Martin Tisdall

Increase in cerebral aerobic metabolism by normobaric hyperoxia after traumatic brain injury.

OBJECT Traumatic brain injury (TBI) is associated with depressed aerobic metabolism and mitochondrial dysfunction. Normobaric hyperoxia (NBH) has been suggested as a treatment for TBI, but studies in humans have produced equivocal results. In this study the authors used brain tissue O(2) tension measurement, cerebral microdialysis, and near-infrared spectroscopy to study the effects of NBH after TBI. They investigated the effects on cellular and mitochondrial redox states measured by the brain tissue lactate/pyruvate ratio (LPR) and the change in oxidized cytochrome c oxidase (CCO) concentration, respectively. METHODS The authors studied 8 adults with TBI within the first 48 hours postinjury. Inspired oxygen percentage at normobaric pressure was increased from baseline to 60% for 60 minutes and then to 100% for 60 minutes before being returned to baseline for 30 minutes. RESULTS The results are presented as the median with the interquartile range in parentheses. During the 100% inspired oxygen percentage phase, brain tissue O2 tension increased by 7.2 kPa (range 4.5-9.6 kPa) (p < 0.0001), microdialysate lactate concentration decreased by 0.26 mmol/L (range 0.0-0.45 mmol/L) (p = 0.01), microdialysate LPR decreased by 1.6 (range 1.0-2.3) (p = 0.02), and change in oxidized CCO concentration increased by 0.21 mumol/L (0.13-0.38 micromol/L) (p = 0.0003). There were no significant changes in intracranial pressure or arterial or microdialysate glucose concentration. The change in oxidized CCO concentration correlated with changes in brain tissue O(2) tension (r(s)= 0.57, p = 0.005) and in LPR (r(s)= -0.53, p = 0.006). CONCLUSIONS The authors have demonstrated oxidation in cerebral cellular and mitochondrial redox states during NBH in adults with TBI. These findings are consistent with increased aerobic metabolism and suggest that NBH has the potential to improve outcome after TBI. Further studies are warranted.

Near-infrared spectroscopic quantification of changes in the concentration of oxidized cytochrome c oxidase in the healthy human brain during hypoxemia

The near-IR cytochrome c oxidase (CCO) signal has potential as a clinical marker of changes in mitochondrial oxygen utilization. We examine the CCO signal response to reduced oxygen delivery in the healthy human brain. We induced a reduction in arterial oxygen saturation from baseline levels to 80% in eight healthy adult humans, while minimizing changes in end tidal carbon dioxide tension. We measured changes in the cerebral concentrations of oxidized CCO (Delta[oxCCO]), oxyhemoglobin (Delta[HbO(2)]), and deoxyhemoglobin (Delta[HHb]) using broadband near-IR spectroscopy (NIRS), and estimated changes in cerebral oxygen delivery (ecDO(2)) using pulse oximetry and transcranial Doppler ultrasonography. Results are presented as median (interquartile range). At the nadir of hypoxemia ecDO(2) decreased by 9.2 (5.4 to 12.1)% (p<0.0001), Delta[oxCCO] decreased by 0.24 (0.06 to 0.28) micromoles/l (p<0.01), total hemoglobin concentration increased by 2.83 (2.27 to 4.46) micromoles/l (p<0.0001), and change in hemoglobin difference concentration (Delta[Hbdiff]=Delta[HbO(2)]-Delta[HHb]) decreased by 12.72 (11.32 to 16.34) micromoles/l (p<0.0001). Change in ecDO(2) correlated with Delta[oxCCO] (r=0.78, p<0.001), but not with either change in total hemoglobin concentration or Delta[Hbdiff]. This is the first description of cerebral Delta[oxCCO] during hypoxemia in healthy adults. Studies are ongoing to investigate the clinical relevance of this signal in patients with traumatic brain injury.

The effect on cerebral tissue oxygenation index of changes in the concentrations of inspired oxygen and end-tidal carbon dioxide in healthy adult volunteers.

