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Background: Erector spinae plane block (ESPB) has been described as an effective regional anesthesia technique in thoracic parenchymal surgery. Evidence highlighting the use of this technique continuously via perifascial catheter is lacking., Case Presentation: In this case report, we present the case of a patient scheduled for robotic-assisted thoracic surgery for a pulmonary neoformation in the lower right lobe. We decided to manage this patient with a multimodal approach in order to have an opioid-sparing effect. This is the first reported case of continuous ESPB in robot-assisted thoracic surgery., Conclusions: Anesthesiologists should consider this method in surgery that is slower than conventional surgery, such as robot-assisted, and less invasive than thoracotomy, which does not warrant the use of neuroaxial or paravertebral techniques that increase the risk of iatrogenic complications.

Remdesivir is one of the most encouraging treatments against SARS-CoV-2 infection. After intravenous infusion, RDV is rapidly metabolized (t 1/2  = 1 h) within the cells to its active adenosine triphosphate analogue form (GS-443902) and then it can be found in plasma in its nucleoside analogue form (GS-441524). In this real-life study, we describe the remdesivir and GS-441524 concentrations at three time points in nine ICU patients, through a validated ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method. The observed data confirmed the very rapid conversion of RDV to its metabolite and the quite long half-life of GS-441524. The mean C min , C max and AUC 0-24 , were < 0.24 ng/mL and 122.3 ng/mL, 2637.3 ng/mL and 157.8 ng/mL, and 5171.2 ng*h/mL and 3676.5 ng*h/ml, respectively, for RDV and GS-441524. Three out of nine patients achieved a C max  > 2610 ng/mL and 140 ng/mL and AUC 0-24  > 1560 ng*h/mL and 2230 ng*h/mL for RDV and GS-441524, respectively. The mean t 1/2 value for GS-441524 was 26.3 h. Despite the low number of patients, these data can represent an interesting preliminary report on the variability of RDV and GS-441524 concentrations in a real-life ICU setting., (© 2021 British Pharmacological Society.)

Veno-venous extracorporeal membrane oxygenation (VV-ECMO) is a life-saving rescue therapy in patients with Acute Respiratory Distress Syndrome (ARDS). ECMO has been associated with development of lymphocytopenia that is also common in COVID-19. Hyperinflammation may complicate SARS-CoV-2 pneumonia, prompting therapy with steroids and immunomodulatory drugs. We aimed to evaluate the association of therapies such as steroids and Tocilizumab with trajectories of the total leukocytes, lymphocyte subpopulation count, and inflammatory and fibrinolysis markers in COVID-19-related ARDS, requiring or not VV-ECMO support. The association of the trajectories of the leukocytes, lymphocyte subpopulation count, and inflammatory and fibrinolysis markers with treatment with steroids ( Steroids ), Tocilizumab ( Tocilizumab ), both drugs ( Steroids + Tocilizumab ), and absence of treatment ( No Treatment ) were analyzed using mixed effects regression models, where ECMO was considered as a potential effect modifier. One hundred and thirty-nine leukocyte and eighty-one lymphocyte subpopulation counts were obtained from thirty-one patients who required (VV- ECMO , N = 13) or not ( no VV-ECMO , N = 18) extracorporeal support. In both groups, treatment with Steroids + Tocilizumab was independently associated with a significant reduction of 46% and 67% in total lymphocytes, 22% and 60% in CD3 + , and 61% and 91% in CD19 + (B lymphocytes) compared to those obtained without treatment, respectively. In the no VV-ECMO group, Tocilizumab was associated with a 79% increase in total lymphocytes and with a reduction in procalcitonin compared to no treatment. CD45 + , CD3 + CD4 + (Th cell), CD3 + CD8 + , CD4 + /CD8 + , the NK cell subpopulation, neutrophils, monocytes, and basophils were significantly reduced by Steroids + Tocilizumab without an effect modification by VV-ECMO support. In critically ill COVID-19 patients with ARDS, concomitant therapies with steroids and Tocilizumab, beside mitigating the inflammation and fibrinolysis, could reduce the total leukocyte, lymphocyte, and subpopulation count. Moreover, the effect of Tocilizumab in increasing the total lymphocytes and reducing procalcitonin might be blunted by VV-ECMO.

Background: Postoperative analgesia in SCOLA (subcutaneous onlay laparoscopic approach) surgery is traditionally based on intravenous opioids. The aim of this retrospective observational study was to evaluate the efficacy of bilateral subcostal transversus abdominis plane (SCTAP) block on postoperative pain relief in the first 48 postoperative hours following SCOLA., Materials and Methods: From August 2017 to December 2019, 163 patients were eligible for the analysis. Postoperative analgesia was managed either with an intravenous tramadol continuous infusion (opioid group) or a multimodal opioid-sparing strategy based on bilateral SCTAP block (SCTAP group), according to the anesthesiologist's postoperative plan. After data collection, 103 patients were assigned post hoc to the SCTAP group and 60 patients to the opioid group. The primary outcome was the evaluation of postoperative pain, considering both the Numeric Rating Scale score and the percentage of patients with uncontrolled pain at 6, 12, 24, or 48 hours. Secondary outcomes were differences in the administration of ketorolac rescue analgesia and incidence of mild adverse effects., Results: There were no significant differences in median Numeric Rating Scale at 6, 12, 24, and 48 hours and ketorolac rescue dose consumption in both groups. Five patients (4.85% of a total of 103 patients) referred postoperative nausea and vomiting in the SCTAP group versus 10 patients (16.67% of a total of 60 patients) in the opioid group (P=0.02)., Conclusion: Analgesia with SCTAP block seems to represent a feasible and efficient strategy for pain management in patients undergoing SCOLA surgery, allowing good quality analgesia, low opioids requirements, and reduced incidence of postoperative nausea and vomiting., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Risks associated with video-assisted surgical lung biopsy (VASLB) for interstitial lung disease (ILD) with endotracheal intubation and mechanical ventilation are not nil. Awake video-assisted surgical lung biopsy (Awake-VASLB) has been proposed as a method to obtain a precise diagnosis in several different thoracic diseases., Objectives: To compare clinical outcomes of Awake-VASLB and Intubated-VASLB in patients with suspected ILDs., Methods: From June 2016 to February 2020, all patients submitted to elective VASLB for suspected ILD were included. Differences in outcomes between Awake-VASLB and Intubated-VASLB were assessed through univariable, multivariable-adjusted, and a propensity score-matched analysis., Results: Awake-VASLB was performed in 66 out of 100 patients, while 34 underwent Intubated-VASLB. The Awake-VASLB resulted in a lower post-operative morbidity (OR 0.025; 95% CI 0.001-0.35; p=0.006), less unexpected intensive care unit admission, less need for rescue therapy for pain, a reduced surgical and anaesthesiologic time, a reduced chest drain duration, and a lower post-operative length of stay., Conclusion: Awake-VASLB in patients affected by ILD is feasible and seems safer than Intubated-VASLB., Competing Interests: Conflict of interest: F. Guerrera has nothing to disclose. Conflict of interest: L. Costardi has nothing to disclose. Conflict of interest: G.L. Rosboch has nothing to disclose. Conflict of interest: P. Lyberis has nothing to disclose. Conflict of interest: E. Ceraolo has nothing to disclose. Conflict of interest: P. Solidoro has served as investigator in clinical trials, consultant or speaker for Alfasigma, AstraZeneca, Boehringer Ingelheim, GSK, Menarini, Novartis, Chiesi, Guidotti & Malesci and ABC Farmaceutici outside this work. Conflict of interest: C. Filippini has nothing to disclose. Conflict of interest: G. Verri has nothing to disclose. Conflict of interest: L. Brazzi has nothing to disclose. Conflict of interest: C. Albera has nothing to disclose regarding this work, but has served as investigator in clinical trials, consultant, speaker, steering committee or scientific advisory board member for Bayer, Boehringer Ingelheim, FibroGen, Gilead, Grifols, GSK, Roche, MSD, Sanofi Aventis outside this work. Conflict of interest: E. Ruffini has nothing to disclose., (Copyright ©The authors 2021.)

