Abstract

BACKGROUND

The glucocorticoid dexamethasone prevents nausea and vomiting after surgery, but there is concern that it may increase the risk of surgical-site infection.

METHODS

In this pragmatic, international, noninferiority trial, we randomly assigned 8880 adult patients who were undergoing nonurgent, noncardiac surgery of at least 2 hours’ duration, with a skin incision length longer than 5 cm and a postoperative overnight hospital stay, to receive 8 mg of intravenous dexamethasone or matching placebo while under anesthesia. Randomization was stratified according to diabetes status and trial center. The primary outcome was surgical-site infection within 30 days after surgery. The prespecified noninferiority margin was 2.0 percentage points.

RESULTS

A total of 8725 participants were included in the modified intention-to-treat population (4372 in the dexamethasone group and 4353 in the placebo group), of whom 13.2% (576 in the dexamethasone group and 572 in the placebo group) had diabetes mellitus. Of the 8678 patients included in the primary analysis, surgical-site infection occurred in 8.1% (354 of 4350 patients) assigned to dexamethasone and in 9.1% (394 of 4328) assigned to placebo (risk difference adjusted for diabetes status, −0.9 percentage points; 95.6% confidence interval [CI], −2.1 to 0.3; P<0.001 for noninferiority). The results for superficial, deep, and organ-space surgical-site infections and in patients with diabetes were similar to those of the primary analysis. Postoperative nausea and vomiting in the first 24 hours after surgery occurred in 42.2% of patients in the dexamethasone group and in 53.9% in the placebo group (risk ratio, 0.78; 95% CI, 0.75 to 0.82). Hyperglycemic events in patients without diabetes occurred in 22 of 3787 (0.6%) in the dexamethasone group and in 6 of 3776 (0.2%) in the placebo group.

CONCLUSIONS

Dexamethasone was noninferior to placebo with respect to the incidence of surgical-site infection within 30 days after nonurgent, noncardiac surgery. (Funded by the Australian National Health and Medical Research Council and others; PADDI Australian New Zealand Clinical Trials Registry number, ACTRN12614001226695

Methods

TRIAL DESIGN

In this pragmatic, international, multicenter, randomized, placebo-controlled, triple-blind (patient, anesthesiologist, and assessor), noninferiority trial, patients were assigned to receive 8 mg of intravenous dexamethasone or matching placebo after induction of general anesthesia and before surgical incision. The rationale and design of the trial have been reported previously.¹¹ The trial and the protocol (available with the full text of this article at NEJM.org) were approved by the institutional review board at each participating site.

PATIENT SELECTION AND RANDOMIZATION

Eligible adult patients had an American Society of Anesthesiologists (ASA) physical status classification of I to IV (on a scale of I to VI, with higher classes indicating more severe systemic disease) and were undergoing elective or expedited nonurgent, noncardiac surgery with general anesthesia and an expected operative duration of at least 2 hours as well as an expected postoperative hospital stay of at least 1 night. Patients were excluded if they were undergoing surgery that was time critical, that involved an expected total incision length of 5 cm or shorter, that was associated with a primary infection (e.g., infection related to a prosthesis), or that required the use of intraoperative dexamethasone. Patients were also excluded if they had poorly controlled diabetes mellitus (defined as a glycated hemoglobin level of >9.0%). Eligible patients were randomly assigned in a 1:1 ratio by means of a Web-based service to receive dexamethasone or placebo in random permuted blocks of size 6 and 12, stratified according to trial center and a diagnosis of diabetes mellitus.

TRIAL PROCEDURES

Dexamethasone or placebo (supplied in a 2-ml vial and labeled with a randomization letter) was administered as an intravenous bolus within 5 minutes after induction of anesthesia by the attending anesthesiologist. All other aspects of patient care (including prophylactic antibiotic agents, management of blood glucose levels, and medication for patients with diabetes) followed local protocols and established guidelines. Nontrial glucocorticoids were prohibited for up to 30 days after the index surgical procedure.

The primary outcome was assessed in the modified intention-to-treat, per-protocol, and as-treated populations. The primary analysis was performed in the modified intention-to-treat population, which excluded patients who did not undergo eligible surgery (i.e., surgery with a total incision length of >5 cm when the patient was under general anesthesia), who withdrew consent or whose clinician withdrew the patient from the trial, who could not receive dexamethasone or placebo because they were not available at the center, or who met other exclusion criteria. The per-protocol population included the same criteria as those for the modified intention-to-treat population and further excluded patients who did not receive dexamethasone or placebo or who received open-label dexamethasone (or other glucocorticoid) either intraoperatively or within 30 days postoperatively. All secondary and tertiary outcomes were assessed in the modified intention-to-treat population only.

