Nosocomial Infections During Extracorporeal Membrane Oxygenation: Incidence, Etiology, and Impact on Patients' Outcome.

OBJECTIVE: To study incidence, type, etiology, risk factors, and impact on outcome of nosocomial infections during extracorporeal membrane oxygenation. DESIGN: Retrospective analysis of prospectively collected data. SETTING: Italian tertiary referral center medical-surgical ICU. PATIENTS: One hundred five consecutive patients who were treated with extracorporeal membrane oxygenation from January 2010 to November 2015. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Ninety-two patients were included in the analysis (48.5 [37-56] years old, simplified acute physiology score II 37 [32-47]) who underwent peripheral extracorporeal membrane oxygenation (87% veno-venous) for medical indications (78% acute respiratory distress syndrome). Fifty-two patients (55%) were infected (50.4 infections/1,000 person-days of extracorporeal membrane oxygenation). We identified 32 ventilator-associated pneumonia, eight urinary tract infections, five blood stream infections, three catheter-related blood stream infections, two colitis, one extracorporeal membrane oxygenation cannula infection, and one pulmonary-catheter infection. G+ infections (35%) occurred earlier compared with G- (48%) (4 [2-10] vs. 13 [7-23] days from extracorporeal membrane oxygenation initiation; p < 0.001). Multidrug-resistant organisms caused 56% of bacterial infections. Younger age (2-35 years old) was independently associated with higher risk for nosocomial infections. Twenty-nine patients (31.5%) died (13.0 deaths/1,000 person-days of extracorporeal membrane oxygenation). Infected patients had higher risk for death (18 vs. 8 deaths/1,000 person-days of extracorporeal membrane oxygenation; p = 0.037) and longer ICU stay (32.5 [19.5-78] vs. 19 [10.5-27.5] days; p = 0.003), mechanical ventilation (36.5 [20-80.5] vs. 16.5 [9-25.5] days; p < 0.001), and extracorporeal membrane oxygenation (25.5 [10.75-54] vs. 10 [5-13] days; p < 0.001). Older age (> 50 years old), reason for connection different from acute respiratory distress syndrome, higher simplified acute physiology score II, diagnosis of ventilator-associated pneumonia, and infection by multidrug-resistant bacteria were independently associated to increased death rate. CONCLUSIONS: Infections (especially ventilator-associated pneumonia) during extracorporeal membrane oxygenation therapy are common and frequently involve multidrug-resistant organisms. In addition, they have a negative impact on patients' outcomes.

ECMO for intractable status asthmaticus following atracurium.

Intraoperative allergic reactions are rare but serious events associated with increased morbidity and mortality. We report the salvage of intraoperative anaphylaxis leading to extreme hypercapnic respiratory failure by veno-venous extracorporeal membrane oxygenation (ECMO). A 38-year-old woman undergoing thyroidectomy developed intractable bronchospasm after administration of atracurium, leading to extreme hypercapnic respiratory failure (PaCO2 > 250 mmHg, pH 6.773). After the failure of conventional medical therapy and ventilatory optimization, the patient was connected to a veno-venous ECMO circuit. PaCO2 of 45.6 mmHg and pH of 7.25 were achieved in 1 h, by slowly increasing sweep gas flows up to 3.5 L/min and using continuous end-tidal CO2 monitoring to gauge the procedure. After extubation and disconnection from ECMO, the patient was discharged on the 6th day without sequelae. Rapid reversal of extreme hypercapnic acidosis by ECMO was feasible, without any neurologic sequelae. Veno-venous ECMO support may be a valuable option for the salvage of intraoperative anaphylaxis.

Alveolar pentraxin 3 as an early marker of microbiologically confirmed pneumonia: a threshold-finding prospective observational study.

