GAMECHANGER

Evidence-based Medicine Presentation by

Mikhail Briones
2nd Year Family and Community Medicine Resident
Iloilo Mission Hospital
Case
• J.B
• 21 y/o female
• student
• Jaro, Iloilo
Chief Complaint
• Right Lower Quadrant Pain
History

1 day PTA, she experienced on and off, colicky

abdominal pain 5/10 on her periumbilical area, aggravated
by movement and relieved by rest, associated with poor
appetite, nausea and undocumented low grade fever. No
meds taken and no consult done
ODA, pain moved to right lower quadrant and
increased severity to 10/10. Patient had 2 episodes of
vomiting and fever of 37.9C. She took a paracetamol and
immediately opted admission
In the Triage Area:
Patient was requested respiratory panel 2.0 prior to
admission in which after 2 hours revealed a negative
result.
Chest Xray (PA View) was done and was
unremarkable. Patient was forwarded to clean E.R for
admission.
In the interim, CBC and urinalysis revealed
leukocytocis with neutrophil predominance and
unremarkable urinalysis findings. Stat Whole abdomen
ultrasound also showed inflamed and enlarged appendix.
Patient was then scheduled for STAT appendectomy.
Past Medical History
• (-) no known comorbidities
• (-)surgery/hospitalization
• (-) food and drug allergies
Personal History
• Non-smoker, non-alcoholic beverage drinker
OB-Gyne History
• G0
• LMP: January 20, 2021
• PMP: December 15, 2020
• Menarche: 13 years old
• Regular monthly interval
• 3 - 5 days duration
• 2 - 3 pads per day, moderately soaked
• no dysmenorrhea
Coitarche : 18 y/o
Sexual Partner: 1
No History of contraceptive use.
No history of STDs
Family History
• Hypertension - Paternal Side
• Bronchial Asthma - Maternal Side
Physical Examination

GCS 15, conscious, conversant and coherent. Not in

cardiopulmonary distress.
Patient is afebrile, non-tachycardic, non-tachypneic with BP
of 110/80.No pertinent Finding except that (+) rovsing sign,
rebound tenderness, (+) psoas sign and (+) cough sign. (-)
Goldflamms Test.
Evidence-based Medicine
Introduction

“Doc, pabulig bi, bisan oxygen lang. Tatlo na ka

hospital gin kadtuan namun kag sarado na sila. Indi
sila magbaton sa amun.”
“There is NO EMERGENCY during a pandemic.”
• Appendicitis is one of the most common causes of
acute abdominal pain in adults and children
• Lifetime risk of 8.6% in males and 6.7% in females
• Most common nonobstetric surgical emergency
during pregnancy.
• Right lower quadrant pain, abdominal rigidity, and
periumbilical pain radiating to the right lower quadrant -
best signs in adults
• (+) psoas sign, (+) obturator sign, and (+) Rovsing sign
- most reliable for ruling in children
• Alvarado score
• Pediatric Appendicitis Score
• Appendicitis Inflammatory Response score

• Ultrasonography - Recommended first-line imaging

• Open laparotomy or laparoscopy - standard treatment
• Intravenous antibiotics - first-line therapy in selected
patients
• Pain control with opioids, nonsteroidal anti-
inflammatory drugs, and acetaminophen should be a
priority and does not result in delayed or unnecessary
intervention.
• Perforation can lead to sepsis and occurs in 17% to 32% of
patients

Copyright © 2018 American Academy of Family Physicians.)

Philippine CPG for Appendicitis
Philippine College of Surgeons, 2002

Appendectomy(Open) is the appropriate treatment for

acute appendicitis.
Laparoscopic Appendectomy is suggested for
pediatric appendicitis.

