The Effect of Renal Replacement Therapy and Antibiotic Dose on Antibiotic Concentrations in Critically Ill Patients: Data From the Multinational Sampling Antibiotics in Renal Replacement Therapy Study.

BACKGROUND: The optimal dosing of antibiotics in critically ill patients receiving renal replacement therapy (RRT) remains unclear. In this study, we describe the variability in RRT techniques and antibiotic dosing in critically ill patients receiving RRT and relate observed trough antibiotic concentrations to optimal targets. METHODS: We performed a prospective, observational, multinational, pharmacokinetic study in 29 intensive care units from 14 countries. We collected demographic, clinical, and RRT data. We measured trough antibiotic concentrations of meropenem, piperacillin-tazobactam, and vancomycin and related them to high- and low-target trough concentrations. RESULTS: We studied 381 patients and obtained 508 trough antibiotic concentrations. There was wide variability (4-8-fold) in antibiotic dosing regimens, RRT prescription, and estimated endogenous renal function. The overall median estimated total renal clearance (eTRCL) was 50 mL/minute (interquartile range [IQR], 35-65) and higher eTRCL was associated with lower trough concentrations for all antibiotics (P < .05). The median (IQR) trough concentration for meropenem was 12.1 mg/L (7.9-18.8), piperacillin was 78.6 mg/L (49.5-127.3), tazobactam was 9.5 mg/L (6.3-14.2), and vancomycin was 14.3 mg/L (11.6-21.8). Trough concentrations failed to meet optimal higher limits in 26%, 36%, and 72% and optimal lower limits in 4%, 4%, and 55% of patients for meropenem, piperacillin, and vancomycin, respectively. CONCLUSIONS: In critically ill patients treated with RRT, antibiotic dosing regimens, RRT prescription, and eTRCL varied markedly and resulted in highly variable antibiotic concentrations that failed to meet therapeutic targets in many patients.

The effect of regional citrate anti-coagulation on the coagulation system in critically ill patients receiving continuous renal replacement therapy for acute kidney injury - an observational cohort study.

BACKGROUND: Regional anticoagulation with citrate is the recommended first line treatment for patients receiving continuous renal replacement therapy (CRRT). There is wide variability in filter patency which may be due to differences in patient characteristics and local practice. It is also possible that citrate has effects on primary and secondary haemostasis, fibrinolysis and platelet function that are still unknown. The primary aim of the study is to describe the effect of citrate on coagulation and fibrinolysis pathways in both the patient and the haemodialysis circuit. METHODS: The study will recruit 12 adult patients admitted to the intensive care unit, requiring CRRT with regional citrate anticoagulation for acute kidney injury. Patients with pre-existing thrombotic or bleeding tendencies will be excluded. Thrombin generation, clot lysis and platelet function will be measured at baseline and at 12, 24, 36, 48 and 72 h after commencing CRRT (from the patient and from the circuit). We will describe the evolution of parameters over time as well as the differences in parameters between the patient and the circuit. DISCUSSION: The study will provide new data on the effects of citrate during continuous renal replacement therapy which is not currently available. We will minimise confounding factors through the use of tight exclusion criteria and accept that this will slow down recruitment. Depending on the results, we hope to incorporate the findings into existing clinical guidelines and clinical practice with the aim to prevent premature filter clotting and interruptions in treatment. TRIAL REGISTRATION: The study was registered with clinicaltrials.gov on 10th June 2015 ( NCT02486614 ).

Electromagnetically guided bedside placement of post-pyloric feeding tubes in critical care.

Post-pyloric feeding is recommended in critically ill patients with gastro-intestinal intolerance. However, traditional placement methods are logistically difficult and carry potential risks. The authors retrospectively compared the position of post-pyloric feeding tubes (PPFTs) using an electromagnetic device that demonstrated by X-ray and analysed the complication rates, proportion of lung placements avoided and the time taken to establish enteral feeding. Forty placements in 37 mechanically ventilated patients were analysed; there was a success rate of 87.5%. Sensitivity and specificity were 77% (95% CI 59.9-89.6%) and 100% (95% CI 48.0-100%). Five lung placements were identified in real time and therefore avoided. The mean (SD) time from PPFT placement to X-ray was 134 minutes (± 139 minutes) and, to feeding, 276 minutes (± 213 minutes). In conclusion, placement of PPFT using an electromagnetic device carries a high success rate, is safe and feasible to undertake at the bedside in mechanically ventilated patients.

