Impact of hypoalbuminemia on clinical outcomes among patients with obesity treated with ceftriaxone.

The use of ceftriaxone, a highly protein-bound drug, in the setting of hypoalbuminemia may result in suboptimal drug exposure. Patients with obesity also exhibit higher absolute drug clearance. We aimed to evaluate the impact of hypoalbuminemia on clinical success among hospitalized adults with obesity who were treated with ceftriaxone. This retrospective review included adult inpatients with weight >100 kg or body mass index >40 kg/m2 who received ceftriaxone 2 g intravenously every 12 hours for at least 72 hours. The primary outcome was clinical success, a composite of clinical cure and microbiologic cure. Secondary outcomes included clinical cure, microbiologic cure, length of stay, ICU length of stay, mortality, 30-day readmission, and adverse events. In all, 137 patients were included, 34 of whom had a serum albumin of ≤2.5 g/dL. In a propensity-score-weighted analysis, clinical success was significantly more common among those without hypoalbuminemia (91.2%) as compared to those with hypoalbuminemia (77.8%) (P = 0.038). Death within 30 days (13.7% vs 0%, P < 0.001) and 30-day readmission (31.6% vs 12.0%, P = 0.008) were more common in the hypoalbuminemia group. In a univariate analysis, serum albumin and indication for ceftriaxone use were found to be predictors of clinical success. Hypoalbuminemia was associated with a lower rate of clinical success among patients with obesity who were treated with ceftriaxone 2 g every 12 hours.

Controversies Surrounding Albumin Use in Sepsis: Lessons from Cirrhosis.

This narrative review critically examines the role of albumin in sepsis management and compares it to its well-established application in liver cirrhosis. Albumin, a key plasma protein, is effective in the management of fluid imbalance, circulatory dysfunction, and inflammation-related complications. However, its role in sepsis is more intricate and characterized by ongoing debate and varied results from clinical studies. In sepsis, the potential benefits of albumin include maintaining vascular integrity and modulating inflammation, yet its consistent clinical efficacy is not as definitive as that in cirrhosis. This review evaluated various clinical trials and evidence, highlighting their limitations and providing practical insights for clinicians. It emphasizes identifying sepsis patient subgroups that are most likely to benefit from albumin therapy, particularly exploring the correction of hypoalbuminemia. This condition, which is significantly corrected in patients with cirrhosis, may have similar therapeutic advantages in sepsis. The potential effectiveness of albumin in the low-volume resuscitation and deresuscitation phases of sepsis management was noted. Given the safety concerns observed in cirrhosis, such as pulmonary edema and hypervolemia associated with albumin therapy, cautious integration of albumin into sepsis treatment is mandatory. Personalized albumin therapy is advocated for tailoring strategies to the specific needs of each patient, based on their clinical presentation and underlying conditions. The need for further research to delineate the role of albumin in sepsis pathophysiology is underscored. The review emphasizes the importance of conducting trials to assess the effectiveness of albumin in correcting hypoalbuminemia in sepsis, its impact on patient outcomes, and the establishment of appropriate dosing and administration methods. This approach to albumin use in sepsis management is posited as a way to potentially improve patient outcomes in this complex clinical scenario while being mindful of the lessons learned from its use in cirrhosis.

Doxorubicin and zoledronate treatment in a dog with hemophagocytic histiocytic sarcoma.

A 6-year-old castrated male greyhound dog was referred for hemophagocytic histiocytic sarcoma (HHS) diagnosed following splenectomy. Severe thrombocytopenia, mild hypoalbuminemia, mild hypocholesterolemia, and mild hyperbilirubinemia were present. Abdominal ultrasound findings were concerning for hepatic metastasis. Doxorubicin and zoledronate combination therapy was initiated. The dog improved clinically and its thrombocytopenia, hypoalbuminemia, and hyperbilirubinemia resolved. The dog appeared well for 147 d before tumor progression was noted. The dog was treated with lomustine as a final measure, with no response. The dog survived for 6 mo with chemotherapy. To the authors' knowledge, this is the first report of clinical benefit of chemotherapy for HHS. Key clinical message: Doxorubicin should be considered for treating canine HHS since this variant of the disease is historically refractory to lomustine. Further research regarding efficacy of doxorubicin and zoledronate should be pursued.

