Renae Deans

Pharmacokinetics of Colistin Methanesulfonate and Colistin in a Critically Ill Patient Receiving Continuous Venovenous Hemodiafiltration

Intravenous colistin methanesulfonate (CMS) is increasingly the last line of defense for multidrug-resistant gram-negative bacteria and is now being used as “salvage” therapy in critically ill patients ([1][1], [7][2], [9][3], [11][4]). CMS is converted in vivo to colistin, and these two

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 m2 in women and >160 mL/min/1.73 m2 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 m2 while receiving CPP therapy (95% confidence interval [CI], 159–198), returning to a mean of 111 mL/min/1.73 m2 (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 m2 (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.

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

ABSTRACT 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.

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

ABSTRACT 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-&bgr; hydroxysteroid dehydrogenase 2 and global 11-&bgr; 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-&bgr; hydroxysteroid dehydrogenase activity. Total plasma cortisol measurements may not reflect the global adrenal response in septic shock. ABBREVIATIONS 11&bgr;-HSD—11&bgr;-hydroxysteroid dehydrogenase APACHE—Acute Physiology and Chronic Health Evaluation CBG—corticosteroid-binding globulin FC—free plasma cortisol F:E ratio—cortisol-cortisone ratio SOFA—Sequential Organ Failure Assessment

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

IntroductionThe 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.MethodsA 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.ResultsIn 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.ConclusionsIn 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.

Autonomic dysfunction in tetanus - what lessons can be learnt with specific reference to alpha-2 agonists?

Severe tetanus is seen infrequently in the developed world, but often requires intensive care support. Mechanical ventilation with neuromuscular blockade and heavy sedation, good wound care and prompt administration of antitoxin are important. The management of autonomic dysfunction remains challenging. We measured serum catecholamine levels in a patient with severe tetanus in whom autonomic crises were a major and persistent feature, and investigated the impact of sedatives plus α2‐agonists on these levels. Serum adrenaline levels were elevated up to 100‐fold with clinically observed crises, although noradrenaline levels were much more difficult to interpret. There was no appreciable difference in catecholamine levels following administration of α2‐agonists in the doses we used, although clonidine did allow easier control of crises with other agents. This case highlights some important lessons in the management of severe tetanus.

Tissue Accumulation of Cephalothin in Burns: a Comparative Study by Microdialysis of Subcutaneous Interstitial Fluid Cephalothin Concentrations in Burn Patients and Healthy Volunteers

ABSTRACT 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.

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

BackgroundOptimal 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/DesignWe 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.DiscussionUsing 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 registrationAustralian New Zealand Clinical Trial Registry (ACTRN12613000241730) registered 28 February 2013

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

ABSTRACT 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.