Prophylactic Administration of Vasopressors Prior to Emergency Intubation in Critically Ill Patients: A Secondary Analysis of Two Multicenter Clinical Trials.

Hypotension affects approximately 40% of critically ill patients undergoing emergency intubation and is associated with an increased risk of death. The objective of this study was to examine the association between prophylactic vasopressor administration and the incidence of peri-intubation hypotension and other clinical outcomes. DESIGN: A secondary analysis of two multicenter randomized clinical trials. The clinical effect of prophylactic vasopressor administration was estimated using a one-to-one propensity-matched cohort of patients with and without prophylactic vasopressors. SETTING: Seven emergency departments and 17 ICUs across the United States. PATIENTS: One thousand seven hundred ninety-eight critically ill patients who underwent emergency intubation at the study sites between February 1, 2019, and May 24, 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was peri-intubation hypotension defined as a systolic blood pressure less than 90 mm Hg occurring between induction and 2 minutes after tracheal intubation. A total of 187 patients (10%) received prophylactic vasopressors prior to intubation. Compared with patients who did not receive prophylactic vasopressors, those who did were older, had higher Acute Physiology and Chronic Health Evaluation II scores, were more likely to have a diagnosis of sepsis, had lower pre-induction systolic blood pressures, and were more likely to be on continuous vasopressor infusions prior to intubation. In our propensity-matched cohort, prophylactic vasopressor administration was not associated with reduced risk of peri-intubation hypotension (41% vs 32%; p = 0.08) or change in systolic blood pressure from baseline (-12 vs -11 mm Hg; p = 0.66). CONCLUSIONS: The administration of prophylactic vasopressors was not associated with a lower incidence of peri-intubation hypotension in our propensity-matched analysis. To address potential residual confounding, randomized clinical trials should examine the effect of prophylactic vasopressor administration on peri-intubation outcomes.

Angiotensin II for the Treatment of Refractory Shock: A Matched Analysis.

OBJECTIVES: To determine if angiotensin II is associated with improved outcomes as measured by 30- and 90-day mortality as well as other secondary outcomes such as organ dysfunction and adverse events. DESIGN: Retrospective, matched analysis of patients receiving angiotensin II compared with both historical and concurrent controls receiving equivalent doses of nonangiotensin II vasopressors. SETTING: Multiple ICUs in a large, university-based hospital. PATIENTS: Eight hundred thirteen adult patients with shock admitted to an ICU and requiring vasopressor support. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Angiotensin II use had no association with the primary outcome of 30-day mortality (60% vs 56%; p = 0.292). The secondary outcome of 90-day mortality was also similar (65% vs 63%; p = 0.440) as were changes in Sequential Organ Failure Assessment scores over a 5-day monitoring period after enrollment. Angiotensin II was not associated with increased rates of kidney replacement therapy (odds ratio [OR], 1.39; 95% CI, 0.88-2.19; p = 0.158) or receipt of mechanical ventilation (OR, 1.50; 95% CI, 0.41-5.51; p = 0.539) after enrollment, and the rate of thrombotic events was similar between angiotensin II and control patients (OR, 1.02; 95% CI, 0.71-1.48; p = 0.912). CONCLUSIONS: In patients with severe shock, angiotensin II was not associated with improved mortality or organ dysfunction and was not associated with an increased rate of adverse events.

Defining Successful Intubation on the First Attempt Using Both Laryngoscope and Endotracheal Tube Insertions: A Secondary Analysis of Clinical Trial Data.