BLINDING, DATA QUALITY, AND SAFETY

The members of the clinical end-point committee, who were unaware of trial-group assignments, adjudicated all primary-outcome events. A list of committee members and details regarding the monitoring of data quality and site audits are provided in the Supplementary Appendix, available at NEJM.org. Two interim analyses were conducted (after 3379 and 5380 patients had been enrolled) by the independent data and safety monitoring committee, and the trial proceeded to completion.

ETHICS, GOVERNANCE, AND FUNDING

Written informed consent was obtained from all participants. Alfred Health oversaw the trial. The members of the steering committee designed the trial, gathered and analyzed the data, and vouch for the accuracy and completeness of the data and adherence of the trial to the protocol. The writing committee wrote the first draft of the manuscript, and the authors, some of whom were members of the steering committee, prepared the manuscript and made the decision to submit it for publication. There was no commercial involvement in the trial. The statistical analysis plan is available with the protocol at NEJM.org.

OUTCOMES

The primary outcome was the occurrence of a surgical-site infection within 30 days after surgery, determined according to the Centers for Disease Control and Prevention definitions, which comprise three categories: superficial incisional, deep incisional, and organ-space infection (Tables S1 and S2 in the Supplementary Appendix).¹² Secondary outcomes included superficial, deep, and organ-space infections within 30 days after surgery, assessed separately; deep and organ-space infections within 90 days after surgery in patients who had insertion of prosthetic material, considered separately; other infections (including urinary tract infections, pneumonia, catheter-related infections, and sepsis) within 30 days after the index procedure; the quality of recovery (as assessed with the use of the 15-item quality-of-recovery [QoR-15] scale, with scores ranging from 0 to 150 and higher scores indicating better quality of recovery) on days 1 and 30¹³; chronic postsurgical pain at 6 months after surgery; and death or persistent new-onset disability within 6 months after surgery.¹⁴ Details regarding tertiary outcomes, adverse events, and safety outcomes (including myocardial infarction, cerebrovascular accident, deep venous thrombosis or pulmonary embolism, and other serious adverse events) are provided in the Supplementary Appendix.

Patients were followed in the postanesthesia care unit, on the first 3 postoperative days, at hospital discharge, and at 30 days and 6 months after surgery. Active postoperative surveillance of surgical-site infection involved several processes. A wound assessment was performed on day 3 if the patient was still hospitalized. On day 30 and at 6 months, patients completed a telephone interview for wound assessment, and their medical records were reviewed to identify the occurrence of trial outcomes. Research staff members collated source documentation to enable outcome adjudication. Scores on the QoR-15 scale were assessed on days 1 and 30.¹³ Details regarding the outcome adjudication process and assessments (including additional assessments of pain and disability that are not included in this article) are provided in the Supplementary Appendix.

STATISTICAL ANALYSIS

A noninferiority margin of 2.0 percentage points was determined with the assistance of clinical experts and was set on the basis of a modified Delphi process and an anticipated incidence of surgical-site infection of 9%.¹⁵ With an expected incidence of infection of 9% in each group, we determined that 4303 patients per group would be needed to give the trial 90% power to detect noninferiority of dexamethasone; noninferiority would be concluded if the upper boundary of the two-sided 95% confidence interval for the difference in infection rates was less than 2.0 percentage points. As prespecified in the trial protocol, two interim analyses were planned — when one third and two thirds of the total number of patients had been enrolled. The analyses would use two-sided repeated asymmetric confidence intervals to preserve an overall confidence level of 95% and would use the O’Brien–Fleming function to determine the upper boundary of the confidence intervals and the power-spending function for the lower boundaries. The 90% power using these confidence intervals was confirmed by means of numerical simulation. Target recruitment was set at 8880 patients to account for a 3% loss to follow-up. An overall 5% significance level was used, and no correction for multiple testing was applied, apart from adjustment for the multiplicity of interim analyses for the primary outcome.

