Department of Intensive Care Medicine VOLUME RESPONSIVENESS IS DIFFERENT FROM NEED FOR FLUIDS BLOOD PRESSURE TARGETS IN SEPSIS
SEPTIC SHOCK : THE CLINICAL SCENARIO HYPOTENSION DESPITE ADEQUATE VOLUME RESUSCITATION or ON VASOPRESSORS TO AVOID HYPOTENSION
OPEN QUESTIONS/ MAJOR CONTROVERSIES Sepsis-3 «need for vasopressors» Ö definition of blood pressure targets «adequate fluid resuscitation» JAMA. 2016;315(8):801-810. doi:10.1001/jama.2016.0287
THE HEMODYNAMIC TARGET BLOOD PRESSURE! Sevransky JE et al, Critical Care 2007, 11:R67 Takala et al, Intensive Care Med 2008 Aug;34:1401-10. Epub 2008 Apr 3 Torgersen et al, Eur J Anaesthesiol 2011;28:284-90
BLOOD PRESSURE TARGETS: a consensus mean arterial pressure in sepsis: 65 70 mmhg...but we do not do what we say...
BLOOD PRESSURE MANAGEMENT IN CLINICAL TRIALS 100 mean arterial blood pressure (mmhg) 90 80 70 60 50 target MAP actual MAP at 24 hrs based on trials cited in Sevransky JE et al: Hemodynamic goals in randomized clinical trials in patients with sepsis: a systematic review of the literature. Critical Care 2007, 11:R67
high blood pressures in clinical trials on hemodynamic management Asfar et al, N Engl J Med 2014, epublished on March 18 Russell JA et al: Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 2008;358:877-87 De Backer D et al: Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med 2010;362:779-89 Annane D et al: Norepinephrine plus dobutamine versus epinephrine alone for management of septic shock: a randomised trial. Lancet. 2007 370:676-684
A CLOSER LOOK AT TRIALS WITH STRICT HEMODYNAMIC MANAGEMENT PROTOCOLS: the CATS trial Annane D et al: Norepinephrine plus dobutamine versus epinephrine alone for management of septic shock: a randomised trial. Lancet. 2007 370:676-684
TARGET MEAN ARTERIAL BLOOD PRESSURE at least 70 mmhg, thereafter stepwise vasopressor withdrawal Annane D et al Lancet 2007; 370:676 684
TIME TO VASOPRESSOR WITHDRAWAL
A CLOSER LOOK: the VASST study Russell JA et al: Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 2008;358:877-87
MAP >85 mmhg safety limit for hypertension, rapid tapering of open label vasopressors and the study drug, if considered necessary An initial target mean arterial pressure of 65 to 75 mm Hg was recommended; however, the attending ICU physician could modify the target blood pressure of each patient Russell et al, N Engl J Med 2008;358:877-87
A CLOSER LOOK: the norepi vs dopa study De Backer D et al: Comparison of dopamine and norepinephrine in the treatment of shock N Engl J Med 2010;362:779-89
The target blood pressure was determined by the doctor in charge for each individual patient De Backer et al, N Engl J Med 2010;362:779-89
A CLOSER LOOK: the SEPSISPAM study Asfar P et al High versus low blood-pressure target in patients with septic shock N Engl J Med 2014;370:1583-93
recommendation: reduce vasopressors hourly, if MAP above target Asfar et al N Engl J Med 2014;370:1583-93
BLOOD PRESSURE IN LARGE CLINICAL TRIALS a dissociation between actual and targeted blood pressure deviation towards higher blood pressure regardless of strict protocols or recommendations
PRECISION MEDICINE or PERSONALIZED MEDICINE?
