The association between hypoalbuminemia and microcirculation, endothelium, and glycocalyx disorders in children with sepsis.

OBJECTIVE: The objective of this study was to evaluate the association between serum albumin levels and microcirculation changes, glycocalyx degradation, and the clinical outcomes of interest. METHODS: Observational, prospective study in children with sepsis. The primary outcome was the association between hypoalbuminemia and microcirculation disorders, endothelial activation and glycocalyx degradation using a perfused boundary region (PBR) (abnormal >2.0 µm on sublingual video microscopy) or plasma biomarkers (syndecan-1, angiopoietin-2). RESULTS: A total of 125 patients with sepsis were included. The median age was 2.0 years (IQR 0.5-12.5). Children with hypoalbuminemia had more abnormal microcirculation with a higher PBR (2.16 µm [IQR 2.03-2.47] vs. 1.92 [1.76-2.28]; p = .01) and more 4-6 µm capillaries recruited (60% vs. 40%; p = .04). The low albumin group that had the worst PBR had the most 4-6 µm capillaries recruited (rho 0.29; p < .01), 48% higher Ang-2 (p = .04), worse annexin A5 (p = 0.03) and no syndecan-1 abnormalities (p = .21). Children with hypoalbuminemia and a greater percentage of blood volume in their capillaries needed mechanical ventilation more often (56.3% vs. 43.7%; aOR 2.01 95% CI 1.38-3.10: p < .01). CONCLUSIONS: In children with sepsis, an association was found between hypoalbuminemia and microcirculation changes, vascular permeability, and greater endothelial glycocalyx degradation.

Hypoalbuminemia affects the spatio-temporal tissue distribution of ochratoxin A in liver and kidneys: consequences for organ toxicity.

Hypoalbuminemia (HA) is frequently observed in systemic inflammatory diseases and in liver disease. However, the influence of HA on the pharmacokinetics and toxicity of compounds with high plasma albumin binding remained insufficiently studied. The 'lack-of-delivery-concept' postulates that HA leads to less carrier mediated uptake of albumin bound substances into hepatocytes and to less glomerular filtration; in contrast, the 'concept-of-higher-free-fraction' argues that increased concentrations of non-albumin bound compounds facilitate hepatocellular uptake and enhance glomerular filtration. To address this question, we performed intravital imaging on livers and kidneys of anesthetized mice to quantify the spatio-temporal tissue distribution of the mycotoxin ochratoxin A (OTA) based on its auto-fluorescence in albumin knockout and wild-type mice. HA strongly enhanced the uptake of OTA from the sinusoidal blood into hepatocytes, followed by faster secretion into bile canaliculi. These toxicokinetic changes were associated with increased hepatotoxicity in heterozygous albumin knockout mice for which serum albumin was reduced to a similar extent as in patients with severe hypoalbuminemia. HA also led to a shorter half-life of OTA in renal capillaries, increased glomerular filtration, and to enhanced uptake of OTA into tubular epithelial cells. In conclusion, the results favor the 'concept-of-higher-free-fraction' in HA; accordingly, HA causes an increased tissue uptake of compounds with high albumin binding and increased organ toxicity. It should be studied if this concept can be generalized to all compounds with high plasma albumin binding that are substrates of hepatocyte and renal tubular epithelial cell carriers.

Variations in the Human Serum Albumin Gene: Molecular and Functional Aspects.

The human albumin gene, the most abundant serum protein, is located in the long arm of chromosome 4, near the centromere, position 4q11-3. It is divided by 14 intervening introns into 15 exons, the last of which is untranslated. To date, 74 nucleotide substitutions (mainly missense) have been reported, determining the circulating variants of albumin or pre-albumin. In a heterozygous state, this condition is known as alloalbuminaemia or bisalbuminaemia (OMIM # 103600). The genetic variants are not associated with disease, neither in the heterozygous nor in the homozygous form. Only the variants resulting in familial dysalbuminaemic hyperthyroxinaemia and hypertriiodothyroninaemia are of clinical relevance because affected individuals are at risk of inappropriate treatment or may have adverse drug effects. In 28 other cases, the pathogenic variants (mainly affecting splicing, nonsense, and deletions), mostly in the homozygous form, cause a premature stop in the synthesis of the protein and lead to the condition known as congenital analbuminaemia. In this review, we will summarize the current knowledge of genetic and molecular aspects, functional consequences and potential therapeutic uses of the variants. We will also discuss the molecular defects resulting in congenital analbuminaemia, as well as the biochemical and clinical features of this rare condition.

