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The terminology such as septic shocks, sepsis and the cardiac dysfunction of organs has become the major health issues for mortality and morbidity. The ACCP/SCCM committee has described the septic shock as the sepsis induced hypotension such as systolic blood pressure with 90 mm Hg or a reduction of 40 mmHg with the fluid resuscitation along with the presence of some perfusion abnormalities. They are not limited to terms such as oliguria, lactic acidosis or an altered mental status. Patients who receive vasopressors or inotropic agents can have the normal level of blood pressure at the time of identification of perfusion abnormalities (American College of Chest Physicians/ Society of Critical Care Medicine Consensus Conference, 1992).
Numerous management processes as well as therapeutic procedures were taken for the sepsis and septic shocks (Baue AE, Durham R, Faist E, 1998; Deitch EA, 1998). These diseases are the major causes for mortality and morbidity in patients in the industrialized as well as non-industrialized world and they are dependent on several factors. The cases of severe sepsis are estimated about 750000 per year in United States over 210000 annual deaths (Angus DC, Linde-Zwirble WT, Lidicker J, et al., 2001). The researchers have found the biological mechanisms for the potential interventions for septic shocks such as corticosteroids. Theses have tested due to its interactions with some major immune responses. These hormones affect the inflammation by their effects on the nitric oxide, white blood cells and cytokines.
Corticosteroids are produced in adrenal cortex and belong to the class of steroid hormones which are involved in a spectrum of physiological processes such as immune response, regulation of inflammation, blood electrolyte levels, etc. Corticosterone, cortisone & aldosterone are some common natural hormones. On the immune system corticosteroids act by blocking the production of allergic & inflammation triggering substances and maintain the proper functioning of the immune system by impeding the white blood cell function of foreign body demolishing.
Glucocorticoid display a wide spectrum of anti-inflammatory properties e.g., inhibition of production of pro-inflammatory cytokines, prostaglandins, free radicals and inhibition of chemotaxis and have reflective effects on the cardiovascular system e.g., increasing mean blood pressure, increasing pressor sensitivity, may work to improve septic shock survival even at low doses.
Aims and objectives
The assignment here aims to perform a thorough and critical review of the available literature on use of corticosteroid in severe sepsis and septic shock and to evaluate its impact on clinical practice. To find research base for our current practice and compare with clinical evidences with ultimate aim to have foundation for concrete base guidance to unify our practice rather than individual based.
In this assignment, the researcher will discuss about the concepts of sepsis and septic shocks. The emphasis would be on the cardiovascular management of sepsis and septic shocks. The outline of septic shock is affected by some multiple sepsis induced changes. This study will also include the Cardiac dysfunction in severe sepsis and septic shock. Thus the research will be conducted for the effectiveness of corticosteroid for the treatment of the patients who are having the problems of sepsis and septic shocks.
Initial assessment of Sepsis and Septic Shock
Sepsis is the outcome of some complex interaction between the immune of host and infecting microorganism, coagulation and inflammatory responses. Sepsis is divided into two phases such as early and late stage. It has been done by fluctuations in the host responses and also for facilitating targeted therapies (Hotchkiss RS, Karl IE, 2003). The early stages of sepsis are defined at first 6 hours and also it is decorated by some early treatment of sepsis and septic shocks and some goal directed therapy Rivers (E, Nguyen B, Havstad S, et al., 2001; Dellinger RP, Levy MM, Carlet JM, et al., 2008).
Early goal-therapy permits the assessment of patients. Thus it results into a decrease in-hospitals and mortality (Rivers E, Nguyen B, Havstad S, et a., 2001; Nguyen HB, Corbett SW, Steele R, et al., 2007). Many critical first line therapy must be administered at the time of crucial period in sever sepsis and septic shocks.
