PowerPoint guidelines for ventilation/perfusion, gastric emptying and gallbladder ejection fraction procedures.

1. Emerging procedure guidelines:
V/Q, gastric emptying and
gallbladder ejection fraction
 Herbert A. Klein, M.D., Ph.D.
 Clinical Professor of Radiology
 University of Pittsburgh

2. The Rev. Thomas Bayes was an 18th century
British minister and mathematician. Why am I
showing his picture? What does he have to do
with the subject? You’ll see.

4. “Clinical practice guidelines are
systematically developed statements to
assist practitioner and patient decisions
about appropriate health care for
specific clinical circumstances"
(Institute of Medicine, 1990). Their
recommendations are based on evidence
from a rigorous systematic review and
synthesis of the published medical
literature.

5.  Procedure/practice/management
guidelines are widespread: nuclear
medicine, radiology, cardiology, cancer,
etc., etc
 Best known in reference to patient care, e.g.
how to manage heart failure or cancer.
 There may be different guidelines for the
same condition, e.g. National
Comprehensive Cancer Network and
American Thyroid Association for thyroid
cancer as well as a procedure guideline
from SNM.

6.  SNM uses the term “procedure
guideline” and says: “These guidelines
are an educational tool designed to assist
practitioners in providing appropriate
nuclear medicine care for patients.”
 “The intent … is to describe a procedure
that will maximize the diagnostic
information obtained and optimize
patient care, while minimizing radiation
exposures and resources expended.”

7.  “They are not inflexible rules or
requirements of practice…An approach
that differs from the guidelines…does
not necessarily imply that the approach
was below the standard of care.”
 So, they are valuable and should be
taken seriously but are not obligatory.
 At UPMC we have sometimes deviated
from the guidelines for what we felt
were good reasons.

8.  SNM makes this distinction: “Practice
guidelines describe the therapeutic
approach to patients with specific clinical
problems such as ’chest pain.’…typically,
the resources required to develop a
practice guideline are much greater than
those necessary to develop a procedure
guideline.”
 However, SNM’s procedure guidelines
are not limited to diagnostic procedures,
but include treatment-- thyroid disease
and painful bone metastases.

9. General issues about practice guidelines
From Wolf et al, World J Urol (2010)
29:303-309
 In cases where multiple organizations
have produced clinical practice
guidelines on the same topic, there is
often disagreement.
 A concerning development is the use of
guidelines to determine the legal
standard of care (malpractice suits),
although this is strongly discouraged.

10. General issues, Wolf, cont.
 Conflicts of interest and biases may
occur. For example, authors may have
undisclosed financial ties to companies
that manufacture the drugs
recommended in the guidelines.

11.  Suppose you did a gallbladder
ejection fraction by a technique
different from the current
recommendation, with an abnormal
result leading to cholecystectomy
with an adverse outcome. Could you
be held legally liable on the basis of
the guideline?

12.  Suppose I were to point out the
advantages of Cyclopharm’s
product Technegas for ventilation
imaging (which I will do) and I was
getting money from Cyclopharm
(which I am not), might you not
suspect me of bias?

13.  “The Society of Nuclear Medicine
cautions against the use of these
guidelines in litigation in which the
clinical decisions of a practitioner
are called into question.”

14. A spokesperson for SNM gave me the
following key points of COI policy
regarding guideline development:
 Financial support from industry to develop its
guidelines is not accepted.
 Conflict of interest statements of each
committee member are reviewed by the SNM
Ethics Committee.
 A majority of the members of the committee
must be free of conflicts.
 Detailed wording of SNM policy is under
review, so it is not yet available to the public in
writing.

15.  I will concentrate on guidelines from
the SNM. Web site.
 www.snm.org
 Practice Management/Procedure
Guidelines.
 I will concentrate on features that I
consider noteworthy and will give
some elaboration of my own. I have
no conflicts of interest. Really.

16.  This site includes multiple
guidelines dated between 1999 to
2011, including updates of
previously written guidelines and a
guideline for developing guidelines
(from which I have quoted above)!
 Theoretically, they are reviewed
about every 5 years.

17.  There are 7 since 2009, of which I will
discuss 3, V/Q (2011), gastric emptying
(2009) and hepatobiliary (2010). As you
will see, new protocols may reflect
changes, both in procedural details and
in interpretation. I will italicize items
that are noteworthy for importance
and/or upgrading. They are authored by
6-8 expert authors and up to 101
references, so they have spared us a lot of
work reviewing literature.

