Rationale and Design of NEUTRALIZE-AKI: A Multicenter, Randomized, Controlled, Pivotal Study to Assess the Safety and Efficacy of a Selective Cytopheretic Device in Patients with Acute Kidney Injury Requiring Continuous Kidney Replacement Therapy.

INTRODUCTION: NEUTRALIZE-AKI is a pivotal study to evaluate the safety and effectiveness of the selective cytopheretic device (SCD) in adult patients with acute kidney injury (AKI) requiring continuous kidney replacement therapy (CKRT). METHODS/DESIGN: This is a two-arm, randomized, open-label, controlled multi-center pivotal US study which will enroll 200 adult patients (age 18-80 years) in the intensive care unit with acute kidney injury requiring CKRT and at least one additional organ failure across 30 clinical centers. Eligible patients will be randomized to CKRT plus SCD therapy versus CKRT alone. Therapy will be administered for up to 10 days, with the hypothesis that the CKRT plus SCD group will demonstrate a lower mortality rate or better rate of renal recovery than the CKRT alone group by day 90. The primary outcome is a composite of dialysis dependence or all-cause mortality at day 90. CONCLUSION: The SCD is a cell-directed extracorporeal therapy that targets and deactivates pro-inflammatory neutrophils and monocytes, with evidence of efficacy across a variety of critically ill patient populations. Knowledge and experience from many of those studies and other AKI trials were incorporated into the design of this pivotal study, with the aim to investigate the role of effector cell immunomodulation in the intervention of AKI.

Safety Summary of the Selective Cytopheretic Device: A Review of Safety Data Across Multiple Clinical Trials in ICU Patients With Acute Kidney Injury and Multiple Organ Failure.

OBJECTIVES: Acute kidney injury (AKI) requiring continuous kidney replacement therapy is a significant complication in ICU patients with mortality rates exceeding 50%. A dysregulated immune response can lead to systemic inflammation caused by hyperactivity of pro-inflammatory neutrophils and monocytes leading to tissue damage. The selective cytopheretic device (SCD) is an investigational medical device in a new class of cell-directed extracorporeal therapies distinct from cytokine adsorbers or filters, as it targets activated leukocytes. These leukocytes are the cellular sources driving this hyperinflammatory process. The objective of this report is to summarize the safety experience from clinical studies of the SCD in ICU patients with AKI or acute respiratory distress syndrome (ARDS) and multiple organ dysfunction (MOD). DATA SOURCES AND STUDY SELECTION: The studies included in this report represent all relevant trials of the SCD conducted in patients with AKI or ARDS and MOD. Adverse event data, clinical laboratory data and mortality rates were described and summarized in this report. DATA EXTRACTION AND DATA SYNTHESIS: Five clinical studies were included in this report, including four adult studies of AKI and/or ARDS and one pediatric AKI study, which involved 151 patients treated with the SCD in an ICU setting. Over 800 SCD sessions were deployed with an estimated 19,000 exposure hours with no device-related infections or attributable serious adverse events. Furthermore, there were no safety signals of leukopenia, thrombocytopenia, or other indications of immunodepletion or immunosuppression. CONCLUSIONS: The SCD has shown to be a promising extracorporeal therapy with promising clinical results and a favorable safety profile. These studies support that the SCD can be added as a therapeutic intervention in critically ill AKI patient populations with multiple organ failure without adding additional safety risks.

Intravenous Autologous Bone Marrow-derived Mesenchymal Stromal Cells Delay Acute Respiratory Distress Syndrome in Swine.

