To study the diagnostic value of individual ultrasonographic findings in acute appendicitis

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To study the diagnostic value of

individual ultrasonographic findings in acute appendicitis

A dissertation submitted in partial fulfilment of MD Radiodiagnosis (Branch VIII) examination of the Tamil Nadu Dr. M.G.R. Medical University, Chennai

to be held in May 2018

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Certificate

This is to certify that the dissertation entitled “To study the diagnostic value of individual ultrasonographic signs in acute appendicitis” is the bonafide original work of Dr. Minu Mary Jose submitted in partial fulfilment of the requirement for MD Radiodiagnosis (Branch VIII) Degree Examination of the Tamil Nadu Dr. M.G.R Medical University, Chennai to be held in May 2018.

Guide

Dr. Sridhar Gibikote

Professor and Head of Department, Department of Radiology,

Christian Medical College & Hospital, Vellore, Tamil Nadu – 632004.

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Certificate

This is to certify that the dissertation entitled “To study the diagnostic value of individual ultrasonographic signs in acute appendicitis” is the bonafide original work of Dr. Minu Mary Jose submitted in partial fulfilment of the requirement for MD Radiodiagnosis (Branch VIII) Degree Examination of the Tamil Nadu Dr. M.G.R Medical University, Chennai to be held in May 2018.

Head of Department

Dr. Sridhar Gibikote Professor, Department of Radiodiagnosis

Christian Medical College Vellore -632004

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Certificate

This is to certify that the dissertation entitled “To study the diagnostic value of individual ultrasonographic signs in acute appendicitis” is the bonafide original work of Dr. Minu Mary Jose submitted in partial fulfilment of the requirement for MD Radiodiagnosis (Branch VIII) Degree Examination of the Tamil Nadu Dr. M.G.R.

Medical University, Chennai to be held in May 2018.

Principal

Dr. Anna B. Pulimood, MD, Ph.D.

Professor, Department of Pathology,

Christian Medical College, Vellore -632004

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Declaration

I, Dr. Minu Mary Jose, hereby declare that this dissertation entitled “To study the diagnostic value of individual ultrasonogaphic signs in acute appendicitis” is an original work done by me in partial fulfilment of the requirement for M.D Radio Diagnosis (Branch - VIII) Degree Examination of The Tamil Nadu Dr. M.G.R.

Medical University, Chennai to be conducted in May 2018.

Dr. Minu Mary Jose

Post Graduate student (MD Radiodiagnosis) Department of Radio Diagnosis,

Christian Medical College, Vellore – 632004.

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Antiplagiarism certificate

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IRB clearance letter

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Acknowledgements:

I wish to express my deep gratitude to my guide Dr. Sridhar Gibikote, Professor, Department of Radiology, Christian Medical College and Hospital, Vellore for his wisdom, expert guidance, involvement & encouragement throughout the work on my dissertation.

I am extremely grateful to Dr. Kirthi Sathyakumuar from the Department of Radiology, Christian Medical College and Hospital, Vellore for always being

approachable and ready with valuable inputs and guidance. I also thank Dr. Sampath Karl, Professor in the Department of Paediatric Surgery & Dr. J. C. Muthusami, Professor in the Department of General Surgery, Christian Medical College and Hospital, Vellore for their advice, support, encouragement and valuable inputs in carrying out this study.

I wish to specially thank all the first on calls in the Department of Radiology, Christian Medical College and Hospital, Vellore for cooperating wholeheartedly in this study and spending additional time for following the study protocol.

I sincerely thank Mr. Bijesh Yadav, Senior Demonstrator, Department of Biostatistics, Christian Medical College, Vellore, for his timely help with statistics & data analysis.

I am grateful most importantly to all the patients without whom this study would not have been possible.

CMC Vellore and all my teachers, for making this study and this course a reality.

My husband Mr. George Yacub, my sister Dr. Anu Jose, all my family & friends for their love, constant support and encouragement.

I dedicate this thesis to my parents Dr. T.M. Jose & Mrs. Beena Kumari Abraham for their many sacrifices, unconditional love and unwavering belief in me.

Above all, I thank the Lord Almighty for his abundant grace.

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INTRODUCTION

Acute appendicitis is one of the commonest causes for acute abdomen.

Overall incidence reported is 107.76 per 100,000 per year in a study in Taiwan and 23.3 per 10,000 population per year in US (age group 10-19 years).

Though it was traditionally considered a clinical diagnosis, imaging modalities like ultrasound and computed tomography have helped in a big way in complimenting the diagnostic flow chart and helping in predicting complications of appendicitis and to reduce the rate of false negative emergency appendicectomies. Although appendicitis has a good prognosis, a delay in diagnosis can result in increased risk of perforation, abscess, peritonitis, sepsis, obstruction and even death.

Since the 1980s, ultrasound is being used in the diagnosis of appendicitis. It is a diagnostic modality which is readily available, inexpensive and has no risk of

radiation. It also does not require any patient preparation prior to the study. Computed tomography, although being more accurate, is expensive, not universally available and has added risk of radiation. This is particularly to be avoided in children.

The seminal work on appendix sonography by Puylaert (1) described the graded compression technique that remains in use today. There are other described techniques such as the posterior manual compression and the non compression technique

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described by Baldisserotto M and Marchiori. (2). However, the reported sensitivities and specificities range from 71.2–99% and 91.3–98.2%. The difficulties in using ultrasound in diagnosing appendicitis are attributed to retrocaecal or retrocolic positions of appendix making it difficult to visualise, poor acoustic window due to ileus and the fact that it is operator dependent. In cases where appendix is not

visualised, secondary signs of appendicitis are useful in diagnosing acute appendicitis.

This study aims to assess the diagnostic value of individual sonographic signs in acute appendicitis, primarily looking at the indirect signs. The secondary objectives are to look at the diagnostic value of direct signs, to provide an ultrasound probability criteria for appendicitis and also to retrospectively look at clinical scoring, Mantrel’s score in those cases where it is available. The gold standard for comparison is

histopathology.Subjects include patients with suspected acute appendicitis who present to Emergency department, general surgery OPD or paediatric surgery OPD and who undergo emergency surgery for acute appendicitis.