A prospective study of the impact of serial troponin measurements on the diagnosis of myocardial infarction and hospital and six-month mortality in patients admitted to ICU with non-cardiac diagnoses.

INTRODUCTION: Troponin T (cTnT) elevation is common in patients in the Intensive Care Unit (ICU) and associated with morbidity and mortality. Our aim was to determine the epidemiology of raised cTnT levels and contemporaneous electrocardiogram (ECG) changes suggesting myocardial infarction (MI) in ICU patients admitted for non-cardiac reasons. METHODS: cTnT and ECGs were recorded daily during week 1 and on alternate days during week 2 until discharge from ICU or death. ECGs were interpreted independently for the presence of ischaemic changes. Patients were classified into four groups: (i) definite MI (cTnT ≥15 ng/L and contemporaneous changes of MI on ECG), (ii) possible MI (cTnT ≥15 ng/L and contemporaneous ischaemic changes on ECG), (iii) troponin rise alone (cTnT ≥15 ng/L), or (iv) normal. Medical notes were screened independently by two ICU clinicians for evidence that the clinical teams had considered a cardiac event. RESULTS: Data from 144 patients were analysed (42% female; mean age 61.9 (SD 16.9)). A total of 121 patients (84%) had at least one cTnT level ≥15 ng/L. A total of 20 patients (14%) had a definite MI, 27% had a possible MI, 43% had a cTNT rise without contemporaneous ECG changes, and 16% had no cTNT rise. ICU, hospital and 180-day mortality was significantly higher in patients with a definite or possible MI. CONCLUSIONS: The majority of critically ill patients (84%) had a cTnT rise and 41% met criteria for a possible or definite MI of whom only 20% were recognised clinically. Mortality up to 180 days was higher in patients with a cTnT rise.

Physiological predictors of survival during high-frequency oscillatory ventilation in adults with acute respiratory distress syndrome.

INTRODUCTION: Data that provide clinical criteria for the identification of patients likely to respond to high-frequency oscillatory ventilation (HFOV) are scarce. Our aim was to describe physiological predictors of survival during HFOV in adults with severe acute respiratory distress syndrome (ARDS) admitted to a respiratory failure center in the United Kingdom. METHODS: Electronic records of 102 adults treated with HFOV were reviewed retrospectively. We used logistic regression and receiving-operator characteristics curve to test associations with oxygenation and mortality. RESULTS: Patients had severe ARDS with a mean (SD) Murray's score of 2.98 (0.7). Partial pressure of oxygen in arterial blood to fraction of inspired oxygen (PaO2/FiO2) ratio and oxygenation index improved only in survivors. The earliest time point at which the two groups differed was at three hours after commencing HFOV. An improvement of >38% in PaO2/FiO2 occurring at any time within the first 72 hours, was the best predictor of survival at 30 days (area under the curve (AUC) of 0.83, sensitivity 93%, specificity 78% and a positive likelihood ratio (LR) of 4.3). These patients also had a 3.5 fold greater reduction in partial pressure of carbon dioxide in arterial blood (PaCO2). Multivariate analysis showed that HFOV was more effective in younger patients, when instituted early, and in patients with milder respiratory acidosis. CONCLUSIONS: HFOV is effective in improving oxygenation in adults with ARDS, particularly when instituted early. Changes in PaO2/FiO2 during the first three hours of HFOV can identify those patients more likely to survive.

Maintaining normal levels of ionized calcium during citrate-based renal replacement therapy is associated with stable parathyroid hormone levels.

BACKGROUND/AIMS: Citrate is an effective anticoagulant during continuous renal replacement therapy (CRRT). Previous studies showed raised parathyroid hormone (PTH) levels when aiming for serum ionized calcium [Cai] between 0.8 and 1.1 mmol/l. Our objective was to assess whether citrate-based CRRT with physiologic target systemic [Ca(i)] between 1.12 and 1.20 mmol/l could maintain stable PTH levels. METHODS: Measurement of intact PTH (PTHi) in 30 consecutive critically ill patients treated with citrate-based CRRT. RESULTS: Thirty patients [mean age: 70.4 (SD 11.3) years; 56.7% males] were enrolled. Mean serum [Ca(i)] was 1.16 mmol/l (SD 0.09), 1.13 mmol/l (SD 0.09), 1.17 mmol/l (SD 0.05) and 1.16 mmol/l (SD 0.04) at baseline, 12, 24 and 48 h, respectively (p = 0.29). Median PTHi levels (interquartile range) at baseline, 12, 24 and 48 h were 66.5 (43-111), 109 (59.5-151.5), 88.5 (47-133) and 85 pg/ml (53-140), respectively. The differences between baseline and 12 h and across all time points were statistically not significant (p = 0.16 and p = 0.49, respectively). In a mixed-effects model, each 0.1 mmol/l increase in serum [Ca(i)] was associated with a 31.2% decrease in PTHi (p < 0.001). Results were unchanged after adjustment for age, gender, magnesium, phosphate, arterial pH and time spent on CRRT. CONCLUSIONS: Maintaining systemic [Ca(i)] within the physiologic range was associated with stable PTHi levels.

