April 2016 FAQs

What are the 2016 guideline recommendations for the management of postoperative pain?

According to the Centers for Disease Control and Prevention (CDC), 51.4 million inpatient surgical procedures were performed in 2010.¹  Ambulatory surgeries are also common, with a reported 57.1 million surgical and other procedures performed in ambulatory settings in 2006.² More than 80% of patients experience acute pain following surgical procedures and less than 50% of these patients achieve adequate pain relief.³ In February 2016, a practice guideline on the management of postoperative pain was published by the American Pain Society, American Society of Regional Anesthesia and Pain Medicine and the American Society of Anesthesiologists (ASA). Although perioperative pain guidelines have been previously published, these prior guidelines were limited by differing evidence grading, inconsistent reporting of the strengths of recommendation, and few pediatric recommendations.^4,5 The 2016 guideline aims to promote evidence-based, effective, and safe postoperative pain management in adults and children.³

This article summarizes the 2016 guideline medication-related recommendations.³ Each recommendation is rated by both the strength of recommendation and the quality of evidence, using methods adapted from the Grading of Recommendations Assessment, Development, and Evaluation Working Group.^3,6 The quality of evidence is either high, moderate, or poor.³ The strength of recommendation is either strong or weak. A recommendation with a rating of “strong” is likely to result in greater benefit than harm, while a recommendation with a rating of “weak” is likely to result in greater harms than benefits. The guideline panel believes that most clinicians would follow a strong recommendation, but weak recommendations may or may not be followed depending on the clinical situation.

Recommendations regarding multimodal analgesia

Multimodal analgesia is the use of several medications and techniques that act by different mechanisms with additive or synergistic effects on pain relief.³ The guideline strongly recommends the use of multimodal analgesia combined with nonpharmacologic interventions to treat postoperative pain in both children and adults. The routine use of around the clock non-opioid analgesics as part of a multimodal analgesia regimen is suggested. Systemic opioids may not be needed if patients experience adequate pain relief with non-opioid and nonpharmacologic treatments. For surgeries of the extremities, abdomen, and thorax, the guideline encourages the use of regional anesthesia with local anesthetics, combined with systemic analgesics. The Table lists the multimodal analgesia options for specific procedures that are highlighted in the guidelines. In general, intra-articular, peripheral regional, and neuraxial analgesia techniques are not used together.

Table. Multimodal analgesia therapy options for common surgery types.^3a

Recommendations regarding systemic pharmacotherapy

The guideline panel strongly recommends that postoperative opioids should be given orally rather than intravenously (IV) in patients who can use the oral route.³ Studies have not shown a clear benefit with preoperative opioid administration. Long-acting opioid formulations are generally not recommended in the postoperative period since they do not allow for the dose titrations that most patients require. If parenteral therapy is needed, the guideline makes a strong recommendation against the intramuscular route and a strong recommendation for IV patient controlled analgesia (PCA). Candidates for PCA include patients who will require analgesia for more than a few hours and who have adequate cognitive function to understand the device. Children as young as 6 years old can use PCA properly. The guideline strongly recommends against the use of routine basal PCA infusions in adults who are opioid-naive. There was insufficient evidence for the guideline panel to make a recommendation regarding basal PCA infusions in children. When PCA is used there may still be a need for IV boluses of opioid medications, such as for rapid pain relief in the first few hours after surgery.

Oral nonsteroidal anti-inflammatory drugs (NSAIDs) and/or acetaminophen should be used as part of multimodal analgesia in children and adults, unless contraindicated since less pain and lower opioid consumption has resulted when these agents are used in combination with opioids (strong recommendation).³ The onset of action is faster with IV versus oral administration of NSAIDs and acetaminophen, but there is no clear difference in pain reduction when these agents are given by the oral and IV routes. A preoperative dose of oral celecoxib (200 to 400 mg given 30 minutes to 1 hour before surgery) can be considered in adults who are undergoing major surgery, unless contraindicated (strong recommendation). Both NSAIDs and celecoxib are contraindicated with coronary artery bypass graft surgery, due to an increased risk of cardiovascular events.

The guideline also recommends consideration for the following medications for multimodal analgesia: gabapentin or pregabalin (strong recommendation), IV ketamine (weak recommendation), and IV lidocaine in adults who undergo open or laparoscopic abdominal surgery (weak recommendation).³

Postoperative pain in patients who are receiving long-term opioids may be more difficult to manage and postoperative opioid requirements may be greater.³ Consultation with a pain specialist should be considered for difficult-to-manage pain or in complex cases. Nonpharmacologic interventions including cognitive-behavioral therapy may have an important role in these patients. Nonopioid systemic therapies (eg, gabapentin, pregabalin, ketamine) and peripheral regional and neuraxial local anesthetic administration may be helpful. Basal opioid infusions may be needed in opioid-experienced patients who receive PCA. Patients should be educated on opioid use before surgery and tapering opioids to appropriate target doses after surgery.