INTRODUCTION: Timely diagnosis of pneumonia in intubated critically ill patients is rather challenging. Pentraxin 3 (PTX3) is an acute-phase mediator produced by various cell types in the lungs. Animal studies have shown that, during pneumonia, PTX3 participates in fine-tuning of inflammation (for example, microbial clearance and recruitment of neutrophils). We previously described an association between alveolar PTX3 and lung infection in a small group of intubated patients. The aim of the present study was to determine a threshold level of alveolar PTX3 with elevated sensitivity and specificity for microbiologically confirmed pneumonia. METHODS: We recruited 82 intubated patients from two intensive care units (San Gerardo Hospital, Monza, Italy, and Massachusetts General Hospital, Boston, MA, USA) undergoing bronchoalveolar lavage (BAL) as per clinical decision. We collected BAL fluid and plasma samples, together with relevant clinical and microbiological data. We assayed PTX3 and soluble triggering receptor expressed on myeloid cells 1 (sTREM-1) in BAL fluid and PTX3, sTREM-1, C-reactive protein (CRP) and procalcitonin (PCT) in plasma. Two blinded independent physicians reviewed patient data to confirm pneumonia. We determined the PTX3 threshold in BAL fluid for pneumonia and compared it to other biomarkers. RESULTS: Microbiologically confirmed pneumonia of bacterial (n =12), viral (n =4) or fungal (n =8) etiology was diagnosed in 24 patients (29%). PTX3 levels in BAL fluid predicted pneumonia with an area under the receiving operator curve of 0.815 (95% CI =0.710 to 0.921, P <0.0001), whereas none of the other biomarkers were effective. In particular, PTX3 levels ≥1 ng/ml in BAL fluid predicted pneumonia in univariate analysis (ß =2.784, SE =0.792, P <0.001) with elevated sensitivity (92%), specificity (60%) and negative predictive value (95%). Net reclassification index PTX3 values ≥1 ng/ml in BAL fluid for pneumonia indicated gain in sensitivity and/or specificity vs. all other mediators. These results did not change when we limited our analyses only to confirmed cases of bacterial pneumonia. Moreover, when we considered only the 70 patients who fulfilled the clinical criteria for the diagnosis of pneumonia at BAL fluid sampling, the diagnostic accuracy of PTX levels was confirmed in univariate and ROC curve analysis. CONCLUSIONS: In this hypothesis-generating convenience sample, a PTX3 level ≥1 ng/ml in BAL fluid was discriminative of microbiologically confirmed pneumonia in mechanically ventilated patients.

Computer clinical decision support that automates personalized clinical care: a challenging but needed healthcare delivery strategy.

How to deliver best care in various clinical settings remains a vexing problem. All pertinent healthcare-related questions have not, cannot, and will not be addressable with costly time- and resource-consuming controlled clinical trials. At present, evidence-based guidelines can address only a small fraction of the types of care that clinicians deliver. Furthermore, underserved areas rarely can access state-of-the-art evidence-based guidelines in real-time, and often lack the wherewithal to implement advanced guidelines. Care providers in such settings frequently do not have sufficient training to undertake advanced guideline implementation. Nevertheless, in advanced modern healthcare delivery environments, use of eActions (validated clinical decision support systems) could help overcome the cognitive limitations of overburdened clinicians. Widespread use of eActions will require surmounting current healthcare technical and cultural barriers and installing clinical evidence/data curation systems. The authors expect that increased numbers of evidence-based guidelines will result from future comparative effectiveness clinical research carried out during routine healthcare delivery within learning healthcare systems.

COVID-19-associated immune-mediated encephalitis mimicking acute-onset Creutzfeldt-Jakob disease.

We report a subtype of immune-mediated encephalitis associated with COVID-19, which closely mimics acute-onset sporadic Creutzfeldt-Jakob disease. A 64-year-old man presented with confusion, aphasia, myoclonus, and a silent interstitial pneumonia. He tested positive for SARS-CoV-2. Cognition and myoclonus rapidly deteriorated, EEG evolved to generalized periodic discharges and brain MRI showed multiple cortical DWI hyperintensities. CSF analysis was normal, except for a positive 14-3-3 protein. RT-QuIC analysis was negative. High levels of pro-inflammatory cytokines were present in the CSF and serum. Treatment with steroids and intravenous immunoglobulins produced EEG and clinical improvement, with a good neurological outcome at a 6-month follow-up.

Enabling a learning healthcare system with automated computer protocols that produce replicable and personalized clinician actions.

Clinical decision-making is based on knowledge, expertise, and authority, with clinicians approving almost every intervention-the starting point for delivery of "All the right care, but only the right care," an unachieved healthcare quality improvement goal. Unaided clinicians suffer from human cognitive limitations and biases when decisions are based only on their training, expertise, and experience. Electronic health records (EHRs) could improve healthcare with robust decision-support tools that reduce unwarranted variation of clinician decisions and actions. Current EHRs, focused on results review, documentation, and accounting, are awkward, time-consuming, and contribute to clinician stress and burnout. Decision-support tools could reduce clinician burden and enable replicable clinician decisions and actions that personalize patient care. Most current clinical decision-support tools or aids lack detail and neither reduce burden nor enable replicable actions. Clinicians must provide subjective interpretation and missing logic, thus introducing personal biases and mindless, unwarranted, variation from evidence-based practice. Replicability occurs when different clinicians, with the same patient information and context, come to the same decision and action. We propose a feasible subset of therapeutic decision-support tools based on credible clinical outcome evidence: computer protocols leading to replicable clinician actions (eActions). eActions enable different clinicians to make consistent decisions and actions when faced with the same patient input data. eActions embrace good everyday decision-making informed by evidence, experience, EHR data, and individual patient status. eActions can reduce unwarranted variation, increase quality of clinical care and research, reduce EHR noise, and could enable a learning healthcare system.

