Blood microbial signatures associated with mortality in patients with sepsis: A pilot study.

Sepsis is a life-threatening illness caused by the dysregulated host response to infection. Nevertheless, our current knowledge of the microbial landscape in the blood of septic patients is still limited. Next-generation sequencing (NGS) is a sensitive method to quantitatively characterize microbiomes at various sites of the human body. In this study, we analyzed the blood microbial DNA of 22 adult patients with sepsis and 3 healthy subjects. The presence of non-human DNA was identified in both healthy and septic subjects. Septic patients had a markedly altered microbial DNA profile compared to healthy subjects over α- and ß-diversity. Unexpectedly, the patients could be further divided into two subgroups (C1 and C2) based on ß-diversity analysis. C1 patients showed much higher bacteria, viruses, fungi, and archaea abundance, and a higher level of α-diversity (Chao1, Observed and Shannon index) than both C2 patients and healthy subjects. The most striking difference was seen in the case of Streptomyces violaceusniger, Phenylobacterium sp. HYN0004, Caulobacter flavus, Streptomyces sp. 11-1-2, and Phenylobacterium zucineum, the abundance of which was the highest in the C1 group. Notably, C1 patients had a significantly poorer outcome than C2 patients. Moreover, by analyzing the patterns of microbe-microbe interactions in healthy and septic subjects, we revealed that C1 and C2 patients exhibited distinct co-occurrence and co-exclusion relationships. Together, our study uncovered two distinct microbial signatures in the blood of septic patients. Compositional and ecological analysis of blood microbial DNA may thus be useful in predicting mortality of septic patients.

Outcomes of respiratory viral-bacterial co-infection in adult hospitalized patients.

BACKGROUND: Viral infections of the respiratory tract represent a major global health concern. Co-infection with bacteria may contribute to severe disease and increased mortality in patients. Nevertheless, viral-bacterial co-infection patterns and their clinical outcomes have not been well characterized to date. This study aimed to evaluate the clinical features and outcomes of patients with viral-bacterial respiratory tract co-infections. METHODS: We included 19,361 patients with respiratory infection due to respiratory viruses [influenza A and B, respiratory syncytial virus (RSV), parainfluenza] and/or bacteria in four tertiary hospitals in Hong Kong from 2013 to 2017 using a large territory-wide healthcare database. All microbiological tests were conducted within 48 h of hospital admission. Four etiological groups were included: (1) viral infection alone; (2) bacterial infection alone; (3) laboratory-confirmed viral-bacterial co-infection and (4) clinically suspected viral-bacterial co-infection who were tested positive for respiratory virus and negative for bacteria but had received at least four days of antibiotics. Clinical features and outcomes were recorded for laboratory-confirmed viral-bacterial co-infection patients compared to other three groups as control. The primary outcome was 30-day mortality. Secondary outcomes were intensive care unit (ICU) admission and length of hospital stay. Propensity score matching estimated by binary logistic regression was used to adjust for the potential bias that may affect the association between outcomes and covariates. FINDINGS: Among 15,906 patients with respiratory viral infection, there were 8451 (53.1%) clinically suspected and 1,087 (6.8%) laboratory-confirmed viral-bacterial co-infection. Among all the bacterial species, Haemophilus influenzae (226/1,087, 20.8%), Pseudomonas aeruginosa (180/1087, 16.6%) and Streptococcus pneumoniae (123/1087, 11.3%) were the three most common bacterial pathogens in the laboratory-confirmed co-infection group. Respiratory viruses co-infected with non-pneumococcal streptococci or methicillin-resistant Staphylococcus aureus was associated with the highest death rate [9/30 (30%) and 13/48 (27.1%), respectively] in this cohort. Compared with other infection groups, patients with laboratory-confirmed co-infection had higher ICU admission rate (p < 0.001) and mortality rate at 30 days (p = 0.028), and these results persisted after adjustment for potential confounders using propensity score matching. Furthermore, patients with laboratory-confirmed co-infection had significantly higher mortality compared to patients with bacterial infection alone. INTERPRETATION: In our cohort, bacterial co-infection is common in hospitalized patients with viral respiratory tract infection and is associated with higher ICU admission rate and mortality. Therefore, active surveillance for bacterial co-infection and early antibiotic treatment may be required to improve outcomes in patients with respiratory viral infection.

