Sepsis Management
Authors: Rakesh Engineer, MD, FACEP, Associate Staff, Department of Emergency Medicine, Cleveland Clinic Foundation, Cleveland, OH; Jamie Blicker, MD, FRCPC, Associate Staff, Department of Emergency Medicine, Cleveland Clinic Foundation, Cleveland, OH; and Aashish Patel, MD, Department of Emergency Medicine, MetroHealth Medical Center, Cleveland, OH.
Peer Reviewers: Robert D. Powers, MD, MPH, Professor and Chief, Emergency Medicine, University of Connecticut School of Medicine, Farmington, CT; and Stephen A. Crabtree, DO, FACEP, Associate Professor of Emergency Medicine, Medical College of Georgia, Augusta.
Sepsis is a major cause of morbidity and mortality in adults and children.1,2 Although the mortality rate has decreased slightly due to improved care, the incidence of sepsis has increased significantly during the past 30 years.3,4 The incidence of severe sepsis alone is estimated to be greater than 750,000 annually in the United States.1 Mortality rates for septic shock continue to remain at about 50%.3 Increased antibiotic resistance, HIV, and an older population contribute to an increasing incidence of sepsis. Additionally, as the number of people receiving organ transplants and chemotherapy continues to escalate, more people are at risk for sepsis. The burden on the health care system also has increased along with the incidence of sepsis. The annual cost of sepsis in the United States is estimated to be $15 billion.4
In the past few years, new strategies in the management of sepsis have shown significant mortality benefits. This article addresses aspects regarding the management of sepsis, including appropriate fluid administration, medications, and other evidence-based strategies necessary for the treatment of septic patients in the emergency department. With the incorporation of these new practice strategies in addition to the guidelines published by the Surviving Sepsis Campaign,5 emergency physicians can contribute to a significant decrease in sepsis mortality in the years to come. — The Editor
Introduction
Sepsis is defined by a systemic inflammatory response syndrome (SIRS) in conjunction with an identified or suspected source of infection. SIRS is recognized by the presence of two or more of the following abnormalities:
- Temperature less than 36°C or greater than 38°C;
- Heart rate greater than 90 beats per minute;
- Respiratory rate greater than 20 breaths per minute, or a PaCO2 less than 32 mmHg;
- White blood cell count less than 4000 or greater than 12,000 cells/mm3, or greater than 10% bands.
Other terms used to further define the disease process of sepsis are severe sepsis and septic shock. (See Table 1.) When sepsis is accompanied by organ dysfunction or evidence of hypoperfusion, it is referred to as severe sepsis.1,6 Hypoperfusion can manifest in several ways, including change in mental status, oliguria, or elevations in lactic acid levels.6 Septic shock is present when hypotension persists in patients with severe sepsis despite aggressive fluid resuscitation with 500-1000 mL of normal saline. Hypotension is present when the systolic blood pressure is less than 90 mmHg, or is decreased by more than 40 mmHg from the patient’s baseline.6,7
Table 1. Definitions
Pathophysiology of Sepsis
The inflammatory process that leads to the resolution of an infection is the same process that leads to sepsis, shock, and multi-organ dysfunction. The patient’s response to infection begins with the inflammatory cascade (see Figure 1), which has been well described in the literature for years. The reaction begins when the invading bacteria’s cell wall components, including endotoxins and other toxins released by bacteria, are encountered by the patient’s immune cells. This response leads to localized release of inflammatory cytokines, mainly TNF-alpha and IL-1, which leads to activation of macrophages. This inflammatory response ultimately leads to the death and disposal of the invading organisms.
Occasionally, this inflammatory response is exaggerated and extends to non-infected areas of the body, leading to SIRS. When this reaction becomes generalized, it may lead to death and destruction of healthy cells. As a result, a number of pertinent organ systems can be affected adversely, including the cardiovascular, respiratory, renal, and gastrointestinal systems.
Vascular system involvement in septic patients occurs when bacterial endotoxins and inflammatory cytokines directly injure vascular endothelial cells.8,9 This leads to both the release of vasodilators such as nitric oxide (NO) causing hypotension, as well as the activation of the coagulation cascade resulting in a hypercoagulable state. Ultimately, the end result is impaired organ perfusion.
NO is thought to be a major contributor in the development of hypotension in septic patients.10 It also may contribute to hypotension by affecting autonomic centers in the central nervous system.10,11 Anti-diuretic hormone (ADH) also has been reported to play a role in septic shock. Decreased levels of ADH have been seen in patients in septic shock compared to patients in cardiogenic shock.12
A hypercoagulable state leading to disseminated intravascular coagulation (DIC) occurs commonly in septic patients. DIC results from endothelial cell damage by cytokines and bacterial toxins, leading to activation of the coagulation cascade. This results in excess intravascular clotting and subsequent thrombosis in the microvasculature that leads to impaired perfusion.9 The body responds by attempting to neutralize the hypercoagulable state by preventing further clot formation via anti-clotting factors, namely anti-thrombin III, protein C, and protein S. Eventually, the anti-clotting factors are consumed, leaving the body in a hypercoagulable state and defenseless against further clot formation and multi-organ failure.13
Hypotension in sepsis also results from myocardial suppression and the resultant decreased cardiac output. TNF-alpha and IL-1 have a synergistic effect on myocardial suppression. It is suspected that myocardial dysfunction in septic patients is related to NO, but there are conflicting data on whether NO is harmful or beneficial in these patients.15
Microvascular thrombi impair blood flow in the lungs. Local endothelial cell damage by cytokines and bacterial toxins leads to increased vascular permeability, resulting in pulmonary edema and possible development of acute respiratory distress syndrome.15 Impaired arterial oxygenation contributes to organs already lacking adequate oxygen.
