ARTICLE IN PRESS

Radiation Safety and Accidental Radiation

Exposures in Nuclear Medicine
Mario Marengo, PhD,* Colin J Martin, PhD,† Sietske Rubow, PhD,z Terez Sera, PhD,x
Zayda Amador, PhD,║ and Leonel Torres, PhD{

Medical radiation accidents and unintended events may lead to accidental or unintended
medical exposure of patients and exposure of staff or the public. Most unintended expo-
sures in nuclear medicine will lead to a small increase in risk; nevertheless, these require
investigation and a clinical and dosimetric assessment. Nuclear medicine staff are exposed
to radiation emitted directly by radiopharmaceuticals and by patients after administration of
radiopharmaceuticals. This is particularly relevant in PET, due to the penetrating 511 keV
g-rays. Dose constraints should be set for planning the exposure of individuals. Staff body
doses of 1-25 mSv/GBq are reported for PET imaging, the largest component being from the
injection. The preparation and administration of radiopharmaceuticals can lead to high
doses to the hands, challenging dose limits for radionuclides such as 90Y and even 18F. The
risks of contamination can be minimized by basic precautions, such as carrying out manipu-
lations in purpose-built facilities, wearing protective clothing, especially gloves, and remov-
ing contaminated gloves or any skin contamination as quickly as possible. Airborne
contamination is a potential problem when handling radioisotopes of iodine or administer-
ing radioaerosols. Manipulating radiopharmaceuticals in laminar air flow cabinets, and
appropriate premises ventilation are necessary to improve safety levels. Ensuring patient
safety and minimizing the risk of incidents require efficient overall quality management.
Critical aspects include: the booking process, particularly if qualified medical supervision
is not present; administration of radiopharmaceuticals to patients, with the risk of misad-
ministration or extravasation; management of patients’ data and images by information
technology systems, considering the possibility of misalignment between patient personal
data and clinical information. Prevention of possible mistakes in patient identification or in
the management of patients with similar names requires particular attention. Appropriate
management of pregnant or breast-feeding patients is another important aspect of radiation
safety. In radiopharmacy activities, strict quality assurance should be implemented at all
operational levels, in addition to adherence to national and international regulations and
guidelines. This includes not only administrative aspects, like checking the request/pre-
scription, patient’s data and the details of the requested procedure, but also quantitative
tests according to national/international pharmacopoeias, and measuring the dispensed
activity with a calibrated activity meter prior to administration. In therapy with radionu-
clides, skin tissue reactions can occur following extravasation, which can result in localized
doses of tens of Grays. Other relevant incidents include confusion of products for patients
administered at the same time or malfunction of administration devices. Furthermore, errors
in internal radiation dosimetry calculations for treatment planning may lead to under or
over-treatment. According to literature, proper instructions are fundamental to keep effec-
tive dose to caregivers and family members after patient discharge below the Dose con-
straints. The IAEA Basic Safety Standards require measures to minimize the likelihood of

*Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Italy.

y
Department of Clinical Physics and Bioengineering, University of Glasgow, UK.
z
Nuclear Medicine Division, Stellenbosch University, Stellenbosch, South Africa.
x
Department of Nuclear Medicine, University of Szeged, Szeged, Hungary.
║
Radiation Protection Department, Centre of Isotopes, Havana, Cuba.
{
Nuclear Medicine Department, Centre of Isotopes, Havana, Cuba.
Address reprint requests to Mario Marengo, PhD, University of Bologna, Bologna, Italy E-mail: [email protected]

https://doi.org/10.1053/j.semnuclmed.2021.11.006 1
0001-2998/© 2021 Elsevier Inc. All rights reserved.
 ARTICLE IN PRESS
2 M. Marengo et al.

any unintended or accidental medical exposures and reporting any radiation incident. The
relative complexity of nuclear medicine practice presents many possibilities for errors. It is
therefore important that all activities are performed according to well established proce-
dures, and that all actions are supported by regular quality assurance/QC procedures.
Semin Nucl Med 00:1-21 © 2021 Elsevier Inc. All rights reserved.

Introduction high doses from external radiation. Emphasis should be

placed during training on the need for technical staff to

N uclear Medicine services adhere to high safety standards

in order to maintain the quality of the service. But safety
cannot be guaranteed in a discipline that uses sophisticated
explain procedures to patients prior to administration of
radiopharmaceuticals and the need for nursing staff to main-
tain a safe distance from patients whenever practicable. Staff
technologies and radioactive materials, as part of a complex, members in other departments may also receive unnecessary
multi-step process. However, the growth of clinical applica- radiation doses, if exposed to NM patients following injection
tions in Nuclear Medicine (NM) has been accompanied by of radiopharmaceuticals. So, for example, NM departments
the development of a culture of an intrinsic multi-disciplin- should not send patients for ultrasound scans during the
ary nature, which has paid close attention to the wide variety periods when they are waiting for radiopharmaceutical
of safety aspects involved. uptake and bio-distribution to be established before imaging.
Tools have evolved that are adapted to ensure the safety of The 511 keV g-rays from PET radionuclides are more pen-
patients, staff, the public, and the environment and this etrating than those from other imaging radionuclides, so
review considers things that can go wrong, illustrated with require a greater level of shielding. Since patients need to rest
examples, together with the development of measures to pre- for a period of time prior to the scan to allow the radiophar-
vent them in the future. maceutical to be taken up in affected tissues, both the design
Medical radiation accidents and ‘unintended events’ that of the facility and the workflow require careful planning to
might lead to ‘accidental or unintended medical exposures’ ensure that staff members are not exposed unnecessarily dur-
of patients or exposures of staff or the public are included ing periods when they are not dealing directly with patients.
here under the umbrella of the term ‘incident’. The term Poor planning of patient workflow and work procedures that
“unintended exposures” in the context of medical procedures
do not provide sufficent protection can increase staff member
is taken as meaning the exposure of a patient to a different
doses considerably. Since there is a risk that doses to staff
radiation level than it was planned for the procedure carried
may be significant, Dose Constraints (DC) well below dose
out.
limits should be set for the purpose of planning the exposure
The majority of unintended medical exposures will lead to
of individuals. DC are tools for optimization of protection
a small increase in risk of stochastic effects, primarily cancer
and safety that are set based on realistic assessments of expo-
induction, and result in no obvious effect on the health of
sures individuals might be expected to receive. They provide
the individual subject. These require a clinical assessment of
values against which managers can compare results from per-
the magnitude of the additional dose and an explanation of
the risk, usually in general terms. However, tissue reactions sonal dosimetry, help to identify individuals receiving higher
(deterministic effects) in the skin can occur occasionally fol- doses so that action can be taken, and so aid in maintaining
lowing extravasation of radiopharmaceuticals used for ther- exposures at levels that are as low as reasonably achievable.
apy, which can result in localized doses of tens of Gy. Realistic values can be determined based on the anticipated
exposure situations and workload within departments. Risk
assessments should be undertaken prior to a service being set
up to plan the workflow and practices to maintain dose levels
Incidents Involving Staff within agreed DC, and these should be reviewed periodically
Exposure thereafter.
Staff body doses reported for PET imaging cover the range
External Exposure of Staff From Radioactive 1-25 mSv per GBq activity administered,1-8 with the largest
Materials component being from the injection.3,9 The wide range in
NM staff are exposed to radiation emitted directly by radio- reported values reflects differences in planning and optimiz-
pharmaceuticals contained within vials and syringes, and ing the protection, the doses can only be used as a rough ini-
sealed sources used for quality control (QC), but will also be tial guide to ones that staff at a particular facility might
irradiated during contact with patients containing radioactiv- receive. As a starting point, the external dose rates from
ity at some stages during the imaging process or the delivery patients injected with 18F-fluorodeoxyglucose (FDG) are
of therapy. Protection when dealing with patients is in most much higher than in conventional NM being typically 45
cases achieved through maintaining distance and limiting the mSv h1 at 1 m5,7,9, compared to 10 mSv h1 or less for
99m
time spent in close contact, but because staff deal directly Tc.10-13 Published whole body dose values for PET staff
with patients, there is a potential for individuals to receive are in the range 4-10 mSv per patient, so a workload of
 ARTICLE IN PRESS
Radiation safety and accidental 3

