A pilot randomized clinical trial of cryopreserved versus liquid-stored platelet transfusion for bleeding in cardiac surgery: The cryopreserved versus liquid platelet-New Zealand pilot trial.

BACKGROUND AND OBJECTIVES: Platelets for transfusion have a shelf-life of 7 days, limiting availability and leading to wastage. Cryopreservation at -80°C extends shelf-life to at least 1 year, but safety and effectiveness are uncertain. MATERIALS AND METHODS: This single centre blinded pilot trial enrolled adult cardiac surgery patients who were at high risk of platelet transfusion. If treating clinicians determined platelet transfusion was required, up to three units of either cryopreserved or liquid-stored platelets intraoperatively or during intensive care unit admission were administered. The primary outcome was protocol safety and feasibility. RESULTS: Over 13 months, 89 patients were randomized, 23 (25.8%) of whom received a platelet transfusion. There were no differences in median blood loss up to 48 h between study groups, or in the quantities of study platelets or other blood components transfused. The median platelet concentration on the day after surgery was lower in the cryopreserved platelet group (122 × 103 /µl vs. 157 × 103 /µl, median difference 39.5 ×103 /µl, p = 0.03). There were no differences in any of the recorded safety outcomes, and no adverse events were reported on any patient. Multivariable adjustment for imbalances in baseline patient characteristics did not find study group to be a predictor of 24-h blood loss, red cell transfusion or a composite bleeding outcome. CONCLUSION: This pilot randomized controlled trial demonstrated the feasibility of the protocol and adds to accumulating data supporting the safety of this intervention. Given the clear advantage of prolonged shelf-life, particularly for regional hospitals in New Zealand, a definitive non-inferiority phase III trial is warranted.

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.

A randomized, controlled pilot clinical trial of cryopreserved platelets for perioperative surgical bleeding: the CLIP-I trial (Editorial, p. 2759).

BACKGROUND: Cryopreservation extends platelet (PLT) shelf life from 5 to 7 days to 2 to 4 years. However, only 73 patients have been transfused cryopreserved PLTs in published randomized controlled trials (RCTs), making safety data insufficient for regulatory approval. STUDY DESIGN AND METHODS: The Cryopreserved vs. Liquid Platelet (CLIP) study was a double-blind, pilot, multicenter RCT involving high-risk cardiothoracic surgical patients in four Australian hospitals. The objective was to test, as the primary outcome, the feasibility and safety of the protocol. Patients were allocated to study group by permuted block randomization, with patients and clinicians blinded by use of an opaque shroud placed over each study PLT unit. Up to 3 units of cryopreserved or liquid-stored PLTs were administered per patient. No other aspect of patient care was affected. Adverse events were actively sought. RESULTS: A total of 121 patients were randomized, of whom 23 received cryopreserved PLTs and 18 received liquid-stored PLTs. There were no differences in blood loss (median, 715 mL vs. 805 mL at 24 hr; difference between groups 90 mL [95% CI, -343.8 to 163.8 mL], p = 0.41), but the Bleeding Academic Research Consortium criterion for significant postoperative hemorrhage in cardiac surgery composite bleeding endpoint occurred in nearly twice as many patients in the liquid-stored group (55.6% vs. 30.4%, p = 0.10). Red blood cell transfusion requirements were a median of 3 units in the cryopreserved group versus 4 units with liquid-stored PLTs (difference between groups, 1 unit [95% CI, -3.1 to 1.1 units]; p = 0.23). Patients in the cryopreserved group were more likely to be transfused fresh-frozen plasma (78.3% vs. 27.8%, p = 0.002) and received more study PLT units (median, 2 units vs. 1 unit; difference between groups, 1 unit [95% CI, -0.03 to 2.0 units]; p = 0.012). There were no between-group differences in potential harms including deep venous thrombosis, myocardial infarction, respiratory function, infection, and renal function. No patient had died at 28 days, and postoperative length of stay was similar in each group. CONCLUSION: In this pilot RCT, compared to liquid-stored PLTs, cryopreserved PLTs were associated with no evidence of harm. A definitive study testing safety and hemostatic effectiveness is warranted.