Recommendations regarding local or topical pharmacotherapy

Infiltration of local anesthetics into the surgical site (eg, subcutaneous, intra-articular administration) has some evidence of efficacy as a part of multimodal analgesia, particularly for certain procedures including total knee replacement, arthroscopic knee surgery, Cesarean section, laparotomy, and hemorrhoid surgery.³ However, some studies have not shown a benefit, which has led to a weak recommendation for this strategy in the guideline. Local administration of local anesthetics (including liposomal bupivacaine) should be limited to procedures with evidence for this technique. The only strong recommendation for topical pharmacotherapy is for local anesthetics in combination with nerve blocks before circumcision. The guidelines strongly recommend against the intrapleural administration of local anesthetics after thoracic surgery.

Recommendations regarding regional anesthesia

The guideline strongly recommends that clinicians consider the use of surgical site-specific peripheral regional anesthesia in adults and children who undergo procedures with evidence supporting the efficacy of peripheral regional anesthesia, especially procedures of the upper or lower extremities.³ These procedures include: thoracotomy, lower extremity joint surgery, shoulder surgery, Cesarean section, hemorrhoid surgery, and circumcision. Clinicians should be aware of case reports of elastomeric pump failures that resulted in early delivery or complete emptying of the pump. Some of these cases were fatal. The guideline states that elastomeric pumps should be used by clinicians and patients who know how to appropriately monitor for pump failure and local anesthetic toxicity. Continuous peripheral regional techniques are strongly recommended over single doses when the duration of postoperative pain is likely to be prolonged.

If a single-injection peripheral nerve block is used, the adjuvant use of clonidine can be considered for prolongation of analgesia (weak recommendation).³ No other adjuvants to peripheral regional anesthesia are mentioned.

Recommendations regarding neuraxial pharmacotherapy

The guideline recommends that neuraxial (epidural or spinal) analgesia should be offered for major thoracic and abdominal procedures (strong recommendation).³ Other specific procedures mentioned in the guideline include Cesarean section, hip surgery, and lower extremity surgeries. The greatest benefit of neuraxial analgesia may be in patients who are at risk for cardiac complications, pulmonary complications, or prolonged ileus. Since spinal analgesia is limited to a single opioid dose, a potential advantage of epidural analgesia is that it can be given as a continuous infusion or PCA with local anesthetics (with or without opioids). Patients receiving neuraxial analgesia should be closely monitored for respiratory depression, hypotension, and motor weakness from spinal cord compression, and for compartment syndrome in patients who have undergone hip or lower extremity surgeries.

The guideline panel found insufficient evidence to recommend the routine use of adjuvant epidural clonidine with local anesthetics.³ The guideline strongly recommends the avoidance of neuraxial magnesium, benzodiazepines, neostigmine, tramadol, and ketamine.

General recommendations

The guideline endorses preoperative patient and family education on changes in analgesic medications that are required before and after surgery (eg, aspirin, NSAIDs), and medications that should be continued to prevent withdrawal symptoms (eg, opioids, baclofen).³ Concurrent medication use and medical conditions, history of chronic pain, history of substance abuse, and response to previous postoperative pain treatment regimens should be considered in the development of the postoperative pain management plan (strong recommendation). Patients should also receive education on the postoperative pain treatment plan, including safe use of pain medications, tapering of analgesics if opioids were used for more than 1 to 2 weeks, and side effect management (strong recommendation). Proper disposal of unused opioids and other pain medications should also be discussed.

After surgery, the pain management plan should be adjusted based on adequacy of pain relief and tolerability/safety (strong recommendation).³ A validated tool should be used to assess postoperative pain (strong recommendation), and high pain intensity ratings that do not respond to usual interventions should be investigated in case there is a new medical issue, surgical complication, opioid tolerance, or psychological distress. Consultation with a pain specialist may be needed for patients with inadequately controlled postoperative pain or patients who are at risk for inadequate pain control due to opioid tolerance or a history of substance abuse (strong recommendation). Institutional policies that promote the safe and effective delivery of postoperative pain control are recommended.³

Conclusion

The 2016 guideline on postoperative pain management emphasizes that pain control should be individualized to the surgical procedure, patient medical history and concurrent medications, and patient preferences.³ Patient education and close monitoring are important elements of safe analgesic use. Although there are numerous medication options and administration techniques, therapy choices should be limited to interventions with evidence supporting their efficacy and safety for the specific procedure.