Antibiotic treatment - prohylaxis for surgical site infection

For uncomplicated appendicitis
• Cefoxitin 2gm IV single dose (adults) 40mg/kg IV single dose (children)

Alternatives:
• Ampicillin-sulbactam 1.5g - 3g IV single dose (adults 75mg/kg IV single
dose (children)
• Amoxicillin - clavulanic acid 1.2g - 2.4 g IV single dose (adults) 45mg/kg
IV single dose (children)

For those with allergy with beta-lactams

• Gentamycin 80-120 mg IV single dose plus clindamycin 600mg IV single
dose (adults)
• Gentamycin 2.5mg/kg IV plus clindamycin 7.5-10mg/kg IV single dose
(children)
For complicated appendicitis (Adults)
– Ertapenem 1gm IV every 12 hours
– Piperacillin-tazobactam 3.75gm IV every 6 hours or 4.5gm IV every 8 hours
For adults with beta-lactam allergy
– Ciprofloxacin 400mg iv q12 plus metronidazole 500 mg iv q6h
Complicated appendicitis in pediatric patients
– Ticarcillin-clavulanic acid 75mg IV q6h
– Imipenem-cilastatin 12-25 mg IV q6h
Pediatric patients with allergy to beta lactam
– Gentamicin 5mg/kg q24h plus clindamycin 7.5-10mg/kg every 6 hours

Treatment duration is around 5-7 days depending on clinicians

assessment after operation. Once with gastrointestinal function has
returned may sequentially shifted to oral antibiotics.
 Review of Related Literature
As recently as 2014, more than 95% of U.S. patients
with appendicitis underwent appendectomy. However, with
the pandemic of coronavirus disease 2019 (Covid-19),
health systems and professional societies such as the
American College of Surgeons have suggested
reconsideration of many aspects of care delivery, including
the role of antibiotics in the treatment of appendicitis.
Source: Findlay et.al; Managing appendicitis during the COVID‐19 pandemic—What do we need to know
from the evidence?(October 17,2020)
Review of Related Literature
In the early 2020, healthcare providers are
overwhelmed and needed to rationalise resources and
minimise transmission of COVID‐19.
In the U.K the Royal Colleges of Surgeons advised
NOTA be implemented “Where reasonable (such as for
early appendicitis),” and that because of the unknown
potential risk of viral transmission laparoscopic
appendectomy only be considered “in selected individual
cases where…benefit to the patient substantially
exceeds the risk of potential viral transmission”.
Source: Findlay et.al; Managing appendicitis during the COVID‐19 pandemic—What do we need to
know from the evidence?(October 17,2020)
 During the early months of the pandemic, more children
started arriving in the emergency department with a ruptured
appendix.
Between March 16 and June 7, 90 children were treated
for appendicitis at Inova Children's Hospital in northern
Virginia. Of those kids, nearly 40% had a ruptured appendix.
That compared with only 19% of 70 children treated during
the same period in 2019.
A reasonable guess is that parents might have delayed
going to the ER because of COVID.
Reference: Rick Place, MD, MHA, medical director, pediatric emergency department, Inova Children's Hospital, Inova Fairfax Medical
Campus, Falls Church, Va.; Peter Minneci, MD, co-director, Center for Surgical Outcomes Research, Nationwide Children's Hospital,
Columbus, Ohio; JAMA Network Open, Dec. 4, 2020, online (December 7,2020)
 The significant increase in the incidence of
complicated appendicitis could indicate that patients are not
seeking timely and appropriate care.
This be explained by various plausible reasons
including the fear of contracting COVID-19 and
encouragement from authorities to avoid unnecessary
presentations to the clinic and/or ER..
Reference: Orthopoulous et. Al, Increasing incidence of complicated appendicitis during COVID-19 pandemic (Sept
20,2020)
Local Statistics
Acute Appendicitis (IMH, 2019 2020
Medical Records Section)

Male 17 34
Female 10 24
Total 27 58

2020 Appendectomy Open Laparoscopic Total

(IMH-IDH Department
of Surgery

Service 47
Pay 103 2
Total 150 2 152
 The Process of EBM

1. Formulate the problem into an answerable

question
2. Conduct a systematic medical literature
search
3. Critically appraise the medical literature
4. Apply the results
5. Evaluate the application
The Searchable Problem

So first we have to ask:

• P - Population – Patients with Imaging confirmed
appendicitis
• I - Intervention – antibiotic treatment compared to
appendectomy
• O - Outcome – resolution of appendicitis
• M - Methodology - randomized controlled trial
 Medical Surgical
Managem VERSUS Management/Appe
ent/Antibi ndectomy
otics
 Is the article a match to the clinical
scenario?

