RESUMO
BACKGROUND: A higher-than-usual resistance to standard sedation regimens in COVID-19 patients suffering from acute respiratory distress syndrome (ARDS) has led to the frequent use of the second-line anaesthetic agent ketamine. Simultaneously, an increased incidence of cholangiopathies in mechanically ventilated patients receiving prolonged infusion of high-dose ketamine has been noted. Therefore, the objective of this study was to investigate a potential dose-response relationship between ketamine and bilirubin levels. METHODS: Post hoc analysis of a prospective observational cohort of patients suffering from COVID-19-associated ARDS between March 2020 and August 2021. A time-varying, multivariable adjusted, cumulative weighted exposure mixed-effects model was employed to analyse the exposure-effect relationship between ketamine infusion and total bilirubin levels. RESULTS: Two-hundred forty-three critically ill patients were included into the analysis. Ketamine was infused to 170 (70%) patients at a rate of 1.4 [0.9-2.0] mg/kg/h for 9 [4-18] days. The mixed-effects model revealed a positively correlated infusion duration-effect as well as dose-effect relationship between ketamine infusion and rising bilirubin levels (p < 0.0001). In comparison, long-term infusion of propofol and sufentanil, even at high doses, was not associated with increasing bilirubin levels (p = 0.421, p = 0.258). Patients having received ketamine infusion had a multivariable adjusted competing risk hazard of developing a cholestatic liver injury during their ICU stay of 3.2 [95% confidence interval, 1.3-7.8] (p = 0.01). CONCLUSIONS: A causally plausible, dose-effect relationship between long-term infusion of ketamine and rising total bilirubin levels, as well as an augmented, ketamine-associated, hazard of cholestatic liver injury in critically ill COVID-19 patients could be shown. High-dose ketamine should be refrained from whenever possible for the long-term analgosedation of mechanically ventilated COVID-19 patients.
Assuntos
COVID-19 , Ketamina , Propofol , Síndrome do Desconforto Respiratório , Bilirrubina , COVID-19/complicações , Estado Terminal , Humanos , Hipnóticos e Sedativos/efeitos adversos , Ketamina/efeitos adversos , Fígado , Respiração Artificial/efeitos adversos , Síndrome do Desconforto Respiratório/induzido quimicamente , Estudos RetrospectivosRESUMO
BACKGROUND: The efficacy of first-generation protease inhibitor based triple-therapy against hepatitis C virus (HCV) infection is limited in HIV/HCV-coinfected patients with advanced liver fibrosis and non-response to previous peginterferon-ribavirin. These patients have a low chance of achieving a sustained virologic response (SVR) using first generation triple-therapy, with a success rate of only 20%. We investigated the efficacy and safety of lead-in therapy with intravenous silibinin followed by triple-therapy in this difficult-to-treat patient group. METHODOLOGY: Inclusion criteria were HIV/HCV coinfection with advanced liver fibrosis and documented previous treatment failure on peginterferon-ribavirin. The intervention was a lead-in therapy with intravenous silibinin 20 mg/kg/day for 14 days, followed by triple-therapy (peginterferon-ribavirin and telaprevir) for 12 weeks, and peginterferon-ribavirin alone for 36 weeks. Outcome measurements were HCV-RNA after silibinin lead-in and during triple-therapy, SVR data at week 12, and safety and tolerability of silibinin. RESULTS: We examined sixteen HIV/HCV-coinfected patients with previous peginterferon-ribavirin failure, of whom 14 had a fibrosis grade METAVIR ≥F3. All were on successful antiretroviral therapy. Median (IQR) HCV-RNA decline after silibinin therapy was 2.65 (2.1-2.8) log10 copies/mL. Fifteen of sixteen patients (94%) had undetectable HCV RNA at weeks 4 and 12, eleven patients (69%) showed end-of-treatment response (i.e., undetectable HCV-RNA at week 48), and ten patients (63%) reached SVR at week 12 (SVR 12). Six of the sixteen patients (37%) did not reach SVR 12: One patient had rapid virologic response (RVR) (i.e., undetectable HCV-RNA at week 4) but stopped treatment at week 8 due to major depression. Five patients had RVR, but experienced viral breakthroughs at week 21, 22, 25, or 32, or a relapse at week 52. The HIV RNA remained below the limit of detection in all patients during the complete treatment period. No serious adverse events and no significant drug-drug interactions were associated with silibinin. CONCLUSION: A lead-in with silibinin before triple-therapy was safe and highly effective in difficult-to-treat HIV/HCV coinfected patients, with a pronounced HCV-RNA decline during the lead-in phase, which translates into 63% SVR. An add-on of intravenous silibinin to standard of care HCV treatment is worth further exploration in selected difficult-to-treat patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT01816490.
