Calcium-Citrate Anticoagulation during Continuous Renal Replacement Therapy in Patients with Metformin Intoxication: A Case Series, Mathematical Estimation of Citrate Accumulation, and Literature Review.

INTRODUCTION: Metformin intoxication causes lactic acidosis by inhibiting Krebs' cycle and oxidative phosphorylation. Continuous renal replacement therapy (CRRT) is recommended for metformin removal in critically ill patients. According to current guidelines, regional citrate anticoagulation (RCA) is the first-line strategy. However, since metformin also inhibits citrate metabolism, a risk of citrate accumulation could be hypothesized. In the present study, we monitored the potential citrate accumulation in metformin-associated lactic acidosis (MALA) patients treated with CRRT and RCA using the physical-chemical approach to acid-base interpretation. METHODS: We collected a case series of 3 patients with MALA. Patients were treated with continuous venovenous hemofiltration (CVVH), and RCA was performed with diluted citrate solution. Citrate accumulation was monitored through two methods: the ratio between total and ionized plasma calcium concentrations (T/I calcium ratio) above 2.5 and the strong ion gap (SIG) to identify an increased concentration of unmeasured anions. Lastly, a mathematical model was developed to estimate the expected citrate accumulation during CVVH and RCA. RESULTS: All 3 patients showed a resolution of MALA after the treatment with CVVH. The T/I calcium ratio was consistently below 2.5, and SIG decreased, reaching values lower than 6 mEq/L after 48 h of CVVH treatment. According to the mathematical model, the estimated SIG without citrate metabolism should have been around 21 mEq/L due to citrate accumulation. CONCLUSIONS: In our clinical management, no signs of citrate accumulation were recorded in MALA patients during treatment with CVVH and RCA. Our data support the safe use of diluted citrate to perform RCA during metformin intoxication.

Detection of patients with COVID-19 by the emergency medical services in Lombardy through an operator-based interview and machine learning models.

BACKGROUND: The regional emergency medical service (EMS) in Lombardy (Italy) developed clinical algorithms based on operator-based interviews to detect patients with COVID-19 and refer them to the most appropriate hospitals. Machine learning (ML)-based models using additional clinical and geospatial epidemiological data may improve the identification of infected patients and guide EMS in detecting COVID-19 cases before confirmation with SARS-CoV-2 reverse transcriptase PCR (rtPCR). METHODS: This was an observational, retrospective cohort study using data from October 2020 to July 2021 (training set) and October 2021 to December 2021 (validation set) from patients who underwent a SARS-CoV-2 rtPCR test within 7 days of an EMS call. The performance of an operator-based interview using close contact history and signs/symptoms of COVID-19 was assessed in the training set for its ability to determine which patients had an rtPCR in the 7 days before or after the call. The interview accuracy was compared with four supervised ML models to predict positivity for SARS-CoV-2 within 7 days using readily available prehospital data retrieved from both training and validation sets. RESULTS: The training set includes 264 976 patients, median age 74 (IQR 55-84). Test characteristics for the detection of COVID-19-positive patients of the operator-based interview were: sensitivity 85.5%, specificity 58.7%, positive predictive value (PPV) 37.5% and negative predictive value (NPV) 93.3%. Contact history, fever and cough showed the highest association with SARS-CoV-2 infection. In the validation set (103 336 patients, median age 73 (IQR 50-84)), the best-performing ML model had an AUC of 0.85 (95% CI 0.84 to 0.86), sensitivity 91.4% (95 CI% 0.91 to 0.92), specificity 44.2% (95% CI 0.44 to 0.45) and accuracy 85% (95% CI 0.84 to 0.85). PPV and NPV were 13.3% (95% CI 0.13 to 0.14) and 98.2% (95% CI 0.98 to 0.98), respectively. Contact history, fever, call geographical distribution and cough were the most important variables in determining the outcome. CONCLUSION: ML-based models might help EMS identify patients with SARS-CoV-2 infection, and in guiding EMS allocation of hospital resources based on prespecified criteria.

How the Italian Formula 1 Grand Prix 2022 Mass Gathering Event Compares to the Arbon Model: A Descriptive Study.

