Necrotizing Soft Tissue Infection, Sepsis
Conditions
Brief summary
Evaluate the impact of HAT therapy versus placebo in the treatment of patients with an acute NSTI and sepsis.
Detailed description
Primary outcome: 1\. Hospital survival Secondary outcomes: 1. Duration of vasopressor therapy 2. Requirement for renal replacement therapy in patients with Acute Kidney Injury (AKI) 3. ICU length of stay (LOS) 4. Change in serum procalcitonin (PCT) over first 72 hours 5. Change in SOFA score over first 72 hours (measured as SOFA score daily for four days, with day one being admission, then 3 days after, totaling 4 days of treatment with HAT) 6. Procalcitonin clearance (formula = initial PCT - 72 hour PCT divided by initial PCT x 100) 7. Number of wound related surgeries 8. Wound status at time of hospital discharge: 1. Open 2. Closed
Interventions
DRUGHAT
hydrocortisone, ascorbic acid (vitamin C), and thiamine (vitamin B1); referred to as HAT
DRUGPlacebo
normal saline solution
Sponsors
University of Kansas
Ascension Via Christi Hospitals Wichita, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
A randomization list will be used to show whether patients will be in group A or B. Only the Research Scientist who made the randomization list and the Pharmacy will know what group patients are in. The Burn Program Coordinator will get consent and enroll patients to the study. After that, the Burn Program Coordinator will call the pharmacy and report what group the patient is enrolled in, A or B. Then, the pharmacy will order the respective medications. The doctors and nurses providing care for the patients will not know who is in what treatment group, and neither will the patients.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Necrotizing soft tissue infection by clinical diagnosis and requiring surgical treatment. 2. Sepsis by clinical diagnosis and/or by Sepsis-3 criteria15, with source attributed to the wound. 3. Anticipated or confirmed intensive care unit
Exclusion criteria
(Adapted from Sevransky et. al's VICTAS protocol) 1. Age \< 18 years of age 2. Weight \< 40 kg 3. Prior enrollment in this study or current enrollment in another study of any kind 4. Surgical findings, pathology/histology findings, or other findings determined to be inconsistent with an infectious acute NSTI such that the clinical diagnosis is no longer that of a NSTI 5. Sepsis deemed unlikely 6. Limitations of care during enrollment \[defined as refusal of cardiovascular and respiratory support modes described in inclusion criteria, including do not intubate (DNI) status and comfort care\] 7. Known allergy or known contraindication to vitamin C, thiamine, or corticosteroids \[including previous history or active diagnosis of primary hyperoxaluria and/or oxalate nephropathy, or known/suspected ethylene glycol ingestion, or known glucose-6-phosphate dehydrogenase (G6PD) deficiency\] 8. Use of vitamin C at a dose of \>1g/day (IV or oral) within the 24 hours preceding first episode of qualifying organ dysfunction during a given Emergency Department or Intensive Care Unit admission 9. Chronic disease/illness that, in the opinion of the site investigator, have an expected lifespan of \< 30 days unrelated to current sepsis diagnosis (e.g., stage IV malignancy, neurodegenerative disease, etc.) 10. Kidney Stone(s) of any kind 11. History of Oxalate Kidney Stone(s) 12. Pregnancy or known active breastfeeding 13. Prisoner or Incarceration 14. Inability or unwillingness of subject or legal surrogate/representative to give written informed consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Hospital Survival | Outcome is measured from date of admission to date of discharge or date of death, whichever comes first, approximately 7 to 10 days. | Hospital survival is a binary variable showing whether the patient survived their time in the hospital. Hospital survival will be assessed from date of randomization until the date of discharge or date of death from any cause, whichever comes first, assessed up to 24 months. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Requirement for Renal Replacement Therapy in Patients With Acute Kidney Injury (AKI) | Outcome is measured from date of admission to date of discharge or date of death, whichever comes first, approximately 7 to 10 days. | This is a binary variable the will record whether the patient did or did not have a requirement for renal replacement therapy in patients with Acute Kidney Injury (AKI). |
| ICU Length of Stay (LOS) | Outcome is measured from date of admission to date of discharge or date of death, whichever comes first, approximately 7 to 10 days. | ICU LOS will be measured by the date and time the patient was admitted to the ICU and by the date and time the patient was discharged from the ICU. |
