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Sepsis is a clinical syndrome that results from the human body's response to infection. While bacteria probably account for most cases, sepsis can also be the result of infection by fungi, viruses and parasites. Traditionally there was considerable confusion regarding specific definitions of the various sequelae associated with sepsis. In 1992, the American College of Chest Physicians and Society of Critical Care Medicine issued a consensus statement establishing uniform criteria defining the sepsis syndromes. New definitions were offered for some terms, while others were discarded completely. Broad definitions of sepsis and the systemic inflammatory response syndrome were determined, as were specific physiologic parameters by which patients may be categorized.1 These definitions are useful in that they help delineate a clinically observable spectrum of disease. This article will explore sepsis in the adult patient, as well as the evolving prehospital and emergency department care of this illness.
An infection is the invasion by and multiplication of pathogenic organisms in a body tissue, which may result in cellular injury and an immune response. Bacteremia is the presence of culturable bacteria in the bloodstream. Fungemia, parasitemia and viremia can occur as a result of fungal, parasitic and viral infections, respectively. Systemic inflammatory response syndrome (SIRS) is defined as an "abnormal, generalized inflammatory reaction remote from the initial insult."2 Clinically, it is the presence of two or more of the following:
• Temperature less than 96.8°F or greater than 100.4°F;
• Heart rate greater than 90 bpm;
• Respiratory rate greater 20 or a PaCO2 less than 32 mmHg;
• White blood cell count less than 4,500 or greater than 10,000 µl/mm3
The identification of SIRS does not confirm a diagnosis of sepsis, or even an infection; other etiologies of SIRS exist, including trauma, burns and pancreatitis.3 Sepsis is said to occur when there is an identifiable infection plus clinical criteria for SIRS. For instance, a 64-year-old female with tachycardia, tachypnea and a fever with no identifiable infection site would be suspected of having SIRS, while that same patient with a known history of urinary tract infection would have sepsis high up on her differential diagnosis.
Contrary to common belief, microbial invasion of the bloodstream is not an essential component of sepsis, since a local inflammatory response can also elicit the characteristic organ dysfunction and hypotension. For example, bacteremia is often present in patients with sepsis, but does not have to be present for patients to receive a diagnosis of sepsis. Severe sepsis is sepsis with organ dysfunction, which may be evidenced by findings such as acute lung injury, oliguria (low urine output), altered mental status or lactic acidosis. A lactate greater than 4.0 mg/dL when an infection is suspected is considered indicative of severe sepsis. Septic shock is severe sepsis plus hypotension that is unresponsive to fluid therapy, with hypotension defined as a systolic blood pressure below 90 mmHg. To continue our example from earlier, a 64-year-old female with tachycardia, tachypnea, fever, oliguria and altered mental status would be considered to have severe sepsis, and the same patient with hypotension refractory to a fluid bolus would be considered in septic shock.
Epidemiology and Pathophysiology
Suspected severe-sepsis patients account for more than 500,000 ED visits annually, with respiratory and genitourinary infections being the most common causes of sepsis.4 Hospitalizations for septicemia more than doubled over the past decade, from 326,000 in 2000 to 727,000 in 2008.5 Sepsis was the seventh-leading cause of infant mortality in 2010, and the 11th-leading cause of death in adults (34,843 total) that same year.6
Approximately 0.7% of emergency department patients present with suspected severe sepsis. More than two thirds of all sepsis patients initially present to EDs, and approximately 17% of these patients reside in nursing homes.3
The incidence of severe sepsis in the U.S. about 3.0 cases per 1,000 population.7 The incidence of sepsis and its related mortality are significantly higher in the elderly population compared to younger persons, and more than half of all sepsis patients presenting to EDs are over 65 years of age.3 The projected growth of the elderly population in the United States will contribute to an increased incidence of 1.5% each year, resulting in an estimated case load of more than 1.1 million by 2020.7
Sepsis and septic shock are the endpoints of an extremely intricate process that is not precisely understood, but involves a complex and often unbalanced interaction between the body's inflammatory and anti-inflammatory responses to an invading microbe. When a microbe breaches the body's protective epithelial barrier and enters the underlying tissue, it is identified by host neutrophils, macrophages, mast cells and other cells of the immune system, including natural antibodies. These cells secrete cytokines (chemical mediators) that activate the local inflammatory response, resulting in increased capillary permeability and blood flow, which in turn allows neutrophils (phagocytes) to access the infected tissue, crossing from circulation into the interstitial space. Neutrophils will then phagocytize (ingest) the invading microorganisms. Having neutrophils do their job in the interstitial space rather than the circulatory system is desirable, as proteases (digestive enzymes) and oxides are released during phagocytosis. If released in the circulatory system and not the interstitial spaces, these chemicals could result in cellular damage to tissues throughout the body.
