Convalescent Plasma Antibody Levels and the Risk of Death from Covid-19.

BACKGROUND: Convalescent plasma has been widely used to treat coronavirus disease 2019 (Covid-19) under the presumption that such plasma contains potentially therapeutic antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that can be passively transferred to the plasma recipient. Whether convalescent plasma with high antibody levels rather than low antibody levels is associated with a lower risk of death is unknown. METHODS: In a retrospective study based on a U.S. national registry, we determined the anti-SARS-CoV-2 IgG antibody levels in convalescent plasma used to treat hospitalized adults with Covid-19. The primary outcome was death within 30 days after plasma transfusion. Patients who were enrolled through July 4, 2020, and for whom data on anti-SARS-CoV-2 antibody levels in plasma transfusions and on 30-day mortality were available were included in the analysis. RESULTS: Of the 3082 patients included in this analysis, death within 30 days after plasma transfusion occurred in 115 of 515 patients (22.3%) in the high-titer group, 549 of 2006 patients (27.4%) in the medium-titer group, and 166 of 561 patients (29.6%) in the low-titer group. The association of anti-SARS-CoV-2 antibody levels with the risk of death from Covid-19 was moderated by mechanical ventilation status. A lower risk of death within 30 days in the high-titer group than in the low-titer group was observed among patients who had not received mechanical ventilation before transfusion (relative risk, 0.66; 95% confidence interval [CI], 0.48 to 0.91), and no effect on the risk of death was observed among patients who had received mechanical ventilation (relative risk, 1.02; 95% CI, 0.78 to 1.32). CONCLUSIONS: Among patients hospitalized with Covid-19 who were not receiving mechanical ventilation, transfusion of plasma with higher anti-SARS-CoV-2 IgG antibody levels was associated with a lower risk of death than transfusion of plasma with lower antibody levels. (Funded by the Department of Health and Human Services and others; ClinicalTrials.gov number, NCT04338360.).

Septic shock in the immunocompromised cancer patient: a narrative review.

Immunosuppressed patients, particularly those with cancer, represent a momentous and increasing portion of the population, especially as cancer incidence rises with population growth and aging. These patients are at a heightened risk of developing severe infections, including sepsis and septic shock, due to multiple immunologic defects such as neutropenia, lymphopenia, and T and B-cell impairment. The diverse and complex nature of these immunologic profiles, compounded by the concomitant use of immunosuppressive therapies (e.g., corticosteroids, cytotoxic drugs, and immunotherapy), superimposed by the breakage of natural protective barriers (e.g., mucosal damage, chronic indwelling catheters, and alterations of anatomical structures), increases the risk of various infections. These and other conditions that mimic sepsis pose substantial diagnostic and therapeutic challenges. Factors that elevate the risk of progression to septic shock in these patients include advanced age, pre-existing comorbidities, frailty, type of cancer, the severity of immunosuppression, hypoalbuminemia, hypophosphatemia, Gram-negative bacteremia, and type and timing of responses to initial treatment. The management of vulnerable cancer patients with sepsis or septic shock varies due to biased clinical practices that may result in delayed access to intensive care and worse outcomes. While septic shock is typically associated with poor outcomes in patients with malignancies, survival has significantly improved over time. Therefore, understanding and addressing the unique needs of cancer patients through a new paradigm, which includes the integration of innovative technologies into our healthcare system (e.g., wireless technologies, medical informatics, precision medicine), targeted management strategies, and robust clinical practices, including early identification and diagnosis, coupled with prompt admission to high-level care facilities that promote a multidisciplinary approach, is crucial for improving their prognosis and overall survival rates.

Orthopnea secondary to brachial plexitis with bilateral diaphragmatic paralysis.

