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Adjunctive Glucocorticoid Therapy in Patients with Septic Shock
Abstract
Background
Whether hydrocortisone reduces mortality among patients with septic shock is unclear.
Methods
We randomly assigned patients with septic shock who were undergoing mechanical ventilation to receive hydrocortisone (at a dose of 200 mg per day) or placebo for 7 days or until death or discharge from the intensive care unit (ICU), whichever came first. The primary outcome was death from any cause at 90 days.
Results
From March 2013 through April 2017, a total of 3800 patients underwent randomization. Status with respect to the primary outcome was ascertained in 3658 patients (1832 of whom had been assigned to the hydrocortisone group and 1826 to the placebo group). At 90 days, 511 patients (27.9%) in the hydrocortisone group and 526 (28.8%) in the placebo group had died (odds ratio, 0.95; 95% confidence interval [CI], 0.82 to 1.10; P=0.50). The effect of the trial regimen was similar in six prespecified subgroups. Patients who had been assigned to receive hydrocortisone had faster resolution of shock than those assigned to the placebo group (median duration, 3 days [interquartile range, 2 to 5] vs. 4 days [interquartile range, 2 to 9]; hazard ratio, 1.32; 95% CI, 1.23 to 1.41; P<0.001). Patients in the hydrocortisone group had a shorter duration of the initial episode of mechanical ventilation than those in the placebo group (median, 6 days [interquartile range, 3 to 18] vs. 7 days [interquartile range, 3 to 24]; hazard ratio, 1.13; 95% CI, 1.05 to 1.22; P<0.001), but taking into account episodes of recurrence of ventilation, there were no significant differences in the number of days alive and free from mechanical ventilation. Fewer patients in the hydrocortisone group than in the placebo group received a blood transfusion (37.0% vs. 41.7%; odds ratio, 0.82; 95% CI, 0.72 to 0.94; P=0.004). There were no significant between-group differences with respect to mortality at 28 days, the rate of recurrence of shock, the number of days alive and out of the ICU, the number of days alive and out of the hospital, the recurrence of mechanical ventilation, the rate of renal-replacement therapy, and the incidence of new-onset bacteremia or fungemia.
Conclusions
Among patients with septic shock undergoing mechanical ventilation, a continuous infusion of hydrocortisone did not result in lower 90-day mortality than placebo. (Funded by the National Health and Medical Research Council of Australia and others; ADRENAL ClinicalTrials.gov number, NCT01448109.)
... In CEDAR, similar associations were observed for ICU stay. These results validated the results from recent relevant trials 10,[34][35][36][37] . The finding that steroids benefit patients who are predicted to have worsening organ dysfunction is consistent with the proposed biologic mechanism for the action of steroids in critically ill patients as RW patients may benefit from the vasopressor effect of systemic corticosteroid to improve tissue perfusion and ameliorate visceral organ dysfunction 38 . ...
... Our findings suggest several avenues for future investigation. First, our study regarding the evaluation of the effectiveness of corticosteroids in patients with sepsis was conducted through a trial-emulated framework with real-world data, which could be important complementary evidence to the findings of RCTs 10,43 . Second, we derived differential hazard ratios based on different predicted organ function trajectory patterns. ...
... The sensitivity analysis where we only included CS administration during baseline further mitigates the potential effect that receiving CS before RI/RW group assignment could have. For example, the decrease in norepinephrine doses and shock resolution were not seen in the ADRENAL trial until two to three days after corticosteroid administration 10 . Fourth, the study's observational design implies that despite rigorous propensity score matching, residual confounding cannot be completely ruled out. ...
Corticosteroids decrease the duration of organ dysfunction in sepsis and a range of overlapping and complementary infectious critical illnesses, including septic shock, pneumonia and the acute respiratory distress syndrome (ARDS). The risk and benefit of corticosteroids are not fully defined using the construct of organ dysfunction duration. This retrospective multicenter, proof-of-concept study aimed to evaluate the association between usage of corticosteroids and mortality of patients with sepsis, pneumonia and ARDS by emulating a target trial framework stratified by predicted organ dysfunction trajectory. The study employed a two staged machine learning (ML) methodology to first subphenotype based on organ dysfunction trajectory then predict this defined trajectory. Once patients were classified by predicted trajectory we conducted a target trial emulation. Our analysis revealed that the association between corticosteroid use and 28-day mortality varied by predicted trajectory and between cohorts.Our findings suggest that matching treatment strategies to empirically observed pathobiology may offer a more nuanced understanding of corticosteroid utility.
... A meta-analysis has indicated that IV corticosteroids may reduce the duration of vasopressor therapy, invasive mechanical ventilation (IMV), and ICU length of stay (LOS), though without significant impact on either short-or long-term mortality [7]. Nevertheless, several randomized controlled trials (RCTs) have evaluated the efficacy of low-dose corticosteroids in reducing mortality in septic shock, with a primary focus on glucocorticoids such as hydrocortisone (with or without fludrocortisone) [8][9][10][11]; in contrast, few studies have assessed methylprednisolone, except in the context of severe community-acquired pneumonia [12,13]. Although the guidelines recommend hydrocortisone, methylprednisolone remains used in real-world clinical practice. ...
... In 2018, two important clinical trials, namely the ADRENAL trial (Adjunctive Corticosteroid Treatment in Critically Ill Patients with Septic Shock) and the APROCCHSS trial (Activated Protein C and Corticosteroids for Human Septic Shock), were published in The New England Journal of Medicine. They reported no survival benefits or, at best, a slight reduction in mortality with low-dose corticosteroid treatment for septic shock, but patients treated with corticosteroids in both studies experienced significantly shorter times to resolution of shock, cessation of MV and discharge from the ICU [10,11]. Thus, the SCC 2021 guidelines suggest using IV hydrocortisone rather than methylprednisolone for patients with septic shock who require ongoing vasopressor therapy [19]. ...
Background
Methylprednisolone is still used to treat adults with septic shock in real-world clinical settings, despite current international guidelines recommending hydrocortisone. The aim of this study was to assess the effect of methylprednisolone vs hydrocortisone on 30-day mortality among critically ill patients with septic shock.
Methods
We conducted a retrospective cohort study on adults with septic shock using the MIMIC-IV v3.0 database. Patients who received methylprednisolone after diagnosis were matched using propensity score matching (PSM) with those received hydrocortisone, to balance confounding factors between groups. The primary outcome was the 30-day mortality rate. Subgroup and sensitivity analyses were performed to assess the robustness of the conclusions.
Results
A total of 1,607 septic shock patents were enrolled in this study, with an overall 30-day mortality rate of 42.1%. After 1:1 PSM, 376 pairs were successfully matched. The primary outcome occurred in 141 patients (37.5%) and in 131 patients (34.8%) in the methylprednisolone and hydrocortisone groups, respectively (HR = 1.105, 95% CI: 0.871–1.402, P = 0.410). In subgroup analyses based on age, sex, blood culture positivity, pneumonia, and invasive mechanical ventilation (IMV), along with sensitivity analyses for deletion of missing values, findings remained consistent. However, the methylprednisolone group exhibited a longer ICU stay, elevated blood glucose levels, and a shorter maintenance duration for vasopressin compared to the hydrocortisone group.
Conclusions
Among adults with septic shock, there was no significant difference in 30-day mortality between those administered methylprednisolone and hydrocortisone. It needs to be further verified in prospective, randomized controlled trials.
... 5 It has been observed that levels of thiamine and vitamin c are reduced in patients of sepsis in addition to HPA axis suppression, Vitamin C has potent antioxidant properties and contributes significantly to the production of vasopressors and increases their reactivity. 6,7 Thiamine also acts as a cofactor in the Krebs cycle and has anti-oxidant properties. Corticosteroids act via two mechanisms: immune modulation and cardiovascular modulation. ...
... 8 Corticosteroids bind to nuclear factor kappa beta receptors and mitigate the vasoconstrictor response to vasopressor drugs. 6 Previous retrospective studies have shown conflicting results regarding the effectiveness of triple therapy (vitamin C, thiamine and hydrocortisone) in preventing septicemic MODS. 9 Therefore, it is presumed that a beneficial effect can only be achieved if triple therapy is initiated at an early stage. ...
Background: Hydrocortisone, vitamin C and thiamine have been suggested as a possible treatment for sepsis and septic shock. However, many trials do not support their use therefore this RCT was conducted to evaluate the efficacy of early administration (within 12 hours of diagnosis) of triple therapy (hydrocortisone, vitamin C and thiamine) in patients of septic shock in north Indian population. The primary objective was to determine the effect of combination on all-cause mortality at day 14. Secondary objectives were change in sofa score at day 3 and day 7, time to shock reversal (in hours) and mean length of hospital stay. Methods: This single centre double blinded RCT was conducted in LLR and Associated hospitals, Kanpur between June, 2023 and June, 2024. The patients were randomly assigned to either Interventional group (n=75) or PLACEBO group (n=75). Interventional group received inj. hydrocort 200 mg once a day, inj. vitamin C 1 gm iv 3 times a day, thiamine 200mg iv 2 times a day for 5 day or until ICU discharge, the patients were then followed up for 14 days. Results: Delta sofa score at day 3 and 7 were not statistically significant (p values- 0.5, 0.241). Significant results were obtained in mean length of hospital stay (11.87 vs 14 days, p value 0.005) and Mean time to shock reversal (176.33 vs 204.40 hours, p value<0.001). Mortality at day 14 was lesser in the interventional group (34.67% vs 45.33%, p value 0.205, statistically insignificant). Conclusions: Thus, in patients with septic shock early treatment (within 12 hours of diagnosis) with injection hydrocortisone, vitamin c and thiamine does not confer mortality benefit but it decreases the length of hospital stay and time to shock reversal.
... The 2016 Surviving Sepsis Campaign guidelines recommend intravenous hydrocortisone only if fluid resuscitation and vasopressor therapy fail to restore hemodynamic stability [1]. Subsequently, two large-scale randomized trials (APROCCHSS trial and ADRENAL trial) investigating adjunctive hydrocortisone in septic shock were published [10,11]. The ADRENAL trial (enrolled 3658 patients) demonstrated that hydrocortisone treatment did not improve 90-day survival but did reduce the duration of mechanical ventilation and shock. ...
... The ADRENAL trial (enrolled 3658 patients) demonstrated that hydrocortisone treatment did not improve 90-day survival but did reduce the duration of mechanical ventilation and shock. Conversely, the APROCCHSS trial (enrolled 1241 patients) found that patients randomized to GCs exhibited lower 90-day mortality [10]. Such disparities may stem from variations in study design and patient heterogeneity (including infection site, etiology, comorbidity, etc) [11]. ...
Background and Aims
Abdominal sepsis refers to a severe and potentially life‐threatening condition characterized by the presence of infection, inflammation, and tissue damage within the abdominal cavity. Glucocorticoids (GCs) play an important role in regulation of the host immune and inflammation responses involved in sepsis and surgery. This study aimed to investigate the potential impact of intraoperative GCs administration on the clinical outcome of surgical patients with abdominal sepsis.
Methods
This retrospective cohort study included a 1:1 propensity score–matched cohort of surgical patients afflicted with abdominal sepsis at two medical centers from January 2008 to December 2022. Patients were classified into low‐GCs, high‐GCs, and non‐GCs groups according to the dosage of steroids used intraoperatively, and in‐hospital mortality was designated as the primary outcome.
Results
This study included a total of 476 patients, with 217 in the non‐GCs group, 213 in the low‐GCs group, and 46 in the high‐GCs group. The overall in‐hospital mortality rate was 7.56%. After propensity score matching (PSM), there were 168 cases in both the low‐GCs group and the non‐GCs group, with no significant differences observed between the groups regarding mortality rate, length of hospital‐stay, and duration of intensive care unit (ICU) stay. In patients with septic shock, the use of low‐dose GCs increased the urine output and decreased the requirements for vasopressors on the first postoperative day, however, it had no impact on the in‐hospital mortality or ICU stay. Moreover, prophylactic use of GCs during anesthesia induction did not decrease the incidence of intraoperative hypotension or necessity of vasopressors use.
Conclusion
Intraoperative administration of low‐dose GCs demonstrates a transient improvement in hemodynamics of patients with septic shock, however, it did not lead to improved clinical outcomes. Further research remains necessary to elucidate the optimal perioperative dosing strategy.
... In recent years, it has been reported that hydrocortisone infusion is effective for patients who have poor response to initial treatment for shock status (i.e., mean arterial pressure <65 mmHg). 4 The treatment strategy is based on the support of relative adrenal insufficiency due to severe stress via sepsis. The European Association of Urology guideline states that hydrocortisone administration may support the rescue of such patients, 5 whereas hydrocortisone usage is not mentioned in guidelines of the American Urological Association, 6 Urological Association of Asia 7 and Japanese Urological Association. ...
... Based on these results, practice guidelines for corticosteroid therapy for sepsis14 and the international guidelines for the management of sepsis and septic shock 15 recommend the use of hydrocortisone for CIRCI if the initial infusion of vasopressors is not sufficiently effective. In addition, these trials primarily focused on septic shock across various organ systems, with the proportion of cases attributable to urological causes ranging from 4.7% to 7.5%.4,16 As urological septic shock constitutes a relatively small subset in these studies, its unique characteristics and management strategies remain underexplored. ...
Objectives
The administration of hydrocortisone in patients with severe septic shock contributes to early recovery in intensive care. The purpose of this study was to evaluate the effect of hydrocortisone on early recovery from severe septic shock in patients with obstructive pyelonephritis due to upper urinary tract stone (stone pyelonephritis).
Methods
From January 2018 to October 2023, of all patients admitted for treatment of stone pyelonephritis, 28 did not respond to initial fluid infusion and vasopressors for urosepsis. Among these 28 patients, 14 were administered hydrocortisone for recovery from early shock. Characteristics and noradrenaline administration time of patients treated or not treated with hydrocortisone were retrospectively analysed.
Results
In patients with septic shock associated with stone pyelonephritis unresponsive to initial fluid and vasopressors, noradrenaline administration time in the hydrocortisone group (28.7 ± 17.5 h) was significantly shorter than in the non‐treated group (46.0 ± 12.8 h, p = 0.006). The factors diabetes, blood culture results, age, performance status, severity of vital signs and laboratory data on sepsis severity were not significantly associated with the duration of noradrenaline administration.
Conclusions
Our findings suggest potential benefits of hydrocortisone administration for stone pyelonephritis unresponsive to initial fluid and vasopressors. Widespread adoption of hydrocortisone in the treatment of sepsis, which is common in intensive care, could become more important in urology.
... This section will provide an overview of these vasopressors and other vasoactive agents with regard to their pharmacological characteristics and clinical use. The characteristics of these vasopressors and other vasoactive agents are summarized in Table 1 [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17]. ...
... Unlike shock resolution, uncertainty remains regarding the effects of corticosteroids on survival. Inconsistent results were reported in two large randomized trials [16,17], which may be explained by the concurrent administration of fludrocortisone. Notably, an individual patient data meta-analysis, which included these trials, showed that hydrocortisone reduced 90-day mortality only when administered concurrently with fludrocortisone [119]. ...
