Hypoxia Inducible Factor 1 Alpha as a Novel Biomarker in Septic Shock
| Status: | Completed |
|---|---|
| Conditions: | Hospital, Hospital |
| Therapuetic Areas: | Other |
| Healthy: | No |
| Age Range: | 18 - 80 |
| Updated: | 4/21/2016 |
| Start Date: | January 2013 |
| End Date: | June 2015 |
The purpose of this research study is to determine if a chemical marker in the blood,
hypoxia-inducible factor (HIF-1 alpha), can be used to predict subject's hospital outcomes
when the subject is diagnosed with sepsis. Sepsis is defined as either the presence of
pathogenic organisms or their toxins in the blood and tissues. Sepsis is one of the most
significant challenges in critical care medicine. The investigators propose that
hypoxia-induced expression of HIF-1 alpha will correlate with the clinical features of
Sepsis and in the future, HIF-1 alpha may be used as a biomarker in Sepsis.
hypoxia-inducible factor (HIF-1 alpha), can be used to predict subject's hospital outcomes
when the subject is diagnosed with sepsis. Sepsis is defined as either the presence of
pathogenic organisms or their toxins in the blood and tissues. Sepsis is one of the most
significant challenges in critical care medicine. The investigators propose that
hypoxia-induced expression of HIF-1 alpha will correlate with the clinical features of
Sepsis and in the future, HIF-1 alpha may be used as a biomarker in Sepsis.
Sepsis is one of the most significant challenges in critical care. Septic shock (SS) is the
most severe form of sepsis and is associated with higher mortality, significant financial
expenses and longer lengths of stay. Pathophysiological mechanisms of SS include 3 key
components: 1) bacterial overgrowth, 2) spill of bacterial product into the blood causing
hemodynamic insufficiency, and 3) both lead to tissue hypoxia (TH). To date the biomarkers
of sepsis/SS are limited to hemodynamic parameters. However, aggressive fluid resuscitation
does not fully prevent development of tissue hypoxia (TH). To date the investigators are
limited in appreciating TH by measurement of lactic acid (LA), which is neither an early nor
an accurate marker. Unfortunately, LA has limited predictive value in SS due to its complex
metabolism. Thus, there is an acute need for biomarkers that would aid diagnosis and
prognosis of sepsis/septic shock.
Cellular responses/adaptations to hypoxia rely on the transcription hypoxia-inducible factor
HIF, a heterodimeric protein composed of a constitutively expressed subunit and an inducible
(types 1, 2, and 3) subunit. More recently HIF was identified in diverse tissues including
blood; it has been also shown that HIF expression in blood cells is representative of
systemic tissues in hypoxic conditions.
most severe form of sepsis and is associated with higher mortality, significant financial
expenses and longer lengths of stay. Pathophysiological mechanisms of SS include 3 key
components: 1) bacterial overgrowth, 2) spill of bacterial product into the blood causing
hemodynamic insufficiency, and 3) both lead to tissue hypoxia (TH). To date the biomarkers
of sepsis/SS are limited to hemodynamic parameters. However, aggressive fluid resuscitation
does not fully prevent development of tissue hypoxia (TH). To date the investigators are
limited in appreciating TH by measurement of lactic acid (LA), which is neither an early nor
an accurate marker. Unfortunately, LA has limited predictive value in SS due to its complex
metabolism. Thus, there is an acute need for biomarkers that would aid diagnosis and
prognosis of sepsis/septic shock.
Cellular responses/adaptations to hypoxia rely on the transcription hypoxia-inducible factor
HIF, a heterodimeric protein composed of a constitutively expressed subunit and an inducible
(types 1, 2, and 3) subunit. More recently HIF was identified in diverse tissues including
blood; it has been also shown that HIF expression in blood cells is representative of
systemic tissues in hypoxic conditions.
Inclusion Criteria: Septic patients
- Age 18 ≤ 80 years
- Negative pregnancy test for women of childbearing potential
- Meets two or more of Systemic Inflammatory Response System (SIRS) criteria
(tachypnea, tachycardia, hypo/hyperthermia, leukopenia/leukocytosis)
- Evidence of tissue hypo-perfusion, or organ dysfunction by any of the following
- Sepsis induced hypotension with systolic blood pressure <90
- Lactate above 1.5 mmol/Liter
- Urine output below 0.5 mL/kg/hr for more than 2 hours despite adequate fluid
resuscitation
- Tissue hypoxia
- Bilirubin > 2 mg/dl in absence of liver cirrhosis
- Creatinine (CR)> 2.0 mg/dL, Acute Kidney Injury as evident by CR increase by 0.5
mg/dL from baseline
- Platelet count < 100,000
- Coagulopathy with international normalized ratio (INR) >1.5
Inclusion: Healthy Controls
- Age and gender-matched to sepsis patients
- Negative pregnancy test in women of childbearing potential
- Never smoker (<1 pack year history)
Exclusion Criteria: Septic patients
- History of Malignancy, including carcinoma during the preceding 5 years.
- Recent surgery, within 48 hours, or anticipated surgery within 24 hours
- Contraindication for neck/chest central venous line
- History of cardiopulmonary resuscitation (CPR) prior to inclusion
- Transfer from another institution
- History of cirrhosis
- Transplant recipient
- Known HIV
- Use of ≥ 15 mg prednisone daily or equivalent
- Severe anemia: hematocrit ≤ 20
Exclusion: Healthy Controls
- History of Malignancy, including carcinoma during the preceding 5 years.
- Taking any prescription medications, other than any type of prescribed hormonal birth
control.
- Current smoking history and/or > 1 pack year history
- Current use (within the last week) anti-inflammatory medications, such as aspirin,
ibuprofen, naproxen and/or prednisone
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