Chemical Pneumonitis Following Inhalation of Fluoride-Based Waterproofing Agent: A Case Series.

Role of Helmet-Delivered Noninvasive Pressure Support Ventilation in COVID-19 Patients

Use of ECMO in Patients With Coronavirus Disease 2019: Does the Evidence Suffice?

Exhaled nitric oxide as a marker of lung injury in coronary artery bypass surgery

Objective To explore the changes and significance of respiratory mechanics parameters and pulmonary arterial pressure (PAP) of prenatal stage neonates with pulmonary acute respiratory distress syndrome (ARDSp) or extrapulmonary acute respiratory distress syndrome (ARDSexp). Methods From May 2015 to August 2017, a total of 78 prenatal stage neonates with acute respiratory distress syndrome (ARDS) who were admitted to department of Neonatology of the Affiliated Yancheng Hospital of Southeast University Medical College, were chosen as research subjects. According to different causes of ARDS, 41 neonates with ARDSp were including into ARDSp group and 37 neonates with ARDSexp were including into ARDSexp group. And from department of Obstetrics in same hospital during the same period, a total of 40 healthy neonates with same age were included into control group. The severity of 78 ARDS neonates were determined as mild, moderate and severe according to oxygenation index (OI). The independent-samples t test, variance analysis and chi-square test were used to compare the following measurement data or numeration data. ①Comparasion of clinical data, OI and respiratory mechanics parameters between ARDSp group and ARDSexp group; PAP values of different severity degrees of ARDS neonates in each group or between two groups. ②PAP values of ARDSp and ARDSexp groups at 0, 24, 48, 72, 96 h after breath support, and pre-extubation time points, also PAP values of control group at corresponding hourly ages. Pearson correlation analysis was used to analyze the correlation between OI and PAP of 78 neonates with ARDS. This study met the requirements of World Medical Association Declaration of Helsinki revised in 2013. Results ①Perinatal stage neonates′gestational age, birth weight, usage rate of pulmonary surfactant (PS), incidence rate of persistent pulmonary hypertension of newborn (PPHN) and mortality rate of ARDSexp group [(37.5±1.7) gestational weeks, (2 548±465) g, 13.5%, 2.7%, 2.7%] were all lower than those of ADRSp group [(38.9±1.7) gestational weeks, (3 188±513) g, 78.0%, 24.4%, 19.5%], while the success rate of continuous positive airway pressure (CPAP) of ARDSexp group (13.5%) was higher than that of ARDSp group (0), and all the differences were statistically significant (t=3.632, P<0.001; t=5.750, P<0.001; χ2=32.491, P<0.001; χ2=7.552, P=0.006; χ2=5.384, P=0.020; χ2=5.920, P=0.015). ②A total of 73 ARDS neonates accepted invasive mechanical ventilation in this study, and at time point of 24 h, the OI, mean airway pressure (MAP) and airway resistance (Raw) of ARDSexp group [(14.8±4.3), (10.4±2.9) cmH2O, (83.9±18.3) cmH2O/(L·s)] (1 cmH2O=0.098 kPa) were all lower than those of ARDSp group [(18.8±3.2), (15.5±2.4) cmH2O, (115.8±30.7) cmH2O/(L·s)], while compliance of the respiratory system (Crs) of ARDSexp group [(0.39±0.09) mL/(cmH2O·kg)] was higher than that of ARDSp group [(0.26±0.05) mL/(cmH2O·kg)], and all the differences were statistically significant (t=4.561, 8.754, 5.537, 7.713; all P<0.001). ③After 24 h of respiratory support, PAP values of moderate or severe ARDS neonates in ARDSexp group [(54.7±5.9) mmHg, (64.2±4.9) mmHg] (1 mmHg=0.133 kPa) were lower than those in ARDSp group [(62.5±5.4) mmHg, (68.0±6.5) mmHg], respectively, and the differences were statistically significant (t=3.258, 2.148; all P<0.05). In ARDSp group, PAP values of severe ARDS neonates was higher than that of moderate ARDS neonates, and the difference was statistically significant (t=2.424, P=0.021). In ARDSexp group, PAP values of severe ARDS neonates were higher than that of mild [(37.8±6.5) mmHg] and moderate ARDS neonates, respectively, while PAP values of moderate ARDS neonates was higher than that of mild ARDS neonates, and all the differences were statistically significant (t=14.060, 4.891, 5.629; all P<0.001). ④Pearson correlation analysis showed that there was a positive linear correlation between OI and PAP in 78 ARDS neonates (r=0.720, P<0.001). ⑤PAP values of neonates in ARDSp and ARDSexp group after respiratory support of 0, 24, 48, 72, 96 h and pre-extubation were higher than those of neonates at the corresponding hourly age after birth in control group, respectively, and the differences were statistically significant (t=16.920, 21.600, 27.200, 24.440, 21.670, 18.690; t=11.380, 24.680, 37.800, 15.670, 14.460, 18.060; all P<0.001). PAP values of neonates in ARDSexp group after 0, 48, 72, 96 h of respiratory support were lower than those in ARDSp group, but higher than that in ARDSp group after 24 h of respiratory support, and all the differences were statistically significant (t=5.136, 4.829, 8.197, 6.691, 7.483, all P<0.001). Conclusions The PAP of perinatal stage neonates with ARDS increased in varying degrees, and its increased degree was related to the severity of ARDS. The respiratory mechanics paramaters and PAP of ADRSp neonates were different from ADRSexp neonates, PAP can be used as a judgement indicator of the severity and prognosis of ARDS. Key words: Respiratory distress syndrome, newborn; Hypertension, pulmonary; Persistent fetal circulation syndrome; Respiratory mechanics; Perinatology; Lung injury; Infant, newbron