Septic shock is a significant challenge in the management of patients with burns and traumatic injuries when complicated by infection, necessitating prompt and effective haemodynamic support. This review provides a comprehensive overview of current strategies for vasopressor and fluid management in septic shock, with the aim to optimize patient outcomes. With regard to vasopressor management, we elaborate on the pharmacologic profiles and clinical applications of catecholamines, vasopressin derivatives, angiotensin II, and other vasoactive agents. Noradrenaline remains central to septic shock management. The addition of vasopressin, when sequentially added to noradrenaline, offers a non-catecholaminergic vasoactive effect with some clinical benefits and risks of adverse effects. Emerging agents such as angiotensin II and hydroxocobalamin are highlighted for their roles in catecholamine-resistant vasodilatory shock. Next, for fluid management, crystalloids are currently preferred for initial resuscitation, with balanced crystalloids showing benefits over saline. The application of albumin in septic shock warrants further research. High-quality evidence does not support large-volume fluid resuscitation, and an individualized strategy based on haemodynamic parameters, including lactate clearance and capillary refill time, is recommended. The existing knowledge suggests that early vasopressor initiation, particularly noradrenaline, may be critical in cases where fluid resuscitation takes inadequate effect. Management of refractory septic shock remains challenging, with novel agents like angiotensin II and methylene blue showing potential in recent studies. In conclusion, Further research is needed to optimize haemodynamic management of septic shock, particularly in developing novel vasopressor usage and fluid management approaches.
... Corticosteroids may be useful in this clinical scenario, as they counteract the uncontrolled inflammatory process that characterizes sepsis and restore cardiovascular homeostasis through salt and water retention [5]. Low dose of hydrocortisone has been showed to be effective in reducing the time until reversal of shock when added to standard therapy in septic shock [6,7]. ...
... Hydrocortisone showed an important role in reversal of shock when added to standard therapy in managing septic shock [6,7,13,15]. But hyperglycemia is one of the most common side effects associated with corticosteroid treatment. ...
Background & Objectives: Septic shock is a serious condition associated with a high mortality rate because of the multiorgan dysfunction caused by dysregulated host immune responses to infection. Giving low dose steroids in septic shock patients has been shown to hasten the reversal of shock and current Surviving Sepsis Guidelines (SSG) also suggest using low dose steroids for the same. Also, the use of steroids causes hyperglycaemia particularly in diabetic patients. The current SSG does not specify the method of administration. The primary objective of our study was to compare continuous infusion vs intermittent boluses of hydrocortisone to obtain a better glycaemic control. Methods: A prospective cohort study was conducted in diabetic patients with septic shock admitted in Multi Disciplinary Intensive Care Unit (MDICU) of PRS hospital from July 2022 to February2023. Hydrocortisone was given as continuous infusion in 55 subjects and the remaining 55 received intermittent boluses of hydrocortisone and average blood glucose values were measured in both the groups. Results: Among 110 patients, 55 patients each received continuous infusion and intermittent boluses of hydrocortisone respectively. The mean blood glucose values in continuous infusion group were 161.1 ± 22.7 and 172.5 ± 21.0 (mg/ dl) in intermittent boluses group which was statistically significant with a p value of 0.007. There was no statistically significant difference among the groups in 28-day mortality, ICU length of stay (LOS), hospital LOS, or other secondary safety outcomes. Conclusions: This study infers that giving hydrocortisone as continuous infusions in septic shock patients leads to better glycaemic control when compared to intermittent boluses of hydrocortisone, without any difference in 28-day mortality.
... Hydrocortisone, a synthetic glucocorticoid, has been used to modulate the exaggerated inflammatory response and restore vascular tone in patients with refractory septic shock [3]. While it has shown modest benefits in improving hemodynamic stability and reducing vasopressor dependence, its impact on longterm outcomes such as mortality and organ recovery remains variable [4]. ...
... In addition, the study was underpowered, limiting the reliability of its conclusions. Notably, the study did not observe a beneficial effect of hydrocortisone treatment, a finding that contrasts with results from larger randomized controlled trials such as APPROACHS and ADRENAL, which have suggested its beneficial effects regarding ICU length of stay, duration of shock, and duration of mechanical ventilation [33,34]. A signal of benefit for early adjunctive vasopressin use compared with late initiation has been assessed in retrospective studies [5,9]. ...
... 37 For patients requiring glucocorticoids, strategies such as prophylactic antimicrobial therapy, regular monitoring for infection signs, and optimizing glucocorticoid dosing to the lowest effective level are essential to mitigate infection risks. 38 Additionally, the potential protective role of radiation therapy highlights the importance of comprehensive care protocols that integrate infection prevention measures across all therapeutic modalities. 39 Despite its strengths, this study has several limitations that must be acknowledged. ...
Objective
Hospital-acquired infections (HAIs) pose significant challenges in rehabilitation hospitals, particularly affecting patients with extended stays and complex medical needs. This study analyzed HAI patterns and risk factors in a Chinese rehabilitation hospital from 2020 to 2024.
Methods
A retrospective observational study was conducted at a tertiary-care rehabilitation hospital with 25 specialized wards. Data collection included patient demographics, clinical parameters, and ward-level characteristics. Statistical analysis employed Poisson and Quasi-Poisson regression models to identify risk factors, with comprehensive diagnostic evaluation.
Results
The study revealed an overall infection rate of 3.64%, representing 385 infections among 10,559 inpatients. The Vegetative State Awakening Department exhibited the highest infection rate at 11.1%, followed by Geriatric Rehabilitation Department (8.2%), and Neuro Rehabilitation Department wards (5.5–7.0%). Respiratory tract infections were most common (42%), with ventilator-associated pneumonia accounting for 28% of all infections. Statistical analysis identified several significant risk factors through both Poisson and Quasi-Poisson regression models. In the more reliable Quasi-Poisson model that accounted for overdispersion, tracheal intubation emerged as the strongest predictor with a coefficient of 2.02 (p < 0.001), followed by use of glucocorticoids (coefficient: 1.78, p < 0.001). While the initial Poisson model suggested a protective effect of radiation therapy, this effect was not significant in the Quasi-Poisson model.
Conclusion
The study highlights the critical role of tracheal intubation and glucocorticoid use in HAI development within rehabilitation settings. The significant ward-level variability in infection rates suggests the need for tailored infection control strategies. Implementation of targeted interventions focusing on these identified risk factors could help reduce HAI incidence in rehabilitation hospitals.
... The literature has focused predominantly on mortality-related risk factors or prognostic models, but few studies have investigated the risk factors and corresponding probability of sepsis in patients with SCAP. However, the early and timely identification of sepsis during the course of SCAP appears to be beneficial for selecting the most appropriate mode of care and empiric antibiotic therapy, shortening the duration of clinical stabilization and length of hospital stay, enhancing pulmonary physiology, and diminishing mortality rates [7,[31][32][33][34][35]. As of June 2024, the present study represents the first study on this specific subject in China. ...
Background
Sepsis represents a high-risk mortality cohort among patients with severe community-acquired pneumonia (SCAP). Rapid and precise identification along with prompt decision-making, serves as a practical approach to improve patient prognosis.
Methods
This retrospective observational study enrolled adult patients with severe community-acquired pneumonia (SCAP) who were continuously hospitalized in the intensive care unit (ICU) of West China Hospital, Sichuan University, from September 2011 to September 2019. Univariate and multivariate logistic regression analyses were employed to identify independent risk factors for co-sepsis, followed by the utilization of LASSO regression to filter features to establish a nomogram. Model robustness was evaluated via the C index, receiver operating characteristic (ROC) analysis, and calculation of the area under the curve (AUC). Furthermore, its predictive accuracy was assessed via decision curve analysis (DCA).
Results
In total, 5855 SCAP patients were included in the present study, of whom 654 developed sepsis. Patients with sepsis exhibited a prolonged length of stay in the ICU and higher mortality rates, indicating a worse prognosis than those without sepsis. We identified 15 independent risk factors associated with the development of sepsis in SCAP patients. Further analysis incorporating 9 of these features to construct a nomogram demonstrated a C index of 0.722 (95%CI 0.702–0.742), including lactate, D-dimer, respiratory rate, heart rate, albumin, hemoglobin, activated partial thromboplastin time (APTT), glucose, and C-reactive protein (CRP) levels. The AUC values and DCA curves demonstrated that the model exhibited superior accuracy and overall net benefit in predicting co-sepsis development compared with the qSOFA, CURB-65, SOFA, and APACHE II scores. Additionally, the calibration curve confirmed good concordance between the predicted probabilities of the model.
Conclusions
This study investigated the risk factors for co-sepsis in SCAP patients and constructed an expedited, cost-effective and personalized model for predicting the probability of co-sepsis.
... p = 0.02) [50]. Conversely, another RCT involving 3800 adults with septic shock on mechanical ventilation found that continuous hydrocortisone infusion did not reduce 90-day mortality compared with a placebo (odds ratio 0.95; 95% confidence interval [CI] 0.82 to 1.10; p = 0.50) [51]. ...
Pediatric sepsis presents a unique clinical challenge due to the distinct characteristics of the developing immune system. The immune response in children differs significantly from that in adults, exhibiting a unique combination of resistance, disease tolerance, and resilience. These factors influence the clinical presentation and prognosis of pediatric patients with sepsis. Over the past few years, various studies have explored the role of immunomodulatory therapies in managing sepsis, including the use of immunoglobulins, corticosteroids, monoclonal antibodies, and immunostimulatory treatments. However, the heterogeneity of the clinical presentations and individual responses makes it difficult to identify universally effective treatments. Recent research has highlighted the importance of a personalized approach based on specific biomarkers and patient phenotyping. Extracorporeal blood purification techniques have emerged as promising strategies for the modulation of hyperinflammation. However, strong evidence supporting their routine use in pediatric sepsis is lacking. This review provides a comprehensive overview of the current knowledge of the immune response in pediatric sepsis and discusses the main immunomodulatory strategies and future perspectives for personalized therapy. A deeper understanding of the immunological differences between children and adults could improve the prognosis and treatment efficacy, paving the way for new approaches to pediatric sepsis management.
... Administering low-dose, short-course glucocorticoids to septic shock patients can reduce the dosage of vasopressors needed and enhance the sensitivity of vascular smooth muscle to catecholamine receptors, thereby effectively correcting shock 15,16 . Moreover, continuous infusion of hydrocortisone can also stabilize the exogenous cortisol concentration, exerting a strong anti-shock effect and maintaining metabolic balance 17 . ...
This study investigates the effects of continuous versus intermittent hydrocortisone administration on septic shock patients. Sixty patients were randomized into two groups: one receiving intermittent doses of 50 mg of hydrocortisone every 6 h and the other a continuous infusion of 200 mg/day. After a 7-day treatment period and a 28-day follow-up, we observed no significant differences in the duration of sustained shock, hospital, and ICU stays between the groups. However, those in the continuous infusion group experienced shorter periods of mechanical ventilation and vasopressor use, with significant improvements in hemodynamic stability. Both treatment approaches improved arterial pressure and lactate clearance, with no significant differences in heart rate or cortisol levels between the groups at the end of the treatment. Notably, shock reversal rates were higher and 28-day mortality rates were lower in the continuous infusion group. These results suggest that continuous hydrocortisone infusion may be more effective for managing septic shock, potentially leading to better patient outcomes without an increase in adverse reactions. This method could be considered for broader clinical implementation in septic shock treatment strategies.
... In exploratory analysis, it is possible that hydrocortisone reduced the duration of vasopressor requirement. This finding is consistent with two international trials of hydrocortisone in septic shock, CORTICUS and ADRENAL, both of which reported no reduction in mortality but faster resolution of shock [30,31]. Both the anti-inflammatory and cardiovascular effects of hydrocortisone could explain the short-term ameliorating effects on shock. ...
... However, broadly acting immunomodulators, such as corticosteroids, may be beneficial in restoring homeostasis during specific phases of sepsis response and in subgroups of patients with hyperinflammatory phenotypes. Different timing and variability in host-response subphenotypes may explain some of the variability in clinical trials of corticosteroids in sepsis [74][75][76][77][78]. ...
Sepsis remains a significant global health threat with a disproportionate burden in low-income countries including those in sub-Saharan Africa where case fatality rates are as high as 30% to 50%. Defined as a severe systemic response to infection, sepsis leads to widespread immune dysregulation and organ dysfunction, including adrenal insufficiency. Critical illness-related corticosteroid insufficiency (CIRCI) arises from dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, altered cortisol metabolism, and tissue resistance to glucocorticoids, all of which can occur during sepsis. Clinical trials of corticosteroids for the treatment of patients with sepsis and septic shock have shown improvements in shock reversal, and in some studies, patient survival; however, their role in the treatment of sepsis in sub-Saharan Africa is unknown. The incidence of sepsis in sub-Saharan Africa is compounded by high rates of human immunodeficiency virus (HIV) and co-infections, including tuberculosis (TB), which is the leading cause of sepsis. Both HIV and TB can cause immune dysregulation and adrenal insufficiency, which may exacerbate CIRCI and prolong shock. Existing sepsis research has been predominantly conducted in high-income countries and has largely excluded people living with HIV or TB. Therefore, there is a need to better understand sepsis and CIRCI pathophysiology in the context of specific regional host and pathogen characteristics. In this narrative review, we explored the pathophysiology of sepsis in sub-Saharan Africa including the existing literature on the immune response to sepsis and the prevalence of adrenal insufficiency in patients with HIV and TB, with a focus on the implications for corticosteroid management. We found a compelling need to further evaluate corticosteroids for the treatment of sepsis in Africa.
... Corticosteroids are the immune modulating therapy that has been most frequently studied in sepsis. In clinical trials these drugs have variably been shown to be beneficial [40][41][42] or to have no effect [43,44], leading to clinical uncertainty around their use. Molecular phenotypes have shown promise in identifying groups with differential responses to these drugs. ...
Heterogeneity between critically ill patients with sepsis is a major barrier to the discovery of effective therapies. The use of machine learning techniques, coupled with improved understanding of sepsis biology, has led to the identification of patient subphenotypes. This exciting development may help overcome the problem of patient heterogeneity and lead to the identification of patient subgroups with treatable traits. Re-analyses of completed clinical trials have demonstrated that patients with different subphenotypes may respond differently to treatments. This suggests that future clinical trials that take a precision medicine approach will have a higher likelihood of identifying effective therapeutics for patients based on their subphenotype. In this review, we describe the emerging subphenotypes identified in the critically ill and outline the promising immune modulation therapies which could have a beneficial treatment effect within some of these subphenotypes. Furthermore, we will also highlight how bringing subphenotype identification to the bedside could enable a new generation of precision-medicine clinical trials.
... In addition, the study was underpowered, limiting the reliability of its conclusions. Notably, the study did not observe a bene cial effect of hydrocortisone treatment, a nding that contrasts with results from larger randomized controlled trials such as APPROACHS and ADRENAL, which have suggested its bene cial effects regarding ICU length of stay, duration of shock, and duration of mechanical ventilation [34,35]. ...
