The following cases and commentary, which address sepsis, are excerpted from ACP's Medical Knowledge Self-Assessment Program (MKSAP 15).
Case 1: Use of activated protein C
A 47-year-old woman is evaluated in the intensive care unit for sepsis. She was admitted with severe lower lobe pneumonia and is in septic shock despite receiving 8 L of fluid. She has a history of stage IIA colon cancer treated with resection. She is receiving vasopressors and mechanical ventilation; neurologic examination shows no focal abnormalities. Her oxygen saturation is 88% on an FiO2 of 0.75 with a positive end-expiratory pressure of 12 cm H2O. Her extremities are becoming cold and show signs of livedo reticularis. The nasogastric return reveals more than 250 mL of bright red blood. She receives an additional 2 L of fluid, but her blood pressure remains 72/48 mm Hg on norepinephrine.
Laboratory studies find hemoglobin 9 g/dL (90 g/L), leukocyte count 15,500/µL (15.5 × 109/L), platelet count 50,000/µL (50 × 109/L) and INR 2.1.
Which of the following would be a contraindication to therapy with activated protein C in this patient?
A. Active gastrointestinal bleeding
B. INR of 2.1
C. Platelet count of 50,000/µL (50 × 109/L)
D. Resected colon cancer in remission
Case 2: Ruptured diverticulum and infection
A 67-year-old man is evaluated in the surgical intensive care unit. He underwent laparotomy and diverting colostomy for a ruptured diverticulum 72 hours ago, and now has a temperature of 40.0°C (104.0°F) and a heart rate of 135/min. In the past 3 hours his mean arterial blood pressure has dropped to 58 mm Hg despite three 1-L boluses of normal saline; urine output was only 15 mL in the past hour. The patient's oxygen saturation is 85% on 100% oxygen by nonrebreather mask. Platelet count is 42,000/µL (42 × 109/L).
A portable chest radiograph shows bilateral alveolar infiltrates. A central venous catheter is placed; invasive mechanical ventilation and broad-spectrum antibiotic therapy are begun.
Which of the following is the most appropriate next step in the management of this patient?
A. Activated protein C
B. Colloid fluid infusion
C. Insulin drip to maintain plasma glucose less than 110 mg/dL (6.1 mmol/L)
D. Low-dose dopamine
Case 3: Sepsis after a dog bite
A 39-year-old woman is evaluated in the emergency department for fever, myalgia, and malaise 2 days after her pet dog bit her on the left lower extremity. Medical history is significant for a splenectomy 5 years ago following a motor vehicle accident. She has received tetanus, pneumococcal, meningococcal, and Haemophilus influenzae type B vaccines, and her dog's immunizations are up-to-date. There are no allergies, and the remainder of the medical history is noncontributory.
On physical examination, temperature is 38.7°C (101.7°F), blood pressure is 90/60 mm Hg, pulse rate is 110/min, and respiration rate is 26/min; BMI is 26. There is erythema and tenderness at the site of the puncture wound on the left thigh. An abdominal laparotomy scar is noted. There is no inguinal lymphadenopathy. The remainder of the physical examination is normal.
Laboratory studies show hemoglobin 10.0 g/dL (100 g/L); leukocyte count 16,600/µL (16.6 × 109/L) with 56% neutrophils, 33% band forms, 10% lymphocytes, and 1% monocytes; platelet count 17,500/µL (17.5 × 109/L); peripheral blood smear with many Howell-Jolly bodies; blood urea nitrogen 40 mg/dL (14.3 mmol/L); creatinine 2.4 mg/dL (212.2 µmol/L); alanine aminotransferase 500 U/L; aspartate aminotransferase 450 U/L. Multiple blood cultures reveal growth of gram-negative rods/bacilli. The urinalysis is normal. Radiographs of the left femur show no gas or foreign body.
Which of the following is the most likely cause of this patient's septic presentation?
