Rapid expansion and extinction of antibiotic resistance mutations during treatment of acute bacterial respiratory infections.

Acute bacterial infections are often treated empirically, with the choice of antibiotic therapy updated during treatment. The effects of such rapid antibiotic switching on the evolution of antibiotic resistance in individual patients are poorly understood. Here we find that low-frequency antibiotic resistance mutations emerge, contract, and even go to extinction within days of changes in therapy. We analyzed Pseudomonas aeruginosa populations in sputum samples collected serially from 7 mechanically ventilated patients at the onset of respiratory infection. Combining short- and long-read sequencing and resistance phenotyping of 420 isolates revealed that while new infections are near-clonal, reflecting a recent colonization bottleneck, resistance mutations could emerge at low frequencies within days of therapy. We then measured the in vivo frequencies of select resistance mutations in intact sputum samples with resistance-targeted deep amplicon sequencing (RETRA-Seq), which revealed that rare resistance mutations not detected by clinically used culture-based methods can increase by nearly 40-fold over 5-12 days in response to antibiotic changes. Conversely, mutations conferring resistance to antibiotics not administered diminish and even go to extinction. Our results underscore how therapy choice shapes the dynamics of low-frequency resistance mutations at short time scales, and the findings provide a possibility for driving resistance mutations to extinction during early stages of infection by designing patient-specific antibiotic cycling strategies informed by deep genomic surveillance.

The synergistic effect of dexmedetomidine on propofol for paediatric deep sedation: A randomised trial.

BACKGROUND: Propofol and dexmedetomidine are used separately, and sometimes together, for paediatric deep sedation. Although their combination has been described in adults, the effect of dexmedetomidine as a potential synergist in children has not been studied before. OBJECTIVES: The primary objective was to compare the propofol requirements of children who receive propofol alone with those who receive it in combination with dexmedetomidine for deep sedation for upper and lower endoscopic gastrointestinal procedures. DESIGN: This was a prospective, open-label, randomised study comparing patients who received propofol alone (group P) with those who received dexmedetomidine and propofol (group DP). The depth of sedation was titrated to a target bispectral (BIS) index. SETTING: A Gastroenterology Procedure Unit at a single, tertiary care academic medical centre from April 2018 until December 2019. PATIENTS: Eligible patients were scheduled for upper endoscopy, lower endoscopy or both. A total of 39 patients were enrolled (20 DP) and (19 P). INTERVENTIONS: Patients in Group DP received dexmedetomidine 0.5 µg kg-1 administered over 1 min followed by an infusion of 0.15 µg kg-1 h-1. In both groups, intravenous propofol was given in bolus increments titrated to a BIS index of 40 to 50 and then a continuous infusion of propofol to maintain BIS at 40 to 50. MAIN OUTCOME MEASURES: The primary outcome measure was propofol requirement in each group. Secondary outcome measures were time to achieve the targeted sedation depth, time to achieve an Aldrete recovery score of 9, duration of sedation, mean BIS values, adverse events, 'PAED' scores and time to discharge from the postanaesthesia care unit (PACU). RESULTS: The median (range) total dose of propofol was 0.23 (0.10 to 0.50) mg kg-1 min-1 in group DP and 0.40 (0.20 to 0.50) mg kg-1 min-1 in group P (P = 0.0004). Time of discharge from the PACU was 60 (20 to 121) min in group DP and 63 (46 to 91) min in group P (P = 0.0409). CONCLUSION: The combination of dexmedetomidine and propofol for paediatric procedural sedation achieved a significant reduction in median propofol dose and a slightly shorter median time to discharge from PACU. Large-scale studies may determine whether this reduction decreases the risk of significant adverse events. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02952222.

Inclusion of non-English-speaking patients in research: A single institution experience.

BACKGROUND: Considering the recent increase in medical care provided to patients from foreign countries and the diversity of languages spoken by families living within the United States, it is important to determine whether non-English-speaking patients have access to participate in clinical research from which they may benefit. AIMS: We aimed to determine the number of non-English-speaking patients presenting to Boston Children's Hospital for medical care between 2011 and 2016, the number of clinical research protocols active within the Department of Anesthesiology, Critical Care and Pain Medicine approved to enroll non-English-speaking patients, as well as the number of both non-English- and English-speaking patients approached and enrolled in these studies. Furthermore, we attempted to determine barriers that may have prevented non-English-speaking patients from inclusion in clinical research. METHODS: We conducted a retrospective review of various data sources during a 5-year period. Data included the number of non-English-speaking patients presenting to Boston Children's Hospital for care as well as the number of English- and non-English-speaking patients approached for studies at the Department of Anesthesiology each year. Additionally, we reviewed data from the IRB which included the justification that research teams provided when opting to exclude non-English-speaking participants. In addition, we attempted to determine the barriers that may have prevented these patients from inclusion in research protocols. RESULTS: We found that the number of non-English-speaking patients presenting to Boston Children's Hospital increased over time. However, the number of studies approved to enroll non-English-speaking patients within the Department of Anesthesiology and the rate of enrollment of these patients did not increase at the same rate. CONCLUSION: In order to increase the number of non-English-speaking patients approached to participate in research, we must improve cultural awareness and provide investigators with resources for interpreter and translation services.