OBJECTIVE: To describe the health-care resources implemented during the Italian Formula 1 Grand Prix (F1GP) and to calculate the patient presentation rate (PPR) based on both real data and a prediction model. METHODS: Observational and descriptive study conducted from September 9 to September 11, 2022, during the Italian F1GP hosted in Monza (Italy). Maurer's formula was applied to decide the number and type of health resources to be allocated. Patient presentation rate (PPR) was computed based on real data (PPR_real) and based on the Arbon formula (PPR_est). RESULTS: Of 336,000 attendees, n = 263 requested medical assistance with most of them receiving treatment at the advanced medical post, and n = 16 needing transport to the hospital. The PPR_real was 51 for Friday, 78 for Saturday, 134 for Sunday, and 263 when considering the whole event as a single event. The PPR_est resulted in 85 for Friday, 93 for Saturday, 97 for Sunday, and 221 for the total population. CONCLUSIONS: A careful organization of health-care resources could mitigate the impact of the Italian F1GP on local hospital facilities. The Arbon formula is an acceptable model to predict and estimate the number of patients requesting medical assistance, but further investigation needs to be conducted to implement the model and tailor it to broader categories of MGE.

PEEP Titration Is Markedly Affected by Trunk Inclination in Mechanically Ventilated Patients with COVID-19 ARDS: A Physiologic, Cross-Over Study.

BACKGROUND: Changing trunk inclination affects lung function in patients with ARDS. However, its impacts on PEEP titration remain unknown. The primary aim of this study was to assess, in mechanically ventilated patients with COVID-19 ARDS, the effects of trunk inclination on PEEP titration. The secondary aim was to compare respiratory mechanics and gas exchange in the semi-recumbent (40° head-of-the-bed) and supine-flat (0°) positions following PEEP titration. METHODS: Twelve patients were positioned both at 40° and 0° trunk inclination (randomized order). The PEEP associated with the best compromise between overdistension and collapse guided by Electrical Impedance Tomography (PEEPEIT) was set. After 30 min of controlled mechanical ventilation, data regarding respiratory mechanics, gas exchange, and EIT parameters were collected. The same procedure was repeated for the other trunk inclination. RESULTS: PEEPEIT was lower in the semi-recumbent than in the supine-flat position (8 ± 2 vs. 13 ± 2 cmH2O, p < 0.001). A semi-recumbent position with optimized PEEP resulted in higher PaO2:FiO2 (141 ± 46 vs. 196 ± 99, p = 0.02) and a lower global inhomogeneity index (46 ± 10 vs. 53 ± 11, p = 0.008). After 30 min of observation, a loss of aeration (measured by EIT) was observed only in the supine-flat position (-153 ± 162 vs. 27 ± 203 mL, p = 0.007). CONCLUSIONS: A semi-recumbent position is associated with lower PEEPEIT and results in better oxygenation, less derecruitment, and more homogenous ventilation compared to the supine-flat position.

Modulation of pulmonary blood flow in patients with acute respiratory failure.

BACKGROUND: Impairment of ventilation and perfusion (V/Q) matching is a common mechanism leading to hypoxemia in patients with acute respiratory failure requiring intensive care unit (ICU) admission. While ventilation has been thoroughly investigated, little progress has been made to monitor pulmonary perfusion at the bedside and treat impaired blood distribution. The study aimed to assess real-time changes in regional pulmonary perfusion in response to a therapeutic intervention. METHODS: Single-center prospective study that enrolled adult patients with ARDS caused by SARS-Cov-2 who were sedated, paralyzed, and mechanically ventilated. The distribution of pulmonary perfusion was assessed through electrical impedance tomography (EIT) after the injection of a 10-ml bolus of hypertonic saline. The therapeutic intervention consisted in the administration of inhaled nitric oxide (iNO), as rescue therapy for refractory hypoxemia. Each patient underwent two 15-min steps at 0 and 20 ppm iNO, respectively. At each step, respiratory, gas exchange, and hemodynamic parameters were recorded, and V/Q distribution was measured, with unchanged ventilatory settings. RESULTS: Ten 65 [56-75] years old patients with moderate (40%) and severe (60%) ARDS were studied 10 [4-20] days after intubation. Gas exchange improved at 20 ppm iNO (PaO2/FiO2 from 86 ± 16 to 110 ± 30 mmHg, p = 0.001; venous admixture from 51 ± 8 to 45 ± 7%, p = 0.0045; dead space from 29 ± 8 to 25 ± 6%, p = 0.008). The respiratory system's elastic properties and ventilation distribution were unaltered by iNO. Hemodynamics did not change after gas initiation (cardiac output 7.6 ± 1.9 vs. 7.7 ± 1.9 L/min, p = 0.66). The EIT pixel perfusion maps showed a variety of patterns of changes in pulmonary blood flow, whose increase positively correlated with PaO2/FiO2 increase (R2 = 0.50, p = 0.049). CONCLUSIONS: The assessment of lung perfusion is feasible at the bedside and blood distribution can be modulated with effects that are visualized in vivo. These findings might lay the foundations for testing new therapies aimed at optimizing the regional perfusion in the lungs.

