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BACKGROUND: Besides balancing burdens and benefits of intensive care, ethical conflicts in the process of decision-making should also be recognised. This calls for an ethical analysis relevant to clinicians. The aim was to analyse ethically difficult situations in the process of deciding whether a patient is admitted to intensive care unit (ICU). METHODS: Analysis using the 'Dilemma method' and 'wide reflective equilibrium', on ethnographic data of 45 patient cases and 96 stakeholder interviews in six UK hospitals. ETHICAL ANALYSIS: Four moral questions and associated value conflicts were identified. (1) Who should have the right to decide whether a patient needs to be reviewed? Conflicting perspectives on safety/security. (2) Does the benefit to the patient of getting the decision right justify the cost to the patient of a delay in making the decision? Preventing longer-term suffering and understanding patient's values conflicted with preventing short-term suffering and provision of security. (3) To what extent should the intensivist gain others' input? Professional independence versus a holistic approach to decision-making. (4) Should the intensivist have an ongoing duty of care to patients not admitted to ICU? Short-term versus longer-term duty to protect patient safety. Safety and security (experienced in a holistic sense of physical and emotional security for patients) were key values at stake in the ethical conflicts identified. The life-threatening nature of the situation meant that the principle of autonomy was overshadowed by the duty to protect patients from harm. The need to fairly balance obligations to the referred patient and to other patients was also recognised. CONCLUSION: Proactive decision-making including advance care planning and escalation of treatment decisions may support the inclusion of patient autonomy. However, our analysis invites binary choices, which may not sufficiently reflect reality. This calls for a complementary relational ethics analysis.
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RATIONALE: Vitamin D deficiency has been implicated as a pathogenic factor in sepsis and intensive therapy unit mortality but has not been assessed as a risk factor for acute respiratory distress syndrome (ARDS). Causality of these associations has never been demonstrated. OBJECTIVES: To determine if ARDS is associated with vitamin D deficiency in a clinical setting and to determine if vitamin D deficiency in experimental models of ARDS influences its severity. METHODS: Human, murine and in vitro primary alveolar epithelial cell work were included in this study. FINDINGS: Vitamin D deficiency (plasma 25(OH)D levels <50â nmol/L) was ubiquitous in patients with ARDS and present in the vast majority of patients at risk of developing ARDS following oesophagectomy. In a murine model of intratracheal lipopolysaccharide challenge, dietary-induced vitamin D deficiency resulted in exaggerated alveolar inflammation, epithelial damage and hypoxia. In vitro, vitamin D has trophic effects on primary human alveolar epithelial cells affecting >600 genes. In a clinical setting, pharmacological repletion of vitamin D prior to oesophagectomy reduced the observed changes of in vivo measurements of alveolar capillary damage seen in deficient patients. CONCLUSIONS: Vitamin D deficiency is common in people who develop ARDS. This deficiency of vitamin D appears to contribute to the development of the condition, and approaches to correct vitamin D deficiency in patients at risk of ARDS should be developed. TRIAL REGISTRATION: UKCRN ID 11994.
Asunto(s)
Síndrome de Dificultad Respiratoria/etiología , Deficiencia de Vitamina D/complicaciones , APACHE , Anciano , Animales , Calcifediol/sangre , Calcifediol/farmacología , Calcitriol/sangre , Células Cultivadas , Modelos Animales de Enfermedad , Células Epiteliales/efectos de los fármacos , Esofagectomía/efectos adversos , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Unidades de Cuidados Intensivos , Masculino , Ratones Endogámicos C57BL , Persona de Mediana Edad , Alveolos Pulmonares/citología , Alveolos Pulmonares/efectos de los fármacos , Síndrome de Dificultad Respiratoria/sangre , Síndrome de Dificultad Respiratoria/prevención & control , Factores de Riesgo , Análisis de Supervivencia , Vitamina D/uso terapéutico , Deficiencia de Vitamina D/sangre , Deficiencia de Vitamina D/tratamiento farmacológicoRESUMEN
OBJECTIVES: Acute respiratory distress syndrome (ARDS) is characterized by alveolar-capillary barrier damage. Matrix metalloproteinases (MMPs) are implicated in the pathogenesis of ARDS. In the Beta Agonists in Acute Lung Injury Trial, intravenous salbutamol reduced extravascular lung water (EVLW) in patients with ARDS at day 4 but not inflammatory cytokines or neutrophil recruitment. We hypothesized that salbutamol reduces MMP activity in ARDS. METHODS: MMP-1/-2/-3/-7/-8/-9/-12/-13 was measured in supernatants of distal lung epithelial cells, type II alveolar cells, and bronchoalveolar lavage (BAL) fluid from patients in the Beta Agonists in Acute Lung Injury study by multiplex bead array and tissue inhibitors of metalloproteinases (TIMPs)-1/-2 by enzyme-linked immunosorbent assay. MMP-9 protein and activity levels were further measured by gelatin zymography and fluorokine assay. MEASUREMENTS AND MAIN RESULTS: BAL fluid MMP-1/-2/-3 declined by day 4, whereas total MMP-9 tended to increase. Unexpectedly, salbutamol augmented MMP-9 activity. Salbutamol induced 33.7- and 13.2-fold upregulation in total and lipocalin-associated MMP-9, respectively at day 4, compared with 2.0- and 1.3-fold increase in the placebo group, p < 0.03. Salbutamol did not affect BAL fluid TIMP-1/-2. Net active MMP-9 was higher in the salbutamol group (4222 pg/mL, interquartile range: 513-7551) at day 4 compared with placebo (151 pg/mL, 124-2108), p = 0.012. Subjects with an increase in BAL fluid MMP-9 during the 4-day period had lower EVLW measurements than those in whom MMP-9 fell (10 vs. 17 mL/kg, p = 0.004): change in lung water correlated inversely with change in MMP-9, r = -.54, p = 0.0296. Salbutamol up-regulated MMP-9 and down-regulated TIMP-1/-2 secretion in vitro by distal lung epithelial cells. Inhibition of MMP-9 activity in cultures of type II alveolar epithelial cells reduced wound healing. CONCLUSIONS: Salbutamol specifically up-regulates MMP-9 in vitro and in vivo in patients with ARDS. Up-regulated MMP-9 is associated with a reduction in EVLW. MMP-9 activity is required for alveolar epithelial wound healing in vitro. Data suggest MMP-9 may have a previously unrecognized beneficial role in reducing pulmonary edema in ARDS by improving alveolar epithelial healing.