The primary objective is to determine which of two commonly used drugs for preoperative management provides the best intraoperative hemodynamic control in patients undergoing resection of a PCC. Secondary Objective(s): o to identify other…
ID
Source
Brief title
Condition
- Adrenal gland disorders
- Endocrine neoplasms benign
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The main study parameter is defined as the number of patients demonstrating
more than three intraoperative episodes of 5 minutes with blood pressure
outside the predefined target range after pretreatment with either
phenoxybenzamine or doxazosin.
Secondary outcome
o success rate of doxazosin and phenoxybenzamine to attain preoperative blood
pressure target values without co-medication
o resolution of (paroxysmal) symptoms and signs
o need for additional antihypertensive agents
o adverse effects of study medication
o length of preoperative period with use of study drugs in either outpatient
or inpatient clinic
o distribution frequency of germline mutations associated with PCC
o control of blood pressure and heart rate a. during surgery: b.
postoperatively during stay at intensive or medium care (at least 24 hours)
- number of episodes with systolic blood pressure (SBP) > 160 mmHg
- number of episodes with mean arterial blood pressure (MAP) < 60
mmHg
- duration (in minutes) of SBP > 160 mmHg
- duration (in minutes) of MAP < 60 mmHg
- number of episodes with heart rate > 100/min
- duration (in minutes) of heart rate > 100/min
- amount and type of vasoactive agents needed during surgery for
adequate blood pressure control
- cumulative amount and type of intravenous fluids administered
o length of postoperative stay at intensive/medium care unit
o length of hospital stay
o composite semi-quantitative score of intra- and postoperative hemodynamic
control based on the following parameters:
- blood pressure and heart rate outside target range
- need for administration of vasoactive agents
- need for administration of intravenous fluids
o measurement of NT-proBNP levels before PCC resection
o postoperative hypoglycaemia: frequency and severity (in mmol/L)
o perioperative mortality (i.e. death from any cause occurring during period
from first administration of study medication until 30 days after surgery)
o perioperative cardiovascular morbidity, i.e. cardiovascular events
occurring during period from first administration of study medication until 30
days after surgery. Cardiovascular events are: myocardial infarction, cardiac
arrhythmia requiring medical intervention, heart failure, cerebrovascular
ischemia, cerebrovascular haemorrhage
o composite endpoint of perioperative mortality and perioperative
cardiovascular morbidity
Background summary
Pheochromocytoma (PCC) is a rare but clinically important catecholamine
secreting neuro-endocrine tumour that typically arises from the adrenal gland.
In addition, this neuro-endocrine tumour can also originate from chromaffin
cells in sympathetic ganglia. In the current study protocol, PCC refers to both
adrenal and extra-adrenal chromaffin tumours with hypersecretion of
catecholamines (i.e. norepinephrine and/or epinephrine). Data on the incidence
and prevalence of PCC in the Netherlands have not been published. Based on the
Dutch registry of pathology diagnoses (PALGA), we found an incidence of 117
cases of PCC in the year 2007 (unpublished observation).
PCCs may occur as part of an autosomal dominant inherited tumor
syndrome, caused by germline mutations in the RET proto-oncogene (Multiple
Endocrine Neoplasia type 2 syndrome), VHL gene (von Hippel-Lindau disease),
NF1 gene (Neurofibromatosis type 1), or in one of the genes encoding the
subunits of mitochondrial complex II, also called succinate dehydrogenase
(SDHB, SDHC, SDHD). PCCs are termed *sporadic* when the family history for PCC
is negative. Recent studies, however, have demonstrated germline mutations in
one of the PCC susceptibility genes in a significant number of patients with a
sporadic PCC, with mutation rates varying between 7.5 - 14.6% in the
populations studied. Therefore, genetic testing is recommended in all patients
with PCC. Novel PCC susceptibility gene have recently s been described, and it
seems likely that future research will result in the discovery of other genetic
mutations associated with PCC.
PCC constitutes a surgically curable cause of hypertension.
Hypertension in patients with PCC can be either persistent or paroxysmal, but
is absent in a minority of patients. It is a potentially life-threatening
disease with a high risk for cardiovascular complications such as myocardial
infarction, arrhythmias, cardiomyopathy, stroke and pulmonary edema. The
clinical picture results from release of catecholamines by the tumour. This
release can be evoked by stimuli that would normally not pose a hazard, such as
surgery or general anaesthesia. Thus, preoperative treatment with
alfa-adrenoceptor antagonists is usually recommended for prevention of these
serious and potentially fatal complications.
