Administration of protein C concentrates in patients without congenital deficit: a systematic review of the literature

Endogenous protein C levels are frequently decreased in septic patients, probably due to increased conversion to activated protein C. Protein C levels inversely correlate with morbidity and mortality of septic patients regardless of age, infecting microorganisms, presence of shock, disseminated intravascular coagulation, degree of hypercoagulation, or severity of illness. Taken together, these considerations suggest a strong correlation between protein C pathways and survival from severe sepsis/septic shock, and reinforce the rationale for the attempts to normalize plasma activity of protein C to improve survival, hamper coagulopathy, and modulate inflammation. We therefore conducted a systematic review of all manuscripts describing protein C concentrates administration in adult and pediatric populations. We identified 28 studies, for a total of 340 patients, 70 of whom died (20.6%). Septic patients were the most represented in this review of case reports and case series. In the majority of these patients sepsis was associated with meningitis, purpura fulminans or disseminated intravascular coagulation. No bleeding complications related to the study drug were reported and most studies underlined normalization of inflammatory markers and of coagulation abnormalities. We conclude that protein C concentrate is an attractive option in septic patients (especially those with meningitis, purpura fulminans, or disseminated intravascular coagulation) and that its cost-benefit ratio must be studied with a large multicenter randomized control trial, possibly including also high risk patients with septic shock and multiple organ failure

Use and reimbursement of off-label drugs in pediatric anesthesia: the Italian experience

BackgroundMost of the drugs used in anesthesia are off-label in children even if they present solid clinical evidence in adults. This lack of authorization is caused by multiple factors including the difficulty in conducting research in this area (due to the ethical concerns and/or the low number of available participants, the high variability of the outcome measures) and the lack of economic interest of the pharmaceutical companies (due to the limited market). ObjectiveDefine a list of medicinal products commonly used off-label in pediatrics anesthesia to be reimbursed by Italian National Health System. Methods and resultsWe hereby describe the methodological framework used to allow reimbursed use of a list of medicinal products, widely used off-label in pediatric patients, ensuring the best therapeutic results with the lowest possible risk for children. A task force of pediatric anesthesiologists from Italy petitioned the Italian Medicines Agency (AIFA) to allow a number of commonly utilized but off-label drugs for pediatric anesthesia to be reimbursed for specific indications. For each drug, both the supporting literature and expert opinion were used, and the resulting list of drugs allowed to be used/reimbursed officially by AIFA was significantly expanded. This paper documents one approach to the problem of off-label use of drugs for pediatric patients that can be a model for future efforts. ConclusionContinuous efforts are needed from government institutions and sponsors on drug development and on drug approval process in pediatrics, as research on drug effectiveness and safety is mandatory in children as in adults. At the same time, clinicians must become more familiar with the drug-approval process, participate to sponsored trials, and perform ztrials themselves

Effect of Continuous Epinephrine Infusion on Survival in Critically Ill Patients. A Meta-Analysis of Randomized Trials

OBJECTIVES Epinephrine is frequently used as an inotropic and vasopressor agent in critically ill patients requiring hemodynamic support. Data from observational trials suggested that epinephrine use is associated with a worse outcome as compared with other adrenergic and nonadrenergic vasoactive drugs. We performed a systematic review and meta-analysis of randomized controlled trials to investigate the effect of epinephrine administration on outcome of critically ill patients. DATA SOURCES PubMed, EMBASE, and Cochrane central register were searched by two independent investigators up to March 2019. STUDY SELECTION Inclusion criteria were: administration of epinephrine as IV continuous infusion, patients admitted to an ICU or undergoing major surgery, and randomized controlled trials. Studies on epinephrine administration as bolus (e.g., during cardiopulmonary resuscitation), were excluded. The primary outcome was mortality at the longest follow-up available. DATA EXTRACTION Two independent investigators examined and extracted data from eligible trials. DATA SYNTHESIS A total of 5,249 studies were assessed, with a total of 12 studies (1,227 patients) finally included in the meta-analysis. The majority of the trials were performed in the setting of septic shock, and the most frequent comparator was a combination of norepinephrine plus dobutamine. We found no difference in all-cause mortality at the longest follow-up available (197/579 [34.0%] in the epinephrine group vs 219/648 [33.8%] in the control group; risk ratio = 0.95; 95% CI, 0.82-1.10; p = 0.49; I = 0%). No differences in the need for renal replacement therapy, occurrence rate of myocardial ischemia, occurrence rate of arrhythmias, and length of ICU stay were observed. CONCLUSIONS Current randomized evidence showed that continuous IV administration of epinephrine as inotropic/vasopressor agent is not associated with a worse outcome in critically ill patients

