Is methemoglobin an inert bystander, biomarker or a mediator of oxidative stress—The example of anemia?

Acute anemia increases the risk for perioperative morbidity and mortality in critically ill patients who experience blood loss and fluid resuscitation (hemodilution). Animal models of acute anemia suggest that neuronal nitric oxide synthase (nNOS)-derived nitric oxide (NO) is adaptive and protects against anemia-induced mortality. During acute anemia, we have observed a small but consistent increase in methemoglobin (MetHb) levels that is inversely proportional to the acute reduction in Hb observed during hemodilution in animals and humans. We hypothesize that this increase in MetHb may be a biomarker of anemia-induced tissue hypoxia. The increase in MetHb may occur by at least two mechanisms: (1) direct hemoglobin oxidation by increased nNOS-derived NO within the perivascular tissue and (2) by increased deoxyhemoglobin (DeoxyHb) nitrite reductase activity within the vascular compartment. Both mechanisms reflect a potential increase in NO signaling from the tissue and vascular compartments during anemia. These responses are thought to be adaptive; as deletion of nNOS results in increased mortality in a model of acute anemia. Finally, it is possible that prolonged activation of these mechanisms may lead to maladaptive changes in redox signaling. We hypothesize, increased MetHb in the vascular compartment during acute anemia may reflect activation of adaptive mechanisms which augment NO signaling. Understanding the link between anemia, MetHb and its treatments (transfusion of stored blood) may help us to develop novel treatment strategies to reduce the risk of anemia-induced morbidity and mortality

Sources of variation influencing concordance between functional MRI and direct cortical stimulation in brain tumor surgery

Object: Preoperative functional magnetic resonance imaging (fMRI) remains a promising method to aid in the surgical management of patients diagnosed with brain tumors. For patients that are candidates for awake craniotomies, surgical decisions can potentially be improved by fMRI but this depends on the level of concordance between preoperative brain maps and the maps provided by the gold standard intraoperative method, direct cortical stimulation (DCS). There have been numerous studies of the concordance between fMRI and DCS using sensitivity and specificity measures, however the results are variable across studies and the key factors influencing variability are not well understood. Thus, the present work addresses the influence of technical factors on fMRI and DCS concordance. Methods: Motor and language mapping data were collected for a group of glioma patients (n = 14) who underwent both preoperative fMRI and intraoperative DCS in an awake craniotomy procedure for tumor removal. Normative fMRI data were also acquired in a healthy control group (n = 12). The fMRI and DCS mapping data were co-registered; true positive (TP), true negative (TN), false positive (FP) and false negative (FN) occurrences were tabulated over the exposed brain surface. Sensitivity and specificity were measured for the total group, and the motor and language sub-groups. The influence of grid placement, fMRI statistical thresholding, and task standardization were assessed. Correlations between proportions of agreement and error were carefully scrutinized to evaluate concordance more in-depth. Results: Concordance was significantly better for motor versus language mapping. There was an inverse relationship between TP and TN with increasing statistical threshold, and FP dominated the total error. Sensitivity and specificity were reduced when tasks were not standardized across fMRI and DCS. Conclusions: Although the agreement between fMRI and DCS is good, variability is introduced by technical factors that can diminish the quality of patient data. Neurosurgeons should evaluate the usefulness of fMRI data while considering that a) discordance arises primarily from FP fMRI results; b) there is an inherent trade-off between sensitivity and specificity with fMRI statistical threshold; and c) best results are achieved using batteries of tasks that are standardized across both mapping methods

Ultrasound detection of abnormal cerebrovascular morphology in a mouse model of sickle cell disease based on wave reflection

Sickle cell disease (SCD) is associated with a high risk of stroke, and affected individuals often have focal brain lesions termed silent cerebral infarcts. The mechanisms leading to these types of injuries are at present poorly understood. Our group has recently demonstrated a non-invasive measurement of cerebrovascular impedance and wave reflection in mice using high-frequency ultrasound in the common carotid artery. To better understand the pathophysiology in SCD, we used this approach in combination with micro-computed tomography to investigate changes in cerebrovascular morphology in the Townes mouse model of SCD. Relative to controls, the SCD mice demonstrated the following: (i) increased carotid artery diameter, blood flow and vessel wall thickness; (ii) elevated pulse wave velocity; (iii) increased reflection coefficient; and (iv) an increase in the total number of vessel segments in the brain. This study highlights the potential for wave reflection to aid the non-invasive clinical assessment of vascular pathology in SCD

Severe hemodilutional anemia increases cerebral tissue injury following acute neurotrauma

