Efficacy and safety of aerosolized intra-tracheal dornase alfa administration in patients with SARS-CoV-2-induced acute respiratory distress syndrome (ARDS): a structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) may trigger severe pneumonia in coronavirus disease of 2019 (COVID-19) patients through release of damage-associated molecular patterns (DAMPs) and recruitment of neutrophils in the lungs. Activated neutrophils induce inflammation and severe alveolar injury by releasing neutrophil extracellular traps (NETs). The backbones of many DAMPs and NETs are made of extracellular, cell-free DNA decorated with highly toxic compounds such as elastase, myeloperoxidase and citrullinated histones. Dornase alfa is a FDA-approved recombinant human DNAse 1 for the treatment of cystic fibrosis, which cleaves extracellular DNA and may break up cell-free DNA, loosening sticky mucus in the distal airways and reducing NETs-induced toxicity on alveolar pneumocytes. The COVIDornase trial intends to define the impact of aerosolized intra-tracheal dornase alfa administration on the severity and progression of acute respiratory distress syndrome (ARDS) in COVID-19 patients. This drug might make lung mucus thinner and looser, promoting improved clearance of secretions and reduce extracellular double-stranded DNA-induced hyperinflammation in alveoli, preventing further damage to the lungs. TRIAL DESIGN: COVIDornase is a prospective, randomized, controlled, 2-arm (1:1 ratio), multicentric, open-label clinical trial. PARTICIPANTS: The study will recruit mechanically ventilated patients hospitalized in the intensive care unit (ICU) in the recruiting centres (at the time of writing: The Rothschild foundation hospital in Paris, the Strasbourg university hospitals, and Metz-Thionville hospital) who have been diagnosed with COVID-19 and meet ARDS criteria. INCLUSION CRITERIA: - Adult patient (age ≥ 18 years old); - Hospitalized in ICU; - With severe COVID-19 pneumonia and ARDS according to Berlin criteria (PaO2/FiO2 < 300 and PEEP > 5 cmH2O); - Intubated for less than 8 days; - With an anticipated duration of mechanical ventilation > 48 hours; - Carrier of an arterial catheter; - For whom 4 PaO2/FiO2 values over the preceding 24 hours are available; NON-INCLUSION CRITERIA: - Known hypersensitivity to dornase alfa or any of its excipients; - Pregnant or breastfeeding status; - Patient under legal protection. INTERVENTION AND COMPARATOR: Intervention 1, Study group Dornase alfa (Pulmozyme®, Roche, Switzerland) will be administered by aerosol, at a dose of 2500 IU twice daily, 12 hours apart, for 7 consecutive days, using a vibrating mesh nebulizer (Aerogen Solo®, Aerogen, Ireland). The remainder of the management will be performed in accordance with good clinical practice, including mechanical ventilation (protective ventilation, PEEP > 5 cmH2O, tracheal balloon pressure check every 4 hours or automatic device, 30° head of the bed elevation, tidal volume 6-8mL/kg, plateau pressure < 30 cmH2O), neuromuscular blockers if necessary, prone position if PaO2/FiO2 < 150, early enteral nutrition, glycemic control and a sedation protocol based on the RASS score. Intervention 2, Comparator Patients will receive usual care in accordance with good practice (as detailed above), without aerosols. MAIN OUTCOMES: The primary outcome is the occurrence of at least one grade improvement between D0 (inclusion) and D7 in the ARDS scale severity (Berlin criteria). For instance from "severe" to "moderate" or from "moderate" to "mild". RANDOMISATION: All consecutive patients meeting the inclusion criteria will be randomised 1:1 using an eCRF-based, computer-generated randomisation table, either to the dornase alfa arm or to the control arm. An interim analysis will be performed after inclusion of 20 patients. Inclusions may be stopped at the interim analysis per data safety and monitoring board (DSMB) advice, if statistical analyses conclude on the futility or efficacy of the intervention or by other DSMB decision. BLINDING (MASKING): The participants and caregivers will not be blinded to study group assignment. Those assessing the outcomes will be blinded to study group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): Fifty patients will be randomized to each group, 100 patients in total. TRIAL STATUS: Protocol version number 2, April 29th, 2020. Recruitment is ongoing. The trial started recruitment on the 21st April 2020. We estimate recruitment will finish August 21st 2020. TRIAL REGISTRATION: The trial was registered in ClinicalTrials.gov on 21 April 2020, updated on 8 May 2020. Trial registration number is NCT04355364. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated. This Letter serves as a summary of the key elements of the full protocol.

