ß-Lactam pharmacodynamics in Gram-negative bloodstream infections in the critically ill.

OBJECTIVES: To determine the ß-lactam exposure associated with positive clinical outcomes for Gram-negative blood stream infection (BSI) in critically ill patients. PATIENTS AND METHODS: Pooled data of critically ill patients with mono-microbial Gram-negative BSI treated with ß-lactams were collected from two databases. Free minimum concentrations (fCmin) of aztreonam, cefepime, ceftazidime, ceftriaxone, piperacillin (co-administered with tazobactam) and meropenem were interpreted in relation to the measured MIC for targeted bacteria (fCmin/MIC). A positive clinical outcome was defined as completion of the treatment course or de-escalation, without other change of antibiotic therapy, and with no additional antibiotics commenced within 48 h of cessation. Drug exposure breakpoints associated with positive clinical outcome were determined by classification and regression tree (CART) analysis. RESULTS: Data from 98 patients were included. Meropenem (46.9%) and piperacillin/tazobactam (36.7%) were the most commonly prescribed antibiotics. The most common pathogens were Escherichia coli (28.6%), Pseudomonas aeruginosa (19.4%) and Klebsiella pneumoniae (13.3%). In all patients, 87.8% and 71.4% achieved fCmin/MIC ≥1 and fCmin/MIC >5, respectively. Seventy-eight patients (79.6%) achieved positive clinical outcome. Two drug exposure breakpoints were identified: fCmin/MIC >1.3 for all ß-lactams (predicted difference in positive outcome 84.5% versus 15.5%, P < 0.05) and fCmin/MIC >4.95 for meropenem, aztreonam or ceftriaxone (predicted difference in positive outcome 97.7% versus 2.3%, P < 0.05). CONCLUSIONS: A ß-lactam fCmin/MIC >1.3 was a significant predictor of a positive clinical outcome in critically ill patients with Gram-negative BSI and could be considered an antibiotic dosing target.

When a Diuretic Causes Pulmonary Oedema.

BACKGROUND: Hydrochlorothiazide (HCTZ) is one of the most popular drugs for the treatment of hypertension and heart failure. Most of its side effects are harmless and predictable, but some studies report a few life-threatening reactions to this drug, one of the most dangerous being acute pulmonary oedema. CASE REPORT: A 73-year-old woman was admitted to the Emergency Department with acute respiratory failure due to pulmonary oedema. Her past medical history included long-lasting hypertension with permanent atrial fibrillation and mitral stenosis. Her blood pressure control had been suboptimal, so her cardiologist had changed amlodipine to combination therapy with ramipril and HCTZ. However, 20 min after taking the new drug, the patient experienced fever, vomiting and diarrhoea immediately followed by acute onset of dyspnoea. CONCLUSION: Since HCTZ is one of the most popular drugs for hypertension treatment and millions of patients take it every day, it is important to keep in mind both the common adverse reactions as well as the dangerous, although rare, ones. LEARNING POINTS: Pulmonary oedema is a very unusual adverse reaction to hydrochlorothiazide, and a rare presentation of a common condition.Pulmonary oedema is not always due to heart problems.It is important to keep in mind that hypersensitivity reactions may have many different presentations.

Can red blood cell distribution width predict outcome after cardiac arrest?

BACKGROUND: In critically ill patients, high red blood cell distribution width (RDW) values have been associated with increased hospital mortality, but there are no data on the impact of RDW on outcomes of patients resuscitated from cardiac arrest (CA). The aim of this study was to investigate the relationship between RDW and long-term neurologic outcome in CA survivors. METHODS: We performed a retrospective analysis of an institutional database including all unconscious adult patients admitted to the intensive care unit (ICU) after non-traumatic CA between January 2007 and January 2015. Patients who survived <24 hours were excluded. The RDW (normal values 10.9-13.4%) was obtained daily from the day of admission to day 3. Patients with a cerebral performance category (CPC) score of 3-5 at 3 months were considered to have an unfavourable neurological outcome. RESULTS: Three hundred and ninety patients were included. The ICU mortality rate was 56% (N.=220) and 64% of patients (N.=251) had an unfavorable 3-month neurological outcome. The median RDW on the day of admission was 14% (13.0-15.2%) and remained stable over the observation period. Two hundred and forty-five patients (63%) had a high RDW (>13.4%) on admission. In multivariable logistic regression analysis, older age, absence of bystander cardiopulmonary resuscitation (CPR), a non-cardiac etiology of the arrest, a non-shockable initial rhythm, high adrenaline dose during CPR and high admission RDW levels were independently associated with an unfavorable outcome at 3 months. CONCLUSIONS: High RDW values are associated with poor neurological outcome among CA survivors.

