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E X PE RT O P I N I O N
Early interventions in severe sepsis and septic shock: a review of the evidence one decade later E. P. RIVERS 1, M. KATRANJI 2, K. A. JAEHNE 1, S. BROWN G. ABOU DAGHER 1, C. CANNON 3, V. COBA 1
1
1Department
of Emergency Medicine and Surgery, Henry Ford Hospital, Wayne State University, Detroit, MI, USA; of Medicine, Pulmonary and Critical Care Medicine, Pontiac Osteopathic Hospital, Pontiac, MI, USA; 3Department of Emergency Medicine, University of Kansas, Medical Center, Kansas City, KS, USA 2Department
ABSTRACT The outcomes of acute myocardial infarction, trauma, and stroke have improved by implementing processes that provide early diagnosis and aggressive interventions at the most proximal point of disease presentation. A common feature in these conditions is the implementation of early intervention strategies. One decade ago, a similar approach to sepsis began when a prospective randomized trial compared early goal-directed therapy (EGDT) to standard care using specific criteria for the early identification of high risk patients with infection. The components of EGDT were derived from expert consensus opinion to produce a protocol to reverse the hemodynamic perturbations of hypovolemia, vasodysregulation, myocardial suppression and increased metabolic demands for patients with severe sepsis in the intensive care unit (ICU). However, EGDT was provided at the most proximal phase of disease presentation in the Emergency Department (ED). With EGDT, a reduction in mortality of over 16% was shown over standard care. Since the EGDT study was published a decade ago, significant emphasis worldwide has been placed on a comprehensive approach to the first 6 hours of sepsis management which is commonly referred to as the resuscitation bundle (RB). The RB consists of early diagnosis, risk stratification using lactate levels, hemodynamic response after a fluid challenge, antibiotics, source control and hemodynamic optimization or EGDT. This review will examine one decade of evidence for the components of the RB examining its impact on systemic inflammation, the progression of organ failure, health care resource consumption and mortality in severe sepsis and septic shock. (Minerva Anestesiol 2012;78:712-24) Key words: Sepsis - Shock, septic - Lactatic acid - Resuscitation.
S
epsis represents a continuum beginning with a host-pathogen interaction that triggers a complex interplay between pro-inflammatory, anti-inflammatory and apoptotic mediators.1 As the disease progresses, organ dysfunction can result from circulatory insufficiency from hypovolemia, myocardial depression, increased metabolic demands and vasoregulatory perfusion abnormalities. These hemodynamic perturbations lead to an imbalance between systemic oxygen supply and demand, leading to global tissue hypoxia and shock. These pathogenic events significantly contribute to the morbidity and mortality in early sepsis.2, 3
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A critical decrease in systemic oxygen delivery (DO2) is followed by an increase in the systemic oxygen extraction ratio (O2ER) and a decrease in central venous oxygen saturation (ScvO2) or mixed venous oxygen saturation (SvO2). This increase in OER is a compensatory mechanism to match systemic oxygen demands. When the limit of this compensatory mechanism (OER>50 to 60%) is reached, anaerobic metabolism ensures leading to lactate production.4 In this critical delivery dependent or hypodynamic phase, lactate concentrations are inversely related to DO2 and ScvO2/SvO2 (Figure 1).5 This phase can occur with normal vital signs and is commonly referred
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Figure 1.—Oxygen delivery and consumption.