Background In septic shock, the optimal timing of adjunctive vasopressin initiation shock is unknown. We aimed to assess the effect of its early initiation for patients with septic shock. Methods We conducted a multicenter target trial emulation to estimate the intensive care unit (ICU) mortality effect of early (≤ 6 hours) adjunctive vasopressin compared with usual care. Eligible patients had septic shock diagnosed within 6 hours of ICU admission. The primary outcome of this study was 30-day ICU mortality. Subgroup analyses were conducted to test the interaction of early vasopressin start with peak norepinephrine-equivalent dose (NED) at 6 hours, APACHE score, peak lactate at 6 hours and invasive mechanical ventilation. Secondary outcomes were the impact of delayed vasopressin introduction on 30-day ICU mortality and effect of NED at vasopressin start on 30-day ICU mortality. We used the parametric g-formula to emulate a target trial. Results Overall, 3,105 patients fulfilled the inclusion criteria. Mean age was 62 years and mean APACHE III score was 83. In the first six hours of vasopressor therapy, 1,864 (60%) patients were invasively ventilated. Estimated 30-day ICU mortality was 19.34% (95%CI, 17.0 to 21.68) in the no vasopressin group and 18.45% (95%CI, 16.26 to 20.63) in the early vasopressin group; relative risk 0.95 (95%CI, 0.93 to 0.98). The estimated 30-day ICU mortality effect of starting vasopressin was particularly strong at lower norepinephrine doses (< 0.25 µg.kg − 1 .min − 1 ) and significant at lower norepinephrine doses than recommended by the Surviving Sepsis Campaign Guidelines. Vasopressin administration progressively increased over the study period, from 35.2% (95%CI, 30.0 to 40.5) in 2015 to 45.1% (95%CI, 40.7 to 49.6) in 2021 (ß = +1.3% per year; 95%CI, + 0.46 to + 2.16, p = 0.011). Patients had progressively lower norepinephrine equivalent dose (ß = -0.05 µg.kg − 1 .min − 1 per year; 95%CI, -0.09 to -0.002, p = 0.038) and lower total SOFA score (ß = -0.1 point per year; 95%CI, -0.18 to -0.07, p < 0.001) at vasopressin start. Conclusions In this emulation of a hypothetical target trial, patients with septic shock benefited from early vasopressin administration. These findings can help design prospective randomised-control trials of early adjunctive vasopressin use in septic shock.
... Nonetheless, the precise patient phenotypes that could effectively determine those who would derive the most significant advantages from corticosteroid intervention still need to be fully identified as of current knowledge (5,(13)(14)(15)(16). Furthermore, the interaction between corticosteroid and different antibiotic combinations remains poorly understood. ...
Background
Streptococcus pneumoniae , a primary cause of community-acquired pneumonia (CAP), is typically treated with β-lactams and macrolides or quinolones. Corticosteroids are now recommended as adjunctive therapy in severe CAP to improve outcomes. I n this prospective randomized animal study, we evaluated the bactericidal efficacy of various antibiotic regimens combined with corticosteroids using a porcine pneumococcal pneumonia model.
Results
In 30 White-Landrace female pigs, pneumonia was induced by intrabronchial inoculation of macrolide-resistant S. pneumoniae 19A isolate. Animals were randomized to receive saline, ceftriaxone (CRO) with levofloxacin (LVX), CRO with azithromycin (AZM), or combinations of these with methylprednisolone (MP). The primary outcome, S. pneumoniae concentrations in lung tissue after 48 h of treatment, showed that the CRO + LVX, CRO + AZM, CRO + LVX + MP, and CRO + AZM + MP groups were equally effective in reducing bacterial load. However, complete bacterial eradication from lung tissue was achieved only in the CRO + AZM + MP group. Secondary outcomes, including bacterial burden in tracheal aspirates and bronchoalveolar lavage (BAL) samples, showed similar bactericidal activity across all treatment groups. The CRO + AZM + MP group demonstrated the most controlled inflammatory response, achieving baseline levels of inflammation, while other groups exhibited elevated inflammatory markers.
Conclusions
Despite using a macrolide-resistant S. pneumoniae isolate, the combination of CRO, AZM, and MP achieves similar or even superior results compared to other antibiotic combinations. This regimen provides both bactericidal and immunomodulatory benefits, suggesting its effectiveness in treating macrolide-resistant S. pneumoniae pneumonia.
... [92][93][94] In differences were found between the treatment and placebo groups in terms of 28-day mortality, the number of days alive and out of the ICU, the number of days alive and out of the hospital, the rate of recurrence of shock, the rate of patients requiring renal replacement therapy, or the incidence of secondary infections. 95 A multicenter, double-blind RCT (NCT00625209) evaluated whether hydrocortisone plus fludrocortisone or with drotrecogin alfa (activated) could improve outcomes in patients with septic shock. Compared with placebo, hydrocortisone plus fludrocortisone significantly reduced patient mortality, with 90-day mortality rates of 43.0% (264 of 614 patients) and 49.1% (308 of 627 patients), respectively (p = 0.03). ...
The mortality rate of sepsis is approximately 22.5%, accounting for 19.7% of the total global mortality. Since Lewis Thomas proposed in 1972 that “it is our response that makes the disease (sepsis)” rather than the invading microorganisms, numerous drugs have been developed to suppress the “overwhelming” inflammatory response, but none of them has achieved the desired effect. Continued failure has led investigators to question whether deaths in septic patients are indeed caused by uncontrolled inflammation. Here, we review the history of clinical trials based on evolving concepts of sepsis pathogenesis over the past half century, summarize the factors that led to the failure of these historical drugs and the prerequisites for the success of future drugs, and propose the basic principles of preclinical research to ensure successful clinical translation. The strategy of targeting inflammatory factors are like attempting to eliminate invaders by suppressing the host's armed forces, which is logically untenable. Sepsis may not be that complex; rather, sepsis may be the result of a failure to fight microbes when the force of an invading pathogen overwhelms our defenses. Thus, strengthening the body's defense forces instead of suppressing them may be the correct strategy to overcome sepsis.
... The number of participants in the study by Moskowitz et al. (2020) study is smaller (205), which potentially limits the results' generalizability. Also, the drugs under investigation were administered to the participants 13.5 hours after the administration of vasopressors; the same limitation was noticed in other studies (Annane et al., 2018;Fujii et al., 2020;Venkatesh et al., 2018). Moskowitz et al. (2020) assumed a shorter duration between the initiation of vasopressor and study agent might have resulted in better outcomes. ...
Sepsis is one of the most common conditions causing prolonged hospitalizations. Sepsis is a systemic infectious process that can be caused by multiple sources and types of infection in the human body. In developing and developed countries, sepsis is a condition that can put a financial burden on the health system due to longer stays in the hospital and the need for mechanical ventilators and vasopressors. Also, sepsis has a higher rate of mortality and morbidity for patients in lower-income countries due to lower levels of symptom awareness, health inequity, delay in care, and under-resourced healthcare facilities. Healthcare professionals are interested in finding evidence-based approaches to decrease mortality and morbidity and reduce the financial burden on an already stressed health system. This systematic article review aims to appraise articles using a hierarchy of evidence to address the clinical question regarding the efficacy of vitamin C, steroids, and thiamine in sepsis and septic patients when added to the standard treatment. After reviewing the randomized control trial, we found that study results on the regular use of vitamin C, steroids, and thiamine in sepsis and septic shock are conflicting. More research is needed to assess the efficacy of vitamin C, steroids, and thiamine in sepsis and septic shock to improve patient outcomes and reduce the length of hospitalizations.
... SPRUNG et al. [24] showed an increased incidence of superinfection, including new episodes of sepsis or septic shock, in patients with sepsis and septic shock who were treated with hydrocortisone, although none of the subsequent trials on corticosteroids in sepsis and septic shock reported a higher risk of superinfection [7,25,26]. ...
The systemic use of corticosteroids for patients with severe community-acquired pneumonia (sCAP) remains controversial in clinical practice, particularly in terms of the safety profile of these drugs. This narrative review aims to analyse the available literature data concerning the safety of short-term steroid use in the treatment of sCAP, while also highlighting potential future research directions. Several trials and meta-analyses have evaluated corticosteroid therapy as an adjuvant treatment for sCAP, yielding heterogeneous results regarding its efficacy and safety. Despite the wide variability in results, it is generally accepted that steroids are not associated with a significant risk of healthcare-associated infections, gastrointestinal bleeding or acute kidney injury in patients with sCAP in the short term. Nevertheless, such drugs are linked to hyperglycaemia, necessitating regular monitoring and appropriate management. The influence of steroids on long-term outcomes and their potential risks in viral sCAP still needs to be investigated.
... Nevertheless, we failed to prove the hypothesis of a higher effect with a high bolus dose of MB. This may be attributed to the unpredictable duration of systemic inflammation in septic shock [23]. Thus, the cumulative dose of MB appears more valuable than the bolus dose in septic shock, probably due to a half-life of 5-6 h [19]. ...
Purpose
Septic shock is a common threat, and is the primary cause of death in almost all critical care units. Mortality of septic shock remains exceedingly high. The early use of methylene blue (MB) in different doses as adjunctive to vasopressors has promising results.
Methods
This double-blind, randomized, controlled trial comprised 90 patients divided into 3 groups: Group A received a 100 ml 0.9% NaCl placebo over 20 min; Group B received an MB bolus of 1 mg/kg in 100 ml 0.9% NaCl, and Group C received MB bolus of 4 mg/kg in 100 ml 0.9% NaCl during the same period. Groups B and C were given a 0.25 mg/kg/hour infusion of MB for 72 h after the bolus dose. All patients were started on noradrenaline at an infusion rate of 0.1–0.2 µ/kg/min and were adjusted accordingly to maintain MAP ≥ 65 mmHg. Time of vasopressor discontinuation was the primary outcome while total doses of vasopressors, ventilation days, vasopressors free days, total ICU stay, total hospital stay, and mortality rate were the secondary outcomes.
Results
Groups B and C exhibited significantly decreased time to vasopressor termination, and vasopressor-free days at 28 days in comparison to Group A. However, there was no significant difference between Groups B and C. Groups B and C had significantly lower noradrenaline dosages compared to Group A, however, no significant difference between Group B and Group C was found. The difference between the three groups in mortality rate was near statistical significance (p = 0.083). Using the logistic regression model, the 4 mg/kg group was protective against mortality with a hazard ratio of 0.29 (95%CI: 0.09–0.90).
Conclusion
In cancer patients with septic shock, early adjunctive MB delivery reduces the time to a vasopressor stoppage and increases the vasopressor-free days. No significant difference between high and low MB bolus doses, and no significant adverse effects were noted. Compared to placebo, the 4 mg/kg bolus dose shows a survival advantage.
Trial registration
Prospectively registered at clinicaltrials.gov [NCT 06005558]. (Date of registration 15/08/2023).
International clinical practice guidelines addressing corticosteroid treatment for patients hospitalised with non-viral community-acquired pneumonia (CAP) are inconsistent.
We conducted a systematic review of randomized controlled trials (RCTs) evaluating the use of corticosteroids in hospitalised adult patients with suspected or probable CAP. We performed random effects pairwise, Bayesian, and dose–response meta-analyses using the restricted maximum likelihood (REML) heterogeneity estimator. We assessed certainty of evidence using GRADE methodology.
We identified 30 eligible RCTs, including a total of 7519 patients. The prednisone-equivalent doses ranged between 29 mg/day and 100 mg/day. Corticosteroids probably reduced short-term (28–30 days) mortality (RR 0.82 [95% CI 0.74–0.91]; moderate certainty) while the reduction in longer term (60–90 day) mortality is less certain (RR 0.89 [95% CI 0.76–1.03]; low certainty). Corticosteroids reduced the need for invasive mechanical ventilation (IMV) (RR 0.63 [95% CI 0.48–0.82]; high certainty) and may reduce duration of ICU stay (MD 1.53 days fewer [95% CI 0.31–2.75 days fewer]; low certainty), and hospital stay (MD 2.30 days fewer [95% CI 0.81–3.81 days fewer]; low certainty). Corticosteroids probably increased hyperglycaemia requiring intervention (RR 1.32 [95% CI 1.12–1.56]; moderate certainty) but probably have no effect on secondary infections (RR 0.97 [95% CI 0.85–1.11]; moderate certainty).
Corticosteroids probably reduced short-term mortality and reduce the need for invasive mechanical ventilation in hospitalised patients with CAP.
CRD42024521536.
Sepsis is the life‐threatening organ dysfunction arising from a dysregulated host response to infection. Although the specific mechanisms leading to organ dysfunction are still debated, impaired tissue oxygenation appears to play a major role, and concomitant hemodynamic alterations are invariably present. The hemodynamic phenotype of affected individuals is highly variable for reasons that have been partially elucidated. Indeed, each patient's circulatory condition is shaped by the complex interplay between the medical history, the volemic status, the interval from disease onset, the pathogen, the site of infection, and the attempted resuscitation. Moreover, the same hemodynamic pattern can be generated by different combinations of various pathophysiological processes, so the presence of a given hemodynamic pattern cannot be directly related to a unique cluster of alterations. Research based on endotoxin administration to healthy volunteers and animal models compensate, to an extent, for the scarcity of clinical studies on the evolution of sepsis hemodynamics. Their results, however, cannot be directly extrapolated to the clinical setting, due to fundamental differences between the septic patient, the healthy volunteer, and the experimental model. Numerous microcirculatory derangements might exist in the septic host, even in the presence of a preserved macrocirculation. This dissociation between the macro‐ and the microcirculation might account for the limited success of therapeutic interventions targeting typical hemodynamic parameters, such as arterial and cardiac filling pressures, and cardiac output. Finally, physiological studies point to an early contribution of cardiac dysfunction to the septic phenotype, however, our defective diagnostic tools preclude its clinical recognition. © 2021 American Physiological Society. Compr Physiol 11:1605‐1652, 2021.
Aims/Background Severe septic shock (SS) is a life-threatening condition characterized by systemic inflammation and organ dysfunction. Hydrocortisone is used to reduce inflammation, while norepinephrine raises blood pressure and supports vasoconstriction, helping to maintain organ perfusion. This study aims to investigate the efficacy of hydrocortisone combined with norepinephrine in the treatment of SS and its effect on immunoinflammatory indexes.
Methods A total of 126 patients with severe SS admitted to Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University from December 2020 to December 2023 were retrospectively selected as the study subjects. Patients were divided into control group (n = 67) and observation group (n = 59) according to the treatment given. The control group was treated with norepinephrine, whereas the observation group was treated with hydrocortisone combined with norepinephrine. The clinical efficacy of the treatment given between the two groups was compared. The serum levels of interleukin 6 (IL-6), C-reactive protein (CRP), procalcitonin (PCT) and serum amyloid A (SAA) were compared between the two groups before and after treatment. The occurrence of adverse reactions was compared between the two groups. The clinical prognostic indexes of the two groups were analyzed.
Results The total efficacy rate of observation group (93.22%) was significantly higher than that of control group (74.63%) (p = 0.005). After treatment, the levels of CRP, PCT, IL-6 and SAA in both groups were significantly decreased, with the observation group exhibiting significantly lower levels of these inflammatory indexes than the control group (p < 0.05). There was no significant difference in the incidence of adverse reactions between the two groups (p > 0.05). After 7 days of treatment, compared with the control group, the observation group showed significantly lower Acute Physiology and Chronic Health Evaluation (APACHE) II score and Sepsis-related Organ Failure Assessment (SOFA) score, required shorter mechanical ventilation time and total emergency intensive care unit (EICU) treatment time, and had lower mortality within 4 weeks (p < 0.05).
Conclusion Hydrocortisone combined with norepinephrine holds high degree of efficacy in the treatment of severe SS by alleviating inflammation, improving prognosis and reducing mortality, while maintaining a good safety profile.
Catecholamines, essential neurotransmitters and hormones, play a critical role in the body’s physiological response to stress and are pivotal in the management of various clinical conditions, particularly in critical care settings. This narrative review delves into the pharmacological properties of catecholamines, including their mechanisms of action, pharmacokinetics, and pharmacodynamics. Key clinical applications of catecholamines, especially in the cardiovascular and immune systems, are highlighted, emphasizing their roles in modulating heart rate, vascular tone, and immune responses during critical conditions such as sepsis and septic shock. Additionally, the review explores catecholamines’ immunomodulatory effects and their interactions with other therapeutic agents, such as corticosteroids, in the management of septic shock. Further research is suggested to optimize catecholamine usage and improve patient outcomes in critical care settings.
