Rationale for the Study

Monitoring of ICP is well established in the clinical management of TBI and the practise is supported by international guidelines(54). ICP monitoring is typically performed using an intraventricular or intraparenchymal catheter with a

microtransducer system. Both of these techniques are associated with significant complications such as bleeding and infection and their availability in TBI is

largely restricted to specialist neurosurgical centres. A safe, simple and accurate non-invasive device would therefore increase the clinical availability of ICP monitoring.

Transcranial bioimpedance (TCB) has been considered for the early detection of multiple brain pathologies in humans(120, 121, 125). In addition, previous animal experiments have shown a relationship between TCB and ICP(127, 130). Based on the known relationship between bioimpedance and the volume of the intracellular and extracellular spaces, the potential use of TCB was investigated as an estimate of ICP in TBI.

5.3 Data Collection

All study patients were recruited from the neurological intensive care unit

of the typical population of patients suffering a TBI in terms of age range and the diverse pathologies identified on computed tomography (CT) scanning of the brain. While the range of pathologies was a strength of the study in terms of its clinical applicability it may have limited the prospects of successfully identifying a relationship between TCB and ICP.

In the animal studies that had previously defined a relationship between TCB and ICP, the experimental models resulted in a uniform pathological process that would effect TCB measurements in a predictable manner. In the neonatal piglet model described by Lingwood et al(127), brain hypoxia was presumed to lead to intracellular swelling and a consequent decrease in the extra-cellular fluid space that was associated with a rise in ICP. In the sheep model described by Shaw et al(130), intracranial hypertension (ICH) was induced by injection of mock cerebrospinal fluid (CSF) into the ventricle. The nature of the brain injuries in the patients recruited to the BioTBI study meant that there were likely to be multiple pathological processes evolving, even within an individual patient. The aetiology of increases in ICP could include intracellular or vasogenic oedema, expansion of intra or extra-axial haematoma or a disruption to CSF flow. All of these pathologies are likely to have had different influences upon TCB measurements that complicated the process of modelling ICP.

A failure to translate promising animal research into successful human studies has been a very well recognised problem in TBI(139) and over the past 30 years more than 20 large phase III trials have failed to show a significant treatment effect of a neuroprotective agent(140). Many of the issues related to therapeutic trials relate equally well to monitoring studies. One of the primary problems in converting positive findings in animal models of TBI into positive findings in the clinical environment is believed to be the heterogeneity of human TBI compared to that in controlled animal models(141). The International Mission on Prognosis and Clinical Trial Design in TBI (IMPACT) study group was initiated in 2003(142). They were given access to individual patient data from several large randomised controlled trials (RCTs) with the aim of optimising the design and analysis of trials in TBI. Proposed techniques for dealing with heterogeneity in TBI have been to maintain broad inclusion criteria but to pre-specify covariate

As already detailed in the results section, recruitment to the BioTBI Study was slower than had been anticipated. Although the intended sample size was not achieved, the number of patients and individual TCB measurements should have been sufficient to detect a strong relationship between TCB and ICP if it existed.

5.3.2 TCB Measurements

Measurement of TCB proved to have a number of technical difficulties in the population of TBI patients studied. The presence of rigid collars to immobilise the cervical spine in a number of patients meant that positioning the electrodes in mastoid or occipital positions was not feasible. Similarly the risk of

undiagnosed cervical spine injury in this patient population means that the head and neck can only be moved with caution to allow electrode attachment.

In several patients the application of electrodes was complicated by the position of dressings following cranial surgery or because of associated maxillo-facial injuries. Indeed the presence of significant soft-tissue swelling in some cases made the successful measurement of TCB difficult. In these cases there was the concern that a significant portion of the current path would be extra-cranial and therefore impedance would not necessarily reflect intra-cranial pathology. Attempts were made to mitigate this risk by measuring soft tissue thickness and brain diameter on CT scan and including these measurements in the adjusted models.

5.3.3 ICP Measurements

In the BioTBI Study, only patients who were undergoing ICP monitoring as part of their routine clinical care following severe TBI were recruited. In these patients, one of the principle aims of NICU care is to prevent ICH and thus intervene when ICP is rising. As can be seen from Figure 4.2, the vast majority of ICP summary measures from all patients were in the range of 10 to 25 mmHg. Therefore there were a limited number of extreme ICP values to facilitate model building. All studies investigating non-invasive ICP devices in the real clinical environment face a similar problem. For example in the study by Brandi et al, comparing multiple transcranial Doppler sonography (TCD) derived models of ICP, across

601 measurements in 45 patients, there were only four values above 25 mmHg(80).

ICP values used for modelling purposes were taken as a median of ICP in the five minutes following a TCD measurement. This time window was chosen as being long enough to provide a stable value but short enough to reflect any changes in pathophysiology. The R code used to provide the summary measure would allow the window length to be easily adjusted in any future studies.

5.4 Modelling of ICP Using TCB Data

The TCB parameters selected for modelling were based upon the animal studies referred to above. Shaw et al had demonstrated an inverse relationship between the log of ICP and Zc(130), while Lingwood et al had demonstrated a direct

relationship between ICP and R0(127). Visual inspection of plots of ICP against

the Zc and R0 (Figures 4.3 and 4.5) did not suggest any strong relationship. Given

the low sample size, plots were performed for each individual patient (Figures 4.4 and 4.6) but even on an individual patient basis there was no clear trend between either Zc or R0 and ICP.

The lack of a strong relationship was then supported by the results of the linear modelling approach, where there was no demonstrable relationship between the measured values of either Zc or R0 and ICP. When TCB variables were normalised

per patient (as was done in the previous animal studies) there was a small but significant relationship.

5.4.2 Adjusted Models

In an attempt to account for some of the patient heterogeneity in the study population, a number of patient specific variables were used in adjusted linear models and backward stepwise regression. Using measured values, the TCB parameter R0 in combination with the variables of gender, age, weight, height,

brain diameter and whole body Zc provided the adjusted linear model of ICP

(4.11) with the largest adjusted r-squared value (0.19). Using normalised values, the TCB parameters of 1/Zc and R0 in combination with the variables of gender,

soft tissue thickness, temperature and whole body Zc provide the model of ICP

(4.12) with the largest adjusted r-squared value (0.32). The models and values calculated using backward stepwise regression were almost identical.

The relatively low r-squared values in the above models mean that a large

component of ICP is unexplained by the model incorporating TCB measurements. This is particularly relevant given that there is a significant risk of model over fitting to the small study population. Therefore the likelihood that either of the models could be generalised to provide clinically meaningful estimates of ICP in a population of patients admitted with severe TBI is low.

5.4 Results in the Context of Similar Studies