Surviving Sepsis: Part 2

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Review by Ryan Petersen, MD
Column organized by Evan Schwarz, MD
Washington University in St. Louis
Division of Emergency Medicine

Nguyen HB, Rivers EP, et al.  Severe sepsis and septic shock:  review of the literature and emergency department management guidelines.  Annals of Emergency Medicine.  July 2006; 48 (1):  28-54.


A 75-year-old male presents to your department.  Per the family he is typically an alert and active gentleman, but over the last week his condition has quickly deteriorated with increased confusion and less interaction. His initial vitals are T38.5, RR32, P140, BP86/42, and his physical exam significant for palpable distended and tender bladder.  You order a Foley catheter which is placed returning dark cloudy urine.  Concerned for urosepsis you begin your typical management and order early antimicrobials.  You wonder if there have been any recent advances in the management of patients with sepsis and how you could apply these to your patient’s care.   
Sepsis has been defined as the presence or presumed presence of an infection accompanied by a systemic inflammatory response syndrome (SIRS).  SIRS is defined as the presence of 2 or more of the following: temperature greater than 38 degrees or less than 36 degress, pulse rate greater than 90, respiratory rate greater than 20, WBC count >12,000/mm3, or <4,000/mm3, or greater than 10% bands.  Severe sepsis is defined as the presence of sepsis and one or more organ dysfunctions, septic shock simply adds the component of refractory hypotension. The newer definition of sepsis, while more vague, includes many other findings (such as an elevation of inflammatory markers, thrombocytopenia, and coagulation abnormalities) in addition to the suspicion of infection.  As septic patients may not always have a low bicarbonate level or anion gap, lactate levels can be useful in both making the diagnosis and judging the patient’s response to therapy.  Arterial levels correlate well with mixed venous or central venous lactate levels.  Peripheral venous lactate levels do not always correlate well with arterial levels.  However the likelihood of arterial hyperlactemia is reduced with a normal peripheral lactate but only slightly increased with an elevated value.  Severe sepsis and septic shock are conditions, which have mortality approaching nearly 50%.  Sepsis kills more people each year than myocardial infarctions, lung cancer, or breast cancer.
Sepsis at its most basic element is a disruption between the systemic oxygen delivery to cells and the systemic oxygen consumption resulting in a global tissue hypoxia.  A goal directed hemodynamic approach to severe sepsis and septic shock involving the restoration of systemic oxygen delivery through the manipulation of preload, afterload, and contractility to preserve tissue perfusion and maintain coronary perfusion within the first six hours of presentation has been termed early goal directed therapy (EGDT).  EGDT involves the use of crystalloid or colloid solution (in those that are less able to handle a large amount of crystalloid such as CHF patients) to reach a goal CVP (central venous pressure) between 8-12, the use of vasoactive agents to maintain a MAP goal of 65-90 mm Hg, transfusion of blood products to achieve a HCT >30%, and if needed intubation, sedation, and paralysis and the addition of dobutamine, to achieve a goal ScvO2 of >70%.  Rivers et al, who developed and implemented the therapy demonstrated a decrease of in hospital mortality from 46.5% to 30.5% (relative reduction in morality rate 34.4%, number needed to treat of 6).  The use of antibiotics is not new in the treatment of sepsis, but there are specific recommendations in regards to the choice, timing, and use of combination therapy for EGDT.  Studies have demonstrated that choosing the appropriate antibiotic has led to a decrease in mortality.  Antibiotics should be chosen which possess in vitro activity against the pathogen.  Understanding the local, regional, and national resistance patterns and trends should guide this selection. Although there is insufficient data to conclude that delays in antibiotic treatment on the order of hours worsens outcomes, antibiotics should be provided within the ED care time, and some say within 3 hours of ED admission.  The initial selection should be broad and utilize a combination approach, increasing the likelihood that the infectious organism is covered with less concern regarding developing antibiotic resistance in the septic patient.  The antibiotic therapy can later be tailored according to the pathogen’s identification and antibiotic susceptibility.
The administration of recombinant human activated Protein C (drotrecogin alpha or Xigris) demonstrated a decrease in mortality in sepsis/septic shock in the PROWESS study.  This study enrolled patients with clinical evidence of infection, presence of SIRS, and at least one sepsis induced organ dysfunction present for 25 or > 2 sepsis-induced organ dysfunctions.  A later trial demonstrated no benefit for patients with APACHE II scores 25 despite adequate hemodynamic optimization with EGDT and proper antimicrobial therapy if contraindications do not exist. However while some studies show an increased benefit if activated Protein C is started in the first 24 hours after diagnosis, there are currently no recommendations concerning initiation of therapy in the emergency department versus early on in the ICU.
Patients with sepsis should have increased levels of stress hormones such as cortisol, but a subset of these patients will have a relative adrenal insufficiency. This is defined as an increase in serum cortisol < 9ug/dL one hour after administration of 250 µg of adrenocorticotropic hormone.  Annane et al performed a study involving patients with greater than 1 hour of fluid unresponsive hypotension and greater than 5µg/kg/min requirement for dopamine or other vasopressors. 
Patients were randomized to receive 50 mg of hydrocortisone I.V. and 50 µg of fludrocortisone P.O. for 7 days after an adrenocorticotropic hormone stimulation test was performed or a placebo.  Patients with relative adrenal insufficiency had decreased 28-day mortality of 53% compared to the control rate of 63%.  The recommendation is to provide mechanically ventilated septic shock patients with organ dysfunction requiring vasopressors despite EGDT and appropriate antibiotics with low–dose corticosteroids following an adrenocorticotropic hormone stimulation test.  A current multi-center trial of corticosteroid therapy in septic shock called CORTICUS may clarify this therapy.  Keep in mind that in a setting where an adrenocorticotropic hormone stimulation is not practical, dexamethasone can be given without interfering with the stimulation test once the patient arrives in an ICU setting.
Patients with septic shock typically require mechanical ventilation, and although not a specific treatment for sepsis, mechanical ventilation can be optimized.  The Acute Respiratory Distress Syndrome Network demonstrated that low volume ventilation use when acute lung injury is present reduced morality rates from 39.8% in conventionally ventilated patients to 31% in low tidal volume ventilated patients (relative reduction in morality rate of 22.1%).  Patients with severe sepsis/septic shock with acute lung injury requiring mechanical ventilation should receive low tidal volume ventilation, reducing the tidal volume to as low as 4 ml/kg if necessary to maintain airway plateau pressures less than or equal to 30 cm H2O.
Over the past few years the treatment of sepsis and septic shock has changed substantially.  Many of the new therapies place the impetus on the emergency room physician whose initial actions are critical in the long-term outcomes of these patients.  Emergency physicians must identify those patients who meet sepsis criteria.  They need to utilize the principles of early goal directed therapy and provide timely and adequate antibiotic therapy to these patients.  A subset of which may benefit from activated Protein C or steroid therapy, and those who require mechanical ventilation should receive low tidal volume ventilation.  Lastly, the emergency physician must stay abreast of new developments and information in an effort to provide the latest and best care possible.   


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