Characterization of the Inflammatory Response to Severe COVID-19 Illness.

Rationale: Coronavirus disease (COVID-19) is a global threat to health. Its inflammatory characteristics are incompletely understood.Objectives: To define the cytokine profile of COVID-19 and to identify evidence of immunometabolic alterations in those with severe illness.Methods: Levels of IL-1ß, IL-6, IL-8, IL-10, and sTNFR1 (soluble tumor necrosis factor receptor 1) were assessed in plasma from healthy volunteers, hospitalized but stable patients with COVID-19 (COVIDstable patients), patients with COVID-19 requiring ICU admission (COVIDICU patients), and patients with severe community-acquired pneumonia requiring ICU support (CAPICU patients). Immunometabolic markers were measured in circulating neutrophils from patients with severe COVID-19. The acute phase response of AAT (alpha-1 antitrypsin) to COVID-19 was also evaluated.Measurements and Main Results: IL-1ß, IL-6, IL-8, and sTNFR1 were all increased in patients with COVID-19. COVIDICU patients could be clearly differentiated from COVIDstable patients, and demonstrated higher levels of IL-1ß, IL-6, and sTNFR1 but lower IL-10 than CAPICU patients. COVID-19 neutrophils displayed altered immunometabolism, with increased cytosolic PKM2 (pyruvate kinase M2), phosphorylated PKM2, HIF-1α (hypoxia-inducible factor-1α), and lactate. The production and sialylation of AAT increased in COVID-19, but this antiinflammatory response was overwhelmed in severe illness, with the IL-6:AAT ratio markedly higher in patients requiring ICU admission (P < 0.0001). In critically unwell patients with COVID-19, increases in IL-6:AAT predicted prolonged ICU stay and mortality, whereas improvement in IL-6:AAT was associated with clinical resolution (P < 0.0001).Conclusions: The COVID-19 cytokinemia is distinct from that of other types of pneumonia, leading to organ failure and ICU need. Neutrophils undergo immunometabolic reprogramming in severe COVID-19 illness. Cytokine ratios may predict outcomes in this population.

The Royal College of surgeons multidisciplinary guidelines on elective tracheostomy insertion in COVID-19 ventilated patients.

BACKGROUND: The current COVID-19 pandemic has placed enormous strain on healthcare systems worldwide. Understanding of COVID-19 is rapidly evolving. Pneumonia associated with COVID-19 may lead to respiratory failure requiring mechanical ventilation. The rise in patients requiring mechanical ventilation may lead to an increase in tracheostomies being performed in patients with COVID-19. Performing tracheostomy in patients with active SARS-CoV-2 infection poses a number of challenges. METHODS: These guidelines were written following multidisciplinary agreement between Otolaryngology, Head and Neck Surgery, Respiratory Medicine and the Department of Anaesthetics and Critical Care Medicine in the Royal College of Surgeons in Ireland. A literature review was performed and a guideline for elective tracheostomy insertion in patients with COVID-19 proposed. CONCLUSION: The decision to perform tracheostomy in patients with COVID-19 should be undertaken by senior members of the multidisciplinary team. Steps should be taken to minimise risks to healthcare workers.

Initial Assessment of the Percutaneous Electrical Phrenic Nerve Stimulation System in Patients on Mechanical Ventilation.

