3. Road Map
• When to start vasopressors
1. Is this patient’s BP too low?
2. Why is this patient’s BP low?
3. How should I bring this patient’s BP up?
• What vasopressor to use (the easy part)
• Practical considerations
• When to use adjuncts to NE
• How to use peripheral pressors
4. Case 1
• 64M with T2DM and chronic dry flaky skin on his feet. He comes in
with R non-purulent cellulitis. Receives 30cc/kg LR in the ED, then is
admitted to medicine.
• 1h after admission, RN pages you that his BP is 90 / 40 (MAP 60).
What do you want to do?
5. When to start vasopressors
Steps to decide when to start vasopressors:
1. Is this patient’s BP too low?
2. Why is this patient’s BP low?
3. How should I bring this patient’s BP up?
6. Is this patient’s BP too low?
BP target = open question in ICU
medicine
• Mean Arterial Pressure of 65 mmHg =
classic teaching (e.g. Surviving Sepsis)
• Should we tailor to baseline
BP/comorbidities?
• Mechanistic rationalization but has not
been demonstrated empirically.
Beware: BP =/= Perfusion
Can you think of a way BP can go up and
perfusion goes down?
7. Is it real?
• Assess Mental status, urine output, cap refill,
lactate, gestalt.
• Avoid sedating meds in patients with borderline BP
• lose ability to monitor (and often cause hypotension)
• You probably don’t need an arterial line…
Duration of hypotension is important
• “[Ischemic] Time is Brain”
• “[Hypotensive] Time is Organ Function”
Increasing time with perfusion
deficit = increased risk of adverse
kidney event. MPP = Mean
Perfusion Pressure
Am J Respir Crit Care Med, 2020
https://www.atsjournals.org/doi/ab
s/10.1164/rccm.201912-2316OC
8.
9. When to start vasopressors
Steps to decide when to start vasopressors:
1. Is this patient’s BP too low?
2. Why is this patient’s BP low?
3. How should I bring this patient’s BP up?
11. When to start vasopressors
Steps to decide when to start vasopressors:
1. Is this patient’s BP too low?
2. Why is this patient’s BP low?
3. How should I bring this patient’s BP up?
12. Case 1b
• 64M with T2DM and chronic dry flaky skin on his feet. He comes in
with R non-purulent cellulitis syncope and BRBPR, which is ongoing.
Receives 30cc/kg LR in the ED, then is admitted to medicine.
• 1h after admission, RN pages you that his BP is 85 / 50 (MAP 60).
What do you want to do?
13. Why is this patient’s BP low?
Obstructive Shock
• Tamponade
• PE
• Tension Pneumothorax
Remove the obstruction
Distributive Shock
• Sepsis – Antibiotics, Source Control
• Pancreatitis
• Neurogenic
• Anaphylactic
Vasopressors
Hypovolemic Shock
• Hemorrhagic shock
• Diarrhea
• Insensible Losses
Replace volume
Cardiogenic Shock
• Valve
• Arrythmia
• Cardiomyopathy
Fix or augment the pump
14. Case 2
• 70M presents with urinary retention, fever, AMS. Initially normal BP.
UA with WBC and bacteriuria – started on broad spectrum antibiotics.
BP tanks after the patient is admitted despite 2L LR. You suspect E
Coli bacteremia, with worsening shock as endotoxin is released.
Lactate is 5 mmol/l. You have a trainee on your team who asks…
• “Lactate is elevated because not enough O2 is being delivered to the
tissues… LR doesn’t carry any oxygen, and NE works by raising
vascular resistance which ought to lower flow… how would either of
these help?”
• How would you respond?
15. Mechanism of improved DO2
(SV * HR) = CO = MAP-CVP / SVR:
• Isolated increase in SVR would make CO drop?
Non-LV-cardiogenic shock states, Venous return is
commonly the limiting step (blood pools in dilated
veins)
• Unstressed volume: no increase in pressure as more
added.