Anemia may worsen neurological outcomes following traumatic brain injury (TBI) by undefined mechanisms. We hypothesized that hemodilutional anemia accentuates hypoxic cerebral injury following TBI. Anesthetized rats underwent unilateral TBI or sham injury (n ≥ 7). Target hemoglobin concentrations between 50 and 70 g/l were achieved by exchanging 40-50% of the blood volume (1:1) with pentastarch. The effect of TBI, anemia, and TBI-anemia was assessed by measuring brain tissue oxygen tension (PbrO ), regional cerebral blood flow (rCBF), jugular venous oxygen saturation (SjvO ), cerebral contusion area, and nuclear staining for programmed cell death. Baseline postinjury PbrO values in the TBI and TBI-anemia groups (9.3 ± 1.3 and 11.3 ± 4.1 Torr, respectively) were lower than the uninjured controls (18.2 ± 5.2 Torr, P \u3c 0.05 for both). Hemodilution caused a further reduction in PbrO in the TBI-anemia group relative to the TBI group without anemia (7.8 ± 2.7 vs. 14.8 ± 3.9 Torr, P \u3c 0.05). The rCBF remained stable after TBI and increased comparably after hemodilution in both anemia and TBI-anemia groups. The SjvO was elevated after TBI (87.4 ± 8.9%, P \u3c 0.05) and increased further following hemodilution (95.0 ± 1.6%, P \u3c 0.05). Cerebral contusion area and nuclear counts for programmed cell death were increased following TBI-anemia (4.1 ± 3.0 mm and 686 ± 192, respectively) relative to TBI alone (1.3 ± 0.3 mm and 404 ± 133, respectively, P \u3c 0.05 for both). Hemodilutional anemia reduced cerebral PbrO and oxygen extraction and increased cell death following TBI. These results support our hypothesis that acute anemia accentuated hypoxic cerebral injury after neurotrauma. Copyright © 2007 the American Physiological Society. 2 2 2 2 2 2 2

Severe hemodilutional anemia increases cerebral tissue injury following acute neurotrauma

Anemia may worsen neurological outcomes following traumatic brain injury (TBI) by undefined mechanisms. We hypothesized that hemodilutional anemia accentuates hypoxic cerebral injury following TBI. Anesthetized rats underwent unilateral TBI or sham injury (n ≥ 7). Target hemoglobin concentrations between 50 and 70 g/l were achieved by exchanging 40-50% of the blood volume (1:1) with pentastarch. The effect of TBI, anemia, and TBI-anemia was assessed by measuring brain tissue oxygen tension (PbrO ), regional cerebral blood flow (rCBF), jugular venous oxygen saturation (SjvO ), cerebral contusion area, and nuclear staining for programmed cell death. Baseline postinjury PbrO values in the TBI and TBI-anemia groups (9.3 ± 1.3 and 11.3 ± 4.1 Torr, respectively) were lower than the uninjured controls (18.2 ± 5.2 Torr, P \u3c 0.05 for both). Hemodilution caused a further reduction in PbrO in the TBI-anemia group relative to the TBI group without anemia (7.8 ± 2.7 vs. 14.8 ± 3.9 Torr, P \u3c 0.05). The rCBF remained stable after TBI and increased comparably after hemodilution in both anemia and TBI-anemia groups. The SjvO was elevated after TBI (87.4 ± 8.9%, P \u3c 0.05) and increased further following hemodilution (95.0 ± 1.6%, P \u3c 0.05). Cerebral contusion area and nuclear counts for programmed cell death were increased following TBI-anemia (4.1 ± 3.0 mm and 686 ± 192, respectively) relative to TBI alone (1.3 ± 0.3 mm and 404 ± 133, respectively, P \u3c 0.05 for both). Hemodilutional anemia reduced cerebral PbrO and oxygen extraction and increased cell death following TBI. These results support our hypothesis that acute anemia accentuated hypoxic cerebral injury after neurotrauma. Copyright © 2007 the American Physiological Society. 2 2 2 2 2 2 2

