Francesco Della Corte

Inhibition of Poly(Adenosine Diphosphate-Ribose) Polymerase Attenuates Ventilator-induced Lung Injury

Background:Mechanical ventilation can induce organ injury associated with overwhelming inflammatory responses. Excessive activation of poly(adenosine diphosphate–ribose) polymerase enzyme after massive DNA damage may aggravate inflammatory responses. Therefore, the authors hypothesized that the pharmacologic inhibition of poly(adenosine diphosphate–ribose) polymerase by PJ-34 would attenuate ventilator-induced lung injury. Methods:Anesthetized rats were subjected to intratracheal instillation of lipopolysaccharide at a dose of 6 mg/kg. The animals were then randomly assigned to receive mechanical ventilation at either low tidal volume (6 ml/kg) with 5 cm H2O positive end-expiratory pressure or high tidal volume (15 ml/kg) with zero positive end-expiratory pressure, in the presence and absence of intravenous administration of PJ-34. Results:The high-tidal-volume ventilation resulted in an increase in poly(adenosine diphosphate–ribose) polymerase activity in the lung. The treatment with PJ-34 maintained a greater oxygenation and a lower airway plateau pressure than the vehicle control group. This was associated with a decreased level of interleukin 6, active plasminogen activator inhibitor 1 in the lung, attenuated leukocyte lung transmigration, and reduced pulmonary edema and apoptosis. The administration of PJ-34 also decreased the systemic levels of tumor necrosis factor &agr; and interleukin 6, and attenuated the degree of apoptosis in the kidney. Conclusion:The pharmacologic inhibition of poly(adenosine diphosphate–ribose) polymerase reduces ventilator-induced lung injury and protects kidney function.

Effects of propofol on patient-ventilator synchrony and interaction during pressure support ventilation and neurally adjusted ventilatory assist.

Objectives:Evaluating the physiologic effects of varying depths of propofol sedation on patient-ventilator interaction and synchrony during pressure support ventilation and neurally adjusted ventilatory assist. Design:Prospective crossover randomized controlled trial. Setting:University hospital ICU. Patients:Fourteen intubated patients mechanically ventilated for acute respiratory failure. Interventions:Six 25-minute trials randomly performed applying both pressure support ventilation and neurally adjusted ventilatory assist during wakefulness and with two doses of propofol, administered by Target Control Infusion, determining light (1.26 ± 0.35 &mgr;g/mL) and deep (2.52 ± 0.71 &mgr;g/mL) sedation, as defined by the bispectral index and Ramsay Sedation Scale. Measurements and Main Results:We measured electrical activity of the diaphragm to assess neural drive and calculated its integral over time during 1 minute (∫electrical activity of the diaphragm/min) to estimate diaphragm energy expenditure (effort), arterial blood gases, airway pressure, tidal volume and its coefficient of variation, respiratory rate, neural timing components, and calculated the ineffective triggering index. Increasing the depth of sedation did not cause significant modifications of respiratory timing, while determined a progressive significant decrease in neural drive (with both modes) and effort (in pressure support ventilation only). In pressure support ventilation, the difference in ineffective triggering index between wakefulness and light sedation was negligible (from 5.9% to 7.6%, p = 0.97); with deep sedation, however, ineffective triggering index increased up to 21.8% (p < 0.0001, compared to both wakefulness and light sedation). With neurally adjusted ventilatory assist, ineffective triggering index fell to 0%, regardless of the depth of sedation. With both modes, deep sedation caused a significant increase in PaCO2, which resulted, however, from different breathing patterns and patient-ventilator interactions. Conclusions:In pressure support ventilation, deep propofol sedation increased asynchronies, while light sedation did not. Propofol reduced the respiratory drive, while breathing timing was not significantly affected. Gas exchange and breathing pattern were also influenced by propofol infusion to an extent that varied with the depth of sedation and the mode of ventilation.

