Murphy, Glenn S. MD*; Szokol, Joseph W. MD*; Avram, Michael J. PhD†; Greenberg, Steven B. MD*; Shear, Torin MD*; Vender, Jeffery S. MD*; Gray, Jayla BA*; Landry, Elizabeth BA*
Dexamethasone is a potent corticosteroid with anti-inflammatory, immunomodulating, analgesic, and antiemetic effects. In the perioperative setting, low-dose (<10 mg) dexamethasone is administered primarily for nausea and vomiting prophylaxis. A quantitative systematic review concluded that a single prophylactic dose of dexamethasone had significant antiemetic effects without clinically relevant toxicity.1 In addition, corticosteroids may enhance clinical recovery in the postoperative period by modulating the neuroendocrine and inflammatory stress response induced by surgery. Clinical investigations have demonstrated that the administration of a single low-dose dexamethasone in the operating room resulted in reduced pain scores and analgesic requirements, improved mood, attenuated fatigue scores, and enhanced quality of recovery after surgery.2–4
Although the benefits of dexamethasone treatment have been well documented, adverse events related to glucocorticoid administration have been less well defined. The administration of single low-dose dexamethasone at induction of anesthesia may induce intraoperative and postoperative hyperglycemia. A small number of previous studies have suggested that blood glucose concentrations are increased after dexamethasone administration (8–14 mg).5–8 Interpretation of these findings is complicated by limitations in study design, which include small study samples (20–63 subjects), absence of a control group, lack of randomization and standardization of anesthetic and surgical management, and inadequate duration of follow-up for hyperglycemic events.
Acute hyperglycemia may produce a number of adverse physiologic effects that include osmotic diuresis and hypovolemia, decreased immune function, increased circulating inflammatory cytokine concentrations and adhesion molecule expression, endothelial dysfunction, and electrolyte and acid-base imbalances.9,10 Although optimal glucose targets have not been identified, avoidance of hyperglycemia should be a goal of perioperative management. In order for clinicians to adequately evaluate the risk-benefit ratio of corticosteroids in the surgical setting, the effect of dexamethasone on blood glucose concentrations should be determined. The aim of this randomized, double-blinded, placebo-controlled investigation was to test the hypothesis that 2 standard doses of dexamethasone (4 and 8 mg) would not produce either early (1–4 hours) or late (8–24 hours) increases in blood glucose concentrations that differed from those of placebo or result in a higher risk of perioperative hyperglycemia.
This study was conducted at NorthShore University HealthSystem (a single tertiary medical center affiliated with the University of Chicago Pritzker School of Medicine) and was registered with ClinicalTrials.gov (NCT #01545700). Participants were recruited by reviewing operating room schedules and contacted by telephone on the day before surgery. After approval from the NorthShore University HealthSystem IRB and obtaining written informed consent, 200 women inpatients were enrolled in this clinical trial. Adult (age 18–80 years) patients presenting for elective hysterectomies (either transabdominal or laparoscopic transvaginal approach) under general anesthesia were enrolled. Exclusion criteria included: preoperative use of steroids or antiemetic drugs; history of allergy to any study medications; preoperative diagnosis of Type I or II diabetes; severe renal (serum creatinine >1.6 mg/dL) or liver (liver enzymes >2x normal values) disease; or ASA physical status IV and V patients.
Two hundred patients were allocated randomly (block randomization computer-generated randomization code) to 1 of 6 groups (3 early groups, 3 late groups) to determine the effect of dexamethasone on the incidence of early and late hyperglycemic events. A study design using an early and late set of groups was selected to limit the number of fingerstick blood samples required per patient. The randomization code for the 200 subjects was provided to the operating room pharmacy before the start of the study; all care providers, patients, and researchers were blinded to group assignment. Study medications were prepared by the operating room pharmacy in 3-mL syringes labeled with the patient’s name. Either dexamethasone (4 mg with 1 mL saline or 8 mg-2 mL total volume) or saline (control-2 mL total volume) was drawn into each syringe. In the early group, 100 patients were randomly assigned to receive either saline (Early-control), 4 mg dexamethasone (Early-4 mg), or 8 mg dexamethasone (Early-8 mg) to assess the effect of dexamethasone on blood glucose concentrations during the first 4 hours after administration. In the late group, 100 patients were randomized to receive either saline (Late-control), 4 mg dexamethasone (Late-4 mg), or 8 mg dexamethasone (Late-8 mg) to determine the late (8–24 hours) effect of dexamethasone on blood glucose concentrations. The study drug or saline-control was administered at induction of anesthesia.