Immunological abnormalities in patients with early-onset ataxia with ocular motor apraxia and hypoalbuminemia.

Early-onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH) is a neurodegenerative disorder caused by mutation in the aprataxin (APTX)-coding gene APTX, which is involved in DNA single-strand break repair (SSBR). The neurological abnormalities associated with EAOH are similar to those observed in patients with ataxia-telangiectasia. However, the immunological abnormalities in patients with EAOH have not been described. In this study, we report that EAOH patients have immunological abnormalities, including lymphopenia; decreased levels of CD4+ T-cells, CD8+ T-cells, and B-cells; hypogammaglobulinemia; low T-cell recombination excision circles and kappa-deleting element recombination circles; and oligoclonality of T-cell receptor ß-chain variable repertoire. These immunological abnormalities vary among the EAOH patients. Additionally, mild radiosensitivity in the lymphocytes obtained from the patients with EAOH was demonstrated. These findings suggested that the immunological abnormalities and mild radiosensitivity evident in patients with EAOH could be probably caused by the DNA repair defects.

Hypoalbuminemia as a prognostic biomarker for higher mortality and treatment complications in acute myeloid leukemia.

Older age and poor performance status lead to worse outcomes in acute myeloid leukemia (AML) patients. Hypoalbuminemia is a negative predictor of morbidity and mortality in several malignancies. We evaluated the relationship between baseline serum albumin levels on treatment-related complications, as well as short-term mortality and overall survival (OS) in 756 newly diagnosed AML patients. We conducted a retrospective multicenter study to examine treatment-related complications and OS according to pretreatment serum albumin levels: normal albumin ≥3.5 g/dl, marked hypoalbuminemia <2.5 g/dl, and hypoalbuminemia 2.5-3.4 g/dl. In an adjusted multivariate analysis, a lower baseline albumin was independently associated with a higher number of grade ≥3 complications when adjusting for age, secondary AML, sex and intensive treatment. When comparing normal to markedly low albumin levels, the estimated mean number of complications increases by a factor of 1.35. Patients who had a normal baseline albumin had a 30 day-mortality rate of 4.8%, which was significantly lower compared with patients with hypoalbuminemia (16.5%) and marked hypoalbuminemia (33.9%; p < 0.01). Similarly, 60-day mortality rate was significantly higher in the hypoalbuminemia group (24.0%) and marked hypoalbuminemia group (45%) compared with normal albumin group (8.3%; p < 0.01). Patients with lower baseline albumin levels have increased treatment-related morbidity and mortality, suggesting that pre-treatment serum albumin is an important independent prognostic marker.

Once-daily 1 g ceftriaxone optimizes exposure in patients with septic shock and hypoalbuminemia receiving continuous veno-venous hemodiafiltration.

PURPOSE: Ceftriaxone total and unbound pharmacokinetics (PK) can be altered in critically ill patients with septic shock and hypoalbuminemia receiving continuous veno-venous hemodiafiltration (CVVHDF). The objective of this study was to determine the dosing strategy of ceftriaxone that maximizes the probability of maintaining the concentration above the MIC of the susceptible bacteria (≤2 mg/L by the EUCAST) for a 100% of the dosing interval (100% ƒuT>MIC). METHODS: In a prospective PK study in the intensive care units of two tertiary Spanish hospitals, six timed blood samples were collected per patient; for each sample, ceftriaxone total and unbound concentrations were measured using a liquid chromatography coupled to tandem mass spectrometry method. Population PK analysis and Monte-Carlo simulations were performed using NONMEMv.7.3®. RESULTS: We enrolled 8 critically ill patients that met the inclusion criteria (47 blood samples). Median age (range) was 70 years (47-85), weight 72.5 kg (40-95), albumin concentration 24.2 g/L (22-34), APACHE II score at admission 26 (17-36), and SOFA score on the day of study 12 (9-15). The unbound fraction (ƒu) of ceftriaxone was 44%, and total CL was 1.27 L/h, 25-30% higher than the CL reported in septic critically ill patients not receiving renal replacement therapies, and dependent on albumin concentration and weight. Despite this increment in ƒu and CL, Monte-Carlo simulations showed that a dose of 1 g once-daily ceftriaxone is sufficient to achieve a 100% ƒuT>MIC for MICs ≤2 mg/L for any range of weight and albumin concentration. CONCLUSION: Once-daily 1 g ceftriaxone provides optimal exposure in critically ill patients with septic shock and hypoalbuminemia receiving CVVHDF.

