Blood pressure targets in patients with septic shock APH Journal Club: 01/07/16 Dr. Thomas Conley CMT1 Nephrology/Gastroenterology/Critical Care

Aims Recap updated definition of sepsis Consider current guidance Consider APH trust guidance Critical appraisal of study selected Discussion re results and their significance Impact on current practice

Introduction Sepsis is a systemic, deleterious host response to infection leading to severe sepsis (acute organ dysfunction secondary to documented or suspected infection) and septic shock (severe sepsis plus hypotension not reversed with fluid resuscitation). Severe sepsis and septic shock are major healthcare problems, affecting millions of people around the world each year, killing one in four (and often more), and increasing in incidence. Similar to polytrauma, acute myocardial infarction, or stroke, the speed and appropriateness of therapy administered in the initial hours after severe sepsis develops are likely to influence outcome. The recommendations in this document are intended to provide guidance for the clinician caring for a patient with severe sepsis or septic shock. Recommendations from these guidelines cannot replace the clinician’s decision-making capability when he or she is presented with a patient’s unique set of clinical variables. Most of these recommendations are appropriate for the severe sepsis patient in the ICU and non-ICU settings. In fact, the committee believes that the greatest outcome improvement can be made through education and process change for those caring for severe sepsis patients in the nonICU setting and across the spectrum of acute care. Resource limitations in some institutions and countries may prevent physicians from accomplishing particular recommendations. Thus, these recommendations are intended to be best practice (the committee considers this a goal for clinical practice) and not created to represent standard of care. The Surviving Sepsis Campaign (SSC) Guidelines Committee hopes that over time, particularly through education programs and formal audit and feedback performance improvement initiatives, the guidelines will influence bedside healthcare practitioner behavior that will reduce the burden of sepsis worldwide

Introduction Sepsis is a systemic, deleterious host response to infection leading to severe sepsis (acute organ dysfunction secondary to documented or suspected infection) and septic shock (severe sepsis plus hypotension not reversed with fluid resuscitation). Severe sepsis and septic shock are major healthcare problems, affecting millions of people around the world each year, killing one in four (and often more), and increasing in incidence. Similar to polytrauma, acute myocardial infarction, or stroke, the speed and appropriateness of therapy administered in the initial hours after severe sepsis develops are likely to influence outcome. The recommendations in this document are intended to provide guidance for the clinician caring for a patient with severe sepsis or septic shock. Recommendations from these guidelines cannot replace the clinician’s decision-making capability when he or she is presented with a patient’s unique set of clinical variables. Most of these recommendations are appropriate for the severe sepsis patient in the ICU and non-ICU settings. In fact, the committee believes that the greatest outcome improvement can be made through education and process change for those caring for severe sepsis patients in the nonICU setting and across the spectrum of acute care. Resource limitations in some institutions and countries may prevent physicians from accomplishing particular recommendations. Thus, these recommendations are intended to be best practice (the committee considers this a goal for clinical practice) and not created to represent standard of care. The Surviving Sepsis Campaign (SSC) Guidelines Committee hopes that over time, particularly through education programs and formal audit and feedback performance improvement initiatives, the guidelines will influence bedside healthcare practitioner behavior that will reduce the burden of sepsis worldwide

Introduction “…affecting millions of people around the world each year, killing one in four (and often more), and increasing in incidence. Similar to polytrauma, acute myocardial infarction, or stroke, the speed and appropriateness of therapy administered in the initial hours after severe sepsis develops are likely to influence outcome”

Quick sepsis recap Why is this study important?

What is the relevance of this study? Sepsis: Vasodilation Increased permeability  relative and absolute hypovolaemia Reduced contractility Among patients with hypertension, a rightward shift of the curve for organ pressure-flow autoregulation is expected, which means that an increased MAP could theoretically result in improved organ perfusion.