Potentiometric MIP-Modified Screen-Printed Cell for Phenoxy Herbicides Detection.

In this study, a molecularly imprinted polymer (MIP)-based screen-printed cell is developed for detecting phenoxy herbicides using 2-methyl-4-chlorophenoxyacetic acid (MCPA) as the template. MCPA is a phenoxy herbicide widely used since 1945 to control broadleaf weeds via growth regulation, primarily in pasture and cereal crops. The potentiometric cell consists of a silver/silver chloride pseudo-reference electrode and a graphite working electrode coated with a MIP film. The polymeric layer is thermally formed after drop-coating of a pre-polymeric mixture composed of the reagents at the following molar ratio: 1 MCPA: 15 MAA (methacrylic acid): 7 EGDMA (ethylene glycol dimethacrylate). After template removal, the recognition cavities function as the ionophore of a classical ion selective electrode (ISE) membrane. The detected ion is the deprotonated MCPA specie, negatively charged, so the measurements were performed in phosphate buffer at pH 5.5. A linear decrease of the potential with MCPA concentration, ranging from 4 × 10-8 to 1 × 10-6 mol L-1, was obtained. The detection limit and the limit of quantification were, respectively, 10 nmol L-1 and 40 nmol L-1. A Nernstian slope of about -59 mV/dec was achieved. The method has precision and LOD required for MCPA determination in contaminated environmental samples.

Intravenous fluid therapy in patients with severe acute pancreatitis admitted to the intensive care unit: a narrative review.

Patients with acute pancreatitis (AP) often require ICU admission, especially when signs of multiorgan failure are present, a condition that defines AP as severe. This disease is characterized by a massive pancreatic release of pro-inflammatory cytokines that causes a systemic inflammatory response syndrome and a profound intravascular fluid loss. This leads to a mixed hypovolemic and distributive shock and ultimately to multiorgan failure. Aggressive fluid resuscitation is traditionally considered the mainstay treatment of AP. In fact, all available guidelines underline the importance of fluid therapy, particularly in the first 24-48 h after disease onset. However, there is currently no consensus neither about the type, nor about the optimal fluid rate, total volume, or goal of fluid administration. In general, a starting fluid rate of 5-10 ml/kg/h of Ringer's lactate solution for the first 24 h has been recommended. Fluid administration should be aggressive in the first hours, and continued only for the appropriate time frame, being usually discontinued, or significantly reduced after the first 24-48 h after admission. Close clinical and hemodynamic monitoring along with the definition of clear resuscitation goals are fundamental. Generally accepted targets are urinary output, reversal of tachycardia and hypotension, and improvement of laboratory markers. However, the usefulness of different endpoints to guide fluid therapy is highly debated. The importance of close monitoring of fluid infusion and balance is acknowledged by most available guidelines to avoid the deleterious effect of fluid overload. Fluid therapy should be carefully tailored in patients with severe AP, as for other conditions frequently managed in the ICU requiring large fluid amounts, such as septic shock and burn injury. A combination of both noninvasive clinical and invasive hemodynamic parameters, and laboratory markers should guide clinicians in the early phase of severe AP to meet organ perfusion requirements with the proper administration of fluids while avoiding fluid overload. In this narrative review the most recent evidence about fluid therapy in severe AP is discussed and an operative algorithm for fluid administration based on an individualized approach is proposed.

Acute perchloroethylene intoxication in an elderly woman: a case report.

