John D. Pickard

Monitoring of Cerebral Autoregulation in Head-Injured Patients

BACKGROUND AND PURPOSEnDisturbed cerebral autoregulation has been reported to correlate with an unfavorable outcome after head injury. Using transcranial Doppler ultrasonography, we investigated whether hemodynamic responses to spontaneous variations of cerebral perfusion pressure (CPP) provide reliable information on cerebral autoregulatory reserve.nnnMETHODSnWe studied 82 patients with head injury daily. Waveforms of intracranial pressure (ICP), arterial pressure, and transcranial Doppler flow velocity (FV) were captured during 2-hour periods. Time-averaged mean FV (FVm) and the FV during cardiac systole (FVs) were resolved. The correlation coefficient indices between FVm and CPP (Mx) and between FVs and CPP (Sx) during spontaneous fluctuations of CPP were calculated during 3-minute epochs and averaged for each investigation.nnnRESULTSnMx and Sx correlated with CPP (r = -.34, P = < .002; r = -.2, P = NS. respectively), with ICP (r = .46, P < .0001; r = .34, P < .003, respectively), with admission Glasgow Coma Scale score (r = -.34, P < .0025; r = -.38, P < .0008, respectively), and with outcome after head injury (r = .41, P < .0002; r = .48, P < .00009, respectively). In patients who died, cerebral autoregulation was severely disturbed during the first 2 days after injury.nnnCONCLUSIONSnIndices derived from spontaneous fluctuations of FV waveform and CPP describe cerebral vascular pressure reactivity. They correlate with outcome after head injury and therefore may be used to guide autoregulation-oriented intensive therapy.

Redefining the functional organization of working memory processes within human lateral prefrontal cortex.

It is widely held that the frontal cortex plays a critical part in certain aspects of spatial and non‐spatial working memory. One unresolved issue is whether there are functionally distinct subdivisions of the lateral frontal cortex that subserve different aspects of working memory. The present study used positron emission tomography (PET) to demonstrate that working memory processes within the human mid‐dorsolateral and mid‐ventrolateral frontal regions are organized according to the type of processing required rather than according to the nature (i.e. spatial or non‐spatial), of the information being processed, as has been widely assumed. Two spatial working memory tasks were used which varied in the extent to which they required different executive processes. During a ‘spatial span’ task that required the subject to hold a sequence of five previously remembered locations in working memory a significant change in blood‐flow was observed in the right mid‐ventrolateral frontal cortex, but not in the anatomically and cytoarchitectonically distinct mid‐dorsolateral frontal‐lobe region. By contrast, during a ‘2‐back’ task that required the subject to continually update and manipulate an ongoing sequence of locations within working memory, significant blood flow increases were observed in both mid‐ventrolateral and mid‐dorsolateral frontal regions. When the two working memory tasks were compared directly, the one that emphasized manipulation of information within working memory yielded significantly greater activity in the right mid‐dorsolateral frontal cortex only. This dissociation provides unambiguous evidence that the mid‐dorsolateral and mid‐ventrolateral frontal cortical areas make distinct functional contributions to spatial working memory and corresponds with a fractionation of working memory processes in psychological terms.

Can Cerebrovascular Reactivity Be Measured With Near-Infrared Spectroscopy?

BACKGROUND AND PURPOSEnWe used near-infrared spectroscopy (NIRS) to monitor the cerebral oxygenation changes during CO2 reactivity tests.nnnMETHODSnFifty healthy volunteers were examined (age range, 19 to 68 years). The monitored parameters were as follows: transcranial Doppler (TCD) time-averaged middle cerebral artery flow velocity end-tidal CO2 (EtCO2); change in concentration of cerebral oxyhemoglobin (HbO2), deoxyhemoglobin (Hb), and total hemoglobin; mean arterial blood pressure; peripheral arterial oxygen saturation (SaO2); and extracranial tissue perfusion with the use of cutaneous laser-Doppler flowmetry. The examination protocol included both hypercapnia and hypocapnia. The cerebrovascular reactivity indexes were calculated as follows: TCD, relative change in flow velocity per 1 kPa increase in EtCO2; NIRS, absolute change in HbO2, Hb, and total hemoglobin concentration (micromoles per liter) per 1 kPa increase in EtCO2.nnnRESULTSnMean middle cerebral artery flow velocity was found to be 58 cm/s at a mean baseline EtCO2 of 4.7 kPa. Mean cerebrovascular reactivities were as follows: TCD, 24%/kPa (SEM, 1.1); HbO2, 2.06 mumol/L per kilopascal (SEM, 0.08); Hb, -0.63 mumol/L per kilopascal (SEM, 0.09); and total hemoglobin concentration, 1.44 mumol/L per kilopascal (SEM, 0.1). Statistical analysis revealed significant correlation between reactivities calculated with the use of NIRS and TCD (P < .001). Although some fluctuations were observed in SaO2 and laser-Doppler flux, they were not correlated with either EtCO2 or NIRS.nnnCONCLUSIONSnNIRS signal changes in HbO2, Hb, and total hemoglobin concentration are very sensitive to alterations in EtCO2, which are largely independent of extracranial tissue perfusion. NIRS may be developed as an alternative method for testing cerebrovascular reactivity and may be of particular clinical importance when the ultrasound window is poor.

