Carbogen Inhalation Research Articles

Hypoxia modulation vs. chemotherapy and tumor shrinkage on early response assessment in diffuse large B-cell lymphoma

Background: Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy remains the standard of first-line treatment for diffuse large B-cell lymphoma (DLBCL). Up to 40% of DLBCL is characterized by relapse and refractory after treatment. Preliminary study reported Hypoxia-inducible factor-1? (HIF-1?) overexpression in 88.5% of DLBCL tumors in the Dr. Kariadi Hospital. Moreover, the role of hypoxia and HIF-1? has previously never been explored in DLBCL. Objectives: To evaluate the effect of hypoxia modulation to increased chemotherapeutic response in DLBCL. Methods: Single blind randomized control study was performed, with pre-test and post-test control group design. Research sampling consisted of DLBCL patients. The inclusion criteria include newly diagnosed DLBCL with HIF-1? overexpression and randomized to receive hypoxia modulation consisting of carbogen inhalation and nicotinamide administration, before R-CHOP chemotherapy. The tissue biopsy, histopathology and immunohistochemical studies were done. Chemotherapeutic responses were evaluated after 10-14 days following the first cycle of R-CHOP chemotherapy. Results: Out of twenty-six DLBCL participants with HIF-1? overexpression, there were 20 participants who completed the research protocol: 10 participants each in the intervention and control group. Demographic, clinicopathological, laboratory and disease characteristics were not statistically different between the two research groups (p>0.05). Baseline tumor volume to be evaluated was also considered equal (172.3 cm3 vs. 152.8 cm3, p=0.597). Following the carbogen inhalation and nicotinamide administration, serum HIF-1? and lactate reduction can be observed. There was also a significant tumor volume shrinkage in both the intervention and control (mean ?85.7 cm3 vs. ?118.27 cm3) group, though the reduction was not statistically different (Delta 58.85% vs. 65.63%, p=0.474). Conclusion: The addition of hypoxia modulation to R-CHOP chemotherapy for DLBCL has shown beneficial effects on both serum HIF-1? and lactate concentration. However, the benefits did not correlate to increase a better tumor response compared to the control group.

Reproducibility and diurnal variation in middle cerebral artery blood velocity in healthy humans.

What is the central question of this study? We sought to establish between-day reproducibility in estimates of middle cerebral artery blood velocity (MCAv) and cerebrovascular reactivity (CVR) in young, healthy male and female adults in tightly controlled experimental conditions. What is the main finding and its importance? Measures of MCAv assessed during morning, afternoon and evening hours are reproducible between days. There is diurnal variation in CVR, with values being highest during the evening compared with the morning. Greater diurnal variation in CVR is associated with more efficient sleep and greater nocturnal blood pressure dipping. These data enhance our understanding of modulators of MCAv and CVR. Transcranial Doppler (TCD) is used to assess cerebral blood velocity (CBV) and cerebrovascular reactivity (CVR). Assessments of TCD reproducibility are limited, and few include multiple within-day measurements. We sought to establish reproducibility of CBV and CVR in healthy adults during three time periods (morning, afternoon and evening). We hypothesized that CBV and CVR measured at the same time of day are reproducible between days. We also hypothesized that CBV and CVR exhibit diurnal variation, with measurements being higher in the evening compared with morning/afternoon hours. Twelve adults [six male and six female, 27 years (95% CI, 22-31 years)] completed three measurements (morning, afternoon and evening) on two separate days in controlled conditions (e.g., meals, activity and sleep). Middle cerebral artery blood velocity (MCAv, TCD) was measured continuously at rest and during two CVR tests (end-expiratory apnoea and carbogen inhalation). Intraclass correlation coefficients for resting MCAv showed moderate to good reproducibility, which did not differ between morning, afternoon and evening (0.87, 0.56 and 0.67, respectively; P>0.05). Intraclass correlation coefficients for peak MCAv during apnoea (0.80, 0.46 and 0.65, respectively; P>0.05) and minute 2 of carbogen inhalation (0.81, 0.74 and 0.73, respectively; P>0.05) were also not different from morning compared with afternoon/evening. Time of day had no effect on resting MCAv (F=0.69, P=0.51, ƞp 2 =0.06) or the peak response to apnoea (F=1.00, P=0.39, ƞp 2 =0.08); however, peak MCAv during carbogen breathing exhibited diurnal variation, with highest values in the evening (F=3.41, P=0.05, ƞp 2 =0.24). Measures of CBV and CVR assessed via TCD during morning, afternoon and evening hours are reproducible between days. There is diurnal variation in the MCAv response to carbogen exposure, with CVR being highest during evening compared with morning hours.

