The impact of religion on changes in end-of-life practices in European intensive care units: a comparative analysis over 16 years.

PURPOSE Religious beliefs affect end-of-life practices in intensive care units (ICUs). Changes over time in end-of-life practices were not investigated regarding religions. METHODS Twenty-two European ICUs (3 regions: Northern, Central, and Southern Europe) participated in both Ethicus-1 (years 1999-2000) and Ethicus-2 studies (years 2015-2016). Data of ICU patients who died or had limitations of life-sustaining therapy were analysed regarding changes in end-of-life practices and patient/physician religious affiliations. Frequencies, timing of decision-making, and religious affiliations of physicians/patients were compared using the same definitions. RESULTS In total, 4592 adult ICU patients (n = 2807 Ethicus-1, n = 1785 Ethicus-2) were analysed. In both studies, patient and physician religious affiliations were mostly Catholic, Greek Orthodox, Jewish, Protestant, or unknown. Treating physicians (but not patients) commonly reported no religious affiliation (18%). Distribution of end-of-life practices with respect to religion and geographical regions were comparable between the two studies. Withholding [n = 1143 (40.7%) Ethicus-1 and n = 892 (50%) Ethicus-2] and withdrawing [n = 695 (24.8%) Ethicus-1 and n = 692 (38.8%) Ethicus-2] were most commonly decided. No significant changes in end-of-life practices were observed for any religion over 16 years. The number of end-of-life discussions with patients/ families/ physicians increased, while mortality and time until first decision decreased. CONCLUSIONS Changes in end-of-life practices observed over 16 years appear unrelated to religious affiliations of ICU patients or their treating physicians, but the effects of religiosity and/or culture could not be assessed. Shorter time until decision in the ICU and increased numbers of patient and family discussions may indicate increased awareness of the importance of end-of-life decision-making in the ICU

Lung-protective ventilation for the surgical patient: international expert panel-based consensus recommendations

Postoperative pulmonary complications (PPCs) occur frequently and are associated with substantial morbidity and mortality. Evidence suggests that reduction of PPCs can be accomplished by using lung-protective ventilation strategies intraoperatively, but a consensus on perioperative management has not been established. We sought to determine recommendations for lung protection for the surgical patient at an international consensus development conference. Seven experts produced 24 questions concerning preoperative assessment and intraoperative mechanical ventilation for patients at risk of developing PPCs. Six researchers assessed the literature using questions as a framework for their review. The modified Delphi method was utilised by a team of experts to produce recommendations and statements from study questions. An expert consensus was reached for 22 recommendations and four statements. The following are the highlights: (i) a dedicated score should be used for preoperative pulmonary risk evaluation; and (ii) an individualised mechanical ventilation may improve the mechanics of breathing and respiratory function, and prevent PPCs. The ventilator should initially be set to a tidal volume of 6-8 ml kg-1 predicted body weight and positive end-expiratory pressure (PEEP) 5 cm H2O. PEEP should be individualised thereafter. When recruitment manoeuvres are performed, the lowest effective pressure and shortest effective time or fewest number of breaths should be used. ispartof: BJA: British Journal of Anaesthesia vol:123 issue:6 pages:898-913 ispartof: location:England status: Published onlin

Predisposition to Cancer Caused by Genetic and Functional Defects of Mammalian Atad5

ATAD5, the human ortholog of yeast Elg1, plays a role in PCNA deubiquitination. Since PCNA modification is important to regulate DNA damage bypass, ATAD5 may be important for suppression of genomic instability in mammals in vivo. To test this hypothesis, we generated heterozygous (Atad5+/m) mice that were haploinsuffficient for Atad5. Atad5+/m mice displayed high levels of genomic instability in vivo, and Atad5+/m mouse embryonic fibroblasts (MEFs) exhibited molecular defects in PCNA deubiquitination in response to DNA damage, as well as DNA damage hypersensitivity and high levels of genomic instability, apoptosis, and aneuploidy. Importantly, 90% of haploinsufficient Atad5+/m mice developed tumors, including sarcomas, carcinomas, and adenocarcinomas, between 11 and 20 months of age. High levels of genomic alterations were evident in tumors that arose in the Atad5+/m mice. Consistent with a role for Atad5 in suppressing tumorigenesis, we also identified somatic mutations of ATAD5 in 4.6% of sporadic human endometrial tumors, including two nonsense mutations that resulted in loss of proper ATAD5 function. Taken together, our findings indicate that loss-of-function mutations in mammalian Atad5 are sufficient to cause genomic instability and tumorigenesis

Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012

OBJECTIVE: To provide an update to the "Surviving Sepsis Campaign Guidelines for Management of Severe Sepsis and Septic Shock," last published in 2008. DESIGN: A consensus committee of 68 international experts representing 30 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict of interest policy was developed at the onset of the process and enforced throughout. The entire guidelines process was conducted independent of any industry funding. A stand-alone meeting was held for all subgroup heads, co- and vice-chairs, and selected individuals. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development. METHODS: The authors were advised to follow the principles of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to guide assessment of quality of evidence from high (A) to very low (D) and to determine the strength of recommendations as strong (1) or weak (2). The potential drawbacks of making strong recommendations in the presence of low-quality evidence were emphasized. Recommendations were classified into three groups: (1) those directly targeting severe sepsis; (2) those targeting general care of the critically ill patient and considered high priority in severe sepsis; and (3) pediatric considerations. RESULTS: Key recommendations and suggestions, listed by category, include: early quantitative resuscitation of the septic patient during the first 6 h after recognition (1C); blood cultures before antibiotic therapy (1C); imaging studies performed promptly to confirm a potential source of infection (UG); administration of broad-spectrum antimicrobials therapy within 1 h of the recognition of septic shock (1B) and severe sepsis without septic shock (1C) as the goal of therapy; reassessment of antimicrobial therapy daily for de-escalation, when appropriate (1B); infection source control with attention to the balance of risks and benefits of the chosen method within 12 h of diagnosis (1C); initial fluid resuscitation with crystalloid (1B) and consideration of the addition of albumin in patients who continue to require substantial amounts of crystalloid to maintain adequate mean arterial pressure (2C) and the avoidance of hetastarch formulations (1B); initial fluid challenge in patients with sepsis-induced tissue hypoperfusion and suspicion of hypovolemia to achieve a minimum of 30 mL/kg of crystalloids (more rapid administration and greater amounts of fluid may be needed in some patients (1C); fluid challenge technique continued as long as hemodynamic improvement is based on either dynamic or static variables (UG); norepinephrine as the first-choice vasopressor to maintain mean arterial pressure ≥65 mmHg (1B); epinephrine when an additional agent is needed to maintain adequate blood pressure (2B); vasopressin (0.03 U/min) can be added to norepinephrine to either raise mean arterial pressure to target or to decrease norepinephrine dose but should not be used as the initial vasopressor (UG); dopamine is not recommended except in highly selected circumstances (2C); dobutamine infusion administered or added to vasopressor in the presence of (a) myocardial dysfunction as suggested by elevated cardiac filling pressures and low cardiac output, or (b) ongoing signs of hypoperfusion despite achieving adequate intravascular volume and adequate mean arterial pressure (1C); avoiding use of intravenous hydrocortisone in adult septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability (2C); hemoglobin target of 7-9 g/dL in the absence of tissue hypoperfusion, ischemic coronary artery disease, or acute hemorrhage (1B); low tidal volume (1A) and limitation of inspiratory plateau pressure (1B) for acute respiratory distress syndrome (ARDS); application of at least a minimal amount of positive end-expiratory pressure (PEEP) in ARDS (1B); higher rather than lower level of PEEP for patients with sepsis-induced moderate or severe ARDS (2C); recruitment maneuvers in sepsis patients with severe refractory hypoxemia due to ARDS (2C); prone positioning in sepsis-induced ARDS patients with a PaO (2)/FiO (2) ratio of ≤100 mm Hg in facilities that have experience with such practices (2C); head-of-bed elevation in mechanically ventilated patients unless contraindicated (1B); a conservative fluid strategy for patients with established ARDS who do not have evidence of tissue hypoperfusion (1C); protocols for weaning and sedation (1A); minimizing use of either intermittent bolus sedation or continuous infusion sedation targeting specific titration endpoints (1B); avoidance of neuromuscular blockers if possible in the septic patient without ARDS (1C); a short course of neuromuscular blocker (no longer than 48 h) for patients with early ARDS and a PaO (2)/FI O (2) 180 mg/dL, targeting an upper blood glucose ≤180 mg/dL (1A); equivalency of continuous veno-venous hemofiltration or intermittent hemodialysis (2B); prophylaxis for deep vein thrombosis (1B); use of stress ulcer prophylaxis to prevent upper gastrointestinal bleeding in patients with bleeding risk factors (1B); oral or enteral (if necessary) feedings, as tolerated, rather than either complete fasting or provision of only intravenous glucose within the first 48 h after a diagnosis of severe sepsis/septic shock (2C); and addressing goals of care, including treatment plans and end-of-life planning (as appropriate) (1B), as early as feasible, but within 72 h of intensive care unit admission (2C). Recommendations specific to pediatric severe sepsis include: therapy with face mask oxygen, high flow nasal cannula oxygen, or nasopharyngeal continuous PEEP in the presence of respiratory distress and hypoxemia (2C), use of physical examination therapeutic endpoints such as capillary refill (2C); for septic shock associated with hypovolemia, the use of crystalloids or albumin to deliver a bolus of 20 mL/kg of crystalloids (or albumin equivalent) over 5-10 min (2C); more common use of inotropes and vasodilators for low cardiac output septic shock associated with elevated systemic vascular resistance (2C); and use of hydrocortisone only in children with suspected or proven "absolute"' adrenal insufficiency (2C). CONCLUSIONS: Strong agreement existed among a large cohort of international experts regarding many level 1 recommendations for the best care of patients with severe sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for this important group of critically ill patients