STUDY OBJECTIVES: Successful intubation on the first attempt has historically been defined as successful placement of an endotracheal tube (ETT) using a single laryngoscope insertion. More recent studies have defined successful placement of an ETT using a single laryngoscope insertion followed by a single ETT insertion. We sought to estimate the prevalence of first-attempt success using these 2 definitions and estimate their associations with the duration of intubation and serious complications. METHODS: We performed a secondary analysis of data from 2 multicenter randomized trials of critically ill adults being intubated in the emergency department or ICU. We calculated the percent difference in successful intubations on the first attempt, median difference in the duration of intubation, and percent difference in the development of serious complications by definition. RESULTS: The study population included 1,863 patients. Successful intubation on the first attempt decreased by 4.9% (95% confidence interval 2.5% to 7.3%) when defined as 1 laryngoscope insertion followed by 1 ETT insertion (81.2%) compared with when defined as only 1 laryngoscope insertion (86.0%). When successful intubation with 1 laryngoscope and 1 ETT insertion was compared with 1 laryngoscope and multiple ETT insertions, the median duration of intubation decreased by 35.0 seconds (95% confidence interval 8.9 to 61.1 seconds). CONCLUSION: Defining successful intubation on the first attempt as placement of an ETT in the trachea using 1 laryngoscope and 1 ETT insertion identifies attempts with the shortest apneic time.

Laryngoscopy and Tracheal Intubation: Does Use of a Video Laryngoscope Facilitate Both Steps of the Procedure?

STUDY OBJECTIVE: To compare the effect of the use of a video laryngoscope versus a direct laryngoscope on each step of emergency intubation: laryngoscopy (step 1) and intubation of the trachea (step 2). METHODS: In a secondary observational analysis of data from 2 multicenter, randomized trials that enrolled critically ill adults undergoing tracheal intubation but did not control for laryngoscope type (video laryngoscope vs direct laryngoscope), we fit mixed-effects logistic regression models examining the 1) the association between laryngoscope type (video laryngoscope vs direct laryngoscope) and the Cormack-Lehane grade of view and 2) the interaction between grade of view, laryngoscope type (video laryngoscope vs direct laryngoscope), and the incidence of successful intubation on the first attempt. RESULTS: We analyzed 1,786 patients: 467 (26.2%) in the direct laryngoscope group and 1,319 (73.9%) in the video laryngoscope group. The use of a video laryngoscope was associated with an improved grade of view as compared with a direct laryngoscope (adjusted odds ratio for increasingly favorable grade of view 3.14, 95% confidence interval [CI] 2.47 to 3.99). Successful intubation on the first attempt occurred in 83.2% of patients in the video laryngoscope group and 72.2% of patients in the direct laryngoscope group (absolute difference 11.1%, 95% CI 6.5% to 15.6%). Video laryngoscope use modified the association between grade of view and successful intubation on the first attempt such that intubation on the first attempt was similar between video laryngoscope and direct laryngoscope at a grade 1 view and higher for video laryngoscope than direct laryngoscope at grade 2 to 4 views (P<.001 for interaction term). CONCLUSIONS: Among critically ill adults undergoing tracheal intubation, the use of a video laryngoscope was associated both with a better view of the vocal cords and with a higher probability of successfully intubating the trachea when the view of the vocal cords was incomplete in this observational analysis. However, a multicenter, randomized trial directly comparing the effect of a video laryngoscope with a direct laryngoscope on the grade of view, success, and complications is needed.

Individualized Treatment Effects of Bougie versus Stylet for Tracheal Intubation in Critical Illness.

Rationale: A recent randomized trial found that using a bougie did not increase the incidence of successful intubation on first attempt in critically ill adults. The average effect of treatment in a trial population, however, may differ from effects for individuals. Objective: We hypothesized that application of a machine learning model to data from a clinical trial could estimate the effect of treatment (bougie vs. stylet) for individual patients based on their baseline characteristics ("individualized treatment effects"). Methods: This was a secondary analysis of the BOUGIE (Bougie or Stylet in Patients Undergoing Intubation Emergently) trial. A causal forest algorithm was used to model differences in outcome probabilities by randomized group assignment (bougie vs. stylet) for each patient in the first half of the trial (training cohort). This model was used to predict individualized treatment effects for each patient in the second half (validation cohort). Measurements and Main Results: Of 1,102 patients in the BOUGIE trial, 558 (50.6%) were the training cohort, and 544 (49.4%) were the validation cohort. In the validation cohort, individualized treatment effects predicted by the model significantly modified the effect of trial group assignment on the primary outcome (P value for interaction = 0.02; adjusted qini coefficient, 2.46). The most important model variables were difficult airway characteristics, body mass index, and Acute Physiology and Chronic Health Evaluation II score. Conclusions: In this hypothesis-generating secondary analysis of a randomized trial with no average treatment effect and no treatment effect in any prespecified subgroups, a causal forest machine learning algorithm identified patients who appeared to benefit from the use of a bougie over a stylet and from the use of a stylet over a bougie using complex interactions between baseline patient and operator characteristics.

