RESUMO
BACKGROUND: The efficacy of serratus anterior plane block (SAPB) for treatment of pain after minimally invasive thoracic surgery remains unclear. This trial assesses the impact of SAPB on postoperative opioid consumption and on measures of early recovery after thoracoscopic lung resection. METHODS: Patients undergoing minimally invasive anatomic lung resection at a single center were randomized to undergo SAPB with 40 mL of injectate containing bupivacaine 0.25%, clonidine 100 mcg, and dexamethasone 4 mg (SAPB group) or sham block with 40 mL of normal saline (placebo group) at the conclusion of surgery. The primary outcome was cumulative intravenous morphine equivalents during the first 24 h postoperatively. Secondary outcomes were intravenous morphine equivalents, pain scores at rest and with cough, inspiratory volume on incentive spirometry, and incidence of nausea/vomiting during the first 48 h postoperatively; Quality of Recovery-15 score on postoperative day 7; and length of stay. RESULTS: Using the protocol-specified intention-to-treat analysis, the median (interquartile range, IQR) intravenous morphine equivalents was 10.6 (5.0 to 27.1) mg in SAPB patients (n=46) versus 18.8 (9.9 to 29.6) mg in placebo patients (n=46) (32% reduction; ratio=0.68 [95% CI, 0.44 to 1.06]; P=0.085). Of the secondary outcomes, only the composite pain with cough scores differed significantly in the SAPB group by a coefficient of -0.41 (95% CI, -0.81 to -0.01; P=0.044). A sensitivity as-treated analysis reported median (IQR) intravenous morphine equivalents of 10.0 (5.0 to 27.2) mg in SAPB patients (n=44) versus 19.9 (10.4 to 29.0) mg in placebo patients (n=48) (36% reduction; ratio=0.64 [95% CI, 0.41 to 1.00]; P=0.048). CONCLUSIONS: The protocol-specified intention-to-treat analysis demonstrated that SAPB did not result in a significant reduction in opioid consumption when added to a multimodal analgesic regimen after thoracoscopic anatomic lung resection. The sensitivity as-treated analysis showed a significant and modest clinical reduction in the primary outcome that warrants further investigation.
RESUMO
BACKGROUND: The K65R substitution in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) is the major resistance mutation selected in patients treated with first-line antiretroviral tenofovir disoproxil fumarate (TDF). 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA), is the most potent nucleoside analog RT inhibitor (NRTI) that unlike all approved NRTIs retains a 3'-hydroxyl group and has remarkable potency against wild-type (WT) and drug-resistant HIVs. EFdA acts primarily as a chain terminator by blocking translocation following its incorporation into the nascent DNA chain. EFdA is in preclinical development and its effect on clinically relevant drug resistant HIV strains is critically important for the design of optimal regimens prior to initiation of clinical trials. RESULTS: Here we report that the K65R RT mutation causes hypersusceptibility to EFdA. Specifically, in single replication cycle experiments we found that EFdA blocks WT HIV ten times more efficiently than TDF. Under the same conditions K65R HIV was inhibited over 70 times more efficiently by EFdA than TDF. We determined the molecular mechanism of this hypersensitivity using enzymatic studies with WT and K65R RT. This substitution causes minor changes in the efficiency of EFdA incorporation with respect to the natural dATP substrate and also in the efficiency of RT translocation following incorporation of the inhibitor into the nascent DNA. However, a significant decrease in the excision efficiency of EFdA-MP from the 3' primer terminus appears to be the primary cause of increased susceptibility to the inhibitor. Notably, the effects of the mutation are DNA-sequence dependent. CONCLUSION: We have elucidated the mechanism of K65R HIV hypersusceptibility to EFdA. Our findings highlight the potential of EFdA to improve combination strategies against TDF-resistant HIV-1 strains.