Rationale: Early post injury mitigation strategies in ARDS are in short supply. Treatments with allogeneic stromal cells are administered after ARDS develops, require specialized expertise and equipment, and to date have shown limited benefit. Objectives: Assess the efficacy of immediate post injury intravenous administration of autologous or allogeneic bone marrow-derived mesenchymal stromal cells (MSCs) for the treatment of acute respiratory distress syndrome (ARDS) due to smoke inhalation and burns. Methods: Yorkshire swine (n = 32, 44.3 ± 0.5 kg) underwent intravenous anesthesia, placement of lines, severe smoke inhalation, and 40% total body surface area flame burns, followed by 72 hours of around-the-clock ICU care. Mechanical ventilation, fluids, pressors, bronchoscopic cast removal, daily lung computed tomography scans, and arterial blood assays were performed. After injury and 24 and 48 hours later, animals were randomized to receive autologous concentrated bone marrow aspirate (n = 10; 3 × 106 white blood cells and a mean of 56.6 × 106 platelets per dose), allogeneic MSCs (n = 10; 6.1 × 106 MSCs per dose) harvested from healthy donor swine, or no treatment in injured control animals (n = 12). Measurements and Main Results: The intravenous administration of MSCs after injury and at 24 and 48 hours delayed the onset of ARDS in swine treated with autologous MSCs (48 ± 10 h) versus control animals (14 ± 2 h) (P = 0.004), reduced ARDS severity at 24 (P < 0.001) and 48 (P = 0.003) hours, and demonstrated visibly diminished consolidation on computed tomography (not significant). Mortality at 72 hours was 1 in 10 (10%) in the autologous group, 5 in 10 (50%) in the allogeneic group, and 6 in 12 (50%) in injured control animals (not significant). Both autologous and allogeneic MSCs suppressed systemic concentrations of TNF-α (tumor necrosis factor-α). Conclusions: The intravenous administration of three doses of freshly processed autologous bone marrow-derived MSCs delays ARDS development and reduces its severity in swine. Bedside retrieval and administration of autologous MSCs in swine is feasible and may be a viable injury mitigation strategy for ARDS.

Surviving Sepsis After Burn Campaign.

INTRODUCTION: The Surviving Sepsis Campaign was developed to improve outcomes for all patients with sepsis. Despite sepsis being the primary cause of death after thermal injury, burns have always been excluded from the Surviving Sepsis efforts. To improve sepsis outcomes in burn patients, an international group of burn experts developed the Surviving Sepsis After Burn Campaign (SSABC) as a testable guideline to improve burn sepsis outcomes. METHODS: The International Society for Burn Injuries (ISBI) reached out to regional or national burn organizations to recommend members to participate in the program. Two members of the ISBI developed specific "patient/population, intervention, comparison and outcome" (PICO) questions that paralleled the 2021 Surviving Sepsis Campaign [1]. SSABC participants were asked to search the current literature and rate its quality for each topic. At the Congress of the ISBI, in Guadalajara, Mexico, August 28, 2022, a majority of the participants met to create "statements" based on the literature. The "summary statements" were then sent to all members for comment with the hope of developing an 80% consensus. After four reviews, a consensus statement for each topic was created or "no consensus" was reported. RESULTS: The committee developed sixty statements within fourteen topics that provide guidance for the early treatment of sepsis in burn patients. These statements should be used to improve the care of sepsis in burn patients. The statements should not be considered as "static" comments but should rather be used as guidelines for future testing of the best treatments for sepsis in burn patients. They should be updated on a regular basis. CONCLUSION: Members of the burn community from the around the world have developed the Surviving Sepsis After Burn Campaign guidelines with the goal of improving the outcome of sepsis in burn patients.

Adsorption of Pathogens and Blockade of Sepsis Cascade.

Sepsis is caused by the host response to an infectious organism. It is common among hospitalized patients and is associated with significant morbidity and mortality. The current standard of care for sepsis is predominantly supportive, with early detection followed by prompt antibiotic administration. While this approach has undoubtedly improved patient outcomes, it has significant limitations. First, mortality from sepsis remains unacceptably high. Second, emerging pathogen resistance to antimicrobial therapies threatens a return to the pre-antimicrobial era of patient care. Lastly, the early stages of a pandemic (e.g., the recent coronavirus 19 pandemic) lack effective therapeutics. Given these limitations, novel treatment strategies are needed to advance the field and care for patients. One potential class of therapy is extracorporeal blood purification (EBP). While EBP is a broad classification, encompassing a wide range of techniques, this article will focus on three emerging EBP therapies that have been shown to bind and remove a wide variety of viral, bacterial, and fungal pathogens directly from circulation. These devices utilize different mechanisms of action for pathogen removal. The Seraph® 100 is composed of heparin coated beads. The Hemopurifier® combines the concept of plasma exchange with mannose-binding lectin (MBL). Lastly, the GARNET® utilizes a MBL fused to an IgG antibody. Via these mechanisms, these devices have been demonstrated to remove pathogens and pathogen-associated molecular patterns. The hope is that by directly removing pathogens, these EBP techniques may result in the biggest breakthrough in the management of sepsis since the advent of antibiotics almost 100 years ago.

