Sedation Research in Critically Ill Pediatric Patients: Proposals for Future Study Design From the Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research IV Workshop.

OBJECTIVES: Sedation and analgesia for infants and children requiring mechanical ventilation in the PICU is uniquely challenging due to the wide spectrum of ages, developmental stages, and pathophysiological processes encountered. Studies evaluating the safety and efficacy of sedative and analgesic management in pediatric patients have used heterogeneous methodologies. The Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research (SCEPTER) IV hosted a series of multidisciplinary meetings to establish consensus statements for future clinical study design and implementation as a guide for investigators studying PICU sedation and analgesia. DESIGN: Twenty-five key elements framed as consensus statements were developed in five domains: study design, enrollment, protocol, outcomes and measurement instruments, and future directions. SETTING: A virtual meeting was held on March 2-3, 2022, followed by an in-person meeting in Washington, DC, on June 15-16, 2022. Subsequent iterative online meetings were held to achieve consensus. SUBJECTS: Fifty-one multidisciplinary, international participants from academia, industry, the U.S. Food and Drug Administration, and family members of PICU patients attended the virtual and in-person meetings. Participants were invited based on their background and experience. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Common themes throughout the SCEPTER IV consensus statements included using coordinated multidisciplinary and interprofessional teams to ensure culturally appropriate study design and diverse patient enrollment, obtaining input from PICU survivors and their families, engaging community members, and using developmentally appropriate and validated instruments for assessments of sedation, pain, iatrogenic withdrawal, and ICU delirium. CONCLUSIONS: These SCEPTER IV consensus statements are comprehensive and may assist investigators in the design, enrollment, implementation, and dissemination of studies involving sedation and analgesia of PICU patients requiring mechanical ventilation. Implementation may strengthen the rigor and reproducibility of research studies on PICU sedation and analgesia and facilitate the synthesis of evidence across studies to improve the safety and quality of care for PICU patients.

Design of Clinical Trials Evaluating Sedation in Critically Ill Adults Undergoing Mechanical Ventilation: Recommendations From Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research (SCEPTER) Recommendation III.

OBJECTIVES: Clinical trials evaluating the safety and effectiveness of sedative medication use in critically ill adults undergoing mechanical ventilation differ considerably in their methodological approach. This heterogeneity impedes the ability to compare results across studies. The Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research Recommendations convened a meeting of multidisciplinary experts to develop recommendations for key methodologic elements of sedation trials in the ICU to help guide academic and industry clinical investigators. DESIGN: A 2-day in-person meeting was held in Washington, DC, on March 28-29, 2019, followed by a three-round, online modified Delphi consensus process. PARTICIPANTS: Thirty-six participants from academia, industry, and the Food and Drug Administration with expertise in relevant content areas, including two former ICU patients attended the in-person meeting, and the majority completed an online follow-up survey and participated in the modified Delphi process. MEASUREMENTS AND MAIN RESULTS: The final recommendations were iteratively refined based on the survey results, participants' reactions to those results, summaries written by panel moderators, and a review of the meeting transcripts made from audio recordings. Fifteen recommendations were developed for study design and conduct, subject enrollment, outcomes, and measurement instruments. Consensus recommendations included obtaining input from ICU survivors and/or their families, ensuring adequate training for personnel using validated instruments for assessments of sedation, pain, and delirium in the ICU environment, and the need for methodological standardization. CONCLUSIONS: These recommendations are intended to assist researchers in the design, conduct, selection of endpoints, and reporting of clinical trials involving sedative medications and/or sedation protocols for adult ICU patients who require mechanical ventilation. These recommendations should be viewed as a starting point to improve clinical trials and help reduce methodological heterogeneity in future clinical trials.

Academic Anesthesiology Career Development: A Mixed-Methods Evaluation of the Role of Foundation for Anesthesiology Education and Research Funding.