Traitement à la doxorubicine et au zolédronate chez un chien atteint de sarcome histiocytaire hémophagocytaire. Un lévrier mâle castré de 6 ans a été vu pour un sarcome histiocytaire hémophagocytaire (HHS) diagnostiqué à la suite d'une splénectomie. Une thrombopénie sévère, une hypoalbuminémie légère, une hypocholestérolémie légère et une hyperbilirubinémie légère étaient présentes. Les résultats de l'échographie abdominale étaient préoccupants quant aux métastases hépatiques. Un traitement associant doxorubicine et zolédronate a été instauré. Le chien s'est amélioré cliniquement et sa thrombocytopénie, son hypoalbuminémie et son hyperbilirubinémie ont disparu. Le chien semblait en bonne santé pendant 147 jours avant de constater une progression tumorale. Le chien a été traité avec de la lomustine comme mesure finale, sans réponse. Le chien a survécu 6 mois grâce à la chimiothérapie. À la connaissance des auteurs, il s'agit du premier rapport faisant état d'un bénéfice clinique de la chimiothérapie pour le HHS.Message clinique clé :La doxorubicine doit être envisagée pour traiter le HHS canin puisque cette variante de la maladie est historiquement réfractaire à la lomustine. Des recherches plus approfondies concernant l'efficacité de la doxorubicine et du zolédronate devraient être poursuivies.(Traduit par Dr Serge Messier).

Eosinophilic enteritis accompanied by cytomegalovirus disease: a case report.

BACKGROUND: Eosinophilic enteritis is a chronic inflammatory disorder of the intestinal tract that is characterized by eosinophil infiltration. Cytomegalovirus (CMV), a common virus, has a broad infectivity range. CMV is retained in the host body after infection. Impairment of host immune defences may reactivate the latent CMV, leading to symptoms of overt disease. CASE PRESENTATION: A Japanese female in her 70 s was admitted to a hospital due to diarrhoea and then transferred to our hospital. Laboratory data showed hypoalbuminemia. Computed tomography (CT) revealed oedema of the small intestine. Lower gastrointestinal endoscopy revealed oedema of the submucosa, without any remarkable changes in the mucosa of the terminal ileum. Histological examination of the terminal ileum revealed infiltration of > 20 eosinophils per high-power field (HPF). These findings aided in diagnosing eosinophilic enteritis. We administered methylprednisolone (500 mg/day) for three days, followed by tapering prednisolone. However, the patient's general condition and hypoalbuminemia failed to improve. Immunoglobulin (Ig) G- CMV and IgM-CMV tests were positive. CMV antigenemia was extremely high. Therefore, we administered ganciclovir intravenously, which improved the patient's condition. Furthermore, azathioprine was administered to taper and discontinue prednisolone without relapse of eosinophilic enteritis. This treatment helped stabilize the patient's condition for approximately four years. CONCLUSION: We present a case of eosinophilic enteritis accompanied by CMV disease during prednisolone treatment. The patient's condition improved after administration of ganciclovir. Azathioprine aided in discontinuing prednisolone and stabilizing the patient's condition for approximately four years.

A 6-Month clinical practice pilot study of sucroferric oxyhydroxide on nutritional status in patients on peritoneal dialysis.

