Anesthetist-Directed Sedation Favors Success of Advanced Endoscopic Procedures.

OBJECTIVES: Sedation is required to perform endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic ultrasound (EUS) given the duration and complexity of these advanced procedures. Sedation options include anesthetist-directed sedation (ADS) vs. gastroenterologist-directed sedation (GDS). Although ADS has been shown to shorten induction and recovery times, it is not established whether it impacts likelihood of procedure completion. Our aim was to assess whether ADS impacts the success of advanced endoscopy procedures. METHODS: We prospectively assessed the sedation strategy for patients undergoing ERCP and EUS between October 2010 and October 2013. Although assignment to ADS vs. GDS was not randomized, it was determined by day of the week. A sensitivity analysis using propensity score matching was used to model a randomized trial. The main outcome, procedure failure, was defined as an inability to satisfactorily complete the ERCP or EUS such that an additional endoscopic, radiographic, or surgical procedure was required. Failure was further categorized as failure due to inadequate sedation vs. technical problems. RESULTS: During the 3-year study period, 60% of the 1,171 procedures were carried out with GDS and 40% were carried out with ADS. Failed procedures occurred in 13.0% of GDS cases compared with 8.9% of ADS procedures (multivariate odds ratio (OR): 2.4 (95% confidence interval (CI): 1.5-3.6)).This was driven by a higher rate of sedation failures in the GDS group, 7.0%, than in the ADS group, 1.3% (multivariate OR: 7.8 (95% CI: 3.3-18.8)). There was no difference in technical success between the GDS and ADS groups (multivariate OR: 1.2 (95% CI: 0.7-1.9)). We were able to match 417 GDS cases to 417 ADS cases based on procedure type, indication, and propensity score. Analysis of the propensity score-matched patients confirmed our findings of increased sedation failure (multivariate OR: 8.9 (95% CI: 2.5-32.1)) but not technical failure (multivariate OR: 1.2 (0.7-2.2)) in GDS compared with ADS procedures. Adverse events of sedation were rare in both groups. Failed ERCP in the GDS group resulted in a total of 93 additional days of hospitalization. We estimate that $67,891 would have been saved if ADS had been used for all ERCP procedures. No statistically significant difference in EUS success was identified, although this sub-analysis was limited by sample size. CONCLUSION: ADS improves the success of advanced endoscopic procedures. Its routine use may increase the quality and efficiency of these services.

Optimal Timing of Endoscopic Retrograde Cholangiopancreatography in Acute Cholangitis.

OBJECTIVES: Acute cholangitis mandates resuscitation, antibiotic therapy, and biliary decompression. Our aim was to define the optimal timing of endoscopic retrograde cholangiopancreatography (ERCP) for patients with acute cholangitis. METHODS: Clinical data on all cases of cholangitis managed by ERCP were prospectively collected from September 2010 to July 2013. The clinical impact of the time to ERCP, defined as the time from presentation in the emergency department to the commencement of the ERCP, was determined. The primary outcome was length of hospitalization. Secondary outcomes included vasopressor use, endotracheal intubation, intensive care unit admission, and death. RESULTS: ERCP was successful in 182 (92%) of 199 patients with cholangitis. Length of hospitalization was significantly longer for patients undergoing ERCP at ≥48 versus <48 hours (median 9.1 vs. 6.5 d, P=0.004) even though patients having ERCP at ≥48 hours were less sick as indicated by less frequent intensive care unit admission [odds ratio,0.3; 95% confidence interval (CI), 0.2-0.6]. Multivariate analysis revealed that hospitalization increased by 1.44 days for every day ERCP was delayed (P<0.001). Comparison of ERCP≥72 versus <72 hours revealed odds ratios of 2.6 (95% CI, 1.0-7.0) for vasopressor requirement and 3.6 (95% CI, 0.8-15.9) for mortality. Time to ERCP did not impact technical success or procedural adverse events. CONCLUSIONS: ERCP should be performed within 2 days of presentation as a delay of 48 or more hours is associated with disproportionate increase in hospital stay. Delay>72 hours is associated with additional adverse outcomes including hypotension requiring vasopressor support.

