|Year : 2017 | Volume
| Issue : 4 | Page : 971-977
Efficacy of early goal-directed therapy in severe sepsis and septic shock
Khaled M Abu El-Einein1, Enas Abd El-Mohsen Shaaheen1, Neveen I Samy2, Naglaa S Abd El-Hady Hammad2
1 Department of Anesthesiology, Intensive Care and Pain Management, Faculty of Medicine, Menoufia University, Shebeen El-Kom, Egypt
2 Department of Cardiology, Faculty of Medicine, Menoufia University, Shebeen El-Kom, Egypt
|Date of Submission||08-Apr-2017|
|Date of Acceptance||11-Jun-2017|
|Date of Web Publication||04-Apr-2018|
Naglaa S Abd El-Hady Hammad
Department of Anesthesiology, Intensive Care and Pain Management, Faculty of Medicine, Menoufia University, Shebeen El-Kom
Source of Support: None, Conflict of Interest: None
The aim of this review was to present the current trends and methodologies of the use of early goal-directed therapy (EGDT) and its efficacy in patients in severe sepsis and septic shock.
Data were obtained from Medline databases (PubMed, Medscape, and Science Direct) and from materials available on the Internet from the start date of each database to February 2017.
The selected articles are systematic reviews and experimental studies that address EGDT in severe sepsis and septic shock.
Extraction was performed according to the validity, quality, and originality of the selected reviews and studies that fulfilled the previous criteria; in addition, the focus was on studies that present the latest or the most updated findings on application of EGDT.
Each review and study was reviewed. The layout was selected to present a wide range of data including the most recent findings on this subject. Significant data were collected; thus, a structured review was performed.
Most of studies conclude that EGDT is very important and its use markedly decreases mortality and morbidity in patients with severe sepsis and septic shock.
The main conclusion of the reviews and studies that were presented in the current research paper is that the use of EGDT in severe sepsis and septic shock reduces the length of hospital stay and reduces the hospital mortality rate in selected patients.
Keywords: early goal-directed therapy, hypotension, lactate, mixed venous oxyhemoglobin saturation, norepinephrine, sepsis, septic shock
|How to cite this article:|
Abu El-Einein KM, Abd El-Mohsen Shaaheen E, Samy NI, Abd El-Hady Hammad NS. Efficacy of early goal-directed therapy in severe sepsis and septic shock. Menoufia Med J 2017;30:971-7
|How to cite this URL:|
Abu El-Einein KM, Abd El-Mohsen Shaaheen E, Samy NI, Abd El-Hady Hammad NS. Efficacy of early goal-directed therapy in severe sepsis and septic shock. Menoufia Med J [serial online] 2017 [cited 2018 Dec 12];30:971-7. Available from: http://www.mmj.eg.net/text.asp?2017/30/4/971/229213
| Introduction|| |
The protocol of early goal-directed therapy (EGDT) refers to the administration of intravenous fluids within the first 6 h of patients' presentation with the use of physiologic targets to guide this fluid management.
Early goal-directed therapy targets
Mean arterial pressure (MAP) of at least 65 mmHg (MAP = [(2 × diastolic) + systolic]/3).
Urine output of at least 0.5 ml/kg/h.
Central venous pressure (CVP) 8–12 mmHg.
Central venous (superior vena cava) oxyhemoglobin saturation (ScvO2) of at least 70% (when central access is available) or mixed venous oxyhemoglobin saturation (SvO2) of at least ≥65% (if pulmonary artery catheter is being used).
Lactate clearance should be followed.
The history of development of early goal-directed therapy
It began in the early 1990s; the EGDT Collaborative Group challenged the paradigm of sepsis care as an 'ICU disease' by applying similar urgent early diagnostic and therapeutic principles as that used in acute myocardial infarction, stroke, and trauma at the point of presentation in the emergency department.
| Background|| |
The early hemodynamic and physiologic response to severe sepsis and septic shock in animals and human models of early sepsis, global tissue hypoxia results from hemodynamic changes that create an imbalance between systemic oxygen delivery and demands. These changes can include decreased vasomotor tone, hypovolemia, decrease in arterial oxygen content, myocardial depression, increase in metabolic demands, and impairment in systemic oxygen utilization through microcirculatory or mitochondrial derangements (cytopathic tissue hypoxia).
| Patients and Methods|| |
We reviewed papers on efficacy of EGDT in the treatment of severe sepsis and septic shock from Medline databases (PubMed, Medscape and Science Direct) and also from materials available on the internet. We used early goal-directed therapy septic shock, severe sepsis as searching items in the title of the papers. The search was performed in the electronic databases from the start date of each database to February 2017.