A Robust Statistical Approach to Analyse Population Pharmacokinetic Data in Critically Ill Patients Receiving Renal Replacement Therapy.

BACKGROUND AND AIM: Current approaches to antibiotic dose determination in critically ill patients requiring renal replacement therapy are primarily based on the assessment of highly heterogeneous data from small number of patients. The standard modelling approaches limit the scope of constructing robust confidence boundaries of the distribution of pharmacokinetics (PK) parameters, especially when the evaluation of possible association of demographic and clinical factors at different levels of the distribution of drug clearance is of interest. Commonly used compartmental models generally construct the inferences through a linear or non-linear mean regression, which is inadequate when the distribution is skewed, multi-modal or effected by atypical observation. In this study, we discuss the statistical challenges in robust estimation of the confidence boundaries of the PK parameters in the presence of highly heterogenous patient characteristics. METHODS: A novel stepwise approach to evaluate the confidence boundaries of PK parameters is proposed by combining PK modelling with mixed-effects quantile regression (MEQR) methods. RESULTS: This method allows the assessment demographic and clinical factors' effects at any arbitrary quantiles of the outcome of interest, without restricting assumptions on the distributions. The MEQR approach allows us to investigate if the levels of association of the covariates are different at low, medium or high concentration. CONCLUSIONS: This methodological assessment is deemed as a background initial approach to support the development of a class of statistical algorithm in constructing robust confidence intervals of PK parameters which can be used for developing an optimised antibiotic dosing guideline for critically ill patients requiring renal replacement therapy.

Augmented Renal Clearance in Traumatic Brain Injury: A Single-Center Observational Study of Atrial Natriuretic Peptide, Cardiac Output, and Creatinine Clearance.

Augmented renal clearance (ARC) is being increasingly described in neurocritical care practice. The mechanisms driving this phenomenon are largely unknown. The aim of this project was therefore to explore changes in renal function, cardiac output (CO), and atrial natriuretic peptide (ANP) concentrations in patients with isolated traumatic brain injury (TBI). This prospective observational cohort study was conducted in a tertiary-level, university-affiliated intensive care unit (ICU). Patients with normal plasma creatinine concentrations (<120 µmol/L) at admission and no history of chronic kidney disease, admitted with isolated TBI, were eligible for enrollment. Continuous CO measures were obtained using arterial pulse waveform analysis. Eight-hour urinary creatinine clearances (CLCR) were used to quantify renal function. ANP concentrations in plasma were measured on alternate days. Data were collected from study enrollment until ICU discharge, death, or day 15, which ever came first. Eleven patients, contributing 100 ICU days of physiological data, were enrolled into the study. Most participants were young men, requiring mechanical ventilation. Median ICU length of stay was 9.6 [7.8-13.0] days. Elevated CLCR measures (>150 mL/min) were frequent and appeared to parallel changes in CO. Plasma ANP concentrations were also significantly elevated over the study period (minimum value = 243 pg/mL). These data suggest that ARC is likely to complicate the care of TBI patients with normal plasma creatinine concentrations, and may be driven by associated cardiovascular changes and/or elevated plasma ANP concentrations. However, significant additional research is required to further understand these findings.

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.

A comparative assessment of two conservative methods for the diagnosis of catheter-related infection in critically ill patients.