BACKGROUND: Hyperphosphatemia is common in patients on peritoneal dialysis (PD). Restricting dietary phosphorus often leads to a decrease in protein intake, which may result in hypoalbuminemia. The high pill burden of phosphate binders may also contribute to compromised appetite and dietary intake. Hypoalbuminemia is associated with an increased risk of morbidity and mortality in PD patients. The goal of this study was to determine if sucroferric oxyhydroxide improves albumin and self-reported measures of appetite in PD patients. METHODS: We performed a prospective, open-label, 6-month, pilot study of 17 adult PD patients from the Denver Metro Area. Patients had to use automated peritoneal dialysis for ≥ 3 months, have a serum albumin ≤ 3.8 g/dL, and have serum phosphate ≥ 5.5 mg/dL or ≤ 5.5 mg/dL on a binder other than SO. SO was titrated to a goal serum phosphate of < 5.5 mg/dL. The primary outcome was change in serum phosphate, albumin, and phosphorus-attuned albumin (defined as albumin divided by phosphorus) over 6 months. RESULTS: The mean (SD) age and dialysis vintage was 55 ± 13 years and 3.8 ± 2.7 years, respectively. Participants' serum phosphate significantly decreased with fewer phosphate binder pills/day after switching to SO. There was no change in serum albumin, appetite, or dietary intake. However, participants had significant improvements in phosphorus-attuned albumin. CONCLUSION: The transition to SO improved phosphorus control, phosphorus-attuned albumin, and pill burden. There were no significant changes in self-reported appetite or dietary intake during the study. These findings suggest that PD patients maintained nutritional status with SO therapy. TRIAL REGISTRATION: First registered at ClinicalTrials.gov ( NCT04046263 ) on 06/08/2019.

The correlation between paclitaxel chemotoxicity and the plasma albumin level in cancer patients.

WHAT IS KNOWN AND OBJECTIVE: The aim of this study was to evaluate the pharmacokinetics of paclitaxel in cancer patients with hypoalbuminemia following paclitaxel-containing chemotherapy and to provide a reference for the prevention of adverse events (AEs) after paclitaxel administration. METHODS: Peripheral blood was collected from cancer patients treated with paclitaxel. The plasma concentration of paclitaxel was determined by ultra-high performance liquid chromatography after 24 ± 8 h of chemotherapy, and individual paclitaxel time above a threshold concentration of 0.05 µmol/L (Tc>0.05 ) was calculated using the population pharmacokinetic model. Haematological and non-haematological toxicities were monitored after chemotherapy, and the correlation between different chemotherapy toxicities and Tc>0.05 was evaluated using the Prism software. RESULTS AND DISCUSSION: The enrolled patients were divided into the hypoalbuminemia group and normal albumin level group. The mean Tc>0.05 values in the normal albumin level and hypoalbuminemia groups were 36.89 and 24.93 h, respectively (P < 0.001). The risk of myelosuppression was positively correlated with Tc>0.05 . Due to the lower Tc>0.05 , the incidences of immediate AEs such as gastrointestinal reactions and rashes were higher in the hypoalbuminemia group than in the normal albumin level group, and the incidences of delayed AEs such as myelosuppression and neurotoxicity were lower in the hypoalbuminemia group. WHAT IS NEW AND CONCLUSIONS: Plasma albumin level has a conclusive effect on Tc>0.05 , which can predict the potential clinical toxicity of paclitaxel. The study provides a theoretical basis for administration of paclitaxel.

Moderator Effect of Hypoalbuminemia in Volume Resuscitation and Plasma Expansion with Intravenous Albumin Solution.

Intravenous administration of crystalloid or colloid solutions is the most common intervention for correcting hypovolemia in intensive care unit patients. In critical illness, especially sepsis and severe trauma, vascular wall permeability increases, and trans-endothelial escape of serum albumin, the major oncotic plasma constituent, contributes to the development of hypoalbuminemia and edema formation. The volume effects of intravenous human albumin solution exceed those of crystalloid solutions. If hypoalbuminemia is an effect moderator, the crystalloid-to-albumin ratio of fluid resuscitation volumes is not well characterized. Randomized controlled trials have confirmed that intravenous administration of human albumin solutions for volume resuscitation results in a lower net fluid balance compared with crystalloids, and smaller infusion volumes may be sufficient for hemodynamic stabilization when human albumin solutions are used. This narrative review summarizes the current evidence and conclusions drawn regarding the role of hypoalbuminemia in volume resuscitation. In the 'Saline versus Albumin Fluid Evaluation' study using 4% human albumin solution or saline, the saline-to-albumin ratio of study fluids was significantly higher in patients with baseline serum albumin concentrations of 25 g/L or less as compared to patients with baseline serum albumin concentrations of more than 25 g/L. In patients receiving renal replacement therapy, intravenous administration of 20-25% human albumin solution reduces intradialytic hypotension and improves fluid removal better than saline if serum albumin levels are similarly reduced. These data suggest that hypoalbuminemia acts as an effect moderator in volume resuscitation and plasma expansion with albumin solution. The volume effectiveness of intravenous human albumin solution in resuscitation appears to be greater when the serum albumin levels are low. In clinical situations, serum albumin concentrations per se may inform when and how to include intravenous albumin in fluid resuscitation if large amounts of crystalloids are needed, which requires further studies.

