Steroid Therapy Issues - Literature review Example

?TABLE OF CONTENTS 3 INTRODUCTION 4 AIMS AND OBJECTIVES 6 SEARCH STRATEGY 6 KEYWORDS 7 REVIEW OF LITEREATURE 8 STEROID THERAPY- CURRENT INDICATIONS IN PRACTICE AND RECOMMENDATIONS 22 CONCLUSIONS AND RECOMMENDATIONS 24 REFERENCES 26 TABLES Table 1: CEBM based steps in finding evidence for different type of questions (CEBM) 7 Table 2: Therapies Used in the Treatment of Severe Sepsis and Septic Shock (Morrel et al., 2009) 9 Table 3: Critical Appraisal for Therapy Articles Reviewed 17 Table 4: Major Recommendations of SSC 2008 for Corticosteroid usage in Severe Sepsis and Septic Shock (Miyashita, 2010) 23 FIGURES Figure 1: Protocol for Earle Goal-Directed Therapy (EGDT) (Rivers et al., 2001) 10 Figure 2: Mechanism of Myocardial Dysfunction in Sepsis (Zanotti-Cavazzoni and Hollenberg, 2009) 11 Figure 3: Configuration of basic Corticosteroid Structure 12 Figure 4: Molecular Structure of Cortisol 13 Figure 5: Molecular Structure of Aldosterone 13 ABSTRACT Severe sepsis and septic shock are inflammatory conditions resulting from the systemic response to bacterial infection leading to acute failure of multiple organs. Treatment involves aggressive fluid resuscitation, antibiotics, surgical excision of infected or necrotic tissues and drainage of pus, supportive care, and sometimes intensive control of blood glucose and administration of corticosteroid and activated protein c. Adjunctive corticosteroid therapy is commonly prescribed to patients with septic shock, despite the fact that few trials show survival value. A reduction in time to shock reversal has been observed. The present study aimed to review the literature available for the efficacy of corticosteroids in the treatment of severe sepsis and septic shock. Data was gathered from articles published in peer reviewed journals. Despite the lack of consensus in the efficacy of corticosteroids in the published literature, corticosteroids were found to be safe and effective as first line treatment for septic shock, though there efficacy in severe sepsis treatment is not documented. {Key Words: Septic shock, severe sepsis, corticosteroids, hydrocortisone, critical care, adrenal insufficiency, organ dysfunction} EFFICACY OF CORTICOSTEROIDS IN TREATMENT OF SEVERE SEPSIS AND SEPTIC SHOCK INTRODUCTION Septic shock is one of the most critical complications associated with surgical cases and still one of the major causes of mortality in the intensive care units (ICUs). Shock, in general refers to a scarcity of oxygen supply leading to hypotension and hypoperfusion followed by cellular dysfunction; sepsis refers to a systemic inflammatory response to infection (Wang et al. 2009). Thus, severe sepsis can be defined as sepsis complicated by organ dysfunction, tissue or organ hypofusion; or hypotension (Balk, 2000). The organ dysfunctions associated with severe sepsis include renal, respiratory, cardiovascular, hematologic, hepatic and gastrointestinal dysfunction. Septic shock is systemic inflammatory response to infection occurring with acute respiratory failure, persistent arterial hypotension and perfusion abnormalities, in severe case leading to organ dysfunction (Bridges, 2005). Progressively increasing incidences of mortality and morbidity are reported for sepsis, severe sepsis and septic shock, respectively (Zanotti-Cavazzoni & Hollenberg, 2009). An epidemiological study of cases of severe sepsis in England, Wales and Northern Ireland for the period spanning 1996 to 2004 reported hospital mortality of 48.3% in the year 1996, which has marginally decreased to 44.7% in 2004. Moreover the total number of deaths due to severe sepsis has risen from 9,000 to 14,000 during this period due to rise in incidences of severe sepsis (Harrison et al., 2006). Another study to evaluate worldwide incidences of mortality as consequence of severe sepsis reported a marginal fall in number of deaths due to the condition, the mortality still remaining as high as 30-50% (Laterre et al., 2004). Cardiovascular and hemodynamic instability are closely associated with increase in the severity of sepsis and development of septic shock, and are the major causes of morbidity Septic patients with myocardial dysfunction have been reported to have a higher mortality