OBJECTIVES: Maintaining diaphragm work using electrical stimulation during mechanical ventilation has been proposed to attenuate ventilator-induced diaphragm dysfunction. This study assessed the safety and feasibility of temporary percutaneous electrical phrenic nerve stimulation on user-specified inspiratory breaths while on mechanical ventilation. DESIGN: Two-center, nonblinded, nonrandomized study. SETTING: Hospital ICU. PATIENTS: Twelve patients mechanically ventilated from 48 hours to an expected 7 days. INTERVENTIONS: Leads were inserted to lie close to the phrenic nerve in the neck region using ultrasound guidance. Two initial patients had left-sided placement only with remaining patients undergoing bilateral lead placement. Percutaneous electrical phrenic nerve stimulation was used for six 2-hour sessions at 8-hour intervals over 48 hours. MEASUREMENTS AND MAIN RESULTS: Data collected included lead deployment success, nerve conduction, ventilation variables, work of breathing, electrical stimulation variables, stimulation breath synchrony, and diaphragm thickness measured by ultrasound at baseline, 24, and 48 hours. Primary endpoints included ability to capture the left and/or right phrenic nerves and maintenance of work of breathing within defined limits for 80% of stimulated breaths. Lead insertion was successful in 21 of 22 attempts (95.5%). Analysis of 36,059 stimulated breaths from 10 patients with attempted bilateral lead placement demonstrated a mean inspiratory lag for phrenic nerve stimulation of 23.7 ms (p < 0.001 vs null hypothesis of <88ms). Work of breathing was maintained between 0.2 and 2.0 joules/L 96.8% of the time, exceeding the 80% target. Mean diaphragm thickness increased from baseline by 7.8% at 24 hours (p = 0.022) and 15.0% at 48 hours (p = 0.0001) for patients receiving bilateral stimulation after excluding one patient with pleural effusion. No serious device/procedure-related adverse events were reported. CONCLUSIONS: The present study demonstrated the ability to safely and successfully place percutaneous electrical phrenic nerve stimulation leads in patients on mechanical ventilation and the feasibility of using this approach to synchronize electrical stimulation with inspiration while maintaining work of breathing within defined limits.

Clinical value of the red blood cell distribution width to albumin ratio in the assessment of prognosis in critically ill patients with sepsis: a retrospective analysis.

Background: Red blood cell (RBC) distribution width (RDW) to albumin ratio is a novel biomarker and its prognostic effect on critically ill patients with sepsis has not been extensively investigated. The objective of this study was to identify the prognostic value of the RDW to albumin ratio in these patients. Methods: Data were extracted from the Medical Information Mart for Intensive Care III (MIMIC-III) database. A Cox proportional hazards model and restricted cubic spline model were used to determine the association of RDW to albumin ratio with mortality. Receiver operating characteristic (ROC) curves and Kaplan-Meier survival curves were applied, and the area under the curve (AUC) was used to compare the predictive value. Results: A total of 3,969 eligible patients were enrolled. The median RDW to albumin ratio was significantly higher in non-survivors than in survivors at 30 and 90 days. Patients were divided into groups according to the RDW to albumin ratio, and the risk of 30- and 90-day mortality markedly increased in the group with a higher ratio. The relationship between the RDW to albumin ratio as a continuous variable and 30-day mortality also showed an upward trend in the restricted cubic spline. The AUC of the RDW to albumin ratio was 0.633 in discriminating 30-day mortality which was similar to that of the lactate to albumin ratio (AUC =0.617; P=0.133) and higher than that of the neutrophil percentage to albumin ratio (AUC =0.559; P<0.001). Conclusions: The RDW to albumin ratio is a promising biomarker for assessing the prognosis of critically ill patients with sepsis. Its predictive value in determining mortality was found to be similar to that of the lactate to albumin ratio and superior to that of the neutrophil percentage to albumin ratio.

Airway decision making in major head and neck surgery: Irish multicenter, multidisciplinary recommendations.

Major head and neck surgery poses a threat to perioperative airway patency. Adverse airway events are associated with significant morbidity, potentially leading to hypoxic brain injury and even death. Following a review of the literature, recommendations regarding airway management in head and neck surgery were developed with multicenter, multidisciplinary agreement among all Irish head and neck units. Immediate extubation is appropriate in many cases where there is a low risk of adverse airway events. Where a prolonged definitive airway is required, elective tracheostomy provides increased airway security postoperatively while delayed extubation may be appropriate in select cases to reduce postoperative morbidity. Local institutional protocols should be developed to care for a tracheostomy once inserted. We provide guidance on decision making surrounding airway management at time of head and neck surgery. All decisions should be agreed between the operating, anesthetic, and critical care teams.

Tumescent anaesthesia.