Critical Care of the Burn Patient.

Care of the critically ill burned patient must integrate a multidisciplinary care team composed of burn care specialists. As resuscitative mortality decreases more patients are surviving to experience multisystem organ failure relating to complications of their injuries. Clinicians must be aware of physiologic changes following burn injury and the implicated impacts on management strategy. Promoting wound closure and rehabilitation should be the backdrop for which management decisions are made.

Intensive Care and Organ Support Related Mortality in Patients With COVID-19: A Systematic Review and Meta-Analysis.

To perform a systematic review and meta-analysis to generate estimates of mortality in patients with COVID-19 that required hospitalization, ICU admission, and organ support. DATA SOURCES: A systematic search of PubMed, Embase, and the Cochrane databases was conducted up to December 31, 2021. STUDY SELECTION: Previously peer-reviewed observational studies that reported ICU, mechanical ventilation (MV), renal replacement therapy (RRT) or extracorporeal membrane oxygenation (ECMO)-related mortality among greater than or equal to 100 individual patients. DATA EXTRACTION: Random-effects meta-analysis was used to generate pooled estimates of case fatality rates (CFRs) for in-hospital, ICU, MV, RRT, and ECMO-related mortality. ICU-related mortality was additionally analyzed by the study country of origin. Sensitivity analyses of CFR were assessed based on completeness of follow-up data, by year, and when only studies judged to be of high quality were included. DATA SYNTHESIS: One hundred fifty-seven studies evaluating 948,309 patients were included. The CFR for in-hospital mortality, ICU mortality, MV, RRT, and ECMO were 25.9% (95% CI: 24.0-27.8%), 37.3% (95% CI: 34.6-40.1%), 51.6% (95% CI: 46.1-57.0%), 66.1% (95% CI: 59.7-72.2%), and 58.0% (95% CI: 46.9-68.9%), respectively. MV (52.7%, 95% CI: 47.5-58.0% vs 31.3%, 95% CI: 16.1-48.9%; p = 0.023) and RRT-related mortality (66.7%, 95% CI: 60.1-73.0% vs 50.3%, 95% CI: 42.4-58.2%; p = 0.003) decreased from 2020 to 2021. CONCLUSIONS: We present updated estimates of CFR for patients hospitalized and requiring intensive care for the management of COVID-19. Although mortality remain high and varies considerably worldwide, we found the CFR in patients supported with MV significantly improved since 2020.

Hemoperfusion with Seraph 100 Microbind Affinity Blood Filter Unlikely to Require Increased Antibiotic Dosing: A Simulations Study Using a Pharmacokinetic/Pharmacodynamic Approach.

INTRODUCTION: The Seraph® 100 Microbind® Affinity Blood Filter (Seraph 100) is a hemoperfusion device that can remove pathogens from central circulation. However, the effect of Seraph 100 on achieving pharmacodynamic (PD) targets is not well described. We sought to determine the impact of Seraph 100 on ability to achieve PD targets for commonly used antibiotics. METHODS: Estimates of Seraph 100 antibiotic clearance were obtained via literature. For vancomycin and gentamicin, published pharmacokinetic models were used to explore the effect of Seraph 100 on ability to achieve probability of target attainment (PTA). For meropenem and imipenem, the reported effect of continuous kidney replacement therapy (CKRT) on achieving PTA was used to extrapolate decisions for Seraph 100. RESULTS: Seraph 100 antibiotic clearance is likely less than 0.5 L/h for most antibiotics. Theoretical Seraph 100 clearance up to 0.5 L/h and 2 L/h had a negligible effect on vancomycin PTA in virtual patients with creatinine clearance (CrCl) = 14 mL/min and CrCl >14 mL/min, respectively. Theoretical Seraph 100 clearance up to 0.5 L/h and 2 L/h had a negligible effect on gentamicin PTA in virtual patients with CrCl = 120 mL/min and CrCl <60 mL/min, respectively. CKRT intensity resulting in antibiotic clearance up to 2 L/h generally does not require dose increases for meropenem or imipenem. As Seraph 100 is prescribed intermittently and likely contributes far less to antibiotic clearance, dose increases would also not be required. CONCLUSION: Seraph 100 clearance of vancomycin, gentamicin, meropenem, and imipenem is likely clinically insignificant. There is insufficient evidence to recommend increased doses. For aminoglycosides, we recommend extended interval dosing and initiating Seraph 100 at least 30 min to 1 h after completion of infusion to avoid the possibility of interference with maximum concentrations.

