RESUMEN
OBJECTIVES: To investigate risk factors for non-invasive/invasive ventilatory support (NI/I-VS) in patients with coronavirus disease 2019 (COVID-19). METHODS: All consecutive patients admitted to the Infectious Diseases Unit and Intensive Care Unit (ICU) of Santa Maria Annunziata Hospital (Florence, Italy), from February 25 to April 25, 2020, with a confirmed COVID-19 diagnosis were enrolled in this retrospective cohort study. NI/I-VS was defined as the need for continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BPAP) (non-invasive ventilation) or mechanical ventilation, not including low-flow systems of oxygen therapy such as the Venturi mask or nasal cannula. RESULTS: Ninety-seven patients were enrolled; 61.9% (60/97) were male and the median patient age was 64 years. The in-hospital mortality was 9.3%. Thirty-five of the 97 patients (36%) required ICU admission and 94.8% (92/97) were prescribed oxygen therapy: 10.8% (10/92) by nasal cannula, 44.5% (41/92) by Venturi mask, 31.5% (29/92) by CPAP, 2.2% (2/92) by BPAP, and 10.8% (10/92) by mechanical ventilation following intubation. On univariate analysis, patients with a body mass index >30, type II diabetes mellitus, and those presenting with dyspnoea, asthenia, SOFA score ≥2 points, PaO2/FiO2 <300, temperature >38 °C, increased levels of lactate dehydrogenase (LDH), alanine aminotransferase, and C-reactive protein, and a d-dimer >1000 ng/mL at admission more frequently underwent NI/I-VS. Multivariate logistic regression analysis confirmed temperature >38 °C (odds ratio (OR) 21.2, 95% confidential interval (95% CI) 3.5-124.5, p = 0.001), LDH >250 U/l (OR 15.2, 95% CI 1.8-128.8, p = 0.012), and d-dimer >1000 ng/mL (OR 4.5, 95% CI 1.2-17.3, p = 0.027) as significantly associated with the requirement for NI/I-VS. A non-significant trend (p = 0.051) was described for PaO2/FiO2 <300. CONCLUSIONS: Temperature >38 °C, LDH > 250 U/l, and d-dimer >1000 ng/mL were found to be independent risk factors for NI/I-VS in COVID-19 patients. In order to quickly identify patients likely at risk of developing a critical illness, inflammatory markers should be assessed upon hospital admission.
Asunto(s)
COVID-19/terapia , Respiración Artificial , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Enfermedad Crítica , Diabetes Mellitus Tipo 2/complicaciones , Femenino , Mortalidad Hospitalaria , Hospitalización , Humanos , Unidades de Cuidados Intensivos , Masculino , Persona de Mediana Edad , Pandemias , Estudios Retrospectivos , Factores de Riesgo , SARS-CoV-2RESUMEN
BACKGROUND: Sepsis is characterized by the loss of the perm-selectivity properties of the glomerular filtration barrier (GFB) with consequent albuminuria. We examined whether the pharmacokinetics-pharmacodynamics (PK/PD) of ceftriaxone (CTX), an extensively protein-bound 3rd generation cephalosporin, is altered during early sepsis and whether an increase in urinary loss of bound-CTX, due to GFB alteration, can occur in this condition. METHODS: A prospective, experimental, randomized study was carried out in adult male Sprague-Dawley rats. Sepsis was induced by cecal ligation and puncture (CLP). Rats were divided into two groups: Sham-operated and CLP. CTX (100 mg i.p., equivalent to 1 g dose in humans) was administered in order to measure plasma and lung CTX concentrations at several time-points: baseline and 1, 2, 4 and 6 h after administration. CTX was measured by High Performance Liquid Chromatography (HPLC). The morphological status of the sialic components of the GFB barrier was assessed by lectin histo-chemistry. Monte Carlo simulation was performed to calculate the probability of target attainment (PTA >90%) for 80 and 100% of Tfree > minimum inhibitory concentration (MIC) for 80 and 100% of dosing interval. MEASUREMENTS AND MAIN RESULTS: After CLP, sepsis developed in rats as documented by