Endobronchial Phenylephrine in Airway Bleeding During Bronchoscopy Does not Cause Hypertension: A Retrospective Observational Study.

BACKGROUND: Bleeding is a known complication during bronchoscopy, with increased incidence in patients undergoing a more invasive procedure. Phenylephrine is a potent vasoconstrictor that can control airway bleeding when applied topically and has been used as an alternative to epinephrine. The clinical effects of endobronchial phenylephrine on systemic vasoconstriction have not been clearly evaluated. Here, we compared the effects of endobronchial phenylephrine versus cold saline on systemic blood pressure. METHODS: In all, 160 patients who underwent bronchoscopy and received either endobronchial phenylephrine or cold saline from July 1, 2017 to June 30, 2022 were included in this retrospective observational study. Intra-procedural blood pressure absolute and percent changes were measured and compared between the 2 groups. RESULTS: There were no observed statistical differences in blood pressure changes between groups. The median absolute change between the median and the maximum intra-procedural systolic blood pressure in the cold saline group was 29 mm Hg (IQR 19 to 41) compared with 31.8 mm Hg (IQR 18 to 45.5) in the phenylephrine group. The corresponding median percent changes in SBP were 33.6 % (IQR 18.8 to 39.4) and 28% (IQR 16.8 to 43.5) for the cold saline and phenylephrine groups, respectively. Similarly, there were no statistically significant differences in diastolic and mean arterial blood pressure changes between both groups. CONCLUSIONS: We found no significant differences in median intra-procedural systemic blood pressure changes comparing patients who received endobronchial cold saline to those receiving phenylephrine. Overall, this argues for the vascular and systemic safety of phenylephrine for airway bleeding as a reasonable alternative to epinephrine.

Using the ROX Index to Predict Treatment Outcome for High-Flow Nasal Cannula and/or Noninvasive Ventilation in Patients With COPD Exacerbations.

BACKGROUND: The ratio of oxygen saturation index (ROX index; or SpO2 /FIO2 /breathing frequency) has been shown to predict risk of intubation after high-flow nasal cannula (HFNC) support among adults with acute hypoxemic respiratory failure primarily due to pneumonia. However, its predictive value for other subtypes of respiratory failure is unknown. This study investigated whether the ROX index predicts liberation from HFNC or noninvasive ventilation (NIV), intubation with mechanical ventilation, or death in adults admitted for respiratory failure due to an exacerbation of COPD. METHODS: We performed a retrospective study of 260 adults hospitalized with a COPD exacerbation and treated with HFNC and/or NIV (continuous or bi-level). ROX index scores were collected at treatment initiation and predefined time intervals throughout HFNC and/or NIV treatment or until the subject was intubated or died. A ROX index score of ≥ 4.88 was applied to the cohort to determine if the same score would perform similarly in this different cohort. Accuracy of the ROX index was determined by calculating the area under the receiver operator curve. RESULTS: A total of 47 subjects (18%) required invasive mechanical ventilation or died while on HFNC/NIV. The ROX index at treatment initiation, 1 h, and 6 h demonstrated the best prediction accuracy for avoidance of invasive mechanical ventilation or death (area under the receiver operator curve 0.73 [95% CI 0.66-0.80], 0.72 [95% CI 0.65-0.79], and 0.72 [95% CI 0.63-0.82], respectively). The optimal cutoff value for sensitivity (Sn) and specificity (Sp) was a ROX index score > 6.88 (sensitivity 62%, specificity 57%). CONCLUSIONS: The ROX index applied to adults with COPD exacerbations treated with HFNC and/or NIV required higher scores to achieve similar prediction of low risk of treatment failure when compared to subjects with hypoxemic respiratory failure/pneumonia. ROX scores < 4.88 did not accurately predict intubation or death.

Early Mobility Index and Patient Outcomes: A Retrospective Study in Multiple Intensive Care Units.