to as “occult shock”, where the patient outwardly appears less ill. As a result organ dysfunction and sudden cardiopulmonary collapse are complications associated with this phase if unrecognized or left untreated.2, 6, 7 This state predominantly characterizes the early sepsis presentation (Figure 2) and is an important distinction from previous unsuccessful sepsis resuscitation trials performed in the ICU setting.8-11 After adequate resuscitation, a hyperdynamic phase follows the hypodynamic phase. Compensated sepsis is characterized by an elevated ScvO2/SvO2 and normal lactate. Later an elevated lactate and elevated ScvO2/SvO2 denote pathologic delivery dependence or delivery independence and is associated with increased mortality.12 The failure to increase OER and thus increase systemic oxygen consymption (VO2) may be secondary to impairment of microvascular oxygen perfusion or mitochondrial dysfunction. Origin of the resuscitation bundle (RB) components The RB and its components are not novel strategies. Wilson et al. wrote a series of expert opinions beginning in 1976 that comprised the tenets of early sepsis management (Figure 2).13 These recommendations included the following: early identification of high risk patients, appropriate cultures, source control, and appropriate antibiotic administration. This was followed by strategies aimed at early hemodynamic optimization of oxygen delivery guided by preload (central venous pressure or surrogate, fluids), afterload (mean arterial pressure, vasopressors),
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arterial oxygen content (packed red blood cells, oxygen), and contractility (inotropes) if ScvO2 remained low (Figure 2). In the 2001 publication, these components which were also recommended by a consensus of expert opinion 14 were applied at the most proximal site of hospital presentation mirroring the approach to trauma, stroke and acute myocardial infarction.14 This approach called early good-directed therapy (EGDT) was tested against standard care in a randomized control trial resulting in a mortality benefit of over 16%. In order to avoid the ethical issues (withholding life saving therapy), the control or standard care arm also received continuous central venous pressure (CVP), arterial blood pressure and urine output monitoring. This was not a standard of care in emergency department (ED) throughout the United States at the time where baseline mortality was estimated to be over 50%. In regards to the success of the EGDT group, it must be emphasized that control group therapy also reduced mortality (46.5%) compared to the historical care mortality which was over 50%.15 Over the last decade the various components of EGDT or the resuscitation bundle have been examined, validated and incorporated into evidence based guidelines.16, 17 Early risk stratification using blood pressure and lactate levels EGDT begins with early identification of high risk patients based on hypotension (systolic blood pressure 4 mmol/L (Figure 2). Although it is intuitive, a hypotensive episode is associated with an increase risk for sudden and unexpected death.18 After Aduen et al. established the general prognostic value of a lactate of 4 mM/L on hospital admission; multiple studies have confirmed the risk stratification of this level for illness severity and mortality in both the prehospital and in-hospital setting.19-23 Antibiotic therapy Once patients are identified, source control and appropriate cultures should be obtained.24 While there are no prospective outcome trials to support early administration of antibiotics, the animal and retrospective human literature
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Early interventions in severe sepsis and septic shock
Figure 2.—The early goal directed therapy algorithm.
regarding the benefits of early and appropriate antibiotic administration is present in both animal and multiple human studies of sepsis.25-28 The time period for the combination of antibi-
otics and early hemodynamic optimization has been shown to be approximately 3-6 hours to archive the best outcomes in human studies.26, 29 Hutchinson et al. showed that early antibiotic