Carbogen inhalation during non-convulsive status epilepticus: A quantitative exploratory analysis of EEG recordings.

To quantify the effect of inhaled 5% carbon-dioxide/95% oxygen on EEG recordings from patients in non-convulsive status epilepticus (NCSE). Five children of mixed aetiology in NCSE were given high flow of inhaled carbogen (5% carbon dioxide/95% oxygen) using a face mask for maximum 120s. EEG was recorded concurrently in all patients. The effects of inhaled carbogen on patient EEG recordings were investigated using band-power, functional connectivity and graph theory measures. Carbogen effect was quantified by measuring effect size (Cohen's d) between "before", "during" and "after" carbogen delivery states. Carbogen's apparent effect on EEG band-power and network metrics across all patients for "before-during" and "before-after" inhalation comparisons was inconsistent across the five patients. The changes in different measures suggest a potentially non-homogeneous effect of carbogen on the patients' EEG. Different aetiology and duration of the inhalation may underlie these non-homogeneous effects. Tuning the carbogen parameters (such as ratio between CO2 and O2, duration of inhalation) on a personalised basis may improve seizure suppression in future.

Isoflurane attenuates carbogen-induced blood-brain barrier disruption independent of body temperature in mice and rats.

Isoflurane protects the blood-brain barrier (BBB) against cerebral extravasation of Evans blue dye (EBD), a commonly used serum protein tracer, in animals subjected to BBB disruption. As such, it has been implicated as a therapeutic agent that can prevent brain edema and damage caused by a number of brain insults, including focal ischemia and subarachnoid hemorrhage. Recently, it has been shown that isoflurane inhibits the cerebral extravasation of EBD following ischemic stroke chiefly by inducing hypothermia, raising the intriguing possibility that isoflurane protected against other causes of BBB disruption also through hypothermia. To test this hypothesis, we subjected mice and rats to inhalation of 20-30% carbogen, an inducer of BBB disruption, in the presence or absence of isoflurane while measuring their rectal temperature. In mice, carbogen inhalation on its own decreased rectal temperature from 36.4 ± 0.4 to 26.2 ± 0.6°C over a period of 60 minutes, and under this condition, isoflurane had no additional effect on body temperature. Nevertheless, isoflurane protected against carbogen-induced cerebral extravasation of EBD. In addition, when the body temperature was maintained in the normothermic range using an automated heating pad, isoflurane remained protective against cerebral extravasation of EBD. In rats, isoflurane also protected against cerebral extravasation of EBD, while having no effect on plasma pH, electrolyte concentrations, or osmolarity. In conclusion, isoflurane protected against BBB disruption caused by carbogen inhalation in mice and rats, but unlike isoflurane-mediated protection against ischemic BBB disruption, the effect could not be explained by anesthesia-induced hypothermia.

Carbogen inhalation opens the blood-brain barrier in rats without causing long-term metabolic or neurological deficit

The blood-brain barrier (BBB) prevents many drugs from entering the brain. Yet, conventional methods that open the BBB are technically demanding, poorly reversible, and can be associated with long-term adverse effects. In comparison, carbogen, which is introduced nearly a century ago as a treatment for psychiatric disorders, is easy to administer and readily available to many labs and hospitals. Here, we show that carbogen inhalation opened the BBB in rats, as indicated by the extravasation of an intravenous protein tracer. When the tracer was injected immediately or hours after carbogen inhalation, less tracer was detected in the rat brains, suggesting at least partial reversibility of this response after carbogen exhalation. Despite marked increase in BBB permeability, inhalation of carbogen for 30–90 min had no acute effect on the level of neuroinflammation or apoptosis in the brain, and had no long-term effect on body weight, food intake, locomotor activity, or learning and memory performance. Our study demonstrated that carbogen inhalation is a safe method to open the BBB.