Purpose: Vasoplegia often complicates on-pump cardiac surgery. Systemic inflammatory response induced by extracorporeal circulation represents the major determinant, but adrenal insufficiency and postoperative vasopressin deficiency may have a role. Pathophysiological meaning of perioperative changes in endocrine markers of hydro-electrolyte balance has not still fully elucidated. Objectives of the present research study were to estimate the incidence of vasoplegia in a homogeneous cohort of not severe cardiopathic patients, to define the role of presurgical adrenal insufficiency, to evaluate copeptin and NT-proBNP trends in the perioperative., Methods: We conducted a prospective cohort study in the cardiac intensive care unit of a tertiary referral center. We evaluated 350 consecutive patients scheduled for cardiac surgery; 55 subjects completed the study. Both standard and low-dose corticotropin stimulation tests were performed in the preoperative; copeptin and NT-proBNP were evaluated in the preoperative (T0), on day 1 (T1) and day 7 (T2) after surgery., Results: Nine subjects (16.3%) developed vasoplegic syndrome with longer bypass and clamping time (p < 0.001). Reduced response to low-dose ACTH test was not associated to vasoplegia. Preoperative copeptin > 16.9 pmol/L accurately predicted the syndrome (AUC 0.86, 95% CI 0.73-0.94; OR 1.17, 95% CI 1.04-1.32). An evident correlation was observed at 7 days postoperative between NT-proBNP and copeptin (r 0.88, 95% CI 0.8-0.93; p < 0.001)., Conclusion: Preoperative impaired response to low-dose ACTH stimulation test is not a risk factor for post-cardiotomic vasoplegia; conversely, higher preoperative copeptin predicts the complication. On-pump cardiac surgery could be an interesting model of rapid heart failure progression.

Since the beginning of the COVID-19 emergency, the referral Intensive Care Unit for the Extracorporeal Membrane Oxygenation (ECMO) support of Piedmont Region (Italy), in cooperation with infectious disease specialists, perfusionists and cardiac surgeons, developed a protocol to guarantee operator safety during invasive procedures, among which the ECMO positioning or inter-hospital transport. The use of powered air-purifying respirators, filtering facepiece particles (FFP) 2-3 masks, protective suits, disposable sterile surgical gowns, and two pairs of sterile gloves as a part of a protocol seemed effective and feasible for trained healthcare workers and allow all the complex activities connected with the positioning of the ECMO support to be completed effectively. The simulation training on donning and doffing procedures and the presence of a dedicated team member to verify the compliance with the safety procedure effectively reassured operators and likely reduced the risk of self-contamination. From 1 March to 31 December 2020, we used the procedure in 35 severe acute respiratory distress syndrome (ARDS) patients and one acute respiratory failure caused by neoplastic total tracheal obstruction, all positive to COVID-19, to be connected to veno-venous ECMO in peripheral hospitals and centralized for ECMO management. This preliminary experience seems to confirm that the use of ECMO during COVID-19 outbreaks is feasible and the risks associated with its positioning and management are sustainable for the health-care workers and safe for patients.

Background: To assess diagnostic performance of lung ultrasound (LUS) in identifying ARDS morphology (focal vs non-focal), compared with the gold standard computed tomography., Methods: Mechanically ventilated ARDS patients undergoing lung computed tomography and ultrasound were enrolled. Twelve fields, were evaluated. LUS score was graded from 0 (normal) to 3 (consolidation) according to B-lines extent. Total and regional LUS score as the sum of the four ventral (LUS V ), intermediate (LUS I ) or dorsal (LUS D ) fields, were calculated. Based on lung CT, ARDS morphology was defined as (1) focal (loss of aeration with lobar distribution); (2) non-focal (widespread loss of aeration or segmental loss of aeration distribution associated with uneven lung attenuation areas), and diagnostic accuracy of LUS in discriminating ARDS morphology was determined by AU-ROC in training and validation set of patients., Results: Forty-seven patients with ARDS (25 training set and 22 validation set) were enrolled. LUS TOT , LUS V and LUS I but not LUS D score were significantly lower in focal than in non-focal ARDS morphologies (p < .01). The AU-ROC curve of LUS TOT , LUS V , LUS I and LUS D for identification of non-focal ARDS morphology were 0.890, 0.958, 0.884 and 0.421, respectively. LUS V value ≥ 3 had the best predictive value (sensitivity = 0.95, specificity = 1.00) in identifying non-focal ARDS morphology. In the validation set, an LUS V score ≥ 3 confirmed to be highly predictive of non-focal ARDS morphology, with a sensitivity and a specificity of 94% and 100%., Conclusions: LUS had a valuable performance in distinguishing ARDS morphology.

