Supportive care in the acute phase of Stevens-Johnson syndrome and toxic epidermal necrolysis: an international, multidisciplinary Delphi-based consensus.

BACKGROUND: Supportive care is the cornerstone of management of adult and paediatric Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). However, consensus on the modalities of supportive care is lacking. OBJECTIVES: Our aim in this international multicentric Delphi exercise was to establish a multidisciplinary expert consensus to standardize recommendations regarding supportive care in the acute phase of SJS/TEN. METHODS: Participants were sent a survey via the online tool SurveyMonkey, consisting of 103 statements organized into 11 topics: multidisciplinary team composition, suspect drug management, infection prevention, fluid resuscitation and prevention of hypothermia, nutritional support, pain and psychological distress management, management of acute respiratory failure, local skincare, ophthalmological management, management of other mucosa, and additional measures. Participants evaluated the level of appropriateness of each statement on a scale of 1 (extremely inappropriate) to 9 (extremely appropriate). The results were analysed according to the RAND/UCLA Appropriateness Method. RESULTS: Forty-five participants from 13 countries (on three continents) participated. After the first round, a consensus was obtained for 82.5% of the 103 initially proposed statements. After the second round, a final consensus was obtained for 102 statements. CONCLUSIONS: We have reached an international Delphi-based consensus on best supportive care practice for SJS/TEN. Our expert consensus should help guide physicians in treating patients with SJS/TEN and thereby improve short-term prognosis and the risk of sequelae.

Clinical characteristics and management of acute generalized exanthematous pustulosis with haemodynamic instability.

Background: Acute generalized exanthematous pustulosis (AGEP) is a severe pustular drug eruption with rare reports of haemodynamic instability. Objective: To describe the clinical characteristics, management, and outcomes of patients with AGEP-associated haemodynamic instability. Methods: This retrospective case series identified adult patients diagnosed with AGEP who had haemodynamic instability from November 2012 to February 2020 that were seen at two academic teaching hospitals with roles as a burn centre and tertiary referral centre at the University of Texas Southwestern Medical Center in Dallas, TX USA. Patients with a discharge diagnosis of AGEP that had haemodynamic instability during their eruption were included. Patients with a history of psoriasis, presentations thought to be a flare of generalized pustular psoriasis, or concurrent infection during eruption were excluded. AGEP with haemodynamic instability was characterized by degree of hypotension, dermatologic phenotype at time of dermatologic consultation, and management approach. Results: This study included 19 patients with AGEP-associated haemodynamic instability (mean age, 52 years; age range, 29-76 years; 11 (58%) female). Patients were classified on a spectrum of haemodynamic instability; three had sustained hypotension, 10 had hypotension with organ dysfunction, and six had shock. Patients with AGEP-associated haemodynamic instability had a range of dermatologic phenotypes at initial consultation: subtle exanthematous eruption with minimal pustules, typical eruption with pustules and flexural predominance, and severe eruption with features of Stevens-Johnson syndrome. Both topical and systemic corticosteroids were used for treatment of several patients. Of the patients that required vasopressors and received systemic steroids, the majority were off vasopressors within 24 h of steroid initiation. Conclusion: Approximately 22% of patients presenting with AGEP to a tertiary referral center had haemodynamic instability. Clinicians should be aware that dermatologic phenotype of AGEP at presentation does not correlate with development of haemodynamic instability.

Structures and Electronic Properties of TinV (n = 1-16) Clusters: First-Principles Calculations.

Structures and electronic properties of TinV (n = 1-16) clusters have been investigated using density functional theory with the generalized gradient approximatio. The calculations have shown that the TinV clusters favor compact spherical structures having similar conformations to the pure Tin clusters. The results show that the vanadium atom remains on the surface when n ⩽ 8 and n = 16, while for n = 9-15, it occupies the endohedral position. The Ti6V, Ti12V, and Ti14V clusters are found to be more stable than their neighbors, consistent with pure Tin clusters that have the same size. Additionally Ti4V has been found to be also magic, consistent with recent reports of B- and Al-doped Ti clusters. Small TinV (n ⩽ 4) clusters exhibit a transition from metallic-like to semimetallic electronic structure, while for n = 5 onward, no significant changes are observed compared with pure Tin clusters.

Size and structure effects of PtN (N = 12 - 13) clusters for the oxygen reduction reaction: First-principles calculations.

