This is the protocol for a review and there is no abstract. The objectives are as follows:
To assess from the current literature the utility and sensitivity of CT cerebral angiography as a confirmatory or add-on test following a clinical diagnosis of death using neurological criteria. For the purpose of this review, CT angiography will be considered as an add-on or confirmatory test. As described above, CT angiography demonstrates opacification or otherwise of the intracranial vasculature following the intravenous injection of iodinated contrast media. As such, it is very similar in nature to conventional catheter angiography (where contrast is injected intra-arterially, usually selectively into the major extracranial neck vessels).
No secondary objective is to be examined.
We will attempt to fully investigate all possible sources of heterogeneity. We anticipate this may include, but not be limited to, variances in methods of clinical diagnosis and heterogeneity in imaging techniques, as well as methodological sources of heterogeneity.
Wherever possible, we will consider the following:
There are several specific factors that we anticipate may contribute to clinical heterogeneity, which we will divide into clinical and imaging factors.
As has previously been mentioned, the clinical criteria involved in establishing a diagnosis of brain death vary between countries. If study authors do not clarify the protocols used in clinical testing, we will seek further clarification from relevant lead authors. However, all international clinical standards also act as legal standards and we anticipate that, for this reason, there is likely to be strict adherence to testing protocols within individual studies.
Although there is anticipated heterogeneity in testing for whole brain function, all current clinical protocols necessitate the satisfaction of the minimum clinical criteria as outline above.
It is possible that there may be greater differences between patients diagnosed according to irreversible cessation of brain-stem function and those diagnosed according to cessation of all functions of the entire brain. We will aim, therefore, to identify the clinical protocol used to diagnose brain death. Should there be sufficient available data, we will analyse these two major groups as subgroups.
A further source of bias to consider is the possibility that any clinical diagnosis of brain death may potentially be influenced by an existing CT angiographic study; that is, the role of CT angiography may have inadvertently become the reference standard. This will be difficult to account for in the published literature unless authors explicitly clarify the blinded states of both clinical testers and image reviewers. However, as clinical testing for brain death is a legal standard (regardless of the clinical protocol used), in all countries, it should be subject to a higher level of scrutiny than many other clinical tests and as such is considered much less likely to be influenced by other tests.
There is moderate heterogeneity in the exact protocol and CT angiographic technique between CT scanner manufacturers and centres. The following aspects of the investigation and reporting will need to be defined: timing, contrast dose, quality of study (that is absence of motion artefact, which may degrade a CT series), volume of contrast, volume of acquisition, scanner type (single spiral, multislice, detector type, scan time), single or double reviewer, and experience of reviewer. If this is not clear in the selected studies we will seek further information from the relevant lead authors.
In particular, there may be heterogeneity in the protocols used for imaging, which may have significant effects on the quality of any subsequent report. It would be expected that most centres will follow a protocol similar to that detailed by Frampas et al (Frampas 2009) wherein three separate CT acquisitions are performed within the study: one pre-contrast, one 20 sec following contrast (to confirm opacification of the superficial temporal arteries and hence appropriate contrast injection and cardiac output to deliver contrast to the vessels of the neck and head), and one at 60 sec to evaluate opacification of the cortical segments of the middle cerebral arteries and the deep cerebral veins. This protocol differs from the typical CT angiographic protocol used for assessment of the intracranial vasculature in other clinical groups but is considered necessary in this group to confirm appropriate contrast passage and absence of pre-contrast vessel opacification or densities. We will specifically look for the protocol used. If this is not available, we will seek further information from the relevant lead authors. If further information is not forthcoming and the protocol cannot be clarified, we will not include the study.
In addition, we will also consider the time of imaging compared with clinical assessment (that is time from suspected onset of the target condition, or time interval between the index test and the reference standard). In the anticipated patient cohort, the time interval between the index test and reference standard is of importance as significant changes in clinical condition may occur over a relatively short space of time. We will also attempt to establish that patients are not in a state of hypovolaemia or cardiovascular insufficiency (factors which would contribute to cerebral hypoperfusion and potential variance in imaging findings), although this may be accounted for depending on the imaging protocols used, as described above.
We will also consider heterogeneity that may be introduced due to the interpretation of imaging test results and the variance of interpretation between reviewers. Again, due to the ethically sensitive nature of this subject, we anticipate that many studies will be interpreted by at least two authors and although the reports of these studies will naturally fall into two dichotomous groupings ('intracranial vessel enhancement' versus 'no intracranial vessel enhancement) there may be a small number of studies reported with a more indeterminate or intermediate opinion.