Rationale: Prone positioning reduces mortality in patients with severe acute respiratory distress syndrome (ARDS). To date, no evidence supports the use of prone positioning (PP) during venovenous extracorporeal oxygenation (ECMO). Objectives: The aim of the study was to assess the feasibility, safety, and effect on oxygenation and lung mechanics of PP during ECMO. As a secondary exploratory aim, we assessed the association between PP and hospital mortality. Methods: We performed a multicenter retrospective cohort study in six Italian ECMO centers, including patients managed with PP during ECMO support (prone group; four centers) and patients managed in the supine position (control group; two centers). Physiological variables were analyzed at four time points (supine before PP, start of PP, end of PP, and supine after PP). The association between PP and hospital mortality was assessed by multivariate analysis and propensity score-matching. Results: A total of 240 patients were included, with 107 in the prone group and 133 in the supine group. The median duration of the 326 pronation cycles was 15 (12-18) hours. Minor reversible complications were reported in 6% of PP maneuvers. PP improved oxygenation and reduced intrapulmonary shunt. Unadjusted hospital mortality was lower in the prone group (34 vs. 50%; P  = 0.017). After adjusting for covariates, PP remained significantly associated with a reduction of hospital mortality (odds ratio, 0.50; 95% confidence interval, 0.29-0.87). Sixty-six propensity score-matched patients were identified in each group. In this matched sample, patients who underwent pronation had higher ECMO duration (16 vs. 10 d; P  = 0.0344) but lower hospital mortality (30% vs. 53%; P  = 0.0241). Conclusions: PP during ECMO improved oxygenation and was associated with a reduction of hospital mortality.

Objective: To test the effectiveness of mid-regional pro-adrenomedullin (MR-proADM) in comparison to C-reactive protein (CRP), procalcitonin (PCT), D-dimer, lactate dehydrogenase (LDH) in predicting mortality in COVID-19-ICU-patients., Methods: All consecutive COVID-19 adult patients admitted between March and June 2020 to the ICU of a referral, university hospital in Northern-Italy were enrolled. MR-proADM and routine laboratory test were measured within 48 hours from ICU admission, on day 3, 7 and 14. Survival curves difference with MR-proADM cut-off set to 1.8 nmol/L were tested using log-rank test. Predictive ability was compared using area under the curve and 95% confidence interval of different receiver-operating characteristics curves., Results: 57 patients were enrolled. ICU and overall mortality were 54.4%. At admission, lymphocytopenia was present in 86% of patients; increased D-dimer and CRP levels were found in 84.2% and 87.7% of patients respectively, while PCT values > 0.5 μg/L were observed in 47.4% of patients. MR-proADM, CRP and LDH were significantly different between surviving and non-surviving patients and over time, while PCT, D-dimer and NT-pro-BNP did not show any difference between the groups and over time; lymphocytes were different between surviving and non-surviving patients only. MR-proADM was higher in dying patients (2.65±2.33vs1.18±0.47, p<0.001) and a higher mortality characterized patients with MR-proADM >1.8 nmol/L (p = 0.016). The logistic regression model adjusted for age, gender, cardiovascular disease, diabetes mellitus and PCT values confirmed an odds ratio = 10.3 [95%CI:1.9-53.6] (p = 0.006) for MR-proADM >1.8 nmol/L and = 22.2 [95%CI:1.6-316.9] (p = 0.022) for cardiovascular disease. Overall, MR-proADM had the best predictive ability (AUC = 0.85 [95%CI:0.78-0.90])., Conclusions: In COVID-19 ICU-patients, MR-proADM seems to have constantly higher values in non-survivor patients and predict mortality more precisely than other biomarkers. Repeated MR-proADM measurement may support a rapid and effective decision-making. Further studies are needed to better explain the mechanisms responsible of the increase in MR-proADM in COVID-19 patients., Competing Interests: The authors have declared that no competing interests exist.

