Adverse side effects of dexamethasone in surgical patients

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Abstract

In the perioperative period, dexamethasone is widely and effectively used for prophylaxis of postoperative nausea and vomiting (PONV), for pain management, and to facilitate early discharge after ambulatory surgery. Long‐term treatment with steroids has many side effects, such as adrenal insufficiency, increased infection risk, hyperglycaemia, high blood pressure, osteoporosis, and development of diabetes mellitus. However, whether a single steroid load during surgery has negative effects during the postoperative period has not yet been studied. To assess the effects of a steroid load of dexamethasone on postoperative systemic or wound infection, delayed wound healing, and blood glucose change in adult surgical patients (with planned subgroup analysis of patients with and without diabetes). We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), in the Cochrane Library, and the Web of Science for relevant articles on 29 January 2018. We searched without language or date restriction two clinical trial registries to identify ongoing studies, and we handsearched the reference lists of relevant publications to identify all eligible trials. We searched for randomized controlled trials comparing an incidental steroid load of dexamethasone versus a control intervention for adult patients undergoing surgery. We required that studies include a follow‐up of 30 days for proper assessment of the number of postoperative infections, delayed wound healing, and the glycaemic response. Two review authors independently screened studies for eligibility, extracted data from relevant studies, and assessed all included studies for bias. We resolved differences by discussion and pooled included studies in a meta‐analysis. We calculated Peto odds ratios (ORs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes. Our primary outcomes were postoperative systemic or wound infection, delayed wound healing, and glycaemic response within 24 hours. We created a funnel plot for the primary outcome postoperative (wound or systemic) infection. We used GRADE to assess the quality of evidence for each outcome. We included in the meta‐analysis 38 studies that included adults undergoing a large variety of surgical procedures (i.e. abdominal surgery, cardiac surgery, neurosurgery, and orthopaedic surgery). Age range of participants was 18 to 80 years. There is probably little or no difference in the risk of postoperative (wound or systemic) infection with dexamethasone compared with no treatment, placebo, or active control (ramosetron, ondansetron, or tropisetron) (Peto OR 1.01, 95% confidence interval (CI) 0.80 to 1.27; 4931 participants, 27 studies; I² = 27%; moderate‐quality evidence). The effects of dexamethasone on delayed wound healing are unclear because the wide confidence interval includes both meaningful benefit and harm (Peto OR 0.99, 95% CI 0.28 to 3.43; 1072 participants, eight studies; I² = 0%; low‐quality evidence). Dexamethasone may produce a mild increase in glucose levels among participants without diabetes during the first 12 hours after surgery (MD 13 mg/dL, 95% CI 6 to 21; 10 studies; 595 participants; I² = 50%; low‐quality evidence). We identified two studies reporting on glycaemic response after dexamethasone in participants with diabetes within 24 hours after surgery (MD 32 mg/dL, 95% CI 15 to 49; 74 participants; I² = 0%; very low‐quality evidence). A single dose of dexamethasone probably does not increase the risk for postoperative infection. It is uncertain whether dexamethasone has an effect on delayed wound healing in the general surgical population owing to imprecision in trial results. Participants with increased risk for delayed wound healing (e.g. participants with diabetes, those taking immunosuppressive drugs) were not included in the randomized studies reporting on delayed wound healing included in this meta‐analysis; therefore our findings should be extrapolated to the clinical setting with caution. Furthermore, one has to keep in mind that dexamethasone induces a mild increase in glucose. For patients with diabetes, very limited evidence suggests a more pronounced increase in glucose. Whether this influences wound healing in a clinically relevant way remains to be established. Once assessed, the three studies awaiting classification and two that are ongoing may alter the conclusions of this review . Background In the presence of an infection, the body starts an inflammation process. Dexamethasone is a steroid drug that slows down this inflammation process. Long‐term treatment with steroid drugs has many side effects such as increased risk of infection, high blood pressure, and development of diabetes. During surgery, dexamethasone is given to the patient to reduce the risk of nausea and vomiting after surgery, to relieve pain, and to make the patient feel better. However, whether short‐term treatment with dexamethasone leads to any adverse side effects is not known. Question The reviewers examined current evidence on the adverse side effects of short‐term treatment with dexamethasone during surgery. They compared patients receiving dexamethasone to patients not receiving dexamethasone. They particularly looked at the number of infections after surgery and the number of wounds that did not heal well. Furthermore, as long‐term treatment with steroids can lead to high blood sugar, they looked at the response of blood sugar within the first 24 hours postoperatively. What we found. Study characteristics: the reviewers searched four digital databases to find all relevant studies on this topic. The evidence is current to 29 January 2018. In total, they retrieved 38 relevant studies. All studies included adults undergoing surgery. A total of 27 studies (4931 participants) had assessed the occurrence of infection after surgery, nine studies (1072 participants) had investigated delayed wound healing, and 10 studies (595 participants) had looked at the effect of dexamethasone on blood sugar. Key results: after pooling results, reviewers found that dexamethasone had no effect on the development of an infection after surgery, and that wounds healed equally well in both groups. However, the quality of the studies was moderate to low, which means that more studies are needed to support a definitive conclusion. Finally, the mean blood sugar of patients without diabetes receiving dexamethasone was slightly higher than that of patients not receiving dexamethasone (low‐quality evidence). In patients with diabetes, this effect seemed to be larger. However, blood sugar was measured in only 74 patients with diabetes, which means that reviewers did not obtain a very accurate estimate. They qualified this as very low‐quality evidence. Authors' conclusions: dexamethasone probably does not increase the risk of infection after surgery. Not enough information is available to determine whether dexamethasone has an effect on the time it takes for surgical wounds to heal. However, included studies did not focus on patients with high risk for delayed wound healing, for example, patients with diabetes or those taking steroids; thus more studies are needed on this topic. Additionally, one has to keep in mind that taking dexamethasone leads to a mild increase in blood sugar. For patients with diabetes, very limited evidence suggests a greater increase in blood sugar. Whether or not the small increase in blood sugar has any effect on healing of surgical wounds has yet to be established. Three studies awaiting classification and two ongoing trials may alter the conclusions of this review, once assessed.