Assuntos
Terapia Antirretroviral de Alta Atividade , Antivirais/uso terapêutico , Infecções por HIV/tratamento farmacológico , Hepatite C Crônica/tratamento farmacológico , Cirrose Hepática/tratamento farmacológico , RNA Viral/antagonistas & inibidores , Silimarina/uso terapêutico , Adulto , Coinfecção , Esquema de Medicação , Feminino , HIV/efeitos dos fármacos , HIV/crescimento & desenvolvimento , Infecções por HIV/sangue , Infecções por HIV/patologia , Infecções por HIV/virologia , Hepacivirus/efeitos dos fármacos , Hepacivirus/crescimento & desenvolvimento , Hepatite C Crônica/sangue , Hepatite C Crônica/patologia , Hepatite C Crônica/virologia , Humanos , Injeções Intravenosas , Interferon-alfa/uso terapêutico , Cirrose Hepática/sangue , Cirrose Hepática/patologia , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade , Oligopeptídeos/uso terapêutico , Segurança do Paciente , Polietilenoglicóis/uso terapêutico , Estudos Prospectivos , Inibidores de Proteases/uso terapêutico , RNA Viral/sangue , Proteínas Recombinantes/uso terapêutico , Ribavirina/uso terapêutico , Silibina , Resultado do Tratamento , Carga Viral/efeitos dos fármacosRESUMO
AIM: To investigate the effects of sorafenib when combined with radiofrequency ablation treatment in liver tissue, the necrosis volume, tissue repair and hepatocellular growth signals were analyzed in rats. Radiofrequency ablation (RFA) is a widely applied treatment for hepatocellular carcinoma (HCC). Radiofrequency ablation is combined with the multi-tyrosinkinase-inhibitor sorafenib in ongoing clinical trials. Whether this combination treatment affects liver tissue repair is unknown. MATERIALS AND METHODS: Male Sprague Dawley (SD) rats received RFA or sham puncture with concomitant sorafenib (5mg/kg qd from day 2) or vehicle. Necrosis volume was calculated from resected specimens. Proliferation and micro vessel density were determined by Ki67 and CD31 immunofluorescence, respectively. mRNA expression of hepatocyte growth factor (HGF), epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) was quantified. RESULTS: While ablation size was identical in all treatment groups at day 1, sorafenib treated animals showed sustained necroses (219 ± 24 vs. 88 ± 52 mm(3) in controls; P = 0.03), elevated alanine aminotransferase (ALT) and elevated glutamate dehydrogenase (GLDH) (76 ± 37 vs. 47 ± 58 mm(3); P=0.50) at day 3. By day 7 necrosis volumes equalized for the treatment groups. Ki67 and CD31 staining showed reduced proliferation and micro vessel density at days 1 and 3 following sorafenib. Growth factors HGF and EGF were significantly overexpressed in liver tissue after sorafenib. CONCLUSION: Sorafenib initially promotes necrosis after RFA in liver tissue. The delay in tissue repair is overcome at day 7 presumably by transient compensatory overexpression of growth signals. Based on these data from animal studies further investigation of adjuvant sorafenib in humans is warranted.