| Change in Serum Procalcitonin (PCT) Over First 72 Hours | Over the first 72 hours from admission. | This is a binary variable that will show whether there was a decrease in serum procalcitonin (PCT) over first 72 hours. |
| Duration of Vasopressor Therapy | Outcome is measured from date of admission to date of discharge or date of death, whichever comes first, approximately 7 to 10 days. | The duration of vasopressor therapy is measured after date of randomization in hours and minutes from the initiation of vasopressor therapy until the termination of vasopressor therapy. |
| Procalcitonin Clearance | Outcome is measured from date of admission to date of discharge or date of death, whichever comes first, approximately 7 to 10 days. | Procalcitonin clearance (formula = initial PCT - 72 hour PCT divided by initial PCT x 100). The reported measure is median and range for those patients that |
| Number of Wound Related Surgeries | Outcome is measured from date of admission to date of discharge or date of death, whichever comes first, approximately 7 to 10 days. | This is a variable that will show the count of wound related surgeries during the time the patient is admitted to the hospital. |
| Wound Status at Time of Hospital Discharge: Open | Outcome is measured from date of admission to date of discharge or date of death, whichever comes first, approximately 7 to 10 days. | This shows the number of participants with an open wound at time of hospital discharge. |
| Change in Sequential Organ Failure Assessment (SOFA) Score Over First 72 Hours (Measured as SOFA Score Daily for Four Days, With Day One Being Admission, Then 3 Days After, Totaling 4 Days of Treatment With HAT) | Outcome is measured from date of admission to date of discharge or date of death, whichever comes first, approximately 7 to 10 days. | This is a binary variable that will shows whether there was a decrease in SOFA score over the first 72 hours (measured as SOFA score daily for four days, with day one being admission, then 3 days after, totaling 4 days of treatment with HAT). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment Arm Patients will be enrolled within 24 hours of diagnosis of sepsis related to a necrotizing soft-tissue infections (NSTI). HAT will be initiated within 4 hours of enrollment (thus treatment with HAT can occur no later than 28 hours from diagnosis).
Per Dr. Marik's original study, HAT consists of:
1. 1.5 g vitamin C every 6 hours for 4 days or until ICU discharge
2. 50 mg hydrocortisone every 6 hours for 7 days or until ICU discharge (followed by a taper over 3 days)
3. 200 mg thiamine every 12 hours for 4 days or until ICU discharge In our study, due to the prolonged ICU course typical of most patients with NSTIs, it is not felt feasible to continue indefinitely until ICU discharge. Thus, treatment will be continued for 4 to 7 days plus a 3 day taper (respectively) as above, with no plan for a longer duration of treatment.
HAT: hydrocortisone, ascorbic acid (vitamin C), and thiamine (vitamin B1); referred to as HAT | 5 |
| Control Arm The control arm will receive the same standard ICU care for NSTI but will not receive HAT. They will receive a placebo consisting of normal saline, indistinguishable to the treatment team (blinded) but known to the pharmacy team (unblinded to treatment and placebo groups). This is so that if the treatment team elects to give stress dose steroids, they can be administered without breaking protocol (i.e. if the patient is getting HAT, it includes steroids, so if the treating team wanted to start hydrocortisone - because they didn't know if the patient was on HAT or placebo and felt steroids were indicated - the pharmacist could ensure the patient was on steroids one way or another without unblinding the providers).
Placebo: normal saline solution | 5 |
| Total | 10 |
Baseline characteristics
| Characteristic | Control Arm | Total | Treatment Arm |
|---|---|---|---|
| Age, Continuous | 54.0 years | 60.5 years | 66.0 years |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment United States | 5 participants | 10 participants | 5 participants |
| Sex: Female, Male Female | 1 Participants | 4 Participants | 3 Participants |
| Sex: Female, Male Male | 4 Participants | 6 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 5 | 0 / 5 |
| other Total, other adverse events | 0 / 5 | 0 / 5 |
| serious Total, serious adverse events | 0 / 5 | 0 / 5 |
Outcome results
Primary
Hospital Survival
Hospital survival is a binary variable showing whether the patient survived their time in the hospital. Hospital survival will be assessed from date of randomization until the date of discharge or date of death from any cause, whichever comes first, assessed up to 24 months.