Background: Patients treated with mechanical ventilation in intensive care units (ICUs) have a high risk of developing respiratory tract infections (RTIs). Ventilator-associated pneumonia (VAP) has been estimated to affect 5% to 40% of patients treated with mechanical ventilation for at least 48 hours. The attributable mortality rate of VAP has been estimated at about 9%. Selective digestive decontamination (SDD), which consists of the topical application of non-absorbable antimicrobial agents to the oropharynx and gastroenteric tract during the whole period of mechanical ventilation, is often used to reduce the risk of VAP. A related treatment is selective oropharyngeal decontamination (SOD), in which topical antibiotics are applied to the oropharynx only. This is an update of a review first published in 1997 and updated in 2002, 2004, and 2009., Objectives: To assess the effect of topical antibiotic regimens (SDD and SOD), given alone or in combination with systemic antibiotics, to prevent mortality and respiratory infections in patients receiving mechanical ventilation for at least 48 hours in ICUs., Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), which contains the Cochrane Acute Respiratory Infections (ARI) Group's Specialised Register, PubMed, and Embase on 5 February 2020. We also searched the WHO ICTRP and ClinicalTrials.gov for ongoing and unpublished studies on 5 February 2020. All searches included non-English language literature. We handsearched references of topic-related systematic reviews and the included studies., Selection Criteria: Randomised controlled trials (RCTs) and cluster-RCTs assessing the efficacy and safety of topical prophylactic antibiotic regimens in adults receiving intensive care and mechanical ventilation. The included studies compared topical plus systemic antibiotics versus placebo or no treatment; topical antibiotics versus no treatment; and topical plus systemic antibiotics versus systemic antibiotics., Data Collection and Analysis: We used standard methodological procedures expected by Cochrane., Main Results: We included a total of 41 trials involving 11,004 participants (five new studies were added in this update). The minimum duration of mechanical ventilation ranged from 2 (19 studies) to 6 days (one study). Thirteen studies reported the mean length of ICU stay, ranging from 11 to 33 days. The percentage of immunocompromised patients ranged from 0% (10 studies) to 22% (1 study). The reporting quality of the majority of included studies was very poor, so we judged more than 40% of the studies as at unclear risk of selection bias. We judged all studies to be at low risk of performance bias, though 47.6% were open-label, because hospitals usually have standardised infection control programmes, and possible subjective decisions on who should be tested for the presence or absence of RTIs are unlikely in an ICU setting. Regarding detection bias, we judged all included studies as at low risk for the outcome mortality. For the outcome RTIs, we judged all double-blind studies as at low risk of detection bias. We judged five open-label studies as at high risk of detection bias, as the diagnosis of RTI was not based on microbiological exams; we judged the remaining open-label studies as at low risk of detection bias, as a standardised set of diagnostic criteria, including results of microbiological exams, were used. Topical plus systemic antibiotic prophylaxis reduces overall mortality compared with placebo or no treatment (risk ratio (RR) 0.84, 95% confidence interval (CI) 0.73 to 0.96; 18 studies; 5290 participants; high-certainty evidence). Based on an illustrative risk of 303 deaths in 1000 people this equates to 48 (95% CI 15 to 79) fewer deaths with topical plus systemic antibiotic prophylaxis. Topical plus systemic antibiotic prophylaxis probably reduces RTIs (RR 0.43, 95% CI 0.35 to 0.53; 17 studies; 2951 participants; moderate-certainty evidence). Based on an illustrative risk of 417 RTIs in 1000 people this equates to 238 (95% CI 196 to 271) fewer RTIs with topical plus systemic antibiotic prophylaxis. Topical antibiotic prophylaxis probably reduces overall mortality compared with no topical antibiotic prophylaxis (RR 0.96, 95% CI 0.87 to 1.05; 22 studies, 4213 participants; moderate-certainty evidence). Based on an illustrative risk of 290 deaths in 1000 people this equates to 19 (95% CI 37 fewer to 15 more) fewer deaths with topical antibiotic prophylaxis. Topical antibiotic prophylaxis may reduce RTIs (RR 0.57, 95% CI 0.44 to 0.74; 19 studies, 2698 participants; low-certainty evidence). Based on an illustrative risk of 318 RTIs in 1000 people this equates to 137 (95% CI 83 to 178) fewer RTIs with topical antibiotic prophylaxis. Sixteen studies reported adverse events and dropouts due to adverse events, which were poorly reported with sparse data. The certainty of the evidence ranged from low to very low., Authors' Conclusions: Treatments based on topical prophylaxis probably reduce respiratory infections, but not mortality, in adult patients receiving mechanical ventilation for at least 48 hours, whereas a combination of topical and systemic prophylactic antibiotics reduces both overall mortality and RTIs. However, we cannot rule out that the systemic component of the combined treatment provides a relevant contribution in the observed reduction of mortality. No conclusion can be drawn about adverse events as they were poorly reported with sparse data., (Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Objective: Regional anesthesia with thoracic wall blocks could represent an opioid-sparing alternative for mitral valve surgery in right minithoracotomy (mini-MVS). For the present study, an opioid-free analgesia using continuous deep serratus anterior plane block was compared with intravenous morphine., Design: Prospective, observational cohort study., Setting: Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, University of Turin, Italy., Participants: The present study enrolled patients who underwent mini-MVS from March to October 2019 (63 patients) and divided them into the following 2 groups, according to pain control strategy: a morphine group and a serratus anterior plane (SAP) group., Interventions: Primary outcomes were pain evaluation and total postoperative opioid consumption, and secondary outcomes were incidence of postoperative nausea and vomiting, time to extubation, mechanical ventilation duration, and bowel dysfunction., Measurements and Main Results: The mean number rating scale at 24 hours was 2.15 (95% confidence interval [CI] 1.22-3.09) in the SAP group versus 3.23 (95% CI 2.28-4.29) in the morphine group (p = 0.07), whereas the mean number rating scale at 48 hours was significantly less in the SAP group compared with the morphine group (1.77 [95% CI 0.99-2.54] v 3.23 [95% CI 2.13-4.33], respectively; p = 0.03). Mean morphine consumption at 48 postoperative hours was 12.98 mg (95% CI 10.90-15.05 mg) in the morphine group and 2.22 mg (95% CI 0.99-3.44 mg) in the SAP group; p < 0.01. Cumulative morphine consumption at 24 postoperative hours was 10.44 mg (95% CI 8.36-12.52) in the morphine group and 1.16 mg (95% CI 0.37-1.95) in the SAP group; p < 0.01. There were no significant differences for secondary outcomes., Conclusions: Continuous deep serratus anterior plane block seems to be a valid alternative to intravenous opioids in terms of efficacy for patients undergoing mini-MVS with a lower opioid requirement., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Opioid-related adverse events are a serious problem in hospitalized patients. Little is known about patients who are likely to experience opioid-induced respiratory depression events on the general care floor and may benefit from improved monitoring and early intervention. The trial objective was to derive and validate a risk prediction tool for respiratory depression in patients receiving opioids, as detected by continuous pulse oximetry and capnography monitoring., Methods: PRediction of Opioid-induced respiratory Depression In patients monitored by capnoGraphY (PRODIGY) was a prospective, observational trial of blinded continuous capnography and oximetry conducted at 16 sites in the United States, Europe, and Asia. Vital signs were intermittently monitored per standard of care. A total of 1335 patients receiving parenteral opioids and continuously monitored on the general care floor were included in the analysis. A respiratory depression episode was defined as respiratory rate ≤5 breaths/min (bpm), oxygen saturation ≤85%, or end-tidal carbon dioxide ≤15 or ≥60 mm Hg for ≥3 minutes; apnea episode lasting >30 seconds; or any respiratory opioid-related adverse event. A risk prediction tool was derived using a multivariable logistic regression model of 46 a priori defined risk factors with stepwise selection and was internally validated by bootstrapping., Results: One or more respiratory depression episodes were detected in 614 (46%) of 1335 general care floor patients (43% male; mean age, 58 ± 14 years) continuously monitored for a median of 24 hours (interquartile range [IQR], 17-26). A multivariable respiratory depression prediction model with area under the curve of 0.740 was developed using 5 independent variables: age ≥60 (in decades), sex, opioid naivety, sleep disorders, and chronic heart failure. The PRODIGY risk prediction tool showed significant separation between patients with and without respiratory depression (P < .001) and an odds ratio of 6.07 (95% confidence interval [CI], 4.44-8.30; P < .001) between the high- and low-risk groups. Compared to patients without respiratory depression episodes, mean hospital length of stay was 3 days longer in patients with ≥1 respiratory depression episode (10.5 ± 10.8 vs 7.7 ± 7.8 days; P < .0001) identified using continuous oximetry and capnography monitoring., Conclusions: A PRODIGY risk prediction model, derived from continuous oximetry and capnography, accurately predicts respiratory depression episodes in patients receiving opioids on the general care floor. Implementation of the PRODIGY score to determine the need for continuous monitoring may be a first step to reduce the incidence and consequences of respiratory compromise in patients receiving opioids on the general care floor.

