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

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.

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