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.

Rapid cycle system improvement for COVID-19 readiness: integrating deliberate practice, psychological safety and vicarious learning.

Introduction: In the face of a rapidly advancing pandemic with uncertain pathophysiology, pop-up healthcare units, ad hoc teams and unpredictable personal protective equipment supply, it is difficult for healthcare institutions and front-line teams to invent and test robust and safe clinical care pathways for patients and clinicians. Conventional simulation-based education was not designed for the time-pressured and emergent needs of readiness in a pandemic. We used 'rapid cycle system improvement' to create a psychologically safe learning oasis in the midst of a pandemic. This oasis provided a context to build staff technical and teamwork capacity and improve clinical workflows simultaneously. Methods: At the Department of Anaesthesia and Intensive Care in Prince of Wales Hospital, a tertiary institution, in situ simulations were carried out in the operating theatres and intensive care unit (ICU). The translational simulation design leveraged principles of psychological safety, rapid cycle deliberate practice, direct and vicarious learning to ready over 200 staff with 51 sessions and achieve iterative system improvement all within 7 days. Staff evaluations and system improvements were documented postsimulation. Results/Findings: Staff in both operating theatres and ICU were significantly more comfortable and confident in managing patients with COVID-19 postsimulation. Teamwork, communication and collective ability to manage infectious cases were enhanced. Key system issues were also identified and improved. Discussion: To develop readiness in the rapidly progressing COVID-19 pandemic, we demonstrated that 'rapid cycle system improvement' can efficiently help achieve three intertwined goals: (1) ready staff for new clinical processes, (2) build team competence and confidence and (3) improve workflows and procedures.

In-vitro adsorption and sieving coefficient of ticarcillin-clavulanate during continuous haemofiltration.

There are very limited data on ticarcillin-clavulanate elimination by haemofiltration. We measured in vitro ticarcillin-clavulanate adsorption to polyacrylonitrile (PAN) filters and the sieving coefficient using a well-described bench model of haemofiltration. The dose of ticarcillin-clavulanate was 60/2 mg or 180/3 mg, and 0 or 12 g albumin was added to the 1 L of circulating blood-crystalloid mixture to produce four different experimental conditions. The experiment was repeated four times under each condition. Median (interquartile range [IQR] ) ticarcillin adsorption varied from 28 (27-30) mg to 85 (78-90) mg. Adsorption was increased when the dose of ticarcillin was higher (P<0.001), but was not affected by the addition of albumin. Median (IQR) adsorption of clavulanate ranged from 0.67 (0.55-0.75) mg to 1.8 (0.33-3.5) mg and was neither dose dependent (P = 0.505) nor significantly affected by the addition of albumin. Median (IQR) ticarcillin sieving coefficient ranged from 0.73 (0.67-0.75) to 0.99 (0.97-1.03). It was significantly higher with a higher dose of ticarcillin (P = 0.021) and without addition of albumin (P = 0.015). Median (IQR) clavulanate sieving coefficient ranged from 1.03 (1.00-2.24) to 2.0 (1.98-2.47). Clavulanate sieving coefficient was not significantly affected by dose or the addition of albumin. These data indicate that significant adsorption of both ticarcillin and clavulanate occurs in vitro; however, this requires confirmation by clinical pharmacokinetic studies. The sieving coefficient data may help guide appropriate dosing of critically ill patients receiving haemofiltration until more extensive clinical pharmacokinetic data are available.

Pathological Role and Diagnostic Value of Endogenous Host Defense Peptides in Adult and Neonatal Sepsis: A Systematic Review.