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Most cited references 67

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Acute hyperglycemia and the innate immune system: clinical, cellular, and molecular aspects.

Matthias Turina, Donald E Fry, Hiram Polk (2005)

To extract from the biomedical literature the reported effects of acute hyperglycemia on the major components of the innate immune system and to describe the clinical benefits of strict blood glucose control in certain patients. A Medline/PubMed search (1966 to July 2004) with manual cross-referencing was conducted, including all relevant articles investigating the effects of acutely elevated glucose levels on innate immunity. All publication types, languages, or subsets were searched. Original and selected review articles, short communications, letters to the editor, and chapters of selected textbooks were extracted. Most recent and relevant clinical trials were reviewed for the introductory section to provide the clinical background to this topic. The selected bench laboratory articles were then divided into three main categories based on the timing of events: a) the early phase of the innate immune reaction; b) the cytokine network; and c) the phagocytic phase. The most obvious findings related to hyperglycemia included reduced neutrophil activity (e.g., chemotaxis, formation of reactive oxygen species, phagocytosis of bacteria), despite accelerated diapedesis of leukocytes into peripheral tissue, as well as specific alterations of cytokine patterns with increased concentrations of the early proinflammatory cytokines tumor necrosis factor-alpha and interleukin-6. Furthermore, a reduction of endothelial nitric oxide formation takes place, thus decreasing microvascular reactivity to dilating agents such as bradykinin, and complement function (e.g., opsonization, chemotaxis) is impaired, despite elevations of certain complement factors. Acute, short-term hyperglycemia affects all major components of innate immunity and impairs the ability of the host to combat infection, even though certain distinctive proinflammatory alterations of the immune response can be observed under these conditions.

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Hyperglycemia Induced by Glucocorticoids in Nondiabetic Patients: A Meta-Analysis

Xiao-xia LIU, Xiao-ming Zhu, Qing Miao … (2014)

Background/Aims: Glucocorticoids are associated with a number of side effects including the development of new-onset hyperglycemia or diabetes. The diagnosis and treatment of glucocorticoid-induced hyperglycemia are surprisingly undervalued by many health-care professionals, probably due to the lack of quality studies that assess specific reasons for and prevention of hyperglycemia. The aim of this meta-analysis was to evaluate the long-term incidence of glucocorticoid-induced hyperglycemia and diabetes in nondiabetic patients who received glucocorticoid treatment. Methods: We searched Medline, Embase, and the Cochrane Library (Central) until January 2014 for studies in which subjects received systematic glucocorticoid treatment and which evaluated whether subjects developed hyperglycemia or were diagnosed with diabetes following treatment. The primary outcome for this analysis was the incidence of hyperglycemia and the secondary outcome was the frequency of diabetes. Results: We identified 13 studies that met our inclusion criteria; 12 of the studies were retrospective or observational in design. We found that the rate at which patients developed glucocorticoid-induced hyperglycemia or diabetes was 32.3% (p = 0.003) and 18.6% (p = 0.002), respectively. Conclusions: Our meta-analysis indicated that glucocorticoid-induced hyperglycemia occurs fairly frequently and points to the need for the design of prospective, randomized, controlled studies to further investigate and better understand this medical problem.