500 patients/year per individual staff member might be Protection of the Hands When Handling
expected to give rise to an annual effective dose of 2-5 mSv. Radiopharmaceuticals
It is important to have comprehensive dose monitoring Protection of the body when handling radiopharmaceuticals
arrangements in place to establish realistic doses that staff is provided through local shielding of vials and syringes, and
members are receiving. Instruction on wearing and use of bench top shields, but the preparation and administration of
dosemeters should be included in staff training and data on radiopharmaceuticals can lead to high doses to the hands.
dose levels reported to staff members at regular intervals to The tips of the fingers receive the highest doses when manip-
enable them to review their practices in relation to the doses
ulating syringes and vials during the dispensing of radiophar-
measured. In certain circumstances where staff work between
maceuticals. Measurements made in 30 nuclear medicine
PET and other radionuclide imaging areas, the constraint
departments from six European countries showed finger
may require staff to be rotated between locations, in order to
doses ranging from about 20-800 mSv per GBq for prepara-
maintain their doses below an agreed DC. This can all be
tion and administration of 99mTc.16 The hands can receive
evaluated in the risk assessment, based on which practices
high doses if appropriate protection measures are not in
are planned.
place. The dose is dependent upon both the technique used
In order to draw attention to any doses received by staff
that might approach the constraint, it is useful to establish and more particularly the amount of shielding. Vials should
investigation levels set below the DC. These provide a tool to be shielded at all times either by specialized tungsten vial
highlight doses higher than anticipated. Dose constraints shields, recommended for radiopharmacies, or lead pots.
and investigation levels are generally set in terms of the Syringe shields can reduce finger doses by 85% during dis-
annual dose received during a calendar year. Investigation pensing and drawing up of injections, and should be used
levels are based on assessments of local practices and should wherever practicable.17 Tungsten or lead glass can provide
be included in the local rules. If an individual exceeds an good protection for most g-ray emitters and Poly-methyl-
investigation level the employer should complete an investi- methacrylate, possibly with an outer layer of lead to reduce
gation to determine the cause(s) as soon as possible, so that bremsstrahlung radiation, for b-emitters. The fingers are also
action can be taken to evaluate what has led to doses being irradiated when radiopharmaceuticals are injected and doses
higher than expected, and ensure that adequate controls are can again be significant if syringes are not shielded17 or fin-
put in place to maintain the individual’s doses below the con- gers are placed on the needle during an injection.18 Place-
straint in the future. In addition to investigation levels that ment of a butterfly syringe or cannula in a vein prior to
apply to the annual dose, it can sometimes be helpful to have introduction of a radiopharmaceutical can reduce finger
additional action levels linked to measurements from single exposure where there are potential problems in delivering
dosemeters in order to identify when an unusual exposure injections. Where practicable, automated modules for dis-
has occurred within a shorter time frame. pensing and drawing up radiopharmaceuticals, especially
with PET radionuclides, can reduce doses substantially,
although cost may be an issue.19,20
Staff Members Who are Pregnant Doses from administration of b-emitting radionuclides
If a female worker has declared that she is pregnant, such as 90Y and 32P and even 18F can reach the level where
additional controls may need to be considered to protect dose limits are exceeded21 or even cause tissue reactions.22
the embryo/fetus. Since protection of the fetus should be Since radionuclides used for therapy emit particle radiations
broadly similar to that applied to members of the public, which are capable of delivering significant doses, consider-
the working conditions should be such as to ensure that ation of potential finger doses and protection is extremely
the additional dose to the embryo/fetus would not exceed important. A survey of extremity doses for therapy involving
90
1 mGy during the remainder of the pregnancy. This Y conducted in the ORAMED project measured finger
might equate to a dose of 1 mSv to the surface of the doses for 54 workers from six European countries.21 This
abdomen for staff working with 18F, but 1.3 mSv for staff study recorded finger doses from the preparation of 90Y ibri-
working with 99mTc. A risk assessment should be carried tumomab tiuxetan ranging from 1.2 to 43.9 mSv GBq1 and
out to carefully review the exposure conditions of the doses up to 7.4 mSv GBq1 for the administration. The wide
pregnant woman and assess whether the current work range resulted from variations in training and protection
performed is likely to result in the fetal dose approaching facilities in the different institutions. Other workers have
the agreed DC. Their working conditions should be published similar values for finger doses during 90Y ther-
changed, if required, to ensure that the dose to the fetus apy22-25, or for 177Lu therapy.26 The contact dose rate for a
from routine work, and from radionuclide intakes is vial containing 1 GBq of 90Y can be as high as 700 mSv/
extremely low, and the probability of any accidental min127, so there is a potential for staff to receive doses not
exposures is low.14,15 Restrictions may or may not be only above the dose limit, but ones that would result in tissue
required, but should not mean that the pregnant women reactions if shielding, handling tongs and other appropriate
need to avoid work with radiation or should not work in protection measures are not used. In order to check dose lev-
designated radiation areas. However, females who have els and identify problems, monitoring using finger stall dose-
declared that they are pregnant should not be involved in meters on the tips of the thumb and first three fingers of
dealing with radiation incidents and emergencies. each hand is recommended for workers handling 90Y
 ARTICLE IN PRESS
4 M. Marengo et al.

therapy.18 The dosemeters require thin active layers to enable radiopharmaceutical involved. The risk from the majority of
the true value for Hp(0.07) to be measured.28 diagnostic procedures will be relatively small and trivial after
the first day, but there are greater potential risks of contami-
nation from treatment of therapy patients and these may per-
Contamination With Radiopharmaceuticals sist for several days.
Any handling of unsealed radionuclides will be accompanied Risk assessments should be carried out to identify the
by the potential for spread of contamination and intake of safest approach taking account of the facilities available
radiopharmaceutical into the body. The risks can be mini- and the patient cohort. If an 131I therapy patient fails to
mized by taking basic precautions, such as always carrying swallow the radio-iodine or regurgitates it, significant
out manipulations in purpose-built facilities, wearing appro- contamination could occur. Any vomit will be highly
priate protective clothing, especially gloves, and removing active in the period following an oral administration of
131
contaminated gloves or any skin contamination as quickly as I therapy. The use of capsules for oral administration
possible. The potential for a spill is kept to a minimum by of 131I therapy rather than liquid, where possible, will
using vials with a rubber and metal closure and avoiding vials reduce the scale of spread of radioactivity during and
or any other vessels containing radioactive liquid being left in immediately after the administration, as a patient may
places where they may be knocked over and broken. In addi- cough when drinking a liquid. However, a patient may
tion, a spill kit should be available where radionuclides are vomit when swallowing a capsule, so the choice of
handled to deal with any spillage that does occur.29 method needs to take the patient’s condition into
Most radiopharmaceuticals for imaging and other diagnos- account, as well as the difference in cost, which will be
tic applications are administered by intravenous injection, significant for some countries. In order to reduce the risk
and a cannula or butterfly is often used to reduce levels of of a contamination event occurring in a public area,
finger exposure. However, this means that there are more which would be more difficult to contain, iodine therapy
connections at which leaks may occur, so it is important for patients should remain in the department in an area with
staff to ensure that these are secure and that there is no a wash-basin and toilet for 15-20 minutes following
blockage that could result in radiopharmaceutical being administrations.
sprayed over the operator or patient. All physicians, technol-
ogists, and nurses who may carry out injections should have
been thoroughly trained in injection technique, including Incontinent Patients
assessment of the patency of the patient’s venous pathway, The treatment of incontinent patients will inevitably have the
and precautions such as flushing needles and cannulas with potential for leading to contamination and a risk assessment
saline before starting an injection, and not exerting excess should always be carried out, to determine how a therapy is
pressure if the resistance is high. The training should also to be undertaken. Sanitary pads may be adequate for patients
include practices for needle disposal into a sharps container undergoing diagnostic NM tests, but are unlikely to be
to reduce the risk of needle stick injuries and use of safe appropriate for therapy patients. Catheterization may be con-
recapping devices if it is necessary to measure the residual sidered, but there will be associated contamination problems
activity in the syringe.30,31 from leakage and disposal of the liquid of which carers will
Aerial contamination is a potential problem when han- need to be aware, so that they can take any necessary precau-
dling radioisotopes of iodine that can readily vaporize32, and tions. A split urine bag or inadvertent opening of the tap will
manipulations of significant quantities of radioactive iodine lead to a spill of contaminated urine, so there is a need to
should be carried out in laminar air flow cabinets. Aerial con- protect the bags when patients are moved and empty them
tamination may be produced from apparatus delivering gas- frequently using basic biologic protection measures to mini-
eous or aerosol radiopharmaceuticals if it is not used mize the potential risks.
effectively by a patient. Checks need to be made that mask Methods that can be used for clean-up of spills and decon-
used for lung ventilation studies fit closely to the patient’s tamination, together with items that should be contained in
facial contours and that the patient is able to tolerate wearing the spill kit are described in other texts35,36 and will not be
the mask for the duration of the procedure. Low levels of considered here. If the skin becomes contaminated from rou-
personnel contamination resulting from release of radioactive tine procedures or during any decontamination following a
gas to the environment have been reported in cases of inade- spill, absorbed dose rates at the skin surface can be signifi-
quate patient collaboration33,34, and if this occurs, the results cant. If this is the case, an evaluation of the skin dose in terms
of the ventilation study being performed will not be reliable. of Hp(0.07) should be undertaken.37,38
It is good practice to have a dedicated room for radio-
pharmaceutical administrations, that has a sealed floor
Contamination From Patient Fluids with coving for easy decontamination, wash-basin/sink,
Another source of potential contamination that can be more drip trays, shields, supplies of absorbent material, and a
difficult to deal with is that from body fluids of patients to spill kit.39 Then if an accident occurs, only this room is
whom a radiopharmaceutical has been administered. The contaminated and it can be cleaned and returned to a
period over which there is a risk will depend on the physical safe state in a controlled manner, without other activities
half-life of the radionuclide and the biological half-life of the within the department being affected. Such a room can
 ARTICLE IN PRESS
Radiation safety and accidental 5