BACKGROUND: Sepsis is a systemic host response to an infection leading to organ failure. This is associated with dynamic expression of endogenous host defense peptides. Dysregulation of these peptides is associated with septic morbidity and mortality. METHODS: We performed a systematic search of articles indexed in PubMed, ISI Web of Knowledge, EmBase, and Scopus database from inception to October 2016. Both preclinical and clinical studies investigating the role of host defense peptides in pathogenesis and as biomarkers for sepsis were included. RESULTS: Of the available literature, cathelicidin, defensin, and hepcidin are among the best-characterized peptides. These regulate immune response, and crosstalk with pyroptosis and coagulation cascades. The applicability of these peptides as septic biomarkers has been investigated in vitro and in vivo studies. However, numerous studies were based on endotoxemia without an infection, jeopardizing interpretation of the outcomes. Cathelicidin and defensin were frequently reported in adult sepsis while hepcidin in neonatal sepsis. The expression level of these peptides is significantly associated with septic condition. Most of the studies employed a cross-sectional design, precluding the establishment of a temporal relationship between candidate peptide biomarkers and sepsis. CONCLUSIONS: Innate defense peptides have been insufficiently evaluated as either diagnostic or prognostic biomarkers. In the future, evaluation of host defense peptides as septic biomarkers may employ a longitudinal design and consider a panel of multiple peptides.

Asian venous thromboembolism guidelines: updated recommendations for the prevention of venous thromboembolism.

The Asian venous thromboembolism (VTE) prophylaxis guidelines were first published in 2012. Since its first edition, the Asian Venous Thrombosis Forum (AVTF) working group have updated the Asian VTE epidemiology and reviewed issues that were not addressed in the previous guidelines. The authors noted that the rising incidence of VTE across Asia may be attributable to aging population, dietary changes, and increasing incidence of obesity and diabetes. The new additions in the guideline include role of thrombophilia in VTE, bleeding risk in Asians, individual risk assessment, updates in the prevention of VTE in medically ill, bariatric surgery, cancer, orthopedic and trauma patients. The influence of primary thrombophilia in perioperative VTE is still unclear. The secondary risk factors, however, are similar between Asians and Caucasians. The group found no evidence of increased risk of bleeding while using pharmacological agents, including the use of novel anti-coagulants. At present, Caprini risk assessment model is widely used for individual risk assessment. Further validation of this model is needed in Asia. In medically ill patients, pharmacological agents are preferred if there is no bleeding risk. Intermittent pneumatic compression device (IPC) is recommended in patients with bleeding risk but we do not recommend using graduated compressive stockings. In bariatric patients, data on VTE is lacking in Asia. We recommend following current international guidelines. A high index of suspicion should be maintained during postbariatric surgery to detect and promptly treat portomesenteric venous thrombosis. Different cancer types have different thrombotic risks and the types of surgery influence to a large extent the overall VTE risk. Cancer patients should receive further risk assessment. In patients with higher thrombotic risk, either due to predisposing risk or concomitant surgery, low molecular weight heparin is indicated. Different countries appear to have different incidence of VTE following trauma and major orthopedic surgery. We recommend mechanical prophylaxis using IPC as the main method and additional pharmacological prophylaxis if the thrombotic risk is high. As for obstetric practice, we propose adherence to the UK Greentop guideline that is widely accepted and utilized across Asia. To improve VTE thromboprophylaxis implementation in the region, we propose that there should be better health education, establishment of hospital-based guidelines and multidisciplinary collaboration.

The involvement of regulatory non-coding RNAs in sepsis: a systematic review.

