Corresponding author. Address for correspondence: Woo Hyun Cho, M. Phone: , Fax: , ten. All rights reserved.
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Corresponding author. Address for correspondence: Woo Hyun Cho, M. Phone: , Fax: , ten. All rights reserved. Abstract Severe sepsis and septic shock is a life-threatening disease. It is combined with multi-organ failure. In the past decade, early goal directed therapy has been proposed as an effective treatment strategy for better outcome. Recent epidemiologic studies showed that the outcome of sepsis has been improved with the introduction of early goal directed therapy.
However, it is unclear which elements of early goal directed therapy contributed to the better outcome. Recent prospective and randomized trials suggested that some elements of early goal directed therapy did not have any effect on the outcome benefit.
In this paper, recent articles about early goal directed therapy will be reviewed and the effectiveness of individual elements of early goal directed therapy will be discussed.
Keywords: Sepsis, Shock, Septic, Therapeutics Introduction During the past 30 years, the incidence of sepsis has been increased and the related mortality rate amounts to 50 percent in the most severe cases 1 , 2. In , Rivers et al. EGDT refers to a treatment bundle including early intensive fluid administration using physiologic targets to guide resuscitation within first six hours in severe sepsis and septic shock. Thereafter, EGDT has widely accepted in clinical practice; however, there is conflicting evidences regarding the effectiveness of individual resuscitation elements and targets 3 , 4 , 5.
In order to solve this controversy, well designed, large scaled, randomized trial has been published. However, there are recent evidences supporting the benefit of EGDT 6 , 7 , 8 , 9. In this review, therefore, debates on EGDT and recent evidences regarding sepsis treatments will be discussed.
Diagnostic Criteria of Sepsis Sepsis is defined as a systemic inflammatory response syndrome caused by bacterial infection According to severity of sepsis, it is classified into sepsis, severe sepsis and septic shock. Severe sepsis is defined as the state which is combined with sepsis induced organ failure or tissue hypoperfusion. Septic shock is defined as sepsis-induced hypotension persisting despite adequate fluid administration.
Hospitalization due to sepsis has been increased by 7. This increase in incidence is thought to be related to the increase in immunocompromised host, the elderly and multi-drug resistant strains 11 , 12 , 13 , In contrast to the increase in the incidence of sepsis, mortality has decreased over the past decade 7 , 9 , 15 , One of these studies showed that sepsis mortality in was Notably in this study, mortality of sepsis was reduced down from to even after adjusting for the effects of increased incidence, co-morbidities, age and severity.
This suggested that the outcome of sepsis has been improved during a few past decades regardless of increased early detection of sepsis.
The causes of recent improvement of sepsis outcome might be multi-factorial. The SSC established and updated the sepsis guideline every four years since 10 , 17 , In this study, the mortality of severe sepsis was Recent Evidences about Resuscitation Elements of EGDT Since the introduction of EGDT in , the importance of early treatment for tissue oxygenation tissue oxygenation in sepsis is emphasized to improve the prognosis.
In particular, treatment goals for improving tissue oxygenation, such as central venous pressure CVP , mean arterial blood pressure MAP , central venous oxygen saturation ScvO2 , and blood lactate concentration were achieved as a protocolized bundle within 6 hour and effort to raise resuscitation bundle compliance was emphasized Table 1. However, the evidences of each of the goals and the resuscitation element are controversial and not validated.
Recently, many studies about these controversies have been published. So, these controversies and potential guidance about sepsis treatment will be discussed afterward. Effectiveness of resuscitation bundle As mentioned earlier, recent evidences showed that the resuscitation bundle including EGDT improved the prognosis of sepsis 6 , 8 , 9.
Especially if initial resuscitation element which is performed within 3 hours is well done, this prevented the worsening severity of sepsis and the requirements for further resuscitation factors, such as vasopressor, transfusion of red blood cells, steroid use, and low tidal ventilation in many cases.
Therefore, this can warrant once again the importance of early implementation of the sepsis bundle. Recently, ProCESS study suggested the contradictory results relative risk with protocol-based therapy vs. However, in these studies, the mortality of both treatment group was relatively low In addition, both treatment group were early diagnosed with severe sepsis or septic shock and thereafter received the substantial amount L of crystalloid.
These facts imply that 3hr resuscitation of the SSC guideline was basically achieved in both treatment groups. However, there is a controversy about the optimal volume and types of resuscitative fluid. Here, the evidences about this controversy will be reviewed. There were no differences between two groups for mortality.
From this result, the SAFE Study Investigators evaluated the safety of albumin as a resuscitative fluid in severe sepsis As a result, they concluded that administration of albumin compared to saline did not impair renal or other organ function To confirm this topic, the SAFE Study Investigators recently published another multicenter open-label randomized trial of patients with severe sepsis or septic shock However, albumin replacement in addition to crystalloids did not improve the day mortality and any other end points including day mortality, the number and the degree of organ dysfunction, and hospital stays.