References

1. Centers for Disease Control and Prevention. National Center for Health Statistics. Inpatient Surgery. http://www.cdc.gov/nchs/fastats/inpatient-surgery.htm. Updated April 29, 2015. Accessed March 18, 2016.
2. Centers for Disease Control and Prevention. National Center for Health Statistics. U.S. Outpatient Surgeries on the Rise. http://www.cdc.gov/nchs/pressroom/09newsreleases/outpatientsurgeries.htm. Updated June 11, 2009. Accessed March 18, 2016.
3. Chou R, Gordon DB, de Leon-Casasola, et al. Management of postoperative pain: a clinical practice guideline from the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists' Committee on Regional Anesthesia, Executive Committee, and Administrative Council. J Pain. 2016;17(2):131-157.
4. American Society of Anesthesiologists Task Force on Acute Pain Management. Practice guidelines for acute pain management in the perioperative setting: an updated report by the American Society of Anesthesiologists Task Force on Acute Pain Management. Anesthesiology. 2012;116(2):248-273.
5. Gordon DB, de Leon-Casasola OA, Wu CL, Sluka KA, Brennan TJ, Chou R. Research gaps in practice guidelines for acute postoperative pain management in adults: findings from a review of the evidence for an American Pain Society clinical practice guideline. J Pain. 2016;17(2):158-166.
6. GRADE working group. http://www.gradeworkinggroup.org/. Accessed March 23, 2016.

April 2016

The information presented is current as March 18, 2016. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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What is the most recent evidence for using probiotics in patients with Clostridium difficile? 

Background

Probiotics are known as live microbial organisms that have beneficial effects on health.¹ The interest in use of probiotics is rising due to assumed safety of these organisms and potential enhancement of gastrointestinal microflora. Researchers and practitioners are exploring use of the organisms in clinical settings, mainly for conditions such as antibiotic-associated diarrhea (AAD) and Clostridium difficile infection (CDI).^1,2 Presence of 3 or more stools within 24 hours and positive testing for C. difficile toxin are key components for diagnosis of CDI.³ Clostridium difficile-associated diarrhea (CDAD) may be AAD but the testing must show positive results for C. difficile toxin.² Some studies differentiate between CDI and CDAD by defining CDI as an infection with positive stool testing for C. difficile and CDAD as an infection with positive stool testing in addition to presence of diarrhea.^2,4 This review discusses recent literature for probiotics use only for CDI or CDAD but not AAD alone.

The exact mechanism of action for probiotics in CDAD and CDI is unknown but several proposed theories exist.¹ Probiotics are thought to reestablish gut flora that has been altered by antibiotics and improve the mucosal gut barrier. Some studies proposed that probiotics may inhibit C. difficile colonization as well as decrease inflammation caused by CDI. Strains that are most often studied in patients with CDAD include Lactobacillus species, Bifidobacteria species, Streptococcus thermophiles, and Saccharomyces boulardii.

Guidelines

Recently, 2 organizations released their guidance on use of probiotics in management of CDI. The American Society of Colon and Rectal Surgeons gave a weak recommendation for use of probiotics for both prevention and treatment of CDI in its 2015 guideline.⁵ The guideline also described potential use of probiotics as an adjunctive agent in recurrent CDI.

The European Society of Colon and Rectal Surgeons released a 2014 update to its guideline on treatment of CDI.⁶ The organization does not support use of probiotics and cites evidence for live organisms causing invasive disease in immunocompromised patients and a potential increase in mortality in patients with mesenteric ischemia.

The guideline from the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA) on CDI was last updated in 2010 and recommends against administration of probiotics for prevention and/or treatment of CDI or CDAD.³ The newly updated guideline is scheduled to be released during spring 2016.

Key evidence on probiotics use for CDI

Some of the studies on using probiotics for CDI date back to the late 1980s, and several meta-analyses have been performed over the past decade to understand how probiotics affect outcomes in patients with CDAD and/or CDI. Many of these meta-analyses incorporate the same studies, and therefore, Table 1 lists only most recent and relevant meta-analyses that are widely discussed in the current literature, that focus specifically on outcomes in CDI and/or CDAD, and include at least 10 randomized control trials.