BACKGROUND: Diaphragmatic paralysis can present with orthopnea. We report a unique presentation of bilateral diaphragmatic paralysis, an uncommon diagnosis secondary to an unusual cause, brachial plexitis. This report thoroughly describes the patient's presentation, workup, management, and outcome. It also reviews the literature on diaphragmatic paralysis and Parsonage-Turner syndrome. CASE PRESENTATION: A 50-year-old male patient developed insidious orthopnea associated with left shoulder and neck pain over three months with no associated symptoms. On examination, marked dyspnea was observed when the patient was asked to lie down; breath sounds were present and symmetrical, and the neurological examination was normal. The chest radiograph showed an elevated right hemidiaphragm. Echocardiogram was normal. There was a 63% positional reduction in Forced Vital Capacity and maximal inspiratory and expiratory pressures on pulmonary function testing. The electromyogram was consistent with neuromuscular weakness involving both brachial plexus and diaphragmatic muscle (Parsonage and Turner syndrome). CONCLUSIONS: Compared to unilateral, bilateral diaphragmatic paralysis may be more challenging to diagnose. On PFT, reduced maximal respiratory pressures, especially the maximal inspiratory pressure, are suggestive. Parsonage-Turner syndrome is rare, usually with unilateral diaphragmatic paralysis, but bilateral cases have been reported.

Access to and safety of COVID-19 convalescent plasma in the United States Expanded Access Program: A national registry study.

BACKGROUND: The United States (US) Expanded Access Program (EAP) to coronavirus disease 2019 (COVID-19) convalescent plasma was initiated in response to the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19. While randomized clinical trials were in various stages of development and enrollment, there was an urgent need for widespread access to potential therapeutic agents. The objective of this study is to report on the demographic, geographical, and chronological characteristics of patients in the EAP, and key safety metrics following transfusion of COVID-19 convalescent plasma. METHODS AND FINDINGS: Mayo Clinic served as the central institutional review board for all participating facilities, and any US physician could participate as a local physician-principal investigator. Eligible patients were hospitalized, were aged 18 years or older, and had-or were at risk of progression to-severe or life-threatening COVID-19; eligible patients were enrolled through the EAP central website. Blood collection facilities rapidly implemented programs to collect convalescent plasma for hospitalized patients with COVID-19. Demographic and clinical characteristics of all enrolled patients in the EAP were summarized. Temporal patterns in access to COVID-19 convalescent plasma were investigated by comparing daily and weekly changes in EAP enrollment in response to changes in infection rate at the state level. Geographical analyses on access to convalescent plasma included assessing EAP enrollment in all national hospital referral regions, as well as assessing enrollment in metropolitan areas and less populated areas that did not have access to COVID-19 clinical trials. From April 3 to August 23, 2020, 105,717 hospitalized patients with severe or life-threatening COVID-19 were enrolled in the EAP. The majority of patients were 60 years of age or older (57.8%), were male (58.4%), and had overweight or obesity (83.8%). There was substantial inclusion of minorities and underserved populations: 46.4% of patients were of a race other than white, and 37.2% of patients were of Hispanic ethnicity. Chronologically and geographically, increases in the number of both enrollments and transfusions in the EAP closely followed confirmed infections across all 50 states. Nearly all national hospital referral regions enrolled and transfused patients in the EAP, including both in metropolitan and in less populated areas. The incidence of serious adverse events was objectively low (<1%), and the overall crude 30-day mortality rate was 25.2% (95% CI, 25.0% to 25.5%). This registry study was limited by the observational and pragmatic study design that did not include a control or comparator group; thus, the data should not be used to infer definitive treatment effects. CONCLUSIONS: These results suggest that the EAP provided widespread access to COVID-19 convalescent plasma in all 50 states, including for underserved racial and ethnic minority populations. The study design of the EAP may serve as a model for future efforts when broad access to a treatment is needed in response to an emerging infectious disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT#: NCT04338360.

Outcome after intubation for septic shock with respiratory distress and hemodynamic compromise: an observational study.

