Beyond Ether Day: Betsey Magoun, The Forgotten Patient.

Although the analgesic effects of ether were conclusively established during a series of public demonstrations of anesthesia at Massachusetts General Hospital in 1846, ether anesthesia was neither immediately nor universally introduced into practice. Betsey Magoun, the fourth patient undergoing surgery under anesthesia at the hospital, suffered life-threatening hypoxia and respiratory complications. Severe intraoperative problems witnessed by large audience may have contributed to the cautious introduction of anesthesia into routine practice. Ether inhalation was not commonly used until more effective methods of induction and maintenance of anesthesia were discovered.

How to optimize the perioperative care of patients with orphan diseases: what the anesthesiologist needs to know.

PURPOSE OF REVIEW: Despite a very low individual prevalence, rare or orphan diseases are estimated to collectively affect as much as 6-8% of the general population. These diseases provide a challenge to anesthetic delivery because of the lack of evidence to guide optimal management. RECENT FINDINGS: The expansion of information technology has made facts about individual orphan diseases easier to find. Several reputable websites, hosted variously by anesthetic societies, rare disease organizations, and government agencies, provide information about rare diseases and anesthetic management. SUMMARY: Improved access to resources of knowledge may allow for more informed anesthetic management of orphan diseases. The combination of a thorough review of existing knowledge about individual diseases and a structured anesthetic assessment may assist in the delivery of well tolerated anesthetic care of rare conditions.

Ether Day Revisited: The Surgical Records of Edward Gilbert Abbott.

Background: The details of the public demonstration of the effects of ether that initiated the modern era of surgery and anesthesia are often misreported. Existing published transcripts of the clinical records are incomplete or inaccurate. Methods: The patient notes of Gilbert Abbott were photographed, transcribed, and reviewed. Results: The records are handwritten in "Surgical Records for 1846; Volume 30," of the Massachusetts General Hospital. The patient was admitted on September 25. The presenting condition was a congenital, mobile, compressible, multilobed, small lesion at the angle of the left mandible, and base of tongue. The operation on October 16 was an attempted ligation of the blood supply to the lesion. The postoperative diagnosis was a vascular lesion ("erectile tumor"). Postoperative management included application of sclerosants. The mass was unchanged in size on discharge on December 7. There is no documentation of the anesthetic administration in the progress note but a retrospective report of the anesthetic is pasted into the Records book. This account reported that the patient did not respond to the initial incision. He moved and cried out during the latter part of the procedure. Although he was aware of the operation taking place, he later said he had not experienced pain. The commentary concluded that the demonstration of the analgesic effectiveness of ether was inconclusive but that subsequently ether was shown to be effective. Conclusions: The surgery on October 16, an unsuccessful ligation of a congenital lymphovascular malformation, was performed under incomplete general anesthesia. Examination of the primary documents may allow for more accurate accounts of circumstances surrounding the discovery of anesthesia.

Surgical, Obstetric, and Anesthetic Mortality Measurement at a Ugandan Secondary Referral Hospital.

BACKGROUND: The health care systems of low-income countries have severely limited capacity to treat surgical diseases and conditions. There is limited information about which hospital mortality outcomes are suitable metrics in these settings. METHODS: We did a 1-year observational cohort study of patient admissions to the Surgery and the Obstetrics and Gynecology departments and of newborns delivered at a Ugandan secondary referral hospital. We examined the proportion of deaths captured by standardized metrics of mortality. RESULTS: There were 17,015 admissions and 9612 deliveries. A total of 847 deaths were documented: 385 (45.5%) admission deaths and 462 (54.5%) perinatal deaths. Less than one-third of admission deaths occurred during or after an operation (n = 126/385, 32.7%). Trauma and maternal mortality combined with perioperative mortality produced 79.2% (n = 305/385) of admission deaths. Of 462 perinatal deaths, 412 (90.1%) were stillborn, and 50 (10.9%) were early neonatal deaths. The combined metrics of the trauma mortality rate, maternal mortality ratio, thirty-day perioperative mortality rate, and perinatal mortality rate captured 89.8% (n = 761/847) of all deaths documented at the hospital. CONCLUSIONS: The combination of perinatal, maternal, trauma, and perioperative mortality metrics captured most deaths documented at a Ugandan referral hospital.