Table 1. Recent meta-analyses exploring use of probiotics in patients with CDI and/or CDAD.^4,7,8

The meta-analyses described in Table 1 showed varying results. The Cochrane review by Goldenberg and colleagues and meta-analysis by Johnston and colleagues revealed that the use of probiotics reduced CDAD incidence.^4,8 The same research group published both meta-analyses.  Probiotics did not improve incidence of CDI in the Goldenberg meta-analysis while the Pattani meta-analysis showed reduction in CDI with probiotics.^4,7 The results for adverse events also differ among meta-analyses with one showing decreased incidence of adverse events with probiotics while another meta-analysis noted no significant differences in rate of adverse events with probiotic versus placebo or no treatment.^4,8 These meta-analyses rated the quality of their results as moderate or low depending on the outcome measured.

The PLACIDE trial, the largest randomized, double-blind, multicenter clinical trial to date, was not included in any of the above mentioned meta-analyses due to its recent publication date.⁹ The placebo-controlled trial of probiotics was conducted in inpatient adults ages 65 years and older who were taking an antibiotic, were exposed to one in the previous 7 days, or would start an antibiotic therapy. The trial enrolled 2981 patients, who received one probiotic capsule daily for 21 days, consisting of Lactobacillus acidophilus, Bifidobacterium bifidum, and Bifidobacterium lactis. The results showed no statistically significant rates for incidence of AAD at 8 weeks (relative risk (RR) 1.04; 95% confidence interval (CI) 0.84 to 1.28; p=0.71) and CDAD at 12 weeks (RR 0.71; 95% CI 0.34 to 1.47; p=0.35) between the probiotics and placebo groups. Lack of ethnic diversity, location of study centers in the United Kingdom, and including only patients 65 years and older were the main drawbacks of the trial.

The guideline from the American Society of Colon and Rectal Surgeons incorporated evidence from the Goldenberg and Johnston meta-analyses when forming its recommendations regarding probiotics, while the European guideline only included information from the Johnston meta-analysis.^5,6 The European guideline also discussed evidence from studies that focused more on AAD and not necessarily on CDI and included an older Cochrane review that analyzed results only from 4 randomized clinical trials.^6,10,11 Both guidelines did not mention the PLACIDE trial in their analysis of probiotics use.^5,6 Therefore, caution should be exercised when interpreting currently published guidelines on probiotic use for CDI and/or CDAD.

Strains, dose, and duration

The guideline from the American Society of Colon and Rectal Surgeons does not provide any recommendations regarding strain, dose, and length of therapy.⁵ It briefly mentions that previous meta-analyses found that the most effective strains for prevention of CDI are Lactobacillus acidophilus CL1285, Lactobacillus casei LBC80R, and Saccharomyces boulardii. However, not enough evidence exists to give clear guidance on strains to use, dosing, and duration of probiotic to prevent CDI/CDAD.

The meta-analyses from Table 1 performed subgroup analyses to determine effects of strains on outcomes with probiotics.  The Cochrane review noted that the combination of Lactobacillus acidophilus and Lactobacillus casei (RR 0.21; 95% CI 0.11 to 0.42) had a more favorable outcome for CDAD compared to Lactobacillus rhamnosus (RR 0.63; 95% CI 0.30 to 1.33).⁴ But authors highlighted that the subgroup analysis was performed between study comparisons and may not be credible since no previous evidence was found to support the difference in outcomes with these specific Lactobacillus strains. A subgroup analysis in the Johnston meta-analysis showed tendencies for more favorable outcomes with probiotics containing multiple species as compared to single species.⁸ A subgroup analysis from the Pattani meta-analysis favored probiotics containing Lactobacillus strains (RR 0.33; 95% CI 0.18 to 0.60) for reduction of CDI compared to placebo while probiotics containing Saccharomyces boulardii (RR 0.49; 95% CI 0.17 to 1.40) did not differ from placebo for CDI outcome.⁷ The results of subgroup analyses must be carefully interpreted since differences in trial designs could affect assessed outcomes. The meta-analyses were not able to perform subgroup analyses for dose and duration of probiotics use due to variability in study designs.^4,7,8

The PLACIDE trial showed no benefit in CDI prevention with the use of probiotics that contained Lactobacillus acidophilus CUL60 and CUL21, Bifidobacterium bifidum CUL20, and Bifidobacterium lactis CUL34.⁹ Each probiotics capsule contained 6 × 10¹⁰ live bacteria and was given once daily for 21 days.

