Effect of Dexamethasone on Mortality in Adult and Elderly Patients with Sepsis: a Systematic Review

Abstract

Sepsis is a serious disease that affects many people worldwide, and many therapies are used, including corticosteroids such as dexamethasone. However, there is no conclusion as yet, concerning the use of dexamethasone in patients with sepsis or septic shock. The aim of this study was to perform a literature review to assess the mortality of patients with sepsis or septic shock using dexamethasone, answering the following question: What is the effect of dexamethasone on mortality in adult and elderly patients with sepsis compared with mortality in patients who do not use anti-inflammatory therapy? The protocol of this study was registered in the PROSPERO database. The systematic literature search was performed in four electronic databases. Bias risk assessments were performed using the Cochrane Collaboration tool, and notification quality was assessed using the CONSORT-based checklist. The literature search initially identified 13,999 records. The three selected studies included eighty adult patients with sepsis or septic shock who had received dexamethasone as an intervention. Of the three articles, two concluded that the use of dexamethasone significantly reduces the mortality in patients with sepsis or septic shock. The Cochrane Collaboration tool bias risk results showed that none of the studies was completely bias-free and through the CONSORT checklist, it was found that none of the studies met 50% or more of the applicable requirements. Thus, it is clear from this review that further randomized clinical trials comparing the use of dexamethasone to placebo in adjunctive therapy for sepsis patients are needed. The registration number in the PROSPERO database is CRD42018088150.

Introduction

Sepsis is currently defined as a fatal organic dysfunction, which is caused by an infection with dysregulated host response, causing physiological, pathological, and biochemical abnormalities. Septic shock is defined as a subset of sepsis in which abnormalities in circulatory and cellular metabolism are more severe, significantly increasing the risk of death to the patient. Thus, septic shock is considered a more serious condition, with a higher probability of death than isolated sepsis [1, 2].

In clinical practice, sepsis is represented by an increase in the Sequential Organ Failure Assessment (SOFA) of 2 points or more. Patients with septic shock should be clinically identified as having sepsis and requiring vasopressor therapy, maintaining a mean arterial pressure of 65 mmHg or greater and serum lactate levels greater than 2 mmol/L (> 18 mg/dL) in the absence of hypovolemia [3]. Hospital sepsis mortality rates are higher than 10%, while septic shock rates are higher than 40%. It is estimated that 5 million people die from sepsis annually worldwide. In the USA, hospital costs due to sepsis represent more than US $ 24 billion per year [4, 5].

The initial treatment for sepsis is early and adequate administration of antimicrobials. Clinical signs and symptoms, appropriate microbiological cultures, and relevant imaging techniques should be used to determine the source of infection. The use of the appropriate antimicrobial at the start of treatment significantly reduces the risk of death [6]. Other additional treatments may be useful, such as vasopressors and inotropes in cases of septic shock, mechanical ventilation for sepsis developed by severe pneumonia, and renal replacement therapy in cases where there is acute renal injury [4]. Efforts are currently underway to produce a drug that could block the exaggerated and uncontrolled inflammatory phenomena and consequent endothelial damage that are characteristic of sepsis [6].

Corticosteroids have long been used in intensive therapy for septic shock. In the 1980s, clinical trials were conducted to evaluate the benefits of high-dose treatment protocols in a short space of time with dexamethasone in septic patients, and the conclusion was that these protocols were not effective. Since then, several studies have shown that small doses of corticosteroids decrease the need for vasopressor drugs to maintain cardiovascular homeostasis, improving patients’ clinical status [7]. Glucocorticoids inhibit inflammation through different mechanisms and may act as immunosuppressants, depending on the treatment protocol. Some of the most commonly used glucocorticoids are methylprednisolone, dexamethasone, and hydrocortisone [8]. The use of glucocorticoids as anti-inflammatory agents administered in sepsis cases has a long history, but it has not been possible to clinically establish whether this treatment is effective [9]. The specific effect of dexamethasone on sepsis is not yet clear; however, it is known that this glucocorticoid differs from others in that it has greater immunosuppressive power, a longer half-life, and requires lower doses to achieve the desired pharmacological effects [10, 11].

In this context, the objective of this systematic review is to clarify whether the glucocorticoid dexamethasone is effective in reducing mortality in adult and elderly patients with sepsis or septic shock.