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administration was associated with a significantly reduced hospital length of stay and hospital costs.30 Central venous pressure and fluid therapy While some question the accuracy of CVP in assessing volume status; equivalent outcomes have been shown when compared to the pulmonary artery catheter for assessment of fluid status in acute lung injury.31 CVP measurement is indicative of fluid responsiveness in the lower ranges and a CVP >10 is the upper limit for algorithms of fluid challenges.32 CVP has been shown to have a significant association with 30day mortality.33 Ferrer et al.34 and Boyd et al. concluded a negative impact on survival when CVP was used as a guide to fluid management.35 The use of CVP appears to be time sensitive. Early, aggressive fluid therapy which is associated with improved outcomes must be distinguished from late aggressive fluid therapy.36 The administered volume in the EGDT group within the first 6 hours was significantly greater compared to standard therapy group, but over 72 hours there were no differences in the amount of fluid between the two groups. In a meta-analysis, the use of albumin is associated with lower mortality.37 Mean arterial pressure and vasopressor use The mean arterial blood pressure target in EGDT is supported by Varpula and Dunser et al.33, 38 They examined hemodynamic variables in septic shock patients during the first 24-48 h of treatment and found a MAP below 60-65 mmHg to be most predictive of 28-30-day mortality and organ function. It is preferable that this endpoint be met with fluid versus vasopressor therapy. EGDT is associated with greater volume administration and diminished vasopressor use over first 6 hours of resuscitation. However, an equal amount of fluid is used over the first 72 hours of hospitalization. In the absence of diminished early volume therapy, there was an increase in the incidence of sudden hemodynamic deterioration and vasopressor use. These observations reveal that hypotension is more refractory to fluid administration at the
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later stage of disease presentation. It may be because of this that administration and duration of vasopressors also correlates with worse outcome. Levy et al. has shown that the delayed use of vasopressor therapy for cardiovascular support is incrementally associated with a significantly higher mortality than any other organ failure beyond the first 24 hours of sepsis.3 One of the attributes of early volume therapy is a significant reduction in vasopressor therapy which further reduced need for vasopressin and corticosteroid therapy.3,14, 39-41 De Backer et al. showed that there was no significant difference in the rate of death between patients treated with dopamine as the first-line vasopressor agent and those who were treated with norepinephrine, however, the use of dopamine was associated with a greater number of adverse events.42 Central venous and tissue oxygen saturation Many of the salutary effects of ScvO2 monitoring are based on its ability to detect imbalances of DO2 to VO2 in the delivery dependent phase even with normal vitals signs.6 In the presence of a low value, therapeutic maneuvers to increase DO2 or decrease VO2 are required to normalize this number. Thus, ScvO2 becomes a trigger for increasing inspired oxygen concentration (arterial hypoxia), red blood cell transfusion (decreased arterial oxygen content), inotrope therapy (myocardial suppression), and mechanical ventilation (increased oxygen demands).43-46 Multiple studies have compared ScvO2 with SvO2 showing that there is an absolute difference (5%) between the two sites.47, 48 While there is a difference, the clinical utility of both sites is comparable and validated by outcome studies.48 In a multicenter study, Pope et al. found that the failure to reach a ScvO2 greater than 70% within the first six hours is associated with significantly increased (14%) mortality.12 Castellanos-Ortega et al. examined all of the sepsis bundle elements at 6 and 24 hours of sepsis and found that the attainment of an ScvO2 >70% had the statistically most significant impact on survival than all other bundle elements.49 In a meta-analysis examining five studies comprising over 11000 patients, it was shown that patients reaching this
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endpoint were twice as likely to survive than patients without reaching this endpoint.50 ScvO2 remains significantly predictive of outcome 47 hours after the onset of acute lung injury and up to 48 hours in the ICU phase of sepsis.33, 51 Further evidence exists showing that continuous ScvO2 monitoring is superior to intermittent monitoring.52 Tissue oxygenation (StO2) can be obtained using near-infrared spectroscopy using a probe applied to the thenar portion of the hand. Napoli showed that while a statistically significant relationship existed between StO2 and ScvO2, StO2 appears to systematically overestimate lower ScvO2 values and underestimate at higher ScvO2 values.53 Mesquida et al. found that StO2 values below 75% predicted low ScvO2 values with high specificity, but this predictive value did not hold for StO2 values above 75%. In examining this variable in early resuscitation, Colin et al. found masseter tissue oxygen saturation predictive of 28-day mortality.54 Thus, StO2 might be useful very early in resuscitation, before ScvO2 is available.55 Hemoglobin threshold and red blood cell transfusion Anemia in early severe sepsis and septic