Safety

Although use of probiotics is considered to be safe for most patients, certain patient groups are at increased risk for developing several adverse events.² Previous reports discussed cases of Lactobacillus endocarditis and bacteremia from probiotic use in infants, thoracic transplant patients, and geriatric patients afflicted by cardiovascular or gastrointestinal diseases, and cases of Saccharomyces invasive infections in debilitated and immunocompromised patients.^2,6 A multicenter randomized controlled trial entitled PROPATRIA found a statistically significant increase in mortality and bowel ischemia in patients with acute pancreatitis treated with probiotics compared to patients who received placebo.¹² This trial and other case reports were discussed in the European guideline for management of CDI and formed the evidence for the recommendation against probiotic use in patients with CDI.⁶

A review article published in 2006 proposed major and minor risk factors that predispose patients to developing sepsis related to probiotics (see Table 2).^2,13 Inpatient healthcare providers should give special consideration to presence of central venous catheter as a minor risk factor. Healthcare workers can potentially contaminate vascular catheters, and therefore, capsules or packets should not be open around patients with central venous catheters. If a clinical situation calls for administration of probiotics in the vicinity of patients with these catheters, healthcare workers should wear gloves while opening capsules or packets and change them before proceeding to a next patient.  

Table 2. Risk factors for developing sepsis from probiotics.^2,13

Conclusion

The interest for probiotics use is rising because these microorganisms have the potential to reestablish gut flora and improve intestinal mucosal barrier. Several guidelines mention use of probiotics in CDI and CDAD but recommendations are inconsistent mainly because supporting evidence reports contradictory results. Several meta-analyses showed trends towards better outcomes with probiotic use in patients with CDI and/or CDAD but the recent large randomized trial entitled PLACIDE revealed no benefits with probiotics use in this condition.  However, the trial included only patients who are older than 65 years old suggesting that results may differ for a younger population. Subgroup analyses from the meta-analyses showed that most benefit may be seen with probiotics that contain multiple strains within a preparation and that include at least Lactobacillus species. If the choice has been made in favor of using probiotics, careful assessment of patient characteristics and factors is necessary because certain patient groups are at risk for developing probiotics-related sepsis, endocarditis, or another invasive infection. For example, probiotics should be avoided in immunocompromised patients, premature infants, and patients with acute pancreatitis. At this moment, no clear guidance exists regarding appropriate dose, strains, and duration for probiotics. Most of these decisions are left up to treating providers and individual organizations.

References

1.            Allen SJ. The potential of probiotics to prevent Clostridium difficile infection. Infect Dis Clin North Am. 2015;29(1):135-144.

2.            Crow JR, Davis SL, Chaykosky DM, Smith TT, Smith JM. Probiotics and Fecal Microbiota Transplant for Primary and Secondary Prevention of Clostridium difficile Infection. Pharmacotherapy. 2015;35(11):1016-1025.

3.            Cohen SH, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the society for healthcare epidemiology of America (SHEA) and the infectious diseases society of America (IDSA). Infect Control Hosp Epidemiol. 2010;31(5):431-455.

4.            Goldenberg JZ, Ma SS, Saxton JD, et al. Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children. Cochrane Database Syst Rev. 2013;5:Cd006095.

5.            Steele SR, McCormick J, Melton GB, et al. Practice parameters for the management of Clostridium difficile infection. Dis Colon Rectum. 2015;58(1):10-24.

6.            Debast SB, Bauer MP, Kuijper EJ. European Society of Clinical Microbiology and Infectious Diseases: update of the treatment guidance document for Clostridium difficile infection. Clin Microbiol Infect. 2014;20 Suppl 2:1-26.

7.            Pattani R, Palda VA, Hwang SW, Shah PS. Probiotics for the prevention of antibiotic-associated diarrhea and Clostridium difficile infection among hospitalized patients: systematic review and meta-analysis. Open Med. 2013;7(2):e56-67.

8.            Johnston BC, Ma SS, Goldenberg JZ, et al. Probiotics for the prevention of Clostridium difficile-associated diarrhea: a systematic review and meta-analysis. Ann Intern Med. 2012;157(12):878-888.

9.            Allen SJ, Wareham K, Wang D, et al. Lactobacilli and bifidobacteria in the prevention of antibiotic-associated diarrhoea and Clostridium difficile diarrhoea in older inpatients (PLACIDE): a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2013;382(9900):1249-1257.

10.          Hempel S, Newberry SJ, Maher AR, et al. Probiotics for the prevention and treatment of antibiotic-associated diarrhea: a systematic review and meta-analysis. Jama. 2012;307(18):1959-1969.