Background: Blood products are a lifesaving commodity in the treatment of major trauma. Although there is little evidence for use of pre-hospital blood products (PHBP) in seriously injured patients, an increasing number of emergency medical services have started using PHBP for treatment of major haemorrhage. The primary aim of this survey was to establish the degree of prehospital blood product use throughout Europe and discover main indications. The secondary aim was to evaluate opinions about PHBP and also the experience and the personal views of its users., Methods: The subcommittee for Critical Emergency Medicine of the European Society of Anaesthesiology (ESA) held an online survey of European Helicopter Emergency Services (HEMS) and all French Services d'Aide Médicale Urgente (SAMU) regions. It contained 13 questions both open and multiple-choice about the frequency transfusions are carried out, the PHBP used and the perceived benefit. The survey was distributed to the corresponding HEMS leads in 14 European countries., Results: In total there were 172 valid responses; overall 48% of all respondents have prehospital access to packed red cells, 22% to fresh plasma and 14% use lyophilised plasma. Besides blood product administration, 94% of all services use tranexamic acid. Sixty five percent of all replies came from French and from German services (37 and 28% respectively). PHBP were mainly used for trauma related emergencies. France has the highest uptake of use of blood products at 89%, whereas the rate in Germany was far lower at 6%. Fifty five percent of the service leads felt that PHBP are beneficial, and even lifesaving in individual cases despite being needed infrequently., Conclusions: We found remarkable dissimilarities in practice between the different European countries. Even if there is not an absolute consensus amongst providers on the benefit of PHBP, the majority feel they are beneficial. The difference in practice is possibly related to the perceived lack of evidence on prehospital blood transfusion. We suggest to include the use of PHBP in trauma registries in order to consolidate the existing evidence.

Purpose: Perioperative myocardial dysfunction occurs frequently in cardiac surgery, and is a risk factor for morbidity and mortality. Levosimendan has been suggested to reduce mortality of patients with perioperative myocardial dysfunction. However, long-term outcome data on its efficacy in cardiac surgery are lacking., Materials and Methods: Cardiac surgery patients with perioperative myocardial dysfunction were randomized to levosimendan or placebo, in addition to standard inotropic care. One-year mortality data were collected., Results: We randomized 506 patients (248 to levosimendan 258 to placebo). At 1-year follow-up, 41 patients (16.5%) died in the levosimendan group, while 47 (18.3%) died in the placebo group (absolute risk difference -1.8; 95% CI -8.4 to 4.9; P = .60). Female sex, history of chronic obstructive pulmonary disease, previous myocardial infarction, serum creatinine, hematocrit, mean arterial pressure, and duration of cardiopulmonary bypass were independently associated with 1-year mortality., Conclusions: Levosimendan administration does not improve 1-year survival in cardiac surgery patients with perioperative myocardial dysfunction. One-year mortality in these patients is 17%. Six predictive factors for long-term mortality were identified., Study Registration Number: NCT00994825 (ClinicalTrials.gov)., Competing Interests: Declaration of Competing Interest Dr. Fabio Guarracino received speaker fees from Amomed, Baxter, Edwards, Masimo and Orion. Dr. Valery Likhvantsev, and Dr. Vladimir V. Lomivorotov received speaker fees from Orion., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Normothermic ex-vivo lung perfusion (EVLP) limits organ donor shortage by potentially using high-risk donor lungs. Microbial burden reduction has been demonstrated after EVLP using antibiotic prophylaxis with imipenem. However, no data have been published on the clinical consequences of the potential residual bacterial burden., Methods: Imipenem concentration was measured every hour (T0 to T6) in the lung perfusate and at the end of EVLP (Tf) in biopsies. The antimicrobial activity of perfusate at T1 and Tf against E. coli and K. pneumoniae was evaluated. Lungs were distinguished: no bacterial species in recipients and donors (donor-/recipient-); bacterial species isolated from donors and not from recipients (donor+/recipient-); same bacterial species in both recipients and donors (donor+/recipient+). Interleukin 6 (IL-6) and IL-8 concentrations in lung perfusate, clinical pulmonary infection score (CPIS) and primary graft dysfunction (PGD) were evaluated., Results: Imipenem concentration in perfusate decreased over time. T1 and Tf perfusates exhibited bactericidal activity against E. coli and K. pneumoniae. Overall, T1 perfusates yielded higher bactericidal titers (BTs) than Tf. The donor+/recipient+ group (26% of cases) had higher IL-6 and IL-8 in perfusate and higher CPIS., Conclusions: Recipients with the same bacterial species isolated in their donors had higher risk of pulmonary inflammation and early post-transplant pneumonia. Improvements in antimicrobial strategies during EVLP are warranted to minimize the consequences of donor associated respiratory infection.

Importance: Infection is frequent among patients in the intensive care unit (ICU). Contemporary information about the types of infections, causative pathogens, and outcomes can aid the development of policies for prevention, diagnosis, treatment, and resource allocation and may assist in the design of interventional studies., Objective: To provide information about the prevalence and outcomes of infection and the available resources in ICUs worldwide., Design, Setting, and Participants: Observational 24-hour point prevalence study with longitudinal follow-up at 1150 centers in 88 countries. All adult patients (aged ≥18 years) treated at a participating ICU during a 24-hour period commencing at 08:00 on September 13, 2017, were included. The final follow-up date was November 13, 2017., Exposures: Infection diagnosis and receipt of antibiotics., Main Outcomes and Measures: Prevalence of infection and antibiotic exposure (cross-sectional design) and all-cause in-hospital mortality (longitudinal design)., Results: Among 15 202 included patients (mean age, 61.1 years [SD, 17.3 years]; 9181 were men [60.4%]), infection data were available for 15 165 (99.8%); 8135 (54%) had suspected or proven infection, including 1760 (22%) with ICU-acquired infection. A total of 10 640 patients (70%) received at least 1 antibiotic. The proportion of patients with suspected or proven infection ranged from 43% (141/328) in Australasia to 60% (1892/3150) in Asia and the Middle East. Among the 8135 patients with suspected or proven infection, 5259 (65%) had at least 1 positive microbiological culture; gram-negative microorganisms were identified in 67% of these patients (n = 3540), gram-positive microorganisms in 37% (n = 1946), and fungal microorganisms in 16% (n = 864). The in-hospital mortality rate was 30% (2404/7936) in patients with suspected or proven infection. In a multilevel analysis, ICU-acquired infection was independently associated with higher risk of mortality compared with community-acquired infection (odds ratio [OR], 1.32 [95% CI, 1.10-1.60]; P = .003). Among antibiotic-resistant microorganisms, infection with vancomycin-resistant Enterococcus (OR, 2.41 [95% CI, 1.43-4.06]; P = .001), Klebsiella resistant to β-lactam antibiotics, including third-generation cephalosporins and carbapenems (OR, 1.29 [95% CI, 1.02-1.63]; P = .03), or carbapenem-resistant Acinetobacter species (OR, 1.40 [95% CI, 1.08-1.81]; P = .01) was independently associated with a higher risk of death vs infection with another microorganism., Conclusions and Relevance: In a worldwide sample of patients admitted to ICUs in September 2017, the prevalence of suspected or proven infection was high, with a substantial risk of in-hospital mortality.

