EFFECT OF EARLY VASOPRESSIN VS NOREPINEPHRINE ON KIDNEY FAILURE IN PATIENTS WITH SEPTIC SHOCK Alexandria Rydz
BACKGROUND- SEPSIS Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection Organ dysfunction is classified as a change in total SOFA score >2 Septic shock patients present with signs of sepsis plus: Hypotension requiring vasopressors to maintain MAP >65 mmhg Serum lactate >2 mmol/l (18 mg/dl) JAMA. 2016;315(8):801-810. doi:10.1001/jama.2016.0287
SIRS CRITERIA Systemic Inflammatory Response Syndrome Two or more of the following: Temperature >38 ºC or <36 ºC Heart rate >90/min Respiratory rate >20/min or PaCO 2 <32 mmhg White blood cell count >12,000/mm 3 or <4000/mm 3 or >10% immature bands JAMA. 2016;315(8):801-810. doi:10.1001/jama.2016.0287
SOFA SCORE JAMA. 2016;315(8):801-810. doi:10.1001/jama.2016.0287
GOALS OF THERAPY To be completed within 3 hours: 1. Measure lactate level 2. Obtain blood cultures prior to administration of antibiotics 3. Administer broad spectrum antibiotics 4. Administer 30 ml/kg crystalloid for hypotension or lactate >4 mmol/l To be completed within 6 hours: 1. Apply vasopressors to maintain MAP of >65 mmhg 2. In the event of persistent arterial hypotension or initial lactate >4 mmol/l 1. Measure central venous pressure(cvp) 2. Measure central venous oxygen saturation (ScVO 2 ) 3. Re-measure lactate if initial lactate was elevated Crit Care Med. Surviving Sepsis Campaign. 41(2): 580-637.
VASOPRESSORS Drug Name Dose Range Titration Comments Norepinephrine 0.01-3 mcg/kg/min 0.05-0.1 mcg/kg/min every 5 minutes Epinephrine 0.02-0.2 mcg/kg/min 0.05-0.1 mcg/kg/min every 5 minutes Vasopressin 0.03-0.04 units/min 0.005-0.01 units/min every 20 minutes Dopamine 2-20 mcg/kg/min 2-2.5 mcg/kg/min every 5 minutes Phenylephrine 0.5-5 mcg/kg/min 0.1-0.2 mcg/kg/min every 10 minutes Dobutamine 20 mcg/kg/min First line for septic shock Dose dependent receptor effects Dose dependent receptor effects Crit Care Med. Surviving Sepsis Campaign. 41(2): 580-637 Uptodate, Vasopressors in shock. 2016.
VASOPRESSIN VS NOREPINEPHRINE INFUSION IN PATIENTS WITH SEPTIC SHOCK (VASST) Primary endpoint: death from any cause Secondary endpoints: 90-day mortality; Days alive and free of organ dysfunction during the first 28 days; Days alive and free of vasopressor use; Mechanical ventilation or renal replacement therapy; Days alive and free of systemic inflammatory response syndrome (SIRS); Days alive and free of corticosteroid use; ICU and Hospital LOS No Significant difference in the primary outcome between groups Addition of low dose vasopressin allowed for a rapid decrease in the total norepinephrine dose while maintaining MAP Vasopressin showed some benefit in patients with less severe shock The combination of vasopressin and corticosteroids had a lower mortality rate than norepinephrine alone N Engl J.; 358 (9(:877-887MedVASST.2008
THE INTERACTION OF VASOPRESSIN AND CORTICOSTEROIDS IN SEPTIC SHOCK: A PILOT RANDOMIZED CONTROLLED TRIAL Purpose To evaluate the interaction between vasopressin and corticosteroids in septic shock patients Treatment arms Vasopressin + hydrocortisone Vasopressin +placebo Primary outcome Difference in plasma vasopressin concentration between treatment groups Results Patients in the hydrocortisone group were weaned off vasopressin faster than placebo Duration of norepinephrine infusion was shorter in the hydrocortisone group compared to placebo CritCare Med. 2009; 37 (3):811-818
JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Gordon, Anthony C., et. al. Effect of Early Vasopressin vs Norepinephrine on Kidney Failure in Patients With Septic Shock. JAMA. 2016; 316(5):509-518.