Outcomes Associated With Intensive Care and Organ Support Among Patients With COVID-19: A Systematic Review and Meta-Analysis.

BACKGROUND: Accurate accounting of coronavirus disease 2019 (COVID-19) critical care outcomes has important implications for health care delivery. RESEARCH QUESTION: We aimed to determine critical care and organ support outcomes of intensive care unit (ICU) COVID-19 patients and whether they varied depending on the completeness of study follow-up or admission time period. STUDY DESIGN AND METHODS: We conducted a systematic review and meta-analysis of reports describing ICU, mechanical ventilation (MV), renal replacement therapy (RRT), and extracorporeal membrane oxygenation (ECMO) mortality. A search was conducted using PubMed, Embase, and Cochrane databases.We included English language observational studies of COVID-19 patients, reporting ICU admission, MV, and ICU case fatality, published from December 1, 2019 to December 31, 2020. We excluded reports of less than 5 ICU patients and pediatric populations. Study characteristics, patient demographics, and outcomes were extracted from each article. Subgroup meta-analyses were performed based on the admission end date and the completeness of data. RESULTS: Of 6,778 generated articles, 145 were retained for inclusion (n = 60,357 patients). Case fatality rates across all studies were 34.0% (95% CI = 30.7%, 37.5%, P < 0.001) for ICU deaths, 47.9% (95% CI = 41.6%, 54.2%, P < 0.001) for MV deaths, 58.7% (95% CI = 50.0%, 67.2%, P < 0.001) for RRT deaths, and 43.3% (95% CI = 31.4%, 55.4%, P < 0.001) for extracorporeal membrane oxygenation deaths. There was no statistically significant difference in ICU and organ support outcomes between studies with complete follow-up versus studies without complete follow-up. Case fatality rates for ICU, MV, and RRT deaths were significantly higher in studies with patients admitted before April 31st 2020. INTERPRETATION: Coronavirus disease 2019 critical care outcomes have significantly improved since the start of the pandemic. Intensive care unit outcomes should be evaluated contextually (study quality, data completeness, and time) for the most accurate reporting and to effectively guide mortality predictions.

Adverse outcomes with extracorporeal adsorbent blood treatments in toxic systemic inflammation: a perspective on possible mechanisms.

BACKGROUND: Extracorporeal blood purification (EBP) treatments may be used in patients with sepsis and related conditions to mitigate toxic systemic inflammation, prevent or reverse vital organ injury, and improve outcome. These treatments lack demonstrable efficacy, but are generally considered safe. However, since late 2020, four clinical studies of EBP treatment using adsorbent devices in inflammatory disease reported significantly increased patient mortality associated with the adsorbent treatments. Criticisms of study design and execution were published, but revealed no decisive flaws. None of these critiques considered possible toxic effects of the adsorbent treatments per se. PERSPECTIVE AND CONCLUSION: In adsorbent EBP treatment of systemic inflammatory disease the adsorbent media are deployed in patient blood or plasma flow for the purpose of broad spectrum, non-specific adsorptive removal of inflammatory mediators. Adsorption and sequestration of inflammatory mediators by adsorbent media is intended to reduce mediator concentrations in circulating blood and neutralize their activity. However, in the past two decades developments in both biomedical engineering and the science of cytokine molecular dynamics suggest that immobilization of inflammatory proteins on solid scaffolds or molecular carriers may stabilize protein structure and preserve or amplify protein function. It is unknown if these mechanisms are operative in EBP adsorbent treatments. If these mechanisms are operative, then the adsorbent medium could become reactive, promoting inflammatory activity which could result in negative outcomes. Considering the recent reports of harm with adsorbent treatments in diverse inflammatory conditions, caution urges investigation of these potentially harmful mechanisms in these devices. Candidate mechanisms for possible inquiry are discussed.