BACKGROUND: Perchloroethylene is a colorless, strong-smelling substance commonly used for dry cleaning. Liver and kidney toxicities and carcinogenicity are well-known occupational hazards caused by chronic perchloroethylene exposure. Acute intoxication by ingestion of nondiluted perchloroethylene is rare in the adult population owing to its strong smell and taste. Very few data are available to physicians managing patients in this situation. CASE PRESENTATION: An 89-year-old Caucasian woman accidentally drank perchloroethylene while visiting her laundry, leading to a coma within a few minutes. The poison control center provided little information about perchloroethylene toxicity after ingestion, including an estimated long biological half-life (144 hour) and detrimental effects to liver and kidneys. A long intensive care unit stay was thus expected, potentially leading to several complications. After intubation, transitory hypoxemia appeared and rapidly resolved, while mild hemodynamic instability was managed with fluid resuscitation and anti-arrhythmic drugs. Twelve hours after perchloroethylene ingestion, the patient suddenly woke up and self-extubated. Less than 24 hours after ingestion, she was discharged from the intensive care unit, and 4 days later she was discharged home. CONCLUSION: The patient drank perchloroethylene from a bottle, which prevented her from smelling it, and owing to its taste, only a small sip was likely drunk. However, a much larger intake was presumed, given her rapid and profound central nervous system depression. This case was challenging owing to the paucity of information available regarding acute perchloroethylene ingestion and the duration and magnitude of its effect. The present report will hopefully be of support for clinicians managing patients with this rare acute intoxication.

External chest-wall compression in prolonged COVID-19 ARDS with low-compliance: a physiological study.

BACKGROUND: External chest-wall compression (ECC) is sometimes used in ARDS patients despite lack of evidence. It is currently unknown whether this practice has any clinical benefit in patients with COVID-19 ARDS (C-ARDS) characterized by a respiratory system compliance (Crs) < 35 mL/cmH2O. OBJECTIVES: To test if an ECC with a 5 L-bag in low-compliance C-ARDS can lead to a reduction in driving pressure (DP) and improve gas exchange, and to understand the underlying mechanisms. METHODS: Eleven patients with low-compliance C-ARDS were enrolled and underwent 4 steps: baseline, ECC for 60 min, ECC discontinuation and PEEP reduction. Respiratory mechanics, gas exchange, hemodynamics and electrical impedance tomography were recorded. Four pigs with acute ARDS were studied with ECC to understand the effect of ECC on pleural pressure gradient using pleural pressure transducers in both non-dependent and dependent lung regions. RESULTS: Five minutes of ECC reduced DP from baseline 14.2 ± 1.3 to 12.3 ± 1.3 cmH2O (P < 0.001), explained by an improved lung compliance. Changes in DP by ECC were strongly correlated with changes in DP obtained with PEEP reduction (R2 = 0.82, P < 0.001). The initial benefit of ECC decreased over time (DP = 13.3 ± 1.5 cmH2O at 60 min, P = 0.03 vs. baseline). Gas exchange and hemodynamics were unaffected by ECC. In four pigs with lung injury, ECC led to a decrease in the pleural pressure gradient at end-inspiration [2.2 (1.1-3) vs. 3.0 (2.2-4.1) cmH2O, P = 0.035]. CONCLUSIONS: In C-ARDS patients with Crs < 35 mL/cmH2O, ECC acutely reduces DP. ECC does not improve oxygenation but it can be used as a simple tool to detect hyperinflation as it improves Crs and reduces Ppl gradient. ECC benefits seem to partially fade over time. ECC produces similar changes compared to PEEP reduction.

Rapid reorganization of the Milan metropolitan public safety answering point operations during the initial phase of the COVID-19 outbreak in Italy.