BACKGROUND: In 1986, the American Society of Anesthesiologists created the Foundation for Anesthesiology Education and Research (FAER) to fund young anesthesiology investigators toward the goal of helping launch their academic careers. Determining the impact of the FAER grant program has been of importance. METHODS: This mixed-methods study included quantitative data collection through a Research Electronic Data Capture survey and curriculum vitae (CV) submission and qualitative interviews. CVs were abstracted for education history, faculty appointment(s), first and last author peer-reviewed publications, grant funding, and leadership positions. Survey nonrespondents were sent up to 3 reminders. Interview questions elicited details about the experience of submitting a FAER grant. Quantitative data were summarized descriptively, and qualitative data were analyzed with NVivo. RESULTS: Of 830 eligible participants, 38.3% (N = 318) completed surveys, 170 submitted CVs, and 21 participated in interviews. Roughly 85% held an academic appointment. Funded applicants were more likely than unfunded applicants to apply for National Institutes of Health funding (60% vs 35%, respectively; P < .01), but the probability of successfully receiving an National Institutes of Health grant did not differ (83% vs 85%, respectively; P = .82). The peer-reviewed publication rate (publications per year since attending medical school) did not differ between funded and unfunded applicants, with an estimated difference in means (95% confidence interval) of 1.3 (-0.3 to 2.9) publications per year. The primary FAER grant mentor for over one-third of interview participants was a nonanesthesiologist. Interview participants commonly discussed the value of having multiple mentors. Key mentor attributes mentioned were availability, guidance, reputation, and history of success. CONCLUSIONS: This cross-sectional data demonstrated career success in publications, grants, and leadership positions for faculty who apply for a FAER grant. A FAER grant application may be a marker for an anesthesiologist who is interested in pursuing a physician-scientist career.

Efficacy Outcome Measures for Pediatric Procedural Sedation Clinical Trials: An ACTTION Systematic Review.

Objective evaluations comparing different techniques and approaches to pediatric procedural sedation studies have been limited by a lack of consistency among the outcome measures used in assessment. This study reviewed those existing measures, which have undergone psychometric analysis in a pediatric procedural sedation setting, to determine to what extent and in what circumstances their use is justified across the spectrum of procedures, age groups, and techniques. The results of our study suggest that a wide range of measures has been used to assess the efficacy and effectiveness of pediatric procedural sedation. Most lack the evidence of validity and reliability that is necessary to facilitate rigorous clinical trial design, as well as the evaluation of new drugs and devices. A set of core pediatric sedation outcome domains and outcome measures can be developed on the basis of our findings. We believe that consensus among all stakeholders regarding appropriate domains and measures to evaluate pediatric procedural sedation is possible and that widespread implementation of such recommendations should be pursued.

Evaluating Patient-Centered Outcomes in Clinical Trials of Procedural Sedation, Part 2 Safety: Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research Recommendations.

The Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research, established by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks, a public-private partnership with the US Food and Drug Administration, convened a second meeting of sedation experts from a variety of clinical specialties and research backgrounds to develop recommendations for procedural sedation research. The previous meeting addressed efficacy and patient- and/or family-centered outcomes. This meeting addressed issues of safety, which was defined as "the avoidance of physical or psychological harm." A literature review identified 133 articles addressing safety measures in procedural sedation clinical trials. After basic reporting of vital signs, the most commonly measured safety parameter was oxygen saturation. Adverse events were inconsistently defined throughout the studies. Only 6 of the 133 studies used a previously validated measure of safety. The meeting identified methodological problems associated with measuring infrequent adverse events. With a consensus discussion, a set of core and supplemental measures were recommended to code for safety in future procedural clinical trials. When adopted, these measures should improve the integration of safety data across studies and facilitate comparisons in systematic reviews and meta-analyses.

Evaluating Patient-Centered Outcomes in Clinical Trials of Procedural Sedation, Part 1 Efficacy: Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research Recommendations.

The Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research, established by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks public-private partnership with the US Food and Drug Administration, convened a meeting of sedation experts from a variety of clinical specialties and research backgrounds with the objective of developing recommendations for procedural sedation research. Four core outcome domains were recommended for consideration in sedation clinical trials: (1) safety, (2) efficacy, (3) patient-centered and/or family-centered outcomes, and (4) efficiency. This meeting identified core outcome measures within the efficacy and patient-centered and/or family-centered domains. Safety will be addressed in a subsequent meeting, and efficiency will not be addressed at this time. These measures encompass depth and levels of sedation, proceduralist and patient satisfaction, patient recall, and degree of pain experienced. Consistent use of the recommended outcome measures will facilitate the comprehensive reporting across sedation trials, along with meaningful comparisons among studies and interventions in systematic reviews and meta-analyses.

Evaluation of the Foundation for Anesthesia Education and Research Medical Student Anesthesia Research Fellowship Program Participants' Scholarly Activity and Career Choices.

