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

2. 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

3. 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

4. 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

5. 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”

6. Quick sepsis recap
Why is this study important?

7. 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.

8. 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%

9. 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.

10. Current guidance

11. 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.

12. APH guidance

13. 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)

14. 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

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

16. 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

17. 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

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

19. 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 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

20. 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

21. 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%)

22. Results Secondary outcomes
Death at day 90: Survival at day 28 w/o organ support:
p= p=0.66
Hazard ratio 1.04
95% CI ( )
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)

23. 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%)

24. 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

25. 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

26. 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

27. 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

28. 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

29. Cost-benefit
No mention of LOS

30. 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

31. 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

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

33. 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

34. Questions Thomasconley@doctors.org.uk
Dellinger RP, et al. Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock: CCM 2013: 41:
Surviving sepsis campaign responds to sepsis-3. SSC /06/
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):
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.