Detecting and Treating Sepsis in the Emergency Department

Article Outline

• Progression of Sepsis
  • Local Infection
  • Sepsis
  • Progression to Severe Sepsis
  • Septic Shock
• Risk Factors
• Medical Treatment
• How Can Sepsis Be Accurately Detected?
  • Serum Lactic Acid Levels
  • Screening Using Sirs Criteria
  • Ten Symptoms of Physiologic Instability
  • Assessing Changes in Brain Function
• Need for Further Research
• Implications for Emergency Nurses
• Conclusion
• References
• Biography
• Copyright

Sepsis is a common life-threatening condition that occurs when a once localized bacterial or fungal infection becomes systemic and produces an unregulated inflammatory immune response. Unless promptly treated, sepsis progresses to septic shock, which is a state of severe intravascular volume depletion and cellular hypoxia, usually leading to multiple organ failure and death. Early recognition and treatment of sepsis in the emergency department have been shown to significantly improve survival rates. However, it is difficult to predict when a local infection will progress to sepsis, as well as to recognize sepsis in its early stages when symptoms are vague and often attributed to other problems. This article addresses these issues and discusses possible solutions.

Sepsis is the 10th leading cause of death in the United States and accounted for 6% of all deaths between 1999 and 2005.¹ It is expected to become even more prevalent because of the aging population, greater use of implantable devices, more immunocompromised patients, increased use of life-sustaining technology, and greater resistance of bacteria to antimicrobial therapy.² About 28.6% of those with sepsis die,³ and the rate reaches 40% to 60% for those who progress to severe sepsis or septic shock, even when given optimal treatment.⁴, ⁵

Early recognition and treatment significantly improve the odds of surviving sepsis.⁶, ⁷ Broad-spectrum antibiotics should be started as soon as possible and always within 1 hour of recognizing that the patient has severe sepsis or septic shock.⁸ Early initiation of medical interventions (eg, fluid resuscitation) is essential for maintaining blood flow through the microcirculation to prevent organ damage.⁹

Most patients with sepsis enter the health care system through the emergency department,⁹, ¹⁰ and because time is of the essence, it seems reasonable to begin aggressive treatment there, rather than waiting until the patient arrives in a critical care unit.¹¹ In a landmark study, Rivers et al¹² showed that early goal-directed therapy in the emergency department significantly decreases the mortality rate from sepsis, and the findings were verified by later studies.⁶, ¹³, ¹⁴ Treatment involved a set of interventions called bundles that included starting antibiotics quickly and aggressive fluid replacement. Respiratory support, red blood cell transfusion, and vasopressors were also used when needed.

The success of the study of Rivers et al¹² stimulated an international effort to increase survival from sepsis. In 2004 a group of 55 international experts developed consensus guidelines for treating severe sepsis and septic shock and based the guidelines on both expert opinion and research data.¹⁵ Their efforts became known as the Surviving Sepsis Campaign.

Unfortunately, ED personnel have resisted using the severe sepsis care bundles published by the Surviving Sepsis Campaign.⁹, ¹⁶ A major problem was identifying patients who needed early goal-directed therapy.¹⁶ By the time patients with sepsis have obvious vital sign abnormalities, they are already significantly decompensated and in need of rapid and aggressive resuscitative measures. Therapeutic interventions are costly and risky; therefore, if there is any doubt about whether the patient requires sepsis treatment, clinicians may choose less aggressive and, consequently, less effective options.¹⁷

Early sepsis detection also has implications for triage, because triage is used to categorize a patient's acuity level and resource requirements, to determine treatment priorities. Acute myocardial infarctions and acute strokes are triaged as high priority because positive outcomes occur only with immediate treatment. Currently, sepsis is not classified as a high priority, possibly because it is so difficult to detect. If emergency nurses were able to recognize early signs of sepsis, they would know to assess further and provide immediate treatment.

Therefore the focus of this article is on early detection of sepsis. We begin by showing how the pathophysiology of sepsis and its progression to septic shock are shown in physical assessment and laboratory findings. Known risk factors are listed, because they tell us when sepsis is most likely to appear. We will then discuss 4 ways that could be useful for detecting sepsis in ED patients. Finally, we will briefly describe current treatment of sepsis and implications for emergency nurses.