The absolute difference in 30-day infection rates was estimated with the use of binomial regression with an identity-link function, with adjustment for diabetes status; a risk ratio was also calculated using a logarithmic-link function. The analyses used 95.6% asymmetric confidence intervals based on the actual timing of the two interim analyses and spending functions. Noninferiority P values were calculated as one-sided, based on a null hypothesis of inferiority, with a significance level of 2.37% to account for the interim analyses.¹⁶ Sensitivity analyses were performed to account for missing data by imputing outcomes under “worst–best” and “best–worst” case scenarios (Table S10).¹⁷

Comparisons between groups for secondary and tertiary outcomes were estimated as risk ratios (for binary outcomes), differences in medians (for continuous outcomes), and hazard ratios (for time-to-event outcomes). Information regarding all statistical analyses is provided in the statistical analysis plan.

Continuing Education Activity

Dexamethasone has a wide variety of uses in the medical field. As a treatment, dexamethasone has been useful in treating acute exacerbation of multiple sclerosis, allergies, cerebral edema, inflammation, and shock. Patients with COVID-19, asthma, atopic and contact dermatitis, and drug hypersensitivity reactions have benefited from dexamethasone. Clinicians use it as a diagnostic agent for Cushing disease. This activity will highlight the mechanism of action, adverse event profile, FDA-approved, and off-label uses, administration, dosing, contraindications, pharmacodynamics, pharmacokinetics, monitoring parameters, and relevant interactions of dexamethasone, pertinent for interprofessional team members using dexamethasone for any of its intended indications.

Objectives:

• Outline the various indications of dexamethasone.
• Summarize the mechanism of action of dexamethasone.
• Describe the contraindications of dexamethasone.
• Review the importance of improving care coordination among interprofessional team members to improve outcomes for patients where dexamethasone can play a role in diagnosis or treatment.

Indications

Dexamethasone has a wide variety of uses in the medical field. As a treatment, dexamethasone has been useful in treating acute exacerbations of multiple sclerosis, allergies, cerebral edema, inflammation, and shock. Patients with conditions such as asthma, atopic and contact dermatitis, and drug hypersensitivity reactions have benefited from dexamethasone.[1] In endocrinology, dexamethasone has been found useful as a test for Cushing syndrome.[2]

Off-label indications are as follows. Dexamethasone is useful in the treatment of chemotherapy-induced nausea and vomiting. It is also used in the prevention and treatment of altitude sickness. It has also seen use in the treatment of spinal cord compression due to metastases in oncological cases.[3]

Dexamethasone is recommended for severely ill patients with COVID-19 who are on supplemental oxygen or ventilatory support; however, clinicians should not use it to manage patients with mild to moderate COVID-19.[4]

Mechanism of Action

Dexamethasone is a potent glucocorticoid with very little, if any, mineralocorticoid activity.[5] Dexamethasone’s effect on the body occurs in a variety of ways. It works by suppressing the migration of neutrophils and decreasing lymphocyte colony proliferation. The capillary membrane becomes less permeable, as well. Lysosomal membranes have increased stability. There are higher concentrations of vitamin A compounds in the serum, prostaglandin, and some cytokines (interleukin-1, interleukin-12, interleukin-18, tumor necrosis factor, interferon-gamma, and granulocyte-macrophage colony-stimulating factor) become inhibited. Increased surfactant levels and improved pulmonary circulation have also been shown with dexamethasone. Dexamethasone is metabolized by the liver and excreted in the urine mainly.

COVID-19 produces a hyperinflammatory state. Hence therapeutic effectiveness of dexamethasone is likely due to the broad anti-inflammatory activities of glucocorticoids.[6] In a clinical trial of hospitalized patients with COVID-19, the use of dexamethasone resulted in lower 28-day mortality among those receiving either mechanical ventilation or oxygen.[7]

Pharmacokinetics: According to the manufacturer’s labeling, the pharmacokinetics of oral dexamethasone is dose-proportional between the dose range of 0.5 to 40 mg.

Absorption: Dexamethasone median time to peak concentrations (Tmax) is 1 hour (range: 0.5 to 4 hours). A high-fat, high-calorie diet decreased C max by 23% of a single 20 mg dose of dexamethasone.
Distribution: Dexamethasone is about 77% bound to human plasma proteins in vitro.
Elimination: The mean terminal half-life of dexamethasone is 4 hours (18%), and oral clearance is 15.7 L/hr following a single dose of dexamethasone.
Metabolism: Dexamethasone is metabolized by CYP3A4.
Excretion: Renal excretion of dexamethasone is less than 10% of total body clearance. Less than 10% of dexamethasone is excreted in the urine.

