Causes and attributable fraction of death from ARDS in inflammatory phenotypes of sepsis.

BACKGROUND: Hypoinflammatory and hyperinflammatory phenotypes have been identified in both Acute Respiratory Distress Syndrome (ARDS) and sepsis. Attributable mortality of ARDS in each phenotype of sepsis is yet to be determined. We aimed to estimate the population attributable fraction of death from ARDS (PAFARDS) in hypoinflammatory and hyperinflammatory sepsis, and to determine the primary cause of death within each phenotype. METHODS: We studied 1737 patients with sepsis from two prospective cohorts. Patients were previously assigned to the hyperinflammatory or hypoinflammatory phenotype using latent class analysis. The PAFARDS in patients with sepsis was estimated separately in the hypo and hyperinflammatory phenotypes. Organ dysfunction, severe comorbidities, and withdrawal of life support were abstracted from the medical record in a subset of patients from the EARLI cohort who died (n = 130/179). Primary cause of death was defined as the organ system that most directly contributed to death or withdrawal of life support. RESULTS: The PAFARDS was 19% (95%CI 10,28%) in hypoinflammatory sepsis and, 14% (95%CI 6,20%) in hyperinflammatory sepsis. Cause of death differed between the two phenotypes (p < 0.001). Respiratory failure was the most common cause of death in hypoinflammatory sepsis, whereas circulatory shock was the most common cause in hyperinflammatory sepsis. Death with severe underlying comorbidities was more frequent in hypoinflammatory sepsis (81% vs. 67%, p = 0.004). CONCLUSIONS: The PAFARDS is modest in both phenotypes whereas primary cause of death among patients with sepsis differed substantially by phenotype. This study identifies challenges in powering future clinical trials to detect changes in mortality outcomes among patients with sepsis and ARDS.

Rapidly improving ARDS differs clinically and biologically from persistent ARDS.

BACKGROUND: Rapidly improving acute respiratory distress syndrome (RIARDS) is an increasingly appreciated subgroup of ARDS in which hypoxemia improves within 24 h after initiation of mechanical ventilation. Detailed clinical and biological features of RIARDS have not been clearly defined, and it is unknown whether RIARDS is associated with the hypoinflammatory or hyperinflammatory phenotype of ARDS. The purpose of this study was to define the clinical and biological features of RIARDS and its association with inflammatory subphenotypes. METHODS: We analyzed data from 215 patients who met Berlin criteria for ARDS (endotracheally intubated) and were enrolled in a prospective observational cohort conducted at two sites, one tertiary care center and one urban safety net hospital. RIARDS was defined according to previous studies as improvement of hypoxemia defined as (i) PaO2:FiO2 > 300 or (ii) SpO2: FiO2 > 315 on the day following diagnosis of ARDS (day 2) or (iii) unassisted breathing by day 2 and for the next 48 h (defined as absence of endotracheal intubation on day 2 through day 4). Plasma biomarkers were measured on samples collected on the day of study enrollment, and ARDS phenotypes were allocated as previously described. RESULTS: RIARDS accounted for 21% of all ARDS participants. Patients with RIARDS had better clinical outcomes compared to those with persistent ARDS, with lower hospital mortality (13% vs. 57%; p value < 0.001) and more ICU-free days (median 24 vs. 0; p value < 0.001). Plasma levels of interleukin-6, interleukin-8, and plasminogen activator inhibitor-1 were significantly lower among patients with RIARDS. The hypoinflammatory phenotype of ARDS was more common among patients with RIARDS (78% vs. 51% in persistent ARDS; p value = 0.001). CONCLUSIONS: This study identifies a high prevalence of RIARDS in a multicenter observational cohort and confirms the more benign clinical course of these patients. We report the novel finding that RIARDS is characterized by lower concentrations of plasma biomarkers of inflammation compared to persistent ARDS, and that hypoinflammatory ARDS is more prevalent among patients with RIARDS. Identification and exclusion of RIARDS could potentially improve prognostic and predictive enrichment in clinical trials.

