Altered Oxygenation, Vascular and Ischemic Pain Responses in Adults with Sickle Cell Anemia

Abstract The clinical hallmark of sickle cell anemia is the vaso-occlusive pain crisis. Although the exact cause for severe vaso-occlusive painful events is unknown, sickle cell microvasculature occlusion is thought to be the proximate cause producing tissue hypoxia, reperfusion injury and acute pain. Endothelial dysfunction is a prominent characteristic of sickle cell anemia, and it is unclear to what extent this abnormal vascular response contributes to vaso-occlusion and pain. We sought to evaluate the effects of hypoxia on sickle cell pain by performing a forearm ischemic pain test as a potential in vivo model for vaso-occlusion. We hypothesized that sickle cell anemia patients would tolerate a shorter period of ischemia before reaching pain tolerance. We further hypothesized that sickle patients would show more hypoxia and increased vasodilation. Thirty adults with sickle cell anemia were recruited and matched by age and sex to 30 normal volunteers. We first performed a timed ischemic pain test with brachial artery occlusion until subjects first reported pain (pain threshold) and until maximum pain tolerated (pain tolerance). Sickle cell subjects first reported pain at 411 vs. 589 s for normal volunteers (mean, p=0.07). Occlusion time to pain tolerance was significantly shorter for sickle cell patients (637 vs. 918 s, mean, p=0.004). Despite this difference, both groups reported nearly identical pain scores at threshold and tolerance. Stepwise linear regression for all subjects against 8 variables likely to influence pain showed sickle status (p=0.002) and gender (p=0.0008) were independently associated with time to tolerance, supporting our initial hypothesis. Testing with continuous physiological monitoring was next repeated in sub-groups of 7 sickle cell and 9 normal subjects in an effort to understand the association between ischemia and pain progression. Before, during, and after brachial artery occlusion, oxygenated/deoxygenated hemoglobin concentration and tissue oxygen saturation were continuously monitored with near-infrared spectroscopy at the thenar eminence. We also recorded cutaneous blood flow with a Laser Speckle Contrast Imager (FLPI-2) in the volar aspect of forearm and continuous blood pressure and pulse in the contralateral arm. Monitoring was performed during steady state prior to occlusion (15 min), during occlusion until pain tolerance, and during recovery (20 min). At steady state, sickle cell subjects had higher median heart rate (68 vs. 62 bpm, p=0.05) and cutaneous blood flow (81.8 vs. 46.8 a.u., p<0.0001). They also had lower median oxygenated hemoglobin (51.3 vs. 68 μM, p<0.0001), tissue oxygen saturation (62 vs. 68%, p<0.0001) and blood pressure (110/75 vs. 126/80, p<0.0001). During occlusion, the absolute decline in blood flow, calculated as a difference between median steady state flow and flow at 2 min of occlusion, was greater with sickle group (40.8 vs. 20.63 a.u., p=0.05). However, sickle cell oxygenated hemoglobin decreased at a slower rate (-0.12 vs. -0.15, median, p<0.0001). As before, time to pain tolerance was shorter with sickle cell (566 vs. 1460 sec., median, p=0.009). Surprisingly, sickle subjects had higher median tissue oxygen saturation (28.9 vs. 25.7%, p=0.005) and oxygenated hemoglobin (22.9 vs. 20.0 μM, p=0.006) at pain tolerance, but blood flow was not different. Consistent with this pattern, recovery of oxygenated hemoglobin occurred at a slower rate in the sickle group (0.61 vs. 0.84, median, p<0.0001). Sickle subjects had a brief hyperemic recovery period during which they returned to lower baseline levels of tissue oxygen saturation and oxygenated hemoglobin, and the duration of this hyperemic recovery was the same in normal volunteers. Overall, sickle cell subjects have significantly lower steady state tissue oxygenation, but they are less tolerant of hypoxia and develop pain at higher oxygenated hemoglobin levels during ischemia. Despite higher oxygenated hemoglobin during ischemia, sickle cell subjects have a significantly higher absolute decline in blood flow during occlusion, suggesting an altered hypoxic response compared to controls. This might suggest a hypersensitive hypoxic pain response, possibly due to the presence of chronic pain, and altered oxygen sensing. The ischemic pain test is a potential in vivo model for early stage trials of drugs that alter either acute pain transmission or oxygen delivery to tissues. Disclosures No relevant conflicts of interest to declare.