• In health: 85% of total volume
• Stressed volume: pressure increases as volume
added, so increases venous return.
• In health: 15% of volume.
16. Mechanism of improved DO2
Venous return is
proportional to the stressed
volume
• Fluids: increase stressed
volume by increasing
overall volume
• Vasopressors: move
unstressed volume to
stressed volume
(venoconstricting =
tightening the tube)
DOI: 10.4103/ija.IJA_209_17
MSFP: mean systemic filling pressure (in the venules)
VR: Venous return
17. Case 3
• 70F with OA on NSAIDs who has reduced PO intake for 1 week due to
epigastric pain. Acute onset 10/10 abd pain night of presentation.
Rigid on the gurney
• Taken to OR – perf’ed ulcer, gets Gram Patch, admitted afterward with
secondary peritonitis. 30cc/kg LR. Lactate is 8 mmol/L. MAP is 60
mmHg
• What do you do? Fluids or vasopressors?
18. Sepsis: how much fluids?
• Hypovolemia due to: reduced PO, increased insensible losses/fever,
3rd space losses due to vascular permeability).
• Replete based on duration of symptoms, severity of reduced intake, etc.
• Vasodilated due to: endothelial injury, altered vascular tone
• Surviving Sepsis: 30 ml/kg. However, this has not (yet) been tested
• Comes from Observational data, trial protocols (e.g. Early Goal Directed
Therapy – PROCESS, ARISE trials), and common practice
19. Sepsis
• Paradigm: ”Fluids first, then NE if refractory hypotension”
• CENSER Trial: Should patients get both (fluids, pressors) up front?
• blinded RCT
• 0.05 mcg/kg/min NE x 24h through PIV vs placebo & std of care (surviving
sepsis)
• Outcome: Improvement in shock
• 65+ MAP and 0.5L/kg/hr UOP or 10% drop in lactate in 6h
• 76.1% NE vs 48.4% Placebo. No problem with adverse effects.
Clovers: June 2021. PETAL Network RCT
of Vasopressors first with rescue fluids vs
fluids first vs rescue vasopressors
20. Case 3
• 70F with OA on NSAIDs who has reduced PO intake for 1 week due to
epigastric pain. Acute onset 10/10 abd pain night of presentation.
Rigid on the gurney
• Taken to OR – perf’ed ulcer, gets Gram Patch, admitted afterward with
secondary peritonitis. 30cc/kg LR. Lactate is 8 mmol/L. MAP is 60
mmHg
• You decide to give another 1L of fluids. MAP increases to 70, then
trends down to 60 mmHg over then next hour.
• Do you continue to give more fluids?
21. ‘Fluid responsiveness’, Resuscitation Targets
• Organizational and mental barriers to starting vasopressors
• Sepsis 3 septic shock definition: ‘Requires vasopressors’
• If BP increases with fluids (or + NICOM), should you give more?
• To maintain 20% increase in intravascular volume (1L), 2-3L of fluid are going
to end up in the interstitium and tissues
More fluids = Worse outcomes (observational)
• Malbrain et al, 2014 meta-analysis
Resuscitation targets: unknown if helpful
• Lactate (if elevated, give more IVF?)
• Mixed Venous O2 (invasive, no better)
• Cap Refill (as good as lactate,
ANDROMEDA-SHOCK)
22. Road Map
• When to start vasopressors
1. Is this patient’s BP too low?
2. Why is this patient’s BP low?
3. How should I bring this patient’s BP up?
• What vasopressor to use (the easy part)
• Practical considerations
• When to use adjuncts to NE
• How to use peripheral pressors
23. Use Norepinephrine
Norepinephrine Epinephrine Vasopressin Phenylephrine
Action Alpha1 - vasoconstriction
Beta1 - contractility
Alpha1 - “
Beta1 – “
Beta2 – inotropic
effect.