Janus Kinase Inhibitors Ameliorated Gastrointestinal Amyloidosis and Hypoalbuminemia in Persistent Dermatitis Mouse Model.

Malnutrition is not only regarded as a complication of rheumatoid arthritis and inflammatory bowel disease but also that of inflammatory skin disease; however, the mechanisms and efficacy of its treatment have not been elucidated. Using a mouse model of dermatitis, we investigated the pathophysiology of malnutrition in inflammatory skin conditions and efficacy of its treatment. We employed spontaneous skin inflammation mice models overexpressing human caspase-1 in the epidermal keratinocytes. Body weight, nutrition level, and α1-antitrypsin fecal concentration were measured. The gastrointestinal tract was histologically and functionally investigated. Fluorescein isothiocyanate (FITC)-dextran was forcibly fed on an empty stomach, and plasma FITC-dextran was measured. The treatment efficacy of antibodies against tumor necrosis factor-α (TNF-α) and interleukin (IL)-α/ß as well as Janus kinase (JAK) inhibitors was investigated. Compared with wild-type littermates, the inflammatory skin mice models showed a lowered body weight, reduction of serum albumin level, amyloid deposition in the stomach, small intestine, and large intestine, and increased α1-antitrypsin fecal concentration. However, the plasma FITC-dextran was unchanged between the dermatitis models and wild-type littermates. The over-produced serum amyloid A1 in the liver was detected in the plasma in the dermatitis model. Antibodies against TNF-α and IL-α/ß showed partial effects on amyloid deposition; however, JAK inhibitors improved gastrointestinal amyloidosis with the improvement of skin symptoms. Chronic dermatitis is closely related to secondary amyloidosis in the gastrointestinal tract, resulting in hypoalbuminemia. Therefore, active control of skin inflammation is essential for preventing gastrointestinal complications.

DGAT1 mutations leading to delayed chronic diarrhoea: a case report.

BACKGROUND: Early-onset chronic diarrhoea often indicates a congenital disorder. Mutation in diacylglycerol o-acyltransferase 1 (DGAT1) has recently been linked to early-onset chronic diarrhoea. To date, only a few cases of DGAT1 deficiency have been reported. Diarrhoea in those cases was severe and developed in the neonatal period or within 2 months after birth. CASE PRESENTATION: Here, we report a female patient with DGAT1 mutations with delayed-onset chronic diarrhoea. The patient had vomiting, hypoalbuminemia, hypertriglyceridemia, and failure to thrive at early infancy. Her intractable chronic diarrhoea occurred until she was 8 months of age. A compound heterozygous DGAT1 mutation was found in the patient, which was first found in the Chinese population. Her symptoms and nutrition status improved after nutritional therapy, including a fat restriction diet. CONCLUSIONS: This case expanded our knowledge of the clinical features of patients with DGAT1 mutations. Intractable diarrhoea with delayed onset could also be a congenital disorder.

Prediction of Serum-Free and Cerebrospinal Fluid Valproic Acid Levels in Patients With Hypoalbuminemia After Craniotomy.