BACKGROUND:A variety of near-infrared spectroscopy devices can be used to make noninvasive measurements of cerebral tissue oxygen saturation (ScO2). The ScO2 measured by the NIRO 300 spectrometer (Hamamatsu Photonics, Japan) is called the cerebral tissue oxygenation index (TOI) and is an assessment of the balance between cerebral oxygen delivery and utilization. We designed this study to investigate the effect of systemic and intracranial physiological changes on TOI. METHODS:Fifteen healthy volunteers were studied during isocapneic hyperoxia and hypoxemia, and normoxic hypercapnea and hypocapnea. Absolute cerebral TOI and changes in oxy- and deoxyhemoglobin concentrations were measured using a NIRO 300 spectrometer. Changes in arterial oxygen saturation (Sao2), ETco2, heart rate, mean arterial blood pressure (MBP), and middle cerebral artery blood flow velocity (Vmca) were also measured during these physiological challenges. Changes in cerebral blood volume (CBV) were subsequently calculated from changes in total cerebral hemoglobin concentration. RESULTS:Baseline TOI was 67.3% with an interquartile range (IQR) of 65.2%–71.9%. Hypoxemia was associated with a median decrease in TOI of 7.1% (IQR −9.1% to −5.4%) from baseline (P < 0.0001) and hyperoxia with a median increase of 2.3% (IQR 2.0%–2.5%) (P < 0.0001). Hypocapnea caused a reduction in TOI of 2.1% (IQR −3.3% to −1.3%) from baseline (P < 0.0001) and hypercapnea an increase of 2.6% (IQR 1.4%–3.7%) (P < 0.0001). Changes in Sao2 (P < 0.0001), ETco2 (P < 0.0001), CBV (P = 0.0003), and MBP (P = 0.03) were significant variables affecting TOI. Changes in Vmca (P = 0.7) and heart rate (P = 0.2) were not significant factors. CONCLUSION:TOI is an easy-to-monitor variable that provides real-time, multisite, and noninvasive assessment of the balance between cerebral oxygen delivery and utilization. However, TOI is a complex variable that is affected by Sao2 and ETco2, and, to a lesser extent, by MBP and CBV. Clinicians need to be aware of the systemic and cerebral physiological changes that can affect TOI to interpret changes in this variable during clinical monitoring.

In vivo monitoring of neuronal loss in traumatic brain injury: a microdialysis study

Traumatic brain injury causes diffuse axonal injury and loss of cortical neurons. These features are well recognized histologically, but their in vivo monitoring remains challenging. In vivo cortical microdialysis samples the extracellular fluid adjacent to neurons and axons. Here, we describe a novel neuronal proteolytic pathway and demonstrate the exclusive neuro-axonal expression of Pavlov’s enterokinase. Enterokinase is membrane bound and cleaves the neurofilament heavy chain at positions 476 and 986. Using a 100 kDa microdialysis cut-off membrane the two proteolytic breakdown products, extracellular fluid neurofilament heavy chains NfH476−986 and NfH476−1026, can be quantified with a relative recovery of 20%. In a prospective clinical in vivo study, we included 10 patients with traumatic brain injury with a median Glasgow Coma Score of 9, providing 640 cortical extracellular fluid samples for longitudinal data analysis. Following high-velocity impact traumatic brain injury, microdialysate extracellular fluid neurofilament heavy chain levels were significantly higher (6.18 ± 2.94 ng/ml) and detectable for longer (>4 days) compared with traumatic brain injury secondary to falls (0.84 ± 1.77 ng/ml, <2 days). During the initial 16 h following traumatic brain injury, strong correlations were found between extracellular fluid neurofilament heavy chain levels and physiological parameters (systemic blood pressure, anaerobic cerebral metabolism, excessive brain tissue oxygenation, elevated brain temperature). Finally, extracellular fluid neurofilament heavy chain levels were of prognostic value, predicting mortality with an odds ratio of 7.68 (confidence interval 2.15–27.46, P = 0.001). In conclusion, this study describes the discovery of Pavlov’s enterokinase in the human brain, a novel neuronal proteolytic pathway that gives rise to specific protein biomarkers (NfH476−986 and NfH476−1026) applicable to in vivo monitoring of diffuse axonal injury and neuronal loss in traumatic brain injury.

Investigation of frontal cortex, motor cortex and systemic haemodynamic changes during anagram solving.