V1 receptor Alpha1 – “
*Beta1 – “
Use First line, generally • Relative bradycardia
• Low cardiac output
• Anaphylaxis
• Pure
vasoconstrictor.
• Used as adjunct
Physiologically VERY
similar to NE
Dosage • Start at 0.04 mcg/kg/min
• There is no maximum dose
Gtt: same as NE
Push dose: 1mg (only
for use in arrest, 5-
10min)
0.04 U (no titration
because half-life is 30
minutes)
Push dose: 100 mcg
(10-20 min)
24. Use Norepinephrine
No solid evidence suggesting NE is
best
• Vaso 1st: VANISH trial, equivalent
• Epi 1st: CAT trial, equivalent
NE is logistically convenient.
Titrate q5-15 minutes
25. Road Map
• When to start vasopressors
1. Is this patient’s BP too low?
2. Why is this patient’s BP low?
3. How should I bring this patient’s BP up?
• What vasopressor to use (the easy part)
• Practical considerations
• When to use adjuncts to NE
• How to use peripheral pressors
26. Adjuncts
Common practice pattern: once NE at 0.20 mcg/kg/min.
• consider adding Vasopressin 0.04U, no titration, based on VASST trial
(no benefit, but post-hoc analysis most useful in that range)
• Stress dose steroids (hydrocortisone 100 mg q8 or 50 mg q6)
• Consider central venous catheter and arterial line
27. Do you need a central line?
• Pittard, 2013: RCT of 135 vs 128 pts randomized peripheral vs
central. Most frequent PIV complication = couldn't start.
Allowed 33.3+ mcg/min
NE. DOI: 10.1177/0310057X1704500614
• Tian, 2019: Systematic review extravasation rate: 3.4%, but
no true adverse outcomes in about 1500 patients. DOI
10.1111/1742-6723.13406
• Cardenas-Garcia, 2015: Cohort of 734 ICU received mean
duration 49+/- 22 hours, max 72h of peripheral pressors: 2%
had extravasation , none had lasting damage, 13% eventually
needed central line. DOI: 10.1002/jhm.2394
• Loubani, 2015: Systematic review: average time to
extravasation = 35h DOI: 10.1016/j.jcrc.2015.01.014
• Midlines: controversial. Data soon.
Compared to central venous catheter complication rates:
3SITES study, NEJM
28. How to do peripheral pressors
• You need to know about the IV
• Best: 18g or 20g in AC fossa or proximal (less risk, and less
risk of damage)
• protocoled extremity check (e.g. q2h)
• must flush and draw without pain
• Not US guided placement (this means was hard, and is
usually deeper and thus harder to monitor for
extravasation)
• Don't have BP cuff on that arm.
• If extravasation: administer SQ phentolamine (0.1-
0.2 mg/kg up to 10) and possibly nitroglycerin paste.
• If their BP drops: Check their arm
• This is the main reason to place CVC as dose increases –
reliable access
PIV
TODO:
[ ] split in to 3 smaller sub-talks
Increase emphasis on the questions:
Question 1 around BP targets: MAP 65 with SBP 100 vs 85
Question 2 around mechanism of increased DO2 with vasopressor use (stressed volume increase, inotropy) – use data supporting increase in DO2 in stem
Question 3 Peripheral Pressors
Question 4 art line reliability? In comparison between NIBP, Radial, and Femoral
Question 5 titration of vasopressors.
Learning objectives:
There are probably some small refinements to this, but they generally haven’t been empirically demonstrated and only apply in the minority of cases.
80/20 rule based approach
Just do it: cognitive effort to reclassify as now “in shock” – feels like a big transition, but really it’s a continuum.
Emphasis on Sepsis
Vasopressors themselves are relatively simple: when to use is hard.
Pareto Principle
Applied: Focus on the 20% of the decisions that lead to 80% of the improved outcomes
There’s a lot we don’t know – Equipoise remains
Don’t get bogged down in the physiology, controversies, small choices
Good care = reliable delivery of the things we do know
Use a Group A strep cellulitis -> toxic shock syndrome case – classic for starting out OK, then progressing to shock.