Complement Activation and Corticosteroid Therapy in the Development of the Adult Respiratory Distress Syndrome

Fifty-nine patients in septic shock were observed for the development of the adult respiratory distress syndrome (ARDS) prior to and after receiving either 30 mg/kg methylprednisolone sodium succinate, 6 mg/kg dexamethasone sodium phosphate or no steroid. Serum levels of C3, C4 and Factor B allowed classification of 42 patients by activation of complement pathways. Despite a trend toward patients with severe septic shock who activate the alternative pathway being protected from the development of ARDS, complement pathway determination did not allow prediction of the development of ARDS and steroid pretreatment did not influence complement levels or prevent ARDS

How to use an article on therapy or prevention: Pneumonia prevention using subglottic secretion drainage

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The Effects of High-Dose Corticosteroids in Patients with Septic Shock A Prospective, Controlled Study

To determine whether corticosteroids are efficacious in severe septic shock, we conducted a prospective study of 59 patients randomly assigned to a methylprednisolone, dexamethasone, or control group. Patients were treated 17.5±5.4 hours (mean ±S.E.M.) after the onset of shock, and 55 patients required vasopressor agents. Early in the hospital course, reversal of shock was more likely in patients who received corticosteroids than in those who did not. Four (19 per cent) of 21 methylprednisolone-treated, 7 (32 per cent) of 22 dexamethasone-treated, and none of 16 control patients had reversal of shock 24 hours after drug administration (corticosteroid groups vs. control group, P<0.05). Patients treated with corticosteroids within four hours after the onset of shock had a higher incidence of shock reversal (P<0.05). At 133 hours after drug administration, 17 (40 per cent) of 43 corticosteroid-treated patients had died, and 11 (69 per cent) of 16 control patients had died (P<0.05). However, these differences in reversal of shock and survival disappeared later in the course. Overall, 16 (76 per cent) of 21 patients receiving methylprednisolone, 17 (77 per cent) of 22 patients receiving dexamethasone, and 11 (69 per cent) of 16 controls in the hospital died. We conclude that corticosteroids do not improve the overall survival of patients with severe, late septic shock but may be helpful early in the course and in certain subgroups of patients. (N Engl J Med 1984; 311:1137–43.) SEPTIC shock is a serious and life-threatening complication of infection. Despite the advent of sophisticated intensive-care techniques and potent antimicrobial therapy, the mortality among patients with septic shock remains high. 1 , 2 Various nonspecific pharmacologic agents, including corticosteroids, have been proposed to improve the survival of patients with septic shock. 3 The use of corticosteroids for septic shock, however, remains extremely controversial, 3 , 4 partly because of deficiencies in the design of many studies. 5 Analyzing investigations of septic shock in 1970, Motsay et al. 6 reported that 83 per cent of patients receiving corticosteroids survived. Christy noted that 82 per cent of patients given corticosteroids survived, . .