Novel subtypes of severe COVID-19 respiratory failure based on biological heterogeneity: a secondary analysis of a randomized controlled trial.

BACKGROUND: Despite evidence associating inflammatory biomarkers with worse outcomes in hospitalized adults with COVID-19, trials of immunomodulatory therapies have met with mixed results, likely due in part to biological heterogeneity of participants. Latent class analysis (LCA) of clinical and protein biomarker data has identified two subtypes of non-COVID acute respiratory distress syndrome (ARDS) with different clinical outcomes and treatment responses. We studied biological heterogeneity and clinical outcomes in a multi-institutional platform randomized controlled trial of adults with severe COVID-19 hypoxemic respiratory failure (I-SPY COVID). METHODS: Clinical and plasma protein biomarker data were analyzed from 400 trial participants enrolled from September 2020 until October 2021 with severe COVID-19 requiring ≥ 6 L/min supplemental oxygen. Seventeen hypothesis-directed protein biomarkers were measured at enrollment using multiplex Luminex panels or single analyte enzyme linked immunoassay methods (ELISA). Biomarkers and clinical variables were used to test for latent subtypes and longitudinal biomarker changes by subtype were explored. A validated parsimonious model using interleukin-8, bicarbonate, and protein C was used for comparison with non-COVID hyper- and hypo-inflammatory ARDS subtypes. RESULTS: Average participant age was 60 ± 14 years; 67% were male, and 28-day mortality was 25%. At trial enrollment, 85% of participants required high flow oxygen or non-invasive ventilation, and 97% were receiving dexamethasone. Several biomarkers of inflammation (IL-6, IL-8, IL-10, sTNFR-1, TREM-1), epithelial injury (sRAGE), and endothelial injury (Ang-1, thrombomodulin) were associated with 28- and 60-day mortality. Two latent subtypes were identified. Subtype 2 (27% of participants) was characterized by persistent derangements in biomarkers of inflammation, endothelial and epithelial injury, and disordered coagulation and had twice the mortality rate compared with Subtype 1. Only one person was classified as hyper-inflammatory using the previously validated non-COVID ARDS model. CONCLUSIONS: We discovered evidence of two novel biological subtypes of severe COVID-19 with significantly different clinical outcomes. These subtypes differed from previously established hyper- and hypo-inflammatory non-COVID subtypes of ARDS. Biological heterogeneity may explain inconsistent findings from trials of hospitalized patients with COVID-19 and guide treatment approaches.

Distinct pulmonary and systemic effects of dexamethasone in severe COVID-19.

Dexamethasone is the standard of care for critically ill patients with COVID-19, but the mechanisms by which it decreases mortality and its immunological effects in this setting are not understood. We performed bulk and single-cell RNA sequencing of the lower respiratory tract and blood, and plasma cytokine profiling to study the effect of dexamethasone on systemic and pulmonary immune cells. We find decreased signatures of antigen presentation, T cell recruitment, and viral injury in patients treated with dexamethasone. We identify compartment- and cell- specific differences in the effect of dexamethasone in patients with severe COVID-19 that are reproducible in publicly available datasets. Our results highlight the importance of studying compartmentalized inflammation in critically ill patients.

Identifying molecular phenotypes in sepsis: an analysis of two prospective observational cohorts and secondary analysis of two randomised controlled trials.