Personalized BP targets?
Rationale: Among patients with chronic hypertension, a rightward shift of the curve for organ pressure-flow autoregulation is expected, which means that an increased mean arterial pressure could hypothetically result in improved organ perfusion - Strandgaard S, Olesen J, Skinhoj E, Lassen NA. Autoregulation of brain circulation in severe arterial hypertension. Br Med J 1973;1:507-510
doi: 10.1164/rccm.202004-1124ED
They Advocate for
80+ if baseline hypertension (argument: less kidney injury in this group)
65 in undifferentiated
<65 if baseline hypotension (to my knowledge, no solid empirical evidence here)
‘Relative Hypotension’: stiff vessels, fall off the autoregulation curve despite nominally ok BP
Baseline hypotension: cirrhosis. Younger, smaller, female.
Well tolerated hypotension: anecdotally: tamponade / CHF
TODO: Hypotension and mortality: https://pubmed.ncbi.nlm.nih.gov/24887489/
Mechanisms that sedatives cause hypotension:
-direct med effects
-loss of adrenergic tone
"[Ischemic] Time is Brain" :: "[Hypotensive] Time is Kidney”
Use MAP for all inpatient medicine – it’s what the cuff measures (less error), and is more tightly linked to outcomes (whether using cuff or art line) - MAP reflects the mean perfusion pressure.
Wide pulse pressure – adjust blood pressure target? (e.g. 100 / 30) No evidence that we should change the target. Trust the MAP
Note: radial arterial lines likely significantly underestimate the central BP (e.g. https://pubmed.ncbi.nlm.nih.gov/28523028/) – if you need to know, go for fem or axillary. The degree of uncertainty between Cuff => Radial is about the same for Radial => Fem, in general.
“Cuff vs. radial A-line: The 95% confidence interval of the MAP measured using an oscollometric noninvasive BP cuff is roughly +/- 12 mm when compared to a radial A-line.
Radial A-line vs. femoral A-line: The 95% confidence interval of the MAP measured with a radial A-line appears to range between ~5 mm higher and ~15 mm lower that measured with a femoral artery A-line. Among sicker patients on higher vasopressor doses, correlation may be worse.” IBCC
Femoral is probably “gold standard” because it reflects the renal perfusion pressure, which is usually the first organ to lose autoregulation as Bp drops (classical teaching: Renal 65-70, Heart and CNS 50, Gut slightly lower. Obviously depends on atherosclerosis, chronic HTN, etc.)
Don’t miss this. All management will be incorrect if you mis-diagnose the reason for hypotension.
Hemorrhagic Shock = give volume back.
Give blood – don’t wait for Hgb to drop if they are in shock (blood won’t necessarily have equilibrated yet)
Infusion rate
Cordis 8.5F > Shiley > 16g PIV > 7F CVC > 18g PIV >... > 24g PIV > 18g PICC
Can temporize with vasopressors (better than leaving them hypotensive while you wait for blood
Analogy – inflating a bike tire or sleeping pad. Pressure only starts to build once you’ve expanded the tubing/pad.
SCCM guidelines do support that increasing NE dose to higher target increases output (page 311) in several studies – so the presumption is supported. Likely due to increasing venous return (and some improvement in contractility)
Another take:
“However, lactate is not a marker of tissue perfusion: Increases in the serum lactate level may represent tissue hypoxia, accelerated aerobic glycolysis driven by excess beta-adrenergic stimulation, or other causes (e.g., liver failure)”
Levy B (2006) Lactate and shock state: the metabolic view. Curr Opin Crit Care. 12(4):315–321
Of course, increasing the Cardiac Output will then lead to increased blood pressure if the vascular resistance remains the same (or increases). This brings up the point, then, if BP is totally incidental to delivery of oxygen? Probably not, as the true role of blood pressure (e.g. why we are not evolved with a BP of 40/20 with lower resistance vessels) is to allow for control of where the blood goes. So, the BP itself is required to make sure that blood does not end-up mal-distributed to the organs.