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Progression of Sepsis 

To accurately identify sepsis and understand the approach to treatment, it is important to understand the pathophysiology of sepsis, as well as how it progresses to severe sepsis and septic shock. (See Table 1 for a summary of the stages of sepsis.)

Table 1. Recognizing stages of sepsis

Stages of sepsis	Signs and symptoms
Sepsis	SIRS criteria
	Suspected or confirmed infection
Severe sepsis	Elevated serum lactate level (>2 mmol/L)
	Profound hypovolemia that responds to fluid resuscitation
	Signs of tissue hypoperfusion in the following: • Brain—delirium • Heart and circulation—hypotension, tachycardia, mottled skin, and capillary refill >3 s • Blood—thrombocytopenia (platelet count <100,000 platelets/mL) • Lungs—increased respiratory rate and hypoxia • Kidney—decreased urine output (<0.5 mL/kg for at least 1 h) and elevated blood urea nitrogen and creatinine • Gut—decreased motility, decreased bowel sounds, and anorexia • Liver—increased bilirubin and liver enzymes
Septic shock	Profound hypovolemia, hypoperfusion, and hypoxia
	Hypovolemia does not respond to fluid resuscitation
	Multiple organ failure
	Usually fatal

Local Infection 

The body normally recognizes foreign invaders (eg, bacteria, viruses, protozoa, and fungi) and starts the immune response to isolate and remove the infection. White blood cells release endotoxins to initiate both proinflammatory and anti-inflammatory responses.⁴, ¹⁸ Proinflammatory activities include local vasodilation to deliver the body's infection-fighting agents to the infection site and increased capillary permeability to allow them to move from the bloodstream into infected tissue. Anti-inflammatory agents regulate proinflammatory mediators to prevent them from becoming unmanageable. When these 2 elements are balanced, the inflammation is localized, infection is contained and removed at the site of insult, and tissue integrity is restored.

Sepsis 

Inflammation sometimes does more damage than the foreign invader. In these cases the invader is usually a bacterium, but it can also be a fungus. The first symptoms of pathologic inflammation are called the systemic inflammatory response syndrome (SIRS). SIRS is diagnosed clinically by the presence of 2 or more of the following¹⁹, ²⁰:

Cytokines released during inflammation account for the symptoms of SIRS. Both gram-positive and gram-negative bacteria release endotoxins that directly attack cells and stimulate the release of proinflammatory mediators, including cytokines and neutrophils. Cytokines attract neutrophils and other complements of the immune system to kill the invader. They produce fever, tachycardia, and tachypnea (3 signs of SIRS), as well as peripheral vasodilation that makes the skin appear flushed.²¹, ²²

The fourth sign of SIRS, changes in the number of leukocytes, is a reflection of neutrophil activity. Neutrophils are white blood cells (leukocytes) that are recruited early in the inflammatory response to engulf and kill bacteria. They are rapidly depleted as they fight the invader, so the body responds by increasing neutrophil production (leukocytosis) and releasing immature neutrophils (called bands) from the bone marrow. The white blood cell count may be low (<4,000/μL) because neutrophils have been depleted or high (>1,200/μL) because of an increased release of immature neutrophils (>10% immature band forms).²³

Because SIRS also occurs in situations unrelated to sepsis (eg, burns, surgery, severe trauma, and pancreatitis), a diagnosis of sepsis depends on the presence of 2 or more SIRS criteria plus confirmed infection or high suspicion of infection.¹⁹, ²¹, ²⁴, ²⁵

Progression to Severe Sepsis 

The immune response in sepsis is systemic, excessive, and uncontrolled. Proinflammatory mediators overwhelm anti-inflammatory regulators, enter the bloodstream, and create havoc throughout the body's vasculature.²¹ Severe sepsis occurs when sepsis is accompanied by signs of hypoperfusion and organ dysfunction²⁴, ²⁶ (Table 1). Scientists theorize that the process occurs in the following way.

Inflammatory agents, such as nitric oxide and peroxynitrite, produce vasodilation of large vessels. Small arterioles lose the ability to constrict in response to the body's own vasoregulatory hormones, and blood pools in the dilated vessels.²⁷ At the same time, neutrophils adhere to capillary endothelial cells and release oxidants, phospholipases, and proteases that damage the capillary walls, allowing protein and fluid to leak into the interstitial space. Vasodilation and capillary fluid losses produce profound hypovolemia, thus compromising tissue perfusion.