Micronutrients in critically ill patients with severe acute kidney injury - a prospective study.

Malnutrition is common in patients with acute kidney injury (AKI) and the risk of mortality is high, especially if renal replacement therapy is needed. Between April 2013 through April 2014, we recruited critically ill adult patients (≥18 years) with severe AKI in two University hospitals in London, UK, and measured serial plasma concentrations of vitamin B1, B6, B12, C and D, folate, selenium, zinc, copper, iron, carnitine and 22 amino acids for six consecutive days. In patients receiving continuous renal replacement therapy (CRRT), the concentrations of the same nutrients in the effluent were also determined. CRRT patients (n = 31) had lower plasma concentrations of citrulline, glutamic acid and carnitine at 24 hrs after enrolment and significantly lower plasma glutamic acid concentrations (74.4 versus 98.2 µmol/L) at day 6 compared to non-CRRT patients (n = 24). All amino acids, trace elements, vitamin C and folate were detectable in effluent fluid. In >30% of CRRT and non-CRRT patients, the plasma nutrient concentrations of zinc, iron, selenium, vitamin D3, vitamin C, trytophan, taurine, histidine and hydroxyproline were below the reference range throughout the 6-day period. In conclusion, altered micronutrient status is common in patients with severe AKI regardless of treatment with CRRT.

Early enteral supplementation with key pharmaconutrients improves Sequential Organ Failure Assessment score in critically ill patients with sepsis: outcome of a randomized, controlled, double-blind trial.

OBJECTIVE: To assess the safety and efficacy of an early enteral pharmaconutrition supplement containing glutamine dipeptides, antioxidative vitamins and trace elements, and butyrate in critically ill, septic patients. DESIGN: A prospective, randomized, controlled, double-blind clinical trial. SETTING: Adult intensive care unit in a university hospital. PATIENTS: Fifty-five critically ill, septic patients requiring enteral feeding. INTERVENTIONS: Patients received either an enteral supplement (500 mL of Intestamin, Fresenius Kabi) containing conditionally essential nutrients or a control solution via the nasogastric route for up to 10 days. Inclusion occurred within 24 hrs of intensive care unit admission. Additionally, patients received enteral feeding with an immunonutrition formula (experimental group) or standard formula (control group) initiated within 48 hrs after enrollment. MEASUREMENTS AND MAIN RESULTS: Organ dysfunction was assessed by daily total Sequential Organ Failure Assessment (SOFA) score over the 10-day study period in both patient groups. Patients receiving the experimental supplement showed a significantly faster decline in the regression slopes of delta daily total SOFA score over time compared with control. The difference between the regression coefficients of the two slopes was significant irrespective of the level of analysis: intent to treat -0.32 vs. -0.14, p < .0001; per protocol -0.34 vs. -0.14, p < .0001; and completers (patients receiving > or = 80% of the calculated caloric target over a period of 6 days), -0.26 vs. -0.16, p = .0005. Vitamin C, as a marker of supplement absorption, increased from 10.6 (1.9-159.4) micromol/L (normal range 20-50 micromol/L) on day 1 to 58.7 (5.4-189.9) micromol/L by day 3 (p = .002) in the intervention group but remained below the normal range in the control group 17.0 (2.8-78.5) on day 1 and 14.3 (2.4-179.6) on day 3. Serum levels of glycine, serine, arginine, ornithine, vitamin E, and beta-carotene all increased significantly with treatment in the supplementation group. CONCLUSIONS: In medical patients with sepsis, early enteral pharmaconutrition with glutamine dipeptides, vitamin C and E, beta-carotene, selenium, zinc, and butyrate in combination with an immunonutrition formula results in significantly faster recovery of organ function compared with control.