Acute respiratory distress syndrome (ARDS) is an end-point for multiple heterogeneous disease processes. Most current treatment strategies have focused on minimizing the harm placed on the patient by mechanical ventilation (Table 1). Today, the mainstay of treatment for ARDS has been reduced to treating the underlying condition and maintaining lung protective mechanical ventilation. Unfortunately, even with these protective measures, there is still ventilator-induced lung injury. Ventilator-induced lung injury is a well described, multifactorial phenomenon experienced by the patient during ventilation that encompasses barotrauma, volutrauma, atelectrauma, biotrauma, and newly described energy trauma.1,5,9,10 Table 1. - The History and Management of ARDS1–11 1967: ARDS was first described by Ashbaugh et al.1 1975: Suter et al. found that the optimum PEEP for optimizing oxygen delivery was the PEEP that achieved the best compliance.1 1975: Kirby et al. described a high PEEP strategy to minimize shunting.1 1979: NIH did the first trial looking at ECMO for ARDS.1 1981: Lemaire et al. found that the minimal PEEP for the patient should be 2 cm H2O above the lower inflection point.1 1987: Gattinoni et al. described the concept of "baby lung" and that the lungs were not stiff, but the size of the usable lung was that of a child's lung.2 1990: Hickling et al. described lung rest with low tidal volume ventilation.1 1994: NIH-NHLBI ARDSNet was created.3 1999: Ranieri et al. published a paper showing reduced inflammatory markers when using lung protective strategies.4 1999: Slutsky described the four accepted ventilator-induced lung injuries.5 2000: ARMA trial was published which showed that 6 ml/kg is better than 12 ml/kg.6 2009: CESAR trial showed improved outcomes in patients who went to an ECMO center.7 2011: The Berlin definition of ARDS was described.8 2015: Amato et al. described ΔP. A ΔP ≤ 15 cm H2O reduced mortality.9 2016: Energy trauma, based on ΔP, was described as a new type of VILI.10 2019: Rozencwajg et al.8 described ultra-lung protection ventilation on ECMO was shown to reduce biotrauma.11 ΔP, driving pressure; ARDS, acute respiratory distress syndrome; ARDSNet, Acute Respiratory Distress Syndrome Network; ARMA, lower tidal volume ventilation in ALI/ARDS; CESAR, efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure; ECMO, extracorporeal membrane oxygenation; NHLBI, National Heart, Lung, and Blood Institute; NIH, National Institute of Health; PEEP, positive end-expiratory pressure; VILI, ventilator-induced lung injury. Over the past 2 decades, extracorporeal membrane oxygenation (ECMO) has gained popularity as a life-sustaining modality for patients who cannot be adequately oxygenated or ventilated using more conventional means. Using ECMO, in conjunction with ultraprotective lung ventilation (UPLV), has been shown to reduce barotrauma, volutrauma, atelectrauma, and energy trauma.11 Additionally, the ability to reduce the fraction of inspired oxygen on ECMO decreases oxygen free radicals. This reduction, and the reduction in injurious ventilator settings, reduces inflammation and cytokine production which decreases biotrauma.11–13 Despite these advantages of ECMO, several problems remain. Notably, while ECMO/UPLV can reduce the iatrogenic inflammation from mechanical ventilation, it does not address the underlying inflammatory insult of the disease. Furthermore, the ECMO circuit itself is a pro-inflammatory. The artificial surface of the circuit initiates several inflammatory cascades which contribute to biotrauma, end-organ damage, and coagulopathies.12,13 The coronavirus disease 2019 (COVID-19) epidemic has brought biotrauma to the forefront as a major contributor to mortality in ARDS. Coronavirus disease 2019 is extremely pro-inflammatory and can spiral into cytokine storm, which carries a high mortality rate. Cytokines are released when the body recognizes an infection and are responsible for the immune response mounted to fight off the invading organism. Cytokines are responsible for their own regulation which allows it to help specify the pathogen, limit itself to an appropriate response level, and downregulate during the resolution phase. Cytokine storms occur when the immune system either does not regulate its response, leading to inappropriately elevated levels, or does not appropriately enter the resolution phase, leading to prolonged inflammation. When there is an inappropriate response or prolonged response, the result is collateral damage to the body. It is unclear the exact mechanism of how COVID-19 infections cause cytokine storm, but the end result is supratherapeutic cytokine levels. When the cytokine levels reach hyperactive response level, it causes a more systemic response by activating the release and mobilization of neutrophils and monocytes to the infected site. This response inappropriately activates the coagulation, fibrinolytic, and complement cascades out of proportion to the infection causing shock, thromboembolic disease, and organ failure, especially lung damage. Interleukin (IL)–6 and tumor necrosis factor (TNF)–α are two of the pro-inflammatory cytokines most associated with cytokine storm and the resulting biotrauma leading to lung injury. Increased IL-2 levels are associated with capillary leak which causes the breakdown of cell bridges and increases the vascular permeability leading to pulmonary edema, kidney injury, and third-spacing. Capillary leak, with the addition of inflammatory vasodilation, is a major cause of the severe hypotension/shock also seen in these critically ill patients. Interleukin-10 is an anti-inflammatory cytokine and part of the Compensatory Anti-inflammatory Response Syndrome.14 Interleukin-10 downregulates the immune response and helps to keep the inflammatory response at an appropriate level. In cytokine storm, the IL-10 levels are also inappropriately elevated since it is trying to decrease the response.15 In 2007, Kellum et al.14 looked at the inflammatory markers in patients with pneumonia and sepsis. Cytokine levels were the highest in patients with the worst outcomes. The highest risk of death was in patients with high levels of both pro-inflammatory (IL-6) and anti-inflammatory markers (IL-10).16 Medications to target the