Demosthenes Makris

Vasopressin, Steroids, and Epinephrine and Neurologically Favorable Survival After In-Hospital Cardiac Arrest: A Randomized Clinical Trial

IMPORTANCEnAmong patients with cardiac arrest, preliminary data have shown improved return of spontaneous circulation and survival to hospital discharge with the vasopressin-steroids-epinephrine (VSE) combination.nnnOBJECTIVEnTo determine whether combined vasopressin-epinephrine during cardiopulmonary resuscitation (CPR) and corticosteroid supplementation during and after CPR improve survival to hospital discharge with a Cerebral Performance Category (CPC) score of 1 or 2 in vasopressor-requiring, in-hospital cardiac arrest.nnnDESIGN, SETTING, AND PARTICIPANTSnRandomized, double-blind, placebo-controlled, parallel-group trial performed from September 1, 2008, to October 1, 2010, in 3 Greek tertiary care centers (2400 beds) with 268 consecutive patients with cardiac arrest requiring epinephrine according to resuscitation guidelines (from 364 patients assessed for eligibility).nnnINTERVENTIONSnPatients received either vasopressin (20 IU/CPR cycle) plus epinephrine (1 mg/CPR cycle; cycle duration approximately 3 minutes) (VSE group, nu2009=u2009130) or saline placebo plus epinephrine (1 mg/CPR cycle; cycle duration approximately 3 minutes) (control group, nu2009=u2009138) for the first 5 CPR cycles after randomization, followed by additional epinephrine if needed. During the first CPR cycle after randomization, patients in the VSE group received methylprednisolone (40 mg) and patients in the control group received saline placebo. Shock after resuscitation was treated with stress-dose hydrocortisone (300 mg daily for 7 days maximum and gradual taper) (VSE group, nu2009=u200976) or saline placebo (control group, nu2009=u200973).nnnMAIN OUTCOMES AND MEASURESnReturn of spontaneous circulation (ROSC) for 20 minutes or longer and survival to hospital discharge with a CPC score of 1 or 2.nnnRESULTSnFollow-up was completed in all resuscitated patients. Patients in the VSE group vs patients in the control group had higher probability for ROSC of 20 minutes or longer (109/130 [83.9%] vs 91/138 [65.9%]; odds ratio [OR], 2.98; 95% CI, 1.39-6.40; Pu2009=u2009.005) and survival to hospital discharge with CPC score of 1 or 2 (18/130 [13.9%] vs 7/138 [5.1%]; OR, 3.28; 95% CI, 1.17-9.20; Pu2009=u2009.02). Patients in the VSE group with postresuscitation shock vs corresponding patients in the control group had higher probability for survival to hospital discharge with CPC scores of 1 or 2 (16/76 [21.1%] vs 6/73 [8.2%]; OR, 3.74; 95% CI, 1.20-11.62; Pu2009=u2009.02), improved hemodynamics and central venous oxygen saturation, and less organ dysfunction. Adverse event rates were similar in the 2 groups.nnnCONCLUSION AND RELEVANCEnAmong patients with cardiac arrest requiring vasopressors, combined vasopressin-epinephrine and methylprednisolone during CPR and stress-dose hydrocortisone in postresuscitation shock, compared with epinephrine/saline placebo, resulted in improved survival to hospital discharge with favorable neurological status.nnnTRIAL REGISTRATIONnclinicaltrials.gov Identifier: NCT00729794.

New insights into weaning from mechanical ventilation: left ventricular diastolic dysfunction is a key player

PurposeTo investigate the diagnostic performance of Doppler echocardiography (DE) in predicting the outcome of weaning from mechanical ventilation in patients without overt cardiac disease.MethodsFifty critical care noncardiac patients who fulfilled predetermined criteria for weaning underwent DE before and at the end of spontaneous breathing trial (pre-SBT/end-SBT, respectively). “Conventional” mitral inflow analysis and “advanced” DE parameters [tissue Doppler imaging (TDI)-derived mitral/tricuspid annular velocities and color M-mode Doppler velocity of propagation (Vp)] were used to assess left ventricular (LV) diastolic function/filling pressures. Weaning was considered successful if patients had been extubated after successful SBT and sustained spontaneous breathing for more than 48xa0h.ResultsTwenty-eight patients (56%) failed weaning: 23 patients failed SBT and 5 required reintubation within 48xa0h. Weaning failure was associated with the degree of LV diastolic dysfunction at pre-SBT (Pxa0=xa00.01). Patients who failed weaning presented evidence of increased LV filling pressures at pre-SBT, by demonstrating increased E/Em and E/Vp ratios compared with patients with successful outcome (Pxa0≤xa00.004); pre-SBT values of lateral E/Em greater than 7.8 and E/Vp greater than 1.51 predicted weaning failure with an area under the curve, sensitivity (%), and specificity (%) of 0.86, 79, and 100, and 0.74, 75, and 73, respectively. Lateral E/Em was the only factor independently associated with weaning failure before SBT; OR (95% CI) 5.62 (1.17–26.96), Pxa0=xa00.03.ConclusionsOur findings suggest that LV diastolic dysfunction is significantly associated with weaning outcome in critically ill patients with preserved LV systolic function. An E/Em ratio greater than 7.8 may identify patients at high risk of weaning failure.