Material and Methods

This systematic review was conducted in accordance with the Cochrane Handbook for Systematic Reviews of Intervention [12] and the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement [13]. It aims to answer the following question: What is the effect of dexamethasone on mortality in adult and elderly patients with sepsis compared with mortality in patients who do not use anti-inflammatory therapy? The protocol of this study was registered on the PROSPERO (www.crd.york.ac.uk/PROSPERO/) database (registration number: CRD42018088150). PICO criteria (population, intervention/exposure, comparison, and outcome) and the research questions used to determine the keywords and search strategy are shown in Table 1.

Table 1 PICO criteria description and research question defined to systematic review

Literature Search

A systematic literature search was performed at the Cochrane Central Register of Controlled Trials (CENTRAL), Scopus, Web of Science, and PubMed to identify all relevant studies up until February 6, 2018, and an update search was performed on November 1, 2019. We used search terms, keywords, or medical subject headings related to the groups of the acronym PICO (patient, intervention, comparison, and outcome): Patient (P), Adult and elderly patients diagnosed with sepsis (Sepsis OR Sepsi OR Septicemia OR Septicaemia OR Bacteremia OR Pyemia OR Pyemias OR Pyaemia OR Pyaemias OR “Septic Infection” OR “Septic Infections” OR “Generalized infection” OR “Severe sepsis” OR “Systemic inflammation” OR “Systemic inflammatory response syndrome” OR “Septic shock” OR Toxemia OR Toxemias OR Toxaemia OR Toxaemias) AND (Adult OR Adults OR Patients OR Patient OR Old OR Ancient OR Old-aged OR Elder OR Elders); Intervention (I), dexamethasone (Dexamethasone OR Dexametasone OR Dex OR “Dexamethasone acetate” OR Dexa OR Glucocoricoids OR Glucocorticoid OR Corticosteroid OR Corticosteroids OR Corticoid OR Corticoids OR Antiinflammatory OR Anti-inflammatory OR “Anti inflammatory” OR Antiinflammatories OR Anti-inflammatories OR “Anti inflammatories” OR Hexadrol OR Decadron); Comparison (C), no anti-inflammatory intervention (omitted in the search strategy); and Outcomes (O), mortality (Mortality OR Death OR “Negative outcome” OR Outcome OR Survival OR Decease OR Dying OR Demise).

The search terms were combined using Boolean operators (OR was used to combine search terms from the same PICOs group, AND to combine search terms from different groups, and NOT to exclude search terms). No filter was used in the search. The searches were conducted in the online database, and the results exported to the reference manager software Mendeley® (RELX Group, New York, USA) for further analysis and organization.

Selection Criteria

Duplicated or triplicated papers were excluded from the analysis using Mendeley®. When available, information on titles and abstracts were sufficient. The papers were read in full, to identify the inclusion/exclusion criteria. Clinical trials that met the following criteria were included:

  1. 1)

    Controlled or randomized clinical trials carried out in humans

  2. 2)

    Fully published papers (published abstracts were not included)

  3. 3)

    Papers published in English

  4. 4)

    Studies sample composed only of patients diagnosed with sepsis (over 18 years old)

  5. 5)

    Dexamethasone as treatment (in any treatment protocol)

  6. 6)

    Assessment of patient mortality (study outcome)

Data Extraction

Papers that met all the inclusion criteria were carefully read by three independent reviewers to ensure adequate data extraction. The following data were extracted:

  1. 1)

    Place

  2. 2)

    Period of data collection

  3. 3)

    Study design

  4. 4)

    Sample size and losses

  5. 5)

    Intervention/exposure characteristics (treatment protocol)

  6. 6)

    Patients’ age and sex

  7. 7)

    Mortality

  8. 8)

    Main results

Once the raw data had been stratified, the corresponding authors of the papers that met the inclusion criteria for this review were contacted for further information. Since no further data was forthcoming from the authors, these papers were excluded from this review. The data extracted from the final selected papers were organized in Microsoft Excel® spreadsheets by both reviewers and crosschecked.

