Glucocorticoid Sensitivity Is Highly Variable in Critically Ill Patients With Septic Shock and Is Associated With Disease Severity.

OBJECTIVES: To measure tissue glucocorticoid sensitivity in patients with septic shock and determine its relationship to standard measurements of adrenal function and of outcome. DESIGN: Prospective observational trial. SETTING: Teaching hospital ICU. SUBJECTS: Forty-one patients and 20 controls were studied. INTERVENTIONS: Glucocorticoid sensitivity was measured by in vitro suppression of cytokine production from lipopolysaccharide-stimulated leukocytes. MEASUREMENTS AND MAIN RESULTS: There was no significant difference between the groups in the relative suppression of cytokine production, although there was a greater range and variance in the patient data. Patients in the lowest quartile of glucocorticoid sensitivity had higher Acute Physiology and Chronic Health Evaluation II scores (25 [24-28] vs 20 [14-23]; p = 0.02) and a trend toward higher mortality (30% vs 0%; p = 0.2) compared to those in the highest. The mRNA expression of the ß variant of the glucocorticoid receptor and the 11-ß hydroxysteroid dehydrogenase 2 isozyme were significantly higher in patients compared to controls (8.6-fold, p = 0.002 and 10.1-fold, p = 0.0002, respectively). Changes in mRNA expression of these genes did not correlate with measurements of glucocorticoid sensitivity. CONCLUSIONS: Patients with septic shock and controls do not differ in their median glucocorticoid sensitivity. However, patients exhibited a greater variability in glucocorticoid responsiveness and had evidence of association between increased sickness sensitivity and reduced glucocorticoid sensitivity. Sensitivity to glucocorticoids did not appear to be mediated by changes in the expression of the ß variant of the glucocorticoid receptor or the 11-ß hydroxysteroid dehydrogenase 2 isozyme.

Doripenem population pharmacokinetics and dosing requirements for critically ill patients receiving continuous venovenous haemodiafiltration.

OBJECTIVES: Doripenem is a newer carbapenem with little data available to guide effective dosing during renal replacement therapy in critically ill patients. The objective of this study was to determine the population pharmacokinetics of doripenem in critically ill patients undergoing continuous venovenous haemodiafiltration (CVVHDF) for acute kidney injury (AKI). METHODS: This was an observational pharmacokinetic study in 12 infected critically ill adult patients with AKI undergoing CVVHDF and receiving 500 mg of doripenem intravenously every 8 h as a 60 min infusion. Serial blood samples were taken on 2 days of treatment and used for population pharmacokinetic analysis with S-ADAPT. RESULTS: The median (IQR) age was 62 (53-71) years, the median (IQR) weight was 77 (67-96) kg and the median (IQR) APACHE II score was 29 (19-32). The median blood, dialysate and replacement fluid rates were 200, 1000 and 1000 mL/h, respectively. A two-compartment linear model with doripenem clearance described by CVVHDF, renal or non-renal mechanisms was most appropriate. The mean value for total doripenem clearance was 4.46 L/h and volume of distribution was 38.0 L. Doripenem clearance by CVVHDF was significantly correlated with the replacement fluid flow rate and accounted for ∼30%-37% of total clearance. A dose of 500 mg intravenously every 8 h achieved favourable pharmacokinetic/pharmacodynamics for all patients up to an MIC of 4 mg/L. CONCLUSIONS: This is the first paper describing the pharmacokinetics/pharmacodynamics of doripenem in critically ill patients with AKI receiving CVVHDF. A dose of 500 mg intravenously every 8 h was appropriate for our CVVHDF settings for infections caused by susceptible bacteria.

Determining the mechanisms underlying augmented renal drug clearance in the critically ill: use of exogenous marker compounds.