Is the objective of the article similar to your clinical dilemma ?

Will it answer the questions

you actually want answered?
Is the objective of the article similar to my clinical
dillema? YES
Patient
Exclusions
Guide Questions
 GUIDE QUESTIONS
PRIMARY GUIDES
1. Was the assignment of patients to treatment randomized?

2. Were all the patients who entered the trial properly accounted for and attributed at its
conclusion?
a. Was follow-up complete?
b. Were the patients analyzed in the groups to which they were randomized?

SECONDARY GUIDES

1. Were the patients, health workers, and study personnel “blind” to treatment?

2. Were the groups similar at the start of the trial?

3. Aside from the experimental intervention, were the groups treated equally?
Was the assignment of patients to treatment randomized?
YES
Was the assignment of patients to treatment randomized?
Treatment (Antibiotics Group)

INTRAVENOUS ANTIBIOTICS at least

24 HOURS
then shifted to
ORAL ANTIBIOTICS
for a total of 10 DAY COURSE
Antibiotics from Surgical Infection Society and
Infectious Diseases Society of America guidelines for
intraabdominal infections.

• Ertapenem • Cefoxitin
• Moxofloxacin • Cefotaxime
• Tigecycline • Ciprofloxacin
• Ticarcillin-Clavullanic • Levofloxacin
Acid
• Metronid
 Participants were either hospitalized for the
administration of intravenous antibiotics or were discharged
from the emergency department after they had received
intravenous antibiotics for 24 hours or with 24 hours of
bioavailability.
How do we evaluate the outcome?

Primary Outcome
European Quality of Life–5 Dimensions (EQ Scoring Diagram)
European Quality of Life–5 Dimensions (EQ-5D)
questionnaire (scores range from 0 to 1, with higher
scores indicating better health status; noninferiority
margin, 0.05 points).
Secondary Outcome

We evaluate for the present of events like appendectomy,

Emergency Room visits, Clinic visits, etc.
Were all the patients who entered the trial
properly accounted for and attributed at its
conclusion?
Antibiotics Appendectom Antibiotics Appendectom
Group(776) y Group(776) Group(776) y Group(776)
30-Day EQ 702 (90%) 695 (90%) 90 day EQ 676 (87%) 655 (85%)
Completed Completed Completed Completed
Evaluation Evaluation
4 (1%) 6 (1%) 4 (1%) 6 (1%)
Withdrew Withdrew Withdrew Withdrew
70 (9%) Lost 75 (10%) Lost 96 (12%) Lost 114 (15%) Lost
to follow up to Follow-up to follow up to Follow-up
Were all the patients who entered the trial properly accounted for and attributed at its conclusion?
Was follow-up complete?
 GUIDE QUESTIONS
PRIMARY GUIDES
1. Was the assignment of patients to treatment randomized?

2. Were all the patients who entered the trial properly accounted for and attributed at its
conclusion?
a. Was follow-up complete?
b. Were the patients analyzed in the groups to which they were randomized?

SECONDARY GUIDES

1. Were the patients, health workers, and study personnel “blind” to treatment?

2. Were the groups similar at the start of the trial?

3. Aside from the experimental intervention, were the groups treated equally?
Were the patients, health workers and study personnel “blind” to treatment?

NO
This study is a pragmatic, nonblinded, noninferiority,
randomized trial comparing antibiotic therapy (10-day
course) with appendectomy in patients with appendicitis at
25 U.S. centers.
Were the groups similar at the start of the trial?

YES
Sociodemographic and clinical characteristics
of the participants were similar in the two groups
(Table 1 and Table S3). Imaging to confirm appendicitis
was computed tomography (CT) alone or in combination
with ultrasonography or magnetic resonance imaging in
96% of the participants.
2.Were the groups similar at the start of the trial?
3. Aside from the experimental intervention, were the groups treated equally?

• YES
• Standard discharge criteria
• Appendectomy recommendation (for diffuse peritonitis or septic shock)
• Usual preoperative and postoperative care and discharge criteria were
used.