Optical coherence tomography findings in a case of cilioretinal artery occlusion reversal, treated with mannitol and carbogen administration

To present spectral domain optical coherence tomography (OCT) findings during treatment in a case of acute isolated cilioretinal artery occlusion (CLRAO) reversed with intravenous systemic administration of mannitol and carbogen inhalation. Close monitoring with OCT thickness topographic map and cross section scans, every 12 hours, during treatment and till complete reversal of retinal nerve fiber layer edema. Fundus photography and fluorescein angiography (FFA) were used to illustrate occlusion and recanalization. After 72 hours of therapy, visual acuity improved from counting fingers (CF) to 7/10, Snellen’s chart. Consecutively OCT scans showed that the initial macular edema was gradually restored to typical 72 hours of treatment initiation. FFA performed after treatment confirmed recanalization of the cilioretinal artery. Early intervention with the combined intravenous administration of mannitol and carbogen inhalation can reverse acute onset loss of vision due to CLRAO. The reflectivity of retinal layers differs significantly regarding stages of acute CLRAO. In our case report increased reflectivity of the innermost layers of the retina was illustrated and a corresponding reduction in the outer retina and the retinal pigment epithelium and choriocapillaris layers. Macular thickness follow-up data recorded the course of intracellular edema to normal.

Comparative Analysis of the Combined Therapeutic Effects of Lipoprostaglandin E1 on Sudden Idiopathic Sensorineural Hearing Loss.

Background and ObjectivesViral and vascular disorders are considered to be a major cause of idiopathic sudden sensorineural hearing loss (ISSNHL). Lipoprostaglandin E1 (lipo-PGE1) has vasodilating activity and has been used to treat ISSNHL. The purpose of this study was to determine the specific therapeutic effects of lipo-PGE1 and compare them to other treatment modalities for ISSNHL.Subjects and MethodsThe study group had 1,052 patients diagnosed with ISSNHL. All were treated with steroid, carbogen inhalation, stellate ganglion block (SGB), or PGE1. The CP group (steroid, carbogen inhalation, and PGE1 injection; 288 patients) was treated with lipo-PGE1 and carbogen inhalation, the CS group (steroid, carbogen inhalation, and stellate ganglion block; 232 patients) with steroid, carbogen inhalation, and SGB, the C group (steroid and carbogen inhalation; 284 patients) with steroid and carbogen, and the control group (steroid only; 248 patients) with steroid only. Patients in the groups receiving lipo-PGE1 received a continuous infusion of 10 µL lipo-PGE1.ResultsThe overall recovery rate after treatment was 52.2%, and recovery rates by group were 67.7% in the CP group, 54.3% in the CS group, 52.1% in the C group, and 32.2% in the control group. Therefore, the therapeutic results in groups treated with lipo-PGE1 were better than results in other groups. The difference was statistically significant.ConclusionsThe study results suggested that the CP group received effective treatment modalities for ISSNHL. The combined therapy of lipo-PGE1 with carbogen inhalation in patients with ISSNHL was more beneficial than other treatment modalities.

Hypercapnia-induced brain acidosis: Effects and putative mechanisms on acute kainate induced seizures

AimsThis study investigated the mechanism of the anticonvulsant effects of carbogen containing 5% CO2 in a kainic acid (KA) rat model. Main methodsFour-week-old Sprague–Dawley rats were divided into four groups: control, carbogen, KA+air, and KA+carbogen. Carbogen containing 5% CO2 was applied immediately after KA injection, and cortical pH was recorded. High-performance liquid chromatography was used to detect the release of γ-aminobutyric acid (GABA) and glutamate. We used electrophysiology to measure cortical and hippocampal activities. Key findingsCarbogen increased the onset latency of seizure (KA+air group, 26.12±2.11min; KA+carbogen group 43.65±2.78min, P<0.001) and reduced the frequency of seizures (KA+air group, 12.50±1.77; KA+carbogen group, 5.63±1.59, P<0.001). Carbogen inhalation could reduce cortical pH (KA+air group, 7.04±0.04; KA+carbogen group, 6.82±0.03, P<0.001). After carbogen inhalation, the levels of excitatory amino acid glutamate decreased (595.90±7.51 in KA+air group vs. 467.95±4.82 in KA+carbogen s group, P<0.001), whereas GABA increased significantly (158.30±5.05 in KA+air group vs. 216.62±5.59 in KA+carbogen, P<0.05). Carbogen reduced both electrohippocampalogram (119.57±2.83 in KA+air group vs. 107.48±2.95 in KA+carbogen group, P<0.01) and electrocorticogram (130.74±2.48 in KA+air group vs. 115.35±2.11 in KA+carbogen group, P<0.01). SignificanceCarbogen containing 5% CO2 decreased seizures by reducing cortical pH, by increasing GABA release, and by affecting electrical activity of the brain.