shock results from a combination of pre-existing disease, acute volume resuscitation, impaired bone marrow response and a proposed decrease in the sensitivity of erythropoietin receptors.56 Anemia leads to a compensatory increase in systemic oxygen extraction to systemic oxygen needs. When this compensatory response is inadequate, the physiologic rationale for transfusion of red blood cells (RBCs) during this delivery dependent physiology (increased lactate and low ScvO2) is warranted. This concept has been supported by Vallet et al. who found that mortality is optimized when an ScvO2 of 69.5% is used as a trigger for transfusion.43 Because hemoglobin concentrations may vary in the central, peripheral and microvascular circulations, the oxygen carrying capacity and rheological characteristics of a specific region is unpredictable. For instance, findings suggest that the sublingual microcirculation is globally unaltered by RBC transfusion in septic patients yet can improve in patients
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with altered capillary perfusion at baseline.57 While there are many publications that incriminate RBC transfusions with worse outcome, a recent large observational study found that RBC transfusion was associated with decreased mortality rates.58 Further studies are needed to support the current recommendation for a hemoglobin of 10 mg/dL during septic shock.59 Myocardial dysfunction and inotrope therapy The early recognition of myocardial dysfunction requiring inotropic use was found to be at a 12.9% greater frequency in the EGDT versus the control group in the original EGDT study and this incidence is consistent with previous findings by Parrillo et al.60 Grissom et al. established that physical examination findings of inadequate circulation are not useful for predicting low cardiac index or ScvO2.51 Afessa et al. examined 962 patients using a propensity score for each bundle element and found that compliance with lactate measurement and inotrope administration was independently associated with decreased risk of mortality.61 Shah et al. performed a retrospective review of 183 sepsis episodes in patients with pre-existing echocardiograms (prior to the sepsis event) documenting systolic dysfunction. In the 135 patients who did not meet EGDT adherence requirements, the mortality rate was 36.3% and in the 48 patients who met EGDT adherence requirements, the mortality rate was 16.67%, P3 mm/L) to decrease lactate by 20% or more per two hours for the initial eight hours in the lactate group. In the control group, the treatment team had no knowledge of lactate levels (except for the admission value). The lactate group received more fluids and vasodilators. However, there were no significant differences in lactate clearance between treatment groups. Hospital mortality was significantly reduced from 43.5% in the control group versus 33.9% in the lactate group. In the lactate group, there was a decrease in organ failure, duration of inotrope therapy, mechanical ventilation from 7-72 hours and ICU length of stay.70 The lactate group treatment did not result in faster reduction of lactate when compared with control group therapy. This might actually argue against lactate as a target of hemodynamic therapy. However, given that ScvO2 monitoring was mandatory in the lactate group and facultative in the control group, this study could not exclude the possibility that this had an impact on the observed outcome difference. The disturbances of lactate metabolism that occur during sepsis are probably more complex than an isolated defect of cellular oxygenation.71 Further a normal lactate in isolation does not exclude the presence of tissue hypoperfusion. Twenty to 50% of septic shock patients will never elevate lactate levels at presentation or during the clinical course and frequently develop multi-system organ failure.72-74 These observations indicate that using lactate and ScvO2 are complimentary endpoints and not mutually exclusive. Modified versions of the resuscitation bundle Lin et al. employed a modified EGDT protocol in a medical ICU without the use of ScvO2 compared to a control group. Targeting CVP,
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Table I.—Comparison of sepsis intervention studies using the resuscitation bundle compared to the original EGDT study.8, 41, 49, 68, 80-128 Summary of implementation study
Number of patients APACHE II score Sex, % Males Age (years) Mortality before (SD)** Relative risk reduction Absolute risk reduction NNT
Rivers et al.
Before or control
After
Control
EGDT
9527 24.24 58.15 63.84 46.8 (26)%
9884 24.2 57.3 62.9 29.1 (12)%
133 20.4 50.4 64.4 46.5%
130 21.4 50.8 67.1 30.5%
0.37 18.3% 5.45
0.34 16.0% 6.25
*Includes before and after and concurrent implementation studies. **The average mortality of each study. NNT=number needed to treat.