Critical Appraisal

Bias risk assessments were performed using the Cochrane Collaboration tool [13], and the quality of the notification was assessed using the CONSORT checklist of potential bias [14]. The first tool analyzes the risk of occurrence of the six bias domains: selection bias, performance bias, detection bias, friction bias, report bias, and other bias. The trial was conducted by three reviewers, and the studies were classified as having high, low, or uncertain risk of bias. The second tool consists of a checklist that covers aspects of all sections of a clinical trial, from the title to the discussion, among other important information. Each correctly reported item received a score of 1, or otherwise 0, and at the end, each study had a final score (possible range of 0 to 37 points).

Disagreements between the authors in the attribution of scores were resolved by discussion until a consensus was reached.

Results

Search Results

The literature search initially identified 13,999 records (2224 from PubMed, 9641 from Scopus, 366 from Cochrane, and 1768 from Web of Science). Repeated articles were excluded, and the remaining 11,808 articles were screened. After reading the titles, 11,511 articles were deleted. Subsequently, the abstracts were read, and 258 articles were excluded. Thirty-nine articles were evaluated through the full text, and 6 were selected. Of these articles, three presented incomplete data, and the authors were contacted to request further data [15,16,17]. These further data were not provided by the authors. Finally, 3 articles were included [18,19,20]. The selection process is shown in Fig. 1.

Fig. 1
figure1

Flowchart of the literature search, screening, and selection process for eligible trials

Baseline Characteristics

The characteristics of the three studies included in the review are shown in Table 2.

Table 2 Characteristics of included studies

In 2007, Cicarelli, Vieira, and Benseñor published the results of a study conducted in Brazil with 29 patients diagnosed with septic shock, 13 men and 16 women, aged 34 to 88 years. The prospective, randomized, double-blind, placebo-controlled study was conducted between November 2004 and December 2005. The patients were divided into two groups: who received 0.2 mg/kg in three doses at 36-h intervals of dexamethasone (n = 14); and the placebo group, which received 0.9% saline three doses at 36-h intervals (n = 15). Patients received conventional therapy regarding antibiotic regimens, blood cultures, and discharge criteria. Clinical test and laboratory were performed daily throughout the study. Patients were evaluated during ICU stay for duration of vasopressor support (SOFA score for cardiovascular system of two or more), time on mechanical ventilation, and mortality. All patients who developed refractory septic shock were excluded from the study, and hydrocortisone administration was started. The results of the study, for the mortality outcome, were evaluated at 7 and 28 days. Treating septic shock patients with dexamethasone reduced mortality by 21% compared with placebo group, for which the reduction was 67%. The treatment group showed a 28-day trend toward a reduction in mortality; the dexamethasone-treated group reduced mortality by 50% and the placebo by 80% [18].

A paper published by Schumer (1976) reported two studies, one prospective and one retrospective, on septic shock patients treated with dexamethasone and methylprednisolone. Given that the retrospective study lacked detail on the groups that received the different corticosteroids, only the prospective study will be included in this review. The survey was conducted with 172 patients in the USA, between 1967 and 1975. Patients were diagnosed based on case history, blood pressure, and blood culture. The study was a randomized clinical trial in which patients were divided into groups receiving placebo, dexamethasone, and methylprednisolone as treatment. In our study, we evaluate only outcomes with placebo and dexamethasone administration, so the methylprednisolone group was excluded. The placebo group (n = 86) received saline alone, and the dexamethasone group (n = 43) received 3 mg/kg of the drug in saline. The treatment was administered as a single bolus infusion through a central venous catheter. The antibiotic administered in the early years of the study (1967–1969) was chloromycetin; 48 patients received this treatment: 24 in the control group and 12 in the dexamethasone group. In 1970, patients began receiving the combination of gentamicin and clindamycin. A total of 124 patients received this treatment: 62 in the control group and 31 in the dexamethasone group. The patients’ ages ranged from 22 to 84 years, with 167 males and 5 females. The results of this study showed that the mortality rate was 38.4% (33/86) in the saline-treated patients and 9.3% (4/43) in the dexamethasone-treated patients [19].