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Dexamethasone as an adjuvant to peripheral nerve block

Carolyne Pehora, Annabel Pearson, Alka Kaushal … (2017)

Peripheral nerve block (infiltration of local anaesthetic around a nerve) is used for anaesthesia or analgesia. A limitation to its use for postoperative analgesia is that the analgesic effect lasts only a few hours, after which moderate to severe pain at the surgical site may result in the need for alternative analgesic therapy. Several adjuvants have been used to prolong the analgesic duration of peripheral nerve block, including perineural or intravenous dexamethasone. To evaluate the comparative efficacy and safety of perineural dexamethasone versus placebo, intravenous dexamethasone versus placebo, and perineural dexamethasone versus intravenous dexamethasone when added to peripheral nerve block for postoperative pain control in people undergoing surgery. We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, DARE, Web of Science and Scopus from inception to 25 April 2017. We also searched trial registry databases, Google Scholar and meeting abstracts from the American Society of Anesthesiologists, the Canadian Anesthesiologists' Society, the American Society of Regional Anesthesia, and the European Society of Regional Anaesthesia. We included all randomized controlled trials (RCTs) comparing perineural dexamethasone with placebo, intravenous dexamethasone with placebo, or perineural dexamethasone with intravenous dexamethasone in participants receiving peripheral nerve block for upper or lower limb surgery. We used standard methodological procedures expected by Cochrane. We included 35 trials of 2702 participants aged 15 to 78 years; 33 studies enrolled participants undergoing upper limb surgery and two undergoing lower limb surgery. Risk of bias was low in 13 studies and high/unclear in 22. Perineural dexamethasone versus placebo Duration of sensory block was significantly longer in the perineural dexamethasone group compared with placebo (mean difference (MD) 6.70 hours, 95% confidence interval (CI) 5.54 to 7.85; participants1625; studies 27). Postoperative pain intensity at 12 and 24 hours was significantly lower in the perineural dexamethasone group compared with control (MD ‐2.08, 95% CI ‐2.63 to ‐1.53; participants 257; studies 5) and (MD ‐1.63, 95% CI ‐2.34 to ‐0.93; participants 469; studies 9), respectively. There was no significant difference at 48 hours (MD ‐0.61, 95% CI ‐1.24 to 0.03; participants 296; studies 4). The quality of evidence is very low for postoperative pain intensity at 12 hours and low for the remaining outcomes. Cumulative 24‐hour postoperative opioid consumption was significantly lower in the perineural dexamethasone group compared with placebo (MD 19.25 mg, 95% CI 5.99 to 32.51; participants 380; studies 6). Intravenous dexamethasone versus placebo Duration of sensory block was significantly longer in the intravenous dexamethasone group compared with placebo (MD 6.21, 95% CI 3.53 to 8.88; participants 499; studies 8). Postoperative pain intensity at 12 and 24 hours was significantly lower in the intravenous dexamethasone group compared with placebo (MD ‐1.24, 95% CI ‐2.44 to ‐0.04; participants 162; studies 3) and (MD ‐1.26, 95% CI ‐2.23 to ‐0.29; participants 257; studies 5), respectively. There was no significant difference at 48 hours (MD ‐0.21, 95% CI ‐0.83 to 0.41; participants 172; studies 3). The quality of evidence is moderate for duration of sensory block and postoperative pain intensity at 24 hours, and low for the remaining outcomes. Cumulative 24‐hour postoperative opioid consumption was significantly lower in the intravenous dexamethasone group compared with placebo (MD ‐6.58 mg, 95% CI ‐10.56 to ‐2.60; participants 287; studies 5). Perinerual versus intravenous dexamethasone Duration of sensory block was significantly longer in the perineural dexamethasone group compared with intravenous by three hours (MD 3.14 hours, 95% CI 1.68 to 4.59; participants 720; studies 9). We found that postoperative pain intensity at 12 hours and 24 hours was significantly lower in the perineural dexamethasone group compared with intravenous, however, the MD did not surpass our pre‐determined minimally important difference of 1.2 on the Visual Analgue Scale/Numerical Rating Scale, therefore the results are not clinically significant (MD ‐1.01, 95% CI ‐1.51 to ‐0.50; participants 217; studies 3) and (MD ‐0.77, 95% CI ‐1.47 to ‐0.08; participants 309; studies 5), respectively. There was no significant difference in severity of postoperative pain at 48 hours (MD 0.13, 95% CI ‐0.35 to 0.61; participants 227; studies 3). The quality of evidence is moderate for duration of sensory block and postoperative pain intensity at 24 hours, and low for the remaining outcomes. There was no difference in cumulative postoperative 24‐hour opioid consumption (MD ‐3.87 mg, 95% CI ‐9.93 to 2.19; participants 242; studies 4). Incidence of severe adverse events Five serious adverse events were reported. One block‐related event (pneumothorax) occurred in one participant in a trial comparing perineural dexamethasone and placebo; however group allocation was not reported. Four non‐block‐related events occurred in two trials comparing perineural