Test yourself: Sepsis

Case 1: Acute respiratory distress syndrome

A 67-year-old man is receiving mechanical ventilation for acute respiratory distress syndrome. He underwent laparotomy and diverting colostomy for a ruptured diverticulum 72 hours ago, and now has fever to 40.0°C (104.0°F) and has diffuse bilateral infiltrates that have been present for the past day. Two deep tracheal suction specimens are sent for culture, and Gram stains show 4+ gram-negative rods.

The patient's oxygen saturation is worsening, and his mean arterial blood pressure has dropped to 58 mm Hg despite three 1-L boluses of normal saline, with only 15 mL of urine output in the past hour. He is also noted to have a lactic acidosis and thrombocytopenia, with a platelet count now falling to 42,000 cells/µL (42 × 109 cells/L) in the absence of heparin or H2-antagonist therapy.

Which of the following would be appropriate management for this patient?

A. Start resuscitation with colloids
B. Avoid activated protein C
C. Start low-dose dopamine
D. Adjust the ventilator with 6 mL/kg of ideal body weight and a plateau pressure less than 30 cm H2O

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Case 2: Confusion and fever

A 71-year-old woman is brought to the emergency department from a nursing home because of confusion, fever, and flank pain. Her temperature is 38.5°C (101.3°F), blood pressure is 82/48 mm Hg, pulse rate is 123 beats/minute, and respiration rate is 27 breaths/minute. Physical examination reveals dry mucous membranes, costovertebral tenderness, poor skin turgor and no edema. Leukocyte count is 15,600 cells/µL (15.6 × 109 cells/L); urinalysis shows 50 to 100 leukocytes and many bacteria per high-powered field. The patient has a metabolic acidosis and high lactate levels believed due to septic shock. Antibiotic therapy is started.

Which of the following is most likely to improve survival for this patient?

A. 25% albumin infusion
B. Aggressive fluid resuscitation
C. Maintaining hemoglobin above 12 g/dL
D. Maintaining a Paco2 below 50 mm Hg
E. Hemodynamic monitoring with a pulmonary artery catheter

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Case 3: Severe lower-lobe pneumonia

A 47-year-old woman with severe lower-lobe pneumonia is in shock despite receiving 8 L of fluid, on vasopressors and mechanical ventilation, with a nonfocal neurological examination. Her oxygen saturation is 88% on 75% Fio2 with a positive end-expiratory pressure of 12 cm H2O. Her extremities are becoming cold and show signs of livedo reticularis. She receives an additional 2 L of fluid therapy but her blood pressure remains 48/72 mm Hg on norepinephrine.

Which of the following would be a contraindication to activated protein C therapy in this patient?

A. Platelet count of 48,000 cells/µL (48 × 109 cells/L)
B. Active gastrointestinal bleed
C. Resected colon cancer in remission
D. Age over 75 years
E. Previous therapy with activated protein C

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Case 4: Gram-negative sepsis

A 65-year-old man is admitted to the intensive care unit with gram-negative sepsis. His medical history is significant only for borderline hyperthyroidism for which he takes methimazole. On intensive care unit day two, he undergoes rapid sequence intubation with propofol and succinylcholine for worsening hypoxemic respiratory failure resulting from the acute respiratory distress syndrome. The patient receives 2-mg lorazepam and 50-µg fentanyl boluses intravenously for sedation and 1 to 2 mg of intravenous haloperidol for episodic hyperactive delirium. On day 3, the patient is febrile (temperature 40°C [104°F]), hypertensive, and tachycardic.

On physical examination, the patient is diaphoretic and rigid when turned in the bed. Arterial blood gas analysis shows a metabolic acidosis with respiratory compensation, and laboratory tests are significant for an elevated creatinine kinase.

Which of the following is the most likely cause of this patient's clinical deterioration?

A. Thyroid storm
B. Malignant hyperthermia
C. Neuroleptic malignant syndrome
D. Worsening gram-negative sepsis
E. Pheochromocytoma

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Case 5: Aneurysmal subarachnoid bleed

A 28-year-old man is admitted to the intensive care unit after having 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 per minute. The patient's medical course is complicated by gram-positive sepsis and adrenal insufficiency on day three in the intensive care unit, for which he is treated with appropriate broad-spectrum antibiotic therapy, volume resuscitation, norepinephrine, and hydrocortisone with the goal of maintaining a mean arterial pressure above 65 mm Hg.