The study includes a complete abdominal ultrasound scan, followed by focused scanning of right iliac fossa by non compression technique described by

Baldisserotto M and Marchiori E (2) and graded compression technique described by Puylaert (1) and also posterior manual compression technique.

Ultrasound will be done using the USG machine, currently being used in our department for doing emergency abdominal ultrasounds which is TOSHIBA XARIO.

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AIMS & OBJECTIVES

Aims:

To study the diagnostic value of individual ultrasonographic signs in acute appendicitis

Objectives:

1. To study the diagnostic value of indirect signs in appendicitis

a) increased thickness and echogenicity of mesenteric fat in the right iliac fossa b) increased vascularity in the right iliac fossa

c) focal fluid collection d) free fluid

e) thickened caecal wall

f) hypoperistalsis of regional bowel

g) mesenteric lymphadenopathy in the right iliac fossa h) probe tenderness in the right iliac fossa

2. To study the diagnostic value of direct signs in appendicitis a) diameter of appendix > 6 mm

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b) lack of compressibility

c) hyperaemia to the wall of appendix d) loss of wall stratification of appendix e) presence of appendicolith

3. To look at the probability of acute appendicitis using ultrasonographic criteria by dividing it into the following categories

a) unequivocally positive (appendix is seen and is inflamed)

b) probably positive (appendix is not seen; indirect signs are present) c) probably negative (appendix is not seen; indirect signs are not present) d) unequivocally negative (appendix is seen and is normal)

4. To look at the probability of appendicitis by history, clinical examination and initial lab parameters using the Alvarado score (Mantrel’s criteria) when available

5. To see which of the signs best matches the Mantrel’s criteria or Alvarado score

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Table 1 - Alvarado score or Mantrel's criteria

Characteristics Point

Migration of pain to right lower quadrant 1

Anorexia 1

Nausea & vomiting 1

Tenderness in right lower quadrant 2

Rebound tenderness 1

Elevated temperature 1

Leucocytosis 2

Shift of WBC count to the left 1

Total 10

<5 Appendicitis unlikely

5 or 6 Appendicitis possible

7 or 8 Appendicitis likely

9 or 10 Appendicitis highly likely

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REVIEW OF LITERATURE

Anatomy of appendix

The vermiform appendix is a true diverticulum from the base of the caecum. It is located where the taenia coli converge. Its wall contains all the layers of the colon, ie.

mucosa, submucosa, muscularis propria and serosa.

Figure 1 – Illustration of gross anatomy Figure 2 – Histopathology of appendix

of appendix; Courtesy: webmd.com Courtesy: appendicitis.pro

The lumen of the appendix opens into the caecum. The base of the appendix is always attached to the caecum. However, the tip can have various positions.

- retrocaecal - subcaecal

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- paracaecal - preileal - postileal

- pelvic

Figure 3: Illustration of various positions of appendix

Courtesy: webmd.com

Because of these variants in anatomy, diagnosis of appendicitis is challenging as these leads to variations in symptomatology and imaging, especially ultrasonography. A retrocaecal location has been reported in 5 to 28 % of cases, making identification by ultrasound technically difficult due to artefact from overlying bowel gas/faeces. (3) A higher percentage of retrocaecal and retrocolic appendix (58%) has been reported in a cadaveric study in India.(4)

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Pathogenesis of acute appendicitis

Vermiform appendix has traditionally been considered a vestigial organ. Its function is not yet well understood. The histology of the appendix is distinctly different from that of caecum from which it originates. There are B and T lymphoid cells in the mucosa and lamina propria. Thus, it is postulated that appendix has a role in immune function by producing Ig A and is a part of gut associated lymphoid system.

The pathogenesis of acute appendicitis is still very poorly understood. There are various hypotheses; none of which are proven.

The oldest hypothesis depicts the initiating event to be appendicular luminal obstruction. This can be from various cases, ranging from fecoliths, lymphoid hyperplasia, parasites, foreign bodies to tumours. Lymphoid hyperplasia being

common in paediatric age group and fecoliths and neoplasia though to be the causes in older age group. Parasites are age independent and are possible causes in endemic areas.

The obstruction results in mucus retention and further distension of the appendix. This in turn increases the intraluminal pressure with resultant venous outflow obstruction and stasis with thrombosis of the venules and also lymphatic flow obstruction.

The appendix progressively becomes engorged. This results in the stimulation of visceral afferent nerve fibres (T8-T10) and patients develop the periumbilical, diffuse, abdominal pain.(5)

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Further compromise of vascular supply, leads to ischemia, followed by necrosis of the wall.

Once there is loss of mucosal integrity, owing to ischemia and ulceration, there is bacterial invasion of the appendicular wall with ensuing infection and inflammation with a neutrophilic exudate.

This results in a serosal reaction which causes parietal peritoneal irritation and

stimulation of somatic nerves which cause localisation of pain to the right iliac fossa.

Further inflammation and necrosis lead to perforation, which can form localised abscess or diffuse peritonitis.

Figure 4: Illustration of pathogenesis of acute appendicitis

However this hypothesis has been disputed in recent times. (6)

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The theories postulated are genetic, environmental and infectious aetiologies.

Risk factors:

The risk factors for developing acute appendicitis are - Positive family history

- Summer season - Non-white ethnicity - Non-pregnant state

(6) Microbiology:

The microorganisms isolated from inflamed appendices are a mixture of aerobic and anaerobic bacteria Escherichia coli and Bacteroides spp. Also, presence of

Fusobacterium spp. was associated with increased severity of the disease. (6) Classification:

A clinic pathological classiﬁcation that is most followed is as follows - Simple (non-perforated)

- Complex (gangrenous or perforated)

This classification helps in stratification of patients with respect to management.

It enables decision making with respect to timing of surgery, non operative management and also antibiotic post surgery (6)

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Complications:

Complications of acute appendicitis range from local abscess formation to peritonitis and sepsis.

There are reports of anterior abdominal wall abscess and necrotising fasciitis, as a complication of acute appendicitis.