Crotalid Polyvalent F(ab)2 Antivenom Treatment in a Red-Tailed Hawk (Buteo jamaicensis).

Envenomation in avian species can result in death, with few cases of successful treatment described. A juvenile, wild-caught, intact female red-tailed hawk (Buteo jamaicensis) used in falconry was presented for emergency evaluation after being bitten by a Northern Pacific rattlesnake (Crotalus oreganus) approximately 2 hours before presentation. On presentation, the bird was quiet, alert, and responsive, with moderate swelling and discomfort of the digits on the right foot. Complete blood count (CBC) and plasma biochemistry abnormalities included a regenerative left shift, severe lymphopenia, and a moderate hypoproteinemia characterized by moderate hypoalbuminemia. Analgesic and antibiotic medications were administered during hospitalization. In addition, 5 mL of VenomVet was administered intravenously with crystalloid fluids over 60 minutes; no adverse effects were noted secondary to infusion. Improvement in the swelling was observed immediately after antivenom administration and nearly resolved within 12 hours. Complete resolution of digital swelling with no discomfort on palpation of that foot was observed 1 week after initial presentation. Blood collected at the 1 week reexamination was submitted for a CBC and plasma biochemistry panel. The results of the CBC revealed a reduced regenerative left shift, increased heterophil count, and a moderate monocytosis; the lymphopenia was resolved. A mild hypoalbuminemia still persisted. Ten months after presentation, the bird was reported to be doing well with no changes in function of the right foot and subsequently released from captivity.

Impact of hypoalbuminemia on the prognosis of relapsed/refractory B-cell lymphoma treated with axicabtagene ciloleucel.

INTRODUCTION: Hypoalbuminemia is a known adverse prognostic factor in lymphomas. Yet, it is unknown if axicabtagene ciloleucel (axi-cel) overcomes the adverse prognostic impact of hypoalbuminemia in relapsed/refractory large B-cell lymphoma. METHODS: We conducted a retrospective analysis across three Mayo Clinic centers to assess the relationship of hypoalbuminemia (defined as a serum albumin (SA) levels ≤ 3.5 g/dL) on outcomes of patients treated with axi-cel. RESULTS: This analysis included 81 patients. Two patients had no available SA levels preceding axi-cel infusion. Eighteen patients (22.8%) had hypoalbuminemia with a median SA of 3.3 g/dL. Patients with normal SA had a statistically higher ORR than those without hypoalbuminemia (P = .018). There was no difference in 1-year PFS and OS between the group with hypoalbuminemia and the group with normal SA levels (48% vs 49%, P = .81) and (74% vs 73%, P = .97), respectively. There was no difference in the severity or median duration of cytokine release syndrome or neurotoxicity between the two groups. CONCLUSION: Notwithstanding the limitations related to the relatively small sample size, axi-cel therapy appears to overcome the adverse effect of hypoalbuminemia on OS and PFS. Large multicenter clinical studies are certainly needed to validate these findings.

Population Pharmacokinetic Analysis and Dosing Optimization Based on Unbound Daptomycin Concentration and Cystatin C in Nonobese Elderly Patients with Hypoalbuminemia and Chronic Kidney Disease.

PURPOSE: This study evaluated the population pharmacokinetics of daptomycin in nonobese elderly patients with hypoalbuminemia and chronic kidney disease (CKD) using the glomerular filtration rate estimated from cystatin C (eGFRcys) and estimated its optimal dose. METHODS: We performed population pharmacokinetic analysis of the unbound concentrations of daptomycin. The probability of target attainment of 90% for achieving an area under the concentration-time curve of unbound daptomycin at steady state/ minimum inhibitory concentration ratio of ≥66.6 was stochastically simulated. RESULTS: In the population pharmacokinetic analysis of 25 patients aged ≥65 years, the two-compartment model using eGFRcys and age as covariates of clearance in central compartment of unbound daptomycin were optimal. The unbound fraction rate (fu) was 0.05-0.14. According to the Monte Carlo simulation, the optimal doses for patients with eGFRcys of 20-60 mL/min and aged 65-95 years were calculated as 200-500 mg q24h. CONCLUSION: These results suggest that establishing the dose using total concentrations may result in under- or overestimation caused by alterations in fu. The optimal dose for nonobese elderly patients with hypoalbuminemia and CKD depends on eGFRcys and age, and a standard dose may be insufficient for some patients.

