Septic Shock
Conditions
Brief summary
Prior work has shown that exogenous L-carnitine administration enhances glucose and lactate oxidation, attenuates fatty acid toxicity, and improves endothelial-smooth muscle coupling and cardiac mechanical efficiency. The overall goal of this proposal is to investigate L-carnitine as a novel adjunctive treatment of septic shock. In this study the investigators will test our primary hypothesis: Early adjunctive L-carnitine administration in vasopressor dependent septic shock will significantly reduce cumulative organ failure at 48 hours with an associated decrease in 28-day mortality suggesting the need for further phase III study. To accomplish this the investigators will conduct a phase II, double blinded, placebo controlled, adaptive randomized trial of 250 eligible patients with vasopressor-dependent septic shock. Study subjects will be assigned to one of four arms: low (6g), medium (12g) or high (18g) dose intravenous L-carnitine or placebo for 12 hours as a part of early resuscitative care.
Interventions
DRUGLevo-Carnitine
DRUGplacebo
Sponsors
National Institute of General Medical Sciences (NIGMS)
University of Mississippi Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Suspected or confirmed infection (examples include but are not limited to: white cells in a normally sterile body fluid; perforated viscus; radiographic evidence of pneumonia in clinical symptoms; a syndrome associated with a high risk of infection e.g. cellulitis, cutaneous abscess, ascending cholangitis, toxic shock syndrome, fever of unknown origin with high suspicion of infectious etiology) 2. Any two of four criteria of systemic inflammatory response as defined by the 2001 ACCP/SCCM Consensus Conference Committee; 3. Recognition of septic shock and initiation of quantitative resuscitation within 24 hours of enrollment; 4. Requirement of high dose vasopressors for ≥4 hours to treat shock: Norepinephrine \> 0.05mcg/kg/min; dopamine \>10mcg/kg/min; Phenylephrine \>0.4 mcg/kg/min; epinephrine \> 0.05 mcg/kg/min; 5. Cumulative sequential organ failure assessment (SOFA) score of ≥ 6; 6. Blood lactate level of \>2.0 mMol/L.
Exclusion criteria
1. Age \<18 years; 2. Pregnancy or breastfeeding; 3. Any primary diagnosis other than sepsis; 4. Established Do Not Resuscitate status or advanced directives restricting aggressive care or treating physician deems aggressive care unsuitable; 5. Any history of seizures or a known seizure disorder; 6. Any known inborn error of metabolism; 7. Anticipated requirement for surgery that would interfere with the 12 hour infusion time; 8. Active participation in another interventional study; 9. Cardiopulmonary resuscitation (chest compression or defibrillation) prior to enrollment; 10. Known systemic allergy to L-carnitine. 11. Severe immunocompromised state (e.g. subject has neutropenia \[receiving cytotoxic chemotherapy with absolute neutrophil count \<500/uL or expected to decline to \< 500 uL within the next three days). 12. Active Treatment with Coumadin
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Delta SOFA Score | 48 hours | Sequential Organ Failure Assessment Score (0-24 range). Delta SOFA is calculated as (SOFA Score at 48 hours post enrollment minus SOFA Score at enrollment). A negative value indicates improvement in the score. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Control Normal saline
placebo | 75 |
| Carnitine Low Levo-Carnitine 6g
Levo-Carnitine | 35 |
| Carnitine Medium Levo-Carnitine 12 g
Levo-Carnitine | 34 |
| Carnitine High Levo-Carnitine 18 g
Levo-Carnitine | 106 |
| Total | 250 |
Baseline characteristics
| Characteristic | Control | Carnitine Low | Carnitine Medium | Carnitine High | Total |
|---|---|---|---|---|---|
| Age, Continuous | 60.22 years STANDARD_DEVIATION 16.5 | 67.51 years STANDARD_DEVIATION 12.01 | 64.91 years STANDARD_DEVIATION 12.56 | 59.67 years STANDARD_DEVIATION 14.5 | 62 years STANDARD_DEVIATION 14 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 0 Participants | 3 Participants | 6 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 72 Participants | 35 Participants | 31 Participants | 100 Participants | 238 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 75 Participants | 35 Participants | 34 Participants | 106 Participants | 250 Participants |
| Sex: Female, Male Female | 36 Participants | 17 Participants | 13 Participants | 42 Participants | 108 Participants |
| Sex: Female, Male Male | 39 Participants | 18 Participants | 21 Participants | 64 Participants | 142 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 34 / 75 | 20 / 35 | 16 / 34 | 45 / 106 |
| other Total, other adverse events | 0 / 75 | 0 / 35 | 0 / 34 | 0 / 106 |
| serious Total, serious adverse events | 0 / 75 | 0 / 35 | 0 / 34 | 0 / 106 |
Outcome results
Primary
Delta SOFA Score
Sequential Organ Failure Assessment Score (0-24 range). Delta SOFA is calculated as (SOFA Score at 48 hours post enrollment minus SOFA Score at enrollment). A negative value indicates improvement in the score.
Time frame: 48 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Control | Delta SOFA Score | -1.8 units on a scale | Standard Deviation 0.35 |
| Carnitine Low | Delta SOFA Score | -0.34 units on a scale | Standard Deviation 0.66 |
| Carnitine Medium | Delta SOFA Score | -1.68 units on a scale | Standard Deviation 0.61 |
| Carnitine High | Delta SOFA Score | -2.15 units on a scale | Standard Deviation 0.37 |