Using OxyLite TM fiber-optic microprobes to verify the reliability of detecting the oxygenation in rats C6 glioma by blood oxygenation level dependent functional MRI with non-hemodynamic response function analysis

Objective Using MRI compatible OxyLiteTM fiber-optic microprobes to verify the reliability of detecting the oxygenation changes in rats C6 glioma by BOLD fMRI with non-hemodynamic response function (non-HRF) post-processing algorithm. Methods A total of 20 male SD rats were used to establish the subcutaneous C6 glioma model. GRE-EPI BOLD fMRI scans were performed in the tumor-bearing rats with Carbogen inhalation after anatomic scans using 1.5 T MR imaging system with Micro-47 microscopic coil. Fiber-optic microprobes were implanted in tumor to acquire the dynamic pO2 indications during BOLD fMRI scan. Oxy-localization map and oxy-amplitude map were generated from BOLD functional image data by non-HRF post-processing algorithm analysis. A ROI about 1.5 mm on a side centered to the tip of microprobe was defined on the MRI morphological image, and then was copied onto the oxy-localization map and oxy-amplitude map to extract the values of significant re-oxygenation (T), percent BOLD signal change (ΔPSC). The mean difference of pO2(ΔpO2) measured by fiber-optic microprobes before (pO2-Air) and after (pO2-Car) Carbogen inhalation in the ROI areas was calculated. Correlation analysis was madebetween cov (T value, Δ pO2) and cov (ΔPSC value, Δ pO2). The difference between pO2-Air and pO2-Car were tested by Mann Whitney U test. Results pO2 was successfully measured and recorded from 23 points in tumor using fiber-optic microprobe during the BOLD fMRI scan. The analysis results both of physiological and functional imaging parameters were as follows: pO2-Air=2.285 (19.056) mmHg, pO2-Car=14.701 (48.390) mmHg, ΔpO2=8.107 (33.557) mmHg, ΔPSC=0.402 (2.192) %, T=2.025 (8.293) . (1) 10 points were identified clearly in parenchyma area of tumor. The mean value of pO2 during air inhalation [19.462(21.511)mmHg] significantly increased after Carbogen inhalation [59.904(56.710)mmHg] (U=14.000, P=0.007) . (2) 5 points were identified in tumor necrosis area. The mean value of pO2 during air inhalation [0.149 (0.479) mmHg] showed no significant change comparing with Carbogen inhalation[0.273 (8.050) mmHg] (U=9.000, P=0.465) . (3) 8 points were identified in the boundary of tumor parenchyma and necrosis areas. Among which, 5 showed the similar pO2 change to that located in tumor necrosis area, 2 showed the similar to the tumor parenchyma. However, the pO2 showed continuously decrease after Carbogen inhalation in the last 1 point. The ΔpO2 measured from the total of 23 points correlated positively to ΔPSC and T value extracted from the corresponding ROI (r=0.660, 0.576, P<0.01). The ΔpO2 measured from 10 points in tumor parenchyma correlated positively to ΔPSC(r=0.717, P=0.020). Conclusion Oxy-localization map and oxy-amplitude map generated from BOLD fMRI combined with non-HRF post-processing algorithm could show reliably not only the location but also the extent where the re-oxygenation occurred within tumor. Key words: Glioma; Magnetic resonance imaging; Animal experimentation