18. The SNM Practice Guideline for Lung
Scintigraphy V4.0, revised 2011
 The most common (but not the
only)indication for lung scintigraphy is
to determine the likelihood of pulmonary
embolism.
 Usual procedure:
 Ventilation images of the lungs in
multiple views
 Perfusion images of the lungs in the same
views.
 Chest x-ray (or CT) for comparison.

19. Ventilation agents include:
 Tc-99m diethylenetriamine-pentaacetic acid
(DTPA) aeorosol is the most commonly used
radiopharmaceutical.
 Xe-133 gas may be used, and is used in some
institutions.
 Tc-99m labeled ultrafine carbon suspension has
more uniform distribution in the lungs than Tc-
99m DTPA aerosol, but is currently not available in
the United States though it is used in many other
countries.

20. Bulletin of 12/13/2011:
 “…Cyclopharm …is set to move the company's
Technegas product forward, after receiving
approval from the United States Food and
Drug Administration (FDA) to commence
Phase 3 clinical trials…
 “The significance of the U.S. trials is that they
represent the largest nuclear medicine market
in the world.
 “ Subject to patient recruitment frequency we
expect that marketing approval could be
granted by 2014.”

21.  Aerosol imaging is usually performed
before perfusion imaging. Because both
agents are labeled with Tc-99m, it is
extremely important that the count rate
of the second study is at least three to
four times the count rate of the first
study.

22. 58-y.o. Female with dyspnea, R-sided chest pain.

23. 55-y.o. male with dyspnea.

24.  Failure to achieve the desired excess
of counts may be due to the doses
that are chosen, to the aerosol
apparatus that is used, other features
of technique, or the patient’s
breathing pattern.

25.  SPECT can be used to obtain a 3D evaluation of
ventilation and perfusion. This is more common
in other countries (e.g. Europe) than in the U.S.,
and the opinion has been expressed that it is
best done with Technegas.
 The guidelines for V/Q scintigraphy of
European Association of Nuclear Medicine
advocate SPECT as well as the use of Tc-99m
DTPA only when Technegas is not available.
An entire issue of the Seminars in Nuclear
Medicine is devoted to SPECT for V/Q
imaging (Nov, 2010).
 Schemes for interpretation are simpler, with
reduction in the number of indeterminate
studies.

27. Interpretation:
 Criteria have evolved for categories like
high probability, intermediate
probability, low probability, very low
probability and normal. They involve
the size and character of perfusion
defects and, usually, their relationship to
ventilation imaging and chest x-ray. They
are based on clinical studies of patients,
some of whom did and some of whom
did not have PE.

28. The new guideline lists four
alternative sets of criteria
 PIOPED
 modified PIOPED II
 Perfusion Only Modified PIOPED II
 Perfusion only PISAPED
 The last two eliminate ventilation imaging.
 Clearly none of these is set in stone.

29. We have not accepted any of them, but
use a scheme that divides findings into
the following categories with associated
probabilities of PE
 High probability (>80%)
 Intermediate probability (20-80%)
 Low probability (10-20%)
 Very low probability (<10%)
 Normal (negligible probability)

30.  Almost hidden in the guideline is a subtle but
important change in this approach. Instead of
saying “high probability,” etc., as we are
accustomed to doing, the categories are called, “high
likelihood ratio (LR),” “intermediate LR,” “low
LR,” etc. Oddly, the guideline does not give an
explanation, but I will attempt to do so.
 The LR for a given presentation set of findings
with regard to defects, means the likelihood
that the set of findings would be expected in a
patient with PE divided by the likelihood that
the same result would be expected in a patient
without PE.

31.  This gets into complex concepts of
medical decision making, involving
specificity, sensitivity, probability, etc.
For a brief account, see Royal JD. Hillier
DA, “Thrombo-Embolism Imaging” in
Schiepers C (ed), Diagnostic Nuclear
Medicine, 2nd Revised Edition, 2006. I
will not attempt to cover this subject,
even before lunch, other than to
emphasize the important concept of pre-
test probability and to give you the gist
of the problem.

