Development, Reporting, and Evaluation of Clinical Practice Guidelines Clinical practice parameters have been published with greater frequency by professional societies and groups of experts. These publications run the gamut of practice standards, practice guidelines, consensus statements or practice advisories, position statements, and practice alerts. The definitions of these terms have been clarified in an accompanying article. In this article, we present the criteria for high-quality clinical practice parameters and outline a process for developing them, specifically the Delphi method, which is increasingly being used to build consensus among content experts and stakeholders. Several tools for grading the level of evidence and strength of recommendation are offered and compared. The speciousness of categorizing guidelines as evidence-based or consensus-based will be explained. We examine the recommended checklist for reporting and appraise the tools for evaluating a practice guideline. This article is geared toward developers and reviewers of clinical practice guidelines and consensus statements. Accepted for publication August 12, 2019. Funding: None. The authors declare no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (www.anesthesia-analgesia.org). Reprints will not be available from the authors. Address correspondence to Honorio T. Benzon, MD, Department of Anesthesiology, Northwestern University Feinberg School of Medicine, Feinberg Pavilion, Suite 5-704, 251 E Huron St, Chicago, IL 60611. Address e-mail to h-benzon@northwestern.edu. © 2019 International Anesthesia Research Society

Perioperative Oxidative Stress: The Unseen Enemy Reactive oxygen species (ROS) are essential for cellular signaling and physiological function. An imbalance between ROS production and antioxidant protection results in a state of oxidative stress (OS), which is associated with perturbations in reduction/oxidation (redox) regulation, cellular dysfunction, organ failure, and disease. The pathophysiology of OS is closely interlinked with inflammation, mitochondrial dysfunction, and, in the case of surgery, ischemia/reperfusion injury (IRI). Perioperative OS is a complex response that involves patient, surgical, and anesthetic factors. The magnitude of tissue injury inflicted by the surgery affects the degree of OS, and both duration and nature of the anesthetic procedure applied can modify this. Moreover, the interindividual susceptibility to the impact of OS is likely to be highly variable and potentially linked to underlying comorbidities. The pathological link between OS and postoperative complications remains unclear, in part due to the complexities of measuring ROS- and OS-mediated damage. Exogenous antioxidant use and exercise have been shown to modulate OS and may have potential as countermeasures to improve postoperative recovery. A better understanding of the underlying mechanisms of OS, redox signaling, and regulation can provide an opportunity for patient-specific phenotyping and development of targeted interventions to reduce the disruption that surgery can cause to our physiology. Anesthesiologists are in a unique position to deliver countermeasures to OS and improve physiological resilience. To shy away from a process so fundamental to the welfare of these patients would be foolhardy and negligent, thus calling for an improved understanding of this complex facet of human biology. Accepted for publication August 20, 2019. Funding: None. Conflicts of Interest: See Disclosures at the end of the article. Reprints will not be available from the authors. Address correspondence to Jia L. Stevens, MBBS, Division of Surgery and Interventional Science, Royal Free Hospital, University College London, 3rd Floor, Pond St, London NW3 2QG, United Kingdom. Address e-mail to jia.stevens@ucl.ac.uk. © 2019 International Anesthesia Research Society