A. Capnocytophaga canimorsus
B. Escherichia coli
C. Salmonella species
D. Staphylococcus aureus
E. Streptococcus pyogenes
Case 4: Glucose management in a septic patient
A 42-year-old man is evaluated in the surgical intensive care unit after surgery for a bowel obstruction. He presented yesterday to the emergency department for a 2-day history of fever, confusion, and abdominal pain. On examination, the patient's temperature was 38.4°C (101.1°F). Cardiac examination was normal; examination of the lungs revealed diffuse bilateral crackles. The abdomen was diffusely and markedly tender, with rebound and guarding. Leukocyte count was 18,400/µL (18.4 × 109/L) with 80% segmented neutrophils and 6% band forms. In the emergency department, his plasma glucose concentration was 205 mg/dL (11.4 mmol/L); the patient has no history of diabetes mellitus. Chest radiograph showed pulmonary edema, and the patient was hospitalized; imipenem/cilastatin was started, and he was taken to surgery. The patient was found to have a bowel obstruction with perforation and contamination of the peritoneal cavity. After surgery, the plasma glucose concentration is 300 mg/dL (16.7 mmol/L).
Which of the following is the most appropriate management of the patient's hyperglycemia?
A. Any insulin regimen that follows a sliding scale
B. Intravenous insulin drip
C. Subcutaneous intermediate-acting basal insulin
D. Subcutaneous long-acting basal insulin
Case 5: Sepsis in a previously healthy young man
A 25-year-old man is brought to the emergency department because of a 1-day history of fever and progressive delirium.
On physical examination, temperature is 38.5°C (101.3°F), blood pressure is 86/58 mm Hg, pulse rate is 122/min, and respiration rate is 34/min. The patient is oriented only to person. On pulmonary examination, he demonstrates increased work of breathing. There is no lymphadenitis. Abdominal examination is normal.
The leukocyte count is 32,000/µL (32 × 109/L). A chest radiograph shows bilateral diffuse alveolar infiltrates. An initial blood smear shows small gram-negative coccobacilli, and special stains show bacteria that look like safety pins.
Infection with which of the following organisms is most likely?
A. Francisella tularensis
B. Salmonella enterica
C. Staphylococcus aureus
D. Streptococcus pneumoniae
E. Yersinia pestis
Case 6: Recognition of the propofol syndrome
A 28-year-old man is admitted to the intensive care unit after having sustained a large aneurysmal subarachnoid bleed and is intubated for airway protection and ventilatory support. Because of increased intracranial pressure and patient-ventilator dyssynchrony, propofol infusion is started at 100 µg/kg/min. The patient's medical course is complicated by gram-positive sepsis and adrenal insufficiency on day 3 in the intensive care unit, for which he is treated with broad-spectrum antibiotic therapy, volume resuscitation, norepinephrine, and hydrocortisone with the goal of maintaining a mean arterial pressure greater than 65 mm Hg. On day 4, the patient remains sedated on mechanical ventilation, and he appears to be improving.
On day 5, the patient develops acute kidney injury, hyperkalemia, metabolic acidosis, rhabdomyolysis, and jugular venous distention with cardiac failure. Electrocardiogram shows no signs of an acute myocardial infarction or ischemia and no peaked T waves or conduction disturbances.
Which of the following is the most urgent next step in the management of this patient?
A. CT scan of the head without contrast
B. Discontinuation of propofol
C. Intravenous heparin
Answers and commentary
Correct answer: A. Active gastrointestinal bleeding.
All the contraindications for therapy with activated protein C (APC, drotrecogin alfa activated) therapy refer to bleeding risk. Heme-positive upper gastrointestinal aspirate or fecal occult blood testing in the absence of active bleeding (often present in intensive care unit patients) is not a contraindication to APC, but this patient's moderate upper gastrointestinal bleeding is a contraindication. As a rule of thumb, when systemic heparin is contraindicated, APC is also contraindicated.
A low platelet count (or elevated INR) is evidence of coagulopathy, which is a good reason to give APC (relative risk reduction of greater than 30%) as long as the platelet count is greater than 30,000/µL (30 × 109/L) and the INR is 3.0 or less. An active malignancy that would predict less than 1 month of survival was an exclusion in the PROWESS study of the efficacy and safety of APC, and such patients were not investigated because they often have do-not-resuscitate orders early in severe life-threatening acute illness such as sepsis. In this case, a history of colon cancer in remission would not be a contraindication.
- Activated protein C has anticoagulant properties, and evidence of active bleeding is a contraindication to its use in patients with sepsis.
Correct answer: A. Activated protein C.