Mathematical modeling and digital design of an intensified filtration-washing-drying unit for pharmaceutical continuous manufacturing.

This paper introduces a comprehensive mathematical model of a novel integrated filter-dryer carousel system, designed for continuously filtering, washing and drying a slurry stream into a crystals cake. The digital twin includes models for dead-end filtration, cake washing and convective cake drying, based on dynamic multi-component mass, energy and momentum balances. For set of feed conditions and control inputs, the model allows tracking the solvents and impurities content in the cake (critical quality attributes, CQAs) throughout the whole process. The model parameters were identified for the isolation of paracetamol from a multi-component slurry, containing a non-volatile impurity. The calibrated model was used for identifying the probabilistic design space and maximum throughput for the process, expressing the combinations of the carousel feed conditions and control inputs for which the probability of meeting the target CQAs is acceptable.

Understanding API Static Drying with Hot Gas Flow: Design and Test of a Drying Rig Prototype and Drying Modeling Development.

Developing a continuous isolation process to produce a pure, dry, free-flowing active pharmaceutical ingredient (API) is the final barrier to the implementation of continuous end-to-end pharmaceutical manufacturing. Recent work has led to the development of continuous filtration and washing prototypes for pharmaceutical process development and small-scale manufacture. Here, we address the challenge of static drying of a solvent-wet crystalline API in a fixed bed to facilitate the design of a continuous filter dryer for pharmaceutical development, without excessive particle breakage or the formation of interparticle bridges leading to lump formation. We demonstrate the feasibility of drying small batches on a time scale suitable for continuous manufacturing, complemented by the development of a drying model that provides a design tool for process development. We also evaluate the impact of alternative washing and drying approaches on particle agglomeration. We conclude that our approach yields effective technology, with a performance that is amenable to predictive modeling.

Outcome Measurement at a Ugandan Referral Hospital: Validation of the Mbarara Surgical Services Quality Assurance Database.

BACKGROUND: Five billion people lack access to surgery. Accurate and complete data have been identified as essential to the global scale-up of perioperative care. This study retrospectively validates the Mbarara Surgical Services Quality Assurance Database (SQUAD), an electronic outcomes database at a Ugandan secondary referral hospital. METHODS: SQUAD data were compared to paper records from August 2013 to January 2017. To assess data entry accuracy, two researchers independently extracted 24 patient variables from 170 charts. To assess completeness of patient capture, SQUAD entries were compared to a sample of charts returned to the Medical Records Department, and to a sample of entries in ward and operating room logbooks. Two-tailed binomial proportions with 95% CI were calculated from the comparative results of patient observations, against a predefined accuracy of 0.85-0.95. RESULTS: Agreement between completed validation observations from charts and SQUAD data was 91.5% (n = 3734/4080 data points). Binomial tests indicated that 15 variables had higher than 95% accuracy. A total 19 of 24 variables had ≥ 85% accuracy. The completeness of SQUAD patient capture was 98.2% (n = 167/170) of charts returned to the Medical Records Department, 97.5% (n = 198/203) of operating logbook entries, and 100% (n = 111/111) of ward logbook entries, respectively. CONCLUSION: SQUAD closely reflects the primary surgical and anaesthetic data at a Ugandan secondary hospital. Data accuracy of key variables and completeness of population capture were comparable to those of databases in high-income countries and outperformed those of other low- and middle-income countries.

End-to-end continuous manufacturing of conventional compressed tablets: From flow synthesis to tableting through integrated crystallization and filtration.

