Thoracic Aneurysm Clinical Trial
Official title:
A Randomised Controlled Trial of the Effectiveness of Acetazolamide in Reducing Cerebrospinal Fluid Pressure for Patients Undergoing Thoracic-abdominal Aortic Repair
The aorta is a large vessel that carries blood away from the heart. Sometimes it becomes
dilated (swells) and this is known as 'aneurysm'. It may cause either dissection (splitting
of the wall) or rupture (bursting).
Treatments could be through open surgery or by use of stents (tubular mesh) through the
groin. There is a risk of causing paraplegia, which is the loss/weakness of leg function as
well as incontinence (loss of bladder and/or bowel control).
To try and prevent this, a number of techniques are used such as removing/draining of
cerebrospinal fluid (CSF) (the clear fluid surrounding the brain and spinal cord).
Sometimes however;
- CSF cannot be drained
- drain cannot be inserted
- draining is unlikely to improve the situation
- Paralysis/weakness of the leg is seen
In these situations, the use of a drug called acetazolamide may be helpful. This reduces the
production of CSF and therefore decreases the need for CSF draining. It may also have an
effect in decreasing the risk of paraplegia.
Patients will be randomly (by chance) placed into one of two groups. One will get the drug
as tablets and injection and the other will not receive any acetazolamide at all. Blood
tests will be done in both groups. We expect to have 100 patients in the study, with patient
involvement for a total of 10 days (maximum).
Aortic aneurysms are classified according to the extent and position of the aorta involved:
thoracic aneurysms (TA), include the ascending or descending aorta within the thoracic
cavity, thoracic-abdominal aneurysms (TAA), involving the thoracic and abdominal aorta, and
abdominal aortic aneurysms (AAA, involving the abdominal aorta). The outlook for patients
with the most extensive aneurysms is very poor if treated medically with a 5 year survival
of 20%1. Intervention has been shown to significantly improve survival to greater than 70%
over 5 years 2. However, intervention comes with significant risk, with mortality between 3
and 40% and paraplegia between 5-20% dependent on the series1-2. Additional risks are of
renal and pulmonary failure requiring prolonged intensive care unit stays. However,
paraplegia remains of most concern to doctor and patient. Paraplegia is a consequence of the
tenuous nature of the spinal cord blood supply originating from the aorta. Interruption of
the blood supply during aortic repair is responsible for neurological dysfunction. Several
adjuncts have been developed to reduce this risk including sequential clamping, left-heart
bypass, evoked potentials, intercostal reattachment and cerebrospinal fluid (CSF) drainage-
all of which are employed at the Liverpool Heart & Chest Hospital. Drainage of spinal fluid
and reducing intracranial CSF pressure favours blood perfusion of the spine. In order to
perform CSF drainage a spinal drain is inserted in patients preoperatively. This process is
tightly regulated through the existing "Spinal Drainage Protocol" produced by the Trust.
Issues arise in the following scenarios:
1. A CSF drain cannot be inserted for technical reasons
2. The CSF is blood stained precluding use
3. Drainage per hour is outside of the protocol guidelines (>20mls/hr)
4. Intracranial Pressure (ICP) remains high despite drainage
5. There is neurological impairment (detection; clinical or Motor Evoked Potentials)
despite adhering to the protocol.
A hypothesis has been developed by the team that a drug called acetazolamide may be of use
when these scenarios are encountered. Acetazolamide (carbonic anhydrase inhibitor) is a
conventional diuretic but is also a drug used by travellers to counteract mountain sickness
and one of its effects is to reduce CSF production. A low-dose (250mg orally) of the drug
has been shown to be effective as a prophylaxis method in acute mountain sickness 3. Its
oral form has also been utilised to reduce shunt CSF volume in children4. Additionally,
Acetazolamide has been suggested as a 'first-line treatment' in Idiopathic intracranial
hypertension 9, 10. To date, we have used this drug intravenously in 7 thoracic-abdominal
patients, off licence, and had encouraging results (SEE APPENDIX 1) with a reduction of
intracranial pressure (ICP) in some but not all patients. At the moment however, this drug
is only licenced (approved by the Medicines and Healthcare products Regulatory Agency
(MHRA)) for use in glaucoma, epileptic patients and patients with abnormal fluid retention.
We hypothesize that the use of acetazolamide post operatively, in the 5 scenarios just
described, results in the reduction of CSF production and hence ICP. Following from this we
believe there was a reduced need for vasopressors and improved spinal cord blood perfusion.
Undoubtedly in some patients this drug has a dramatic effect on CSF production, ICP and the
need for drainage and vasopressors, all potential beneficial consequences. We do not know
however whether the drug works in all patients and whether there are consequences from the
other effects of this drug such as acidosis, hypercapnia or diuresis. In addition, we do not
know whether the drug is best given preoperatively, as a prophylactic measure, or whether
the preoperative treatment will improve the response to the intravenous postoperative dose.
In addition, we do not know whether these measures which intuitively should lower the risk
of paraplegia, actually translate into a lowering of this complication.
General hypothesis: Acetazolamide may safely be used as a preoperative prophylactic measure
(orally), as well as postoperatively (intravenous) as a treatment measure when the spinal
drain protocol is exceeded, to modify CSF production and reduce the risk of neurological
impairment as measured biochemically, spectroscopically, electrically and clinically.
This study cannot be powered to test for a statistical effect on clinically evident
paraplegia as its frequency in our institution is 5% thus at our current activity of 30
cases per year of TAA and ..??… cases of thoracic stents., the study would need to run over
5 years. The numbers are sufficient to demonstrate a significant change in the relatively
common end-points noted below. This study therefore serves to prove the utility of
acetazolamide in modifying factors we consider influential in the development of paraplegia.
Should this study prove positive we aim to roll out to an international multicentre study to
test for clinical effectiveness in reducing paraplegia.
Hypothesis
Acetazolamide reduces the following clinically relevant end-points:
1. Intracranial pressure recorded immediately after line insertion, throughout surgery and
post-operatively (only recordings post-operatively will be treated as an end-point)
2. Need to drain large quantities of CSF
3. Incidence of non-clinically evident paraplegia (measured by motor evoked potential
only)
4. Incidence of clinically evident paraplegia
5. The need for vasopressor drugs
6. Incidence of non-clinically evident neurological dysfunction (measured by microwave
technology)
7. Incidence of non-clinically evident neurological dysfunction (measured by CSF/serum
biomarkers)
Research Objective: The randomised trial aims to investigate the inhibitory properties of
the drug to decrease CSF production and reduce ICP, which would in effect decline paraplegia
risk induced by elevated ICP.
Study design: A single-centre, randomized, unblinded, controlled trial comparing
acetazolamide versus usual practice
Sample size: n=100 (50 patients per group)
Power calculation was estimated as follows:
1. For a reduction of 50% from the control group to the treatment group; We require 32
patients in each group for a significant difference of 5% (P<0.05) We require 54
patients in each group for a significant difference of 1% (P<0.01)
2. For a reduction of 25% from the control group to the treatment group; We require 116
patients in each group for a significant difference of 5% (P<0.05). We require 192
patients in each group for a significant difference of 1% (P<0.01
We chose to recruit a total of 100 patients in the sample size due to the limitations of
availability sufficient numbers of patients undergoing this type of surgery in a single
centre.
;
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
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