cytokine cascades have always been of interest in research. If there was a way to prevent this inappropriate response, it could prevent the capillary leak, organ failure, and shock. Unfortunately, medications that target a specific part of a cascade have not been shown to be successful. Recombinant activated protein C was trialed to replete the reduced levels seen in septic shock. Initial studies were promising, but it was found to increase bleeding and not improve outcomes after further studies. Anti–TNF-α medications were also studied in patients with septic shock. The results are more controversial with heterogeneous studies but may have a positive role in patients in shock or with elevated IL-6 levels.17 Due to the poor results using medications, a variety of methods for extracorporeal blood purification have been explored to reduce the amount of circulating inflammatory markers in the body. Many modalities have been described in sepsis and ARDS, including continuous venovenous hemofiltration (CVVH), hemoperfusion, and plasma exchange. CVVH in ARDS was studied in the 2000s, and success with plasma exchange with H1N1 ARDS in 2009 was also described in a case series.18,19 The efficacy of these modalities has been controversial with conflicting trial results.20,21 In patients infected with COVID-19, immunomodulation has again become a major target for research and intervention. Currently, the standard of care for immunomodulator use is steroids and IL-6 inhibitors. Corticosteroids reduce the inflammatory response by binding to intracellular receptors that inhibit transcription factors, phospholipase A2, and cyclooxygenase 2, all of which reduce the production of pro-inflammatory cytokines. Dexamethasone was shown to reduce mortality in COVID-19 patients.22 Tocilizumab is an IL-6 receptor antibody that prevents IL-6 binding to the receptor which reduces the inflammatory response. Tocilizumab was initially shown in case reports and retrospective trials to reduce the need for mechanical ventilation and improve mortality. However, a recent prospective randomized controlled trial failed to repeat these results.23,24 Given the theoretical benefits, but mixed real-world efficacy of immunomodulation, the novel method of a selective cytopheretic device (SCD) presented by Yessayan et al.25 is intriguing. The device approaches the inflammatory cascade upstream of typical cytokine scavenging or inhibition methods by binding the most active neutrophils and monocytes. Through an unclear mechanism, the circulating neutrophils and monocytes are reduced to a less inflammatory state decreasing cytokine production. In this two-patient study, there was a clear reduction in inflammatory cytokine markers and improvement in the patient's respiratory status after initiation of SCD. Other studies looking at the SCD in acute kidney injury have shown improvements and no side effects attributable to the device itself.26 One concern to consider is that looking at limited data can lead to misleading results. The inability to repeat a beneficial response to immunomodulation interventions has been seen over and over again. This study of two patients was limited and therefore has a high risk that similar results of improvement will not be seen when expanded to larger trials. At our institution, we have currently managed nine COVID-19 patients on venovenous ECMO with results similar to the national average (Extracorporeal Life Support Organization Registry as of December 9, 2020: 989/1,846 [53%] discharged alive). We have had four survive to discharge, three were unable to be weaned, and two who are currently still on ECMO. When looking at our IL-6 data, the average level was 167 pg/mL, and we also saw a large distribution (37–519 pg/mL). We did have one patient with a level greater than 3,000 pg/mL that did not get tocilizumab. This level was a significant outlier and was not included in the average. Using the inclusion criteria of the SCD study, we would have had two patients qualify for the device, both which had prolonged courses and did not survive. Looking at these initial SCD results, this treatment option would be something we would want to have moving forward. The limitations of needing an elevated IL-6 level and having not received Tocilizumab decreases the use of the SCD. Only 22% of our patients would have qualified for the study, which leaves a large population of critically ill patients excluded. As mentioned in the article, six patients with COVID-19 and ARDS were screened and did not have an IL-6 level elevated enough to meet criteria, and four of these patients were on ECMO at the time of screening. I think future trials would need to look at decreasing the limitations on SCD use to either mechanically ventilated COVID-19 patients with severe ARDS or any mechanically ventilated patients with elevated IL-6 levels. With such a small percentage of ECMO patients qualifying, small to medium centers for ECMO may not have enough patients meet the qualifications to be in a trial. Finally, the use of steroids as an anti-inflammatory was not mentioned in the article. Dexamethasone was shown to decrease 28 day mortality in patients with COVID-19 who were receiving mechanical ventilation or supplemental oxygen.20 With steroids now being used early-on as an anti-inflammatory drug, it remains to be seen how the SCD would work as a supplement to steroid use and if it would reach statistical significance. Additionally, another consideration for future trials is that tocilizumab use is increasing, and if it prevents the use of SCD treatment, it could limit patient recruitment. In conclusion, beyond treatment of the viral associated cytokine storms, the implications of being able to reduce inflammation and lung injury associated with ARDS and ECMO cannulation are intriguing. This has the potential to be the missing piece needed to address the nonventilator biotrauma that current management strategies for ARDS do not address. More trials need to be conducted to study the impact of the SCD for COVID-19 patients. Future trials are needed to look at the effectiveness of SCD in other patient populations. There is high potential for the SCD to be another treatment tool for ARDS, especially in COVID-19, and look forward to further studies.