Managing Severe Hypoxic Respiratory Failure in COVID-19.

Purpose of Review: Adult respiratory distress syndrome is a life-threatening complication from severe COVID-19 infection resulting in severe hypoxic respiratory failure. Strategies at improving oxygenation have evolved over the course of the pandemic. Recent Findings: Although non-invasive respiratory support reduces the need for intubation, a significant number of patients with COVID-19 progress to invasive mechanical ventilation. Once intubated, a lung protective ventilation strategy should be employed that limits tidal volumes to 6 ml/kg of predicted body weight and employs sufficient positive end-expiratory pressure to maximize oxygen delivery while minimizing the fraction of inspired oxygen. Intermittent prone positioning is effective at improving survival, and there is a growing body of evidence that it can be safely performed in spontaneously breathing patients to reduce the need for invasive mechanical ventilation. Inhaled pulmonary vasodilators have not been shown to improve survival or cost-effectiveness in COVID-19 and should be used selectively. Summary: Finally, the best outcomes are likely achieved at centers with experience at severe ARDS management and protocols for escalation of care.

Effect of Use of a Bougie vs Endotracheal Tube With Stylet on Successful Intubation on the First Attempt Among Critically Ill Patients Undergoing Tracheal Intubation: A Randomized Clinical Trial.

Importance: For critically ill adults undergoing emergency tracheal intubation, failure to intubate the trachea on the first attempt occurs in up to 20% of cases and is associated with severe hypoxemia and cardiac arrest. Whether using a tracheal tube introducer ("bougie") increases the likelihood of successful intubation compared with using an endotracheal tube with stylet remains uncertain. Objective: To determine the effect of use of a bougie vs an endotracheal tube with stylet on successful intubation on the first attempt. Design, Setting, and Participants: The Bougie or Stylet in Patients Undergoing Intubation Emergently (BOUGIE) trial was a multicenter, randomized clinical trial among 1102 critically ill adults undergoing tracheal intubation in 7 emergency departments and 8 intensive care units in the US between April 29, 2019, and February 14, 2021; the date of final follow-up was March 14, 2021. Interventions: Patients were randomly assigned to use of a bougie (n = 556) or use of an endotracheal tube with stylet (n = 546). Main Outcomes and Measures: The primary outcome was successful intubation on the first attempt. The secondary outcome was the incidence of severe hypoxemia, defined as a peripheral oxygen saturation less than 80%. Results: Among 1106 patients randomized, 1102 (99.6%) completed the trial and were included in the primary analysis (median age, 58 years; 41.0% women). Successful intubation on the first attempt occurred in 447 patients (80.4%) in the bougie group and 453 patients (83.0%) in the stylet group (absolute risk difference, -2.6 percentage points [95% CI, -7.3 to 2.2]; P = .27). A total of 58 patients (11.0%) in the bougie group experienced severe hypoxemia, compared with 46 patients (8.8%) in the stylet group (absolute risk difference, 2.2 percentage points [95% CI, -1.6 to 6.0]). Esophageal intubation occurred in 4 patients (0.7%) in the bougie group and 5 patients (0.9%) in the stylet group, pneumothorax was present after intubation in 14 patients (2.5%) in the bougie group and 15 patients (2.7%) in the stylet group, and injury to oral, glottic, or thoracic structures occurred in 0 patients in the bougie group and 3 patients (0.5%) in the stylet group. Conclusions and Relevance: Among critically ill adults undergoing tracheal intubation, use of a bougie did not significantly increase the incidence of successful intubation on the first attempt compared with use of an endotracheal tube with stylet. Trial Registration: ClinicalTrials.gov Identifier: NCT03928925

BOugie or stylet in patients UnderGoing Intubation Emergently (BOUGIE): protocol and statistical analysis plan for a randomised clinical trial.