Tissue perfusion is further impaired by changes in the capillaries. Capillaries normally dilate when oxygen demand is high and constrict when oxygen demand is low, but with sepsis, widespread edema from leaking capillaries causes so much interstitial pressure that capillaries cannot dilate.²⁷ Capillary blood flow is also obstructed because red blood cells lose their ability to change shape to squeeze through narrow capillaries.²⁸

Damage to the endothelium and alterations in blood flow trigger the extrinsic clotting system, which then activates the clotting cascade and increases platelet activity.⁴, ²⁹ Release of plasminogen activator inhibitor 1 decreases the normal fibrinolytic response. The combination of increased clotting and decreased fibrinolysis can lead to disseminated intravascular coagulopathy.²¹

The combination of increased clotting, vasoregulatory dysfunction, and microaggregation in the vasculature decreases blood flow and oxygen delivery to the tissues, ultimately resulting in tissue hypoxia. Because insufficient oxygen is available for aerobic metabolism, cellular mitochondria change to anaerobic metabolism. In turn, anaerobic metabolism produces lactic acid, causing a rise in serum lactate levels.³⁰ Poor liver function also contributes to the rising lactate levels, because lactate is cleared by the liver. Increased lactic acid produces metabolic acidosis, and the body compensates by increasing respirations to blow off carbon dioxide. Respirations also increase in response to tissue hypoxia.

Inadequate perfusion and poor oxygenation disrupt function of organs throughout the body including the brain, lungs, kidneys, liver, and gut.²⁸, ³¹ Disruption of neurotransmission in the brain produces delirium, a serious deterioration in mental status characterized by disorganized thinking, difficulty focusing and maintaining attention, and changes in the level of consciousness.³², ³³ Capillary leakage in the lung leads to pulmonary edema, ventilation-perfusion mismatch, impaired gas exchange, and arterial hypoxemia.²⁸ If the lung is injured, the person starts expending lots of oxygen just to keep breathing, at the same time as other organs are undergoing hypoperfusion and therefore hypoxia. Hence support of breathing and possibly even intubation and ventilator support may be necessary.³⁴

Poor kidney perfusion decreases urine output, raises serum creatinine and blood urea nitrogen levels, and impairs acid-base regulation.²⁸ Inadequate blood flow to the gut decreases peristalsis, promotes bacterial overgrowth, and leads to an increased risk of translocation of bacteria into the circulation because the gut's mucosal barrier is disrupted. Liver dysfunction is reflected in rising levels of bilirubin and liver enzymes.³¹, ³⁵

Septic Shock 

Septic shock occurs when sepsis has progressed to the point where hypotension does not respond to fluid resuscitation and vasopressors are needed. If the septic patient is not yet in shock, an intravenous fluid challenge of 40 to 60 mL/kg of a crystalloid solution will raise the central venous pressure (CVP) to 8 mm Hg or more. The person in septic shock has refractory hypotension, with a systolic blood pressure lower than 90 mm Hg or mean arterial pressure (MAP) lower than 65 mm Hg despite adequate volume resuscitation.¹⁹, ²⁶

Relatively few people survive septic shock. Widespread, systemic disruption of homeostasis leads to catastrophic hypovolemia, hypoperfusion, and hypoxia. The end result is multiple organ dysfunction syndrome and, ultimately, death. Therefore rapid recognition and treatment of sepsis in its earliest stage are vital.¹⁹, ²¹, ³⁶

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Risk Factors 

Because early symptoms of sepsis are vague and easily confused with other medical conditions, it is useful to understand who is most likely to have sepsis develop. Uncontrolled inflammation is more likely to occur when the pathogen is a neutrophil-resistant super-invader, the host has a compromised immune system, or the host is invaded a second time while the immune system is already primed from a recent infection.⁴, ³⁷ Certain types of people are at greater risk, and certain types of infection are more likely to lead to sepsis (Table 2).

Table 2. Who is at greatest risk?