Serum levels of osteopontin are increased in SIRS and sepsis

ObjectiveIn sepsis, dysregulation of the immune response leads to rapid multiorgan failure and death. Accurate and timely diagnosis is lifesaving and should discriminate sepsis from the systemic inflammatory response syndrome (SIRS) caused by non-infectious agents. Osteopontin acts as an extracellular matrix component or a soluble cytokine in inflamed tissues. Its exact role in immune response and sepsis remains to be elucidated. Therefore, we investigated the role of osteopontin in SIRS and sepsis.DesignProspective, observational study.SettingIntensive care unit of a university hospital.Patients and participantsFifty-six patients with SIRS or sepsis and 56 healthy subjects were enrolled.InterventionsWe analyzed the serum levels of osteopontin and TH1–TH2 cytokines and investigated the role of osteopontin on interleukin 6 secretion by monocytes.Measurements and main resultsSerum osteopontin levels were strikingly higher in patients than in controls and in sepsis than in SIRS, and decreased during the resolution of both the disorders. Receiver operating characteristic curves showed that osteopontin levels have discriminative power between SIRS and sepsis with an area under the curve of 0.796. Osteopontin levels directly correlated with those of interleukin 6 and in vitro, recombinant osteopontin increased interleukin 6 secretion by monocytes in both the absence and presence of high doses of lipopolysaccharide.ConclusionThese data suggest that osteopontin might be a mediator involved in the pathogenesis of SIRS and sepsis, possibly by supporting interleukin 6 secretion.Descriptor45. SIRS/Sepsis: clinical studies.

A Proposed Universal Medical and Public Health Definition of Terrorism

The lack of a universally applicable definition of terrorism has confounded the understanding of terrorism since the term was first coined in 18th Century France. Although a myriad of definitions of terrorism have been advanced over the years, virtually all of these definitions have been crisis-centered, frequently reflecting the political perspectives of those who seek to define it. In this article, we deconstruct these previously used definitions of terrorism in order to reconstruct a definition of terrorism that is consequence-centered, medically relevant, and universally harmonized. A universal medical and public health definition of terrorism will facilitate clinical and scientific research, education, and communication about terrorism-related events or disasters. We propose the following universal medical and public definition of terrorism: The intentional use of violence--real or threatened--against one or more non-combatants and/or those services essential for or protective of their health, resulting in adverse health effects in those immediately affected and their community, ranging from a loss of well-being or security to injury, illness, or death.

Serial multimodality-evoked potentials in severely head-injured patients: diagnostic and prognostic implications.

ObjectivesTo assess the prognostic reliability of multimodality-evoked potentials and to evaluate the diagnostic implications and define the limits of these evoked potentials. SettingAn ICU in a university hospital. DesignProspective clinical study. PatientsSeventy-three severely head-injured patients aged 10 to 75 yrs. MethodsSerial recording of brainstem auditory-evoked potentials and somatosensory-evoked potentials between days 1 and 21 after trauma. Comparison between evoked potential findings and prognosis, along with clinical data. ResultsConsidering the single recordings of both brainstem auditory-evoked potentials and somatosensory-evoked potentials, the accuracy of prognostication in predicting a bad outcome was good only for severely abnormal brainstem auditory-evoked potentials. Serial brainstem auditory-evoked potential recordings and simultaneous recordings of brainstem auditory-evoked potentials and somatosensory-evoked potentials proved to be good prognostic indices in predicting a favorable outcome. Brainstem auditory-evoked potentials correlated well with brainstem reflexes and with pupil asymmetries but did not correlate with Glasgow Coma Scale scores. ConclusionsSerial recording and the use of a multimodality approach provided the best prognostic capabilities. The main diagnostic implications were: a) the possibility of detecting brainstem compression by means of brainstem auditory-evoked potentials before the appearance of pupil abnormalities; b) the usefulness of brainstem auditory-evoked potentials in monitoring brainstem function in patients undergoing high-dose barbiturate therapy.The main limitations of evoked potentials were the occurrence of peripheral acoustic damage, the electromagnetic sources of artifacts in the ICU, and the administration of ototoxic drugs.