Competing Interests: Conflict of interest: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: One-lung ventilation (OLV) in thoracic anesthesia is required to provide good surgical exposure. OLV is commonly achieved through a double lumen tube (DLT) or a bronchial blocker (BB). Malposition is a relevant issue related to these devices use. No prospective studies with adequately large sample size have been performed to evaluate the malposition rate of DLTs and BBs., Methods: A total of 2,127 patients requiring OLV during thoracic surgery were enrolled. The aim of this multicenter prospective observational study performed across 26 academic and community hospitals is to evaluate intraoperative malposition rate of DLTs and BBs. We also aim to assess: which device is the most used to achieve OLV, the frequency of bronchoscope (BRO) use, the incidence rate of desaturation during OLV and the role of other factors that can correlate to this event, and incidence of difficult airway., Results: Malposition rate for DLTs was 14%, for BBs 33%. DLTs were used in 95% of patients and BBs in 5%. Mean positioning time was shorter for DLT than BB (156±230 vs. 321±290 s). BRO was used in 54% of patients to check the correct positioning of the DLT. Desaturation occurred in 20% of all cases during OLV achieved through a DLT. Predicting factors of desaturation were dislocation (OR 2.03) and big size of DLT (OR 1.15). BRO use (OR 0.69) and left surgical side (OR 0.41) proved to be protective factors. Difficult airway prevalence was 16%; 10.8% predicted and 5.2% unpredicted., Conclusions: DLT has a low malpositioning rate and is the preferred device to achieve OLV. BRO use recorded was unexpectedly low. The possibility of encountering a difficult airway is frequent, with an overall prevalence of 16%. Risk factors of desaturation are malposition and increased size of DLT. Left procedures and BRO use could lead to fewer episodes of desaturation., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Background: Normal levels of plasma antithrombin (AT) activity might decrease heparin requirements to achieve an adequate level of anticoagulation during treatment with extracorporeal membrane oxygenation (ECMO). Acquired AT deficiency during ECMO is common, but formal recommendations on target, timing, and rate of AT supplementation are lacking. Thus, we conceived a pilot trial to evaluate the feasibility and safety of prolonged AT supplementation in patients requiring veno-venous ECMO for respiratory failure., Methods: Grifols Antithrombin Research Awards (GATRA) is a prospective, randomized, single blinded, multicenter, controlled two-arm trial. Patients undergoing veno-venous ECMO will be randomized to either receive AT supplementation to maintain a functional AT level between 80 and 120% (AT supplementation group) or not (control group) for the entire ECMO course. In both study groups, anticoagulation will be provided with unfractionated heparin following a standardized protocol. The primary endpoint will be the dose of heparin required to maintain the ratio of activated partial thromboplastin time between 1.5 and 2. Secondary endpoints will be the adequacy of anticoagulation and the incidence of hemorrhagic and thrombotic complications., Discussion: GATRA is a pilot trial that will test the efficacy of a protocol of AT supplementation in decreasing the heparin dose and improving anticoagulation adequacy during ECMO. If positive, it might provide the basis for a future larger trial aimed at verifying the impact of AT supplementation on a composite outcome endpoint including hemorrhagic events, transfusion requirements, and mortality., Trial Registration: ClinicalTrials.gov, NCT03208270 . Registered on 5 July 2017.

Background: During orthotopic liver transplantation (OLT), liver graft ischemia-reperfusion injury (IRI) triggers a cytokine-mediated systemic inflammatory response, which impairs graft function and disrupts distal organ homeostasis. The objective of this prospective, observational trial was to assess the effects of IRI on lung and chest wall mechanics in the intraoperative period of patients undergoing OLT., Methods: In 26 patients undergoing OLT, we measured elastance of the respiratory system (ERS), partitioned into lung (EL) and chest wall (ECW), hemodynamics, and fluid and blood product intake before laparotomy (T1), after portal/caval surgical clamp (T2), and immediately (T3) and, at 90 and 180 minutes post-reperfusion (T4 and T5, respectively). Interleukin-6 (IL-6), monocyte chemotactic protein-1 (MCP-1), IL-1β and tumor necrosis factor-α plasma concentrations were assessed at T1, T4 and T5., Results: EL significantly decreased from T1 to T2 (13.5±4.4 vs 9.7±4.8 cmH2O/L, P<0.05), remained stable at T3, while at T4 (12.3±4.4 cmH2O/L, P<0.05) was well above levels recorded at T2, reaching its highest value at T5 (15±3.9 cmH2O/L, P<0.05). Variations in ERS, EL, driving pressure (∆P) and trans-pulmonary pressure (∆PL) significantly correlated with changes in IL-6 and MCP-1 plasma concentrations, but not with changes in wedge pressure, fluid amounts, and red blood cells and platelets administered. No correlation was found between changes in cytokine concentrations and ECW., Conclusions: We found that EL, ECW, ∆P and ∆PL underwent significant variations during the OLT procedure. Further, we documented a significant association between the respiratory mechanics changes and the inflammatory response following liver graft reperfusion.