BACKGROUND: The Foundation for Anesthesia Education and Research Medical Student Anesthesia Research Fellowship (MSARF) program is an 8-week program that pairs medical students with anesthesiologists performing anesthesia-related research. This study evaluated the proportion of students who published an article from their work, as well as the percentage of students who entered anesthesiology residency programs. METHODS: A list of previous MSARF participants (2005 to 2012), site, and project information was obtained. Searches for publications were performed using PubMed. The primary outcome was the publication rate for MSARF projects. The MSARF abstract-to-publication ratio was compared with the percentage of abstracts presented at biomedical meetings that resulted in publication as estimated by a Cochrane review (44%). For students who had graduated from medical school, match lists from the students' medical schools were reviewed for specialty choice. RESULTS: Forty-two percent of the 346 MSARF projects were subsequently published. There was no difference between the MSARF abstract-to-publication ratio and the publication rate of articles from abstracts presented at scientific meetings (P = 0.57). Thirty percent (n = 105; 95% CI, 25 to 35%) of all the MSARF students were authors on a publication. Fifty-eight percent of the students for whom residency match data (n = 255) were available matched into anesthesiology residencies (95% CI, 52 to 64%). CONCLUSIONS: The MSARF program resulted in many students being included as a co-author on a published article; the majority of these students entered anesthesiology residency programs. Future research should determine whether the program has a long-term impact on the development of academic anesthesiologists.

A Randomized, Prospective, Double-Blinded Study of Physostigmine to Prevent Sedation-Induced Ventilatory Arrhythmias.

BACKGROUND: Physostigmine, a centrally acting acetylcholinesterase inhibitor, is most commonly used by anesthesiologists in the postanesthetic setting to reverse confusion caused by central anticholinergic medication effects. It has also been proposed as a treatment for sleep-disordered breathing. We investigated whether physostigmine was effective in decreasing the frequency of ventilatory arrhythmias produced during moderate sedation with midazolam and remifentanil during the conditions of breathing room air or 2 L/min nasal O2. METHODS: Ten healthy male volunteers participated in this randomized, double-blind control trial of physostigmine (0.24 µg·kg·min) versus placebo. Moderate sedation was achieved with infusions of midazolam and remifentanil and monitored with full and processed electroencephalogram. Analgesia was quantified with subjective pain score to thermal stimulation. Ventilatory arrhythmias, as measured by the sedation apnea-hypopnea index (S-AHI), were scored as the number of apneas and hypopneas during two 1-hour periods on room air or 2 L/min nasal O2. RESULTS: All subjects tolerated the sedation and physostigmine without significant adverse effects. Sedation during placebo infusion resulted in clinically significant (S-AHI > 15) ventilatory arrhythmias in 5 conditions in 3 subjects (2 on room air and then O2, and 1 on O2 only). Physostigmine did not significantly (P > 0.46) reduce the total number of ventilatory arrhythmias on either room air or O2 (13.4 ± 18.8 events/h [mean ± SEM], 95% confidence interval [CI] = -9.9 to 62.7; and 6.2 ± 8.0, 95% CI = -3.1 to 28.7, respectively). Physostigmine did reduce the S-AHI in all 5 instances of clinically significant ventilatory arrhythmias (S-AHI decreased by 67.0 ± 22.2; CI = 29.2-111.7; P = 0.04). CONCLUSIONS: Physostigmine does not appear to be useful as a pretreatment to prevent ventilatory arrhythmias during moderate sedation. However, it may be useful as a treatment for clinically significant ventilatory arrhythmias during moderate sedation.

Engaging students and faculty: implications of self-determination theory for teachers and leaders in academic medicine.

BACKGROUND: Much of the work of teachers and leaders at academic health centers involves engaging learners and faculty members in shared goals. Strategies to do so, however, are seldom informed by empirically-supported theories of human motivation. DISCUSSION: This article summarizes a substantial body of motivational research that yields insights and approaches of importance to academic faculty leaders. After identification of key limitations of traditional rewards-based (i.e., incentives, or 'carrots and sticks') approaches, key findings are summarized from the science of self-determination theory. These findings demonstrate the importance of fostering autonomous motivation by supporting the fundamental human needs for autonomy, competence, and relatedness. In turn, these considerations lead to specific recommendations about approaches to engaging autonomous motivation, using examples in academic health centers. SUMMARY: Since supporting autonomous motivation maximizes both functioning and well-being (i.e., people are both happier and more productive), the approaches recommended will help academic health centers recruit, retain, and foster the success of learners and faculty members. Such goals are particularly important to address the multiple challenges confronting these institutions.

Validation of a measurement to predict upper airway collapsibility during sedation for colonoscopy.