We have previously reported changes in the concentrations of oxy-(delta[HbO2]) deoxy- (delta[HHb]) and total haemoglobin (delta[HbT] = delta[HbO2] + delta[HHb]) measured using near infrared spectroscopy (NIRS) over the frontal cortex (FC) during an anagram solving task. These changes were associated with a significant increase in both mean blood pressure (MBP) and heart rate (HR). The aim of this study was to investigate whether the changes in MBP previously recorded during an anagram solving task produces associated changes in scalp blood flow (flux) measured by laser Doppler and whether any changes are seen in NIRS haemodynamic measurements over a control region of the brain (motor cortex: MC). During the 4-Letter anagram task significant changes were observed in the delta[HbO2], delta[HHb] and delta[HbT] in both the frontal and motor cortex (n = 11, FC p < 0.01, MC p < 0.01). These changes were accompanied by significant changes in both MBP (n = 11, p < 0.01) and scalp flux (n = 9, p = 0.01). During the 7-Letter anagram task significant changes were observed in the delta[HbO2] and delta[HbT] (n = 11, FC p < 0.01, MC p < 0.01), which were accompanied by significant changes in both MBP (n = 11, p = 0.05) and flux (n = 9, p = 0.05). The task-related changes seen in MBP and flux in this study appear to contribute to the changes in the NIRS signals over both the activated and control regions of the cortex.

Measurement of Cerebral Tissue Oxygenation in Young Healthy Volunteers During Acetazolamide Provocation: A Transcranial Doppler and Near-Infrared Spectroscopy Investigation

Recent advances in near-infrared spectroscopy (NIRS) allow measurements of absolute tissue oxygen saturation (TOI) using spatially resolved spectroscopy (SRS), while enabling better depth sensitivity. However concerns remain regarding the relative contribution of the extracranial circulation to the cerebral NIRS TOI signal. In this study we investigated this during a period of selective rise in cerebral blood flow (CBF) produced by the administration of acetazolamide (ACZ) in 10 healthy volunteers. A two channel spectrometer (NIRO 300, Hamamatsu Photonics KK) was used to measure absolute cerebral TOI over the frontal cortex using the SRS technique using an optode spacing of 5 cm and 1.5 cm for channel 1 and 2 respectively. After ACZ administration we were able to observe a significant increase in the velocity of middle cerebral artery (V(mca), measured with the transcranial Doppler (TCD)) which was accompanied by an increase in TOI as monitored by the NIRO 300 with an optode spacing of 5 cm but not with an optode spacing of 1.5 cm. Furthermore a direct relationship was seen between the V(mca) and the TOI measured at 5 cm optode spacing. This work suggests that using this commercial NIRS instrument with an optode spacing of 5 cm one is able to detect the intracranial changes.

Investigation of in vivo measurement of cerebral cytochrome-c-oxidase redox changes using near-infrared spectroscopy in patients with orthostatic hypotension

We have previously used a continuous four-wavelength near-infrared spectrometer to measure changes in the cerebral concentrations of oxy-haemoglobin (Delta[HbO(2)] and deoxy-haemoglobin (Delta[HHb]) during head-up tilt in patients with primary autonomic failure. The measured changes in light attenuation also allow calculation of changes in the concentration of oxidized cytochrome-c-oxidase (Delta[(ox)CCO]), and this paper analyses the Delta[(ox)CCO] during the severe episodes of orthostatic hypotension produced by this experimental protocol. We studied 12 patients during a passive change in position from supine to a 60 degrees head-up tilt. The challenge caused a reduction in mean blood pressure of 59.93 (+/-26.12) mmHg (Mean (+/-SD), p < 0.0001), which was associated with a reduction in the total concentration of haemoglobin (Delta[HbT] = Delta[HbO(2)] + Delta[HHb]) of 5.02 (+/-3.81) microM (p < 0.0001) and a reduction in the haemoglobin difference concentration (Delta[Hb(diff)] = Delta[HbO(2)] - Delta[HHb]) of 14.4 (+/-6.73) microM (p < 0.0001). We observed a wide range of responses in Delta[(ox)CCO]. Six patients demonstrated a drop in Delta[(ox)CCO] (0.17 +/- 0.15 microM); four patients demonstrated no change (0.01 +/- 0.12 microM) and two patients showed an increase in Delta[(ox)CCO] (0.21 +/- 0.01 microM). Investigation of the association between the changes in concentrations of haemoglobin species and the Delta[(ox)CCO] for each patient show a range of relationships. This suggests that a simple mechanism for crosstalk, which might produce artefactual changes in [(ox)CCO], is not present between the haemoglobin and the (ox)CCO NIRS signals. Further investigation is required to determine the clinical significance of the changes in [(ox)CCO].