BACKGROUND: Early mobility interventions in intensive care units (ICUs) are safe and improve outcomes in subsets of critically ill adults. However, implementation varies, and the optimal mobility dose remains unclear. OBJECTIVE: To test for associations between daily dose of out-of-bed mobility and patient outcomes in different ICUs. METHODS: In this retrospective cohort study of electronic records from 7 adult ICUs in an academic quarternary hospital, multivariable linear regression was used to examine the effects of out-of-bed events per mobility-eligible day on mechanical ventilation duration and length of ICU and hospital stays. RESULTS: In total, 8609 adults hospitalized in ICUs from 2015 through 2018 were included. Patients were mobilized out of bed on 46.5% of ICU days and were eligible for mobility interventions on a median (IQR) of 2.0 (1-3) of 2.7 (2-9) ICU days. Median (IQR) out-of-bed events per mobility-eligible day were 0.5 (0-1.2) among all patients. For every unit increase in out-of-bed events per mobility-eligible day before extubation, mechanical ventilation duration decreased by 10% (adjusted coefficient [95% CI], -0.10 [-0.18 to -0.01]). Daily mobility increased ICU stays by 4% (adjusted coefficient [95% CI], 0.04 [0.03-0.06]) and decreased hospital stays by 5% (adjusted coefficient [95% CI], -0.05 [-0.07 to -0.03]). Effect sizes differed among ICUs. CONCLUSIONS: More daily out-of-bed mobility for ICU patients was associated with shorter mechanical ventilation duration and hospital stays, suggesting a dose-response relationship between daily mobility and patient outcomes. However, relationships differed across ICU subpopulations.

Controls, comparator arms, and designs for critical care comparative effectiveness research: It's complicated.

BACKGROUND: Comparative effectiveness research is meant to determine which commonly employed medical interventions are most beneficial, least harmful, and/or most costly in a real-world setting. While the objectives for comparative effectiveness research are clear, the field has failed to develop either a uniform definition of comparative effectiveness research or an appropriate set of recommendations to provide standards for the design of critical care comparative effectiveness research trials, spurring controversy in recent years. The insertion of non-representative control and/or comparator arm subjects into critical care comparative effectiveness research trials can threaten trial subjects' safety. Nonetheless, the broader scientific community does not always appreciate the importance of defining and maintaining critical care practices during a trial, especially when vulnerable, critically ill populations are studied. Consequently, critical care comparative effectiveness research trials sometimes lack properly constructed control or active comparator arms altogether and/or suffer from the inclusion of "unusual critical care" that may adversely affect groups enrolled in one or more arms. This oversight has led to critical care comparative effectiveness research trial designs that impair informed consent, confound interpretation of trial results, and increase the risk of harm for trial participants. METHODS/EXAMPLES: We propose a novel approach to performing critical care comparative effectiveness research trials that mandates the documentation of critical care practices prior to trial initiation. We also classify the most common types of critical care comparative effectiveness research trials, as well as the most frequent errors in trial design. We present examples of these design flaws drawn from past and recently published trials as well as examples of trials that avoided those errors. Finally, we summarize strategies employed successfully in well-designed trials, in hopes of suggesting a comprehensive standard for the field. CONCLUSION: Flawed critical care comparative effectiveness research trial designs can lead to unsound trial conclusions, compromise informed consent, and increase risks to research subjects, undermining the major goal of comparative effectiveness research: to inform current practice. Well-constructed control and comparator arms comprise indispensable elements of critical care comparative effectiveness research trials, key to improving the trials' safety and to generating trial results likely to improve patient outcomes in clinical practice.

Cross-cultural adaptation of the FRAIL scale for critically ill patients in Spain.

