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.

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.

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.

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.

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.

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.

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.

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.

Adsorption of amikacin, a significant mechanism of elimination by hemofiltration.

We used an in vitro model of continuous venovenous hemofiltration (CVVH) to characterize amikacin adsorption by polyacrylonitrile (PAN) and polyamide filters. A blood-crystalloid mixture dosed with amikacin was pumped from a reservoir through a hemofiltration circuit and back to the reservoir. All ultrafiltrate was also returned to the reservoir. The level of adsorption was calculated from the fall in the amikacin concentration. The dose and the initial concentration of amikacin were varied, as were the pH, the type of hemofilter, and the hemofilter surface area. The reversibility of adsorption and the effect of repeated dosing were also studied. The level of adsorption by 0.6-m2 PAN filters was significantly greater than that by 0.6-m2 polyamide filters. Adsorption was increased by increasing the dose of amikacin even when the initial concentration was unchanged. It was unaffected by the pH (pH 6.8 or 7.4) or the hemofilter surface area (0.6 m2 or 0.9 m2). Repeated doses of amikacin resulted in further adsorption. In a saturation experiment, the maximum adsorptive capacity of 0.6-m2 PAN hemofilters was at least 546.9 mg (range, 427.6 to 577.5 mg). The adsorption of amikacin by hemofilters is irreversible and was associated with the dose and the hemofilter material but not the hemofilter surface area. Close monitoring of peak amikacin levels should be considered for patients receiving CVVH with PAN hemofilters.