Patients were nil per os for solids and liquids for at least 8 hours before the surgical procedure. Anesthetic management was standardized in all study groups. Patients received midazolam 2 mg before transport to the operating room. After the application of standard intraoperative monitoring (manual arterial blood pressure cuff, electrocardiography, pulse oximetry), anesthesia was induced with propofol 2 mg/kg, lidocaine 50 mg, rocuronium 0.6 mg/kg, and fentanyl 100 µg. Anesthesia was maintained with sevoflurane (1.5%–2.5%), which was titrated to a Bispectral Index (BIS® system, Aspect Medical Systems, Newton, MA) of 40 to 60 and a mean arterial blood pressure value within 20% of baseline measures. Approximately 1 µg·kg−1·h−1 fentanyl was administered intraoperatively; the use of additional opioids at the conclusion of the anesthetic (hydromorphone 1–2 mg) was at the discretion of the anesthesia care team. Additional rocuronium (5–10 mg) was given to maintain a train-of-four count of 2 to 3. Patients’ lungs were mechanically ventilated to an end-tidal carbon dioxide concentration of 30 to 34 mm Hg using a 50% oxygen: air gas mixture. Intraoperative fluid replacement therapy consisted of lactated Ringer’s solution at a rate of approximately 10 mL·kg−1·h−1; glucose-containing fluids were avoided in the perioperative period. Normothermia was maintained using forced-air warming devices (Bair Hugger®; Augustine Medical, Minneapolis, MN). Thirty minutes before the anticipated conclusion of the surgical procedure, patients received ondansetron 4 mg. Neuromuscular blockade was reversed with neostigmine (50 µg/kg) and glycopyrrolate.
Postoperative care was standardized. Postanesthesia care unit (PACU) nurses evaluated patients for nausea, vomiting, and pain during the PACU admission. Pain in the PACU and on the surgical wards (first 24 hours) was treated with IV hydromorphone. Episodes of postoperative nausea and vomiting were treated with additional ondansetron 4 mg.
Perioperative glucose concentrations were the primary outcome variables in this investigation, which were measured in all patients using a point-of-care device (Nova StatStrip® glucose meter, Nova Biomedical, Waltham, MA). Data were collected for research purposes, and no therapy (insulin) was administered based on measured values. Treatment with insulin of increased blood glucose concentrations based on formal laboratory testing was at the discretion of the surgical service. The StatStrip® glucose meter was calibrated daily. Blood used to determine glucose concentrations was collected from fingerprick capillary blood samples drawn from a warmed upper extremity. In the early groups (Early-control, Early-4 mg, Early-8 mg), samples were collected at induction of anesthesia (baseline) and then 1, 2, 3, and 4 hours after induction of anesthesia. Blood samples were drawn in the late group (Late-control, Late-4 mg, Late-8 mg) at induction of anesthesia (baseline) and then 8 and 24 hours after induction. At the 8 and 24 hours measurement intervals, no samples were obtained within 2 hours of oral intake. In addition to the analysis of differences in blood glucose concentrations between groups over time, the incidence of hyperglycemic episodes (the number of patients with at least 1 blood glucose concentration >180 mg/dL during the study period) was determined as a secondary outcome.
A data collection sheet was used in the PACU to record recovery variables. Patients were assessed for the presence of nausea or vomiting every 15 minutes and the need for rescue antiemetics (ondansetron 4 mg) determined. At the time of discharge from the PACU, patients were asked to quantify pain on a 100-point visual analog scale (0 = no pain, 100 = worst pain imaginable) by a research assistant. Total doses of hydromorphone required to provide acceptable analgesia during the admission were noted. Postoperative fatigue, which may be reduced by steroids, was assessed at PACU discharge using a 4-point ordinal scale (0 = none, 1 = mild fatigue, 2 = moderate fatigue, 3 = severe fatigue). PACU nurses evaluated patients every 15 minutes using an Aldrete scoring system; the times required to meet discharge criteria (score ≥8 of 10 points) and to achieve actual discharge were recorded.
All patients were followed until the time of discharge from the hospital for any postoperative complications, including any evidence of postoperative wound infection or impaired wound healing (diagnosed by the surgical service).
