The SARS-CoV-2 pandemic as a source of unprecedented bioethical and biolaw issues: lessons for intensivists.

The following article presents the relevant and unprecedented bioethical and biolaw issues posed by the SARS-COV-2 pandemic and summarizes the initiatives adopted by the Italian Society of Anesthesia and Resuscitation (SIAARTI) as well as by the Veneto Region ICU Network. Since the initial phase of the pandemic, in March 2020, there has been a strong appeal from both SIAARTI and the Veneto Region ICU Network to consider "the appropriate intensive treatment." During the pandemic, the principle of proportionality must be applied, in compliance with the main principle in bioethics. This encompasses the concept of clinical appropriateness, based on the efficacy of the treatment in specific case and context, as well as the concept of ethical appropriateness, which refers to ethical and juridical principles of acceptance of health care. The "appropriate treatment" must never interfere with the withdrawal of patients, who are not eligible for intensive treatments since they would not benefit from them and who are eligible for ordinary treatments that must be maintained, and, where necessary, palliative treatments were initiated. On the other hand, it must not encroach on unreasonable obstinacy. At the end of 2020, the SIAARTI-SIMLA (Italian Society of Insurance and Legal Medicine) document provides healthcare professionals with a tool for responding appropriately to the emergency of the pandemic, in the event of an imbalance between healthcare demand and available resources. The document states that the ICU triage should be based on global evaluation of each patient, taking into account well-defined parameters and stresses that each person potentially eligible for intensive care should have a shared care planning (SCP) stipulated, and, when necessary, a proxy should be nominated. This has illustrated how the biolaw issues encountered by intensivists during the pandemic, such as those relating to consent and refusal to medical treatment, even when it is lifesaving, as well as requests for treatment of unproven clinical efficacy, were subject to appropriate guidelines and solutions through the application of Law 219/2017 (provisions for informed consent and advance directives treatment). Communication with family members and the management of sensitive personal data; the evaluation of "legal capacity" of comprehension and informed decision-making regarding the proposed treatment plan; and the need for emergency medical intervention in the absence of consent are all addressed in light of the relevant regulations and the particular conditions of social isolation induced by the pandemic. The collaborative ICUs network sustained by the Veneto Region has given great prominence to clinical bioethics issues, and as a result, multidisciplinary integration with the help of legal and juridical experts was developed. This has led to an increase in skills in the bioethical field, as well as providing a valuable lesson for the improvement of therapeutic relationships with critically ill patients and their families.

The PROVENT-C19 registry: A study protocol for international multicenter SIAARTI registry on the use of prone positioning in mechanically ventilated patients with COVID-19 ARDS.

BACKGROUND: The worldwide use of prone position (PP) for invasively ventilated patients with COVID-19 is progressively increasing from the first pandemic wave in everyday clinical practice. Among the suggested treatments for the management of ARDS patients, PP was recommended in the Surviving Sepsis Campaign COVID-19 guidelines as an adjuvant therapy for improving ventilation. In patients with severe classical ARDS, some authors reported that early application of prolonged PP sessions significantly decreases 28-day and 90-day mortality. METHODS AND ANALYSIS: Since January 2021, the COVID19 Veneto ICU Network research group has developed and implemented nationally and internationally the "PROVENT-C19 Registry", endorsed by the Italian Society of Anesthesia Analgesia Resuscitation and Intensive Care…'(SIAARTI). The PROVENT-C19 Registry wishes to describe 1. The real clinical practice on the use of PP in COVID-19 patients during the pandemic at a National and International level; and 2. Potential baseline and clinical characteristics that identify subpopulations of invasively ventilated patients with COVID-19 that may improve daily from PP therapy. This web-based registry will provide relevant information on how the database research tools may improve our daily clinical practice. CONCLUSIONS: This multicenter, prospective registry is the first to identify and characterize the role of PP on clinical outcome in COVID-19 patients. In recent years, data emerging from large registries have been increasingly used to provide real-world evidence on the effectiveness, quality, and safety of a clinical intervention. Indeed observation-based registries could be effective tools aimed at identifying specific clusters of patients within a large study population with widely heterogeneous clinical characteristics. TRIAL REGISTRATION: The registry was registered (ClinicalTrial.Gov Trials Register NCT04905875) on May 28,2021.

The impact of the SARS-CoV-2 epidemic outbreak on the vascular access team operations after conversion to COVID-19 dedicated hospital.

