Publications by authors named "Brian J Anderson"

243 Publications

Incidence of post-induction hypoxemia in children and the effect of induction gas composition.

Paediatr Anaesth 2021 Feb 22. Epub 2021 Feb 22.

Department of Anaesthesiology, University of Auckland, Auckland, New Zealand.

Background: Pediatric preoxygenation and inhalation induction of anesthesia can include a mixture of gases. In children, the clinical impact on oxygenation while using other gases with oxygen during an inhalation induction is unknown.

Aim: We aimed to determine the impact of oxygen, nitrous oxide, and air concentrations added to the volatile agent by recording the incidence of hypoxemia following an inhalation gaseous induction in children.

Method: Records from an Automated Information Management System were used to find the incidence of hypoxemia following an inhalation induction of anesthesia. Episodes of hypoxemia (SaO < 90% sustained for at least 120 seconds) were recorded in the 10 minutes after the three-minute induction period. Nitrous oxide and oxygen concentrations were recorded and nitrogen concentration was deduced. We also considered patient sex, age and ASA status as covariates.

Results: A total of 27,258 cases were included in the analysis. The overall incidence of hypoxemia following an inhalation induction of anesthesia was 5.08% (95% CI 4.83 5.35). Hypoxemia was more common in younger patients and those with higher ASA scores. Controlling for those factors and sex, the incidence of hypoxemia increased 1.2 fold when inspired oxygen concentration was less than 60% and hypoxemia was 2.37 times greater than the overall incidence when the inspired oxygen concentration was less than 40%. There was no clear effect of different concentrations of nitrous oxide or nitrogen when those were factored into the model.

Conclusion: The risk of hypoxemia following an inhalation induction of anesthesia in children is minimised when the inspired concentration of oxygen is greater than 60%.
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http://dx.doi.org/10.1111/pan.14161DOI Listing
February 2021

Characteristics, Outcomes, and Trends of Patients With COVID-19-Related Critical Illness at a Learning Health System in the United States.

Ann Intern Med 2021 Jan 19. Epub 2021 Jan 19.

University of Pennsylvania Health System, Philadelphia, Pennsylvania (G.L.A., J.J., M.O.H., J.H.A., J.B., C.B., P.J.B., C.L.C., L.M.C., M.F.C., J.M.C., J.D.C., T.C., K.R.C., B.D.F., E.G., J.C.G., S.G., A.H., C.W.H., M.H., P.K., Z.N.K., G.B.K., M.L., N.D.M., M.E.M., D.N., J.L.P., M.B.P., S.C.P., Z.A.Q., J.P.R., J.S., W.D.S., M.J.S., M.G.S., C.P.S., J.K.W., W.W., A.A.W., B.J.A., J.T.G.).

Background: The coronavirus disease 2019 (COVID-19) pandemic continues to surge in the United States and globally.

Objective: To describe the epidemiology of COVID-19-related critical illness, including trends in outcomes and care delivery.

Design: Single-health system, multihospital retrospective cohort study.

Setting: 5 hospitals within the University of Pennsylvania Health System.

Patients: Adults with COVID-19-related critical illness who were admitted to an intensive care unit (ICU) with acute respiratory failure or shock during the initial surge of the pandemic.

Measurements: The primary exposure for outcomes and care delivery trend analyses was longitudinal time during the pandemic. The primary outcome was all-cause 28-day in-hospital mortality. Secondary outcomes were all-cause death at any time, receipt of mechanical ventilation (MV), and readmissions.

Results: Among 468 patients with COVID-19-related critical illness, 319 (68.2%) were treated with MV and 121 (25.9%) with vasopressors. Outcomes were notable for an all-cause 28-day in-hospital mortality rate of 29.9%, a median ICU stay of 8 days (interquartile range [IQR], 3 to 17 days), a median hospital stay of 13 days (IQR, 7 to 25 days), and an all-cause 30-day readmission rate (among nonhospice survivors) of 10.8%. Mortality decreased over time, from 43.5% (95% CI, 31.3% to 53.8%) to 19.2% (CI, 11.6% to 26.7%) between the first and last 15-day periods in the core adjusted model, whereas patient acuity and other factors did not change.

Limitation: Single-health system study; use of, or highly dynamic trends in, other clinical interventions were not evaluated, nor were complications.

Conclusion: Among patients with COVID-19-related critical illness admitted to ICUs of a learning health system in the United States, mortality seemed to decrease over time despite stable patient characteristics. Further studies are necessary to confirm this result and to investigate causal mechanisms.

Primary Funding Source: Agency for Healthcare Research and Quality.
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http://dx.doi.org/10.7326/M20-5327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901669PMC
January 2021

Dose estimation for bivalirudin during pediatric cardiopulmonary bypass.

Paediatr Anaesth 2021 Jan 10. Epub 2021 Jan 10.

Department of Anaesthesiology, University of Auckland, Auckland, New Zealand.

Aim: A typical adult-based bivalirudin regimen during cardiopulmonary bypass uses a loading dose of 1 mg kg and a circuit prime (volume L × 13 mg) with a subsequent intravenous infusion 2.5 mg h  kg . Dose in children remains unknown. We wished to determine a practical bivalirudin dosing schedule for children undergoing surgery with cardiopulmonary bypass.

Methods: Published pharmacokinetic parameters in children who were anticoagulated for cardiac catheterization using bivalirudin were compared to adult by scaling for size using allometry. An infusion regimen suitable for children was determined using a bivalirudin target concentration (13 mg L ) common in adults for effect during cardiopulmonary bypass. Predicted bivalirudin infusion rates in children were compared to regimens published as case reports.

Results: Current pediatric bivalirudin infusion rates are based on those used in adults with titration during cardiopulmonary bypass to achieve activated clotting times longer than 400 s. Bivalirudin clearance (mL min  kg ) can be estimated in children by scaling adult parameters using allometry. Clearance decreases through childhood and higher infusion rates in children would achieve target concentration rapidly without the need to titrate initial infusion rate. An infusion rate of 4.5 mg h  kg in a 10 kg infant, 4 mg h  kg in a 20 kg child and 3.5 mg h  kg in a child 30-40 kg will target an activated clotting time slower than 400 s. Adult regimens could be used in those children heavier than 50 kg.

Conclusion: Bivalirudin infusion in children should be started after loading dose at rates greater than those used in adults. Dose in neonates remains uncertain because neither pharmacokinetics nor coagulation pharmacodynamics have been adequately characterized.
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http://dx.doi.org/10.1111/pan.14125DOI Listing
January 2021

Benchmarking Critical Care Well-Being: Before and After the Coronavirus Disease 2019 Pandemic.

Crit Care Explor 2020 Oct 21;2(10):e0233. Epub 2020 Oct 21.

Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.