Serious adverse events and deaths linked to poor ventilator use: A report of four closed claims.

Through this series of four closed claims, we highlight examples of accidents stemming from poor ventilator use. We then review the main issues in this regard as reported in the literature and by learned societies. This case series has led us to emphasise the need for safety procedures involving systematic checks prior to use, declaration and analysis of the risk, as well as feedback and teaching regarding ventilation systems.

Norepinephrine exerts an inotropic effect during the early phase of human septic shock.

BACKGROUND: We conducted this study to investigate whether norepinephrine increases cardiac contractility when administered during the early phase of septic shock. METHODS: We studied 38 patients with septic shock who had been resuscitated for <3 h and whose mean arterial pressure (MAP) remained <65 mm Hg. Echocardiographic variables were obtained before (T0) and after either initiation or an increase in the dose of a norepinephrine infusion to increase MAP to ≥ 65 mm Hg (T1). We collected left ventricular ejection fraction (LVEF), velocity-time integral of the left ventricular outflow tract (VTI), tissue Doppler imaging of mean systolic velocity of the lateral tricuspid annulus (Sa) and of the lateral mitral annulus (Sm), and tricuspid annular plane systolic excursion (TAPSE). RESULTS: There were significant (P<0.05) increases from T0 to T1 in MAP [mean (sd): from 56 (7) to 80 (9) mm Hg], LVEF [from 49 (13) to 56 (13)%], VTI [from 18 (5) to 20 (6) cm], Sm [from 10.8 (5.1) to 12.1 (5.0) cm s-1], TAPSE [from 1.8 (0.5) to 2.0 (0.5) cm], and Sa [from 13.0 (5.6) to 15.1 (6.4) cm s-1]. In the subgroup of 15 patients with LVEF ≤45%, significant increases in VTI [from 16 (8) to 18 (7) cm] and in LVEF [from 36 (7) to 44 (10)%] were observed. CONCLUSIONS: Norepinephrine administration during early resuscitation in patients with septic shock increased the cardiac systolic function despite the presumed increase in left ventricular afterload secondary to the increased arterial pressure. Whether such an effect persists over time remains to be evaluated. CLINICAL TRIAL REGISTRATION: NCT02750683.

Description and analysis of hospital pharmacies in Madagascar.

OBJECTIVE: Madagascar's health care system has operated without formal hospital pharmacies for more than two decades. The gradual integration of pharmacists in public hospitals since 2012 will allow the structuring of this field. This study was conducted to characterize the current situation regarding all aspects relating to the general functioning of hospital pharmacies and the services provided. METHODS: This qualitative research used semi-structured interviews. Interviewees' perceptions about the general organization and functioning of hospital pharmacies and details on services provided were collected. The 16 interviewees were Ministry of Health staff members involved in hospital pharmacy, hospital directors, medical staff members and hospital pharmacy managers. Interviews were recorded, translated into French if conducted in Malagasy, and fully transcribed. Verbatim transcripts were coded according to the themes of hospital pharmacy and topical content analysis was performed. RESULTS: The principal issue perceived by interviewees was the heterogeneity of the system in terms of technical and financing management, with a main impact on the restocking of pharmaceutical products. The drug supply chain is not under control: no internal procedure has been established for the selection of pharmaceutical products, the quantification of needs is complex, stock management is difficult to supervise, a standard prescription protocol is lacking, dispensing is performed by unqualified staff, no pharmaceutical preparation is manufactured in the hospitals and administration occurs without pharmaceutical support. CONCLUSIONS: Progressive structuring of efficient hospital pharmacy services using the Basel statements for the future of hospital pharmacy is urgently needed to improve health care in Madagascar.