BACKGROUND: On February 21 2020, in Schiavonia Hospital occurred the first death by COVID-19 in Italy and since this date SARS-CoV-2 caused more than 100,000 deaths in our country. Our hospital was immediately closed and re-opened after 15 days as a reference Covid Hospital. Among services involved in a process of destruction and rebirth there was also the Vascular Access Team. METHODS: We analyzed our Vascular Access Team activity comparing data from the first month (March) in which basically it did not work and data from the following month (April) in which we began to re-build the Team adapting it to the new reality. RESULTS: In all patients admitted to Intensive Care Unit a Centrally Inserted Central Catheter multilumen was placed, but in March only 5.5% of patients admitted to Medicine-Sub-intensive Unit had a catheter different from the short peripheral cannula while in April it was possible to guarantee a more suitable catheter 31.7% of patients admitted to Medicine-Sub-intensive Unit (p < 0.000). In April, compared to March, a significant higher number of Midline were implanted in Medicine-Sub-intensive Unit (36/139 vs 12/238 p < 0.000) where also a higher number of Centrally Inserted Central Catheter and Femoral Inserted Central Catheter were implanted (8/139 vs 1/238 p = 0.003). This change allowed us to implant more vascular accesses in Medicine-Sub-intensive Unit favoring Midline with a longer average duration. Only one patient with Midline developed a catheter vein thrombosis, and in only one patient the device was removed for suspected infection. CONCLUSIONS: The experience we gained will allow us to be more prepared in the future and our experience has highlighted that a structured Vascular Access Team is necessary to respond adequately to COVID-19 patients' needs, to ensure the effectiveness of the maneuver, to reduce complications and to avoid the waste of resources, always working in safe condition.

Static compliance and driving pressure are associated with ICU mortality in intubated COVID-19 ARDS.

BACKGROUND: Pathophysiological features of coronavirus disease 2019-associated acute respiratory distress syndrome (COVID-19 ARDS) were indicated to be somewhat different from those described in nonCOVID-19 ARDS, because of relatively preserved compliance of the respiratory system despite marked hypoxemia. We aim ascertaining whether respiratory system static compliance (Crs), driving pressure (DP), and tidal volume normalized for ideal body weight (VT/kg IBW) at the 1st day of controlled mechanical ventilation are associated with intensive care unit (ICU) mortality in COVID-19 ARDS. METHODS: Observational multicenter cohort study. All consecutive COVID-19 adult patients admitted to 25 ICUs belonging to the COVID-19 VENETO ICU network (February 28th-April 28th, 2020), who received controlled mechanical ventilation, were screened. Only patients fulfilling ARDS criteria and with complete records of Crs, DP and VT/kg IBW within the 1st day of controlled mechanical ventilation were included. Crs, DP and VT/kg IBW were collected in sedated, paralyzed and supine patients. RESULTS: A total of 704 COVID-19 patients were screened and 241 enrolled. Seventy-one patients (29%) died in ICU. The logistic regression analysis showed that: (1) Crs was not linearly associated with ICU mortality (p value for nonlinearity = 0.01), with a greater risk of death for values < 48 ml/cmH2O; (2) the association between DP and ICU mortality was linear (p value for nonlinearity = 0.68), and increasing DP from 10 to 14 cmH2O caused significant higher odds of in-ICU death (OR 1.45, 95% CI 1.06-1.99); (3) VT/kg IBW was not associated with a significant increase of the risk of death (OR 0.92, 95% CI 0.55-1.52). Multivariable analysis confirmed these findings. CONCLUSIONS: Crs < 48 ml/cmH2O was associated with ICU mortality, while DP was linearly associated with mortality. DP should be kept as low as possible, even in the case of relatively preserved Crs, irrespective of VT/kg IBW, to reduce the risk of death.

Pacemaker implantation in a COVID-19 patient. Balancing the patient's needs and the team's risk of exposure.

COVID-19 patients may have cardiovascular complications requiring invasive treatment. Pacemaker implantation procedure may be challenging because of the necessity of personal protective equipment use. We report pacemaker implantation in a 78-year-old man with severe bilateral COVID-19 interstitial pneumonia, a second degree 2:1 atrioventricular block, and concomitant aortic stenosis.

COVID-19 ICU mortality prediction: a machine learning approach using SuperLearner algorithm.