Delirium has been recognised in the medical literature since antiquity and is particularly common in mechanically ventilated intensive care patients. Given the sheer number of potential precipitating and predisposing factors that can contribute to the development of delirium, predicting and preventing delirium remain challenging. However, as it is associated with a variety of adverse outcomes, including increased mortality and dependence, as well as increased costs, reliable delirium prevention remains the goal. Dexmedetomidine is the agent with the strongest evidence of both a preventative and a therapeutic effect. The benefit of multicomponent non-pharmacological interventions has not been demonstrated to improve outcomes in randomised controlled trials, but is associated with a reduction in delirium occurrence and severity in the observational data.
Future studies should address novel preventative and therapeutic interventions and examine evidence of benefit across motoric subtypes, as well as seek to understand data-driven classifications of delirium. With modern technology and design, as well as more effective therapeutics and an integrated multimodal approach to prevention, a future in the intensive care unit (ICU) without delirium may be possible.
Vasopressor agents are prescribed when hypotension persists despite fluid administration or in cases of severe hypotension during ongoing fluid resuscitation. It is essential to recognize that the criteria for initiating vasopressors are subjective and lack precise definitions. Therefore, clinicians must conduct a patient-specific evaluation to determine what constitutes severe hypotension or hypotension refractory to fluid therapy in each individual case. This personalized assessment ensures that treatment decisions are tailored to the patient’s unique clinical presentation and needs. The choice of a particular vasopressor agent is primarily influenced by expert opinion and individual clinician preference.
The 2024 revised edition of the Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock (J-SSCG 2024) is published by the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine. This is the fourth revision since the first edition was published in 2012. The purpose of the guidelines is to assist healthcare providers in making appropriate decisions in the treatment of sepsis and septic shock, leading to improved patient outcomes. We aimed to create guidelines that are easy to understand and use for physicians who recognize sepsis and provide initial management, specialized physicians who take over the treatment, and multidisciplinary healthcare providers, including nurses, physical therapists, clinical engineers, and pharmacists. The J-SSCG 2024 covers the following nine areas: diagnosis of sepsis and source control, antimicrobial therapy, initial resuscitation, blood purification, disseminated intravascular coagulation, adjunctive therapy, post-intensive care syndrome, patient and family care, and pediatrics. In these areas, we extracted 78 important clinical issues. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) method was adopted for making recommendations, and the modified Delphi method was used to determine recommendations by voting from all committee members. As a result, 42 GRADE-based recommendations, 7 good practice statements, and 22 information-to-background questions were created as responses to clinical questions. We also described 12 future research questions.
Background
Sepsis is a life-threatening condition caused by a dysregulated immune response to infection and remains a major cause of mortality in intensive care units (ICUs). Recent studies have identified microRNAs (miRNAs), a class of small RNA molecules, as potential biomarkers for diagnosing and predicting outcomes in sepsis patients. However, the results of these studies have been inconsistent. This meta-analysis aims to comprehensively evaluate the diagnostic and prognostic value of miRNAs in predicting sepsis-related mortality.
Methods
A comprehensive literature search was performed across major databases, including PubMed, Cochrane Library, EMBASE, and CNKI, up to April 7, 2024. Data extraction and meta-analysis were conducted using Meta-disk 1.4 and STATA 15.1, employing both fixed- and random-effects models to ensure robust statistical analysis.
Results
A total of 55 studies met the inclusion criteria and were analyzed. The pooled sensitivity, specificity, and area under the summary receiver operating characteristic (SROC) curve for miRNA detection were calculated. The overall performance of total miRNA detection demonstrated a sensitivity of 0.76 (95% confidence interval [CI]: 0.74–0.77), a specificity of 0.72 (95% CI: 0.71–0.73), and an SROC value of 0.83. Subgroup analyses revealed that miR-133a-3p exhibited the highest diagnostic accuracy, with a pooled sensitivity of 0.83 (95% CI: 0.70–0.92), specificity of 0.79 (95% CI: 0.71–0.86), and an SROC value of 0.90. Additionally, other miRNAs, including miR-146a, miR-21, miR-210, miR-223-3p, miR-155, miR-25, miR-122, miR-125a, miR-125b, and miR-150, also demonstrated high SROC values (0.84 to 0.76).
Conclusion
This meta-analysis underscores the potential of several microRNAs (miRNAs) as reliable biomarkers for predicting sepsis mortality. Specifically, miR-133a-3p, miR-146a, miR-21, miR-210, miR-223-3p, miR-155, miR-25, miR-122, miR-125b, and miR-150 emerge as promising candidates for clinical applications in sepsis prognosis.
In critical illness, all elements of gut function are perturbed. Dysbiosis develops as the gut microbial community loses taxonomic diversity and new virulence factors appear. Intestinal permeability increases, allowing for translocation of bacteria and/or bacterial products. Epithelial function is altered at a cellular level and homeostasis of the epithelial monolayer is compromised by increased intestinal epithelial cell death and decreased proliferation. Gut immunity is impaired with simultaneous activation of maladaptive pro- and anti-inflammatory signals leading to both tissue damage and susceptibility to infections. Additionally, splanchnic vasoconstriction leads to decreased blood flow with local ischemic changes. Together, these interrelated elements of gastrointestinal dysfunction drive and then perpetuate multi-organ dysfunction syndrome. Despite the clear importance of maintaining gut homeostasis, there are very few reliable measures of gut function in critical illness. Further, while multiple therapeutic strategies have been proposed, most have not been shown to conclusively demonstrate benefit, and care is still largely supportive. The key role of the gut in critical illness was the subject of the tenth Perioperative Quality Initiative meeting, a conference to summarize the current state of the literature and identify key knowledge gaps for future study. This review is the product of that conference.
Objective
To evaluate the evidence for the use of ascorbic acid, thiamine, or a combination of both agents without corticosteroids in the management of sepsis and septic shock.
Data Sources
A review of the literature was conducted through August 2023 on PubMed, MEDLINE, Web of Science, and CINAHL using the following terminology: “ascorbic acid” OR “vitamin C” OR “thiamine” OR “vitamin B” OR “vitamin B 1” AND “sepsis” OR “septic shock” NOT “steroid” OR “hydrocortisone” OR “corticosteroid.”
Study Selection and Data Extraction
Trials that described patient outcomes, medication efficacy, and medication safety data were considered for inclusion, while reports describing the use of either or both thiamine and ascorbic acid for a non-sepsis indication and reports that were not readily translatable to English were excluded. Studies that allowed corticosteroid use in both the intervention and control cohorts as part of a standard-of-care protocol were eligible for inclusion.
Data Synthesis
Heterogeneity of data exists, marked by divergent quantifications for successful pharmacotherapy interventions. Whereas some data support changes in patient outcome scores or critical illness indices, others have failed to demonstrate any meaningful benefit to ICU length of stay, ventilator status, or mortality.
Conclusion
Exploring the individual and synergistic effects of ascorbic acid and thiamine on key pathways implicated in sepsis pathophysiology has not yielded unequivocal evidence supporting their use without concomitant corticosteroids.
The 2024 revised edition of the Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock (J‐SSCG 2024) is published by the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine. This is the fourth revision since the first edition was published in 2012. The purpose of the guidelines is to assist healthcare providers in making appropriate decisions in the treatment of sepsis and septic shock, leading to improved patient outcomes. We aimed to create guidelines that are easy to understand and use for physicians who recognize sepsis and provide initial management, specialized physicians who take over the treatment, and multidisciplinary healthcare providers, including nurses, physical therapists, clinical engineers, and pharmacists. The J‐SSCG 2024 covers the following nine areas: diagnosis of sepsis and source control, antimicrobial therapy, initial resuscitation, blood purification, disseminated intravascular coagulation, adjunctive therapy, post‐intensive care syndrome, patient and family care, and pediatrics. In these areas, we extracted 78 important clinical issues. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) method was adopted for making recommendations, and the modified Delphi method was used to determine recommendations by voting from all committee members. As a result, 42 GRADE‐based recommendations, 7 good practice statements, and 22 information‐to‐background questions were created as responses to clinical questions. We also described 12 future research questions.
Circadian rhythms are critical to coordinating body processes to external environmental cues, such as light and feeding, to ensure efficiency and maintain optimal health. These rhythms are controlled by ‘clock’ transcription factors, such as Clock, Bmal1, Per1/2, Cry1/2, and Rev-erbs, which are present in almost every tissue. In modern society, disruptions to normal circadian rhythms are increasingly prevalent due to extended lighting, shift work, and long-distance travel. These disruptions misalign external cues to body processes and contribute to diseases such as obesity and non-alcoholic fatty liver disease. They also exacerbate pre-existing health issues, such as depression and inflammatory bowel disease. The normal inflammatory response to acute infection displays remarkable circadian rhythmicity in humans with increased inflammatory activity during the normal night or rest period. Severe bloodborne infections, exemplified in sepsis and the progression to septic shock, can not only disrupt the circadian rhythmicity of inflammatory processes but can be exacerbated by circadian misalignment. Examples of circadian disruptions during sepsis and septic shock include alteration or loss of hormonal rhythms controlling blood pressure and inflammation, white blood cell counts, and cytokine secretions. These changes to circadian rhythms hinder sepsis and septic shock recovery and also increase mortality. Chronotherapy and chronopharmacotherapy are promising approaches to resynchronise circadian rhythms or leverage circadian rhythms to optimise medication efficacy, respectively, and hold much potential in the treatment of sepsis and septic shock. Despite knowledge of how circadian rhythms change in these grave conditions, very little research has been undertaken on the use of these therapies in support of sepsis management. This review details the circadian disruptions associated with sepsis and septic shock, the influence they have on morbidity and mortality, and the potential clinical benefits of circadian-modulating therapies.
Sepsis, a heterogeneous illness produced by a dysregulated host response to infection, remains a severe mortality risk. Recent discoveries in sepsis research have stressed phenotyping as a feasible strategy for tackling heterogeneity and enhancing therapy precision. Sepsis phenotyping has moved from traditional stratifications based on severity and prognosis to dynamic, phenotype-driven therapeutic options. This review covers recent progress in connecting sepsis subgroups to personalized treatments, with a focus on phenotype-based therapeutic predictions and decision-support systems. Despite ongoing challenges, such as standardizing phenotyping frameworks and incorporating findings into clinical practice, this topic has enormous promise. By investigating phenotypic variation in therapy responses, we hope to uncover new biomarkers and phenotype-driven therapeutic solutions, laying the groundwork for more effective therapies and, ultimately improving patient outcomes.
How to cite this article: Sharma S, Paneru HR, Shrestha GS, Shrestha PS, Acharya SP. Author Response: Appropriately Designed Studies are Needed before Thiamine and Vitamin C Plus Hydrocortisone are Judged Nonbeneficial in Septic Shock. Indian J Crit Care Med 2025;29(2):193–194.
O choque séptico é uma condição crítica caracterizada por disfunção orgânica associada a sepse e hipotensão refratária à reposição volêmica, sendo uma das principais causas de mortalidade em ambientes de emergência. Vasopressores são fundamentais na ressuscitação hemodinâmica, contribuindo para a restauração da perfusão tecidual e redução de desfechos adversos. Este estudo teve como objetivo revisar de forma integrativa a literatura científica sobre o uso de vasopressores na ressuscitação de pacientes com choque séptico em serviços de emergência, com foco na eficácia, segurança e diretrizes de manejo. A metodologia incluiu buscas em bases de dados indexadas, aplicando critérios rigorosos de inclusão e exclusão. Os resultados evidenciam que norepinefrina permanece o vasopressor de primeira linha, enquanto agentes como vasopressina e angiotensina II apresentam benefícios em casos refratários. Adicionalmente, o início precoce da terapia mostrou-se associado à melhora nos desfechos clínicos. Contudo, lacunas relacionadas à individualização do tratamento e impacto de combinações terapêuticas foram identificadas. Conclui-se que, embora diretrizes atualizadas suportem o uso criterioso de vasopressores, são necessárias mais pesquisas para otimizar estratégias terapêuticas e minimizar riscos associados.
Importance
Eligibility criteria for randomized clinical trials (RCTs) are designed to select clinically relevant patient populations. However, not all eligibility criteria are strongly justified, potentially excluding marginalized groups, and limiting the generalizability of trial findings.
Objective
To summarize and evaluate the justification of exclusion criteria in published RCTs in critical care medicine.
Evidence Review
A systematic sampling review of parallel-group RCTs published in the top 5 general internal medicine journals by impact factor ( The Lancet, New England Journal of Medicine, Journal of the American Medical Association, British Medical Journal, and Annals of Internal Medicine ) between January 1, 2018, and February 23, 2023, was conducted. RCTs enrolling adults in intensive care units (ICUs) and RCTs enrolling critically ill patients who required life-sustaining interventions typically initiated in the ICU were included. All study exclusion criteria were categorized as either poorly justified, potentially justified, or strongly justified, adapting previously established criteria, independently and in duplicate.
Findings
In total, 225 studies were identified, 75 of which were included. The median (IQR) number of exclusion criteria per trial was 19 (14-24), with 1455 total exclusion criteria. Common exclusion criteria were related to the risk of adverse reaction to interventions (302 criteria [20.8%]), followed by inability to obtain consent (120 criteria [8.2%]), and treatment limitation decisions (97 criteria [6.7%]). Most exclusion criteria were either strongly justified (1080 criteria [74.2%]) or potentially justified (297 criteria [20.4%]), whereas 5.4% (78 criteria) were poorly justified. Of the 78 poorly justified exclusion criteria, the most common were pregnancy (19 criteria [24.4%]), communication barriers (11 criteria [14.1%]), lactation (10 criteria [12.8%]), and lack of health insurance (10 criteria [12.8%]). Overall, 45 of 75 studies (60.0%) had at least 1 poorly justified exclusion criteria.
Conclusions and Relevance
Most exclusion criteria in critical care medicine RCTs were strongly justifiable. Across poorly justified criteria, the most common exclusions were pregnant or lactating persons, those with communication barriers, and individuals without health insurance. This highlights the need to carefully consider exclusion criteria when designing trials to minimize the inappropriate exclusion of participants and enhance generalizability.
According to the latest definition, sepsis is characterized by life-threatening organ dysfunction caused by a dysregulated host response to an infection. However, this definition fails to grasp the heterogeneous nature and the underlying dynamic pathophysiology of the syndrome. In response to this heterogeneity, efforts have been made to stratify sepsis patients into subtypes, either based on their clinical presentation or pathophysiological characteristics. Subtyping introduces the possibility of the implementation of personalized medicine, whereby each patient receives treatment tailored to their individual disease manifestation. This review explores the currently known subtypes, categorized by subphenotypes and endotypes, as well as the treatments that have been researched thus far in the context of sepsis subtypes and personalized medicine.
Cordyceps spp. (CS), a well-known medicinal mushroom that belongs to Tibetan medicine and is predominantly found in the high altitudes in the Himalayas. CS is a rich reservoir of various bioactive substances including nucleosides, sterols flavonoids, peptides, and phenolic compounds. The bioactive compounds and CS extract have antibacterial, antioxidant, immunomodulatory, and inflammatory properties in addition to organ protection properties across a range of disease states. The study aimed to review the potential of CS, a medicinal mushroom, as a treatment for sepsis. While current sepsis drugs have side effects, CS shows promise due to its anti-inflammatory, antioxidant, and antibacterial properties. We have performed an extensive literature search based on published original and review articles in Scopus and PubMed. The keywords used were Cordyceps, sepsis, and inflammation. Studies indicate that CS extract and bioactive compounds target free radicals including oxidative as well as nitrosative stress, lower inflammation, and modulate the immune system, all of which are critical components in sepsis. The brain, liver, kidneys, lungs, and heart are among the organs that CS extracts may be able to shield against harm during sepsis. Traditional remedies with anti-inflammatory and protective qualities, such as Cordyceps mushrooms, are promising in sepsis. However, more research including clinical trials is required to validate the usefulness of CS metabolites in terms of organ protection and fight infections in sepsis.