be used for both injections and oral administrations, and wrong radiopharmaceutical chosen; or an inappropriate time
the room can provide a location where iodine therapy selected for the study.
patients can be asked to remain for a period before being All of these may cause a non-justified exposure of the
discharged. patient to radiation, and result not only in an unnecessary
radiation dose, but also a failure to carry out the examination
and provide the diagnosis at the time it was required.

Quality Management and

Misadministration
Fundamentals of Patient Safety Many incidents in NM are connected with identification of
NM has some very special characteristics, compared to other patients. Misadministration is a typical incident that may
disciplines in diagnostic imaging and to the broad field of occur in NM. Indeed, it should be noted that there is no uni-
radiology. The exposure of patients to ionizing radiation is form and generally accepted terminology for defining
not from radiation emitted by a medical device, but depends unwanted events in NM, and this does not favor full aware-
on the administration of a radiopharmaceutical. The expo- ness of the type of events, their systematic reporting, and the
sure may occur at a different time, even hours before a diag- dissemination of information. In this paper, the term misad-
nostic procedure; in case of therapy, the irradiation of the ministration is used to indicate events in which:
patient may continue for days or even weeks after discharge
of the patient from hospital.  a different radiopharmaceutical is administered instead
Furthermore, the desired result does not simply depend of the intended one;
on the action of the radioactive pharmaceutical; in most  a different activity is given instead of the prescribed
cases, the preparation of the patient, and pre-treatment or one;
medical interventions during the procedure, are instrumental  a unit dose prepared for patient A is administered to
in determining the final result. Examples are the preparation patient B, even if it is the correct radiopharmaceutical
of the patient (fasting, avoiding physical activity, etc.) with- and activity;
out which 18F-FDG would not provide any useful informa-  a wrong administration route is used.
tion; the absence or introduction of stress testing in
myocardial single photon emission computed tomography In the literature, some authors refer to this type of event as
(SPECT), or the administration of other medicines, like ACE “maladministration”.47 We decided to use “misadminitra-
inhibitors in dynamic renal scintigraphy. An example of an tion”, following the UK Radiopharmacy Group.48
intervention affecting the outcome of the use of a therapeutic One of the root causes of this type of incident may be the
radiopharmaceutical is the discontinuation of thyroid hor- incorrect identification of the patient; labeling and identifica-
mone replacement therapy before administration of 131I. tion of the radiopharmaceuticals are dealt with in another
Therefore, the result of a NM procedure, both in terms of section.
clinical efficacy and safety, is not simply determined by a Even in the case of a diagnostic examination, using limited
device or a pharmaceutical, but by the entire process. The activity of a short-lived NM radionuclide, a misadministra-
whole process needs to be well controlled in order to pro- tion is considered a serious event, since exposure of the
duce quality results in a safe manner. Only a comprehensive patient in this case is completely unjustified.
approach can ensure justified and optimized patient expo- Correct patient identification is actually an issue in all hos-
sure and consistent reduction in the risk of incidents.40-43 pital activities.49,50 There are several methods to properly
identify patients:

Critical Steps in the Process: Booking  confirm the patient's name by asking at every step of
Requests for a NM examination should include all necessary the process; the question should be “Can you please
information, and be reviewed and accepted by a qualified tell me your name?” and not “Are you Mr. . . . ?”, sug-
NM (or equivalently recognized) practitioner. This is not gesting the name;
merely an administrative task, but it is closely related to the  ask the patient to give at least one more element to
justification of a NM procedure. Nowadays, this aspect is tak- define their identification, such as their date of birth or
ing on new facets as a consequence of the increasing digitali- address;
zation of the booking process: in an increasing number of  check the patient’s ID card, if feasible;
situations, it is now possible for the referring phyisician, or  assign to every patient an identification number and
directly for a patient with a prescription, to book a procedure cross-check the number at every step of the process;
online without intermediate filters. This is in general a posi-  assign to each patient a wristband or equivalent, with
tive development made available by information technology an identification bar code.
and internet connectivity, but it is not free from risks.44-46 If
the requests are not reviewed and finally approved by a quali- A color in the background of the wristband, or of the label
fied NM physician, errors may be introduced in the booking bearing the patient number, can help to identify specific
process: a wrong procedure or wrong indication picked; the groups of patients.
 ARTICLE IN PRESS
6 M. Marengo et al.

It is recommended that at least two independent identifiers when there is a potential risk of confusion; labels/stickers
are used to confirm patient identity. should be printed and placed on patients' forms.
Initially introduced in the 1990s, in recent years, wrist-
bands have been adopted in many hospitals, to improve
patient identification51,52, thanks also to the availability and Extravasation of an Injection
accessible cost of computer connected scanning devices. As we have already seen in the case of misadministration, for
Identification wristbands are widely used for inpatients, but extravasation, a relatively frequent type of incident, there is
they are of great use and should be recommended for all also not a generally accepted standard term.
cases of outpatients undergoing procedures that pose a risk. Some authors refer to extravasation as the inadvertent
However, even wristbands are not error free53,54, but when administration of a vesicant pharmaceutical into surrounding
available, can grant a consistent reduction of risks of wrong tissues, which can lead to tissue necrosis, while the inadver-
identification. When their introduction is not feasible, for tent administration of non-vesicant products into the sur-
example, for cost reasons, or absence of Hospital infrastruc- rounding tissues is termed infiltration. Even if for some
ture, labels with a coded patient number can be a satisfactory, relevant radionuclides, such as 99mTc, it is unlikely that there
less costly option. will be any noticeable consequence after such an event, since
Other factors that have been shown to contribute to caus- radiopharmaceuticals in general have the potential to pro-
ing misadministrations are55 : duce tissue reactions, use of the term extravasation is pre-
ferred in this paper; this is also in agreement with the general
 high workload; definition given in NHS England Guidelines.60
 multitasking work of staff members; Management of extravasation is actually a general problem
 interruptions during the performance of key opera- in the administration of any kind of pharmaceutical. In the
tions; radiology field, reports have been published for both CT and
 stress; MR contrast media61,62, and general recommendations for
 need for re-training, for example, after a long leave. the prevention of extravasation are available.63
As to NM, a comprehensive review has been published in
recent years.64 This paper included an extensive biblio-
graphic search that identified 37 publications, reporting
Data Management 3016 cases of extravasation of diagnostic radiopharmaceuti-
The management of patient data and images by means of cals, of which three cases reported some symptoms. Eight
Hospital Information Systems, specific Radiological Informa- publications reported 10 cases of therapeutic tracer extrava-
tion Systems (RIS) and Picture Archiving and Communica- sation, indicating skin ulceration as the most severe symp-
tion Systems (PACS) has greatly improved quality and safety tom.
in diagnostic imaging departments. Nevertheless, on the Tracer extravasation has been identified in several reports
other side, these new, powerful digital systems have intro- of scans of the whole body that included the injection site in
duced new types of potential errors; furthermore, the distri- the acquired images, like 99mTc-MDP bone scintigraphy or
bution of errors along the process is changing.56 In the past, 18
F-FDG positron emission tomography (PET).
diagnostic imaging departments used films and the patient Although there was no specific clinical follow-up after
name was photo-stamped on each film, using an analog light extravasations described in these publications, no adverse
device; an eventual error, once identified, could be corrected reactions have been reported following events involving the
simply using a pen. Nowadays, an error in the patient data most widely used diagnostic radionuclides, such as 99mTc,
201
should be very carefully managed, since the procedure of for Tl, 123I, 18F and 68Ga. Nevertheless, it should be remem-
example, entering patient folders, modifying names or codes, bered that the possible consequences of an extravasation are
or moving an image from one folder to another, involves the not limited to local reactions, but will have a more subtle
potential risk of disrupting data integrity and compounding effect when quantitative or semiquantitative imaging proce-
the error through the introduction of further mistakes while dures are involved. For example, the standardized uptake
attempting to address the initial problem.57,58 These activi- values obtained would be influenced by a significant extrava-
ties should form part of a well-defined and carefully moni- sation of 18F-FDG, and this should be taken into account
tored process of Patient Information Reconciliation59, aiming while analyzing images and reporting. Extravasations should
to coordinate all operations of correction/updating of identi- not only be avoided wherever possible, but also reported in
fication data, correction of errors, merging of different image order to avoid false interpretations of the PET/CT exam.65
acquisitions etc.58 Developing a quality improvement plan and monitoring PET
It should be noted that, despite the complexity, sophisti- injections can lead to reduced extravasation rates.66
cated features, and high cost of RIS / PACS systems, they still A few complications following therapeutic extravasation
do not provide specific functions to manage cases where have been reported, some of which caused severe soft tissue
patients have the same or similar names safely. The booking damage. Until recently orally administered 131I has been the
of patients with similar names on the same working day therapeutic radionuclide used most widely, but with the
should be avoided; when this is not feasible, at least a warn- increasing focus on intravenously administered beta and
ing should be issued by software platforms, alerting staff alpha emitters, like 177Lu, 223Ra, and 225Ac, increasing
 ARTICLE IN PRESS
Radiation safety and accidental 7