Controlled Multifactorial Coagulopathy: Effects of Dilution, Hypothermia, and Acidosis on Thrombin Generation In Vitro BACKGROUND: Coagulopathy and hemostatic abnormalities remain a challenge in patients following trauma and major surgery. Coagulopathy in this setting has a multifactorial nature due to tissue injury, hemodilution, hypothermia, and acidosis, the severity of which may vary. In this study, we combined computational kinetic modeling and in vitro experimentation to investigate the effects of multifactorial coagulopathy on thrombin, the central enzyme in the coagulation system. METHODS: We measured thrombin generation in platelet-poor plasma from 10 healthy volunteers using the calibrated automated thrombogram assay (CAT). We considered 3 temperature levels (31°C, 34°C, and 37°C), 3 pH levels (6.9, 7.1, and 7.4), and 3 degrees of dilution with normal saline (no dilution, 3-fold dilution, and 5-fold dilution). We measured thrombin-generation time courses for all possible combinations of these conditions. For each combination, we analyzed 2 scenarios: without and with (15 nM) supplementation of thrombomodulin, a key natural regulator of thrombin generation. For each measured thrombin time course, we recorded 5 quantitative parameters and analyzed them using multivariable regression. Moreover, for multiple combinations of coagulopathic conditions, we performed routine coagulation tests: prothrombin time (PT) and activated partial thromboplastin time (aPTT). We compared the experimental results with simulations using a newly developed version of our computational kinetic model of blood coagulation. RESULTS: Regression analysis allowed us to identify trends in our data (P < 10−5). In both model simulations and experiments, dilution progressively reduced the peak of thrombin generation. However, we did not experimentally detect the model-predicted delay in the onset of thrombin generation. In accord with the model predictions, hypothermia delayed the onset of thrombin generation; it also increased the thrombin peak time (up to 1.30-fold). Moreover, as predicted by the kinetic model, the experiments showed that hypothermia increased the area under the thrombin curve (up to 1.97-fold); it also increased the height of the thrombin peak (up to 1.48-fold). Progressive acidosis reduced the velocity index by up to 24%; acidosis-induced changes in other thrombin generation parameters were much smaller or none. Acidosis increased PT by 14% but did not influence aPTT. In contrast, dilution markedly prolonged both PT and aPTT. In our experiments, thrombomodulin affected thrombin-generation parameters mainly in undiluted plasma. CONCLUSIONS: Dilution with normal saline reduced the amount of generated thrombin, whereas hypothermia increased it and delayed the time of thrombin accumulation. In contrast, acidosis in vitro had little effect on thrombin generation. Accepted for publication September 10, 2019. Funding: This research was supported by the US Army Network Science Initiative, US Army Medical Research and Development Command, Ft Detrick, MD. The authors declare no conflicts of interest. The opinions and assertions contained herein are private views of the authors and are not to be construed as official or as reflecting the views of the US Army, the US Department of Defense, or The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. This paper has been approved for public release with unlimited distribution. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (www.anesthesia-analgesia.org). The computer code implementing our kinetic model is available from the authors on request. Reprints will not be available from the authors. Address correspondence to Alexander Y. Mitrophanov, PhD, DoD Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, US Army Medical Research and Development Command, ATTN: FCMR-TT, 504 Scott St, Ft Detrick, MD 21702. Address e-mail to alex@bhsai.org; and Jaques Reifman, PhD, DoD Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, US Army Medical Research and Development Command, ATTN: FCMR-TT, 504 Scott St, Ft Detrick, MD 21702. Address e-mail to jaques.reifman.civ@mail.mil. © 2019 International Anesthesia Research Society

Goal-Directed Fluid Therapy Does Not Improve Early Glomerular Filtration Rate in a Porcine Renal Transplantation Model BACKGROUND: Insufficient fluid administration intra- and postoperatively may lead to delayed renal graft function (DGF), while fluid overload increases the risk of heart failure, infection, and obstipation. Several different fluid protocols have been suggested to ensure optimal fluid state. However, there is a lack of evidence of the clinical impact of these regimens. This study aimed to determine whether individualized goal-directed fluid therapy (IGDT) positively affects the initial renal function compared to a high-volume fluid therapy (HVFT) and to examine the effects on renal endothelial glycocalyx, inflammatory and oxidative stress markers, and medullary tissue oxygenation. The hypothesis was that IGDT improves early glomerular filtration rate (GFR) in pigs subjected to renal transplantation. METHODS: This was an experimental randomized study. Using a porcine renal transplantation model, animals