rate (70%), compared to those without one (20%) (Blanco et al., 2008). Management of septic shock is mainly supportive. Early recognition of the condition and resuscitation to prevent organ dysfunction is critical, since organ failure is the chief cause of death. Further treatment requires identification of the cause of infection, and use of suitable antibiotic therapeutic regime along with removal of infected body fluids as well as necrotic tissues (Morrell et al., 2009). In past few years the two treatment modalities that have shown reasonable levels of efficacy are drotrecogin alfa (activated) (Bernard et al., 2001) and early goal directed therapy (EGDT) (Rivers et al., 2001). Besides these very few adjunctive therapies are known to help in the management of this condition one of which is the corticosteroid. Corticosteroids have been commonly used as anti-inflammatory therapeutic agents for prevention of development of septic shock. However, not much evidence is available to support the efficacy, and for determination of doses and conditions under which corticosteroids can be administered. Moreover there are also studies indicating the lack of efficacy and even adverse effects of corticosteroids. With rising vulnerability to severe sepsis and septic shock in individuals with multiple comorbidities, immunosuppression, older individuals and those that have undergone organ transplantation; it is imperative that the management strategies and technologies are developed to enhance the efficacy of treatment modalities (Sligl et al., 2009). The present study thus makes an attempt to understand the efficacy of corticosteroids in the treatment of severe sepsis and septic shock in critical care with the help of available literature. AIMS AND OBJECTIVES The present research aims to evaluate the efficacy of corticosteroids in the treatment of severe sepsis and septic shock in order to develop a research based information resource guiding its utilization in clinical practice. In order to achieve this aim, the following objectives will be pursued during the course of the research: 1. Study of the concept of sepsis, severe sepsis and septic shock with special emphasis on the cardiovascular aspects of the condition. 2. Identification and critical analysis of literature supporting or contradicting the efficacy of corticosteroids in the treatment of severe sepsis and septic shock. 3. Evaluation of the overall efficacy of corticosteroids in the treatment of severe sepsis and septic shock based on the literature studied. SEARCH STRATEGY Data was collected from articles published in peer reviewed journals as primary researches or as secondary (systematic and meta-analysis researches), published between 1995 and 2011, along with cross referencing to explore relevant trials or reviews. Articles more than ten year old are included in this review to enable inclusion of the remarkable studies of Bollaert et al (1998), which was the first study demonstrating the affectivity of low doses of corticosteroids in reversal of septic shock in intensive care patients. The literature will further be critiqued making use of the CASP tool (Critical Appraisal Skills Programme). In addition to this, the evidence’s strength would be considered on the basis of Centre of Evidence Based Medicine (CEBM) hierarchy of evidence (table 1). The principal sources for data collection were Medline, EMBASE, OVID, Cinahl, Scopus, Pubmed, Krager, Springerlink, Cochrane database, NIH database, and manual search of peer reviewed journal publications. Table 1: CEBM based steps in finding evidence for different type of questions (CEBM) KEYWORDS The key words used in the search strategy were steroids, corticosteroids, sepsis, septic shock, organ failure, cardiac dysfunction. The terms were used separately or in combination. REVIEW OF LITEREATURE Last two decades have witnessed remarkable development in the understanding of the pathophysiology and management of sepsis and associated complexities. Sepsis results either as a consequence of infection due to bacteria, fungi (especially Candida) or viruses. In absence of these microbes, sepsis can still develop and is attributed to microbial toxins and endogenous cytokine production (Tavares et al., 2006). As a consequence, of these