The mortality rate is increased in septic patients who develop renal failure.16 Although the exact cause is unknown, multiple factors are thought to contribute to renal failure in sepsis, including hypoperfusion and the direct cytotoxic effects of cytokines and endotoxins.
Hypoperfusion of the intestinal tract in sepsis leads to alterations of gut barrier function. This facilitates bacterial translocation and further invasion of bacteria. An association between increased intestinal permeability and the development of multi-organ dysfunction syndrome has been suggested.17
Although other organ systems also can be affected by the inflammatory process leading to sepsis, involvement of the vascular system, heart, lungs, kidneys, and gastrointestinal tract can lead to worsening of overall function. As more organs are affected by sepsis, chances of recovery decline rapidly.
Monitoring and Vascular Access
Frequent monitoring of heart rate, blood pressure, and indices of end-organ perfusion such as mental status and urine output is crucial in the management of the patient with severe sepsis or septic shock. This should include continuous cardiac monitoring and pulse oximetry. At a minimum, peripheral intravenous access with two large-bore catheters should be established. An arterial catheter should be inserted early in the course of management of the patient with septic shock.18 Intra-arterial blood pressure monitoring allows continuous and accurate measurement of blood pressure. Additionally, it enables convenient access for repeated measurements of arterial blood gases and lactate to monitor response to therapy. A Foley catheter should be inserted to facilitate accurate measurement of urine output.
Consideration should be given to the early insertion of a central venous catheter and is suggested in patients who do not respond readily to a trial of fluid resuscitation.19 Patient factors, such as history of heart failure or impaired ejection fraction, also should have an impact on the timing of this intervention. If there is available expertise, consideration should be given to using ultrasound guidance for central venous catheter insertion as there is mounting evidence that this may increase the incidence of successful first-pass insertion and decrease complications.20 A central venous catheter will enable rapid volume expansion as well as administration of vasopressors. Central venous catheterization also allows measurement of central venous pressure (CVP), which, as a surrogate for right atrial filling pressure or preload, can be used to guide fluid resuscitation.21 Commonly used insertion sites include the internal jugular, subclavian, and femoral veins. Choice of an insertion site should be dictated by patient factors and the practitioner’s experience, including a knowledge of the relative indications and the contraindications to each approach. Typically, the incidence of immediate mechanical complications such as pneumothorax is highest with the subclavian approach, whereas the incidence of delayed complications (e.g., thrombosis and infection) is highest with femoral vein cannulation.22,23 A number of studies suggest that femoral vein catheterization can be used to reliably measure CVP.24-27
Since its introduction to clinical medicine in 1970, the balloon flotation pulmonary artery (PAC) or Swan-Ganz catheter (hereafter referred to as PAC) has become an almost ubiquitous tool in critical care medicine.28 In 1996 an estimated 2 million PACs were sold worldwide.29 That same year an estimated two billion dollars were spent on PACs in the United States alone.30 However, the widespread use of PACs was called into question in 1996 when a retrospective analysis of PACs in post-operative surgical patients suggested there was increased mortality associated with their use.31 A more recent prospective clinical trial failed to demonstrate an improvement in outcome associated with PAC use in patients in shock with ARDS.32 The controversy continues while clinicians await further evidence from pending randomized prospective clinical trials.33-41
Hemodynamic Support
Volume Resuscitation. The goals of hemodynamic support in septic shock are to restore tissue perfusion and normalize cellular metabolism. Early and vigorous circulatory resuscitation is a cornerstone in the management of septic shock.42 This includes aggressive replenishment of intravascular volume and vasopressor support if necessary.41 The patient with severe sepsis or septic shock is typically profoundly volume depleted. Contributing factors include increases in vascular capacitance and capillary permeability, reduced oral intake, and increased insensitive losses due to fever and tachypnea.21 In some cases adequate volume resuscitation may be all that is required to restore perfusion pressure.43,44 A decision on whether or not vasopressor support is indicated usually is deferred until the patient has received adequate volume resuscitation. On occasion, however, vasopressors are initiated to support blood pressure while volume resuscitation is ongoing. A mean arterial pressure (MAP) of 65 mmHg and CVP of 8-12 mmHg are widely agreed upon as reasonable goals of hemodynamic resuscitation.42-44 Note that a higher target CVP of 12-15 mmHg is recommended in ventilated patients to account for increases in intrathoracic pressure.42
Controversy exists regarding the best choice of fluid for volume replacement. Available options include crystalloid solutions (0.9% normal saline, Lactated Ringer’s solution) and colloid solutions (serum albumin, artificial solutions such as the hetastarches). Putative advantages of colloid over crystalloid solutions are predicated upon their oncotic effect resulting in greater plasma expansion compared to a similar volume of crystalloid. While this may allow administration of less volume and result in less peripheral edema, there is no evidence that administration of colloid improves outcomes compared to equivalent volumes of crystalloid.42,45,46 Given the ready availability and low cost of crystalloid solutions it is likely they will remain the solutions of choice in most emergency departments for the time being.
Vasopressors. Vasoactive medications are required in the face of persistent shock despite adequate replacement of intravascular volume. As with fluid therapy, goals are a MAP greater than 65 mmHg and improvement in indices of end-organ perfusion such as of acid-base status (lactate, base excess), SVO2, urine output, and mental status. Note that the chronically hypertensive patient may require a higher MAP to achieve adequate tissue perfusion. As with any important intervention in emergency medicine, it is crucial to evaluate the response to therapy frequently. It is particularly import to reassess relevant parameters after changes in vasopressor dosage.