PURPOSE: To assess the utility of two in situ techniques, differential time to positivity (DTP) and semiquantitative superficial cultures (SQSC) for diagnosing catheter-related bloodstream infection (CR-BSI) in critically ill adults. METHODS: This was a prospective cohort study in patients with suspected CR-BSI arising from a short-term arterial catheter (AC) or a central venous catheter (CVC). On suspicion of CR-BSI, devices were removed. Blood, skin, catheter tip and hub cultures were taken. Infection rates were compared against the diagnosis of CR-BSI using matched tip and blood cultures. RESULTS: Of 120 episodes of clinically suspected CR-BSI in 101 patients examined, 9 (7.5 %) were confirmed as CR-BSI. Validity values (95 % CI) for the diagnosis of CR-BSI arising from both AC and CVC for DTP were: sensitivity 44 % (15-77 %), specificity 98 % (93-100 %), positive predictive value (PPV) 67 % (24-94 %), negative predictive value (NPV) 96 % (90-98 %), positive likelihood ratio (LR+) 25 (5-117), negative likelihood ratio (LR-) 0.6 (0.3-1.0), diagnostic odds ratio (DOR) 44 (7-258), and accuracy 94 % (92-98 %). Validity values (95 % CI) for SQSC were: sensitivity 78 % (41-96 %), specificity 60 % (50-69 %), PPV 14 % (6-26 %), NPV 97 % (89-99 %), LR+ 1.9 (1.0-2.3), LR- 0.4 (0.1-1.3), DOR 5.1 (1.1-19), and accuracy 61 % (51-69 %). DTP combined with SQSC improved sensitivity and NPV to 100 % whilst the DOR increased to 25.8 (95 % CI 3-454). CONCLUSIONS: CR-BSI can be ruled out by undertaking DTP and SQSC concurrently for both ACs and CVCs with 100 % sensitivity and NPV.

Serial changes in plasma total cortisol, plasma free cortisol, and tissue cortisol activity in patients with septic shock: an observational study.

Published data on adrenocortical function in septic shock have enrolled patients at various stages of critical illness and predominantly used plasma total cortisol, with minimal information on serial changes. Moreover, plasma free cortisol and tissue corticosteroid activity may not be strongly associated; however, few published data exist. The aim of this prospective observational study was to investigate serial changes in plasma total and free cortisol and tissue cortisol activity in septic shock. Twenty-nine adult patients admitted with septic shock to a tertiary-level intensive care unit were enrolled. A low-dose corticotropin test was performed on day 1. Plasma total and free cortisol, cortisone, transcortin, and urinary free cortisol and cortisone were analyzed on days 1 to 5, 7, and 10. Urinary and plasma cortisol-cortisone ratios (F:E ratio) were calculated as indices of 11-ß hydroxysteroid dehydrogenase 2 and global 11-ß hydroxysteroid dehydrogenase activity, respectively. Baseline total and free plasma cortisol values from 10 healthy control subjects were obtained for comparative analysis. Baseline plasma total and free cortisol levels were significantly higher than controls (457.8 ± 193 vs. 252 ± 66 nmol/L, P = 0.0002; and 50.83 ± 43.19 vs. 6.4 ± 3.2, P < 0.0001, respectively). Plasma free cortisol rose proportionately higher than total cortisol (124% ± 217.3% vs. 40% ± 33.2%, P = 0.007) following corticotropin. Baseline plasma and urinary F:E ratios were elevated over the reference ranges (13.13 ± 1.5, 1.69 ± 2.8) and were not correlated with plasma free cortisol values (r = 0.2, 0.3 respectively). Over the study period, total cortisol levels and plasma F:E ratios remained elevated, whereas plasma free cortisol levels and urinary F:E ratio declined. At baseline, plasma free cortisol levels were higher in patients who subsequently survived (23.7 ± 10.5 vs. 57.9 ± 45.8 nmol/L, P = 0.04). In septic shock, there is a differential response of plasma total and free cortisol over time and in response to corticotropin. Changes in plasma and urinary F:E ratios suggest tissue modulation of 11-ß hydroxysteroid dehydrogenase activity. Total plasma cortisol measurements may not reflect the global adrenal response in septic shock.

Plasma and tissue pharmacokinetics of cefazolin in patients undergoing elective and semielective abdominal aortic aneurysm open repair surgery.