Tolerability of Highly Protein Bound Targeted Oral Oncolytic Drugs in Patients With Hypoalbuminemia: A Retrospective Analysis.

BACKGROUND: Hypoalbuminemia is commonly observed in cancer patients. Given the pharmacokinetic interactions between serum proteins and protein bound medications, administration of highly protein bound targeted oral oncolytic drugs may result in elevated unbound drug levels and decreased tolerability in those with hypoalbuminemia. OBJECTIVE: To describe the impact of hypoalbuminemia on oral oncolytic drug tolerability. METHODS: A retrospective study was conducted of adult patients receiving treatment with targeted oral oncolytic drugs with ≥95% protein binding. The primary end point of this study was to compare time to discontinuation resulting from documented toxicity in those with and without hypoalbuminemia. RESULTS: The study included 143 patients receiving 16 targeted oral oncolytic drugs (42% with hypoalbuminemia, 58% without hypoalbuminemia). Adverse events were common, with similar incidence among patients with and without hypoalbuminemia (73% vs 76%, respectively; P = 0.727). Median time to therapy discontinuation resulting from documented toxicity was significantly shorter in those with hypoalbuminemia (22 months vs not reached; P = 0.003). Cox regression demonstrated that hypoalbuminemia was the only significant risk factor for shorter time to discontinuation resulting from documented adverse effects (hazard ratio = 3.0; 95% CI = 1.15-8.0; P = 0.025). CONCLUSION AND RELEVANCE: This represents the first report of the impact of hypoalbuminemia on tolerability of highly protein bound oral oncolytic drugs, demonstrating that patients with hypoalbuminemia may be at increased risk for early discontinuation resulting from toxicity. Given the importance of maintaining dose intensity in patients receiving oncolytic therapy, albumin levels should be monitored throughout treatment and supportive care maximized in those developing hypoalbuminemia.

A randomized trial of albumin infusion to prevent intradialytic hypotension in hospitalized hypoalbuminemic patients.

BACKGROUND: Intradialytic hypotension (IDH) is a frequent complication of intermittent hemodialysis (IHD), occurring from 15 to 50% of ambulatory sessions, and is more frequent among hospitalized patients with hypoalbuminemia. IDH limits adequate fluid removal and increases the risk for vascular access thrombosis, early hemodialysis (HD) termination, and mortality. Albumin infusion before and during therapy has been used for treating IDH with the varying results. We evaluated the efficacy of albumin infusion in preventing IDH during IHD in hypoalbuminemic inpatients. METHODS: A randomized, crossover trial was performed in 65 AKI or ESKD patients with hypoalbuminemia (albumin < 3 g/dl) who required HD during hospitalization. Patients were randomized to receive 100 ml of either 0.9%sodium chloride or 25% albumin intravenously at the initiation of each dialysis. These two solutions were alternated for up to six sessions. Patients' vital signs and ultrafiltration removal rate were recorded every 15 to 30 min during dialysis. IDH was assessed by different definitions reported in the literature. All symptoms associated with a noted hypotensive event as well as interventions during the dialysis were recorded. RESULTS: Sixty-five patients were submitted to 249 sessions; the mean age was 58 ([Formula: see text] 12), and 46 (70%) were male with a mean weight of 76 ([Formula: see text] 18) kg. The presence of IDH was lower during albumin sessions based on all definitions. The hypotension risk was significantly decreased based on the Kidney Disease Outcomes Quality Initiative definition; (15% with NS vs. 7% with albumin, p = 0.002). The lowest intradialytic SBP was significantly worse in patients who received 0.9% sodium chloride than albumin (NS 83 vs. albumin 90 mmHg, p = 0.035). Overall ultrafiltration rate was significantly higher in the albumin therapies [NS - 8.25 ml/kg/h (- 11.18 5.80) vs. 8.27 ml/kg/h (- 12.22 to 5.53) with albumin, p = 0.011]. CONCLUSION: In hypoalbuminemic patients who need HD, albumin administration before the dialysis results in fewer episodes of hypotension and improves fluid removal. Albumin infusion may be of benefit to improve the safety of HD and achievement of fluid balance in these high-risk patients. ClinicalTrials.gov Identifier: NCT04522635.