Objective: To quantify how the first public announcement of confirmed coronavirus disease 2019 (COVID-19) in Italy affected a metropolitan region's emergency medical services (EMS) call volume and how rapid introduction of alternative procedures at the public safety answering point (PSAP) managed system resources. Methods: PSAP processes were modified over several days including (1) referral of non-ill callers to public health information call centers; (2) algorithms for detection, isolation, or hospitalization of suspected COVID-19 patients; and (3) specialized medical teams sent to the PSAP for triage and case management, including ambulance dispatches or alternative dispositions. Call volumes, ambulance dispatches, and response intervals for the 2 weeks after announcement were compared to 2017-2019 data and the week before. Results: For 2 weeks following outbreak announcement, the primary-level PSAP (police/fire/EMS) averaged 56% more daily calls compared to prior years and recorded 9281 (106% increase) on Day 4, averaging ∼400/hour. The secondary-level (EMS) PSAP recorded an analogous 63% increase with 3863 calls (∼161/hour; 264% increase) on Day 3. The COVID-19 response team processed the more complex cases (n = 5361), averaging 432 ± 110 daily (∼one-fifth of EMS calls). Although community COVID-19 cases increased exponentially, ambulance response intervals and dispatches (averaging 1120 ± 46 daily) were successfully contained, particularly compared with the week before (1174 ± 40; P = 0.02). Conclusion: With sudden escalating EMS call volumes, rapid reorganization of dispatch operations using tailored algorithms and specially assigned personnel can protect EMS system resources by optimizing patient dispositions, controlling ambulance allocations and mitigating hospital impact. Prudent population-based disaster planning should strongly consider pre-establishing similar highly coordinated medical taskforce contingencies.

High-Dose Inhaled Nitric Oxide as Adjunct Therapy in Cystic Fibrosis Targeting Burkholderia multivorans.

BACKGROUND: Individuals with cystic fibrosis (CF) have persistent lung infections, necessitating the frequent use of antibiotics for pulmonary exacerbations. Some respiratory pathogens have intrinsic resistance to the currently available antibiotics, and any pathogen may acquire resistance over time, posing a challenge to CF care. Gaseous nitric oxide has been shown to have antimicrobial activity against a wide variety of microorganisms, including common CF pathogens, and offers a potential inhaled antimicrobial therapy. Case Presentation. Here, we present the case of a 16-year-old female with CF who experienced a precipitous decline in lung function over the prior year in conjunction with worsening antibiotic resistance of her primary pathogen, Burkholderia multivorans. She received 46 intermittent inhalations of 160 parts-per-million nitric oxide over a 28-day period. The gas was administered via a mechanical ventilator fitted with nitrogen dioxide scavenging chambers. CONCLUSIONS: High-dose inhaled nitric oxide was safe, well tolerated, and showed clinical benefit in an adolescent with cystic fibrosis and pulmonary colonization with Burkholderia multivorans.

Protocol for a randomized controlled trial testing inhaled nitric oxide therapy in spontaneously breathing patients with COVID-19.

Introduction: the current worldwide outbreak of Coronavirus disease 2019 (COVID-19) due to a novel coronavirus (SARS-CoV-2) is seriously threatening the public health. The number of infected patients is continuously increasing and the need for Intensive Care Unit admission ranges from 5 to 26%. The mortality is reported to be around 3.4% with higher values for the elderly and in patients with comorbidities. Moreover, this condition is challenging the healthcare system where the outbreak reached its highest value. To date there is still no available treatment for SARS-CoV-2. Clinical and preclinical evidence suggests that nitric oxide (NO) has a beneficial effect on the coronavirus-mediated acute respiratory syndrome, and this can be related to its viricidal effect. The time from the symptoms' onset to the development of severe respiratory distress is relatively long. We hypothesize that high concentrations of inhaled NO administered during early phases of COVID-19 infection can prevent the progression of the disease. Methods and analysis: This is a multicenter randomized controlled trial. Spontaneous breathing patients admitted to the hospital for symptomatic COVID-19 infection will be eligible to enter the study. Patients in the treatment group will receive inhaled NO at high doses (140-180 parts per million) for 30 minutes, 2 sessions every day for 14 days in addition to the hospital care. Patient in the control group will receive only hospital care. The primary outcome is the percentage of patients requiring endotracheal intubation due to the progression of the disease in the first 28 days from enrollment in the study. Secondary outcomes include mortality at 28 days, proportion of negative test for SARS-CoV-2 at 7 days and time to clinical recovery. Ethics and dissemination: The trial protocol has been approved at the Investigation Review Boards of Xijing Hospital (Xi'an, China) and The Partners Human Research Committee of Massachusetts General Hospital (Boston, USA) is pending. Recruitment is expected to start in March 2020. Results of this study will be published in scientific journals, presented at scientific meetings, and on related website or media in fighting this widespread contagious disease.