An end-to-end continuous pharmaceutical manufacturing process was developed for the production of conventional direct compressed tablets on a proof-of-concept level for the first time. The output reaction mixture of the flow synthesis of acetylsalicylic acid was crystallized continuously in a mixed suspension mixed product removal crystallizer. The crystallizer was directly connected to a continuous filtration carousel device, thus the crystallization, filtration and drying of acetylsalicylic acid (ASA) was carried out in an integrated 2-step process. Steady state was reached during longer operations and the interaction of process parameters was evaluated in a series of experiments. The filtered crystals were ready for further processing in a following continuous blending and tableting experiment due to the good flowability of the material. The ASA collected during the crystallization-filtration experiments was fed into a continuous twin-screw blender along with microcrystalline cellulose as tableting excipient. After continuous blending Near-Infrared spectroscopy was applied to in-line analyze the drug content of the powder mixture. A belt conveyor carried the mixture towards an eccentric lab-scale tablet press, which continuously produced 500 mg ASA-loaded compressed tablets of 100 mg dose strength. Thus, starting from raw materials, the final drug product was obtained by continuous manufacturing steps with appropriate quality.

Developing a Batch Isolation Procedure and Running It in an Automated Semicontinuous Unit: AWL CFD25 Case Study.

A key challenge during the transition from laboratory/small batch to continuous manufacturing is the development of a process strategy that can easily be adopted for a larger batch/continuous process. Industrial practice is to develop the isolation strategy for a new drug/process in batch using the design of experiment (DoE) approach to determine the best isolation conditions and then transfer the isolation parameters selected to a large batch equipment/continuous isolation process. This stage requires a series of extra investigations to evaluate the effect of different equipment geometry or even the adaptation of the parameters selected to a different isolation mechanism (e.g., from dead end to cross flow filtration) with a consequent increase of R&D cost and time along with an increase in material consumption. The CFD25 is an isolation device used in the first instance to develop an isolation strategy in batch (optimization mode) using a screening DoE approach and to then verify the transferability of the strategy to a semicontinuous process (production mode). A d-optimal screening DoE was used to determine the effect of varying the input slurry. Properties such as solid loading, particle size distribution, and crystallization solvent were investigated to determine their impact on the filtration and washing performance and the characteristics of the dry isolated product. A series of crystallization (ethanol, isopropanol, and 3-methylbutan-1-ol) and wash solvents (n-heptane, isopropyl acetate and n-dodcane) were used for the process. To mimic a real isolation process, paracetamol-related impurities, acetanilide and metacetamol, were dissolved in the mother liquor. The selected batch isolation strategy was used for the semicontinuous isolation run. Throughput and filtration parameters, such as cake resistance and flow rate, cake residual liquid content and composition, cake purity, particle-particle aggregation, and extent and strength of agglomerates, were measured to evaluate the consistency of the isolated product produced during a continuous experiment and compared with the isolated product properties obtained during the batch process development. Overall, the CFD25 is a versatile tool which allows both new chemical entity process development in batch and the production of the active pharmaceutical ingredient in semicontinuous mode using the same process parameters without changing equipment. The isolated product properties gained during the semicontinuous run are overall comparable between samples. The residual solvent content and composition differs between some samples due to filter plate blockage. In general, the mean properties obtained during semicontinuous running are comparable with the product properties simulated using the DoE.

The evolution of pediatric sedation and anesthesia patient safety: An interview with Dr Charles J. "Charlie" Coté.

The career of Dr Charles J. Coté covered a period of major advances in pediatric anesthesia patient safety. Dr Coté (1946 --), Professor Emeritus in Anaesthesia at Harvard Medical School, helped develop pediatric sedation guidelines, conducted influential clinical research, edited a major textbook, and promoted pediatric anesthesia training fellowships in low- and middle-income countries. Based on a series of interviews with Dr Coté, this article reviews the career of this Robert M. Smith Award winner through the lens of improvements in pediatric sedation and anesthesia patient safety.

Development of a Novel Continuous Filtration Unit for Pharmaceutical Process Development and Manufacturing.

The lack of a commercial laboratory, pilot and small manufacturing scale dead end continuous filtration and drying unit it is a significant gap in the development of continuous pharmaceutical manufacturing processes for new active pharmaceutical ingredients (APIs). To move small-scale pharmaceutical isolation forward from traditional batch Nutsche filtration to continuous processing a continuous filter dryer prototype unit (CFD20) was developed in collaboration with Alconbury Weston Ltd. The performance of the prototype was evaluated by comparison with manual best practice exemplified using a modified Biotage VacMaster unit to gather data and process understanding for API filtration and washing. The ultimate objective was to link the chemical and physical attributes of an API slurry with equipment and processing parameters to improve API isolation processes. Filtration performance was characterized by assessing filtrate flow rate by application of Darcy's law, the impact on product crystal size distribution and product purity were investigated using classical analytical methods. The overall performance of the 2 units was similar, showing that the prototype CFD20 can match best manual lab practice for filtration and washing while allowing continuous processing and real-time data logging. This result is encouraging and the data gathered provides further insight to inform the development of CFD20.