Surgical site infections are common, so effective antibiotic concentrations at the sites of infection, i.e., in the interstitial fluid (ISF), are required. The aim of this study was to evaluate contemporary perioperative prophylactic dosing of cefazolin by determining plasma and subcutaneous ISF concentrations in patients undergoing elective/semielective abdominal aortic aneurysm (AAA) open repair surgery. This was a prospective pharmacokinetic study in a tertiary referral hospital. Cefazolin (2 g) was administered as a 3-min slow bolus 30 min prior to incision in 12 enrolled patients undergoing elective/semielective AAA open repair surgery. Serial blood, urine, and ISF (via microdialysis) samples were collected and analyzed using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Cardiac output was determined using pulse waveform contours with Vigileo. The recruited patients had a median (interquartile range) age of 70 (66 to 76) years and weight of 88 (81 to 95) kg. The median (interquartile range) terminal volume of distribution was 0.14 (0.11 to 0.15) liter/kg, total clearance was 0.05 (0.03 to 0.06) liter/h, and minimum observed unbound concentration was 5.7 (5.4 to 8.1) mg/liter. The penetration of unbound drug from plasma to ISF was 85% (78% to 106%). We found correlations present, albeit weak, between cefazolin clearance and cardiac output (r(2) = 0.11) and urinary creatinine clearance (r(2) = 0.12). In conclusion, we found that a single 2-g dose of cefazolin administered 30 min before incision provides plasma and ISF concentrations in excess of the likely MICs for susceptible pathogens in patients undergoing AAA open repair surgery.

Augmented creatinine clearance in traumatic brain injury.

BACKGROUND: Hypertonic saline and/or norepinephrine infusion are routinely used to achieve a desired cerebral perfusion pressure (CPP) in the management of traumatic brain injury (TBI). We hypothesized that creatinine clearances (CrCls) would be significantly augmented in this setting. METHODS: This was an observational cohort study in TBI patients older than 16 years with normal serum creatinine concentrations, requiring maintenance of CPP. Eight-hour urinary CrCl collections were performed while on and off active management. Demographic data, use of vasoactive medications, fluid balance, feeding regimen, and hemodynamic variables were recorded throughout the study period. Augmented CrCl was defined as >150 mL/min/1.73 m(2) in women and >160 mL/min/1.73 m(2) in men. RESULTS: Twenty patients were enrolled, and augmented clearances were demonstrated in 17 (85%). The mean maximum CrCl was 179 mL/min/1.73 m(2) while receiving CPP therapy (95% confidence interval [CI], 159-198), returning to a mean of 111 mL/min/1.73 m(2) (95% CI, 91-131; P < 0.001) when measured after discharge from the intensive care unit. The mean CrCl in the intensive care unit while not receiving CPP therapy was 150 mL/min/1.73 m(2) (95% CI, 134-167; P = 0.03). The mean time to reach peak CrCl while receiving active treatment was 4.7 days (95% CI, 3.0-6.4). In a multivariate analysis, norepinephrine use, saline loading, mean arterial blood pressure, and central venous pressure were associated with augmented CrCl on the day of measurement. CONCLUSIONS: Augmented CrCls are common in TBI patients receiving active management of CPP and persist even after discontinuation of such therapy. Further work is needed to clarify the impact of such clearances on renally excreted drugs in this setting.

Measurement of tissue cortisol levels in patients with severe burns: a preliminary investigation.

INTRODUCTION: The assessment of adrenal function in critically ill patients is problematic, and there is evidence to suggest that measurement of tissue glucocorticoid activity may be more useful than estimation of plasma cortisol concentrations. Interstitial cortisol concentrations of cortisol represent the available pool of glucocorticoids able to enter the cell and bind to the glucocorticoid receptor. However the concentrations of plasma cortisol may not accurately reflect interstitial concentrations. We elected to perform a preliminary study into the feasibility of measuring interstitial cortisol by microdialysis, and to investigate the relationship between total plasma cortisol, free plasma cortisol and interstitial cortisol in patients with severe burns. METHODS: A prospective observational study carried out in a tertiary intensive care unit. Ten adult patients with a mean total burn surface area of 48% were studied. Interstitial cortisol was measured by microdialysis from patient-matched burnt and non-burnt tissue and compared with that of 3 healthy volunteers. Plasma sampling for estimations of total and free cortisol concentrations was performed concurrently. RESULTS: In the burn patients, mean total plasma and free plasma cortisol concentrations were 8.8 +/- 3.9, and 1.7 +/- 1.1 mcg/dL, (p < 0.001), respectively. Mean subcutaneous microdialysis cortisol concentrations in the burn and non-burn tissue were 0.80 +/- 0.31 vs 0.74 +/- 0.41 mcg/dL (p = 0.8), respectively, and were significantly elevated over the mean subcutaneous microdialysis cortisol concentrations in the healthy volunteers. There was no significant correlation between total plasma or free plasma and microdialysis cortisol concentrations. Plasma free cortisol was better correlated with total burn surface area than total cortisol. CONCLUSIONS: In this preliminary study, interstitial cortisol concentrations measured by microdialysis in burnt and non-burnt skin from patients with severe thermal injury are significantly elevated over those from healthy volunteers. Plasma estimations of cortisol do not correlate with the microdialysis levels, raising the possibility that plasma cortisol may be an unreliable guide to tissue cortisol activity.