Two-thirds of those in whom sepsis develops are older than 65 years, and elderly people also have the highest mortality rate.²², ²⁴ Infection in the elderly is sometimes unrecognized because symptoms are atypical.³⁸ For example, the only symptom may be altered mental status.

Sepsis is more common in men than women, and genetic factors also seem to influence susceptibility.³⁹ African Americans are more prone to sepsis than any other race, and Asians have a lower incidence than white persons and African Americans.¹, ⁴⁰ Nosocomial infections are associated with higher mortality rates than community-acquired infections.⁴¹ Patients with central venous catheters, Foley catheters, mechanical ventilators, and other invasive devices have an increased risk of sepsis. The 4 major sites of infection that progress to sepsis are the lungs, gastrointestinal tract, urinary tract, and bloodstream.²⁴

A bacterial infection is a major risk factor for sepsis. Gram-positive bacteria are somewhat more commonly associated with sepsis than are gram-negative bacteria. The most common gram-positive organisms associated with severe sepsis are methicillin-sensitive Staphylococcus aureus and methicillin-resistant Staphylococcus aureus and pneumococcus, and the most common gram-negative bacteria are Escherichia coli and Pseudomonas spp.²⁴, ²⁶ Sepsis is also more likely develop after an infection in those who have poorly functioning immune systems because of immunosuppressive therapy, diabetes, cancer, alcohol abuse, and AIDS/HIV.²⁴

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Medical Treatment 

Medical treatment includes 4 major actions: (1) respiratory support, (2) maintenance of circulating blood volume, (3) immediate antibiotic administration, and (4) removal of the source of the infection. During sepsis, adequate circulating volume and respirations must be maintained or body tissues will not be adequately oxygenated. Rivers et al¹² showed a significant decrease in mortality rate by using a group, or bundle, of interventions that were initiated in the emergency department to (1) recognize sepsis, (2) treat infection rapidly, and (3) maintain tissue perfusion and oxygenation. The major goal was to achieve a central venous oxygen saturation (ScVO₂) of 70% or more, because ScVO₂ reflects cellular oxygen extraction, an early indicator of cellular hypoxia. They did this by keeping the CVP between 8 and 12 mm Hg, the MAP above 65 mm Hg, and urine output greater than or equal to 0.5 mL/kg per hour because these measurements reflect adequate circulating volume. The bundle of interventions was named “early goal-directed therapy” and included the following actions:

Survival depends on early antibiotic treatment. Before antibiotics are started, cultures must be obtained from the blood, wounds, sputum, and urine, as well as any devices, to identify the source and type of infection. An infectious disease specialist may be helpful in choosing the antibiotics that are most likely to be effective, because organisms take time to grow on culture medium and because the specific organisms causing infection are frequently never identified.⁴² Because the source of an infection is usually the lungs, abdomen, urine, wounds, and catheters,⁴² it can be contained by (1) removing external devices (eg, urinary or intravenous catheters) that may harbor the infection, (2) debriding infected tissues, and (3) draining infected fluids.⁸, ¹³

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How Can Sepsis Be Accurately Detected? 

A review of the literature found several strategies that might be useful for detecting sepsis. We address 4 of them here: (1) serum lactate levels, (2) SIRS criteria, (3) 10 vital indicators of body function, and (4) cognitive changes.

Serum Lactic Acid Levels 

Because the serum lactate level reflects cellular hypoxia, it seems logical to measure it to detect and track sepsis. The pathophysiology of sepsis suggests that lactate levels would rise early in the development of shock before organs start to fail.

Serum lactate measurement is practical because results are obtained quite rapidly, and it is detected in venous blood, which is easy to obtain. Rivers et al¹² measured serum lactate levels in ED patients with a suspected infection and instituted goal-directed therapy when the lactic acid level was greater than 4 mmol/L. This threshold was also recommended in the Stop Sepsis Campaign. However, 4 mmol/L may be too high for deciding to initiate early, aggressive treatment. In a retrospective study of 830 adults admitted to the emergency department with severe sepsis, Mikkelsen et al⁴³ found that mortality rates were very high for patients with serum lactate levels ranging from 2 to 3.9 mmol/L and suggested that these patients might also benefit from early goal-directed therapy.