• Decision to perform appendectomy was ultimately made by the

treating clinician.
• Management of recurrent appendicitis or symptoms
• Laparoscopic and conventional (open)
• technique was not standardized.
 GUIDE QUESTIONS
PRIMARY GUIDES

1. Was the assignment of patients to treatment randomized?

2. Were all the patients who entered the trial properly accounted for and
attributed at its conclusion?
a. Was follow-up complete?
b. Were the patients analyzed in the groups to which they were
randomized?
SECONDARY GUIDES
1. Were the patients, health workers, and study personnel “blind” to
treatment?
2. Were the groups similar at the start of the trial?

3. Aside from the experimental intervention, were the groups treated equally?
Study Validity
The Primary Outcome
 Results in subgroups of participants with an appendicolith and those
without an appendicolith also showed noninferiority of antibiotics with
respect to the primary outcome (Table 2)

EQ 30
Days

Resolution of
symptoms
No/Total

7 days

14 Days

30 Days
 Secondary Outcome
• Secondary outcomes included patient-reported resolution
of symptoms
• National Surgical Quality Improvement Program (NSQIP)
• Clostridioides difficile infections
• More extensive procedures
• Appendiceal perforation found during an operation or on
pathological review
• Appendiceal neoplasm
• Appendectomy in the antibiotics group.
In short...

Was there a reportable event that happened within

90 days?
Relative Risk/Risk Ratio:
 If the risk ratio is 1 (or close to 1), it suggests no difference or
little difference in each group is the same).

 A risk ratio >1 suggest an increased risk of that outcome in the

exposed group.
 A risk ratio <1 suggests a reduced risk in the exposed group
>1 Serious Adverse Adverse No Adverse Total Cumulative
events within 90 Event Event Index
Days
Antibiotics 19 657 676 0.0281
Appendectomy 19 637 651 0.0289

Formula: C.I = #of event / Total

1. 19/676 = 0.0281
2. 19/651 = 0.0289
Formula: Risk Ratio
RR = C.I of A/C.I of B

RR= 0.281/0.289

RR = 0.97
Percent Relative Risk

PRR
if RR< 1 = (1-RR) x 100
if RR >1 = (RR - 1) x 100

RR - 0.92
= (1-0.92) x 100 = 8
PRR = 8%
>1 Serious Adverse events Adverse No Total Cumulative
within 90 Days Event Adverse Index
to those with Appendicolith Event

Antibiotics 11 172 183 0.0601

Appendectomy 6 163 169 0.0355

Formula: C.I = #of event / Total

1. 11/183 = 0.0601
2. 6/169 = 0.0355
 In patients with
Appendicolith RR is
1.69

• Formula: Risk Ratio

• RR = C.I of A/C.I of B

• RR= 0.0601/0.0355

• RR = 1.69
Percent Relative Risk

PRR
if RR< 1 = (1-RR) x 100
if RR >1 = (RR - 1) x 100

RR - 0.92
= (1-1.69) x 100 = 69
PRR = 69%
>1 Serious Adverse Adve No Adverse Total Cumulative
events within 90 Days rse Event Index
to those without Even
Appendicolith t
Antibiotics 8 485 493 0.0162
Appendectomy 13 474 487 0.0267

Formula: C.I = #of event / Total

1. 8/493 = 0.0162
2. 13/487 = 0.0267
Formula: Risk Ratio
RR = C.I of A/C.I of B

RR= 0.0162/0.0267

RR = 0.61
Percent Relative Risk

PRR
if RR< 1 = (1-RR) x 100
if RR >1 = (RR - 1) x 100

RR - 0.92
= (1-0.61) x 100 = 39
PRR = 39%
Antibiotic Success
Results

In this large, randomized trial of antibiotics for appendicitis,

antibiotics were noninferior to appendectomy on the basis
of results of a commonly used measure of health status at
30 days.
 Results
1552 adults underwent randomization
• 414 with an appendicolith

30d EQ-5D Questionnaire:

• Antibiotics: 0.92 +/- 0.13
• Surgery: 0.91 +/- 0.13
• Mean difference 0.01 points; 95% CI -0.001 to 0.03
In the antibiotics group:
• 11% underwent surgery by 48hrs
• 20% underwent surgery by 30d
• 29% underwent surgery by 90 days
• 41% underwent surgery by 90 days if appendicolith present
• 25% underwent surgery by 90days if no appendicolith was present
NSQIP-Defined Complications:
• Antibiotics: 8.1 per 100 participants
• Surgery: 3.5 per 100 participants
• Rate Ratio 2.28; 95% CI 1.30 to 3.98
Complications in Pts with Appendicolith:
• Antibiotics: 20.2 per 100 participants
• Surgery: 3.6 per 100 participants
• Rate Ratio: 5.69; 95% CI 2.11 to 15.38
Complications in Pts without Appendicolith:
• Antibiotics: 3.7 per 100 participants
• Surgery: 3.5 per 100 participants
• Rate Ratio: 1.05; 95% CI 0.45 to 2.43

• No difference in resolution of symptoms by day 7, 14, or 30

between groups
• The mean number of missed workdays for patients was 5.26d
in the antibiotics group and 8.73 in the appendectomy group
• No deaths in either group
Discussion

Most common antibiotics in the trial:

• Initial IV use (at least 24hrs): ertapenem, cefoxitin OR
metronidazole plus one of the following…ceftriaxone,
cefazolin, levofloxacin
• For oral use (remainder of 10 total days): metronidazole
plus one of the following…ciprofloxacin, cefdinir
• Authors initially planned to report the results after all
participants had at least 1 year of follow up however given
the COVID-19 pandemic the results are based on the first
90 days after randomization
• Although surgeons had the option to perform
appendectomy either laparoscopically or open, 96% were
performed laparoscopically. In prior studies, open
appendectomy was more common, and this procedure is
associated with more complications. The predominance of
laparoscopic appendectomy is a better reflection of
current practice
• Time to discharge from either the ED or the hospital for index treatment
was 1.33d in the antibiotics group and 1.3d in the appendectomy group
(i.e. no difference)
• Percutaneous drainage procedures were more common in the
antibiotics group vs appendectomy group overall (2.5 vs 0.5 per 100
participants; rate ratio 5.36; 95% CI 1.55 to 18.50) particularly those
with an appendicolith
• When the analysis was limited to participants in either group who had
undergone appendectomy the percentage with a perforation was higher
in the antibiotics group vs appendectomy group (32% vs 16%). This
higher rate was attributable to those with an appendicolith (61% vs
24%) and not to those without an appendicolith (14% vs 13%)
APPAC VS CODA Trial

CODA's population included patients with "more severe

appendicitis" and also included those with appendicolith,
who were excluded from APPAC. While the sicker
population of CODA may explain the differences in overall
outcome, at least at 90 days, I wonder what happens when
one compares the population subsets, looking at more
similar populations.
Outcome Comparison Comparison

APPAC CODA
Among patients with CT-proven, uncomplicated For the treatment of appendicitis, antibiotics were
appendicitis, antibiotic treatment did not meet noninferior to appendectomy on
the prespecified criterion for noninferiority the basis of results of a standard health-status
compared with appendectomy. Most patients measure. In the antibiotics group,
randomized to antibiotic treatment for nearly 3 in 10 participants had undergone
uncomplicated appendicitis did not require appendectomy by 90 days. Participants
appendectomy during the 1-year follow-up period, with an appendicolith were at a higher risk for
and those who required appendectomy did not appendectomy and for complications
experience significant complications. than those without an appendicolith.
APPAC Study

The expected non-inferiority margin of 24% was optimistic

compared to previous reviews (Cochrane review average
26.6%, 95% confidence intervals 18-37%), and together
with halting the trial early, statistical proof of non-inferiority
was unlikely.

In this study, non-inferiority was not achieved because the

lower limit of the CI was -9.7% which is larger than the
preset threshold to establish non-inferiority (-6%).
Intervention Comparison