Tumescent anaesthesia describes the practice of injecting a very dilute solution of local anaesthetic combined with epinephrine and sodium bicarbonate into tissue until it becomes firm and tense (tumescent). It was initially described in the field of liposuction but now surgical applications for the technique are widely varied ranging across vascular surgery, breast surgery, plastic surgery and ENT procedures. It is widely used in both hospital- and office-based environments and may form the sole method of anaesthesia for surgery. Advantages include a reduction in blood loss through both epinephrine-induced vasoconstriction as well as hydrostatic compression from the tumescent effect. Sodium bicarbonate reduces pain associated with the injection of an acidic local anaesthetic solution. Due to the unique pharmacokinetic profile of this technique lidocaine doses of 35 mg/kg bodyweight have been shown to be safe for liposuction procedures. Tumescent lidocaine is absorbed very slowly from subcutaneous tissues producing lower, and more delayed, peak blood levels compared to other routes, as well as extended postoperative analgesia. Slow systemic absorption allows the rapid hepatic plasma clearance of lidocaine to maintain safe local anaesthetic blood levels. This slow absorption from subcutaneous tissue has been likened to a depot injection. Careful attention must be given to appropriate local anaesthetic dosage alterations in cases of co-administration with agents affecting hepatic drug clearance or conditions reducing liver blood supply. Adherence to these pharmacological principles has produced an exemplary safety record for this technique to date.

Tracheostomy insertion in COVID-19: insertion practice and factors leading to unplanned tube exchange.

Background: Tracheostomy insertion in patients with coronavirus disease 2019 (COVID-19) presents unique challenges. Patients frequently have high ventilatory requirements, and as an aerosol generating procedure, tracheostomy insertion creates the potential for staff transmission. Problems with tracheostomies contribute to morbidity and mortality, and tracheostomy changes may increase risks of staff transmission. We sought to quantify the incidence of clinically necessitated tracheostomy changes, establish the indications for change and investigate the incidence of staff transmission. Methods: We conducted a single institution, retrospective, observational cohort study of all intensive care unit (ICU) patients with COVID-19 who had a tracheostomy between March 2020 and April 2021. The institution is a large tertiary referral centre in Ireland. Results: Forty-three patients had a tracheostomy during the study period. All were a Shiley™ Flexible Adult Taperguard or Shiley™ XLT Tracheostomy. 14 patients (33%) required a tracheostomy change, with the majority (57%) involving a change from a standard size to an extended length tracheostomy. Persistent leak was the most common indication for change (71.6%). Other indications included patient-ventilator dyssynchrony, persistent cough and accidental decannulation. No staff transmission of COVID-19 occurred during this study. Conclusions: The incidence of tracheostomy change was 33%, highlighting the importance of selecting the right tracheostomy for each patient. We discuss how key characteristics of tracheostomies such as type, size, length and inner diameter may impact flow, resistance and work of breathing, leading to unplanned tracheostomy change. No staff transmission occurred arising from tracheostomy insertion, adding to increasing evidence that tracheostomy insertion in COVID-19 appears safe with adherence to guidelines describing the correct use of personal protective equipment.

Preparation of the Drager Fabius CE and Drager Zeus anaesthetic machines for patients susceptible to malignant hyperthermia.

CONTEXT: Malignant hyperthermia may follow exposure to trace quantities of inhalational anaesthetics. In susceptible patients, the complete avoidance of these triggers is advised when possible; however, failing this, it is essential to washout or purge the anaesthesia machine of residual inhalational anaesthetics. OBJECTIVE: This study examined the washout profile of sevoflurane from the Drager Fabius CE and the Drager Zeus machines. DESIGN: The washout profile of sevoflurane was measured from the Fabius CE and Zeus anaesthesia machines following a standard period of exposure. The disposable tubing, CO2 absorber and other components of each machine were then replaced to examine their impact on the retention of sevoflurane. The effect of autoclaving the ventilator diaphragm and non-disposable ventilator tube or substituting for a new diaphragm and ventilation tube were examined in later parts of this study. SETTING: University teaching hospital. MAIN OUTCOME MEASURE: Time taken to reach 5 parts per million of sevoflurane when machines underwent standard washout with fresh gas flush. RESULTS: The concentration of sevoflurane reached 5 parts per million in the Fabius CE machines after an mean (SD) of 140 min (46) at a fresh gas flow (FGF) of 10 l min(-1). The time taken for sevoflurane to reach 5 parts per million was significantly reduced when the ventilator diaphragm and non-disposable tube were replaced with either new or autoclaved components [14 or 22 min, respectively (P = 0.017, P = 0.031)]. The concentration of sevoflurane reached 5 parts per million in the Zeus machines after an mean (SD) of 85 min (6) at a fresh gas flow of 10 l min(-1). When the fresh gas flow was increased to 18 l min(-1) (the maximum allowable), the time to reach 5 parts per million was reduced to 16 min. CONCLUSION: When preparing the Fabius CE for the malignant hyperthermia susceptible patient, remove the vaporiser, replace the disposable tubing, the reservoir bag and the CO2 absorber. Replace the ventilator diaphragm and non-disposable ventilator tube with new or autoclaved components and flush the machine at 10 l min(-1) for at least 36 min. When preparing the Zeus, remove the vaporiser, replace the disposable tubing, the reservoir bag and CO2 absorber and flush at a fresh gas flow of 10 l min(-1) for at least 90 min. In both the Fabius and Zeus, continue at a fresh gas flow of 10 l min(-1) for the duration of the operation.

