Hemodynamic and Inflammatory Effects of Abrupt Versus Tapered Corticosteroid Discontinuation in Septic Shock

Current therapy for septic shock includes antimicrobials, fluid resuscitation,
catecholamines, and measures to improve tissue oxygen delivery. The use of corticosteroids as
an adjunctive treatment in septic shock has been an area of intensive research over the past
decade. A handful of studies suggest that patients in septic shock benefit from low-dose
glucocorticoids.Low-dose corticosteroids may improve hemodynamics, decrease vasopressor
requirements, and reduce 28-day mortality in patients with vasopressor-refractory septic
shock. A meta-analysis from 2004 also suggested that the use of low-dose corticosteroids does
not significantly increase the risk of superimposed infections, gastrointestinal bleeding, or
hyperglycemia.

The exact mechanism for this beneficial effect has not been completely established, although
direct vascular effects and anti-inflammatory effects of corticosteroids have been proposed.
While there is ongoing debate over which subpopulations of patients derive benefit from
corticosteroids, there is as much controversy regarding the appropriate duration of therapy.
The current Surviving Sepsis Campaign suggests that intravenous IV hydrocortisone
200-300mg/day should be given to adult septic shock patients after it has been confirmed that
their blood pressure is poorly responsive to fluid resuscitation and vasopressor therapy. The
duration of therapy is not specified. There is also no clear evidence to suggest that
patients benefit from tapering steroids as opposed to stopping them abruptly; both strategies
have been employed. Annane showed both a mortality benefit and shorter duration of
vasopressor therapy with an abrupt end to a 7-day course of hydrocortisone and
fludrocortisone in patients with septic shock compared to placebo; while others showed a
similar benefit with a taper.Keh demonstrated reversal of both hemodynamic and immunologic
effects after a three-day treatment of "low-dose" hydrocortisone, suggesting that some of the
beneficial effects of steroids disappear in less than 24 hours. Interestingly, 30% of
patients had to restart vasopressor therapy after discontinuation of corticosteroids in one
of the Keh's study arms.

Inclusion Criteria:Patients who meet the following criteria will be enrolled in the study:

- suspected septic shock

- initiation of hydrocortisone 50mg IV Q6H (per MICU protocol)

- written informed consent signed by patient or legal surrogate

- Septic shock is defined by meeting all of the following requirements:

- Clinical evidence of infection. Clinical evidence of infection is defined as the
presence of a known or probable source of infection that has necessitated the
initiation of systemic antimicrobial therapy. Clinical evidence of infection could
include (but is not limited to) one or more of the following:

1. presence of increased number of PMNs (neutrophils) in normally sterile body fluid

2. positive culture or gram stain of blood, sputum, urine, or normally sterile body
for a pathogenic microorganism

3. chest radiograph consistent with a diagnosis of pneumonia with a positive
culture, gram stain, diagnostic bronchoalveolar lavage, or protected specimen
brush for a respiratory tract pathogen

4. focus of infection identified by visual inspection (e.g., ruptured bowel found at
surgery, wound with purulent drainage, radiographic or Computed tomographic
evidence of an abscess or osteomyelitis, etc.) and

5. patient has an underlying disease or condition that is highly likely to be
associated with infection (e.g., ascending cholangitis, ischemic bowel, etc.)

- Two of the following:

1. Core temperature either > 38°C (> 100.4°F) or < 36°C (< 96.8°F)

2. Tachycardia. Heart rate greater > 90 beats/minute

3. Respiratory rate > 20 b/min or PaCO2 < 32 torr, or need for mechanical
ventilation due to sepsis

4. WBC > 12 or < 4 K/mm3

- End-organ cardiovascular dysfunction defined as hypotension unresponsive to fluid
replacement necessitating vasopressor therapy, or lactate ≥4 mmol/L

Exclusion Criteria:

- age less than 18

- previous systemic corticosteroid therapy in the past 90 days (prednisone >5 mg/d or
equivalent)

- pregnancy

- Acquired Immune Deficiency Syndrome (AIDS)

- hematological malignancies

- advanced form of cancer with less than 30-day life expectancy

- patients who receive fludrocortisone

- evidence of prior acute myocardial infarction