Vasopressor availability in the ED may vary from one institution to another. Commonly available vasopressors are dopamine, norepinephrine (Levophed), epinephrine (Adrenalin), phenylephrine (Neo-Synephrine), and vasopressin (Pitressin). Dopamine is probably the most widely available and commonly used vasopressor and has long been considered the agent of choice in septic shock. Current recommendations from the Society of Critical Care Medicine are for the use of dopamine or norepinephrine as first-line vasopressor therapy.42
Dopamine is the natural precursor of epinephrine and norepinephrine. It has distinct dose-dependent effects. At doses less than 5 mcg/kg/min, effects on dopaminergic DA1 and DA2 receptors predominate and cause vasodilatation of the renal, mesenteric, and coronary beds. At doses of 5-10 mcg/kg/min, beta1-adrenergic effects predominate, resulting in increased contractility and heart rate. At doses greater than 10 mcg/kg/min, alpha1-adrenergic effects supervene and increase blood pressure via arterial constriction. This dose-response relationship is variable but it offered a theoretical framework for the use of so-called renal-dose dopamine, which entailed using low-dose dopamine in an effort to improve renal perfusion and function. This practice no longer is recommended in light of a recent randomized clinical trial that failed to show any improvement in renal function with the use of low-dose dopamine.47
Norepinephrine is a potent alpha-adrenergic agonist with less prominent beta-adrenergic effects. It increases MAP primarily by vasoconstriction with little change in heart rate or cardiac output. Reported doses range from 0.01 mcg/kg/min to 3.3 mcg/kg/min.48 There is scant evidence to support the use of one catecholamine over another in the treatment of septic shock.42,49 However, there are several small studies that suggest norepinephrine should supplant dopamine as the agent of choice in septic shock. One randomized, double-blind study compared dopamine to norepinephrine in patients with septic shock.50 The norepinephrine group showed improved hemodynamic response. Another study comparing dopamine and norepinephrine in patients with sepsis found that while whole body oxygen consumption increased with both agents, intramucosal gastric pH increased with norepinephrine, suggesting that it improved splanchnic perfusion.51 Another study of a non-randomized cohort of 97 patients in septic shock compared norepinephrine to dopamine and found a substantial decrease in 28-day mortality.52
Phenylephrine is a pure alpha-1 adrenergic agonist. It increases MAP, systemic vascular resistance (SVR), and stroke index without attendant increases in heart rate.42,53 Furthermore, phenylephrine does not decrease cardiac or renal function. However, it may increase oxygen consumption. Although not recommended as first-line therapy in the treatment of septic shock, phenylephrine may be a reasonable choice when tachyarrhythmias are a concern.42
Epinephrine increases MAP primarily via increased cardiac index and stroke volume with some increase in SVR and heart rate. Concerns over its use center around evidence that it decreases splanchnic blood flow and increases lactate concentration and oxygen consumption. Nonetheless, there is clear evidence that epinephrine can improve hemodynamic parameters in patients unresponsive to volume resuscitation or other vasopressors.42 Thus, while not recommended as a first-line vasopressor, epinephrine has a role to play as rescue therapy in patients with septic shock refractory to more traditional vasopressors.
Vasopressin is a novel vasopressor that recently has seen more widespread use in the therapy of septic shock. It is a peptide hormone that is synthesized in the hypothalamus and then stored in the pituitary gland. Vasopressin mediates vasoconstriction though its action on V1 receptors. It also may increase blood pressure by increasing the sensitivity of the vasculature to circulating catecholamines and reducing production of nitric oxide by vascular smooth muscle.42 Researchers hypothesize that septic shock causes a relative deficiency of vasopressin via pituitary depletion that contributes to persistent hypotension.54 A number of studies have demonstrated that the addition of vasopressin in low doses (0.01-0.08 units/min) to traditional vasopressors improves hemodynamic parameters and reduces dosage requirements of adrenergic agents.55 Note that vasopressin typically is initiated without titration. Vasopressin also causes increased urine production, probably via an increase in glomerular filtration rate. Although the data regarding vasopressin are promising, there is some concern that it may cause a reduction in cardiac output. It should be used cautiously in patients with cardiac dysfunction. Currently, vasopressin is recommended primarily as add-on therapy in cases of septic shock refractory to traditional vasopressors.42,55
Antimicrobial Therapy
The impact of antimicrobial therapy in sepsis syndrome is not well known. There is little high-quality literature to guide the emergency physician; however, general recommendations have been made that appear intuitive and reasonable. The treatment of underlying shock with vascular access, aggressive fluid resuscitation, and vasopressor administration should occur as the first priority. Urine, blood, and other potential sources also should be cultured before antimicrobials are given. A goal of administration within one hour of recognition has been proposed, but administering the appropriate antibiotic regimen may be of greater benefit than the early use of incorrect agents.56
Some studies have shown mortality benefit based on appropriateness of empiric antibiotics.57,58 In these studies, however, appropriate antibiotic therapy was determined after results of cultures and sensitivities became known. Obviously, this information will not be available to the emergency physician. However, this does emphasize the need to make a reasonable investigation into the potential source of infection prior to the initiation of antibiotic therapy. In the PROWESS study, the most frequent sources of infection in severe sepsis were the lung (54%), the abdomen (20%), other sources (16%), and the urinary tract (10%).59 Where an infection was acquired—community, nursing home, or hospital—also will help determine potential organisms. Once a potential source is identified, then community and hospital prevalence and resistance patterns should be incorporated. In addition, valuable information may be gained from review of prior culture results from previous hospitalizations. This may help identify patients at risk for methicillin resistant Staphylococcus aureus and vancomycin resistant Enterococcus.60 (See Table 2.)