Iatrogenic peritonitis following an incident during ablation of a pedicle screw.

Immediate complications can arise due to faulty implantation of material during fusion procedures, but none have been reported in connection with ablation of material in the spine. We report a case of intraperitoneal migration of a pedicle screw during attempted removal. It crossed the psoas muscle and perforated a small-intestine loop, triggering hemorrhagic shock and peritonitis by perforation. We analyze the causes and mechanisms underlying this exceptional case of migration, with a view to sharing preventive measures. Initial extra-pedicular screw positioning and the pressure exerted to remove it were responsible for this serious incident.

Efficacy and safety of a new coverlet device on skin microclimate management: a pilot study in critical care patients.

OBJECTIVE: To test the effect of a new coverlet device, allowing air circulation at the body/underlying surface interface, on skin microclimate management. METHOD: This prospective observational pilot study took place in a 15-bed university-affiliated intensive care unit. Overall, 34 mechanically ventilated patients were included. Skin humidity and temperature were monitored before and after the implementation of the tested device at the occiput, scapulas, buttocks and sacrum. Humidity and temperature were evaluated through surface skin impedance and an infra-red thermometer, respectively. Health professionals were asked to evaluate the device. RESULTS: After implementation of the coverlet device, there was a rapid, sustained and significant decrease in skin humidity at all sites ranging from 6 % to 15 %, excluding the occiput. Skin temperature also significantly decreased from 1 % at both scapulas, but not at the other studied body sites. No side effects were observed. Health professionals reported that the device was easy and quick to install. Although they did not report a subjective improvement in skin moisture or temperature, they considered the device to be efficient. CONCLUSION: Although limited by its design, this pilot study suggests a good efficacy of the studied device on skin microclimate management. Further data are warranted to test the clinical implications of our findings.

How obesity relates to socio-economic status: identification of eating behavior mediators.

BACKGROUND: Socio-economic status (SES) is a strong determinant of eating behavior and the obesity risk. OBJECTIVE: To determine which eating and lifestyle behaviors mediate the association between SES and obesity. METHODS: We performed a case-control study of 318 obese people and 371 non-obese people in northern France. Ten eating behavior traits were assessed using the Three-Factor Eating Questionnaire Revised 21-Item and an eating attitude questionnaire (on plate size, the number of servings, reasons for stopping eating and the frequency of eating standing up, eating in front of the television set (TV) and eating at night). The SES score (in three categories) was based on occupation, education and income categories. Mediation analysis was performed using the test of joint significance and the difference of coefficients test. RESULTS: The age- and gender-adjusted obesity risk was higher for individuals in the low-SES groups (odds ratio (OR) (95% confidence interval (CI)=1.82 (1.48-2.24), P<0.0001). Additional servings were associated with a higher obesity risk (OR=3.43, P<0.0001). Cognitive restraint (P<0.0001) and emotional eating (P<0.0001) scores were higher in obese participants than in non-obese participants but did not depend on SES. Of the 10 potential factors tested, eating off a large plate (P=0.01), eating at night (P=0.04) and uncontrolled eating (P=0.03) significantly mediated the relationship between SES and obesity. CONCLUSION: Our results highlighted a number of obesogenic behaviors among socially disadvantaged participants: large plate size, uncontrolled eating and eating at night were significant mediators of the relationship between SES and the obesity risk.

[In vitro study of the flow duration of antibiotics solutions prepared in elastomeric infusion devices: effect of cold storage for 3 to 7days]. / Étude in vitro de la durée d'écoulement de solutions antibiotiques préparées dans des diffuseurs portables élastomériques : effet du stockage au froid pendant trois à sept jours.

