Hemodynamic Failure Staging With Blood Oxygenation Level-Dependent Cerebrovascular Reactivity and Acetazolamide-Challenged (15O-)H2O-Positron Emission Tomography Across Individual Cerebrovascular Territories.

BACKGROUND: Staging of hemodynamic failure (HF) in symptomatic patients with cerebrovascular steno-occlusive disease is required to assess the risk of ischemic stroke. Since the gold standard positron emission tomography-based perfusion reserve is unsuitable as a routine clinical imaging tool, blood oxygenation level-dependent cerebrovascular reactivity (BOLD-CVR) with CO2 is a promising surrogate imaging approach. We investigated the accuracy of standardized BOLD-CVR to classify the extent of HF. METHODS AND RESULTS: Patients with symptomatic unilateral cerebrovascular steno-occlusive disease, who underwent both an acetazolamide challenge (15O-)H2O-positron emission tomography and BOLD-CVR examination, were included. HF staging of vascular territories was assessed using qualitative inspection of the positron emission tomography perfusion reserve images. The optimum BOLD-CVR cutoff points between HF stages 0-1-2 were determined by comparing the quantitative BOLD-CVR data to the qualitative (15O-)H2O-positron emission tomography classification using the 3-dimensional accuracy index to the randomly assigned training and test data sets with the following determination of a single cutoff for clinical application. In the 2-case scenario, classifying data points as HF 0 or 1-2 and HF 0-1 or 2, BOLD-CVR showed an accuracy of >0.7 for all vascular territories for HF 1 and HF 2 cutoff points. In particular, the middle cerebral artery territory had an accuracy of 0.79 for HF 1 and 0.83 for HF 2, whereas the anterior cerebral artery had an accuracy of 0.78 for HF 1 and 0.82 for HF 2. CONCLUSIONS: Standardized and clinically accessible BOLD-CVR examinations harbor sufficient data to provide specific cerebrovascular reactivity cutoff points for HF staging across individual vascular territories in symptomatic patients with unilateral cerebrovascular steno-occlusive disease.

Determining the effects of elevated partial pressure of oxygen on hypercapnia-induced cerebrovascular reactivity.

Evaluation of cerebrovascular reactivity (CVR) to hypo- and hypercapnia is a valuable test for the assessment of vasodilatory reserve. While hypercapnia-induced CVR testing is usually performed at normoxia, mild hyperoxia may increase tolerability of hypercapnia by reducing the ventilatory distress. However, the effects of mild hyperoxia on CVR was unknown. We therefore recruited 21 patients with a range of steno-occlusive diseases and 12 healthy participants who underwent a standardized 13-minute step plus ramp CVR test with a carbon dioxide gas challenge at the subject's resting end-tidal partial pressure of oxygen or at mild hyperoxia (PetO2 = 150 mmHg) depending on to which group they were assigned. In 11 patients, the second CVR test was at normoxia to examine test-retest differences. CVR was defined as % Δ Signal/ΔPetCO2. We found that there was no significant difference between CVR test results conducted at normoxia and at mild hyperoxia for participants in Groups 1 and 2 for the step and ramp portion. We also found no difference between test and retest CVR at normoxia for patients with cerebrovascular pathology (Group 3) for step and ramp portion. We concluded normoxic CVR is repeatable, and that mild hyperoxia does not affect CVR.

Sickle cell cerebrovascular reactivity to a CO2 stimulus: Too little, too slow.

Background: Despite increased cerebral blood flow (CBF), cerebral infarcts occur in patients with sickle cell disease (SCD). This suggests increased CBF does not meet metabolic demand possibly due to compromised cerebral vasodilatory response. Hypothesis: In adult SCD patients, cerebrovascular reactivity (CVR) and speed of vasodilatory response (tau) to a standardized vasodilatory stimulus, are reduced compared to normal subjects. Methods: Functional brain imaging performed as part of routine care in adult SCD patients without known large vessel cerebral vasculopathy was reviewed retrospectively. CVR was calculated as the change in CBF measured as the blood-oxygenation-level-dependent (BOLD)-magnetic resonance imaging signal, in response to a standard vasoactive stimulus of carbon dioxide (CO2). The tau corresponding to the best fit between the convolved end-tidal partial pressures of CO2 and BOLD signal was defined as the speed of vascular response. CVR and tau were normalized using a previously generated atlas of 42 healthy controls. Results: Fifteen patients were included. CVR was reduced in grey and white matter (mean Z-score for CVR -0.5 [-1.8 to 0.3] and -0.6 [-2.3 to 0.7], respectively). Tau Z-scores were lengthened in grey and white matter (+0.9 [-0.5 to 3.3] and +0.8 [-0.7 to 2.7], respectively). Hematocrit was the only significant independent predictor of CVR on multivariable regression. Conclusion: Both measures of cerebrovascular health (CVR and tau) in SCD patients were attenuated compared to normal controls. These findings show that CVR represents a promising tool to assess disease state, stroke risk, and therapeutic efficacy of treatments in SCD and merits further investigation.

