Background The effect on cardiovascular outcomes of withholding angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers in chronic users before noncardiac surgery is unknown. Methods In this international prospective cohort study, the authors analyzed data from 14,687 patients (including 4,802 angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker users) at least 45 yr old who had in-patient noncardiac surgery from 2007 to 2011. Using multivariable regression models, the authors studied the relationship between withholding angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers and a primary composite outcome of all-cause death, stroke, or myocardial injury after noncardiac surgery at 30 days, with intraoperative and postoperative clinically important hypotension as secondary outcomes. Results Compared to patients who continued their angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, the 1,245 (26%) angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker users who withheld their angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers in the 24 h before surgery were less likely to suffer the primary composite outcome of all-cause death, stroke, or myocardial injury (150/1,245 [12.0%] vs. 459/3,557 [12.9%]; adjusted relative risk, 0.82; 95% CI, 0.70 to 0.96; P = 0.01) and intraoperative hypotension (adjusted relative risk, 0.80; 95% CI, 0.72 to 0.93; P < 0.001). The risk of postoperative hypotension was similar between the two groups (adjusted relative risk, 0.92; 95% CI, 0.77 to 1.10; P = 0.36). Results were consistent across the range of preoperative blood pressures. The practice of withholding angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers was only modestly correlated with patient characteristics and the type and timing of surgery. Conclusions Withholding angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers before major noncardiac surgery was associated with a lower risk of death and postoperative vascular events. A large randomized trial is needed to confirm this finding. In the interim, clinicians should consider recommending that patients withhold angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers 24 h before surgery.

No abstract

Pacemaker channels are formed by co-assembly of hyperpolarization-activated cyclic nucleotide-gated (HCN) subunits. Previously, we suggested that the NH 2 termini of the mouse HCN2 isoform were important for subunit co-assembly and functional channel expression. Using an alignment strategy together with yeast twohybrid assays, patch clamp electrophysiology, and confocal imaging, we have now identified a domain within the NH 2 terminus of the HCN2 subunit that is responsible for interactions between NH 2 termini and promoting the trafficking of functional channels to the plasma membrane. This domain is composed of 52 amino acids, is located adjacent to the putative first transmembrane segment, and is highly conserved among the mammalian HCN isoforms. This conserved domain, but not the remaining unconserved NH 2 -terminal regions of HCN2, specifically interacted with itself in yeast two-hybrid assays. Moreover, the conserved domain was important for expression of currents. Whereas relatively normal whole cell HCN2 currents were produced by channels containing only the conserved domain, further deletion of this region, leaving only a more polar and putative coiled-coil segment, eliminated HCN2 currents and resulted in proteins that localized predominantly in perinuclear compartments. Thus, we suggest that this conserved domain is the critical NH 2 -terminal determinant of subunit co-assembly and trafficking of pacemaker channels.Pacemaker channels are formed by hyperpolarization-activated cyclic nucleotide-gated (HCN) 1 subunits and are important for generating spontaneous activity in a variety of excitable cells (1, 2). Their primary amino acid sequence predicts a structure similar to those of voltage-gated potassium channels and cyclic nucleotide-gated channels. Thus, HCN subunits are thought to have six transmembrane helices with cytoplasmic amino and carboxyl termini, and to co-assemble as tetramers when forming functional channels. Four mammalian HCN isoforms (HCN1-4) are known (3-5). Co-assembly of different mammalian HCN isoforms has been suggested using electrophysiological analyses (6, 7), and different isoforms have been found in the same cells (8 -12). These findings suggest that the formation of heteromeric channels contributes to the diversity of pacemaker current phenotypes described in vivo.Recently, we suggested that NH 2 -terminal interactions are required for subunit co-assembly and targeting of functional channels to the plasma membrane (13). However, we have not yet determined the region(s) responsible. To identify the critical region, we subdivided the NH 2 terminus based on homology among the different mammalian isoforms of HCN channels. An alignment of NH 2 -terminal amino acid sequences from these isoforms revealed a 52-amino acid domain, which has a high sequence identity (Ͼ90%), and is located immediately adjacent to the first putative transmembrane domain (S1). Using yeast two-hybrid assays, confocal imaging, and patch clamp electrophysiology, we have found that the conserved domain inter...

BACKGROUND: Inadvertent perioperative hypothermia is a common complication of surgery, and active body surface warming (ABSW) systems are used to prevent adverse clinical outcomes. Prior data on certain outcomes are equivocal (ie, blood loss) or limited (ie, pain and opioid consumption). The objective of this study was to provide an updated review on the effect of ABSW on clinical outcomes and temperature maintenance. METHODS: We conducted a systematic review of randomized controlled trials evaluating ABSW systems compared to nonactive warming controls in noncardiac surgeries. Outcomes studied included postoperative pain scores and opioid consumption (primary outcomes) and other perioperative clinical variables such as temperature changes, blood loss, and wound infection (secondary outcomes). We searched Ovid MEDLINE daily, Ovid MEDLINE, EMBASE, CINHAL, Cochrane CENTRAL, and Web of Science from inception to June 2019. Quality of evidence (QoE) was rated according to the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. Subgroup analysis sought to determine the effect of preoperative + intraoperative warming versus intraoperative warming alone. Metaregression evaluated the effect of year of publication, use of neuromuscular blockers, anesthesia, and surgery type on outcomes. RESULTS: Fifty-four articles (3976 patients) were included. Pooled results demonstrated that ABSW maintained normothermia compared to controls, during surgery (30 minutes postinduction [mean difference {MD}: 0.3°C, 95% confidence interval {CI}, 0.2–0.4, moderate QoE]), end of surgery (MD: 1.1°C, 95% CI, 0.9–1.3, high QoE), and up to 4 hours postoperatively (MD: 0.3°C, 95% CI, 0.2–0.5, high QoE). ABSW was not associated with difference in pain scores (<24 hours postoperatively, moderate to low QoE) or perioperative opioid consumption (very low QoE). ABSW increased patient satisfaction (MD: 2.2 points, 95% CI, 0.9–3.6, moderate QoE), reduced blood transfusions (odds ratio [OR] = 0.6, 95% CI, 0.4–1.0, moderate QoE), shivering (OR = 0.2, 95% CI, 0.1–0.4, high QoE), and wound infections (OR = 0.3, 95% CI, 0.2–0.7, high QoE). No significant differences were found for fluid administration (low QoE), blood loss (very low QoE), major adverse cardiovascular events (very low QoE), or mortality (very low QoE). Subgroup analysis and metaregression suggested increased temperature benefit with pre + intraoperative warming, use of neuromuscular blockers, and recent publication year. ABSW seemed to confer less temperature benefit in cesarean deliveries and neurosurgical/spinal cases compared to abdominal surgeries. CONCLUSIONS: ABSW is effective in maintaining physiological normothermia, decreasing wound infections, shivering, blood transfusions, and increasing patient satisfaction but does not appear to affect postoperative pain and opioid use.