The Evaluation of a Noninvasive Respiratory Volume Monitor in Pediatric Patients Undergoing General Anesthesia.

BACKGROUND: Pediatric patients following surgery are at risk for respiratory compromise such as hypoventilation and hypoxemia depending on their age, comorbidities, and type of surgery. Quantitative measurement of ventilation in nonintubated infants/children is a difficult and inexact undertaking. Current respiratory assessment in nonintubated patients relies on oximetry data, respiratory rate (RR) monitors, and subjective clinical assessment, but there is no objective measure of respiratory parameters that could be utilized to predict early respiratory compromise. New advances in technology and digital signal processing have led to the development of an impedance-based respiratory volume monitor (RVM, ExSpiron, Respiratory Motion, Inc, Waltham, MA). The RVM has been shown to provide accurate real-time, continuous, noninvasive measurements of tidal volume (TV), minute ventilation (MV), and RR in adult patients.In this prospective observational study, our primary aim was to determine whether the RVM accurately measures TV, RR, and MV in pediatric patients. METHODS: A total of 72 pediatric patients (27 females, 45 males), ASA I to III, undergoing general anesthesia with endotracheal intubation were enrolled. After endotracheal intubation, continuous data of MV, TV, and RR were recorded from the RVM and an in-line monitoring spirometer (NM3 monitor, Phillips Healthcare). RVM and NM3 measurements of MV, TV, and RR were compared during a 10-minute period prior to the incision ("Presurgery") and a 10-minute period after the end of surgery ("Postsurgery"). Relative errors were calculated over 1-minute segment within each 10-minute period. Bias, precision, and accuracy were calculated using Bland-Altman analyses and paired-difference equivalence tests were performed. RESULTS: Combined across the Presurgery and Postsurgery periods, the RVM's mean measurement bias (RVM - NM3 measurement) for MV was -3.8% (95% limits of agreement) (±1.96 SD): (-19.9% to 12.2%), for TV it was -4.9 (-21.0% to 11.3%), and for RR it was 1.1% (-4.1% to 6.2%). The mean measurement accuracies for MV, TV, and RR were 11.9%, 12.0%, and 4.2% (0.6 breaths/min), respectively. Note that lower accuracy numbers correspond to more accurate RVM measurements. The equivalence tests rejected the null hypothesis that the RVM and NM3 have different mean values and conclude with 90% power that the measurements of MV, TV, and RR from the RVM and NM3 are equivalent within ±10%. CONCLUSIONS: Our data indicate acceptable agreement between RVM and NM3 measurements in pediatric mechanically-ventilated patients. Future studies assessing the capability of the RVM to detect respiratory compromise in other clinical settings are needed.

Relationship Between Transfusion of Blood Products and the Incidence of Thrombotic Complications in Neonates and Infants Undergoing Cardiac Surgery.

OBJECTIVES: The authors hypothesized that transfusion of blood products in neonates and infants undergoing high-risk cardiac surgery in the absence of intraoperative coagulation monitoring increases the risk of thrombotic complications. DESIGN: Prospective observational study. SETTING: Neonates and infants undergoing cardiac surgery at a tertiary pediatric center. PARTICIPANTS: Neonates weighing >2.5 kg and infants ≤12 months of age undergoing elective cardiac surgery with cardiopulmonary bypass were included in this prospective observational study. INTERVENTION: None. MEASUREMENTS AND RESULTS: Demographic data, surgical characteristics, transfusion data, and coagulation parameters (thromboelastography and thromboelastometry) were collected. Logistic regression analysis was performed to identify potential determinants of postoperative thrombotic complications. Among the 138 neonates and infants included in the study, 12 (9%) developed a postoperative thrombotic complication. Unadjusted logistic regression analysis confirmed that the number and volume of blood products transfused were associated significantly with the increased incidence of thrombotic complication (odds ratio: 2.78, 95% confidence interval: 1.30-5.94, p = 0.008). This association persisted after adjustment for patient's age, the need for deep hypothermic cardiac arrest, and bypass time (odds ratio: 2.23, 95% confidence interval: 1.02-4.87, p = 0.044). The number of blood products transfused was associated with a significant increase in parameters of clot amplitudes measured at cardiac intensive care unit admission, while no difference was reported when measured after the administration of protamine. CONCLUSIONS: This prospective observational study reports a significant association between transfusion of blood products in neonates and young infants undergoing cardiac surgery and an increased incidence of thrombotic complications in the absence of intraoperative coagulation monitoring.