Neutropenic patients and those in whom Pseudomonas is suspected should receive combination therapy. Patients with fungemia often do not receive appropriate antimicrobials and thus have poor outcomes. Patients at increased risk for fungemia include those with Hickman catheters, prior hemodialysis, antibiotic therapy for more than two weeks, patients on multiple antibiotics, or those with a prior history of Candida colonization in two or more sites.61,62
In the rush to resuscitate the patient, identify the potential focus of infection, and administer the appropriate antibiotic, physicians still should remember the tenet of "do no harm." Always assess the patient for possible allergies and give consideration for side effects and drug interactions that may be detrimental to the patient.63
Source Control
Once a focus of infection has been identified, efforts to remove it should be undertaken. This is at least as important as antimicrobial therapy, if not more so.57 Most abscesses should be surgically drained, however percutaneous CT-guided drainage may be considered when the location of an intra-abdominal abscess is amenable. Necrotizing fasciitis requires immediate surgical debridement to reduce mortality and morbidity.61 Foreign bodies such as central access catheters and Foley catheters should be removed promptly. Appropriate surgical consultation to evaluate vascular grafts and shunts, peritoneal dialysis catheters, and prosthetic heart valves also may be needed.
Early Goal Directed Therapy
The theory of goal-directed therapy for sepsis is based on adjusting cardiac preload, afterload, and contractility to meet predefined goals to balance oxygen supply and demand.64 Several prospective trials have been done comparing goal-directed therapy in septic patients to standard therapy. Studies done in the intensive care unit setting have not shown benefit in mortality in the goal-directed group.65,66 Early restoration of tissue perfusion was theorized to be the important step in the interruption of the cascade of cellular, tissue, organ, and organ system failures. A well-performed study showed impressive results in the goal-directed therapy group in an emergency department setting.64
This emergency department-based study took place in an academic tertiary care hospital. This randomized, prospective study consisting of 263 patients in septic shock divided patients into a standard therapy group (n = 133) and an early goal directed-therapy (EGDT) group (n = 130). Management of the patients in the standard therapy group was guided by a hemodynamic support protocol, and treatment was at the discretion of the emergency physician. The standard protocol included intravenous fluid boluses to reach a central venous pressure (CVP) of 8-12 mmHg. Then, vasopressors were used if needed to reach a mean arterial pressure (MAP) greater than 65 mmHg and a urine output (UO) greater than 0.5 mL/kg/hr. The MAP and UO were monitored by an arterial line and urethral catheter, respectively. Also, antibiotic use was at the discretion of the emergency physician. Critical-care consultation was obtained, and patients were admitted as soon as possible.
In addition to the treatment administered to the standard therapy group, the EGDT patients were kept in the emergency department for 6 hours and treatment was titrated to increase the central venous oxygen saturation (ScvO2) to a goal of 70% by optimizing preload, afterload, and myocardial contractility. The ScvO2 was measured continuously by a specialized central venous catheter. ScvO2 differs from mixed venous oxygen saturation in that the former measures oxygen saturation in the right atrium or superior vena cava instead of the pulmonary artery.67 In addition to keeping the MAP greater than 65 mmHg, vasodilators were used to keep the MAP less than 90 mmHg if needed. If the ScvO2 remained less than 70%, blood was transfused to keep the hematocrit (HCT) greater than 30%. Dobutamine infusion was initiated if the ScvO2 continued to remain less than 70%. Finally, patients who did not achieve the goal were intubated and sedated to decrease oxygen consumption. (See Figure 2.)
The primary end point of the study was in hospital mortality. The EGDT group’s mortality was 30.5%, significantly lower than the mortality of 46.5% in the standard group (P = 0.009). The absolute risk reduction (ARR) was 16%. Therefore, the number needed to treat (NNT) to save one life was 6.25 patients resuscitated by EGDT. The authors of the study attributed the impressive difference in mortality to early aggressive management, which is guided by individualized physiologic titration of therapy.68 Furthermore, the authors of the EGDT study did a subset analysis in a group of patients termed to be in "cryptic shock." These patients had an initial MAP of greater than 100 mmHg, combined with a lactic acid level greater than 4 mmol/L. In this subset of patients, the EGDT group had a mortality that was 40% less than that of the standard therapy group.68
Although the study was published in 2001, EGDT is not widely practiced in emergency departments across the country. Some critical care physicians feel that a larger multi-center study needs to be done to validate the use of EGDT before it is accepted as standard of care.69 The authors of the EGDT study believe that time is better spent applying principals accepted as standard of care for sepsis early in its disease process.68 Although many emergency departments do not have sufficient nursing support, invasive monitoring capabilities, and other resources necessary to provide the aggressive therapy required for EGDT, implementing protocols to detect and treat septic patients early on in the disease process can be life-saving.