BACKGROUND: In patients with hypoalbuminemia after craniotomy, total serum concentrations of valproic acid (VPA) may provide poor clinical insights, owing to saturated protein binding and increased unbound fractions. However, very few clinical laboratories routinely analyze free concentrations of the drug. The aim of this study was to develop a model to predict serum-free and cerebrospinal fluid (CSF) levels of VPA based on its total concentration and to investigate the model's applicability. METHODS: Total serum and CSF concentrations of VPA in 79 patients were measured using a validated immunoassay between January 2015 and December 2015. The demographic, clinical, and laboratory information of patients were retrieved from medical records. A multiple linear regression analysis was adopted to determine the potential variations and establish the functional relationship between CSF concentration and significant clinical factors. RESULTS: Based on the stepwise multiple linear regression analysis performed using the natural logarithm of the concentration of VPA in the CSF as the dependent variable, serum concentrations of VPA (X1, ß' = 0.844), serum albumin concentration (X2, ß' = -0.393), and CSF protein concentration (X3, ß' = 0.098) were identified as the 3 variables that significantly predicted the dependent variable: (Equation is included in full-text article.), with a coefficient of determination (R) of 0.874. As the CSF protein level is often unavailable, the model was redefined to include 2 variables-serum concentrations of VPA (X1, ß' = 0.840) and serum albumin concentration (X2, ß' = -0.359): (Equation is included in full-text article.), with R = 0.813. CONCLUSIONS: Based on total VPA and serum albumin concentrations, we developed a model to predict serum-free and CSF levels of VPA. This model is useful for correcting dose adjustment in patients with hypoalbuminemia after craniotomy.

Pharmacokinetics of Caspofungin in Critically Ill Patients in Relation to Liver Dysfunction: Differential Impact of Plasma Albumin and Bilirubin Levels.

Caspofungin has a liver-dependent metabolism. Reduction of the dose is recommended based on Child-Pugh (C-P) score. In critically ill patients, drug pharmacokinetics (PK) may be altered. The aim of this study was to investigate the prevalence of abnormal liver function tests, increased C-P scores, their effects on caspofungin PK, and whether pharmacokinetic-pharmacodynamic (PK/PD) targets were attained in patients with suspected candidiasis. Intensive care unit patients receiving caspofungin were prospectively included. PK parameters were determined on days 2, 5, and 10, and their correlations to the individual liver function tests and the C-P score were analyzed. Forty-six patients were included with C-P class A (n = 5), B (n = 40), and C (n = 1). On day 5 (steady state), the median and interquartile range for area under the curve from 0 to 24 h (AUC0-24), clearance (CL), and central volume of distribution (V1) were 57.8 (51.6 to 69.8) mg·h/liter, 0.88 (0.78 to 1.04) liters/h, and 11.9 (9.6 to 13.1) liters, respectively. The C-P score did not correlate with AUC0-24 (r = 0.03; P = 0.84), CL (r = -0.07; P = 0.68), or V1 (r = 0.19; P = 0.26), but there was a bilirubin-driven negative correlation with the elimination rate constant (r = -0.46; P = 0.004). Hypoalbuminemia correlated with low AUC0-24 (r = 0.45; P = 0.005) and was associated with higher clearance (r = -0.31; P = 0.062) and somewhat higher V1 (r = -0.15; P = 0.37), resulting in a negative correlation with the elimination rate constant (r = -0.34; P = 0.042). For Candida strains with minimal inhibitory concentrations of ≥0.064 µg/ml, PK/PD targets were not attained in all patients. The caspofungin dose should not be reduced in critically ill patients in the absence of cirrhosis, and we advise against the use of the C-P score in patients with trauma- or sepsis-induced liver injury.

Serum albumin and hospitalization among pediatric patients with end-stage renal disease who started dialysis therapy.