MAP, hemoglobin and urine output, not only led to a significant decrease of the mortality rate, but also to shortening the length of ICU stay, duration of mechanical ventilator support and duration of antibiotic administration. There was more rapid reversal of shock and less delayed vasopressor administration. For medical ICUs without facility to monitor ScvO2, this modified therapeutic protocol provides an alternative that reduces mortality, ICU stay, ventilator support duration, and tissue hypoperfusion associated major organ dysfunction. The authors added that with ScvO2 measurement there was a chance of improving clinical outcomes further. Impact on inflammation, the microcirculation and organ failure The association between global tissue hypoxia and inflammation has been well described in vivo models. Boulos et al. have shown that SvO2 is significantly associated with mitochondrial function and that inflammatory mediators in septic patients can significantly alter mitochondrial function.75 In a further analysis of EGDT patients, Rivers also showed that the persistence of global tissue hypoxia (increased lactate and low ScvO2) correlates significantly with the activity of inflammatory mediators. In patients treated with EGDT, alteration of the inflammatory cascade is evidenced by significantly lower IL-8 levels. When untreated, this pathogenic mechanism of inflammation can lead to a “second hit” phenomenon of multi-organ failure and worsening
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inflammation.76 The observation of a 15% reduction in mechanical ventilation over 72 hours is an example of preventing this second hit.73 Adjunctive therapies to further modulate the inflammatory response when used early may enhance the beneficial effects of EGDT.77 Therapeutic efforts targeting the microcirculation are in progress but to date having not shown outcome benefit.78 Kiers et al. found that a delay in achieving hemodynamic goals of EGDT was significantly associated with the development of acute kidney injury (P=0.02) and resulted in a 3.4% greater creatinine level rise per hour (P=0.03) in patients admitted from the hospital ward.79 In a subanalysis of patients enrolled in the Fluid and Catheter Treatment Trial (FACTT) of the National Institutes of Health, Acute Respiratory Distress Syndrome Network, an improved SvO2 was significantly associated with improved mortality and decrease in duration of mechanical ventilation.51 These findings support the observations of a decreased need for mechanical ventilation over the first 72 hours of presentation in the original EGDT trial. Outcome evidence in adult patients Over the last decade, the external validity and generalizability of the RB containing varying versions of EGDT has been established in multiple studies. These studies comprise over 50 publications containing over 18000 adult patients (Table I).8, 41, 49, 68, 80-128 The outcome benefit of these studies combined equal or exceed the reduction in mortality found in the original
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trial. It has been stated that the original EGDT study enrolled patients of higher illness severity than that observed in other studies. However, the mean age, baseline APACHE II scores and mortality rate of these previous adult studies are similar to the original EGDT study.129-131 These outcomes results have been observed in community and tertiary care hospitals, ED and ICU settings, medical and surgical patients.98 Studies that are in the process of examining the components of EGDT can be found at www.clinicaltrials.gov. Outcome evidence in pediatric patients EGDT has shown to be beneficial in a prospective randomized pediatric trial.129, 132 A recent study in children showed that fluid boluses significantly increased 48-hour mortality in critically ill children with impaired perfusion in these resource-limited settings in Africa.133 These findings are a departure from previous trials finding that aggressive fluid therapy and EGDT improves mortality in pediatric sepsis.134, 135 The difference between these studies may be multifactorial including the etiology of the infection which was primarily malaria not bacterial. Peer reviewed evidence based guidelines currently exist for the management of sepsis in the pediatric patient.136 It is important to note that therapies confirmed in adults are not necessarily translated to pediatric patients.137 Health care resource consumption The associated cost for sepsis in the United States approaches over $ 50 billion per year or 2.5% of the health care expenditure, making it the most expensive disease treated in hospital since 1997.138 EGDT has been shown to decrease hospital related costs consistently by 20%.139, 140 The cost savings are largely driven by a significant decrease in hospital length of stay by five days per patient.141 Importance of timing Does the effectiveness of the RB attenuate over time? Coba et al. examined the impact of com-