Utstein-Style Template for Uniform Data Reporting of Acute Medical Response in Disasters

Background: In 2003, the Task Force on Quality Control of Disaster Management (WADEM) published guidelines for evaluation and research on health disaster management and recommended the development of a uniform data reporting tool. Standardized and complete reporting of data related to disaster medical response activities will facilitate the interpretation of results, comparisons between medical response systems and quality improvement in the management of disaster victims. Methods: Over a two-year period, a group of 16 experts in the fields of research, education, ethics and operational aspects of disaster medical management from 8 countries carried out a consensus process based on a modified Delphi method and Utstein-style technique. Results: The EMDM Academy Consensus Group produced an Utstein-style template for uniform data reporting of acute disaster medical response, including 15 data elements with indicators, that can be used for both research and quality improvement. Conclusion: It is anticipated that the Utstein-style template will enable better and more accurate completion of reports on disaster medical response and contribute to further scientific evidence and knowledge related to disaster medical management in order to optimize medical response system interventions and to improve outcomes of disaster victims.

Renal hypoperfusion and impaired endothelium-dependent vasodilation in an animal model of VILI: the role of the peroxynitrite-PARP pathway

IntroductionMechanical ventilation (MV) can injure the lungs and contribute to an overwhelming inflammatory response, leading to acute renal failure (ARF). We previously showed that poly(adenosine diphosphate-ribose) polymerase (PARP) is involved in the development of ventilator-induced lung injury (VILI) and the related ARF, but the mechanisms underneath remain unclear. In the current study we therefore tested the hypothesis that renal blood flow and endothelial, functional and tissue changes in the kidney of rats with lipopolysaccharide (LPS)-induced lung injury aggravated by MV, is caused, in part, by activation of PARP by peroxynitrite.MethodsAnesthetized Sprague Dawley rats (n = 31), were subjected to intratracheal instillation of lipopolysaccharide at 10 mg/kg followed by 210 min of mechanical ventilation at either low tidal volume (6 mL/kg) with 5 cm H2O positive end-expiratory pressure or high tidal volume (19 mL/kg) with zero positive end-expiratory pressure in the presence or absence of a peroxynitrite decomposition catalyst, WW85 or a PARP inhibitor, PJ-34. During the experiment, hemodynamics and blood gas variables were monitored. At time (t) t = 0 and t = 180 min, renal blood flow was measured. Blood and urine were collected for creatinine clearance measurement. Arcuate renal arteries were isolated for vasoreactivity experiment and kidneys snap frozen for staining.ResultsHigh tidal volume ventilation resulted in lung injury, hypotension, renal hypoperfusion and impaired renal endothelium-dependent vasodilation, associated with renal dysfunction and tissue changes (leukocyte accumulation and increased expression of neutrophil gelatinase-associated lipocalin). Both WW85 and PJ-34 treatments attenuated lung injury, preserved blood pressure, attenuated renal endothelial dysfunction and maintained renal blood flow. In multivariable analysis, renal blood flow improvement was, independently from each other, associated with both maintained blood pressure and endothelium-dependent vasodilation by drug treatment. Finally, drug treatment improved renal function and reduced tissue changes.ConclusionsThe peroxynitrite-induced PARP activation is involved in renal hypoperfusion, impaired endothelium-dependent vasodilation and resultant dysfunction, and injury, in a model of lung injury.

Education and training initiatives for crisis management in the European Union: a web-based analysis of available programs.