Background: Volatile (inhaled) anesthetic agents have cardioprotective effects, which might improve clinical outcomes in patients undergoing coronary-artery bypass grafting (CABG)., Methods: We conducted a pragmatic, multicenter, single-blind, controlled trial at 36 centers in 13 countries. Patients scheduled to undergo elective CABG were randomly assigned to an intraoperative anesthetic regimen that included a volatile anesthetic (desflurane, isoflurane, or sevoflurane) or to total intravenous anesthesia. The primary outcome was death from any cause at 1 year., Results: A total of 5400 patients were randomly assigned: 2709 to the volatile anesthetics group and 2691 to the total intravenous anesthesia group. On-pump CABG was performed in 64% of patients, with a mean duration of cardiopulmonary bypass of 79 minutes. The two groups were similar with respect to demographic and clinical characteristics at baseline, the duration of cardiopulmonary bypass, and the number of grafts. At the time of the second interim analysis, the data and safety monitoring board advised that the trial should be stopped for futility. No significant difference between the groups with respect to deaths from any cause was seen at 1 year (2.8% in the volatile anesthetics group and 3.0% in the total intravenous anesthesia group; relative risk, 0.94; 95% confidence interval [CI], 0.69 to 1.29; P = 0.71), with data available for 5353 patients (99.1%), or at 30 days (1.4% and 1.3%, respectively; relative risk, 1.11; 95% CI, 0.70 to 1.76), with data available for 5398 patients (99.9%). There were no significant differences between the groups in any of the secondary outcomes or in the incidence of prespecified adverse events, including myocardial infarction., Conclusions: Among patients undergoing elective CABG, anesthesia with a volatile agent did not result in significantly fewer deaths at 1 year than total intravenous anesthesia. (Funded by the Italian Ministry of Health; MYRIAD ClinicalTrials.gov number, NCT02105610.)., (Copyright © 2019 Massachusetts Medical Society.)

Background: Lung metabolism during ex vivo lung perfusion (EVLP) is increasingly studied. Microdialysis (MD) allows metabolic monitoring by sampling parenchymal interstitial fluid. This study investigated lung metabolism using MD during EVLP and evaluated whether microdialysate metabolites could improve selection and discriminate outcome of donor lungs., Methods: MD monitoring was used during 14 clinical EVLP procedures. Paired microdialysate and perfusate samples were analyzed for glucose, lactate, pyruvate, glutamate, and the lactate/pyruvate (L/P) ratio, and values that best discriminated an unfavorable outcome were determined. Outcome was defined as unfavorable (lungs not transplanted or transplanted with primary graft dysfunction at 72 hours ≥ 2) or favorable (lungs transplanted with primary graft dysfunction < 2)., Results: Microdialysate markers and the perfusate L/P ratio could discriminate unfavorable outcome with sensitivity and specificity of 0.85 and 0.81 for MD glutamate > 18.4 μmol/liter, 0.81 and 0.74 for MD lactate > 685 μmol/liter, 0.92 and 0.75 for MD glucose > 530 μmol/liter, 0.85 and 0.65 for MD pyruvate > 25 μmol/liter, and 0.73 and 0.67 for perfusate L/P ratio > 24.17. All microdialysate markers, perfusate and microdialysate L/P ratio, and perfusate lactate discriminated outcome when we limited analysis only to transplanted lungs., Conclusions: We report the use of MD to evaluate lung metabolism during clinical EVLP, demonstrating that MD metabolites can contribute to selection of reconditioned lungs and discriminate early outcome after transplantation. Furthermore, glutamate as a marker of lung injury during EVLP is proposed and could hence be used as a potential target for future therapies., (Copyright © 2018 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Lung transplantation is the treatment of choice for end-stage pulmonary disease in selected patients. However, severe primary graft dysfunction is a significant complication of transplant and requires the implantation of an extracorporeal support. The aim of the study is to evaluate the impact of extracorporeal membrane oxygenation (ECMO) after transplant in our center., Methods: From January 2008 till June 2018, 195 consecutive unselected patients receiving a lung transplant were considered. Mean age was 49±15 years. Main indications for transplant were idiopathic pulmonary fibrosis in 72 patients, chronic obstructive pulmonary disease in 60 patients, and cystic fibrosis in 40 patients. Prior to transplant, 18 patients were on mechanical ventilation and 14 were on ECMO., Results: Twenty-five patients required venous-venous ECMO after transplant. Vascular disease as cause of transplant [relative risk (RR) 7.8, 95% CI: 1.5-41, P=0.02], donor age (RR 1.6, 95% CI: 1.03-2.3, P=0.03) and need for cardiopulmonary by-pass during transplant (RR 3.1, 95% CI: 1.02-9, P=0.04) were associated with ECMO implantation. Patients requiring post-transplant ECMO received more transfusions (P<0.01), had a longer mechanical ventilation (P<0.01) and ICU stay (P<0.01) and had a higher hospital mortality (P<0.01). Post-transplant ECMO significantly influenced one- and five-year survival [hazard ratio (HR) 5.5, 95% CI: 3-10, P<0.001 and HR 3.5, 95% CI: 2-6, P<0.001, respectively]. However, conditional survival after t months is similar for patients with or without post-transplant ECMO., Conclusions: In our experience, although ECMO is a reliable and effective strategy to support pulmonary function, severe graft dysfunction after lung transplantation still has a significant impact on early and late results., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

More than two-thirds of critically ill patients receive an antimicrobial therapy with a percentage between 30% and 50% of all prescribed antibiotics reported to be unnecessary, inappropriate or misused. Since inappropriate prescription of antibiotic drugs concurs to dissemination of the multidrug resistant organisms, a reasoned antibiotics use is crucial especially in Intensive Care Unit (ICU), where up to 60% of the admitted patients develops an infection during their ICU stay. Even if the concept of antimicrobial stewardship (AS) has been clearly described as a series of coordinated interventions designed to improve antimicrobial agents use, few studies are reporting about its effectiveness to improve outcomes, reduce adverse events and costs and decrease resistance rate spread. Moreover, although it is recognized that AS programs are particularly indicated in the critical setting due to the huge number of antimicrobial drugs used, the optimal characteristics of these interventions and the best system to evaluate their effectiveness are still unclear. Specific interventions, designed tacking into account the peculiarities of the ICU setting, are hence necessary to set-up an "in-ICU-stewardship," including prompt identification of infected patients, selection of appropriate empiric treatments, optimization of dosing and route of administration, improvement of diagnostic techniques, early de-escalation to achieve shorter duration and avoid unnecessary therapies. The present narrative review summarizes the "state of art" about AS programmes and discusses the effects of the interventions possibly applied in ICU setting to optimize the patient's treatment, reduce the micro-organisms resistance and contain the hospital resources utilization.