attention will be needed on extravasation of therapeutic reporting of incidents in nuclear medicine therapeutic appli-
radiopharmaceuticals. This is particularly important since cations. These include therapies with radiopharmaceuticals
the therapeutic options after an extravasation are and radioactive medical devices such as SIRT.70,71
limited64,67,68, thus prevention is the most important aspect. Like other state of the art reporting systems, the SAFRON
Examples of incidents involving therapeutic extravasation has an easy, guided data introduction, completely anony-
are discussed later in the section on radionuclide therapy. mous, guaranteeing the privacy of patients and reporting
Suggested preventive measures include the choice of opti- institutions. It makes possible for professionals in the field to
mal needles and cannulas for intravenous administration and obtain relevant information on incidents, a statistical analysis
proper training of staff in the injection technique. A check of of their modality, consequences and possibilities for mitiga-
patency by flushing with saline solution should be made tion, and contributing then to diffuse knowledge and learn
before injecting any therapeutic radiopharmaceutical via an from previous lessons.
intravenous catheter. It is of utmost importance to stop the
administration immediately when a problem is
recognized.64,68
Some published preventive measures67 are: Risks and Incidents in
 to recognize the symptoms (erythema, venous discol- Radiopharmacy
oration and swelling), Quality assurance (QA) programs should be implemented in
 to know the risk factors (which are related to radio- radiopharmacies at all operational levels.72,73 In addition to
pharmaceutical, patient, site of injection and injection national regulations, international guidelines and protocols
technique), are available for compounding of radiopharmaceuticals in
 to assess severity (from erythema to skin necrosis, hospitals.72,74 Special guidelines for Good Manufacturing
depending on the radionuclide) and Practice provide information on radiopharmaceutical pro-
 to know how to avoid them (training and awareness of duction for wider application, taking limitations due to the
staff, choice of injection site, testing the route of drug radioactive properties into account.75-77 QA and Good
administration and using a catheter for administration Manufacturing Practice guidelines cover a very wide field,
of therapeutic radiopharmaceuticals). including receipt and basic control of radiopharmaceuticals
received ready to use from an external radiopharmacy, up to
The management of extravasation should be immediate prevention of microbiological contamination of radiophar-
and a specific emergency kit should always be available. Gen- maceuticals.78 The design of the radiopharmacy, selection,
eral measures recommended are the immediate cessation of validation, maintenance and calibration of equipment, and
injection, aspiration of fluid extravasation, delineation of the staff education and training79-81 all contribute to safety of
extravasated area with an indelible pen and informing the rel- staff and patients, but a full discussion of all these factors is
evant physicians responsible for the patient. beyond the scope of this paper.
Specific measures should be implemented, based on the As discussed elsewhere in this review, patient identifica-
radiotoxicity of the radionuclide and the type of radiophar- tion is of utmost importance. Equally important is the correct
maceutical. identification of the radiopharmaceutical product, beginning
A multidisciplinary approach is essential from an early with the radionuclide or generator eluate, right through to
stage to manage the extravasation effectively.67 The NM Phy- the individual patient dose, be it in a syringe, capsule, or
sician should inform the patient about the risks and how other form. Identification labels should always indicate the
they will be managed. radionuclide and pharmaceutical product82, dosage form,
The knowledge of any possible patient-specific risk factors and calibration date and time. The expiry date and time are
is particularly important in the cases of infants and young crucial, especially for products containing short-lived radio-
children. Recommendations are available on treatment of nuclides.83 The International Pharmacopoeia and WHO
extravasation injuries in pediatric patients.69 guidelines on good manufacturing procedures provide com-
plete lists of details that should be given on the primary con-
tainer of any radiopharmaceutical, as well as those to be
Incident Reporting provided on the outer container (often the vial or syringe
Incident reporting systems are a tool in health institutions to shield).75,83 Clearly indicating the route of administration is
monitor unexpected events, incidents and close calls, activate especially important for products that can be used for several
corrective actions and provide useful information to the clini- types of studies, for example, 99mTc-DTPA used as an aerosol
cians to prevent repetitions. for lung ventilation imaging, or injected intravenously to
In addition to local reporting systems, or reporting sys- evaluate kidney function. Incorrect or incomplete identifica-
tems descending from regulatory requirements, given also tion of radiopharmaceuticals can lead to several problems,
the relatively low frequency of incidents in NM, it is useful to including cross-contamination of products in the radiophar-
have a wider base of data collection. The IAEA introduced macy, dispensing of the wrong product, or confusion of
SAFRON in 2012, a web-based system for incident reporting patient doses, which could result in the exposure of one or
in radiotherapy. In 2019 this has been extended also to the more patients to radiation without any benefit in obtaining
 ARTICLE IN PRESS
8 M. Marengo et al.