Hypoalbuminemia and Bandemia Predict Failure of Infliximab Rescue Therapy in Acute Severe Ulcerative Colitis.

BACKGROUND AND AIMS: Infliximab rescue therapy is effective in patients with corticosteroid refractory acute severe ulcerative colitis, but predictors of response remain poorly understood. We aimed to identify predictors of colectomy in this high-risk patient population. METHODS: Patients hospitalized with acute severe ulcerative colitis who received infliximab after failing intravenous corticosteroid therapy between July 2012 and June 2017 were retrospectively identified. Stepwise regression with backward elimination was used to identify predictors of colectomy at 90 days and 1 year. Ninety-day and 1-year colectomy rates were compared between the patients who received 5 mg/kg and 10 mg/kg IFX rescue dose. RESULTS: Sixty-three patients met the eligibility criteria. Twenty-nine patients received 5 mg/kg, and 34 received 10 mg/kg infliximab dose. Serum albumin on admission (OR 0.10; p = 0.04) and band neutrophil percentage at the time of infliximab administration (OR 1.21; p = 0.02) were independent predictors of 90-day colectomy. A combination of serum albumin ≤ 2.5 g/dl and band neutrophil count ≥ 13% had a 100% positive predictive value for 90-day colectomy. Unadjusted 90-day and 1-year colectomy rates were similar in the 5 mg/kg and 10 mg/kg infliximab groups. After adjusting for confounding factors, 10 mg/kg infliximab dose was potentially protective for 90-day (OR 0.07; p = 0.06) but not for 1-year colectomy (OR 0.19; p = 0.16). CONCLUSIONS: Bandemia and low serum albumin are independent predictors of failure of infliximab rescue therapy in acute severe ulcerative colitis. Serum albumin ≤ 2.5 g/dl and band neutrophil count ≥ 13% had a 100% positive predictive value for 90-day colectomy.

Hypothesis of using albumin to improve drug efficacy in cancers accompanied by hypoalbuminemia.

A common problem in many cancers is the resistance of some patients to common drugs or relapse. Hypoalbuminemia has been reported in some of resistant cancer patients.This article evaluates the usefulness of albumin in the treatment of drug-resistant cancers with hypoalbuminemia based on available evidences.Rapid metabolism and drug excretion from the body is one of the causes of drug resistance. Albumin is the major plasma protein to which almost all drugs are bound. There is some evidence that increasing drug binding to albumin has beneficial effects on drug efficacy in some cancers and cancer cells. On the other hand, some reports have shown that cancer cells can use albumin as the energy and amino acid source.We have hypothesized that in this particular group of cancers, adding albumin to a treatment regimen could have a beneficial effect on drug efficacy and dosage. In fact, excess albumin can prevent rapid metabolism of drug by increasing the fraction of albumin-bound drug, and can increase drug delivery to cancer cells due to the absorption of drug-albumin complex by cancer cells.

Hypoalbuminemia as Surrogate and Culprit of Infections.