INTRODUCTION: Intubation-related complications are less frequent when intubation is successful on the first attempt. The rate of first attempt success in the emergency department (ED) and intensive care unit (ICU) is typically less than 90%. The bougie, a semirigid introducer that can be placed into the trachea to facilitate a Seldinger-like technique of tracheal intubation and is typically reserved for difficult or failed intubations, might improve first attempt success. Evidence supporting its use, however, is from a single academic ED with frequent bougie use. Validation of these findings is needed before widespread implementation. METHODS AND ANALYSIS: The BOugie or stylet in patients Undergoing Intubation Emergently trial is a prospective, multicentre, non-blinded randomised trial being conducted in six EDs and six ICUs in the USA. The trial plans to enrol 1106 critically ill adults undergoing orotracheal intubation. Eligible patients are randomised 1:1 for the use of a bougie or use of an endotracheal tube with stylet for the first intubation attempt. The primary outcome is successful intubation on the first attempt. The secondary outcome is severe hypoxaemia, defined as an oxygen saturation less than 80% between induction until 2 min after completion of intubation. Enrolment began on 29 April 2019 and is expected to be completed in 2021. ETHICS AND DISSEMINATION: The trial protocol was approved with waiver of informed consent by the Central Institutional Review Board at Vanderbilt University Medical Center or the local institutional review board at an enrolling site. The results will be submitted for publication in a peer-reviewed journal and presented at scientific conferences. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT03928925).

Portable Neuromonitoring Device Detects Large Vessel Occlusion in Suspected Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: Early detection of large vessel occlusion (LVO) stroke optimizes endovascular therapy and improves outcomes. Clinical stroke severity scales used for LVO identification have variable accuracy. We investigated a portable LVO-detection device (PLD), using electroencephalography and somatosensory-evoked potentials, to identify LVO stroke. METHODS: We obtained PLD data in suspected patients with stroke enrolled prospectively via a convenience sample in 8 emergency departments within 24 hours of symptom onset. LVO discriminative signals were integrated into a binary classifier. The National Institutes of Health Stroke Scale was documented, and 4 prehospital stroke scales were retrospectively calculated. We compared PLD and scale performance to diagnostic neuroimaging. RESULTS: Of 109 patients, there were 25 LVO (23%), 38 non-LVO ischemic (35%), 14 hemorrhages (13%), and 32 stroke mimics (29%). The PLD had higher sensitivity (80% [95% CI, 74-85]) and similar specificity (80% [95% CI, 77-83]) to all prehospital scales at their predetermined high probability LVO thresholds. The PLD had high discrimination for LVO (C-statistic=0.88). CONCLUSIONS: The PLD identifies LVO with superior accuracy compared with prehospital stroke scales in emergency department suspected stroke. Future studies need to validate the PLD's potential as an LVO triage aid in prehospital undifferentiated stroke populations.

Donor to recipient transmission of SARS-CoV-2 by lung transplantation despite negative donor upper respiratory tract testing.