Opioid Free Anesthesia in Thoracic Surgery: A Systematic Review and Meta Analysis

Introduction: Recent studies showed that balanced opioid-free anesthesia is feasible and desirable in several surgical settings. However, in thoracic surgery, scientific evidence is still lacking. Thus, we conducted the first systematic review and meta-analysis of opioid-free anesthesia in this field. Methods: The primary outcome was the occurrence of any complication. Secondary outcomes were the length of hospital stay, recovery room length of stay, postoperative pain at 24 and 48 h, and morphine equivalent consumption at 48 h. Results: Out of 375 potentially relevant articles, 6 studies (1 randomized controlled trial and 5 observational cohort studies) counting a total of 904 patients were included. Opioid-free anesthesia compared to opioid-based anesthesia, was associated with a lower rate of any complication (74 of 175 [42%] vs. 200 of 294 [68%]; RR = 0.76; 95% CI, 0.65–0.89; p 2 = 0%), lower 48 h morphine equivalent consumption (MD −14.5 [−29.17/−0.22]; p = 0.05; I2 = 95%) and lower pain at 48 h (MD −1.95 [−3.6/0.3]; p = 0.02, I = 98%). Conclusions: Opioid-free anesthesia in thoracic surgery is associated with lower postoperative complications, and less opioid demand with better postoperative analgesia at 48 h compared to opioid-based anesthesia

Extracorporeal cardiopulmonary resuscitation for refractory out-of-hospital cardiac arrest: 10-year experience in a metropolitan cardiac arrest centre in Milan, Italy

Introduction: Growing evidence supports extracorporeal cardiopulmonary resuscitation (ECPR) for refractory out-of-hospital cardiac arrest (OHCA) patients, especially in experienced centres. We present characteristics, treatments, and outcomes of patients treated with ECPR in a high-volume cardiac arrest centre in the metropolitan area of Milan, Italy and determine prognostic factors. Methods: Refractory OHCA patients treated with ECPR between 2013 and 2022 at IRCCS San Raffaele Scientific Institute in Milan had survival and neurological outcome assessed at hospital discharge. Results: Out of 307 consecutive OHCA patients treated with ECPR (95% witnessed, 66% shockable, low-flow 70 [IQR 58–81] minutes), 17% survived and 9.4% had favourable neurological outcome. Survival and favourable neurological outcome increased to 51% (OR = 8.7; 95% CI, 4.3–18) and 28% (OR = 6.3; 95% CI, 2.8–14) when initial rhythm was shockable and low-flow (time between CPR initiation and ROSC or ECMO flow) ≤60 minutes and decreased to 9.5% and 6.3% when low-flow exceeded 60 minutes (72% of patients). At multivariable analysis, shockable rhythm (aOR for survival = 2.39; 95% CI, 1.04–5.48), shorter low-flow (aOR = 0.95; 95% CI, 0.94–0.97), intermittent ROSC (aOR = 2.5; 95% CI, 1.2–5.6), and signs of life (aOR = 3.7; 95% CI, 1.5–8.7) were associated with better outcomes. Survival reached 10% after treating 104 patients (p for trend <0.001). Conclusions: Patients with initial shockable rhythm, intermittent ROSC, signs of life, and low-flow ≤60 minutes had higher success of ECPR for refractory OHCA. Favourable outcomes were possible beyond 60 minutes of low-flow, especially with concomitant favourable prognostic factors. Outcomes improved as the case-volume increased, supporting treatment in high-volume cardiac arrest centres

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): A National Analysis of Data from 10-Year Post-marketing Surveillance

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare, severe and potentially fatal cutaneous adverse drug reaction (the mortality rate is up to 10 %) associated with numerous and apparently heterogeneous drugs. The aetiology is unknown. To report Italian cases of DRESS over a 10-year period. We searched the National Pharmacovigilance Network (NPN) for the term 'drug reaction with eosinophilia and systemic symptoms' from 1 January 2004 to 1 January 2014, to identify all reports of DRESS. Each case was checked to avoid duplication. In the NPN, we identified 91 serious cases of DRESS: 68 were spontaneous, still-unpublished reports, while 23 additional cases were derived from screening of the scientific literature, performed by marketing authorization holders. Notably, the single common element linking all cases of DRESS was intake of a drug containing an aromatic ring. Thanks to the largest national DRESS case series ever reported, we were able to hypothesize, for the first time, that there is an association between use of drugs containing an aromatic ring in their chemical structure and DRESS. This might aid understanding of the aetiology of DRESS and facilitate diagnosis

Reducing mortality in acute kidney injury patients: systematic review and international web-based survey.

To identify all interventions that increase or reduce mortality in patients with acute kidney injury (AKI) and to establish the agreement between stated beliefs and actual practice in this setting