AIM: To translate and culturally adapt the FRAIL scale into Spanish and perform a preliminary test of diagnostic accuracy in patients admitted to intensive care units. DESIGN: Cross-sectional diagnostic study. METHODS: Five intensive care units (ICU) in Spain were participated. Stage 1: Three native Spanish-speaking bilingual translators familiar with the field of critical care translated the scale from English into Spanish. Stage 2: Three native English-speaking bilingual translators familiar with critical care medicine. Stage 3: Authors of the original scale compared the English original and back-translated versions of the scale. Stage 4: Five nurses with more than 5 years of ICU experience and five critical care physicians assessed the comprehension and relevance of each of the items of the Spanish version in 30 patients of 3 different age ranges (<50, 50-65 and >65 years). RESULTS: The FRAIL scale was translated and adapted cross-culturally for patients admitted to intensive care units in Spain. The process consisted of four stages: translation, back translation, comparison and pilot test. There was good correspondence between the original scale and the Spanish version in 100% of the items. The participating patients assessed the relevance (content validity) and comprehensibility (face validity) of each of the items of the first Spanish version. The relevance of some of the items scored low when the scale was used in patients younger than 65 years. CONCLUSIONS: We have cross-culturally adapted the FRAIL scale, originally in English, to Spanish for its use in the critical care medical setting in Spanish-speaking countries. IMPLICATIONS FOR PROFESSIONALS: Physicians and nurses can apply the new scale to all patients admitted to the intensive care units. Nursing care can be adapted according to frailty, trying to reduce the side effects of admission to these units for the most fragile patients. REPORTING METHOD: The manuscript's authors have adhered to the EQUATOR guidelines, using the COSMIN reporting guideline for studies on the measurement properties of patient-reported outcome measures. PATIENT OR PUBLIC CONTRIBUTION: In a pilot clinical study, we applied the first version of the FRAIL-Spain scale to intensive care unit (ICU) patients. Five nurses with more than 5 years of ICU experience and five critical care physicians assessed the relevance (content validity) and comprehensibility (face validity) of the five items of the first Spanish version. Relevance was assessed using a 4-point Likert scale ranging from 1 (no relevance) to 4 (high relevance), and comprehensibility was assessed as poor, acceptable or good. Each health professional applied the scale to three patients (total number of patients = 30) of three different age ranges (<50, 50-65 and >65 years) and recorded the time of application of the scale to each patient. Although the frailty scales were initially created by geriatricians to be applied to the elders, there is little experience with their application in critically ill patients of any age. Therefore, more information is needed to determine the relevance of using this scale in critical care patients. In this pilot study, we considered that nurses and critical care physicians should evaluate frailty using this adapted scale in adult patients admitted to the Intensive Care Units.

Work of Breathing During Proportional Assist Ventilation as a Predictor of Extubation Failure.

BACKGROUND: Despite decades of research on predictors of extubation success, use of ventilatory support after extubation is common and 10-20% of patients require re-intubation. Proportional assist ventilation (PAV) mode automatically calculates estimated total work of breathing (total WOB). Here, we assessed the performance of total WOB to predict extubation failure in invasively ventilated subjects. METHODS: This prospective observational study was conducted in 6 adult ICUs at an academic medical center. We enrolled intubated subjects who successfully completed a spontaneous breathing trial, had a rapid shallow breathing index < 105 breaths/min/L, and were deemed ready for extubation by the primary team. Total WOB values were recorded at the end of a 30-min PAV trial. Extubation failure was defined as any respiratory support and/or re-intubation within 72 h of extubation. We compared total WOB scores between groups and performance of total WOB for predicting extubation failure with receiver operating characteristic curves. RESULTS: Of 61 subjects enrolled, 9.8% (n = 6) required re-intubation, and 50.8% (n = 31) required any respiratory support within 72 h of extubation. Median total WOB at 30 min on PAV was 0.9 J/L (interquartile range 0.7-1.3 J/L). Total WOB was significantly different between subjects who failed or were successfully extubated (median 1.1 J/L vs 0.7 J/L, P = .004). The area under the curve was 0.71 [95% CI 0.58-0.85] for predicting any requirement of respiratory support and 0.85 [95% CI 0.69-1.00] for predicting re-intubation alone within 72 h of extubation. Total WOB cutoff values maximizing sensitivity and specificity equally were 1.0 J/L for any respiratory support (positive predictive value [PPV] 70.0%, negative predictive value [NPV] 67.7%) and 1.3 J/L for re-intubation (PPV 26.3%, NPV 97.6%). CONCLUSIONS: The discriminative performance of a PAV-derived total WOB value to predict extubation failure was good, indicating total WOB may represent an adjunctive tool for assessing extubation readiness. However, these results should be interpreted as preliminary, with specific thresholds of PAV-derived total WOB requiring further investigation in a large multi-center study.