Clinical efficacy and nephrotoxicity of intravenous colistin sulfate in the treatment of carbapenem-resistant gram-negative bacterial infections: a retrospective cohort study.

Background: Carbapenem-resistant gram-negative bacteria (CR-GNB) are becoming increasingly important bacterial pathogens in critically ill patients. Several clinicians use Intravenous colistin sulfate to treat infections due to CR-GNB, although the clinical data is limited. The aim of our retrospective observational study was to evaluate the effectiveness and nephrotoxicity of intravenous colistin sulfate in the treatment of CR-GNB infections. Methods: Fifty critically ill intensive care patients with infections due to CR-GNB were retrospectively enrolled between January 2020 and December 2021 in the Zhejiang Provincial People's Hospital. Favorable clinical response rate, bacterial clearance rate, nephrotoxicity, and 28-day mortality were evaluated. Results: The overall favorable clinical response rate was 58%, the bacterial clearance rate was 40%, and the 28-day all-cause mortality was 44%. Temperature, neutrophil count, C-reaction protein (CRP), procalcitonin (PCT), creatinine (Cr), and lactate levels were also significantly decreased (P<0.05). The major adverse reaction is nephrotoxicity, and renal function was evaluated on the day before and after treatment with colistin sulfate. Possible nephrotoxicity was observed in three patients (6%). Backward logistic regression was conducted to determine risk factors for the nephrotoxicity of colistin sulfate, the result showed there were no significant differences in the duration and dose of colistin sulfate. Conclusions: Our results provide evidence for the positive clinical efficacy and safety of colistin sulfate. Appropriate use of colistin sulfate may be viable and safe in the treatment of severe infections caused by CR-GNB.

Alpha-1 antitrypsin for cystic fibrosis complicated by severe cytokinemic COVID-19.

BACKGROUND: The clinical course of severe COVID-19 in cystic fibrosis (CF) is incompletely understood. We describe the use of alpha-1 antitrypsin (AAT) as a salvage therapy in a critically unwell patient with CF (PWCF) who developed COVID-19 while awaiting lung transplantation. METHODS: IV AAT was administered at 120 mg/kg/week for 4 consecutive weeks. Levels of interleukin (IL)-1ß, IL-6, IL-8, and soluble TNF receptor 1 (sTNFR1) were assessed at regular intervals in plasma, with IL-1ß, IL-6, IL-8 and neutrophil elastase (NE) activity measured in airway secretions. Levels were compared to baseline and historic severe exacerbation measurements. RESULTS: Systemic and airway inflammatory markers were increased compared to both prior exacerbation and baseline levels, in particular IL-6, IL-1ß and NE activity. Following each AAT dose, rapid decreases in each inflammatory parameter were observed. These were matched by marked clinical and radiographic improvement. CONCLUSIONS: The results support further investigation of AAT as a COVID-19 therapeutic, and re-exploration of its use in CF.

T cell sensitivity to TGF-beta is required for the effector function but not the generation of splenic CD8+ regulatory T cells induced via the injection of antigen into the anterior chamber.