Techniques to quantify the effects of sedation on upper airway collapsibility have been used as research tools in the laboratory and operating room. However, they have not been used previously in the usual clinical practice environment of colonoscopy sedation. The propensity for upper airway collapsibility, quantified as the critical pharyngeal pressure (P(crit)), was hypothesized to correlate with the need for clinical intervention to maintain ventilation. Twenty patients scheduled for colonoscopy with sedation were prospectively recruited to undergo measurement of upper airway collapsibility using negative airway pressure (NAP) provocation with a minimum pressure of -18 cmH(2)O. The P(crit) was the negative pressure that collapses the airway, either directly or by extrapolation from the pressure-flow relationship. An exponential transformation was applied to the P(crit) data for statistical analysis. A clinical intervention score (CIS) was used to quantify required interventions by the sedation nurse. The measurement of the P(crit) during sedation was significantly larger (less negative) than both the baseline ("awake") (P = 0.0029) and late recovery (P = 0.01) values. The CIS was not predicted by the transformed baseline or sedated P(crit) with or without including demographics associated with sleep apnea syndrome. Although the NAP technique showed the expected changes with sedation in this clinical situation, we did not find that it predicted the need for clinical intervention during endoscopy. Our study was not large enough to test for subpopulations in which the test might be predictive; further studies of these particular groups are needed to determine the clinical utility of the NAP measurement.

Research approaches for evaluating opioid sparing in clinical trials of acute and chronic pain treatments: Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials recommendations.

ABSTRACT: Randomized clinical trials have demonstrated the efficacy of opioid analgesics for the treatment of acute and chronic pain conditions, and for some patients, these medications may be the only effective treatment available. Unfortunately, opioid analgesics are also associated with major risks (eg, opioid use disorder) and adverse outcomes (eg, respiratory depression and falls). The risks and adverse outcomes associated with opioid analgesics have prompted efforts to reduce their use in the treatment of both acute and chronic pain. This article presents Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) consensus recommendations for the design of opioid-sparing clinical trials. The recommendations presented in this article are based on the following definition of an opioid-sparing intervention: any intervention that (1) prevents the initiation of treatment with opioid analgesics, (2) decreases the duration of such treatment, (3) reduces the total dosages of opioids that are prescribed for or used by patients, or (4) reduces opioid-related adverse outcomes (without increasing opioid dosages), all without causing an unacceptable increase in pain. These recommendations are based on the results of a background review, presentations and discussions at an IMMPACT consensus meeting, and iterative drafts of this article modified to accommodate input from the co-authors. We discuss opioid sparing definitions, study objectives, outcome measures, the assessment of opioid-related adverse events, incorporation of adequate pain control in trial design, interpretation of research findings, and future research priorities to inform opioid-sparing trial methods. The considerations and recommendations presented in this article are meant to help guide the design, conduct, analysis, and interpretation of future trials.

Patterns of communication during the preanesthesia visit.

BACKGROUND: Effective communication in the preanesthesia clinic is important in patient-centered care. Although patient-physician communication has been studied by recordings in other contexts, there have been no observational studies of the communication patterns of anesthesiologists and patients during the preanesthesia interview. METHODS: Two experienced standardized patients were trained to portray the same clinical situation by using different coping styles (maximizing information or "monitoring" vs. minimizing information or "blunting"). Interviews of standardized patients by anesthesiologists took place in the preanesthesia clinic and recorded with the knowledge of the subjects. Audio recordings were analyzed, and the visit was separated into nine components. Discussion of the risks/informed consent process was examined, looking for discussion of common morbidities. The standardized patients completed a survey on the patient-centeredness of the interview. RESULTS: Twenty-seven subjects participated in this study. Interviews with the monitor required more time: 17.4 min (confidence interval [CI] 15.2-19.6, n = 24) versus 14.5 min (CI 13.1-16.0, n = 25), P < 0.05. Most interview time was spent in obtaining the history; 2.4 min (CI 1.8-3.1) was spent discussing risks with the monitor, and only 1.6 min (CI 1.2-2.0) was spent with the blunter (P < 0.05). Neither the monitor nor the blunter scored the interview highly for involving the patient in determining the goals of the anesthetic and recovery. CONCLUSIONS: Direct recording of interactions with standardized patients is a feasible method of studying the communication skills of anesthesiologists. For this study, the anesthesia providers were able to modify their approach depending on patient type, but the monitor received more information.

The role of the carotid bodies in the counter-regulatory response to hypoglycemia.