Evaluation of tumour vascular distribution and function using immunohistochemistry and BOLD fMRI with carbogen inhalation

To evaluate oxygenation changes in rat subcutaneous C6 gliomas using blood-oxygen-level dependent (BOLD) functional magnetic resonance imaging (fMRI) combined with non-haemodynamic response function (non-HRF) analysis. BOLD fMRI were performed during carbogen inhalation in 20 Wistar rats bearing gliomas. Statistical maps of spatial oxygenation changes were computed by a dedicated non-HRF analysis algorithm. Three types of regions of interest (ROIs) were defined: (1) maximum re-oxygenation zone (ROImax), (2) re-oxygenation zones that were less than the maximum re-oxygenation (ROInon-max), and (3) zones without significant re-oxygenation (ROInone). The values of percent BOLD signal change (PSC), percent enhancement (ΔSI), and significant re-oxygenation (T) were extracted from each ROI. Tumours were sectioned for histology using the fMRI scan orientation and were stained with haematoxylin and eosin and CD105. The number of microvessels (MVN) in each ROI was counted. Differences and correlations among the values for T, PSC, ΔSI, and MVN were determined. After carbogen inhalation, the PSC significantly increased in the ROImax areas (p<0.01) located in the tumour parenchyma. No changes occurred in any of the ROInone areas (20/20). Some changes occurred in a minority of the ROInon-max areas (3/60) corresponding to tumour necrosis. MVN and PSC (R=0.59, p=0.01) were significantly correlated in the ROImax areas. In the ROInon-max areas, MVN was significantly correlated with PSC (R=0.55, p=0.00) and ΔSI (R=0.37, p=0.00). Statistical maps obtained via BOLD fMRI with non-HRF analysis can assess the re-oxygenation of gliomas.

Monitoring oxygen levels in orthotopic human glioma xenograft following carbogen inhalation and chemotherapy by implantable resonator-based oximetry.

Hypoxia is a critical hallmark of glioma, and significantly compromises treatment efficacy. Unfortunately, techniques for monitoring glioma pO2 to facilitate translational research are lacking. Furthermore, poor prognosis of patients with malignant glioma, in particular glioblastoma multiforme, warrant effective strategies that can inhibit hypoxia and improve treatment outcome. EPR oximetry using implantable resonators was implemented for monitoring pO2 in normal cerebral tissue and U251 glioma in mice. Breathing carbogen (95% O2 + 5% CO2 ) was tested for hyperoxia in the normal brain and glioma xenografts. A new strategy to inhibit glioma growth by rationally combining gemcitabine and MK-8776, a cell cycle checkpoint inhibitor, was also investigated. The mean pO2 of left and right hemisphere were ∼56-69 mmHg in the normal cerebral tissue of mice. The mean baseline pO2 of U251 glioma on the first and fifth day of measurement was 21.9 ± 3.7 and 14.1 ± 2.4 mmHg, respectively. The mean brain pO2 including glioma increased by at least 100% on carbogen inhalation, although the response varied between the animals over days. Treatment with gemcitabine + MK-8776 significantly increased pO2 and inhibited glioma growth assessed by MRI. In conclusion, EPR oximetry with implantable resonators can be used to monitor the efficacy of carbogen inhalation and chemotherapy on orthotopic glioma in mice. The increase in glioma pO2 of mice breathing carbogen can be used to improve treatment outcome. The treatment with gemcitabine + MK-8776 is a promising strategy that warrants further investigation.

Skeletal muscle and glioma oxygenation by carbogen inhalation in rats: a longitudinal study by EPR oximetry using single-probe implantable oxygen sensors.

