Bioavailability of Orally Administered Drugs in Critically Ill Patients.

Critically ill patients managed in the Intensive Care Unit (ICU) suffer from several pathophysiological alterations due to critical illness resulting in potential changes in the pharmacokinetics of drugs including systemic absorption. Nevertheless, these patients are still given some medications in unadjusted doses thereby putting the patients at a risk for therapy failure. The objective for this study was to summarize the available evidence regarding oral drug absorption in the ICU. A literature search of the databases MEDLINE, EMBASE, and PubMed was conducted on (February 24, 2020). Articles discussing the rate and/or extent of orally administered drugs in critically ill patients were included. A total of 58 studies were found: 17 interventional studies, 33 observational studies (30 prospective, 3 retrospective) and 8 case reports. A total of 43 articles reported altered drug absorption in critically ill patients suggesting the need for alternative measures to facilitate treatment success. The absorption of orally administered drugs may be altered in critically ill patients. Measures for altered drug absorption in critically ill patients were suggested such as holding tube feeding before and after medication administration, increasing doses of orally administrated drugs and using alternate routes of administration.

Sex-Specific Catabolic Metabolism Alterations in the Critically Ill following High Dose Vitamin D.

Pharmacological interventions are essential for the treatment and management of critical illness. Although women comprise a large proportion of the critically ill, sex-specific pharmacological properties are poorly described in critical care. The sex-specific effects of vitamin D3 treatment in the critically ill are not known. Therefore, we performed a metabolomics cohort study with 1215 plasma samples from 428 patients from the VITdAL-ICU trial to study sex-specific differences in the metabolic response to critical illness following high-dose oral vitamin D3 intervention. In women, despite the dose of vitamin D3 being higher, pharmacokinetics demonstrated a lower extent of vitamin D3 absorption compared to men. Metabolic response to high-dose oral vitamin D3 is sex-specific. Sex-stratified individual metabolite associations with elevations in 25(OH)D following intervention showed female-specific positive associations in long-chain acylcarnitines and male-specific positive associations in free fatty acids. In subjects who responded to vitamin D3 intervention, significant negative associations were observed in short-chain acylcarnitines and branched chain amino acid metabolites in women as compared to men. Acylcarnitines and branched chain amino acids are reflective of fatty acid B oxidation, and bioenergesis may represent notable metabolic signatures of the sex-specific response to vitamin D. Demonstrating sex-specific pharmacometabolomics differences following intervention is an important movement towards the understanding of personalized medicine.

Stress-Related Gastrointestinal Bleeding in Patients with Aneurysmal Subarachnoid Hemorrhage: A Multicenter Retrospective Observational Study.

BACKGROUND/OBJECTIVE: Stress-related mucosal bleeding (SRMB) occurs in approximately 2-4% of critically ill patients. Patients with aneurysmal subarachnoid hemorrhage (aSAH) have a (diffuse) space-occupying lesion, are critically ill, often require mechanical ventilation, and frequently receive anticoagulation or antiplatelet therapy after aneurysm embolization, all of which may be risk factors for SRMB. However, no studies have evaluated SRMB in patients with aSAH. Aims of the study were to determine the incidence of SRMB in aSAH patients, evaluate the effect of acid suppression on SRMB, and identify specific risk factors for SRMB. METHODS: This was a multicenter, retrospective, observational study conducted across 17 centers. Each center reviewed up to 50 of the most recent cases of aSAH. Patients with length of stay (LOS) < 48 h or active GI bleeding on admission were excluded. Variables related to demographics, aSAH severity, gastrointestinal (GI) bleeding, provision of SRMB prophylaxis, adverse events, intensive care unit (ICU), and hospital LOS were collected for the first 21 days of admission or until hospital discharge, whichever came first. Descriptive statistics were used to analyze the data. A multivariate logistic regression modeling was utilized to examine the relationship between specific risk factors and the incidence of clinically important GI bleeding in patients with aSAH. RESULTS: A total of 627 patients were included. The overall incidence of clinically important GI bleeding was 4.9%. Of the patients with clinically important GI bleeding, 19 (61%) received pharmacologic prophylaxis prior to evidence of GI bleeding, while 12 (39%) were not on pharmacologic prophylaxis at the onset of GI bleeding. Patients who received an acid suppressant agent were less likely to experience GI bleeding than patients who did not receive pharmacologic prophylaxis prior to evidence of bleeding (OR 0.39, 95% CI 0.18-0.83). The multivariate regression analysis identified any instance of elevated intracranial pressure, creatinine clearance < 60 ml/min and the incidence of cerebral vasospasm as specific risk factors associated with GI bleeding. Cerebral vasospasm has not previously been described as a risk for GI bleeding (OR 2.5 95% CI 1.09-5.79). CONCLUSIONS: Clinically important GI bleeding occurred in 4.9% of patients with aSAH, similar to the general critical care population. Risk factors associated with GI bleeding were prolonged mechanical ventilation (> 48 h), creatinine clearance < 60 ml/min, presence of coagulopathy, elevation of intracranial pressure, and cerebral vasospasm. Further prospective research is needed to confirm this observation within this patient population.