32.  The basic theorem on which this type of
analysis is based was formulated by a
man who probably had no idea how
influential his ideas would be, none other
than

33. Rev. Thomas Bayes

34.  Before a V/Q scan, a well patient who had a little
twitch in the chest is different from one who has
deep venous thrombosis, tachycardia, surgery in
the previous four weeks and hemoptysis. The
first patient has a low pre-test probability and the
second patient a high pre-test probability of PE.
There are specific criteria for evaluating pre-test
probability. For a given result, of a V/Q study, the
probability of PE is higher in the second than the
first patient, but we have generally not made that
clear.
 (Post-test probability)=LR x (Pre-test probability)

35.  Royal and Hillier state, “To make a
management recommendation based
solely on test results without accounting
for pre-test probability is wrong. At our
institution we have tried to emphasize
the importance of incorporating the pre-
test probability with the test results in
order to calculate the post-test
probability by reporting the ventilation-
perfusion imaging results as likelihood
ratios rather than probabilities which are
easily confused with post-test
probabilities.”

36.  This seems rather idealistic. I am not
optimistic about getting our providers to
grasp likelihood ratios. My personal
solution is to dictate impressions like,
“Intermediate probability of pulmonary
embolism, 20-80%, subject to
consideration of pre-test probability.”
Evidently, the new guidelines endorse
the principle of respecting pre-test
probability. One hopes for further
guidance on this point.

37. Procedure Guideline for Adult
Solid-Meal Gastric-Emptying Study
3.0, 2009
 It is worth emphasizing that the
guideline is a collaborative effort
involving both the Society of Nuclear
Medicine and the American
Neurogastroenterological and Motility
Society. Such interdisciplinary
collaboration is considered very
desirable.

38. Background and indications
 Nuclear medicine gastric emptying
studies are a useful, physiologic,
noninvasive and quantitative
method of evaluating patients for
gastroparesis, which is suggested by
symptoms such as nausea, vomiting,
early satiety, postprandial fullness,
abdominal discomfort or pain, in the
absence of obstruction.

39.  Patient should be NPO at least 4
hours. Medications can interfere and
should preferably be stopped, some for 2
days: Prokinetic agents like
metoclopramide (Reglan) (unless the
objective is to see if it’s working),
opiates, antispasmodic agents, atropine,
nifedipine, progesterone, octreotide,
theophylline, benzodiazepines and
phentolamine. Caffeine and smoking
interfere.

40. Radiopharmaceutical
 Solid test meal: Egg-white
preparation, 4 oz. cooked as an omelet
after addition of Tc-99m sulfur colloid 1
mCi, toast, jelly and water, comprising a
standardized solid test meal of about 255
calories, ingested optimally within 10
min.

41. Which came first?

42.  It is important to establish that the tracer
is truly bound to the solid medium.
Otherwise, one is really assessing liquid
emptying. This has been done in the past
with many different media. An early
method was as follows: Tc-99m sulfur
colloid, the liver-scanning agent that is
phagocytized by the Küpffer cells in the
liver, was injected in the wing vein of a
live chicken. The chicken was killed and
the liver removed, diced and cooked in a
microwave oven. In time, it was realized
that such an elaborate procedure was not
necessary.

43.  A number of alternative media have been
used like whole eggs cooked with added
Tc-99m SC. Egg-white preparations are
preferred because of low fat content.
They also have better binding of Tc-99m
SC.
 ”Use of a standardized meal will allow
referring physicians to compare results
between institutions more easily…If another
meal is used, the reference values cited for
this standardized meal do not apply.” This
appears to be an important motivation for the
new protocol, favored by patient advocates.

44.  Unlike V/Q scanning, normal limits
were determined only by study of
normal subjects, not ones with
symptoms, presumably because of the
difficulty of defining abnormal subjects
by means of some “gold standard.” The
upper limits of gastric retention were
defined as the 95th percentile.

45. Percentage emptying as geometric
mean of decay-corrected data.
Time (min) Upper limit
of gastric
emptying
Lower limit
of gastric
emptying
30 30%
60 70% 10%
120 40%(>55%↑,
<35%↓)
180 70%
240 90%

46.  Study may be terminated early only if
90% emptying has been achieved.
 To be considered unequivocally
normal, all percentages should be
normal, although the clinical
importance of delayed emptying
observed at only certain time points
is unknown. The 240 min result is
considered the most accurate.

49. The SNM Procedure Guideline for
Hepatobiliary Scintigraphy, 4.0,
revised 2010
 I will limit this to gallbladder ejection
fraction. This is described briefly in the
guideline with extensive elaboration in 2
identical publications, with 2 authors in
common between the guideline and the
paper:
 DiBaise et al, Clin Nuc Med 2012;37:63-
70and
 DiBaise et al Clin Gastroenterol Hepatol.
2011:9:376-384

50. Background
 Cholecystokinin (CCK) is a polypeptide
hormone produced in small bowel and
released after eating a meal. Along with neural
mechanisms, it normally promotes contraction
of the gallbladder and relaxation of the
sphincter of Oddi, with consequent increase of
bile flow into the intestine. The C-terminal
octapeptide of CCK, sincalide (Kinevac) is
administered to test the normalcy of the
response, as represented by the ejection
fraction. If it is abnormally low, the patient
may have relief of symptoms after a
cholecystectomy.