Objectives: Examine well-being, measured as burnout and professional fulfillment, across critical care healthcare professionals, ICUs, and hospitals within a health system; examine the impact of the coronavirus disease 2019 pandemic.

Design: To complement a longitudinal survey administered to medical critical care physicians at the end of an ICU rotation, which began in May 2018, we conducted a cross-sectional survey among critical care professionals across four hospitals in December 2018 to January 2019. We report the results of the cross-sectional survey and, to examine the impact of the coronavirus disease 2019 pandemic, the longitudinal survey results from July 2019 to May 2020.

Setting: Academic medical center.

Subjects: Four-hundred eighty-one critical care professionals, including 353 critical care nurses, 58 advanced practice providers, 57 physicians, and 13 pharmacists, participated in the cross-sectional survey; 15 medical critical care physicians participated in the longitudinal survey through the coronavirus disease 2019 pandemic.

Interventions: None.

Measurements And Main Results: Burnout was present in 50% of ICU clinicians, ranging from 42% for critical care physicians to 55% for advanced practice providers. Professional fulfillment was less common at 37%, with significant variability across provider ( = 0.04), with a low of 23% among critical care pharmacists and a high of 53% among physicians. Well-being varied significantly at the hospital and ICU level. Workload and job demand were identified as drivers of burnout and meaning in work, culture and values of work community, control and flexibility, and social support and community at work were each identified as drivers of well-being. Between July 2019 and March 2020, burnout and professional fulfillment were present in 35% (15/43) and 58% (25/43) of medical critical care physician responses, respectively. In comparison, during the coronavirus disease 2019 pandemic, burnout and professional fulfillment were present in 57% (12/21) and 38% (8/21), respectively.

Conclusions: Burnout was common across roles, yet differed across ICUs and hospitals. Professional fulfillment varied by provider role. We identified potentially modifiable factors related to clinician well-being that can inform organizational strategies at the ICU and hospital level. Longitudinal studies, designed to assess the long-term impact of the coronavirus disease 2019 pandemic on the well-being of the critical care workforce, are urgently needed.
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http://dx.doi.org/10.1097/CCE.0000000000000233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7587602PMC
October 2020

A Universal Pharmacokinetic Model for Dexmedetomidine in Children and Adults.

J Clin Med 2020 Oct 28;9(11). Epub 2020 Oct 28.

Department of Anaesthesiology, University of Auckland, Park Road, Auckland 1023, New Zealand.

A universal pharmacokinetic model was developed from pooled paediatric and adult data (40.6 postmenstrual weeks, 70.8 years, 3.1-152 kg). A three-compartment pharmacokinetic model with first-order elimination was superior to a two-compartment model to describe these pooled dexmedetomidine data. Population parameter estimates (population parameter variability%) were clearance (CL) 0.9 L/min/70 kg (36); intercompartmental clearances (Q2) 1.68 L/min/70 kg (63); Q3 0.62 L/min/70 kg (90); volume of distribution in the central compartment (V1) 25.2 L/70 kg (103.9); rapidly equilibrating peripheral compartment (V2) 34.4 L/70 kg (41.8); slow equilibrating peripheral compartment (V3) 65.4 L/70 kg (62). Obesity was best described by fat-free mass for clearances and normal fat mass for volumes with a factor for fat mass (FfatV) of 0.293. Models describing dexmedetomidine pharmacokinetics in adults can be applied to children by accounting for size (allometry) and age (maturation). This universal dexmedetomidine model is applicable to a broad range of ages and weights: neonates through to obese adults. Lean body weight is a better size descriptor for dexmedetomidine clearance than total body weight. This parameter set could be programmed into target-controlled infusion pumps for use in a broad population.
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http://dx.doi.org/10.3390/jcm9113480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692360PMC
October 2020

Prediction Models for Physical, Cognitive, and Mental Health Impairments After Critical Illness: A Systematic Review and Critical Appraisal.

Crit Care Med 2020 Dec;48(12):1871-1880

1Department of Physiotherapy, Western Health, Sunshine Hospital, Melbourne, VIC, Australia. 2The University of Melbourne, Melbourne, VIC, Australia. 3Glasgow Royal Infirmary, NHS Greater Glasgow and Clyde, Scotland, United Kingdom. 4THIS Institute, University of Cambridge, Cambridge, United Kingdom. 5School of Medicine, Dentistry and Nursing, University of Glasgow, Scotland, United Kingdom. 6Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. 7Division of Pulmonary, Allergy, and Critical Care Medicine, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA. 8Society of Critical Care Medicine, Chicago, IL. 9Division of Pulmonary, Critical Care, and Sleep Medicine, The Ohio State University Wexner Medical Center, Columbus, OH. 10Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT. 11Department of Psychology and Neuroscience Center, Brigham Young University, Provo, UT. 12Pulmonary and Critical Care Medicine, Intermountain Medical Center, Murray, UT. 13Center for Humanizing Critical Care, Intermountain Health Care, Murray, UT. 14Division of Pulmonary and Critical Care Medicine, Oregon Health & Science University, Portland, OR. 15Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN. 16Division of Pulmonary, Critical Care and Sleep Medicine, University of Kentucky, Lexington, KY. 17Pulmonary and Critical Care Medicine, and Physical Medicine and Rehabilitation, Johns Hopkins University, Baltimore, MD. 18Vanderbilt University School of Medicine, Nashville, TN. 19Independent Information Specialist, Ottawa, ON, Canada. 20Emory University Hospital (Emory Healthcare), Atlanta, GA. 21Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands. 22Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology & Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom. 23Department of Biostatistics, Epidemiology and Informatics, and Palliative and Advanced Illness Research (PAIR) Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Objectives: Improved ability to predict impairments after critical illness could guide clinical decision-making, inform trial enrollment, and facilitate comprehensive patient recovery. A systematic review of the literature was conducted to investigate whether physical, cognitive, and mental health impairments could be predicted in adult survivors of critical illness.

Data Sources: A systematic search of PubMed and the Cochrane Library (Prospective Register of Systematic Reviews ID: CRD42018117255) was undertaken on December 8, 2018, and the final searches updated on January 20, 2019.

Study Selection: Four independent reviewers assessed titles and abstracts against study eligibility criteria. Studies were eligible if a prediction model was developed, validated, or updated for impairments after critical illness in adult patients. Discrepancies were resolved by consensus or an independent adjudicator.

Data Extraction: Data on study characteristics, timing of outcome measurement, candidate predictors, and analytic strategies used were extracted. Risk of bias was assessed using the Prediction model Risk Of Bias Assessment Tool.

Data Synthesis: Of 8,549 screened studies, three studies met inclusion. All three studies focused on the development of a prediction model to predict (1) a mental health composite outcome at 3 months post discharge, (2) return-to-pre-ICU functioning and residence at 6 months post discharge, and (3) physical function 2 months post discharge. Only one model had been externally validated. All studies had a high risk of bias, primarily due to the sample size, and statistical methods used to develop and select the predictors for the prediction published model.