BACKGROUND: Sepsis coincides with altered gene expression in different tissues. Accumulating evidence has suggested that microRNAs, long non-coding RNAs, and circular RNAs are important molecules involved in the crosstalk with various pathways pertinent to innate immunity, mitochondrial functions, and apoptosis. METHODS: We searched articles indexed in PubMed (MEDLINE), EMBASE and Europe PubMed Central databases using the Medical Subject Heading (MeSH) or Title/Abstract words ("microRNA", "long non-coding RNA", "circular RNA", "sepsis" and/or "septic shock") from inception to Sep 2016. Studies investigating the role of host-derived microRNA, long non-coding RNA, and circular RNA in the pathogenesis of and as biomarkers or therapeutics in sepsis were included. Data were extracted in terms of the role of non-coding RNAs in pathogenesis, and their applicability for use as biomarkers or therapeutics in sepsis. Two independent researchers assessed the quality of studies using a modified guideline from the Systematic Review Center for Laboratory animal Experimentation (SYRCLE), a tool based on the Cochrane Collaboration Risk of Bias tool. RESULTS: Observational studies revealed dysregulation of non-coding RNAs in septic patients. Experimental studies confirmed their crosstalk with JNK/NF-κB and other cellular pathways pertinent to innate immunity, mitochondrial function, and apoptosis. Of the included studies, the SYRCLE scores ranged from 3 to 7 (average score of 4.55). This suggests a moderate risk of bias. Of the 10 articles investigating non-coding RNAs as biomarkers, none of them included a validation cohort. Selective reporting of sensitivity, specificity, and receiver operating curve was common. CONCLUSIONS: Although non-coding RNAs appear to be good candidates as biomarkers and therapeutics for sepsis, their differential expression across tissues complicated the process. Further investigation on organ-specific delivery of these regulatory molecules may be useful.

Autophagy in sepsis: Degradation into exhaustion?

Autophagy is one of the innate immune defense mechanisms against microbial challenges. Previous in vitro and in vivo models of sepsis demonstrated that autophagy was activated initially in sepsis, followed by a subsequent phase of impairment. Autophagy modulation appears to be protective against multiple organ injuries in these murine sepsis models. This is achieved in part by preventing apoptosis, maintaining a balance between the productions of pro- and anti-inflammatory cytokines, and preserving mitochondrial functions. This article aims to discuss the role of autophagy in sepsis and the therapeutic potential of autophagy enhancers.

SaMpling Antibiotics in Renal Replacement Therapy (SMARRT): an observational pharmacokinetic study in critically ill patients.

BACKGROUND: Optimal antibiotic dosing is key to maximising patient survival, and minimising the emergence of bacterial resistance. Evidence-based antibiotic dosing guidelines for critically ill patients receiving RRT are currently not available, as RRT techniques and settings vary greatly between ICUs and even individual patients. We aim to develop a robust, evidence-based antibiotic dosing guideline for critically ill patients receiving various forms of RRT. We further aim to observe whether therapeutic antibiotic concentrations are associated with reduced 28-day mortality. METHODS/DESIGN: We designed a multi-national, observational pharmacokinetic study in critically ill patients requiring RRT. The study antibiotics will be vancomycin, linezolid, piperacillin/tazobactam and meropenem. Pharmacokinetic sampling of each patient's blood, RRT effluent and urine will take place during two separate dosing intervals. In addition, a comprehensive data set, which includes the patients' demographic and clinical parameters, as well as modality, technique and settings of RRT, will be collected. Pharmacokinetic data will be analysed using a population pharmacokinetic approach to identify covariates associated with changes in pharmacokinetic parameters in critically ill patients with AKI who are undergoing RRT for the five commonly prescribed antibiotics. DISCUSSION: Using the comprehensive data set collected, the pharmacokinetic profile of the five antibiotics will be constructed, including identification of RRT and other factors indicative of the need for altered antibiotic dosing requirements. This will enable us to develop a dosing guideline for each individual antibiotic that is likely to be relevant to any critically ill patient with acute kidney injury receiving any of the included forms of RRT. TRIAL REGISTRATION: Australian New Zealand Clinical Trial Registry ( ACTRN12613000241730 ) registered 28 February 2013.

To increase or decrease dosage of antimicrobials in septic patients during continuous renal replacement therapy: the eternal doubt.

Critical illness, acute renal failure and continuous renal replacement therapy (CRRT) are associated with changes in pharmacokinetics. Initial antibiotic dose should be based on published volume of distribution and generally be at least the standard dose, as volume of distribution is usually unchanged or increased. Subsequent doses should be based on total clearance. Total clearance varies with the CRRT clearance which mainly depends on effluent flow rate, sieving coefficient/saturation coefficient. As antibiotic clearance by healthy kidneys is usually higher than clearance by CRRT, except for colistin, subsequent doses should generally be lower than given to patients without renal dysfunction. In the future therapeutic drug monitoring, together with sophisticated pharmacokinetic models taking into account the pharmacokinetic variability, may enable more appropriate individualized dosing.

