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

Primary Purpose

Septic Shock

Status

Terminated

Phase

Phase 4

Locations

United States

Study Type

Interventional

Intervention

hydrocortisone

Normal Saline

About this trial

This is an interventional treatment trial for Septic Shock focused on measuring Sepsis, hydrocortisone

Eligibility Criteria

18 Years - 99 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Cleveland Clinic

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

hydrocortisone

Normal Saline (placebo)

Arm Description

Hydrocortisone 50 mg IV every 12 hours x 4 doses (2 days), followed by Hydrocortisone 50 mg IV every 24 hours x 2 doses (2 days)

0.9% sodium chloride (equal volume to hydrocortisone) IV every 12 hours x 4 doses (2-days), followed by 0.9% sodium chloride (equal volume to hydrocortisone) IV every 24 hours x 2 doses (2-days)

Outcomes

Primary Outcome Measures

Incidence of Hypotension Between Study Days 8 and 14 (Within 7 Days of the Initiation of Study Drug).

Study screening/enrollment stopped due to lack of eligible subjects. No outcome measures were analyzed due to the low enrollment.

Secondary Outcome Measures

Full Information

NCT ID

NCT01150409

First Posted

June 21, 2010

Last Updated

March 6, 2018

Sponsor

The Cleveland Clinic

1. Study Identification

Unique Protocol Identification Number

NCT01150409

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

March 2018

Overall Recruitment Status

Terminated

Why Stopped

Difficulty in recruiting eligible subjects

Study Start Date

May 2008 (undefined)

Primary Completion Date

August 2010 (Actual)

Study Completion Date

August 2010 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

The Cleveland Clinic

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The proposed study will evaluate the potential benefit of a tapered course of hydrocortisone compared to abrupt cessation in patients initiated on hydrocortisone for septic shock. The study will include adult patients in the medical intensive care unit (MICU) who meet criteria for corticosteroid therapy for septic shock according to the current MICU protocol.All patients will receive 7 days of hydrocortisone (50mg/Q6hrs) as part of the routine management of septic shock, before being randomly assigned to receive hydrocortisone taper versus no taper. The primary study endpoint is the incidence of hypotension within 7 days after randomization. Secondary endpoints will include incidence of adrenal insufficiency, and changes in the inflammatory status (assessed by cytokine measurements) before, during, and after corticosteroid discontinuation. The cytokines to be measured include IL-1, IL-6, IL-9, IL-10, and TNF. Since there has not been a randomized clinical trial to investigate the potential benefit of weaning septic patients off low-dose hydrocortisone as opposed to stopping abruptly, this study has potential to change clinical practice by leading to a consistent approach of corticosteroid discontinuation and to a better understanding of their impact on the inflammatory modulation in septic shock.

Detailed Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Septic Shock

Keywords

Sepsis, hydrocortisone

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

11 (Actual)

8. Arms, Groups, and Interventions

Arm Title

hydrocortisone

Arm Type

Experimental

Arm Description

Hydrocortisone 50 mg IV every 12 hours x 4 doses (2 days), followed by Hydrocortisone 50 mg IV every 24 hours x 2 doses (2 days)

Arm Title

Normal Saline (placebo)

Arm Type

Placebo Comparator

Arm Description

0.9% sodium chloride (equal volume to hydrocortisone) IV every 12 hours x 4 doses (2-days), followed by 0.9% sodium chloride (equal volume to hydrocortisone) IV every 24 hours x 2 doses (2-days)

Intervention Type

Drug

Intervention Name(s)

hydrocortisone

Other Intervention Name(s)

11β,17α,21-trihydroxypregn-4-ene-3,20-dione

Intervention Description

1) Hydrocortisone 50 mg IV every 12 hours x 4 doses (2 days), followed by Hydrocortisone 50 mg IV every 24 hours x 2 doses (2 days)

Intervention Type

Drug

Intervention Name(s)

Normal Saline

Other Intervention Name(s)

0.9% sodium chloride

Intervention Description

0.9% sodium chloride (equal volume to hydrocortisone) IV every 12 hours x 4 doses (2-days), followed by 0.9% sodium chloride (equal volume to hydrocortisone) IV every 24 hours x 2 doses (2-days)

Primary Outcome Measure Information:

Title

Incidence of Hypotension Between Study Days 8 and 14 (Within 7 Days of the Initiation of Study Drug).

Description

Study screening/enrollment stopped due to lack of eligible subjects. No outcome measures were analyzed due to the low enrollment.

Time Frame

Day 14

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

99 Years

Accepts Healthy Volunteers

Eligibility Criteria

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: presence of increased number of PMNs (neutrophils) in normally sterile body fluid positive culture or gram stain of blood, sputum, urine, or normally sterile body for a pathogenic microorganism 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 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 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: Core temperature either > 38°C (> 100.4°F) or < 36°C (< 96.8°F) Tachycardia. Heart rate greater > 90 beats/minute Respiratory rate > 20 b/min or PaCO2 < 32 torr, or need for mechanical ventilation due to sepsis 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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Jorge A Guzman, MD

Organizational Affiliation

The Cleveland Clinic

Official's Role

Principal Investigator

Facility Information:

Facility Name

Cleveland Clinic

City

Cleveland

State/Province

Ohio

ZIP/Postal Code

44195

Country

United States

12. IPD Sharing Statement

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

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