Conclusions: We only found three studies that developed a prediction model of any post-ICU impairment. There are several opportunities for improvement for future prediction model development, including the use of standardized outcomes and time horizons, and improved study design and statistical methodology.
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http://dx.doi.org/10.1097/CCM.0000000000004659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673641PMC
December 2020

Society of Critical Care Medicine's International Consensus Conference on Prediction and Identification of Long-Term Impairments After Critical Illness.

Crit Care Med 2020 Nov;48(11):1670-1679

Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN.

Background: After critical illness, new or worsening impairments in physical, cognitive, and/or mental health function are common among patients who have survived. Who should be screened for long-term impairments, what tools to use, and when remain unclear.

Objectives: Provide pragmatic recommendations to clinicians caring for adult survivors of critical illness related to screening for postdischarge impairments.

Participants: Thirty-one international experts in risk-stratification and assessment of survivors of critical illness, including practitioners involved in the Society of Critical Care Medicine's Thrive Post-ICU Collaboratives, survivors of critical illness, and clinical researchers.

Design: Society of Critical Care Medicine consensus conference on post-intensive care syndrome prediction and assessment, held in Dallas, in May 2019. A systematic search of PubMed and the Cochrane Library was conducted in 2018 and updated in 2019 to complete an original systematic review and to identify pre-existing systematic reviews.

Meeting Outcomes: We concluded that existing tools are insufficient to reliably predict post-intensive care syndrome. We identified factors before (e.g., frailty, preexisting functional impairments), during (e.g., duration of delirium, sepsis, acute respiratory distress syndrome), and after (e.g., early symptoms of anxiety, depression, or post-traumatic stress disorder) critical illness that can be used to identify patients at high-risk for cognitive, mental health, and physical impairments after critical illness in whom screening is recommended. We recommend serial assessments, beginning within 2-4 weeks of hospital discharge, using the following screening tools: Montreal Cognitive Assessment test; Hospital Anxiety and Depression Scale; Impact of Event Scale-Revised (post-traumatic stress disorder); 6-minute walk; and/or the EuroQol-5D-5L, a health-related quality of life measure (physical function).

Conclusions: Beginning with an assessment of a patient's pre-ICU functional abilities at ICU admission, clinicians have a care coordination strategy to identify and manage impairments across the continuum. As hospital discharge approaches, clinicians should use brief, standardized assessments and compare these results to patient's pre-ICU functional abilities ("functional reconciliation"). We recommend serial assessments for post-intensive care syndrome-related problems continue within 2-4 weeks of hospital discharge, be prioritized among high-risk patients, using the identified screening tools to prompt referrals for services and/or more detailed assessments.
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http://dx.doi.org/10.1097/CCM.0000000000004586DOI Listing
November 2020

Bioavailability of oxycodone by mouth in coronary artery bypass surgery patients - a randomized trial.

J Drug Assess 2020 Jul 28;9(1):117-128. Epub 2020 Jul 28.

School of Medicine, University of Eastern Finland, Kuopio, Finland.

Objective: Pain after coronary artery by-pass (CAB) surgery is severe. Analgesic administration by mouth is unreliable until after gastrointestinal function has recovered. We evaluated the bioavailability of oxycodone co-administered with naloxone by mouth in patients after CAB surgery using either a conventional extracorporeal circulation (CECC) or off-pump surgery (OPCAB).

Methods: Twenty-four patients, 50-73 years, 12 with CECC and 12 with OPCAB, were administered a 10/5 mg oxycodone-naloxone controlled-release tablet by mouth on the preoperative day and for the first seven postoperative days (PODs) thereafter. Blood samples were collected up to 24 h after the preoperative administration, and then randomly either on POD1 and POD3 or on POD2 and POD4. The oxycodone concentration in plasma was analyzed using liquid chromatography-mass spectrometry.

Results: On POD1 oxycodone absorption was markedly delayed in five of six patients after CECC and in all six patients after OPCAB surgery; median of t after CECC 630 [range 270-1420] minutes and after OPCAB 1020 [720-1410] minutes, compared to median of 120-315 min preoperatively and on POD2-POD4. The carry-over corrected AUC values on the PODs did not differ from the preoperative values, but were higher on POD3 compared with POD1 in both CECC and OPCAB groups. The rate and extent of oxycodone absorption equaled preoperative values on POD2 and onwards in patients with CAB surgery.

Conclusions: Bioavailability of oxycodone by mouth was similar after CAB surgery CECC or having OPCAB. Data indicate that POD2 is an appropriate time to start oxycodone administration by mouth after CAB surgery.
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http://dx.doi.org/10.1080/21556660.2020.1797753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470105PMC
July 2020

The ABO histo-blood group, endothelial activation, and acute respiratory distress syndrome risk in critical illness.

J Clin Invest 2021 Jan;131(1)

Division of Pulmonary, Allergy, and Critical Care.

BACKGROUNDThe ABO histo-blood group is defined by carbohydrate modifications and is associated with risk for multiple diseases, including acute respiratory distress syndrome (ARDS). We hypothesized that genetically determined blood subtype A1 is associated with increased risk of ARDS and markers of microvascular dysfunction and coagulation.METHODSWe conducted analyses in 3 cohorts of critically ill trauma and sepsis patients (n = 3710) genotyped on genome-wide platforms to determine the association of the A1 blood type genotype with ARDS risk. We subsequently determined whether associations were present in FUT2-defined nonsecretors who lack ABO antigens on epithelium, but not endothelium. In a patient subgroup, we determined the associations of blood type with plasma levels of endothelial glycoproteins and disseminated intravascular coagulation (DIC). Lastly, we tested whether blood type A was associated with less donor lung injury recovery during human ex vivo lung perfusion (EVLP).RESULTSThe A1 genotype was associated with a higher risk of moderate to severe ARDS relative to type O in all 3 populations. In sepsis, this relationship was strongest in nonpulmonary infections. The association persisted in nonsecretors, suggesting a vascular mechanism. The A1 genotype was also associated with higher DIC risk as well as concentrations of thrombomodulin and von Willebrand factor, which in turn were associated with ARDS risk. Blood type A was also associated with less lung injury recovery during EVLP.CONCLUSIONWe identified a replicable association between ABO blood type A1 and risk of ARDS among the critically ill, possibly mediated through microvascular dysfunction and coagulation.FUNDINGNIH HL122075, HL125723, HL137006, HL137915, DK097307, HL115354, HL101779, and the University of Pennsylvania McCabe Fund Fellowship Award.
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http://dx.doi.org/10.1172/JCI139700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773362PMC
January 2021

Dexmedetomidine Sedation in Mechanically Ventilated Critically Ill Children: A Pilot Randomized Controlled Trial.