Management of severe sepsis and septic shocks
Considering source control
Evaluation for nutrition
Assessment of perfusion
Administering blood products for anemia
Initiation of vasoactive agents (only if it is needed)
Initiating intravenous insulin for the problem of hyperglycemia
Obtaining antimicrobial cultures
Administering the empiric appropriate antibiotics
Initiating prophylactic measures (such as for gastro intestinal hemorrhage and for venous
Placement of central venous catheter and arterial canula ( only if it is necessary)
Assessing need for activated protein C
Starting of goal directed fluid resuscitation
Instituting corticosteroids (if it is appropriate)
Instituting lung protective ventilation strategies
Table 1: Therapies used in the treatment of severe sepsis and septic shock.
Source: Matthew R.Morrell, MDa,*, Scott T.Micek, PharmDb,Marin H. Kollef, (2009)
The first preference in the patients who have some sepsis and septic shocks includes some stabilization of breathing and airways. Supplemental Oxygen is provided to the patient and it should be preformed if it is necessary. The assessment of perfusion must be preformed. Blood pressure is assessed by using arterial catheter if the blood pressure is labile.
Results of trials of glucocorticoid in humans with sepsis
The clinical trials of corticosteroids performed a study of severe infection in the sepsis. One researcher found the corticosteroids therapy for sepsis. These studies were compared with the high dose dexamethasone, the methylprednisolone and saline infusion with the patients with septic shock. The mortality rate was almost 10.5% in the steroid groups such as almost 9.5% with dexamethasone and 11.5% with methylprednisolone and that was compared with the 14% of steroid treatment.
Cardiac dysfunction in severe sepsis and septic shock
The proper understanding of the mechanisms and the treatment strategies along with the sepsis and septic shocks remains important (Martin GS, Mannino DM, Eaton S, Moss M., 2003). The development process of the hypoperfusion of tissues and dysfunction of organs leads to severe sepsis. Septic shock is known as hypotension refraction to the fluid resuscitation. The progression of this series from sepsis-severe sepsis-septic shock is linked with the increased morbidity and mortality. The first part of the process is the development of the cardiovascular and hemodynamic instability. It has been found by some previously conducted researches that patients who were having the problem of myocardial dysfunction have the mortality rate of about 70%. Those patients were compared with the septic patients with impairment of cardiovascular part of almost 20% (Blanco J, Muriel-Bombin A, Sagredo V, et al.,2008; Parrillo JE, Parker MM, Natanson C, et al.,1990).
Clinical characteristics of sepsis-induced cardiac dysfunction
The researches have clearly stated that the sepsis induced cardiovascular dysfunctions were totally based on the clinical patterns which were identified in those patients who were having the physical examination of septic shock (Rabuel C, Mebazaa A., 2006). Generally two types of shocks were described: cold shock and warm shock. Cold shocks were linked with the clammy skin, low pulses rates, patients who are having the problem of severe illness. Warm shocks were identified by oliguria, hypotension, fever and high pulse rates. At that time, they were considered as the phases of that process with cold shocks. Thus it became the end result of the patients who were dying from the severe septic shock. Then the pulmonary artery catheter and the ability for measuring cardiac output and some other parameters were emerged for the hyperdynamic state of septic shock.
Some studies have demonstrated that the patients, who were kept under the intensive care unit, were having the hyperdynamic state of septic shock. It was highly characterized by the low systematic resistance of vascular and high cardiac output (Rabuel C, Mebazaa A., 2006). That profile persisted in the patients who were dying due to the septic shocks. The importance of fluid resuscitation to change the hyperdynamic state of sepsis is highly appreciated (Dellinger RP. 2003; Zanotti-Cavazzoni SL, Dellinger RP, 2006; Zanotti-Cavazzoni SL, Guglielmi M, Parrillo JE et al., 2009). The early phase of sepsis decreased the volume of intravascular and thus it led to the lower cardiac output. The patients develop high cardiac output with destructive resuscitation of volume and also the improvement in intravascular volume. The increased of cardiac was seen in the volume resuscitated patients with severe sepsis that was driven by low vascular resistance systematically. It is probable that most of the patients were not described as having the problem of cold shock and they were insufficiently volume resuscitated.