The feasibility of EPR oximetry using a single-probe implantable oxygen sensor (ImOS) was tested for repeated measurement of pO₂ in skeletal muscle and ectopic 9L tumors in rats. The ImOS (50 mm length) were constructed using nickel-chromium alloy wires, with lithium phthalocyanine (LiPc, oximetry probe) crystals loaded in the sensor loop and coated with AF 2400(®) Teflon. These ImOS were implanted into the skeletal muscle in the thigh and subcutaneous 9L tumors. Dynamic changes in tissue pO₂ were assessed by EPR oximetry at baseline, during tumor growth, and repeated hyperoxygenation with carbogen breathing. The mean skeletal muscle pO₂ of normal rats was stable and significantly increased during carbogen inhalation in experiments repeated for 12 weeks. The 9L tumors were hypoxic with a tissue pO₂ of 12.8 ± 6.4 mmHg on day 1; however, the response to carbogen inhalation varied among the animals. A significant increase in the glioma pO₂ was observed during carbogen inhalation on day 9 and day 14 only. In summary, EPR oximetry with ImOS allowed direct and longitudinal oxygen measurements in deep muscle tissue and tumors. The heterogeneity of 9L tumors in response to carbogen highlights the need to repeatedly monitor pO₂ to confirm tumor oxygenation so that such changes can be taken into account in planning therapies and interpreting results.

Regional Cerebral Blood Flow and Cerebrovascular Reactivity in Alzheimer's Disease and Vascular Dementia Assessed by Arterial Spinlabeling Magnetic Resonance Imaging

Hemodynamic disturbance in cerebral blood flow (CBF) is common in both Alzheimer's disease (AD) and vascular dementia (VaD).The aim of this study is to investigate the different patterns of regional cerebral blood flow (rCBF) change and cerebrovascular reactivity (CVR) in these two types of dementia. Mean flow velocity (MFV) of middle cerebral artery and rCBF were measured by Transcranial Doppler ultrasound (TCD) and arterial spin-labeling (ASL) magnetic resonance, separately. CVR was evaluated by MFV or rCBF change in response to 5% CO2 inhalation. The ASL results showed that, rCBF was significantly lower in both the bilateral frontal and temporal lobes in AD group and lower in left frontal and temporal white matter in patients with VaD. CVR calculated by rCBF was impaired more severely in bilateral frontal cortices in AD. Conversely, TCD tests failed to demonstrate significant difference in MFV and CVR between the two groups. It is concluded that the different patterns detected by ASL in resting rCBF change and cerebrovascular reactivity in response to carbogen inhalation may serve as a potential marker to distinguish AD and VaD.

Sudden Sensorineural Hearing Loss After Laparoscopic Cholecystectomy Under General Anesthesia

Sudden sensorineural hearing loss is infrequent, but it is considered an otologic emergency. Although multiple etiologies have been identified, idiopathic sudden sensorineural hearing loss is most common. Sudden sensorineural hearing loss following non-otologic surgery under general anesthesia is an extremely rare complication. A 55-year-old man presented with hearing loss, tinnitus in his right ear, which developed right after laparoscopic cholecystectomy. Pure tone audiogram showed profound sensorineural hearing loss in the right ear. Treatment included intravenous prednisolone, intratympanic dexamethasone, vasodilator and carbogen inhalation. The patient had improved hearing and resolution of tinnitus. This report represents the first documented case of unilateral sudden sensorineural hearing loss after laparoscopic cholecystectomy under general anesthesia. J Med Cases. 2013;4(11):742-745 doi: https://doi.org/10.4021/jmc1512w

Levodopa does not change cerebral vasoreactivity in Parkinson's disease

The aim of this work was to study cerebral vasoreactivity to hypercapnia in Parkinson's disease (PD) before and after levodopa administration. The prospective study was conducted in 20 patients presenting with PD, using 3T blood oxygenation level-dependent (BOLD) functional MRI (fMRI) covering the whole brain. The hypercapnic stimulus was block-designed using carbogen inhalation, a gas mixture of 7% CO2 and 93% O2, before (OFF) and 60 minutes after administration of a suprathreshold (120%) therapeutic L-dopa dose (ON). Ten age-matched controls were enrolled for between-group comparisons. Analyses were conducted with a random effects model and corrected for multiple comparisons. No adverse reaction to the hypercapnic stimulus was reported. However, 10 patients and 2 controls were excluded because of incomplete protocol realization, inappropriate hypercapnic stimulus, or excessive movements, leaving 10 patients and 8 controls for further analyses. The hypercapnic stimulus increased whole-brain BOLD signal of 1.48% ± 0.06% (mean ± standard error) in controls, 1.59% ± 0.05% in patients OFF, and 1.62% ± 0.09% in patients ON. Regions of interest analyses showed a signal increase in gray matter of 2.60% ± 0.16% in controls, 2.89% ± 0.21% in patients OFF, and 2.87% ± 0.12% in patients ON. No global or regional significant difference was detected, when comparing patients OFF and ON L-dopa, or between patients and controls. Contrary to Alzheimer's disease, the vasoreactivity to hypercapnia was normal in PD before and after L-dopa administration, compared to controls. This negative result is an important finding, especially for neuroscientists using fMRI to investigate motricity and cognition, discarding a significant confounding effect.

