj4 value*).tw.
43 Comparative Study.pt.
44 (Validation Studies or Evaluation Studies).pt.
45 Randomized Controlled Trial.pt.
46 Controlled Clinical Trial.pt.
47 (Clinical Trial or Clinical Trial, Phase II or Clinical Trial, Phase III or Clinical Trial, Phase IV).pt.
48 Multicenter Study.pt.
49 (random* or sham or placebo*).ti.
50 ((singl* or doubl*) adj (blind* or dumm* or mask*)).ti.
51 ((tripl* or trebl*) adj (blind* or dumm* or mask*)).ti.
52 (control* adj3 (study or studies or trial*)).ti.
53 (non-random* or nonrandom* or quasi-random* or quasirandom*).ti.
54 (allocated adj "to").ti,ab.
55 Cohort Studies/
56 Longitudinal Studies/
57 Prospective Studies/
58 Follow-Up Studies/
59 Retrospective Studies/
60 Case-Control Studies/
61 Cross-Sectional Study/
62 (observational adj3 (study or studies or design or analysis or analyses)).ti.
63 cohort.ti.
64 (prospective adj7 (study or studies or design or analysis or analyses or cohort)).ti.
65 (prospective adj7 (study or studies or design or analysis or analyses or cohort)).ti.
66 ((follow up or followup) adj7 (study or studies or design or analysis or analyses)).ti.
67 ((longitudinal or longterm or (long adj term)) adj7 (study or studies or design or analysis or analyses or data or cohort)).ti.
68 (retrospective adj7 (study or studies or design or analysis or analyses or cohort or data or review)).ti.
69 ((case adj control) or (case adj comparison) or (case adj controlled)).ti.
70 (case-referent adj3 (study or studies or design or analysis or analyses)).ti.
71 (population adj3 (study or studies or analysis or analyses)).ti.
72 (cross adj sectional adj7 (study or studies or design or research or analysis or analyses or survey or findings)).ti.
73 or/37-72
74 5 and 20 and 73
75 74 not case reports.pt.
76 76
77 limit 77 to english language
78 77
79 limit 78 to yr="1996 -Current"

 

OTHER DATABASES
PubMed Same MeSH, keywords, limits, and study types used as per MEDLINE search, with appropriate syntax used.

Cochrane Library
(Issue 2, 2011)

Same MeSH, keywords, and date limits used as per MEDLINE search, excluding study types and Human restrictions. Syntax adjusted for Cochrane Library databases.

 

GREY LITERATURE SEARCHING
Dates for Search: March 3 to 4, 2011
Keywords: Included terms for cholecystitis and radionuclide imaging
Limits: English language

The following sections of the CADTH grey literature checklist, "Grey matters: a practical search tool for evidence-based medicine" (http://www.cadth.ca/en/resources/grey-matters) were searched:

  • Health Technology Assessment Agencies (selected)
  • Clinical Practice Guidelines
  • Databases (free)
  • Internet Search

 

Appendix 3: Diagnostic Accuracy Studies

Shea et al.15

Shea et al.15 conducted a systematic review and meta-analysis in order to estimate the diagnostic accuracy of various tests for biliary tract disease. Acute cholecystitis was one of the biliary diseases that were evaluated. The authors searched for studies published from 1966 to September 1992 on MEDLINE. Bibliographies of selected studies were also reviewed for relevant articles. The search identified articles with MeSH descriptors or either cholelithiasis or cholecystitis AND MeSH descriptors of any of cholecystography, ultrasonography, ultrasonics, tomography, nuclear magnetic resonance, or radionuclide imaging.

Titles and abstracts of potential articles were screened by research staff. The full text of articles included after title and abstract screening was screened for inclusion by research staff and by a review committee if the research staff could not determine whether it should be included. Article exclusion criteria included the absence of original study data, sample size less than 20, inability to calculate sensitivity and specificity from data presented, atypical patient population, retrospective review, lack of description of criteria for positive diagnosis, whether the study used an atypical or outdated variant of a diagnostic test, the diagnosis was not confirmed with an acceptable gold standard, or more than 10% of patients were unavailable for follow-up.

Sensitivity and specificity for the tests were pooled by what the authors describe as cluster sampling methods for estimating a proportion. The authors corrected their estimate to account for verification bias. The authors state that most diagnostic test studies suffer from verification bias because only a subset of patients have their diagnosis verified with a gold standard. In the case of patients with gallstones, more patients with a positive imaging test result are likely to have the most common gold standard, cholecystectomy.

Twenty articles, with a total of 2,466 patients, were included in the cholescintigraphy diagnostic accuracy estimates. Five studies, with a total of 532 patients, were used to estimate diagnostic accuracy of ultrasound (U/S). The authors estimated sensitivity and specificity of cholescintigraphy to be 0.97 (confidence interval [CI], 0.96 to 0.99) and 0.90 (0.86 to 0.95), respectively. No verification bias adjustment was made for cholescintigraphy.

The authors estimated verification bias adjusted sensitivity and specificity of U/S to be 0.88 (0.74 to 1.00) and 0.80 (0.62 to 0.98), respectively. The unadjusted sensitivity and specificity of U/S was estimated to be 0.94 (0.92 to 0.96) and 0.78 (0.61 to 0.96), respectively.