The depressed myocardial dysfunction in sepsis with the measurements of hemodynamic conditions showed an increase in the cardiac output which was emerged from the study of radionuclide cineangiography.
Some researchers had performed some radionuclide ventriculograms within the group of septic patients. Those patients were able to display the depression of some myocardial function (Parker MM, Shelhamer JH, Bacharach SL et al., 1984). It was believed that the survivors of septic shock were having the decreased fractions of ejections with the volume index of end- diastolic. But the non survivors were having the preserved cardiac volumes with the less important decrease in the ejection fraction. The changes in the myocardial function along with the volumes were reversible incase of survivors for the period of 8-10 days (Parker et.al, 1984). Several studies showed that the patients with severe sepsis and septic shock impaired some intrinsic myocardial performances as a functioning of abnormal responses in the LVSWI (left ventricular stroke work index) to the infusion of fluids (Ognibene FP, Parker MM, Natanson C, et al, 1988). Some changes were described in the right ventricle Parker MM, McCarthy KE, Ognibene FP, Parrillo JE (1990). Patients who were having the septic shock developed the right ventricular dilation and right ventricular contractility (abnormal right ventricular stroke of work index).
Corticosteroids for septic shock
Corticosteroids were used to treat patient who were having the sepsis in early 1940s (Perla D, Marmorston J, 1940). After an initial eagerness of the related topic, some well conducted controlled and customized trials directed doubts on the usefulness and the importance of the steroids for treating the patients of sever sepsis. The summary of all randomized and customized trials were performed between 1966 and 1933. It was suggested that high dose corticosteroids for the treatment of patients with the sepsis can be discarded (Lefering R, Neugebauer EA, 1995; Cronin L, Cook DJ, Carlet J, et al, 1995). But this doubt still has persisted for the usefulness of the replacement therapy in the case of catecholamine- dependent septic shock. This strategy of replacement therapy believes on the concept that these septic shocks may become complicated by peripheral glucocorticoid resistant syndromes and some adrenal insufficiency.
Normally septic shock is considered as major complication of some infectious disease with the mortality of about 60% within the short period of time. The classification or discussion of coagulation, immune and neuroendocrine has become the important step to understand the cellular and molecular basis of sepsis. The disturbance of the hypothalamic pituitary adrenal axis has become the key factor of the series from infectious part to septic shock (Annane D, Bellissant E, Cavaillon JM, 2005). The corticosteroids for treating the patients who are having with the septic shock have gained interest in this field from past few decades.
Since the discovery of corticosteroids, it has accepted numerous and broad range of clinical indications. The reason is that corticosteroids are considered as most powerful anti-inflammatory drugs and that are the most know drugs to the till date. The first study on the use of corticosteroid therapy was presented by Hahn et al (1951) and Perla & Marmorston (1940) in the patients who were having the problem of generalize infection, pneumonia, bacteremia etc. but still it is controversial topic. Numerous studies were carried out for using high doses of corticosteroids such as methylprednisolone or dexamethasone for very short period of time (Bone RC, Fisher CJ Jr, Clemmer TP, Slotman GJ, Metz CA, Balk RA, 1987; Long WM,et al.,1984). These studies aimed at the effects of corticosteroids in the patients with the severe sepsis and septic shocks.
Table 4 - Recent studies on corticosteroid therapy: type of corticosteroid to be used, dose and duration of treatment
Source: Annane D, Sébille V, Charpentier C, Bollaert PE, François B,
Korach JM, et al (2002),
Some recent studies have shown that the good outcomes for using of low doses of hydrocortisone (200-300 mg/day) and it was offered for longer period of time (Bollaert PE, Charpentier C, Levy B, Debouverie M, Audibert G,Larcan A., 1998). It has been demonstrated that the amount of 20mg hydrocortisone is equivalent to the 0.05mg of fludrocortisone. The amount of .05-2mg fludrocortisone is recommended as the mineralocorticoid replacement in adrenal insufficiency (Keh D, Sprung CL., 2004).