A clinical investigation indicated that average blood glucose concentrations 3 hours after gynecologic surgery were 148 ± 25 mg/dL in patients not receiving dexamethasone.11 An increase in blood glucose concentrations of at least 37 mg/dL more than this value would be clinically significant because such blood glucose concentrations have been characterized as hyperglycemia (i.e., >180 mg/dL). In a single factor analysis of variance (ANOVA) study, sample sizes of 33, 33, and 33 were obtained from the 3 groups whose means were to be compared in each part of the present study. To test our hypothesis, the total sample of 99 subjects in each part of the present study achieved 83% power to detect a difference of at least 37.00 mg/dL using the Tukey–Kramer (Pairwise) multiple comparison test at a 0.01670 (to allow for similar comparisons at multiple times) significance level. The common standard deviation (SD) within a group was assumed to be 25.00. Discrete data are reported as the number of subjects and the percent of the group they represent. They were compared among the groups using the χ2 test or the Fisher-Freeman-Halton exact test while post hoc comparisons between groups were made with the Fisher-Freeman-Halton exact test when indicated by the comparison among groups (StatsDirect, Cheshire, United Kingdom). The 99% confidence intervals (CIs) for the differences in percentages of patients with blood glucose concentrations higher than 180 mg/dL were calculated using the Farrington and Manning score. Ordinal data and continuous data that were not normally distributed, as determined by the Shapiro-Wilk W test for nonnormality, are presented as median and range. These data were compared among groups using the Kruskal-Wallis test, which was adjusted for ties (StatsDirect). Normally distributed continuous data are reported as mean and SD. These data were compared among groups using a 1-way ANOVA.
The blood glucose concentrations, which were measured repeatedly across time in the same individuals, were first analyzed using a 2-factor ANOVA with repeated measures on 1 factor (NCSS, Kaysville, UT). The assumption of equality of the between-group covariance matrices was tested with Box’s M test, but it was not necessary to test the assumption of covariance matrix circularity because Box’s Geisser-Greenhouse correction of the F-test probabilities corrects for noncircularity in the covariance matrix. The early group blood glucose data failed the assumption of equality of the between-group covariance matrices so were log transformed because some of the data were not normally distributed, and the repeated measures ANOVA was rerun. The transformed data passed the assumption of equality of the between-group covariance matrices. Although the late group blood glucose concentrations did not fail this assumption, these data were also log transformed and similarly analyzed for the sake of consistency. Post hoc within-group comparisons of untransformed data with untransformed control were made with Wilcoxon signed rank test (StatsDirect) when indicated by the ANOVA (i.e., for both early and late group blood glucose concentrations in Tables 1 and 2) with the Bonferroni correction of the criterion for rejection of the null hypothesis to compensate for multiple applications of the test to the same data. Comparisons between groups at the various times were not indicated by either repeated measures ANOVA. Blood glucose concentrations are reported as median and range with median differences from baseline values and the 99% CIs for the difference between population medians, calculated using the Hodges-Lehmann approach for shift (StatsDirect).
Given the large number of comparisons being made, the criterion for rejection of the null hypothesis was a 2-tailed P < 0.01 to help minimize the chance of a type I error.
Two hundred patients were enrolled in this clinical trial. One patient was excluded for a protocol violation, and 4 patients refused postoperative blood sampling. Therefore, complete data were collected on 96 patients in the early groups and 99 patients in the late groups. Patient characteristics are presented in Tables 3 and 4. There were no significant differences between the control, 4 mg, or 8 mg groups in baseline demographic characteristics (including preexisting medical conditions or use of preoperative medications, data not presented). The number of patients undergoing either a transabdominal or laparoscopic transvaginal surgical approach did not differ between groups.
Intraoperative management data and postoperative recovery data are presented in Tables 5 and 6. Total anesthesia time and use of intraoperative anesthetic drugs did not differ between groups. During the PACU admission, although fewer patients in the 4 and 8 mg groups had nausea, vomiting, or need for treatment for emetic symptoms, these differences did not reach statistical significance. Similarly, in relation to postoperative pain management, statistically significant differences between treatment and control groups were only noted in the number of patients requiring pain medication in the Early-4 mg group (P = 0.005). No differences were observed between groups in the times required to meet PACU discharge criteria and achieve actual discharge.