infections, host immune system is activated as a protective measure; but in individuals with septic shock, a poorly regulated immune system leads to most severe form of host response to infection. On the basis of specific host responses, sepsis is demarcated in to two phases. The early phase spanning the initial six hours are critical and demand prompt diagnosis and immediate institution of EGDT. Circulatory abnormalities in the early phases lead to global tissue hypoxia or shock, which can further lead to multiple organ failure and death. This can be interrupted during the critical “golden hours” of early phase when diagnosis and treatment can be life saving (Rivers et al., 2001). In early phase assessment of vital signs, physical symptoms, central venous pressure and urinary output are not indicative of global tissue hypoxia and therefore, a more definitive resuscitation strategy is pursued. This strategy or EGDT involves a goal oriented manipulation of cardiovascular aspects such as cardiac preload and afterload, as well as contractility to overcome tissue hypoxia. The protocol followed to achieve this goal referred as resuscitation end point is depicted in figure 1. EGDT has multifactorial advantages in allowing early diagnosis and preventing cardiovascular collapse through immediate interventions (Rivers et al., 2001). Most of the first line critical therapies are instituted in the early phase (Table 2). Table 2: Therapies Used in the Treatment of Severe Sepsis and Septic Shock (Morrel et al., 2009) Figure 1: Protocol for Earle Goal-Directed Therapy (EGDT) (Rivers et al., 2001) Study of cardiovascular aspects of severe sepsis and septic shock have revealed these to be hyperdynamic states involving high cardiac output and low systemic vascular resistance, which further supports the significance of fluid resuscitation therapeutic modalities. Reports are available for development of high cardiac output post aggressive fluid resuscitation and intravascular volume improvement. Lower cardiac output in spite of the increased cardiac output in septic shock along with abnormal response in ventricular stroke work index to fluid effusion was demonstrated by Parker et al (1984). Impaired left ventricular diastolic and systolic function have been found to be associated with septic shock in many recent studies. Right ventricle has been also reported to acquire parallel abnormalities however; further studies are needed to elucidate this aspect (Zanotti-Cavazzoni and Hollenberg, 2009). Several theories have been proposed to describe the mechanism underlying development of myocardial dysfunction in sepsis which definitely is multifactorial; yet the mechanism is still incompletely understood. Various myocardial suppressant factors, nitric oxide, calcium, mitochondrial dysfunction and apoptosis have been found to be involved in the cardiovascular aspects of sepsis and septic shock. Recent reports stress the role of overproduction of nitric oxide and consequential activation of cNOS in cardiac cells resulting in the production of cyclic guanosine monophosphate (cGMP). The mechanism of development of myocardial dysfunction in severe sepsis and septic shock is illustrated in figure 2 (Zanotti-Cavazzoni and Hollenberg, 2009). Figure 2: Mechanism of Myocardial Dysfunction in Sepsis (Zanotti-Cavazzoni and Hollenberg, 2009) Besides myocardial dysfunction, adrenal insufficiency is another symptom frequently associated with septic shock. Moreover the systemic inflammation induced glucocorticoid receptor resistance observed during septic shock lead to the use of adrenal steroids, specifically corticosteroids, in replacement therapies for severe sepsis and septic shock. Corticosteroids are a group of adrenal steroids, including glucocorticoids (such as cortisol) and mineralocorticoids (such as aldosterone), produced by the adrenal cortex (Figure 3, 4 and 5). Adrenal cortex comprises of three zones, viz. zona glomerulosa, zona fasciculate and zona reticularis producing mineralcoticoids, glucocorticoids and androgens respectively. Of these the corticosteroids are 21 carbon molecules with following major characteristics: An oxo-group at the third carbon and double bond at carbon 4 Carbon 17 with two carbon side chain Carbon 20 with an oxo group and