Global epidemiology

Acute appendicitis is one of the commonest causes for acute abdomen.

The overall incidence reported are 107.76 per 100,000 per year in a study in Taiwan (7) and 23.3 per 10,000 population per year in US (age group 10-19 years) (8)

Indian epidemiology

There is no epidemiological data on acute appendicitis in India

Clinical evaluation & scoring systems

Symptoms

The classical symptoms are periumbilical pain with migration to right lower quadrant of the abdomen.

The other symptoms are nausea, vomiting which occurs after onset of pain. And as inflammation progresses, fever can set in.

The atypical symptoms include indigestion, bowel irregularity, diarrhoea, malaise, etc.

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Classical symptoms are seen only in about 60 % of patients. Also, symptoms also vary with location of the appendix. For example, retrocaecal appendicitis cause dull

abdominal ache and pelvic appendix present with urinary frequency, dysuria, tenesmus and diarrhoea.

Signs

Many signs are described in acute appendicitis. However, none of these may be seen in the early stages. The most classical sign described is tenderness in the Mc Burney’s point, with a reported sensitivity ranging from 50 to 94 percent; specificity 75 to 86%.

Figure 5 – Illustration showing the Mc Burney’s point

Rovsing’s sign is tenderness in the right lower quadrant on palpation of the left lower quadrant and has a reported sensitivity 22 to 68 %; specificity 58 to 96%.

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Psoas sign is described as right lower quadrant pain on extension of right hip and is seen in retrocaecal appendix; sensitivity 13 to 42%; specificity 79 to 97%.

Obturator sign is a sign described in pelvic appendix. However, it is no longer used since it has a very low sensitivity.

Patients may have low grade fever.

Laboratory findings

Mild leucocytosis (white blood cell count >10,000 cells/microL) is the most

frequently present laboratory finding in acute appendicitis. It has a sensitivity of 80 % and a specificity of 55 %. Another useful finding is a left shift seen in the differential count.

The other marker which is elevated is CRP (c- reactive protein).

An elevated WBC count along with raised CRP level had a PPV of 71%, whereas normal WBC count along with normal CRP value had an NPV of 84%. (9)

Total serum bilirubin >1.0 mg/dL is supposed to be a marker of appendiceal perforation with a sensitivity of 70% and a specificity of 86%.

Clinical scoring systems

Various clinical risk scoring systems have been made over the years.The purpose of such a system is to assess the probability of appendicitis. It should help in

management algorithm in terms of deciding which patient need emergency surgery,

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Which patient requires imaging and which patient needs to be kept under observation.

Furthermore, it has to be simple and easy to calculate. (10)

The clinical scoring helps in predicting acute appendicitis to a certain level. However they do not obviate the need for imaging in a number of cases. (11)

Alvarado score

This is the earliest and most commonly used clinical scoring system. It was first reported in 1986. It is also called ‘MANTRELS’ criteria

Table 2 – Alvarado score – characteristics & scoring

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Table 3: Alvarado score - interpretation

There are multiple studies over the years which looked at the accuracy of this score.

A meta-analysis of 42 such studies was done in 2011.(12)

According to this study, a score of 5 was good in ruling out appendicitis with an overall sensitivity of 99 % , 96 % in men, 99% in women and 99% in children).

However, at the recommended score of 7, which rules in appendicitis, the

performance was poor in all the subgroups with overall specificity of 81%, 57% in men, 73% in women, 76% in children). It was concluded that the Alvarado score is well calibrated in men across all risk strata; it over- appendicitis in children in the intermediate and high-risk groups and in women across all risk strata.

Modified Alvarado score

It differs from Alvarado score in that the left shift has been excluded and the

maximum score possible is 9, rather than 10. The rationale in excluding left shift is the fact that it is not easily and quickly available in an emergency clinical scenario.

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Table 4 – Modified Alvarado score – characteristic & scoring

Table 5 – Modified Alvarado score - interpretation

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A study published from Bugando Medical Centre, Tanzania, in 2011 assessed the diagnostic value of modified Alvarado score. It reported a sensitivity of 94.1 % (male – 95.8 % & female 88.3 %) and a specificity of 90.4 % (male – 92.9 % & female – 89.7 %). (13)

Many studies have shown this score to have a very high false positive rate in women leading to a high negative appendicectomy rate. One of the prospective studies published in 1994 showed a false positive rate of 33 % in women, even when the score was equal to or above 7, indicating a sensitivity of only 67 %. In the same study there was a sensitivity of 93 % for men and 100 % for children when score was equal to or above 7. (14)

So, the recommendations were that a score of 7 and above is a definite indication for emergency appendicectomy. However in females, it should be complemented with imaging such as ultrasound.(13)

Appendicitis inflammatory response score

It is one of the more recently introduced scoring system. It was first reported in 2008.

It was designed to overcome the major draw backs of the previous scoring systems. It incorporated C- reactive protein as one of the criteria.

A retrospective study to validate AIR score was published in 2012. It included 942 patients with suspected appendicitis. The area under the ROC curve for AIR score was significantly higher, 0.92, when compared to Alvarado score, 0.82.

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It also performed better than the Alvarado score in women, children and geriatric population. (10)The better performance in children and elderly is likely because the parameters are more objective and easier to assess.

Table 6 – Appendicitis Inflammatory Response score (AIR)– characteristics & scoring

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Table 7 – AIR score - Interpretation

RIPASA score

It stands for ‘Raja Isteri Pengiran Anak Saleha Appendicitis’ score.

It was developed because Alvarado score had a poor diagnostic performance in Asian population. It was developed in 2010. (15)

In 2011, a prospective study published from Brunei, validated the score. RIPASA score performed much better than Alvarado score in the south east Asian population.

The sensitivity was 98 % and negative predictive value was 97.4%, compared to Alvarado score which had a sensitivity of 68.3 % and negative predictive value of 71.4 % (16).

A prospective study from South India in 2014 also proved RIPASA score to be superior to Alvarado score in the Indian population. The sensitivity and specificity was 96.2 % and 90.5 % for RIPASA score at cut off of >7.5. The sensitivity and specificity of the Alvarado score was 58.9% and 85.7% respectively at cut off of >7.