Predicting delayed ischemic deficits after aneurysmal subarachnoid hemorrhage using a transient hyperemic response test of cerebral autoregulation.

OBJECTIVETo assess whether the development of delayed ischemic deficits (DIDs) after aneurysmal subarachnoid hemorrhage can be predicted using transcranial Doppler ultrasonography and the transient hyperemic response test (THRT). METHODSAn increase in the middle cerebral artery peak flow velocity (FV) of more than 9% of baseline values after 5 to 9 seconds of carotid artery compression was defined as a normal THRT result, indicating good autoregulatory reserve. The transcranial Doppler criteria for vasospasm were a FV of more than 120 cm/s and a Lindegaard ratio of more than 3. Twenty patients with no immediate postoperative neurological deficits were studied. The FVs at all of the major cerebral arteries were measured daily after surgery, and the THRT results were assessed bilaterally. RESULTSFive of six patients with abnormal THRT results in the first examination after surgery (primary THRT impairment) developed DIDs; none of the remaining patients developed DIDs (Fisher exact test, P = 0.0004). All five patients with DIDs initially exhibited low FVs but all subsequently developed increases in FVs to values of more than 150 cm/s and four exhibited FVs of more than 200 cm/s. The time of onset of DIDs corresponded to the time of onset of moderate vasospasm (FV > 150 cm/s). None of the patients with initially normal THRT results developed DIDs, although four patients did exhibit late (secondary) THRT impairment, which was associated with FVs of more than 120 cm/s. CONCLUSIONWhen the effects of primarily impaired (after surgery) autoregulation are magnified by vasospasm, the risk of DIDs seems to be very high. Vasospasm alone does not seem to cause DIDs. The development of DIDs could therefore be predicted using the THRT for patients after aneurysm clipping.

Clinical Evaluation of Near-Infrared Spectroscopy for Testing Cerebrovascular Reactivity in Patients With Carotid Artery Disease

BACKGROUND AND PURPOSEnNear-infrared spectroscopy (NIRS) derives information about the concentrations of oxyhemoglobin (HbO2) and deoxyhemoglobin (Hb) from measurements of light attenuation caused by these chromosphores. The aim of this study was to assess NIRS as a tool for testing CO2 reactivity in patients with carotid artery disease.nnnMETHODSnOne hundred patients with symptomatic carotid occlusive disease were examined (age range, 44 to 83 years). The severity of stenosis ranged from 30% to 100% (median, 80%) on the ipsilateral side and 0% to 100% (median, 30%) on the contralateral side. Monitored parameters included transcranial Doppler flow velocity, changes in concentration of HbO2 and Hb, cutaneous laser-Doppler blood flow, endtidal CO2, arterial blood pressure, and arterial oxygen saturation. Hypercapnia was induced with the use of a 5% CO2/air mixture for inhalation. To estimate the contribution of skin flow to NIRS during reactivity testing, the superficial temporal artery was compressed, and the NIRS changes in response to the fall in laser-Doppler blood flow were recorded. Finally, reproducibility of reactivity testing was assessed in 10 patients who were subjected to repeated examinations over 3 days.nnnRESULTSnFlow velocity- and HbO2-derived reactivity values were related to the severity of the stenosis (P = .0001 and P = .017, respectively). The correlation between the two reactivity modalities was significant (r = .49, P < .000001). The median estimated contribution of skin flow to NIRS changes was 15.8%. Another variable affecting HbO2 signal changes during the CO2 challenge was arterial blood pressure (P = .025). Reproducibility of HbO2 reactivity was similar to flow velocity reactivity (14.3% and 18.6% variation, respectively).nnnCONCLUSIONSnNIRS shows potential as an alternative technique for testing CO2 reactivity in patients with carotid disease provided that conditions are carefully controlled. Marked changes in arterial blood pressure may render the NIRS reactivity indices unreliable, and the contribution from extracranial tissue must be taken into account when significant.