Therapeutic Value of a Lung Protective Ventilation Strategy in Acute Lung Injury

Ineffective lung repair in patients with unresolving acute respiratory distress syndrome (ARDS) is accompanied by progressive fibroproliferation, inability to improve lung injury score (LIS), progressive multiple organ dysfunction syndrome (MODS), and an unfavorable outcome. Our aim was to investigate the relationship between fibrogenesis, pulmonary and extrapulmonary organ dysfunction, and outcome during the natural course of ARDS and in response to prolonged methylprednisolone treatment. We investigated 29 patients with ARDS. We obtained serial measurements of plasma and BAL procollagen aminoterminal propeptide type I (PINP) and type III (PIIINP) levels and components of the lung injury score (LIS) and MODS score. A reduction in LIS greater than one point from day 1 to day 7 of ARDS divided patients in improvers (group 1, n = 7) and nonimprovers (n = 22). Nonimprovers included those who were recruited (day 9 +/- 3 of ARDS) into a prospective, randomized, double-blind, placebo-controlled trial investigating prolonged methylprednisolone therapy in unresolving ARDS (group 2, n = 17), and those who died (all by day 10 of ARDS) prior to meeting eligibility criteria for the randomized trial (group 3, n = 5). On day 1 of ARDS, plasma PINP or PIIINP levels were elevated in all patients. By day 7 of ARDS, mean plasma PINP or PIIINP levels were unchanged in group 1 but increased significantly in group 2 (p = 0. 0002) and group 3 (p = 0.03). On day 7, patients with plasma PINP levels less than 100 ng/ml were 2.5 times more likely to survive (95% CI: 0.855-7.314), and patients with plasma PIIINP levels greater than 25 ng/ml were nine times more likely to die (95% CI: 1. 418-55.556). In group 2, patients taking placebo (n = 6) had no change in plasma PINP or PIIINP levels over time, while patients treated with methylprednisolone (n = 11) had a rapid and sustained reduction in mean plasma and bronchoalveolar lavage (BAL) PINP and PIIINP levels. By day 3 of treatment, mean plasma PINP and PIIINP levels (ng/ml) decreased from 100 +/- 9 to 45 +/- 8 (p = 0.0001) and 31 +/- 3 to 12 +/- 3 (p = 0.0008), respectively. After 8 to 15 d of methylprednisolone, mean BAL PINP and PIIINP levels (ng/ml) decreased from 63 +/- 25 to 6 +/- 23 (p = 0.002) and 42 +/- 5 to 10 +/- 3 (p = 0.003), respectively. Estimated partial correlation coefficients indicated that as plasma PINP and PIIINP levels decreased over the first 7 d of methylprednisolone treatment, positive end-expiratory pressure, creatinine, bilirubin, and temperature also decreased, while PaO2:FIO2 increased. In early ARDS, plasma PINP and PIIINP levels are elevated and continue to increase over time in those not improving. Among nonimprovers, those randomized to prolonged methylprednisolone treatment had a rapid and significant reduction in plasma and BAL aminoterminal propeptide levels and similar changes in lung injury and MODS scores. These findings provide additional evidence of an association between biological efficacy and physiologic response during prolonged methylprednisolone treatment of unresolving ARDS.