A total of 777 blood glucose measurements were obtained in the early and late groups to test the hypothesis that 2 standard doses of dexamethasone (4 and 8 mg) would not produce either early (1 to 4 hours) or late (8 to 24 hours) increases in blood glucose concentrations that differed from those of placebo or increase the risk of hyperglycemic events. Blood glucose concentration data from the early groups are presented in Table 1. Baseline blood glucose concentrations did not differ among groups (median baseline concentrations ranged from 94–102 mg/dL). Peak median (range) blood glucose concentrations of 141 (64–230), 161.5 (101–208), and 153 (106–193) mg/dL were measured in the Early-control, Early-4 mg, and Early-8 mg groups, respectively. Median increases in blood glucose concentrations from baseline values ranged from 30 to 50.5 mg/dL in all groups at 1, 2, 3, and 4 hours after dexamethasone administration (P < 0.0001 versus within-group baselines for all groups; the 99% upper confidence limits for increases from baseline at 2 hours were 52.5, 60.5, and 54 mg/dL for control and 4 and 8 mg dexamethasone groups, respectively). However, this increase was not significantly greater in either of the dexamethasone groups compared with the Early-control group at any time or between the Early-4 mg groups and the Early-8 mg groups at any time.
Blood glucose concentrations in the late groups are presented in Table 2. Peak median glucose concentrations of 156 (82–229), 145.5 (108–237), and 148 (76–231) mg/dL were measured at 8 hours in the Late-control, Late-4 mg, and Late-8 mg groups, respectively. Although concentrations within groups at 8 and 24 hours were higher than their respective baseline concentrations, glucose concentrations were decreasing by the 24-hour measurement time. No differences in glucose concentrations were noted between the control and dexamethasone groups or between the dexamethasone groups at any measurement time.
The number of patients in the control and dexamethasone groups with at least 1 hyperglycemic event (blood glucose measurement >180 mg/dL, a secondary outcome variable) did not differ in any of the early (21%–28%, P = 0.807; the 99% CI for difference from control for the 4 mg dose was −21% to 34% while that for the 8 mg dose was −23 to 32%) or late (13%–24%, P = 0.552; the 99% CI for difference from control for the 4 mg dose was −36% to 15% while that for the 8 mg dose was −31% to 21%) groups (Table 7). Furthermore, the median number of hyperglycemic events (0 in all groups) in each group were not significantly different. No insulin was administered to any study subjects in the postoperative period.
In this randomized, double-blinded, placebo-controlled investigation, the effect of 2 standard intraoperative doses of dexamethasone (4 and 8 mg) on intraoperative and postoperative blood glucose concentrations was examined. Perioperative blood glucose concentrations during the first 24 hours after administration of single low-dose dexamethasone did not differ from those observed after saline administrations (a maximum median difference from baseline of 50.5 mg/dL at 4 hours in the 4 mg dexamethasone group versus a maximum median increase of 68 mg/dL at 8 hours in the control group). Furthermore, the incidence of perioperative hyperglycemic episodes, defined as a blood glucose measurement >180 mg/dL, did not differ among study groups. Our findings support the safety of dexamethasone in the perioperative setting.
As noted in a recent editorial, hyperglycemia is a recognized steroid-induced complication, but the effect of single low-dose therapy on blood glucose concentrations has not been well characterized.12 In healthy volunteers, short-term dexamethasone treatment induces reversible extrahepatic insulin resistance and increased endogenous glucose production.13 In contrast, the effect of single-dose dexamethasone treatment on glucose regulation in the surgical patient has been poorly studied. An examination of this question in the perioperative setting is further complicated by the stress response to surgery, which results in metabolic changes that increase blood glucose concentrations. Surgical trauma is followed by the release of glucagon, epinephrine, and cortisol, leading to increases in hepatic gluconeogenesis and glycogenolysis.9,10 In patients undergoing hysterectomies not administered corticosteroids, glucose concentrations increased from a mean ± SD of 89 ± 21 mg/dL preoperatively to 148 ± 25 mg/dL 2 hours after surgical closure.11 It is possible that an induction dose of dexamethasone may accentuate the metabolic changes induced by surgical tissue injury (increased endogenous glucose production and insulin resistance). Conversely, attenuation of surgical stress by a single dose of corticosteroids may beneficially affect perioperative glucose homeostasis by reducing release of counter-regulatory hormones (epinephrine, cortisol, glucagon).