We describe a case of proven transmission of SARS-CoV-2 from lung donor to recipient. The donor had no clinical history or findings suggestive of infection with SARS-CoV-2 and tested negative by reverse transcriptase polymerase chain reaction (RT-PCR) on a nasopharyngeal (NP) swab obtained within 48 h of procurement. Lower respiratory tract testing was not performed. The recipient developed fever, hypotension, and pulmonary infiltrates on posttransplant day (PTD) 3, and RT-PCR testing for SARS-CoV-2 on an NP swab specimen was non-reactive, but positive on bronchoalveolar lavage (BAL) fluid. One thoracic surgeon present during the transplantation procedure developed COVID-19. Sequence analysis of isolates from donor BAL fluid (obtained at procurement), the recipient, and the infected thoracic surgeon proved donor origin of recipient and health-care worker (HCW) infection. No other organs were procured from this donor. Transplant centers and organ procurement organizations should perform SARS-CoV-2 testing of lower respiratory tract specimens from potential lung donors, and consider enhanced personal protective equipment for HCWs involved in lung procurement and transplantation.

Prehospital use of a modified HEART Pathway and point-of-care troponin to predict cardiovascular events.

CLINICAL TRIAL REGISTRATION: clinicaltrials.gov (NCT02709135).

Identification of very low-risk acute chest pain patients without troponin testing.

BACKGROUND: The HEART Pathway combines a History ECG Age Risk factor (HEAR) score and serial troponins to risk stratify patients with acute chest pain. However, it is unclear whether patients with HEAR scores of <1 require troponin testing. The objective of this study is to measure the major adverse cardiac event (MACE) rate among patients with <1 HEAR scores and determine whether serial troponin testing is needed to achieve a miss rate <1%. METHODS: A secondary analysis of the HEART Pathway Implementation Study was conducted. HEART Pathway risk assessments (HEAR scores and serial troponin testing at 0 and 3 hours) were completed by the providers on adult patients with chest pain from three US sites between November 2014 and January 2016. MACE (composite of death, myocardial infarction (MI) and coronary revascularisation) at 30 days was determined. The proportion of patients with HEAR scores of <1 diagnosed with MACE within 30 days was calculated. The impact of troponin testing on patients with HEAR scores of <1 was determined using Net Reclassification Improvement Index (NRI). RESULTS: Providers completed HEAR assessments on 4979 patients and HEAR scores<1 occurred in 9.0% (447/4979) of patients. Among these patients, MACE at 30 days occurred in 0.9% (4/447; 95% CI 0.2% to 2.3%) with two deaths, two MIs and 0 revascularisations. The sensitivity and negative predictive value for MACE in the HEAR <1 was 97.8% (95%CI 94.5% to 99.4%) and 99.1% (95% CI 97.7% to 99.8%), respectively, and were not improved by troponin testing. Troponin testing in patients with HEAR <1 correctly reclassified two patients diagnosed with MACE, and was elevated among seven patients without MACE yielding an NRI of 0.9% (95%CI -0.7 to 2.4%). CONCLUSION: These data suggest that patients with HEAR scores of 0 and 1 represent a very low-risk group that may not require troponin testing to achieve a missed MACE rate <1%. Trial registration number NCT02056964.

Point-of-Care Troponin Testing during Ambulance Transport to Detect Acute Myocardial Infarction.