carbon 21 with a hydroxyl group Figure 3: Configuration of basic Corticosteroid Structure Figure 4: Molecular Structure of Cortisol Figure 5: Molecular Structure of Aldosterone Corticosteroids have been used for long as a part of the anti-inflammatory therapy to prevent chain of events leading to development of septic shock. However, till late 90s the issue of use of corticosteroids for shock reversal in cases of septic shock remained controversial, with reports available for its lack of efficacy or even negative impact (Sprung et al., 1984; Minneci et al., 2004). It was only in 2000, with a study by Annane and associates (2000), that the interest in the use of corticosteroids in septic shock was revived. The study reported that the corticosteroids are mainly beneficial in overcoming adrenal insufficiency resulting as consequence of septic shock in some cases. The first study to specifically address the efficacy of low doses of corticosteroids in shock reversal in cases of septic shock was reported by Bollaert et al (1998). Of the 41 patients studied, 22 were administered corticosteroids (table 3). 68% of the hydrocortisone treated patients compared to 21% of the placebo group were found to achieve shock reversal within 7 days. Moreover mortality was reported in 32% of treated patients compared to 63% of placebo group during the 28 days follow up. Thus this was the first study to successfully demonstrate the improvement in hemodynamics as a consequence of hydrocortisone administration and hence its survival value in septic shock patients. The study conducted by Briegel and associates (1999), involved 40 patients with septic shock condition that met the criteria specified by the American college of chest physicians/Society of critical care medicine (ACCP/SCCM) (table 3). The patients were diagnosed with high output cardiac failure post fluid resuscitation. An initial dose of 100mg of hydrocortisone administered within 30 min was followed by continuous doses of 0.18mg/kg/hr in the test group. Once the shock reversal was achieved the dose was lowered to 0.08mg/kg/hr, for 6 days. Shock reversal was reported for 16 of 20 patients administered hydrocortisone compared to 18 of 20 on placebo. However, the significant observation was that the treatment with hydrocortisone reduced the time of vasopressor therapy from 7 days (median value) in placebo cases, to 2 days for hydrocortisone treated subjects. Thus even though shock reversal and mortality was equivalent for control and hydrocortisone groups, the role of hydrocortisone in faster recovery from organ dysfunction as a consequence of sepsis, was successfully proved. One of the most powerful studies demonstrating the efficacy of corticosteroids in shock reversal was conducted by Annane and associates (2002). The 300 selected patients underwent a corticotrophin test at time of enrollment. Of the 229 non responders to corticotrophin test 114 were administered corticosteroids and 115 were provided placebo. Of the 70 responders 36 were administered corticosteroids and 34 were provided placebo. The dosage as described in table3 was continued for a period of 7 days. Among the non responders 53% mortality was reported for the test group and 63% for the placebo group. During the 28 day follow up period, vasopressor therapy could be withdrawn from 40% of placebo group and 57% of test group. No significant difference was observed among the two groups in responders to corticotrophin test. Thus the study was the first one to demonstrate the efficacy of low doses of corticosteroids in shock reversal and improving survival rate in catecholamine dependent septic shock patients diagnosed with relative adrenal insufficiency during a 28 day follow up. The same in patients with no adrenal insufficiency could not be demonstrated through this study. No adverse reaction was reported as a consequence of use of corticosteroid therapy in the patients. Oppert and associates (2005) conducted a similar single center study involving 41 patients. After an initial adrenocorticotrpin test, the subjects were either administered the low dose hydrocortisone (table 3), or placebo. Post shock reversal the dosage of hydrocortisone was reduced to 0.06mg/kg/hr and gradually removed. Hydrocortisone treated patients