11.          Pillai A, Nelson R. Probiotics for treatment of Clostridium difficile-associated colitis in adults. Cochrane Database Syst Rev. 2008(1):Cd004611.

12.          Besselink MG, van Santvoort HC, Buskens E, et al. Probiotic prophylaxis in predicted severe acute pancreatitis: a randomised, double-blind, placebo-controlled trial. Lancet. 2008;371(9613):651-659.

13.          Boyle RJ, Robins-Browne RM, Tang ML. Probiotic use in clinical practice: what are the risks? Am J Clin Nutr. 2006;83(6):1256-1264; quiz 1446-1257.

April 2016

The information presented is current as March 5, 2016. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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Does adjunctive corticosteroid therapy improve outcomes in patients with community-acquired pneumonia?

Introduction

Community-acquired pneumonia (CAP) is a common lower respiratory tract infection, with more than 5 million cases occurring annually in the US.¹ Infection is normally caused by bacterial pathogens including Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella species. Numerous anti-infectives are Food and Drug Administration (FDA)-approved and have demonstrated efficacy in the management of pneumonia; however, mortality rates remain concerning.^1,2 For example, the mortality rate among outpatients is estimated below 1%, yet mortality can range from 12% to 40% among hospitalized patients. Patients with severe CAP, estimated at 8% to 10% of pneumonia cases, are at especially high risk of death; this includes patients with shock or hypoxemia, patients who require mechanical ventilation, and patients with elevated markers of inflammatory response, as defined in guidelines from the Infectious Disease Society of America/American Thoracic Society (IDSA/ATS) and the British Thoracic Society (BTS).^2,3

A characteristic of severe CAP is the deleterious inflammatory response, characterized by expression of cytokines, chemokines, interleukins and tumor necrosis factor.⁴  These inflammatory mediators can promote alveolar capillary leak similar to that present in acute respiratory distress syndrome (ARDS). This may result in lung infiltrates, rales, hypoxemia, and respiratory alkalosis. Corticosteroids have been proposed as adjunctive therapy in patients with severe CAP because of their ability to decrease this excessive inflammation.

Corticosteroid use is only briefly mentioned in BTS and IDSA/ATS guidelines based on preliminary and limited studies.^2,3 Since publication of these guidelines, more intensive research has focused on defining the true benefit of adjunctive corticosteroid therapy in patients with CAP. This article will review recent literature describing these findings, relying on meta-analyses published in recent years.

Effect of adjunctive corticosteroids in reducing CAP-related mortality

Based on the results of numerous randomized controlled trials (RCTs) and meta-analyses, findings suggest that adjunctive corticosteroid therapy in CAP has no significant effect on mortality.^5-7 The most recent meta-analysis by Wan and colleagues found that corticosteroids did not provide a significant reduction in mortality when results from 9 RCTs (n=1667 patients) were meta-analyzed (relative risk [RR], 0.72; 95% CI, 0.43 to 1.21).⁵ Results were consistent using data from 6 cohort studies (n=4095 patients; RR, 1.00; 95% CI, 0.86 to 1.17).

This meta-analysis followed another by Siemieniuk in 2015, which included 4 RCTs (n=1974) not included by Wan and colleagues.^5,8 These included 2 older studies from 1956 and 1972, which may not represent current practice and did not offer clear definitions of CAP.^9,10 Overall, results were nonetheless consistent with findings by Wan and colleagues, finding no significant mortality benefit with adjunctive corticosteroids in all CAP patients, although data trended closer toward significance (RR, 0.67; 95% CI, 0.45 to 1.01).⁸ Similarly, another 2015 meta-analysis by Horita and colleagues, which used data from 10 RCTs included in both Wan and Siemieniuk meta-analyses, found no overall significant benefit from adjunctive corticosteroid therapy on all-cause mortality (odds ratio [OR], 0.8; 95% CI 0.53 to 1.21). ¹¹ 

Patients with severe CAP have been analyzed separately in subgroup analyses, which to date have offered the only significant findings of mortality benefit with adjunctive corticosteroid therapy.^8,11 Two meta-analyses reported significant reductions of approximately 60% in all-cause mortality with adjunctive corticosteroids in patients with severe CAP (RR, 0.39; 95% CI, 0.20 to 0.77 in Siemieniuk et al; RR, 0.41; 95% CI, 0.19 to 0.90 in Horita et al). In contrast, Wan and colleagues did not find significant benefit in this subgroup (RR, 0.72; 95% CI, 0.43 to 1.21). ⁵ Some propose the benefit in severe CAP may be rooted in the greater inflammatory response in these patients following the release of endotoxin or cytokines from high bacterial loads upon initiation of antimicrobial therapy.¹²