BACKGROUND: In sepsis and acute respiratory distress syndrome (ARDS), heterogeneity has contributed to difficulty identifying effective pharmacotherapies. In ARDS, two molecular phenotypes (hypoinflammatory and hyperinflammatory) have consistently been identified, with divergent outcomes and treatment responses. In this study, we sought to derive molecular phenotypes in critically ill adults with sepsis, determine their overlap with previous ARDS phenotypes, and evaluate whether they respond differently to treatment in completed sepsis trials. METHODS: We used clinical data and plasma biomarkers from two prospective sepsis cohorts, the Validating Acute Lung Injury biomarkers for Diagnosis (VALID) study (N=1140) and the Early Assessment of Renal and Lung Injury (EARLI) study (N=818), in latent class analysis (LCA) to identify the optimal number of classes in each cohort independently. We used validated models trained to classify ARDS phenotypes to evaluate concordance of sepsis and ARDS phenotypes. We applied these models retrospectively to the previously published Prospective Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis and Septic Shock (PROWESS-SHOCK) trial and Vasopressin and Septic Shock Trial (VASST) to assign phenotypes and evaluate heterogeneity of treatment effect. FINDINGS: A two-class model best fit both VALID and EARLI (p<0·0001). In VALID, 804 (70·5%) of the 1140 patients were classified as hypoinflammatory and 336 (29·5%) as hyperinflammatory; in EARLI, 530 (64·8%) of 818 were hypoinflammatory and 288 (35·2%) hyperinflammatory. We observed higher plasma pro-inflammatory cytokines, more vasopressor use, more bacteraemia, lower protein C, and higher mortality in the hyperinflammatory than in the hypoinflammatory phenotype (p<0·0001 for all). Classifier models indicated strong concordance between sepsis phenotypes and previously identified ARDS phenotypes (area under the curve 0·87-0·96, depending on the model). Findings were similar excluding participants with both sepsis and ARDS. In PROWESS-SHOCK, 1142 (68·0%) of 1680 patients had the hypoinflammatory phenotype and 538 (32·0%) had the hyperinflammatory phenotype, and response to activated protein C differed by phenotype (p=0·0043). In VASST, phenotype proportions were similar to other cohorts; however, no treatment interaction with the type of vasopressor was observed (p=0·72). INTERPRETATION: Molecular phenotypes previously identified in ARDS are also identifiable in multiple sepsis cohorts and respond differently to activated protein C. Molecular phenotypes could represent a treatable trait in critical illness beyond the patient's syndromic diagnosis. FUNDING: US National Institutes of Health.

Plasma metabolic profiling implicates dysregulated lipid metabolism and glycolytic shift in hyperinflammatory ARDS.

Using latent class analysis (LCA) of clinical and protein biomarkers, researchers have identified two phenotypes of the acute respiratory distress syndrome (ARDS) with divergent clinical trajectories and treatment responses. We investigated whether plasma metabolites differed among patients with LCA-derived hyperinflammatory and hypoinflammatory ARDS, and we tested the prognostic utility of adding metabolic clusters to LCA phenotypes. We analyzed data from 93 patients with ARDS and sepsis enrolled in a multicenter prospective cohort of critically ill patients, comparing 970 metabolites between the two LCA-derived phenotypes. In all, 188 metabolites were differentially abundant between the two LCA-derived phenotypes. After adjusting for age, sex, confounding medications, and comorbid liver and kidney disease, 82 metabolites remained significantly different. Patients with hyperinflammatory ARDS had reduced circulating lipids but high levels of pyruvate, lactate, and malate. Metabolic cluster and LCA-derived phenotypes were each significantly and independently associated with survival. Patients with hyperinflammatory ARDS may be experiencing a glycolytic shift leading to dysregulated lipid metabolism. Metabolic profiling offers prognostic information beyond what is captured by LCA phenotypes alone. Deeper biological profiling may identify key differences in pathogenesis among patients with ARDS and may lead to novel targeted therapies.

Plasma SARS-CoV-2 nucleocapsid antigen levels are associated with progression to severe disease in hospitalized COVID-19.

