Clinical Trial Details
— Status: Not yet recruiting
Administrative data
NCT number |
NCT06065137 |
Other study ID # |
2023-5451 |
Secondary ID |
3265 |
Status |
Not yet recruiting |
Phase |
Phase 4
|
First received |
|
Last updated |
|
Start date |
October 31, 2023 |
Est. completion date |
October 30, 2025 |
Study information
Verified date |
September 2023 |
Source |
University Hospital, Antwerp |
Contact |
Nils Vlaeminck, MD |
Phone |
038215865 |
Email |
nils.vlaeminck[@]uza.be |
Is FDA regulated |
No |
Health authority |
|
Study type |
Interventional
|
Clinical Trial Summary
The goal of this clinical trial is to evaluate the safety and outcome of systematic drug
provocation testing with anaesthetics at therapeutic doses in adult patients undergoing
diagnostic work-up for perioperative hypersensitivity.
Description:
Perioperative hypersensitivity reactions (POH) pose a risk for major morbidity and mortality
in the perioperative period. After resolution of the initial reaction it is crucial to
determine the culprit drug to allow safe anaesthetics for future procedures.However this is
not easy, as many drugs are administered near simultaneously and both anaesthesia and surgery
may provoke or mask many of the symptoms of a hypersensitivity reaction. Conventional testing
seems to offer good predictive value based on the low incidence of POH in subsequent
re-exposures after negative work-up. Despite negative work-up anaesthetists often chose not
to re-administer an neuromuscular blocking agent (NMBA) used in the index reaction,
especially if no other culprit was found. This introduces an important bias as this group (no
culprit found, NMBA not re-exposed) might be at the highest risk of containing false
negatives as NMBA are the most frequent cause of POH in our region.The same remark can be
made regarding earlier attempts by our group and others at establishing the negative
predictive value (NPV) of conventional testing through retrospective analysis of subsequent
re-exposures.To truly establish the NPV for conventional testing and thus the need for DPT, a
prospective approach is needed where all patients are challenged with index drugs after
negative conventional testing.
Adult patients that are referred for diagnostic work-up for POH will be included if they have
a clinical history fitting with POH.
All patients will first receive a full diagnostic work-up for all index products consisting
of in vivo (skin tests) and in vitro (specific IgE and -for drugs in which it is available-
basophil activation tests). Clinical reactions (both index reactions and any reactions during
DPT) will be classified according to the National Audit Program (NAP-6) classification which
separates non-fatal POH in 4 grades:
- NAP 1 (only cutaneous/mucosal signs)
- NAP 2 (circulatory or respiratory symptoms which don't require treatment)
- NAP 3 (circulatory or respiratory symptoms which require treatment or potential airway
compromise)
- NAP 4 (fulfilling indications for cardiopulmonary resuscitation)
Skin tests will be performed at the allergology day clinic following the protocols of the
French Society for Anaesthesia and Intensive Care and the French Society of Allergology.
Based on these results we make a distinction between patients with an identified culprit and
those without an identified culprit.
If a culprit has been found, all other index drugs are challenged at therapeutic doses. The
standard testing is performed for alternatives for the culprit drug in the same drug class
(such as NMBA) and one drug from this class that tests negative is also used in a challenge
at a therapeutic dose.
If no culprit has been found after the initial work-up of skin tests and in vitro tests the
next step is determined by the severity of the initial reaction. In NAP-6 grade 1-3 reactions
all index drugs are challenged at therapeutic doses. As the benefits of DPT have yet to be
fully quantified the risk-benefit analysis in the most severe reactions (NAP 4) is difficult
to make. Hence, we use an 'confirmation by elimination' principle in these cases in which we
only challenge with the drugs that do not carry the highest likelihood of being the culprit.
This likelihood is based on both timing and epidemiology as NMBA are a much more common cause
of POH in our region than all other anaesthetics combined. By eliminating all other drugs we
'clear' them for future use and gain confidence in our suspicion of the most likely culprit
without having to administer them in this population.