Relative Adrenal Insufficiency/Steroid Therapy
Steroids have long been theorized to have benefit in mitigating the inflammatory cascade of sepsis syndromes. They were first investigated in stress doses over four decades ago in a double-blind study that did not reveal therapeutic benefit. Over the years, many have hypothesized that they may exhibit benefit in pharmacologic or in high-dose regimens.70 Survival was decreased in patients receiving high-dose steroid regimens.71,72
Later, a small study found that treatment of patients in septic shock with stress doses of steroids resulted in fewer days of vasopressor support. It also found a trend toward fewer days of mechanical ventilation and intensive care unit stay, although this was not statistically significant due to the small number of patients.70
The concept of relative adrenal insufficiency arose as a pathophysiologic process in sepsis. Annane found that, among patients presenting with septic shock and not responding to a corticotropin stimulation test, a low-dose regimen of hydrocortisone infusion and fludrocortisone resulted in a significant reduction in mortality compared with placebo (53% vs. 63%).73 There is some disagreement as to the appropriate cut-off to determine relative adrenal insufficiency. There also is criticism that patients with normal adrenal function had a non-significant trend toward increased mortality when given corticosteroids.74
The Surviving Sepsis Campaign, a multidisciplinary consensus conference to improve the care of septic patients, suggests 200-300 mg/day of hydrocortisone (Cortef) as either continuous infusion or in four divided doses for seven days. This may be supplemented with 50 mcg fludrocortisone (Florinef Acetate) orally (or via nasogastric tube) four times per day, as in the trial by Annane. Adrenal function should be determined by using a 250 mcg ACTH stimulation test to identify responders. Corticosteroids should not be withheld pending these results. Dexamethasone may be considered until an ACTH stimulation test can be performed. A rise of more than 9 mcg/dL above pre-test levels at either 30 or 60 minutes will identify normal adrenal function (responders). Steroids should be discontinued in these patients.18 It should be stressed that increasing doses of steroids, especially high-dose regimens, are not beneficial and have been linked to increased mortality.72 Additionally, no study has shown benefit of corticosteroids in sepsis in the absence of shock.
Physicians may have concerns about increased rates of hyperglycemia, gastrointestinal bleeding, adult respiratory distress syndrome (ARDS), and secondary infections with the use of corticosteroids. Results vary somewhat by study, but generally there are no differences or only very small increases. Annane found no significant differences in the rate of these adverse events with the low-dose steroid regimen.73 Since most studies look at all-cause mortality, the adverse events already are included in the results.
Recombinant Human Activated Protein C
Over the last two decades, more than 30 different compounds have been evaluated in hopes of arresting the progression of sepsis and improving the staggering mortality rates that have remained unchanged since the mid-1960s. All have been unsuccessful, until recently.
Inflammatory cytokines cause activation of the coagulation cascade and suppression of the fibrinolysis on multiple levels. Protein C is an endogenous molecule that, when activated, interrupts the coagulation cascade and increases fibrinolysis. Activated protein C has been shown in phase II trials to reduce markers of coagulopathy and inflammation.59,75,76 (See Figure 1.)
Recombinant human activated protein C, known as drotrecogin alpha (activated), is indicated for treatment of patients with severe sepsis and septic shock. It is administered as a continuous infusion at 24 micrograms per kilogram per hour for 96 hours. It should be held one hour before and one hour after any percutaneous procedure. It also should be held one hour before and 12 hours after any major surgery. The infusion should not be restarted if either has a bleeding complication.75
The PROWESS trial was a multicenter, randomized, double-blind, placebo-controlled trial to assess the effect of activated protein C on 28-day mortality in patients presenting with severe sepsis of fewer than 24 hours duration. It was terminated at the second interim analysis due to a mortality benefit, after enrolling 840 patients to the placebo group and 850 patients to the activated protein C group. The study found an absolute risk reduction (ARR) of mortality of 6.1%, (30.8% vs. 24.7%, respectively; P = 0.005). Thus, the number of patients needed to treat (NNT) to save one additional life was 16.75 A consistent benefit was seen across most subgroups.77 Patients older than 50 years, with more than one organ dysfunction, APACHE II score greater than 24, and shock during infusion had greater benefit, while post-operative patients and those with only one organ dysfunction did not have benefit.78 A small increase in mortality was seen in subgroups of patients with urinary tract infections, APACHE II scores less than 20, and those with lower predicted mortality.77 While the size of each subgroup was small, this suggests that the drug is more efficacious in sicker patients, and that it may be of little benefit or possibly harmful in those of less serious illness.
Differences in treatment effect were seen over the course of the study, leading to questions about the validity of the study. Some have attributed a reduced mortality in the activated protein C group during the second half of the study to changes in the exclusion criteria and changes in the master cell line. However, the FDA has found that the changes excluded sicker patients from the second half of the trial who actually had a greater mortality benefit with the drug in the first half of the trial. The manufacturer and the FDA reported that the new master cell line did not have any in vitro differences from the old cell line. If the new cell line does produce a better drug, than it may show more benefit.79,80
The main adverse effect reported was serious bleeding, which occurred in 2.0% of placebo patients and 3.5% of activated protein C patients. The survival benefit, however, is inclusive of this adverse event. The rate of serious bleeding may be greater in open-label use of the drug than it was in the controlled trial.78,79 Given this, the drug should be held both before and after any percutaneous or surgical procedure, as stated above. The drug should not be used in patients with marked thrombocytopenia (less than 30,000), prolonged prothrombin times, those currently receiving anticoagulant therapy, or those with other contraindications.59,77,80
One other concern about the drug is its significant cost, estimated at $1700 per day. Some contend that activated protein C compares favorably with regard to absolute risk reductions and number needed to treat when compared to streptokinase, tPA, implantable cardiac defibrillators, and other treatments. Other researchers contend that the costs are reasonable when spread over the years of life saved. They suggest that acute therapy with activated protein C is less expensive ($60,000 per quality-adjusted life-year) than a chronic therapy such as hemodialysis ($150,000 per quality-adjusted life-year ).81 Finally, some have suggested that other less costly and more efficacious treatments such as EGDT, corticosteroids in relative adrenal insufficiency, low tidal volumes in ARDS, and tight blood sugar control in the ICU be implemented before high cost medications become the standard.82 (See Table 3.)