The introduction of antigen into the anterior chamber (AC) of the eye induces the production of antigen-specific splenic CD8(+) regulatory T cells (AC-SPL cells) that suppress a delayed-type hypersensitivity (DTH) reaction in immunized mice. Because the generation of these regulatory T cells is also induced by exposure to transforming growth factor (TGF)-beta and antigen or F4/80(+) cells exposed to TGF-beta and antigen in vitro, we investigated (i) whether these cells are produced in dominant negative receptor for transforming growth factor beta receptor type II (dnTGFbetaRII) or Cbl-b(-/-) mice whose T cells are resistant to TGF-beta, (ii) whether DTH is suppressed by wild type (WT) CD8(+) AC-SPL cells in Cbl-b(-/-) and dnTGFbetaRII mice and (iii) the effect of antibodies to TGF-beta on the suppression of DTH by CD8(+) AC-SPL cells. DnTGFbetaRII immunized and Cbl-b(-/-) mice produced splenic CD8(+) regulatory cells after the intracameral injection of antigen and immunization. The suppression of a DTH reaction by CD8(+) AC-SPL cells in WT mice was blocked by the local inclusion of antibodies to TGF-beta when WT splenic CD8(+) AC-SPL cells were injected into the DTH reaction site. Moreover, the DTH reaction in immunized dnTGFbetaRII and Cbl-b(-/-) mice was not suppressed by the transfer of WT CD8(+) AC-SPL cells to the site challenged with antigen. In aggregate, these observations suggest that T cell sensitivity to TGF-beta is not an obligate requirement for the in vivo induction of CD8(+) AC-SPL T cells but the suppression of an in vivo DTH reaction by CD8(+) AC-SPL cells is dependent on TGF-beta.

Wall teichoic acids govern cationic gold nanoparticle interaction with Gram-positive bacterial cell walls.

Molecular-level understanding of nanomaterial interactions with bacterial cell surfaces can facilitate design of antimicrobial and antifouling surfaces and inform assessment of potential consequences of nanomaterial release into the environment. Here, we investigate the interaction of cationic nanoparticles with the main surface components of Gram-positive bacteria: peptidoglycan and teichoic acids. We employed intact cells and isolated cell walls from wild type Bacillus subtilis and two mutant strains differing in wall teichoic acid composition to investigate interaction with gold nanoparticles functionalized with cationic, branched polyethylenimine. We quantified nanoparticle association with intact cells by flow cytometry and determined sites of interaction by solid-state 31P- and 13C-NMR spectroscopy. We find that wall teichoic acid structure and composition were important determinants for the extent of interaction with cationic gold nanoparticles. The nanoparticles interacted more with wall teichoic acids from the wild type and mutant lacking glucose in its wall teichoic acids than those from the mutant having wall teichoic acids lacking alanine and exhibiting more restricted molecular motion. Our experimental evidence supports the interpretation that electrostatic forces contributed to nanoparticle-cell interactions and that the accessibility of negatively charged moieties in teichoic acid chains influences the degree of interaction. The approaches employed in this study can be applied to engineered nanomaterials differing in core composition, shape, or surface functional groups as well as to other types of bacteria to elucidate the influence of nanoparticle and cell surface properties on interactions with Gram-positive bacteria.

Implication for the CD94/NKG2A-Qa-1 system in the generation and function of ocular-induced splenic CD8+ regulatory T cells.

The injection of antigen into the anterior chamber (AC) induces the production of antigen-specific splenic CD8+ regulatory T cells (Tregs) /suppressor T cells that perform the local suppression of delayed-type hypersensitivity (DTH) responses. Because CD94/NKG2A-Qa-1-dependent interactions have been implicated in CD8+ Treg-mediated immune suppression and DBA/2J mice are deficient in CD94/NKG2R, we have utilized these mice to test the hypothesis that the CD94/NKG2A-Qa-1 system is essential to the induction and immunosuppressive function of CD8+ Tregs in anterior chamber-associated immune deviation (ACAID). We show that: (i) neither ACAID-mediated suppression of DTH to ovalbumin nor splenic Tregs/suppressor T cells was induced in DBA/2J mice that received an injection of antigen into the AC; (ii) splenic CD8+ Tregs from ACAID-induced DBA/2NCr mice suppressed the initiation of DTH when transferred to DBA/2J mice; (iii) following injection of antigen into the AC, intravenous administration of splenocytes or Peripheral Blood Mononuclear Cells (PBMC) isolated from DBA/2NCr but not from DBA/2J mice transferred suppression of DTH to DBA/2NCr mice; (iv) antibodies to CD94/NKG2A reduced the ACAID CD8+ T cell-mediated suppression of DTH and (v) The deficiency of such immune regulation in DBA/2J mice also correlated with a decreased number of Qa-1(b+) B cells, F4/80+ cells, a deficient number of CD94/NKG2AR and Qa-1 tetramer binding by CD8+ T cells. These results demonstrate that defective ACAID in DBA/2J mice involves multiple regulatory lesions resulting in a lack of induction of a CD8+ Treg response and possibly defective CD94/NKG2A-dependent suppression of peripheral cell-mediated immunity.

