Severe Sepsis Case File

Severe Sepsis Case File

Eugene C. Toy, MD, Barry C. Simon, MD, Terrence H. Liu, MD, MHP, Katrin Y. Takenaka, MD, Adam J. Rosh, MD, MS

Case 6

A 73-year-old woman is brought to the emergency department (ED) from an assisted-living facility. The patient has a history of dementia, hypertension, and type II diabetes mellitus. By report, she has had chills and a productive cough for several days. In the past 24 hours she has become weaker and does not want to get out of bed. The physical examination reveals a thin, elderly woman who is somnolent but arousable. Her rectal temperature is 36.0°C (96.8°F), pulse rate is 118 beats per minute, blood pressure is 84/50 mm Hg, and respiratory rate is 22 breaths per minute. Her mucous membranes are dry. Her heart is tachycardic but regular. She has crackles at her right lung base with a scant wheeze. Her abdomen is soft and nontender. The extremities feel cool and her pulses are rapid and thready. The patient is moving all extremities, without focal deficits.

⯈ What is the most likely diagnosis?

ANSWER TO CASE 6:

Severe Sepsis

Summary: A 73-year-old woman presents from an assisted-living facility with cough, lethargy, and hypotension of unknown etiology.

• Most likely diagnosis: Severe sepsis due to healthcare-associated pneumonia

ANALYSIS

Objectives

1. Learn to recognize the clinical presentations of systemic inflammatory response syndrome (SIRS)/sepsis and the atypical presentations in children and the elderly.
2. Learn the pathophysiology, systemic effects, and management of sepsis and its common complications.
3. Become familiar with early goal-directed therapy in the treatment of sepsis and septic shock.

Considerations

This woman appears to be suffering from severe sepsis, a clinical entity on the continuum from systemic inflammatory response syndrome to septic shock with multiorgan system dysfunction (see below for definitions). In her case, the etiology is likely pneumonia, an extremely common cause of sepsis in elderly patients. Sepsis caused by a urinary tract infection (ie, urosepsis) is another important cause of sepsis in this population.

There are over 750,000 cases of sepsis in the United States each year. Overall mortality is 30% and, while the mortality rate has been decreasing, the rise in number of cases has led to an increase in the total number of deaths caused by sepsis: the most recent US figures attribute >215,000 deaths annually to sepsis. As this woman falls into the classification of septic shock, her risk of death may be closer to 70%, even with treatment.

The current standard of care for treating sepsis uses an algorithm known as early goal-directed therapy (EGDT), which has been shown to dramatically improve hemodynamic outcomes and mortality (see below).

Approach To:

Severe Sepsis

DEFINITIONS

SYSTEMIC INFLAMMATORY RESPONSE SYNDROME (SIRS): At least two of the following:

• Temperature >38°C or <36°C
• Heart rate >90 beats per minute
• Tachypnea or hyperventilation (respiratory rate >20 breaths per minute or Paco2 <32 mm Hg)
• White blood cell count >12,000 cells/mL or <4000 cells/mL, or >10% bands

SEPSIS: SIRS with an infectious source.

SEVERE SEPSIS: Sepsis in conjunction with at least one sign of organ failure or hypoperfusion, such as lactic acidosis (lactate ≥4 mmol/L), oliguria (urine output ≤0.5 mL/kg for 1 hour), abrupt change in mental status, mottled skin or delayed capillary refill, thrombocytopenia (platelets ≤ 100,000 cells/mL) or disseminated intravascular coagulation, or acute lung injury/acute respiratory distress syndrome.

SEPTIC SHOCK: Severe sepsis with hypotension (or requirement of vasoactive agents, eg, dopamine or norepinephrine) despite adequate fluid resuscitation in the form of a 20- to 40-cc/kg bolus.

MULTIORGAN DYSFUNCTION SYNDROME (MODS): MODS is the far end of the spectrum that begins with SIRS. It is defined as dysfunction of two or more organ systems such that homeostasis cannot be maintained without intervention.