Fluids first then add on pressors only if the BP remains low after 30 ml/kg?
Surviving Sepsis Guidelines codify
Address the hypovolemia portion based on hypoalb, duration of symptoms, severity of reduced intake – address vasodilation with pressors.
EGDT = Theory is: fluid resuscitation to address hypovolemic component (normalize the mixed venous saturation), then pressors.
Where does 30 cc/kg come from? Average amount given in PROCESS and ARISE trials interrogating EGDT.
Fluids first then add on pressors only if the BP remains low after 30 ml/kg?
Surviving Sepsis Guidelines, Sepsis 3 definition codify
Abdominal Sepsis – greater fluid resuscitation, anecdotally
Keep giving fluids until lactate normalizes?
If it’s possible to support your blood pressure with more fluids if you can?
ONLY 30% of fluids remains in the vessels after 30 minutes. (More if you are hypovolemic)
Cap refill
“The traditional strategy of flogging the patient with fluid for hours before starting pressors is ill-conceived.
Fluid responsiveness assessment, NICOM, etc. Lactate elevated =/= more fluids
Keep giving fluids until lactate normalizes? SCCM recommends, but also ill conceived
If it’s possible to support your blood pressure with more fluids if you can?
https://litfl.com/deresuscitation-and-positive-fluid-balance/
Positive fluid balance is associated with worse morbidity and mortality in multiple studies:
worse overall mortality in critically ill patients (systematic review by Malbrain et al, 2014)
increased mortality in patients with acute kidney injury (AKI) (SOAP study)
prolonged recovery in patients with acute lung injury/ acute respiratory distress syndrome (ALI/ARDS) (FACTT trial); improved mortality in ARDSNET patients if they had negative fluid balance at day 4 (Rosenberg et al, 2009)
worse mortality in septic shock patients (VAST trial)
worse morbidity in colorectal surgery patients
associated with intra-abdominal hypertension (Malbrain et al, 2014)
Argument against lactate being about DO2
Lactate increasing after epinephrine usage is associated with BETTER outcome - https://pubmed.ncbi.nlm.nih.gov/20016405/
Pareto Principle
Alpha1 agonist (vasoconstriction), beta1 agonism (myocardial contractility)
Start at 0.04 mcg/kg/min, titrate up or down to reach MAP 65 mmHg
There is no maximum dose of norepinephrine
-association between digit (and gut) ischemia and high dose vasopressors is fraught - https://www.aliem.com/myth-vasopressors-ischemia/ Unknown
Beware if they are having ectopy, as beta2 activation from epinephrine will worsen this.
Epinephrine 1st is the practice pattern in Europe.
Beware if they are having ectopy, as beta2 activation from epinephrine will worsen this.
Pareto Principle
Digit necrosis – is it known if this is from the vasopressor or from the illness severity?
This is just common practice, and has not been empirically shown to be an optimal resuscitation strategy.
TODO: UPDATE with this meta-analysis: https://pubmed.ncbi.nlm.nih.gov/33039229/, broken down here: https://rebelem.com/are-peripheral-vasopressors-causing-too-many-complications/
Vs central venous catheters: 3SITES study in NEJM https://www.nejm.org/doi/full/10.1056/NEJMoa1500964?downloadfile=showPowerPoint&articleTools=true&doi=10.1056/NEJMoa1500964
3-4% complication rates (infection, symptomatic DVT, or mechaniucal complication)
Censer trial (early pressors trial mentioned earlier), did not have them insert a CVC on each patient as part of the protocol: had no excess I major adverse events compared to fluid group
There are probably some small refinements to this, but they generally haven’t been empirically demonstrated and only apply in the minority of cases.
80/20 rule based approach