diagnostic information or the desired therapeutic effect. distribute radiopharmaceuticals to other facilities, have to
Errors in labelling of radiopharmaceutical vials can lead to a implement the necessary QA and QC procedures to ensure
cluster effect, that is, misadministration of products to several that products meet pharmacopoeial standards, including
patients.84-86 Color coding of labels on product vials and radionuclidic purity.92,78 Similarly, facilities which prepare
syringes or syringe shields may assist in distinguishing radiopharmaceuticals from generator eluates, often hospital
between different radiopharmaceuticals. Radiopharmacy radiopharmacies, are responsible for testing the eluates prior
management software often uses bar codes to identify vials to use. While 99Mo breakthrough can easily be tested using a
containing generator eluates, radionuclides or radiopharma- lead pot which attenuates the 140 keV gamma photons from
ceuticals, and doses dispensed for specific patients.87 99m
Tc in an activity meter93, this is not the case for all radio-
The limited number of incidents relating to diagnostic nuclide generators. Procedures for evaluation of 68Ge/68Ga
radiopharmaceuticals found in literature88-90, all addressed generators have been described.94-96 Breakthrough of 68Ge
microbiological problems, rather than radiation incidents. exceeding pharmacopoeial limits in 68Ga eluates has been
Regarding therapeutic radiopharmaceuticals, the SAFRON reported, especially in ageing 68Ge/68Ga generators97,98, but
system70 collects reports on safety-related events in radio- cannot be easily measured prior to use of the eluate.
therapy. Of the 24 reports logged under "radionuclide ther- Although the product can be released before completion of
apy" until May 27, 2021, 10 reports describe incidents due the germanium breakthrough test, retention samples of 68Ga
to misreading or failing to verify the prescribed amount of eluates or 68Ga-labeled radiopharmaceuticals should be mea-
radioactivity, selecting the wrong dose or exchange of doses sured after a delay of 24-48 hours to check the trend of 68Ge
for different patients, or not realizing that rescheduling the breakthrough as the generator ages.99
date of treatment would affect the activity of the ordered An interesting impurity is 177mLu present in 177Lu pro-
dose. In all these cases, the intended organ dose was duced by neutron activation of 176Lu.100 As the impurity has
exceeded. Two of the cases were reported as major, and one a longer half-life than the primary radionuclide (160 days vs
as a potentially serious incident. The high number of human 6.7 days), the percentage of the impurity increases as the
177
errors are ascribed to miscommunication, not following writ- Lu decays. Although the absorbed dose due to 177mLu is
ten instructions or protocols, and failure to attend to all the described to be negligible101, the impurity will affect waste
required checking steps. Clearly, radiopharmacy staff should management procedures.
carefully attend to the following points to ensure that the Radionuclidic impurities are closely linked with the pro-
appropriate radiopharmaceutical and dose are dispensed.91 duction method used to obtain a specific radionuclide. For
this reason, the Pharmacopoeia list different radionuclidic
 Check details on the request or prescription, including impurity limits for 99mTc obtained from 99Mo produced by
the patient's age and weight and the details of the neutron activation, by fission, or directly produced by an
requested procedure accelerator.
 Check that the correct kit, injection, or capsule is Radiochemical impurities in radiopharmaceutical products
selected generally have biodistributions that differ from that of the
 Verify the radiopharmaceutical details against patient intended radiopharmaceutical.93 This can affect interpreta-
details tion of diagnostic images and invalidate quantitative
 Verify the dispensed dose against the prescribed and results102 like measurement of radionuclide excretion or the
ordered dose standard uptake value in PET. In therapeutic radiopharma-
 Measure the dispensed activity with an activity meter ceuticals, even low percentages of radiochemical impurities
prior to administration. can lead to significant radiation dose to organs other than the
target, for instance the bone marrow, which can have serious
consequences for the patient's health.102
One of the quality parameters for radiopharmaceuticals is
Lack of Quality Control of Products that the amount of radioactivity, frequently called "dose" in
A wide range of quality tests are prescribed for radiopharma- the pharmaceutical context, should be measured and not
ceutical products. For the current discussion, the focus will deviate more than a specified percentage from the prescribed
remain on the parameters that affect the radiation dose or intended amount. Note that pharmacopoeial monographs
directly, that is, radionuclidic and radiochemical purity, and for diagnostic radiopharmaceuticals set content limits at
the measurement of radioactivity. between 90% and 110% of the declared radioactivity at the
Both for diagnostic and therapeutic purposes, it is critical time and date stated on the label, for example, International
that only the relevant radionuclide is administered, without Pharmacopoeia monograph for pertechnetate103, USP mono-
any radionuclidic impurities. Impurities can add to radiation graphs for Sodium Pertechnetate 99mTc Injection and USP
18
exposure of individual organs or the effective dose due to F-FDG Injection.195 For therapeutic radiopharmaceuticals,
longer half-lives and unwanted emissions, such as beta emis- the IAEA recommends stricter tolerance levels, less than 5%
sions in diagnostic imaging products. For most radionu- deviation from the prescribed administered activity.29 In fact,
clides, the manufacturer is responsible for ensuring this is technically achievable, if the activity meters are prop-
radionuclidic purity. Cyclotrons with accompanying radio- erly and accurately calibrated.104,105,106,107,108,109 It is also
chemistry facilities that are located in hospitals, and do not important for any radiopharmacy to be aware of the
 ARTICLE IN PRESS
Radiation safety and accidental 9

minimum activity that a measuring instrument can reliably In addition to patient-related considerations, any patient
quantify.110 Diagnostic Reference Levels should be estab- exposure should not be considered fully justified if it is not
lished in terms of administered activity for every specific performed using medical devices that are properly installed,
facility based on national or international guidance99,111,112, maintained, correctly calibrated and regularly subjected to all
taking into account the available equipment and patient char- QA/QC procedures aimed to confirm their optimal working
acteristics.29 Incorrect use of activity meters (often called status.
dose calibrators), for example, selection of an incorrect radio- In diagnostic NM procedures, effective doses from the
nuclide calibration factor, or failure to perform regular testing administration of radiopharmaceuticals are typically in the
of the instrument, including stability tests and calibration68, range of 1-10 mSv. A quick assessment of the effective doses
can lead to administration of too much or too little activ- and organ doses for most radiopharmaceuticals can be
ity.113 If the administered activity is too low, the image qual- obtained using published factors.117,118
ity may be sub-optimal, impeding the diagnostic process, The scenario is made more complex by multi-modality
and in extreme cases requiring repetition of the entire study, procedures. The effective dose due to the CT component of
which means that the patient receives unnecessary radiation multi-modality studies can vary over approximately two
exposure and diagnosis is delayed. Exceeding acceptable tol- orders of magnitude, depending on the type of NM proce-
erance levels of the recommended dosage should be reported dure, the volume of the body irradiated by the transmitted
as a misadministration causing excessive radiation exposure. beam and by whether the CT component is simply for atten-
For therapeutic radiopharmaceuticals, errors in both direc- uation correction or anatomical localization, or a full diag-
tions have more serious consequences for the patient. nostic scan is required.119 As an example, in cardiac SPECT-
In some cases, doses are scaled for the specific patient. CT a transmission scan, typically of short duration, is per-
This is especially important for pediatric patients and recom- formed for attenuation correction, with an effective dose
mendations for pediatric dosages are available, for example, from the CT component of the order of 0.5 mSv. For a bone
the European Association of Nuclear Medicine (EANM) dos- SPECT-CT scan in which a diagnostic spot CT acquisition is
age card.114,115 Radiopharmacy staff and NM physicians performed on a single field of view, in addition to attenuation
should be familiar with the calculation methods and mini- correction, the effective dose from the CT component
mum recommended doses. Doses may have to be adapted increases to 6-7 mSv.120-123
depending on the imaging or study protocol. In PET-CT scans with 18F-FDG, probably the most com-
The last version of the IAEA Basic Safety Standards116 mon practice is to perform a CT for attenuation correction
introduces a relevant novel adjustment compared to previous using a tube current just above the minimal level, to obtain
editions: calibration and QA/QC of medical equipment are images that allow proper navigation in the CT data set, and
clearly seen as components of patient safety and of optimiza- accurate localization of the emission data. The effective dose
tion of protection. This is a relevant improvement in the per- due to the CT component used in this way is of the order of
ception of QA/QC: while in the past these activities were 4-5 mSv. If a fully diagnostic CT scan is performed, in an
seen as necessary, due to legal obligation, now their function optimized context the effective dose can rise to an order of 7-
in the process of ensuring patient safety and optimization of 8 mSv; but if all of the available tools for dose reduction
radiation protection is evident. In other words, QA/QC and (tube current modulation, beam collimation, iterative recon-
calibration are not simply to comply with legal requirements, struction, etc) are not used properly, the effective dose for
but they are included in legal requirements because they are the CT component can easily be double and even
necessary! In NM this involves all types of scanners, probes higher.120,124,125 Training of CT scan operators in the appli-
and radionuclide activity meters. cation of dose saving systems is of utmost importance to
ensure that examinations are performed optimally.