CLINICAL APPROACH

Pathophysiology

Sepsis is usually caused by bacterial infection (see Table 6–1 for common bacterial causes of infection). However, it may be caused by viral or, increasingly, by fungal infection. In general, sepsis is a complex interaction between the direct toxic effects of the infecting organism and derangement of the normal inflammatory host response to infection.

Normally, in the setting of infection, there is concurrent local activation of the immune system and of down-regulatory mechanisms to control the reaction. The devastating effects of the sepsis syndrome are caused by a combination of (1) generalization of the immune response to sites remote from that of the infection and (2) derangement of the balance between proinflammatory and anti-inflammatory cellular regulators, as well as (3) dissemination of the infecting organism.

In general, the immune response to infection optimizes the ability of immune cells to leave the circulation and enter the site of infection. Microbial antigens trigger local cells to release proinflammatory cytokines. These molecules attract leukocytes, slow blood flow through venules and capillaries, and trigger dilation of vessels and increased “leakiness” of vessel walls. At the same time, the cytokines induce the release and production of acute-phase reactants, which fight microbes but are also procoagulants. It is when the two main effects of the inflammatory cascade— vasodilation and coagulation—spread beyond the site of local infection that the syndrome of sepsis manifests in systemic hypotension, hypoperfusion, coagulopathy, and resultant organ failure. In the face of hypoperfusion and lack of oxygen, organs are forced to use anaerobic metabolism, leading to an elevation in serum lactic acid.

The degree of elevation correlates strongly with prognosis: higher presenting lactate levels and slow decline of lactate during resuscitation are associated with significantly higher mortality.

Clinical Presentation

Sepsis begins with signs of a systemic inflammatory response (ie, fever, tachycardia, tachypnea, leukocytosis) and progresses to hypotension in the setting of either peripheral vasodilation (“warm” or hyperdynamic septic shock, with generalized flushing and warmth and increased cardiac output) or peripheral vasoconstriction (“cold” or hypodynamic septic shock, with cold blue or white extremities). In a patient with this presentation and physical examination findings consistent with infection, diagnosis is easy and treatment can be begun early.

It is important to remember that, especially in infants and the elderly, initial presentation may lack some of the more salient features—that is, they may present with hypothermia rather than hyperthermia, leukopenia rather than leukocytosis, and they may not be able to mount a tachycardia (as in elderly patients on β- or calcium-channel blockers) or they may have a tachycardia attributed to other causes (as in anxious infants). In a patient at the extremes of age, any nonspecific systemic complaint—vomiting, fatigue, behavioral changes—should prompt concern for sepsis, and consideration of at least initial screens for infection, such as a chest radiograph and urinalysis.

Be aware that a patient not initially meeting the criteria for sepsis may progress to full-blown sepsis even during the course of an emergency department stay, with initially only subtle changes in examination. Altered mental status is often the first sign of organ dysfunction, as it is assessable without laboratory studies, but it is easily missed in the elderly, the very young, and those with other potential causes for altered level of consciousness, such as intoxication. Decreased urine output (≤0.5 mL/kg/h) is another sign that may be apparent prior to the return of laboratory values and should raise clinical concern.

Evaluation/Management

Initial Treatment Considerations The patient should immediately be placed on a cardiac and pulse-oxygenation monitor, and a manual blood pressure obtained. Supplemental oxygen by nasal canula or facemask should be titrated to keep oxygen saturation >93%, two large-bore, peripheral IVs should rapidly be inserted, and, in the absence of a fluid overload condition (eg, congestive heart failure, renal failure) a fluid bolus of 20 to 40 mL/kg (2-4 L in adults) crystalloid administered (Table 6–2). If available, a point of care lactic acid should be obtained without delay. Ideally, it should be obtained prior to the initial fluid bolus; however, this should under no circumstances cause a delay resuscitation. If the patient clearly has severely increased work of breathing or cannot protect her airway, the patient should be intubated, with care taken with selection of induction agents, as many cause hypotension.