Predicting patterns of glioma recurrence using diffusion tensor imaging

Although multimodality therapy for high-grade gliomas is making some improvement in outcome, most patients will still die from their disease within a short time. We need tools that allow treatments to be tailored to an individual. In this study we used diffusion tensor imaging (DTI), a technique sensitive to subtle disruption of white-matter tracts due to tumour infiltration, to see if it can be used to predict patterns of glioma recurrence. In this study we imaged 26 patients with gliomas using DTI. Patients were imaged after 2xa0years or on symptomatic tumour recurrence. The diffusion tensor was split into its isotropic (p) and anisotropic (q) components, and these were plotted on T2-weighted images to show the pattern of DTI abnormality. This was compared to the pattern of recurrence. Three DTI patterns could be identified: (a) a diffuse pattern of abnormality where p exceeded q in all directions and was associated with diffuse increase in tumour size; (b) a localised pattern of abnormality where the tumour recurred in one particular direction; and (c) a pattern of minimal abnormality seen in some patients with or without evidence of recurrence. Diffusion tensor imaging is able to predict patterns of tumour recurrence and may allow better individualisation of tumour management and stratification for randomised controlled trials.

The SILVER (Silver Impregnated Line Versus EVD Randomized trial): a double-blind, prospective, randomized, controlled trial of an intervention to reduce the rate of external ventricular drain infection.

BACKGROUNDnCerebrospinal fluid (CSF) infections associated with external ventricular drain (EVD) placement attract major consequences. Silver impregnation of catheters attempts to reduce infection.nnnOBJECTIVEnTo assess the efficacy of silver catheters against CSF infection.nnnMETHODSnWe performed a randomized, controlled trial involving 2 neurosurgical centers (June 2005 to September 2009). A total of 356 patients requiring an EVD were assessed for eligibility; 325 patients were enrolled and randomized (167 plain, 158 silver); 278 patients were analyzed (140 plain, 138 silver). The primary outcome measure was CSF infection as defined by organisms seen on Gram stain or isolated by culture. Secondary outcome measures included ventriculoperitoneal (VP) shunting.nnnRESULTSnThere was a significant difference in infection risk between the 2 study arms: 21.4% (30/140) for plain catheters vs 12.3% (17/138) for silver catheters (P = .0427; 95% confidence interval [CI]: 1.015-3.713). Patients who had an EVD infection had more than double the risk of requiring a VP shunt compared with patients without an EVD infection (45.7% [21/46] vs 19.7% [45/229], respectively, P = .0002; 95% CI: 1.766-6.682). There was also a significant difference in VP shunt risk with infection: plain (55.2%; 16/29) vs the silver arm (29.4%; 5/17); P = .0244 (95% CI: 1.144-11.695). A multivariate analysis demonstrated that infection risk was increased by duration of EVD placement (odds ratio: 1.160), spontaneous intracranial hemorrhage (odds ratio 4.958) and decreased by silver catheters (odds ratio: 0.423).nnnCONCLUSIONnThe study provides Class I evidence that silver-impregnated catheters reduce CSF infection.

Internal and External Carotid Contributions to Near-Infrared Spectroscopy During Carotid Endarterectomy

BACKGROUND AND PURPOSEnThe internal carotid (ICA) and external carotid (ECA) contributions to changing concentrations of oxyhemoglobin (Hbo2) and deoxyhemoglobin (Hb) during carotid endarterectomy were assessed with the use of near-infrared spectroscopy (NIRS).nnnMETHODSnNIRS optodes were placed on the forehead with an interoptode distance of 6 cm, and laser-Doppler flowmetry (LDF) was used to monitor the change in skin blood flow between the optodes. Hb, Hbo2, LDF, arterial blood pressure, and middle cerebral artery flow velocity were recorded continuously. The ECA was clamped 2 minutes before the ICA was clamped. Suitable multimodal recordings were achieved in 44 patients.nnnRESULTSnWhen the ECA was clamped, 76% of patients showed a fall in Hbo2 and 65% an increase in Hb. When corrected for changes in arterial blood pressure, an accompanying fall in cutaneous LDF predicted the fall in Hbo2 with high sensitivity (100%) and specificity (100%). Among those with no NIRS changes during ECA clamping, 56% had severe ECA stenosis or occlusion; none of these showed an accompanying fall in LDF. In contrast, when the ICA was clamped, substantial additional changes in NIRS occurred in 55% of cases, all of which were associated with a fall in flow velocity, but none with a change in LDF. Patients with a constant flow velocity after ICA clamping also showed no change in NIRS.nnnCONCLUSIONSnBoth the ECA and ICA vascular territories contribute to NIRS changes during carotid endarterectomy. The external carotid contribution to NIRS can be monitored with cutaneous LDF.