BACKGROUND: Hypoalbuminemia is a strong predictor of hospitalization and mortality among adult dialysis patients. However, data are scant on the association between serum albumin and hospitalization among children new to dialysis. METHODS: In a retrospective cohort study of children 1-17 years old with end-stage renal disease receiving dialysis therapy in a large US dialysis organization 2007-2011, we examined the association of serum albumin with hospitalization frequency and total hospitalization days using a negative binomial regression model. RESULTS: Among 416 eligible patients, median (interquartile range) age was 14 (10-16) years and mean ± SD baseline serum albumin level was 3.7 ± 0.8 g/dL. Two hundred sixty-six patients (64%) were hospitalized during follow-up with an incidence rate of 2.2 (95%CI, 1.9-2.4) admissions per patient-year. There was a U-shaped association between serum albumin and hospitalization frequency; hospitalization rates (95%CI) were 2.7 (2.2-3.2), 1.9 (1.5-2.4), 1.6 (1.3-1.9), and 2.7 (1.7-3.6) per patient-year among patients with serum albumin levels < 3.5, 3.5- < 4.0, 4.0- < 4.5, and ≥ 4.5 g/dL, respectively. Case mix-adjusted hospitalization incidence rate ratios (IRRs) (95%CI) were 1.63 (1.24-2.13), 1.32 (1.10-1.58), and 1.25 (1.06-1.49) at serum albumin levels 3.0, 3.5, and 4.5 g/dL, respectively (reference: 4.0 g/dL). Similar trends were observed in hospitalization days. These associations remained robust against further adjustment for laboratory variables associated with malnutrition and inflammation. CONCLUSIONS: Both high and low serum albumin were associated with higher hospitalization in children starting dialysis. Because the observed association is novel and not fully explainable especially for high serum albumin levels, interpreting the results requires caution and further studies are needed to confirm and elucidate this association before clinical recommendations are made.

Clinical Features of Nephrotic Syndrome with Cerebral Hemorrhage.

BACKGROUND Cerebral hemorrhage has been increasingly reported in patients with nephrotic syndrome (NS). However, the clinical features and pathogenesis of NS patients with cerebral hemorrhage remain unclear. MATERIAL AND METHODS From January 2007 to August 2017, continuous NS patients with cerebral hemorrhage at the First Affiliated Hospital of Guangxi Medical University were selected. The clinical manifestations, laboratory measurements, and neurological images of these patients were collected and analyzed. RESULTS Acute cerebral hemorrhage was recorded in 15 of 10 461 NS patients. The average age of these 15 patients (9 males and 6 females) was 50.87±23.27 years old. Among these 15 patients, conventional vascular risk factors were identified in 8 patients, hypoalbuminemia and proteinuria were recorded in all 15 patients, coagulopathy was observed in 9 patients, increased D-dimer level was recorded in 13 patients, hyperlipidemia was recorded in 11 patients, and impaired renal function was recorded in 9 patients. The hemorrhage developed in the lobe (n=9), basal ganglia (n=3), cerebellum (n=2), and cerebral hemisphere (n=1). Eight patients were in a coma on the day the cerebral hemorrhage occurred, while 12 patients had a poor prognosis after 30 days of hemorrhage onset. CONCLUSIONS Poor prognosis was recorded in NS patients with cerebral hemorrhage. Although conventional vascular risk factors have only been identified in 8 patients, biochemical abnormalities (hypoalbuminemia, proteinuria, elevated D-dimer, and hyperlipidemia) were recorded in the majority of these 15 patients. Furthermore, most of the hemorrhages developed in the lobes. Coagulopathy might be the potential pathogenesis of cerebral hemorrhage in NS patients.

Body Fluids in End-Stage Renal Disease: Statics and Dynamics.

BACKGROUND: Abnormalities in fluid status in hemodialysis (HD) patients are highly prevalent and are related to adverse outcomes. SUMMARY: The inherent discontinuity of the HD procedure in combination with an often compromised cardiovascular response is a major contributor to this phenomenon. In addition, systemic inflammation and endothelial dysfunction are related to extracellular fluid overload (FO). Underlying this relation may be factors such as hypoalbuminemia and an increased capillary permeability, leading to an altered fluid distribution between the blood volume (BV) and the interstitial fluid compartments, compromising fluid removal during dialysis. Indeed, whereas estimates of extracellular volume by bioimpedance spectroscopy are highly predictive of mortality, absolute BV assessed by the saline dilution technique was predictive of intra-dialytic morbidity. Changes in relative BV during HD are positively related to ultrafiltration rate (UFR) and, at least in some studies, negatively to FO. High UFR is also related to changes in central venous oxygen saturation (ScvO2), a marker for tissue perfusion. On the one hand, high UFR and more pronounced declines in ScvO2, but on the other hand, flat relative BV curves are also predictive of mortality; the relation between outcome which statics and dynamics of fluid status appears to be complex. Key Message: While technological developments enable the clinician to monitor statics and dynamics of fluid status and hemodynamics during HD in an accessible way, the role of technology-based interventions needs further study.