Elevated plasma and alveolar levels of soluble receptor for advanced glycation endproducts are associated with severity of lung dysfunction in ARDS patients.

Acute lung injury and acute respiratory distress syndrome (ALI/ARDS) are severe forms of bilateral lung inflammation with poor clinical outcomes. However, the pathophysiology of ALI/ARDS remains largely obscure. Soluble receptor for advanced glycation endproducts (sRAGE) plays a key regulatory role during the acute phase of inflammation, and baseline plasma levels of sRAGE were recently found to be associated with severity of ALI/ARDS. We analyzed, in ALI/ARDS patients, plasma and alveolar levels of sRAGE over time and the association with severity of lung injury. We enrolled 21 ALI/ARDS patients admitted to our intensive care unit (ICU) and assayed plasma sRAGE on the first 2 days after diagnosis, every three days for the first month and then once a week, until ICU discharge or death. We also measured sRAGE levels in bronchoalveolar lavage fluids, obtained when clinically indicated. At each sampling time, we recorded physiological and clinical data of the patients. Plasma sRAGE levels peaked at day 1 and decreased over time. When all samples were considered, plasma and alveolar sRAGE levels were significantly higher in patients with worse oxygenation and higher need for ventilatory support (i.e., patients with more severe lung dysfunction). Moreover, the presence of lung infection yielded higher alveolar sRAGE levels. In conclusion, we show that the plasma and alveolar levels of sRAGE in ALI/ARDS patients are correlated to lung injury severity and to lung infection. Our findings may, in time, lead to the development of more effective therapies against ALI/ARDS.

Remdesivir Use in Patients Requiring Mechanical Ventilation due to COVID-19.

BACKGROUND: Remdesivir has been associated with accelerated recovery of severe coronavirus disease 2019 (COVID-19). However, whether it is also beneficial in patients requiring mechanical ventilation is uncertain. METHODS: All consecutive intensive care unit (ICU) patients requiring mechanical ventilation due to COVID-19 were enrolled. Univariate and multivariable Cox models were used to explore the possible association between in-hospital death or hospital discharge, considered competing-risk events, and baseline or treatment-related factors, including the use of remdesivir. The rate of extubation and the number of ventilator-free days were also calculated and compared between treatment groups. RESULTS: One hundred thirteen patients requiring mechanical ventilation were observed for a median of 31 days of follow-up; 32% died, 69% were extubated, and 66% were discharged alive from the hospital. Among 33 treated with remdesivir (RDV), lower mortality (15.2% vs 38.8%) and higher rates of extubation (88% vs 60%), ventilator-free days (median [interquartile range], 11 [0-16] vs 5 [0-14.5]), and hospital discharge (85% vs 59%) were observed. Using multivariable analysis, RDV was significantly associated with hospital discharge (hazard ratio [HR], 2.25; 95% CI, 1.27-3.97; P = .005) and with a nonsignificantly lower mortality (HR, 0.73; 95% CI, 0.26-2.1; P = .560). RDV was also independently associated with extubation (HR, 2.10; 95% CI, 1.19-3.73; P = .011), which was considered a competing risk to death in the ICU in an additional survival model. CONCLUSIONS: In our cohort of mechanically ventilated patients, RDV was not associated with a significant reduction of mortality, but it was consistently associated with shorter duration of mechanical ventilation and higher probability of hospital discharge, independent of other risk factors.

Gastrointestinal colonization with multidrug-resistant Gram-negative bacteria during extracorporeal membrane oxygenation: effect on the risk of subsequent infections and impact on patient outcome.