51. Basic procedure
 Do standard dynamic anterior imaging for 1
hour after injection of Tc-99m mebrofenin. If
gallbladder fills, place the camera in the 35-40
degree LAO projection to ensure minimal
overlap of the GB with small intestine.
Visualization of small bowel is not necessary
for step 2.
 Infuse 0.02 µg/kg of sincalide continuously
over x minutes via infusion pump with
simultaneous dynamic imaging. Generate
GBEF from a gallbladder region of interest with
background subtraction using a nearby liver
region. Abnormal EF is <y%.

52. What are x and y?
 There are numerous past protocols for
this, in which sincalide is administered
over different time periods: of time for
the infusion: 3, 10, 15, 30, 45 and 60
minutes. As with gastric emptying:
 In order to optimize and standardize the
procedure, a new protocol has emerged, with
a 60-minute infusion, longer than has often
been the case.
 The normal range was determined using only
normals, no subjects with symptoms.

53.  The lower limit of normal is based on
5th percentile of the normal group,
leading to a cut-off at GBEF of 38%.
 The protocol is the result of an
interdisciplinary collaboration, with a
panel of 12 members whose specialties
included gastroenterology, surgery,
primary care, nuclear medicine and
nuclear medicine technology.
 x = 60 min. y = 38%.

54. The 60-min infusion was based on
minimizing variability of normal results.

55.  Drugs possibly leading to false positives
(low GBEF) are important and should
preferably be withheld, some for as much
as 48 hours, include primarily opioid
analgesics, calcium channel blockers,
oral contraceptive agents, histamine-2
receptor antagonists and
benzodiazepines. Nicotine and alcohol
should be avoided.

56.  Indications: Evaluation of upper abdominal pain
thought to be biliary in origin, with
ultrasonographically normal appearing gallbladder,
including absence of cholelithiasis. The preferred
criteria, called “Rome III” gives details of the
character of the pain.
 False positives may occur in hospitalized or acutely
ill patients because of their acute illness and/or
medications.

61.  What is the condition we are
diagnosing? Various terms have been
used: gallbladder dyskinesia, chronic
acalculous gallbladder dysfunction,
acalculous biliary disease, chronic
acalculous cholecystitis or biliary
dyskinesia. To prevent confusion, the
authors have proposed the term
“functional gallbladder disorder.”

62.  The new recommendations emphasize that the
likelihood of a positive result being valid and
indicating a benefit from cholecystectomy
depend strongly on pretest probability (as in
V/Q scanning, etc.) “[The report of a
positive result] generally should conclude
with a statement…such as ‘In the appropriate
clinical setting, this is consistent with
functional gallbladder disorder’ leaving the
final interpretation to the ordering clinician
who is most familiar with the patient
involved…”

63. Rev. Thomas Bayes

64.  Ziessman, Semin Nucl Med 39:174-185, 2009:
“[In cases of gallstones with atypical symptoms,
GBEF] may be helpful. Poor gallbladder
contraction strongly suggests that the pain and
gallstones are related and the patient needs
cholecystectomy.”
 New recommendations (DiBaise et al, Ziessman
coauthor): “There is no evidence that GBEF
measurement adds to clinical judgment alone in
predicting the surgical outcome of patients with
cholelithiasis, as when symptoms are atypical or
ambiguous.”

65.  Contraindications to sincalide are
known allergic reaction, intestinal
obstruction and pregnancy.
 False positive results may occur with a
variety of medical conditions, including
diabetes, celiac disease or irritable
bowel syndrome.
 Although symptoms following sincalide
infusion may be reported, they do not
have proven diagnostic value and may
not reflect the presence of gallbladder
disease.

66.  If the gallbladder has not filled within
the initial hour, the finding should be
reported as abnormal, potentially
consistent with either acute or chronic
cholecystitis depending upon the clinical
presentation.

67.  There are arguments for perfusion before
ventilation, but it is more difficult to deliver a larger
dose of the Tc-99m aerosol than it is to deliver a
larger dose of Tc-99m MAA.

68. 31-y.o. female with dyspnea.