Retinal and choroidal thickness in paediatric patients with hypoalbuminaemia caused by nephrotic syndrome.

BACKGROUND: A study was conducted to evaluate the choroidal thickness (CT) and retinal thickness (RT) in paediatric patients with hypoalbuminaemia caused by nephrotic syndrome (NS). We also studied the correlation between the subfoveal choroidal thickness (SFCT) and serum protein concentration. METHODS: This was a cross-sectional study. Fifty-one paediatric patients with hypoalbuminaemia caused by NS and 41 normal subjects were included in the study. Enhanced depth imaging optical coherence tomography (EDI-OCT) was performed to measure the RT and CT. The RT and CT were measured manually at intervals of 0.5 mm along a horizontal line through the macular fovea between 2.5 mm nasal and 2.5 mm temporal to the fovea. Clinical data including measurements of serum proteins were obtained. RESULTS: The mean RTs at the T2.5, T2, N1.5, N2, and N2.5 locations and the average macular horizontal RT were slightly greater in the NS group than those in the control group. The mean CTs at all locations were significantly greater in the NS group than those in the control group; the difference was most significant at the fovea (373.8 ± 74.9 µm vs. 280.2 ± 57.1; p < 0.001). The SFCT in patients with NS was correlated with age (r = - 0.307, p = 0.003), body height (r = - 0.320, p = 0.022), body weight (r = - 0.343, p = 0.014), axial length (AL, r = - 0.237, p = 0.023), total protein (TP, r = - 0.302, p = 0.031), albumin (ALB, r = - 0.285, p = 0.042), prealbumin (PA, r = - 0.303, p = 0.033) and 24-h urine volume (UV, r = - 0.298, p = 0.034). Multiple linear regression analysis showed that the TP concentration and body weight had the highest correlation with the SFCT (R2 = 0.220, p < 0.05). CONCLUSIONS: The macular RT is slightly increased and the macular CT is significantly increased in paediatric patients with hypoalbuminaemia caused by NS, indicating fluid accumulation in the retina and choroid. There is a negative correlation between the SFCT and serum TP concentration. Thus, the serum TP concentration is an important indicator of CT in patients with hypoalbuminaemia.

Prognostic value of the Glasgow Prognostic Score in renal cell carcinoma: a meta-analysis.

PURPOSE: Glasgow Prognostic Score (GPS) has been reported to predict oncologic outcomes in various type of cancer. However, their prognostic value in patients with renal cell carcinoma (RCC) is unclear. In this meta-analysis, we evaluated the prognostic significance of GPS in RCC patients. METHODS: We performed comprehensive searches of electronic databases to identify studies that evaluated the prognostic impact of pretreatment GPS in RCC patients. The end points were cancer-specific survival (CSS), recurrence-free/disease-free survival (RFS/DFS). Meta-analysis using random-effects models was performed to calculate hazard ratios (HRs) or odds ratios with 95 % confidence intervals (CIs). RESULTS: Nine retrospective, observational, cohort studies involving 2096 patients were included. Seven studies evaluated CSS, and three evaluated RFS. Our results showed that higher GPS (0 vs. 1 vs. 2) was significantly predictive of poorer CSS (HR 3.68, 95 % CI 2.52-5.40, p < 0.001) and RFS/DFS (HR 2.83, 95 % CI 1.86-4.30, p < 0.001) in patients with RCC. These findings were robust when stratified by sample size, presence of metastasis, and study region. We also conducted subgroup analysis by assessment of Newcastle-Ottawa quality assessment scale (NOS) score, and the HRs were 2.708 (95 % CI 1.969, 3.725) in under 7 points group, 3.685 (95 % CI 2.516, 5.396) in over than 7 points group in CSS. Meta-regression analysis indicated that NOS score group had a significant difference in HRs (p = 0.032). CONCLUSIONS: Higher GPS is associated with tumor progression and is predictive of poorer survival in patients with RCC. Therefore, GPS may help to inform treatment decisions and predict treatment outcomes.