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Table 8 – RIPASA score – characteristic & scoring

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Table 9 – RIPASA score - Interpretation

Paediatric appendicitis score

Paediatric appendicitis score was formulated in 2002. It is also called ‘Samuel’ score.

(18).

Later, in 2009, it was validated by another study (19) which said

- scores of <or=4: rules out appendicitis (sensitivity OF 97.6%, NPV of 97.7%) - scores of >or=8: predict appendicitis (specificity was 95.1% with a PPV of

85.2%)

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- scores of 5-7: need further radiologic evaluation

Table 10 Paediatric appendicitis score – diagnostic criteria & scoring

Table 11 Paediatric appendicitis score - interpretation

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Imaging evaluation of acute appendicitis

Though it was traditionally considered a clinical diagnosis, imaging modalities like ultrasound and CT have helped in a big way in complementing the diagnostic flow chart and helping in predicting complications of appendicitis and to reduce the rate of false negative appendicectomies.

Although appendicitis has a good prognosis, a delay in the diagnosis can result in increased risk of sepsis, obstruction, perforation, abscess, peritonitis and even death.

USG in acute appendicitis

The seminal work on appendix sonography by Puylaert described the graded compression technique that remains in use today. (1)

Ultrasound is known to have a high positive and negative predictive value [PPV 98%, NPV 98%] if appendix is visualized. (9)

However, studies have shown that in a considerable proportion of patients, appendix is not visualized. (42-47%) (20). This can mainly be attributed to difficulty in visualization of appendix per say due to its location like a retrocaecal appendix, poor acoustic window due to ileus or operator dependability of the modality.

A retrocaecal location has been reported in 5 to 28% of cases, making identification of appendix by ultrasound technically difficult due to artefact from overlying bowel gas/faeces. (3)

A higher percentage of retrocaecal and retrocolic appendix (58%) has been reported in a cadaveric study in India. (4)

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The lack of a visible appendix makes determining diameter and other previously mentioned direct criteria impossible to assess, highlighting the potential diagnostic use of more readily visible secondary signs of appendicitis.

Role of direct signs

Direct signs are when appendix is visualised and there are features of inflammation.

Ultrasound is known to have a high positive and negative predictive value [PPV 98%, NPV 98%] if appendix is visualized. (9)

In a prospective study done by Kessler et.al, 125 consecutive patients with suspected appendicitis were scanned; the prevalence of appendicitis was 46%.

The most accurate direct sign was appendiceal diameter of 6 mm or more under compression. This sign had a sensitivity, specificity, negative predictive value and positive predictive value of 98%.(9)

The other direct signs are non-compressibility, loss of wall stratification, increased vascularity to the wall and presence of appendicolith.

Role of indirect signs

There are several secondary sonographic signs of appendicitis that can be useful diagnostic indicators, and potential positive or negative predictors in the absence of a visible appendix or an otherwise equivocal study.

The following have been studied previously:

One such sign is echogenic mesenteric fat, which has been proven to have a PPV for appendicitis of 99%. Free intra-peritoneal fluid in the RLQ can also be an indication of appendicitis, as can the presence of enlarged intra-peritoneal lymph

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nodes. In addition, other potential secondary signs of a perforated appendix are thickening of adjacent bowel wall, local bowel hypokinesia, local collection, echogenic sludge in the urinary bladder in children (3)

In a study of 146 children, Wiersma et al. reported that the absence of secondary signs and non-visualisation of the appendix had a high NPV, and conversely that the presence of secondary signs alone was a strong positive predictor of appendicitis.(21) Reliance on secondary signs however has also been associated with a high number of false positives. (21)

Estey et al. and more recently Ross et al. confirmed the PPV of secondary signs, yet their absence did not permit reliable exclusion of appendicitis. (22) (23)

These contradictory findings warrant further studies to validate the same and determine the diagnostic potential of individual or certain combinations of secondary signs to obtain the most comprehensive and meaningful sonographic conclusion.

Role of USG in differentiating complicated appendicitis

There are studies that mention specific ultrasound features to diagnose gangrenous and perforated appendix. This differentiation is important because management is different for complicated and uncomplicated appendicitis.

Carpenter et.al did a prospective study on 577 patients with acute appendicitis. They concluded that several USG findings were positively associated with perforation, such

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as complex fluid collection in RIF, greater diameter of appendix and presence of appendicolith. Also, a fluid filled lumen has a negative association with perforation.

Thus, USG has a good specificity of 93 % in picking up complicated appendicitis.

However, the sensitivity of USG was only 44 %. (24)

More recently, Xu et. al did a retrospective study on 119 patients with acute appendicitis. They concluded that the loss of normal hyperechogenicity of the submucosa is the most contributory finding in differentiating complicated and

uncomplicated appendicitis. The sensitivity was 100 % (95% CI, 89.1%–100.0%) and specificity was 92.0% (95% CI, 84.1%–96.7%). (25)

Tulin-Silver et.al did a retrospective study in 116 children. They concluded that the useful findings in diagnosing perforation are dilated bowel loops, complex fluid collection in RIF and increasing free fluid in the abdomen. Increased hepatic periportal echogenicity was another finding which had a statistically significant association with perforation. Also, select constellation of findings provide more specificity than individual findings.(26)

Pitfalls in USG diagnosis of acute appendicitis

There are a few difficulties in USG diagnosis of acute appendicitis in terms of visualisation and interpretation of signs. This can lead to false negative and false positive results. It is important to be aware of these conditions. (27)

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False negative

‘Tip’ appendicitis

It is essentially appendicitis involving just the tip of the appendix. In this, the entire appendix excluding the tip appears normal. It is very important to have visualised the appendix including the tip before excluding appendicitis. The tip can be made out by the fact that it is blind ending.

Gas filled appendix

Sometimes, an inflamed appendix will have gas within the lumen, owing to gas forming organisms. This caused dirty shadowing and limited visualisation. However, in most cases, only a part of the appendix has gas within and the rest of the appendix can be visualised.