Objective: Use of point-of-care (POC) troponin (cTn) testing in the Emergency Department (ED) is well established. However, data examining POC cTn measurement in the prehospital setting, during ambulance transport, are limited. The objective of this study was to prospectively test the performance of POC cTn measurement by paramedics to detect myocardial infarction (MI) among patients transported to the ED for acute chest pain. Methods: A prospective cohort study of adults with non-traumatic chest pain was conducted in three Emergency Medical Services agencies (December 2016 to January 2018). Patients with ST-elevation MI on ECG were excluded. During ambulance transport paramedics initiated intravenous access, collected blood, and used a POC device (i-STAT; Abbott Laboratories) to measure cTn. Following ED arrival, participants received standard evaluations including clinical blood draws for cTn measurement in the hospital central lab (AccuTnI +3 assay; Beckman Coulter, or cTnI-Ultra assay; Siemens). Blood collected during ambulance transport was also analyzed for cTn in the central lab. Index visit MI was adjudicated by 3 experts using central lab cTn measures from the patient's clinical blood draws. Test characteristics (sensitivity, specificity, and predictive values) for detection of MI were calculated for POC and central lab cTn measurement of prehospital blood and compared with McNemar's test. Results: During the study period prehospital POC cTn results were obtained on 421 patients, of which 5.0% (21/421) had results >99th percentile upper reference limit. MI was adjudicated in 16.2% (68/421) during the index visit. The specificity and positive predictive value of the POC cTn measurement were 99.2% (95% CI 97.5-99.8%) and 85.7% (95% CI 63.7-97.0%) for MI. However, the sensitivity and NPV of prehospital POC cTn were 26.5% (95% CI 16.5-38.6%) and 87.5% (95% CI 83.9-90.6%). Compared to POC cTn, the central lab cTn measurement of prehospital blood resulted in a higher sensitivity of 67.9% (95% CI 53.7-80.1%, p < 0.0001), but lower specificity of 92.4% (95% CI 88.4-95.4%, p = 0.0001). Conclusions: Prehospital POC i-STAT cTn measurement in patients transported with acute chest pain was highly specific for MI but had low sensitivity. This suggests that prehospital i-STAT POC cTn could be useful to rule-in MI, but should not be used to exclude MI.

The peripheral blood transcriptome in septic cardiomyopathy: an observational, pilot study.

BACKGROUND: Septic cardiomyopathy (SCM) is common in sepsis and associated with increased morbidity and mortality. Left ventricular global longitudinal strain (LV GLS), measured by speckle tracking echocardiography, allows improved identification of impaired cardiac contractility. The peripheral blood transcriptome may be an important window into SCM pathophysiology. We therefore studied the peripheral blood transcriptome and LV GLS in a prospective cohort of patients with sepsis. RESULTS: In this single-center observational pilot study, we enrolled adult patients (age > 18) with sepsis within 48 h of admission to the ICU. SCM was defined as LV GLS > - 17% based on echocardiograms performed within 72 h of admission. We enrolled 27 patients, 24 of whom had high-quality RNA results; 18 (75%) of 24 had SCM. The group was 50% female and had a median (IQR) age of 59.5 (48.5-67.0) years and admission APACHE II score of 21.0 (16.0-32.3). Forty-six percent had septic shock. After filtering for low-expression and non-coding genes, 15,418 protein coding genes were expressed and 73 had significantly different expression between patients with vs. without SCM. In patients with SCM, 43 genes were upregulated and 30 were downregulated. Pathway analysis identified enrichment in type 1 interferon signaling (adjusted p < 10-5). CONCLUSIONS: In this hypothesis-generating study, SCM was associated with upregulation of genes in the type 1 interferon signaling pathway. Interferons are cytokines that stimulate the innate and adaptive immune response and are implicated in the early proinflammatory and delayed immunosuppression phases of sepsis. While type 1 interferons have not been implicated previously in SCM, interferon therapy (for viral hepatitis and Kaposi sarcoma) has been associated with reversible cardiomyopathy, perhaps suggesting a role for interferon signaling in SCM.

Incomplete Stevens-Johnson Syndrome Caused by Sulfonamide Antimicrobial Exposure.

Stevens-Johnson syndrome (SJS) is a mucocutaneous reaction typically brought on by medications or infections. The diagnosis of SJS is typically made when patients present with a variable appearing rash and involvement of the oral, ocular, or genital mucosa. However, there are rare reports of atypical or incomplete SJS. These cases are usually associated with children infected with Mycoplasma pneumoniae, which presents with severe mucositis but no rash. Herein, we report the first case of adult incomplete SJS brought on by sulfonamide antimicrobial use without clinical or laboratory evidence of M. pneumoniae infection.

SIRT1 Mediates Septic Cardiomyopathy in a Murine Model of Polymicrobial Sepsis.