BACKGROUND: In ICU patients, digestive tract colonization by multidrug-resistant (MDR) Gram-negative (G-) bacteria is a significant risk factor for the development of infections. In patients undergoing extracorporeal membrane oxygenation (ECMO), colonization by MDR bacteria and risk of subsequent nosocomial infections (NIs) have not been studied yet. The aim of this study is to evaluate the incidence, etiology, risk factors, impact on outcome of gastrointestinal colonization by MDR G- bacteria, and risk of subsequent infections in patients undergoing ECMO. METHODS: This is a retrospective analysis of prospectively collected data: 105 consecutive patients, treated with ECMO, were admitted to the ICU of an Italian tertiary referral center (San Gerardo Hospital, Monza, Italy) from January 2010 to November 2015. Rectal swabs for MDR G- bacteria were cultured at admission and twice a week. Only colonization and NIs by MDR G- bacteria were analyzed. RESULTS: Ninety-one included patients [48.5 (37-56) years old, 63% male, simplified acute physiology score II 37 (32-47)] underwent peripheral ECMO (87% veno-venous) for medical indications (79% ARDS). Nineteen (21%) patients were colonized by MDR G- bacteria. Male gender (OR 4.03, p = 0.029) and duration of mechanical ventilation (MV) before ECMO > 3 days (OR 3.57, p = 0.014) were associated with increased risk of colonization. Colonized patients had increased odds of infections by the colonizing germs (84% vs. 29%, p < 0.001, OR 12.9), longer ICU length of stay (LOS) (43 vs. 24 days, p = 0.002), MV (50 vs. 22 days, p < 0.001) and ECMO (28 vs. 12 days, p < 0.001), but did not have higher risk of death (survival rate 58% vs. 67%, p = 0.480, OR 0.68). Infected patients had almost halved ICU survival (46% vs. 78%, p < 0.001, OR 4.11). CONCLUSIONS: In patients undergoing ECMO for respiratory and/or circulatory failure, colonization by MDR G- bacteria is frequent and associated with more the tenfold odds for subsequent infection. Those infections are associated with an increased risk of death.

Pentraxin 3 in acute respiratory distress syndrome: an early marker of severity.

OBJECTIVE: Pentraxin 3 is a fluid phase receptor involved in innate immunity. It belongs to the Pentraxins family, as C-reactive protein does. Pentraxin 3 is produced by a variety of tissue cells, whereas only the liver produces C-reactive protein. Pentraxin 3 plays a unique role in the regulation of inflammation. Acute lung injury and acute respiratory distress syndrome are characterized by an important inflammatory reaction. We investigated the role of pentraxin 3 as a marker of severity and outcome predictor of acute lung injury and acute respiratory distress syndrome. DESIGN: We measured circulating pentraxin 3 and C-reactive protein levels within 24 hrs from intubation (day 1), after 24 hrs from the first sample, then every 3 days for the first month and then once a week, until discharge from the intensive care unit. Pentraxin 3 was also measured in bronchoalveolar lavages, performed when clinically indicated. SETTING: One university medical center general intensive care unit. PATIENTS: The study included 21 patients affected by acute lung injury and acute respiratory distress syndrome (1994 Consensus Conference criteria). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Pentraxin 3 plasma levels were high with a peak on the first day (median 71.05 ng/mL, interquartile range 52.37-117.38 ng/mL, normal values <2 ng/mL), declining thereafter. C-reactive protein peaked later and remained at relatively high values. Out of several day 1 parameters, pentraxin 3 was the only significant difference between survivors and nonsurvivors. Pentraxin 3 levels were positively correlated with lung injury score values (p < 0.001) and number of organ failures (p < 0.001). Pentraxin 3 was present in bronchoalveolar lavages fluids (5.03 ng/mL, interquartile range 1.52-8.48 ng/mL) and bronchoalveolar lavages positive to bacterial culture were associated with significantly higher pentraxin 3 values (p < 0.05). CONCLUSIONS: The results presented here show that pentraxin 3 is elevated in acute lung injury and acute respiratory distress syndrome and that its levels correlate with parameters of lung injury and systemic involvement. The clinical and pathophysiological significance of pentraxin 3 in acute lung injury and acute respiratory distress syndrome deserves further scrutiny.

A mathematical model of oxygenation during venovenous extracorporeal membrane oxygenation support.