Modeling current practices in critical care comparative effectiveness research.

Objective: To determine whether contemporaneous practices are adequately represented in recent critical care comparative effectiveness research studies. Design: All critical care comparative effectiveness research trials published in the New England Journal of Medicine from April 2019 to March 2020 were identified. To examine studies published in other high impact medical journals during the same period, such trials were subsequently also identified in the Journal of the American Medical Association and The Lancet. All cited sources were reviewed, and the medical literature was searched to find studies describing contemporary practices. Then, the designated control group or the comparable therapies studied were examined to determine if they represented contemporaneous critical care practices as described in the medical literature. Results: Twenty-five of 332 randomised clinical trials published in these three journals during this 1-year period described critical care comparative effectiveness research that met our inclusion criteria. Seventeen characterised current practices before enrolment (using surveys, observational studies and guidelines) and then incorporated current practices into one or more study arm. In the other eight, usual care arms appeared insufficient. Four of these trials randomly assigned patients to one of two fixed approaches at either end of a range of usually titrated care. However, due to randomisation, different subgroups within each arm received care that was inappropriate for their specific clinical conditions. In the other four of these trials, common practices influencing treatment choice were not reflected in the trial design, despite a prior effort to characterise usual care. Conclusion: One-third of critical care comparative effectiveness research trials published in widely read medical journals during a recent year did not include a designated control arm or comparable therapies representative of contemporary practices. Failure to incorporate contemporary practices into critical care comparative effectiveness trials appears to be a widespread design weakness.

Plasma Linoleate Diols Are Potential Biomarkers for Severe COVID-19 Infections.

Polyunsaturated fatty acids are metabolized into regulatory lipids important for initiating inflammatory responses in the event of disease or injury and for signaling the resolution of inflammation and return to homeostasis. The epoxides of linoleic acid (leukotoxins) regulate skin barrier function, perivascular and alveolar permeability and have been associated with poor outcomes in burn patients and in sepsis. It was later reported that blocking metabolism of leukotoxins into the vicinal diols ameliorated the deleterious effects of leukotoxins, suggesting that the leukotoxin diols are contributing to the toxicity. During quantitative profiling of fatty acid chemical mediators (eicosanoids) in COVID-19 patients, we found increases in the regioisomeric leukotoxin diols in plasma samples of hospitalized patients suffering from severe pulmonary involvement. In rodents these leukotoxin diols cause dramatic vascular permeability and are associated with acute adult respiratory like symptoms. Thus, pathways involved in the biosynthesis and degradation of these regulatory lipids should be investigated in larger biomarker studies to determine their significance in COVID-19 disease. In addition, incorporating diols in plasma multi-omics of patients could illuminate the COVID-19 pathological signature along with other lipid mediators and blood chemistry.

Movement to the Clinic of Soluble Epoxide Hydrolase Inhibitor EC5026 as an Analgesic for Neuropathic Pain and for Use as a Nonaddictive Opioid Alternative.