This concept of local response to infection is important, and the body has mechanisms to suppress inflammation within the bloodstream so that a systemic response does not occur. This response includes anti-inflammatory, procoagulant and thermoregulatory actions. Anti-inflammatory actions include the release of antioxidants, anti-inflammatory mediators, cytokine antagonists and protease inhibitors. Procoagulant activity helps wall off the developing infection and prevent systemic spread, increases clot formation by decreasing the synthesis of fibrinogen, and decreases the release of antithrombin, an enzyme that inactivates several enzymes of the coagulation system. Thermoregulatory responses to infection include the creation of fever, which inhibits bacterial growth and increases the activity of neutrophils and macrophages.
Patients with sepsis are arguably still maintaining the balance between their local inflammatory and systemic anti-inflammatory responses. These may be patients experiencing a bacterial or viral infection such as the flu, pneumonia or a bladder infection. In otherwise healthy patients, over-the-counter medications or prescription medications from physicians may be sufficient to treat the illness.
Severe sepsis occurs when the body's systemic anti-inflammatory efforts are insufficient to attenuate the massive pro-inflammatory response mounted by the body. Systemic arterial vasodilation leads to a relative hypovolemia, and an increase in systemic microvascular permeability leads to edema formation through third-spacing of fluids. In the lungs this can lead to development of acute respiratory distress syndrome (ARDS).
This third-spacing of fluids contributes to a decrease in circulating blood volume and decreased preload. To maintain blood pressure, the heart will beat harder and faster, leading to a hyperdynamic state in which cardiac output is maintained early in the progression of sepsis. As sepsis continues, cardiac function can become depressed and systemic vascular resistance can decrease, leading to hypotension. Early in sepsis, derangements in the normal distribution of blood volume contribute to the development of tissue and organ hypoxia. When tissues and organs lack access to adequate oxygen, they will convert to anaerobic metabolism that will result in a metabolic acidosis from elevated lactate and other acids. To compensate, a respiratory alkalosis will develop, and the patient will increase their respiratory rate in an effort to blow off the accumulating acids in the blood in the form of carbon dioxide. Despite the increase in respiratory rate, hypoxia can develop secondary to a ventilation-perfusion mismatch that occurs as a result of the derangements in blood distribution.
As early sepsis progresses to moderate and later severe sepsis, a coagulation imbalance occurs, leading to the clinical condition of disseminated intravascular coagulation (DIC). DIC leads to clot formation in the microvasculature, and the result is thrombosis of these vessels, with impaired tissue perfusion. As the body attempts to control these multiple small clots, it overproduces and disperses anticoagulants. The downward spiral of DIC can progress rapidly as more clots form in response and then are also dissolved. Ultimately, platelets and clotting factors are consumed, and diffuse bleeding leading to petechiae and purpura will develop. End-organ failure to the heart, lungs, kidneys and liver will ensue if the situation is not corrected.
Patient History and Clinical Exam Findings
The patient with sepsis is not always easy to identify. Early signs and symptoms can be subtle, often mimicking non-life-threatening illnesses such as the common cold or flu. Familiarity with risk factors can help identify patients who are at high risk, such as the elderly and very young. Other risk factors include recent trauma or surgeries and indwelling devices such as central venous catheters, arterial catheters, urinary catheters, feeding tubes and endotracheal tubes. The immunosuppressed patient is at significant risk, as are those taking medications such as steroids, antibiotics or immunosuppressants.
All cases of severe sepsis and septic shock began as local infection. EMS providers can play a crucial role in sepsis prevention by helping identify infection sources. Identification of an infection site significantly increases your suspicion for sepsis; look during the clinical exam. Inspect bedridden patients for pressure ulcers or other open wounds, and diabetics for wounds on their legs and feet. Assess any indwelling devices for indications of infection such as redness and irritation around the insertion site. Assess for the presence of pulmonary, genitourinary, gastrointestinal or musculoskeletal infections.