Retrocaecal appendix

When appendix is located retrocaecally, it is very difficult to visualise it. Hence the direct signs cannot be commented upon. But usually, the indirect signs of

inflammation is present to point towards acute appendicitis. The technique that helps in visualisation of a retrocaecal appendix is scanning through the flank.

Complicated appendicitis – gangrenous / perforated

This results in peritonitis and ileus ensues. Thus, the gas shadows from overlying dilated bowel loops limit visualisation. Again, in these cases, though the appendix per say may not be visualised; the indirect signs will definitely be present.

Grossly enlarged appendix

Sometimes, the inflamed appendix become so dilated that it gets mistaken for a bowel loop. Identifying it as blind ending helps in diagnosis.

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False positive

Lymphoid hyperplasia or ‘pink appendix’

The lymphoid follicles in the lamina propria hypertrophies, secondary to

inflammatory diseases such as viral gastroenteritis and mesenteric adenitis. This is seen most commonly in children. When the follicles enlarge, there is thickening of the lamina propria which appears as a hypoechoic layer. This results in overall increase in diameter of appendix to more than 6 mm. The hypertrophied lymphoid follicles

reduce the compliance of the appendiceal wall and this is manifested as non- compressibility. Since enlargement and non-compressibility are 2 important direct signs described in acute appendicitis, lymphoid hyperplasia is often misdiagnosed as acute appendicitis.

The characteristic finding is the thickening of the lamina propria which is seen as a hypoechoic layer.(28)

Figure 6 – USG image showing normal appearance of lamina propria of appendix, Courtesy: AJR 206, January 2016

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Figure 7 – USG images showing thickened and hypoechoic lamina propria of

appendix & HPE showing hypertrophied lymphoid follicles in lamina propria Courtesy: AJR 206, January 2016

In a small number of patients, these 2 conditions can coexist. However in these cases, there will be at least 2 of the following 3 additional USG findings, which are

mesenteric fat hyperechogenicity of RIF, fluid in RIF and increased vascularity of appendicular wall. (28)

Figure 8 – USG image(A) showing hypoechoic thickening of lamina propria and (B) showing mural hyperaemia in a case of appendix with lymphoid hyperplasia with tip appendicitis

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Figure 9 – USG images showing hypoechoic thickening of lamina propria of appendix and associated thickened and hyperechoic mesenteric fat in a case of lymphoid

hyperplasia of appendix with acute appendicitis

Meckel’s diverticulitis

It is also seen as a tubular blind ending loop of bowel in the right lower quadrant.

There are surrounding inflammatory changes. Only way to distinguish it from appendix is to trace its origin to an ileal loop which is often difficult when there is inflammation or perforation.(29)

Peri appendicitis due to surrounding inflammation

Inflammation of the adjacent structures can result in edema of the serosa and

thickening of appendix. In these cases, submucosal layer is intact. It is seen with tubo ovarian abscess, Crohn’s disease etc.(27)

Resolving appendicitis

Sometimes, inflammation can resolve by itself and follow up sonography will be normal. In these cases, appendicolith is not seen. (27)

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CT in acute appendicitis

CT is proven without doubt to be superior to USG in accurate diagnosis of acute appendicitis.

A meta-analysis published in Radiology in 2008 compared the diagnostic performance of CT and graded compression ultrasound. CT was more accurate with a positive LR of 9.29 (95% confidence interval 6.9, 12.6). USG has LR of 4.50 (95% CI: 3.0, 6.7).

Hence the post-test probability for a positive CT was 90 % while that of USG was 82

%. Similarly the post-test probability of a negative CT was 9 % and that of a negative USG was 21 %. (30)

CT is helpful in differentiating appendicitis with perforation and without perforation.

This differentiation is crucial in making management decisions. Some of the signs in CT can help in diagnosing even early perforation. Transverse appendicular diameter of 11 mm or more has a high sensitivity of 62.7 %; however, specificity was only 66.3 %.

Focal defect in the wall of appendix has the highest specificity of 98.9 %. The positive predictive value was 88 % and accuracy was 83.5 %. (31)

Role of unenhanced, limited CT

In children, non-contrast limited CT of the abdomen is found to have diagnostic value comparable to that of ultrasound with less time taken and less discomfort to the

children. The sensitivity, specificity and accuracy of such a CT was 97 %, 100 % &

99 % respectively. In the same study, the sensitivity, specificity and accuracy of USG wad 100 %, 88 % and 91 % respectively.(32)

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Poortman et. al did a prospective study on 199 patients with suspected appendicitis, to compare the non-contrast, focussed, single detector helical CT and graded

compression USG. The sensitivity and specificity of were 76 % & 83 % for CT and 83 %& 79 % for USG. The diagnostic accuracy was the same for and for both CT &

USG; 78 %. (33) Role of low dose CT

A randomised, controlled, non-inferiority trial published in the Lancet in September, 2017, assessed the effectiveness of low dose CT in diagnosing acute appendicitis in adolescents and young adults. It said, that there was non impairment of clinical outcome in lowering the radiation dose to 2 mSv.(34)

The superiority of CT is due to its capability in locating appendix which are difficult to visualised on USG such as retrocaecal, subhepatic, inguinal canal, femoral canal, left sided location in malrotation etc. (35). Also, visualisation of appendix in CT is not limited by overlying bowel. It is quick and does not cause any discomfort to the patient as there is no need for compression technique.

However, the disadvantages are that there is an added risk of radiation, especially in children and pregnant women. And it is not universally available in a developing country like ours. Also, it is expensive. The requirement of intra venous contrast is also a factor to be considered.

CT in paediatric age group

A staged imaging pathway is beneficial in children. In this USG is the first imaging choice and CT is performed only if USG is inconclusive.

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Krishnamoorthi et. al reported a sensitivity of 98.6 % for such a protocol which is comparable to that of CT alone. Also there was a reduction in CT examination by 52.7

%. (36)

MRI in acute appendicitis

There are specific patient sub groups of acute appendicitis where MRI has a great role in diagnosis. These are paediatric age group and pregnant women. In both these groups it is better to avoid CT.

MRI in pregnant women with suspected appendicitis

MRI has s high diagnostic value evaluation of pregnant women with suspected acute appendicitis.