were randomly assigned to receive IGDT or HVFT during and until 1 hour after transplantation from brain-dead donors. The kidneys were exposed to 18 hours of cold ischemia. The recipients were observed until 10 hours after reperfusion, which included GFR measured as clearance of chrom-51-ethylendiamintetraacetat (51Cr-EDTA), animal weight, and renal tissue oxygenation by fiber optic probes. The renal expression of inflammatory and oxidative stress markers as well as glomerular endothelial glycocalyx were analyzed in the graft using polymerase chain reaction (PCR) technique and immunofluorescence. RESULTS: Twenty-eight recipient pigs were included for analysis. We found no evidence that IGDT improved early GFR compared to HVFT (P = .45), while animal weight increased more in the HVFT group (a mean difference of 3.4 kg [1.96–4.90]; P < .0001). A better, however nonsignificant, preservation of glomerular glycocalyx (P = .098) and significantly lower levels of the inflammatory marker cyclooxygenase 2 (COX-2) was observed in the IGDT group when compared to HVFT. COX-2 was 1.94 (1.50–2.39; P = .012) times greater in the HVFT group when compared to the IGDT group. No differences were observed in outer medullary tissue oxygenation or oxidative stress markers. CONCLUSIONS: IGDT did not improve early GFR; however, it may reduce tissue inflammation and could possibly lead to preservation of the glycocalyx compared to HVFT. Accepted for publication August 20, 2019. Funding: This study was supported by the Danish Council for Independent Research | Medical Sciences, Aarhus University Foundation, and Novo Nordisk Foundation. The authors declare no conflicts of interest. J. K. Eriksen, L. H. Nielsen, and N. Moeslund contributed equally and share first authorship. Reprints will not be available from the authors. Address correspondence to Rikke Norregaard, PhD, Department of Clinical Medicine, Aarhus University, Palle Juul Jensens Blvd 99, DK-8200 Aarhus N, Denmark. Address e-mail to rn@clin.au.dk. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. © 2019 International Anesthesia Research Society

Variation Between and Within Hospitals in Single Injection Caudal Local Anesthetic Dose: A Report From the Pediatric Regional Anesthesia Network BACKGROUND: Given that variation exists in health care utilization, expenditure, and medical practice, there is a paucity of data on variation within the practice of anesthesia. The Pediatric Regional Anesthesia Network (PRAN) data lend itself to explore whether different medical practice patterns exist and if there are nerve blocks with more local anesthetic dosing variation than others. The primary aim of this study was to quantify variation in single injection caudal block dosing, and the secondary aim was to explore possible causes for variation (eg, number of blocks performed versus geographic location). METHODS: We queried the PRAN database for single injection caudal blocks in children <1 year of age. Data were analyzed for local anesthetic dose, variation within and across institutions, and possible causes. RESULTS: Mean dose of bupivacaine equivalents per kilogram (BE·kg−1) among sites ranged from 1.39 to 2.22 with an interdecile range (IDR) containing the mid 80% of all doses ranging from 0.21 to 1.48. Mean dose (BE·kg−1) was associated with site, age, weight, and local anesthetic used (all P < .0001). Cohen’s F effect size estimate was 10 times higher for site (0.65) than for age (0.05) or weight (0.02). Variation (IDR) was not related to number of blocks done at each site (P = .23). Mean volume per kilogram was 0.9± ± 0.2 (mean ± ±standard deviation) and was more strongly associated with site (Cohen’s F 0.3) than age (0.04) or weight (0.07). CONCLUSIONS: Wide variation in caudal local anesthetic dosing and administered volume exists. This variation is independent of the number of cases performed at each center but rather is determined by study site (ie, variation between centers) with considerable additional variation within study centers, suggesting additional variability dependent on individual practitioners. While there are legitimate reasons to vary dosing, the current approach is inconsistent and not supported by strong evidence over giving a standardized dose. Accepted for publication August 15, 2019. Funding: None. The authors declare no conflicts of interest. A full list of contributors can be found at the end of the article. The study proposal was reviewed and accepted by Pediatric Regional Anesthesia Network's (PRAN's) steering committee, and the manuscript was approved by PRAN’s publication committee. Reprints will not be available from the authors. Address correspondence to Andreas H. Taenzer, MD, MS, Department of Anesthesiology, Dartmouth Hitchcock Medical Center, One Medical Center Dr, Lebanon, NH 03756. Address e-mail to andreas.h.taenzer@dartmouth.edu. © 2019 International Anesthesia Research Society