The respiratory system is the most common location of infection in the septic patient.7 Question the patient or caregiver about any history of upper respiratory infection or symptoms, throat or ear pain, fever, chills or productive cough. Look for signs of infection during the clinical exam. Rales (crackles) or rhonchi on auscultation, obviously infected tonsils, and sinus or lymph node tenderness may be indicators of an infection source.
Signs and symptoms characteristic of genitourinary infection include issues with urination such as dysuria, polyuria or passing small, frequent amounts of urine. Flank pain may be present, particularly over the kidneys, as may bloody or purulent discharge from the urethra. Foley catheter placement increases the risk of urinary tract infection and has a particularly high rate of infection when Foleys are maintained in the out-of-hospital setting (e.g., skilled nursing facilities, private residences). Inspect any Foley catheter closely for evidence of infection, such as particulate matter in the urine. If a urinary collection bag is being used, inspect the urine for amount, color and clarity. Urine that appears cloudy, has frank blood in it, is cola-colored (indicating blood in the urine) or smells foul indicates a UTI. Inspect the genitalia for penile or vulvar ulcers or lesions and discharge as well as erythema or discharge near the catheter insertion site.
The gastrointestinal system is a common source of infection leading to sepsis, and both acute and chronic disease can lead to infection (Image 1). For example, a patient with a history of diverticulosis may experience an acute diverticulitis, and rupture of an infected diverticulum can lead to sepsis. A thorough history and clinical exam should be performed on the abdomen with the specific intent of identifying an infection source. Ask the patient or caregiver about any history of abdominal pain, and be sure to determine the pain's description, location, onset, what makes it better or worse, quality, if it radiates and the events leading up to it. Seek information regarding the time and quality of the patient's bowel movements and any history of nausea or vomiting. Jaundice may be present if the patient is experiencing liver failure. Physical exam findings associated with specific sources of gastrointestinal infection include rebound tenderness (peritonitis), left lower quadrant pain (diverticulitis), pain at McBurney's point (appendicitis), Murphy's sign (cholecystitis) and shifting dullness (ascites).
A musculoskeletal or cutaneous source of infection for sepsis may not seem obvious but is a legitimate risk. Ask the patient or caregiver about any pain or discomfort localizing to a specific joint. Assess each joint for swelling, redness, pain with palpation or movement, decrease of movement, or warmth. Check the patient's skin for open wounds or sores, pressure ulcers (particularly in dependent areas such as the buttocks, heels and back), abscesses, cellulitis or any other source of infection. Localized pain to lymph nodes and swelling is also a sign of infection.
Patients with sepsis may or may not present with fever. This may seem counterintuitive; however, the profound vasodilation that occurs in sepsis can result in significant heat loss and the development of hypothermia. Patients may experience chills or shivering as they try to compensate for this loss of heat. A core temperature below 36°C (96°F) or above 38°C (100.4°F) indicates hypothermia or fever, respectively.
Patients progressing from sepsis to severe sepsis become profoundly dehydrated. Assess for signs of dehydration such as poor skin turgor, dry mucus membranes and decreased urine output.
A diagnostic tool that is presently uncommon but may be seen in the future is the lactate monitor. Looking and operating much like blood glucose monitors, lactate monitors are a reliable method for determining circulating blood lactate levels. Lactate is released by hypoxic tissues and is a reliable early indicator of hypoperfusion. Lactate levels above 4 mmol/L suggest hypoperfusion and sepsis. These meters have been effectively used in prehospital settings for identifying patients who have severe sepsis.8 Because early recognition of sepsis correlates with decreased mortality, it makes sense to consider using lactate meters for early sepsis recognition.
A New Approach
The prehospital treatment of sepsis has traditionally revolved around addressing issues related to airway, breathing and circulation, and unlike patients with, say, heart attack or stroke, the patient with severe sepsis or septic shock has traditionally been treated like a "routine" patient.