Although controversial, animal and tissue studies indicate that carotid bodies are sensitive to changes in glucose as well as in oxygen, thereby functioning as metabolic sensors. This study was designed to test the hypothesis that carotid bodies in humans participate in the counter-regulatory response to insulin-induced hypoglycemia.Dopamine and hyperoxia were used to suppress the carotid bodies' responsiveness in 16 normal subjects. Insulin and glucose infusions were used to clamp the plasma glucose in a step-wise decrease to 2.5,mmol/l over 4 hours while counter-regulatory hormones were measured.The hypoglycemic trajectories were similar under all three interventions (dopa-mine, hyperoxia and control), but the total glucose infused was significantly larger for hyperoxia than for dopamine. Cortisol and epinephrine both showed the expected increase with hypoglycemia, but there was no difference among interventions. Glucagon and norepinephrine levels were increased by dopamine, but only the normalized increase in glucagon was lower with dopamine and hyperoxia than control.The decrease in total glucose required for the dopamine experiments was most likely due to the higher baseline glucagon and norepinephrine levels. Hyperoxia did require more infused glucose, indicating some increased insulin sensitivity, but it was not clearly due to a decrease in cortisol or epinephrine responses. Thus, we did not find direct evidence of the carotid bodies' role in glucose homeostasis in humans.

Upper airway collapsibility in anesthetized children.

We sought to establish the feasibility of measuring upper airway narrowing in spontaneously breathing, anesthetized children using dynamic application of negative airway pressure. A secondary aim was to compare differences in upper airway collapsibility after the administration of sevoflurane or halothane. Subjects were randomized to either drug for inhaled anesthetic induction. Each was adjusted to their 1 MAC value (0.9% for halothane and 2.5% for sevoflurane) and a blinded anesthesia provider held the facemask without performing manual airway opening maneuvers but with inclusion of an oral airway device. Inspiratory flows were measured during partial upper airway obstruction created by an adjustable negative pressure-generating vacuum motor inserted into the anesthesia circuit. Critical closing pressure of the pharynx (Pcrit) was obtained by plotting the peak inspiratory flow of the obstructed breaths against the corresponding negative pressure in the facemask and extrapolating to zero airflow using linear correlation. Fourteen children were enrolled, seven in each anesthetic group. Two children in the halothane group did not develop flow-limited airway obstruction despite negative pressures as low as -9 cm H2O. Pcrit for sevoflurane ranged from -6.7 to -11.6 (mean +/- sd, -9.8 +/- 1.9) cm H2O. Pcrit for halothane ranged from -8.1 to -33 (mean +/- sd, -19.4 +/- 9.3) cm H2O (sevoflurane versus halothane, P = 0.048). We conclude that when using dynamic application of negative airway pressure, halothane appears to cause less upper airway obstruction than sevoflurane at equipotent concentrations.

Comparison of direct and video-assisted views of the larynx during routine intubation.

OBJECTIVE: To compare the direct and indirect (video monitor) views of the glottic opening using a new Macintosh blade that is modified to provide a video image of airway structures during laryngoscopy. DESIGN: Prospective multicenter trial. SETTING: 11 university-affiliated hospitals. PATIENTS: 867 adults undergoing elective surgery requiring general anesthesia and tracheal intubation. INTERVENTIONS: Patients received general anesthesia and were paralyzed. Direct laryngoscopy was supervised by one of the investigators at each institution. The best possible view was obtained with a Macintosh video laryngoscope during direct vision using standard techniques such as external laryngeal manipulation and backward, upward, and rightward pressure, if necessary. The laryngoscopist then looked at the video monitor and performed any necessary maneuvers to obtain the best view on the video monitor. Thus, 2 assessments were made during the same laryngoscopy (direct naked-eye view vs video monitor view). Tracheal intubation was then performed using the monitor view. Glottic views were rated according to the Cormack-Lehane scoring system, as modified by Yentis and Lee. A questionnaire was completed for each patient. MEASUREMENTS AND MAIN RESULTS: Data from 865 patients were suitable for analysis. Visualization was considered easy (Cormack-Lehane score<3) in 737 patients and difficult (Cormack-Lehane score=3 or 4) in 21 for both direct and video-assisted views. In 7 patients, the view was considered easy during direct visualization yet difficult on the video monitor view. On the other hand, the view was considered difficult in 100 patients during direct visualization yet easy on the video monitor view (P<0.001). CONCLUSIONS: Video-assisted laryngoscopy provides an improved view of the larynx, as compared with direct visualization. This technique may be useful for cases of difficult intubation and reintubation as well as for teaching laryngoscopy and intubation.