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Ischemic Pain Testing Demonstrates Hypoxia Dependent Early Pain and Hypoxia Independent Persistent Pain Responses in Adults with Sickle Cell Anemia

Blood ◽

10.1182/blood.v128.22.3657.3657 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3657-3657

Author(s):

Kathleen Vaughan ◽

Joseph Kim ◽

Daniel Lichy ◽

Nathan S Fishman ◽

Amit Khandhadia ◽

...

Keyword(s):

Sickle Cell ◽

Sickle Cell Anemia ◽

Pain Threshold ◽

Tissue Oxygenation ◽

Pain Tolerance ◽

Ischemic Pain ◽

Repeat Testing ◽

Pain Scores ◽

Pain Test ◽

Pain Testing

Abstract The hallmark manifestation of homozygous sickle cell disease (SCD) is acute pain. The underlying etiology is unknown. It is believed that hypoxia induces changes in erythrocyte shape and produces microvasculature occlusion by sickled red cells. Vascular occlusion is believed to represent the event inducing tissue hypoxia, reperfusion injury and pain. Studies have only recently characterized pain responses to experimental stimuli in rodents and humans with SCD using quantitative sensory testing (QST). SCD is characterized by thermal and mechanical sensitivity, and there is evidence of central sensitization (heightened sensitivity to pain) from QST, temporal summation and functional MRI studies. However, the effect of hypoxia upon nociception has not been studied despite the need for hypoxia to induce sickle hemoglobin polymerization. The ischemic tourniquet pain test is a QST used to investigate nociception. It was the first QST to demonstrate opioid analgesia. While it is assumed that the resulting pain is due to hypoxia, no studies have demonstrated the degree of hypoxia needed to produce pain. Methods: Thirty adults with SCD and 30 age and sex matched 30 controls underwent the ischemic pain test. A pneumatic cuff was inflated around the upper arm to induce forearm hypoxia, and the time from cuff inflation to first reported pain (pain threshold) and until pain became intolerable (pain tolerance) was measured. Pain was quantified on a 20 point scale. Time to pain threshold and tolerance were the primary end points. Testing was repeated after a washout period in a subset of the initial subjects: 18 SCD patients and 22 controls. Repeat testing proceeded with a 15 minute observation period followed by the ischemic pain test with the time and pain score recorded at threshold and tolerance. Subjects were monitored after cuff deflation during recovery with pain scores obtained at 30 seconds, then every minute for 5 minutes and finally every 3 minutes over a total recovery period of 20 minutes. Skeletal muscle tissue oxygenation at the thenar eminence was measured continuously with a near infrared spectroscopy (NIRS) monitor (OxiplexTS; ISS, Champaign, IL). Results: SCD subjects reached the pain threshold at a mean of 6.44 versus 11.57 minutes in controls (p=0.07). Time to pain tolerance was significantly different (SS 11.29 versus controls 19.59 minutes; p=0.004). Both groups reported identical pain scores. By stepwise linear regression, SCD (p=0.002) and gender (p=0.0008) were associated with time to pain tolerance (r2=0.29), while recent opioid use and pain crisis frequency were not. Because these results demonstrated that SCD adults reach tolerance more rapidly than controls, we sought to determine if this difference was due to tissue hypoxia. Pain scores with repeat testing were not significantly different at threshold or tolerance. However, pain score curves over testing and recovery were significantly different (p=0.003, Fig 1A). SCA had pain above baseline after 11 minutes of recovery (p=0.02) suggesting a persistent pain response compared to controls. Oxyhemoglobin and deoxyhemoglobin from NIRS were not different between groups at the primary endpoints (Fig 1B and 1C). StO2 (% tissue oxygenation, Fig 1D) at both threshold and tolerance was not different between SCD and controls, suggesting that the onset and maximal level of pain during this QST is defined an StO2 thresholds 40% common to sickle cell patients and controls. However, oxyhemoglobin, deoxyhemoglobin and StO2 had already recovered to baseline by the time the pain was evident (Fig 1B, 1C and 1D). Conclusions: Adults with SCD reach hypoxia induced, experimental pain earlier than NVs. Time to maximal pain is associated with SCD and sex. NIRS showed that pain tolerance occurred at a uniform tissue oxygenation threshold indicating hypoxia is the primary determinant for sensing acute pain. However, persistent SCD pain was independent of tissue oxygenation, and could be explained by the presence of peripheral or central sensitization. These data suggest that SCD pain treatment may require improved oxygen delivery to affected tissues and analgesics. Figure 1. Nociceptive and NIRS responses to ischemic pain testing in adults with sickle cell anemia. Figure 1. Nociceptive and NIRS responses to ischemic pain testing in adults with sickle cell anemia. Disclosures No relevant conflicts of interest to declare.