Introducing Final-Year Medical Students to Pocket-Sized Ultrasound Imaging: Teaching Transthoracic Echocardiography on a 2-Week Anesthesia Rotation.

PROBLEM: The availability of less expensive and smaller ultrasound machines has enabled the use of ultrasound in virtually all major medical/surgical disciplines. Some medical schools have incorporated point-of-care ultrasound training into their undergraduate curriculum, whereas many postgraduate programs have made ultrasound training a standard. The Chinese University of Hong Kong has charged its Department of Anaesthesia and Intensive Care to spearhead the introduction of ultrasound into the final-year medical curriculum by introducing handheld transthoracic echocardiography as part of perioperative assessment. INTERVENTION: All 133 final-year students completed a 2-week anesthesia rotation, which began with a half-day session consisting of a lecture and hands-on practice session during which they learned 9 basic transthoracic echocardiography views using 4 basic ultrasound probe positions. CONTEXT: Each student was required to perform a transthoracic echocardiography-examine under supervision of 1 patient/week for 2 weeks, and their results were compared against that of the supervisor's. Most patients were elective cardiac surgery patients. One long question on transthoracic echocardiography was included in their end-of-year surgery examination paper. Students provided feedback on their experience. OUTCOME: Most students learned the basic transthoracic echocardiography views fairly efficiently and had variable, though generally favorable, success rates in identifying obvious cardiac anomalies, including use of color Doppler. A few common mistakes were identified but were easily correctable. Logistics for mobilizing enough bedside supervision were challenging. Students reported positive feedback on the teaching initiative. LESSONS LEARNED: We were able to execute a successful short training course on transthoracic echocardiography during the final-year medical degree anesthesia rotation. Our initiative may set an example for other clinical departments to design similar courses pertinent to their specialties and syllabuses.

How can we ensure effective antibiotic dosing in critically ill patients receiving different types of renal replacement therapy?

Determining appropriate antibiotic dosing for critically ill patients receiving renal replacement therapy (RRT) is complex. Worldwide unstandardized and heterogeneous prescribing of RRT as well as altered patient physiology and pathogen susceptibility all cause drug disposition to be much different to that seen in non-critically ill patients. Significant changes to pharmacokinetic parameters, including volume of distribution and clearance, could be expected, in particular, for antibiotics that are hydrophilic with low plasma protein binding and that are usually primarily eliminated by the renal system. Antibiotic clearance is likely to be significantly increased when higher RRT intensities are used. The combined effect of these factors that alter antibiotic disposition is that non-standard dosing strategies should be considered to achieve therapeutic exposure. In particular, an aggressive early approach to dosing should be considered and this may include administration of a 'loading dose', to rapidly achieve therapeutic concentrations and maximally reduce the inoculum of the pathogen. This approach is particularly important given the pharmacokinetic changes in the critically ill as well as the increased likelihood of less susceptible pathogens. Dose individualization that applies knowledge of the RRT and patient factors causing altered pharmacokinetics remains the key approach for ensuring effective antibiotic therapy for these patients. Where possible, therapeutic drug monitoring should also be used to ensure more accurate therapy. A lack of pharmacokinetic data for antibiotics during the prolonged intermittent RRT and intermittent hemodialysis currently limits evidence-based antibiotic dose recommendations for these patients.

How to optimise antimicrobial prescriptions in the Intensive Care Unit: principles of individualised dosing using pharmacokinetics and pharmacodynamics.