Development of a Lung Rescue Team to Improve Care of Subjects With Refractory Acute Respiratory Failure.

BACKGROUND: A lung-protective mechanical ventilation strategy has become the hallmark of ventilation management for patients with acute respiratory failure. However, some patients progress to more severe forms of acute respiratory failure with refractory hypoxemia. In such circumstances, individualized titration of mechanical ventilation according to the patient's specific respiratory and cardiovascular pathophysiology is desirable. A lung rescue team (LRT) was recently established at our institution to improve the medical care of patients with acute respiratory failure when conventional treatment fails. The aim of this report is to describe the consultation processes, the cardiopulmonary assessment, and the procedures of the LRT. METHODS: This was a retrospective review of the LRT management of patients with acute respiratory failure and refractory hypoxemia at Massachusetts General Hospital in Boston, Massachusetts. The LRT is composed of a critical care physician, the ICU respiratory therapist on duty, the ICU nurse on duty, and 2 critical care fellows. In the LRT approach, respiratory mechanics are evaluated through lung recruitment maneuvers and decremental PEEP trials by means of 3 tools: esophageal manometry, echocardiography, and electrical impedance tomography lung imaging. RESULTS: The LRT was consulted 89 times from 2014 to 2019 for evaluation and management of severely critically ill patients with acute respiratory failure and refractory hypoxemia on mechanical ventilation. The LRT was requested a median of 2 (interquartile range 1-6) d after intubation to optimize mechanical ventilation and to titrate PEEP in 77 (86%) subjects, to manage ventilation in 8 (9%) subjects on extracorporeal membrane oxygenation (ECMO), and to manage weaning strategy from mechanical ventilation in 4 (5%) subjects. The LRT found consolidations with atelectasis responsive to recruitment maneuvers in 79% (n = 70) of consultations. The LRT findings translated into a change of care in 81% (n = 72) of subjects. CONCLUSIONS: The LRT individualized the management of severe acute respiratory failure. The LRT consultations were shown to be effective, safe, and efficient, with an impact on decision-making in the ICU.

Effect of nitric oxide on postoperative acute kidney injury in patients who underwent cardiopulmonary bypass: a systematic review and meta-analysis with trial sequential analysis.

BACKGROUND: The effect of nitric oxide (NO) on renal function is controversial in critical illness. We performed a systematic meta-analysis and trial sequential analysis to determine the effect of NO gas on renal function and other clinical outcomes in patients requiring cardiopulmonary bypass (CPB). The primary outcome was the relative risk (RR) of acute kidney injury (AKI), irrespective of the AKI stage. The secondary outcome was the mean difference (MD) in the length of ICU and hospital stay, the RR of postoperative hemorrhage, and the MD in levels of methemoglobin. Trial sequential analysis (TSA) was performed for the primary outcome. RESULTS: 54 trials were assessed for eligibility and 5 studies (579 patients) were eligible for meta-analysis. NO was associated with reduced risk of AKI (RR 0.76, 95% confidential interval [CI], 0.62 to 0.93, I2 = 0%). In the subgroup analysis by NO initiation timing, NO did not decrease the risk of AKI when started at the end of CPB (RR 1.20, 95% CI 0.52-2.78, I2 = 0%). However, NO did significantly reduce the risk of AKI when started from the beginning of CPB (RR 0.71, 95% CI 0.54-0.94, I2 = 10%). We conducted TSA based on three trials (400 patients) using KDIGO criteria and with low risk of bias. TSA indicated a CI of 0.50-1.02 and an optimal information size of 589 patients, suggesting a lack of definitive conclusion. Furthermore, NO does not affect the length of ICU and hospital stay or the risk of postoperative hemorrhage. NO slightly increased the level of methemoglobin at the end of CPB (MD 0.52%, 95% CI 0.27-0.78%, I2 = 90%), but it was clinically negligible. CONCLUSIONS: NO appeared to reduce the risk of postoperative AKI in patients undergoing CPB. Additional studies are required to ascertain the finding and further determine the dosage, timing and duration of NO administration.