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Imaging hemoglobin oxygen saturation in sickle cell disease patients using noninvasive visible reflectance hyperspectral techniques: effects of nitric oxide

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00243.2003 ◽

2003 ◽

Vol 285 (3) ◽

pp. H1183-H1189 ◽

Cited By ~ 34

Author(s):

Karel J. Zuzak ◽

Mark T. Gladwin ◽

Richard O. Cannon ◽

Ira W. Levin

Keyword(s):

Blood Flow ◽

Sickle Cell Disease ◽

Oxygen Saturation ◽

Sickle Cell ◽

Skin Tissue ◽

Tissue Oxygen Saturation ◽

Cell Disease ◽

Tissue Oxygen ◽

Blood Flows ◽

Visible Reflectance

Sickle cell disease is characterized by microvascular occlusion and hemolytic anemia, factors that impair tissue oxygen delivery. We use visible reflectance hyperspectral imaging to quantitate skin tissue hemoglobin oxygen saturation (HbO2) and to determine whether changes in blood flow during nitric oxide (NO) stimulation or gas administration (therapies proposed for this disease) improve skin tissue oxygen saturation in five patients with sickle cell disease. Compared with six healthy African-American subjects, sickle cell patients exhibited higher forearm blood flows (7.4 ± 1.8 vs. 3.2 ± 0.4 ml·min–1·100 ml tissue–1, P = 0.037) but significantly reduced percentages of skin HbO2 (61.0 ± 0.2 vs. 77.5 ± 0.2%, P < 0.001). Administration of acetylcholine to patients increased blood flow by 15.1 ± 3.8 ml·min–1·100 ml tissue–1 and the percentage of skin HbO2 by 4.1 ± 0.3% ( P = 0.02, P < 0.001, respectively, from baseline values). Sodium nitroprusside, a direct NO donor, increased blood flow by 3.9 ± 1.1 ml/min and the percentage of skin HbO2 by 2.9 ± 0.3% ( P = 0.02, P < 0.001, respectively). NO inhalation had no effect on forearm blood flow, yet increased the percentage of skin HbO2 by 2.3 ± 0.3% ( P < 0.001). Percentages of skin HbO2 were exponentially related to blood flow ( R = 0.97, P < 0.001), indicating a limit to skin tissue oxygen saturation at high blood flows. Thus, for acetylcholine infusion leading to blood flows sevenfold greater than those of healthy resting African-American subjects, patients still exhibited lower percentages of skin HbO2 (65.2 ± 0.2 vs. 77.5 ± 0.2%, P < 0.001). Visible reflectance hyperspectral imaging demonstrates that either the stimulation or the administration of NO pharmacologically or by gas inhalation improves, but does not normalize, skin tissue oxygen saturation in patients with sickle cell disease.

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Is there a role for selective vasodilation in the management of sickle cell disease?