The sensitivity reported in a study published in Abdominal Imaging in 2017 is 100

%.The negative predictive value was 100 % and specificity was 99.5 %.(37) T1 bright appendix sign

This sign is defined as linear high signal intensity within the appendix, which is present in more than half the length of appendix. It is caused by stool within the appendix and is thought to be a feature of normal appendix.(38)

A study published in European Society of Radiology in January 2017, reviewed MRI images of 134 pregnant women with suspected appendicitis. It had a high specificity of 95.5 % in the diagnosis of a healthy appendix. The negative predictive value was 98 %. However, the sensitivity was only 51%. It is a very useful sign in excluding appendicitis in appendices with borderline measurements.(38)

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Figure 10 – MRI axial sections of abdomen showing a normal appendix with hypointense signal within the appendix on T2 and hyperintense signal within the

appendix on T1(T1 bright sign) Image courtesy: Eur Radiol (2017) 27: 3310 – 3316

MRI in children with suspected appendicitis

A systematic review and meta-analysis was published in August, 2017, to assess the performance of MRI in diagnosing paediatric appendicitis and its effect on negative appendicectomy rate.

It concluded that MRI performed excellently in diagnosing appendicitis in paediatric age group. This was independent of use of IV contrast. The sensitivity was 97 % (95%

CT of 95 to 98 %). The specificity was 97% (95% CI, 93-98%).The area under the curve (HSROC) was 0.98 (95% CI, 0.97-0.99).(39)

MRI is accurate in diagnosis of acute appendicitis in children, independent of the duration of pain.(40)

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However, USG is still better as initial imaging modality in children and young adult patients with suspected appendicitis. It is more time efficient and cost effective than even rapid MRI. (41)

MRI should be used as a problem-solving tool when USG is inconclusive or equivocal.

MRI vs CT in children with equivocal appendicitis

Dillman et. al did a retrospective study in which 103 children underwent non-contrast MRI with no sedation and 58 children underwent CECT for evaluation of equivocal appendicitis. They concluded that the MRI had a diagnostic performance comparable to that of CT in evaluation of equivocal appendicitis. Also, it performed similar to CT in diagnosing appendiceal perforation. The proportion with alternative diagnosis identified on MRI was similar to that of CT. (42)

Role of contrast MRI in children

Non-contrast MRI is sufficient in diagnosing acute appendicitis in most children.

Administration of contrast improves diagnostic accuracy only in a select few cases.

Hence contrast should be administered only in those cases where the non contrast MRI is inconclusive.(43)

Gold standard – surgery & histopathology

The gold standard for the diagnosis of acute appendicitis is surgery which can be laparoscopic or open and histopathological examination of the excised appendix.

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Non-radiation imaging – advantages, limitations:

The imaging modalities with no radiation risk are ultrasonography and MRI. USG is the least expensive and most widely available modality. It can even be done as a bed side imaging. It has no radiation risk. It is useful for follow up imaging as well.

However, the disadvantage is that it is operator dependent. Also in some situations as discussed earlier, the imaging is suboptimal. Also, the technique involves compression and this causes pain.

The major advantage of MRI is that it has no radiation risk and is safe to use

especially in children and pregnant women. It is not operator dependent and atypically located appendices can be visualised. Overlying bowel gas do not obscure appendix in MRI. The disadvantage is that it is expensive, not widely available. It is also a

comparatively time-consuming imaging modality.

Mimics of acute appendicitis

There are various mimics for acute appendicitis. These cause diagnostic dilemma on clinical examination as well as imaging.

Mesenteric lymphadenitis

It is a common cause for right lower abdominal pain. It is more frequently seen in children. It is a benign inflammation of the mesenteric lymph nodes in the right iliac fossa. Clustered, oval lymph nodes are seen on USG and CT. The minimum diameter of these nodes should be 6 mm; some authors even say 4 mm as the cut off. (44) It is

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important to visualise a normal appendix before making a diagnosis of mesenteric lymphadenitis. (45)

Figure 11 – USG image of mesenteric lymphadenitis, Courtesy – AJR:186, April 2006

Infectious enterocolitis

Infectious colitis caused by bacteria such as Yesenia, Campylobacter, Salmonella often present with clinical features that resemble acute appendicitis. On imaging, there is wall thickening of terminal ileum and caecum. The adjacent fat is usually not

stranded. There is associated mesenteric adenopathy. (45)

CT is often required to rule out acute appendicitis in the cases when appendix is not visualised on USG.

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Epiploic appendagitis

Epiploic appendages are small fat containing protrusions from the serosal of the colon.

They can get inflamed. This caused symptoms that are like that of acute appendicitis if the inflamed appendage is in the RIF. It is a self-limiting condition.

USG shows hyperechoic, inflamed fat adjacent to the colon. CT shows a a hyperattenuating ring around the inflamed fat. This is the thickened visceral

peritoneum and is characteristic of epiploic appendagitis and helps in differentiating from omental infarction. (45)

Figure 12 – USG & CT images of epiploic appendagitis

Courtesy – AJR:186, April 2006

Omental infarction

Infarction of the right side of the omentum can present like acute appendicitis. USG shows inflamed hyperechoic fatty mass. It is cake like and larger than what is seen in epiploic appendagitis. CT helps in differentiating as there is no hyperattenuating ring.

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Figure 13 – USG & CT images of omental infarction;Courtesy – AJR:186, April 2006

Meckel’s diverticulitis

Meckel’s diverticulum is persistent omphalomesenteric duct. It arises from the

antimesenteric border of distal ileum. It can get inflamed, resulting in clinical features like acute appendicitis. USG will show a tubular cyst like structure with surrounding inflammation. It can be easily mistaken for an inflamed appendix. However, it originates from ileum and not caecum. (44). This may be appreciated on USG.

However, CT is more accurate in diagnosing Meckel’s diverticulitis.

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Figure 14 – USG images of Meckel’s diverticulitis Courtesy: IJR 2014 Apr-Jun; 24(2): 163 – 170

Colonic diverticulitis

Inflammation of right sided colonic diverticulum can mimic acute appendicitis.