Only a few investigations have been designed to examine the effect of single low-dose IV dexamethasone on the incidence of perioperative hyperglycemia. Two nonrandomized studies were performed in a neurosurgical patient population.5,6 In 20 patients undergoing craniotomies, Pasternak et al.5 observed that patients administered 10 mg dexamethasone had higher peak intraoperative blood glucose concentrations (149 mg/dL) than did those receiving placebo saline (103 mg/dL). Another small investigation (n = 34) in neurosurgical patients observed higher peak blood glucose concentrations in patients receiving 14 mg dexamethasone (198 mg/dL) compared with those not receiving corticosteroids (140 mg/dL).6 An unequal distribution of preoperative and intraoperative risk factors for hyperglycemia between study groups complicates interpretation of the findings from both investigations. Two additional studies have been conducted in patients undergoing abdominal surgery.7,8 Hans et al.7 administered 10 mg dexamethasone to nondiabetic (n = 32) and type 2 diabetic (n = 32) patients. Blood glucose concentrations increased similarly in both groups and peaked at 120 minutes. The lack of a control group without corticosteroids precludes conclusions as to whether hyperglycemia was secondary to dexamethasone or the stress response to surgery. In another small study of 30 obese subjects, patients randomized to receive 8 mg dexamethasone had higher maximum blood glucose concentrations (187 mg/dl) compared with controls (158 mg/dL).8 However, an important limitation of the investigation was that glucose-containing IV fluids were used during the period of the investigation when differences between groups were observed. In contrast to these investigations, 2 larger studies (in pediatric14 and cardiac surgical patients)15 found no differences in postoperative glucose values between patients receiving low-dose dexamethasone and placebo.
A number of preoperative patient variables may influence the incidence of perioperative hyperglycemia, which include age, sex, body weight, and preoperative medications.7,10,16,17 These risk factors were evenly divided among study groups. Intraoperative anesthetic management was standardized in all study groups, and no differences were noted in any measured variables. Inhaled anesthetic drugs depress glucose-stimulated insulin release,18,19 and deeper levels of anesthesia may attenuate the stress response to surgery. Therefore, BIS monitoring was used to control depth of anesthesia. In addition, glucose-containing IV fluids were avoided. Type, location, and duration of surgical procedure also has a significant effect on the neuroendocrine response to surgery and subsequent risk of hyperglycemia.10,11,20 All of these factors were similar between the dexamethasone and control groups. Finally, while pain and analgesic medications may influence perioperative glucose values,21,22 intraoperative and postoperative use of analgesic medications did not differ between groups, and pain scores at discharge from the PACU were similar.
The doses of dexamethasone examined in this investigation, 4 and 8 mg, are the most commonly administered low-dose regimens used in clinical practice. Most clinical studies assessing the effect of dexamethasone on the incidence of postoperative nausea and vomiting have used a single 8 mg dose. A dose of approximately 8 mg has also been demonstrated to be effective in providing postoperative analgesia, reducing pain medication usage, and improving postoperative quality of recovery.2–4 However, other studies have suggested that 4 to 5 mg doses are effective in preventing nausea and vomiting,23,24 and guidelines for ambulatory patients have recommended prophylactic doses of 4 to 5 mg for the prevention of emetic symptoms.25 The impact of different doses of dexamethasone on the incidence of hyperglycemia has not been established. A consensus statement on diabetic patients undergoing ambulatory surgery concluded, “It is highly likely that the increase in blood glucose levels with dexamethasone 4 mg would be lower than that after dexamethasone 8 mg.”26 Our findings do not support this hypothesis in a nondiabetic patient population. No significant differences between the 4 and 8 mg groups were observed during the study period.
In the present investigation, we defined hyperglycemia as a blood glucose concentration of >180 mg/dL. At the present time, there is no standardized definition of perioperative hyperglycemia. Clinically relevant hyperglycemia has been previously defined by investigators using thresholds ranging from 100 to 270 mg/dL.10 Available evidence supports a recommendation that perioperative glucose concentrations should be maintained below 180 mg/dL. Consensus statements and reviews in ambulatory diabetic patients, inpatient diabetic patients, and nondiabetic surgical patients have concluded that intraoperative blood glucose concentrations should be targeted at <180 mg/dL.10,26,27 Using this threshold definition, we observed that the incidence of perioperative hyperglycemia did not significantly differ between patients receiving saline or 4 and 8 mg dexamethasone. These findings suggest that although blood glucose concentrations were slightly increased in patients receiving dexamethasone compared with control groups, the clinical significance of this effect (at least in relation to glycemic control) is likely minimal.
