Hypoxia Inducible Factor 1 Alpha as a Novel Biomarker in Septic Shock

Completed

Brief Summary: 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.

Detailed Description: 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.

Recruitment & Eligibility

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

Exclusion Criteria

Septic patients

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

Arm && Interventions

Group	Intervention	Description
Septic patients	Septic patients	Blood Draw Biological samples: The investigators will collect blood and compare the expression of HIF complex in 3 distinct ways: between patients and controls, within the same patient in a time-dependent fashion, and between different patients.
Healthy Control	Healthy Control	The investigators will collect blood and compare the expression of HIF complex in 3 distinct ways: between patients and controls, within the same patient in a time-dependent fashion, and between different patients.

Primary Outcome Measures

Name	Time	Method
Hypoxia-inducible factor as a predictive biomarker of sepsis.	Baseline,	Hypoxia-inducible factor will be measured at initial diagnosis (baseline) and 24 hours later in subjects with clinical presentation of sepsis and correlated with lactic acidosis.
Hypoxia-inducible factor as a predictive biomarker of sepsis	24 hours	Hypoxia-inducible factor will be measured at initial diagnosis (baseline) and 24 hours later in subjects with clinical presentation of sepsis and correlated with lactic acidosis.

Secondary Outcome Measures

Name	Time	Method
Evaluate the role of HIF complex as biomarker and its correlation with "Survive the Sepsis Campaign 2012" gold standard septic shock severity and morbidity/mortality predictors.	28 days	At discharge a detailed chart analysis will be performed for the first 24 hrs, survival at 28 day; correlations of clinical course-derived data and serum cytokine content with the HIF content/expression and function will be analyzed by Spearman's rank correlation test.