BACKGROUND: Cardiac dysfunction, a common complication from severe sepsis, is associated with increased morbidity and mortality. However, the molecular mechanisms of septic cardiac dysfunction are poorly understood. SIRT1, a member of the sirtuin family of NAD+-dependent protein deacetylases, is an important immunometabolic regulator of sepsis, and sustained SIRT1 elevation is associated with worse outcomes and organ dysfunction in severe sepsis. Herein, we explore the role of SIRT1 in septic cardiac dysfunction using a murine model of sepsis. METHODS: An in vitro model of inflammation in isolated H9c2 cardiomyocytes was used to confirm SIRT1 response to stimulation with lipopolysaccharide (LPS), followed by a murine model of cecal ligation and puncture (CLP) to investigate the molecular and echocardiographic response to sepsis. A selective SIRT1 inhibitor, EX-527, was employed to test for SIRT1 participation in septic cardiac dysfunction. RESULTS: SIRT1 mRNA and protein levels in cultured H9c2 cardiomyocytes were significantly elevated at later time points after stimulation with LPS. Similarly, cardiac tissue harvested from C57BL/6 mice 36 h after CLP demonstrated increased expression of SIRT1 mRNA and protein compared with sham controls. Administration of EX-527 18 h after CLP reduced SIRT1 protein expression in cardiac tissue at 36 h. Moreover, treatment with EX-527 improved cardiac performance with increased global longitudinal strain and longitudinal strain rate. CONCLUSIONS: Our findings reveal that SIRT1 expression increases in isolated cardiomyocytes and cardiac tissue after sepsis inflammation. Moreover, rebalancing SIRT1 excess in late sepsis improves cardiac performance, suggesting that SIRT1 may serve as a therapeutic target for septic cardiomyopathy.

Erythrocytic bioactivation of nitrite and its potentiation by far-red light.

BACKGROUND: Nitrite is reduced by heme-proteins and molybdenum-containing enzymes to form the important signaling molecule nitric oxide (NO), mediating NO signaling. Substantial evidence suggests that deoxygenated hemoglobin within red blood cells (RBCs) is the main erythrocytic protein responsible for mediating nitrite-dependent NO signaling. In other work, infrared and far red light have been shown to have therapeutic potential that some attribute to production of NO. Here we explore whether a combination of nitrite and far red light treatment has an additive effect in NO-dependent processes, and whether this effect is mediated by RBCs. METHODS AND RESULTS: Using photoacoustic imaging in a rat model as a function of varying inspired oxygen, we found that far red light (660 nm, five min. exposure) and nitrite feeding (three weeks in drinking water at 100 mg/L) each separately increased tissue oxygenation and vessel diameter, and the combined treatment was additive. We also employed inhibition of human platelet activation measured by flow cytometry to assess RBC-dependent nitrite bioactivation and found that far red light dramatically potentiates platelet inhibition by nitrite. Blocking RBC-surface thiols abrogated these effects of nitrite and far-red light. RBC-dependent production of NO was also shown to be enhanced by far red light using a chemiluminescence-based nitric oxide analyzer. In addition, RBC-dependent bioactivation of nitrite led to prolonged lag times for clotting in platelet poor plasma that was enhanced by exposure to far red light. CONCLUSIONS: Our results suggest that nitrite leads to the formation of a photolabile RBC surface thiol-bound species such as an S-nitrosothiol or heme-nitrosyl (NO-bound heme) for which far red light enhances NO signaling. These findings expand our understanding of RBC-mediated NO production from nitrite. This pathway of NO production may have therapeutic potential in several applications including thrombosis, and, thus, warrants further study.

Implementation of the HEART Pathway: Using the Consolidated Framework for Implementation Research.