Theoretical investigation of measuring cerebral blood flow in the adult human head using bolus Indocyanine Green injection and near-infrared spectroscopy

To investigate the accuracy of measuring cerebral blood flow (CBF) using a bolus injection of Indocyanine Green (ICG) detected by near-infrared spectroscopy in adult human heads, simulations were performed using a two-layered model representing the extracerebral and intracerebral layers. Modeled optical data were converted into tissue ICG concentration using either the one-detector modified Beer-Lambert law (MBLL) method, or the two-detector partial path-length (PPL) method. The CBFs were estimated using deconvolution and blood flow index techniques. Using the MBLL method, the CBFs were significantly underestimated but the PPL method improved their accuracy and robustness, especially when used as relative measures. The dispersion of the arterial input function also affected the CBF estimates.

Relationship Between Brain Tissue Haemodynamics, Oxygenation And Metabolism In The Healthy Human Adult Brain During Hyperoxia And Hypercapnea

This study investigates the relationship between changes in brain tissue haemodynamics, oxygenation and oxidised cytochrome-c-oxidase ([oxCCO]) in the adult brain during hyperoxia and hypercapnea. 10 healthy volunteers were studied. We measured the mean blood flow velocity of the right middle cerebral artery (Vmca) with transcranial Doppler (TCD) and changes in concentrations of total haemoglobin ([HbT]=[HbO2]+[HHb]), haemoglobin difference ([Hbdiff]=[HbO2]-[HHb]) and [oxCCO] with broadband near-infrared spectroscopy (NIRS). We also measured the absolute tissue oxygenation index (TOI) using NIR spatially resolved spectroscopy. During hyperoxia there was an increase in TOI (2.33 +/- 0.29%), [Hbdiff] (4.57 +/- 1.27 microM) and in the oxidation of [oxCCO] (0.09 +/- 0.12 microM); but a reduction in Vmca (5.85 +/- 4.85%) and HbT (1.29 +/- 0.91 microM). During hyperoxia there was a positive correlation between [oxCCO] and TOI and [Hbdiff] (r=0.83 and r=0.95) and a negative association between [oxCCO] and Vmca and [HbT] (r=-0.74 and r=-0.87). During hypercapnea there was an increase in TOI (2.76 +/- 2.16%), [Hbdiff] (7.36 +/- 2.64), [HbT] (2.61 +/- 2.7 microM), Vmca (14.92 +/- 17.5%) and in the oxidation of [oxCCO] (0.25 +/- 0.17 microM). Correlation analysis shows that there was association between [oxCCO] and TOI, [Hbdiff] and [HbT] (r=0.83, r=0.93 and r=0.82) but not with Vmca (r=0.33). We conclude that an increase in [oxCCO] was seen during both challenges and it was highly associated with brain tissue oxygenation.

Analysis of the Changes in the Oxidation of Brain Tissue Cytochrome-c-Oxidase in Traumatic Brain Injury Patients during Hypercapnoea A Broadband NIRS Study

Using broadband near-infrared spectroscopy (NIRS) and cerebral microdialysis (MD) we investigated cerebral cellular metabolism and mitochondrial redox states, following hypercapnoea in 6 patients with traumatic brain injury (TBI). In all patients hypercapnoea increased intracranial pressure and cerebral blood flow velocity measured with transcranial Doppler. Despite the likely increase in cerebral oxygen delivery, we did not see an increase in the oxidation status of cytochrome-c-oxidase [oxCCO] in every patient. Analysis of the NIRS data demonstrated two patterns of the changes; Group A (n=4) showed an increase in [oxCCO] of 0.34(±0.34)µM and Group B (n=2) a decrease of 0.40(±0.41)µM. Although no obvious association was seen between the Δ[oxCCO] and the MD measured changes in lactate and pyruvate concentrations, further work using model informed data interpretation may be helpful in understanding the multimodal signals acquired in this heterogeneous patient group.