BACKGROUND: Acute respiratory failure in septic patients contributes to higher in-hospital mortality. Intubation may improve outcome but there are no specific criteria for intubation. Intubation of septic patients with respiratory distress and hemodynamic compromise may result in clinical deterioration and precipitate cardiovascular failure. The decision to intubate is complex and multifactorial. The purpose of this study was to evaluate the impact of intubation in patients with respiratory distress and predominant hemodynamic instability within 24 h after ICU admission for septic shock. METHODS: We conducted a retrospective analysis of a prospective registry of adult patients with septic shock admitted to the medical ICU at Mayo Clinic, between April 30, 2014 and December 31, 2017. Septic shock was defined by persistent lactate > 4 mmol/L, mean arterial pressure < 65 mmHg, or vasopressor use after 30 mL/kg fluid boluses and suspected or confirmed infection. Patients who remained hospitalized in the ICU at 24 h were separated into intubated while in the ICU and non-intubated groups. The primary outcome was hospital mortality. The first analysis used linear regression models and the second analysis used time-dependent propensity score matching to match intubated to non-intubated patients. RESULTS: Overall, 358 (33%) ICU patients were eventually intubated after their ICU admission and 738 (67%) were not. Intubated patients were younger, transferred more often from an outside facility, more critically ill, had more lung infection, and achieved blood pressure goals more often, but lactate normalization within 6 h occurred less often. Among those who remained hospitalized in the ICU 24 h after sepsis diagnosis, the crude in-hospital mortality was higher in intubated than non-intubated patients, 89 (26%) vs. 82 (12%), p < 0.001, as was the ICU mortality and ICU and hospital length of stay. After adjustment, intubation showed no effect on hospital mortality but resulted in fewer hospital-free days through day 28. One-to-one propensity resulted in similar conclusion. CONCLUSIONS: Intubation within 24 h of sepsis was not associated with hospital mortality but resulted in fewer 28-day hospital-free days. Although intubation remains a high-risk procedure, we did not identify an increased risk in mortality among septic shock patients with predominant hemodynamic compromise.

The clinical relevance of oliguria in the critically ill patient: analysis of a large observational database.

BACKGROUND: Urine output is widely used as one of the criteria for the diagnosis and staging of acute renal failure, but few studies have specifically assessed the role of oliguria as a marker of acute renal failure or outcomes in general intensive care unit (ICU) patients. Using a large multinational database, we therefore evaluated the occurrence of oliguria (defined as a urine output < 0.5 ml/kg/h) in acutely ill patients and its association with the need for renal replacement therapy (RRT) and outcome. METHODS: International observational study. All adult (> 16 years) patients in the ICON audit who had a urine output measurement on the day of admission were included. To investigate the association between oliguria and mortality, we used a multilevel analysis. RESULTS: Of the 8292 patients included, 2050 (24.7%) were oliguric during the first 24 h of admission. Patients with oliguria on admission who had at least one additional 24-h urine output recorded during their ICU stay (n = 1349) were divided into three groups: transient-oliguria resolved within 48 h after the admission day (n = 390 [28.9%]), prolonged-oliguria resolved > 48 h after the admission day (n = 141 [10.5%]), and permanent-oliguria persisting for the whole ICU stay or again present at the end of the ICU stay (n = 818 [60.6%]). ICU and hospital mortality rates were higher in patients with oliguria than in those without, except for patients with transient oliguria who had significantly lower mortality rates than non-oliguric patients. In multilevel analysis, the need for RRT was associated with a significantly higher risk of death (OR = 1.51 [95% CI 1.19-1.91], p = 0.001), but the presence of oliguria on admission was not (OR = 1.14 [95% CI 0.97-1.34], p = 0.103). CONCLUSIONS: Oliguria is common in ICU patients and may have a relatively benign nature if only transient. The duration of oliguria and need for RRT are associated with worse outcome.

Diagnosis and outcome of acute respiratory failure in immunocompromised patients after bronchoscopy.