Identification of Mycobacterium avium genes associated with resistance to host antimicrobial peptides.

Antimicrobial peptides are an important component of the innate immune defence. Mycobacterium avium subsp. hominissuis (M. avium) is an organism that establishes contact with the respiratory and gastrointestinal mucosa as a necessary step for infection. M. avium is resistant to high concentrations of polymyxin B, a surrogate for antimicrobial peptides. To determine gene-encoding proteins that are associated with this resistance, we screened a transposon library of M. avium strain 104 for susceptibility to polymyxin B. Ten susceptible mutants were identified and the inactivated genes sequenced. The great majority of the genes were related to cell wall synthesis and permeability. The mutants were then examined for their ability to enter macrophages and to survive macrophage killing. Three clones among the mutants had impaired uptake by macrophages compared with the WT strain, and all ten clones were attenuated in macrophages. The mutants were also shown to be susceptible to cathelicidin (LL-37), in contrast to the WT bacterium. All but one of the mutants were significantly attenuated in mice. In conclusion, this study indicated that the M. avium envelope is the primary defence against host antimicrobial peptides.

The efficacy of clarithromycin and the bicyclolide EDP-420 against Mycobacterium avium in a mouse model of pulmonary infection.

Lung disease caused by Mycobacterium avium complex (MAC) is increasing in prevalence. MAC disease occurs in patients with chronic preexisting obstructive pulmonary diseases but is also diagnosed in individuals with no history of lung pathology or identifiable immune defect. Histologically, the disease is characterized by either the development of nodular granulomatous lesions in the peribronchial region or cavitary peripheral disease in smokers. Response to long-term treatment is poor. Limited comparative-efficacy data on treatment exist. A model that resembles nodular MAC disease was established in C57 (bg+/bg+) mice infected intranasally. Therapy with clarithromycin, a compound commonly used to treat MAC disease, was evaluated in parallel with treatment using a new bicyclolide, EDP-420, that achieves high levels of intrapulmonary concentrations. Although clarithromycin administered daily resulted in a reduction in the bacterial load in the lung, EDP-420 administered either daily or twice a week was significantly more effective. These results suggest that this animal model can be used to evaluate novel regimens against MAC disease and that compounds with high concentration in the lung might have a significant impact on the outcome of MAC lung disease.

EDP-420, a bicyclolide (bridged bicyclic macrolide), is active against Mycobacterium avium.

Infection caused by Mycobacterium avium complex (MAC) is common in patients with immunosuppression, such as AIDS, and deficiencies of gamma interferon and interleukin-12, as well as patients with chronic lung diseases. Treatment of MAC disease is limited since few drugs show in vivo activity. We tested a new bridged bicyclic macrolide, EDP-420, against MAC in vitro and in beige mice. EDP-420 was inhibitory in vitro at a concentration ranging from 2 to 8 microg/ml (MIC(50) of 4 microg/ml and MIC(90) of 8 microg/ml). In macrophages, EDP-420 was inhibitory at 0.5 microg/ml, suggesting that the drug concentrates intracellularly. Mice infected with macrolide-susceptible MAC strain 101 were given 100 mg of EDP-420/kg of body weight daily for 4 weeks and showed a significant reduction in the number of bacteria in both liver and spleen which was greater than the reduction observed with clarithromycin treatment at the same dose (P < 0.05). However, macrolide-resistant MAC 101 did not respond to EDP-420 treatment. A combination of EDP-420 with mefloquine was shown to be indifferent; mefloquine alone was active against macrolide-resistant MAC. The frequency of resistance to EDP-420 in MAC 101 was 10(-9), which is significantly less than the emergence of resistance to clarithromycin, approximately 10(-7) (P < 0.05). Further evaluation of EDP-420 in the treatment of MAC disease is warranted.