Filter survival time and requirement of blood products in patients with severe sepsis receiving drotrecogin alfa (activated) and requiring renal replacement therapy.

INTRODUCTION: Drotrecogin alfa (activated) (DrotAA) is licensed in the United States and the European Union for the treatment of severe sepsis with multiple organ failure. Patients with severe sepsis on renal replacement therapy (RRT), who typically receive additional anticoagulation to prevent circuit clotting, may be at higher risk of bleeding when DrotAA is administered in addition to standard anticoagulation. However, the effects of DrotAA on filter duration in the absence of additional anticoagulation have not been established. The aim of this study was to analyse the filter survival time (FST), and to quantify the requirement of packed red cells (PRC) and blood products during DrotAA infusion. METHODS: This was a single-centre, retrospective observational study conducted in an adult intensive care unit (ICU). Thirty-five patients with severe sepsis who had received both RRT and DrotAA were identified, and all relevant clinical and laboratory data were retrieved from the departmental electronic patient record. We compared haemofilter parameters, requirement of blood products and haemodynamic data recorded during RRT and the infusion of DrotAA with those recorded on RRT with standard anticoagulation after the DrotAA infusion had been completed (post-DrotAA). RESULTS: The proportion of filter changes due to filter clotting was similar during DrotAA infusion and with conventional anticoagulation post-DrotAA infusion. There was no difference in the FST and filter parameters during DrotAA in the presence or absence of additional anticoagulation with heparin or epoprostenol. A similar proportion of patients required red cell transfusion, although a greater proportion of patients received platelet and fresh frozen plasma during DrotAA infusion compared with the post-DrotAA period with no difference between medical and surgical patients. CONCLUSIONS: Additional anticoagulation during DrotAA infusion does not appear to improve FST. The use of DrotAA in patients with severe sepsis requiring RRT is safe and is not associated with an increased need for PRC transfusion or major bleeding events.

Cardiac Troponin Release is Associated with Biomarkers of Inflammation and Ventricular Dilatation During Critical Illness.

INTRODUCTION: Troponin release is common during critical illness. We hypothesized that there was an association between cardiac troponin T (cTnT) and biomarkers of systemic inflammation and ventricular dilatation. METHODS: In an observational prospective cohort study, we enrolled consecutive adult patients admitted for noncardiac reasons to the intensive care unit (ICU) in two tertiary care centers. We measured cTnT, C-reactive protein (CRP), interleukin-6 (IL-6), procalcitonin (PCT), and N-terminal pro brain natriuretic peptide (NT-proBNP) daily in the first week, and on alternate days in the second week. Using a peak cTnT cutoff ≥15 ng/L and concomitant changes on electrocardiogram, patients were categorized as "definite myocardial infarction (MI)," "possible MI," "cTnT rise only," or "no cTnT rise." Within each group, associations between CRP, IL-6, PCT, NT-proBNP, and cTnT were investigated using mixed effect models. RESULTS: One hundred seventy-two patients were included in the analysis of whom 84% had a cTnT rise ≥15 ng/L. Twenty-one patients (12%) had a definite MI, 51 (30%) had a possible MI, and 73 (42%) had a cTnT rise only. At the time of peak cTnT, 71% of patients were septic and 67% were on vasopressors.Multivariable analysis showed a significant association between cTnT and IL-6 in all patients with a cTnT rise independent of age, gender, renal function, and cardiovascular risk factors. In patients without a definite MI, cTnT levels were significantly associated with PCT and NT-proBNP values. In patients without elevated cTnT levels, there was no associated NT-proBNP rise. CONCLUSIONS: In ICU patients admitted for non-cardiac reasons, serial cTnT levels were independently associated with markers of systemic inflammation and NT-proBNP.

Vitamin D levels in critically ill patients with acute kidney injury: a protocol for a prospective cohort study (VID-AKI).