Blood should be drawn for a complete blood count (with differential), comprehensive metabolic panel, blood cultures (two sets), and lactic acid (if not already obtained). A urinalysis with culture and chest x-ray should be ordered immediately as part of what must be an aggressive search for the source of the infection (the majority of sepsis in this country is caused by either pneumonia or urinary tract infections). An ECG should also be ordered early in the workup, to evaluate for cardiac ischemia secondary to hypoperfusion.

Broad-spectrum intravenous antibiotics should be started rapidly—ideally after the cultures have been drawn, but antibiotic infusion should not be delayed if cultures cannot be obtained in a timely fashion (<1 h after presentation), particularly in a patient like this one, who is extremely ill and hemodynamically unstable. Initial therapy should be empiric, with good coverage for all possible sites and organisms, as there is good evidence that inappropriate antibiotic selection doubles mortality (see Table 6–1 for suggested antibiotics).

Subsequent Priorities Immediately upon termination of the fi rst fl uid bolus, the patient should be reassessed. If the patient continues to be hypotensive or has a lactate level greater than 4 mmol/dL or has other signs of continued hypoperfusion, then early goal-directed therapy (EGDT) should be initiated. EGDT is a method of continual assessment and reassessment of clinical and laboratory markers, with interventions aimed at normalizing those markers. The overarching goal of EGDT is to eliminate mismatch between oxygen demand and oxygen supply (the hallmark of sepsis) by increasing supply and—where possible—by decreasing demand.

Early Goal-Directed Therapy

Goal 1: central venous pressure (CVP) 8-12 mm Hg: CVP should be kept between 8 and 12 mm Hg (or >12 mm Hg if mechanically ventilated), with continued fluid boluses (which may total as much as 6 to 10 L of crystalloid over the first hours) to maintain an adequate CVP. In practice, 500 cc of normal saline can be bolused every 15 to 30 minutes until the CVP goal is met.

Goal 2: mean arterial pressure (MAP) ê65 mm Hg: If the patient’s MAP remains <65 mm Hg despite adequate fluid resuscitation, vasopressors should be initiated, with either norepinephrine or dopamine usually recommended as the starting agents. They should be titrated to a goal of MAP ≥65 mm Hg. If blood pressure is unresponsive to the first vasopressor, a second agent may be added. Low-dose vasopressin can be used as a second- or third-line agent.

Goal 3: central venous oxygen saturation (ScvO2) >70%: On placement of the central line, blood obtained should be sent for an oxygen saturation. If the ScvO2 is ≤70% (meaning the tissues are extracting as much oxygen as possible from the blood, and therefore that tissue demand is not being met), then oxygen delivery should be optimized by

• Transfusing packed red blood cells to a hematocrit ≥30%.
• If the ScvO2 continues to be <70% despite achieving CVP 8 to 12 mm Hg, MAP ≥65 mm Hg, and HCT ≥30%, then dobutamine infusion should be started to boost cardiac output.
• If all of the above measures are taken and ScvO2 continues to be <70%, then patient can be intubated to maximize oxygenation and sedated in an attempt to decrease oxygen demand.

Additional goal: lactate clearance of >10%: An initial lactate should be sent in every patient with suspected sepsis. After a minimum of 2 hours of resuscitation a repeat lactate should be checked to ensure that at least 10% of the lactate has been cleared. If the lactate clearance is not at least 10% then oxygen delivery should be optimized in much the same way that is described in the ScvO2 section by

• Transfusing packed red blood cells if the hematocrit is <30%.
• If there is not a lactate clearance of at least 10% after transfusion then dobutamine infusion should be started and titrated to achieve a 10% clearance.

If a 10% clearance is not achieved, lactate levels should be checked at 1 to 2 hour intervals and repeat clearance calculated each time. New data show that in hospitals where ScvO2 cannot easily be monitored, lactate can be used in lieu of ScvO2 monitoring.

A patient in severe sepsis or septic shock should be admitted to an intensive care unit. Throughout her stay in the emergency department, she should be frequently reassessed, using measurements of blood pressure, central venous pressure, oxygen saturation, central venous saturation, urine output, and lactate to direct therapy. If severe sepsis progresses to multiorgan dysfunction syndrome, therapy includes support or replacement of the affected organs/systems as indicated below under complications.