This report describes the development of an orally active analgesic that resolves inflammation and neuropathic pain without the addictive potential of opioids. EC5026 acts on the cytochrome P450 branch of the arachidonate cascade to stabilize epoxides of polyunsaturated fatty acids (EpFA), which are natural mediators that reduce pain, resolve inflammation, and maintain normal blood pressure. EC5026 is a slow-tight binding transition-state mimic that inhibits the soluble epoxide hydrolase (sEH) at picomolar concentrations. The sEH rapidly degrades EpFA; thus, inhibiting sEH increases EpFA in vivo and confers beneficial effects. This mechanism addresses disease states by shifting endoplasmic reticulum stress from promoting cellular senescence and inflammation toward cell survival and homeostasis. We describe the synthesis and optimization of EC5026 and its development through human Phase 1a trials with no drug-related adverse events. Additionally, we outline fundamental work leading to discovery of the analgesic and inflammation-resolving CYP450 branch of the arachidonate cascade.

Use of Machine Learning to Screen for Acute Respiratory Distress Syndrome Using Raw Ventilator Waveform Data.

To develop and characterize a machine learning algorithm to discriminate acute respiratory distress syndrome from other causes of respiratory failure using only ventilator waveform data. DESIGN: Retrospective, observational cohort study. SETTING: Academic medical center ICU. PATIENTS: Adults admitted to the ICU requiring invasive mechanical ventilation, including 50 patients with acute respiratory distress syndrome and 50 patients with primary indications for mechanical ventilation other than hypoxemic respiratory failure. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Pressure and flow time series data from mechanical ventilation during the first 24-hours after meeting acute respiratory distress syndrome criteria (or first 24-hr of mechanical ventilation for non-acute respiratory distress syndrome patients) were processed to extract nine physiologic features. A random forest machine learning algorithm was trained to discriminate between the patients with and without acute respiratory distress syndrome. Model performance was assessed using the area under the receiver operating characteristic curve, sensitivity, specificity, positive predictive value, and negative predictive value. Analyses examined performance when the model was trained using data from the first 24 hours and tested using withheld data from either the first 24 hours (24/24 model) or 6 hours (24/6 model). Area under the receiver operating characteristic curve, sensitivity, specificity, positive predictive value, and negative predictive value were 0.88, 0.90, 0.71, 0.77, and 0.90 (24/24); and 0.89, 0.90, 0.75, 0.83, and 0.83 (24/6). CONCLUSIONS: Use of machine learning and physiologic information derived from raw ventilator waveform data may enable acute respiratory distress syndrome screening at early time points after intubation. This approach, combined with traditional diagnostic criteria, could improve timely acute respiratory distress syndrome recognition and enable automated clinical decision support, especially in settings with limited availability of conventional diagnostic tests and electronic health records.

Leveraging IoTs and Machine Learning for Patient Diagnosis and Ventilation Management in the Intensive Care Unit.

Future healthcare systems will rely heavily on clinical decision support systems (CDSS) to improve the decision-making processes of clinicians. To explore the design of future CDSS, we developed a research-focused CDSS for the management of patients in the intensive care unit that leverages Internet of Things (IoT) devices capable of collecting streaming physiologic data from ventilators and other medical devices. We then created machine learning (ML) models that could analyze the collected physiologic data to determine if the ventilator was delivering potentially harmful therapy and if a deadly respiratory condition, acute respiratory distress syndrome (ARDS), was present. We also present work to aggregate these models into a mobile application that can provide responsive, real-time alerts of changes in ventilation to providers. As illustrated in the recent COVID-19 pandemic, being able to accurately predict ARDS in newly infected patients can assist in prioritizing care. We show that CDSS may be used to analyze physiologic data for clinical event recognition and automated diagnosis, and we also highlight future research avenues for hospital CDSS.

Inflammation resolution: a dual-pronged approach to averting cytokine storms in COVID-19?