INTRODUCTION: Acute kidney injury (AKI) affects more than 50% of critically ill patients. The formation of calcitriol, the active vitamin D metabolite, from the main inactive circulating form, 25-hydroxyvitamin D (25(OH)D), occurs primarily in the proximal renal tubules. This results in a theoretical basis for reduction in levels of calcitriol over the course of an AKI. Vitamin D deficiency is highly prevalent in critically ill adults, and has been associated with increased rates of sepsis, longer hospital stays and increased mortality. The primary objective of this study is to perform serial measurements of 25(OH)D and calcitriol (1,25(OH)2D), as well as parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) levels, in critically ill adult patients with and without AKI, and to determine whether patients with AKI have significantly lower vitamin D metabolite concentrations. The secondary objectives are to describe dynamic changes in vitamin D metabolites, PTH and FGF23 during critical illness; to compare vitamin D metabolite concentrations in patients with AKI with and without renal replacement therapy; and to investigate whether there is an association between vitamin D status and outcomes. METHODS AND ANALYSIS: 230 general adult intensive care patients will be recruited. The AKI arm will include 115 critically ill patients with AKI Kidney Disease Improving Global Outcome stage II or stage III. The comparison group will include 115 patients who require cardiovascular or respiratory support, but who do not have AKI. Serial measurements of vitamin D metabolites and associated hormones will be taken on prespecified days. Patients will be recruited from two large teaching Trusts in England. Data will be analysed using standard statistical methods. ETHICS AND DISSEMINATION: Ethical approval was obtained. Upon completion, the study team will submit the study report for publication in a peer-reviewed scientific journal and for conference presentation. TRIAL REGISTRATION NUMBER: NCT02869919; Pre-results.

Use of an Electromagnetic Device Compared With Chest X-ray to Confirm Nasogastric Feeding Tube Position in Critical Care.

BACKGROUND: Insertion of nasogastric feeding tubes (NGTs) is common in critical care. However, misplacement is frequent and can carry a significant morbidity. Current methods to confirm position of NGTs are not reliable in this setting. We retrospectively compared the position of NGTs using an electromagnetically guided nasogastric tube (e-NGT) with that demonstrated by chest x-ray (CXR), the proportion of lung placements avoided, and the time taken to establish enteral feeding. METHODS: This was a retrospective, observational study undertaken in a tertiary referral, adult intensive care unit between February 2006 and November 2013. Patients were included if they had a radiologically confirmed NGT. All CXRs were independently reviewed by an intensivist to determine position, and a subset of patients had their e-NGT image independently reviewed for quality control. Statistical analysis was in the form of sensitivity and specificity and descriptive where indicated. RESULTS: In total, 121 NGT placements in 113 patients were analyzed. We found a sensitivity of 98% (95% confidence interval [CI], 93.9%-99.7%) and a specificity of 100% (95% CI, 48.0%-100.0%) when using the e-NGT compared with CXR. In the subset of 51 independently reviewed e-NGT images, 9 lung placements were avoided. The mean (SD) time from e-NGT placement to CXR was 185 (264.4) minutes and to feeding was 404 (77.8) minutes. CONCLUSION: When placed by a dedicated team, e-NGT allowed immediate detection of tube misplacement. As such, if used as the sole method for determining NGT position, e-NGTs minimize feeding delay and the need for multiple CXRs with subsequent cost savings.

ARDS of early or late onset: does it make a difference?

BACKGROUND: Differences in outcomes have been demonstrated for critically ill patients with late-onset compared with early-onset renal failure and late-onset compared with early-onset shock, which could cause a lead-time bias in clinical trials assessing potential therapies for these conditions. We used data from a large, multicenter observational study to assess whether late-onset ARDS was similarly associated with worse outcomes compared with early-onset ARDS. METHODS: Data were extracted from the Sepsis Occurrence in Acutely Ill Patients (SOAP) study, which involved 198 ICUs from 24 European countries. All adult patients admitted to a participating ICU between May 1, 2002 and May 15, 2002, were eligible, except those admitted for uncomplicated postoperative surveillance. Early/late onset acute lung injury (ALI)/ARDS was defined as ALI/ARDS occurring within/after 48 h of ICU admission. RESULTS: Of the 3,147 patients included in the SOAP study, 393 (12.5%) had a diagnosis of ALI/ARDS; 254 had early-onset ALI/ARDS (64.6%), and 139 (35.5%) late-onset. Patients with early-onset ALI/ARDS had higher Simplified Acute Physiology II scores on admission and higher initial Sequential Organ Failure Assessment scores. Patients with late-onset ALI/ARDS had longer ICU and hospital lengths of stay than patients with early-onset ALI/ARDS. ICU and hospital mortality rates were, if anything, lower in late-onset ALI/ARDS than in early-onset ALI/ARDS, but these differences were not statistically significant. CONCLUSIONS: There were no significant differences in mortality rates between early- and late-onset ARDS, but patients with late-onset ALI/ARDS had longer ICU and hospital lengths of stay.