OBJECTIVE: We wished to explore the use, diagnostic capability and outcomes of bronchoscopy added to noninvasive testing in immunocompromised patients. In this setting, an inability to identify the cause of acute hypoxaemic respiratory failure is associated with worse outcome. Every effort should be made to obtain a diagnosis, either with noninvasive testing alone or combined with bronchoscopy. However, our understanding of the risks and benefits of bronchoscopy remains uncertain. PATIENTS AND METHODS: This was a pre-planned secondary analysis of Efraim, a prospective, multinational, observational study of 1611 immunocompromised patients with acute respiratory failure admitted to the intensive care unit (ICU). We compared patients with noninvasive testing only to those who had also received bronchoscopy by bivariate analysis and after propensity score matching. RESULTS: Bronchoscopy was performed in 618 (39%) patients who were more likely to have haematological malignancy and a higher severity of illness score. Bronchoscopy alone achieved a diagnosis in 165 patients (27% adjusted diagnostic yield). Bronchoscopy resulted in a management change in 236 patients (38% therapeutic yield). Bronchoscopy was associated with worsening of respiratory status in 69 (11%) patients. Bronchoscopy was associated with higher ICU (40% versus 28%; p<0.0001) and hospital mortality (49% versus 41%; p=0.003). The overall rate of undiagnosed causes was 13%. After propensity score matching, bronchoscopy remained associated with increased risk of hospital mortality (OR 1.41, 95% CI 1.08-1.81). CONCLUSIONS: Bronchoscopy was associated with improved diagnosis and changes in management, but also increased hospital mortality. Balancing risk and benefit in individualised cases should be investigated further.

Influenza and associated co-infections in critically ill immunosuppressed patients.

BACKGROUND: It is unclear whether influenza infection and associated co-infection are associated with patient-important outcomes in critically ill immunocompromised patients with acute respiratory failure. METHODS: Preplanned secondary analysis of EFRAIM, a prospective cohort study of 68 hospitals in 16 countries. We included 1611 patients aged 18 years or older with non-AIDS-related immunocompromise, who were admitted to the ICU with acute hypoxemic respiratory failure. The main exposure of interest was influenza infection status. The primary outcome of interest was all-cause hospital mortality, and secondary outcomes ICU length of stay (LOS) and 90-day mortality. RESULTS: Influenza infection status was categorized into four groups: patients with influenza alone (n = 95, 5.8%), patients with influenza plus pulmonary co-infection (n = 58, 3.6%), patients with non-influenza pulmonary infection (n = 820, 50.9%), and patients without pulmonary infection (n = 638, 39.6%). Influenza infection status was associated with a requirement for intubation and with LOS in ICU (P < 0.001). Patients with influenza plus co-infection had the highest rates of intubation and longest ICU LOS. On crude analysis, influenza infection status was associated with ICU mortality (P < 0.001) but not hospital mortality (P = 0.09). Patients with influenza plus co-infection and patients with non-influenza infection alone had similar ICU mortality (41% and 37% respectively) that was higher than patients with influenza alone or those without infection (33% and 26% respectively). A propensity score-matched analysis did not show a difference in hospital mortality attributable to influenza infection (OR = 1.01, 95%CI 0.90-1.13, P = 0.85). Age, severity scores, ARDS, and performance status were all associated with ICU, hospital, and 90-day mortality. CONCLUSIONS: Category of infectious etiology of respiratory failure (influenza, non-influenza, influenza plus co-infection, and non-infectious) was associated with ICU but not hospital mortality. In a propensity score-matched analysis, influenza infection was not associated with the primary outcome of hospital mortality. Overall, influenza infection alone may not be an independent risk factor for hospital mortality in immunosuppressed patients.

Noninvasive Ventilation of Patients with Acute Respiratory Distress Syndrome. Insights from the LUNG SAFE Study.

RATIONALE: Noninvasive ventilation (NIV) is increasingly used in patients with acute respiratory distress syndrome (ARDS). The evidence supporting NIV use in patients with ARDS remains relatively sparse. OBJECTIVES: To determine whether, during NIV, the categorization of ARDS severity based on the PaO2/FiO2 Berlin criteria is useful. METHODS: The LUNG SAFE (Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure) study described the management of patients with ARDS. This substudy examines the current practice of NIV use in ARDS, the utility of the PaO2/FiO2 ratio in classifying patients receiving NIV, and the impact of NIV on outcome. MEASUREMENTS AND MAIN RESULTS: Of 2,813 patients with ARDS, 436 (15.5%) were managed with NIV on Days 1 and 2 following fulfillment of diagnostic criteria. Classification of ARDS severity based on PaO2/FiO2 ratio was associated with an increase in intensity of ventilatory support, NIV failure, and intensive care unit (ICU) mortality. NIV failure occurred in 22.2% of mild, 42.3% of moderate, and 47.1% of patients with severe ARDS. Hospital mortality in patients with NIV success and failure was 16.1% and 45.4%, respectively. NIV use was independently associated with increased ICU (hazard ratio, 1.446 [95% confidence interval, 1.159-1.805]), but not hospital, mortality. In a propensity matched analysis, ICU mortality was higher in NIV than invasively ventilated patients with a PaO2/FiO2 lower than 150 mm Hg. CONCLUSIONS: NIV was used in 15% of patients with ARDS, irrespective of severity category. NIV seems to be associated with higher ICU mortality in patients with a PaO2/FiO2 lower than 150 mm Hg. Clinical trial registered with www.clinicaltrials.gov (NCT 02010073).