Treatment options for central retinal artery occlusion.

Opinion statementCentral retinal artery occlusion (CRAO) is an ocular emergency and is the ocular analogue of cerebral stroke. It results in profound, usually monocular vision loss, and is associated with significant functional morbidity. The risk factors for CRAO are the same atherosclerotic risk factors as for stroke and heart disease. As such, individuals with CRAO may be at risk of ischemic end organ damage such as a cerebral stroke. Therefore, the management of CRAO is not only to restore vision, but at the same time to manage risk factors that may lead to other vascular conditions. There are a number of therapies that has been used in the treatment of CRAO in the past. These include carbogen inhalation, acetazolamide infusion, ocular massage and paracentesis, as well as various vasodilators such as intravenous glyceryl trinitrate. None of these “standard agents” have been shown to alter the natural history of disease definitively. There has been recent interest shown in the use of thrombolytic therapy, delivered either intravenously or intra-arterially by direct catheterisation of the ophthalmic artery. Whilst a number of observational series have shown that the recovery of vision can be quite dramatic, two recent randomised controlled trials have not demonstrated efficacy. On the contrary, intra-arterial delivery of thrombolytic may result in an increased risk of intracranial and systemic haemorrhage, while the intravenous use of tissue plasminogen activator (tPA) was not shown to be efficacious within 24 h of symptom onset. Nevertheless, both of these studies have shown one thing in common, and that is for treatment to be effective in CRAO, it must be deployed within a short time window, probably within 6 h of symptom onset. Therefore, while CRAO is a disease that does not have a treatment, nevertheless it needs to follow the same principles of treatment as any other vascular end organ ischaemic disease. That is, to attempt to reperfuse ischemic tissue as quickly as possible and to institute secondary prevention early.

Effects of Carbogen on Cochlear Blood Flow and Hearing Function Following Acute Acoustic Trauma in Guinea Pigs

Disturbances of microcirculation and hemorheological changes in the inner ear are the results of noise-induced hearing loss (NIHL). Both the disturbances of microcirculation and hemorheological changes are the etiologies of NIHL development, but they are also the results. Although previous reports that inhalation of high concentration of CO(2) may increase cochlear blood flow (CoBF), the effects of carbogen on the cochlear microcirculation and NIHL remain unclear. Changes induced by noise, carbogen and pure oxygen within the cochlear lateral wall microvasculature and in hearing thresholds were observed in guinea pigs using intravital microscopy and the auditory brainstem response. At the same time, arterial oxygen saturation and morphologic changes of cochlear hair cells were observed. Carbogen inhalation increased vessel diameters and blood flow velocities. Hearing thresholds elevation in the carbogen group was smaller than those in the control and oxygen group (p <0.05). Carbogen inhalation produced a trend toward less threshold shift after noise exposure, which reached statistical significance after day 3 (p <0.01). Respiratory acidosis was not found in our study. The segmented basal membranes of Corti in three groups indicated that no losses or discorders of hair cells were found. Carbogen inhalation can preserve hearing in animal models after acute acoustic trauma.