dexamethasone, intravenous dexamethasone and placebo. Two participants in the placebo group required hospitalization within one week of surgery; one for a fall and one for a bowel infection. One participant in the placebo group developed Complex Regional Pain Syndrome Type I and one in the intravenous dexamethasone group developed pneumonia. The quality of evidence is very low due to the sparse number of events. Low‐ to moderate‐quality evidence suggests that when used as an adjuvant to peripheral nerve block in upper limb surgery, both perineural and intravenous dexamethasone may prolong duration of sensory block and are effective in reducing postoperative pain intensity and opioid consumption. There is not enough evidence to determine the effectiveness of dexamethasone as an adjuvant to peripheral nerve block in lower limb surgeries and there is no evidence in children. The results of our review may not apply to participants at risk of dexamethasone‐related adverse events for whom clinical trials would probably be unsafe. There is not enough evidence to determine the effectiveness of dexamethasone as an adjuvant to peripheral nerve block in lower limb surgeries and there is no evidence in children. The results of our review may not be apply to participants who at risk of dexamethasone‐related adverse events for whom clinical trials would probably be unsafe. The nine ongoing trials registered at ClinicalTrials.gov may change the results of this review. Dexamethasone and peripheral nerve block What is a peripheral nerve block? A nerve block prevents or relieves pain by interrupting pain signals that travel along a nerve to the brain. It involves an injection of local anaesthetic (a numbing agent) around a nerve either during or immediately after surgery. Pain relief from nerve block may last only a few hours after surgery, after which people may experience moderate to severe pain. What is dexamethasone? Dexamethasone is a steroid that may reduce pain and the inflammatory response to tissue damage after surgery (heat, pain, redness and swelling). In people receiving nerve block, dexamethasone may be given with the local anaesthetic around the nerve (perineural) or into a vein (intravenous) to prolong the pain relief from the peripheral nerve block. What did the researchers investigate? We looked for randomized controlled trials that investigated whether perineural or intravenous dexamethasone prolongs the length of time people experience pain relief from the peripheral nerve block when undergoing upper and lower limb surgery and reduces the intensity of pain after surgery. We also investigated whether perineural or intravenous dexamethasone cause any side effects or harms. We searched the medical literature for articles that included either adults or children undergoing upper or lower limb surgery with peripheral nerve block published up until 25 April 2017. We also assessed the quality of evidence for each outcome. What did the researchers find? We included 35 studies involving 2702 aged 15 to 78 years. When compared with placebo, the duration of sensory block was prolonged in the perineural dexamethasone group by 6 and a half hours (27 studies, 1625 participants, low‐quality evidence) and in the intravenous dexamethasone group by six hours (8 studies, 499 participants, moderate‐quality evidence). When perineural and intravenous dexamethasone were compared, the duration of sensory block was longer in the perineural dexamethasone group by three hours (9 studies, 720 participants, moderate‐quality evidence). Postoperative pain intensity at 12 hours after surgery was lower in the perineural dexamethasone group compared with placebo (5 studies, 257 participants, very low‐quality evidence) and at 24 hours after surgery (9 studies, 469 participants, low‐quality evidence). When we compared intravenous dexamethasone with placebo, postoperative pain intensity was also lower in the intravenous dexamethasone group than in the placebo group at 12 hours (3 studies, 162 participants, low‐quality evidence) and 24 hours (5 studies, 257 participants, low‐quality evidence). The amount of opioid pain medication required was also lower in participants receiving perineural and intravenous dexamethasone. There was no difference in postoperative pain intensity or the amount of opioid pain medication required when perineural and intravenous dexamethasone were compared. We concluded that one way of administering dexamethasone does not provide better pain relief over the other. Five serious adverse events were reported in three studies. One block‐related adverse event (pneumothorax or collapsed lung) occurred in one participant in a trial comparing perineural dexamethasone and placebo; however group allocation was not reported. The remaining events were non‐block‐related and occurred in two trials comparing perineural dexamethasone, intravenous dexamethasone and placebo. Two participants in the control group required hospitalization within one week of surgery; one for a fall and one for a bowel infection. One participant in the placebo group developed a chronic pain syndrome called Complex Regional Pain Sydrome, and one participant in the intravenous dexamethasone group developed pneumonia. The quality of evidence for safety issues was very low.