Elevated ß-lactam concentrations associated with neurological deterioration in ICU septic patients.

BACKGROUND: Although ß-lactams are considered to have a safe therapeutic profile, neurotoxicity has been reported. The aim of this study was to assess the association between ß-lactam concentrations and neurological alterations in septic ICU patients. METHODS: Retrospective study on all ICU patients who were treated with meropenem (MEM), piperacillin-tazobactam (TZP) or ceftazidime/cefepime (CEF) and in whom at least one ß-lactam trough concentration (C min) was determined. Drug levels were measured using high-performance liquid chromatography; C min was normalized to the clinical breakpoint of Pseudomonas aeruginosa (as determined by EUCAST) for each drug (C min/MIC). Changes in neurological status were evaluated using changes in the neurological sequential organ failure assessment score (ΔnSOFA) using the formula: ΔnSOFA = nSOFA(day of TDM) - nSOFA(ICU admission). Worsening neurological status (NWS) was defined as a ΔnSOFA ≥ 1 for an nSOFA on admission of 0-2. RESULTS: We collected 262 C min in 199 patients (130 MEM, 85 TZP, 47 CEF). Median APACHE II score and GCS on admission were 17 and 15, respectively. Overall ICU mortality was 27 %. There were no differences in the occurrence of NWS between antibiotics (39% for MEM, 32% for TZP and 35% for CEF). The occurrence of NWS increased with increasing C min/MIC ranges (P = 0.008); this correlation was found for TZP (P = 0.05) and MEM (P = 0.01), but not for CEF. C min/MIC was an independent predictive factor for NWS (OR 1.12 [1.04-1.20]). CONCLUSION: We found a correlation between high ß-lactam trough concentrations and increased occurrence of neurological deterioration in septic ICU patients. Although our data cannot determine causality, monitoring of ß-lactam levels should be considered when deterioration of neurological status occurs during critical illness.

Broad-spectrum ß-lactams in obese non-critically ill patients.

OBJECTIVES: Obesity may alter the pharmacokinetics of ß-lactams. The goal of this study was to evaluate if and why serum concentrations are inadequate when standard ß-lactam regimens are administered to obese, non-critically ill patients. SUBJECTS AND METHODS: During first year, we consecutively included infected, obese patients (body mass index (BMI) ⩾30 kg m(-2)) who received meropenem (MEM), piperacillin-tazobactam (TZP) or cefepime/ceftazidime (CEF). Patients with severe sepsis or septic shock, or those hospitalized in the intensive care unit were excluded. Serum drug concentrations were measured twice during the elimination phase by high-performance liquid chromatography. We evaluated whether free or total drug concentrations were >1 time (fT>minimal inhibition concentration (MIC)) or >4 times (T>4MIC) the clinical breakpoints for Pseudomonas aeruginosa during optimal periods of time: ⩾40% for MEM, ⩾50% for TZP and ⩾70% for CEF. RESULTS: We included 56 patients (median BMI: 36 kg m(-2)): 14 received MEM, 31 TZP and 11 CEF. The percentage of patients who attained target fT>MIC and T>4MIC were 93% and 21% for MEM, 68% and 19% for TZP, and 73% and 18% for CEF, respectively. High creatinine clearance (107 (range: 6-398) ml min(-1)) was the only risk factor in univariate and multivariate analyses to predict insufficient serum concentrations. CONCLUSIONS: In obese, non-critically ill patients, standard drug regimens of TZP and CEF resulted in insufficient drug concentrations to treat infections due to less susceptible bacteria. Augmented renal clearance was responsible for these low serum concentrations. New dosage regimens need to be explored in this patient population (EUDRA-CT: 2011-004239-29).

Development of acute kidney injury during continuous infusion of vancomycin in septic patients.

PURPOSE: Few data are available on the occurrence of renal failure during continuous infusion of vancomycin in critically ill patients. METHODS: We reviewed the data of all patients admitted to the intensive care unit (ICU) between January 2008 and December 2009 in whom vancomycin was given as a continuous infusion for more than 48 h in the absence of renal replacement therapy. We collected data on the doses of vancomycin and blood concentrations during therapy. Acute kidney injury (AKI) was defined as a daily urine output <0.5 ml/kg/h and/or an increase in the serum creatinine of ≥0.3 mg/dl from baseline levels during vancomycin therapy or within 72 h after its discontinuation. Multivariable logistic regression analysis was performed to identify predictors of AKI. RESULTS: Of 207 patients who met the inclusion criteria, 50 (24 %) developed AKI. These patients were more severely ill, had lower creatinine clearance at admission, were more frequently exposed to other nephrotoxic agents, had a longer duration of therapy, and had higher concentrations of vancomycin during the first 3 days of treatment (C(mean)). The C(mean) was independently associated with early AKI (within 48 h from the onset of therapy) and the duration of vancomycin administration with late AKI. CONCLUSIONS: AKI occurred in almost 25 % of critically ill patients treated with a continuous infusion of vancomycin. Vancomycin concentrations and duration of therapy were the strongest variables associated with the development of early and late AKI during therapy, respectively.

When, where and how to initiate hypothermia after adult cardiac arrest.

Therapeutich hypothermia (TH) has been shown to improve neurological outcome and survival after witnessed cardiac arrest (CA) that is due to ventricular fibrillation. Although TH is widely used following witnessed CA as well as all forms of initial rhythm, the mortality rate after CA remains unacceptably high, and additional study is needed to understand when and how to implement hypothermia in the post-resuscitation phase. Experimental studies have emphasized the importance of initiating cooling soon after the return of spontaneous circulation (ROSC) or even during cardiopulmonary resuscitation (CPR). Clinical studies have shown that pre-hospital induction of hypothermia is feasible and has no major adverse events-even when used intra-arrest-and may provide some additional benefits compared to delayed in-hospital cooling. Thus, hypothermia use should not be limited to the Intensive Care Unit but can be initiated in the field/ambulance or in the Emergency Department, then continued after hospital admission- even during specific procedures such as coronary angiography-as part of the global management of CA patients. Various methods (both non-invasive and invasive) are available to achieve and maintain the target temperature; however, only some of these methods-which include cold fluids, ice packs, iced pads and helmet and trans-nasal cooling- are easily deployed in the pre-hospital setting.