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plying with the goals of EGDT on patient outcomes when completed beyond the six-hour recommendation period. Compliance was assessed at 6, 18 and 24 hours after diagnosis of severe sepsis or septic shock. The compliers at 18 h had an absolute 10.2% significantly lower in-hospital mortality compared to the non-compliers at 18 h (37.1% vs. 47.3%). When adjusted for differences in baseline illness severity, the compliers at 18 h had a greater reduction in predicted mortality of 26.8% versus 9.4% (P 4 mm/L –– Systolic blood pressure 8 mmHg –– MAP >65 mmHg –– Hematocrit >30% –– ScvO2 >70% –– Threshold for red blood cell transfusion –– Need for inotropic therapy –– Indication for and response to mechanical ventilation –– Is not equivalent to lactate clearance
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telemedicine and comprehensive CQI feedback is feasible, modifies clinician behavior and is associated with decreased hospital mortality.41, 87, 103, 122, 126, 143
Conclusions One decade later, multiple studies (Table II) have not only validated the RB and its elements but also provide evidence that this therapy modulates inflammation, decreases organ failure progression and conserves health care resource consumption. This approach consistently saves 1 out of every 6 lives for patients presenting with severe sepsis and septic shock. While implementation remains challenging, the RB remains one of the most effective interventions in the management of severe sepsis and septic shock. References 1. Rackow EC, Astiz ME. Pathophysiology and treatment of septic shock. JAMA 1991;266:548-54. 2. Brun-Buisson C, Doyon F, Carlet J, Dellamonica P, Gouin F, Lepoutre A et al. Incidence, risk factors, and outcome of severe sepsis and septic shock in adults. A multicenter prospective study in intensive care units. French ICU Group for Severe Sepsis. JAMA 1995;274:968-74. 3. Levy MM, Macias WL, Vincent JL, Russell JA, Silva E, Trzaskoma B et al. Early changes in organ function predict eventual survival in severe sepsis. Crit Care Med 2005;33:2194-201. 4. Kasnitz P, Druger GL, Yorra F, Simmons DH. Mixed venous oxygen tension and hyperlactatemia. Survival in severe cardiopulmonary disease. JAMA 1976;236:570-4. 5. Astiz ME, Rackow EC, Weil MH. Oxygen delivery and utilization during rapidly fatal septic shock in rats. Circ Shock 1986;20:281-90. 6. Rady MY, Rivers EP, Nowak RM. Resuscitation of the critically ill in the ED: responses of blood pressure, heart rate, shock index, central venous oxygen saturation, and lactate. Am J Emerg Med 1996;14:218-25. 7. Vincent JL, De Backer D. Oxygen uptake/oxygen supply dependency: fact or fiction? Acta Anaesthesiol Scand Suppl 1995;107:229-37. 8. Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001;345:1368-77. 9. Friedman G, De Backer D, Shahla M, Vincent JL. Oxygen supply dependency can characterize septic shock. Intensive Care Med 1998;24:118-23. 10. Rahal L, Garrido AG, Cruz RJ Jr, Silva E, Poli-de-Figueiredo LF. Fluid replacement with hypertonic or isotonic solutions guided by mixed venous oxygen saturation in experimental hypodynamic sepsis. J Trauma 2009;67:120512. 11. Astiz ME, Rackow EC, Kaufman B, Falk JL, Weil MH. Relationship of oxygen delivery and mixed venous oxygenation to lactic acidosis in patients with sepsis and acute myocardial infarction. Crit Care Med 1988;16:655-8.
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Conflicts of interest.—None related to this publication. Dr. Rivers receives research support from the National Institute of Health, Aggennix and Alere Corporation. In the past four years, he has been a onetime consultant for Aggennix, Esai Pharmaceuticals Idaho Technologies, Astra Zeneca, Massimo and Sangard. Dr. Rivers has never personally owned any patents or Early Interventions in Severe Sepsis and Septic Shock: The Evidence One Decade Later received royalties, stock or research support associated with the EGDT study. Dr. Cannon has received consulting fees from Eisai Pharmaceuticals. Received on May 3, 2011 - Accepted for publication on March 21, 2012. Corresponding author: E. P. Rivers, MD, MPH, Vice Chairman and Research Director, Department of Emergency Medicine, Senior Staff Attending in Surgical Critical Care and Emergency Medicine, Clinical Professor, Wayne State University, 270-Clara Ford Pavilion, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, MI 48202, USA. E-mail:
[email protected] This article is freely available at www.minervamedica.it
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