Outcomes of Acute Respiratory Failure in Patients With Cancer in the United States.

OBJECTIVE: To determine the epidemiological effect-magnitude and outcomes of patients with cancer vs those without cancer who are hospitalized with acute respiratory failure (ARF). PATIENTS AND METHODS: We reviewed hospitalizations within the National Inpatient Sample (NIS) database between January 1, 2016, and December 31, 2018. Patients were classified based on a diagnosis of solid-organ cancer, hematologic cancer, or no cancer. Noninvasive positive pressure ventilation (NIPPV) failure was defined as patients who initially received NIPPV and had progression to invasive mechanical ventilation. Weighted samples were used to derive population estimates. RESULTS: During the study period, there were an estimated 8,837,209 admissions with ARF in the United States, 8.9% (783,625) of which had solid-organ cancer and 2.0% (176,095) had hematologic cancers. Annually, 319,907 patients with cancer are admitted with ARF, with 27.3% (87,302) requiring invasive mechanical ventilation and 10.0% (31,998) requiring NIPPV. In-hospital mortality was higher in patients with cancer vs those without cancer (24.0% [76,813] vs 12.3% [322,465]; P<.001), and this proprotion persisted when stratified by the highest method of oxygen delivery. Patients with cancer had longer hospital length of stay (7.0 days [3.0 to 12.0 days] vs 5.0 days [3.0 to 10.0 days]; P<.001) and were more likely to have NIPPV failure (14.9% [3,992] vs 12.8% [41,875]). Compared with those with solid-organ cancer, patients with hematologic cancers experienced worse outcomes. The association between underlying cancer diagnosis and outcomes remained consistent when adjusted for age, sex, and comorbidities. CONCLUSION: In the United States, patients with cancer account for over 10% of ARF hospital admissions (959,720 of 8,837,209). They experience an approximately 2-fold higher mortality versus those without cancer. Those with hematologic cancers appear to experience worse outcomes than patients with solid-organ cancers.

Tracheal intubation in critically ill adults with a physiologically difficult airway. An international Delphi study.

PURPOSE: Our study aimed to provide consensus and expert clinical practice statements related to airway management in critically ill adults with a physiologically difficult airway (PDA). METHODS: An international Steering Committee involving seven intensivists and one Delphi methodology expert was convened by the Society of Critical Care Anaesthesiologists (SOCCA) Physiologically Difficult Airway Task Force. The committee selected an international panel of 35 expert clinician-researchers with expertise in airway management in critically ill adults. A Delphi process based on an iterative approach was used to obtain the final consensus statements. RESULTS: The Delphi process included seven survey rounds. A stable consensus was achieved for 53 (87%) out of 61 statements. The experts agreed that in addition to pathophysiological conditions, physiological alterations associated with pregnancy and obesity also constitute a physiologically difficult airway. They suggested having an intubation team consisting of at least three healthcare providers including two airway operators, implementing an appropriately designed checklist, and optimizing hemodynamics prior to tracheal intubation. Similarly, the experts agreed on the head elevated laryngoscopic position, routine use of videolaryngoscopy during the first attempt, preoxygenation with non-invasive ventilation, careful mask ventilation during the apneic phase, and attention to cardiorespiratory status for post-intubation care. CONCLUSION: Using a Delphi method, agreement among a panel of international experts was reached for 53 statements providing guidance to clinicians worldwide on safe tracheal intubation practices in patients with a physiologically difficult airway to help improve patient outcomes. Well-designed studies are needed to assess the effects of these practice statements and address the remaining uncertainties.