Administration

Dexamethasone is available in various formulations. It is available in strengths ranging from 0.5 mg to 6 mg as a tablet. Other administration forms are an injectable suspension or an oral solution.[8]

• Oral tablets: 0.5 mg, 0.75 mg, 1 mg, 1.5 mg, 2 mg, 4 mg, 6 mg
• Oral elixir or solution: 0.5 mg/5 mL
• Oral concentrate: Dexamethasone Intensol: 1 mg/mL ( contains alcohol)
• Injection dexamethasone sodium phosphate: 4 mg/mL, 20 mg/5 mL, 120 mg/30 mL, 10 mg/mL, 100 mg/10 mL

Adult Dosing

• In treating inflammation, it is advisable to start with low doses of 0.75 mg/day, which may be titrated to 9 mg/day, with dosing divided into 2 to 4 doses throughout the day, which applies to intravenous, intramuscular, and oral administrations. Less may be used when directly administered to the lesion or tissue with dosing ranging from 0.2 to 6 mg per day.[9]

• For acute multiple sclerosis exacerbations, 30 mg oral daily doses for seven days are recommended, followed by one month of 4 to 12 mg daily doses.

• As cerebral edema may be a life-threatening condition, aggressive treatment is necessary. The recommendation is for 10 mg of intravenous dexamethasone, followed by 4 mg of intramuscular administration given every 6 hours. In this instance, it is necessary to titrate down over seven days to discontinue dexamethasone therapy.[10]

• The regimen is 1 to 6 mg/kg of intravenous dexamethasone as a one-time bolus in treating circulatory shock. The clinician may substitute this regimen with 40 mg given intravenously every 2 to 6 hours. Treatment with high-dose dexamethasone is not recommended beyond 2 to 3 days.

• Research has shown that allergic reactions improve with a 6-day regiment beginning with 4 to 8 mg intramuscular injection on the first day. This dose is followed by oral doses on days 2 to 6, beginning with 1.5 mg every 12 hours for days 2 and 3, 0.75 mg every 12 hours for the third day, and finally 0.75 mg daily for days 5 and 6. Therefore, the patient should be appropriately titrated by day 7 with no dosing necessary on day 7.

• Patients with COVID-19 (severe COVID-19): 6 mg once daily for ten days.[11]

• Cushing syndrome test begins with a low dose test. There are two versions of this test: the standard two-day and the overnight tests.

  • A 0.5 mg oral dose of dexamethasone is given every 6 hours for two days with the standard test. Six hours after giving the final dose, serum cortisol levels are measured. The overnight test begins with a 1 mg oral dose of dexamethasone at 11:00 PM with a second 1 mg oral dose at midnight. The following morning, serum cortisol levels are tested between 8:00 AM and 9:00 AM. The test is interpreted positive screening for Cushing syndrome if the final cortisol reading is high, signaling that the more specific confirmative high dose dexamethasone suppression test should follow.
  • The high-dose dexamethasone suppression test has three forms: the standard 2-day, overnight, and intravenous (IV). With all three versions of the test, baseline serum cortisol levels need to be determined before commencing with the test. Baseline serum is measurable with a 24-hour urinary free cortisol test.[12] The standard 2-day test uses 2 mg of oral dexamethasone given every 6 hours for two days. During the 2-day exam, urine is collected and tested for free cortisol, and 6 hours after the final dose of dexamethasone, blood is drawn to measure the serum cortisol level. The overnight test begins with an 8 mg oral dose of dexamethasone at 11:00 PM. The following morning between 8:00 AM, and 9:00 AM, serum cortisol is measured. The IV test is the shortest of the tests. The patient receives one milligram of dexamethasone via continuous intravenous infusion hourly for 7 hours. Serum cortisol is measured at the end of 7 hours.

   

Use in Specific Population

Patients with Hepatic Impairment

No dosage adjustments are provided in the manufacturer’s labeling.

Patients with Renal Impairment

The effect of renal impairment on the pharmacokinetics of dexamethasone has not been studied.