Blood ◽

10.1182/blood.v71.3.597.597 ◽

1988 ◽

Vol 71 (3) ◽

pp. 597-602 ◽

Cited By ~ 18

Author(s):

GP Rodgers ◽

MS Roy ◽

CT Noguchi ◽

AN Schechter

Keyword(s):

Blood Flow ◽

Steady State ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Microvascular Obstruction ◽

Controlled Study ◽

Control Group ◽

Cell Disease ◽

Retinal Arteriolar

Abstract To test the hypothesis that microvascular obstruction to blood flow at the level of the arteriole may be significant in individuals with sickle cell anemia, the ophthalmologic effects of orally administered nifedipine were monitored in 11 steady-state patients. Three patients with evidence of acute peripheral retinal arteriolar occlusion displayed a prompt reperfusion of the involved segment. Two other patients showed fading of retroequatorial red retinal lesions. Color vision performance was improved in six of the nine patients tested. The majority of patients also demonstrated a significant decrease in the amount of blanching of the conjunctiva which reflects improved blood flow to this frequently involved area. Such improvements were not observable in a control group of untreated stable sickle cell subjects. These findings support the hypothesis that inappropriate vasoconstriction or frank vasospasm may be a significant factor in the pathogenesis of the microvascular lesions of sickle cell disease and, further, that selective microvascular entrapment inhibition may offer an additional strategy to the management of this disorder. We believe a larger, placebo-controlled study with nifedipine and similar agents is warranted.

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A study of the blood flow restriction pressure of a tourniquet system to facilitate development of a system that can prevent musculoskeletal complications

American Journal of Disaster Medicine ◽

10.5055/ajdm.2017.0267 ◽

2017 ◽

Vol 12 (3) ◽

pp. 139-145 ◽

Cited By ~ 1

Author(s):

Hiroyuki Maeda, MD, PhD ◽

Hideaki Iwase, PhD ◽

Akio Kanda, MD, PhD ◽

Itaru Morohashi, MD, PhD ◽

Kazuo Kaneko, MD, PhD ◽

...

Keyword(s):

Blood Flow ◽

Body Weight ◽

Oxygen Saturation ◽

Blood Flow Restriction ◽

Behavioral Experiment ◽

Tissue Oxygen Saturation ◽

Control Group ◽

Severe Bleeding ◽

Tissue Oxygen ◽

Flow Restriction

Background: After an emergency or disaster, subsequent trauma can cause severe bleeding and this can often prove fatal, so promptly stopping that bleeding is crucial to preventing avoidable trauma deaths. A tourniquet is often used to restrict blood flow to an extremity. In operation and hospital, the tourniquet systems currently in use are pneumatically actuated by an air compressor, so they must have a steady power supply. These devices have several drawbacks: they vibrate and are noisy since they are pneumatically actuated and they are far from portable since they are large and heavy.Introduction: Presumably, the drawbacks of pneumatic tourniquets could be overcome by developing a small, lightweight, vibration-free, quiet, and battery- powered tourniquet system. The current study built a small, vibration-free electrohydrodynamic (EHD) pump and then used that pump to restrict blood flow to the leg of rats in an experiment. This study explored the optimal conditions for effective restriction of blood flow by assessing biochemical and musculoskeletal complications following the restriction of blood flow, and this study also examined whether or not an EHD pump could be used to actuate a tourniquet system.Methods: A tourniquet cuff (width 12 mm × length 150 mm, material: polyolefin) was placed on the thigh of Wistar rats and pressure was applied for 2 hours by a device that uses EHD phenomena to generate pressure (an EHD pump). Animals were divided into four groups based on how much compressive pressure was applied with a tourniquet: 40 kPa (300 mm Hg, n = 13), 30 kPa (225 mm Hg, n = 12), 20 kPa (150 mm Hg, n = 15), or 0 kPa (controls, n = 25). Tissue oxygen saturation (regional oxygen saturation, denoted here as rSO2) was measured to assess the restriction of blood flow. To assess behavior once blood flow resumed, animal activity was monitored for third day and the amount of movement was counted with digital counters. Body weight was measured before and after the behavioral experiment, and changes in body weight were determined. Blood was sampled after a behavioral experiment and biochemically assessed and creatine kinase (CK) levels were measured.Results: Tissue oxygen saturation decreased significantly in each group. When a tourniquet was applied at a pressure of 30 kPa or more, tissue oxygen saturation decreased significantly. The amount of movement (the count) over third day decreased more when a tourniquet was applied at a higher pressure. The control group resumed the same amount of movement per day second after blood flow resumed. Animals to which a tourniquet was applied at a pressure of 20 or 30 kPa resumed the same amount of movement third day after blood flow resumed. In contrast, animals to which a tourniquet was applied at a pressure of 40 kPa did not resume the same amount of movement third day after blood flow resumed. After the behavioral experiment, animals to which a tourniquet was applied at a pressure of 40 kPa had a significantly lower body weight in comparison to the control group. After the behavioral experiment, animals to which a tourniquet was applied at a pressure of 40 kPa had significantly elevated CK levels in comparison to the control group.Discussion and Conclusion: A relationship between blood flow restriction pressure and tissue oxygen saturation was noted. rSO2 measurement can be used to assess the restriction of blood flow during surgery. On the basis of the decrease in rSO2, blood flow was effectively restricted at a pressure of 30 kPa or more. When, however, blood flow was restricted at a pressure of 40 kPa, weight loss and decreased movement were noted and CK levels increased after the behavioral experiment. Thus, complications had presumably developed due to damage to muscle tissue. These findings indicate that blood flow was effectively restricted in this experiment and they also indicate the existence of an optimal blood flow restriction pressure that does not cause musculoskeletal complications. The pressure in question was around 30 kPa. The tourniquet system that was developed here is actuated with an EHD pump that is still in the trial stages. That said, its pressure can readily be controlled and this pump could be used in a tourniquet system since it is quiet, vibration-free, and small. The pressure of this pump can be finely adjusted to prevent musculoskeletal complications.