The studies have shown that fact that the corticosteroid therapy was used for the patients who were having catecholamine refractory shock and they used hydrocortisone as the corticosteroid whereas dexametasone and methylprednisolone do not have this type of activity. Several studies were taken out for the evaluation of clinical practice to make use of corticosteroid in septic shock in the pediatric patients in United Kingdom. The study stated that the corticosteroids were used in 76% of the ICU and only one ICU had a protocol. The 84% of corticosteroid were used in the the presence of hypotension in spite of using vasoactive drugs (Hildebrandt T, Mansour M, Al Samsam R., 2005).
Lower dose taken for Fludrocortisone and Hydrocortisone affect the mortality of patients who are suffering with the problem of septic shock (Annane D, Sebille V, Charpentier C, et al., 2002). There was a research conducted for the placebo controlled study. The research was conducted in the random manner, using parallel group of trials and double blind case from 9 October 1995 to 23 February 1999. The research was conducted in France for the care units of 19 in total. Those patients who undergone the basic criteria used in the septic shock, had been found to enrol after the completion of the corticotrophin test. Random division of patients was done in order to attain fludrocortisone (consuming tablet equal to 50 Î¼g per day), or hydrocortisone (consuming 50 mgintravenous after the regular interval of 6hours, or placebos with the number equal to 149, for the duration of once a week.
The research mainly aimed to analyse if the consumption of corticosteroids of lower dose helps in improving the patients with survivalin and suffering from septic shock, and the extent of insufficiency. Total number of non- respondents chosen was 229 in number. 70 respondents were related to Synacthen test with corticosteroids equalling 36 and placebo equalling 34, whereas the number of respondents related to Synacthen test with corticosteroids equalling 114 and placebo equalling 115.
Not much of the difference was noted in between the respondent groups in the study. The rate of adverse events was equivalent to that of the 2 groups, and relates to vasopressors and to procedures for invasive ICUs.
The study was found to be quite well in its design. It provides quite good number of evidence as per the hierarchy of CEBM. The main focus was laid on the specific group of population. These population groups were found to get benefit by making use of the corticosteroids. This was due to the insufficiency of adrenals, along with the lower dose for the combined use of fludrocortisone and hydrocortisone. The findings for the research were found to be exactly in line with the results that were obtained for the reviews using systematic approach, and the debates conducted about the benefits attached with the steroids of lower dose.
We can conclude that in case of catecholam of patients suffering from septic shock, especially ones having insufficiency of adrenal, with the treatment of once a week using the fludrocortisone and hydrocortisone simultaneously would be safer for the patients. This also associate with the minimization of mortality both for short and long- term.
Steroids in sepsis: Another swing of the pendulum in the clinical trials
The search for the effective therapy for the treatment of sepsis has been associated with the inconsistent results from the clinical researches. There are no harmful effects of corticosteroids have seen with the clinical practices. It results in the well use of steroids in the treatment of patients with the sepsis. High steroids were used in the practices because of the inflammatory responses of sepsis. So it has been proved that anti-inflammatory properties of steroids have become very useful.
The study has demonstrated that the treatment with the doses of corticosteroids (3mg/kg to 30 mg/kg) was totally linked with the reduction of mortality rate with the saline treatment in the patients with the septic shock (Schumer W., 1976). Two randomized and uncontrolled trials were failed to verify these findings (Bone RC, Fisher CJJ, Clemmer TP, Slotman GJ, Metz CA, Balk RA., 1987). In 1990, numerous studies were carried out for suggesting the role for the low doses of steroids to reduce the requirements of vasopressors in the patients with the problem of septic shock (Dellinger RP, Carlet JM et al. 2004; Sprung CL et al, 2008).