Other Therapies/Interventions

Ultrasound: Is a noninvasive method that can be used to monitor CVP that does not require placement of a central venous catheter thus avoiding the time delay and catheter-associated complications. Studies have looked at using compression ultrasound of the forearm or measurement of the internal jugular vein to approximate CVP. In the hands of a well-trained sonographer this can be used as a noninvasive way to estimate central venous catheter.

Steroids: While historically steroids have been used in sepsis, their role is becoming more limited. Recent published data suggest that even “physiologic doses” of steroids do not improve overall mortality in severe sepsis. It is not recommended that they be used in sepsis without shock unless there is a recent history of prolonged steroid use or history suggesting adrenal suppression. In the case of septic shock unresponsive to fluid resuscitation and vasopressors, steroids may be considered.

Activated protein C: Protein C is an enzyme produced in the liver that inhibits thrombosis and promotes fibrinolysis. A patient’s native ability to activate protein C appears to be impaired in sepsis. Given the contribution of coagulopathy and impaired microvascular circulation to mortality in sepsis, it was theorized that exogenous activated protein C might be helpful. There is some evidence that it may decrease mortality in patients who have severe sepsis and have a high risk of death, but it does not benefit patients at low risk of death. Therefore, it should only be given to patients with sepsis-induced organ dysfunction that are deemed to be at a high risk of death. It should not be given if there are contraindications to anticoagulation (ie, active bleeding, risk of bleeding, history of intracranial bleeding, etc). The use of activated protein C is never recommended in children.

Glucose control: This is an area of recent controversy. For a period of time it was thought that there was benefit to maintaining tight control of blood glucose in the range of 80 to 120 mg/dL. However, more recent studies have shown that glucose control this tight leads to significantly more severe hypoglycemia. Therefore, we recommend that in sepsis a patient’s glucose goals should be between 140 and 180 mg/dL.

Intravenous immunoglobulin: In children, administration of intravenous immunoglobulin (IVIG) in both neonates and older children has been shown in some studies to result in improvement in mortality and fewer complications, although a recent meta-analysis was inconclusive as to IVIGs benefit in sepsis. Its presumed mechanism of action is augmented clearance of pathogenic organisms and feedback inhibition of inflammatory cytokines.

Extracorporeal membrane oxygenation: Extracorporeal membrane oxygenation (ECMO), a form of mechanical heart-lung bypass, has been used in septic shock in children with unclear results. It may be tried, when available, to treat a patient in cardiorespiratory failure that is refractory to traditional means of support.

HMG-CoA reductase inhibitors (“statins”): HMG-CoA reductase inhibitors, or statins, are lipid-lowering agents that are thought to have a significant antiinflammatory component. Animal studies have shown increased survival from sepsis with administration of statins, and there is evidence from observational studies that being on a statin lowers human patients’ likelihood of death from sepsis. Statins are relatively safe and inexpensive drugs. If forthcoming studies show benefit, statins may become a standard component of the treatment of sepsis.

Complications

ALI and ARDS (acute lung injury and acute respiratory distress syndrome): The inflammatory milieu of sepsis is especially damaging to the lungs. Buildup of inflammatory fluid in the alveoli impairs gas exchange favors lung collapse, and decreases compliance, with the end result of respiratory distress and hypoxemia. ALI/ARDS is a common complication of severe sepsis and is often visible on chest x-ray, in the form of bilateral pulmonary opacities consistent with pulmonary edema. A septic

patient who did not initially require mechanical ventilation may later require it if she develops ALI/ARDS after fluid resuscitation. In such cases, low tidal volumes (ie, tidal volume set initially to 8 mL/kg then titrated down to 6 mL/kg in the first couple hours of therapy) should be used, with measures taken to limit peak inspiratory pressures and thus limit barotrauma to the lung—a significant risk.