Tracheal Replacement With Cryopreserved Allogenic Aorta

BACKGROUNDnRadical resection of primary tracheal tumors may be challenging when more than one-half of the tracheal length is concerned. The present study evaluated the use of cryopreserved aortic allografts (CAAs) to replace long tracheal segments.nnnMETHODSnSixteen adult minipigs underwent tracheal replacement with a CAA. A silicone stent was used to splint the CAA for the first 12 months. Animals were followed-up using bronchoscopic evaluation and killed at predetermined times, for a period up to 18 months long.nnnRESULTSnIntense inflammation and progressive disappearance of typical histologic structures of the aorta were seen within the first 3 months. All animals studied for more than 3 months showed progressive transformation of the graft into a chimerical conduit sharing aortic and tracheal histologic patterns (eg, islands of disorganized elastic fibers/mature respiratory ciliated epithelium, respiratory glands, islets of cartilage). Stent removal was attempted after 12 months in 10 animals, and critical tracheal stenosis was found in six animals and moderate asymptomatic stenosis in four. Clinical course in these latter animals was uneventful until they were killed at 15 to 18 months. In situ hybridization showed that collagen2a1 mRNA was expressed in the cartilage islets at 1 year. Polymerase chain reaction analysis of the SRY gene demonstrated that the newly formed cartilage cells derived from the host.nnnCONCLUSIONSnCAA may be considered as a valuable tracheal substitute for patients with extensive tracheal tumors. Prolonged stenting will be probably mandatory for the clinical application of the procedure in humans.

Impact of dietary shift to higher-antioxidant foods in COPD: a randomised trial

Chronic obstructive pulmonary disease (COPD) is characterised by increased oxidative stress. Dietary factors, such as ample consumption of foods rich in antioxidants, such as fruit and vegetables, might have beneficial effects in COPD patients. The association between dietary shift to foods rich in antioxidants and lung function in COPD was investigated in a 3-yr prospective study. A total of 120 COPD patients were randomised to follow either a diet based on increased consumption of fresh fruit and vegetables (intervention group (IG)) or a free diet (control group (CG)). The mean consumption of foods containing antioxidants was higher in the IG than in the CG throughout the study period (p<0.05). The relationship between consumption of foods rich in antioxidants and percentage predicted forced expiratory volume in 1 s was assessed using a general linear model for repeated measures; the two groups overall were different in time (p = 0.03), with the IG showing a better outcome. In investigating the effect of several confounders (sex, age, smoking status, comorbid conditions and exacerbation) of group response over time, nonsignificant interactions were found between confounders, group and time. These findings suggest that a dietary shift to higher-antioxidant food intake may be associated with improvement in lung function, and, in this respect, dietary interventions might be considered in COPD management.

Fatal interstitial lung disease associated with oral erlotinib therapy for lung cancer