Lymphopaenia in cardiac arrest patients.

BACKGROUND: A decrease in circulating lymphocytes has been described as a marker of poor prognosis after septic shock; however, scarce data are available after cardiac arrest (CA). The aim of this study was to evaluate the impact of lymphopaenia after successful cardiopulmonary resuscitation. METHODS: This is a retrospective analysis of an institutional database including all adult CA patients admitted to the intensive care unit (ICU) between January 2007 and December 2014 who survived for at least 24 h. Demographic, CA-related data and ICU mortality were recorded as was lymphocyte count on admission and for the first 48 h. A cerebral performance category score of 3-5 at 3 months was considered as an unfavourable neurological outcome. RESULTS: Data from 377 patients were analysed (median age: 62 [IQRs: 52-75] years). Median time to return of spontaneous circulation (ROSC) was 15 [8-25] min and 232 (62%) had a non-shockable initial rhythm. ICU mortality was 58% (n = 217) and 246 (65%) patients had an unfavourable outcome at 3 months. The median lymphocyte count on admission was 1208 [700-2350]/mm3 and 151 (40%) patients had lymphopaenia (lymphocyte count <1000/mm3). Predictors of lymphopaenia on admission were older age, a shorter time to ROSC, prior use of corticosteroid therapy and high C-reactive protein levels on admission. ICU non-survivors had lower lymphocyte counts on admission than survivors (1100 [613-2317] vs. 1316 [891-2395]/mm3; p = 0.05) as did patients with unfavourable compared to those with favourable neurological outcomes (1100 [600-2013] vs. 1350 [919-2614]/mm3; p = 0.003). However, lymphopaenia on admission was not an independent predictor of poor outcomes in the entire population, but only among OHCA patients. CONCLUSIONS: A low lymphocyte count is common in CA survivors and is associated with poor outcome after OHCA.

Prognostic implications for insulin-sensitive and insulin-resistant normal-weight and obese individuals from a population-based cohort.

BACKGROUND: There are few prospective data on the prognosis of insulin-sensitive and insulin-resistant normal-weight (NW) or obese individuals. OBJECTIVES: The estimated liver fat content, incidences of hyperglycemia and cardiovascular disease, and all-cause and cardiovascular mortality rates were investigated in a population-based cohort of 1658 individuals who were categorized according to BMI and insulin resistance as defined by HOMA-IR values ≥2.5 and the presence of metabolic syndrome. DESIGN: This was a prospective cohort study with a 9-y follow-up. Anthropometric values, blood pressure, and blood metabolic variables were measured, and information on vital status was collected from demographic files at follow-up. RESULTS: A total of 137 of 677 NW individuals (20%) were classified as insulin resistant and normal weight (IR-NW), and 72 of 330 obese individuals (22%) were classified as insulin sensitive and obese (IS-obese). Incidences of diabetes, impaired fasting glucose, and cardiovascular events were 0.4%, 6.3%, and 3.3%, respectively, in insulin-sensitive and normal-weight (IS-NW) individuals (reference category); 5.8%, 10.2%, and 6.6%, respectively, in IR-NW individuals; and 5.6%, 8.3%, and 8.3%, respectively, in IS-obese individuals. In a multiple logistic regression model, risks of incident hyperglycemia and cardiovascular events increased in both groups compared with in the reference category [HR (95% CI): 2.54 (1.42, 4.55) and 1.98 (0.86, 4.54) in IR-NW subjects; 2.16 (1.01, 4.63) and 2.76 (1.05, 7.28) in IS-obese subjects]. The estimated liver fat content significantly increased during follow-up only in the IR-NW group in the same model. Cardiovascular mortality was 2-3-fold higher in IR-NW and IS-obese than in IS-NW individuals in a Cox regression model. CONCLUSIONS: Our data refute the existence of healthy obese phenotypes because IS-obese individuals showed increased cardiometabolic risk. The existence of unhealthy NW phenotypes is supported by their increased risk of incident hyperglycemia, fatty liver, cardiovascular events, and death.