Previous SSC definition Systemic inflammatory response syndrome (SIRS) requires 2 or more of the following: 1. T >38 C or <36 C 2. P >90/min 3. RR >20/min or PaCO2 <32 mmHg 4. WCC >12 or >10% immature band forms Sepsis Sepsis is SIRS + confirmed or presumed infections mortality: 10-15% Severe Sepsis Severe Sepsis is sepsis with organ dysfunction mortality: 17-20% Septic Shock Septic shock is defined as sepsis with refractory hypotension hypotension is defined as SBP <90 mmHg or MAP <70 mmHg refractory means that hypotension persists after 30 mL/kg crystalloid; i.e. vasopressor dependence after adequate volume resuscitation mortality: 43-54%

New sepsis-3 definition Sepsis is life-threatening organ dysfunction due to a dysregulated host response to infection Organ dysfunction is defined as an increase of 2 points or more in the Sequential Organ Failure Assessment (SOFA) score Patients with suspected infection who are likely to have a prolonged ICU stay or to die in the hospital can be promptly identified at the bedside with qSOFA (“HAT”); i.e. 2 or more of: Hypotension: SBP less than or equal to 100 mmHg Altered mental status (any GCS less than 15) Tachypnoea: RR greater than or equal to 22 Septic shock: Sepsis and (despite adequate volume resuscitation) both of: Persistent hypotension requiring vasopressors to maintain MAP greater than or equal to 65 mm Hg, and Lactate greater than or equal to 2 mmol/L With these criteria, hospital mortality is in excess of 40% Note that the term “severe sepsis” is no longer in use.

Current guidance

SSC guidance TO BE COMPLETED WITHIN 3 HOURS OF TIME OF PRESENTATION: Measure lactate level Obtain blood cultures prior to administration of antibiotics Administer broad spectrum antibiotics Administer 30ml/kg crystalloid for hypotension or lactate ≥4mmol/L TO BE COMPLETED WITHIN 6 HOURS OF TIME OF PRESENTATION: Apply vasopressors (for hypotension that does not respond to initial fluid resuscitation) to maintain a mean arterial pressure (MAP) ≥65mmHg In the event of persistent hypotension after initial fluid administration (MAP < 65 mm Hg) or if initial lactate was ≥4 mmol/L, re-assess volume status and tissue perfusion and document findings. Re-measure lactate if initial lactate elevated.

APH guidance

Clinical relevance: Global Current guidance focuses on achieving MAP of >65mmHg Score for hypotension on both SOFA and qSOFA (MAP <70mmHg and SBP <100mmHg) Brief mention of relative hypotension: “atherosclerosis/HTN may need higher” Mean arterial pressure OR administration of vasopressors required SOFA score MAP < 70 mm/Hg 1 dop <= 5 or dob (any dose) 2 dop > 5 OR epi <= 0.1 OR nor <= 0.1 3 dop > 15 OR epi > 0.1 OR nor > 0.1 4 Assessment qSOFA score Low blood pressure (SBP ≤ 100 mmHg) 1 High respiratory rate (≥ 22 breaths/min) Altered mentation (GCS < 15)

Clinical relevance: APH MEWS system allows for potentially inappropriate SBP Personally attended many MET calls for septic patients with relative hypotension Sick, “normotensive” people don’t trigger No early trigger, no early goal directed therapy

Critical appraisal Asfar P, et al. High versus Low Blood-Pressure Target in Patients with Septic Shock. NEJM 2014;370:1583-1593

Research question Does resuscitation to a MAP of 80-85mmHg rather than 65-70mmHg in patients with septic shock decrease 28 day mortality, and are these benefits more pronounced among those with chronic hypertension

Study design French, multicentre, open-label RCT of MAP targets in patients with septic shock Stratification after randomisation to HTN/non-HTN n=776 n=388 – low target group n=388 – high target group Very similar at baseline

Exclusion criteria Incompetent No health care Enrolled in other study DNA CPR

Research question (PICO) Population: 18+ Assessed within 6h Septic shock as per SIRS system Refractory to 30ml/kg crystalloid/required norad or adrenaline/clinician choice Intervention: Vasopressor to 65-70 or 80-85mmHg for 5 days or until weaned Allow step down if bleeding/AMI Allow for steroid/APC Comparison: Two groups Usual treatment: MAP >65mmHg Intervention: MAP 80-85mmHg No crossover Outcome: Primary outcome: Death from any cause by 28 days Secondary outcome: 90 day mortality Days alive and free from organ dysfunction by day 28 ICU LOS Hospital LOS

Methods Cox regression for inter group differences Quantitative variable tested via t-test/wilcoxon rank sum Qualitative variable tested via chi squared/fishers exact test Logistic regression analyses used to adjust for known risk factors in the intention to treat group Enrollment of 800 patients should have provided a power of 80% an absolute diffences in primary outcome between groups of 10% (two-sided alpha level 0.05) - underpowered

Results Primary outcome p = 0.57 Hazard ratio 1.07 95% CI (0.84 – 138) MAP 65-70mmHg MAP 80-85mmHg Death from any cause at 28 days 132 (34.0%) 142 (36.6%)