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Cerebral and Skeletal Muscle Tissue Oxygenation during Exercise in Children with Sickle Cell Anemia

Blood ◽

10.1182/blood-2019-124262 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2280-2280

Author(s):

Christina M Barriteau ◽

Abraham Chiu ◽

Mark Rodeghier ◽

Robert I Liem

Keyword(s):

Skeletal Muscle ◽

Oxygen Saturation ◽

Exercise Testing ◽

Sickle Cell Anemia ◽

Tissue Oxygenation ◽

Vastus Lateralis ◽

Work Load ◽

Tissue Oxygen Saturation ◽

Tissue Oxygen ◽

Warm Up

Introduction: Sickle cell anemia (SCA) causes impaired tissue oxygenation. Children with SCA have lower peak fitness levels compared to controls. The contribution of alterations in skeletal muscle and cerebral tissue oxygenation to exercise limitation in SCA remains unclear. Near infrared spectroscopy (NIRS) is a validated, non-invasive method to measure tissue oxygen saturation. We hypothesize that compared to controls, children with SCA will exhibit greater reductions in regional tissue oxygen saturation (StO2) measured in the quadriceps (vastus lateralis) and pre frontal cortex (PFC) across all workloads during maximal cardiopulmonary exercise testing (CPET). Methods: We used the CASMED ELITE NIRS tissue oximeter to measure tissue oxygen saturation in the PFC and vastus lateralis (VL) muscle during all phases of maximal CPET, including warm up, active exercise and recovery, in 17 subjects with SCA (mean age 13.5 years) and 13 controls (mean age 15.2 years). Maximal CPET was conducted by cycle ergometry using a standard ramp protocol until volitional exhaustion was reached by all participants. Peak oxygen consumption (VO2) was measured from breath-by breath gas exchange data collected during CPET. Results: All subjects and controls completed maximal CPET without adverse events. Peak VO2 was not statistically different in subjects with SCA versus controls (25.3±4.7 vs 29.5±8.9 mL/kg/min, p=0.22). Compared to controls, subjects with SCA had significantly lower PFC StO2 at all time points during exercise, including warm up, 20%, 40%, 60%, 80% and 100% of peak work load (p<0.01) (Figure 1a). Subjects with SCA demonstrated a significant decrease in PFC StO2 from warm up to 80% peak work load (-3.0±2.9% , p=0.002) and from warm up to 100% peak work load (-5.4±3.4 %, p<0.001) (Figure 1b). In contrast, controls did not demonstrate significant decreases in PFC StO2 from warm up to any point during exercise testing. VL StO2 did not significantly differ between subjects and controls during exercise (p=0.149, Figure 1c). Subjects with SCA demonstrated a significant increase in VL StO2 from warm up to 0% (+3.2±2.8%, p<0.001) and 20% peak work load (+2.3±2.5%, p=0.002) and a significant decrease in StO2 from warm up to 60% (-4.8±4.6%, p<0.001), 80% (-8.6±5.9%, p<0.001) and 100% peak work load (-10.5±6.3%, p<0.001) (Figure 1d). Controls had significant increase in VL StO2 from warm up to 0% peak work load (+4.3±4.0%, p=0.02) and a significant decrease only at 80% (-6.5±6.3%, p=0.003). Differences in PFC and VL StO2 between subjects and controls were also examined at the highest VO2 achieved by all participants. At a VO2 of 17.6 mL/kg/min, PFC StO2 was significantly lower in subjects with SCA versus controls (69.2±6.6 vs 79.5±5.3%, p<0.001). There was a trend toward lower VL StO2 in subjects versus controls (67.7±9.0 vs 73.2±7.9%, p=0.09). Conclusion: Unlike VL tissue oxygenation, PFC tissue oxygenation is relatively well preserved in subjects with SCA and controls during maximal CPET. However, compared to controls, subjects with SCA have lower PFC tissue oxygenation at warm up and during exercise as well as demonstrate significantly greater decreases in PFC tissue oxygenation during later stages of exercise. In contrast, VL tissue oxygenation is similar at warm up and during exercise for subjects and controls. VL tissue oxygenation increases during initial stages of exercise in a similar fashion in subjects with SCA and controls but subsequent decreases from warm up are greater in subjects with SCA during later stages of exercise. Future studies may further elucidate how SCA contributes to these observed differences in regional tissue oxygenation during exercise and their potential impact on exercise safety and fitness in this population. Disclosures No relevant conflicts of interest to declare.