Time frame: Outcome is measured from date of admission to date of discharge or date of death, whichever comes first, approximately 7 to 10 days.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment Arm | Hospital Survival | 2 Participants |
| Control Arm | Hospital Survival | 5 Participants |
Secondary
Change in Sequential Organ Failure Assessment (SOFA) Score Over First 72 Hours (Measured as SOFA Score Daily for Four Days, With Day One Being Admission, Then 3 Days After, Totaling 4 Days of Treatment With HAT)
This is a binary variable that will shows whether there was a decrease in SOFA score over the first 72 hours (measured as SOFA score daily for four days, with day one being admission, then 3 days after, totaling 4 days of treatment with HAT).
Time frame: Outcome is measured from date of admission to date of discharge or date of death, whichever comes first, approximately 7 to 10 days.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment Arm | Change in Sequential Organ Failure Assessment (SOFA) Score Over First 72 Hours (Measured as SOFA Score Daily for Four Days, With Day One Being Admission, Then 3 Days After, Totaling 4 Days of Treatment With HAT) | 4 Participants |
| Control Arm | Change in Sequential Organ Failure Assessment (SOFA) Score Over First 72 Hours (Measured as SOFA Score Daily for Four Days, With Day One Being Admission, Then 3 Days After, Totaling 4 Days of Treatment With HAT) | 5 Participants |
Secondary
Change in Serum Procalcitonin (PCT) Over First 72 Hours
This is a binary variable that will show whether there was a decrease in serum procalcitonin (PCT) over first 72 hours.
Time frame: Over the first 72 hours from admission.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment Arm | Change in Serum Procalcitonin (PCT) Over First 72 Hours | 3 Participants |
| Control Arm | Change in Serum Procalcitonin (PCT) Over First 72 Hours | 4 Participants |
Secondary
Duration of Vasopressor Therapy
The duration of vasopressor therapy is measured after date of randomization in hours and minutes from the initiation of vasopressor therapy until the termination of vasopressor therapy.
Time frame: Outcome is measured from date of admission to date of discharge or date of death, whichever comes first, approximately 7 to 10 days.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment Arm | Duration of Vasopressor Therapy | 53.8 hours |
| Control Arm | Duration of Vasopressor Therapy | 34.6 hours |
Secondary
ICU Length of Stay (LOS)
ICU LOS will be measured by the date and time the patient was admitted to the ICU and by the date and time the patient was discharged from the ICU.
Time frame: Outcome is measured from date of admission to date of discharge or date of death, whichever comes first, approximately 7 to 10 days.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment Arm | ICU Length of Stay (LOS) | 10.0 days |
| Control Arm | ICU Length of Stay (LOS) | 7.0 days |
Secondary
Number of Wound Related Surgeries
This is a variable that will show the count of wound related surgeries during the time the patient is admitted to the hospital.
Time frame: Outcome is measured from date of admission to date of discharge or date of death, whichever comes first, approximately 7 to 10 days.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment Arm | Number of Wound Related Surgeries | 4.0 Wound related surgeries |
| Control Arm | Number of Wound Related Surgeries | 2.0 Wound related surgeries |
Secondary
Procalcitonin Clearance
Procalcitonin clearance (formula = initial PCT - 72 hour PCT divided by initial PCT x 100). The reported measure is median and range for those patients that
Time frame: Outcome is measured from date of admission to date of discharge or date of death, whichever comes first, approximately 7 to 10 days.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Treatment Arm | Procalcitonin Clearance | 23.5 percentage of decrease in procalcitonin |
| Control Arm | Procalcitonin Clearance | 77.9 percentage of decrease in procalcitonin |
Secondary
Requirement for Renal Replacement Therapy in Patients With Acute Kidney Injury (AKI)
This is a binary variable the will record whether the patient did or did not have a requirement for renal replacement therapy in patients with Acute Kidney Injury (AKI).
Time frame: Outcome is measured from date of admission to date of discharge or date of death, whichever comes first, approximately 7 to 10 days.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment Arm | Requirement for Renal Replacement Therapy in Patients With Acute Kidney Injury (AKI) | 0 Participants |
| Control Arm | Requirement for Renal Replacement Therapy in Patients With Acute Kidney Injury (AKI) | 0 Participants |
Secondary
Wound Status at Time of Hospital Discharge: Open
This shows the number of participants with an open wound at time of hospital discharge.
Time frame: Outcome is measured from date of admission to date of discharge or date of death, whichever comes first, approximately 7 to 10 days.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment Arm | Wound Status at Time of Hospital Discharge: Open | 3 Participants |
| Control Arm | Wound Status at Time of Hospital Discharge: Open | 1 Participants |