Finally, in 1984, Lucas and Ledgerwood published a prospective study of 48 patients with severe sepsis. This study took place from August 1978 to May 1980 in the USA. Initially the patients were treated by infusion of balanced electrolyte solution (BES) to restore plasma volume deficits. Where they presented anemia, administration of RBC concentrate was associated with the therapy. The patients were divided into two groups: 25 people in the untreated group and 23 that received dexamethasone. Treatment was started as a 2 mg/kg bolus followed by a 2 mg/kg/24 h infusion for 2 days, resulting in a total dose of 6 mg/kg over 48 h. The administration was non-blinded. The diagnosis of septic shock was determined by systolic blood pressure below 80 mmHg. Four patients were excluded from treatment due to necrosis. Sodium bicarbonate and calcium supplementation were administered as needed to correct acidosis and hypocalcemia. Antibiotic therapy consisting of aminoglycoside, clindamycin, and penicillin G was administered. These treatments were given to both groups, as needed. Ventilatory insufficiency, pulmonary capillary pressure, plasma volume using serum albumin, body temperature, and white blood cell count were evaluated. Statistical analysis between the two groups was performed by the Student’s t test for independent variables, assuming significance when the confidence level exceeded 95%. Mean age (55 years), disease severity, shock time, and cause of sepsis were similar in patients in both groups. The results found in this study regarding mortality were 5 patients for each group [20].

All trials evaluated death as an outcome. Only two [18, 19] of the three studies observed a significant reduction in mortality in the treated group compared with the untreated group.

Assessment of Risk of Bias and Quality of Reporting

The results of the risk of bias by the Cochrane Collaboration tool [12] are shown in Fig. 2 (Supplementary Table 1). According to this tool, none of the studies was completely free of bias.

Fig. 2
figure2

Summary of risk of bias by Cochrane tool. (+) Low risk; (−) high risk; (?) unclear risk

In all the trials, the selection bias, performance bias, detection bias, and other forms of bias were not identified. There was insufficient information to form judgments in regard to other biases. On the other hand, the three selected studies describe data related to outcomes including loss and exclusion from analysis and therefore have a low friction bias. They also make it clear that they included all desired outcomes, giving them a low risk of reporting bias.

According to the CONSORT checklist [14] (Supplementary Table 2), none of the studies met 50% or more of the applicable requirements. Two trials did not identify the study design in the title [19, 20]. All essays met all requirements for abstracts. No studies detailed how sample size was chosen, or explained any intermediate analyses, the method used to generate random allocation sequence, the type of randomization, the mechanism used to implement random allocation sequence, who the generated random allocation sequence, who enrolled the participants, or who assigned participants to the interventions. One paper did not meet the eligibility criteria for participants [20]. The work [18] did not establish pre-specified primary and secondary outcome measures and trials [18, 20] and did not present the statistical methods used to compare groups for primary and secondary outcomes.

Two trials did not include losses and exclusions in the “Results” section [18, 20]. The number of participants was analyzed for primary outcome in all trials; the period and interruption of work were also recorded by all. The other criteria set out in the results section were not performed by any study. Generalization of the findings and consistent interpretation with results was demonstrated in all trials. Sources of funding, registration number, and accessible protocol were not reported in all the clinical trials.

Discussion

Sepsis is classified as a systemic dysfunction in response to an infection caused by a host, usually a bacterial infection, in which this dysfunction can be fatal. In clinical practice, sepsis is represented by an increase in the Sequential Organ Failure Assessment (SOFA) score of 2 or more points [2, 4]. Septic shock is defined as a subgroup of sepsis, in which circulatory, cellular, and metabolic abnormalities are associated with a higher risk of death than sepsis alone [2]. During sepsis in a patient, simple immune inflammation or suppression occurs, as well as cellular and metabolic reorganization [1].

There is still no agreement as to the best supportive treatment for patients with sepsis who develop septic shock. Despite the need for vasopressor drugs, the use of corticosteroids as adjuncts to the main antibiotic therapy is still controversial; it is advocated by many but opposed by others [9].

Dexamethasone is a glucocorticoid with important immunosuppressive effect, reducing the transcription of pro-inflammatory genes by inhibition of the nuclear factor kappa B [21]. Some studies have focused on the use of corticosteroids to reduce the systemic inflammatory process produced by sepsis and septic shock. Also along the same lines, there have been recent reports that the use of hydrocortisone improved outcomes for patients suffering from septic shock. The use of methylprednisolone to resolve acute respiratory distress syndrome (ARDS) has also been studied. The current recommendations for using corticosteroids to treat sepsis are that this class of drugs should be used during refractory septic shock, but not during severe sepsis in the absence of shock, or when only mild shock is observed. Our review did not limit the use of dexamethasone to this condition only but included studies that used dexamethasone in septic patients at an early stage. Our choice to study the effect of dexamethasone instead of hydrocortisone was due to the fact that this drug has more potency, long-lasting action, higher anti-inflammatory, and lower mineralocorticoid effects than hydrocortisone. Moreover, it does not cause changes in sodium reabsorption and does not interfere in the water balance, thereby avoiding possible sodium disturbances [22].