On day four the patient remains sedated on mechanical ventilation, and he appears to be improving. On day five, the patient develops acute renal failure, hyperkalemia, metabolic acidosis, rhabdomyolysis and jugular venous distention with apparent cardiac failure. Electrocardiography 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 appropriate next management choice?

A. Obtain a CT scan of the head without contrast
B. Start a bicarbonate infusion
C. Start hemodialysis
D. Discontinue propofol and change to fentanyl and midazolam

View correct answer for Case 5

Answers and commentary

Case 1

Correct answer: D. Adjust the ventilator with 6 mL/kg of ideal body weight and a plateau pressure less than 30 cm H2O.

This patient has severe sepsis resulting from nosocomial pneumonia. The appropriate management according to the Surviving Sepsis Campaign guidelines is to adjust the ventilator using a “protective lung strategy” with 6 mL/kg of ideal body weight and a plateau pressure less than 30 cm H2O. This intervention is supported by the landmark ARDSnet trial that demonstrated a 10% absolute risk reduction in mortality using these parameters to guide the ventilator management. Resuscitation with colloids and dopamine are inconsistent with data and current guidelines. Antibiotics, though not mentioned, are considered a time-sensitive intervention that should be instituted within the first hour of admission to the intensive care unit or within three hours of admission to the emergency department. Fluid resuscitation, usually with crystalloids, should be initiated aggressively within the first six hours.

Activated protein C (drotrecogin alfa activated) is also considered one of the time-sensitive interventions (along with corticosteroids, tight glucose control, and ventilator management). In this case, activated protein C administered to patients with a platelet count between 30,000 cells/µL (30 × 109 cells/L) and 50,000 cells/µL (50 × 109 cells/L) actually has a relative risk reduction of more than 30% in the Phase III PROWESS trial. Platelet counts below 30,000 cells/µL (30 × 109 cells/L) are considered a relative contraindication. The patient is more than 12 hours out of surgery, with no ongoing active bleeding, and a platelet count of 42,000 cells/µL (42 × 109 cells/L), with a high risk of death; therefore, activated protein C is an excellent consideration for this patient. Low-dose dopamine is a strong negative recommendation, and should no longer be used in this manner. A well-conducted randomized controlled trial showed that there is no benefit from renal doses of dopamine on renal or other clinical outcomes in early renal dysfunction.

Key points

  • In patients with severe sepsis from nosocomial pneumonia, the ventilator should be adjusted by using a “protective lung strategy” with 6 mL/kg of ideal body weight and a plateau pressure less than 30 cm H2O.
  • Low-dose dopamine has been shown to be of no benefit in critically ill patients with early renal dysfunction.

Case 2

Correct answer: B. Aggressive fluid resuscitation.

Aggressive fluid resuscitation with resolution of lactic acidosis within 6 hours would have a beneficial effect on this patient's survival. The patient has severe sepsis presumptively from pyelonephritis. The point here is that “timing” of resuscitation matters to survival. In a landmark study by Rivers and colleagues, early goal-directed therapy (EGDT) that included interventions delivered within the first six hours to maintain a central venous oxygen saturation of more than 70% and to effect resolution of lactic acidosis resulted in higher survival rates than more delayed resuscitation attempts. Indeed, over the first 72 hours those in the control arm received the same quantity of fluid for their resuscitation, but they had a significantly higher likelihood of dying by discharge or at 60 days.

Crystalloid is given much more frequently than colloid, and there are no data to support routinely using colloid in lieu of crystalloid, especially in patients who are so obviously volume depleted as this patient. Giving blood may be part of resuscitation for anemic patients in shock, but going to hemoglobin levels above 12 g/dL (120 g/L) is not supported by evidence. In stable ICU patients who are not in shock, a transfusion threshold of 7 g/dL is an acceptable conservative approach, but this does not apply to the period of EGDT. There are no data to show that either maintaining a lower Paco2 or using a pulmonary artery catheter would help to increase survival in this patient.