achieved the primary end point of removal of vasopressor therapy much earlier i.e. within 53hrs, compared to 120hrs for placebo group. Individuals with baseline adrenal insufficiency showed more rapid improvement. Cytokine levels were reduced in treatment group which also did not exhibit any negative impact of the hydrocortisone treatment. Thus the study successfully demonstrated the efficacy of low dose hydrocortisone in reversal of shock in patients with early hyperdynamic septic shock. Further declining levels of cytokines indicated the probable role of hydrocortisone as both hemodynamic, and therefore dependent on endogenous corticosteroid levels; as well as immunomodulatory. Sprung and associates (2008) tested the efficacy of low doses of hydrocortisone in shock reversal in a larger group of subjects. Of the 499 patients, 251 were randomly selected to receive 50mg intravenous hydrocortisone and the rest were given placebo (table 1). 46.7% of the subjects who had tested negative for the corticotrophin test showed no response to the hydrocortisone therapy and the primary outcome in these patients, irrespective of hydrocortisone or placebo, remained mortality. During the 28 day follow up 34.3% of hydrocortisone group and 31.5% of placebo group died. However, the shock reversal was reported to be much quicker in former compared to latter. But this was also accompanied by new incidences of sepsis and septic shock. Thus the study revealed that shock reversal as well as survival, was not significant in either the corticotropin responding or non responding group; and even though shock reversal was rapid, there were also frequent incidences of superinfection. A recent study by Arabi and associates (2010) testing the efficacy of low doses of hydrocortisone in individuals with cirrhosis and septic shock too give results similar to those reported earlier. Of the 75 consenting patients meeting the eligibility criteria, 39 were administered hydrocortisone, and the rest were given placebo (table 3). Follow up studies were conducted for a period of 28 days. Compared to the placebo group, the hydrocortisone group showed higher rates of shock reversal and lower 28 day mortality; however there were also frequent incidences of shock relapse along with gastrointestinal bleeding. Thus despite the initial positive influence the hydrocortisone therapy was found to be unfavourable and even with adverse impacts. Table 3: Critical Appraisal for Therapy Articles Reviewed Reference Study design Subject Characteristics Intervention Outcome Applicability Arabi et al., 2010 RCT, Double blind, centralized computer randomization 75 patients with (mean age 60.6, SD 12.6) cirrhosis and septic shock, with adrenal insufficiency in 76% patients. Baseline values for the sample group, including use of etomidate, were comparable. 50mg IV hydrocortisone every 6 hrs till hemodynamic stability achieved, 8 day taper. Cointerventions similar in the sample group. 28 day mortality of in 33 individuals (85%) of hydrocortisone group, and 26 (72%) of placebo group; RR 0.92-1.49. ICU mortality RR 0.66-1.30; hospital mortality RR 0.83-1.16. Shock relapse RR 2.46 RR for primary outcome above anticipated 0.78 at CI 95%. Hydrocortisone therapy is effective only in hemodynamic improvement in cases of septic shock with adrenal insufficiency, with the risk of increased gastrointestinal bleeding and shock relapse probability. Sprung, 2008 RCT Double blind. centralized computer randomization Of 500 patients undergoing randomization, 499 with septic shock (47% diagnosed with adrenal insufficiency). 251 treated with hydrocortisone, 248 received placebo, 1 withdrew consent. The subjects similar at baseline with respect to demographic & clinical characteristics; & the type, site and cause of infection. Hydrocortisone administered intravenously (50mg q 6hrs for 5 days). Cointervention similar for all subjects. Mortality within 28 days for response in 86 (34.3%) of test group, 78 (31.5%) of placebo group (p=0.51) 28 day mortality RR 1.09 (at CI 95%: 0.84-1.41) Hydrocortisone therapy can be used for shock reversal especially for patients who fail to respond to vasopressor therapy. Oppert et al., 2005 RCT Double blind, centralized computer randomization 41 patients with early hyperdynamic septic shock and undergoing vasopressor therapy. Baseline values differed with patients in steroid group older and patients in placebo group with lower platelet count Hydrocortisone 50 mg initial dose followed by a dosage of 0.18mg/kg/hr till shock reversal; 3 day taper Shock reversal along with mortality Cytokine response and organ failure. 