Exclusion of Pregnancy/Justification of Use

Patient Risks and Incidents in
in Pregnancy
Diagnostic Procedures While administration of diagnostic radiopharmaceuticals to
The justification of a NM examination for a specific patient pregnant females should be avoided, there are instances in
requires the involvement of both the referring physician and which the benefit of a diagnostic procedure can outweigh the
the NM physician: the first knows the patient, his or her clin- low risk of radiation exposure of the embryo or fetus. Such
ical history and context, while the second has the advanced cases must be justified, and the selection of radiopharmaceu-
knowledge of the procedure to be performed, including the tical and reduction of the administered dose can assist in
choice of radiopharmaceutical and the optimal acquisition keeping the radiation exposure as low as possible.91 Informa-
technique. The referral for a NM procedure should be con- tion about the exposure of an embryo or fetus from different
sidered more as a request for a professional consultation with radiopharmaceuticals at different stages of gestation is avail-
the specialist, rather than an order to perform. The joint able.29,125-128 It should be noted that termination of preg-
commitment of both the referring physician and the special- nancy would not be warranted after administration of
ist allows assessment of the appropriateness of a procedure diagnostic NM procedures as the dose to the embryo/fetus
for the specific patient.116 would be substantially less than 100 mGy.127 Pregnancy in
 ARTICLE IN PRESS
10 M. Marengo et al.

the use of therapeutic radiopharmaceuticals is discussed else- Factors that can Lead to Radiation Incidents
where in this article. A recent paper by Martin et al68 discussed the prevention of
unintended exposures in NM, taking the cue from the so-
called Bonn Call-for-Action139, of which one specific action
was to ‘Improve prevention of medical radiation incidents
Lactating Patients and accidents’, as well as from recent IAEA guidance.29
Language barriers and literacy can contribute to radiation Table 1 reports, with some integration and updates, the
incidents. A case report describes excretion of 131I in milk analysis made by Martin et al on the possible causes of errors
which almost led to an incident after a patient received a leading to sub-optimal imaging procedures or even to inci-
therapeutic dose of more than 5000 MBq 131I-NaI.129 The dents.
patient came from a rural area, and had brought her baby, Errors can be introduced in almost any step of the imaging
whom she was breast feeding, with her to the hospital. Staff process.
in the therapy ward looked after the baby while the patient Nevertheless, incidents do not occur frequently and a
was in an isolation room. The patient, however, did not study of radiation incidents reported through an internal sys-
understand the main languages used in the hospital very tem over a period of 13 years, found that the frequency at
well, and probably also did not understand the need for sepa- which patient unintended medical exposures occurred was
ration from her baby. During her isolation period, she left her about one in every 3500 procedures and the doses received
room to find her baby, which she had heard crying. Luckily, were relatively low. 80% of the NM patient unintended expo-
ward staff intercepted her and managed to convince her that sures resulted in effective doses less than 10 mSv and in 33%
the baby was well looked after. the effective dose was less than 1 mSv.38 An exposure giving
A further incident illustrates the need for giving clear an effective dose of 10 mSv might have an associated excess
instructions to referring clinicians and checking that they are lifetime risk of cancer incidence of 1 in 2000 if the risk coeffi-
understood by patients. Another example is where a NM cient is applied for a population of all ages.140 Risks from
department only discovered that a patient was breastfeeding exposures between 1 and 10 mSv are described as very low
her 9-month-old baby 48 hours after injection of a dose of and those for effective doses between 0.1 and 1 mSv are con-
67
Ga-citrate. The checkbox to indicate breastfeeding had not sidered minimal.141,142 Unintended medical exposures from
been crossed on the request form, and as the woman was an which the risks of stochastic effects are minimal still need to
in-patient, NM staff did not realize that she had the baby be followed-up, especially if they involve exposure of multi-
with her in the ward. Breastfeeding was immediately ple patients. Incident reporting systems, as previously
stopped, and the baby was treated with laxatives. The com- noticed, are an effective tool in this context, for classifying
plex estimation of the radiation exposure of the infant is incidents, investigating causes and learning from previous
described in a report by Rubow et al.130 experiences, in a pro-active, no blame work environment.
Administration of radiopharmaceuticals to lactating patients The use of effective dose allows the risks to be put into
has three radiation safety consequences: 1) the ingestion of context and compared with exposures from other sources
radioactive milk would render an unwanted radiation dose to such as natural background radiation or cosmic ray exposure
the baby131, 2) the baby would be exposed to radiation from from air travel, but NM staff dealing with specific radionu-
the mother through close contact during breastfeeding or caring clides may find the injected activity to be a more meaningful
for the baby, and 3) the accumulation of the radionuclide in the alternative for internal communication. The use of effective
milk glands would contribute to exposure of radiation-sensitive dose provides a method for giving an indication of detriment
breast tissue. Guidelines for interruption or cessation of breast- from small exposures, but it applies to a reference person
feeding, including expression of milk prior to and during an and is derived from risks averaged over a whole population.
interruption, have been published.29,39,132,133 Briefly, both the When the excess effective dose is much greater than 10 mSv
excreted radionuclide in the milk and the close contact dose a full evaluation of risk for an individual of the same age and
from the mother should be taken into account. Depending sex using doses for individual radiosensitive organs and tis-
on the radionuclide and radiochemical form, breast-feeding sues may be appropriate.142 Conditions vary throughout the
can either continue, be interrupted for a period, or should world as to whether an unintended exposure is regarded as
cease entirely before the radiopharmaceutical is administered. clinically significant, as do requirements for reporting of inci-
For any therapeutic radiopharmaceutical, as well as for diag- dents to the competent authority.
nostic 131I-NaI, 67Ga-citrate and 201Tl-chloride, timely cessa- Naddaf et al reviewed technical errors in planar bone
tion of breast feeding prior to the NM procedure is imaging, showing examples of degradation in image quality
recommended.133-135 The case of radiosynovectomy is not due to selection of the wrong collimator, image matrix size
explicitly considered in Appendix III of IAEA Safety Stand- or energy peak selection.143 A variety of papers have dealt
ards SSG-46.29 A recent study recommended interruption of with errors and pitfalls in myocardial perfusion imaging. The
breastfeeding for a period of at least one month, that substan- role of proper QA/QC and accurate calibration of SPECT
tially means termination, following treatment with 90Y.136 cameras has been shown to be fundamental in order to avoid
Allowing sufficient time for weaning will reduce accumulation artifacts.144 The increased use of gated SPECT, as a more techni-
of milk in the breasts and the associated radiation exposure cally demanding procedure, introduced the possibility of further
of radio-sensitive breast tissue.137,138 technical errors in the gating procedure and synchronization145,
 ARTICLE IN PRESS
Radiation safety and accidental 11

Table 1 Possible Causes of Errors Leading to Sub-Optimal Imaging Procedures or Radiation Incidents, Modified Form the Paper
of Martin et al 201968
Component of the
Process Possible Errors

Gamma camera setup  Wrong collimator / selection of radionuclide / scan duration / matrix size or other acquisi-
tion parameters
 Omitted or inadequate daily QC tests leading to sub-optimal performance of the system
(eg, poor uniformity) or missed detection of faults (eg, a photomultiplier tube not working)
PET scanner setup  Incorrect daily QC procedure (eg, detector block is not working)
 Wrong scan protocol
Multi-modality scans  Wrong or poorly optimized CT protocol selected
 CT study quality unjustifiably too high
In all NM imaging modes  Sub-optimal balance between acquisition time and administered activity that ultimately
determines image noise levels (count statistics)
System calibration  Omitted or outdated calibrations of a SPECT system (eg, energy, linearity, uniformity,
centre of rotation) resulting in poor image quality
 Omitted or outdated calibrations of a PET system (eg, uniformity, cross- calibration
between the activity meter and the PET scanner) resulting in poor image quality or inaccu-
rate standardized uptake value (SUV) results
 Omitted or outdated calibrations of gamma cameras and / or in vivo counting systems,
eg, thyroid uptake counters.
Image reconstruction  Wrong reconstruction parameters
and display  Wrong image re-alignment / preparation / display
Mechanical safety  Patient has not been secured to the imaging bed
 Moving components of the scanner have not been checked
 Tools, furniture or other objects lie in the trajectory of motion

as well as in the quantitative analysis of data and images.146 prescription, radiopharmacy, administration, and technical
Moody et al reviewed myocardial PET-CT, the precision errors in imaging. In their review of the studies acquired in
and accuracy of blood flow measurements, and the pre- one year, they identify a frequency of about 7.5% for failings
cautions to avoid pitfalls and minimize quantification that can be classified as major, and of about 31% of
errors.147 minors.154 Such tools are of great relevance and will become
In a paper reporting some of the results of the IAEA proj- a necessary component in the optimization process.
ect I-MAP as regards auditing intra-operator variability in
reporting myocardial perfusion imaging (MPI) studies, it was
confirmed that several factors, in different phases of the pro-
cedure, might influence the final results of MPI studies, and Risks and Incidents in
require scrutiny. They include pre-examination checks, such
as appropriateness of prescription, QA/QC of equipment and
Radionuclide Therapy
radiopharmaceutical preparation, preparatory steps taken Radionuclide therapies involve mostly radionuclides emitting
during the examination, such as QA/QC of acquisition b- or a-particles, which can kill or control proliferation of
parameters and of processing, and reporting.148 cancer cells, with limited radiation dose to healthy tissues,
The field of PET-CT imaging is also prone to pitfalls and and have been successful in the treatment of a variety of
artifacts that can potentially lead to errors in diagnosis. benign and malignant diseases.155 Nevertheless, the risk of
Alotaibi et al recently reviewed a cohort of 4099 whole damage to normal tissues cannot be completely excluded
body 18F-FDG scans and found 123 errors (2.2%), but even and incidents have been reported.
if relatively infrequent, the number of errors is not negligi- Misadministration and extravasation in the case of radio-
ble.149 Common pitfalls and causes of image misinterpreta- nuclide therapy carry the potential for deterministic effects.
tion in 18F-FDG PET-CT have been discussed in a variety of
papers150,151, and increasingly with other tracers, for
instance in the field of prostate specific agents.152,153 Extravasation of Therapy Radionuclides
Keenan at al. presented a method of periodical technical Chojnowski et al reported four cases of mild radiodermatitis
review, consisting in the re-analysis of all acquired studies by in over 2000 treatments of persistent joint inflammation with
188
experienced NM technologists, searching for any eventual Re (incidence <0.2%)156; while Jacob et al reviewing
error in all phases of the process: request/order, organization, experience with 90Y synovectomy in the management of
 ARTICLE IN PRESS
12 M. Marengo et al.