BACKGROUND: Since the beginning of coronavirus disease 2019 (COVID-19), the development of predictive models has sparked relevant interest due to the initial lack of knowledge about diagnosis, treatment, and prognosis. The present study aimed at developing a model, through a machine learning approach, to predict intensive care unit (ICU) mortality in COVID-19 patients based on predefined clinical parameters. RESULTS: Observational multicenter cohort study. All COVID-19 adult patients admitted to 25 ICUs belonging to the VENETO ICU network (February 28th 2020-april 4th 2021) were enrolled. Patients admitted to the ICUs before 4th March 2021 were used for model training ("training set"), while patients admitted after the 5th of March 2021 were used for external validation ("test set 1"). A further group of patients ("test set 2"), admitted to the ICU of IRCCS Ca' Granda Ospedale Maggiore Policlinico of Milan, was used for external validation. A SuperLearner machine learning algorithm was applied for model development, and both internal and external validation was performed. Clinical variables available for the model were (i) age, gender, sequential organ failure assessment score, Charlson Comorbidity Index score (not adjusted for age), Palliative Performance Score; (ii) need of invasive mechanical ventilation, non-invasive mechanical ventilation, O2 therapy, vasoactive agents, extracorporeal membrane oxygenation, continuous venous-venous hemofiltration, tracheostomy, re-intubation, prone position during ICU stay; and (iii) re-admission in ICU. One thousand two hundred ninety-three (80%) patients were included in the "training set", while 124 (8%) and 199 (12%) patients were included in the "test set 1" and "test set 2," respectively. Three different predictive models were developed. Each model included different sets of clinical variables. The three models showed similar predictive performances, with a training balanced accuracy that ranged between 0.72 and 0.90, while the cross-validation performance ranged from 0.75 to 0.85. Age was the leading predictor for all the considered models. CONCLUSIONS: Our study provides a useful and reliable tool, through a machine learning approach, for predicting ICU mortality in COVID-19 patients. In all the estimated models, age was the variable showing the most important impact on mortality.

QOLEC2: a randomized controlled trial on nutritional and respiratory counseling after esophagectomy for cancer.

BACKGROUND: Esophagectomy for cancer strongly impairs quality of life. The aim of this trial was to evaluate the effect of the nutritional and respiratory counseling on postoperative quality of life. METHODS: At hospital discharge, patients were randomized into four groups receiving respectively: nutritional and respiratory counseling, nutritional counseling alone, respiratory counseling alone, or standard care. The main endpoint was the impairment in quality of life in the first month after surgery. Linear mixed effect models were estimated to assess mean score differences (MDs) in quality of life scores. RESULTS: Patients receiving nutritional counseling reported less appetite loss (MD - 17.7, 95% CI - 32.2 to -3.3) than those not receiving nutritional counseling at 1 month after surgery. Dyspnea was similar between patients receiving vs. those not receiving respiratory counseling (MD - 3.1, 95% CI - 10.8 to 4.6). Global quality of life was clinically similar between patients receiving vs. those not receiving nutritional counseling over time (MD 0.9, 95% CI - 5.5 to 7.3), as well as in patients receiving vs. those not receiving respiratory counseling over time (MD 0.7, 95% CI - 5.9 to 7.2). CONCLUSIONS: Intensive postoperative care does not affect global quality of life even if nutritional counseling reduced appetite loss.

Indications and timing for tracheostomy in patients with SARS CoV2-related.

BACKGROUND: The indications and timing for tracheostomy in patients with SARS CoV2-related are controversial. PURPOSE: In a recent issue published in the European Archives of Otorhinolaryngology, Mattioli et al. published a short communication about tracheostomy timing in patients with COVID-19 (Coronavirus Disease 2019); they reported that the tracheostomy could allow early Intensive Care Units discharge and, in the context of prolonged Invasive Mechanical Ventilation, should be suggested within 7 and 14 days to avoid potential tracheal damages. In this Letter to the Editor we would like to present our experience with tracheostomy in a Hub Covid Hospital. METHODS: 8 patients underwent open tracheostomy in case of intubation prolonged over 14 days, bronchopulmonary overlap infections, and patients undergoing weaning. They were followed up and the number and timing of death were recorded. RESULTS: Two patients died after tracheostomy; the median time between tracheostomy and death was 3 days. A negative prognostic trend was observed for a shorter duration of intubation. CONCLUSION: In our experience, tracheostomy does not seem to influence the clinical course and prognosis of the disease, in the face of possible risks of contagion for healthcare workers. The indication for tracheostomy in COVID-19 patients should be carefully evaluated and reserved for selected patients. Although it is not possible to define an optimal timing, it is our opinion that tracheostomy in a stable or clinically improved COVID-19 patient should not be proposed before the 20th day after orotracheal intubation.

Early Use of Etanercept for Graft-Versus-Host Disease After Liver Transplant: the Importance of Broad Spectrum Infective Prophylaxis.