Despite consistent findings from several investigators using the same data sources, concern has been expressed regarding the potential for these meta-analyses to be underpowered to detect a statistically significant effect of corticosteroids.¹³ These authors caution that the limited sample sizes with low event rates may falsely overestimate the magnitude of the treatment effect of corticosteroids. For example, Wan and colleagues determined a required sample size for meta-analytic purposes of 2546 patients would be required to reliably detect a treatment effect with corticosteroids in patients with severe CAP. ⁵  In addition, Gu calculated a total of 9251 patients would be required to show a 20% risk reduction with corticosteroids, suggesting that the current evidence is inconclusive.¹³ Greater clarity should come from the ESCAPe trial, an RCT evaluating mortality in adult patients with severe CAP treated with methylprednisolone or placebo. ¹⁴ Investigators plan to enroll 1450 patients, considerably more than individual trials of severe CAP included in current meta-analysis. Results are anticipated in January 2018.

Consistent benefit with adjunctive corticosteroids in other CAP-related clinical outcomes

Contrary to the lack of significant benefit on mortality, adjunctive corticosteroid therapy in CAP has consistently shown significant improvement in other meaningful clinical outcomes. For example, the risk of ARDS was significantly reduced by approximately 80% (RR, 0.21; 95% CI, 0.08 to 0.59 in Wan et al; RR, 0.24; 95% CI, 0.10 to 0.56 in Siemieniuk et al).^5,8 Also, the risk for progression to mechanical ventilation was reduced by approximately half (RR, 0.45; 95% CI, 0.26 to 0.79 in Siemieniuk et al).⁸ The reduction in this risk appeared greater for patients with less severe compared to more severe pneumonia (RR, 0.18 vs 0.54, respectively).⁸

Additionally, improvements in the time to various markers of clinical improvement have been identified. The time to clinical stability was reduced with adjunctive corticosteroid therapy, demonstrating achievement of clinical stability on average at least 1 day sooner than control patients (mean difference, ‑1.22 days; 95% CI, ‑2.08 to ‑0.35 in Siemieniuk et al; ‑1.16 days; 95% CI, ‑1.73 to ‑0.58 in Horita et al).^7,8,11 Time to discharge was also improved, with the length of hospital stay significantly reduced by approximately 1 to 3 days (‑0.98 days; 95% CI, ‑1.26 to ‑0.71 in Horita et al; ‑2.96 days; 95% CI, ‑5.18 to ‑0.75 in Siemieniuk et al).^8,11 Likewise, significant reductions in length of intensive care unit stay were detected with adjunctive corticosteroid therapy (‑1.3 days).¹¹

Counterbalancing the reduced risk for these clinical endpoints, hyperglycemia may be just as likely to develop in patients receiving adjunctive corticosteroid therapy for CAP.⁸ The risk increase was found to be approximately 50% in meta-analysis of 6 trials (RR, 1.49; 95% CI, 1.01 to 2.19). However, the risks of gastrointestinal hemorrhage and severe neuropsychiatric complications were unaffected.

Appropriate candidates and drug regimens for adjunctive corticosteroids in CAP

The patient population most likely to benefit from adjunctive corticosteroid therapy in CAP is likely patients with severe disease, based on findings replicated in multiple meta-analyses.^5,8,11 However, definitions of severe pneumonia varied among trials and meta-analyses, which used ATS and BTS definitions, among other criteria. Some authors recommend the use of corticosteroids in patients who have elevated C-reactive protein levels (>15 mg/dL), which are associated with higher rates of treatment failure and mortality.^11,15 Other clear indicators of severe CAP include need for mechanical ventilation, vasopressors, or ICU admission.^15,16 Previous reports estimate that approximately 8% to 10% of patients with pneumonia experience severe disease and may experience benefit in these outcomes with adjunctive corticosteroids. ³ However, consideration should equally be given to patients’ risk for hyperglycemia, which itself has been identified as an independent predictor of 30-day mortality in diabetic patients hospitalized with pneumonia.¹⁷

Less clear from current literature on adjunctive corticosteroids in CAP are the optimal drug and dosage, which remain undefined. Corticosteroids evaluated in RCTs from meta-analyses discussed in this review have included methylprednisolone, prednisolone, hydrocortisone, and dexamethasone. One meta-analysis reported the mean dose, after conversion, was the equivalent of methylprednisolone 30 mg daily for a mean of 7 days. ⁵ Recommendations from other sources are similar to this dosage, including prednisone 50 mg daily, or prednisolone or methylprednisolone 40 mg daily to 1 mg/kg daily for 5 to 7 days.^11,16