Unbound cephalothin pharmacokinetics in adult burn patients are related to the elapsed time after injury.

Cephalothin (cefalotin) pharmacokinetics were evaluated for nine severely burned patients (42% +/- 9% mean burn areas) and five healthy volunteers by using non-plasma-protein-bound concentration-time profiles. Burn patients gave increased mean residence times (36%) and reduced total clearances (25%). Mean residence times and distribution volumes increased between 1 and 4 days posttrauma, suggesting that burn patient pharmacokinetics change during the initial fluid resuscitation phase of treatment.

Tissue accumulation of cephalothin in burns: a comparative study by microdialysis of subcutaneous interstitial fluid cephalothin concentrations in burn patients and healthy volunteers.

Burn tissue sites are a potential source of bacteremia during debridement surgery. Burn injury is likely to affect the distribution of antibiotics to tissues, but direct evidence of this is lacking. The aim of this study was to directly evaluate the influence of burn trauma on the distribution of cephalothin to peripheral tissues. We used subcutaneous microdialysis techniques to monitor interstitial fluid concentrations of cephalothin in the burnt and nonburnt tissues of adult patients with severe burns following parenteral administration of 1 g cephalothin for surgical prophylaxis. Analogous simultaneous studies conducted with healthy adult volunteers provided reference tissue concentration data. Equivalent tissue exposures were seen for burn and nonburn sites, giving overall median interstitial cephalothin concentrations (from 0 to 240 min) of 2.84 mg/liter and 3.06 mg/liter, respectively. A lower overall median interstitial cephalothin concentration of 0.54 mg/liter was observed for healthy individuals, and the patient nonburnt tissue and volunteer control tissue cephalothin concentrations exhibited significantly different data distributions (P < 0.001; Kolmogorov-Smirnov nonparametric test). The duration of tissue residence for cephalothin was longer for burn patients than for healthy volunteers. The results demonstrate the potential fallibility of using healthy population models to extrapolate tissue pharmacodynamic predictions from plasma data for burn patients.

Positioning practices for ventilated intensive care patients: current practice, indications and contraindications.

To investigate the process of providing patient positioning in intensive care units (ICUs), a self-reported survey was distributed to a senior physiotherapist and a nurse in each of the 38 Level 3 Australian ICUs. The survey explored the rationales, aims, type, frequency and duration of directed patient positioning used, and perceived risks that may impede the implementation of an effective positioning regime. The response rate was 93%. Fifty nine respondents (83%) agreed that there is an accepted standard of care for the duration of a position change with ventilated patients. Of these respondents, 51 (86%) agreed that the standard is to turn patients every 2 hours, but this was only achievable "more than 50% of the time" in 47% (n=34) of ICUs. Educational and environmental issues were found to impact on positioning practices. Semi-recumbent and full side-lie positions were recommended in the management of a range of patient conditions. However, full side-lie was less commonly used than supine positioning. The prone and head down tilt positions were the least frequently utilised. Levels of agreement for precautions and contraindications to positioning patients into full side-lie and sitting were high. We conclude that, in Australia, experienced ICU physiotherapy and nursing staff are aware of evidence-based positioning practices and agree on indications and potential risk factors associated with positioning. However, educational and environmental resources are needed to improve the frequency and type of positioning used. Results from this survey can now be incorporated into educational tools to facilitate the safe use of positioning.