Graft-versus-host-disease after orthotopic liver transplant is a rare and life-threatening complication. The diagnosis is challenging and usually confirmed by chimerism and skin biopsies. The most common cause of death is sepsis (60%), and broad-spectrum antibiotics and antifungal prophylaxis are strongly recommended. We present a case of a 61-year-old man with hepatocellular carcinoma and a previous history of metabolic and alcoholic cirrhosis who underwent orthotopic liver transplant. The immunosuppression regimen consisted of corticosteroids, calcineurin inhibitor, and mammalian target of rapamycin complex 1 inhibitor. Nine days after surgery, the patient developed leukopenia and skin rash. After confirmation of graft-versus-host disease by chimerism and skin biopsy, etanercept, a novel anti-tumor necrosis factor-alpha drug used for patients with hematologic and rheumatologic disease, was administrated. Unfortunately, no clinical improvements or bone marrow recovery were noted, and the patient had subsequent fatal sepsis due to Enterococcus faecium, Aspergillus fumigatus, and viral superinfection. There are no US Food and Drug Administration-approved treatments for graft-versus-host disease after orthotopic liver transplant. The main risk factors are recipients > 50 years old, patients with glucose intolerance, patients transplanted due to hepatocellular carcinoma, donor-recipient age difference of > 20 years, and any HLA-class I match. In accordance with the literature, we suggest early use of broad-spectrum antibiotics and antifungal drugs during etanercept treatment. In addition, because of substantially higher risk for severe sepsis, we strongly recommend adding an antiviral prophylaxis to prevent Cytomegalovirus reactivation or unexpected superinfection.

Pulse contour analysis of arterial waveform in a high fidelity human patient simulator.

The measurement of cardiac output (CO) may be useful to improve the assessment of hemodynamics during simulated scenarios. The purpose of this study was to evaluate the feasibility of introducing an uncalibrated pulse contour device (MostCare, Vytech, Vygon, Padova, Italy) into the simulation environment. MostCare device was plugged to a clinical monitor and connected to the METI human patient simulator (HPS) to obtain a continuous arterial waveform analysis and CO calculation. In six different simulated clinical scenarios (baseline, ventricular failure, vasoplegic shock, hypertensive crisis, hypovolemic shock and aortic stenosis), the HPS-CO and the MostCare-CO were simultaneously recorded. The level of concordance between the two methods was assessed by the Bland and Altman analysis. 150-paired CO values were obtained. The HPS-CO values ranged from 2.3 to 6.6 L min-1 and the MostCare-CO values from 2.8 to 6.4 L min-1. The mean difference between HPS-CO and MostCare-CO was - 0.3 L min-1 and the limits of agreement were - 1.5 and 0.9 L min-1. The percentage of error was 23%. A good correlation between HPS-CO and MostCare-CO was observed in each scenario of the study (r = 0.88). Although MostCare-CO tended to underestimate the CO over the study period, good agreements were found between the two methods. Therefore, a pulse contour device can be integrated into the simulation environment, offering the opportunity to create new simulated clinical settings.

Sugammadex for reversal of neuromuscular blockade: a retrospective analysis of clinical outcomes and cost-effectiveness in a single center.

OBJECTIVE: The aim of the study is to evaluate the clinical and economic impact of introducing a rocuronium-neostigmine-sugammadex strategy into a cisatracurium-neostigmine regimen for neuromuscular block (NMB) management. METHODS: We conducted a retrospective analysis of clinical outcomes and cost-effectiveness in five operating rooms at University Hospital of Padova. A clinical outcome evaluation after sugammadex administration as first-choice reversal drug in selected patients (rocuronium-sugammadex) and as rescue therapy after neostigmine reversal (rocuronium-neostigmine-sugammadex) compared to control was performed. A cost-analysis of NMB management accompanying the introduction of a rocuronium-neostigmine-sugammadex strategy into a cisatracurium-neostigmine regimen was carried out. To such purpose, two periods were compared: 2011-2012, without sugammadex available; 2013-2014, with sugammadex available. A subsequent analysis was performed to evaluate if sugammadex replacing neostigmine as first choice reversal drug is cost-effective. RESULTS: The introduction of a rocuronium-neostigmine-sugammadex strategy into a cisatracurium-neostigmine regimen reduced the average cost of NMB management by 36%, from €20.8/case to €13.3/case. Patients receiving sugammadex as a first-choice reversal drug (3%) exhibited significantly better train-of-four ratios at extubation (P<0.001) and were discharged to the surgical ward (P<0.001) more rapidly than controls. The cost-saving of sugammadex as first-choice reversal drug has been estimated to be €2.9/case. Patients receiving sugammadex as rescue therapy after neostigmine reversal (3.2%) showed no difference in time to discharge to the surgical ward (P=0.44) compared to controls. No unplanned intensive care unit (ICU) admissions with rocuronium-neostigmine-sugammadex strategy were observed. The potential economic benefit in avoiding postoperative residual curarization (PORC)-related ICU admission in the 2013-2014 period was estimated at an average value of €13,548 (€9,316-€23,845). CONCLUSION: Sugammadex eliminated PORC and associated morbidities. In our center, sugammadex reduced the costs of NMB management and promoted rapid turnover of patients in operating rooms, with total cost-effectiveness that counteracts the disadvantages of its high cost.