Lactate levels are thought to reflect the degree of hypoperfusion and the severity of shock.³⁰ Shapiro et al⁴⁴ studied the sensitivity and specificity of serum lactate for predicting death from sepsis in an emergency department where the serum lactate level was measured in every patient with an infection-related diagnosis. Of the 1,278 patients in the study, 105 died of sepsis. Higher lactate levels were associated with higher mortality rates. Only 4.9% of patients who had normal serum lactate levels (0-2.5 mmol/L) died, 28.4% died when serum lactate levels were moderately elevated (2.6-4 mmol/L), and 36% died when initial serum lactate levels were high (>4 mmol/L). The authors concluded that serum lactate monitoring helps identify those patients who could benefit from early and aggressive therapy.

As with other physiologic parameters (eg, blood pressure, pulse rate, serum creatinine, and serum electrolytes), normal lactate levels are not absolute but vary over a range from 0 to 2.2 mmol/L. Just as a person with a normally very low creatinine level could already be in kidney failure before the creatinine level rises beyond the normal range, a person with a normally low lactate level might not show an abnormal lactate level as early as someone whose baseline lactate level is higher. Because lactate levels rise as the patient's condition deteriorates, an isolated lactate level collected during early sepsis might not have yet risen beyond normal levels when testing is done. Therefore serial lactate levels that show a steadily increasing lactate level may be a better early predictor of sepsis than an isolated lactate level.

Bakker et al⁴⁵ measured initial serum lactate level at the time of septic shock and serial lactate levels during treatment. They found that only the survivors had a significant decrease in lactate levels during the first 24 hours of treatment and that the duration of elevated lactate levels was a better predictor of death than the initial lactate level. Thus serial lactate levels were helpful for predicting organ failure and death.

Practitioners may err by ignoring an elevated serum lactate level when the pH is normal. However, the pH may be normal despite an elevated lactic acid level because of leakage of albumin (an acid) into the interstitium and because the body compensates for metabolic acidosis by increasing the respiratory rate to blow off carbon dioxide (an acid).⁴⁶ Therefore practitioners should focus on lactate levels regardless of the pH.

Screening Using Sirs Criteria 

Because early sepsis presents as an infection and SIRS, it makes sense to use them as the basis for a screening tool. Moore et al¹⁷ developed a 3-step screening process in a surgical ICU that was based on the SIRS criteria and the presence of infection. Bedside nurses conducted the first screening twice daily using a tool that was based on 4 SIRS criteria: heart rate, respiratory rate, temperature, and white blood cell count. If the total score on the scale was greater than 4, the bedside nurse immediately contacted a nurse practitioner or physician to begin step 2, which involved searching for a verifiable or probable source of infection. If an infection was not ruled out, an intensivist was asked to review all the data, reassess the patient, and initiate treatment (step 3).

The surgical ICU research team evaluated the sensitivity and specificity of the tool using data from 4,991 screenings completed on a total of 920 patients over a 4-month period. Only 4 cases of sepsis were missed, and only 27 patients diagnosed with sepsis were later found not to have it. Some of the 27 patients falsely diagnosed were having early signs of other types of shock and therefore also needed immediate attention. The bedside nurses found the initial screening to be practical and efficient.

Ten Symptoms of Physiologic Instability 

Funk et al³⁴ also recognized the difficulties of recognizing sepsis early. They approached the problem by assessing 10 important symptoms that could be easily assessed at the bedside, namely

The researchers considered changes in these parameters as indicators of physiologic instability. Changes in 2 of more of them were highly specific for sepsis or some other condition that requires immediate attention. They promoted the use of 2 underappreciated measures: capillary refill and respiratory rate. In their experience a capillary refill greater than 3 seconds and a respiratory rate > 20 breaths/min were clear signs of a problem that requires further investigation.

