Effectiveness of Acetazolamide in Reducing Paralysis of the Leg in Patients Undergoing Aortic Aneurysm Surgery Surgery (AZATAAR)

December 30, 2014 updated by: Dr Mark Field, Liverpool Heart and Chest Hospital NHS Foundation Trust

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).

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Unknown

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

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.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Anticipated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
100

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Contact Backup

Study Locations

  • United Kingdom
      • Liverpool, United Kingdom, L14 3PE
      • Liverpool, United Kingdom, L14 3PE
        • Not yet recruiting
        • Liverpool Heart & Chest Hospital
        • Principal Investigator:
          • Mark Field, DPhil, MBCH

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

14 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Patients who have given consent and are 18+ years old
  • Patients who have been able to comply with the pre-operative course of acetazolamide treatment (treatment group) and who have had blood sample collected three days prior to surgery
  • Patients with inserted spinal drain

Exclusion Criteria:

  • Non-elective patients, who were not able to participate in pre-operative acetazolamide treatment and blood sample tests three days prior to surgery
  • Patients without consent
  • Patients in whom a spinal drain could not be positioned
  • Patients with blood stained CSF
  • Patients who have not adhered to pre-operative course of acetazolamide treatment
  • Patients who have had a reaction to the drug, and consequently have had acetazolamide discontinued (but will make note of specific reactions and number of patients involved)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
No Intervention: control group with no acetazolamide
Treatment as usual without acetazolamide treatment
Active Comparator: Acetazolamide
Treatment arm
Drug: Acetazolamide

Acetazolamide twice a day, at 12 hour intervals:

  • 250 mg Tablets; one tablet to be taken twice daily from three days before the day of surgery
  • One tablet to take two hours before surgery
  • 500mg Intravenous Acetazolamide; to be administered upon arrival in critical care post-surgery; continuing at 12 hour intervals until last acetazolamide administration at 72 hours.
Other Names:
  • diamox

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Intracranial pressure recorded immediately after line insertion, throughout surgery and post-operatively (only recordings post-operatively will be treated as an end-point)
Time Frame: hourly from start of surgery upto 72 hrs after surgery
reduction in intracranial pressure
hourly from start of surgery upto 72 hrs after surgery

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Frequency and volume of CSF drainage
Time Frame: hourly during and after the operation up to 72 hours
Reduction in frequency and volume of CSF drainage
hourly during and after the operation up to 72 hours

Other Outcome Measures

Other Outcome Measures

For clinical trials, a planned measurement described in the protocol that is used to determine the effect of an intervention/treatment on participants. For observational studies, a measurement or observation that is used to describe patterns of diseases or traits, or associations with exposures, risk factors, or treatment. Types of outcome measures include primary outcome measure and secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Non-clinical paraplegia measured by amplitude of motor evoked potentials
Time Frame: Measurement of motor evoked potentials measured hourly starting from the time patients are admitted to the critical care unit and the last measurement is when the patient has tracheal extubated
The outcome is non-clinical paraplegia measured by amplitude of the motor evoked potentials during postoperative recovery. The signal amplitudes are compared to baseline established during surgery where the postoperative lower limbs amplitude reduction of over 50% and upper limb reduction of less than 50% equates to a risk of paraplegia.
Measurement of motor evoked potentials measured hourly starting from the time patients are admitted to the critical care unit and the last measurement is when the patient has tracheal extubated
Clinically evident paraplegia
Time Frame: Postoperatively assessments will be conducted hourly from the time the patient is awake and able to move until 72 hours after surgery and then once on the day of hospital discharge
Postoperatively, clinically evident paraplegia is assessed by the ability of patients to move limbs on awakening. This assessment is performed hourly until 72 hours after admission to the critical care unit and then once on the day of hospital discharge.
Postoperatively assessments will be conducted hourly from the time the patient is awake and able to move until 72 hours after surgery and then once on the day of hospital discharge

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Liverpool Heart and Chest Hospital NHS Foundation Trust

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Mark Field, DPhil, MBBCh, Liverpool Heart & Chest Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
July 1, 2014

Primary Completion (Anticipated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
June 1, 2016

Study Completion (Anticipated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
June 1, 2016

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
June 4, 2013

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
June 26, 2013

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
June 28, 2013

Study Record Updates

Last Update Posted (Estimate)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
December 31, 2014

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
December 30, 2014

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
December 1, 2014

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 954
  • 2013-001447-31 (EudraCT Number)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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