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Evaluation of changes in the haemoglobin of skin and muscle tissue of the calf, as induced by topical application of a nonivamide/nicoboxil cream

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2013-0158 ◽

2014 ◽

Vol 92 (2) ◽

pp. 149-154 ◽

Cited By ~ 2

Author(s):

Jan M. Warnecke ◽

Thomas Wendt ◽

Stefan Winkler ◽

Matthias Schak ◽

Thorsten Schiffer ◽

...

Keyword(s):

Blood Flow ◽

Oxygen Saturation ◽

Optical Spectroscopy ◽

Topical Application ◽

Near Infrared ◽

Nir Spectroscopy ◽

Topical Administration ◽

Tissue Oxygen Saturation ◽

Tissue Oxygen

Topical agents like nonivamide and nicoboxil induce hyperaemisation and increase cutaneous blood flow and temperature. This study aimed to determine the effects of a nonivamide–nicoboxil cream on haemodynamics in the skin and calf muscle, via optical spectroscopy, discriminating between the changes for skin and muscle. Optical spectroscopy was applied in the visible (VIS) and near-infrared (NIR) wavelength range. The study determined the effect of the cream on changes in oxygenated (ΔoxyHb) and deoxygenated (ΔdeoxyHb) haemoglobin in skin and muscle, as well as on tissue oxygen saturation (SO2) in the skin of 14 healthy subjects. The left and right calves of the subjects were either treated with nonivamide–nicoboxil cream or were sham-administered. NIR spectroscopy allows noninvasive in-vivo examination of the oxygenation of human skeletal muscle. Topical administration of the nonivamide–nicoboxil cream significantly increased the concentration of oxygenated haemoglobin and tissue oxygen saturation in the skin, as well as the concentration of oxygenated haemoglobin in the muscle of the treated legs after 15 min, but with stronger and faster effects in the skin. The topical application of the nonivamide–nicoboxil cream increased blood flow in (smaller vessels of) the skin and muscle tissues.

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Is there a role for selective vasodilation in the management of sickle cell disease?