Hemoroidal Hastalık Osman Anıl SAVAŞ Kolonun Divertiküler Hastalığı Mehmet Emin GÖNÜLLÜ Erman YEKENKURUL Mehmet Fuat ÇETİN Amyand Herni Mehmet Zeki ÖĞÜT Hemoroidal Hastalık ve Longo Prosedürü Adem TUNÇER Perianal Fistül Hastalığının Tanı ve Tedavisi Ali kemal TAŞKIN Canlı Vericili Karaciğer Nakli Sonrası Erken Re-Laparatomi: Nedenler, Risk Faktörleri ve Sonuçlar Bora BARUT Tek İnsizyon Laparoskopik Apendektomi (Sıla) Arslan Hasan KOCAMAZ Appendiks Mukoseli: Tanı ve Tedavi Bora BARUT İntra-Abdominal Enfeksiyon Yönetimi Mehmet Emin GÖNÜLLÜ Gürkan GÜNERİ Kadir ÇORBACI İnflamatuar Meme Kanseri Seyit Ali Volkan POLATKAN
Importance
Estimates from claims-based analyses suggest that the incidence of sepsis is increasing and mortality rates from sepsis are decreasing. However, estimates from claims data may lack clinical fidelity and can be affected by changing diagnosis and coding practices over time.
Objective
To estimate the US national incidence of sepsis and trends using detailed clinical data from the electronic health record (EHR) systems of diverse hospitals.
Design, Setting, and Population
Retrospective cohort study of adult patients admitted to 409 academic, community, and federal hospitals from 2009-2014.
Exposures
Sepsis was identified using clinical indicators of presumed infection and concurrent acute organ dysfunction, adapting Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) criteria for objective and consistent EHR-based surveillance.
Main Outcomes and Measures
Sepsis incidence, outcomes, and trends from 2009-2014 were calculated using regression models and compared with claims-based estimates using International Classification of Diseases, Ninth Revision, Clinical Modification codes for severe sepsis or septic shock. Case-finding criteria were validated against Sepsis-3 criteria using medical record reviews.
Results
A total of 173 690 sepsis cases (mean age, 66.5 [SD, 15.5] y; 77 660 [42.4%] women) were identified using clinical criteria among 2 901 019 adults admitted to study hospitals in 2014 (6.0% incidence). Of these, 26 061 (15.0%) died in the hospital and 10 731 (6.2%) were discharged to hospice. From 2009-2014, sepsis incidence using clinical criteria was stable (+0.6% relative change/y [95% CI, −2.3% to 3.5%], P = .67) whereas incidence per claims increased (+10.3%/y [95% CI, 7.2% to 13.3%], P < .001). In-hospital mortality using clinical criteria declined (−3.3%/y [95% CI, −5.6% to −1.0%], P = .004), but there was no significant change in the combined outcome of death or discharge to hospice (−1.3%/y [95% CI, −3.2% to 0.6%], P = .19). In contrast, mortality using claims declined significantly (−7.0%/y [95% CI, −8.8% to −5.2%], P < .001), as did death or discharge to hospice (−4.5%/y [95% CI, −6.1% to −2.8%], P < .001). Clinical criteria were more sensitive in identifying sepsis than claims (69.7% [95% CI, 52.9% to 92.0%] vs 32.3% [95% CI, 24.4% to 43.0%], P < .001), with comparable positive predictive value (70.4% [95% CI, 64.0% to 76.8%] vs 75.2% [95% CI, 69.8% to 80.6%], P = .23).
Conclusions and Relevance
In clinical data from 409 hospitals, sepsis was present in 6% of adult hospitalizations, and in contrast to claims-based analyses, neither the incidence of sepsis nor the combined outcome of death or discharge to hospice changed significantly between 2009-2014. The findings also suggest that EHR-based clinical data provide more objective estimates than claims-based data for sepsis surveillance.
AIM
To characterize the prescribing patterns for hydrocortisone for patients with septic shock and perform an exploratory analysis in order to identify the variables associated with better outcomes.
METHODS
This prospective cohort study included 59 patients with septic shock who received stress-dose hydrocortisone. It was performed at 2 critical care units in academic hospitals from June 1st, 2015, to July 31st, 2016. Demographic data, comorbidities, medical management details, adverse effects related to corticosteroids, and outcomes were collected after the critical care physician indicated initiation of hydrocortisone. Univariate comparison between continuous and bolus administration of hydrocortisone was performed, including multivariate analysis, as well as Kaplan-Meier analysis to compare the proportion of shock reversal at 7 d after presentation. Receiver operating characteristic (ROC) curves determined the best cut-off criteria for initiation of hydrocortisone associated with the highest probability of shock reversal. We addressed the effects of the taper strategy for discontinuation of hydrocortisone, noting risk of shock relapse and adverse effects.
RESULTS
All-cause 30-d mortality was 42%. Hydrocortisone was administered as a continuous infusion in 54.2% of patients; time to reversal of shock was 49 h longer in patients who were given a bolus administration [59 h (range, 47.5-90.5) vs 108 h (range, 63.2-189); P = 0.001]. The maximal dose of norepinephrine after initiation of hydrocortisone was lower in patients on continuous infusion [0.19 μg/kg per minute (range, 0.11-0.28 μg)] compared with patients who were given bolus [0.34 μg/kg per minute (range, 0.16-0.49); P = 0.004]. Kaplan-Meier analysis revealed a higher proportion of shock reversal at 7 d in patients with continuous infusion compared to those given bolus (83% vs 63%; P = 0.004). There was a good correlation between time to initiation of hydrocortisone and time to reversal of shock (r = 0.80; P < 0.0001); ROC curve analysis revealed that the best criteria for prediction of shock reversal was a time to initiation of hydrocortisone of ≤ 13 h after administration of norepinephrine, with an area under the curve of 0.81 (P < 0.001). The maximal dose of norepinephrine at initiation of hydrocortisone with the highest association with shock reversal was ≤ 0.28 μg/kg per minute, with an area under the curve of 0.75 (P = 0.0002). On a logistic regression model, hydrocortisone taper was not associated with a lower risk of shock relapse (RR = 1.29; P = 0.17) but was related to a higher probability of hyperglycemia [odds ratio (OR), 5.3; P = 0.04] and hypokalemia (OR = 10.6; P = 0.01).
CONCLUSION
Continuous infusion of hydrocortisone could hasten the resolution of septic shock compared to bolus administration. Earlier initiation corresponds with a higher probability of shock reversal. Tapering strategy is unnecessary.
Objective
To provide an update to “Surviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock: 2012”. DesignA consensus committee of 55 international experts representing 25 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict-of-interest (COI) policy was developed at the onset of the process and enforced throughout. A stand-alone meeting was held for all panel members in December 2015. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development. Methods
The panel consisted of five sections: hemodynamics, infection, adjunctive therapies, metabolic, and ventilation. Population, intervention, comparison, and outcomes (PICO) questions were reviewed and updated as needed, and evidence profiles were generated. Each subgroup generated a list of questions, searched for best available evidence, and then followed the principles of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to assess the quality of evidence from high to very low, and to formulate recommendations as strong or weak, or best practice statement when applicable. ResultsThe Surviving Sepsis Guideline panel provided 93 statements on early management and resuscitation of patients with sepsis or septic shock. Overall, 32 were strong recommendations, 39 were weak recommendations, and 18 were best-practice statements. No recommendation was provided for four questions. Conclusions
Substantial agreement exists among a large cohort of international experts regarding many strong recommendations for the best care of patients with sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for these critically ill patients with high mortality.
Introduction:
Glucocorticosteroids (steroids) are widely used for sepsis patients. However, the potential benefits and harms of both high and low dose steroids remain unclear. A systematic review of randomised clinical trials with meta-analysis and trial sequential analysis (TSA) might shed light on this clinically important question.
Methods:
A systematic review was conducted according to a published protocol and The Cochrane Handbook methodology including meta-analyses, TSA of randomised clinical trials, and external validity estimation (GRADE). Randomised clinical trials evaluating steroids were included for sepsis patients (systemic inflammatory response syndrome, sepsis, severe sepsis or septic shock) aged >18 years. Cochrane Central Register of Controlled Trials (CENTRAL), PubMed/Medline, Embase, Web of Science and Cinahl were searched until 18 February 2015. No language restrictions were applied. Primary outcomes were mortality at longest follow-up and serious adverse events.
Results:
A total of 35 trials randomising 4682 patients were assessed and reviewed in full text. All trials but two had high risk of bias. No statistically significant effect was found for any dose of steroids versus placebo or no intervention on mortality at maximal follow-up [relative risk (RR) 0.89; TSA adjusted confidence interval (CI) 0.74-1.08]. Two trials with low risk of bias also showed no statistically significant difference (random-effects model RR 0.38, 95% CI 0.06-2.42). Similar results were obtained in subgroups of trials stratified according to high (>500 mg) or low (≤ 500 mg) dose hydrocortisone (or equivalent) (RR 0.87; TSA-adjusted CI 0.38-1.99; and RR 0.90; TSA-adjusted CI 0.49-1.67, respectively). There were also no statistically significant effects on serious adverse events other than mortality (RR 1.02; TSA-adjusted CI 0.7-1.48). The effects did not vary according to the degree of sepsis. TSA showed that many more randomised patients are needed before definitive conclusions may be drawn.
Conclusion:
Evidence to support or negate the use of steroids in any dose in sepsis patients is lacking. The results of ongoing and future well-designed, large randomised clinical trials are needed.
This paper presents the form and validation results of APACHE II, a severity of disease classification system. APACHE II uses a point score based upon initial values of 12 routine physiologic measurements, age, and previous health status to provide a general measure of severity of disease. An increasing score (range 0 to 71) was closely correlated with the subsequent risk of hospital death for 5815 intensive care admissions from 13 hospitals. This relationship was also found for many common diseases.When APACHE II scores are combined with an accurate description of disease, they can prognostically stratify acutely ill patients and assist investigators comparing the success of new or differing forms of therapy. This scoring index can be used to evaluate the use of hospital resources and compare the efficacy of intensive care in different hospitals or over time.
There have been conflicting reports on the efficacy of recombinant human activated protein C, or drotrecogin alfa (activated) (DrotAA), for the treatment of patients with septic shock.
In this randomized, double-blind, placebo-controlled, multicenter trial, we assigned 1697 patients with infection, systemic inflammation, and shock who were receiving fluids and vasopressors above a threshold dose for 4 hours to receive either DrotAA (at a dose of 24 μg per kilogram of body weight per hour) or placebo for 96 hours. The primary outcome was death from any cause 28 days after randomization.
At 28 days, 223 of 846 patients (26.4%) in the DrotAA group and 202 of 834 (24.2%) in the placebo group had died (relative risk in the DrotAA group, 1.09; 95% confidence interval [CI], 0.92 to 1.28; P=0.31). At 90 days, 287 of 842 patients (34.1%) in the DrotAA group and 269 of 822 (32.7%) in the placebo group had died (relative risk, 1.04; 95% CI, 0.90 to 1.19; P=0.56). Among patients with severe protein C deficiency at baseline, 98 of 342 (28.7%) in the DrotAA group had died at 28 days, as compared with 102 of 331 (30.8%) in the placebo group (risk ratio, 0.93; 95% CI, 0.74 to 1.17; P=0.54). Similarly, rates of death at 28 and 90 days were not significantly different in other predefined subgroups, including patients at increased risk for death. Serious bleeding during the treatment period occurred in 10 patients in the DrotAA group and 8 in the placebo group (P=0.81).
DrotAA did not significantly reduce mortality at 28 or 90 days, as compared with placebo, in patients with septic shock. (Funded by Eli Lilly; PROWESS-SHOCK ClinicalTrials.gov number, NCT00604214.).
Hospital length of stay (LOS) and time for a patient to reach clinical stability (TCS) have increasingly become important outcomes when investigating ways in which to combat Community Acquired Pneumonia (CAP). Difficulties arise when deciding how to handle in-hospital mortality. Ad-hoc approaches that are commonly used to handle time to event outcomes with mortality can give disparate results and provide conflicting conclusions based on the same data. To ensure compatibility among studies investigating these outcomes, this type of data should be handled in a consistent and appropriate fashion.
Using both simulated data and data from the international Community Acquired Pneumonia Organization (CAPO) database, we evaluate two ad-hoc approaches for handling mortality when estimating the probability of hospital discharge and clinical stability: 1) restricting analysis to those patients who lived, and 2) assigning individuals who die the "worst" outcome (right-censoring them at the longest recorded LOS or TCS). Estimated probability distributions based on these approaches are compared with right-censoring the individuals who died at time of death (the complement of the Kaplan-Meier (KM) estimator), and treating death as a competing risk (the cumulative incidence estimator). Tests for differences in probability distributions based on the four methods are also contrasted.
The two ad-hoc approaches give different estimates of the probability of discharge and clinical stability. Analysis restricted to patients who survived is conceptually problematic, as estimation is conditioned on events that happen at a future time. Estimation based on assigning those patients who died the worst outcome (longest LOS and TCS) coincides with the complement of the KM estimator based on the subdistribution hazard, which has been previously shown to be equivalent to the cumulative incidence estimator. However, in either case the time to in-hospital mortality is ignored, preventing simultaneous assessment of patient mortality in addition to LOS and/or TCS. The power to detect differences in underlying hazards of discharge between patient populations differs for test statistics based on the four approaches, and depends on the underlying hazard ratio of mortality between the patient groups.
Treating death as a competing risk gives estimators which address the clinical questions of interest, and allows for simultaneous modelling of both in-hospital mortality and TCS / LOS. This article advocates treating mortality as a competing risk when investigating other time related outcomes.
The benefits and use of low-dose corticosteroids (LDCs) in severe sepsis and septic shock remain controversial. Surviving sepsis campaign guidelines suggest LDC use for septic shock patients poorly responsive to fluid resuscitation and vasopressor therapy. Their use is suspected to be wide-spread, but paucity of data regarding global practice exists. The purpose of this study was to compare baseline characteristics and clinical outcomes of patients treated or not treated with LDC from the international PROGRESS (PROmoting Global Research Excellence in Severe Sepsis) cohort study of severe sepsis.
Patients enrolled in the PROGRESS registry were evaluated for use of vasopressor and LDC (equivalent or lesser potency to hydrocortisone 50 mg six-hourly plus 50 microg 9-alpha-fludrocortisone) for treatment of severe sepsis at any time in intensive care units (ICUs). Baseline characteristics and hospital mortality were analyzed, and logistic regression techniques used to develop propensity score and outcome models adjusted for baseline imbalances between groups.
A total of 8,968 patients with severe sepsis and sufficient data for analysis were studied. A total of 79.8% (7,160/8,968) of patients received vasopressors, and 34.0% (3,051/8,968) of patients received LDC. Regional use of LDC was highest in Europe (51.1%) and lowest in Asia (21.6%). Country use was highest in Brazil (62.9%) and lowest in Malaysia (9.0%). A total of 14.2% of patients on LDC were not receiving any vasopressor therapy. LDC patients were older, had more co-morbidities and higher disease severity scores. Patients receiving LDC spent longer in ICU than patients who did not (median of 12 versus 8 days; P <0.001). Overall hospital mortality rates were greater in the LDC than in the non-LDC group (58.0% versus 43.0%; P <0.001). After adjusting for baseline imbalances, in all mortality models (with vasopressor use), a consistent association remained between LDC and hospital mortality (odds ratios varying from 1.30 to 1.47).