Activated protein C (drotrecogin alfa activated) is a time-sensitive intervention that can improve survival in patients with severe sepsis at high risk of death. Improved survival has been demonstrated in patients with severe sepsis who have an APACHE score of 25 or greater. Patients with either a single failing organ system or an APACHE score less than 25 do not appear to benefit and are at risk of bleeding complications.
Although activated protein C is an anticoagulant, when administered to patients with a platelet count between 30,000/µL (30 × 109/L) and 50,000/µL (50 × 109/L), there was a relative risk reduction in mortality of more than 30% in the Phase III PROWESS trial. Platelet counts below 30,000/µL are considered a relative contraindication. The patient is more than 12 hours out of surgery, with no ongoing active bleeding, a platelet count of 42,000/µL (42 × 109/L), and a high risk of death; therefore, activated protein C is an excellent consideration.
Hyperglycemia is associated with poor clinical outcomes in critically ill patients. However, the benefit of tight glycemic control (≤110 mg/dL [6.1 mmol/L]) is controversial in critically ill postsurgical patients, and no benefit has been shown in critically ill medical patients.
Vasopressors are part of early goal-directed therapy if the mean arterial pressure is less than 65 mm Hg after initial adequate fluid resuscitation. The most commonly used vasopressor for septic shock is norepinephrine, a potent peripheral vasoconstrictor that reverses the endotoxin-induced vasodilation that is the hallmark of septic shock. Dopamine is also acceptable but is associated with more tachycardia and arrhythmia. Low-dose dopamine, however, is not indicated. A randomized controlled trial showed that there is no benefit from “renal doses” of dopamine on renal or other clinical outcomes in early renal dysfunction.
The goals of fluid resuscitation are a central venous pressure of 8 to 12 mm Hg, mean arterial pressure greater than 65 mm Hg, urine output greater than 0.5 mL/kg/h, and central venous oxygen saturation greater than 70%. Randomized controlled trials have shown no benefit to the use of colloid compared with crystalloid fluids.
- Activated protein C has been shown to improve survival in patients with severe sepsis with an APACHE score of 25 or greater.
Correct answer: A. Capnocytophaga canimorsus.
This splenectomized patient most likely has overwhelming sepsis due to Capnocytophaga canimorsus, a member of the normal oral flora of dogs. Life-threatening infection with this gram-negative bacillus has been associated with dog bites in immunosuppressed patients, including those who have undergone splenectomy and those who abuse alcohol or have cirrhosis. The predisposition to infection with this organism in patients with asplenia is due to impaired ability to clear intravascular bacteria and impaired antibody production. The mortality rate is high in patients with C. canimorsus sepsis, requiring prompt management with antibiotics such as a β-lactam/ β-lactamase inhibitor combination, supportive care, and possible surgical debridement.
Escherichia coli is not classically associated with dog bites.
Salmonella species have been associated with infections after contact with pet reptiles such as turtles and snakes. Gastroenteritis is a common feature of infection in these individuals and is not consistent with the symptoms found in this patient.
Staphylococcus aureus and Streptococcus pyogenes can cause necrotizing skin infections with associated shock; however, both are gram-positive cocci in contrast to the gram-negative bacilli that were isolated from the blood cultures of this patient.
- Capnocytophaga canimorsus should be suspected as a cause of sepsis in an asplenic patient or in a patient who abuses alcohol or has cirrhosis and has recently experienced a dog bite.
Correct answer: B. Intravenous insulin drip.
Glucose control in critically ill patients is now practiced widely. Hyperglycemia is believed to contribute to various physiologic derangements, such as inflammation and coagulopathy, that should be controlled in the septic patient. The exact range and goal for target glucose levels have been controversial, with previous studies suggesting that intensive glucose control (a target level of 80 to 110 mg/dL [4.4 to 6.1 mmol/L]) reduced mortality. However, in a recent large, international, randomized trial (the NICE-SUGAR study), intensive glucose control increased mortality among adults in the intensive care unit; a conventional blood glucose target of less than or equal to 180 mg/dL (10.0 mmol/L) resulted in lower mortality than did a target of 81 to 108 mg/dL (4.5 to 6.0 mmol/L).
Continuous intravenous insulin is the most effective method for adequate glycemic control in these patients. Subcutaneous regular insulin based on a sliding scale and intermediate-acting or long-acting basal insulin do not offer the best acute titration of glucose in intensive care unit patients who may have volatile glucose levels. Furthermore, current guidelines emphasize the need to reconsider the widespread use of regular insulin sliding scales, which often result in labile glucose control, as the sole antihyperglycemic therapy in hospitalized patients. Instead, more active, physiologic insulin regimens are advisable.