Table 3. Sepsis Therapies
Other Therapies
Bicarbonate Therapy. Sodium bicarbonate administration for lactic acidosis secondary to hypoperfusion has not been found to be beneficial. It does not improve hemodynamic variables or reduce the need for vasopressor therapy in patients with a pH greater than 7.15. Bicarbonate therapy has not been well studied in patients with a lower pH or with regard to clinical outcomes. Its use currently is not recommended.56
Blood Transfusion. Anemia in sepsis is a common occurrence. Studies on septic patients examining the effect of red blood cell transfusions on oxygen delivery and consumption have shown no benefits of transfusing blood to maintain a hemoglobin greater than 10 g/dL.83 The results of one large multi-center study showed an increase in mortality among critically ill patients transfused to maintain a hemoglobin of 10-12 g/dL compared to maintaining a level of 7-9 g/dL.84 In contrast, River’s protocol for EGDT showed a significantly decreased rate of mortality. However, these patients were transfused to a hematocrit greater than 30% only after aggressive resuscitation failed to increase ScvO2 greater than 70%.64 The Surviving Sepsis Campaign recommends that once tissue hypoperfusion has been corrected or excluded, red blood cell transfusions should be targeted to maintain a hemoglobin greater than 7.0 g/dL.56
Conclusions
Sepsis remains a major cause of significant morbidity and mortality. The incidence will only grow over the next decade as the population ages, comorbidities increase, more people live with immunosuppression, and antibiotic resistance rises. The emergency department will face an ever-growing role in the care of these patients. With continued challenges in emergency department crowding and the unavailability of ICU beds, appropriate triage and early recognition will play an important role in the care of septic patients. Early and aggressive fluid resuscitation, vasopressor management, and optimization of oxygen delivery form the tenets of early goal-directed therapy and provide the greatest improvements in survival. Efforts should be made to ensure appropriate antibiotic selection, and source control should be initiated in the emergency department when possible. Corticosteroids will benefit patients with a relative adrenal insufficiency. Finally, activated protein C should be considered in patients with septic shock (APACHE II score greater than 25). It is the first drug to have shown a mortality benefit in these patients.
References
1. Osborn TM, Tracy JK, Dunne JR, et al. Epidemiology of sepsis in patients with traumatic injury. Crit Care Med 2004;32:2234-2240.
2. Goldstein B, Giroir B, Randolph A. International Pediatric Sepsis Consensus Conference: Definitions for sepsis and organ dysfunction in pediatrics. Pediatric Crit Care Med 2005;6:2.
3. Friedman G, Silva E, Vincent JL. Has the mortality of septic shock changed with time? Crit Care Med 1998;26:2078-2086.
4. Senior K. Sepsis Poses an Increased Threat. The Lancet Infectious Diseases 2002;2:386.
5. Dellinger RP, Carlet JM, Masur H, et al. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med 2004;32:858-873.
6. Bone RC, Balk RA, Cerra FB, et al. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992;20:864-873.
7. Levy MM, Fink MP, Marshall JC, et al. 2001 SCCM/ESICM/ACCP/ ATS/SIS International Sepsis Definitions Conference. Crit Care Med 2003; 31:1250-1256.
8. Parent C, Eichacker PQ. Neutrophil and endothelial cell interactions in sepsis: The role of adhesion molecules. Infect Dis Clin North Am 1999;12: 427-447.
9. Nimah M, Brilli R. Coagulation dysfunction in sepsis and multiple organ system failure. Crit Care Med 2003;19:441-458.
10. Vincent JL, Zhang H, Szabo C, et al. Effects of nitric oxide in septic shock. Am J Respir Crit Care Med 2000;161:1781.
11. Sharshar T, Gray F, de la Grandmaison GL, et al. Apoptosis of neurons in cardiovascular autonomic centres triggered by inducible nitric oxide synthase after death from septic shock. Lancet 2003;362:1799.
12. Landry DW, Levin HR, Gallant EM, et al. Vasopressin deficiency contributes to the vasodilation of septic shock. Circulation 1997;95:1122.
13. Cate H. Pathophysiology of disseminated intravascular coagulation in sepsis. Crit Care Med 2000;28:S9-S11.
14. Marik, P. Cardiovascular dysfunction of sepsis: A nitric oxide- and l-arginine-deficient state? Crit Care Med 2003;31:971-973.
15. Ghosh S, Latimer RD, Gray BM, et al. Endotoxin-induced organ injury. Crit Care Med 1993;21:S19.
16. Hoste EA. Acute renal failure in patients with sepsis in a surgical ICU: Predictive factors, incidence, comorbidity and outcome. J Am Soc Nephrol 2003;14:1022-1030.
17. Doig DJ, Sutherland LR, Sandham JD, et al. Increased intestinal permeability is associated with the development of multiple organ dysfunction syndrome in critically ill ICU patients. Am J Respir Crit Care Med 1998; 158:444.
18. Beale RJ, Hollenberg SM, Vincent JL et al. Vasopressor and inotropic support in septic shock: An evidence-based review. Crit Care Med 2004;32(11 Suppl):S455-465
19. Hollenberg SM, Ahrens TS, Annane D et al. Practice parameters for hemodynamic support of sepsis in adult patients: 2004 update. Crit Care Med 2004;32:928-948.