Usually patients have a longer history. The right sided colonic diverticulae are true diverticulae and has all layers of bowel wall. USG and CT shows inflammatory changes in the fat and the segment of colon at the level of the diverticulum.(45)

Figure 15 – USG & CT images of caecal diverticulitis Courtesy – AJR:186, April 2006

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Ileocaecal Crohn’s disease

Though, Crohn’s disease is a chronic disease around 1/3^rd of the patients present initially with acute symptoms which can be misdiagnosed as acute appendicitis. USG and CT shows bowel wall thickening that is transmural with predominant involvement of the submucosa and inflammation of the surrounding fat.

Figure 16 – USG & CT images of Ileo- caecal Crohn’s disease Courtesy – AJR:186, April 2006

Typhilitis

It is also called neutropenic colitis. It is a life-threatening condition that occur in immunocompromised patients where there is invasion of the caecal wall by bacteria.

There is edema and inflammation of the cecum. It can extend into the ascending colon and even terminal ileum. It can progress to wall necrosis, perforation and death. CT is the imaging of choice. There is circumferential wall thickening of cecum with

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mesenteric fat stranding. There can be pneumatosis coli, pneumoperitoneum, collections & abscesses.(46)

Other conditions that can mimic acute appendicitis clinically are ileocecal intussusception and gynaecological and urological conditions like torsion ovary, ureteric colic etc.

Management of acute appendicitis

Management of acute appendicitis depends on whether it is complicated or uncomplicated.

Operative management of acute appendicitis

Laparoscopic appendicectomy is the surgery of choice. It has replaced open appendicectomy in most centres. It can be done as an emergency procedure or as interval appendectomy.

Uncomplicated appendicitis the operative management is emergency laparoscopic appendectomy which is usually done within 24 hours, following antibiotic

administration.

For perforated appendicitis, there are 2 options

- emergency appendectomy after hydration and antibiotic administration

- antibiotic administration with or without imaging guided drainage of abscess and interval appendectomy after 6to 8 weeks (47)Non-operative management of acute appendicitis

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This is a recent trend. In this there is only antibiotic therapy. It is used in both complicated and uncomplicated appendicitis.

A meta-analysis was done of 5 adult trials on a total of 980 patients. It said there are fewer complications, better pain control in non-operative management. However there is a higher rate of recurrence. (47)

Lacunae in what is known and justification for the study

There are several secondary sonographic signs of appendicitis that can be useful diagnostic indicators, and potential positive or negative predictors in the absence of a visible appendix or an otherwise equivocal study.

In a study of 146 children, Wiersma et al. reported that the absence of secondary signs and non-visualisation of the appendix had a high NPV, and conversely that the presence of secondary signs alone was a strong positive predictor of appendicitis.

Reliance on secondary signs however has also been associated with a high number of false positives. (21)

Estey et al. and more recently Ross et al. confirmed the PPV of secondary signs, yet their absence did not permit reliable exclusion of appendicitis. (22), (23)

These contradictory findings warrant further studies to validate the same and determine the diagnostic potential of individual or certain combinations of secondary signs to obtain the most comprehensive and meaningful sonographic conclusion.

Furthermore, to our present knowledge, no such studies have been done in our population and would also contribute to the present knowledge and efficiency in the diagnosis and management of acute appendicitis in our institution.

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MATERIALS AND METHODS

INSTITUTIONAL REVIEW BOARD approval & funding:

Institutional review board (IRB) approval was obtained prior to the commencement of the study

(IRB minute number 10211 [DIAGNO] dated 08.08.2016 (Appendix 3)

Study design:

Study of diagnostic test accuracy

Study type:

Analytical

Setting:

Christian Medical College (CMC) Vellore is a tertiary care centre in northern Tamil Nadu. The institution was established in 1900 and is now a 2700 bedded hospital. The annual outpatient visits are around 1.9 million with inpatient admissions of ~ 120,000.

The Department of Radiology in CMC, Vellore was established in 1936.

Digitalization of the system and introduction of PACS (Picture Archival and Communication System) was done in the year 2000. The Department functions independently with around 100 radiologists. The radiological investigations routinely performed are radiographs, IVU, barium studies, ultrasonography and Doppler

studies, mammograms, CT, MRI & Interventional Radiology

Study period:

August 2016 to August 2017 – a period of 12 months

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Inclusion Criteria:

* All patients who present to the emergency department / general surgery OPD / paediatric surgery OPD with suspected acute appendicitis

* Those of the above who undergo emergency surgery in our institution

Exclusion Criteria:

* Patients who are conservatively managed

* Patients who refuse ultrasound or surgery

* Patients with alternate diagnosis on USG* Patients in whom all the direct and indirect signs of acute appendicitis were not looked for / documented

Figure 17 – Flow chart showing multi departmental workflow in this study

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Figure 18 – flow chart showing the methodology of recruitment with inclusion &

exclusion criteria

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METHODOLOGY

Sampling and Consent:

The prospective study patients were referred to us from the emergency department or surgical OPD or ward. All patients who fulfilled the inclusion criteria were included in the study. No specific sampling strategy was employed to enrol patients. The selection of the study population was independent of the results of the reference standard (histopathology). Baseline data of the patients was entered in a numbered proforma (Annexure I). Informed written consent was obtained from the patient / patient’s relative prior to the ultrasound examination.

Assent was obtained in the appropriate age group.

The consent form, assent form along with the Patient Information sheet is attached in Annexure II.

Timing:

The time between the ultrasound examination and surgery would range between 1 hour to 24 hours

Sample size calculation:

The sample size was calculated on the basis of a retrospective study analysing the diagnostic value of indirect USG signs in acute appendicitis which was done in 2 university hospitals in Abidjan and was published in diagnostic and interventional imaging in 2012.(48) The calculation was done with multiple logistic regression as follows and the sample size arrived was 136.