PURPOSE To test whether early vasopressin use would improve kidney outcomes compared with norepinephrine JAMA. 2016;316(5):509-518. doi:10.1001/jama.2016.10485
METHODS Factorial (2x2), multicenter, double bind, randomized clinical trial Across 18 general adult ICUs Granted a waiver of initial consent based on the emergent nature of the trial Randomization in a 1:1:1:1 ratio JAMA. 2016;316(5):509-518. doi:10.1001/jama.2016.10485
TREATMENT GROUPS Patients were randomized into 2 groups for study drug 1 Vasopressin (titrated up to 0.06 U/min) Norepinephrine (titrated up to 12 ug/ml) Once maximum infusion rate was reached for study drug 1, study drug 2 was initiated 50mg of hydrocortisone Placebo 4 treatment groups: Vasopressin and hydrocortisone Vasopressin and placebo Norepinephrine and hydrocortisone Norepinephrine and placebo JAMA. 2016;316(5):509-518. doi:10.1001/jama.2016.10485
INCLUSION CRITERIA Patients >16 years old with sepsis and who required vasopressors despite adequate intravenous fluid resuscitation JAMA. 2016;316(5):509-518. doi:10.1001/jama.2016.10485
EXCLUSION CRITERIA Previous continuous infusion of vasopressors during ICU admission Ongoing requirement for systemic steroid treatment End-stage kidney failure Known mesenteric ischemia Raynaud phenomenon Systemic sclerosis or other vasopastic disease A medical team that was not committed to full active treatment Known pregnancy Enrollment in another interventional trial that could interact with the study drug Hypersensitivity to any of the study drugs JAMA. 2016;316(5):509-518. doi:10.1001/jama.2016.10485
OUTCOME MEASURES Primary Outcome Kidney failure free days The proportion of survivors who never developed kidney failure The median number of days alive and free of kidney failure Secondary Outcome Rate and duration of renal replacement therapy Length of kidney failure in surviors and nonsurviors 28-day ICU and hospital mortality rates Organ failure-free days in the first 28 days JAMA. 2016;316(5):509-518. doi:10.1001/jama.2016.10485
STATISTICAL ANALYSIS Sample size of 400 would provide 80% power to detect 20-25% relative risk reduction of developing kidney failure Mann-Whitney U test was used for the primary analysis Main analysis Modified intent-to-treat Other analysis As-treated basis Per-protocol analysis P value of <0.05 was considered statistically significant JAMA. 2016;316(5):509-518. doi:10.1001/jama.2016.10485
RESULTS RECRUITMENT, RANDOMIZATION, AND PATIENT FLOW JAMA. 2016;316(5):509-518. doi:10.1001/jama.2016.10485
BASELINE CHARACTERISTICS JAMA. 2016;316(5):509-518. doi:10.1001/jama.2016.10485
JAMA. 2016;316(5):509-518. doi:10.1001/jama.2016.10485
JAMA. 2016;316(5):509-518. doi:10.1001/jama.2016.10485
JAMA. 2016;316(5):509-518. doi:10.1001/jama.2016.10485
OUTCOME DATA JAMA. 2016;316(5):509-518. doi:10.1001/jama.2016.10485
DISCUSSION The rationale for this trial was based on the results from the VASST study No significant difference in mortality rates between those treated with vasopressin and norepinephrine for overall septic shock patients. However, a lower mortality rate was noted in a subgroup analysis of patients receiving vasopressin with less severe septic shock This could be explained by the following: Time to administration of the study drug Maximum infusion rate of Vasopressin A harmful interaction between Vasopressin and high-dose norepinephrine OR a chance finding VASST also suggested that vasopressin might have beneficial effects on kidney function N Engl J.; 358 (9(:877-887MedVASST.2008 JAMA. 2016;316(5):509-518. doi:10.1001/jama.2016.10485
LIMITATIONS No parameters for initiation of renal replacement therapy or levels or hemodynamic monitoring Short duration of follow-up JAMA. 2016;316(5):509-518. doi:10.1001/jama.2016.10485
AUTHOR S CONCLUSION Among adults with septic shock, the early use of vasopressin compared to norepinephrine did not improve the number of kidney failure-free days JAMA. 2016;316(5):509-518. doi:10.1001/jama.2016.10485
REFERENCES Singer M, Deutschman CS, Seymour C, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801-810. doi:10.1001/jama.2016.0287. Dellinger R, Levy M, Rhodes A, et al. Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock: 2012. February 2013; 41(2): 580-637. Gordon, Anthony C., et. al. Effect of Early Vasopressin vs Norepinephrine on Kidney Failure in Patients With Septic Shock. JAMA. 2016; 316(5):509-518. Russell J, Walley K, Singer J, et al. Vasopressin versus Norepinephrine Infusion in Patients with Septic Shock. N Engl J Med 2008; 358:877-887. doi:10.1056/nejmoa067373 Gordon AC, Mason AJ, Perkins GD, et al. The Interaction of Vasopressin and Corticosteroids in Septic Shock: A Pilot Randomized Controlled Trial Lauzier F, Levy B, Lamarre P, Lesur O. Vasopressin or norepinephrine in early hyperdynamic septic shock: a randomized clinical trial. Intensive Care Med. 2006;32(11):1782-1789