BACKGROUND: Studies quantifying SARS-CoV-2 have focused on upper respiratory tract or plasma viral RNA with inconsistent association with clinical outcomes. The association between plasma viral antigen levels and clinical outcomes has not been previously studied. Our aim was to investigate the relationship between plasma SARS-CoV-2 nucleocapsid antigen (N-antigen) concentration and both markers of host response and clinical outcomes. METHODS: SARS-CoV-2 N-antigen concentrations were measured in the first study plasma sample (D0), collected within 72 h of hospital admission, from 256 subjects admitted between March 2020 and August 2021 in a prospective observational cohort of hospitalized patients with COVID-19. The rank correlations between plasma N-antigen and plasma biomarkers of tissue damage, coagulation, and inflammation were assessed. Multiple ordinal regression was used to test the association between enrollment N-antigen plasma concentration and the primary outcome of clinical deterioration at one week as measured by a modified World Health Organization (WHO) ordinal scale. Multiple logistic regression was used to test the association between enrollment plasma N-antigen concentration and the secondary outcomes of ICU admission, mechanical ventilation at 28 days, and death at 28 days. The prognostic discrimination of an externally derived "high antigen" cutoff of N-antigen ≥ 1000 pg/mL was also tested. RESULTS: N-antigen on D0 was detectable in 84% of study participants. Plasma N-antigen levels significantly correlated with RAGE (r = 0.61), IL-10 (r = 0.59), and IP-10 (r = 0.59, adjusted p = 0.01 for all correlations). For the primary outcome of clinical status at one week, each 500 pg/mL increase in plasma N-antigen level was associated with an adjusted OR of 1.05 (95% CI 1.03-1.08) for worse WHO ordinal status. D0 plasma N-antigen ≥ 1000 pg/mL was 77% sensitive and 59% specific (AUROC 0.68) with a positive predictive value of 23% and a negative predictive value of 93% for a worse WHO ordinal scale at day 7 compared to baseline. D0 N-antigen concentration was independently associated with ICU admission and 28-day mechanical ventilation, but not with death at 28 days. CONCLUSIONS: Plasma N-antigen levels are readily measured and provide important insight into the pathogenesis and prognosis of COVID-19. The measurement of N-antigen levels early in-hospital course may improve risk stratification, especially for identifying patients who are unlikely to progress to severe disease.

Mass cytometry reveals a conserved immune trajectory of recovery in hospitalized COVID-19 patients.

While studies have elucidated many pathophysiological elements of COVID-19, little is known about immunological changes during COVID-19 resolution. We analyzed immune cells and phosphorylated signaling states at single-cell resolution from longitudinal blood samples of patients hospitalized with COVID-19, pneumonia and/or sepsis, and healthy individuals by mass cytometry. COVID-19 patients showed distinct immune compositions and an early, coordinated, and elevated immune cell signaling profile associated with early hospital discharge. Intra-patient longitudinal analysis revealed changes in myeloid and T cell frequencies and a reduction in immune cell signaling across cell types that accompanied disease resolution and discharge. These changes, together with increases in regulatory T cells and reduced signaling in basophils, also accompanied recovery from respiratory failure and were associated with better outcomes at time of admission. Therefore, although patients have heterogeneous immunological baselines and highly variable disease courses, a core immunological trajectory exists that defines recovery from severe SARS-CoV-2 infection.

Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs.

Life-threatening 'breakthrough' cases of critical COVID-19 are attributed to poor or waning antibody response to the SARS-CoV-2 vaccine in individuals already at risk. Pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; however, their contribution to hypoxemic breakthrough cases in vaccinated people remains unknown. Here, we studied a cohort of 48 individuals (age 20-86 years) who received 2 doses of an mRNA vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Antibody levels to the vaccine, neutralization of the virus, and auto-Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal antibody response to the vaccine. Among them, ten (24%) had auto-Abs neutralizing type I IFNs (aged 43-86 years). Eight of these ten patients had auto-Abs neutralizing both IFN-α2 and IFN-ω, while two neutralized IFN-ω only. No patient neutralized IFN-ß. Seven neutralized 10 ng/mL of type I IFNs, and three 100 pg/mL only. Seven patients neutralized SARS-CoV-2 D614G and the Delta variant (B.1.617.2) efficiently, while one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only 100 pg/mL of type I IFNs neutralized both D61G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating antibodies capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a significant proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population.

The Code Silver Exercise: a low-cost simulation alternative to prepare hospitals for an active shooter event.