BackgroundErlotinib is a Human Epidermal Growth Factor Receptor Type 1/tyrosine kinase (EGFR) inhibitor which is used for non-small-cell lung cancer treatment. Despite that erlotinib is considered to have a favorable safety profile, adverse events such as interstitial lung disease (ILD) were reported in pivotal studies. The authors report the first histologically confirmed case of fatal ILD associated with erlotinib therapy.Case PresentationThe medical record of a patient who developed fatal ILD after receiving erlotinib treatment was reviewed to identify the cause of death and other factors potentially contributive to this adverse outcome. A 55-year-old smoker with no evidence of pre-existing interstitial disease developed bilateral ILD and respiratory failure which could be explained only as a toxicity of erlotinib. He had a history of stage IV left upper lobe squamous-cell carcinoma for which he had received three successive regimens of chemotherapy (ifosfamide plus gemcitabine, docetaxel, mitomycin plus navelbine), followed five months later by erlotinib. At initiation of erlotinib treatment there were no radiological signs suggestive of ILD disease or apparent clinical signs of respiratory distress. While the patient completed two months with erlotinib therapy he developed bilateral interstitial infiltrates; despite discontinuation of erlotinib he was admitted with respiratory failure two weeks later. Diagnostic work up for other causes of pneumonitis including infectious diseases, congestive cardiac failure and pulmonary infraction was negative. Empiric treatment with oxygene, corticosteroids and later with cyclophosphamide was ineffective and the patient progressively deteriorated and died. The clinical and post-mortem examination findings are presented and the possible association relationship between erlotinib induced ILD and previous chemotherapy is discussed.ConclusionPhysicians should be alert to the fact that erlotinib related ILD, although infrequent, is potential fatal. The association between selective EGFR-inhibitors and ILD should be further investigated.

Growth Retardation, Reduced Invasiveness, and Impaired Colistin-Mediated Cell Death Associated with Colistin Resistance Development in Acinetobacter baumannii

ABSTRACT Two colistin-susceptible/colistin-resistant (Cols/Colr) pairs of Acinetobacter baumannii strains assigned to international clone 2, which is prevalent worldwide, were sequentially recovered from two patients after prolonged colistin administration. Compared with the respective Cols isolates (Ab248 and Ab299, both having a colistin MIC of 0.5 μg/ml), both Colr isolates (Ab249 and Ab347, with colistin MICs of 128 and 32 μg/ml, respectively) significantly overexpressed pmrCAB genes, had single-amino-acid shifts in the PmrB protein, and exhibited significantly slower growth. The Colr isolate Ab347, tested by proteomic analysis in comparison with its Cols counterpart Ab299, underexpressed the proteins CsuA/B and C from the csu operon (which is necessary for biofilm formation). This isolate also underexpressed aconitase B and different enzymes involved in the oxidative stress response (KatE catalase, superoxide dismutase, and alkyl hydroperoxide reductase), suggesting a reduced response to reactive oxygen species (ROS) and, consequently, impaired colistin-mediated cell death through hydroxyl radical production. Cols isolates that were indistinguishable by macrorestriction analysis from Ab299 caused six sequential bloodstream infections, and isolates indistinguishable from Ab248 caused severe soft tissue infection, while Colr isolates indistinguishable from Ab347 and Ab249 were mainly colonizers. In particular, a Cols isolate identical to Ab299 was still invading the bloodstream 90 days after the colonization of this patient by Colr isolates. These observations indicate considerably lower invasiveness of A. baumannii clinical isolates following the development of colistin resistance.

Exhaled Breath Condensate 8-Isoprostane, Clinical Parameters, Radiological Indices and Airway Inflammation in COPD

Background: Exhaled breath condensate (EBC) 8-isoprostane levels were found increased in chronic obstructive pulmonary disease. However, the relation between EBC 8-isoprostane and parameters which have a known predictive value in COPD, remains vastly unknown, and so does subsequently its clinical value. Objectives: To investigate the relationship between 8-isoprostane level in EBC and clinical parameters, radiological indices and airway inflammation in COPD patients. Materials and Methods: We studied 18 COPD patients (all ex-smokers) and 12 healthy controls (5 ex-smokers and 7 never-smokers). All patients underwent clinical evaluation, sputum induction, high-resolution computed tomography (HRCT) of the thorax and EBC 8-isoprostane measurement. 8-Isoprostane levels were correlated with markers that reflect disease severity, such as dyspnea severity, FEV1 (%pred), emphysema changes and bronchiectasis in HRCT. Emphysema was quantified as the percentage of lung area with attenuation values < –950 Hounsfield units. Results: 8-Isoprostane levels were significantly elevated in EBC of patients with COPD [mean (SE) 18.1 (2) vs. 5.6 (0.7) pg/ml, p = 0.0001], irrespective of lung function impairment. 8-Isoprostane levels were correlated with emphysema score in HRCT (r2 = 0.43, p = 0.001) as well as with Medical Research Council dyspnea scale score (rho = 0.61, p = 0.005). Conclusion: Our findings suggest that EBC 8-isoprostane levels may reflect the extension of lung emphysema in COPD patients. In this respect, further investigation is required in order to evaluate the possible role of EBC 8-isoprostane in assessing disease progress in COPD patients.