Some results were found in the patients who were having the problem of adrenal insufficiency and it was diagnosed by using nonresponse to the corticotrophin tests. They were treated with the hydrocortisone (50mg for every 6 hours) and fludrocortisone (50µg daily) and it reduced the rate of mortality which was compared with the nonresponders of placebo. The use of Steroid was included into the sepsis with the suggestion that all patients must receive low dose corticosteroids within a day of diagnosis.
The Corticus- corticosteroid therapy was used for the patients with septic shock and it has showed that hydrocortisone were not able to improve the reversal process of shock into the patients (Briegel J, Forst H et al, 1999). They found some significant differences between the Corticus study and the effects on outcome. It includes the larger number of postoperative patients with the abdominal part of sepsis in the low sternness of illness within the Corticus study.
Steroid Therapy - Current Indications in Practice
Steroids are the widely used drugs in the practices of treatment of sepsis and septic shocks with or without any type of indication. These steroids are proved to be of the massive help. The use of steroids in perioperative medicines has become the renewed area of interest.
Steroids as anti-inflammatory
Sepsis is the body's response to an inflammatory process marked by an elevated heart rate, abnormal temperature & rapid breathing. Even minor infections like influenza can set off sepsis. Usually it is not life-threatening but complications may cause serious illness (like-organ dysfunction) and death. When the natural immune response to an infection goes into overdrive, eliciting widespread inflammation and blood clotting in tiny vessels throughout the body- Severe sepsis occurs leading to organ dysfunction or failure. Septic shock occurs when the blood pressure drops dangerously lead by sepsis. Thus the steroids help in removing this problem. Steroids alter the humoral as well as immune responses. This suppresses the inflammation in the responses to the radiation, mechanical, infectious and immunological stimuli. Multiple mechanisms have been involved for suppressing the inflammation by using steroids. They slow down the production of various inflammatory factors that are critical to generate the inflammatory responses such as cytokines, chemotactic agents and interleukins.
Steroids and sepsis/septic shock
Patients who are having the problems of sever sepsis and septic shock was investigated to include adrenal insufficiency and it may become more than 28% in the ill patients (Salem M, Tainsh RE, Bromberg J, Loriaux DL, Chernow B, 1994). It has been found that the adrenal insufficiency sepsis and steroid supplementation was linked with the success of the removal of vasopressors therapy for the treatment of sepsis as well as septic shock. The researches have also given the ideas on the steroid therapy in sepsis that it is not only linked with the clinical improvement but sometime it may be harmful (Schroeder S, Wichers M, Kingmuller D, et al., 2001). It has also been found that the steroids may not be useful in all septic patients but for an identifiable group of patients it may be useful. Steroids are directed to meet the requirements of body to fight with the stressful condition. The commonly used type of steroid is hydrocortisone (100-125 mg/day) (Meikle AW, Tyler FH, 1977).
The sepsis and septic shocks leads to some major health problems. Generally the septic shocks are the major complication of some infectious disease and that increases the rate of mortality. The use of corticosteroids has come into existence from past many years and it has become the major phenomenon for the treatment of the patients with sepsis and septic shocks. There are so many reasons that have led the use of corticosteroids. Steroids are the widely used drugs in the practices of treatment of sepsis and septic shocks with or without any type of indication.
As the cytokines suppress the response from cortisol to the adrenocorticotropin hormone and it causes the poor adrenal activity. Thus the tissues in the body resist to corticosteroids. The adrenal insufficiency in septic shocks contributes about 50%. These are some reasons that have anticipated that use of corticosteroids can become very beneficial in the case of treatment of sepsis as well as septic as shocks. The assignment has discussed about the corticosteroids that how and why they are used? It is concluded that the patients who are suffering from the problem of septic shock or having the problem of adrenal insufficiency, treatment of some corticosteroids hormones such as fludrocortisone and hydrocortisone simultaneously would be safer for them. It would be also associated with them in terms of short as well as long term period. The efficacy of corticosteroids considering the benefits of corticosteroid therapy in sepsis and septic shock treatment is expected to display remarkably in favor of the diseased and the consultant both.