Pediatr Crit Care Med 2020 09;21(9):e731-e739

Paediatric Intensive Care Unit, Queensland Children's Hospital, Brisbane, QLD, Australia.

Objectives: To assess the feasibility, safety, and efficacy of a sedation protocol using dexmedetomidine as the primary sedative in mechanically ventilated critically ill children.

Design: Open-label, pilot, prospective, multicenter, randomized, controlled trial. The primary outcome was the proportion of sedation scores in the target sedation range in the first 48 hours. Safety outcomes included device removal, adverse events, and vasopressor use. Feasibility outcomes included time to randomization and protocol fidelity.

Setting: Six tertiary PICUs in Australia and New Zealand.

Patients: Critically ill children, younger than 16 years old, requiring intubation and mechanical ventilation and expected to be mechanically ventilated for at least 24 hours.

Interventions: Children randomized to dexmedetomidine received a dexmedetomidine-based algorithm targeted to light sedation (State Behavioral Scale -1 to +1). Children randomized to usual care received sedation as determined by the treating clinician (but not dexmedetomidine), also targeted to light sedation.

Measurements And Main Results: Sedation with dexmedetomidine as the primary sedative resulted in a greater proportion of sedation measurements in the light sedation range (State Behavioral Scale -1 to +1) over the first 48 hours (229/325 [71%] vs 181/331 [58%]; p = 0.04) and the first 24 hours (66/103 [64%] vs 48/116 [41%]; p < 0.001) compared with usual care. Cumulative midazolam dosage was significantly reduced in the dexmedetomidine arm compared with usual care (p = 0.002).There were more episodes of hypotension and bradycardia with dexmedetomidine (including one serious adverse event) but no difference in vasopressor requirements. Median time to randomization after intubation was 6.0 hours (interquartile range, 2.0-9.0 hr) in the dexmedetomidine arm compared with 3.0 hours (interquartile range, 1.0-7.0 hr) in the usual care arm (p = 0.24).

Conclusions: A sedation protocol using dexmedetomidine as the primary sedative was feasible, appeared safe, achieved early, light sedation, and reduced midazolam requirements. The findings of this pilot study justify further studies of sedative agents in critically ill children.
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http://dx.doi.org/10.1097/PCC.0000000000002483DOI Listing
September 2020

The time course of pain after tonsillectomy.

Paediatr Anaesth 2020 09 6;30(9):1051-1053. Epub 2020 Aug 6.

Department of Anaesthesiology, University of Auckland, Auckland, New Zealand.

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http://dx.doi.org/10.1111/pan.13970DOI Listing
September 2020

Postoperative admission to paediatric intensive care after tonsillectomy.

SAGE Open Med 2020 20;8:2050312120922027. Epub 2020 May 20.

Department of Paediatric Otolaryngology, Starship Children's Hospital, Auckland, New Zealand.

Objectives: To review interventions required by children admitted for intensive care management following tonsillectomy or adenotonsillectomy either as elective or unplanned admission in a tertiary children's hospital.

Methods: A retrospective chart review over a 10-year period between April 2007 and March 2017 was performed. Charts were interrogated for treatments that were administered in the paediatric intensive care unit. Respiratory support therapies such as supplemental oxygen administration, high-flow nasal oxygen, positive pressure ventilation, continuous positive airway pressure, airway interventions and tracheal intubation were reviewed.

Results: There were 103 children admitted to the paediatric intensive care unit following tonsillectomy or adenotonsillectomy. The average age was 6.2 years (range 7 months-17 years). The main indications for the procedure were sleep disordered breathing or obstructive sleep apnoea syndrome. In all, 53 children had syndromes with medical comorbidities, 31 were current continuous positive airway pressure users and 5 had a tracheostomy in situ. Forty children admitted to paediatric intensive care unit did not require any high-level care. Ten children who had an unplanned admission had their respiratory interventions started in the theatre or in the post-anaesthetic care unit, before paediatric intensive care unit admission, and did not require escalation of care.

Conclusion: Children may not require admission for intensive care after tonsillectomy if they have had an incident-free period in the post-anaesthetic care unit. Some of those who required high-flow nasal oxygen could have been managed on the ward provided with adequate training and monitoring facilities. The level of care they require in post-anaesthetic care unit reflected the level of care for the immediate postoperative period in the paediatric intensive care unit.
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http://dx.doi.org/10.1177/2050312120922027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7249556PMC
May 2020

Pharmacokinetics of an intravenous bolus dose of clonidine in children undergoing surgery.

Paediatr Anaesth 2020 05 2;30(5):607-613. Epub 2020 Apr 2.

Department of Anaesthesia, The Juliane Marie Centre, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.

Background: Clonidine is used off-label in children but only limited pediatric pharmacokinetic data are available for intravenously administered clonidine.

Objectives: To determine pharmacokinetic parameter estimates of clonidine in healthy children undergoing surgery and to investigate age-related differences. Furthermore, to investigate possible pharmacokinetic differences of clonidine between this group of children and a cohort with cardiac diseases.

Methods: In a randomized placebo-controlled trial (The PREVENT AGITATION trial), blood samples for clonidine pharmacokinetic analysis were collected in a proportion of the enrolled patients. Healthy children with ASA score 1-2 in the age-groups 1 to <2 years and 2-5 years were randomized for blood sampling. Clonidine was administered as a single intravenous bolus of 3 µg/kg intraoperatively. Blood samples were drawn at baseline, 5, 10, 15, 30, 60 minutes after dosing and additionally every hour until discharge from the PACU. Clonidine analysis was performed on liquid chromatography-mass spectrometry.

Results: Data form eighteen children were available for pharmacokinetic analysis (ASA I; male/female: 17/1; age: 1-5 years; weight 8.7-24 kg). Population parameter estimates for the 2-compartment model were similar to previous published data for children who underwent cardiac surgery. A pooled analysis including data from 59 children indicated clearance of 14.4 L h  70 kg and volume of distribution of 192.6 L 70 kg . No age-related pharmacokinetic differences and no difference in time from administration of study medication to awakening were found. Children 1 to <2 years had a shorter PACU stay than children 2-5 years (mean difference 17% 95% CI:3%-34%, P = .02).

Conclusion: Pharmacokinetic parameter estimates were similar for children undergoing general surgery and cardiac surgery given a single dose of intravenous clonidine. These results indicated that no dose reduction is needed in children aged 1 to <2 years compared with those 2-5 years, which was supported by pharmacodynamic observations.
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http://dx.doi.org/10.1111/pan.13856DOI Listing
May 2020

Clinical Impact of an Electronic Dashboard and Alert System for Sedation Minimization and Ventilator Liberation: A Before-After Study.

Crit Care Explor 2019 Oct 30;1(10):e0057. Epub 2019 Oct 30.

Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pennsylvania, Philadelphia, PA.

Sedation minimization and ventilator liberation protocols improve outcomes but are challenging to implement. We sought to demonstrate proof-of-concept and impact of an electronic application promoting sedation minimization and ventilator liberation.

Design: Multi-ICU proof-of-concept study and a single ICU before-after study.

Setting: University hospital ICUs.

Patients: Adult patients receiving mechanical ventilation.

Interventions: An automated application consisting of 1) a web-based dashboard with real-time data on spontaneous breathing trial readiness, sedation depth, sedative infusions, and nudges to wean sedation and ventilatory support and 2) text-message alerts once patients met criteria for a spontaneous breathing trial and spontaneous awakening trial. Pre-intervention, sedation minimization, and ventilator liberation were reviewed daily during a multidisciplinary huddle. Post-intervention, the dashboard was used during the multidisciplinary huddle, throughout the day by respiratory therapists, and text alerts were sent to bedside providers.

Measurements And Main Results: We enrolled 115 subjects in the proof-of-concept study. Spontaneous breathing trial alerts were accurate (98.3%), usually sent while patients were receiving mandatory ventilation (88.5%), and 61.9% of patients received concurrent spontaneous awakening trial alerts. We enrolled 457 subjects in the before-after study, 221 pre-intervention and 236 post-intervention. After implementation, patients were 28% more likely to be extubated (hazard ratio, 1.28; 95% CI, 1.01-1.63; = 0.042) and 31% more likely to be discharged from the ICU (hazard ratio, 1.31; 95% CI, 1.03-1.67; = 0.027) at any time point. After implementation, the median duration of mechanical ventilation was 2.20 days (95% CI, 0.09-4.31 d; = 0.042) shorter and the median ICU length of stay was 2.65 days (95% CI, 0.13-5.16 d; = 0.040) shorter, compared with the expected durations without the application.

Conclusions: Implementation of an electronic dashboard and alert system promoting sedation minimization and ventilator liberation was associated with reductions in the duration of mechanical ventilation and ICU length of stay.
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http://dx.doi.org/10.1097/CCE.0000000000000057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063891PMC
October 2019

Pharmacokinetic and pharmacodynamic considerations of general anesthesia in pediatric subjects.

Expert Opin Drug Metab Toxicol 2020 Apr 17;16(4):279-295. Epub 2020 Mar 17.

División Anestesiología, Pontificia Universidad Católica De Chile, Santiago De Chile, Chile.

The target concentration strategy uses PKPD information for dose determination. Models have also quantified exposure-response relationships, improved understanding of developmental pharmacokinetics, rationalized dose prescription, provided insight into the importance of covariate information, explained drug interactions and driven decision-making and learning during drug development. The prime PKPD consideration is parameter estimation and quantification of variability. The main sources of variability in children are age (maturation) and weight (size). Model use is mostly confined to pharmacokinetics, partly because anesthesia effect models in the young are imprecise. Exploration of PK and PD covariates and their variability hold potential to better individualize treatment. The ability to model drugs using computer-based technology is hindered because covariate data required to individualize treatment using these programs remain lacking. Target concentration intervention strategies remain incomplete because covariate information that might better predict individualization of dose is absent. Pharmacogenomics appear a valuable area for investigation for pharmacodynamics and pharmacodynamics. Effect measures in the very young are imprecise. Assessment of the analgesic component of anesthesia is crude. While neuromuscular monitoring is satisfactory, depth of anaesthesia EEG interpretation is inadequate. Closed loop anesthesia is possible with better understanding of EEG changes.
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http://dx.doi.org/10.1080/17425255.2020.1739648DOI Listing
April 2020

Plasma sTNFR1 and IL8 for prognostic enrichment in sepsis trials: a prospective cohort study.

Crit Care 2019 12 9;23(1):400. Epub 2019 Dec 9.

Division of Pulmonary, Allergy and Critical Care Medicine, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, 5036 Gates Building, Philadelphia, PA, 19104, USA.

Background: Enrichment strategies improve therapeutic targeting and trial efficiency, but enrichment factors for sepsis trials are lacking. We determined whether concentrations of soluble tumor necrosis factor receptor-1 (sTNFR1), interleukin-8 (IL8), and angiopoietin-2 (Ang2) could identify sepsis patients at higher mortality risk and serve as prognostic enrichment factors.

Methods: In a multicenter prospective cohort study of 400 critically ill septic patients, we derived and validated thresholds for each marker and expressed prognostic enrichment using risk differences (RD) of 30-day mortality as predictive values. We then used decision curve analysis to simulate the prognostic enrichment of each marker and compare different prognostic enrichment strategies.

Measurements And Main Results: An admission sTNFR1 concentration > 8861 pg/ml identified patients with increased mortality in both the derivation (RD 21.6%) and validation (RD 17.8%) populations. Among immunocompetent patients, an IL8 concentration > 94 pg/ml identified patients with increased mortality in both the derivation (RD 17.7%) and validation (RD 27.0%) populations. An Ang2 level > 9761 pg/ml identified patients at 21.3% and 12.3% increased risk of mortality in the derivation and validation populations, respectively. Using sTNFR1 or IL8 to select high-risk patients improved clinical trial power and efficiency compared to selecting patients with septic shock. Ang2 did not outperform septic shock as an enrichment factor.

Conclusions: Thresholds for sTNFR1 and IL8 consistently identified sepsis patients with higher mortality risk and may have utility for prognostic enrichment in sepsis trials.
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http://dx.doi.org/10.1186/s13054-019-2684-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902425PMC
December 2019

Plasma Mitochondrial DNA Levels Are Associated With ARDS in Trauma and Sepsis Patients.

Chest 2020 01 14;157(1):67-76. Epub 2019 Oct 14.

Pulmonary, Allergy and Critical Care Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Center for Translational Lung Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Background: Critically ill patients who develop ARDS have substantial associated morbidity and mortality. Circulating mitochondrial DNA (mtDNA) released during critical illness causes endothelial dysfunction and lung injury in experimental models. This study hypothesized that elevated plasma mtDNA is associated with ARDS in critically ill patients with trauma and sepsis.

Methods: Plasma mtDNA concentrations were measured at ED presentation and approximately 48 h later in separate prospective cohorts of critically ill patients with trauma and sepsis. ARDS was classified according to the Berlin definition. The association of mtDNA with ARDS was tested by using multivariable logistic regression, adjusted for covariates previously shown to contribute to ARDS risk in each population.