High-Frequency Oscillatory Ventilation for Adult Patients With ARDS

in the last decade there have been many advances in our understanding of the pathogenesis of acute lung injury (ALI), but there have been frustratingly few successful therapeutic interventions. In fact, the only treatment proven to reduce mortality is low tidal volume lung-protective mechanical

COVID-19-related coagulopathy is a known complication of SARS-CoV-2 infection and can lead to intracranial hemorrhage (ICH), one of the most feared complications of extracorporeal membrane oxygenation (ECMO). We sought to evaluate the incidence and etiology of ICH in patients with COVID-19 requiring ECMO. Patients at two academic medical centers with COVID-19 who required venovenous-ECMO support for acute respiratory distress syndrome (ARDS) were evaluated retrospectively. During the study period, 33 patients required ECMO support; 16 (48.5%) were discharged alive, 13 died (39.4%), and 4 (12.1%) had ongoing care. Eleven patients had ICH (33.3%). All ICH events occurred in patients who received intravenous anticoagulation. The ICH group had higher C-reactive protein (P = 0.04), procalcitonin levels (P = 0.02), and IL-6 levels (P = 0.05), lower blood pH before and after ECMO (P < 0.01), and higher activated partial thromboplastin times throughout the hospital stay (P < 0.0001). ICH-free survival was lower in COVID-19 patients than in patients on ECMO for ARDS caused by other viruses (49% vs. 79%, P = 0.02). In conclusion, patients with COVID-19 can be successfully bridged to recovery using ECMO but may suffer higher rates of ICH compared to those with other viral respiratory infections.

Nitric oxide as mediator, marker and modulator of microvascular damage in ARDS.