Severe coronavirus disease (COVID-19) is characterized by pulmonary hyper-inflammation and potentially life-threatening "cytokine storms". Controlling the local and systemic inflammatory response in COVID-19 may be as important as anti-viral therapies. Endogenous lipid autacoid mediators, referred to as eicosanoids, play a critical role in the induction of inflammation and pro-inflammatory cytokine production. SARS-CoV-2 may trigger a cell death ("debris")-induced "eicosanoid storm", including prostaglandins and leukotrienes, which in turn initiates a robust inflammatory response. A paradigm shift is emerging in our understanding of the resolution of inflammation as an active biochemical process with the discovery of novel endogenous specialized pro-resolving lipid autacoid mediators (SPMs), such as resolvins. Resolvins and other SPMs stimulate macrophage-mediated clearance of debris and counter pro-inflammatory cytokine production, a process called inflammation resolution. SPMs and their lipid precursors exhibit anti-viral activity at nanogram doses in the setting of influenza without being immunosuppressive. SPMs also promote anti-viral B cell antibodies and lymphocyte activity, highlighting their potential use in the treatment of COVID-19. Soluble epoxide hydrolase (sEH) inhibitors stabilize arachidonic acid-derived epoxyeicosatrienoic acids (EETs), which also stimulate inflammation resolution by promoting the production of pro-resolution mediators, activating anti-inflammatory processes, and preventing the cytokine storm. Both resolvins and EETs also attenuate pathological thrombosis and promote clot removal, which is emerging as a key pathology of COVID-19 infection. Thus, both SPMs and sEH inhibitors may promote the resolution of inflammation in COVID-19, thereby reducing acute respiratory distress syndrome (ARDS) and other life-threatening complications associated with robust viral-induced inflammation. While most COVID-19 clinical trials focus on "anti-viral" and "anti-inflammatory" strategies, stimulating inflammation resolution is a novel host-centric therapeutic avenue. Importantly, SPMs and sEH inhibitors are currently in clinical trials for other inflammatory diseases and could be rapidly translated for the management of COVID-19 via debris clearance and inflammatory cytokine suppression. Here, we discuss using pro-resolution mediators as a potential complement to current anti-viral strategies for COVID-19.

In canine bacterial pneumonia circulating granulocyte counts determine outcome from donor cells.

BACKGROUND: In experimental canine septic shock, depressed circulating granulocyte counts were associated with a poor outcome and increasing counts with prophylactic granulocyte colony-stimulating factor (G-CSF) improved outcome. Therapeutic G-CSF, in contrast, did not improve circulating counts or outcome, and therefore investigation was undertaken to determine whether transfusing granulocytes therapeutically would improve outcome. STUDY DESIGN AND METHODS: Twenty-eight purpose-bred beagles underwent an intrabronchial Staphylococcus aureus challenge and 4 hours later were randomly assigned to granulocyte (40-100 × 109 cells) or plasma transfusion. RESULTS: Granulocyte transfusion significantly expanded the low circulating counts for hours compared to septic controls but was not associated with significant mortality benefit (1/14, 7% vs. 2/14, 14%, respectively; p = 0.29). Septic animals with higher granulocyte count at 4 hours (median [interquartile range] of 3.81 3.39-5.05] vs. 1.77 [1.25-2.50]) had significantly increased survival independent of whether they were transfused with granulocytes. In a subgroup analysis, animals with higher circulating granulocyte counts receiving donor granulocytes had worsened lung injury compared to septic controls. Conversely, donor granulocytes decreased lung injury in septic animals with lower counts. CONCLUSION: During bacterial pneumonia, circulating counts predict the outcome of transfusing granulocytes. With low but normal counts, transfusing granulocytes does not improve survival and injures the lung, whereas for animals with very low counts, but not absolute neutropenia, granulocyte transfusion improves lung function.

Haptoglobin therapy has differential effects depending on severity of canine septic shock and cell-free hemoglobin level.