28 day mortality RR 0.90 (at 95% CI 0.40-1.67 Hemodynamic and immunomodulatory effects lead to speedier shock reversal. Annane, 2002 RCT Double blind, centralized computer randomization 300 individuals, on ventilation with 76% diagnosed with adrenal insufficiency. 151 received steroids with analysis done on 150 (1 withdrew consent); 149 assigned for placebo, 148 received placebo, 1 died before intervention. Baseline values similar for the two groups both with respect to general characteristics and clinical features. Hydrocotisone (50mg q 6 hrs) fludrocortisones (50mcg qd). Cointerventions similar in two groups 28 day mortality RR 0.90 (at CI 95% 0.74-1.09) Low dose combination of Hydrocortisone and Fludrocortisone effective for increasing short term and long term survival in septic shock patients. Results are promising and can be further assessed. Briegel, 1999 RCT Double blind 40 patients undergoing vasopressor therapy with no differences at baseline among patient groups Hydrocortisone 100 mg bolus, 0.18mg/kg/hr Mortality Shock reversal in 18 of 20 treated with Hydrocortisone. 28 day mortality RR 0.75 (at 95% CI 0.19-2.93) Usefulness of hydrocortisone therapy for shock reversal leading to early withdrawal of vasopressor therapy Chawla et al., 1999 RCT Double blind 44 patients with no differences at baseline among patient groups Hydrocortisone 100mg, intravenously, for 3 days at every 8 hrs; followed by 4 day taper. Treatment 72 hrs aftershock onset Shock reversal along with mortality during 28 day follow up. 28 day mortality RR 0.55 (at 95% CI 0.24-01.25) Usefulness of hydrocortisone therapy for shock reversal leading to early withdrawal of vasopressor therapy Bollaert, 1998 RCT Double blind 41 individuals with no differences at baseline among patient groups. 22 hydrocortisone treated and 19 in placebo group. Hydrocortisone 100mg tid * 5days Mortality RR 0.50 (at 95% CI 0.25-1.02) Hydrocortisone treatment effective for shock reversal and enhance survival probability. STEROID THERAPY- CURRENT INDICATIONS IN PRACTICE AND RECOMMENDATIONS Steroids are commonly used for pain management in clinical practice. The glucocorticoids are known to suppress inflammation, while the mineralocorticoids are involved in salt and water balance modification (Li et al., 2007). The major steroid preparations administered as injections epidurally, as well as for intraarticular, periarticular and intramuscular injections are methylprednisolone actetate, dexamethasone, betamethasone etc (Benzon et al. 2007). The molecular mechanism of anti-inflammatory action of corticosteroids is not yet completely understood, though a multifactorial influence on the inflammatory components such as cytokines is reported. It influences the transcription of many genes and NF-Kappa B involved in cytokine gene transcription. It also exhibits pro-apoptotic activity and inhibition of platelet aggregation (Cohen, 2011). The initial controversy over the use of corticosteroids in severe sepsis and septic shock, was mainly due to the confusion over the definitions of these conditions. In 1987 a randomized control trial by Bone and associates demonstrated that 30mg/kg dosage of methylprednisolone raised the mortality rates in patients with severe sepsis or septic shock. As a result corticosteroids lost their popularity as therapeutic agents for these conditions. However, the study by Annane et al (2000) reestablished the use of corticosteroids, especially in cases of septic shock with adrenal insufficiency. According to Surviving sepsis campaign (SSC) guidelines 2008, intravenous dosage of hydrocortisone have been recommended for adult septic shock patients who fail to respond to vasopresssor therapy and fluid resuscitations (table 4) (Dellinger et al. 2008). Table 4: Major Recommendations of SSC 2008 for Corticosteroid usage in Severe Sepsis and Septic Shock (Miyashita, 2010) 1. Consider intravenous hydrocortisone for adult septic shock when hypotension remains poorly responsive to adequate fluid resuscitation and vasopressor. 