Mass-shooting incidents have been increasing in recent years and Code Silver-the hospital response to a person with a weapon such as an active shooter in many Provinces or States in North America-is quickly shifting from a theoretical safety measure to a realistic scenario for which hospitals must prepare their staff. A Code Silver Exercise (CSE) involving an independent mental practice exercise with written responses to scenarios and questions, followed by a facilitated debrief with all participants, was conceptualized and trialled for feasibility and efficacy. The CSE was piloted as a quality improvement and emergency preparedness initiative in three different settings including in situ within a hospital Emergency Department or Intensive Care Unit, offsite in a large conference room workshop, and online via virtual platform. These sessions took place in 4 different cities in Canada and included 3 academic teaching hospitals. Participants of the in situ and virtual CSE completed pre- and post-simulation surveys which showed improved understanding of Code Silver protocols following participation.The CSE is a reproducible simulation alternative, designed to operationalize a Code Silver policy at a large healthcare institution in a sustainable way. This training model can be administered in multiple settings in-person (in situ or offsite), and virtually, making it versatile and easily accessible for participants. This exercise enables participants to mentally rehearse practical responses to an active shooter in their unique work environments and to discuss ethical and medical-legal implications of their responses during a facilitated debrief with fellow healthcare providers. Implementation of a CSE for training in hospitals may help staff to create a mental schema prior to an active shooter event, and thus indirectly improve the chances of survivability in the event of a real active shooter situation.

Remember that patient you saw last week: characteristics and frequency of patients experiencing anticipated and unanticipated death following ED discharge.

BACKGROUND: The emergency department (ED) is an at-risk area for medical error. We determined the characteristics of patients with unanticipated and anticipated death within 7 days of ED discharge and whether medical error contributed. METHODS: We performed a single-centre health records review of 200 consecutive cases during a 3-year period from 2014 to 2017 in two urban, academic, tertiary care EDs. We included patients evaluated by an emergency physician who were discharged and died within 7 days. Three trained and blinded reviewers determined if deaths were related to the index visit, anticipated or unanticipated, and/or due to potential medical error. Reviewers performed content analysis to identify themes. RESULTS: Of 200 cases, 129 had sufficient information for analysis, translating to 44 deaths per 100,000 ED discharges (200/458,634). 13 cases per 100,000 ED discharges (58/458,634) were related and unanticipated deaths. 4 cases per 100,000 were due to potential medical errors (18/458,634). Over half (52.7%) of 129 patients displayed abnormal vital signs at discharge. Pneumonia (27.1%) was the most common cause of death. Patient themes were: difficult historian, multiple complaints, multiple comorbidities, acute progression of chronic disease, and recurrent falls. Provider themes were: failure to consider infectious etiology, failure to admit high-risk elderly patient, and missed diagnosis. System themes were: multiple ED visits or recent admission, and no repeat vital signs recorded. CONCLUSION: Though the frequency of related and unanticipated deaths and those due to medical error was low, clinicians should carefully consider the highlighted common patient, provider, and system themes to facilitate safe discharge from the ED.