What Shapes Pulse Amplitude of Intracranial Pressure

The pulsatile component of intracranial pressure (ICP) has been shown to be a predictor of outcome in normal pressure hydrocephalus (NPH) and traumatic brain injury (TBI). Experimental studies have demonstrated that the pulse amplitude of ICP (AMP(ICP)) is dependent on the mean ICP (mICP), and on the pulse amplitude of the cerebral arterial blood volume (AMP(CaBV)), according to the exponential craniospinal compliance curve. In this study, we compared the influence of mICP and AMP(CaBV) on AMP(ICP) in patients with NPH (infusion study) and TBI (spontaneous recording). We retrospectively analyzed 25 NPH and 43 TBI patients with continuous monitoring of ICP and cerebral blood flow velocity (CBFV), as assessed with transcranial doppler. AMP(CaBV) was extracted from the CBFV waveform. The influence of mICP and AMP(CaBV) on AMP(ICP) were determined using partial coefficients a, b, and c of the multiple regression model: AMP(ICP) = a * mICP + b * AMP(CaBV) + c. AMP(ICP) was more dependent on mICP in NPH patients than in TBI patients (partial coefficient a = 0.93 versus -0.03; p < 0.001). On the contrary, AMP(ICP) was more dependent on AMP(CaBV) in patients with TBI than in those with NPH (b = 0.86 versus 0.10; p < 0.001). This study shows that AMP(ICP) depends mostly on changes in mean ICP during cerebrospinal fluid (CSF) infusion studies in patients with NPH, and on changes in cerebral arterial blood volume (AMP(CaBV)) in TBI patients. Further clinical studies will reveal whether AMP(ICP) is a better indicator of clinical severity and outcome than mICP in TBI and NPH patients.

Imaging regional variation of cellular proliferation in gliomas using 3′-deoxy-3′-[18F]fluorothymidine positron-emission tomography: an image-guided biopsy study

AIMnTo compare regional variations in uptake of 3-deoxy-3- [(18)F]-fluorothymidine (FLT) images using positron-emission tomography (PET) with measures of cellular proliferation from biopsy specimens obtained by image-guided brain biopsies.nnnMATERIALS AND METHODSnFourteen patients with a supratentorial glioma that required an image-guided brain biopsy were imaged preoperatively with dynamic PET after the administration of FLT. Maps of FLT irreversible uptake rate (K(i)) and standardized uptake value (SUV) were calculated. These maps were co-registered to a gadolinium-enhanced T1-weighted spoiled gradient echo (SPGR) sequence that was used for biopsy guidance, and the mean and maximum K(i) and SUV determined for each biopsy site. These values were correlated with the MIB-1 labelling index (a tissue marker of proliferation) from these biopsy sites.nnnRESULTSnA total of 57 biopsy sites were studied. Although all measures correlated with MIB-1 labelling index, K(i)(max) provided the best correlation (Pearson coefficient, r=0.68; p<0.001). In low-grade gliomas the K(i)(mean) (+/-SD) was significantly higher than in normal tissue (3.3+/-1.7x10(-3)ml(plasma)/min/ml(tissue) versus 1.2+/-0.7x10(-3)ml(plasma)/min/ml(tissue); p=0.001). High-grade gliomas showed heterogeneous uptake with a mean K(i) of 7.7+/-4x10(-3)ml(plasma)/min/ml(tissue). A threshold K(i)(mean) of 1.8x10(-3) differentiates between normal tissue and tumour (sensitivity 84%, specificity 88%); however, the latter threshold underestimated the extent of tumour in half the cases. SUV closely agreed with K(i) measurements.nnnCONCLUSIONnFLT PET is a useful marker of cellular proliferation that correlates with regional variation in cellular proliferation; however, it is unable to identify the margin of gliomas.