Objective: Acute kidney injury (AKI) occurs frequently after cardiac surgery. Levosimendan might reduce the incidence of AKI in patients undergoing cardiac surgery. The authors investigated whether levosimendan administration could reduce AKI incidence in a high-risk cardiac surgical population., Design: Post hoc analysis of a multicenter randomized trial., Setting: Cardiac surgery operating rooms and intensive care units of 14 centers in 3 countries., Participants: The study comprised 90 patients who underwent mitral valve surgery with an estimated glomerular filtration rate <60 mL/min/1.73 m 2 and perioperative myocardial dysfunction., Interventions: Patients were assigned randomly to receive levosimendan (0.025-0.2 μg/kg/min) or placebo in addition to standard inotropic treatment., Measurements and Main Results: Forty-six patients were assigned to receive levosimendan and 44 to receive placebo. Postoperative AKI occurred in 14 (30%) patients in the levosimendan group versus 23 (52%) in the placebo group (absolute difference -21.8; 95% confidence interval -41.7 to -1.97; p = 0.035). The incidence of major complications also was lower (18 [39%]) in the levosimendan group versus that in the placebo group (29 [66%]) (absolute difference -26.8 [-46.7 to -6.90]; p = 0.011). A trend toward lower serum creatinine at intensive care unit discharge was observed in the levosimendan group (1.18 [0.99-1.49] mg/dL) versus that in the placebo group (1.39 [1.05-1.76] mg/dL) (95% confidence interval -0.23 [-0.49 to 0.01]; p = 0.07)., Conclusions: Levosimendan may improve renal outcome in cardiac surgery patients with chronic kidney disease undergoing mitral valve surgery who develop perioperative myocardial dysfunction. Results of this exploratory analysis should be investigated in future properly designed randomized controlled trials., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: Apparent life-threatening event (ALTE) refers to a constellation of unexpected events suddenly occurring in infants that extremely alarm the observers. The objectives of this study were to evaluate 1) intervention of Emergency Service (ES) at home, 2) parental behavior before ES intervention, 3) patients' outcome at follow-up of a minimum of 6 months., Methods: Retrospective study of infants younger than 12 months whose parents called ES and were evaluated for ALTE from 2005 to 2014. Tactile stimulation (TS) was defined as any maneuver performed by parents or ES staff aimed at rescuing patients without cardiopulmonary resuscitation attempts. Cardiopulmonary resuscitation was defined according to American Heart Association Guidelines 2010., Results: One hundred eighty-eight patients were eligible. Emergency Service provided intervention for 178 infants (10 were assisted only by phone). All patients received TS by parents before ES arrival. Mean time for ES to reach patient location was 15 ± 10 minutes. On examination, 136 patients (76.5%) seemed normal and 42 symptomatic. One hundred sixty-three patients were brought to the emergency department where 23 patients were found symptomatic. One hundred six of 163 patients underwent capillary blood gas determination and, in 28 (26%) of 106, alterations were found. No infant had subsequent cardiopulmonary arrest or clinically evident adverse neurological outcome. Six were found to be epileptic. No infant died during the episode or during follow-up., Conclusions: Our findings suggest that ALTE is an alarming but self-limiting phenomenon that can be resolved either spontaneously or by simple TS in most cases. Emergency Service should solicit patients' physiological responses through TS first while considering a cardiopulmonary resuscitation maneuver.

Background: The feasibility and safety of transanal endoscopic microsurgery (TEM) performed under spinal anesthesia (SA) has been recently demonstrated. This retrospective study compared the differences in opioid consumption and postoperative recovery in patients undergoing TEM under GA and SA., Methods: All consecutive patients who underwent TEM at Città della Salute e della Scienza Hospital of Turin (Italy) between January 2012 and December 2015 were enrolled. Data related to demographic characteristics, surgery, anesthesia management and postoperative course were recorded from the hospital electronic registry of medical records. Patients were treated according to a standardized protocol by a team of three anesthesiologists with experience in both GA and SA., Results: The study included 148 patients: 77 in GA group and 71 in SA, with no switch among groups. Hospital length of stay was shorter in SA group (3 vs. 4 days, P=0.0201). SA patients were earlier mobilized and applied to oral postoperative intake (18 vs. 24 hours and 24 vs. 48 hours, respectively, P<0.0001). Peri-procedural complications, postoperative nausea, vomiting and pain were comparable between groups. Percentage of patients requiring postoperative rescue therapy with Tramadol was similar between groups, but SA patients received a lower opioid dosage (176.6±67.8 mg vs. 238.3±79.5 mg, P=0.0011). Operating room occupancy times was longer in GA group (120 vs. 100 minutes, P=0.0008)., Conclusions: SA seems to be the treatment of choice, when not contraindicated, in patients undergoing TEM, allowing a reduction in perioperative opioid consumption and a faster postoperative recovery.

Background: Acute pain is among the leading causes of referral to the emergency department (ED) in industrialized countries. Its management mainly depends on intensity. Moderate-to-severe pain is treated with intravenous (IV) administered opioids, of which morphine is the most commonly used in the ED. We have estimated the burden of IV administration of morphine in the five key European countries (EU5) using a micro-costing approach., Scope: A structured literature review was conducted to identify clinical guidelines for acute pain management in EU5 and clinical studies conducted in the ED setting. The data identified in this literature review constituted the source for all model input parameters, which were clustered as analgesic (morphine), material used for IV morphine administration, nurse workforce time and management of morphine-related adverse events and IV-related complications., Findings: The cost per patient of IV morphine administration in the ED ranges between €18.31 in Spain and €28.38 in Germany. If costs associated with the management of morphine-related adverse events and IV-related complications are also considered, the total costs amount to €121.13-€132.43. The main driver of those total costs is the management of IV-related complications (phlebitis, extravasation and IV prescription errors; 73% of all costs) followed by workforce time (14%)., Conclusions: IV morphine provides effective pain relief in the ED, but the costs associated with the IV administration inflict an economic burden on the respective national health services in EU5. An equally rapid-onset and efficacious analgesic that does not require IV administration could reduce this burden., Competing Interests: Disclosure and potential conflicts of interest: The research described in this article, the drafting of this manuscript and its publication were funded by AcelRx. KD is an employee of AcelRx. The work of IQVIA was funded by AcelRx. MC and MH are consultants to AcelRx. LB and GP are physicians. LB reports honorarium from BBraun Italia, Medtronic and MSD, and GP from AcelRx. The International Committee of Medical Journal Editors (ICMJE) Potential Conflicts of Interests form for the authors are available for download at: http://www.drugsincontext.com/wp-content/uploads/2018/03/dic.212524-COI.pdf