RéSUMé: CONTEXTE: Le service des urgences (SU) est un secteur à risque pour les erreurs médicales. Nous avons déterminé les caractéristiques des patients dont le décès a été anticipé ou non dans les 7 jours suivant la sortie des urgences et si une erreur médicale y a contribué. MéTHODES: Nous avons réalisé une étude monocentrique des dossiers médicaux de 200 cas consécutifs sur une période de trois ans, de 2014 à 2017, dans deux urgences urbaines, universitaires et de soins tertiaires. Nous avons inclus les patients évalués par un médecin urgentiste qui sont sortis de l'hôpital et sont décédés dans les 7 jours. Trois examinateurs formés et en aveugle ont déterminé si les décès étaient liés à la visite de référence, anticipés ou non, et/ou dus à une erreur médicale potentielle. Les examinateurs ont effectué une analyse de contenu pour identifier les thèmes. RéSULTATS: Sur 200 cas, 129 disposaient d'informations suffisantes pour l'analyse, ce qui correspond à 44 décès pour 100 000 sorties des urgences (200/458 634). 13 cas pour 100 000 sorties des urgences (58/458 634) étaient des décès liés et imprévus. 4 cas pour 100 000 étaient dus à des erreurs médicales potentielles (18/458 634). Plus de la moitié (52,7%) des 129 patients présentaient des signes vitaux anormaux à la sortie de l'hôpital. La pneumonie (27,1%) était la cause de décès la plus fréquente. Les thèmes des patients étaient les suivants: patient difficile, plaintes multiples, comorbidités multiples, progression aiguë d'une maladie chronique et chutes récurrentes. Les thèmes abordés par les prestataires étaient les suivants: omission de tenir compte de l'étiologie infectieuse, omission d'admettre un patient âgé à haut risque et omission de diagnostic. Les thèmes du système étaient les suivants: visites multiples à l'urgence ou admission récente, et aucun signe vital répété n'a été enregistré. CONCLUSION: Bien que la fréquence des décès liés et imprévus et ceux dus à une erreur médicale soit faible, les cliniciens doivent examiner attentivement les thèmes communs mis en évidence pour les patients, les prestataires et les systèmes afin de faciliter une sortie en toute sécurité des urgences.

Tracheal aspirate RNA sequencing identifies distinct immunological features of COVID-19 ARDS.

The immunological features that distinguish COVID-19-associated acute respiratory distress syndrome (ARDS) from other causes of ARDS are incompletely understood. Here, we report the results of comparative lower respiratory tract transcriptional profiling of tracheal aspirate from 52 critically ill patients with ARDS from COVID-19 or from other etiologies, as well as controls without ARDS. In contrast to a "cytokine storm," we observe reduced proinflammatory gene expression in COVID-19 ARDS when compared to ARDS due to other causes. COVID-19 ARDS is characterized by a dysregulated host response with increased PTEN signaling and elevated expression of genes with non-canonical roles in inflammation and immunity. In silico analysis of gene expression identifies several candidate drugs that may modulate gene expression in COVID-19 ARDS, including dexamethasone and granulocyte colony stimulating factor. Compared to ARDS due to other types of viral pneumonia, COVID-19 is characterized by impaired interferon-stimulated gene (ISG) expression. The relationship between SARS-CoV-2 viral load and expression of ISGs is decoupled in patients with COVID-19 ARDS when compared to patients with mild COVID-19. In summary, assessment of host gene expression in the lower airways of patients reveals distinct immunological features of COVID-19 ARDS.

Ten (+1) lessons from conducting a mass casualty in situ simulation exercise in a Canadian academic hospital setting.

Providing care in a twenty-first century urban emergency department (ED) and trauma center is a complex high-pressure practice environment. The pressure is intensified during patient surge scenarios commonly seen during mass casualty incidents, such that response must be practiced regularly. Beyond clinical mastery of individual patient trauma care, a coordinated system-level response is essential to optimize patient care during these relatively infrequent events. This paper highlights the need to perform exercises in hospitals while providing practical advice on how to utilize in situ simulation for mass casualty testing. Eleven lessons are presented to assist other emergency management professionals, hospital administrators, or clinical staff to achieve success with in situ simulation. Based upon our experience designing and executing an in situ mass casualty simulation within an ED, we offer lessons applicable to any type of disaster exercise. Simulation offers a powerful tool for the conduct of disaster preparedness exercises for staff across multiple hospital departments and professions.

Integration of In Situ Simulation Into an Emergency Department Code Orange Exercise in a Tertiary Care Trauma Referral Center.

OBJECTIVES: Disaster-preparedness and response are a commonly overlooked aspect of hospital policy and can frequently be outdated and undertested. Simulation-based education has become a core education modality within Canadian medical training programs. We hypothesized that integrating in situ simulation (ISS) into a hospital-wide, mass-casualty response exercise would enhance realism and our ability to identify latent safety threats (LSTs). METHODS: Using ISS we created a simulated mass shooting scenario with 20 patients, played by actors in full moulage, presenting to a large tertiary care hospital over a 50-minute period. RESULTS: Integrating ISS into our exercise created a realistic experience for the participants involved and improved participant education, while imparting enough systemic stress to expose LSTs associated within patient care and hospital policy. CONCLUSION: Overall, ISS was successfully used and enhanced a large-scale test of our hospital's mass-casualty response plan.