Results Secondary outcomes Death at day 90: Survival at day 28 w/o organ support: p=0.74 p=0.66 Hazard ratio 1.04 95% CI (0.83-1.30) MAP 65-70mmHg MAP 80-85mmHg Death at day 90 164 (42.3) 170 (43.8) Survival at day 28 w/o organ support 241 (62.1) 235 (60.6)

Results Pre-existing hypertension Doubling of plasma creatinine MAP 65-70mmHg MAP 80-85mmHg Normotensive 71/215 (33.0%) 85/221 (38.5%) Hypertensive 90/173 (52.0%) 65/167 (31.7%) RRT in first 7 days MAP 65-70mmHg MAP 80-85mmHg Normotensive 66/215 (30.7%) 77/221 (34.8%) Hypertensive 73/173 (42.2%) 53/167 (31.7%)

Results Significant adverse events p=0.02 Acute MI VF/VT Digital ischaemia No significant difference Mesenteric ischaemia Bleeding MAP 65-70mmHg MAP 80-85mmHg Atrial fibrillation 11 (2.8%) 26 (6.7%) High target: 19.1% Low target: 17.8% p=0.64

Validity post critical appraisal Clearly focused on and addressed one issue Outcomes appropriate Intervention specific Patient allocation randomised by computer generator Patients, research staff blinded Doctors aware – open label

Validity post critical appraisal Intervention/control groups sufficiently similar Both groups treated equally – other than intervention MAP 65-70mmHg MAP 80-85mmHg Age 65 +/- 15 65 +/- 13 Male sex 250 (64.4%) 267 (68.8%) SOFA score 10.8 +/- 3.1 10.7 +/- 3.1 Source of infection To within 2.3% Serum lactate 3.7 +/- 3.7 3.3 +/- 3.2 Fluid before inclusion 2946 +/- 1360 2973 +/- 1331 Serum Cr at inclusion 1.96 +/- 1.39 1.93 +/- 1.47

Validity post critical appraisal All patients accounted for at its conclusion Even those that did not meet the allocated target MAP, or those that had to be stepped down due to risk were included in intention to treat analysis

How precise was the estimate of treatment effect? Low MAP target: 65-70mmHg Actually was 70-75mmHg High MAP target: 80-85mmHg Actually was 85-90mmHg High target group required higher doses of NA for longer durations Lower than expected death rate – ‘study under-powered’ Possible that a difference significant difference does exist but was not detected Possible type two error Use of steroids/APC not recorded Poukkeanen M et al suggest that hypotensive episodes (MAP under 73 mmHg) are associated with progression of AKI in critically ill patients with severe sepsis

Cost-benefit No mention of LOS

Can these results be applied to our treatment population? Yes Study was well matched No increased harm in aiming for higher MAP Possible reduction in reno-vascular adverse effects if selection of high MAP targets appropriate – i.e. chronic hypertensives Only unknown is the effect of steroid on result

My own personal practice Will not change Enhances my current practice Consider suggesting high MAP targets in appropriate patients Be mindful of reno-vascular effects associated with low MAP in hypertensive patients Be mindful of A.Fib in patients with higher MAP

Thanks Library: Linda Taylor Critical care: Dr. Prashast Dr. Williams Special thanks: Ron For keeping the night shifts nice and quiet

Summary Valid study Would be interesting to study the effect of steroid on this population No harm in aiming for higher MAP targets in septic shock No benefit in aiming for higher MAP targets in septic shock Possible benefit conveyed to the chronic hypertensive patient with septic shock in avoiding reno-vascular adverse events

Questions Thomasconley@doctors.org.uk Dellinger RP, et al. Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock: 2012. CCM 2013: 41: 580-637 Surviving sepsis campaign responds to sepsis-3. SSC 2016. 27/06/2016. http://www.survivingsepsis.org/SiteCollectionDocuments/SSC-Statements-Sepsis-Definitions-3-2016.pdf Abraham E. New Definitions for Sepsis and Septic Shock. JAMA 2016;315(8):757 Strandgaard S, Oleson J, Skinhoj E, Lassen NA. Autoregulation of Brain Circulation in Severe Arterial Hypertension. BMJ 1973;1(5852):507-510. Poukkanen M, Wilkman E, Vaara ST, et al. Haemodynamic variables and progression of acute kidney injury in critically ill patients with severe sepsis: date from the prospective observational FINNAKI study. Crit Care 2013;17:R295. Thomasconley@doctors.org.uk