Complications Associated With the Anesthesia Transport of Pediatric Patients: An Analysis of the Wake Up Safe Database BACKGROUND: Transporting patients under anesthesia care incurs numerous potential risks, especially for those with critical illness. The purpose of this study is to identify and report all pediatric anesthesia transport-associated adverse events from a preexisting database of perioperative adverse events. METHODS: An extract of the Wake Up Safe database was obtained on December 14, 2017, and screened for anesthesia transport-associated complications. This was defined as events occurring during or immediately after transport or movement of a pediatric patient during or in proximity to their care by anesthesiologists, including repositioning and transfer to recovery or an inpatient unit, if the cause was noted to be associated with anesthesia or handover. Events were excluded if the narrative clearly states that an event was ongoing and not impacted by anesthesia transport, such as a patient who develops cardiac arrest that then requires emergent transfer to the operating room. The search methodology included specific existing data elements that indicate transport of the patient, handover or intensive care status preoperatively as well as a free-text search of the narrative for fragments of words indicating movement. Screened events were reviewed by 3 anesthesiologists for inclusion, and all data elements were extracted for analysis. RESULTS: Of 2971 events in the database extract, 63.8% met screening criteria and 5.0% (148 events) were related to transport. Events were primarily respiratory in nature. Nearly 40% of all reported events occurred in infants age ≤6 months. A total of 59.7% of events were at least somewhat preventable and 36.4% were associated with patient harm, usually temporary. Of the 86 reported cardiac arrests, 50 (58.1%) had respiratory causes, of which 74% related to anesthesia or perioperative team factors. Respiratory events occurred at all stages of care, with 21.4% during preoperative transport and 75.5% postoperatively. Ninety-three percent of unplanned extubations occurred in patients 6 months and younger. Ten medication events were noted, 2 of which resulted in cardiac arrest. Root causes in all events related primarily to provider and patient factors, with occasional references to verbal miscommunication. CONCLUSIONS: Five percent of reported pediatric anesthesia adverse events are associated with transport. Learning points highlight the risk of emergence from anesthesia during transport to recovery or intensive care unit (ICU). ICU patients undergoing anesthesia transport face risks relating to transitions in providers, equipment, sedation, and physical positioning. Sedation and neuromuscular blockade may be necessary for transport in some patients but has been associated with adverse events in others. Accepted for publication August 6, 2019. Funding: Departmental. The authors declare no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (www.anesthesia-analgesia.org). Reprints will not be available from the authors. Address correspondence to Bishr Haydar, MD, Section of Pediatric Anesthesia, Department of Anesthesiology, Michigan Medicine, 4–911 Mott Hospital, 1540 E Hospital Dr SPC 4245, Ann Arbor, MI 48109. Address e-mail to bhaydar@med.umich.edu. © 2019 International Anesthesia Research Society

Prevention of Early Postoperative Decline: A Randomized, Controlled Feasibility Trial of Perioperative Cognitive Training Background: Postoperative delirium and postoperative cognitive dysfunction (POCD) are common after cardiac surgery and contribute to an increased risk of postoperative complications, longer length of stay, and increased hospital mortality. Cognitive training (CT) may be able to durably improve cognitive reserve in areas deficient in delirium and POCD and, therefore, may potentially reduce the risk of these conditions. We sought to determine the feasibility and potential efficacy of a perioperative CT program to reduce the incidence of postoperative delirium and POCD in older cardiac surgery patients. Methods: Randomized controlled trial at a single tertiary care center. Participants