EVIDENCE-BASED STRATEGIES IN THE MANAGEMENT OF THE PATIENT WITH SEVERE SEPSIS AND/OR SEPTIC SHOCK
In the management of the patient with severe sepsis and/or septic shock, there is clear evidence on the appropriate strategies to endeavour to achieve haemodynamic stability.
The purpose of this essay is to critically discuss the above statement from the perspective of the management of severe sepsis and/or septic shock in intensive care. In addition to the critical analysis of appropriate strategies, further research perspectives will also be mentioned. This discussion is not intended to be inclusive on the management of severe sepsis or septic shock and only strategies that endeavour to achieve haemodynamic stability will be commented on.
This paper will prove that there is clear evidence on 3 major strategies used to achieve haemodynamic stability in patients with severe sepsis and/or septic shock. However, there is also other intervention that are recommended in the management of severe sepsis and/or shock, that do not have a high quality of evidence in support but have shown promising results related to achieving haemodynamic stability.
Despite differences in the description of severe sepsis and septic shock, most definitions consist of the same characteristics. Sepsis has been defined by Latto (2008), Robson and Daniels (2008) as a clinical condition characterized by the presence of both infection and a systemic inflammatory response, while severe sepsis is defined as sepsis that is complicated by organ dysfunction. Bridges and Dukes (2005), King (2007) and Nelson, LeMaster, Plost and Zahner (2009) classify septic shock when the patient in severe sepsis remains hypotensive despite fluid resuscitation. Garretson and Malberti (2007) and Sommers (2003) expand on this describing septic shock as the result of an overwhelming infection which leads to hypotension, altered coagulation, inflammation, impaired circulation, anaerobic metabolism, changes in mental status and multi-organ failure.
Haemodynamic stability is harder to classify. Bridges and Dukes (2005) identified standard indices of hemodynamic stability as blood pressure, heart rate and urine output. Latto (2008) agrees, stating that haemodynamic variables are related to changes in a patient's mean arterial or systolic blood pressure. Therefore, the strategies discussed below aim to achieve an appropriate heart rate and blood pressure.
Sepsis is a common and serious complication for ICU patients which affect 18 million people worldwide, each year (Robson & Newell, 2005). The annual rate of occurrence of severe sepsis in the United States is 750000 cases with an estimated annual cost of $16.7 billion (Durthaler, Ernst & Johnston, 2009, Garretson & Malberti, 2007, Gluck & Opal, 2004, Hanna, 2003, Huang, Clermont, Dremsizov & Angus, 2007, Moore, Jones, Kreiner, McKinley & Sucher et al. 2009). In 1999, an epidemiological study calculated the incidence of severe sepsis in Australia and New Zealand was 77 per 100,000 inhabitants (Kortgen, Hofmann & Bauer, 2006). Sepsis also has a reported mortality rate of between 28% and 50% and causes massive financial implications for all healthcare systems (Wong, 2009). The identification and treatment of sepsis remains an important challenge to healthcare providers (Moore et al. 2009).
Before examining the strategies that endeavour to achieve haemodynamic stability, one must understand the cause of haemodynamic instability in septic shock. In severe sepsis or septic shock, blood flow to organ tissue is limited due to the microvascular disturbances associated with the immune response and the imbalance in coagulation (Ahrens & Vollman, 2003). Reduced tissue perfusion can result in life-threatening consequences including organ failure. The most common clinical indicator of blood flow and perfusion is blood pressure however it is only an indirect indication of peripheral blood flow (Ahrens & Vollman, 2003).
Riddell and Blackwood (2006) state that increased vasodilation and capillary permeability of severe sepsis cause hypovolaemia. Venous blood returning to the heart decreases. As a result, stroke volume, cardiac output and blood pressure decrease. This decrease in blood pressure is sensed by baroreceptors which are conveyed to the vasomotor centre. The vasomotor centre activates the sympathetic compensatory mechanism which causes the heart rate to increase (Riddell and Blackwood, 2006). This basic interpretation of the pathophysiology explains the hypotension and tachycardia that is common in patients with severe sepsis and septic shock.