Workflow:
- Negative in vitro (sIgE, BAT) and negative in vivo (skintests) tests for all index
products
- NAP 1-3: provocation tests for all index drugs
- NAP 4: confirmation by elimination: provocation with index products in order of
ascending likelihood so as to clear drugs unlikely to be the culprit and 'confirm' the
likely culprits such as NMBA without administering them
- Positive in vitro (sIgE, BAT) and/or positive in vivo (skintests) test for one or more
index products
- For the positive index products: sIgE, BAT and skintests for alternatives in same drug
class
- NAP 1-4: Provocation test for one safe alternative after negative tests
- For the negative index products:
- NAP 1-4: provocation test for index products Concurrently with the work-up for
anaesthetics, possible non-anaesthetic triggers (antibiotics, antiseptics, latex, …) are
investigated in the same sequence (first in vitro and in vivo tests, followed by DPT)
with provocations taking place in the allergology day hospital using the regular
standardized protocols.
DPT with anaesthetics take place in the OR or PACU under supervision of an anaesthetist. In a
first session hypnotics, benzodiazepines, opiates and/or NMBA's are administered in the PACU.
In this first session up to 1/10th of a therapeutic dose of NMBA's is administered while for
all other drugs we use a full therapeutic dose. In a second session that takes places in the
OR NMBA's are given up to a full therapeutic dose after induction -with anaesthetics that
have previously been deemed safe- and intubation.
Both in the OR and PACU all patients will receive standard monitoring according to the
American Society of Anesthesiologists which includes pulse oximetry, 5-lead
electrocardiography and non-invasive blood pressure measurements. During spontaneous
ventilation oxygen will be supplemented through a nasal cannula equipped with a gas sampling
line for capnography. Quantitative neuromuscular monitoring will be available in all cases
where NMBA are administered. All drugs for emergent treatment of any hypersensitivity
reaction (including adrenaline and vasopressors) and equipment for respiratory support will
be present for any provocation. Before the procedure is started baseline parameters are
established, the skin is investigated for rashes and the patient is asked whether they have
any respiratory or cutaneous complaints to establish a baseline. During the DPT the
circulatory and respiratory system as well as the skin and mucosa will be actively monitored
for signs of POH. If symptoms develop caused by a hypersensitivity reaction, the DPT is
suspended, prompt treatment according to current recommendations is initiated and tryptase is
sampled within the appropriate timeframe. The DPT is then considered positive. If no reaction
occurs, the DPT is considered negative.
Therapeutic doses are listed in the table below. In the first session doses are administered
in a stepwise approach every 15 minutes starting at 1/100th of the dose, followed by 1/10th
of the dose, 3/10th of the dose and ultimately 6/10th of the dose. After the last
administration of a drug a 60 minute interval is observed before moving on to the next drug.
After the last administration of the last drug the patient is observed for at least 60
minutes and until the usual PACU discharge criteria are met. For NMBA's the first session
ends after 1/10th of the therapeutic dose. If the provocation is negative, the patient is
planned for a second session under general anaesthesia where the NMBA will be administered at
3/10th of the therapeutic dose followed 15 minutes later by 7/10th of the therapeutic dose.
For each provocation a checklist will be available containing all information regarding the
drugs to be administered and their doses as well as drugs to be used in case of anaphylaxis
or need for emergency intubation.
Therapeutic dosis of anaesthetic drugs: full dose (1/100th-1/10th-3/10th-6/10th) (for NMBA:
1/100th-1/10th-3/10th-7/10th)
- Hypnotics
- Propofol 2mg/kg (0.02-0.2-0.6-1.2mg/kg)
- Ketamine 1mg/kg (0.01-0.1-0.3-0.6mg/kg)
- Etomidate 0.2mg/kg (0.002-0.02-0.06-1.2mg/kg)
- Benzodiazepines
- Midazolam 0.05mg/kg (0.0005-0.005-0.015-0.03mg/kg)
- Analgesics
- Fentanyl 1µg/kg (0.01-0.1-0.3-0.6µg/kg)
- Sufentanil 0.1µg/kg (0.001-0.01-0.03-0.06µg/kg)
- Remifentanil 0.5µg/kg (0.005-0.05-0.15-0.3µg/kg)
- Alfentanil 10µg/kg (0.1-1-3-6µg/kg)
- NMBA
- Rocuronium 0.6mg/kg (0.006-0.06-0.18-0.42mg/kg)
- Atracurium 0.5mg/kg (0.005-0.05-0.15-0.35mg/kg)
- Cisatracurium 0.15mg/kg (0.0015-0.015-0.045-0.105mg/kg)
- Succinylcholine 1mg/kg (0.01-0.1-0.3-0.7mg/kg)