INTRODUCTION: The aim of this study was to explore changes in glomerular filtration (GFR) and renal tubular function in critically ill patients at risk of augmented renal clearance (ARC), using exogenous marker compounds. METHODS: This prospective, observational pharmacokinetic (PK) study was performed in a university-affiliated, tertiary-level, adult intensive care unit (ICU). Patients aged less than or equal to 60 years, manifesting a systemic inflammatory response, with an expected ICU length of stay more than 24 hours, no evidence of acute renal impairment (plasma creatinine concentration < 120 µmol/L) and no history of chronic kidney disease or renal replacement therapy were eligible for inclusion. The following study markers were administered concurrently: sinistrin 2,500 mg (Inutest; Laevosan, Linz, Austria), p-aminohippuric acid (PAH) 440 mg (4% p-aminohippuric acid sodium salt; CFM Oskar Tropitzsch, Marktredwitz, Germany), rac-pindolol 5 or 15 mg (Barbloc; Alphapharm, Millers Point, NSW, Australia) and fluconazole 100 mg (Diflucan; Pfizer Australia Pty Ltd, West Ryde, NSW, Australia). Plasma concentrations were then measured at 5, 10, 15, 30, 60 and 120 minutes and 4, 6, 12 and 24 hours post-administration. Non-compartmental PK analysis was used to quantify GFR, tubular secretion and tubular reabsorption. RESULTS: Twenty patients were included in the study. Marker administration was well tolerated, with no adverse events reported. Sinistrin clearance as a marker of GFR was significantly elevated (mean, 180 (95% confidence interval (CI), 141 to 219) ml/min) and correlated well with creatinine clearance (r = 0.70, P < 0.01). Net tubular secretion of PAH, a marker of tubular anion secretion, was also elevated (mean, 428 (95% CI, 306 to 550) ml/min), as was net tubular reabsorption of fluconazole (mean, 135 (95% CI, 100 to 169) ml/min). Net tubular secretion of (S)- and (R)-pinodolol, a marker of tubular cation secretion, was impaired. CONCLUSIONS: In critically ill patients at risk of ARC, significant alterations in glomerular filtration, renal tubular secretion and tubular reabsorption are apparent. This has implications for accurate dosing of renally eliminated drugs.

A comparison of CKD-EPI estimated glomerular filtration rate and measured creatinine clearance in recently admitted critically ill patients with normal plasma creatinine concentrations.

BACKGROUND: The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) estimated glomerular filtration rate (eGFR) has been widely integrated into clinical practice. Although useful in screening for CKD, its' application in critically ill patients with normal plasma creatinine concentrations remains uncertain. The aim of this study was to assess the performance of CKD-EPI eGFR in comparison to creatinine clearance (CLCR) in this setting. METHODS: This prospective observational study was performed in a tertiary level, university affiliated intensive care unit (ICU). Study participants had to have an expected ICU length of stay > 24 hours, a plasma creatinine concentration < 121 µmol/L, and no history of prior renal replacement therapy or CKD. CKD-EPI eGFR was compared against 8-hour measured urinary CLCR. Data capture occurred within 48 hours of admission. RESULTS: One hundred and ten patients (n = 110) were enrolled in the study. 63.6% were male, the mean age was 50.9 (16.9) years, 57.3% received invasive mechanical ventilation, and 30% required vasopressor support. The mean CLCR was 125 (45.1) ml/min/1.73 m(2), compared to a CKD-EPI eGFR of 101 (23.7) ml/min/1.73 m(2) (P < 0.001). Moderate correlation was evident (r = 0.72), although there was significant bias and imprecision (24.4 +/- 32.5 ml/min/1.73 m(2)). In those patients with a CKD-EPI eGFR between 60-119 ml/min/1.73 m(2) (n = 77), 41.6% displayed augmented renal clearance (CLCR ≥ 130 ml/min/1.73 m(2)), while 7.8% had a CLCR < 60 ml/min/1.73 m(2). CONCLUSIONS: These data suggest CKD-EPI eGFR and measured CLCR produce significantly disparate results when estimating renal function in this population. Clinicians should consider carefully which value they employ in clinical practice, particularly drug dose modification.

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.

Pulp therapy in pediatric patients with congenital heart disease: survey of American Academy of Pediatric Dentistry members.

PURPOSE: The purpose of this study was to identify treatment options recommended by American Academy of Pediatric Dentistry (AAPD) members concerning pulp treatment in primary teeth in pediatric patients with congenital heart disease (CHD). METHODS: A web-based survey was sent to all active members of the AAPD. The survey contained radiographs of pulpally involved primary teeth, a description of associated signs/symptoms, and a medical history of the patient who was positive for a type of CHD. Pediatric dentists were requested to report treatment recommendations. RESULTS: Of the 6,590 surveys sent, 1,493 surveys (23%) were completed. Most respondents preferred to extract the tooth with the clinical presentation of irreversible pulpitis followed by distal shoe space maintenance when the patient presented with a negative medical history. By contrast, approximately half of the respondents elected to extract this tooth without space maintenance for all of the cardiac conditions. By contrast, most respondents elected to perform a pulpotomy in the case of reversible pulpitis regardless of the medical history. Indirect or direct pulp therapy were the least chosen options for both presentations. CONCLUSIONS: The presence of CHD affects treatment decisions in teeth exhibiting irreversible pulpitis with symptomatic apical periodontitis but not in teeth displaying reversible pulpitis with a normal periodontal status.