Pre-operative serum albumin level substantially predicts post-operative morbidity and mortality among patients with colorectal cancer who undergo elective colectomy.

The quantitative relationship between serum albumin level and surgical outcomes has not been clearly established. This study included 3732 patients with colon cancer who underwent a potentially curative colectomy. Post-operative mortality and morbidity were analysed according to the patients' demographic data, pre-operative comorbidities, and tumour-related factors. Age, asthma, renal impairment, and albumin level were significantly associated with post-operative morbidity and mortality in the multivariate analyses. Logistic regression analysis revealed linear relationships of post-operative morbidity and mortality with albumin level. The morbidity and mortality rates decreased by 7.3% and 15.6%, respectively, for each 0.1 g/dL increase in albumin level. This finding remained significant in the hypoalbuminaemia subgroup but not in the normoalbuminaemia subgroup. That is, the morbidity and mortality rates significantly decreased by 8.7% and 17.7%, respectively (both P < 0.001), in the former group and decreased by 2.7% (P = 0.112) and 11.6% (P = 0.092), respectively, in the latter group. This study demonstrated that serum albumin level linearly predicted the post-operative morbidity and mortality among the colorectal cancer patients. Pre-operative serum albumin level may therefore be used as a continuous rather than a categorical marker of disease severity, especially among patients with hypoalbuminaemia.

Simultaneous assessment of the synthesis rate and transcapillary escape rate of albumin in inflammation and surgery.

BACKGROUND: Better knowledge of albumin kinetics is needed to define the indications for albumin use in clinical practice. This study involved two approaches: the synthesis rate and transcapillary escape rate of albumin were measured simultaneously at different levels of plasma albumin concentration in relation to acute inflammation and surgery; and two different tracers were compared to determine plasma volume and the transcapillary escape rate. METHODS: Healthy volunteers (n = 10), patients with acute inflammatory abdominal disease (n = 10), and patients undergoing elective pancreatic resection (n = 10) were studied. The albumin synthesis rate was measured by the incorporation of deuterium-labeled phenylalanine. Plasma volume and the transcapillary escape rate were assessed using 123I-labeled and 125I-labeled albumin. RESULTS: A 50 % elevated de-novo albumin synthesis rate was seen in patients with acute inflammation and marked hypoalbuminemia, while patients with marginal hypoalbuminemia before the start of surgery had a normal albumin synthesis rate. The transcapillary escape rate was elevated intraoperatively during the reconstructive phase of pancreatic surgery, when plasma albumin was decreased but stable. In acute inflammation with marked hypoalbuminemia, the transcapillary escape rate was no different from normal. 123I-labeled and 125I-labeled albumin were found exchangeable for plasma volume determinations, but could be used only in groups of patients for the transcapillary escape rate. CONCLUSIONS: This observational study illustrates the limited information contained in albumin plasma concentrations to reflect albumin kinetics. On the contrary, single measurements of the synthesis rate and/or transcapillary escape rate of albumin obviously cannot explain the plasma level of albumin or the changes seen in plasma albumin concentration. TRIAL REGISTRATION: www.clinicaltrials.gov , study number NCT01686776 . Registered 13 September 2012.

Serum albumin level is associated with the recurrence of acute ischemic stroke.