To the Editor: Severe coronavirus disease infection continues to carry a high mortality with no definitive therapy to improve outcomes. Profound inflammation and coagulopathy are often present and predict a poor outcome. Therapeutic plasma exchange has been proposed as a potential therapy in this critically ill subset of coronavirus disease patients through its actions along these pathways. In our series of eight patients receiving adjunct therapeutic plasma exchange for severe coronavirus disease pneumonia complicated by sepsis with multiple organ dysfunction, C-reactive protein and ferritin levels significantly decreased with therapeutic plasma exchange, whereas D-dimer decreased to a lesser degree. Sequential Organ Failure Assessment scores also improved although the clinical impact cannot be assessed due to lack of controls. Our findings offer potentially useful information for the development of prospective trials of therapeutic plasma exchange for severe coronavirus disease infection. During the severe acute respiratory syndrome (SARS) epidemic of 2012, researchers noted that late-term disease progression was unrelated to the initial viremia, rather to the host's immunopathologic response (1). This pathologic cascade of cytokine storm, endothelial activation, and microcirculatory thrombosis has been well described in sepsis and appears to be common to coronavirus disease 2019 (COVID-19) (1,2). Early autopsy reports have demonstrated von Willebrand factor and fibrin clots along with severe endothelial injury and widespread microthrombosis in the lungs of coronavirus disease (COVID) nonsurvivors (3). Therapeutic plasma exchange (TPE) offers potentially unique therapy by removing excessive, harmful cytokines, stabilizing injured endothelial membranes, and restoring the normal hemostatic milieu. Busundet al (4) showed a trend toward improved mortality is sepsis of any cause with adjunct TPE, whereas Patel et al (5) demonstrated clinical improvement in a case series of pediatric patients with acute respiratory distress syndrome (ARDS) and shock receiving adjunct TPE during the H1N1 influenza pandemic of 2009. These data raise the hypothesis that TPE may be efficacious in critically ill patients with severe COVID infection. We report outcomes of eight critically ill patients with severe COVID complicated by ARDS, sepsis, and multiple organ dysfunction syndrome (MODS) treated with adjunct TPE. METHODS We performed a retrospective review of medical records of eight adult patients admitted to Lexington Medical Center (LMC) with laboratory-confirmed SARS coronavirus-2 infection, complicated by ARDS, sepsis, and MODS who received adjunct TPE as part of their management. Patients were considered for TPE under the 2019 American Society for Apheresis guidelines for sepsis with multiple organ failure (6) if they fulfilled the following criteria: 1) sepsis due to COVID-19 infection, 2) ARDS (as defined by the Berlin criteria), and 3) evidence of greater than or equal to two organ dysfunctions. Patients with poor long-term prognosis not due to COVID-19 were not considered for TPE. Baseline characteristics of the patients are outlined in Table 1. All patients received standard care for sepsis and ARDS according to the Surviving Sepsis Campaign and ARDS network guidelines. Patients also received specific therapies for COVID-19, as outlined in Table 1. TABLE 1. - Clinical Characteristics, Treatment, and Outcomes of Eight Patients Treated for Coronavirus Disease 2019 With Therapeutic Plasma Exchange Patient Characteristic Patient Demographics 1 2 3 4 5 6 7 8 Sex Male Male Male Male Male Male Female Female Age, yr 73 68 67 61 78 41 68 65 Comorbid conditions Hyperlipidemia, gastroesophageal reflux disease Hypertension Cerebral palsy, diabetes mellitus Systemic lupus erythematosus, hypertension, benign prostatic hypertrophy Prostate cancer status post transurethral resection of the prostate Obesity Dementia, pseudotumor cerebri, end-stage renal disease, hypertension, stroke Hypertension, obstructive sleep apnea, chronic kidney disease, obesity, atrial fibrillation, diastolic heart failure Living situation, prior to admission Home Home Extended care Home Home Home Home Home COVID 2019 disease presentation Admit to ICU transfer, d 1 2 5 0 3 0 3 2 ICU Admission SOFA 2 4 7 10 3 15 8 5 Admit to first TPE, d 9 9 11 6 3 0 7 4 Number of TPE treatments 2 3 4 7 4 2 1 1 Maximum respiratory support Mechanical ventilation Mechanical ventilation Mechanical ventilation Mechanical ventilation Mechanical ventilation Mechanical ventilation Mechanical ventilation Bilevel positive airway pressure Proned, yes/no No Yes No Yes Yes Yes No No Inhaled nitric oxide, yes/no No No No Yes Yes Yes No No Paralytic infusion, yes/no No Yes No Yes Yes Yes No No Vasopressor therapy, hr 50 7 42 219 42 13 2 30 Other therapeutic interventions Steroids Methylprednisolone Methylprednisolone Methylprednisolone Methylprednisolone Methylprednisolone Methylprednisolone Methylprednisolone None COVID-specific medications Hydroxychloroquine, azithromycin, zinc Hydroxychloroquine, azithromycin, zinc Hydroxychloroquine, azithromycin, zinc, tocilizumabe Hydroxychloroquine, azithromycin, zinc, tocilizumabe Hydroxychloroquine, azithromycin, zinc Azithromycin Azithromycin, Ivermectin None Convalescent plasma, yes/no No No No Yes Yes Yes Yes No Anticoagulation Enoxaparin prophylaxis Heparin prophylaxis Argatroban, apixaban Enoxaparin full-dose, argatroban Argatroban, heparin infusion Argatroban, apixaban Argatroban, apixaban Apixaban Clinical outcomes Number of ventilator days 2 7 6 21 13 9 2 0 ICU stay, d 10 11 18 29 23 11 17 7 Hospital stay, d 19 17 33 29 26 35 22 14 Hospital discharge SOFA 2 0 1 N/a N/a 4 4 0 Discharge disposition Acute rehabilitation Home Extended care Deceased Deceased Home Home Home COVID = coronavirus disease, SOFA = Sequential Organ Failure Assessment, TPE = therapeutic plasma exchange. The primary outcomes were change in Sequential Organ Failure Assessment (SOFA) score, C-reactive protein (CRP), ferritin, and D-dimer levels in relation to TPE. One way repeated measure analysis of variance was used to compare before and after effect of the earliest TPE session on available values. Secondary outcomes included effect on oxygen support, hospital mortality, ICU and hospital lengths of stay, and discharge disposition. The study was performed in accordance with the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the Institutional Review Board at LMC. Consent for treatment was obtained from each patient or his/her surrogate decision-maker at the time of treatment as part of routine care. TPE TREATMENT Vascular access was obtained by venous insertion of a 14-French double-lumen temporary hemodialysis catheter. TPE was performed with the