included 45 older adults age 60–90 undergoing cardiac surgery at least 10 days from enrollment. Participants were randomly assigned in a 1:1 fashion to either perioperative CT via a mobile device or a usual care control. The primary outcome of feasibility was evaluated by enrollment patterns and adherence to protocol. Secondary outcomes of postoperative delirium and POCD were assessed using the Confusion Assessment Method and the Montreal Cognitive Assessment, respectively. Patient satisfaction was assessed via a postoperative survey. Results: Sixty-five percent of eligible patients were enrolled. Median (interquartile range [IQR]) adherence (as a percentage of prescribed minutes played) was 39% (20%–68%), 6% (0%–37%), and 19% (0%–56%) for the preoperative, immediate postoperative, and postdischarge periods, respectively. Median (IQR) training times were 245 (136–536), 18 (0–40), and 122 (0–281) minutes for each period, respectively. The incidence of postoperative delirium (CT group 5/20 [25%] versus control 3/20 [15%]; P = .69) and POCD (CT group 53% versus control 37%; P = .33) was not significantly different between groups for either outcome in this limited sample. CT participants reported a high level of agreement (on a scale of 0–100) with statements that the program was easy to use (median [IQR], 87 [75–97]) and enjoyable (85 [79–91]). CT participants agreed significantly more than controls that their memory (median [IQR], 75 [54–82] vs 51 [49–54]; P = .01) and thinking ability (median [IQR], 78 [64–83] vs 50 [41–68]; P = .01) improved as a result of their participation in the study. Conclusions: A CT program designed for use in the preoperative period is an attractive target for future investigations of cognitive prehabilitation in older cardiac surgery patients. Changes in the functionality of the program and enrichment techniques may improve adherence in future trials. Further investigation is necessary to determine the potential efficacy of cognitive prehabilitation to reduce the risk of postoperative delirium and POCD. Accepted for publication August 27, 2019. Funding: The conduct of this trial was performed with support from a Beth Israel Deaconess Medical Center (BIDMC) Department of Anesthesia Internal Research Award (John Hedley-White Award, via Harvard Medical School’s Eleanor and Miles Shore Foundation). A portion of this work was conducted while Dr B.P.O.’G. was a member of the Harvard Anesthesia National Institutes of Health (NIH) T32 program (NIH T32GM007592-38). Research subscriptions to the training program were provided free of charge by Lumos Labs, Inc. Conflicts of Interest: See Disclosures at the end of the article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (www.anesthesia-analgesia.org). The sponsor had no role in the design/conduct of the study, data collection or analysis, interpretation of the data, manuscript preparation and review, or decision to submit the manuscript for publication. Clinical Trial Registration: Clinicaltrials.gov # NCT02908464 https://clinicaltrials.gov/ct2/show/NCT02908464. Reprints will not be available from the authors. Address correspondence to Brian P. O’Gara, MD, MPH, Department of Anesthesia, Beth Israel Deaconess Medical Center, 1 Deaconess Rd, Rosenberg 470, Boston, MA 02215. Address e-mail to bpogara@bidmc.harvard.edu. © 2019 International Anesthesia Research Society

Association Between Race and Ethnicity in the Delivery of Regional Anesthesia for Pediatric Patients: A Single-Center Study of 3189 Regional Anesthetics in 25,664 Surgeries BACKGROUND: Racial and ethnic disparities in health care are well documented in the United States, although evidence of disparities in pediatric anesthesia is limited. We sought to determine whether there is an association between race and ethnicity and the use of intraoperative regional anesthesia at a single academic children’s hospital. METHODS: We performed a retrospective review of all anesthetics at an academic tertiary children’s hospital between May 4, 2014, and May 31, 2018. The primary outcome was delivery of regional anesthesia, defined as a neuraxial or peripheral nerve block. The association between patient race and ethnicity (white non-Hispanic or minority) and receipt of regional anesthesia was assessed using multivariable logistic regression. Sensitivity analyses were performed comparing white non-Hispanic to an expansion of the single minority group to individual racial and ethnic groups and on patients undergoing surgeries most likely to receive regional anesthesia (orthopedic