Mitochondrial Function in Septic Patients

Aim #1 To investigate the prevalence, risk and correlation of the level of sepsis with mitochondrial dysfunction in sepsis patients Aim 1.1 To investigate the prevalence of mitochondria dysfunction among sepsis patients Aim 1.2 To investigate the risk associated with mitochondrial dysfunction in sepsis patients.

Aim 1.3 To investigate the association between sepsis severity (SOFA scoring system) and the degree of mitochondrial dysfunction Aim #2 To investigate the association of mitochondrial dysfunction in sepsis with ScvO2, lactate and ∆PCO2 Aim 3.1 To investigate the therapeutic efficacy of steroids on the improvement mitochondrial function in sepsis patients Aim 3.2. To investigate the efficacy of steroids on the reduction mortality rate in sepsis patients with norepinephrine-resistant hypotension

Aim #1 To investigate the prevalence, risk and correlation of the level of sepsis with mitochondrial dysfunction in sepsis patients Aim 1.1 To investigate the prevalence of mitochondria dysfunction among sepsis patients Hypothesis: Most of sepsis patients are affected by mitochondria dysfunction. Since there are many suspected cases of sepsis in the emergency department, mitochondrial function measurements will be collected. After the patients are diagnosed, the degree of mitochondrial function will be reported as a percent among all of sepsis patients.

Aim 1.2 To investigate the risk associated with mitochondrial dysfunction in sepsis patients.

Hypothesis: Some risks other than infection are associated with mitochondrial dysfunction in septic patient.

Since there are many suspected cases of sepsis in the emergency department, mitochondrial function measurements will be collected. After the patients are diagnosed, the degree of mitochondrial function will be reported at intervals. Additionally, the correlation among sex, age, obesity, underlying symptoms, cause of infection, pathogen, onset of fever before emergency department visit, number of organ dysfunction, presence of shock and other hemodynamic parameter will be collected.

Aim 1.3 To investigate the association between sepsis severity (SOFA scoring system) and the degree of mitochondrial dysfunction Hypothesis: The severity of sepsis and organ dysfunction are associated with the severity of mitochondrial dysfunction.

Since there are many suspected cases of sepsis in the emergency department, mitochondrial function measurements will be collected. After the patients are diagnosed, the degree of mitochondrial function will be reported at intervals along with the correlation with the severity of sepsis in SOFA scoring system.

Aim #2 To investigate the association of mitochondrial dysfunction in sepsis with ScvO2, lactate and ∆PCO2 Hypothesis: Persistence of high lactate and extreme change of ScvO2 or ∆PCO2 after sepsis bundle care are associated with severity of mitochondrial dysfunction.

Since patients are suspected of having sepsis with hypoperfusion (1. Blood lactate \> 4 mmol/L, 2. Refractory hypotension: after bolus fluid 20 mL/kg and Systolic Blood Pressure still \< 90 mmHg or require vasopressor), the sepsis bundle care will be started in the emergency department. The goals of this treatment are 1. A mean arterial pressure of \> 65 is achieved by fluid resuscitation and vasopressor, 2. Lactate \> 4 mmol/L or ScvO2 \> 70 is achieved. After 6 hours following the beginning of resuscitation, blood examination for mitochondrial function, ScvO2 and ∆PCO2 will be determined. The correlation between these physiologic/biomarkers and mitochondrial function will be evaluated.

Aim #3 To investigate the roles of steroid administration on mitochondrial function in sepsis patients (Therapeutic trial) Aim 3.1 To investigate the therapeutic efficacy of steroids on the improvement mitochondrial function in sepsis patients Hypothesis: Steroids administration improve mitochondrial function in norepinephrine-resistant sepsis.

After resuscitation, hypoperfusion in the sepsis patients will be treated by fluid resuscitation and vasopressor. Some groups of patients may be not responsive to this treatment (MAP \<65 mmHg), administration of steroids to this group will be blindly randomized (treatment and control group). During resuscitation of septic shock patients with fluid resuscitation and vasopressors, some may not respond to treatment (MAP \< 65 mmHg). Patients who have shock refractory to fluid resuscitation and norepinephrine therapy for more than 0.5 mcg/kg/min will be blindly randomized to receive steroid (treatment group) or placebo (control group). Blood samples will be obtained to determine mitochondrial functioning before, at day 1 and day 7 after administration of study medications in both groups.

Aim 3.2. To investigate the efficacy of steroids on the reduction mortality rate in sepsis patients with norepinephrine-resistant hypotension Hypothesis: Steroids improve survival in septic shock patients with norepinephrine-resistant hypotension.

During resuscitation of septic shock patients with fluid resuscitation and vasopressors, some may not respond to treatment (MAP \< 65 mmHg). Patients who have shock refractory to fluid resuscitation and norepinephrine administration more than 0.5 mcg/kg/min will be blindly randomized to receive steroid (treatment group) or placebo (control group). Blood samples will be obtained to determine mitochondrial functioning before, at day 1 and day 7 after administration of study medications in both groups. Thirty-day survival will be analyzed by a survival analysis.

Eligibility Criteria:
Inclusion Criteria:

1. Adults (≥18 years of age)
2. Diagnosis of sepsis within 1 hour after presentation to the emergency department: known or presumed infection and SOFA score \> 2 (table1)
3. Norepinephrine-resistant hypotension (refractory hypotension and not response to norepinephrine dose ≥ 0.5 mcg/k/min)

Exclusion Criteria:

1. Known pregnancy
2. Primary diagnosis of:

   1. acute cerebral vascular event
   2. acute coronary syndrome
   3. acute cardiogenic pulmonary edema
   4. status asthmaticus
   5. major cardiac arrhythmia (as part of primary diagnosis)
   6. seizure
   7. drug overdose
   8. injury from burn or trauma
3. Hemodynamic instability due to active hemorrhage
4. Requirement for immediate surgery
5. Do-Not-Attempt-Resuscitation (DNAR) order
6. Advanced directives restricting implementation of the resuscitation protocol
7. Transferred from another in-hospital setting
8. Sepsis or septic shock is not final diagnosis
9. Known history of HIV infection with suspected or known Cluster of differentiation 4 (CD4) \<100 /mm2
10. Contraindication to central venous catheterization
11. Contraindication to blood transfusion
12. Attending clinician deems aggressive resuscitation unsuitable
13. Known history of HIV infection with suspected or known CD4 \<100 /mm2
14. Neurodegenerative disease (effected mitochondria function)
15. known case adrenal insufficiency or chronic steroid user (Patient in this group should receive Hydrocortisone)