Pregnancy Considerations

Corticosteroids, including dexamethasone, readily cross the placenta. Adverse developmental consequences, including orofacial clefts (cleft lip with or without cleft palate), and intrauterine growth restriction (IUGR), have been documented using corticosteroids during pregnancy. In animal studies, the administration of corticosteroids to pregnant animals during organogenesis resulted in structural abnormalities, embryo-fetal mortality, and growth alteration. Advise pregnant women of dexamethasone’s potential risk to a fetus. Dexamethasone is administered with anti-myeloma products that can cause embryo-fetal harm and are contraindicated for use in pregnancy. Human Data suggests that dexamethasone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Multiple courses of antenatal dexamethasone had been associated with reduced birth weight, susceptibility to infections, and increased blood glucose levels in newborns. Neonatal hypoglycemia was also reported. Also, infants should be carefully observed for signs of hypoadrenalism with in-utero exposure to substantial doses of corticosteroids via maternal administration.

Breastfeeding Considerations

Systemically administered corticosteroids appear in human milk and interfere with endogenous corticosteroid production, suppressing growth. Therefore, instruct women not to breastfeed during treatment two weeks after the last dose. Dexamethasone can decrease basal serum prolactin and thyrotropin-releasing hormone-stimulated serum prolactin increase in nonnursing women.[13]

Adverse Effects

Although dexamethasone is generally well tolerated, it does have its drawbacks as a medication. The most frequently reported adverse effect by patients is the presence of insomnia after use. Other frequent adverse effects include acne, indigestion, fluid retention, electrolyte imbalances, weight gain, increased appetite, anorexia, nausea, vomiting, acne, agitation, and depression. There have been reports of adrenal suppression, arrhythmias, spermatogenic changes, glaucoma, hypokalemia, pulmonary edema, pseudotumor cerebri, and increased intracranial pressure.[14]

Steroid-induced osteonecrosis of the femoral head(long-term treatment).[15]

Hepatotoxicity: Likelihood score: A (well-established cause of liver injury when given in high doses, due to reactivation of hepatitis-B or a hepatocellular injury after high dose treatment.[16]

Contraindications

Dexamethasone use is contraindicated if patients have systemic fungal infections, hypersensitivity to dexamethasone, or cerebral malaria. Another contraindicated is to administer live or live-attenuated vaccines during dexamethasone use. The immune system will be suppressed, placing the patient at risk of infection. It is still permissible to administer killed or inactivated vaccines. However, it bears mentioning that corticosteroids may attenuate immune response, and it is unpredictable if immunity develops.[17]

In patients with cirrhosis, diverticulitis, myasthenia gravis, renal insufficiency, or ulcerative diseases such as peptic ulcer disease or ulcerative colitis, it is important to use caution when prescribing dexamethasone.

Recommendations include using dexamethasone cautiously during pregnancy as there is an increased risk of oral cleft formations.

Clinical experience has shown that large doses can increase blood pressure. In patients with recent myocardial infarction, it is advised to caution as an increase in free wall rupture of the left ventricle has been reported using dexamethasone.

Suppression of the hypothalamus-pituitary-adrenal axis (HPA axis) occurs with use, and therefore the rapid withdrawal of dexamethasone is not recommended. It is important to gradually increase and decrease any corticosteroid due to its effect on the HPA axis.

Latent diseases such as fungal (candida, cryptococcus, pneumocystis), parasitic (toxoplasmosis, amebiasis, strongyloides), and bacterial (mycobacterium, nocardia) infections may become active due to suppression of the immune system.[18]

Steroid use may inhibit bone formation and may lead to the formation of osteoporosis. Therefore, caution is necessary when prescribing dexamethasone to populations at higher risk for osteoporosis.[19]

Monitoring

• Serum electrolytes levels, blood pressure
• Serum glucose levels, HbA1c[20]
• Periodic eye examination (long term dexamethasone increases the risk of cataracts and glaucoma)[21]
• Bone mineral density scans[22]
• Creatine kinase levels (long term use of glucocorticoids such as dexamethasone predisposes to myopathy; weakness is primarily proximal)[23]

Toxicity

According to the manufacturer’s labeling information, the oral LD50 of dexamethasone in female mice is 6.5 g/kg. The intravenous formulation of dexamethasone has LD50 of 794 mg/kg in female mice. In the case of overdosage, no specific antidote is available. Therefore, treatment is supportive and symptomatic.

Enhancing Healthcare Team Outcomes