Conclusion

No conclusive evidence exists to demonstrate an overall mortality benefit with the adjunctive use of corticosteroids in all patients with pneumonia, although mortality may be reduced in the subset of patients with severe CAP. However, these patients represent a small estimated portion of all CAP patients, and definitions of severe pneumonia have varied in studies to date. There appears to be a large benefit with the use of adjunctive corticosteroids in decreasing risk of ARDS and need for mechanical ventilation, and time to clinical stability may be reduced by several days, but this benefit is tempered by the increased risk of corticosteroid-induced hyperglycemia.

References

1.         Mandell LA, Wunderink RG. Pneumonia. In: Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J, eds. Harrison's Principles of Internal Medicine. 19th ed. New York, NY: McGraw-Hill; 2015. http://accessmedicine.mhmedical.com/content.aspx?bookid=1130&Sectionid=79733578. Accessed March 24, 2016.

2.         Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007;44(Suppl 2):S27-72.

3.         Lim WS, Baudouin SV, George RC, et al. BTS guidelines for the management of community acquired pneumonia in adults: update 2009. Thorax. 2009;64(Suppl 3):iii1-55.

4.         Blum CA, Nigro N, Briel M, et al. Adjunct prednisone therapy for patients with community-acquired pneumonia: a multicentre, double-blind, randomised, placebo-controlled trial. Lancet. 2015;385(9977):1511-1518.

5.         Wan YD, Sun TW, Liu ZQ, Zhang SG, Wang LX, Kan QC. Efficacy and safety of corticosteroids for community-acquired pneumonia: a systematic review and meta-analysis. Chest. 2016;149(1):209-219.

6.         Torres A, Sibila O, Ferrer M, et al. Effect of corticosteroids on treatment failure among hospitalized patients with severe community-acquired pneumonia and high inflammatory response: a randomized clinical trial. JAMA. 2015;313(7):677-686.

7.         Shrikant Kulkarni N. Steroids beneficial as adjunctive treatment for community-acquired pneumonia. Am Fam Physician. 2016;93(3):227.

8.         Siemieniuk RA, Meade MO, Alonso-Coello P, et al. Corticosteroid therapy for patients hospitalized with community-acquired pneumonia: a systematic review and meta-analysis. Ann Intern Med. 2015;163:519-528.

9.         McHardy VU, Schonell ME. Ampicillin dosage and use of prednisolone in treatment of pneumonia: co-operative controlled trial. Br Med J. 1972;4(5840):569-573.

10.       Wagner HN, Jr., Bennett IL, Jr., Lasagna L, Cluff LE, Rosenthal MB, Mirick GS. The effect of hydrocortisone upon the course of pneumococcal pneumonia treated with penicillin. Bull Johns Hopkins Hosp. 1956;98(3):197-215.

11.       Horita N, Otsuka T, Haranaga S, et al. Adjunctive systemic corticosteroids for hospitalized community-acquired pneumonia: systematic review and meta-analysis 2015 Update. Sci Rep. 2015;5:14061.

12.       Wunderink RG. Corticosteroids for severe community-acquired pneumonia: not for everyone. JAMA. 2015;313(7):673-674.

13.       Gu WJ. Caution! Overestimation of treatment effects of corticosteroid therapy for community-acquired pneumonia in a meta-analysis of randomized controlled trials. J Thorac Dis. 2015;7(11):1885-1886.

14.       Extended Steroid in CAP(e) (ESCAPe). ClinicalTrials.gov website. http://www.clinicaltrials.gov/. Published January 21, 2011. Updated January 20, 2016. Accessed March 29, 2016.

15.       Restrepo MI, Anzueto A, Torres A. Corticosteroids for severe community-acquired pneumonia: time to change clinical practice. Ann Intern Med. 2015;163:560-561.

16.       File TM. UpToDate. In: Post TW, ed. Treatment of community-acquired pneumonia in adults who require hospitalization. Waltham, MA: UpToDate; 2016. http://www.uptodate.com/. Accessed March 28, 2016.

17.       Hirata Y, Tomioka H, Sekiya R, et al. Association of hyperglycemia on admission and during hospitalization with mortality in diabetic patients admitted for pneumonia. Intern Med. 2013;52(21):2431-2438.

April 2016

The information presented is current as of March 24, 2016.  This information is intended as an educational piece and should not be used as the sole source for clinical decision making.

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