PURPOSE: To develop a mathematical model of oxygenation during venovenous extracorporeal membrane oxygenation (vv-ECMO). MATERIAL AND METHODS: Total oxygen consumption, cardiac output, blood flow, recirculation, intrapulmonary shunt, hemoglobin, natural lung, and membrane lung oxygen fractions were chosen as inputs. Content, partial pressure, and hemoglobin saturation of oxygen in arterial, venous, pulmonary, and extracorporeal blood were outputs. To assess accuracy and predictive power of the model, we retrospectively analyzed data of 25 vv-ECMO patients. We compiled 2 software (with numerical, 2D and 3D graphical outputs) to study the impact of each variable on oxygenation. RESULTS: The model showed high accuracy and predictive power. Raising blood flow and oxygen fraction to the membrane lung or reducing total oxygen consumption improves arterial and venous oxygenation, especially in severe cases; raising oxygen fraction to the natural lung improves oxygenation only in milder cases; raising hemoglobin always improves oxygenation, especially in the venous district; recirculation fraction severely impairs oxygenation. In severely ill patients, increasing cardiac output worsens arterial oxygenation but enhances venous oxygenation. Oxygen saturation of ECMO inlet is critical to evaluate the appropriateness of oxygen delivery. CONCLUSIONS: The model with the software can be a useful teaching tool and a valuable decision-making aid for the management of hypoxic patients supported by vv-ECMO.

Use of extracorporeal respiratory support during pregnancy: a case report and literature review.

We describe the case of a 25 year-old woman at 27 weeks of gestation who was admitted to our intensive care unit (ICU) for acute respiratory distress syndrome (ARDS) caused by pandemic 2009 H1N1 influenza A. She presented with septic shock and refractory hypoxemia unresponsive to rescue therapies such as recruitment maneuvers, prone positioning, and nitric oxide inhalation. Extracorporeal membrane oxygenation (ECMO) for respiratory support was instituted, and the patient's clinical conditions progressively improved: she was extubated after 16 days and discharged from the ICU 3 days later. No fetal complications were observed. At 38 weeks of gestation she gave birth to a healthy baby.

Bronchopleural fistulae and pulmonary ossification in posttraumatic acute respiratory distress syndrome: successful treatment with extracorporeal support.

We report a case of severe posttraumatic acute respiratory distress syndrome (ARDS) complicated by bronchopleural fistulae (BPF). The stiff ARDS lung and huge air leaks from BPF resulted in the failure of different protective mechanical ventilation strategies to provide viable gas exchange. Lung rest, achieved by extracorporeal carbon dioxide removal (ECCO2R), allowed weaning from mechanical ventilation, closure of BPF, and resumption of spontaneous breathing.

Extracorporeal membrane oxygenation for interhospital transfer of severe acute respiratory distress syndrome patients: 5-year experience.

PURPOSE: Transfer of severely hypoxic patients is a high-risk procedure. Extracorporeal membrane oxygenation (ECMO) allows safe transport of these patients to tertiary care institutions. Our ECMO transportation program was instituted in 2004; here we report results after 5 years of activity. METHODS: This is a clinical observational study. Criteria for ECMO center activation were: potentially reversibile respiratory failure, PaO2 <50 mmHg with FiO2 >0.6 for >12 hours, PEEP >5 cmH20, Lung Injury Score (LIS) ≥3 or respiratory acidosis with pH <7.2, no intracranial bleeding, and no absolute contraindication to anticoagulation. If eligible, a skilled crew applied ECMO at the referral hospital. Transportation was performed with a specially equipped ambulance. RESULTS: Sixteen patients were possible candidates for ECMO transfer. Two patients were excluded while 14 (mean±SD, age 35.4±18.6, SOFA 8.4±3.7, Oxygenation Index 43.7±13.4) were transported to our institution (distance covered 102±114 km, global duration of transport 589±186 minutes). Two patients improved after iNO-trial and were transferred and subsequently managed without ECMO. The remaining 12 patients were transferred on veno-venous ECMO with extracorporeal blood flow 2.7±1 L·min⁻¹, gas flow 3.8±1.8 L·min⁻¹, and FiO2 1. Data were recorded 30 minutes before and 60 minutes after initiation of ECMO. ECMO improved PCO2 (75±23 vs. 53±9 mmHg, p<0.01) thus improving pH (7.28±0.13 vs. 7.39±0.05, p<0.01) and allowing a reduction in respiratory rate (35±14 vs. 10±4 breaths/min, p<0.01), minute ventilation (10.1±3.8 vs. 3.7±1.7 L·min⁻¹, p<0.01), and mean airway pressure (26±6.5 vs. 22±5 cmH2O, p<0.01). No major clinical or technical complications were observed. CONCLUSIONS: ECMO effectively enabled high-risk ground transfer of severely hypoxic patients.