2. ACTH stimulation test is not recommended to identify the subsets of adults with septic shock who should receive hydrocortisone 3. Hydrocortisone preferred to dexamethasone 4. Fludrocortisone (50µg/ day) may be included if an alternative to hydrocortisone is being used when lacks mineralocorticoid activity. Fludrocortisone is optional if hydrocortisone is being used 5. Steroid therapy may be warranted once vasopressors are no longer required 6. Hydrocortisone dose should be below 300mg/day 7. Corticosteroids should not be used to treat sepsis in absence of shock unless patients’ endocrine or corticosteroid history warrants it Even though the studies by Sprung et al (2008) questioned the efficacy of corticosteroids in septic shock, the recommendations by SSC (2008) are still accepted since the study by Sprung et al (2008) did report higher rates of shock reversal as a consequence of corticosteroid therapy, which can postpone immediate death and therefore provide time for other therapies. Besides it has also been shown that the shock relapse resulting in mortality is mainly due to infection resulting from agents which cannot be controlled. Another point to consider is that corticosteroids do intensify the severity of sepsis if infection cause remains uncontrolled (Miyashita, 2010). CONCLUSIONS AND RECOMMENDATIONS Conclusively low doses of corticosteroids can be considered to be safe for septic shock patients. Since most cases of septic shock are associated with adrenal insufficiency, corticosteroids can be used for reversing the condition. Even in studies reporting relapse or mortality; no significant difference was reported for such results in the control and the test group. Though the therapy fails to reduce the mortality rate it has definite advantage in reducing the time for shock reversal and therefore is a significant first line treatment to enable the administration of other therapeutic measures, while controlling shock reaction as a primary measure. Moreover the corticotropin stimulation test used to assess the activity of adrenal glands fails to provide accurate results especially under conditions of critical illness. Thus it is recommended that the corticosteroid therapy be used for both responders and non responders of the test. For severe sepsis the use of corticosteroids requires further research. Despite the reasonable number of studies, a consensus as to efficacy of corticosteroids in severe sepsis and septic shock therapy is lacking. It is recommended on the basis of the literature reviewed that large scale studies with well defined patient characteristics forming definite subclasses be conducted to get an accurate assessment of the corticosteroid therapy on patient characteristics and improvement in various aspects of septic shock and severe sepsis. Only then a generalized opinion can be formed for the usage of corticosteroid therapy with respect to patient class, dosage levels and duration. Till the time corticosteroids can be considered to be safe and reasonable therapy for septic shock. REFERENCES 1. Annane, D. (2002). Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA , 862-71. 2. Annane, D., Sebille, V., Troche, G., & al, e. (2000). A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin. JAMA , 1038-45. 3. Arabi, Y. M., Aljumah, A., Dabbagh, O., Tamim, H. M., Rishu, A. H., & Tamimi, W. (2010). Low dose hydrocortisone in patients with cirrhosis and septic shock: a randomized controlled trial. CMAJ , 1971-8. 4. Balk, R. A. (2000). Pathogenesis and managemnt of multiple organ dysfunction or failure in severe sepsis and septic shock. Critical care clinics . 5. Benzon, H., Teng-Leong, C., McCarthy, R., & Benzon, H. (2007). Comparison of the particulate sizes of different steroids and the effect of dilution: a review of relative neurotoxicity of the steroids. Anesthesiology , 331-8. 6. Bernard, G. R., Vincent, J. L., Laterre, P. F., LaRosa, S. P., Dhainaut, J. F., Lopez-Rodriguez, A., et al. (2001). Efficacy and safety of recombinant recombinant human activated protein C for severe sepsis. N Engl J Med , 699-709. 7. Blanco, J., Muriel-Bombin, A., & Sagredo, V. (2008). Incidence, organ dysfuction and mortality in severe sepsis: a Spanish multicentre study. Crit care , R158. 