Spectra Optia (TerumoBCT, Denver, CO) apheresis system. Unless specified, treatment consisted of three consecutive daily treatments using approximately 100% of the calculated total plasma volume, using fresh frozen plasma as replacement fluid. Patients may not have received all three TPE treatments if their clinical status improved prior to the third treatment. In patients receiving convalescent plasma, no further treatments were planned after convalescent transfusion. Patients with a prolonged course may have received additional treatments based on hemodynamic and/or laboratory values suggesting ongoing organ failure, including inflammation and coagulopathy. RESULTS Eight patients were treated with TPE (age range, 41–78 yr; 6 males, 2 females). Six patients were alive at the time of submission, whereas two patients died in the ICU. All six survivors have been discharged from the hospital. Four were discharged home, one discharged to acute rehabilitation, and one returned to extended care (from which he was admitted). ICU lengths of stay were 7–18 days with total hospital stays 14–35 days (Table 1). SOFA scores were calculated at ICU admission and hospital discharge, as well as prior to, and following, each TPE procedure (Tables 1 and 2). Mean ICU admission SOFA score was 6.8, and mean discharge SOFA was 2.2. A total of 24 TPE procedures were performed: 16 (66.7%) had improved SOFA scores post TPE, six (25%) had no change, whereas two (8.3%) had a worsening SOFA score. SOFA scores significantly decreased with the first TPE treatment (mean ± sd) pre = 9.3 ± 4.5 to post = 6.4 ± 3.5; ratio of variance (F) = 18.6; p = 0.004) (Table 2). TABLE 2. - Change in Sequential Organ Failure Assessment and Inflammatory Biomarkers Before and After Therapeutic Plasma Exchange Among Eight Patients with Severe Coronavirus Disease 2019 Infection Patient TPE Treatment Sequential Organ Failure Assessment C-Reactive Protein Ferritin D-Dimer Pre Post Pre Post Pre Post Pre Post 1 1 3 3 147 76 1,009 445 2,346 1,880 2 3 3 83 35 679 445 2,215 1,009 2 1 13 7 — — — — 4,172 6,111 2 7 5 115 94 1,324 714 6,111 4,720 3 4 3 125 24 1,397 1,980 2,854 3,323 3 1 12 8 73 23 516 427 25,000 9,148 2 8 7 14 10 393 556 7,777 3,315 3 7 7 10 36 556 904 3,315 9,553 4 7 7 36 37 904 388 9,553 1,772 4 1 10 7 588 514 1,845 1,610 8,729 5,318 2 7 4 514 114 1,610 847 5,318 1,542 3 4 3 74 37 841 595 2,450 3,535 4 6 6 48 28 745 407 6,242 4,275 5 5 8 105 109 601 495 2,853 3,278 6 13 9 93 19 1,044 365 2,811 950 7 18 14 164 74 1,600 600 1,030 672 5 1 3 2 281 113 1,586 990 432 405 2 2 2 113 26 990 702 405 339 3 2 5 26 11 702 523 339 541 4 6 5 52 121 926 1,063 3,045 2,286 6 1 15 12 311 200 925 494 800 353 2 12 11 370 80 1,721 1,025 2,811 2,911 7 1 11 9 348 168 2,629 2,211 1,832 1,907 8 1 7 3 — — — — — — Means (first TPE Treatment) 9.3 6.4 266.1 176.5 1,404.9 984.4 6,187.3 3,588.8 Pre-post comparison F, p 18.6, p < 0.01 18.3, p < 0.01 32.0, p < 0.01 1.3, p = 0.3 F = ratio of variance, TPE = therapeutic plasma exchange.Dashes indicate values are unavailable as they were not measured. CRP, ferritin, and D-dimer levels in relation to TPE are reported in Table 2. All three typically decreased with each treatment (18/22 CRP; 18/22 ferritin; 15/23 D-dimer). CRP (mean ±SD) pre = 266.1 ± 169.7 to post = 176.5 ± 162.6; F = 18.3; (p = 0.005) and ferritin (mean ± SD) pre = 1404.9 ± 696.3 to post = 984.4 ± 684.5; F = 32.0; (p = 0.001) significantly decreased with the first TPE treatment, whereas D-dimer did not (mean ± SD) pre = 6187.3 ± 8,758.9 to post = 3,588.8 ± 3,332.0; F = 1.3; (p = 0.3). Daily arterial blood gases were not routinely checked, so Pao2/Fio2 ratios could not be trended to objectively assess changes in respiratory status. Instead, Figure 1 demonstrates changes in the mode of supplemental oxygen support required by each patient. All seven mechanically ventilated patients were initially liberated from the ventilator, although two patients required reintubation and ultimately died from their acute illness. Four survivors were weaned to room air prior to discharge, and two survivors were discharged on low-flow oxygen.Figure 1.: Respiratory support timeline for patients with coronavirus disease 2019 who received therapeutic plasma exchange (TPE) (n = 8).DISCUSSION We observed a clinical and laboratory response that may not have been predicted based on early outcome data in severe COVID infection (7), but the relationship of these findings to TPE is uncertain. The temporal relationship of our outcome measures to TPE is undeniable, but the clinical relationship and impact cannot be determined. Without matched controls, it is impossible to determine if these patients would have improved without TPE as part of the natural disease course, or whether other treatments, alone or in combination, are responsible for the outcomes we observed. Identifying patients with poor prognosis and potential to benefit from adjunct therapy is key in sepsis. Hypercytokinemia is associated with increased mortality in sepsis and may manifest clinically as hypotension and multiple organ failure. CRP, ferritin, and D-dimer may serve as nonspecific markers, and elevated levels have been associated with increased mortality in COVID-19 (8,9). These levels all generally improved with TPE in our patients. Defining pathologic levels, evaluating their response to TPE, and correlating these values with clinical outlines may prove valuable in future studies of TPE for severe COVID infection. Although others have reported the feasibility and safety of TPE for sepsis (10), it is important to note that TPE alters the immune system in a nonselective way, and the net effect is not certain. The effect on humoral immunity is a concern, with the potential removal of host-generated antibodies that theoretically may adversely affect the clinical condition. Prospective studies should be performed, not only to evaluate the efficacy of TPE but any potential adverse effects. As the number of critically ill patients with COVID-19 continues to grow, it is important that we continue to investigate treatment options. TPE offers treatment that targets the pathologic host response on multiple levels and has been effective in patients with a similar presentation of sepsis due to other pathogens. A well-designed prospective trial is desired to investigate this promising therapy for critically ill COVID patients. CONCLUSIONS TPE offers a potential therapy in critically ill patients with COVID-19 through its action on the inflammatory and coagulation pathways. Our case series shows favorable decreases in nonspecific markers of these pathways following TPE, but the clinical effect of these changes is uncertain. Prospective trials are needed to investigate the efficacy and safety of TPE in this patient population.