chronic knee arthritis at one centre, observed two cases of of the staff and disturbing or even disrupting operation of a
skin ulceration and three cases of minor pigmentation at the NM department.
injection site, in a total of 38 knees treated in 28 patients Reports on failures of delivery systems are collected in the
(incidence 13.2%).157 database of incident reporting of the Nuclear Regulatory
Extravasation during intravenous administration of beta Commission of the United States.173
emitters has a high probability of causing deterministic Several involve failure to administer the full planned activ-
effects in the skin or pain in the patient`s arm; and a number ity in treatments with 90Y micropsheres, and recent examples
of examples have been reported for therapy using 90Y-ibritu- report under-dosages by 34.5% and 61.5%, due to stasis or
momab tiuxetan158,159, 90Y-DOTATOC160, and 89Sr.161,162 adeherence in tubing or catheters (NRC Event Numbers:
Extravasation incidents involving iodinated molecules have 54967, 2020 and number 53879, 2019).
also been reported. Delayed NM images proved to be useful In a case of intravenous administration of an investiga-
in dosimetric assessment for a therapeutic dose of 131I-meta- tional drug, 131I-apamistamab (Iomab-B), during a Phase 3
iodobenzylguanidine and a protocol of controlled catheter trial, only 53% of the prescribed value was administered, due
placement was adopted to prevent similar occurrences.163 to leakage from tubing (NRC event number 55142, 2021),
For the administration of 223Ra dichloride, Wright et al sug- while in a treatment with 153Sm-EDTMP the patient received
gested an image acquisition be made immediately after injec- only 4% of the prescribed dose as most of the radiopharma-
tion to exclude extravasation given the potential risk from an ceutical leaked out through a crack in the locking assembly
alpha emitter.164 A report on a skin lesion following adminis- of the IV tubing connection (NRC Event Number: 53847,
tration of this alpha emitter165 does not clarify whether the 2019).
event was actually an extravasation or a result of skin con- Leaks in the delivery systems can also result in contamina-
tamination, since the patient refused to undergo any verifica- tion of the patient's skin, that may not be easy to identify, as
tion imaging. The International Commission on Radiological in a case of administration of 131I-MIBG for a brain tumor,
Protection (ICRP) recommends that therapy patients should where the contamination went undetected until the patient
be monitored for extravasation during infusion and the infu- developed erythema (NRC Event Number: 53430, 2018).
sion halted immediately in the event of extravasation.155 Some incidents can be caused by unforeseen circumstan-
Although there is no specific treatment for extravasa- ces: for example, an administered therapeutic dose of 131I
tion, ICRP suggest that local hyperthermia, elevation of was delivered to a patient through a gastrostomy feeding
the extremity, and gentle massage may promote spreading tube (g-tube), but most of the administered 131I activity
of the radiopharmaceutical and reduce the local absorbed remained in the wrong portion of the g-tube, resulting in an
dose.155 Basic prevention and mitigation actions have underdose to the patient’s thyroid, and a significant unin-
been included in updated EANM procedure guidelines tended dose to the patient’s stomach.174
for treatment of metastatic prostate cancer with 223Ra166, There are also specific risks associated with oral adminis-
as well as in the Society of Nuclear Medicine and Molecu- tration of therapeutic radiopharmaceuticals such as 131I cap-
lar Imaging procedure standard for somatostatin receptor- sules or solution. In these cases, a variety of problems that
based peptide receptor radionuclide therapy with 177Lu- can be generated by the patient him/herself in the ingestion
DOTATATE167; similar recommendations for treatments of the product.
have not been common in the past, with the exception of There are several reports of errors in cases in which the
90
Y-radiolabelled ibritumomab tiuxetan.168 It is to be prescribed activity was given to the patient in two capsules
hoped that the future updates of guidelines for both instead of a single one. Examples are a case in which the
international bodies and major scientific societies, will patient may have assumed that only one was to be taken,
systematically consider the problem of extravasation of and that the second was the result of an error by a second
therapeutic radiopharmaceuticals and provide precise staff member assisting in the administration. In another the
indications. Several recent reports on 177Lu extravasation patient may inadvertently have swallowed only one of the
have shown that, when timely actions, such as suction, two capsules, leaving the second stuck on the container
local heating, massage or exercise were taken, severe con- (NRC Event Number: 55208, 2019).
sequences and complications could be avoided.169-172 Contamination incidents may occur if the patient is unable
to swallow a capsule and spits it out, or if he or she coughs
or sneezes at the time of ingesting iodine solution175,176, or if
Misadministration of Therapy Radionuclides an uncooperative patient does not follow instructions.
The incorrect use or malfunction of delivery systems or devi- One case reported in 2017, that lead to wide-spread con-
ces used in the administration of radiopharmaceuticals to tamination, involved an adolescent patient who received a
patients creates another potential risk. These problems may 1.1 GBq capsule of 131I; secretly, taking advantage of going
result in significant differences between the planned activity to the bathroom, the patient spat out the capsule and kept it
and the one actually administered, producing either an hidden in his hand. During the time needed to understand
under-treatment and reduction of clinical efficacy and ther- what had happened, staff moved the patient to several differ-
apy response, or an unjustified increase in absorbed dose ent rooms, to investigate the reason for the abnormal radia-
(over-treatment). Additionally, they can lead to radioactive tion background, with the result that virtually the entire
contamination, affecting the radiation protection of patients, department was contaminated, including the SPECT-CT and
 ARTICLE IN PRESS
Radiation safety and accidental 13