Historically, the noncompetitive and nonselective alfa-adrenoceptor
antagonist phenoxybenzamine has been the drug of choice. Alternatively,
doxazosin - a competitive and selective*alfa1-adrenoceptor antagonist - might
be at least as effective as phenoxybenzamine with fewer side effects. Notably,
it has been suggested that doxazosin results in a significant and clinically
relevant reduction of postoperative hypotension. Severe postoperative
hypotension necessitates admission to the intensive care unit (ICU), where
volume resuscitation and norepinephrine are administered under strict
monitoring of hemodynamics. Data on the optimal preoperative pharmacological
management of patients with PCC are conflicting. Available studies thus far
have all been retrospective in design and suffer from several limitations in
methodology such as lack of randomisation, use of historical controls and non
standardized intraoperative care. Until now, prospective randomised controlled
trials comparing phenoxybenzamine and doxazosin have not been conducted. Thus,
the preoperative drug therapy of choice remains an unresolved issue, and at a
recent international PCC symposium it was concluded that no specific
recommendations can be made on this subject. We performed a survey among all
university medical centers in the Netherlands, showing that almost half of the
centers prescribed phenoxybenzamine, whereas the other centers used doxazosine
as the preoperative drug of choice for patients with PCC. Usually, these drugs
are administered during 2-3 weeks before surgery. This preoperative medical
preparation takes place either in the outpatient or inpatient clinic, depending
on patient-related factors (e.g. disease severity, geographical considerations)
and local experience.
Preoperative volume expansion is recommended in all patients with PCC.
The rationale behind this recommendation is based on the notion that PCC is
associated with a decreased intravascular volume, which is restored under
influence of treatment with alfa-adrenoceptor antagonists. Without
administration of volume expansion severe hypotension might ensue. Therefore,
it is common practice to advise a liberal salt intake during alfa-adrenoceptor
antagonist therapy and to administer a saline infusion (e.g. 2L NaCL 0.9% in 24
hours) shortly before surgery.
Several drugs, including certain anaesthetics, may evoke an
uncontrolled catecholamine release with resulting severe hemodynamic
instability. Patients are advised to carry a document enlisting all medications
which are contra-indicated in case of a PCC. There is no consensus on the
optimal anaesthetic management during resection of a PCC, as randomised
controlled trials on this subject are not available.
PRESCRIPT represents the first randomised controlled trial comparing
the effects of pretreatment with either phenoxybenzamine or doxazosin on the
intraoperative hemodynamic control in patients with PCC. In addition, PRESCRIPT
provides a unique opportunity to prospectively collect data containing detailed
information on items such as presenting symptoms and signs, perioperative
outcome and results of biochemical, imaging and genetic studies in patients
with PCC. Of interest, results of this study are expected to have a direct
impact on national and international guidelines regarding the perioperative
care of patients with PCC.
Study objective
The primary objective is to determine which of two commonly used drugs for
preoperative management provides the best intraoperative hemodynamic control in
patients undergoing resection of a PCC.
Secondary Objective(s):
o to identify other determinants of intraoperative hemodynamic control.
Potential determinants are: gender or age of the patient, clinical setting for
preoperative management (i.e. outpatient or inpatient clinic), preoperative
levels, of catecholamines or N-terminal pro-brain-type natriuretic peptide
(NT-proBNP) PCC size, sporadic or hereditary PCC,
o to describe prospectively symptoms and signs of PCC in a large cohort of
patients. Note: until now, data on symptoms and signs have been described
retrospectively
o to describe prospectively the results of several diagnostic techniques
o to assess prospectively the distribution of sporadic and hereditary PCC in a
large cohort of Dutch patients
o to build a biobank with blood and tissue samples for future studies on PCC
Study design
Randomised open-label controlled trial.
Intervention
Not applicable.
Study burden and risks
Participating patients are not exposed to any additional risks, as PRESCRIPT
merely compares the efficacy of two frequently prescribed alfa-adrenoreceptor
antagonists. In addition, diagnostic work-up and clinical management are almost
completely similar to current clinical practice, except for a limited number of
extra measurements.
Hanzeplein 1
Groningen 9700 RB
NL
Hanzeplein 1
Groningen 9700 RB
NL
Listed location countries
Age
Inclusion criteria
o age > 18 years
o diagnosis of benign PCC (adrenal or extra-adrenal, sporadic or hereditary)
- elevated plasma and/or urinary (nor)metanephrines
- localisation of PCC by anatomical (MRI/CT) and functional imaging (I123-MIBG scintigraphy or 18F-DOPA PET)
o planned for surgical removal of the PCC
o size of PCC on anatomical imaging =/ > 1 cm in diameter
Exclusion criteria
o age < 18 years
o malignant PCC, i.e. presence of lesions on imaging studies suggestive of distant metastases
o severe hemodynamic instability before surgery necessitating admission to intensive care unit
o pregnancy
o incapability to adhere to the study protocol
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2010-022417-25-NL |
| ClinicalTrials.gov | NCT01379898 |
| CCMO | NL33608.042.10 |