the growth of polymicrobial flora in the peritoneal fluid (≤1 × 101 CFU in sham rats vs 5 × 104-1 × 105 CFU in CLP rats). CTX plasma concentrations were higher in CLP than in sham rats at 2 and 4 h after administration (difference at 2 h was 47.3, p = 0.012; difference at 4 h was 24.94, p = 0.004), while lung penetration tended to be lower. An increased urinary elimination of protein-bound CTX occurred (553 ± 689 vs 149 ± 128 mg/L, p < 0.05; % of bound/total CTX 22 ± 6 in septic rats vs 11 ± 4 in sham rats, p < 0.01) and it was associated with loss of the GFB sialic components. According to Monte Carlo simulation a PTA > 90% for 100% of the dosing interval was reached neither for sham nor CLP rats using MIC = 1 mg/L, the clinical breakpoint for Enterobacteriacee. CONCLUSIONS: Sepsis causes changes in the PK of CTX and an alteration in the sialic components of the GFB, with consequent loss of protein-bound CTX. Among factors that can affect drug pharmacokinetics during the early phases of sepsis, urinary loss of both free and albumin-bound antimicrobials should be considered.
Asunto(s)
Ceftriaxona/farmacología , Ceftriaxona/farmacocinética , Sepsis/tratamiento farmacológico , Animales , Ciego/efectos de los fármacos , Ciego/patología , Ceftriaxona/sangre , Ceftriaxona/uso terapéutico , Simulación por Computador , Ligadura , Masculino , Método de Montecarlo , Fitohemaglutininas/metabolismo , Estudios Prospectivos , Punciones , Ratas Sprague-Dawley , Sepsis/patologíaRESUMEN
OBJECTIVE: The development of sepsis in patients with traumatic brain injury increases mortality, exacerbates morphological and functional cerebral damage, and causes persistent neuroinflammation, including microglial activation. The administration of antibiotics possessing both antimicrobial and immunomodulatory activity might attenuate both sepsis and posttraumatic cerebral inflammation. We compared the potential therapeutic efficacy of two tetracyclines, minocycline and the newer generation tigecycline, on functional neurobehavioral impairment and regional histopathological damage in an experimental model of combined traumatic brain injury and sepsis. DESIGN: Prospective, experimental animal study. SETTING: University Research Laboratory. SUBJECTS: Adult male Sprague-Dawley rats. INTERVENTIONS: Controlled cortical impact was used to induce traumatic brain injury and cecal ligation and puncture for sepsis. Immediately following injury, animals were treated with minocycline (45 mg/kg intraperitoneal), tigecycline (7.5 mg/kg intraperitoneal), or saline every 12 hours for 3 days. MEASUREMENTS AND MAIN RESULTS: The development of sepsis and cerebral inflammatory response were evaluated, respectively, by 1) growth of peritoneal microorganisms and clinical variables and 2) tumor necrosis factor-α expression in the perilesional cortex. To assess posttraumatic outcome, vestibulomotor and cognitive function were evaluated at different time points for 14 days post injury whereupon animals were killed and cerebral tissue analyzed for lesion volume, regional hippocampal (CA1/CA3) cell death, and microglial activation in the perilesional cortex, lesion core zone, and choroid plexus. Treatment with both antibiotics reduced microorganism growth, body weight loss, and mortality but had no effect on vestibulomotor or cognitive function. Minocycline alone attenuated postinjury cortical lesion volume, hippocampal CA3 neuronal cell loss, tumor necrosis factor-α expression, and the extent of microglial activation and infiltration. CONCLUSIONS: The significantly heightened mortality caused by the superimposition of sepsis upon traumatic brain injury can be reduced by administration of both antibiotics but only minocycline can decrease the extent of cell death in selectively cortical and hippocampal brain regions, via, in part, a reduction in cerebral inflammation.