Half a century of anesthesia for children: An interview with Dr. Nishan G. 'Nick' Goudsouzian.

The career of Dr Nishan Goudsouzian spanned half a century of pediatric anesthesia. His 50 years saw seminal contributions to the use of neuromuscular blocking agents in children, the development of proton beam therapy and magnetic resonance imaging for pediatric cancer, the introduction of the laryngeal mask airway, an explosion in the volume and depth of knowledge about pediatric anesthesia, the expansion of formal training in pediatric anesthesia, and the widening of academic efforts to improve anesthetic care for children worldwide. Based on interviews with Dr Goudsouzian, this article reviews the contributions of this Robert M. Smith Award winner to the development of pediatric anesthesia.

Age-Dependent Changes in the Propofol-Induced Electroencephalogram in Children With Autism Spectrum Disorder.

Patients with autism spectrum disorder (ASD) often require sedation or general anesthesia. ASD is thought to arise from deficits in GABAergic signaling leading to abnormal neurodevelopment. We sought to investigate differences in how ASD patients respond to the GABAergic drug propofol by comparing the propofol-induced electroencephalogram (EEG) of ASD and neurotypical (NT) patients. This investigation was a prospective observational study. Continuous 4-channel frontal EEG was recorded during routine anesthetic care of patients undergoing endoscopic procedures between July 1, 2014 and May 1, 2016. Study patients were defined as those with previously diagnosed ASD by DSM-V criteria, aged 2-30 years old. NT patients were defined as those lacking neurological or psychiatric abnormalities, aged 2-30 years old. The primary outcome was changes in propofol-induced alpha (8-13 Hz) and slow (0.1-1 Hz) oscillation power by age. A post hoc analysis was performed to characterize incidence of burst suppression during propofol anesthesia. The primary risk factor of interest was a prior diagnosis of ASD. Outcomes were compared between ASD and NT patients using Bayesian methods. Compared to NT patients, slow oscillation power was initially higher in ASD patients (17.05 vs. 14.20 dB at 2.33 years), but progressively declined with age (11.56 vs. 13.95 dB at 22.5 years). Frontal alpha power was initially lower in ASD patients (17.65 vs. 18.86 dB at 5.42 years) and continued to decline with age (6.37 vs. 11.89 dB at 22.5 years). The incidence of burst suppression was significantly higher in ASD vs. NT patients (23.0% vs. 12.2%, p < 0.01) despite reduced total propofol dosing in ASD patients. Ultimately, we found that ASD patients respond differently to propofol compared to NT patients. A similar pattern of decreased alpha power and increased sensitivity to burst suppression develops in older NT adults; one interpretation of our data could be that ASD patients undergo a form of accelerated neuronal aging in adolescence. Our results suggest that investigations of the propofol-induced EEG in ASD patients may enable insights into the underlying differences in neural circuitry of ASD and yield safer practices for managing patients with ASD.

Validation of an Electronic Surgical Outcomes Database at Mbarara Regional Referral Hospital, Uganda.

BACKGROUND: Accurate, complete and sustainable methods of tracking patients and outcomes in low-resource settings are imperative as we launch efforts to improve surgical care globally. The Surgical services QUality Assessment Database (SQUAD) at the Mbarara Regional Referral Hospital in Uganda is one of very few electronic surgical databases in a low-resource setting. We evaluated the completeness and accuracy of SQUAD. METHODS: Data were prospectively collected on 20 of the most clinically relevant variables captured by SQUAD for all general surgery patients admitted to MRRH over a two-week period. Patients were followed until discharge, death or hospital day 30; whichever occurred first. These data were compared to that in SQUAD for the same time period for completeness and accuracy. RESULTS: Of 186 unique patients seen over the two-week period, 172 (92.5%) were captured by SQUAD. The capture rate was greater than 86% for each of the 20 variables evaluated, except American Society of Anesthesiologists score, which had a 69% capture rate. Regarding accuracy, there was almost perfect agreement for 16/20 variables (all k > 0.81), substantial agreement for 2/20 variables (k 0.63, 0.73) and moderate agreement for the remaining 2/20 variables (k 0.43, 0.48) between SQUAD and the prospectively collected data. CONCLUSION: SQUAD is an electronic surgical database that has been implemented and sustained in a low-resource setting. For the 20 variables evaluated, the data within SQUAD are highly complete and accurate. This database may serve as a model for the development of additional surgical databases in low-resource environments.