Large Differences in Urinary Benzene Metabolite S-Phenylmercapturic Acid Quantitation: A Comparison of Five LC-MS-MS Methods.

Benzene is a known genotoxic carcinogen linked to many hematological abnormalities. S-phenylmercapturic acid (PHMA, N-acetyl-S-(phenyl)-L-cysteine, CAS# 4775-80-8) is a urinary metabolite of benzene and is used as a biomarker to assess benzene exposure. Pre-S-phenylmercapturic acid (pre-PHMA) is a PHMA precursor that dehydrates to PHMA at acidic pH. Published analytical methods that measure urinary PHMA adjust urine samples to a wide range of pH values using several types of acid, potentially leading to highly variable results depending on the concentration of pre-PHMA in a sample. Information is lacking on the variation in sample preparation among laboratories regularly measuring PHMA and the effect of those differences on PHMA quantitation in human urine samples. To investigate the differences in PHMA quantitation, we conducted an inter-laboratory comparison that included the analysis of 50 anonymous human urine samples (25 self-identified smokers and 25 self-identified non-smokers), quality control samples and commercially available reference samples in five laboratories using different analytical methods. Observed urinary PHMA concentrations were proportionally higher at lower pH, and results for anonymous urine samples varied widely among the methods. The method with the neutral preparation pH yielded results about 60% lower than the method using the most acidic conditions. Samples spiked with PHMA showed little variation, suggesting that the variability in results in human urine samples across methods is driven by the acid-mediated conversion of pre-PHMA to PHMA.

Effectiveness and safety of a prehospital program of continuous positive airway pressure (CPAP) in an urban setting.

BACKGROUND: Continuous positive airway pressure (CPAP) is commonly used in the treatment of acute cardiogenic pulmonary edema (ACPE) and acute exacerbations of chronic obstructive pulmonary disease (AECOPD). In-hospital evidence is robust: CPAP has been shown to improve respiratory status and to reduce intubation rates. There is less evidence on prehospital CPAP, although the emergency medical services (EMS) adoption of this modality is increasing. The objectives of this study were to 1) measure the effectiveness of prehospital CPAP on morbidity, mortality, and transport times; and 2) audit the selection of patients by medics for appropriateness and safety. METHODS: We conducted a before-and-after study from August 1 to October 31 in 2010 and 2011, before and after the implementation of prehospital CPAP in a city of one million people with large rural areas. Medics were trained to apply CPAP to patients with respiratory distress and a presumed diagnosis of ACPE or AECOPD. Charts were selected using the search criteria of the chief complaint of shortness of breath, emergent transport to hospital, and any patients receiving CPAP in the field. Data extracted from ambulance call reports and hospital records were analysed with appropriate univariate statistics. RESULTS: A total of 373 patients enrolled (186 pre-non-invasive ventilation [NIV] and 187 post-NIV), mean age 71.5 years, female 51.4%, and final diagnoses of ACPE 18.9%, AECOPD 21.9%. In the post group of 84 patients meeting NIV criteria, 41.6% received NIV; and of 102 patients not meeting the criteria, 5.2% received NIV. There were 12 minor adverse events in 36 applications (33.3%) as per protocol. Comparing post versus pre, there were higher rates of emergency department (ED) NIV (20.0% v. 13.4%, p<0.0001) and higher overall mortality (18.8% v. 14.9%, p<0.0001). There were no differences in ED intubation (2.1% v. 2.3%, p<0.001) and length of stay (6.8 v. 8.7 days, p=0.24). CONCLUSION: Despite the robust in-hospital data supporting its use, we could not find benefit from CPAP in our prehospital setting with respect to morbidity, mortality, and length of stay. EMS must exercise caution in making the decision to invest in the equipment and training required to implement prehospital CPAP.