High-frequency percussive ventilation: a new strategy for separation from extracorporeal membrane oxygenation.

We report the case of a 48-year-old woman who developed severe septic shock and lung injury after community-acquired pneumonia. She was supported on arteriovenous extracorporeal membrane oxygenation (ECMO) for 19 days. To facilitate decannulation and separation from ECMO, we began trials of high-frequency percussive ventilation (HFPV) using the volumetric diffusive respiration ventilator VDR-4 (Percussionaire Corp, Sandpoint, Idaho) for 4 consecutive days (1 before and 3 after). Decannulation was achieved successfully, and the patient was transferred to the floor 3 months later. During the 4 days of HFPV, the chest radiograph improved, as did gas exchange and clearance of pulmonary secretions. HFPV may be a promising strategy for improving lung recruitment and airway clearance during separation from ECMO in the critically ill patient.

Sleep disturbances and quality of life in postoperative management after esophagectomy for esophageal cancer.

BACKGROUND: The aims of this prospective study were to analyze the predictors of postoperative sleep disturbance after esophagectomy for cancer and to identify patients at risk for postoperative hypnotic administration. METHODS: Sixty two consecutive patients who underwent cancer-related esophagectomy were enrolled in this study from May 2011 to February 2012. Data about perioperative management, postoperative complications, ICU stay, and vasopressor, hypnotic, and painkiller administration were retrieved. The EORTC QLQ-C30 was used and global quality of life (QL2 item) and sleep disturbance (SL item) were the primary endpoints. Univariate and multivariate analyses were performed. RESULTS: Postoperative request of hypnotics independently predicted bad quality of life outcome. Sleep disturbance after esophagectomy was independently predicted by the duration of dopamine infusion in the ICU and the daily request of benzodiazepines. Even in this case, only sleep disturbance at diagnosis revealed to be an independent predictor of hypnotic administration need. ROC curve analysis showed that sleep disturbance at diagnosis was a good predictor of benzodiazepine request (AUC = 73%, P = 0.02). CONCLUSIONS: The use of vasopressors in the ICU affects sleep in the following postoperative period and the use of hypnotics is neither completely successful nor lacking in possible consequences. Sleep disturbance at diagnosis can successfully predict patients who can develop sleep disturbance during the postoperative period.

Protein C concentrate to restore physiological values in adult septic patients.

OBJECTIVE: To describe the efficacy and safety of protein C (PC) concentrate to restore physiological values in adult septic patients having clinical contraindications to activated PC. DESIGN: Case series (pilot study). SETTING: Three adult ICUs of a University Hospital. PATIENTS AND PARTICIPANTS: Twenty adult patients affected by severe sepsis or septic shock with plasma values of PC < 50%. INTERVENTIONS: Patients were treated with PC concentrate (Ceprotin ((R))--Baxter) with a starting bolus followed by a continuous infusion for 72 h [3 IU/(kg h)]. MEASUREMENTS AND RESULTS: PC activity, WBC, platelets, D: -Dimer, fibrinogen, PT, aPTT, AT III, lactate, Sepsis-related Organ Failure Assessment (SOFA), Disseminated Intravascular Coagulation (DIC) score, adverse events, and mortality were measured. Baseline plasma PC activity was 34.5 +/- 9.1%. PC concentrate normalized the PC activity in all patients within 48 h, and then remained stable for the following days. At baseline, several patients showed abnormal PT, aPTT, platelets values, and lactate levels. During the study period, there was a significant increase of platelets, fibrinogen, PT, AT III, and a significant decrease of D: -Dimer, aPTT, DIC score, and lactate. No adverse reactions (hemorrhage or thrombosis) were observed. Mortality at 28 days was 35%. CONCLUSIONS: Our pilot study shows that the administration of PC concentrate to patients having contraindications to the treatment with activated PC was safe and possibly useful to control the coagulopathy triggered and sustained by sepsis. A randomized, double blind study in patients with severe sepsis and contraindications to activated PC administration would be advisable to state the safety and the possible role of this product in the treatment of severe sepsis.