Hypoalbuminemia is associated with the acquisition and severity of infectious diseases, and intact innate and adaptive immune responses depend on albumin. Albumin oxidation and breakdown affect interactions with bioactive lipid mediators that play important roles in antimicrobial defense and repair. There is bio-mechanistic plausibility for a causal link between hypoalbuminemia and increased risks of primary and secondary infections. Serum albumin levels have prognostic value for complications in viral, bacterial and fungal infections, and for infectious complications of non-infective chronic conditions. Hypoalbuminemia predicts the development of healthcare-associated infections, particularly with Clostridium difficile. In coronavirus disease 2019, hypoalbuminemia correlates with viral load and degree of acute lung injury and organ dysfunction. Non-oncotic properties of albumin affect the pharmacokinetics and pharmacodynamics of antimicrobials. Low serum albumin is associated with inadequate antimicrobial treatment. Infusion of human albumin solution (HAS) supplements endogenous albumin in patients with cirrhosis of the liver and effectively supported antimicrobial therapy in randomized controlled trials (RCTs). Evidence of the beneficial effects of HAS on infections in hypoalbuminemic patients without cirrhosis is largely observational. Prospective RCTs are underway and, if hypotheses are confirmed, could lead to changes in clinical practice for the management of hypoalbuminemic patients with infections or at risk of infectious complications.

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.

Comparative Plasma Pharmacokinetics of Ceftriaxone and Ertapenem in Normoalbuminemia, Hypoalbuminemia, and Albumin Replacement in a Sheep Model.

Optimal concentrations of unbound antimicrobials are essential for a maximum microbiological effect. Although hypoalbuminemia and albumin fluid resuscitation are common in critical care, the effects of different albumin concentrations on the unbound concentrations of highly protein-bound antimicrobials are not known. The aim of this study was to compare the effects of different albumin states on total and unbound concentrations of ertapenem and ceftriaxone using an ovine model. The study design was a prospective, three-phase intervention observational study. The subjects were healthy Merino sheep. Eight sheep were subjected to three experimental phases: normoalbuminemia, hypoalbuminemia using plasmapheresis, and albumin replacement using a 25% albumin solution. In each phase, ceftriaxone at 40 mg/kg of body weight and ertapenem at 15 mg/kg were given intravenously. Blood samples were collected at predefined intervals and analyzed using an ultrahigh-performance liquid chromatography-tandem mass spectrometry method. Pharmacokinetic parameters such as the area under the curve from 0 to 24 h (AUC0-24), plasma clearance (CL), and apparent volume of distribution in the terminal phase (V) were estimated and compared between the phases. The protein and albumin concentrations were significantly different between phases. Hypoalbuminemia resulted in a significantly lower AUC0-24 and higher CL of total and unbound concentrations of ceftriaxone than in the other phases, whereas albumin replacement led to higher AUC0-24 and lower CL than in the other phases for both drugs. The V values for total drug concentrations for both drugs were significantly lower with albumin replacement. For highly protein-bound drugs such as ceftriaxone and ertapenem, both hypoalbuminemia and albumin replacement may affect unbound drug exposure.

Effects of Albumin Treatment on Systemic and Portal Hemodynamics and Systemic Inflammation in Patients With Decompensated Cirrhosis.

BACKGROUND & AIMS: We investigated the effect of albumin treatment (20% solution) on hypoalbuminemia, cardiocirculatory dysfunction, portal hypertension, and systemic inflammation in patients with decompensated cirrhosis with and without bacterial infections. METHODS: We performed a prospective study to assess the effects of long-term (12 weeks) treatment with low doses (1 g/kg body weight every 2 weeks) and high doses (1.5 g/kg every week) of albumin on serum albumin, plasma renin, cardiocirculatory function, portal pressure, and plasma levels of cytokines, collecting data from 18 patients without bacterial infections (the Pilot-PRECIOSA study). We also assessed the effect of short-term (1 week) treatment with antibiotics alone vs the combination of albumin plus antibiotics (1.5 g/kg on day 1 and 1 g/kg on day 3) on plasma levels of cytokines in biobanked samples from 78 patients with bacterial infections included in a randomized controlled trial (INFECIR-2 study). RESULTS: Circulatory dysfunction and systemic inflammation were extremely unstable in many patients included in the Pilot-PRECIOSA study; these patients had intense and reversible peaks in plasma levels of renin and interleukin 6. Long-term high-dose albumin, but not low-dose albumin, was associated with normalization of serum level of albumin, improved stability of the circulation and left ventricular function, and reduced plasma levels of cytokines (interleukin 6, granulocyte colony-stimulating factor, interleukin 1 receptor antagonist, and vascular endothelial growth factor) without significant changes in portal pressure. The immune-modulatory effects of albumin observed in the Pilot-PRECIOSA study were confirmed in the INFECIR-2 study. In this study, patients given albumin had significant reductions in plasma levels of cytokines. CONCLUSIONS: In an analysis of data from 2 trials (Pilot-PRECIOSA study and INFECIR-2 study), we found that albumin treatment reduced systemic inflammation and cardiocirculatory dysfunction in patients with decompensated cirrhosis. These effects might be responsible for the beneficial effects of albumin therapy on outcomes of patients with decompensated cirrhosis. ClinicalTrials.gov, Numbers: NCT00968695 and NCT03451292.