The time at which peak blood glucose concentrations occur after intraoperative dexamethasone administration has not been clearly established in previous investigations. Studies have suggested that peak glucose concentrations are measured 2 hours after dexamethasone is given,7 while others demonstrated that peak measurements are recorded 8 to 10 hours after administration.6,8 To perform a more comprehensive assessment of the time course of blood glucose changes, we assessed both early (1–4 hours) and late (8–24 hours) hyperglycemic events. Our findings demonstrated that increases in blood glucose concentrations in the dexamethasone groups closely paralleled changes that occurred in the control groups. Glucose concentrations reached peak values within 2 to 3 hours and remained similarly elevated until the 8 hours measurement time. By 24 hours, blood glucose concentrations had declined. It is possible that maximal values occurred between 8 and 24 hours; however, blood samples were not obtained during this time to avoid awakening patients and to minimize disruptions in oral intake.
Clinical recovery variables did not differ among groups. These findings are not unexpected, as our study was likely not adequately powered to detect differences in several of the secondary outcome variables (nausea, vomiting, pain scores, or use of pain medications). Although postoperative wound infection and impaired wound healing were not observed in any study group, larger investigations are required to determine whether the immunomodulating effects of these low steroid doses increase the risk of surgical site infections.
There are several limitations of this investigation. First, all glucose concentrations were determined using a point-of-care device, the Nova StatStrip glucose monitor. A number of investigations have demonstrated that most tested point-of-care glucose monitors lack accuracy when compared with a central laboratory device or a blood gas analyzer.28 All current glucose measurement devices use an indirect enzymatic technique, and calculation of glucose concentrations may be influenced by a number of factors, including sample source (arterial, venous, or capillary), hematocrit values, oxygen concentrations, pH, hypothermia, hypotension, and use of certain medications.28 However, in physiologically stable patients, point-of-care measurements correlate well with laboratory reference values.10,26 In addition, the accuracy of the StatStrip device is improved over earlier generation point-of-care monitors. During a glucose clamp study, when comparing data from the StatStrip device to a central lab device, 100% of the StatStrip measurements were within zone A using Clarke error grid analysis (clinically acceptable; <20% deviation from reference).29 Other investigations have confirmed the accuracy of the StatStrip device, with less interference from a variety of exogenous factors.30,31 Second, patients were assigned to early and late groups rather than following each patient for 24 hours. This assignment was performed to limit the number of fingerstick blood samples per subject. Third, this investigation assessed perioperative blood glucose concentrations as a primary end point; however, glucose concentrations only represent a surrogate outcome measure. Although hyperglycemia results in a number of adverse physiologic responses, there is little evidence that modest increases of blood glucose concentrations produce adverse clinical outcomes in low-risk patients.
In patients undergoing gynecologic surgery, blood glucose concentrations during the first 24 hours after administration of single low-dose dexamethasone did not differ from those observed after saline administrations. Furthermore, higher dose treatment (8 mg) did not produce higher blood glucose concentrations than lower-dose therapy (4 mg). Clinicians should not avoid using dexamethasone for nausea and vomiting prophylaxis due to concerns related to hyperglycemia.
Name: Glenn S. Murphy, MD.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Attestation: Glenn S. Murphy, MD has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
Name: Joseph W. Szokol, MD.
Contribution: This author helped design the study and write the manuscript.
Attestation: Joseph W. Szokol approved the final manuscript.
Name: Michael J. Avram, PhD.
Contribution: This author helped design the study, analyze the data, and write the manuscript.
Attestation: Michael J. Avram has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Steven B. Greenberg, MD.
Contribution: This author helped conduct the study and write the manuscript.
Attestation: Steven B. Greenberg approved the final manuscript.
Name: Torin Shear, MD.
Contribution: This author helped conduct the study.
Attestation: Torin Shear approved the final manuscript.
Name: Jeffery S. Vender, MD.
Contribution: This author helped write the manuscript.
Attestation: Jeffery S. Vender approved the final manuscript.
Name: Jayla Gray, BA.
Contribution: This author helped conduct the study
Attestation: Jayla Gray has seen the original study data and approved the final manuscript.
Name: Elizabeth Landry, BA.
Contribution: This author helped conduct the study.
Attestation: Elizabeth Landry has seen the original study data and approved the final manuscript.
This manuscript was handled by: Peter S. A. Glass, MB ChB.
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