INTRODUCTION Education and training are key elements of disaster management. Despite national and international educational programs in disaster management, there is no standardized curriculum available to guide the European Union (EU) member states. European- based Disaster Training Curriculum (DITAC), a multiple university-based project financially supported by the EU, is charged with developing a holistic and highly-structured curriculum and courses for responders and crisis managers at a strategic and tactical level. The purpose of this study is to qualitatively assess the prevailing preferences and characteristics of disaster management educational and training initiatives (ETIs) at a postgraduate level that currently exist in the EU countries. METHODS An Internet-based qualitative search was conducted in 2012 to identify and analyze the current training programs in disaster management. The course characteristics were evaluated for curriculum, teaching methods, modality of delivery, target groups, and funding. RESULTS The literature search identified 140 ETIs, the majority (78%) located in United Kingdom, France, and Germany. Master level degrees were the primary certificates granted to graduates. Face-to-face education was the most common teaching method (84%). Approximately 80% of the training initiatives offered multi- and cross-disciplinary disaster management content. A competency-based approach to curriculum content was present in 61% of the programs. Emergency responders at the tactical level were the main target group. Almost all programs were self-funded. CONCLUSION Although ETIs currently exist, they are not broadly available in all 27 EU countries. Also, the curricula do not cover all key elements of disaster management in a standardized and competency-based structure. This study has identified the need to develop a standardized competency-based educational and training program for all European countries that will ensure the practice and policies that meet both the standards of care and the broader expectations for professionalization of the disaster and crisis workforce.

Evaluation of Medical Management During a Mass Casualty Incident Exercise: An Objective Assessment Tool to Enhance Direct Observation

BACKGROUND Functional exercises represent an important link between disaster planning and disaster response. Although these exercises are widely performed, no standardized method exists for their evaluation. STUDY OBJECTIVES To describe a simple and objective method to assess medical performance during functional exercise events. METHODS An evaluation tool comprising three data fields (triage, clinical maneuvers, and radio usage), accompanied by direct anecdotal observational methods, was used to evaluate a large functional mass casualty incident exercise. RESULTS Seventeen medical responders managed 112 victims of a simulated building explosion. Although 81% of the patients were assigned the appropriate triage codes, evacuation from the site did not follow in priority. Required maneuvers were performed correctly in 85.2% of airway maneuvers and 78.7% of breathing maneuvers, however, significant under-treatment occurred, possibly due to equipment shortages. Extensive use of radio communication was documented. In evaluating this tool, the structured markers were informative, but further information provided by direct observation was invaluable. CONCLUSION A three-part tool (triage, medical maneuvers, and radio usage) can provide a method to evaluate functional mass casualty incident exercises, and is easily implemented. For the best results, it should be used in conjunction with direct observation. The evaluation tool has great potential as a reproducible and internationally recognized tool for evaluating disaster management exercises.

Bench-to-bedside review: Ventilation-induced renal injury through systemic mediator release - just theory or a causal relationship?

We review the current literature on the molecular mechanisms involved in the pathogenesis of acute kidney injury induced by plasma mediators released by mechanical ventilation. A comprehensive literature search in the PubMed database was performed and articles were identified that showed increased plasma levels of mediators where the increase was solely attributable to mechanical ventilation. A subsequent search revealed articles delineating the potential effects of each mediator on the kidney or kidney cells. Limited research has focused specifically on the relationship between mechanical ventilation and acute kidney injury. Only a limited number of plasma mediators has been implicated in mechanical ventilation-associated acute kidney injury. The number of mediators released during mechanical ventilation is far greater and includes pro- and anti-inflammatory mediators, but also mediators involved in coagulation, fibrinolysis, cell adhesion, apoptosis and cell growth. The potential effects of these mediators is pleiotropic and include effects on inflammation, cell recruitment, adhesion and infiltration, apoptosis and necrosis, vasoactivity, cell proliferation, coagulation and fibrinolysis, transporter regulation, lipid metabolism and cell signaling. Most research has focused on inflammatory and chemotactic mediators. There is a great disparity of knowledge of potential effects on the kidney between different mediators. From a theoretical point of view, the systemic release of several mediators induced by mechanical ventilation may play an important role in the pathophysiology of acute kidney injury. However, evidence supporting a causal relationship is lacking for the studied mediators.