K+ontrol rapidly and efficiently reduces potassium in donor blood during ex vivo circulation.

BACKGROUND: Patients with kidney failure are at risk for lethal complications from hyperkalemia. Resuscitation, medications, and hemodialysis are used to mitigate increased potassium (K+) levels in circulating blood; however, these approaches may not always be readily available or effective, especially in a resource limited environment. We tested a sorbent cartridge (KC, K+ontrol CytoSorbents Medical Inc., Monmouth Junction, New Jersey) which contains a resin adsorber for K+. The objective of this study was to test the utility of KC in an ex vivo circulation system. We hypothesized that KC reduces K+ levels in extracorporeal circulation of donor swine whole blood infused with KCl. METHODS: A six-hour circulation study was carried out using KC, a NxStage (NxStage Medical, Inc., Lawrence, MA) membrane, blood bag containing heparinized whole blood with KCl infusion, 3/16-inch ID tubing, a peristaltic pump, and flow sensors. The NxStage permeate line was connected back to the main circuit in the Control group (n = 6), creating a recirculation loop. For KC group (n = 6), KC was added to the recirculation loop, and a continuous infusion of KCl at 10 mEq/hour was administered for two hours. Blood samples were acquired at baseline and every hour for 6 h. RESULTS: In the control group, K+ levels remained at ∼9 mmol/L; 9.1 ± 0.4 mmol/L at 6 h. In the KC group, significant decreases in K+ at hour 1 (4.3 ± 0.3 mmol/L) and were sustained for the experiment duration equilibrating at 4.6 ± 0.4 mmol/L after 6 h (p = 0.042). Main loop blood flow was maintained under 400 mL/min; recirculation loop flow varied between 60 and 70 mL/min in the control group and 45-55 mL/min in the KC group. Decreases in recirculation loop flow in KC group required 7% increase of pump RPM. CONCLUSIONS: During ex-vivo extracorporeal circulation using donor swine blood, KC removed approximately 50% of K+, normalizing circulating levels.

Combat Trauma-Related Acute Respiratory Distress Syndrome: A Scoping Review.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are known complications of injuries in combat casualties, but there has been no review characterizing them. This scoping review aims to map the combat trauma-related ALI/ARDS literature and characterize these conditions in the military population. DATA SOURCES: Pubmed was searched from 1969 to April 2022. STUDY SELECTION: Studies were included if they examined ALI/ARDS or related entities (blast lung injury [BLI], transfusion-related acute lung injury, and acute respiratory failure) in combat trauma patients in the military (U.S. or allied forces). DATA EXTRACTION: Study years, design, location, number of patients, target outcomes as related to ALI/ARDS or related entities, and results were collected. DATA SYNTHESIS: The initial search yielded 442 studies, with 22 ultimately included. Literature on ALI/ARDS comes mostly from retrospective data and case studies, with limited prospective studies. The incidence and prevalence of ALI/ARDS range from 3% to 33%, and mortality 12.8% to 33%. BLI, a known antecedent to ALI/ARDS, has an incidence and mortality ranging from 1.4% to 40% and 11% to 56%, respectively. Risk factors for ALI/ARDS include pulmonary injury, inhalation injury, blunt trauma, pneumonia, higher military injury severity score, higher injury severity score, higher fresh frozen plasma volumes, higher plasma and platelet volumes, the use of warm fresh whole blood, female sex, low blood pressure, and tachycardia. Literature has demonstrated the effectiveness in transportation of these patients and the utility of extracorporeal life support. CONCLUSIONS: ALI/ARDS incidences and prevalences in modern conflict range from 3% to 33%, with mortality ranging from 12.8% to 33%. ALI/ARDS has been associated with injury severity metrics, injury type, resuscitative fluid amount and type, vital signs, and patient demographics. Studies are limited to mostly retrospective data, and more data are needed to better characterize these conditions.

Randomized Controlled Trial of Ketamine and Moderate Sedation for Outpatient Endoscopy in Adults.