In 2004, the Surviving Sepsis Campaign was formed with the initial goal of reducing the mortality associated with severe sepsis (Dellinger, Carlet, Masur, Gerlach & Calandra et al. 2004). Hurtado and Nin (2006) stated that most of the summarised guidelines presented were not supported by high levels of evidence. Several years later, an updated version of the International guidelines was released (Dellinger, Levy, Carlet, Bion & Parker et al. 2008). An assessment of the quality of evidence and the strength of recommendations was completed. This resulted in graded evidenced-based recommendations regarding the management of sepsis and septic shock. These guidelines have now been described as evidence-based by Durthaler et al. (2009).
Rivers, Nguyen, Havstad, Ressler and Muzzin et al. (2001) showed that early haemodynamic optimisation (known as early goal directed therapy), significantly reduced morbidity and mortality in patients with severe sepsis or septic shock. The investigators used strategies such as colloid or crystalloid infusions, inotropes, vasopressors and red blood cell transfusions to achieve haemodynamic optimisation.
According to Bridges and Dukes (2005) guidelines from 3 major consensus panels are commonly used to direct the hemodynamic support of adult patients with septic shock. In the article by Bridges and Dukes (2005), hemodynamic support for patients with septic shock can be classified into 3 main categories: fluid resuscitation, vasopressor therapy and inotropic therapy. These fundamental strategies have been evaluated and discussed below. Blood transfusions, corticosteroids and activated protein C will be the other interventions included in this essay.
In patients with severe sepsis, venodilatation occurs which produces a relative hypovolemia as stated previously (Riddell & Blackwood, 2006). The dilating of the peripherally vessels results in hemodynamic instability as it causes hypotension (Ahrens & Vollman, 2003). The administration of fluids is the standard first-line treatment for haemodynamic instability associated with severe sepsis. This strategy has been supported by many studies and literature reviews (Bridges & Dukes, 2005, Hanna, 2003, Trejnowska & Popovich, 2009). Timely and sufficient volume therapy has been demonstrated to be one of the most effective supportive measures in sepsis therapy (Merx & Weber, 2007). Peel (2008) states that fluid challenges must be clearly defined with the purpose to expand the patient's intravascular volume.
Fluid-resuscitation using crystalloid or colloid was recommended by the Surviving Sepsis Campaign (Dellinger et al. 2008). The researchers found that the desirable effects of fluid therapy clearly outweigh the undesirable effects. This was supported by a high quality of evidence (Dellinger et al., 2008).
Hanna (2003) states that rapid, large volume infusions of intravenous fluids are usually indicated in patients with septic shock. Vincent and Gerlach (2004) recommend that fluid challenges should be administered and repeated based on response and tolerance. Administration of volume is usually initiated with crystalloid or colloid boluses of up to 1000ml titrated to cardiovascular goals, such as MAP and heart rate (Trejnowska and Popovich, 2009).
A fluid bolus is usually given over 5-10 minutes and should be given if systolic blood pressure is <90mmHg or >40mmHg lower than the patient's normal blood pressure (Robson and Newell, 2005). Slightly different haemodynamic indices have also been used to guide fluid resuscitation. Dellinger et al. (2008) have reported a mean arterial pressure (MAP) of ≥65mmHg as a goal indicator.
Ruffell (2004) advises that physicians should aim for a central venous pressure (CVP) of 8-12mmHg with 500ml of crystalloid given every 30 minutes to maintain that. Other indicators of adequate fluid resuscitation include a urine output greater than 0.5ml/kg/hr, mixed venous oxygen saturation ≥70% and a CVP of 12-15mmHg for patients receiving mechanical ventilation (Garretson & Malberti, 2007, King, 2007). This is because most patients with sepsis have inadequate preload due to peripheral vasodilatation (Bridges &Dukes, 2005).
The fluid of choice for resuscitation in patients with severe sepsis and/or septic shock is still unclear. The Surviving Sepsis Campaign states that there is no evidence-based support for one fluid type over another (Dellinger et al. 2008). Finfer, Bellomo, Boyce, French and Myburgh et al. (2004) conducted a multicenter, randomised, double-blind trial to compare the effect of fluid resuscitation with albumin or saline on mortality in a heterogeneous population of patients in the ICU. Known as the SAFE study, Finfer et al. (2004) concluded that the use of either four percent albumin or normal saline for fluid resuscitation results in similar outcomes at 28 days. Although patients with severe sepsis were included in the study, they only made up 18% of participants. An evidence-based review done by Vincent and Gerlach (2004) also found that fluid resuscitation of severe sepsis may consist of either colloids or crystalloids.