Blood ◽

10.1182/blood.v71.3.597.bloodjournal713597 ◽

1988 ◽

Vol 71 (3) ◽

pp. 597-602

Author(s):

GP Rodgers ◽

MS Roy ◽

CT Noguchi ◽

AN Schechter

Keyword(s):

Blood Flow ◽

Steady State ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Microvascular Obstruction ◽

Controlled Study ◽

Control Group ◽

Cell Disease ◽

Retinal Arteriolar

To test the hypothesis that microvascular obstruction to blood flow at the level of the arteriole may be significant in individuals with sickle cell anemia, the ophthalmologic effects of orally administered nifedipine were monitored in 11 steady-state patients. Three patients with evidence of acute peripheral retinal arteriolar occlusion displayed a prompt reperfusion of the involved segment. Two other patients showed fading of retroequatorial red retinal lesions. Color vision performance was improved in six of the nine patients tested. The majority of patients also demonstrated a significant decrease in the amount of blanching of the conjunctiva which reflects improved blood flow to this frequently involved area. Such improvements were not observable in a control group of untreated stable sickle cell subjects. These findings support the hypothesis that inappropriate vasoconstriction or frank vasospasm may be a significant factor in the pathogenesis of the microvascular lesions of sickle cell disease and, further, that selective microvascular entrapment inhibition may offer an additional strategy to the management of this disorder. We believe a larger, placebo-controlled study with nifedipine and similar agents is warranted.

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The Association of White Matter Hyperintensity Volume and Sickle Cell Anemia

Blood ◽

10.1182/blood.v128.22.1321.1321 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1321-1321

Author(s):

Nicholas Farris ◽

Henny H Billett ◽

Craig A Branch ◽

Caterina Minniti ◽

Kelsey Branch ◽

...

Keyword(s):

Blood Flow ◽

Cerebral Blood Flow ◽

White Matter ◽

Oxygen Saturation ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Laboratory Evaluation ◽

Exclusion Criterion ◽

Neurocognitive Performance ◽

3T Mri

Abstract Background:While overt cerebrovascular accidents (CVAs) are well recognized in patients with Sickle Cell Anemia (SCA), more subtle cerebrovascular diseases, including neurocognitive performance deficits and silent cerebral infarcts (SCIs), are present but less well understood, particularly in adults. SCI manifests as asymptomatic white matter hyperintensities (WMH) found on T2-weighted, diffusion-weighted or Fluid Attenuated Inversion Recovery (FLAIR) magnetic resonance images. WMH volume has been found to be negatively associated with IQ in SCA. We sought to clarify the role of WMH load by MRI using region of interest volume calculations in patients particularly at risk, adult patients with SCA. Methods: SCA (HbSS/HbSβ0) and AA subjects, ages 18-55 years old, with no evidence of TIA/Stroke, prothrombotic history, clotting or bleeding disorder, and not on anticoagulation were recruited. Hydroxyurea use was noted but was neither an inclusion nor exclusion criterion. Evaluation included a routine questionnaire for basic social, educational and health information. Steady state laboratory evaluation was obtained within one week of imaging. Neurocognitive performance was evaluated by the Cogstate battery at the time of the MRI. Cogstate analysis included tests of executive function (the Groton Maze Learning Test or GMLT), recall, social and emotional cognition and learning. 3T MRI included 3D-T1w , T2, FLAIR, pseudo-continuous arterial spin labeling and diffusion tensor imaging (DTI). Fractional anisotropy (FA) and mean diffusivity (MD) were extracted from DTI data and calculated for gray matter (GM) and white matter (WM). Cerebral blood flow (CBF) was also calculated for GM and WM separately. FLAIR images were reviewed (reviewer was blind for group) for WMHs using the NIH image analysis package MIPAV (http://mipav.cit.nih.gov/). WMH signal regions (ROI) were identified and selected/masked using the 'levelSet' ROI function on a slice-by-slice basis. ROIs were grouped, and average WMH volume (using slice thickness) calculated for each subject using the MIPAV Statistics Generator. Results:15 SCA and 11 AA subjects were recruited for the tailored questionnaire, 3T MRI, routine laboratory testing and neurocognitive testing. Both number and volume of ROI were increased in SCA patients (p=0.018 and p=0.052 respectively). GM and WM CBF were markedly increased in SCA patients (p=0.005 for both). GM-MD was increased in SCA patients (p=0.046) while increases in WM-FA and MD were of borderline significance (p=0.055 and p=0.564) respectively. These data are shown in the Table below. Although SCA patients fared significantly worse on the GMLT, p=0.020, there was no association of the GMLT with ROI volume (p=0.96). ROI volume was positively associated with MCHC (p=0.035), a dense cell biomarker, but we could not find an association with Hb, indirect bilirubin or reticulocyte count. MDWM FA and GM-MD also correlated significantly with MCHC but the major associations of DTI measurements, like those of both grey matter (GM) and white matter (WM) cerebral blood flow, were correlated with Hb levels (both GM and WM MD, p=0.004). There was no association of oxygen saturation or change in oxygen saturation with ROI number of volume. Conclusions: The etiology of the documented cognitive difference between SCA and HbA is unclear. Although there is some suggestion that WMH correlates with SCA outcome and may explain this discrepancy, the association is weak. We could not find as association of ROI number or ROI volume with cognitive outcome, nor could we find an association of ROI volume with any pertinent laboratory parameters except MCHC. Unlike CBF, WMH volume load, as represented by ROI volume, does not appear to correlate with the degree of anemia or with clinical disease. Whether cognitive impairment requires a "second hit" or whether it is multifactorial in nature, stemming from chronic oxidative stress, intermittent hypoxia or other factors, remains to be determined. Table Table. Disclosures No relevant conflicts of interest to declare.