Results: ARDS developed in 41 of 224 (18%) trauma patients and in 45 of 120 (38%) patients with sepsis. Forty-eight-hour mtDNA levels were significantly associated with ARDS (trauma: OR, 1.58/log copies/μL; 95% CI, 1.14-2.19 [P = .006]; sepsis: OR, 1.52/log copies/μL; 95% CI, 1.12-2.06 [P = .007]). Plasma mtDNA on presentation was not significantly associated with ARDS in either cohort. In patients with sepsis, 48-h mtDNA was more strongly associated with ARDS among those with a nonpulmonary infectious source (OR, 2.20/log copies/μL; 95% CI, 1.36-3.55 [P = .001], n = 69) than those with a pulmonary source (OR, 1.04/log copies/μL; 95% CI, 0.68-1.59 [P = .84], n = 51; P = .014 for interaction).

Conclusions: Plasma mtDNA levels were associated with incident ARDS in two critical illness populations. Given supportive preclinical data, our findings suggest a potential link between circulating mtDNA and lung injury and merit further investigation as a potentially targetable mediator of ARDS.
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http://dx.doi.org/10.1016/j.chest.2019.09.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6965693PMC
January 2020

Dosing clonidine for sedation in intensive care.

Paediatr Anaesth 2019 10;29(10):983-984

Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Boston, Massachusetts.

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http://dx.doi.org/10.1111/pan.13719DOI Listing
October 2019

Plasma sRAGE Acts as a Genetically Regulated Causal Intermediate in Sepsis-associated Acute Respiratory Distress Syndrome.

Am J Respir Crit Care Med 2020 01;201(1):47-56

Pulmonary, Allergy, and Critical Care Medicine Division, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.

Acute respiratory distress syndrome (ARDS) lacks known causal biomarkers. Plasma concentrations of sRAGE (soluble receptor for advanced glycation end products) strongly associate with ARDS risk. However, whether plasma sRAGE contributes causally to ARDS remains unknown. Evaluate plasma sRAGE as a causal intermediate in ARDS by Mendelian randomization (MR), a statistical method to infer causality using observational data. We measured early plasma sRAGE in two critically ill populations with sepsis. The cohorts were whole-genome genotyped and phenotyped for ARDS. To select validated genetic instruments for MR, we regressed plasma sRAGE on genome-wide genotypes in both cohorts. The causal effect of plasma sRAGE on ARDS was inferred using the top variants with significant associations in both populations ( < 0.01,  > 0.02). We applied the inverse variance-weighted method to obtain consistent estimates of the causal effect of plasma sRAGE on ARDS risk. There were 393 European and 266 African ancestry patients in the first cohort and 843 European ancestry patients in the second cohort. Plasma sRAGE was strongly associated with ARDS risk in both populations (odds ratio, 1.86; 95% confidence interval [1.54-2.25]; 2.56 [2.14-3.06] per log increase). Using genetic instruments common to both populations, plasma sRAGE had a consistent causal effect on ARDS risk with a β estimate of 0.50 (95% confidence interval [0.09-0.91] per log increase). Plasma sRAGE is genetically regulated during sepsis, and MR analysis indicates that increased plasma sRAGE leads to increased ARDS risk, suggesting plasma sRAGE acts as a causal intermediate in sepsis-related ARDS.
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http://dx.doi.org/10.1164/rccm.201810-2033OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938154PMC
January 2020

A target concentration strategy to determine ibuprofen dosing in children.

Paediatr Anaesth 2019 11 25;29(11):1107-1113. Epub 2019 Sep 25.

Department of Pharmacology & Clinical Pharmacology, Auckland University, Auckland, New Zealand.

Background: Ibuprofen is widely used for ductus arteriosus closure in premature neonates and for analgesia in children and adults. There are no maturation descriptors of clearance. This lack of maturation understanding limits dosing recommendations from premature neonates to adulthood.

Methods: Published clearance estimates from different aged patients determined after administration from time-concentration profiles were used to construct a maturation model based on size and age. Curve fitting was performed using nonlinear mixed-effects models. A target concentration strategy was used to estimate maintenance dose at different ages.

Results: There were three publications reporting an estimate of individual clearance estimates in premature neonates, three reporting population clearances in infants, 11 in children 2-15 years (1 with individual and 9 with population clearances), and 13 adult studies (1 with individual and 12 with population clearances). Clearance maturation, standardized to a 70 kg person was described using the Hill equation. Mature clearance was 3.81 (CV 15.5%, 95%CI 3.72, 3.92) L/h/70 kg. The maturation half-time was 36.8 (CV 9.2%, 95%CI 34.7, 40.9) weeks postmenstrual age and the Hill coefficient 11.5 (95%CI 8.1, 15). A target effect of four units (visual analogue scale 0-10) correlated with an effect site concentration of 6.3 mg/L: a concentration achieved at trough after 400 mg 8 hourly in adults.

Conclusion: Previously published pharmacokinetic parameters can be used to develop maturation models that address gaps in current knowledge regarding the influence of age on a drug's disposition. Maturation of ibuprofen clearance was rapid and was 90% of adult values by the first month of life in term neonates (ie, 44 weeks postmenstrual age) and 98% of standardized adult estimates by 3 months of age (53 weeks postmenstrual age). Clearance informed dosing predictions in all ages (premature neonate to adult) and matched those doses in common use in children older than 3 months.
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http://dx.doi.org/10.1111/pan.13731DOI Listing
November 2019

In Response to Hemodynamic and Pharmacokinetic Analysis of Oxymetazoline Use During Nasal Surgery in Children.

Laryngoscope 2019 10 22;129(10):E348. Epub 2019 Jul 22.

Department of Anesthesiology and Pain Medicine, Nationwide Children's Hospital, Columbus, Ohio.

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http://dx.doi.org/10.1002/lary.28198DOI Listing
October 2019

A manual propofol infusion regimen for neonates and infants.

Paediatr Anaesth 2019 09 12;29(9):907-914. Epub 2019 Aug 12.

Department of Anaesthesiology, University of Auckland, Auckland, New Zealand.

Aims: Manual propofol infusion regimens for neonates and infants have been determined from clinical observations in children under the age of 3 years undergoing anesthesia. We assessed the performance of these regimens using reported age-specific pharmacokinetic parameters for propofol. Where performance was poor, we propose alternative dosing regimens.

Methods: Simulations using a reported general purpose pharmacokinetic propofol model were used to predict propofol blood plasma concentrations during manual infusion regimens recommended for children 0-3 years. Simulated steady state concentrations were 6-8 µg.mL in the first 30 minutes that were not sustained during 100 minutes infusions. Pooled clinical data (n = 161, 1902 plasma concentrations) were used to determine an alternative pharmacokinetic parameter set for propofol using nonlinear mixed effects models. A new manual infusion regimen for propofol that achieves a steady-state concentration of 3 µg.mL was determined using a heuristic approach.