Despite this, other fluids have shown preference to a particular fluid type. Schulman and Hare (2003) found that fluid resuscitation with crystalloid should be used to restore intravascular volume lost through third-spacing and bodily secretions in the septic patient.
However, if fluid resuscitation is delayed, the benefits of fluid therapy (such as hemodynamic stability) are reduced as fluid alone cannot improve the cellular problems seen in severe sepsis. Also due to increased permeability in the capillaries, fluid will leak from the interstitial space (Ahrens & Vollman, 2003). Van der Heijden et al. (2009) hypothesised that crystalloid loading results in more edema formation than colloid loading. The investigators completed a randomised clinical trial looking at the effect of fluid in 24 septic patients with clinical hypovolemia. They discovered that pulmonary edema and lung injury score are not affected by the type of fluid loading in the steep part of the cardiac function curve even when complicated by increased pulmonary permeability.
Thiel et al. (2009) completed a retrospective before and after study using 400 bacteremic patients with severe sepsis. They compared the impacted of a standardized order set for the management of bacteremic severe sepsis. Thiel et al. (2009) discovered that the group of patients that received the standardized order set were less likely to require vasopressors after the initial fluid resuscitation.
Sommers (2003) states that when the volume deficit is restored, a pattern of tachycardia, increased cardiac output and decreased systemic vascular resistance often occurs. If these target goals are not met by fluid administration then vasopressor therapy should be instituted (King, 2007).
If adequate fluid therapy does not restore arterial pressure and organ perfusion, treatment with vasopressors should be started (Latto, 2008 and Trejnowska and Popovich, 2009). Vasopressors can also be used transiently to maintain the blood pressure until adequate volume resuscitation can be achieved (Bridges & Dukes, 2005 and Trejnowska and Popovich, 2009).
Dopamine, adrenaline, noradrenaline, phenylephrine and vasopressin have been demonstrated to be effective in raising blood pressure in patients with septic shock (Dellinger, 2003). In 2001, Holmes et al. identified that vasopressin was emerging as a rational therapy for the hemodynamic support of septic shock. They reviewed numerous trials of low-dose vasopressin in human septic and vasodilatory shock but concluded that clinical use of vasopressin should await a randomized controlled trial of its effects on clinical outcomes such as organ failure and mortality.
Dellinger et al. (2008) recommend that mean arterial pressure (MAP) be maintained ≥65mmHg using either noradrenaline or dopamine as first choice vasopressors to correct hypotension. The rationale behind this guideline is that below a certain MAP autoregulation can be lost and perfusion can become linearly dependant on pressure. Schulman and Hare (2005) stated that cardiovascular status can be further supported using vasopressors. The use of noradrenaline as a vasopressor of hemodynamic support was associated with a significantly lower hospital mortality rate compared to high dose dopamine or adrenaline. An evidence-based review by Beale et al. (2004) found that vasopressors are indicated to maintain a MAP of <65mmHg, both during and following adequate fluid resuscitation. Noradrenaline or dopamine are the vasopressors of choice in the treatment of septic shock. Noradrenaline may be combined with dobutamine when cardiac output is being measured (Beale et al. 2004). Despite this, Merx and Weber (2007) concluded that although the combination of noradrenaline as vasopressor and dobutamine as inotropic agent is probably the most frequently applied in septic shock, there is currently no evidence to recommend one catecholamine over the other. Some patients do not respond to vasopressor therapy (Ahrens & Vollman, 2003). Ruffell (2004) also suggests that the MAP be between 65 and 90mmHg with the use of vasopressors and vasodilators administered to maintain within that range.
Albanese et al. (2005) completed a relatively small study comparing the effects of noradrenaline or terlipressin on hemodynamic variables and renal function. Twenty patients were included in the study, all had a severe form of septic shock with hemodynamic instability (mean arterial pressure <60mmHg) and two or more organ dysfunction. They discovered that both noradrenaline and terlipressin were effective to raise mean arterial blood pressure however, terlipressin causes a decrease in cardiac index and oxygen consumption (Albanese et al., 2005).
Durthaler et al. (2009) distributed 414 surveys to nurse managers to analyse current practices for managing severe sepsis in U.S. hospitals. They found that a number of the Surving Sepsis Campaign treatment guidelines have been widely adopted including the administration of vasopressors to hypotensive patients not responding to initial fluid resuscitation. This represents that the intervention is relatively simple to implement, well endorsed and noncontroversial.