PLoSONE 12(1): e0167840
FAILURE TO TITRATE (REDUCE) VASOPRESSORS Lamontagne et al, PLoSONE 12(1): e0167840
FAILURE TO TITRATE (REDUCE) VASOPRESSORS Lamontagne et al, Intensive Care Med 2016;42:542 550
80 % not clinically justified
DO HIGHER BLOOD PRESSURES MATTER? MAP-levels of 60-65 mmhg do not hurt and higher levels offer no mortality benefits Ö Ö Varpula M et al: Hemodynamic variables related to outcome in septic shock. Intensive Care Med 2005; 31:1066-1071 retrospective analysis of 111 patients Dünser MW et al: Arterial blood pressure during early sepsis and outcome. Intensive Care Med. 2009;35:1225-1233. Epub 2009 Feb 3 retrospective analysis of 274 patients
DO HIGHER BLOOD PRESSURES MATTER? increased catecholamine load at MAP>70 mmhg may harm retrospective analysis of the control group in the L-NMMA phase III trial Ö adjusted for age, chronic arterial hypertension mean vasopressor load, SAPS II, geographic region, center MAP levels above 70 mmhg were not associated with 28- day mortality Dünser MW et al: Association of arterial blood pressure and vasopressor load with septic shock mortality: a post hoc analysis of a multicenter trial. Crit Care. 2009;13:R181. [Epub ahead of print]
MEAN VASOPRESSOR LOAD was associated with INCREASED RISK OF 28-DAY MORTALITY (P<.001) occurrence of disease-related adverse events Dünser MW et al: Association of arterial blood pressure and vasopressor load with septic shock mortality: a post hoc analysis of a multicenter trial. Crit Care. 2009;13:R181. [Epub ahead of print]
DO HIGHER BLOOD PRESSURES MATTER? any further increases in blood pressure above 70 mmhg achieved by catecholamine vasopressors may increase the risk of mortality
HIGH DOSE OF NOREPINEPHINE: independently associated with risk of death Martin et al, Shock 2015;44,:305 309
HIGH DOSE OF NOREPINEPHINE: independently associated with risk of death Martin et al, Shock 2015;44,:305 309
L-NMMA MAP RESPONSE IN PHASE II SUPERIMPOSED ON PHASE III L-NMMA phase III control phase III Takala J, Crit Care Med 2010; 38[Suppl.]:S613 S619
L-NMMA SURVIVAL CURVE OF PHASE II SUPERIMPOSED ON PHASE III data points for 28-day survival curve for L-NMMA in the phase II study lower MAP higher MAP control phase III L-NMMA phase III blood pressure more relevant to outcome than the drug(s)? Takala J, Crit Care Med 2010; 38[Suppl.]:S613 S619
REDUCING CATECHOLAMINE VASOPRESSORS? benefit for less severe septic shock in the VASST trial NE 5-14 µg/min protection from unnecessary exposure to catecholamines?
ADVERSE EFFECTS OF CATECHOLAMINES? excess vasoconstriction impaired microcirculation increased metabolic demands altered immune response increased myocardial oxygen demand risk of myocardial ischemia etc.
DISSOCIATION BETWEEN BLOOD FLOW AND BLOOD PRESSURE
39 Septic Patients (15,836 pulmonary artery catheter measurements) r²=0.003
TREATMENT TARGETS TO RESTORE HEMODYNAMIC STABILITY? A. Jarisch: Fortschritte der gesamten Medizin Dtsch Med Wochenschr 1928;28:1173-1213 A. Jarisch Fortschritte der gesamten Medizin IT HAS BEEN A CERTAIN DISASTER FOR THE DEVELOPMENT OF THE SCIENCE OF CIRCULATION THAT BLOOD FLOW IS SO DIFFICULT TO Dtsch MEASURE Med IN Wochenschr CONTRAST TO 1928;28:1173-1213 THE EASE OF MEASURING BLOOD PRESSURE THEREFORE, BLOOD PRESSURE MANOMETER ACHIEVED ITS EVEN FASCINATING IMPACT, DESPITE THE FACT THAT MOST ORGANS DO NOT NEED BLOOD PRESSURE THEY NEED BLOOD FLOW Rev. S. Hales 1731 2017???
CONCERNS TO BE ADDRESSED: does accepting lower MAP risk the kidney? do patients with hypertension profit from higher MAP?