Methemoglobin as a marker of acute anemic stress in cardiac surgery

Summary: Biological evidence supports plasma methemoglobin as a biomarker for anemia-induced tissue hypoxia. In this translational planned substudy of the multinational randomized controlled transfusion thresholds in cardiac surgery (TRICS-III) trial, which included adults undergoing cardiac surgery requiring cardiopulmonary bypass with a moderate-to-high risk of death, we investigated the relationship between perioperative hemoglobin concentration (Hb) and methemoglobin; and evaluated its association with postoperative outcomes. The primary endpoint was a composite of death, myocardial infarction, stroke, and severe acute kidney injury at 28 days. We observe weak non-linear associations between decreasing Hb and increasing methemoglobin, which were strongest in magnitude at the post-surgical time point. Increased levels of post-surgical methemoglobin were associated with a trend toward an elevated risk for stroke and exploratory neurological outcomes. Our generalizable study demonstrates post-surgical methemoglobin may be a marker of anemia-induced organ injury/dysfunction, and may have utility for guiding personalized approaches to anemia management. Clinicaltrials.gov registration NCT02042898

A rationale for universal tranexamic acid in major joint arthroplasty: overall efficacy and impact of risk factors for transfusion

© 2018 AABB BACKGROUND: Tranexamic acid (TXA) therapy is effective in reducing postoperative red blood cell (RBC) transfusion in total joint arthroplasty (TJA), yet uncertainty persists regarding comparative efficacy and safety among specific patient subgroups. We assessed the impact of a universal TXA protocol on RBC transfusion, postoperative hemoglobin (Hb), and adverse outcomes to determine whether TXA is safe and effective in TJA, both overall and in clinically relevant subgroups. STUDY DESIGN AND METHODS: A retrospective observational study was performed on patients undergoing TJA at our institution spanning 1 year before and after the implementation of a universal protocol to administer intravenous (IV) TXA. The primary outcome was percentage of patients transfused, and secondary outcomes were perioperative Hb and occurrence of adverse events (death, myocardial infarction, stroke, seizure, pulmonary embolism, deep vein thrombosis, and acute kidney injury). Outcomes were compared in pre- and post-protocol groups with χ 2 analysis. Logistic regression compared risk of transfusion in pre- and post-protocol subgroups of patients with differing risk for transfusion (anemia, body mass index [BMI], and sex). RESULTS: No differences were found in baseline patient characteristics across pre- and post-protocol groups (n = 1084 and 912, respectively). TXA use increased from 32.3% to 92.2% while transfusion rates decreased from 10.3% to 4.8% (p \u3c 0.001). Postoperative Day 3 Hb increased from 95.8 to 101.4 g/L (p \u3c 0.001). Logistic regression demonstrated reduced transfusion in post-protocol subgroups regardless of sex, anemia, or BMI (p \u3c 0.001). No increase in adverse events was observed (p = 0.8451). CONCLUSIONS: Universal TXA was associated with a reduction of RBC transfusion, overall and in clinically relevant subgroups, strengthening the rationale for universal therapy

Universal tranexamic acid therapy to minimize transfusion for major joint arthroplasty: a retrospective analysis of protocol implementation

© 2015, Canadian Anesthesiologists\u27 Society. Purpose: Tranexamic acid (TXA) therapy can reduce red blood cell (RBC) transfusion; however, this therapy remains underutilized in many surgical patient populations. We assessed whether implementation of a protocol to facilitate universal administration of TXA in patients undergoing total hip or knee arthroplasty would reduce the incidence of RBC transfusion without increasing adverse clinical outcomes. Methods: We implemented a quality of care policy to provide universal administration of intravenous TXA at a dose of 20 mg·kg−1iv to all eligible patients undergoing total hip or knee arthroplasty from October 21, 2013 to April 30, 2014. We compared data from an equal number of patients before and after protocol implementation (n = 422 per group). The primary outcome was RBC transfusion with secondary outcomes including postoperative hemoglobin concentration (Hb) and length of hospital stay. Adverse events were identified from the electronic medical records. Data were analyzed by a Chi square test and adjusted logistic and linear regression analysis. Results: Implementation of the protocol resulted in an increase in TXA utilization from 45.8% to 95.3% [change 49.5%; 95% confidence interval (CI), 44.1 to 54.5; P \u3c 0.001]. This change was associated with a reduction in the rate of RBC transfusion from 8.8% to 5.2%, (change −3.6%; 95% CI, −0.1 to −7.0; P = 0.043). Pre- and post-protocol mean [standard deviation (SD)] Hb values were similar, including the nadir Hb prior to RBC transfusion [72 (8) g·L−1vs 70 (8) g·L−1, respectively; mean difference −1 g·L−1; 95% CI, −3 to 5; P = 0.569]. Length of stay was not altered, and no increase in adverse events was observed. Conclusions: Implementation of a perioperative TXA protocol was associated with both an increase in TXA use and a reduction in RBC transfusion following hip or knee arthroplasty. Adverse events and length of hospital stay were not influenced by the protocol