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Abstract 105: Changes in NIRS-Measured Cerebral Tissue Oxygen Saturation During Hyperventilation: A Comparison Between NIRO™ and INVOS™

Circulation ◽

10.1161/circ.130.suppl_2.105 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Tetsuo Hatanaka ◽

Hiroshi Kaneko ◽

Aki Nagase ◽

Seishiro Marukawa

Keyword(s):

Blood Flow ◽

Oxygen Saturation ◽

Healthy Volunteers ◽

Near Infrared ◽

Tissue Oxygen Saturation ◽

Induced Response ◽

Tissue Oxygen ◽

Cerebral Tissue ◽

End Tidal ◽

Cerebral Tissue Oxygen Saturation

Introduction: Cerebral tissue oxygen saturation measured with transcranial near-infrared spectroscopy (NIRS) has been reported to predict neurological outcome of cardiac arrest patients. Because NIRS values are confounded by extracranial tissues, there can be considerable inter-device variation in the measured values. We compared hyperventilation-induced changes in NIRS values measured with 2 commercially available devices in healthy volunteers. Methods: After obtaining an approval from the ethics committee at Iseikai hospital and written informed consents, 29 healthy volunteers joined the study. Probes of NIRO™ 200NX (Hamamatsu Photonics, Japan) and INVOS™ 5100C (Covidien, USA) were applied respectively on the right and left side of the volunteers’ forehead. After obtaining the baseline values, the volunteers were asked to hyperventilate for 40 seconds attempting to reduce the end-tidal CO 2 by ~20 mmHg. Measurements were repeated, after 20 minutes of resting interval, with the probes applied on the contralateral sides. Hyperventilation-induced response of the NIRS value was categorized as “correct” when the average value over the 5 second period toward the end of the hyperventilation decreased by >15% the baseline or “erroneous” otherwise. Results: The mean (± SD) end-tidal CO 2 decreased from the baseline value of 36 ± 5.1 mmHg to 15.2 ± 4.4 mmHg during hyperventilation. Out of 58 measurements with each of the devices, NIRO values were “correct” in 54 (93.1%) measurements, whereas INVOS values were “correct” in 32 (52.2%) measurements. NIRO presented “erroneous” values on both sides of the forehead in no volunteers whereas INVOS presented “erroneous” values in 7 (35%) of 29 volunteers. Discussion: Hyperventilation consistently decreases cerebral blood flow in healthy subjects. Thus, the results of the present study suggest that NIRS devices may fail to reflect correct changes in cerebral tissue oxygen saturation in ~7% of measurements with NIRO and in ~48% with INVOS. The bilateral “erroneous” measurements with INVOS in 7 (35%) volunteers may suggest that INVOS is subject to confounding by extracranial tissues. A potential source of confounding may include the scalp where blood flow increases during hyperventilation.

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