A Novel Correction Equation Avoids High-Magnitude Errors in Interpreting Therapeutic Drug Monitoring of Phenytoin Among Critically Ill Patients.

BACKGROUND: Phenytoin has a narrow therapeutic index and the potential of under-treatment or toxicity. Available equations are used to correct for the impact of hypoalbuminemia on unbound (free) phenytoin levels. The authors aimed to determine the accuracy of equations used to estimate free phenytoin in hospitalized patients and assess the impact of using additional clinical data. METHODS: Concurrently measured total and free phenytoin levels in hospitalized patients (2014-2018) were retrospectively evaluated, excluding those from patients on renal replacement therapy and valproic acid. Differences between actual and estimated free phenytoin levels by the original (Original WTZ), Anderson-modified, and Kane-modified Winter-Tozer equations were assessed using Pearson correlations and Bland-Altman analysis. Thereafter, a population-derived formula was developed and validated in a testing cohort. RESULTS: In the 4-year training cohort (n = 81), the Original WTZ equation had the smallest mean difference of all equations. A higher mean difference [-0.362 mcg/mL (95% CI -0.585 to -0.138) vs. -0.054 mcg/mL (95% CI -0.186 to 0.078)] was observed in intensive care unit (ICU) patients compared with non-ICU patients. A cross-validated multivariable model improved the accuracy of free phenytoin estimation in ICU and non-ICU patients, even in the separate testing cohort (n = 52) with respective mean differences of -0.322 mcg/mL (95% CI -0.545 to -0.098) and -0.025 mcg/mL (95% CI -0.379 to 0.329) and was superior to the Original WTZ [mean difference -0.858 mcg/mL (95% CI -1.069 to -0.647) vs. -0.106 mcg/mL (95% CI -0.362 to 0.151), respectively]. CONCLUSIONS: Free phenytoin levels in hospitalized patients cannot be accurately determined using available estimation equations, particularly in critically ill patients. Combining ICU status and other available clinical data can improve therapeutic drug monitoring and prevent high-magnitude errors, particularly when free phenytoin assays are not readily available.

Successful management of portal vein thrombosis in a Yorkshire Terrier with protein-losing enteropathy.

BACKGROUND: Portal vein thrombosis (PVT) is a rare presentation in dogs with protein-losing enteropathy (PLE). Rivaroxaban, an oral, selective, direct factor Xa inhibitor, has not been reported to be administrated for canine PVT and the effect is unclear in dogs with PLE. CASE PRESENTATION: An 11-year-old Yorkshire Terrier presented with moderate ascites. The dog had severe hypoalbuminemia (1.2 g/dL), and a portal vein thrombus was confirmed on computed tomographic angiography (CTA). On endoscopic examination, it became apparent that the hypoalbuminemia was caused by PLE, which was consequent of lymphatic dilation and lymphoplasmacytic enteritis. Therefore, the dog was initially treated with oral administrations of spironolactone and clopidogrel, with dietary fat restriction. However, a follow-up CTA showed no changes in the ascites, thrombus, and portal vein to aorta (PV/Ao) ratio. Therefore, the dog was additionally prescribed rivaroxaban and low-dose prednisolone for the portal vein thrombus and hypoalbuminemia due to lymphoplasmacytic enteritis, respectively. Following the treatment, the PV/Ao ratio decreased because of a decrease in the thrombus and the ascites disappeared completely with an elevation of albumin concentration (1.9 g/dL). CONCLUSIONS: This case report demonstrated that oral administration of rivaroxaban combined with low-dose glucocorticoid was effective management for PVT in a dog with PLE.