Inotropes increase cardiac contractility whereas vasopressors cause vasoconstriction. However, some drugs have both inotropic and vasopressor effects.
Marx and Weber (2007) reported that as early as the mid-1980's, significant reductions in both stoke volume and ejection fraction in septic patients were observed despite normal total cardiac output.
Dellinger (2003) states that some patients suffering severe sepsis may have decreased global cardiac contractility and therefore inotropic therapy maybe considered. Dobutamine would be used in combination with vasopressor therapy. The Surviving Sepsis Campaign guidelines recommend that a dobutamine infusion be administered in the presence of myocardial dysfunction (Dellinger et al. 2008).
Dobutamine is recommended as the agent of choice to increase cardiac output but should not be used for the purpose of increasing cardiac output above physiologic levels (Beale et al. 2004).
Some patients with severe sepsis and/or septic shock may have myocardial depression and despite being in a hyperdynamic state, myocardial contractility may be decreased (BridgesVollman, 2005). An inotrope such as dobutamine is recommended in these patients. A vasopressor can also be added if the patient remains hypotensive.
Bridges and Dukes (2005) state that blood transfusions may be a part of a therapeutic plan to optimize hemodynamic status and oxygenation. Ruffell (2004) suggests that central venous oxygen saturation (Scv02) ≥70% and transfusion of red cells to maintain a haematocrit of ≥30.
Dellinger et al. (2008) suggest that adult septic shock patients whom blood pressure is poorly responsive to fluid resuscitation and vasopressor therapy can be given intravenous hydrocortisone. This suggestion is however a weak recommendation which indicates that the tradeoff between desirable and undesirable effects are less clear. The quality of evidence for this recommendation is also considered low.
A French multicenter randomised controlled trial (RCT) of patients unresponsive to fluid and vasopressor therapy showed a significant shock reversal and reduction in mortality rate in patients with relative adrenal insufficiency with corticosteroid administration (Dellinger et al. 2008). Wong (2009) also states that the use of hydrocortisone is controversial in septic shock patients.
Trejnowska and Popovich (2009) explain that corticosteroid use demonstrated no significant benefits in mortality but did show reduced time of reversal of shock in patients who showed signs of shock reversal.
Despite the recorded reduction in mortality and significant shock reversal, little is mentioned regarding haemodynamic stability from corticosteroids.
Activated protein C is a naturally occurring protein made by the body and is both an anticoagulant and an anti-inflammatory (Robson and Newell, 2005). Levi (2008) concluded that although randomized controlled trials have indicated that activated protein C is effective in reducing mortality in patients with severe sepsis, additional clinical trials have cast doubts on the usefulness of this treatment.
Despite being shown to reduced mortality of patients suffering severe sepsis and/or septic shock, there is no evidence to show that activated protein C endeavours to achieve haemodynamic stability. Schulman and Hare (2003) even report that activated protein C does not result in an immediate improvement of hemodynamic and pulmonary status such as is seen with the effect of dopamine on a patient's blood pressure.
Immediate identification of the source of infection is one of the guidelines presented in the Surving Sepsis Campaign. However, as stated by Ahrens and Vollman (2003) antibiotics do not directly improve tissue perfusion or the associated delivery of oxygen and nutrients. Robson and Newell (2005) also stated that giving prompt antibiotic therapy may reduce mortality by 10-15 percent.
Durthaler (2009) found that only 57% of patients achieved hemodynamic goals within six hours of onset of acute organ dysfunction. King (2007) states that sepsis has a six hour window of opportunity for stabilization that impacts the mortality and morbidity data.
One of the main goals for the treatment of severe sepsis in ICU is to adjust preload, afterload and contractility to balance oxygen delivery with oxygen demand (Ruffell, 2004).
As explained in this discussion, there are clear evidence-based strategies that endeavour to achieve haemodynamic stability in patients with severe sepsis and/or septic shock. Fluid resuscitation, vasopressors and inotropic therapy are three main evidence-based interventions that have shown to achieve hemodynamic stability. Blood transfusions, corticord steroid use and activated protein c are other strategies that have been used in the management of severe sepsis and septic shock.
Moore et al. (2009) commented that although there are evidence-based guidelines, the complexity and number of recommendations makes it difficult to consistently implement these interventions.