This systematic review was performed with three studies that included 80 adult patients with sepsis or septic shock who received dexamethasone as an intervention. All the studies were conducted with patients in a hospital setting. Of all the articles analyzed, two achieved a reduction in patient mortality with oral dexamethasone compared with placebo [18, 19]. Although it was not the focus of this review to evaluate other parameters, clinical trials have shown that patients receiving dexamethasone achieved an improvement in PaO2/FiO2 and the duration of mechanical ventilation was also shorter [18, 20]. Lactate production [18] and blood pressure [20] showed no difference between the treated and placebo groups. The PaO2/FiO2 ratio is important because it is one of the parameters for the SOFA score definition, where ≥ 400 mmHg has a score of 0 and < 100 mmHg has a maximum score of 4. The work of Cicarelli, Vieira, and Benseñor (2007) was the only one to evaluate patients according to the SOFA score, but that study found no difference between the treated group and the placebo [18]. To determine the SOFA, it is necessary to evaluate the PaO2/FiO2 ratio, platelet counts, blood pressure, bilirubin and serum creatinine, Glasgow coma scale, and urinary volume. The higher the SOFA value, the higher the probability of death [2].

The works of Schumer (1976) and Lucas and Ledgerwood (1984) did not evaluate sepsis through SOFA because the articles were published prior to 1991 [19, 20]. In that year, a conference defined the terms sepsis more precisely than it had done up until then, through literature data and expert reports. It was proposed that sepsis could arise from an infection or not; therefore, it was named systemic inflammatory response syndrome (SIRS). Clinical manifestations corresponded to body temperature above 38 °C or below 36 °C, heart rate greater than 90 bpm, tachypnea, and change in white blood cell count [23]. In 2001, a new conference was held to update the sepsis definitions and related conditions. A list of signs and symptoms was prepared to better reflect the clinical response, in which organ dysfunction could be assessed by SOFA [24], which explains its use in the study by Cicarelli, Vieira, and Benseñor (2007) [18].

Of the three articles selected and then used in this review, two concluded that the use of dexamethasone as an adjuvant therapy the antibiotic therapy significantly reduces the mortality of patients with sepsis or septic shock. In the study conducted by Cicarelli, Vieira, and Benseñor (2007), the use of dexamethasone produced an increase in the effect of vasopressor therapy, a fact that the authors attributed to a reduction in patient mortality after day 7 [18]. In a study conducted by Schumer (1976), the author, using a retrospective and prospective strategy, concluded that the use of glucocorticoids in septic shock patients reduces the mortality rate compared with placebo. In addition, it concluded that there is no difference between the mortality rate of the methylprednisolone-treated group and the dexamethasone-treated group [19]. The study by Lucas and Ledgerwood (1984), however, found no significant difference between the mortality rate in the dexamethasone and placebo groups [20].

Conclusion

This systematic review used three randomized clinical trials, two of them published before 1991 (the year that sepsis was more precisely defined). This fact led to a significant risk of bias when comparing these studies with more recent ones. Thus, it was clear that more randomized controlled trials focusing in adjuvant sepsis therapy are needed, to reach a definitive conclusion as to whether or this clinical conduct reduces the mortality rate in patients with sepsis or systemic shock.

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Funding

This work was supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brazil) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, Brazil).

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Correspondence to Eduardo Monguilhott Dalmarco.

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Fratoni, E., dos Santos Nascimento, M.V.P., Bramorski Mohr, E.T. et al. Effect of Dexamethasone on Mortality in Adult and Elderly Patients with Sepsis: a Systematic Review. SN Compr. Clin. Med. 2, 886–892 (2020). https://doi.org/10.1007/s42399-020-00334-9

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Keywords

  • Sepsis
  • Septic shock
  • Corticosteroids
  • Dexamethasone
  • Therapy