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Table 12- Sample size calculation using multiple logistic regression

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Name and designation of statistician:

Mr. Bijesh Kumar Yadav (Ph.D. Scholar) Senior Demonstrator Department of Biostatistics

Christian Medical College Vellore – 632 002, India

Office Phone: 91- 416 - 2284205 Office Fax: 91- 416 - 2262703

Email: bkyadav2007@yahoo.com, yadavbijesh@gmail.com

Data sources of measurement:

Most of the data was collected and entered from the CRF. Some were collected from electronic medical record.

Ultrasonography:

a) USG scanner

All the scans were done using TOSHIBA XARIO ultrasound scanner. This is the scanner that was used in our Department for doing emergency abdominal scans.

Figure 19 – Image of the TOSHIBA XARIO USG scanner used in the study

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b) Probes - Transducers

The probe used for initial survey of the abdomen and pelvis was the low frequency curved array transducer of frequency range 6 to 1.9 MHz with a centre frequency of 3.5 MHz

Figure 20 – Low frequency curved array transducer

The probe used for focussed scanning of the RIF with graded compression and other techniques was the high frequency, linear transducer of frequency range 11 to 5 MHz and a centre frequency of 7.5 MHz.

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Figure 21 – High frequency linear array transducer

c) Physics – Principles of ultrasound

Ultrasound is high frequency sound wave with frequencies above the auditory limit of human ear which is 20,000 Hz.

Properties of sound

It is a wave transmitting energy.

It requires a medium for transmission unlike x rays which can pass through vacuum.

They are longitudinal waves and the particles in the transmitting medium move in a direction parallel to the direction of the wave, by producing bands of compression and rarefaction

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Figure 22 – illustration showing propagation of sound through a medium by producing bands of compression & rarefaction Courtesy – Radiographics 2003; 23:1019 – 1033

The velocity of sound is dependent on the nature of the medium through which it passes. i.e. it depends on the rate by which force is transmitted from one molecule to another. So, the velocity depends on the compressibility and density of the medium.

Velocity = Frequency * Wavelength

Velocity is a constant in any particular medium.

The intensity of sound is dependent on the amplitude of the wave.

Transducer

A transducer is a device that can convert one form of energy to another. USG transducer converts electrical energy to ultrasound and vice versa.

The most important component in a transducer is the piezoelectric crystal. It changes its physical dimension when an electrical field is applied. Lead zirconate titanate

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(PZT) is the most commonly used piezo electric ceramic in medical ultrasound scanners.

The voltage is applied in quick bursts and the crystal vibrates and generates sound waves. There is a backing block which dampens these vibrations so that the transducer is ready to detect the returning waves or echoes.

Figure 23 – Illustration of structure of a transducer

Resonant frequency

It is the natural frequency of each transducer at which it is maximum sensitive. It is determined by the thickness of the piezoelectric crystal.

High frequency sound beam has greater resolution with lesser depth penetration. Low frequency sound beam has greater depth penetration and lesser resolution.

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Interaction between ultrasound and matter

There are 3 types of interactions - Reflection

- Refraction - Absorption

c) USG protocol – Technique & Reporting Graded compression technique

It was introduced by Puylaert in 1986.(1)

A linear high-frequency transducer is placed on the right lower quadrant and pressure is applied gradually while imaging, displacing overlying gas-filled loops of bowel.

This is initially done in the transverse plane. More pressure is applied during

expiration. Since compression is gradual, it does not elicit rebound tenderness and is quite well tolerated by patients.

Adequacy of pressure applied can be ascertained by the visualisation of psoas muscle and iliac vessels. Graded compression essentially decreased the distance between the appendix and the probe by displacing the bowel gas and thus enables better

visualisation.

The ascending colon is identified as non peristalsing, mostly gas filled structure along the lateral most aspect. Sometimes haustrations can be made out.

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After identifying the ascending colon, the probe is moved inferiorly. At this position, the terminal ileum can be identified. It is a compressible, peristalsing structure which does not have a blind end.

The land marks for identification of appendix are

- Origin from the cecum, ~ 10-20 mm inferior to the terminal ileum - Anterior to psoas and iliac vessels in most cases

Graded compression is done up to the inferior margin of liver tip and medially as appendix can be located in a subhepatic location.

Figure 24 – Picture demonstrating graded compression technique; Courtesy – J Am Osteopath Coll Radiol 2016; Vol.5, Issue 1

Posterior manual compression

In many patients, appendix is not visualised with graded compression alone.

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Especially in obese patients, those with thick muscular wall and previous surgeries, the graded compression is not enough to cause adequate displacement of bowel gas and reduce the probe to appendix distance.

Manual compression is done posteriorly using the operator’s opposite hand in an anteromedial direction while applying graded compression anteriorly with the probe.

This reduces the distance between the retrocaecal space and the transducer and

thereby increases the spatial resolution. Studies have shown that addition of posterior manual compression improves visualisation on of appendix from 85 % to 95 %.(49)

Figure 25- Picture demonstrating posterior manual compression technique Courtesy – J Am Osteopath Coll Radiol 2016; Vol.5, Issue 1

Left lateral decubitus position

In left lateral, decubitus position, the cecum and terminal ileum are displaced

medially. Thus retrocaecal, retro ileal and subcaecal appendices are visualised better.

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Figure 26 - Picture demonstrating USG scanning in left lateral decubitus position Courtesy – J Am Osteopath Coll Radiol 2016; Vol.5, Issue 1

Non-compression technique in children

This was described by Baldisserotto M & Marchiori E in 2002. (50)

Scanning is done with a low frequency, curved array transducer. The right retrocaecal retroperitoneum is scanned along the right flank in transverse plane from the liver and right kidney up to the iliac crests. Then a longitudinal scan was done from the anterior axillary line, along the flank and up to the posterior axillary line and lumbar region.

Then suprapubic scan is done using a full urinary bladder as acoustic window.

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Figure 27 – Illustration of non-compression technique Courtesy: AJR 2000 Nov;175(5):1387-92

Low frequency scanning of the rest of the abdomen and pelvis

Scanning of the rest of the abdomen and pelvis is mandatory to look for alternate pathology such as a tubo ovarian cause in women and to look for complications of appendicitis such as pelvic abscess.

To study the diagnostic value of individual ultrasonographic findings in acute appendicitis