Key point

  • In patients with severe sepsis, early goal-directed therapy within the first six hours to maintain a central venous oxygen saturation of more than 70% and to resolve lactic acidosis improves survival over more delayed resuscitation attempts.

Case 3

Correct answer: B. Active gastrointestinal bleed.

All the contraindications for activated protein C (APC) therapy center on bleeding risk. Evidence of active bleeding is a contraindication to the use of APC because the drug has anticoagulant properties. Heme-positive upper gastrointestinal aspirate or fecal testing would in the absence of active bleeding (so often present in ICU patients) not be a contraindication to APC. When systemic heparin is contraindicated, APC is analogously contraindicated. This woman is at high risk of death, as evidenced by two sepsis-induced dysfunctional organs (respiratory failure and shock). Though the FDA used the APACHE score to understand the population severity that benefited the most from APC, in practice it is not required to calculate an APACHE score and a very practical way to calculate the “high risk of death” is any two dysfunctional organs due to sepsis. This was the method used for approval by regulatory authorities, for example, in many countries including those in Europe. Low platelet count (or elevated INR) is evidence of coagulopathy, which is a good reason to give the medication as long as the platelets are above 30,000 cells/µL (30 × 109 cells/L) and the INR is 3.0 or less.

An active malignancy that would predict less than one month of survival was an exclusion in the PROWESS study, and such patients were not investigated because they are 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. Patients older than 75 years have a very large absolute risk reduction (15.5%) from APC therapy compared with placebo, and this survival advantage remained statistically significant at two years. Lastly, having received APC in the past is not a contraindication as there are no data to date that demonstrate antibody formation that would pose a risk to patients.

Key point

  • Activated protein C has anticoagulant properties, and evidence of active bleeding is a contraindication to its use in patients with sepsis.

Case 4

Correct answer: C. Neuroleptic malignant syndrome.

Although the syndrome has a variable onset and sometimes evolves rapidly, rigidity and altered mental status usually occur early, followed by autonomic changes and hyperthermia. Specific early signs include obtundation, catatonia, tachycardia, tachypnea, labile blood pressure, dysarthria, dysphagia, diaphoresis, sialorrhea, incontinence, rigidity, myoclonus, tremors, low-grade fevers or serum creatine kinase elevations.

Hyperthermia may be observed in patients with thyrotoxicosis and pheochromocytoma, which can be distinguished from neuroleptic malignant syndrome by the absence of rigidity. Volatile anesthetics and succinylcholine are associated with malignant hyperthermia, but affected patients usually have a profound increase in the metabolic production of carbon dioxide, despite increasing minute ventilation, resulting in a combined respiratory and metabolic acidosis.

Key point

  • The neuroleptic malignant syndrome is a rare, but potentially fatal, complication of the administration of neuroleptic (antipsychotic) drugs such as haloperidol.

Case 5

Correct answer: D. Discontinue propofol and change to fentanyl and midazolam.

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. Recently several cases have been reported in adults, too. These adult cases were mostly patients with acute neurologic illnesses or acute inflammatory diseases complicated by severe infections or even sepsis, and 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 glucocorticoids 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. Imbalance between energy demand and utilization is a key pathogenetic mechanism, which may lead to cardiac and peripheral muscle necrosis.

The syndrome can be lethal if not identified early, and caution should be exercised when using prolonged (>48 hours) propofol sedation at doses higher than 75 µg/kg per minute, 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 cranial CT scan and this would pose added risk of transport for the patient. Neither bicarbonate infusion nor hemodialysis is indicated at this time for his acute renal failure, which will likely resolve with management of 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 receiving catecholamines and/or corticosteroids in addition to propofol.

Key points

  • The propofol infusion syndrome in adults occurs primarily in patients with acute neurologic or acute inflammatory diseases complicated by severe infection or sepsis, and receiving catecholamines and/or corticosteroids in addition to propofol.
  • The main features of the propofol infusion syndrome are cardiac failure, rhabdomyolysis, severe metabolic acidosis, and renal failure associated with hyperkalemia.