Widespread use of LDC for the treatment of severe sepsis with significant regional and country variation exists. In this study, 14.2% of patients received LDC despite the absence of evidence of shock. Hospital mortality was higher in the LDC group and remained higher after adjustment for key determinates of mortality.
The benefit of corticosteroids in severe sepsis and septic shock remains controversial.
We examined the benefits and risks of corticosteroid treatment in severe sepsis and septic shock and the influence of dose and duration.
We searched the CENTRAL, MEDLINE, EMBASE, and LILACS (through March 2009) databases as well as reference lists of articles and proceedings of major meetings, and we contacted trial authors.
Randomized and quasi-randomized trials of corticosteroids vs placebo or supportive treatment in adult patients with severe sepsis/septic shock per the American College of Chest Physicians/Society of Critical Care Medicine consensus definition were included.
All reviewers agreed on trial eligibility. One reviewer extracted data, which were checked by the other reviewers and by the trials' authors whenever possible. Some unpublished data were obtained from the trials' authors. The primary outcome for this review was 28-day mortality.
We identified 17 randomized trials (n = 2138) and 3 quasi-randomized trials (n = 246) that had acceptable methodological quality to pool in a meta-analysis. Twenty-eight-day mortality for treated vs control patients was 388/1099 (35.3%) vs 400/1039 (38.5%) in randomized trials (risk ratio [RR], 0.84; 95% confidence interval [CI], 0.71-1.00; P = .05; I(2) = 53% by random-effects model) and 28/121 (23.1%) vs 24/125 (19.2%) in quasi-randomized trials (RR, 1.05, 95% CI, 0.69-1.58; P = .83). In 12 trials investigating prolonged low-dose corticosteroid treatment, 28-day mortality for treated vs control patients was 236/629 (37.5%) vs 264/599 (44%) (RR, 0.84; 95% CI, 0.72-0.97; P = .02). This treatment increased 28-day shock reversal (6 trials; 322/481 [66.9%] vs 276/471 [58.6%]; RR, 1.12; 95% CI, 1.02-1.23; P = .02; I(2) = 4%) and reduced intensive care unit length of stay by 4.49 days (8 trials; 95% CI, -7.04 to -1.94; P < .001; I(2) = 0%) without increasing the risk of gastroduodenal bleeding (13 trials; 65/800 [8.1%] vs 56/764 [7.3%]; P = .50; I(2) = 0%), superinfection (14 trials; 184/998 [18.4%] vs 170/950 [17.9%]; P = .92; I(2) = 8%), or neuromuscular weakness (3 trials; 4/407 [1%] vs 7/404 [1.7%]; P = .58; I(2) = 30%). Corticosteroids increased the risk of hyperglycemia (9 trials; 363/703 [51.6%] vs 308/670 [46%]; P < .001; I(2) = 0%) and hypernatremia (3 trials; 127/404 [31.4%] vs 77/401 [19.2%]; P < .001; I(2) = 0%).
Corticosteroid therapy has been used in varied doses for sepsis and related syndromes for more than 50 years, with no clear benefit on mortality. Since 1998, studies have consistently used prolonged low-dose corticosteroid therapy, and analysis of this subgroup suggests a beneficial drug effect on short-term mortality.
The use of the intravenous anesthetic etomidate for prolonged sedation has been associated with low levels of plasma cortisol and increased mortality. We measured the cortisol and aldosterone responses to ACTH stimulation in five patients receiving etomidate, and we also studied the direct effects of etomidate on enzymes in the rat steroidogenic pathway. One patient who was receiving a 20-hour infusion of etomidate (1.3 to 1.5 mg per kilogram of body weight per hour) had marked adrenocortical suppression that was still evident four days after etomidate was discontinued. Four surgical patients receiving etomidate during their operations were all found to have adrenal suppression four hours after the operation; mean (+/- S.D.) increases in cortisol and aldosterone after ACTH stimulation were only 1.8 +/- 0.5 micrograms per deciliter and 0.5 +/- 1.1 ng per deciliter, respectively. In rat adrenal cells, etomidate produced a concentration-dependent blockade of the two mitochondrial cytochrome P-450-dependent enzymes, cholesterol-side-chain cleavage enzyme, and 11 beta-hydroxylase, without evident inhibition of the microsomal enzymes in the glucocorticoid pathway. Physicians should be aware that etomidate inhibits adrenal steroidogenesis, and they should consider treating selected patients with corticosteroids if etomidate is used.
Celsus described four of the five cardinal signs of inflammation 2000 years ago, and Eustachio discovered the adrenal glands almost 500 years ago, but not until 1936 did Selye note that in rats exposed to stressors, the adrenal glands were enlarged, and the thymus and lymph nodes shrunken.1–3 Cortisone, the active principle of the adrenal glands, was isolated by Kendall and Reichstein in the late 1940s and shown to suppress immune organs. These scientists, along with Hench, received the Nobel Prize in Physiology and Medicine, after Hench and colleagues showed that cortisone could ameliorate rheumatoid arthritis.4,5 In recent . . .
Septic shock may be associated with relative adrenal insufficiency. Thus, a replacement therapy of low doses of corticosteroids has been proposed to treat septic shock.
To assess whether low doses of corticosteroids improve 28-day survival in patients with septic shock and relative adrenal insufficiency.
Placebo-controlled, randomized, double-blind, parallel-group trial performed in 19 intensive care units in France from October 9, 1995, to February 23, 1999.
Three hundred adult patients who fulfilled usual criteria for septic shock were enrolled after undergoing a short corticotropin test.
Patients were randomly assigned to receive either hydrocortisone (50-mg intravenous bolus every 6 hours) and fludrocortisone (50- micro g tablet once daily) (n = 151) or matching placebos (n = 149) for 7 days.
Twenty-eight-day survival distribution in patients with relative adrenal insufficiency (nonresponders to the corticotropin test).
One patient from the corticosteroid group was excluded from analyses because of consent withdrawal. There were 229 nonresponders to the corticotropin test (placebo, 115; corticosteroids, 114) and 70 responders to the corticotropin test (placebo, 34; corticosteroids, 36). In nonresponders, there were 73 deaths (63%) in the placebo group and 60 deaths (53%) in the corticosteroid group (hazard ratio, 0.67; 95% confidence interval, 0.47-0.95; P =.02). Vasopressor therapy was withdrawn within 28 days in 46 patients (40%) in the placebo group and in 65 patients (57%) in the corticosteroid group (hazard ratio, 1.91; 95% confidence interval, 1.29-2.84; P =.001). There was no significant difference between groups in responders. Adverse events rates were similar in the 2 groups.
In our trial, a 7-day treatment with low doses of hydrocortisone and fludrocortisone significantly reduced the risk of death in patients with septic shock and relative adrenal insufficiency without increasing adverse events.
Within the last few years, increasing evidence of relative adrenal insufficiency in septic shock evoked a reassessment of hydrocortisone therapy. To evaluate the effects of hydrocortisone on the balance between proinflammatory and antiinflammation, 40 patients with septic shock were randomized in a double-blind crossover study to receive either the first 100 mg of hydrocortisone as a loading dose and 10 mg per hour until Day 3 (n = 20) or placebo (n = 20), followed by the opposite medication until Day 6. Hydrocortisone infusion induced an increase of mean arterial pressure, systemic vascular resistance, and a decline of heart rate, cardiac index, and norepinephrine requirement. A reduction of plasma nitrite/nitrate indicated inhibition of nitric oxide formation and correlated with a reduction of vasopressor support. The inflammatory response (interleukin-6 and interleukin-8), endothelial (soluble E-selectin) and neutrophil activation (expression of CD11b, CD64), and antiinflammatory response (soluble tumor necrosis factor receptors I and II and interleukin-10) were attenuated. In peripheral blood monocytes, human leukocyte antigen-DR expression was only slightly depressed, whereas in vitro phagocytosis and the monocyte-activating cytokine interleukin-12 increased. Hydrocortisone withdrawal induced hemodynamic and immunologic rebound effects. In conclusion, hydrocortisone therapy restored hemodynamic stability and differentially modulated the immunologic response to stress in a way of antiinflammation rather than immunosuppression.
Low-dose hydrocortisone treatment is widely accepted therapy for the treatment of vasopressor-dependent septic shock. The question of whether corticosteroids should be given to septic shock patients by continuous or by bolus infusion is still unanswered. Hydrocortisone induces hyperglycemia and it is possible that continuous hydrocortisone infusion would reduce the fluctuations in blood glucose levels and that tight blood glucose control could be better achieved with this approach.
In this prospective randomized study, we compared the blood glucose profiles, insulin requirements, amount of nursing workload needed, and shock reversal in 48 septic shock patients who received hydrocortisone treatment either by bolus or by continuous infusion with equivalent dose (200 mg/day). Duration of hydrocortisone treatment was five days.
The mean blood glucose levels were similar in the two groups, but the number of hyperglycemic episodes was significantly higher in those patients who received bolus therapy (15.7 +/- 8.5 versus 10.5 +/- 8.6 episodes per patient, p = 0.039). Also, more changes in insulin infusion rate were needed to maintain strict normoglycemia in the bolus group (4.7 +/- 2.2 versus 3.4 +/- 1.9 adjustments per patient per day, p = 0.038). Hypoglycemic episodes were rare in both groups. No difference was seen in shock reversal.
Strict normoglycemia is more easily achieved if the hydrocortisone therapy is given to septic shock patients by continuous infusion. This approach also reduces nursing workload needed to maintain tight blood glucose control.
To determine the population incidence and outcome of severe sepsis occurring in adult patients treated in Australian and New Zealand intensive care units (ICUs), and compare with recent retrospective estimates from the USA and UK.
Inception cohort study.
Twenty-three closed multi-disciplinary ICUs of 21 hospitals (16 tertiary and 5 university affiliated) in Australia and New Zealand.
A total of 5878 consecutive ICU admission episodes.
Main outcome measures were population-based incidence of severe sepsis, mortality at ICU discharge, mortality at 28 days after onset of severe sepsis, and mortality at hospital discharge. A total of 691 patients, 11.8 (95% confidence intervals 10.9-12.6) per 100 ICU admissions, were diagnosed with 752 episodes of severe sepsis. Site of infection was pulmonary in 50.3% of episodes and abdominal in 19.3% of episodes. The calculated incidence of severe sepsis in adults treated in Australian and New Zealand ICUs is 0.77 (0.76-0.79) per 1000 of population. 26.5% of patients with severe sepsis died in ICU, 32.4% died within 28 days of the diagnosis of severe sepsis and 37.5% died in hospital.
In this prospective study, 11.8 patients per 100 ICU admissions were diagnosed with severe sepsis and the calculated annual incidence of severe sepsis in adult patients treated in Australian and New Zealand ICUs is 0.77 per 1000 of population. This figure for the population incidence falls in the lower range of recent estimates from retrospective studies in the U.S. and the U.K.
Hydrocortisone is widely used in patients with septic shock even though a survival benefit has been reported only in patients who remained hypotensive after fluid and vasopressor resuscitation and whose plasma cortisol levels did not rise appropriately after the administration of corticotropin.
In this multicenter, randomized, double-blind, placebo-controlled trial, we assigned 251 patients to receive 50 mg of intravenous hydrocortisone and 248 patients to receive placebo every 6 hours for 5 days; the dose was then tapered during a 6-day period. At 28 days, the primary outcome was death among patients who did not have a response to a corticotropin test.
Of the 499 patients in the study, 233 (46.7%) did not have a response to corticotropin (125 in the hydrocortisone group and 108 in the placebo group). At 28 days, there was no significant difference in mortality between patients in the two study groups who did not have a response to corticotropin (39.2% in the hydrocortisone group and 36.1% in the placebo group, P=0.69) or between those who had a response to corticotropin (28.8% in the hydrocortisone group and 28.7% in the placebo group, P=1.00). At 28 days, 86 of 251 patients in the hydrocortisone group (34.3%) and 78 of 248 patients in the placebo group (31.5%) had died (P=0.51). In the hydrocortisone group, shock was reversed more quickly than in the placebo group. However, there were more episodes of superinfection, including new sepsis and septic shock.
Hydrocortisone did not improve survival or reversal of shock in patients with septic shock, either overall or in patients who did not have a response to corticotropin, although hydrocortisone hastened reversal of shock in patients in whom shock was reversed. (ClinicalTrials.gov number, NCT00147004.)
Background
It is uncertain whether the duration of red-cell storage affects mortality after transfusion among critically ill adults.
Methods
In an international, multicenter, randomized, double-blind trial, we assigned critically ill adults to receive either the freshest available, compatible, allogeneic red cells (short-term storage group) or standard-issue (oldest available), compatible, allogeneic red cells (long-term storage group). The primary outcome was 90-day mortality.
Results
From November 2012 through December 2016, at 59 centers in five countries, 4994 patients underwent randomization and 4919 (98.5%) were included in the primary analysis. Among the 2457 patients in the short-term storage group, the mean storage duration was 11.8 days. Among the 2462 patients in the long-term storage group, the mean storage duration was 22.4 days. At 90 days, there were 610 deaths (24.8%) in the short-term storage group and 594 (24.1%) in the long-term storage group (absolute risk difference, 0.7 percentage points; 95% confidence interval [CI], −1.7 to 3.1; P=0.57). At 180 days, the absolute risk difference was 0.4 percentage points (95% CI, −2.1 to 3.0; P=0.75). Most of the prespecified secondary measures showed no significant between-group differences in outcome.
Conclusions
The age of transfused red cells did not affect 90-day mortality among critically ill adults. (Funded by the Australian National Health and Medical Research Council and others; TRANSFUSE Australian and New Zealand Clinical Trials Registry number, ACTRN12612000453886; ClinicalTrials.gov number, NCT01638416.)
Background:
The sepsis burden on acute care services in middle-income countries is a cause for concern. We estimated incidence, prevalence, and mortality of sepsis in adult Brazilian intensive care units (ICUs) and association of ICU organisational factors with outcome.
Methods:
We did a 1-day point prevalence study with follow-up of patients in ICU with sepsis in a nationally representative pseudo-random sample. We produced a sampling frame initially stratified by geographical region. Each stratum was then stratified by hospitals' main source of income (serving general public vs privately insured individuals) and ICU size (ten or fewer beds vs more than ten beds), finally generating 40 strata. In each stratum we selected a random sample of ICUs so as to enrol the total required beds in 1690 Brazilian adult ICUs. We followed up patients until hospital discharge censored at 60 days, estimated incidence from prevalence and length of stay, and generated national estimates. We assessed mortality prognostic factors using random-effects logistic regression models.
Findings:
On Feb 27, 2014, 227 (72%) of 317 ICUs that were randomly selected provided data on 2632 patients, of whom 794 had sepsis (30·2 septic patients per 100 ICU beds, 95% CI 28·4-31·9). The ICU sepsis incidence was 36·3 per 1000 patient-days (95% CI 29·8-44·0) and mortality was observed in 439 (55·7%) of 788 patients (95% CI 52·2-59·2). Low availability of resources (odds ratio [OR] 1·67, 95% CI 1·02-2·75, p=0·045) and adequacy of treatment (OR 0·56, 0·37-0·84, p=0·006) were independently associated with mortality. The projected incidence rate is 290 per 100 000 population (95% CI 237·9-351·2) of adult cases of ICU-treated sepsis per year, which yields about 420 000 cases annually, of whom 230 000 die in hospital.
