Hypertonic Saline and Terlipressin for Sepsis-associated Hypotension

Study Overview
=================
Brief Summary
-----------------
In hypotensive septic patients with controlled source, an hemodynamic management protocol including hypertonic saline (HS)and terlipressin improves MOD (Multiple Organ Dysfunction) Score by at least 3 points compared to the use of physiologic saline and norepinephrine. The appropriate design for this trial would be factorial. For the time being, will consider de intervention as a whole unit for this pilot study. In the future an appropriately sized factorial multicentric study shall be necessary. Other goals of the pilot study: HS restores preload parameters adequately HS associated with terlipressin normalizes blood pressure in septic shock HS associated with terlipressin maintains plasma sodium levels 130-155mEq/L There is an inverse relationship between plasma sodium and procalcitonin levels HS increases plasma levels of vasopressin (AVP) HS rises levels of cortisol but not of adrenocorticotropic hormone (ACTH)

Official Title
-----------------
Hypertonic Saline and Terlipressin Linked To an Early Goal-Driven Protocol for Septic Shock or Sepsis-Associated Hypotension: A Pilot Trial (HYSATESS)

Conditions
-----------------
Septic Shock, Sepsis-associated Hypotension

Intervention / Treatment
-----------------
* Drug: Hypertonic Saline and Terlipressin
* Drug: Normal saline and norepinephrine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Criteria of SIRS: at least 2 of 4: Temperature > 38 °c or < 36 ° C More than 90 bpm heart rate Respiratory rate more than 20rpm or PaCO2 less than 32 mm Hg or patient in mechanical ventilation Less than 4000/ mm³ or more than 12000/mm³, or more than 10% leukocyte bands (immature) Septic source known demonstrated (or at least of high probability) and controlled (if it is controllable) Hematocrit 25% or higher and/or hemoglobin 8 g/dL or higher. If necessary, transfuse RBCs to meet this criteria MAP less than 70 mm Hg. Note there is no requirement for adequate preload evidence Exclusion Criteria: Hypernatremia at base-line of 155 mEq/L or greater Hyponatremia at base-line less than 130mEq / L Prior endocrine disease affecting to the adrenal-pituitary axis. Intracranial Hypertension, brain tumor, seizures, head trauma Coronary Artery Disease active over the past year; or evidence of myocardium at risk by exercise stress test, pharmacological or positive gammagraphy last year without intervention Pregnancy Liver disease Child C, End-Stage-Renal-Disease Under the age of 18 Patients with order do not resuscitate or with minimal chances to survive

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Hypertonic Saline and Terlipressin<br> | Drug: Hypertonic Saline and Terlipressin<br>* Hypertonic saline 3% 7mL/Kg (with a maximum 500 mL)triggered by either Systolic Volume Variation or Pulse Pressure Variation more than 10%; Terlipressin infusion (dilution 1mg in 100mL) triggered by MAP below 70 mmHg for a goal MAP above 70 mmHg<br>|
| Active Comparator: Normal Saline and norepinephrine<br> | Drug: Normal saline and norepinephrine<br>* Normal saline IV bolus 7mL/kg (with a maximum 500 mL)triggered by either Systolic Volume Variation or Pulse Pressure Variation above 10%; Norepinephrine drip (80 micrograms/mL) to keep MAP at least 70 mmHg<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MOD (Multiple Organ Dysfunction) Score |  | daily, as long as the patient stays in the ICU | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hypertonic Saline restores IV fluid response parameters (Pulse Pressure Variation or Systolic Volume Variation) adequately |  | First 48 hours | 
| Hypertonic Saline associated with terlipressin maintains plasma sodium levels 130-155mEq/L |  | As long as Hypertonic saline plus terlipressin are in use and one week later | 
| There is an inverse relationship between plasma sodium and plasma procalcitonin levels measured by a negative Pearson coefficient |  | As long as the patient stays in the ICU | 
| Hypertonic Saline associated with terlipressin normalizes blood pressure in septic shock |  | First 48 hours | 
| Hypertonic Saline boluses increases plasma levels of vasopressin (AVP) |  | First week in ICU | 
| Hypertonic Saline use rises levels of cortisol but not of adrenocorticotropic hormone (ACTH) |  | First week in ICU |