DIC (disseminated intravascular coagulation): In DIC caused by sepsis, the coagulation cascade is diffusely activated as part of the inflammatory response. At the same time, the fibrinolytic system, which normally acts to keep the clotting cascade in check, is activated. These factors begin a feedback spiral in which both systems are constantly and diffusely activated—new clots always being formed, then broken down. A large proportion of the body’s clotting factors and platelets are consumed in such clots. Thus, patients are at risk for complications from both thrombosis and hemorrhage. In this setting, platelets may be given if the platelet count is <5000 cells/mm³ without signs of bleeding, or <30,000 cells/mm³ with active bleeding. Fresh-frozen plasma should be given if there is active bleeding. The development of any coagulopathy in sepsis correlates with a worse outcome.

Cardiac failure: Myocardial depression is an early complication of septic shock, with the mechanism thought to be direct action of inflammatory molecules rather than decreased perfusion of coronary arteries. Supporting the heart’s function involves careful attention to preload (hydration with close monitoring of CVP), afterload (vasopressors), and contractility (supported with dobutamine). Sepsis places an unprecedented workload on a heart, which can precipitate acute coronary syndrome or a myocardial infarction, especially in the elderly. Thus inotropic agents and vasopressors (most of which can result in tachycardia) must be used with care when necessary but never when unwarranted.

Hepatic failure: Liver failure usually manifests as cholestatic jaundice, with increases in bilirubin, aminotransferases, and alkaline phosphatase. Synthetic function is usually not affected unless patients are hemodynamically unstable for long periods.

Renal failure: Hypoperfusion appears to be the main mechanism for renal failure in the setting of sepsis, which is manifested by oliguria, azotemia, and inflammatory cells on urinalysis. The treatment is first to adequately support perfusion with hydration and vasopressors. However, if the renal failure is severe or the kidneys cannot be adequately perfused, then renal replacement therapy (eg, hemodialysis or continuous veno-venous hemofiltration) is indicated.

Multiorgan dysfunction syndrome: Dysfunction of two or more organ systems such

that intervention is required to maintain homeostasis.

• Primary—in which failure of organs is directly caused by infection or injury of them; that is, heart/lung failure in the setting of severe pneumonia
• Secondary—in which failure of organs is caused by generalized inflammatory response to an insult; that is, ALI or ARDS in the setting of urosepsis

COMPREHENSION QUESTIONS

6.1 A 32-year-old woman is noted to have persistent hypotension from suspected toxic shock syndrome despite 6 L of normal saline given intravenously. Which of the following is the best next step?

A. Use colloid (albumin) for the next bolus.

B. Initiate norepinephrine infusion.

C. Administer corticosteroid therapy.

D. Transfuse with fresh-frozen plasma.

E. Activated protein C.

6.2 A 45-year-old man with acute cholecystitis is noted to have a fever of 38.3°C (101°F), hypotension, and altered sensorium. His HCT is noted to be 24%. Broad-spectrum antibiotics and intravenous saline are administered, and, although his CVP is 10 and his MAP is 80, his ScvO2 remains <70%. Which of the following is most likely to be beneficial?

A. Initiate corticosteroids

B. Tight glucose control

C. Acetaminophen 500 mg PR

D. Transfusion

E. Lithotripsy

6.3 A 32-year-old woman is admitted to the hospital for acute pyelonephritis. The patient is treated with oral ciprofloxacin. After 4 days of therapy, she returns to the ED with persistent fever to 38.9°C (102°F) and flank tenderness. The urine culture reveals E coli greater than 100,000 colony-forming units per mL susceptible to ciprofloxacin. When you arrive to examine her, you note that she is tachypneic, tachycardiac, and appears lethargic. Which of the following is the next step?

A. Order an intravenous pyelogram.

B. Obtain IV access and administer a fluid bolus.

C. Initiate a workup for fictitious fever.

D. Consult a surgeon for possible appendicitis.

E. Add antifungal therapy.

6.4 A 66-year-old woman is noted to have acute pneumococcal pneumonia and is being treated with antibiotics, and with norepinephrine and dobutamine to maintain her BP and urine output. Which of the following is a bad prognostic sign?