INTRODUCTION: Within the cystic fibrosis patients' home care, EMERAA network ("Together against Cystic fibrosis in Rhone-Alpes and Auvergne") organizes parenteral antibiotics cures at home prepared in elastomeric infusion devices by hospital pharmacies. However, patients and nurses found that the durations of infusion with these devices were often longer than the nominal duration of infusion indicated by their manufacturer. This study aimed to identify the potential different causes in relation to these discordances. MATERIAL AND METHODS: Three hundred and ninety devices of two different manufacturers are tested in different experimental conditions: three antibiotics each at two different doses, duration of cold storage (three days or seven days) or immediate tests without cold storage, preparation and storage of the solution in the device (protocol Device) or transfer in the device just before measurement (protocol Pocket). RESULTS: All tests highlighted a longer flow duration for devices prepared according to the protocol Device versus the protocol Pocket (P=0.004). Flow duration is increased in the case of high doses of antibiotics with high viscosity such as piperacilline/tazobactam. DISCUSSION: The results of this in vitro study showed the impact of: (1) the time between the filling of the device and the flow of the solution; (2) cold storage of elastomeric infusion devices; (3) concentration of antibiotics and therefore the viscosity of the solution to infuse. CONCLUSION: It is therefore essential that health care teams are aware of factors, which may lead to longer infusion durations with these infusion devices. When the additional time for infusion remain acceptable, it should be necessary to inform the patient and to relativize these lengthening compared to many benefits that these devices provide for home care.

[From medical complication to compensation for the prejudice]. / De la complication médicale à l'indemnisation du préjudice.

Claims in anesthesia and intensive care remains high, despite the reduction of morbidity and mortality associated with this activity. The absence of a national register makes it difficult to quantify. The Medical Committee of MACSF-Sou Medical Group, professional liability insurer of more than half of French physicians, provided us support. The amount of compensation paid is growing and the scope of compensated damage is expanded by the Dintilhac mission. The Act of March 4, 2002 has fully confirmed the principle of medical liability for misconduct. Generally, compensation for bodily injury is based on the demonstration of a causal link between a wrongful event and injury. The proof of fault lies with the applicant. Information accountable to patients and nosocomial infection are a particular setting. The Act of March 4, 2002 has also defined the concept of therapeutic risk. With the establishment of the Regional Commissions of Conciliation and Compensation (RCCI) and the National Office for Compensation of Medical Accident (Oniam), it is now possible for a patient to be compensated for an injury resulting from an accident Medical non-offending, while acknowledging the lack of accountability of the practitioner. The expertise conducted by an RCCI is adversarial. For the practitioner called to the cause, it is important to prepare for both substance and form, with the assistance of the medical board's insurance company.

[Nadroparin-induced skin necrosis then thrombocytosis in intensive care unit: difficulty in diagnosis]. / Nécrose cutanée et thrombocytose induites par la nadroparine en réanimation: un diagnostic inhabituel.

Skin necrosis is a rare complication in intensive care unit. A case-report of nadroparine-induced skin necrosis and thrombocytosis in a patient with traumatic paraplegia is reported. This case emphasised the difficulty in diagnosis despite absence of thrombopenia. A skin necrosis could suggest the diagnosis and a substitutive therapy must be administrated after heparin therapy withdrawal. A thrombocytosis is a little reported complication of low-molecular-weight heparins without complication.

[Prevalence of dysphosphoremia in patients admitted in intensive care unit with an impaired renal function]. / Prévalence des dysphosphorémies chez les patients admis en réanimation avec une altération de la fonction rénale.