Results: A manual dosing regimen predicted to achieve steady-state plasma concentration of 3 µg.mL comprised a loading dose of 2 mg.kg followed by an infusion rate of 9 mg.kg .h for the first 15 minutes, 7 mg.kg .h from 15 to 30 minutes, 6 mg.kg .h from 30 to 60 minutes, 5 mg.kg .h from 1 to 2 hours in neonates (38-44 weeks postmenstrual age). Dose increased with age in those aged 1-2 years with a loading dose of 2.5 mg.kg followed by an infusion rate of 13 mg.kg .h for the first 15 minutes, 12 mg.kg .h from 15 to 30 minutes, 11 mg.kg .h from 30 to 60 minutes, and 10 mg.kg .h from 1 to 2 hours.

Conclusion: Propofol clearance increases throughout infancy to reach 92% that reported in adults (1.93 L.min.70 kg ) by 6 months postnatal age and infusion regimens should reflect clearance maturation and be cognizant of adverse effects from concentrations greater than the target plasma concentration. Predicted concentrations using a published general purpose pharmacokinetic propofol model were similar to those determined using a new parameter set using richer neonatal and infant data.
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http://dx.doi.org/10.1111/pan.13706DOI Listing
September 2019

Plasma receptor interacting protein kinase-3 levels are associated with acute respiratory distress syndrome in sepsis and trauma: a cohort study.

Crit Care 2019 06 28;23(1):235. Epub 2019 Jun 28.

Pulmonary, Allergy, and Critical Care Division, Perelman School of Medicine, University of Pennsylvania, 5039 W Gates Building, 3600 Spruce Street, Philadelphia, PA, 19104, USA.

Background: Necroptosis, a form of programmed cell death mediated by receptor interacting serine/threonine-protein kinase-3 (RIPK3), is implicated in murine models of acute respiratory distress syndrome (ARDS). We hypothesized that plasma RIPK3 concentrations in sepsis and trauma would be associated with ARDS development and that plasma RIPK3 would reflect changes in lung tissue RIPK3 in a murine model of systemic inflammation.

Methods: We utilized prospective cohort studies of critically ill sepsis (n = 120) and trauma (n = 180) patients and measured plasma RIPK3 at presentation and 48 h. Patients were followed for 6 days for ARDS by the Berlin definition. We used multivariable logistic regression to determine the association of plasma RIPK3 with ARDS in each cohort, adjusting for confounders. In mice, we determined whether plasma and lung tissue RIPK3 levels rise concomitantly 4 h after injection with lipopolysaccharide and ZVAD-FMK, an apoptosis inhibitor.

Results: The change in plasma RIPK3 from presentation to 48 h (ΔRIPK3) was associated with ARDS in sepsis (OR 1.30, 95% CI 1.03-1.63, per ½ standard deviation) and trauma (OR 1.79, 95% CI 1.33-2.40). This association was not evident for presentation RIPK3 levels. Secondary analyses showed similar findings for the association of ΔRIPK3 with acute kidney injury and 30-day mortality. Mice injected with lipopolysaccharide and ZVAD-FMK had significantly higher plasma (p < 0.001) and lung (p = 0.005) RIPK3 than control mice.

Conclusions: The change in plasma RIPK3 from presentation to 48 h in both sepsis and trauma patients is independently associated with ARDS, and plasma RIPK3 may reflect RIPK3 activity in lung tissue.
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http://dx.doi.org/10.1186/s13054-019-2482-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599265PMC
June 2019

Burnout, and Fulfillment, in the Profession of Critical Care Medicine.

Am J Respir Crit Care Med 2019 10;200(7):931-933

Perelman School of Medicine at the University of PennsylvaniaPhiladelphia, Pennsylvania.

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http://dx.doi.org/10.1164/rccm.201903-0662LEDOI Listing
October 2019

Pharmacokinetic and Pharmacodynamic Analysis of Alfaxalone Administered as a Bolus Intravenous Injection of Phaxan in a Phase 1 Randomized Trial.

Anesth Analg 2020 03;130(3):704-714

Department of Anaesthesiology, University of Auckland, Auckland, New Zealand.

Background: Previous formulations of alfaxalone have shown it to be a fast-acting intravenous anesthetic with high therapeutic index. Alfaxalone has been reformulated for human use as Phaxan, an aqueous solution of 10 mg/mL of alfaxalone and 13% betadex. This study assessed the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of alfaxalone given as a bolus intravenous injection of this formulation to human male volunteers.

Methods: A dose of 0.5 mg/kg (0.42-0.55 mg/kg) of alfaxalone [mean (range)] was given by single intravenous bolus injection to 12 healthy subjects. Plasma alfaxalone concentrations and bispectral index (BIS) values were analyzed using an integrated pharmacokinetic-pharmacodynamic (PKPD) model using nonlinear mixed-effects models. Effect (BIS) was described using a sigmoidal fractional maximum effect (EMAX) model. All parameters were scaled using allometry and standardized to a 70-kg person using exponents of 0.75 for clearance parameters (CL, Q2, and Q3), 1.0 for volumes (V1, V2, and V3), and 0.25 for time-related parameters half-time keo (t1/2keo).

Results: A 3-compartment model used to fit PK data with an additional compartment, linked by t1/2keo to describe the effect compartment, yielded alfaxalone PK parameter estimates: CL: 1.08 L/min; 0.87-1.34 L/min (median; 95% confidence interval [CI]); central volume of distribution (V1): 0.99 L; 0.53-2.05 L (median; 95% CI); intercompartment CLs (Q2): 0.87 L/min; 0.32-1.71 L/min (median; 95% CI) and Q3: 0.46 L/min; 0.19-1.03 L/min (median; 95% CI); and peripheral volumes of distribution (V2): 6.36 L; 2.79-10.7 L (median; 95% CI) and V3: 19.1 L; 8.61-37.4 L (median; 95% CI). PD interrogation assumed a baseline BIS of 96, with an estimated EMAX: 0.94; 0.71-0.99 (median; 95% CI), a plasma concentration (Cp) for 50% effect (C50): 0.98 mg/L; 0.83-1.09 mg/L (median; 95% CI), and a Hill coefficient (γ): 12.1; 6.7-15 (median; 95% CI). The t1/2keo was 8 minutes; 4.70-12.8 minutes (median; 95% CI). The mean time to a BIS 50 was 0.94 minutes (standard deviation [SD] = 0.2 minutes).

Conclusions: After a single bolus intravenous injection, alfaxalone has a high plasma CL equal to hepatic blood flow as reported for earlier studies of bolus injections of a previous formulation of alfaxalone. The plasma levels associated with BIS values of <60 are comparable to those previously reported in patients anesthetized with alfaxalone. The t1/2keo is relatively high, but the large Hill coefficient contributes to rapid onset and offset of action. This information can inform future studies of this formulation.
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http://dx.doi.org/10.1213/ANE.0000000000004204DOI Listing
March 2020

Pharmacokinetic-pharmacodynamic population modelling in paediatric anaesthesia and its clinical translation.