Optimising antimicrobial dosing for critically ill patients is highly challenging and when it is not achieved can lead to worse patient outcomes. To this end, use of dosing regimens recommended in package inserts from drug manufacturers is frequently insufficient to guide dosing in these patients appropriately. Whilst the effect of critical illness pathophysiology on the pharmacokinetic (PK) behaviour of antimicrobials can be profound, the variability of these changes between patients is still being quantified. The PK effects of hypoproteinaemia, organ dysfunction and the presence of augmented renal clearance may lead to plasma antimicrobial concentrations that are difficult to predict at the bedside, which may result in excess toxicity or suboptimal bacterial killing. This paper outlines the factors that affect pharmacokinetics in critically ill patients and how knowledge of these factors can increase the likelihood of achieving optimal antimicrobial plasma concentrations. In selected settings, we advocate individualised dosing of renally cleared antimicrobials using physiological data such as measured creatinine clearance and published non-renal clearance data. Where such data do not exist, therapeutic drug monitoring may be a useful alternative and has been associated with significant clinical benefits, although it is not currently widely available.

Utilisation and outcome of renal replacement therapy in an Asian tertiary intensive care unit.

OBJECTIVES: To determine the period prevalence, demographic characteristics, cost of treatment, and outcomes of patients admitted to the intensive care unit for continuous renal replacement therapy. DESIGN: Descriptive case series. SETTING: Intensive Care Unit in a Hong Kong tertiary referral, teaching hospital. PATIENTS: All patients admitted to the Intensive Care Unit from January to December 2007 who underwent continuous renal replacement therapy. MAIN OUTCOME MEASURES: Period prevalence of continuous renal replacement therapy, patient demographic data, referral sources by specialty and hospital location, diagnosis, daily cost of disposable items, duration of renal replacement therapy, intensive care unit length of stay, and hospital mortality. RESULTS: Of 1652 patients admitted to the intensive care unit over a 12-month period, 131 (8%) underwent continuous renal replacement therapy, of whom 56% were admitted from general wards (the department of medicine being the source of 59% of referrals). The median age of these continuous renal replacement therapy patients was 67 (interquartile range, 55-76) years, with a slight male predominance (66%). The mean APACHE II score of the patients was 29 (standard deviation, 7). Chronic renal failure requiring either haemodialysis or peritoneal dialysis was present in 20/131 (15%) patients. Sepsis was the diagnosis most commonly associated with renal failure deemed to warrant continuous renal replacement therapy (43%). The median duration of such continuous therapy was 55 (interquartile range, 25-93) hours and the median intensive care unit length of stay was 120 (interquartile range, 51-289) hours. The mean daily cost of disposables for the provision of continuous renal replacement therapy was HK$3510. The overall intensive care unit mortality of patients having continuous renal replacement therapy was 38% and the hospital mortality was 53%. The corresponding rates for patients with acute renal failure were 45% and 56%, respectively. Patients undergoing continuous renal replacement therapy had prolonged intensive care unit stays (120 vs 24 hours; P<0.05) and higher corresponding hospital mortality rates (53% vs 20%; P<0.001) compared to those not having such therapy. CONCLUSION: The 8% period prevalence of patients admitted to the intensive care unit undergoing continuous renal replacement therapy was somewhat higher than in recently published reports in the international literature. However intensive care unit and hospital mortality rates for such patients were lower than previously reported. The corresponding total daily cost of relevant disposables was similar to costs reported internationally, whilst the length of intensive care unit stays for our cohort were relatively short.

Systemic inflammation in the elderly.

Inflammation is an adaptive response to surgery. When the pro-inflammatory responses are unregulated and become over reactive, systemic inflammatory response syndrome may occur. Postoperative systemic inflammation is more common than is generally acknowledged and is observed in about 10-15% of elderly patients undergoing major surgery. Although the vast majority of systemic inflammation is related to infections, other important predisposing risk factors, such as extent of trauma and haemorrhage, should not be overlooked. Increased awareness, modification of risk factors and early recognition are the key elements in the management of systemic inflammation. Prompt resuscitation aiming to correct hypotension, hypovolaemia and tissue hypoxia may improve outcome. Future large prospective observational studies are needed to define the incidence, risk factors and impact of systemic inflammatory syndrome in the elderly surgical patients. A better understanding of the molecular events during the systemic inflammatory response syndrome is required for future development of specific immunotherapy.