Assessing Changes in Brain Function 

Delirium may be the first sign of infection or sepsis, especially in the elderly.³², ⁴⁷ It has 4 major features: (1) acute onset and fluctuating course, (2) inattention, (3) disorganized thinking, and (4) altered level of consciousness. The Confusion Assessment Method (CAM) is a standardized tool that uses patient behavior and standardized questions to assess the 4 features of delirium and differentiate it from dementia.⁴⁸, ⁴⁹ A person is considered to have delirium if he or she has features 1 and 2 and either feature 3 or 4. The short version of the CAM is practical in the emergency department because it is easy to use, takes only 5minutes, and accurately identifies delirium when used by nurses trained in its use.⁴⁹ The CAM is used to detect delirium that is already present when the patient arrives to the emergency department and provides a baseline assessment for recognizing later changes in cognition.⁴⁸

The first feature of delirium, acute onset, must be verified by a family member or other person who knows how the person usually behaves, because some patients, especially the elderly, may already have cognitive and memory deficits. Delirium's fluctuating course is detected by continued reassessments of cognitive status. The second feature, inattention, is assessed by determining whether patients are able to focus during a conversation or whether their attention is constantly shifting. Standard questions include asking the patient to count backward from 20 or to spell the word “world” backward. The third feature, disorganized thinking, is recognized by the patient's disorganized flow of ideas; the person does not make sense when talking. Finally, the person's level of consciousness is labeled as alert, hyper-alert, drowsy, stupor, or coma.⁴⁸

Further information about the CAM can be found at http://www.hartfordign.org, the Web site of the Hartford Institute for Geriatric Nursing at New York University College of Nursing. The information can also be accessed at http://consultgerirn.org/resources (issue 13 under “General Assessment Series”). The training manual for using the CAM can be found at http://elderlife.med.yale.edu/pdf/The%20Confusion%20Assessment%20Method.pdf.

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Need for Further Research 

Our review and analysis of sepsis literature suggest 3 promising approaches for detecting sepsis in its early stages: (1) serum lactate measurement, (2) a SIRS/infection screening tool, and (3) the CAM to detect delirium. With regard to serum lactate measurement, we do not yet know at what level an elevated serum lactate level is significant and whether serial measurement is useful. Perhaps serial lactate levels would be beneficial in cases where sepsis is suspected but not yet confirmed. They may be especially beneficial in the first 24 hours after admission, the time when sepsis is most likely to progress to severe sepsis and septic shock.

The SIRS/infection screening tool of Moore et al¹⁷ seems promising. Further research is needed to determine its validity, specificity, and sensitivity in other settings, particularly the emergency department. Last, acute mental status changes may be a sensitive indicator of early sepsis, and the CAM is a valid and reliable method for assessing delirium in conscious patients.

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Implications for Emergency Nurses 

Because early recognition of sepsis precludes the early, aggressive treatment necessary for survival and emergency nurses are the first ones to assess the patient, it is essential that they

ED personnel should develop and implement protocols and procedures that aid in the early detection of sepsis. For example, assessment of SIRS criteria and serum lactate level could be automatic for patients who are at high risk for sepsis (eg, those aged >65 years, those who are immunocompromised, or those who have a bacterial infection involving the lungs, urinary tract, or gut). Electronic medical records could be programmed to alert the nurse when the assessment data show certain suspicious patterns, warranting further investigation.

Because mental status changes are often subtle and may be the only sign of sepsis, the CAM should be a regular part of screening. Nurses need to listen carefully when the patients' family members express concern about recent changes in mental function or behavior. They also need to be sensitive to changes in the 10 signs of physiologic instability.

ED personnel also need to develop protocols so that the team works together both to manage suspected cases of sepsis and to treat sepsis appropriately. Cultures must be drawn and antibiotics must be ordered and given within 60 minutes of the order to meet the standards of care. Frequent, accurate patient monitoring is essential during treatment to ensure that ventilation and perfusion are re-established and that aggressive fluid replacement does not inadvertently lead to fluid overload and pulmonary problems. Nurses must monitor vital signs, CVP, and urine output to determine whether vascular fluid replacement is effective. They must auscultate the lungs and heart at regular intervals to detect early signs of fluid overload (eg, crackles in lung fields and an extra heart sound).

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Conclusion 

Sepsis is a life-threatening condition that affects thousands of people every year. Studies have shown that early and aggressive treatment in the emergency department can improve morbidity and mortality outcomes, and experts in the Surviving Sepsis Campaign have developed clear, detailed protocols for its treatment. Therefore health care providers must know how to detect and treat sepsis, and they should develop protocols to improve the process. Further research is needed to develop and test strategies for detecting sepsis early, when treatment will be most successful.

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