and urology patients). RESULTS: Of 33,713 patient cases eligible for inclusion, 25,664 met criteria for analysis. Three-thousand one-hundred eighty-nine patients (12.4%) received regional anesthesia. One thousand eighty-six of 8884 (13.3%) white non-Hispanic patients and 2003 of 16,780 (11.9%) minority patients received regional anesthesia. After multivariable adjustment for confounding, race and ethnicity were not found to be significantly associated with receiving intraoperative regional anesthesia (adjusted odds ratios [ORs] = 0.95; 95% confidence interval [CI], 0.86–1.06; P = .36). Sensitivity analyses did not find significant differences between the white non-Hispanic group and individual races and ethnicities, nor did they find significant differences when analyzing only orthopedic and urology patients, despite observing some meaningful clinical differences. CONCLUSIONS: In an analysis of patients undergoing surgical anesthesia at a single academic children’s hospital, race and ethnicity were not significantly associated with the adjusted ORs of receiving intraoperative regional anesthesia. This finding contrasts with much of the existing health care disparities literature and warrants further study with additional datasets to understand the mechanisms involved. Accepted for publication August 22, 2019. Funding: Work by J.M.R. was supported by a National Institutes of Health grant (T32 GM007592; Research Training for Anesthetists). All other support was provided from institutional and/or departmental sources. The authors declare no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (www.anesthesia-analgesia.org). This work was presented in part at the Society for Pediatric Anesthesia-American Academy of Pediatrics Pediatric Anesthesiology Meeting, March 15–17, 2019, Houston, Texas. Reprints will not be available from the authors. Address correspondence to T. Anthony Anderson, PhD, MD, Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, 300 Pasteur Dr, MC5640, Stanford, CA 94305. Address e-mail to tanders0@stanford.edu. © 2019 International Anesthesia Research Society

Anesthetic Management for the Pediatric Airway: Advanced Approaches and Techniques No abstract available

Risk of Major Complications After Perioperative Norepinephrine Infusion Through Peripheral Intravenous Lines in a Multicenter Study BACKGROUND: Continuous infusions of norepinephrine to treat perioperative hypotension are typically administered through a central venous line rather than a peripheral venous catheter to avoid the risk of localized tissue necrosis in case of drug extravasation. There is limited literature to estimate the risk of skin necrosis when peripheral norepinephrine is used to counteract anesthesia-associated hypotension in elective surgical cases. This study aimed to estimate the rate of occurrence of drug-related adverse effects, including skin necrosis requiring surgical management when norepinephrine peripheral extravasation occurs. METHODS: This retrospective cohort study used the perioperative databases of the University Hospitals in Amsterdam and Utrecht, the Netherlands, to identify surgical patients who received norepinephrine peripheral intravenous infusions (20 µg/mL) between 2012 and 2016. The risk of drug-related adverse effects, including skin necrosis, was estimated. Particular care was taken to identify patients who needed plastic surgical or medical attention secondary to extravasation of dilute, peripheral norepinephrine. RESULTS: A total of 14,385 patients who received norepinephrine peripheral continuous infusions were identified. Drug extravasation was observed in 5 patients (5/14,385 = 0.035%). The 95% confidence interval (CI) for infusion extravasation was 0.011%–0.081%, indicating an estimated risk of 1–8 events per every 10,000 patients. There were zero related complications requiring surgical or medical intervention, resulting in a 95% CI of 0%–0.021% and indicating a risk of approximately 0–2 events per 10,000 patients. CONCLUSIONS: In the current database analysis, no significant association was found between the use of peripheral intravenous norepinephrine infusions and adverse events. Accepted for publication August 15, 2019. Funding: Departmental. The authors declare no conflicts of interest. Reprints will not be available from the authors. Address correspondence to Carlo Pancaro, MD, Department of Anesthesiology, University of Michigan, 1500 Medical Center Dr, Ann Arbor, MI 48109. Address e-mail to cpancaro@med.umich.edu. © 2019 International Anesthesia Research Society