Therefore, crystalloid is the first choice of resuscitative fluid in severe sepsis or septic shock. Albumin is safe and useful in intravascular volume expansion consistent with the observations from previous studies 19 , 20 , However, the strength of the evidence about target BP is weak and has not been validated fully 23 , In this multicenter, open-label trial, a total of patients were assigned to the low target group MAP, mm Hg and high target group MAP, mm Hg between the 28th days.
However, there was no difference in mortality rate at 28 day hazard ratio in the high-target group, 1. Patients with a higher MAP had a greater incidence of atrial fibrillation 6.
Therefore, target BP above 65 mm Hg or more is recommended in sepsis or septic shock as mentioned above. ScvO2 is one of useful index for tissue hypoperfusion, however, the effectiveness as single goal of sepsis treatment is questionable. Lactate has been suggested as an alternative goal and monitoring index for resuscitation in severe sepsis or septic shock. In another study 27 , lactate normalization within 6 hours was the strongest predictor of survival adjusted OR, 5.
From these results, serial measurement of lactate is expected to be used as an alternative to ScvO2 if central venous insertion is not available. However, it should be considered that lactate is not sensitive to reflect the change of tissue perfusion after restoration of perfusion However, initial 3-hour bundle of the guideline will not be affected by these trials and SSC bundle did not confer any harm result even though did not confer any benefit.
Therefore, keeping the current guideline is intact until evidences are growing enough. From these evidences, it is obvious that ScvO2 and CVP is not a best goal for resuscitation in severe sepsis and septic shock. However, protocol directed therapy requires the use of a physiologic endpoint to guide fluid management. Therefore, a protocolized therapy is basically targeted to MAP and urine output and additional targets including ScvO2 and CVP can be used according to an individualized clinical situation.
Traditionally, norepinephrine and dopamine is commonly used, but recent trials comparing two vasopressors favor the use of norepinephrine. However, the use of dopamine was associated with more frequent arrhythmic events. In addition, a meta-analysis showed that dopamine administration is associated with greater mortality and a higher incidence of arrhythmic events compared to norepinephrine administration Therefore, norepinephrine is a reasonable first choice in the patients with severe sepsis and septic shock.
This might be still useful in the clinical practice for treatment of refractory septic shock. However, it should be not used to increase the cardiac index to supra-normal level 31 , Data from randomized trial based on EGDT showed conflicting results 3 , 4 , 5. One multicenter randomized trial was conducted to solve this controversy The mortality at 90 days and rates of ischemic events and use of life support were similar among both groups.
Therefore, RBC transfusion in patients below hemoglobin 7. Nevertheless, controversy persists over the each element of resuscitation management or resuscitation goal. As a result, we could identify that initial 3-hour resuscitation is still very important with early detection of the onset of severe sepsis and septic shock. The other resuscitation goals including CVP, ScVO2 and lactate were not proven to be effective in patients with severe sepsis and septic shock.
However, there is no evidence about the harm from keeping these resuscitation goals. Therefore, it is reasonable not to change the current clinical practice. Especially, early detection of severe sepsis and septic shock and 3-hour management bundle should be kept.
Footnotes Conflicts of Interest: No potential conflict of interest relevant to this article was reported. References 1. Septicemia in U. Long-term survival after intensive care unit admission with sepsis.
Crit Care Med. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. Goal-directed resuscitation for patients with early septic shock. A randomized trial of protocol-based care for early septic shock. Management of severe sepsis in patients admitted to Asian intensive care units: prospective cohort study. Hospitalizations, costs, and outcomes of severe sepsis in the United States to Multicenter implementation of a severe sepsis and septic shock treatment bundle.
Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: Incidence, organ dysfunction and mortality in severe sepsis: a Spanish multicentre study.
Surviving Sepsis 2017 Guidelines Overview
An approach including early goal directed therapy with aggressive initial fluid resuscitation has been considered a cornerstone of initial therapy for severe sepsis and septic shock, since a single-center randomized trial showed such a strategy initiated in the emergency department improved survival from septic shock. Crystalloid is recommended for initial fluid resuscitation for severe sepsis and septic shock Grade 1B. Hydroxyethyl starch hetastarch should not be used as therapy for sepsis , according to U. A portion of resuscitation fluids may be given as "albumin-equivalent" Grade 1C. Vasopressors should be begun within 6 hours for patients with hypotension despite aggressive initial fluid resuscitation i. Severe sepsis can also be defined by sepsis-induced organ dysfunction in the presence of a preserved blood pressure.
Early Goal Directed Therapy in Septic Shock
Update of Sepsis: Recent Evidences about Early Goal Directed Therapy
Early goal-directed therapy