INTRODUCTION: Ketamine is an effective sedative agent in a variety of settings due to its desirable properties including preservation of laryngeal reflexes and lack of cardiovascular depression. We hypothesized that ketamine is an effective alternative to standard moderate sedation (SMS) regimens for patients undergoing endoscopy. MATERIALS AND METHODS: We conducted a randomized controlled trial comparing ketamine to SMS for outpatient colonoscopy or esophagogastroduodenoscopy at Brooke Army Medical Center. The ketamine group received a 1-mg dose of midazolam along with ketamine, whereas the SMS group received midazolam/fentanyl. The primary outcome was patient satisfaction measured using the Patient Satisfaction in Sedation Instrument, and secondary outcomes included changes in hemodynamics, time to sedation onset and recovery, and total medication doses. RESULTS: Thirty-three subjects were enrolled in each group. Baseline characteristics were similar. Endoscopies were performed for both diagnostic and screening purposes. Ketamine was superior in the overall sedation experience and in all analyzed categories compared to the SMS group (P = .0096). Sedation onset times and procedure times were similar among groups. The median ketamine dose was 75 mg. The median fentanyl and midazolam doses were 150 mcg and 5 mg, respectively, in SMS. Vital signs remained significantly closer to the physiological baseline in the ketamine group (P = .004). Recovery times were no different between the groups, and no adverse reactions were encountered. CONCLUSIONS: Ketamine is preferred by patients, preserves hemodynamics better than SMS, and can be safely administered by endoscopists. Data suggest that ketamine is a safe and effective sedation option for patients undergoing esophagogastroduodenoscopy or colonoscopy (clinicaltrials.gov NCT03461718).

An analysis of early volume resuscitation and the association with prolonged mechanical ventilation.

BACKGROUND: Previous studies have found that intravenous fluid administration within the first 24 h may be associated with prolonged mechanical ventilation (PMV). We examined the association between initial 24 h fluids and PMV in combat casualties. METHODS: This is a secondary analysis of a previously described dataset from the Department of Defense Trauma Registry (DODTR). We included casualties with at least 24 h on the ventilator and no significant traumatic brain injury. The definition of PMV and associations were constructed using univariable and multivariable logistic regression models. RESULTS: We identified 1508 casualties available for analysis for this study - 1275 in the non-PMV cohort (<9 days on ventilator vs. 233 in the PMV cohort (≥9 days on ventilator). Explosives comprised the most common mechanism of injury for both groups (72% vs. 75%) followed by firearms (21% vs. 16%). The composite injury severity score (ISS) was lower in the non-PMV cohort (18 vs. 30, p < .001). There were lower volumes of all resuscitation fluid within the first 24 h in the non-PMV cohort. When adjusting for composite ISS and mechanism of injury in a multivariable logistic regression model with PMV as the outcome, crystalloid volume (unit odds ratio [UOR] 1.07) and colloid volume (UOR 1.03) were both associated with PMV. CONCLUSIONS: We found that volume of resuscitation fluids were substantially higher in the PMV cohort. Our findings suggest the need for caution with the routine use of crystalloid and colloid in the first 24 h of resuscitation.

A Multicenter Evaluation of the Seraph 100 Microbind Affinity Blood Filter for the Treatment of Severe COVID-19.

The Seraph100 Microbind Affinity Blood Filter (Seraph 100) (ExThera Medical, Martinez, CA) is an extracorporeal therapy that can remove pathogens from blood, including severe acute respiratory syndrome coronavirus 2. The aim of this study was to evaluate safety and efficacy of Seraph 100 treatment for COVID-19. DESIGN: Retrospective cohort study. SETTING: Nine participating ICUs. PATIENTS: COVID-19 patients treated with Seraph 100 (n = 53) and control patients matched by study site (n = 53). INTERVENTION: Treatment with Seraph 100. MEASUREMENTS AND MAIN RESULTS: At baseline, there were no differences between the groups in terms of sex, race/ethnicity, body mass index, and need for mechanical ventilation. However, patients in the Seraph 100 group were younger (median age, 54 yr; interquartile range [IQR], 41-65) compared with controls (median age, 64 yr; IQR, 56-69; p = 0.009). Charlson comorbidity index scores were lower in the Seraph 100 group (2; IQR, 0-3) compared with the control group (3; IQR, 2-4; p = 0.006). Acute Physiology and Chronic Health Evaluation II scores were also lower in Seraph 100 subjects (12; IQR, 9-17) compared with controls (16; IQR, 12-21; p = 0.011). The Seraph 100 group had higher vasopressor-free days with an incidence rate ratio of 1.30 on univariate analysis. This difference was not significant after adjustment. Seraph 100-treated subjects were less likely to die compared with controls (32.1% vs 64.2%; p = 0.001), a difference that remained significant after adjustment. However, no difference in mortality was observed in a post hoc analysis utilizing an external control group. In the full cohort of 86 treated patients, there were 177 total treatments, in which only three serious adverse events were recorded. CONCLUSIONS: Although this study did not demonstrate consistently significant clinical benefit across all endpoints and comparisons, the findings suggest that broad spectrum, pathogen agnostic, blood purification can be safely deployed to meet new pathogen threats while awaiting targeted therapies and vaccines.