Background and Objectives: Acute Respiratory Distress Syndrome (ARDS) is a heterogeneous syndrome that encompasses lung injury from a direct pulmonary or indirect systemic insult. Studies have shown that direct and indirect ARDS differ in their pathophysiologic process. In this study, we aimed to compare the different clinical characteristics and predictors of 28-day mortality between direct and indirect ARDS. Materials and Methods: The data of 1291 ARDS patients from September 2012 to December 2021 at the Second Affiliated Hospital of Chongqing Medical University were reviewed. We enrolled 451 ARDS patients in our study through inclusion and exclusion criteria. According to the risk factors, each patient was divided into direct (n = 239) or indirect (n = 212) ARDS groups. The primary outcome was 28-day mortality. Results: The patients with direct ARDS were more likely to be older (p < 0.001) and male (p = 0.009) and have more comorbidity (p < 0.05) and higher 28-day mortality (p < 0.001) than those with indirect ARDS. Age and multiple organ dysfunction syndrome (MODS) were predictors of 28-day mortality in the direct ARDS group, while age, MODS, creatinine, prothrombin time (PT), and oxygenation index (OI) were independent predictors of 28-day mortality in the indirect ARDS group. Creatinine, PT, and OI have interactions with ARDS types (all p < 0.01). Conclusions: The patients with direct ARDS were more likely to be older and male and have worse conditions and prognoses than those with indirect ARDS. Creatinine, PT, and OI were predictors of 28-day mortality only in the indirect ARDS group. The differences between direct and indirect ARDS suggest the need for different management strategies of ARDS.

Pneumomediastinum in Mechanically Ventilated Coronavirus Disease 2019 Patients

ARDS: progress unlikely with non-biological definition