OBJECTIVE: To assess the frequency of dysphosphoremia in patients admitted in intensive care unit with an impaired renal function and to determine the associated risks factors. Study design. - Epidemiological prospective study. PATIENTS AND METHODS: The creatinine clearance and the phosphoremia were measured in 134 consecutive patients admitted in intensive care unit over a six-month period. Patients with chronic renal failure were excluded. Known risk factors for hypophosphoremia in intensive care unit were recorded. RESULTS: Seventy-nine out of one hundred thirty-four patients (59%) had an impaired renal function (arbitrarily defined by a creatinine clearance < 60 ml/min). The proportion of patients with impaired renal function that where hypo-, normo- (0.8 to 1.2 mmol/l) or hyperphosphoremic was 16, 34 and 50% respectively. Hypophosphoremia was severe (< 0.5 mmol/l) in 5 patients, all with impaired renal function. No risk factors usually associated with hypophosphoremia could be identified. CONCLUSION: As opposed to chronic renal failure patients who are mainly hyperphosphoremic, patients admitted in intensive care unit with an impaired renal function may present with a normo-, or hypophosphoremia. These dysphosphoremias are sometimes severe. Phosphate status should be promptly determined at admission.

Drugs for neglected diseases: a failure of the market and a public health failure?

Infectious diseases cause the suffering of hundreds of millions of people, especially in tropical and subtropical areas. Effective, affordable and easy-to-use medicines to fight these diseases are nearly absent. Although science and technology are sufficiently advanced to provide the necessary medicines, very few new drugs are being developed. However, drug discovery is not the major bottleneck. Today's R&D-based pharmaceutical industry is reluctant to invest in the development of drugs to treat the major diseases of the poor, because return on investment cannot be guaranteed. With national and international politics supporting a free market-based world order, financial opportunities rather than global health needs guide the direction of new drug development. Can we accept that the dearth of effective drugs for diseases that mainly affect the poor is simply the sad but inevitable consequence of a global market economy? Or is it a massive public health failure, and a failure to direct economic development for the benefit of society? An urgent reorientation of priorities in drug development and health policy is needed. The pharmaceutical industry must contribute to this effort, but national and international policies need to direct the global economy to address the true health needs of society. This requires political will, a strong commitment to prioritize health considerations over economic interests, and the enforcement of regulations and other mechanisms to stimulate essential drug development. New and creative strategies involving both the public and the private sector are needed to ensure that affordable medicines for today's neglected diseases are developed. Priority action areas include advocating an essential medicines R&D agenda, capacity-building in and technology transfer to developing countries, elaborating an adapted legal and regulatory framework, prioritizing funding for essential drug development and securing availability, accessibility, distribution and rational use of these drugs.

[Pharmaceutical development concerning diseases predominating in tropical regions: the concept of indigent drugs]. / Le développement pharmaceutique en matière de maladies dominantes de la zone intertropicale: le concept de médicaments indigents.

When the WHO certified the eradication of smallpox in 1981, there was a general impression that the fight against infectious diseases which began with Jenner and Pasteur was entering a phase of achievement: poliomyelitis, dracunculasis, leprosy, Chagas' disease and neonatal tetanus were also responding to eradication campaigns. However, in 1995, infectious diseases are still an important cause of mortality and morbidity and the rising incidence of emerging or re-emerging diseases remains a matter of great concern. Although this situation can be explained, at least partly, by the deterioration of health care systems and diverse socio-economic and ecological disorders, important changes occurring in the drug industry since 1980 have also played a role due to changes in pharmaco-epidemiology and new policies of drug development. Among the 1061 new drugs developed from 1975 to 1994, less than 2.7% concern tropical diseases. Since praziquantel, novel drugs have issued from veterinary medicine (ivermectin), military research (halofantrine, mefloquine) or fortuitous analysis of pharmacopoeia (artesunate). The cost of investments and the lack of market potential and market security in developing countries have dampened interest in developing drugs for tropical diseases. Observing the combined effect of deficient pharmaceutical development, drug wear due to chemoresistance (chloroquine, sulfadoxine-pyrimethamine, aminopenicillins), the cost barrier (second generation molecules) and the potential abandon of major drugs (eflornithine, melarsoprol) has led us to establish a classification of these "indigent" drugs (in opposition to "orphan" drugs) into five classes: true indigent drugs (eflornithine), indigent drugs by indication (pentamidine), indigent drugs by function (ceftriaxone), indigent drugs by formulation (melarsoprol) and indigent drugs by default (suramin). This analysis can serve as a basis for a search for solutions (regulatory, administrative and financial incentives) favoring a reactivation of drug development for diseases predominating in intertropical regions.