APPAC CODA
Patients randomized to antibiotic therapy received Drug: Cefoxitin, Ertapenem, Moxifloxacin,
intravenous ertapenem (1 g/d) for 3 days Tigecycline, Ticarcillin-Clavulanic Acid;
followed by 7 days of oral levofloxacin (500 Metronidazole plus Cefazolin, Cefuroxime,
mg once daily) and metronidazole (500 mg 3 Ceftriaxone, Cefotaxime, Ciprofloxacin, or
times per day). Patients randomized to the Levofloxacin
surgical treatment group were assigned to Patients will be offered a treatment regimen of
undergo standard open appendectomy. antibiotics based on guidelines published jointly
by the Surgical Infection Society and the
Infectious Disease Society of America. After IV
antibiotics are administered for a period of at
least 24 hours, a regimen of oral antibiotics
will be continued for a total treatment length
of 10 days.
Common Antibiotics Used in the Study
Initial IV use (at least 24hrs): ertapenem, cefoxitin
OR metronidazole plus one of the following…
ceftriaxone, cefazolin, levofloxacin
For oral use (remainder of 10 total days):
metronidazole plus one of the following…
“The incidence of appendectomy in APPAC antibx group was 16%
(at 90 days), vs 29% in CODA (at 90 days), or more specifically,
25% when looking at those without appendicolith, which is a better
comparison to APPAC. Why do you think there existed this
difference in crossover rate between the trials (16% vs. 25%) even
when comparing participants w/o appendicoliths, which presumably
gets a closer approximation of similar populations?”

Carissa Huq
Chief Resident
Houston, Texas
Limitations
• Unblinded trial with subjective primary outcome may influence
the results of the trial
• Amount of analgesic agents or pain-control medications provided
was not standardized or monitored in either treatment group
• ≈14% lost to follow-up with no additional information
• 90d follow data may be too short a time to see recurrence rate
and long-term complications in the antibiotic group
• All patients with appendicitis were approached for participation but
only 30% of eligible patients agreed to undergo randomization
• There was no protocol to specify requirements for hospitalization or
for a given antibiotic regimen
Treatment Cost

Price of Appendectomy in the Philippines

There is no exact price or cost of appendix surgery. Different
factors may lead to the actual price. The price of appendectomy
in the Philippines may range from Php 12,000 to Php 65,000 or
more depending on the facility where you will have it.
Appendicitis Surgery Cost
The cost will depend on the professional fee of doctors, the
operating room in the hospital, the type of surgery, medication
and room and board. The number of hospital days will also be a
factor on the final cost that the patient needs to pay for.
Open Appendectomy Price
In some hospitals, about Php 12,000 is the average or minimum
price of open appendectomy. However, the total cost will vary
depending on the patient’s needs.
Laparoscopic Appendectomy Price
This type of procedure is more expensive. In some facilities, the
cost may start from Php 40,000 and up. A camera device may be
needed in this case to see if there are other health concerns involved.
Source:
https://medicalpinas.com/appendectomy-price-philippines-surgery/#Price_of_Appendectomy_in_the_Philippines

Philhealth Case Rate Package: Appendectomy – P24,000.00

Source: https://www.isavta.co.il/en/blog/Case-Rate-Packages-from-PhilHealth (Dec 11,2019)
Author Conclusion

For the treatment of appendicitis, antibiotics were

noninferior to appendectomy on the basis of results of a
standard health-status measure. In the antibiotics group,
nearly 3 in 10 participants had undergone appendectomy by
90 days. Participants with an appendicolith were at a higher
risk for appendectomy and for complications than those
without an appendicolith.
Can this be applied to my patient?
Can this be applied to my patient?

YES
• This is very applicable especially in cases where transportation is not
available and at times requires a lot of paperworks and prerequisite
test(interisland air travel).
• In cases where patient does not consent to surgery and will try if
medication would work.
• In cases where Operating room is non-usuable due to some
circumstances
• Emergency rooms are closed and patient can only be seen in your clinic.
Take Home:

Although an antibiotic 1st strategy was non-inferior in

this trial compared to appendectomy, nearly 3 in 10
patients had undergone appendectomy by 90 days,
there were 3x more ED visits, and 2x more complications
(This could be balanced with less days of missed work).
An alternative perspective is that, in the antibiotics
group, more than 7 in 10 participants avoided surgery,
many were treated on an outpatient basis, and
participants and caregivers missed less time at work than
with appendectomy.
 Patients with an appendicolith are at a much
higher risk of complications and need for surgery and in
these patients an antibiotic 1st strategy should not be
recommended.
Reference
• New England Journal of Medicine
https://www.isavta.co.il/en/blog/Case-Rate-Packages-from-
PhilHealth (Dec 11,2019)
Thank You