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

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

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. © 1997 Published by Elsevier B.V

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

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 (CR) 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

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 (r2 = 0.11) and urinary creatinine clearance (r2 = 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

A randomized, controlled pilot clinical trial of cryopreserved platelets for perioperative surgical bleeding: the CLIP‐I trial

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.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.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.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

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

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 to relate observed trough antibiotic concentrations to optimal targets.We performed a prospective, observational, multi-national, 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.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/min (interquartile range [IQR] 35-65) and higher eTRCL was associated with lower trough concentrations for all antibiotics (

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