Evaluation of squamous cell carcinoma antigen-immunoglobulin M complex (SCCA-IGM) and alpha-L-fucosidase (AFU) as novel diagnostic biomarkers for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) surveillance lacks a reliable biomarker. Alpha-fetoprotein (AFP) is the most widely used. However, not all HCCs secrete AFP. AFP may be elevated with cirrhosis in the absence of HCC. Serum alpha-L-fucosidase (AFU) and squamous cell carcinoma antigen-immunoglobulin M complex (SCCA-IgM) were found to be useful markers in diagnosing HCC. SCCA-IgM and AFU were assessed by ELISA technique; AFP was measured by enzyme chemiluminescence in serum of 40 patients with HCC, 30 patients with liver cirrhosis, and 20 healthy control participants to compare their accuracy in early diagnosis of HCC. Serum SCCA-IgM and AFU levels were significantly elevated in HCC group compared to cirrhotic group (P value<0.001 and <0.001, respectively). Receiver operating characteristic curve showed the optimal cutoff value for SCCA-IgM was 233 AU/ml with sensitivity 87.5% and specificity 66% and for AFU was 25 U/L with sensitivity 87.5% and specificity 98%. AFP cutoff value was 48 ng/mL with sensitivity of 70% and specificity of 53.3%. The simultaneous determination of AFP and SCCA-IgM activity increased the sensitivity to 92.5% and specificity to 62.1%. There were positive significant correlations between SCCA-IgM and each of AFU (r=0.296, P=0.005) and AFP (r=0.284, P=0.007) and no correlation between AFP and AFU. All markers did not correlate with the tumor size or affected by the Child score. The significant difference between SCCA-IgM and AFU levels among HCC and cirrhotic patients suggests their use as potential diagnostic tools and allows identifying a new group of HCC patients even in the absence of elevated AFP.

Hypertonic saline-enhanced radiofrequency versus chemoembolization sequential radiofrequency in the treatment of large hepatocellular carcinoma.

BACKGROUND AND STUDY AIM: Large hepatocellular carcinoma (HCC) appears to be a major obstacle for radiofrequency ablation (RFA); therefore, attempts to increase the volume of coagulation by injecting hypertonic saline before and/or during RFA have been made. Transarterial chemoembolization (TACE) combines the effect of targeted chemotherapy with ischemic necrosis and eliminates heat loss if combined with RFA. Our aim was to compare the efficacy of hypertonic saline-enhanced RFA versus TACE sequential RFA in the treatment of medium and large nodular HCC. PATIENTS AND METHODS: This prospective study was carried out on 40 patients with 40 HCCs between 2008 and 2010 in the Tropical Medicine and Hepatology Department, Faculty of Medicine, Cairo University. They were divided into two groups (20 patients each): the first group received hypertonic saline-enhanced RFA (RFA+HS) and the second group underwent transarterial chemoembolization, followed by RFA (TACE+RFA). RESULTS: Triphasic computed tomography 1 month after the procedure showed that 17 (85%) patients in each group achieved complete ablation, whereas three (15%) in each group achieved partial ablation. In the RFA+HS group, 12/13 (92%) of medium HCC and 5/7 (71%) of large HCC were successfully ablated. In the TACE+RFA group, 8/8 (100%) medium HCC and 9/12 (75%) of large lesions were successfully ablated. The relation between success rate and lesion diameter was statistically significant only in RFA+HS group. After 6 months, 73.7% of patients in the RFA+HS group and 83.3% of patients in the TACE+RFA group showed maintained ablation (P=0.86). CONCLUSION: RFA+HS and TACE+RFA are safe and equally effective treatments for medium to large HCC.