BACKGROUND: During sepsis, higher plasma cell-free hemoglobin (CFH) levels portend worse outcomes. In sepsis models, plasma proteins that bind CFH improve survival. In our canine antibiotic-treated Staphylococcus aureus pneumonia model, with and without red blood cell (RBC) exchange transfusion, commercial human haptoglobin (Hp) concentrates bound and compartmentalized CFH intravascularly, increased CFH clearance, and lowered iron levels, improving shock, lung injury, and survival. We now investigate in our model how very high CFH levels and treatment time affect Hp's beneficial effects. MATERIALS AND METHODS: Two separate canine pneumonia sepsis Hp studies were undertaken: one with exchange transfusion of RBCs after prolonged storage to raise CFH to very high levels and another with rapidly lethal sepsis alone to shorten time to treat. All animals received continuous standard intensive care unit supportive care for 96 hours. RESULTS: Older RBCs markedly elevated plasma CFH levels and, when combined with Hp therapy, created supraphysiologic CFH-Hp complexes that did not increase CFH or iron clearance or improve lung injury and survival. In a rapidly lethal bacterial challenge model without RBC transfusion, Hp binding did not increase clearance of complexes or iron or show benefits seen previously in the less lethal model. DISCUSSION: High-level CFH-Hp complexes may impair clearance mechanisms and eliminate Hp's beneficial effect during sepsis. Rapidly lethal sepsis narrows the therapeutic window for CFH and iron clearance, also decreasing Hp's beneficial effects. In designing clinical trials, dosing and kinetics may be critical factors if Hp infusion is used to treat sepsis.

Inhaled nebulized nitrite and nitrate therapy in a canine model of hypoxia-induced pulmonary hypertension.

Dysfunction in the nitric oxide (NO) signaling pathway can lead to the development of pulmonary hypertension (PH) in mammals. Discovery of an alternative pathway to NO generation involving reduction from nitrate to nitrite and to NO has motivated the evaluation of nitrite as an alternative to inhaled NO for PH. In contrast, inhaled nitrate has not been evaluated to date, and potential benefits include a prolonged half-life and decreased risk of methemoglobinemia. In a canine model of acute hypoxia-induced PH we evaluated the effects of inhaled nitrate to reduce pulmonary arterial pressure (PAP). In a randomized controlled trial, inhaled nitrate was compared to inhaled nitrite and inhaled saline. Exhaled NO, PAP and systemic blood pressures were continuously monitored. Inhaled nitrite significantly decreased PAP and increased exhaled NO. In contrast, inhaled nitrate and inhaled saline did not decrease PAP or increase exhaled NO. Unexpectedly, we found that inhaled nitrite resulted in prolonged (>5 h) exhaled NO release, increase in nitrate venous/arterial levels and a late surge in venous nitrite levels. These findings do not support a therapeutic role for inhaled nitrate in PH but may have therapeutic implications for inhaled nitrite in various disease states.

Impact of different standard red blood cell storage temperatures on human and canine RBC hemolysis and chromium survival.

BACKGROUND: Storage temperature is a critical factor for maintaining red-blood cell (RBC) viability, especially during prolonged cold storage. The target range of 1 to 6°C was established decades ago and may no longer be optimal for current blood-banking practices. STUDY DESIGN AND METHODS: Human and canine RBCs were collected under standard conditions and stored in precision-controlled refrigerators at 2°C, 4°C, or 6°C. RESULTS: During 42-day storage, human and canine RBCs showed progressive increases in supernatant non-transferrin-bound iron, cell-free hemoglobin, base deficit, and lactate levels that were overall greater at 6°C and 4°C than at 2°C. Animals transfused with 7-day-old RBCs had similar plasma cell-free hemoglobin and non-transferrin-bound iron levels at 1 to 72 hours for all three temperature conditions by chromium-51 recovery analysis. However, animals transfused with 35-day-old RBCs stored at higher temperatures developed plasma elevations in non-transferrin-bound iron and cell-free hemoglobin at 24 and 72 hours. Despite apparent impaired 35-day storage at 4°C and 6°C compared to 2°C, posttransfusion chromium-51 recovery at 24 hours was superior at higher temperatures. This finding was confounded by a preparation artifact related to an interaction between temperature and storage duration that leads to removal of fragile cells with repeated washing of the radiolabeled RBC test sample and renders the test sample unrepresentative of the stored unit. CONCLUSIONS: RBCs stored at the lower bounds of the temperature range are less metabolically active and produce less anaerobic acidosis and hemolysis, leading to a more suitable transfusion product. The higher refrigeration temperatures are not optimal during extended RBC storage and may confound chromium viability studies.