Combined Intravenous and Intraventricular Administration of Colistin Methanesulfonate in Critically Ill Patients with Central Nervous System Infection

ABSTRACT Colistin pharmacokinetics were prospectively studied after intravenous administration of colistin methanesulphonate in critically ill patients without central nervous system infection (controls, n = 5) and in patients with external ventricular drain-associated ventriculitis after intravenous administration (EVDViv, n = 3) or combined intravenous/intraventricular administration (EVDVcomb, n = 4). Cerebrospinal fluid (CSF)/serum colistin concentration ratios were higher in EVDViv than in control patients (11% versus 7%, P ≤ 0.05) and in EVDVcomb compared to all other patients (P < 0.0001). CSF colistin concentrations above the MIC of 0.5 μg/ml were achieved only in EVDVcomb patients.

Intensive care unit-acquired infection as a side effect of sedation

IntroductionSedative and analgesic medications are routinely used in mechanically ventilated patients. The aim of this review is to discus epidemiologic data that suggest a relationship between infection and sedation, to review available data for the potential causes and pathophysiology of this relationship, and to identify potential preventive measures.MethodsData for this review were identified through searches of PubMed, and from bibliographies of relevant articles.ResultsSeveral epidemiologic studies suggested a link between sedation and ICU-acquired infection. Prolongation of exposure to risk factors for infection, microaspiration, gastrointestinal motility disturbances, microcirculatory effects are main mechanisms by which sedation may favour infection in critically ill patients. Furthermore, experimental evidence coming from studies both in humans and animals suggest that sedatives and analgesics present immunomodulatory properties that might alter the immunologic response to exogenous stimuli. Clinical studies comparing different sedative agents do not provide evidence to recommend the use of a particular agent to reduce ICU-acquired infection rate. However, sedation strategies aiming to reduce the duration of mechanical ventilation, such as daily interruption of sedatives or nursing-implementing sedation protocol, should be promoted. In addition, the use of short acting opioids, propofol, and dexmedetomidine is associated with shorter duration of mechanical ventilation and ICU stay, and might be helpful in reducing ICU-acquired infection rates.ConclusionsProlongation of exposure to risk factors for infection, microaspiration, gastrointestinal motility disturbances, microcirculatory effects, and immunomodulatory effects are main mechanisms by which sedation may favour infection in critically ill patients. Future studies should compare the effect of different sedative agents, and the impact of progressive opioid discontinuation compared with abrupt discontinuation on ICU-acquired infection rates.

Tc2 Response at the Onset of COPD Exacerbations

BACKGROUNDnT lymphocytes and especially the subpopulations of CD8+ cells are believed to have a key role in COPD pathophysiology, but there are only few data regarding the role of these cells in COPD exacerbation.nnnAIMnWe aimed to study prospectively changes of CD8+ T-lymphocyte subpopulations in the sputum of COPD patients at the onset of mild exacerbations and at a stable condition in order to provide further insight in the pathophysiology of the disease.nnnMETHODSnInduced-sputum samples were collected from 24 COPD patients with median age of 52 years (interquartile range [IQR], 44 to 58 years) and FEV(1) percentage of predicted of 78.05% (IQR, 75.8 to 80.1%) at the onset of mild exacerbations not requiring hospitalization and when stable. Inflammatory cells and T-lymphocyte subpopulations (CD4+, CD8+, and cells producing interferon [IFN]-gamma or interleukin [IL]-4) were measured using flow cytometry and immunocytochemical methods.nnnRESULTSnA significant increase in sputum CD8+ T lymphocytes (p < 0.0001) and significant decreases in CD4+ T lymphocytes as well as in CD4+/CD8+ (p = 0.0001) and CD8+IFN-gamma+/CD8+IL-4+ (p = 0.001), CD4+IFN-gamma+/CD4+IL-4+ (p = 0.0003) sputum cells ratios were found decreased at the onset of exacerbations compared to stable condition. The changes in T-lymphocyte subpopulations were not associated with smoking history, demographic characteristics, or disease severity.nnnCONCLUSIONnThe findings of the present study suggest that CD8+ lymphocytes are increased and potentially polarized toward a Tc2 profile in the airways of COPD patients at the onset of COPD exacerbations with respect to stable condition. The clinical impact of the observed phenomenon requires further investigation.