BACKGROUND: Previous studies have confirmed that low serum albumin levels in acute ischemic stroke patients increased the risk for poor outcome and death, demonstrating the neuroprotective role of albumin. However, there are few studies investigating the relationship between albumin levels and recurrence of stroke. The aim of this study was to evaluate the effect of serum albumin level on the risk of recurrence in patients with acute ischemic stroke. METHODS: Seven hundred fifty-three consecutive patients with acute first-ever ischemic stroke were recruited in this study. Recurrent outcome was measured 1 year after stroke through home interviews (n = 692). RESULTS: Patients with recurrence had significantly lower serum albumin level than those without recurrence (37.07 ± 4.21 vs 38.91 ± 3.25). The multiple logistic regression adjustment for confounding factors showed that the association remained significant for patients in the second albumin quartile, the third quartile, and the fourth quartile compared with patients in the first quartile (adjusted odds ratio [aOR] = 0.543, 95% confidence interval [CI]: 0.307-0.959, P= .036; aOR = 0.449, 95% CI: 0.249-0.812, P= .008; and aOR = 0.290, 95% CI: 0.148-0.570, P < .001). CONCLUSION: Lower serum albumin level increases the risk of recurrence in patients with acute ischemic stroke, suggesting that serum albumin level might be used as an indicator for stroke recurrence.

Pharmacokinetic/pharmacodynamic considerations for the optimization of antimicrobial delivery in the critically ill.

PURPOSE OF REVIEW: Antimicrobials are very commonly used drugs in the intensive care setting. Extensive research has been conducted in recent years to describe their pharmacokinetics/pharmacodynamics in order to maximize the pharmacological benefit and patient outcome. Translating these new findings into clinical practice is encouraged. RECENT FINDINGS: This article will discuss mechanistic data on factors causing changes in antimicrobial pharmacokinetics in critically ill patients, such as the phenomena of augmented renal clearance as well as the effects of hypoalbuminemia, renal replacement therapy, and extracorporeal membrane oxygenation. Failure to achieve clinical cure has been correlated with pharmacokinetics/pharmacodynamics target nonattainment, and a recent meta-analysis suggests an association between dosing strategies aimed at optimizing antimicrobial pharmacokinetics/pharmacodynamics with improvement in clinical cure and survival. Novel dosing strategies including therapeutic drug monitoring are also now being tested to address challenges in the optimization of antimicrobial pharmacokinetics/pharmacodynamics. SUMMARY: Optimization of antimicrobial dosing in accordance with pharmacokinetics/pharmacodynamics targets can improve survival and clinical cure. Dosing regimens for critically ill patients should aim for pharmacokinetics/pharmacodynamics target attainment by utilizing altered dosing strategies including adaptive feedback using therapeutic drug monitoring.

Impact of hypoalbuminemia on voriconazole pharmacokinetics in critically ill adult patients.

Setting the adequate dose for voriconazole is challenging due to its variable pharmacokinetics. We investigated the impact of hypoalbuminemia (<35 g/liter) on voriconazole pharmacokinetics in adult intensive care unit (ICU) patients treated with voriconazole (20 samples in 13 patients) as well as in plasma samples from ICU patients that had been spiked with voriconazole at concentrations of 1.5 mg/liter, 2.9 mg/liter, and 9.0 mg/liter (66 samples from 22 patients). Plasma albumin concentrations ranged from 13.8 to 38.7 g/liter. Total voriconazole concentrations in adult ICU patients treated with voriconazole ranged from 0.5 to 8.7 mg/liter. Unbound and bound voriconazole concentrations were separated using high-throughput equilibrium dialysis followed by liquid chromatography-tandem mass spectrometry (LC-MSMS). Multivariate analysis revealed a positive relationship between voriconazole plasma protein binding and plasma albumin concentrations (P < 0.001), indicating higher unbound voriconazole concentrations with decreasing albumin concentrations. The correlation is more pronounced in the presence of elevated bilirubin concentrations (P = 0.05). We therefore propose to adjust the measured total voriconazole concentrations in patients with abnormal plasma albumin and total serum bilirubin plasma concentrations who show adverse events potentially related to voriconazole via a formula that we developed. Assuming 50% protein binding on average and an upper limit of 5.5 mg/liter for total voriconazole concentrations, the upper limit for unbound voriconazole concentrations is 2.75 mg/liter. Alterations in voriconazole unbound concentrations caused by hypoalbuminemia and/or elevated bilirubin plasma concentrations cannot be countered immediately, due to the adult saturated hepatic metabolism. Consequently, increased unbound voriconazole concentrations can possibly cause adverse events, even when total voriconazole concentrations are within the reference range.