Size and structure effects on the oxygen reduction reaction on PtN clusters with N = 12-13 atoms have been investigated using periodic density functional theory calculations with the generalized gradient approximation. To describe the catalytic activity, we calculated the O and OH adsorption energies on the cluster surface. The oxygen binding on the 3-fold hollow sites on stable Pt12-13 cluster models resulted more favorable for the reaction with O, compared with the Pt13(Ih) and Pt55(Ih) icosahedral particles, in which O binds strongly. However, the rate-limiting step resulted in the removal of the OH species due to strong adsorptions on the vertex sites, reducing the utility of the catalyst surface. On the other hand, the active sites of Pt12-13 clusters have been localized on the edge sites. In particular, the OH adsorption on a bilayer Pt12 cluster is the closest to the optimal target; with 0.0-0.2 eV weaker than the Pt(111) surface. However, more progress is necessary to activate the vertex sites of the clusters. The d-band center of PtN clusters shows that the structural dependence plays a decisive factor in the cluster reactivity.

Population pharmacokinetics of vancomycin in adult and geriatric patients: comparison of eleven approaches.

PURPOSE: A vancomycin population pharmacokinetic prediction model for adult and elderly patients was developed using NONMEM. The predictability of the model was studied and compared with ten other models. METHODS: Data were collected from routine care of 141 subjects. NONMEM was used to derive a population model. After internal evaluation using the bootstrap technique, external validation was studied using an independent dataset that consisted of 95 subjects; a statistical comparison of precision and bias was conducted. RESULTS: A two-compartment open model was derived with body weight, age, and CLcr as covariates. The bootstrap process showed stability of the model. A comparison of subjects older and younger than 65 years found that the older group had a mean clearance of 2.24 (+/- 1.2) l/h compared to 4.03 (+/- 1.7) l/h, and a peripheral volume of 43.7 (+/- 5.1) l compared to 28.4 (+/- 5.3) l compared to younger patients. These values were modeled using CLcr in the clearance equation and Vd as a function of age. The eleven models studied showed a bias in predicting serum concentrations from the test database that ranged from 0.35 mg/l to -5.93 mg/l. Precision ranged from 4.53 mg/l to 8.05 mg/l. Our method ranked in fourth place overall and when compared statistically its bias was different from the method that ranked in second place by -1.45 (95% CI -2.46, -0.42; p = 0.005), and different from all the methods that ranked worse. The only difference in precision was with the method that ranked in eleventh place with a relative precision of 0.49 (95% CI 0.27, 0.70; p < 0.001). CONCLUSIONS: A two-compartment open model fitted the data with weight, age, and CLcr as covariates. The derived method ranked in fourth place overall. The two-compartment nature of two of the equations studied did not provide an advantage. A future study with more data in the distribution phase could provide a model with better predictability.

Pharmacokinetics and hepatotoxicity of diclofenac using an isolated perfused rat liver.

Pharmacokinetics and hepatotoxicity of diclofenac was studied in a recirculating model of isolated perfused rat liver. Ten male Sprague-Dawley rat (weighing 230-330 g) livers were perfused for 2 h with 250 mL Krebs-Henseleit bicarbonate buffer that contained 10.75 mg (group A, n = 5) and 1.075 mg (group B, n = 5) of diclofenac (approximately 100 and 10 times the therapeutic dose in man, respectively). Samples were collected from the efflux at regular time intervals for the determination of diclofenac concentrations by a high performance liquid chromatography (HPLC) method. Pharmacokinetic analyses were carried out using a computer program. To establish viability of the liver and toxicity of the drug, enzyme activity measurements of lactate dehydrogenase (LDH), aspartate aminotransferase (SGOT) and piruvate aminotransferase (SGPT) were performed by a spectrophotometric method. Oxygen consumption was also recorded during the entire perfusion period. Both groups presented bicompartmental kinetics. Concentration profiles showed that group B had a better metabolizing capacity, reflected in a 85.54 +/- 37.05 min half-life, a 0.52 +/- 0.19 mL min-1 g-1 liver clearance and a 0.517 +/- 0.188 extraction ratio, compared to group A, which presented a 123.95 +/- 88.13 min half-life, a 0.1164 +/- 0.067 mL min-1 g-1 liver clearance (P < 0.002) and a 0.116 +/- 0.680 extraction ratio (P < 0.002). LDH activity showed a significant increase in group A at 90 min in comparison with the control group, while in group B this increase was significantly higher at 10 min (P < 0.004). The aminotransferase levels did not show a significant increase. According to these results, diclofenac would not have a direct hepatotoxic effect, even at doses 100 times higher than therapeutic ones.