Vancomycin-Resistant Enterococci (VRE) in The Intensive Care Unit in a Nonoutbreak Setting: Identification of Potential Reservoirs and Epidemiological Associations Between Patient and Environmental VRE.

OBJECTIVE Among nosocomial bloodstream infections caused by enterococcal species, Ireland has the highest proportion caused by vancomycin-resistant enterococci (VRE) in Europe at 45.8%. The contribution of the near-patient environment to VRE transmission outside of outbreaks was investigated. DESIGN A prospective observational study was conducted during 7 sampling periods. METHODS Recovery of VRE isolates by swabbing the near-patient environment and patients in the intensive care unit (ICU) was conducted to identify reservoirs, clinical and molecular epidemiological associations, and the success of active surveillance cultures (ASCs). RESULTS Of 289 sampling occasions involving 157 patients and their bed spaces, VRE isolates were recovered from patient bed spaces, clinical samples, or both on 114 of 289 sampling occasions (39.4%). The patient and their bed space were positive for VRE on 34 of 114 VRE-associated sampling occasions (29.8%). Of 1,647 environment samples, 107 sites (6.5%) were VRE positive, with significantly greater VRE recovery from isolation rooms than from the open-plan area (9.1% vs 4.1%; P < .0001). The most frequently VRE-contaminated sites were the drip stand, bed control panel, and chart holders, which together accounted for 61% of contaminated sites. The use of ASCs resulted in a 172% increase in identification of VRE-colonized patients. Molecular typing revealed 2 environmental clusters, 1 cluster involving 3 patients and generally greater heterogeneity of patient isolates compared to environmental isolates. CONCLUSION Even outside of outbreaks, near-patient ICU environmental contamination with VRE is common. Better infection control policies that limit environmental transmission of VRE in the ICU and that are supported by molecular epidemiological studies, in real time, are needed. Infect Control Hosp Epidemiol 2018;39:40-45.

The induction of splenic suppressor T cells through an immune-privileged site requires an intact sympathetic nervous system.

Antigen injection into the eye's anterior chamber (AC) induces the antigen-specific suppression of delayed-type hypersensitivity (DTH) that is mediated by NKT cells and splenic CD8+ suppressor T cells. Because the AC, uveal tissues, the thymus and spleen required to induce anterior chamber-associated immune deviation (ACAID) have dense sympathetic innervations, we examined the effects of chemical sympathectomy of mice by 6-hydroxydopamine (6-OHDA) on the induction of the suppression of contact sensitivity to trinitrophenol (TNP) induced by the injection of TNP-bovine serum albumin (BSA) into the anterior chamber. DTH measured as contact sensitivity to picrylchloride was not induced in mice that received 6-OHDA before immunization with TNP-BSA. Although spleen cells from 6-OHDA-treated TNP-BSA-immunized mice produced IFN-gamma when stimulated by TNP-BSA, the number of DTH-initiating hepatic NKT cells was reduced markedly in 6-OHDA-treated mice. Chemically denervated mice did not produce splenic suppressor T cells or thymic NKT cells that activate splenic suppressor T cells. We suggest that an intact sympathetic nervous system (SNS) is required to maintain cellular immunoregulation.

Compact bulb pipette simplifies paracentesis.

Anterior chamber paracentesis is typically done using a tuberculin syringe, hypodermic needle, fixation forceps, and lid speculum. A compact suction pipette design simplifies the tap by eliminating unneeded instrumentation and minimizing needle dead space. The short (1/4-inch) 30-gauge needle tip eases limbal penetration. The soft plastic suction bulb provides a prompt and controlled aspiration of small volumes. Compared with syringe-needle methods, the pipette refines paracentesis by reducing the complexity and duration of aqueous withdrawal.