20. Keenan SP. Use of ultrasound to place central lines. J Crit Care 2002;17: 126-137.
21. Balk RA. Optimum Treatment of Severe Sepsis and Septic shock: Evidence in Support of the Recommendations. Dis Mon 2004;50:163-213.
22. Timsit J. Central venous access in intensive care unit patients: Is the subclavian vein the royal route? Intensive Care Med 2002;28:1006-1008.
23. Merrer J, De Jonghe B, Golliot F, et al. Complications of femoral and subclavian venous catheterization in critically ill patients: A randomized controlled trial. JAMA 2001;286:700-707.
24. Nahum E, Dagan O, Sulkes J, et al. A comparison between continuous central venous pressure measurement from right atrium and abdominal vena cava or common iliac vein. Intensive Care Med 1996;22:571-574.
25. Joynt GM, Gomersall CD, Buckley TA, et al. Comparison of intrathoracic and intra-abdominal measurements of central venous pressure. Lancet 1996;347(9009):1155-1157.
26. Ho KM, Joynt GM, Tan P. A comparison of central venous pressure and common iliac venous pressure in critically ill mechanically ventilated patients. Crit Care Med 1998;26:461-464.
27. Walsh JT, Hildick-Smith DJ, Newell SA, et al. Comparison of central venous and inferior vena caval pressures. Am J Cardiol 2000;85:518-520.
28. Wan HJC, Ganz W, Forrester JS, et al. Catheterization of the heart in man with use of a flow-directed balloon-tipped catheter. N Engl J Med 1970;283: 447-451.
29. Ginosar Y, Sprung CL. The Swan-Ganz catheter: Twenty-five years of monitoring. Crit Care Clin 1996;12:771-776.
30. Califano JA jr. America’s Health Care Revolution: Who Lives? Who Dies? Who Pays? New York, Random House, 1986.
31. Connors AF Jr., Speroff T, Dawson NV, et al. The effectiveness of right heart catheterization in the initial care of critically ill patients. SUPPORT Investigators. JAMA 1996;276:889-897.
32. Sandham JD, Hull RD, Brant RF et al, for the Canadian Critical Care Clinical Trials Group. Early use of the pulmonary artery catheter and outcomes in patients with shock and acute respiratory distress syndrome. N Engl J Med 2003;348:5-14.
33. Fowler RA, Cook DJ. The Arc of the Pulmonary Artery Catheter. JAMA 2003;290:2732-2734.
34. Taylor RW. Controversies in Pulmonary Artery Catheterization. New Horizons 1997;5:173-174.
35. Dalen JE, Bone RC. Is it time to pull the pulmonary artery catheter? JAMA 1996;276:916-918.
36. Sandham JD, Hyull RD, Brant RF. The pulmonary artery catheter takes a great fall. Crit Care Med 1998;26:1288-1289.
37. Vincent JL, Dhainaut J-F, Perret C, et al. Is the pulmonary artery catheter misused? A European view. Crit Care Med 1998;26:1283-1287.
38. Cruz K, Franklin C. The pulmonary artery catheter: Uses and controversies. Crit Care Clin 2001;17:271-291.
39. Williams G, Grounds M, Rhodes A. Pulmonary artery catheter. Curr Opin Crit Care 2002;8:251-256.
40. Bellomo R, Uchino S. Cardiovascular monitoring tools: Use and misuse. Curr Opin Crit Care 2003;9:225-229.
41. Jacka MJ, Cohen MM, To T et al. The use of and preferences for the transesophageal echocardiogram and pulmonary artery catheter among cardiovascular anesthesiologists. Anesth Analg 2002;94:1065-1071.
42. Hollenberg SM, Ahrens TS, Annane D, et al. Practice parameters for hemodynamic support of sepsis in adult patients: 2004 update. Crit Care Med 2004;32:1928-1948.
43. Dellinger RP. Cardiovascular management of septic shock. Crit Care Med 2003;31:9-55.
44. Vincent JL. Hemodynamic support in septic shock. Intensive Care Med 2001;27(suppl):S80-92.
45. Choi PT-L, Yip G, Guinonex LG et al. Crystalloids vs colloids in fluid resuscitation: a systematic review. Crit Care Med 1999;27:200-210.
46. Schierhout G, Roberts I. Fluid resuscitation with colloid or cystalloid solutions in critically ill patients: A systematic review of randomized trials. Brit Med J 1998;316:961-964.
47. Bellomo R, Chapman M, Finfer S, et al. Low-dose dopamine in patients with early renal dysfunction: A placebo-controlled randomised trial. Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group. Lancet 2000;356:2139-2143.
48. Meadows D, Edwards JD, Wilkins RG et al. Reversal of intractable septic shock with norepinephrine therapy. Crit Care Med 1988;16:663-667.
49. Mullner M, Urbanek B, Havel C, et al. Vasopressors for shock. Cochrane Database Syst Rev. 2004;(3):CD003709.
50. Martin C, Papazian L, Perrin G, et al. Norepinephrine or dopamine for the treatment of hyperdynamic septic shock? Chest 1993;103:1826-1831.
51. Marik PE, Mohedin M. The contrasting effects of dopamine and norepinephrine on systemic and splanchnic oxygen utilization in hyperdynamic sepsis. JAMA 1994;272:1354-1357.
52. Martin C, Viviand X, Leone M, et al. Effect of norepinephrine on the outcome of septic shock. Crit Care Med 2000;28:2758-2765.