Th e present study was approved by the Ethics Committee of the Faculty of Medicine, Menoufia University. All studies were independently assessed for inclusion criteria. They were included if they fulfilled the following criteria:
- Published in English language
- Published in peer-reviewed journals
- Focused on treatment of severe sepsis and septic shock
- Discussed protocol of EGDT and its role in the management of severe sepsis and septic shock
- If a study had several publications on certain aspects, we used the latest publication giving the most relevant data.
Data from each eligible study were independently abstracted in duplicate using a data collection form to capture information on study characteristics, interventions, and quantitative results reported for each outcome of interest. Conclusion and comments on each study were made. Significant data were collected, and then a structured review was performed with the results tabulated.
The quality of all studies was assessed. Important factors were included, study design, attainment of ethical approval, evidence of a power calculation, specified eligibility criteria, appropriate controls, and adequate information and specified assessment measures. It was expected that confounding factors would be reported and controlled for and appropriate data analysis made, in addition to an explanation of missing data Selected recommendations from the 1999 Society of Critical Care Medicine practice parameters for hemodynamic support of sepsis in adult patients compared with early goal-directed therapy [Table 1].
|Table 1: Selected recommendations from the 1999 Society of Critical Care Medicine practice parameters for hemodynamic support of sepsis in adult patients compared with early goal-directed therapy|
Click here to view
A structured systematic review was performed with the results tabulated [Table 2] and [Table 3].
|Table 3: Early goal-directed therapy and cost-effectiveness in hospitals in patients with severe sepsis and septic shock|
Click here to view
| Results|| |
The selected studies were 13; these studies were deemed eligible by fulfilling the inclusion criteria. They reported data about effect of EGDT on mortality reduction in hospitals and three of them reported data about cost-effectiveness reduction in hospitals using EGDT.
Effect on hospital mortality results
All selected studies presented data about the effect of using EGDT in severe sepsis and septic shock on hospital mortality and these results were tabulated [Table 2]. Seven of these studies reported a decrease in hospital mortality and six reported no difference on mortality.
Cost-effectiveness of early goal-directed therapy results
Three of these studies reported effect of EGDT on cost of hospitals and all showed marked cost reduction and the results are presented in [Table 3].
Huang et al. in a formal cost-effectiveness analysis found that EGDT can provide up to a 23.4% reduction in hospital costs related to the treatment of patients with severe sepsis and septic shock. Similar findings have been noted by other investigators. Shapiro et al. have reported a cost per life saved of $32 336 and Trzeciak et al. found a reduction in median hospital facility charges from $135 199 to $82 233.
| Discussion|| |
Sepsis is a life-threatening inflammatory disorder and also represents the immune system's response to infection. In the USA it affects more than 750 000 persons per year, with a prevalence of three cases per 1000 persons.
The pathophysiology of process of sepsis involves a complex interaction of proinflammatory and anti-inflammatory mediators in response to pathogen invasion. These mechanisms lead to endothelium damage, vascular permeability, microvascular dysfunction, coagulation pathway activation, and impairment in tissue oxygenation resulting in the cascade of sepsis.
The systems most commonly affected are the respiratory system, genitourinary system, and gastrointestinal system, as well as the skin and soft tissue. These sites are involved in more than 80% of all cases of sepsis. Spontaneous bacterial peritonitis and urinary infections are the most frequent infections, followed by pneumonia, cellulitis, and bacteremia. In patients with advanced cirrhosis, infection induces a systemic inflammatory response characterized by high circulating levels of proinflammatory cytokines. This excessive proinflammatory response contributes to the development of sepsis-related organ failures and septic shock in cirrhosis.
Persons in the extremes of age are at a higher risk of developing sepsis. Patients older than 65 years have 13 times greater risk of developing sepsis and have a two-fold higher risk for death from sepsis independent of sex, race, comorbid associated conditions, and severity of illness.
Early management of sepsis requires stabilization of respiration. Supplemental oxygen should be given to all patients with sepsis. Mechanical ventilation is recommended when this supplemental oxygen fails to improve the oxygenation, when respiratory failure is reported, or when airway cannot be protected. The perfusion is then assessed after respiratory stabilization. Hypotension, when occurs, signifies inadequate tissue perfusion. The clinical signs of hypoperfusion include altered mental status, cold or clammy skin, oliguria or anuria, and lactic acidosis. After the initial respiratory stabilization, treatment of severe sepsis and septic shock consists of fluid resuscitation, vasopressor therapy, infection identification and control of the source, proper antibiotic administration, and the removal or drainage of the source of infection [Figure 1] and [Figure 2].