A. Urine output of 1 mL/kg/h

B. Mean arterial blood pressure of 80 mm Hg

C. Lactic acid level of 6 mmol/dL

D. Serum bicarbonate level of 22 mEq/L

E. Hematocrit 35%

ANSWERS

6.1 B. A vasopressor agent such as norepinephrine (or dopamine) is the treatment of choice for hypotension that is unresponsive to intravenous saline infusion. The use of colloids during resuscitation has not been shown to improve outcome compared to crystalloids. Fresh-frozen plasma is not indicated. There is not enough information provided to asses if activated protein C is indicated.

6.2 D. This patient has met two of the three goals of EGDT, but fails to meet the third goal of ScvO2 >70%. In the setting of HCT <30%, transfusion with PRBCs is indicated. Tight glucose control and steroids have not been shown to consistently improve mortality in all comers with severe sepsis.

6.3 B. This patient is progressing to severe sepsis, and possibly septic shock. While an intravenous pyelogram may be needed eventually to rule out mechanical obstruction (eg, an infected stone) as a cause of this patient’s refractory UTI, the urgent need here is prompt fluid resuscitation.

6.4 C. The elevated serum lactate is evidence that oxygen supply is not meeting systemic oxygen demand. A lactate level ≥4 is a poor prognostic sign. The other parameters are normal.

CLINICAL PEARLS

⯈ The most common causes of severe sepsis are urosepsis and pneumonia.

⯈ Older, younger, or immunocompromised individuals may present with subtle signs such as lethargy, decreased appetite, or hypothermia.

⯈ Early goal-directed therapy for sepsis includes careful monitoring of multiple markers of organ perfusion, with aggressive measures to restore any imbalance between oxygen supply and demand.

⯈ Initially, large volumes of fluid administered in multiple boluses may be necessary (and in some cases sufficient) to maintain perfusion.

⯈ An early and thorough search for a source must be undertaken, with immediate measures taken to control it. Whether or not an operable source is found, broad-spectrum antibiotics should be started immediately. If an operable source is found, it should be surgically treated as soon as the patient can tolerate it.

⯈ A vasopressor agent such as norepinephrine or dopamine is the next step in treating hypotension that persists despite intravenous fluids.

References

Dellinger RP, Levy MM, Carlet JM, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med. 2008;36(1):296-327. 

Finfer S, Chittock DR, Su SY, et al. Intensive vs conventional glucose control in critically ill patients. NEJM. 2009:360:1283-1297. 

Gao F, Linhantova L, Johnston AM, et al. Statins and sepsis. Br J Anaesth. 2008;100(3):288-298. 

Ibrahim EH, Sherman G, Ward S, et al. The influence of inadequate antimicrobial treatment of bloodstream infections on patient outcomes in the ICU setting. Chest. 2000;118:146-155. 

Jones AE, Shapiro NI, Trzeciak S, Arnold RC, Claremont HA, Kline JA. Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA. 2010;303 (8):739-746. 

Laterre P. Clinical trials in severe sepsis with drotrecogin alpha (activated). Crit Care Med. 2007;11 (suppl 5):S5. 

Laupland KB, Kirkpatrick AW, Delaney A. Polyclonal intravenous immunoglobulin for the treatment of severe sepsis and septic shock in critically ill adults: a systematic review and meta-analysis. Crit Care Med. December 1, 2007;35(12):2686-2692. 

Nagdev AD, Merchant RC, Tirado-Gonzalez A, et al. Emergency department bedside ultrasonographic measurement of the caval index for noninvasive determination of low central venous pressure. Ann Emerg Med. 2010;55(3):290-295. 

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):1368-1377. 

Trzeciak S, Cinel I, Dellinger RP, et al. Resuscitating the microcirculation in sepsis: the central role of nitric oxide, emerging concepts for novel therapies, and challenges for clinical trials. Acad Emerg Med. 2008;15:399-413.

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