The voxel-wise analysis of false negative fMRI activation in regions of provoked impaired cerebrovascular reactivity.

Task-evoked Blood-oxygenation-level-dependent (BOLD-fMRI) signal activation is widely used to interrogate eloquence of brain areas. However, data interpretation can be improved, especially in regions with absent BOLD-fMRI signal activation. Absent BOLD-fMRI signal activation may actually represent false-negative activation due to impaired cerebrovascular reactivity (BOLD-CVR) of the vascular bed. The relationship between impaired BOLD-CVR and BOLD-fMRI signal activation may be better studied in healthy subjects where neurovascular coupling is known to be intact. Using a model-based prospective end-tidal carbon dioxide (CO2) targeting algorithm, we performed two controlled 3 tesla BOLD-CVR studies on 17 healthy subjects: 1: at the subjects' individual resting end-tidal CO2 baseline. 2: Around +6.0 mmHg CO2 above the subjects' individual resting baseline. Two BOLD-fMRI finger-tapping experiments were performed at similar normo- and hypercapnic levels. Relative BOLD fMRI signal activation and t-values were calculated for BOLD-CVR and BOLD-fMRI data. For each component of the cerebral motor-network (precentral gyrus, postcentral gyrus, supplementary motor area, cerebellum und fronto-operculum), the correlation between BOLD-CVR and BOLD-fMRI signal changes and t-values was investigated. Finally, a voxel-wise quantitative analysis of the impact of BOLD-CVR on BOLD-fMRI was performed. For the motor-network, the linear correlation coefficient between BOLD-CVR and BOLD-fMRI t-values were significant (p<0.01) and in the range 0.33-0.55, similar to the correlations between the CVR and fMRI Δ%signal (p<0.05; range 0.34-0.60). The linear relationship between CVR and fMRI is challenged by our voxel-wise analysis of Δ%signal and t-value change between normo- and hypercapnia. Our main finding is that BOLD fMRI signal activation maps are markedly dampened in the presence of impaired BOLD-CVR and highlights the importance of a complementary BOLD-CVR assessment in addition to a task-evoked BOLD fMRI to identify brain areas at risk for false-negative BOLD-fMRI signal activation.

Smoke Inhalation Injury: Etiopathogenesis, Diagnosis, and Management.

Smoke inhalation injury is a major determinant of morbidity and mortality in fire victims. It is a complex multifaceted injury affecting initially the airway; however, in short time, it can become a complex life-threatening systemic disease affecting every organ in the body. In this review, we provide a summary of the underlying pathophysiology of organ dysfunction and provide an up-to-date survey of the various critical care modalities that have been found beneficial in caring for these patients. Major pathophysiological change is development of edema in the respiratory tract. The tracheobronchial tree is injured by steam and toxic chemicals, leading to bronchoconstriction. Lung parenchyma is damaged by the release of proteolytic elastases, leading to release of inflammatory mediators, increase in transvascular flux of fluids, and development of pulmonary edema and atelectasis. Decreased levels of surfactant and immunomodulators such as interleukins and tumor-necrosis-factor-α accentuate the injury. A primary survey is conducted at the site of fire, to ensure adequate airway, breathing, and circulation. A good intravenous access is obtained for the administration of resuscitation fluids. Early intubation, preferably with fiberoptic bronchoscope, is prudent before development of airway edema. Bronchial hygiene is maintained, which involves therapeutic coughing, chest physiotherapy, deep breathing exercises, and early ambulation. Pharmacological agents such as beta-2 agonists, racemic epinephrine, N-acetyl cysteine, and aerosolized heparin are used for improving oxygenation of lungs. Newer agents being tested are perfluorohexane, porcine pulmonary surfactant, and ClearMate. Early diagnosis and treatment of smoke inhalation injury are the keys for better outcome.

Vascular steal explains early paradoxical blood oxygen level-dependent cerebrovascular response in brain regions with delayed arterial transit times.