- Continuous intravenous insulin is the most effective method for adequate glycemic control in critically ill patients.
Correct answer: E. Yersinia pestis.
The most likely diagnosis is pneumonic plague caused by the gram-negative bacillus Yersinia pestis. This organism may induce overwhelming sepsis in an otherwise healthy person, whether exposure is due to a bioterrorism attack or to aerosols from an infected animal (the naturally occurring form).
Plague occurs in three forms: (1) bubonic plague, which is transmitted from rodents to humans by fleas and is associated with a bubo (lymphadenitis); (2) septicemic plague, which progresses from the bubonic form; and (3) pneumonic plague, which results from inhalation of Y. pestis.
Patients with pneumonic plague present with high fever, headache, myalgia, dyspnea, hemoptysis, and sepsis 2 to 4 days after exposure to aerosols of Y. pestis. Sputum is “watery” and may be blood-tinged, and findings of a patchy bronchopneumonia are found on chest radiograph. The mortality rate approaches 100% if patients are not treated within 24 hours of developing symptoms. The diagnosis can be established by isolating the causative microorganism from blood, respiratory secretions, skin, or cerebrospinal fluid. Wayson stain demonstrates the typical bipolar staining, which resembles a “closed safety pin.” Gram stain shows small gram-negative coccobacilli.
Tularemia is a zoonotic infection that occurs worldwide and is acquired in humans by contact with infected animals or ingestion or inhalation of the causative microorganism; it usually infects the lymph nodes, lungs, spleen, liver, and kidneys. Bacteremia is common. Pneumonic tularemia may have a clinical presentation similar to pneumonic plague, but the bacteria would not be described as shaped like “safety pins.”
Salmonella species can cause acute illness, but most cases occur in the presence of diarrhea, and they do not cause pneumonia. Overwhelming sepsis due to Staphylococcus aureus or Streptococcus pneumoniae would be associated with gram-positive organisms on Gram stain, making this diagnosis unlikely.
- Yersinia pestis, a potential agent of bioterrorism, is a gram-negative bacillus that causes pneumonia and overwhelming sepsis (pneumonic plague).
Correct answer: B. Discontinuation of propofol.
This patient has the propofol infusion syndrome, and the drug should be discontinued and replaced by fentanyl and midazolam. The propofol infusion syndrome is a rare and often fatal syndrome originally described in critically ill children undergoing long-term propofol infusion at high doses. The syndrome has recently been reported in adults, mostly in patients with acute neurologic illnesses or acute inflammatory diseases complicated by severe infections or even sepsis and who are receiving catecholamines and/or corticosteroids in addition to propofol.
The main features of the syndrome consist of cardiac failure, rhabdomyolysis, severe metabolic acidosis, and renal failure associated with hyperkalemia. Central nervous system activation with production of catecholamines and corticosteroids, and systemic inflammation with cytokine production are priming factors for cardiac and peripheral muscle dysfunction. High-dose propofol, but also supportive treatments with catecholamines and corticosteroids act as triggering factors. At the subcellular level, propofol impairs free fatty acid utilization and mitochondrial activity.
The syndrome can be lethal if not identified early, and caution should be exercised when using prolonged (more than 48 h) propofol sedation at doses greater than 75 g/kg/min, particularly in patients with acute neurologic or inflammatory illnesses. In these cases, alternative sedative agents should be considered immediately, and monitoring of the plasma levels of troponin I, creatine kinase, and myoglobin should be undertaken. There is no need to obtain a CT scan of the head, which would pose added risk of transport for the patient.
Beyond immediate discontinuation of the drug, the treatment of propofol infusion syndrome is supportive. Supportive treatment may ultimately include bicarbonate infusion, hemodialysis, treatment of heart failure, and cardiac pacing for profound bradycardia. There is no indication for intravenous heparin at this time. Plasmapheresis has no role in managing the propofol infusion syndrome.
- The propofol infusion syndrome in adults occurs primarily in patients with acute neurologic or acute inflammatory diseases complicated by severe infection or sepsis and who are receiving catecholamines or corticosteroids in addition to propofol.