53. Gregory JS, Bonfiglio M, Dasta J, et al. Early experience with phenylephrine in the treatment of septic shock. Crit Care Med 1991;19:1395-1400.
54. Landry DW, Levin HR, Gallant EM et al. Vasopressin deficiency contributes to the vasodilation of septic shock. Circulation 1997;95:1122-1125.
55. Obritsch MD, Bestul DJ, Jung R, et al. The role of vasopressin in vasodilatory septic shock. Pharmacotherapy 2004;24:1050-1063.
56. Dellinger RP, Carlet JM, Masur H, et al. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med 2004;32:858-873.
57. Garnacho-Montero J, Garcia-Garmendia JL, Barrero-Almodovar A, et al. Impact of adequate empirical antibiotic therapy on the outcome of patients admitted to the intensive care unit with sepsis. Crit Care Med 2003;31: 2742-2751.
58. MacAurthur RD, Miller M, Albertsen T, et al. Adequacy of early empiric antibiotic treatment and survival in severe sepsis: Experience from the MONARCHS trail. Clin Infect Dis 2004;28:284-288.
59. Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant activated protein C for severe sepsis. N Engl J Med 2001;344:699-709.
60. Gilbert DN, Moellering RC Jr., Eliopoulos GM, et al. The Sanford guide to antimicrobial therapy 2004. Antimicrobial Therapy, Inc. 2004.
61. LaRosa SP. Sepsis. The Cleveland Clinic Disease Management Project. www.clevelandclinicmeded.com. Accessed 6-7-2004.
62. Wenzel RP. Nosocomial candidemia: Risk factors and attributable mortality. Clin Infect Dis 1995;20:1531-1534.
63. Playe SJ. Bugs and drugs: Antibiotic use in the emergency department. American College of Emergency Physicians, Scientific Assembly. October 18, 2004.
64. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock N Engl J Med 2001;345: 1368-1377.
65. Gattinoni L, Brazzi L, Pelosi P, et al. A trial of goal-oriented hemodynamic therapy in critically ill patients. SvO2 Collaborative Group. N Engl J Med 1995;333:1025-1031.
66. Hayes MA, Timmins AC, Yau EH, et al. Elevation of systemic oxygen delivery in the treatment of critically ill patients. N Engl J Med 1994;330: 1717-1722.
67. Edwards JD, Mayall RM. Importance of the sampling site for measurement of mixed venous oxygen saturation in shock. Crit Care Med 1998;26: 1356-1360.
68. Rivers EP, Nguyen HB, Huang DT, et al. Early goal-directed therapy. Crit Care Med 2004;32:314-315.
69. Dellinger FP. Cardiovascular management of septic shock. Crit Care Med 2003;31:946-955.
70. Briegel J, Forst H, Haller M, et al. Stress doses of hydrocortisone reverse hyperdynamic septic shock: A prospective, randomized, double-blind, single center study. Crit Care Med 1999;27:723-732.
71. Cronin L, Cook DJ, Carlet J, et al. Corticosteroid treatment for sepsis: A critical appraisal and meta-analysis of the literature. Crit Care Med 1995;23: 1430-1439.
72. Minneci PC, Deans KJ, Banks SM, et al. Meta-analysis: The effects of steroids on survival and shock during sepsis depends on the dose. Ann Intern Med 2004;141:47-56.
73. Annane D, Sebille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002;288:862-871.
74. Steingrub JS. Steroids and drotrecogin alfa (activated) for severe sepsis. Chest 2003;124:2033.
75. Bernard GR, Ely EW, Wright TJ. Safety and dose relationship of recombinant human activated protein C for coagulopathy in severe sepsis. Crit Care Med 2001;2051-2059.
76. Labbos J, Bradsher J, Kirkpatrick P. Drotrecogin alpha (activated). Nat Rev Drug Discov 2003;2:13-14.
77. Ely EW, Laterre PF, Angus DC, et al. Drotrecogin alfa (activated) administration across clinically important subgroups of patients with severe sepsis. Crit Care Med 2003;31:12-19.
78. Warren HS, Suffredini AF, Eichacker PQ, et al. Risks and benefits of activated protein C treatment for severe sepsis. N Engl J Med 2002;347:1027-1030
79. Seigel JP. Assessing the use of activated protein C in the treatment of severe sepsis. N Engl J Med 2002;347:1030-1034.
80. Ely EW, Bernard GR, Vincent JL. Activated protein C for severe sepsis. N Engl J Med 2002;347:1035-1036.
81. Rice TW, Bernard GR. Drotrecogin alfa (activated) for the treatment of severe sepsis and septic shock. Am J Med Sci 2004;328:205-214.
82. Joore JCA, van Leeuwen HJ, Meulenbelt J, et al. Pro/con debate of activated protein C in severe sepsis. [Letters to the editor]. Crit Care Med 2003; 31:2249.
83. Zimmerman JL. Use of blood products in sepsis: An evidence-based review. Crit Care Med 2004;32 (11 suppl):s542-547.
84. Herbert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. N Engl J Med 2001;340:409-417.
In the past few years, new strategies in the management of sepsis have shown significant mortality benefits. This article addresses aspects regarding the management of sepsis, including appropriate fluid administration, medications, and other evidence-based strategies necessary for the treatment of septic patients in the emergency department. With the incorporation of these new practice strategies in addition to the guidelines published by the Surviving Sepsis Campaign, emergency physicians can contribute to a significant decrease in sepsis mortality in the years to come.
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