INTRODUCTION: Blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI) during manipulation of inhaled carbon dioxide (CO2) can be used to measure cerebrovascular reactivity (CVR) and map regions of exhausted cerebrovascular reserve. These regions exhibit a reduced or negative BOLD response to inhaled CO2. In this study, we sought to clarify the mechanism behind the negative BOLD response by investigating its time delay (TD). Dynamic susceptibility contrast (DSC) MRI with the injection of a contrast agent was used as the gold standard in order to provide measurement of the blood arrival time to which CVR TD could be compared. We hypothesize that if negative BOLD responses are the result of a steal phenomenon, they should be synchronized with positive BOLD responses from healthy brain tissue, even though the blood arrival time would be delayed. METHODS: On a 3-tesla MRI system, BOLD CVR and DSC images were collected in a group of 19 patients with steno-occlusive cerebrovascular disease. For each patient, we generated a CVR magnitude map by regressing the BOLD signal with the end-tidal partial pressure of CO2 (PETCO2), and a CVR TD map by extracting the time of maximum cross-correlation between the BOLD signal and PETCO2. In addition, a blood arrival time map was generated by fitting the DSC signal with a gamma variate function. ROI masks corresponding to varying degrees of reactivity were constructed. Within these masks, the mean CVR magnitude, CVR TD and DSC blood arrival time were extracted and averaged over the 19 patients. CVR magnitude and CVR TD were then plotted against DSC blood arrival time. RESULTS: The results show that CVR magnitude is highly correlated to DSC blood arrival time. As expected, the most compromised tissues with the longest blood arrival time have the lowest (most negative) CVR magnitude. However, CVR TD shows a noncontinuous relationship with DSC blood arrival time. CVR TD is well correlated to DSC blood arrival time (p < 0.0001) for tissue of positive reactivity, but fails to maintain this trend for tissue of negative reactivity. Regions with negative reactivity have similar CVR TD than healthy regions. CONCLUSION: These results support the hypothesis that negative reactivity is the result of a steal phenomenon, lowering the BOLD signal as soon as healthier parts of the brain start to react and augment their blood flow. BOLD CVR MRI is capable of identifying this steal distribution, which has particular diagnostic significance as it represents an actual reduction in flow to already compromised tissue.

End-inspiratory rebreathing reduces the end-tidal to arterial PCO2 gradient in mechanically ventilated pigs.

PURPOSE: Noninvasive monitoring of the arterial partial pressures of CO(2) (PaCO(2)) of critically ill patients by measuring their end-tidal partial pressures of CO(2) (PETCO(2)) would be of great clinical value. However, the gradient between PETCO(2) and PaCO(2) (PET-aCO(2)) in such patients typically varies over a wide range. A reduction of the PET-aCO(2) gradient can be achieved in spontaneously breathing healthy humans using an end-inspiratory rebreathing technique. We investigated whether this method would be effective in reducing the PET-aCO(2) gradient in a ventilated animal model. METHODS: Six anesthetized pigs were ventilated mechanically. End-tidal gases were systematically adjusted over a wide range of PETCO(2) (30-55 mmHg) and PETO(2) (35-500 mmHg) while employing the end-inspiratory rebreathing technique and measuring the PET-aCO(2) gradient. Duplicate arterial blood samples were taken for blood gas analysis at each set of gas tensions. RESULTS: PETCO(2) and PaCO(2) remained equal within the error of measurement at all gas tension combinations. The mean ± SD PET-aCO(2) gradient (0.13 ± 0.12 mmHg, 95% CI -0.36, 0.10) was the same (p = 0.66) as that between duplicate PaCO(2) measurements at all PETCO(2) and PETO(2) combinations (0.19 ± 0.06, 95% CI -0.32, -0.06). CONCLUSIONS: The end-inspiratory rebreathing technique is capable of reducing the PET-aCO(2) gradient sufficiently to make the noninvasive measurement of PETCO(2) a useful clinical surrogate for PaCO(2) over a wide range of PETCO(2) and PETO(2) combinations in mechanically ventilated pigs. Further studies in the presence of severe ventilation-perfusion (V/Q) mismatching will be required to identify the limitations of the method.

Steal physiology is spatially associated with cortical thinning.

BACKGROUND: The physiological impact of severely impaired cerebral autoregulatory vascular reactivity on cortical integrity is unknown. The purpose of this study is to determine the relationship between severe impairment of autoregulatory flow control associated with steal phenomenon and its impact on cortical thickness. METHODS: 250 blood oxygen level dependent (BOLD) MRI cerebrovascular reactivity (CVR) studies were reviewed in order to identify subjects with severe unilateral exhausted cerebrovascular reserve demonstrating steal physiology but with normal appearing cortex on fluid attenuated inversion recovery imaging. 17 patients meeting the inclusion criteria were identified. A reconstructed inflated cortical surface map was created for every subject using Freesurfer software (http://surfer.nmr.mgh.harvard.edu/). The region of interest (ROI) reflecting the steal physiology was determined by overlaying the subject's CVR map on to the cortical surface map. This ROI was compared with the corresponding area in the healthy hemisphere which provided control cortical thickness measurement in each subject. RESULTS: The hemisphere with steal physiology showed an 8% thinner cortex (2.23+/-0.28 mm) than the corresponding healthy hemisphere (2.42+/-0.23 mm) (p=0.0005). CONCLUSIONS: Our findings indicate that a spatial correspondence exists between impairment of autoregulatory capacity with steal physiology and cortical thinning.