Curr Opin Anaesthesiol 2019 Jun;32(3):353-362

Department of Anaesthesiology, University of Auckland, New Zealand.

Purpose Of Review: Pharmacokinetic-pharmacodynamic (PKPD) population modelling has advanced adult anaesthesia. Current literature was reviewed to discern use of this analytic technique for benefit in the perioperative management of children.

Recent Findings: Variability in drug response, selection of a dose that achieves a desired target concentration and optimizing sampling protocols for further studies are all facets of paediatric anaesthesia that have benefitted from modelling approaches. PKPD models have driven the maintenance dose rate in target-controlled infusion pumps used for total intravenous anaesthesia. Although many of the models used in these pumps were developed in adults, translation for paediatric use has followed, including subgroups, such as neonates and obese children. The use of drug effect measures (e.g. bispectral index) has improved the predictive performance of pharmacodynamic models. Simulation studies have facilitated an increase in safety by quantifying drug variability, and identifying where possible adverse drug events may occur.

Summary: Modelling and simulation continue to have an important role optimizing drug use during anaesthesia. Models incorporating influential covariates that better describe drug pharmacokinetics and pharmacodynamics improve anaesthetic treatments and safety in diverse populations and clarify drug role and impact. Their use developing paediatric clinical studies improves trial conduct, often with fewer subjects required for study.
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http://dx.doi.org/10.1097/ACO.0000000000000725DOI Listing
June 2019

Practicalities of Total Intravenous Anesthesia and Target-controlled Infusion in Children.

Anesthesiology 2019 07;131(1):164-185

From the Department of Anaesthesiology, University of Auckland, Auckland, New Zealand (B.J.A.) the Department of Anaesthesia, Birmingham Women's and Children's Hospital, Birmingham, United Kingdom (O.B.).

Propofol administered in conjunction with an opioid such as remifentanil is used to provide total intravenous anesthesia for children. Drugs can be given as infusion controlled manually by the physician or as automated target-controlled infusion that targets plasma or effect site. Smart pumps programmed with pharmacokinetic parameter estimates administer drugs to a preset plasma concentration. A linking rate constant parameter (keo) allows estimation of effect site concentration. There are two parameter sets, named after the first author describing them, that are commonly used in pediatric target-controlled infusion for propofol (Absalom and Kataria) and one for remifentanil (Minto). Propofol validation studies suggest that these parameter estimates are satisfactory for the majority of children. Recommended target concentrations for both propofol and remifentanil depend on the type of surgery, the degree of surgical stimulation, the use of local anesthetic blocks, and the ventilatory status of the patient. The use of processed electroencephalographic monitoring is helpful in pediatric total intravenous anesthesia and target-controlled infusion anesthesia, particularly in the presence of neuromuscular blockade.
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http://dx.doi.org/10.1097/ALN.0000000000002657DOI Listing
July 2019

Hemodynamic and pharmacokinetic analysis of oxymetazoline use during nasal surgery in children.

Laryngoscope 2019 12 20;129(12):2775-2781. Epub 2019 Feb 20.

Department of Anesthesiology and Pain Medicine, Nationwide Children's Hospital, Columbus, Ohio, U.S.A.

Objectives/hypothesis: Oxymetazoline is an α-adrenergic agonist that is commonly used as a topical hemostatic agent in the operating room during ear, nose, and throat surgery. There are limited data on oxymetazoline pharmacokinetics in children who undergo general anesthesia. We assessed the hemodynamic effects and systemic absorption of topically applied oxymetazoline in children undergoing various nasal procedures.

Study Design: Prospective trial.

Methods: Children ages 2 to 17 years undergoing functional endoscopic sinus surgery, turbinate resection, or adenoidectomy were enrolled. The surgeon placed oxymetazoline-soaked pledgets (1.5 mL of 0.05% solution) according to our usual clinical practice. Blood samples for oxymetazoline assay were drawn at 5, 10, 20, 45, 90, and 150 minutes, and hemodynamic data were recorded at 5-minute intervals. Data analysis included mixed-effects regression and population pharmacokinetic/pharmacodynamic modeling.

Results: The analysis included 27 patients, age 7 ± 4 years, who received between 2 and 12 pledgets (3-18 mL) of oxymetazoline. Relative bioavailability compared to the spray formulation was 2.3 (95% confidence interval [CI]: 1.6-3.2), with slow absorption from the mucosal surface (absorption half-life 64 minutes; 95% CI: 44-90). Mean arterial pressure did not increase with oxymetazoline instillation at the observed oxymetazoline serum concentrations (0.04-7.6 μg/L).

Conclusions: Despite concerns regarding oxymetazoline administration to mucosal membranes, we found that hemodynamic changes were clinically negligible with our usual clinical use of pledgets soaked in oxymetazoline. Compared to data on oxymetazoline in spray formulation, bioavailability was increased twofold with pledgets, but systemic absorption was very slow, contributing to low serum concentrations and limited hemodynamic effects.

Level Of Evidence: 1b. Laryngoscope, 129:2775-2781, 2019.
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http://dx.doi.org/10.1002/lary.27760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6702099PMC
December 2019

Circulating heparan sulfate fragments mediate septic cognitive dysfunction.

J Clin Invest 2019 04 18;129(4):1779-1784. Epub 2019 Mar 18.

Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA.

Septic patients frequently develop cognitive impairment that persists beyond hospital discharge. The impact of sepsis on electrophysiological and molecular determinants of learning is underexplored. We observed that mice that survived sepsis or endotoxemia experienced loss of hippocampal long-term potentiation (LTP), a brain-derived neurotrophic factor-mediated (BDNF-mediated) process responsible for spatial memory formation. Memory impairment occurred despite preserved hippocampal BDNF content and could be reversed by stimulation of BDNF signaling, suggesting the presence of a local BDNF inhibitor. Sepsis is associated with degradation of the endothelial glycocalyx, releasing heparan sulfate fragments (of sufficient size and sulfation to bind BDNF) into the circulation. Heparan sulfate fragments penetrated the hippocampal blood-brain barrier during sepsis and inhibited BDNF-mediated LTP. Glycoarray approaches demonstrated that the avidity of heparan sulfate for BDNF increased with sulfation at the 2-O position of iduronic acid and the N position of glucosamine. Circulating heparan sulfate in endotoxemic mice and septic humans was enriched in 2-O- and N-sulfated disaccharides; furthermore, the presence of these sulfation patterns in the plasma of septic patients at intensive care unit (ICU) admission predicted persistent cognitive impairment 14 days after ICU discharge or at hospital discharge. Our findings indicate that circulating 2-O- and N-sulfated heparan sulfate fragments contribute to septic cognitive impairment.
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http://dx.doi.org/10.1172/JCI124485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6436867PMC
April 2019