Chatziioannou et al.27

Chatziioannou et al.27 compared the diagnostic accuracy of cholescintigraphy and U/S for the diagnosis of acute cholecystitis. One hundred and seven consecutive patients presenting to a United States hospital emergency department during 1996 suspected of acute cholecystitis were included in the study. Patients received both cholescintigraphy and U/S at the time of presentation. For patients who went on to surgery (n = 44), pathological findings were used as the gold standard with which imaging findings were compared. For patients who did not go on to surgery (n = 63), the diagnosis made by the primary physician was considered to be the gold standard with which results from imaging tests were compared. For cholescintigraphy, nonvisualization of the gallbladder either three to four hours after radiotracer injection or 30 minutes after radiotracer and morphine sulfate injection was considered consistent with acute cholecystitis. The primary finding from U/S that was considered consistent with acute cholecystitis was sonographic Murphy's sign. In the absence of Murphy's sign, other findings considered consistent with acute cholecystitis were gallstones and gallbladder wall thickness greater than 4 mm, gallstones, and a gallbladder more than 5 cm in length. Acalculous acute cholecystitis was diagnosed with findings of thickened gallbladder wall, edema within the wall, sludge pericholecystic fluid, and sonographic Murphy's sign.

The authors presented results separately for all patients, and for patients who went on to surgery and had pathologic confirmation of presence or absence of acute cholecystitis. For all patients, the sensitivity, specificity, positive predictive value, negative predictive and overall accuracy of cholescintigraphy was estimated to be 0.88, 0.93, 0.85, 0.95, and 0.92. For U/S, the sensitivity, specificity, positive predictive value, negative predictive and overall accuracy was estimated to be 0.50, 0.88, 0.64, 0.80, and 0.77.

For the 44 patients who went on to surgery, the sensitivity, specificity, positive predictive value, negative predictive and overall accuracy of cholescintigraphy was estimated to be 0.92, 0.89, 0.92, 0.89, and 0.91. For U/S, the sensitivity, specificity, positive predictive value, negative predictive and overall accuracy was estimated to be 0.40, 0.89, 0.83, 0.53, and 0.61.

Alobaidi et al.25

Alobaidi et al.25 reviewed data from 117 patients pathologically proven to have acute cholecystitis. Patients were seen in a United States hospital between 1999 and 2002. Patients were stratified into groups depending on which imaging test (U/S, cholescintigraphy) or combination of imaging tests they underwent before surgery. The diagnoses made with each test at the time of exam were used to calculate each test. False-negative U/Ss were reviewed by radiologists, along with 40 true-positive scans from the same group as a control. The review was used to estimate a corrected sensitivity estimate to account for what the authors refer to as limiting factors relating to the date of surgery versus the date of imaging. Criteria used to diagnose acute cholecystitis with U/S included sonographic Murphy's sign, gallbladder wall thickening, pericholecystic fluid, biliary dilatation, and gallbladder hydrops. Diagnosis of acute cholecystitis with cholescintigraphy was based on nonvisualization of the gallbladder three hours after injection of radiotracer or 30 minutes after injection of morphine sulfate. Ninety-seven of the 117 patients had U/S as their initial imaging test. Based on initial diagnosis, the authors reported sensitivity for U/S of 62%. Nine false-negative patients reclassified as true positives upon additional review by radiologists. Based on this reclassification, the sensitivity of U/S was estimated to be 70.4%. The authors estimated the sensitivity of cholescintigraphy to be 90.9%.

Kalimi et al.28

Kalimi et al.28 retrospectively reviewed 132 patients admitted to a United States hospital emergency room with upper quadrant pain between 1996 and 2000. These patients were pathologically proven to have acute cholecystitis. At the time of presentation at the emergency room, patients were tested either by means of cholescintigraphy (n = 28), U/S (n = 28), or both cholescintigraphy and U/S (n = 54). Sensitivity for each test or combination of tests was estimated by the number of positive findings at the time of admission. Cholescintigraphy was considered to be positive for acute cholecystitis if there was nonvisualization of the gallbladder despite morphine augmentation. U/S findings considered positive for acute cholecystitis was presence of gallstones along with either wall edema or stone impacted in the gallbladder neck. The authors report the sensitivity of cholescintigraphy and U/S to be 86% (95% CI, 67% to 96%) and 48% (95% CI, 34% to 63%), respectively. The sensitivity for patients undergoing both cholescintigraphy and U/S was 90% (95% CI, 80% to 97%).

Blaivas et al.26

Blaivas et al.26 retrospectively compared findings from U/S and cholescintigraphy in patients suspected of acute cholecystitis. A total of 99 patients presenting at a United States hospital emergency department who received both U/S and cholescintigraphy were included in the study. U/S findings that were considered to be indicative of acute cholecystitis included finding of gallstones with a sonographic Murphy's sign, significant wall thickening greater than 5 mm, pericholecystic fluids, or a combination of these. No gold standard was specified in the study and no estimates of sensitivity or specificity were reported. The authors did report an overall correlation of findings between cholescintigraphy and U/S of 0.74. The authors also reported that U/S diagnosed acute cholecystitis in 38% of the 38 patients diagnosed with cholescintigraphy. Of the 25 patients diagnosed with acute cholecystitis using U/S, 80% were diagnosed positive using cholescintigraphy.