Let's consider stroke. As prehospital care providers, we are trained to aggressively assess for, identify and treat stroke in the field. We obtain thorough histories to determine patients' status regarding fibrinolytic therapy, and transport these patients to specialized stroke centers where they receive specialized care from a team of providers put together for that exact purpose. There is a specialized continuum of care from the prehospital environment to the ED to the ICU, all in an effort to improve outcomes by reducing time to treatment.
In 2001, a team led by Michigan emergency physician Emanuel Rivers published the results of a randomized, controlled trial in which patients presenting to the ED with severe sepsis or septic shock received either a new treatment called early goal-directed therapy or the usual treatment during the first 6 hours of care.9 The core components of early goal-directed therapy include: 1) early identification of patients with sepsis; 2) optimization of oxygenation, ventilation and circulation; 3) initiation of drug therapy, including vasopressors and antibiotics; and 4) controlling the source of infection. In this study, the mortality rate for patients receiving early goal-directed therapy was lower than for those receiving routine care.
Since publication of this data, early goal-directed therapy has been incorporated into the Surviving Sepsis Campaign's most recent international guidelines for management of septic shock, published in 2008.10 Accordingly, the treatment of severe sepsis is now carried out in an organized, systemwide fashion in the hospital environment. Recently, a study from Colorado looked at the role of prehospital care providers in the treatment of sepsis. Paramedics were trained to recognize sepsis in the field through identification of SIRS criteria and alert the hospital in advance, similar to a STEMI notification. Patients whose caregivers provided those alerts had a median arrival-to-antibiotic time of 24 minutes less than those whose caregivers didn't. While 24 minutes may seem unimpressive, in the context of previous research demonstrating a 7.6% increase in mortality for every one hour delay to antibiotics, it becomes more significant.11
Initial management of all critically ill patients should start with ensuring that there is an open airway and adequate ventilation and oxygenation. If breathing is adequate, administer 100% oxygen via nonrebreather mask with the goal of maintaining an SpO2 of at least 94%. CPAP can be useful in the patient with mild respiratory distress, but use as low of a pressure as possible to improve ventilation.
Consider endotracheal intubation not only of patients for whom you cannot maintain an open airway, but also for those with severe respiratory distress and accessory muscle use. Intubation and subsequent positive-pressure ventilation will decrease the work of breathing, decrease oxygen demand and limit the development of acidosis by helping improve the exchange of both oxygen and carbon dioxide. Once they're intubated, ventilate patients to maintain an EtCO2 of 35–45 mmHg. Patients with severe respiratory distress and impending respiratory failure use a disproportionately large amount of energy for the muscles of respiration. As such, improved oxygen delivery to other organs is achieved by mechanical ventilation with sedation and paralysis. Ideally, endotracheal intubation would be performed via rapid sequence intubation, to increase the likelihood of successful intubation, decrease the work of breathing and increase the effectiveness of ventilation. In patients with pulmonary edema or ARDS, the characteristic decrease in lung compliance will result in a greater negative intrathoracic pressure during inspiration, further decreasing preload and possibly lowering blood pressure in the already compromised patient. Whether using a BVM with a face mask or an endotracheal tube, take care with airway pressures while ventilating.
When ventilating the patient with severe sepsis or septic shock, avoid hyperventilation or the use of too much tidal volume (TV) or pressure. Increased TVs and airway pressures are associated with increases in intrathoracic pressure, which can lead to hypotension and barotrauma. Maintaining as low as an airway pressure as possible while increasing end-expiratory pressure by providing PEEP has been shown to increase arterial oxygen delivery.12
Obtain intravenous or intraosseous access in two sites to assist in volume replacement (Image 2). Patients with severe sepsis will require aggressive fluid volume resuscitation to correct the hypovolemia that can occur with the third-spacing of fluids and profound vasodilation. Large volumes of fluid may be necessary to maintain adequate perfusion. Patients with severe sepsis may require 2 liters or more of an isotonic crystalloid during their initial therapy (first 30–60 minutes), and may receive as much as 6–10 liters within the first 24 hours of treatment.13 Administer fluid rapidly; some sources recommend infusion rates as fast as 0.5 liters every 5–10 minutes as needed to restore adequate perfusion (as measured by a systolic blood pressure of 90 mmHg or a mean arterial pressure greater than 60 mmHg). Consider aggressive fluid volume replacement even in patients for whom you'd normally consider withholding it, such as in those with renal or congestive heart failure. As always, refer to local protocols or consult with online medical control when determining fluid volume administration rates (Image 3).