|Figure 1: Management of sepsis. Selected recommendations from the 1999 Society of Critical Care Medicine practice parameters for hemodynamic support of sepsis in adult patients compared with early goal-directed therapy|
Click here to view
Laboratory and radiographic studies
The recommended tests to be performed include the following: basic metabolic profile, complete blood count with differential, measurement of liver enzyme levels and lactate, coagulation profile, and urinalysis. Suspected pulmonary infections should be evaluated using arterial blood gas testing to assess hypoxemia and acid-base abnormalities and chest radiography. Suspected disseminated intravascular coagulation fibrin degradation products, d-dimer levels, and fibrinogen levels should be measured. Several biologic markers of sepsis, such as procalcitonin, C-reactive protein, activated partial thromboplastine time, and interleukin-6 may, have diagnostic and prognostic implications, although the lack of standardized assays limits their practical use. Pan cultures include the following: blood cultures (two peripheral and from each indwelling catheter), urine culture, stool culture (for diarrhea or recent antibiotic use), sputum culture, and skin and soft tissue culture. However, results of blood culture are negative in 50–65% of patients with sepsis.
Cerebrospinal fluid, joint, pleural, and peritoneal fluid should be examined as clinically indicated. Echocardiography is highly recommended to diagnose endocarditis as a source of sepsis, especially in patients with a heart murmur or suspected intravenous drug use. Assessment of pulmonary embolus requires chest computed tomography or ventilation perfusion scanning, and assessment of abdominal or pelvic infection, when suspected, requires abdominal and pelvic computed tomography.
Intravascular hypovolemia in patients with sepsis is typical and may be severe and require rapid fluid resuscitation.
Volume: The adequate optimal volume of resuscitative fluid is unknown. Multiple studies of EGDT reported intravenous fluid infusions targeted to physiologic endpoints and resulted in a range of volume from 3 to 5 l.
Type of fluid: Evidence from randomized trials and meta-analysis have found no actual difference between using crystalloids (e.g., normal saline and Ringer's lactate) and albumin solutions in the treatment of severe sepsis or septic shock, but they have identified reported potential harm from the use of pentastarch or hydroxyethyl starch rather than a crystalloid solution.
Most of the physicians use the measurements of CVP to guide initial fluid therapy. After the first 12 h of sepsis, CVP is poor to predict hemodynamic response to fluid challenge. Thereafter, use of cardiac output monitoring systems to assess changes in arterial waveform is more accurate in predicting whether or not fluid is responsive. Survival rate increases with a positive fluid balance (i.e., intravenous fluid input minus urine output) of 3–4 l at 12 h.
Vasopressors are the second-line agents in the treatment of sepsis and septic shock; we prefer intravenous fluids as long as they increase perfusion without seriously impairing gas exchange. However, intravenous vasopressors are useful in patients who remain hypotensive despite adequate fluid resuscitation or who develop cardiogenic pulmonary edema. In most patients with septic shock, we prefer to use norepinephrine.
Early perfect choice of antibiotic therapy is associated with improved clinical outcomes. Consensus guidelines recommend antibiotic therapy within 1 h of suspected sepsis. In septic shock, the initiation of antibiotic therapy within 1 h increases survival; with each hour antibiotic therapy is delayed, survival decreases by about 8%.
A 2010 meta-analysis included randomized or observational studies of antimicrobial therapy of serious bacterial infections potentially associated with sepsis or septic shock. Fifty studies that met entry criteria compared combination antibiotic therapy with monotherapy, and found that combination therapy demonstrated survival benefit and improved clinical response in patients who had septic shock. However, combination antibiotic therapy did not improve sepsis survival compared with monotherapy in hemodynamically stable patients. When there is a risk for Pseudomonas aeruginosa bacteremia, antipseudomonal combination therapy is recommended.