Dynamic and simultaneous MR measurement of R1 and R2* changes during respiratory challenges for the assessment of blood and tissue oxygenation

This work presents a novel method for the rapid and simultaneous measurement of R1 and R2* relaxation rates. It is based on a dynamic short repetition time steady-state spoiled multigradient-echo sequence and baseline R1 and B1 measurements. The accuracy of the approach was evaluated in simulations and a phantom experiment. The sensitivity and specificity of the method were demonstrated in one volunteer and in four patients with intracranial tumors during carbogen inhalation. We utilized (ΔR2*, ΔR1) scatter plots to analyze the multiparametric response amplitude of each voxel within an area of interest. In normal tissue R2* decreased and R1 increased moderately in response to the elevated blood and tissue oxygenation. A strong negative ΔR2* and ΔR1 response was observed in veins and some tumor areas. Moderate positive ΔR2* and ΔR1 response amplitudes were found in fluid-rich tissue as in cerebrospinal fluid, peritumoral edema, and necrotic areas. The multiparametric approach was shown to increase the specificity and sensitivity of oxygen-enhanced MRI compared to measuring ΔR2* or ΔR1 alone. It is thus expected to provide an optimal tool for the identification of tissue areas with low oxygenation, e.g., in tumors with compromised oxygen supply.

Accelerated Radiotherapy With Carbogen and Nicotinamide for Laryngeal Cancer: Results of a Phase III Randomized Trial

To report the results from a randomized trial comparing accelerated radiotherapy (AR) with accelerated radiotherapy plus carbogen inhalation and nicotinamide (ARCON) in laryngeal cancer. Patients with cT2-4 squamous cell laryngeal cancer were randomly assigned to AR (68 Gy within 36 to 38 days) or ARCON. To limit the risk of laryngeal necrosis, ARCON patients received 64 Gy on the laryngeal cartilage. The primary end point was local control. Secondary end points were regional control, larynx preservation, toxicity, disease-free survival, and overall survival. In a translational side study, the hypoxia marker pimonidazole was used to assess the oxygenation status in tumor biopsies. From April 2001 to February 2008, 345 patients were accrued. After a median follow-up of 44 months, local tumor control rate at 5 years was 78% for AR versus 79% for ARCON (P = .80), with larynx preservation rates of 84% and 87%, respectively (P = .48). The 5-year regional control was significantly better with ARCON (93%) compared with AR (86%, P = .04). The improvement in regional control was specifically observed in patients with hypoxic tumors and not in patients with well-oxygenated tumors (100% v 55%, respectively; P = .01). AR and ARCON produced equal levels of toxicity. Despite lack of benefit in local tumor control for advanced laryngeal cancers, a significant gain in regional control rate, with equal levels of toxicity, was observed in favor of ARCON. The poor regional control of patients with hypoxic tumors is specifically countered by ARCON treatment.

High-Resolution 3D MR Microangiography of the Rat Ocular Circulation

To develop high-spatial-resolution magnetic resonance (MR) microangiography techniques to image the rat ocular circulation. Animal experiments were performed with institutional Animal Care Committee approval. MR microangiography (resolution, 84×84×84 μm or 42×42×84 μm) of the rat eye (eight rats) was performed by using a custom-made small circular surface coil with an 11.7-T MR unit before and after monocrystalline iron oxide nanoparticle (MION) injection. MR microangiography measurements were made during air, oxygen, and carbogen inhalation. From three-dimensional MR microangiography, the retina was virtually flattened to enable en face views of various retinal depths, including the retinal and choroidal vascular layers. Signal intensity changes within the retinal or choroidal arteries and veins associated with gas challenges were analyzed. Statistical analysis was performed by using paired t tests, with P<.05 considered to indicate a significant difference. Bonferroni correction was used to adjust for multiple comparisons. The central retinal artery, long posterior ciliary arteries, and choroidal vasculature could be distinguished on MR microangiograms of the eye. With MR microangiography, retinal arteries and veins could be distinguished on the basis of blood oxygen level-dependent contrast. Carbogen inhalation-enhanced MR microangiography signal intensity in both the retina (P=.001) and choroid (P=.027) compared with oxygen inhalation. Carbogen inhalation showed significantly higher signal intensity changes in the retinal arteries (P=.001, compared with oxygen inhalation), but not in the veins (P=.549). With MION administration, MR microangiography depicted retinal arterial vasoconstriction when the animals were breathing oxygen (P=.02, compared with animals breathing air). MR microangiography of the eye allows depth-resolved imaging of small angiographic details of the ocular circulation. This approach may prove useful in studying microvascular pathologic findings and neurovascular dysfunction in the eye and retina.