The prehospital use of vasoactive medications to manage hypotension in the patient with sepsis is relatively rare for agencies with short transport times, but agencies with extended transports or transfers must be comfortable with their use. Use vasoactive agents to correct hypotension in the patient who remains refractory to fluid volume administration after the first 2 liters. These drugs may also be indicated earlier when there are signs of fluid overload (such as pulmonary edema). Common medications used are dopamine, dobutamine and norepinephrine. Norepinephrine tends to be the preferred drug for patients with sepsis because they are likely to already be tachycardic. Dopamine can exacerbate tachycardia, and dobutamine is generally more indicated for patients with heart failure.
Additional treatment for the patient with sepsis or septic shock includes maintaining body temperature. Recall that patients with sepsis can present hyper- or hypothermic. Regardless of presenting core temperature, patients with sepsis are susceptible to heat loss. Protect them by employing warming measures such as blankets and turning up the heat in the patient compartment.
Monitor the blood sugar of patients with suspected sepsis closely. During the cascade of events that occurs systemically during severe sepsis, profound hyperglycemia becomes common—even in patients without prior histories of diabetes. Most hospitals use insulin to keep blood sugars below 180 mg/dL during sepsis.
The prehospital administration of antibiotics is beyond the scope of paramedics in essentially all EMS systems. However, it is well documented that the earlier sepsis is recognized and managed, the lower its mortality. Intravenous antibiotics may be appropriate to consider in some paramedic systems where lactate levels can be used to confirm the presence of sepsis and ED transport times are greater than 30 minutes.
The administration of intravenous antibiotics is common during interfacility transport of sepsis patients. Typically, once sepsis is confirmed, two different antibiotics are initiated simultaneously. A broad-spectrum antibiotic is given, as well as one specific to the local infection source. Vancomycin and and Zosyn are commonly given as first-line antibiotics for sepsis. If you work in an environment where transport times are long (greater than 30 minutes), consider working with your medical director to implement a sepsis recognition and management plan.
1. Bone R. 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.
2. Bone RC, Grodzin CJ, Balk RA. Sepsis: A new hypothesis for pathogenesis of the disease process. Chest 1997; 112: 235–243.
3. Jui J. "Septic Shock." In Tintinalli's Emergency Medicine: A Comprehensive Study Guide, 7th ed. McGraw-Hill, 2011.
4. Wang HE, Shapiro NI, Angus DC, Yealy DM. National estimates of severe sepsis in United States emergency departments. Crit Care Med 2007; 35: 1,928.
5. Hall MJ, Williams SN, et al. Inpatient Care for Septicemia or Sepsis: A Challenge for Patients and Hospitals. NCHS Data Brief No. 62, June 2011.
6. Murphy ML, Xu J, Kochanek KD. Deaths: Preliminary Data for 2010. National Vital Statistics Report. Hyattsville, MD: National Center for Health Statistics, 2012.
7. Angus DC, Linde-Zwirble WT, Lidicker J, et al. Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001; 29: 1,303–10.
9. 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(19): 1,368–77.
10. Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock. Crit Care Med 2008; 36: 296.
11. Mayfield TR, Meyers M, Guerra W. Decreasing door to antibiotic time in septic shock patients using an EMS sepsis alert. J Emerg Med Serv, www.jems.com/article/training/prehospital-care-research-forum-presents-0.
12. The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000; 342: 1,301–08.
Scott R. Snyder, BS, NREMT-P, is EMS education manager for the San Francisco Paramedic Association, where he is responsible for the original and continuing education of EMTs and paramedics. He has worked on numerous publications as an editor, contributing author and author. Contact him at firstname.lastname@example.org.
Sean M. Kivlehan, MD, MPH, NREMT-P, is an emergency medicine resident at the University of California, San Francisco and a former New York City paramedic. Contact him at email@example.com.
Kevin T. Collopy, BA, FP-C, CCEMT-P, NREMT-P, WEMT, is an educator, e-learning content developer and author of numerous articles and textbook chapters. He is the performance improvement coordinator for Vitalink/Airlink in Wilmington, NC, and a lead instructor for Wilderness Medical Associates. Contact him at firstname.lastname@example.org.