Brief surgical procedure code lists for outcomes measurement and quality improvement in resource-limited settings.

BACKGROUND: The lack of a classification system for surgical procedures in resource-limited settings hinders outcomes measurement and reporting. Existing procedure coding systems are prohibitively large and expensive to implement. We describe the creation and prospective validation of 3 brief procedure code lists applicable in low-resource settings, based on analysis of surgical procedures performed at Mbarara Regional Referral Hospital, Uganda's second largest public hospital. METHODS: We reviewed operating room logbooks to identify all surgical operations performed at Mbarara Regional Referral Hospital during 2014. Based on the documented indication for surgery and procedure(s) performed, we assigned each operation up to 4 procedure codes from the International Classification of Diseases, 9th Revision, Clinical Modification. Coding of procedures was performed by 2 investigators, and a random 20% of procedures were coded by both investigators. These codes were aggregated to generate procedure code lists. RESULTS: During 2014, 6,464 surgical procedures were performed at Mbarara Regional Referral Hospital, to which we assigned 435 unique procedure codes. Substantial inter-rater reliability was achieved (κ = 0.7037). The 111 most common procedure codes accounted for 90% of all codes assigned, 180 accounted for 95%, and 278 accounted for 98%. We considered these sets of codes as 3 procedure code lists. In a prospective validation, we found that these lists described 83.2%, 89.2%, and 92.6% of surgical procedures performed at Mbarara Regional Referral Hospital during August to September of 2015, respectively. CONCLUSION: Empirically generated brief procedure code lists based on International Classification of Diseases, 9th Revision, Clinical Modification can be used to classify almost all surgical procedures performed at a Ugandan referral hospital. Such a standardized procedure coding system may enable better surgical data collection for administration, research, and quality improvement in resource-limited settings.

A Prospective Study of Age-dependent Changes in Propofol-induced Electroencephalogram Oscillations in Children.

BACKGROUND: In adults, frontal electroencephalogram patterns observed during propofol-induced unconsciousness consist of slow oscillations (0.1 to 1 Hz) and coherent alpha oscillations (8 to 13 Hz). Given that the nervous system undergoes significant changes during development, anesthesia-induced electroencephalogram oscillations in children may differ from those observed in adults. Therefore, we investigated age-related changes in frontal electroencephalogram power spectra and coherence during propofol-induced unconsciousness. METHODS: We analyzed electroencephalogram data recorded during propofol-induced unconsciousness in patients between 0 and 21 yr of age (n = 97), using multitaper spectral and coherence methods. We characterized power and coherence as a function of age using multiple linear regression analysis and within four age groups: 4 months to 1 yr old (n = 4), greater than 1 to 7 yr old (n = 16), greater than 7 to 14 yr old (n = 30), and greater than 14 to 21 yr old (n = 47). RESULTS: Total electroencephalogram power (0.1 to 40 Hz) peaked at approximately 8 yr old and subsequently declined with increasing age. For patients greater than 1 yr old, the propofol-induced electroencephalogram structure was qualitatively similar regardless of age, featuring slow and coherent alpha oscillations. For patients under 1 yr of age, frontal alpha oscillations were not coherent. CONCLUSIONS: Neurodevelopmental processes that occur throughout childhood, including thalamocortical development, may underlie age-dependent changes in electroencephalogram power and coherence during anesthesia. These age-dependent anesthesia-induced electroencephalogram oscillations suggest a more principled approach to monitoring brain states in pediatric patients.