Interpretation:
The incidence, prevalence, and mortality of ICU-treated sepsis is high in Brazil. Outcome varies considerably, and is associated with access to adequate resources and treatment. Our results show the burden of sepsis in resource-limited settings, highlighting the need to establish programmes aiming for sepsis prevention, early diagnosis, and adequate treatment.
Funding:
Fundação de Apoio a Pesquisa do Estado de São Paulo (FAPESP).
Background:
The Adjunctive Corticosteroid Treatment in Critically Ill Patients with Septic Shock (ADRENAL) trial, a 3800-patient, multicentre, randomised controlled trial, will be the largest study to date of corticosteroid therapy in patients with septic shock.
Objective:
To describe a statistical analysis plan (SAP) and make it public before completion of patient recruitment and data collection. The SAP will be adhered to for the final data analysis of this trial, to avoid analysis bias arising from knowledge of study findings.
Methods:
The SAP was designed by the chief investigators and statisticians and approved by the ADRENAL management committee. All authors were blind to treatment allocation and to the unblinded data produced during two interim analyses conducted by the Data Safety and Monitoring Committee. The data shells were produced from a previously published protocol. Statistical analyses are described in broad detail. Trial outcomes were selected and categorised into primary, secondary and tertiary outcomes, and appropriate statistical comparisons between groups are planned and described in a way that is transparent, available to the public, verifiable and determined before completion of data collection.
Results:
We developed a standard SAP for the ADRENAL trial, and have produced a trial profile outline and list of mock tables. We describe analyses of baseline characteristics, processes of care, measures of efficacy and outcomes. Six pre-specified subgroups were defined, and statistical comparisons between groups in these subgroups are described.
Conclusion:
We have developed an SAP for the ADRENAL trial. This plan accords with high-quality standards of internal validity to minimise analysis bias.
Importance
Definitions of sepsis and septic shock were last revised in 2001. Considerable advances have since been made into the pathobiology (changes in organ function, morphology, cell biology, biochemistry, immunology, and circulation), management, and epidemiology of sepsis, suggesting the need for reexamination.Objective
To evaluate and, as needed, update definitions for sepsis and septic shock.Process
A task force (n = 19) with expertise in sepsis pathobiology, clinical trials, and epidemiology was convened by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine. Definitions and clinical criteria were generated through meetings, Delphi processes, analysis of electronic health record databases, and voting, followed by circulation to international professional societies, requesting peer review and endorsement (by 31 societies listed in the Acknowledgment).Key Findings From Evidence Synthesis
Limitations of previous definitions included an excessive focus on inflammation, the misleading model that sepsis follows a continuum through severe sepsis to shock, and inadequate specificity and sensitivity of the systemic inflammatory response syndrome (SIRS) criteria. Multiple definitions and terminologies are currently in use for sepsis, septic shock, and organ dysfunction, leading to discrepancies in reported incidence and observed mortality. The task force concluded the term severe sepsis was redundant.Recommendations
Sepsis should be defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. For clinical operationalization, organ dysfunction can be represented by an increase in the Sequential [Sepsis-related] Organ Failure Assessment (SOFA) score of 2 points or more, which is associated with an in-hospital mortality greater than 10%. Septic shock should be defined as a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone. Patients with septic shock can be clinically identified by a vasopressor requirement to maintain a mean arterial pressure of 65 mm Hg or greater and serum lactate level greater than 2 mmol/L (>18 mg/dL) in the absence of hypovolemia. This combination is associated with hospital mortality rates greater than 40%. In out-of-hospital, emergency department, or general hospital ward settings, adult patients with suspected infection can be rapidly identified as being more likely to have poor outcomes typical of sepsis if they have at least 2 of the following clinical criteria that together constitute a new bedside clinical score termed quickSOFA (qSOFA): respiratory rate of 22/min or greater, altered mentation, or systolic blood pressure of 100 mm Hg or less.Conclusions and Relevance
These updated definitions and clinical criteria should replace previous definitions, offer greater consistency for epidemiologic studies and clinical trials, and facilitate earlier recognition and more timely management of patients with sepsis or at risk of developing sepsis.
Background:
Sepsis occurs when an infection is complicated by organ failures as defined by a sequential organ failure assessment (SOFA) score of two or higher. Sepsis may be complicated by impaired corticosteroid metabolism. Giving corticosteroids may benefit patients. The original review was published in 2004 and was updated in 2010 and again in 2015.
Objectives:
To examine the effects of corticosteroids on death at one month in patients with sepsis, and to examine whether dose and duration of corticosteroids influence patient response to this treatment.
Search methods:
We searched the Central Register of Controlled Trials (CENTRAL; 2014, Issue 10), MEDLINE (October 2014), EMBASE (October 2014), Latin American Caribbean Health Sciences Literature (LILACS; October 2014) and reference lists of articles, and we contacted trial authors. The original searches were performed in August 2003 and in October 2009.
Selection criteria:
We included randomized controlled trials of corticosteroids versus placebo or supportive treatment in patients with sepsis.
Data collection and analysis:
All review authors agreed on the eligibility of trials. One review author extracted data, which were checked by the other review authors, and by the primary author of the paper when possible. We obtained some missing data from trial authors. We assessed the methodological quality of trials.
Main results:
We identified nine additional studies since the last update, for a total of 33 eligible trials (n = 4268 participants). Twenty-three of these 33 trials were at low risk of selection bias, 22 were at low risk of performance and detection bias, 27 were at low risk of attrition bias and 14 were at low risk of selective reporting.Corticosteroids reduced 28-day mortality (27 trials; n = 3176; risk ratio (RR) 0.87, 95% confidence interval (CI) 0.76 to 1.00; P value = 0.05, random-effects model). The quality of evidence for this outcome was downgraded from high to low for imprecision (upper limit of 95% CI = 1) and for inconsistency (significant heterogeneity across trial results). Heterogeneity was related in part to the dosing strategy. Treatment with a long course of low-dose corticosteroids significantly reduced 28-day mortality (22 trials; RR 0.87, 95% CI 0.78 to 0.97; P value = 0.01, fixed-effect model). The quality of evidence was downgraded from high to moderate for inconsistency (owing to non-significant effects shown by one large trial). Corticosteroids also reduced mortality rate in the intensive care unit (13 trials; RR 0.82, 95% CI 0.68 to 1.00; P value = 0.04, random-effects model) and at the hospital (17 trials; RR 0.85, 95% CI 0.73 to 0.98; P value = 0.03, random-effects model). Quality of the evidence for in-hospital mortality was downgraded from high to moderate for inconsistency and imprecision (upper limit of 95% CI for RR approaching 1). Corticosteroids increased the proportion of shock reversal by day seven (12 trials; RR 1.31, 95% CI 1.14 to 1.51; P value = 0.0001) and by day 28 (seven trials; n = 1013; RR 1.11, 95% CI 1.02 to 1.21; P value = 0.01) and reduced the SOFA score by day seven (eight trials; mean difference (MD) -1.53, 95% CI -2.04 to -1.03; P value < 0.00001, random-effects model) and survivors' length of stay in the intensive care unit (10 trials; MD -2.19, 95% CI -3.93 to -0.46; P value = 0.01, fixed-effect model) without inducing gastroduodenal bleeding (19 trials; RR 1.24, 95% CI 0. 92 to 1.67; P value = 0.15, fixed-effect model), superinfection (19 trials; RR 1.02, 95% CI 0.87 to 1.20; P value = 0.81, fixed-effect model) or neuromuscular weakness (three trials; RR 0.62, 95% CI 0.21 to 1.88; P value = 0.40, fixed-effect model). Corticosteroid increased the risk of hyperglycaemia (13 trials; RR 1.26, 95% CI 1.16 to 1.37; P value < 0.00001, fixed-effect model) and hypernatraemia (three trials; RR 1.64, 95% CI 1.28 to 2.09; P value < 0.0001, fixed-effect model).
Authors' conclusions:
Overall, low-quality evidence indicates that corticosteroids reduce mortality among patients with sepsis. Moderate-quality evidence suggests that a long course of low-dose corticosteroids reduced 28-day mortality without inducing major complications and led to an increase in metabolic disorders.
Rationale:
Reducing the global burden of sepsis, a recognised global health challenge, requires comprehensive data on the incidence and mortality on a global scale.
Objective:
To estimate the worldwide incidence and mortality of sepsis and to identify knowledge gaps based on available evidence from observational studies.
Methods:
We systematically searched 15 international citation databases for population-level estimates of sepsis incidence rates and fatality in adult populations using consensus criteria and published in the last 36 years.
Main results:
The search yielded 1553 reports from 1979 to 2015, of which 45 met our criteria. 27 studies from 7 high-income-countries provided data for meta-analysis. For these countries, the population incidence rate was 288 [95%CI, 215-386, τ=0.55] hospital-treated sepsis cases and 148 [95%CI, 98-226, τ=0.99] hospital-treated severe sepsis cases per 100 000 person-years. Restricted to the last decade, the incidence rate was 437 [95%CI, 334-571, τ=0.38] sepsis and 270 [95%CI, 176-412, τ=0.60] severe sepsis cases per 100 000 person-years. Hospital mortality was 17% for sepsis and 26% for severe sepsis during this period. There were no population-level sepsis incidence estimates from lower-income-countries, which limits the prediction of global cases and deaths. However, a tentative extrapolation from high-income-country data suggests global estimates of 31.5 million sepsis and 19.4 million severe sepsis cases, with potentially 5.3 million deaths annually.
Conclusions:
Population-level epidemiological data for sepsis are scarce, and non-existent for low- and middle-income-countries. Our analyses underline the urgent need to implement global strategies to measure sepsis morbidity and mortality - particularly in low- and middle-income-countries.
In Reply: Since the 2001 study by van den Berghe et al,1 practices in the intensive care unit have been altered toward avoiding persistent hyperglycemia. Since then, our study and others2 have provided additional evidence suggesting that normalization of blood glucose levels should not be a target, at least with tools available at the bedside. As pointed out by Dr Castellanos and colleagues, hypoglycemia may be the price of blood glucose control. In the COIITSS trial, a total of 62 patients experienced a total of 108 episodes of hypoglycemia, ranging from 1 to 10 per patient. Of these patients, 51 were hypoglycemic on a single day, 10 had hypoglycemic episodes on 2 distinct days, and 1 patient had this complication occurring over 4 days. These findings suggest that hypoglycemia may be predominantly a complication of the initiation of intensive insulin therapy. In the COIITSS trial, this complication was not associated with an increased risk of death.
An American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference was held in Northbrook in August 1991 with the goal of agreeing on a set of definitions that could be applied to patients with sepsis and its sequelae. New definitions were offered for some terms, while others were discarded. Broad definitions of sepsis and the systemic inflammatory response syndrome were proposed, along with detailed physiologic parameters by which a patient may be categorized. Definitions for severe sepsis, septic shock, hypotension, and multiple organ dysfunction syndrome were also offered. The use of severity scoring methods when dealing with septic patients was recommended as an adjunctive tool to assess mortality. Appropriate methods and applications for the use and testing of new therapies were recommended. The use of these terms and techniques should assist clinicians and researchers who deal with sepsis and its sequelae.
One of the most common dynamic testing procedures for assessment of adrenocortical function is the standard corticotropin or the cosyntropin test. The aim of this review is to examine the evidence base underlying the corticotropin test in the management of the critically ill patient.
The principle behind the corticotropin test is the demonstration of an inappropriately low cortisol production in response to exogenous ACTH, a situation analogous to physiological stress The corticotropin test was originally described in non stressed subjects, and its applicability and interpretation in the setting of critical illness continues to generate controversy. Attempting to determine the prevalence of an abnormal corticotropin test in critical illness is complicated by the use of different end points and different populations. Moreover, the test result is also influenced by the assay used for measurement of plasma cortisol. Trials assessing the relationship between corticotropin response and severity of stress and organ dysfunction have produced divergent results, which may reflect differences in the methodology and the association being measured. Moreover controversy exists with respect to the methodology and the interpretation with respect to the following variables: dose of corticotropin, end points for assessment- total or free cortisol, effect of plasma cortisol variability, adrenal blood flow and its equivalence with other tests of adrenocortical function.
The corticotropin test is used widely in the evaluation of adrenocortical function in the endocrine clinics. Its role in the critically ill patient is less well established. Several confounding variables exist and to have a "one size fits all" approach with a single endpoint in the face of several methodological and pathophysiological confounders may be flawed and may result in the institution of inappropriate therapy. The current evidence does not support the use of the corticotrophin test in critical illness to assess adrenocortical function and guiding steroid therapy in critical illness. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
Corresponding Author: Vincent Liu, MD, MS, 2000 Broadway, Oakland, CA 94612 (vincent.x.liu@kp.org).
Published Online: May 18, 2014. doi:10.1001/jama.2014.5804.
Author Contributions: Dr Liu had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Liu, Escobar, Soule, Whippy.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Liu.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Liu, Greene, Iwashyna.
Obtained funding: Liu, Escobar, Iwashyna.
Administrative, technical, or material support: Liu, Escobar, Soule.
Study supervision: Angus.
Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Angus reported receiving nonfinancial support from Edwards Inc; personal fees from Pfizer, MedImmune LLC, Eli Lilly, Ferring Pharmaceuticals, and Roche Diagnostics International Ltd; and a grant from Eisai Inc. No other disclosures were reported.
Funding/Support: This work was supported by the Permanente Medical Group, the Kaiser Foundation Hospitals and Health Plan, the Gordon and Betty Moore Foundation, and US Department of Veterans Affairs Health Services Research & Development grant IIR 11-109.
Role of the Sponsors: The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript, and decision to submit the manuscript for publication.
Disclaimer: Dr Angus, associate editor for JAMA, was not involved in the editorial review of or decision to publish this article.
There is considerable global uncertainty on the role of low-dose corticosteroids in septic shock, which translates into variations in prescribing practices.
To describe the protocol for a large-scale multicentre randomised controlled trial in critically ill patients with septic shock, comparing the effects of hydrocortisone and placebo (in addition to standard treatment) on 90-day mortality and other outcomes such as shock reversal, duration of mechanical ventilation and quality of life.
We will recruit 3800 critically ill patients with septic shock treated in an intensive care unit, to concealed, randomised, parallel assignment of hydrocortisone or placebo. The primary outcome will be all-cause mortality at 90 days postrandomisation. Secondary outcomes will include ICU and hospital mortality, length of ICU stay and quality of life at 6 months. Subgroup analyses will be conducted in two predefined subgroups. All analyses will be conducted on an intention-to-treat basis.
The run-in phase has been completed and the main trial commenced in February 2013. The trial should generate results that will inform and influence prescribing of corticosteroids in septic shock.
In November 2001, the Food and Drug Administration (FDA) approved drotrecogin alfa (activated) (DrotAA) for adults who had severe sepsis and a high risk of death. The FDA required a study to evaluate the efficacy of DrotAA for adults who had severe sepsis and a low risk of death.
We randomly assigned adult patients with severe sepsis and a low risk of death (defined by an Acute Physiology and Chronic Health Evaluation [APACHE II] score <25 or single-organ failure) to receive an intravenous infusion of placebo or DrotAA (24 microg per kilogram of body weight per hour) for 96 hours in a double-blind, placebo-controlled, multicenter trial. The prospectively defined primary end point was death from any cause and was assessed 28 days after the start of the infusion. In-hospital mortality within 90 days after the start of the infusion was measured, and safety information was collected.