Principles of antibacterial dosing in continuous renal replacement therapy.

BACKGROUND: Appropriate antibacterial therapy is important to maximize patient survival in sepsis. Acute renal failure complicates optimal antibiotic administration. METHODS: MEDLINE search from 1986 to 2010 using the terms 'acute renal failure', 'pharmacokinetics', 'clearance', 'dosage', 'h(a)emofiltration', 'h(a)emodialysis', 'h(a)emodiafiltration', 'continuous renal replacement therapy', 'antibiotics', 'intensive care' and 'critically ill'. RESULTS: Maximal bacterial killing and minimization of side effects depend on achieving pharmacokinetic targets appropriate to the selected antibacterial agent. Volume of distribution and clearance may be altered by critical illness and/or acute kidney injury. Clearance is determined by nonrenal clearance, residual renal clearance and continuous renal replacement therapy dose. Sieving and saturation coefficients are membrane specific, but may be altered by changes in protein binding induced by critical illness. A significant proportion of studies failed to report the essential dataset required for adequate antibacterial dosage calculation. CONCLUSIONS: Individualized dosing based on first principles may be the most appropriate method of dosing, particularly when enhanced by therapeutic drug monitoring.

Principles of antibacterial dosing in continuous renal replacement therapy.

OBJECTIVES: To outline the concepts involved in optimizing antibacterial dosing in critically ill patients with acute renal failure undergoing continuous renal replacement therapy (CRRT), provide a strategy for optimizing dosing, and summarize the data required to implement the strategy. DATA SOURCES: MEDLINE search from February 1986 to 2008. DATA EXTRACTION AND SYNTHESIS: Optimal dosing of antibacterials is dependent on achieving pharmacokinetic targets associated with maximal killing of bacteria and improved outcomes. The initial dose is dependent on the volume of distribution. Maintenance doses are dependent on clearance. Both should be adjusted according to the pharmacokinetic target associated with optimal bacterial killing, when known. The volume of distribution of some antibacterials is altered by critical illness or acute renal failure or both. Clearance by CRRT is dependent on the dose and mode of CRRT and the sieving or saturation coefficient of the drug. Both sieving and saturation coefficient are related to the plasma protein binding and thus may be altered in renal failure. CONCLUSIONS: Appropriate dose calculation requires knowledge of the pharmacokinetic target and the usual minimum inhibitory concentration of the suspected organism in the patient's locality (or if unavailable, the break point for the organism), published pharmacokinetic data (volume of distribution, non-CRRT clearance) on critically ill patients receiving CRRT (which may differ substantially from noncritically ill patients or those without renal failure), the sieving or saturation coefficient of the relevant drug in critically ill patients, the dose and mode of CRRT being used, and the actual dose of CRRT that is delivered. This large number of variables results in considerable inter- and intrapatient heterogeneity in dose requirements. This article provides basic principles and relevant data to guide the clinician in prescribing individualized dosing regimes.

The adsorption of vancomycin by polyacrylonitrile, polyamide, and polysulfone hemofilters.

The aim of this study was to characterize vancomycin adsorption by polyacrylonitrile (PAN), polyamide, and polysulfone hemofilters using an in vitro model of hemofiltration. Vancomycin (36 mg) was added to a blood-crystalloid mixture of known volume (target concentration of 50 mg/L) and pumped around a closed circuit. Adsorption, which was calculated from the fall in concentration over 120 min, was significantly greater by 0.6-m(2) PAN filters (10.08 +/- 2.26 mg) than by 0.6-m(2) polyamide (5.20 +/- 1.82 mg) or 0.7-m(2) polysulfone (4.80 +/- 2.40 mg) filters (P < 0.05). Cumulative adsorption was not changed by the addition of 500-mL lactated Ringer's solution (to reduce the circulating vancomycin concentration). These data show that although adsorption of vancomycin by PAN, polyamide, and polysulfone hemofilters occurs, the absolute adsorption is small. Adsorption is dependent on filter material and is not reversed by a decrease in circulating concentration.