| Conclusion|| |
EGDT in severe sepsis and septic shock results in significant reductions in mortality and reduction in hospital costs.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Gauer RL. Early recognition and management of sepsis in adults: the first six hours. Am Fam Physician 2013; 88
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
Rosário AL, Park M, Brunialti MK, Mendes M, Rapozo M, Fernandes D, et al
. SvO(2)-guided resuscitation for experimental septic shock: effects of fluid infusion and dobutamine on hemodynamics, inflammatory response, and cardiovascular oxidative stress. Shock 2011; 36
Otero RM, Nguyen HB, Huang DT, Gaieski DF, Goyal M, Gunnerson KJ, et al
. Early goal-directed therapy in severe sepsis and septic shock revisited: concepts, controversies, and contemporary findings. Chest 2006; 130
Nguyen HB, Corbett SW, Clark RT, Cho T, Wittlake WA. Improving the uniformity of care with a sepsis bundle in the emergency department. Ann Emerg Med 2005; 46(Suppl)
Gao F, Melody T, Daniels DF, Giles S, Fox S. The impact of compliance with 6-hour and 24-hour sepsis bundles on hospital mortality in patients with severe sepsis: a prospective observational study. Crit Care 2005; 9
Kortgen A, Niederprüm P, Bauer M. Implementation of an evidence-based 'standard operating procedure' and outcome in septic shock. Crit Care Med 2006; 34
Sebat F, Johnson D, Musthafa AA, Watnik M, Moore S, Henry K, et al
. A multidisciplinary community hospital program for early and rapid resuscitation of shock in nontrauma patients. Chest 2005; 127
Shapiro NI, Howell MD, Talmor D, Lahey D, Ngo L, Buras J, et al
. Implementation and outcomes of the multiple urgent sepsis therapies (MUST) protocol. Crit Care Med 2006; 34
Trzeciak S, Dellinger RP, Abate NL, Cowan RM, Stauss M, Kilgannon JH, et al
. Translating research to clinical practice: a 1-year experience with implementing early goal-directed therapy for septic shock in the emergency department. Chest 2006; 129
Gaieski D, McCoy J, Zeserson E, Chase M, Goyal M. Mortality benefit after implementation of early goal directed therapy protocol for the treatment of severe sepsis and septic shock. Ann Emerg Med. 2005; 46(Suppl)
Verceles A, Schwarcz RM, Birnbaum P, Mannam P, Patrick H. S.E.P.S.I.S: sepsis education plus successful implementation and sustainability in the absence of a rapid response team [abstract]. Chest 2005; 12
Armstrong R, Salfen SJ. Proceedings of the 43rd
Annual Meeting of the Infectious Diseases Society of America; 6–9 October 2005; San Francisco, California. Arlington, Virginia: Infectious Diseases Society of America; 2005. Results of implementing a rapid response team approach in treatment of shock in a community hospital [abstract]. p. 154.
Micek ST, Roubinian N, Heuring T, Bode M, Williams J, Harrison C, et al
. Before-after study of a standardized hospital order set for the management of septic shock. Crit Care Med 2006; 34
Rogove HPK. Collaboration for instituting the surviving sepsis campaign in a community hospital [abstract]. Crit Care Med 2005; 33(Suppl)
Stenstrom RJ, Hollohan K, Nebre R, MacRedmond R, Grafstein E, Dodek P, et al
. Impact of a sepsis protocol for the management of patients with severe sepsis and septic shock in the emergency department [abstract]. Can J Emerg Med 2006;8
Huang D, Angus D, Dremsizov T, Rivers E, Clermont G. Cost-effectiveness of early goal-directed therapy in the treatment of severe sepsis and septic shock. Crit Care 2003; 7(Suppl 2)
Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001; 29
Kim WS, Lee HJ. Management of sepsis. J Korean Med Assoc 2013; 56
Boghdadi I, Korah T, Abd El-Atty E, Fouad O. Impact of bacterial sepsis on organ failure in patients with liver cirrhosis. Menoufia Med J 2015; 28
Martin GS, Mannino DM, Moss M. The effect of age on the development and outcome of adult sepsis. Crit Care Med 2006; 34
Rivers EP, Ahrens T. Improving outcomes for severe sepsis and septic shock: tools for early identification of at-risk patients and treatment protocol implementation. Crit Care Clin 2008; 24(Suppl)
Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. N
Engl J Med 2003; 348
ARISE Investigators; ANZICS Clinical Trials Group, Peake SL, Delaney A, Bailey M, Bellomo R, Cameron PA, Cooper DJ, et al
. Goal-directed resuscitation for patients with early septic shock. N
Engl J Med 2014; 371:1496–1506.
Finfer S, Bellomo R, Boyce N, French J, Myburgh J, Norton R. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N
Engl J Med 2004; 350
Boyd JH, Forbes J, Nakada T, Walley KR, Russell JA. Fluid resuscitation in septic shock: a positive fluid balance and elevated central venous pressure are associated with increased mortality. Crit Care Med 2011; 39
Reinhart K, Bloos F, Spies C. Vasoactive drug therapy in sepsis
. InClinical Trials for the treatment of sepsis. Springer Berlin Heidelberg 1995. pp. 207-224.
De Backer D, Biston P, Devriendt J, Madl C, Chochrad D, Aldecoa C, et al
. Comparison of dopamine and norepinephrine in the treatment of shock. N
Engl J Med 2010; 362
Gaieski D, Mikkelsen M. Impact of time to antibiotics on survival in patients with severe sepsis or septic shock in whom early goal-directed therapy was initiated in the emergency department. Crit Care Med 2010; 38
Kumar A, Safdar N, Kethireddy S, Chateau D. A survival benefit of combination antibiotic therapy for serious infections associated with sepsis and septic shock is contingent only on the risk of death: a meta-analytic/meta-regression study. Crit Care Med 2010; 38
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]