Magnesium and trace element intake after a lifestyle intervention.

OBJECTIVE: Observational studies suggest that some trace elements and magnesium (Mg) improve glucose metabolism, markers of inflammation, and oxidative stress, but supplementation studies have yielded inconsistent results. Our objective was to evaluate whether a lifestyle intervention trial, aimed at reducing total and saturated fat and increasing fiber intake, can affect also the intake of selenium (Se), zinc (Zn), copper (Cu), chromium (Cr), and Mg. METHODS: Dietary intake of Se, Cr, Zn, Cu, and Mg was evaluated at baseline and at the end of a lifestyle intervention trial performed in 335 dysmetabolic adults. RESULTS: At baseline, trace element and Mg intake in the intervention (n = 169) and control (n = 166) groups of the trial were not significantly different. The former significantly increased their intake of Se, Mg, and Cr, while the latter reduced the intake of Mg, Zn, and Cr. Between-group differences were significant for Mg, Cr, and Se. CONCLUSION: Healthier lifestyle recommendations might improve the pattern of micronutrient and Mg intake, which might play an independent role in ameliorating some metabolic, inflammatory, and oxidative markers.

Effects of TCF7L2 polymorphisms on glucose values after a lifestyle intervention.

BACKGROUND: TCF7L2 is the strongest locus linked to type 2 diabetes that has been identified thus far, and rs7903146 is the most significantly associated variant. Few intervention studies have shown that it has negative effects on metabolic improvement after lifestyle programs. OBJECTIVE: Our objective was to assess the effects of this variant on lifestyle intervention-induced changes in glucose values and metabolic variables at 1- and 4-y follow-ups. DESIGN: The rs7903146 variant was genotyped in 335 nondiabetic, dysmetabolic participants in a randomized lifestyle intervention trial. RESULTS: Subjects with the unfavorable TT genotype showed higher values of fasting glucose and lower homeostasis model assessment of beta cell function at baseline. Lifestyle modifications were successful in the amelioration of metabolic traits in all genetic subgroups after 1 y. At 4-y follow-up most of the metabolic benefits had disappeared. In a multiple regression model, values for glucose and homeostasis model assessment of beta cell function at 4 y were significantly associated with the T allele (for glucose and homeostasis model assessments, respectively: beta = 6.6; 95% CI: 2.5, 10.7; P = 0.001; and beta = -0.37; 95% CI: -0.54, -0.20; P < 0.001) but not with intervention. There was no interaction between genotype and intervention. After 1 y, impaired fasting glucose and diabetes incidence were inversely associated with intervention. After 4 y, the presence of a T allele was associated with impaired fasting glucose (odds ratio: 3.04; 95% CI: 1.53, 6.04; P = 0.001) and diabetes (odds ratio: 2.63; 95% CI: 1.00, 6.96; P = 0.05) but not with intervention. CONCLUSIONS: Lifestyle modifications improved the metabolic pattern in all genetic subgroups. At the end of the trial, however, weight gain occurred, and carriers of the T allele developed first hyperglycemia and decreased insulin secretion, which suggests the need for different "after-care" preventive approaches tailored to each genotype's metabolic risk.

Iron supplementation and gestational diabetes in midpregnancy.

OBJECTIVE: Iron supplementation in pregnancy seems beneficial for neonatal/maternal outcomes, but it was associated with diabetes and hypertension in the general population. STUDY DESIGN: We investigated the association between iron supplementation during midpregnancy and metabolic/hypertensive abnormalities in 500 consecutive gestational diabetes mellitus (GDM) and 500 normoglycemic women. RESULTS: Iron-supplement users (n = 212/1000) showed significantly higher values of prepregnancy body mass index (BMI), actual BMI, waist circumference, blood pressure, fasting glucose, Homeostasis-Model-Assessment-Insulin-Resistance, and lower high-density lipoprotein-cholesterol than nonusers. The prevalence of GDM (70.8% vs 44.4%), hypertension (25.9% vs 9.8%), metabolic syndrome (25.9% vs 10.4%) was significantly higher in the former with a 2- to 3-fold-increased risk at multiple regression analyses. Most glucose values of the oral glucose tolerance test were significantly higher in iron supplemented women, both in GDM and normoglycemic individuals. CONCLUSION: Iron supplementation is associated with glucose impairment and hypertension in midpregnancy; its potential harmful effects might be carefully debated regarding its effectiveness.