Comparison of Piperacillin and Tazobactam Pharmacokinetics in Critically Ill Patients with Trauma or with Burn.

Critical illness caused by burn and sepsis is associated with pathophysiologic changes that may result in the alteration of pharmacokinetics (PK) of antibiotics. However, it is unclear if one mechanism of critical illness alters PK more significantly than another. We developed a population PK model for piperacillin and tazobactam (pip-tazo) using data from 19 critically ill patients (14 non-burn trauma and 5 burn) treated in the Military Health System. A two-compartment model best described pip-tazo data. There were no significant differences found in the volume of distribution or clearance of pip-tazo in burn and non-burn patients. Although exploratory in nature, our data suggest that after accounting for creatinine clearance (CrCl), doses would not need to be increased for burn patients compared to trauma patients on consideration of PK alone. However, there is a high reported incidence of augmented renal clearance (ARC) in burn patients and pharmacodynamic (PD) considerations may lead clinicians to choose higher doses. For critically ill patients with normal kidney function, continuous infusions of 13.5-18 g pip-tazo per day are preferable. If ARC is suspected or the most stringent PD targets are desired, then continuous infusions of 31.5 g pip-tazo or higher may be required. This approach may be reasonable provided that therapeutic drug monitoring is enacted to ensure pip-tazo levels are not supra-therapeutic.

A Review of Extracorporeal Blood Purification Techniques for the Treatment of Critically Ill Coronavirus Disease 2019 Patients.

In late 2019, a novel betacoronavirus, later termed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was discovered in patients with an unknown respiratory illness in Wuhan, China. SARS-CoV-2 and the disease caused by the novel coronavirus, coronavirus disease 2019 (COVID-19), spread rapidly and resulted in the World Health Organization declaring a pandemic in March 2020. In a minority of patients infected with SARS-CoV-2, severe illness develops characterized by a dysregulated immune response, acute respiratory distress syndrome, and multisystem organ failure. Despite the development of antiviral and multiple immunomodulatory therapies, outcomes of severe illness remain poor. In response, the Food and Drug Administration in the United States authorized the emergency use of several extracorporeal blood purification (EBP) devices for critically ill patients with COVID-19. Extracorporeal blood purification devices target various aspects of the host response to infection to reduce immune dysregulation. This review highlights the underlying technology, currently available literature on use in critically ill COVID-19 patients, and future studies involving four EBP platforms: 1) oXiris filter, 2) CytoSorb filter, 3) Seraph 100 Microbind blood affinity filter, and 4) the Spectra Optia Apheresis System with the Depuro D2000 Adsorption Cartridge.

An Analysis of Patient Movements during Sustained Combat Operations in the US Central Command: Implications for Remote Support Capabilities.