Enrollment in the trial was terminated early because of a low likelihood of meeting the prospectively defined objective of demonstrating a significant reduction in the 28-day mortality rate with the use of DrotAA. The study enrolled 2640 patients and collected data on 2613 (1297 in the placebo group and 1316 in the DrotAA group) at the 28-day follow-up. There were no statistically significant differences between the placebo group and the DrotAA group in 28-day mortality (17.0 percent in the placebo group vs. 18.5 percent in the DrotAA group; P=0.34; relative risk, 1.08; 95 percent confidence interval, 0.92 to 1.28) or in in-hospital mortality (20.5 percent vs. 20.6 percent; P=0.98; relative risk, 1.00; 95 percent confidence interval, 0.86 to 1.16). The rate of serious bleeding was greater in the DrotAA group than in the placebo group during both the infusion (2.4 percent vs. 1.2 percent, P=0.02) and the 28-day study period (3.9 percent vs. 2.2 percent, P=0.01).
The absence of a beneficial treatment effect, coupled with an increased incidence of serious bleeding complications, indicates that DrotAA should not be used in patients with severe sepsis who are at low risk for death, such as those with single-organ failure or an APACHE II score less than 25.
This paper presents a simple and widely ap- plicable multiple test procedure of the sequentially rejective type, i.e. hypotheses are rejected one at a tine until no further rejections can be done. It is shown that the test has a prescribed level of significance protection against error of the first kind for any combination of true hypotheses. The power properties of the test and a number of possible applications are also discussed.
To determine whether there was a difference between epinephrine and norepinephrine in achieving a mean arterial pressure (MAP) goal in intensive care (ICU) patients.
Prospective, double-blind, randomised-controlled trial.
Four Australian university-affiliated multidisciplinary ICUs.
Patients who required vasopressors for any cause at randomisation. Patients with septic shock and acute circulatory failure were analysed separately.
Blinded infusions of epinephrine or norepinephrine to achieve a MAP >or=70 mmHg for the duration of ICU admission.
Primary outcome was achievement of MAP goal >24 h without vasopressors. Secondary outcomes were 28 and 90-day mortality. Two hundred and eighty patients were randomised to receive either epinephrine or norepinephrine. Median time to achieve the MAP goal was 35.1 h (interquartile range (IQR) 13.8-70.4 h) with epinephrine compared to 40.0 h (IQR 14.5-120 h) with norepinephrine (relative risk (RR) 0.88; 95% confidence interval (CI) 0.69-1.12; P = 0.26). There was no difference in the time to achieve MAP goals in the subgroups of patients with severe sepsis (n = 158; RR 0.81; 95% CI 0.59-1.12; P = 0.18) or those with acute circulatory failure (n = 192; RR 0.89; 95% CI 0.62-1.27; P = 0.49) between epinephrine and norepinephrine. Epinephrine was associated with the development of significant but transient metabolic effects that prompted the withdrawal of 18/139 (12.9%) patients from the study by attending clinicians. There was no difference in 28 and 90-day mortality.
Despite the development of potential drug-related effects with epinephrine, there was no difference in the achievement of a MAP goal between epinephrine and norepinephrine in a heterogenous population of ICU patients.
Corticosteroid therapy induces potentially detrimental hyperglycemia in septic shock. In addition, the benefit of adding fludrocortisone in this setting is unclear.
To test the efficacy of intensive insulin therapy in patients whose septic shock was treated with hydrocortisone and to assess, as a secondary objective, the benefit of fludrocortisone.
A multicenter, 2 x 2 factorial, randomized trial, involving 509 adults with septic shock who presented with multiple organ dysfunction, as defined by a Sequential Organ Failure Assessment score of 8 or more, and who had received hydrocortisone treatment was conducted from January 2006 to January 2009 in 11 intensive care units in France.
Patients were randomly assigned to 1 of 4 groups: continuous intravenous insulin infusion with hydrocortisone alone, continuous intravenous insulin infusion with hydrocortisone plus fludrocortisone, conventional insulin therapy with hydrocortisone alone, or conventional insulin therapy with intravenous hydrocortisone plus fludrocortisone. Hydrocortisone was administered in a 50-mg bolus every 6 hours, and fludrocortisone was administered orally in 50-microg tablets once a day, each for 7 days.
In-hospital mortality.
Of the 255 patients treated with intensive insulin, 117 (45.9%), and 109 of 254 (42.9%) treated with conventional insulin therapy died (relative risk [RR], 1.07; 95% confidence interval [CI], 0.88-1.30; P = .50). Patients treated with intensive insulin experienced significantly more episodes of severe hypoglycemia (<40 mg/dL) than those in the conventional-treatment group, with a difference in mean number of episodes per patient of 0.15 (95% CI, 0.02-0.28; P = .003). At hospital discharge, 105 of 245 patients treated with fludrocortisone (42.9%) died and 121 of 264 (45.8%) in the control group died (RR, 0.94; 95% CI, 0.77-1.14; P = .50).
Compared with conventional insulin therapy, intensive insulin therapy did not improve in-hospital mortality among patients who were treated with hydrocortisone for septic shock. The addition of oral fludrocortisone did not result in a statistically significant improvement in in-hospital mortality.
clinicaltrials.gov Identifier: NCT00320099.
To compare inter-laboratory and inter-assay measurements of total cortisol in patients with septic shock and to evaluate current recommendations for diagnosis of corticosteroid insufficiency in septic shock.
In the multinational CORTICUS study duplicate serum samples were taken before and after corticotropin stimulation tests in patients with septic shock. Serum cortisol was measured in paired samples, one being measured by the chemical laboratory of each participating site and the other by a central laboratory using an electrochemiluminescence immunoassay. Cortisol levels measured by tandem mass spectrometry were used as a 'gold standard' reference method in a subset of samples.
A total of 425 corticotropin tests (850 cortisol samples) were available for comparison of local and central laboratory measurements. The concordance correlation coefficient between central laboratory immunoassay and local hospital assays was 0.98 (CI 0.97-0.99) when the immunoassay of one manufacturer was used and 0.60 (CI 0.54-0.65) when immunoassays of different manufacturers were used. The comparison with the reference method of mass spectrometry showed concordance correlation coefficients ranging from 0.43 to 0.97 depending on the assay under study. Diagnosis of corticosteroid insufficiency was diverging due to inter-assay variations in up to 27% of cases.
In samples taken from patients in septic shock, there was a high inter-assay variation of total serum cortisol. Comparisons with a reference method revealed both over- and underestimations of true cortisol levels. These inter-assay variations in samples of patients with septic shock complicate the diagnosis of corticosteroid insufficiency.
A prospective (Part I) and a retrospective (Part II) study were used to determine the safety and efficacy of corticosteroids in the treatment of septic shock. In Part I, 172 consecutive patients in septic shock admitted over an 8-year period were treated with either steroid or saline: 43 received dexamethasone (DMP), 43 received methylprednisolone (MPS), and 86 received saline. The study was double-blind and randomized, and the three groups were compared for age, severity of shock, presence of underlying disease, and year of study. In the 86 saline-treated patients, the mortality rate was 38.4% (33/86); in the steroid-treated patients, it was 10.4% (9/86). With MPS the mortality rate was 11.6% (5/43), and with DMP it was 9.3% (4/43). Thus, overall mortality was significantly less in the steroid-treated group than in the control group. Further, there was no significant difference in mortality rate between the DMP- and the MPS-treated patients. In Part II, 328 patients were studied retrospectively. One-hundred sixty were treated without steroid, and 168 were treated with either DMP or MPS. Again, the two groups of patients were compared for severity of shock, underlying disease, age, and year of study. Mortality among patients treated without steroid was 42.5% (68/160) and among patients treated with steroid was 14% (24/168); there was no significant difference in mortality rate between DMP- and MPS-treated patients. In Parts I and II combined, complications occurred in 6% of steroid-treated patients with no significant difference between DMP- and MPS-treated groups.
The use of high-dose corticosteroids in the treatment of severe sepsis and septic shock remains controversial. Our study was designed as a prospective, randomized, double-blind, placebo-controlled trial of high-dose methylprednisolone sodium succinate for severe sepsis and septic shock. Diagnosis was based on the clinical suspicion of infection plus the presence of fever or hypothermia (rectal temperature greater than 38.3 degrees C [101 degrees F] or less than 35.6 degrees C [96 degrees F]), tachypnea (greater than 20 breaths per minute), tachycardia (greater than 90 beats per minute), and the presence of one of the following indications of organ dysfunction: a change in mental status, hypoxemia, elevated lactate levels, or oliguria. Three hundred eighty-two patients were enrolled. Treatment--either methylprednisolone sodium succinate (30 mg per kilogram of body weight) or placebo--was given in four infusions, starting within two hours of diagnosis. No significant differences were found in the prevention of shock, the reversal of shock, or overall mortality. In the subgroup of patients with elevated serum creatinine levels (greater than 2 mg per deciliter) at enrollment, mortality at 14 days was significantly increased among those receiving methylprednisolone (46 of 78 [59 percent] vs. 17 of 58 [29 percent] among those receiving placebo; P less than 0.01). Among patients treated with methylprednisolone, significantly more deaths were related to secondary infection. We conclude that the use of high-dose corticosteroids provides no benefit in the treatment of severe sepsis and septic shock.
To determine whether corticosteroids are efficacious in severe septic shock, we conducted a prospective study of 59 patients randomly assigned to a methylprednisolone, dexamethasone, or control group. Patients were treated 17.5 +/- 5.4 hours (mean +/- S.E.M.) after the onset of shock, and 55 patients required vasopressor agents. Early in the hospital course, reversal of shock was more likely in patients who received corticosteroids than in those who did not. Four (19 per cent) of 21 methylprednisolone-treated, 7 (32 per cent) of 22 dexamethasone-treated, and none of 16 control patients had reversal of shock 24 hours after drug administration (corticosteroid groups vs. control group, P less than 0.05). Patients treated with corticosteroids within four hours after the onset of shock had a higher incidence of shock reversal (P less than 0.05). At 133 hours after drug administration, 17 (40 per cent) of 43 corticosteroid-treated patients had died, and 11 (69 per cent) of 16 control patients had died (P less than 0.05). However, these differences in reversal of shock and survival disappeared later in the course. Overall, 16 (76 per cent) of 21 patients receiving methylprednisolone, 17 (77 per cent) of 22 patients receiving dexamethasone, and 11 (69 per cent) of 16 controls in the hospital died. We conclude that corticosteroids do not improve the overall survival of patients with severe, late septic shock but may be helpful early in the course and in certain subgroups of patients.
There exists a growing literature on the estimation of gamma distributed multiplicative shared frailty models. There is, however, often a need to model more complicated frailty structures, but attempts to extend gamma frailties run into complications. Motivated by hip replacement data with a more complicated dependence structure, we propose a model based on multiplicative frailties with a multivariate log-normal joint distribution. We give a justification and an estimation procedure for this generally structured frailty model, which is a generalization of the one presented by McGilchrist (1993, Biometrics 49, 221-225). The estimation is based on Laplace approximation of the likelihood function. This leads to estimating equations based on a penalized fixed effects partial likelihood, where the marginal distribution of the frailty terms determines the penalty term. The tuning parameters of the penalty function, i.e., the frailty variances, are estimated by maximizing an approximate profile likelihood. The performance of the approximation is evaluated by simulation, and the frailty model is fitted to the hip replacement data.
The effects of corticosterone, a natural glucocorticoid of rat, on the acetylcholine (ACh)-induced current (I(ACh)) were studied in pheochromocytoma (PC12) cells by using whole-cell clamp technique. The I(ACh) proved to be generated through neuronal nicotinic receptor. ACh (30 microM) induced an inward current at a holding potential of -80 mV. When cells were preincubated with corticosterone (0.1-100 microM) for 4 min, an inhibitory effect of corticosterone on the peak of I(ACh) was found. This effect was reversible, concentration-dependent, and voltage-independent. Intracellular application of corticosterone through the patch electrode did not affect the I(ACh). Extracellular application of 10 microM corticosterone neither shifted the dose-response curve of the peak I(ACh) to the right (dissociation constant (K(d)) = 16.5 microM) nor affected its coefficient (1.8) but inhibited the curve amplitudes by approximately 49% in the cells pretreated with corticosterone for 4 min. Bovine serum albumin-conjugated corticosterone (0.1-10 microM) had the inhibition similar to corticosterone. The inhibitor of transcription, actinomycin D (10 microM), and the protein synthesis inhibitor, cycloheximide (50 microM), had no effect on the inhibition induced by corticosterone on I(ACh). These results suggest that corticosterone has rapid inhibitory effect on I(ACh) in PC12 cells, which is mediated by a nongenomic mechanism. It indicates that corticosterone binds to the specific site on the outer cell membrane, probably on the neuronal nicotinic receptor-coupled channel, and inhibits the I(ACh) in a noncompetitive manner, thus controlling the immediate catecholamine release from the sympathetic cells.
It is unclear whether a random plasma cortisol measurement and the corticotropin (ACTH) test adequately reflect glucocorticoid secretory capacity in critical illness. This study aimed to determine whether these tests provide information representative of the 24 hour period.
Plasma cortisol was measured hourly for 24 hours in 21 critically ill septic patients followed by a corticotropin test with 1 μg dose administered intravenously. Serum and urine were analysed for ACTH and free cortisol respectively. Marked hourly variability in plasma cortisol was evident (coefficient of variation 8–30%) with no demonstrable circadian rhythm. The individual mean plasma cortisol concentrations ranged from 286±59 nmol/l to 796± 83 nmol/l. The 24 hour mean plasma cortisol was strongly correlated with both random plasma cortisol (r ² 0.9, P<0.0001) and the cortisol response to corticotropin (r ² 0.72, P<0.001). Only nine percent of patients increased their plasma cortisol by 250 nmol/l after corticotropin (euadrenal response). However, 35% of non-responders had spontaneous hourly rises >250 nmol/l thus highlighting the limitations of a single point corticotropin test. Urinary free cortisol was elevated (865±937 nmol) in both corticotropin responders and non-responders suggesting elevated plasma free cortisol. No significant relationship was demonstrable between plasma cortisol and ACTH.
We conclude that although random cortisol measurements and the low dose corticotropin tests reliably reflect the 24 hour mean cortisol in critical illness, they do not take into account the pulsatile nature of cortisol secretion. Consequently, there is the potential for erroneous conclusions about adrenal function based on a single measurement. We suggest that caution be exercised when drawing conclusions on the adequacy of adrenal function based on a single random plasma cortisol or the corticotropin test.
Septic shock remains one of the leading causes of death in intensive care units. In recent years, there is general use of low to moderate doses of corticosteroids in the treatment of septic shock. However, there are wide variations in the practical modality of this treatment, mainly with regard to patients' selection, treatment's dose, timing, route of administration, duration, and weaning. This review provides opinion-based guidelines for the use of corticosteroids in severe sepsis and septic shock.
A summary of the latest understanding of the mechanisms of action of corticosteroids and the most recent observations in the clinical and biologic responses to corticosteroids in severe sepsis and septic shock is presented.
In septic shock, intravenous hydrocortisone should be started immediately after a 250 microg corticotropin test, at a dose of 200-300 mg per day. When adrenal insufficiency is confirmed, treatment should be continued at full doses for 7 days. Otherwise, hydrocortisone should be stopped. It is worth considering adding enteral fludrocortisone at a dose of 50 microg per day for 7 days. In severe sepsis, despite growing evidence to support the use of a moderate dose of corticosteroids, the efficacy and safety of this treatment needs to be assessed in a large-scale study.
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