Haptoglobin improves shock, lung injury, and survival in canine pneumonia.

During the last half-century, numerous antiinflammatory agents were tested in dozens of clinical trials and have proven ineffective for treating septic shock. The observation in multiple studies that cell-free hemoglobin (CFH) levels are elevated during clinical sepsis and that the degree of increase correlates with higher mortality suggests an alternative approach. Human haptoglobin binds CFH with high affinity and, therefore, can potentially reduce iron availability and oxidative activity. CFH levels are elevated over approximately 24-48 hours in our antibiotic-treated canine model of S. aureus pneumonia that simulates the cardiovascular abnormalities of human septic shock. In this 96-hour model, resuscitative treatments, mechanical ventilation, sedation, and continuous care are translatable to management in human intensive care units. We found, in this S. aureus pneumonia model inducing septic shock, that commercial human haptoglobin concentrate infusions over 48-hours bind canine CFH, increase CFH clearance, and lower circulating iron. Over the 96-hour study, this treatment was associated with an improved metabolic profile (pH, lactate), less lung injury, reversal of shock, and increased survival. Haptoglobin binding compartmentalized CFH to the intravascular space. This observation, in combination with increasing CFHs clearance, reduced available iron as a potential source of bacterial nutrition while decreasing the ability for CFH and iron to cause extravascular oxidative tissue injury. In contrast, haptoglobin therapy had no measurable antiinflammatory effect on elevations in proinflammatory C-reactive protein and cytokine levels. Haptoglobin therapy enhances normal host defense mechanisms in contrast to previously studied antiinflammatory sepsis therapies, making it a biologically plausible novel approach to treat septic shock.

Parenteral irons versus transfused red blood cells for treatment of anemia during canine experimental bacterial pneumonia.

BACKGROUND: No studies have been performed comparing intravenous (IV) iron with transfused red blood cells (RBCs) for treating anemia during infection. In a previous report, transfused older RBCs increased free iron release and mortality in infected animals when compared to fresher cells. We hypothesized that treating anemia during infection with transfused fresh RBCs, with minimal free iron release, would prove superior to IV iron therapy. STUDY DESIGN AND METHODS: Purpose-bred beagles (n = 42) with experimental Staphylococcus aureus pneumonia rendered anemic were randomized to be transfused RBCs stored for 7 days or one of two IV iron preparations (7 mg/kg), iron sucrose, a widely used preparation, or ferumoxytol, a newer formulation that blunts circulating iron levels. RESULTS: Both irons increased the alveolar-arterial oxygen gradient at 24 to 48 hours (p = 0.02-0.001), worsened shock at 16 hours (p = 0.02-0.003, respectively), and reduced survival (transfusion 56%; iron sucrose 8%, p = 0.01; ferumoxytol 9%, p = 0.04). Compared to fresh RBC transfusion, plasma iron measured by non-transferrin-bound iron levels increased with iron sucrose at 7, 10, 13, 16, 24, and 48 hours (p = 0.04 to p < 0.0001) and ferumoxytol at 7, 24, and 48 hours (p = 0.04 to p = 0.004). No significant differences in cardiac filling pressures or performance, hemoglobin (Hb), or cell-free Hb were observed. CONCLUSIONS: During canine experimental bacterial pneumonia, treatment of mild anemia with IV iron significantly increased free iron levels, shock, lung injury, and mortality compared to transfusion of fresh RBCs. This was true for iron preparations that do or do not blunt circulating free iron level elevations. These findings suggest that treatment of anemia with IV iron during infection should be undertaken with caution.