Is orphan drug status beneficial to tropical disease control? Comparison of the American and future European orphan drug acts.

UNLABELLED: OBJECTIVES To quantify past outcomes of tropical pharmacology research and development (R & D) and to assess past benefits of the American orphan drug act and potential benefits of the future European orphan drug regulation on tropical diseases. METHODS: This paper presents two analyses: a 1983-97 retrospective study of the United States Orphan Drug Act concerning rare diseases and a prospective study of the European Proposal for a Regulation Concerning Orphan Drugs and its possible impact on tropical diseases. RESULTS: Different programmes have in the past tried to stimulate R & D in this area, but results remain limited. Of 1450 new chemical entities marketed between 1972 and 1997, 13 were specifically for tropical diseases and considered as essential drugs. Between 1983 & 1997, the US Orphan Drug Act approved 837 drugs and marketing of 152 new molecular entities (NMEs). Three NMEs have been designated for malaria and human African trypanosomiasis. Seven others, already commonly used in tropical diseases, received either orphan designation or an orphan approval for another indication. Pharmaceutical companies benefit from the US framework only when the US market exclusivity clause was applicable. Future European orphan drug regulation appears to be similar to the US Orphan Drug Act. CONCLUSION The orphan drug programmes relating to rare diseases have met with some success. Considering tropical diseases rare diseases seems inadequate to boost pharmaceutical R & D. However, some provisions of the European text may be relevant to tropical diseases, admitting the need for a more specific rule for evaluations of this kind of drug and recognizing the existence of 'diseases of exception'.

Access to essential drugs in poor countries: a lost battle?

Drugs offer a simple, cost-effective solution to many health problems, provided they are available, affordable, and properly used. However, effective treatment is lacking in poor countries for many diseases, including African trypanosomiasis, Shigella dysentery, leishmaniasis, tuberculosis, and bacterial meningitis. Treatment may be precluded because no effective drug exists, it is too expensive, or it has been withdrawn from the market. Moreover, research and development in tropical diseases have come to a near standstill. This article focuses on the problems of access to quality drugs for the treatment of diseases that predominantly affect the developing world: (1) poor-quality and counterfeit drugs; (2) lack of availability of essential drugs due to fluctuating production or prohibitive cost; (3) need to develop field-based drug research to determine optimum utilization and remotivate research and development for new drugs for the developing world; and (4) potential consequences of recent World Trade Organization agreements on the availability of old and new drugs. These problems are not independent and unrelated but are a result of the fundamental nature of the pharmaceutical market and the way it is regulated.

[Research and pharmaceutical development on the subject of communicable diseases in the intertropical region]. / Recherche et développement pharmaceutiques en matière de maladies transmissibles dans la zone intertropicale.

The development of the antimalarial drugs mefloquine and halofantrine in 1988 by American military research teams marked a start in the decline in investment in tropical disease research and drug development. The globalization of the market, increased clinical costs, and constraints on public health spending caused the pharmaceutical industry to concentrate on more profitable market segments (cardiovascular drugs, antineoplastics, anti-infection drugs, etc.). The market in developing countries represents a large volume, but a very low return because the added value is small, generic drugs are used and the state of the populations is impoverished. The ten or so drugs that have been developed recently result from chance (eflornithine), veterinary research (ivermectin), fortuitous analysis of traditional pharmacopoeia (artemether) or reevaluations of former drugs (amopyroquine). The deficiency of research and drug development for diseases of the intertropical zone has a direct negative effect on public health and also reveals health policy inconsistencies, particularly the incompatibility of the pharmaceutical industry's interests and international health priorities. The problem is also aggravated by the closed approach of external health assistance (official development aid) which aims to minimize costs by favoring primary health care.