8. Bollaert, P. e. (1998). Reversal of late septic shock with supraphysiologic doses of hydrocortisone. Crit care med , 645-50. 9. Bone, R. C., Fisher, C. J., Clemmer, T. P., Slotman, G. J., Metz, C. A., & Balk, R. A. (1987). A controlled clinical trial of high dose methylprednisolone in the treatment of seere sepsis and septic shock. N Engl J Med , 653-8. 10. Bridges, E., & Dukes, S. (2005). Cardiovascular aspects of septic shock: pathophysiology, monitoring and treatment. Critical care nurse , 14-38. 11. Briegel, J., Forst, H., Haller, M., Schelling, G., & Kilger, E. (1999). Stress doses of hydrocortisone reverse hyperdynamic septic shock: a prospective randomized, double blind single center study. Crit care med , 723-32. 12. CEBM. (n.d.). Retrieved from http://www.cebm.net 13. Chawla, K., Kupfer, Y., Goldman, I., & Tessler, S. (1999). Hydrocortisone reverses refractory septic shock. Crit care med , A33. 14. Cohen, R. (2011). Use of corticosteroids in septic shock. Minerva Anestesiol , 190-5. 15. Dellinger, R. P., Levy, M. M., Carlet, J. M., Blon, j., Parker, M. M., Reinhart, K., et al. (2008). Surviving sepsis campaign: international guidelines for the management of severe sepsis and septic shock: 2008. Intensive care medical , 17-60. 16. Harrison, D. A., Welch, C. A., & Eddleston, J. M. (2006). The epidemiology of severe sepsis in England, Wales and Northern Ireland, 1996 to 2004: secondary analysis of a high quality clinical database, the ICNARC case mix programme database. Critical care . 17. Laterre, P. F., Levy, H., Clermont, G., Ball, D. E., Garg, R., Nelson, D. R., et al. (2004). Hospital mortality and resource use in subgroups of the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial. Crit care med , 2207-18. 18. Li, H., Xie, W., Strong, J., & Zhang, J. (2007). Syatemic antiinflammatory corticosteroid reduces mechanical pain behavior, sympathetic sprouting, and elevation of proinflammatory cytokines in a rat model of neuropathic pain. Anesthesiology , 469-77. 19. Minneci, P. C., Deans, K. J., Banks, S. M., Eichacker, P. Q., & Natanson, C. (2004). Meta-analysis: the effect of steroids on survival and shock during sepsis depends on the dose. Ann Intern Med , 47-56. 20. Miyashita, m. (2010). Controversy of corticosteroids in septic shock. J Nippon Med Sch , 67-70. 21. Morrell, M. R., Micek, S. T., & Kollef, M. H. (2009). The management of severe sepsis and septic shock. Infect dis clin N Am , 485-501. 22. Oppert, M., Schindler, R., Husung, C., Offermann, K., Klaus-Jurgen, G., & Olaf, b. (2005). Low dose hydrocortisone improves shock reversal and reduces cytokine levels in early hyperdynamic septic shock. Crit care med , 2457-64. 23. Parker, M. M., McCarthy, K. E., Ognibene, F. P., & Parrillo, J. E. (1990). Right ventricular dysfunction and dilatation, similar to left ventricular changes, characterize the cardiac depression of septic shock in humans. Chest , 126-31. 24. Rivers, E., Nguyen, B., Havstad, S., Ressler, J., Muzzin, A., Knoblich, B., et al. (2001). Early goal directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med , 1368-77. 25. Sligl, W. I., Milner, D. A., Sundar, S., Mphatswe, W., & Majumdar, S. (2009). Safety and treatment of corticosteroids forthe treatment of septic shock: a systematic review and meta-analysis. Clinical infectious diseases , 93-101. 26. Sprung, C. L., Annane, D., Keh, D., Moreno, R., Singer, M., Freivogel, K., et al. (2008). Hydrocortisone therapy for patients with septic shock. N Eng J Med , 111-24. 27. Sprung, C. L., Caralis, P. V., & Marcial, E. H. (1984). The effects of high-dose corticosteroids in patients with septic shock. A prospective, controlled study. N Eng J Med , 1137-43. 28. Tavares, E., Minano, F. J., Maldonado, R., & Dascombe, M. J. (2006). Endotoxin fever in granulocytopenic rats: evidence that brain cyclooxygenase-2 is more important than circulating prostaglandin E2. Journal of Leukocyte Biology , 1375-88. 29. Wang, H., Ward, M. F., & Sama, A. E. (2009). Novel HMGB1 inhibiting therapeutic gaents for sepsis. Shock , 348-57. 30. Zanotti-Cavazzoni, S. L., & Hollenberg, S. M. (2009). Cardiac dysfunction in severe sepsis and septic shock. Current opinion in critical care , 392-7. Read More