OBJECTIVE: The HEART Pathway is an evidence-based decision tool for identifying emergency department (ED) patients with acute chest pain who are candidates for early discharge, to reduce unhelpful and potentially harmful hospitalizations. Guided by the Consolidated Framework for Implementation Research, we sought to identify important barriers and facilitators to implementation of the HEART Pathway. STUDY SETTING: Data were collected at 4 academic medical centers. STUDY DESIGN: We conducted semi-structured interviews with 25 key stakeholders (e.g., health system leaders, ED physicians). We conducted interviews before implementation of the HEART Pathway tool to identify potential barriers and facilitators to successful adoption at other regional academic medical centers. We also conducted postimplementation interviews at 1 medical center, to understand factors that contributed to successful adoption. DATA COLLECTION: Interviews were recorded and transcribed verbatim. We used a Consolidated Framework for Implementation Research framework-driven deductive approach for coding and analysis. PRINCIPAL FINDINGS: Potential barriers to implementation include time and resource burden, challenges specific to the electronic health record, sustained communication with and engagement of stakeholders, and patient concerns. Facilitators to implementation include strength of evidence for reduced length of stay and unnecessary testing and iatrogenic complications, ease of use, and supportive provider climate for evidence-based decision tools. CONCLUSIONS: Successful dissemination of the HEART Pathway will require addressing institution-specific barriers, which includes engaging clinical and financial stakeholders. New SMART-FHIR technologies, compatible with many electronic health record systems, can overcome barriers to health systems with limited information technology resources.

Real World Evidence for Treatment of Hyperkalemia in the Emergency Department (REVEAL-ED): A Multicenter, Prospective, Observational Study.

BACKGROUND: Contemporary emergency department (ED) standard-of-care treatment of hyperkalemia is poorly described. OBJECTIVE: Our aim was to determine the treatment patterns of hyperkalemia management in the ED. METHODS: This multicenter, prospective, observational study evaluated patients aged ≥ 18 years with hyperkalemia (potassium [K+] level ≥ 5.5 mmol/L) in the ED from October 25, 2015 to March 30, 2016. K+-lowering therapies and K+ were documented at 0.5, 1, 2, and 4 h after initial ED treatment. The primary end point was change in K+ over 4 h. RESULTS: Overall, 203 patients were enrolled at 14 U.S.-based sites. The initial median K+ was 6.3 (interquartile range [IQR] 5.7-6.8) mmol/L and median time to treatment was 2.7 (IQR 1.9-3.5) h post-ED arrival. Insulin/glucose (n = 130; 64%) was frequently used to treat hyperkalemia; overall, 43 different treatment combinations were employed within the first 4 h. Within 4 h, the median K+ for patients treated with medications alone decreased from 6.3 (IQR, 5.8-6.8) mmol/L to 5.3 (4.8-5.7) mmol/L, while that for patients treated with dialysis decreased from 6.2 (IQR 6.0-6.6) mmol/L to 3.8 (IQR 3.6-4.2) mmol/L. Hypoglycemia occurred in 6% of patients overall and in 17% of patients with K+ > 7.0 mmol/L. Hyperkalemia-related electrocardiogram changes were observed in 23% of all patients; 45% of patients with K+ > 7.0 mmol/L had peaked T waves or widened QRS. Overall, 79% were hospitalized; 3 patients died. CONCLUSIONS: Hyperkalemia practice patterns vary considerably and, although treatment effectively lowered K+, only dialysis normalized median K+ within 4 h.

Preclinical Ultrasound-Guided Photoacoustic Imaging of the Placenta in Normal and Pathologic Pregnancy.

Placental oxygenation varies throughout pregnancy. The detection of early changes in placental oxygenation as pregnancy progresses is important for early identification of preeclampsia or other complications. This invited commentary discusses a recent preclinical study on the application of 3-dimensional photoacoustic imaging (PAI) for assessment of regional variations in placental oxygenation and longitudinal analysis of differences in placental oxygenation throughout normal pregnancy and pregnancy associated with hypertension or placental insufficiency in mice. Three-dimensional PAI more accurately reflects oxygen saturation, hemoglobin concentrations, and changes in oxygen saturation in whole placenta compared to 2-dimensional imaging. These studies suggest that PAI is a sensitive tool to detect different levels of oxygen saturation in the placental and fetal vasculature in pathologic and normal pregnancy in mice.