PET-CT diagnostic rooms. This resulted in the department safety instructions given to the patient prior to discharge can
being closed down in order to decontaminate properly, with be fundamental in controlling and reducing the exposure of
interruption of the service (NRC Event Number: 52514, childern to ionizing radiation in the family context.185
2017). In the case of pediatric patients treated with 131I-MIBG,
most studies published in recent years report effective doses
to caregivers in the range 0.2-9 mSv, with an average level
below 2 mSv186,187, but at least one article quotes a wider
Radiation Protection of Caregivers, Family range of dose values up to about 20 mSv.188
Members, and Work Colleagues Instructions on precautions given to patients on leaving
People, who share accommodation with a relative who has hospital will include recommendations on the delay before
been treated as a patient with radionuclide therapy, or who the patient returns to work, which should take the patient’s
work closely with such individuals, may be exposed to risks work environment and their proximity to others into consid-
of both external exposure and contamination from body flu- eration.
ids. They will be less aware of potential risks and unfamiliar Someone working largely in isolation, for example, an
with the precautions that need to be taken when dealing agricultural worker, can return to work earlier than someone
with radioactive liquids. Therefore, criteria need to be estab- working in close proximity to others, for example, in a small
lished for hospitalization and release of therapy patients and office or on a production line.
these should aim to ensure that the effective doses that mem-
bers of the public in general might receive are less than the
dose limit of 1 mSv/year and preferably below a DC of per-
haps 0.3 mSv. Pregnancy and Radionuclide Therapy
Carers and comforters who may be in close contact with Therapeutic radiopharmaceuticals should not be adminis-
an individual patient can be treated as a special case to tered to pregnant women, and patients should be reminded
whom a source-related dose constraint of a few mSv per epi- of the importance of avoiding pregnancy for a period of time
sode may be applied, with the consent of the person after radiopharmaceutical treatment.29
involved.116 Reports of incidents involving the administration of thera-
The ICRP recommends an effective DC of 5 mSv per epi- peutic radiopharmaceuticals to a pregnant patient can be
sode of treatment for informed caregivers140, excluding chil- found in the IAEA SAFRON database70, in the records of
dren and pregnant women for whom the constraint remains events of the United States Nuclear Regulatory
at the level of the dose limit for the general public of 1 mSv. Commission189,190, as well as in the literature.191-195 Most
Recommendations given by the European Union177 are artic- relate to administration of 131I, either an ablative dose in
ulated as a function of age: a DC of 1 mSv applies to the treatment of cancer, or for treatment of hyperthyroidism, but
embryo, fetus and children up to 10 years; from 10 to a recent report discusses a patient treated with 177Lu.196,197
60 years a constraint of 3 mSv is suggested, while for adults In several cases, patient did not follow instructions, and did
older than 60 years the DC is set at 15 mSv. However, it is not discover that they were pregnant until after the therapy
not expected that the DC of 3 mSv is applicable when com- had been administered.
forting very ill in-patients, such as in the case of mothers tak- Appropriate preventative measures are only possible if the
ing care of hospitalized children. pregnancy is known. Clear signage requesting female patients
Specifying the appropriate length of hospitalization and to report pregnancy to a staff member prior to administration
patient discharge strategy, should take into account the of a radiopharmaceutical should be posted in NM depart-
patients' wishes and lifestyle, socioeconomic conditions ments. Not all patients may be able to understand such sign-
and their ability to comply with radiation protection age, for instance in a multilingual country where a large
instructions.178,179 In some cases, treatment is possible both percentage of the population does not have adequate com-
on an inpatient and outpatient basis, requiring specific radia- mand of the main language(s) or is illiterate, so an additional
tion precautions; Levart and colleagues discuss this situation illustration can be valuable. Lee et al suggest that serum preg-
in the case of treatment of neuroendocrine tumors with nancy tests should be carried out on all female patients in
177
Lu-DOTATATE.180 their reproductive years scheduled for NM procedures that
The effective dose to relatives and caregivers of patients treated could result in exposures to the uterus exceeding 1 mSv.198
with 131I for thyroid cancer has been studied by external mea- If radiation exposure happens in the first three weeks of
surement with TLD dosimeters as well as environmental dosime- pregnancy, the risk for the fetus is considered negligible.
try. Typical results are well blow 1 mSv.181-183 A detailed study During organogenesis, there are small risks that whole body
with stratification of patients in groups taking into account fetal doses above a threshold of 100 mGy may result in mal-
socio-economical conditions, showed that while the general formations, growth restriction, and reduction of IQ, although
average of the dose to members of the family was <1 mSv, in it is unlikely these dose levels will be reached. However, the
the group with the less adequate facilitiess the average value was major risk with 131I is that the radionuclide will accumulate
of the order of 3 mSv.184 in the fetal thyroid with a risk of ablation.
When children and adolescents are in contact with 131I- If the pregnancy is discovered within a few hours of the
therapy patients after release, the role of detailed radiation administration and the fetus is at the stage of having a
 ARTICLE IN PRESS
14 M. Marengo et al.

functional thyroid, blocking uptake using potassium iodide Dealing with Incidents When
may be considered, but will only work in the early stages.155 They Occur
Fetal and neonatal hypothyroidism due to in utero 131I
exposure may require lifelong thyroxine replacement ther- Incident Reporting and Investigation
apy. Furthermore, exposure to radiation in utero may The IAEA Basic Safety Standards require that licensees shall
increase the lifelong risk of cancer for the newborn.29,140 ensure that all practicable measures are taken to minimize
the likelihood of unintended or accidental medical exposures
arising from flaws in design and operational failures of medi-
The Risk of an Error in Dosimetry cal radiological equipment, from failures of and errors in soft-
An important, even if not always fully considered risk in ware, or as a result of human error.116
radionuclide therapy procedures, is related to the potential The first requirement is that organizations have an estab-
errors of internal radiation dosimetry calculations, used for lished system for reporting any radiation incident throughout
planning the treatment.155 an organization.68,205,206 This may cover all types of events
Currently, accurate dose assessments are included in an or be devoted simply to radiation incidents, but must be sup-
increasing number of treatments such as, but not limited to, ported by management and supported by all staff, as being an
177
Lu-PSMA, 90Y or 166Ho microspheres, 131I-mIBG for neu- important element in quality improvement. Moreover, it
roblastoma, and 131I-NaI for benign thyroid diseases199; must be operated through a no blame culture to ensure that
however, wrong therapeutic activity prescriptions resulting staff have no fear in acknowledging when events occur. The
from inaccurate dosimetry calculations, may produce a lim- system should also have appropriate categories to cover the
ited response in the tumor or target volume and/or generate range of incidents that might occur and a method of classify-
unexpected radiotoxicity in normal organs. ing them in terms of severity, which will often be in terms of
Root causes for under- or over absorbed dose estimations a dose quantity such as effective dose. This is likely to deter-
have been typically related to a lack of well-established meth- mine whether an incident needs to be reported to regulatory
ods for activity quantification and dosimetry assessments, authorities.
and also to the non-availability of suitable means or tools to When an incident is reported local staff should undertake
perform accurate and reproducible dose estimations. an initial investigation immediately to assess the consequen-
It was shown that the estimated absorbed radiation dose ces for the patient(s) affected and provide any additional
from 90Y ibritumomab tiuxetan for the treatment of B-cell healthcare necessary, record information about the exposure
lymphomas, was underestimated due to methodological together with any error codes or unusual signals, and provide
problems mainly associated with activity quantification. This a preliminary report on the incident to the service manager.
resulted in a poor relationship between absorbed dose and The adoption here of an open “no blame” approach is partic-
response, both in terms of treatment efficacy and toxicity.168 ularly important for identifying root causes and contributory
Other studies have shown the relevance of methodological factors, not to report the culprit.
aspects in avoiding under or over estimation of absorbed Any corrective medical actions that are required to mini-
doses during the treatment of neuroendocrine tumors with mize the effects should be undertaken immediately and indi-
177
Lu DOTA labeled peptides.200,201 viduals identified who have responsibility for this. When
Errors on dose estimations are also associated with specific required, counselling of any patient involved in a medical
technical issues during the different steps of the dosimetry exposure incident should be undertaken by an individual
calculations.155 with appropriate experience and clinical knowledge.
In radioembolization of surgically unresectable primary The reporting, investigation, and follow-up are crucial in
and metastatic liver tumors with 90Y, doses differing from incident management, in building the capacity to prevent
those planned could be delivered due to variations in the incidents, and enabling staff to react appropriately when an
catheter position during the baseline angiogram with 99mTc- incident does occur.207-209 But in order to gain commitment
Albumin Macroaggregates (MAA), and the second angiogram of everyone, staff should be debriefed following an incident
during microsphere injection.202 The role of the tumoral vol- about contributory factors and any changes made to mini-
ume of interest delineation using the MAA SPECT/CT images mize risks in the future.
versus CT segmentations has been evaluated and described The wider dissemination of information about radiation
as a key aspect to deliver appropriate treatments and avoid incidents and radiation injuries where appropriate can be
unexpected results.203 useful in order to raise awareness and alert others to risks.
In general terms volume delineation and tumor or target An example of a system for this is the SAFRON reporting sys-
volume and mass must be accurately defined in calculations tem operated the IAEA which includes radionuclide therapy
to enable appropriate treatment planning during radionu- exposures and allows the sharing of experiences among
clide therapy. Currently, much research work is devoted to users.70,71
the analysis of sources of uncertainty, and to the techniques
necessary to reduce these uncertainties in dosimetric calcula-
tions. This is in fact a necessary prerequisite in order to guar- Incident Prevention
antee better safety and efficacy of treatments with Problems that could lead to an accidental exposure can be
radionuclides.155,204 reduced through the adoption of a strategy that includes the
 ARTICLE IN PRESS
Radiation safety and accidental 15

regular maintenance and calibration of radionuclide imaging leading to an unintended exposure, staff must recognize their
and measuring equipment and software. There should be a role in dealing with it and reporting through an agreed sys-
comprehensive programme of QA, continuing education and tem at the earliest opportunity. This will provide a route
training of staff, and the promotion of a safety culture involv- through gradual improvement to ensure a high-quality
ing awareness and analysis of all the processes involved. The nuclear medicine service is provided.
IAEA Safety Guide SSG-46 lists measures to minimize the
likelihood of unintended events that might lead to medical
exposures.29
NM is a complex process that requires specialized facilities
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