BACKGROUND: The US Central Command (CENTCOM) area of responsibility (AOR) spans 20 nations in the Middle East, Central, and South Asia. Evacuations outside this AOR include all injury types and severities; however, it remains unclear what proportion of evacuations were due to disease and non-battle injuries (DNBI). Understanding these patterns may be useful for defining future medical support requirements for multi domain operations (MDO). We sought to analyze encounters obtained from the Transportation Command Regulating and Command and Control Evacuation System (TRAC2ES) data for medical evacuations within CENTCOM. METHODS: We obtained all encounters within TRAC2ES from February 2009 to November 2018. We analyzed data using entered demographic data and keyword categorization of free text information provided by the medical officer requesting patient movement. RESULTS: There were 50,036 patient movement requests entered into TRAC2ES originating from the CENTCOM AOR for both military and civilian personnel. After removal of ineligible entries (for example, military working dogs), the number of eligible subjects was 49,259, 13 percent combat (n equals 6,389) and 87 percent were noncombat (n equals 42,870). The primary age group requiring evacuation was 18 through 29 (59 percent) and were mostly male (87 percent). Most went by routine status (80 percent), followed by priority (16 percent). Most of the transfers originated from Afghanistan (58 percent) and Iraq (22 percent), with Germany serving as the primary destination (79 percent). Results showed the total number of patient evacuations increased from 2009 to 2010 and then decreased from 2011 to 2017. The most frequent body region associated with the transfer was the extremities for both combat (54 percent) and noncombat (32 percent). CONCLUSIONS: Out of theater disease and non combat injury evacuation rates were nearly 7 times higher than for combat related injuries. Our results highlight the need for additional research and development resources of DNBI related medical care. As we move into future MDO with limited evacuation capabilities, we will need support solutions to cover the full gamut of DNBI.

Pharmacokinetics of piperacillin and tazobactam in critically Ill patients treated with continuous kidney replacement therapy: A mini-review and population pharmacokinetic analysis.

WHAT IS KNOWN AND OBJECTIVE: Timely and appropriate dosing of antibiotics is essential for the treatment of bacterial sepsis. Critically ill patients treated with continuous kidney replacement therapy (CKRT) often have physiologic derangements that affect pharmacokinetics (PK) of antibiotics and dosing may be challenging. We sought to aggregate previously published piperacillin and tazobactam (pip-tazo) pharmacokinetic data in critically ill patients undergoing CKRT to better understand pharmacokinetics of pip-tazo in this population and better inform dosing. METHODS: The National Library of Medicine Database was searched for original research containing piperacillin or tazobactam clearance (CL) or volume of distribution (V) estimates in patients treated with CKRT. The search yielded 77 articles, of which 26 reported suitable estimates of CL or V. Of the 26 articles, 10 for piperacillin and 8 for tazobactam had complete information suitable for population pharmacokinetic modelling. Also included in the analysis was piperacillin and tazobactam PK data from 4 critically ill patients treated with CKRT in the Military Health System, 2 with burn and 2 without burn. RESULTS AND DISCUSSION: Median and range of literature reported PK parameters for piperacillin (CL 2.76 L/hr, 1.4-7.92 L/hr, V 31.2 L, 16.77-42.27 L) and tazobactam (CL 2.34 L/hr, 0.72-5.2 L/hr, V 36.6 L, 26.2-58.87 L) were highly consistent with population estimates (piperacillin CL 2.7 L/hr, 95%CI 1.99-3.41 L/hr, V 25.83 22.07-29.59 L, tazobactam CL 2.49 L/hr, 95%CI 1.55-3.44, V 30.62 95%CI 23.7-37.54). The proportion of patients meeting pre-defined pharmacodynamic (PD) targets (median 88.7, range 71%-100%) was high despite significant mortality (median 44%, range 35%-60%). High mortality was predicted by baseline severity of illness (median APACHE II score 23, range 21-33.25). Choice of lenient or strict PD targets (ie 100%fT >MIC or 100%fT >4XMIC) had the largest impact on probability of target attainment (PTA), whereas presence or intensity of CKRT had minimal impact on PTA. WHAT IS NEW AND CONCLUSION: Pip-tazo overexposure may be associated with increased mortality, although this is confounded by baseline severity of illness. Achieving adequate pip-tazo exposure is essential; however, risk of harm from overexposure should be considered when choosing a PD target and dose. If lenient PD targets are desired, doses of 2250-3375 mg every 6 h are reasonable for most patients receiving CKRT. However, if a strict PD target is desired, continuous infusion (at least 9000-13500 mg per day) may be required. However, some critically ill CKRT populations may need higher or lower doses and dosing strategies should be tailored to individuals based on all available clinical data including the specific critical care setting.