update on novel shock treatments and approach to utilization...corticus: no difference in responders...

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Update on Novel Shock Treatments and Approach to Utilization

Kayla A. Nichols, BS, PharmD, BCCCPClinical Pharmacist II, Critical Care

Emory University Hospital

Adjunct Clinical InstructorMercer University College of Pharmacy

Atlanta, Georgia

[email protected]


DisclosuresI have nothing to disclose concerning possible financial or personal relationships with commercial entities (or their competitors) that may be referenced in this presentation.

I will be discussing the off-label use of medications.


Objectives• Review standard therapies frequently utilized for shock

• Discuss novel and evolving therapies for shock• Corticosteroid review• Metabolic resuscitation• Angiotensin II• Methylene blue• Hydroxocobalamin

• Apply novel therapies to current regimens often used in practice


Before we tackle the new stuff

Let’s review the old stuff


Definition of Shock• A state of cellular and tissue hypoxia due to one or more

of the following:• inadequate oxygen delivery • overconsumption of oxygen • inadequate oxygen utilization

J Environ Sci Health A Tox Hazard Subst Environ Eng. 2012;47(7):920-39.Image: https://wesavelives.org/alyson-geller-dear-allstate/


Types of Shock: Cardiogenic

J Environ Sci Health A Tox Hazard Subst Environ Eng. 2012;47(7):920-39.Image: http://trendintech.com/2018/05/30/researchers-develop-technique-that-can-remotely-operate-lab-grown-heart-cells/human-heart-anatomical-rendering-on-dark-background/

• Reduction in pump function• Ex: myocardial infarction

• Treatment:• Fluid optimization• Inotropes• Vasopressors


Types of Shock: Hypovolemic

J Environ Sci Health A Tox Hazard Subst Environ Eng. 2012;47(7):920-39.Image: https://www.kisspng.com/png-red-cell-a-red-blood-cell-311605/

• Reduction of intravascular volume• Ex: trauma, high volume

losses

• Treatment:• Fluid resuscitation• Blood• Vasopressors


Types of Shock: Obstructive

J Environ Sci Health A Tox Hazard Subst Environ Eng. 2012;47(7):920-39.Image: https://www.roadtrafficsigns.com/road-closed-signs

• Impaired venous return• Decreased cardiac output

• Ex: pulmonary embolism

• Treatment:• Vasopressors• Removal of obstruction


Types of Shock: Distributive

J Environ Sci Health A Tox Hazard Subst Environ Eng. 2012;47(7):920-39.Image: https://pixabay.com/en/pseudomonas-aeruginosa-bacteria-2034320/

• Most common form of shock

• Loss of microcirculatory autoregulation and/or increased metabolic demand• Ex: sepsis, vasoplegia

• Treatment:• Fluid resuscitation • Vasopressors


Distributive Shock Wheelhouse

Fluids Vasopressors +/- Steroids*

*Individual practice varies


Improving Blood Pressure: a Review

Vasopressors Inotropes

Epinephrine

NorepinephrinePhenylephrine

Dopamine

Dobutamine

Milrinone

Vasopressin


Corticosteroids: a review

Click to edit Master text stylesComput Biol Med. 2015 Dec 1;67:1-12.Crit Care Med. 2001 Jul;29(7 Suppl):S117-20.

Hypothalamus-Pituitary-Adrenal Cortex Axis

Click to edit Master text stylesCrit Care Med. 2001 Jul;29(7 Suppl):S117-20.Eur J Pharmacol 1972;20:1–9

1) Anti-inflammatory: – Hypothalamic-Pituitary-Adrenal axis (HPA)– Reduced cytokine production

2) Cardiovascular – Cytokines cause peripheral decreased response to

catecholamine receptor– Cortisol improves vasoconstrictor response to

epinephrine in animal models

Corticosteroids: two mechanisms


The Corticosteroid Controversy

Crit Care Resusc. 2017 Mar;19(1):3-4.Crit Care Med. 2014 Nov;42(11):2442-3.

1970s

“High dose steroids suppress the sepsis induced inflammatory response”




1970s

1980s

“High dose steroids increase the risk of infection and superinfection, thereby increasing morbidity”




1970s

1980s

1990s

Annane et al: decrease mortality, reduced shock reversal timeCORTICUS: no difference in responders vs non, decrease shock reversal

time



1970s

1980s

1990s

2018

New England Journal of Medicine:ADRENAL 2018

APROCCHSS 2018


• Annane showed a mortality benefit for non-responders that received hydrocortisone and fludrocortisone

• Subsequent studies have failed to duplicate the benefits seen in this trial and even suggested infection-related harm

• Hydrocortisone may lead to a more rapid reversal of shock

• ACTH-stimulation test no longer used in practice

Corticosteroids: Prior to 2018


Corticosteroids: 2018 update

Click to edit Master text stylesN Engl J Med. 2018 Mar 1;378(9):797-808

ADRENAL 2018Objective

• To determine if administration of corticosteroids reduce 90-day mortality in patients with septic shock requiring ventilator and vasopressor support

Study Design• Multicenter, double-blind, parallel-group, randomized controlled trial• Continuous infusion of hydrocortisone 200mg IV daily for 7 days or ICU

death/discharge vs placebo

Population• N = 3,658• Mechanically ventilated• Strong clinical suspicion of infection with ≥2 SIRS criteria• Continuous vasopressors/inotropes for SBP >90 mmHg or MAP > 60

mmHg for ≥4 hours

Click to edit Master text stylesN Engl J Med. 2018 Mar 1;378(9):797-808

ADRENAL 2018Outcome Steroids (n = 1,832) Placebo (n = 1,826) Significance

Mortality at 90 days (%) 27.9 28.8 HR 0.95; 0.82-1.10

Duration of ventilation (days) 6 7 HR 1.13; 1.05-1.22

Median time to shock reversal (days) 3 4 HR 1.32; 1.23-1.41

Median time to ICU discharge (days) 10 12 HR 1.14; 1.06-1.23

28 day mortality (%) 22.3 24.3 OR 0.89; 0.76-1.03

Blood transfusions (%) 37.0 41.7 OR 0.82; 0.72-0.94

Critiques:• Prior trials used bolus doses of steroids• Adverse events were recorded on clinical judgement

Click to edit Master text stylesN Engl J Med. 2018 Mar1;378(9):809-818.

APROCCHSS 2018Objective

• To determine if administration of hydrocortisone plus fludrocortisone therapy would improve the clinical outcomes of patients with septic shock

Study Design

• Multicenter, double-blind, 2 by 2 factorial, randomized trial• Hydrocortisone 50mg IV q6h and fludrocortisone 50 mcg daily for 7 days vs Placebo

Population

• N = 1,241• Admitted to the ICU <7 days with indisputable or probable septic shock <24 hours

• Clinically or microbiologically documented infection• SOFA 3-4 for ≥2 organ systems for ≥6 consecutive hours• Receipt of vasopressor therapy (≥0.25 mcg/kg/min or ≥1mg/hr) for ≥6 hours

Click to edit Master text stylesN Engl J Med. 2018 Mar1;378(9):809-818.

APROCCHSS 2018

Outcome Steroids (n=614) Placebo (n=627)Mortality at 90 days (%) 43 49 RR 0.88; 0.78-0.99Mortality at 28 days (%) 34 39 RR 0.87; 0.75-1.01Mortality at ICU discharge (%) 35 41 RR 0.86; 0.75-0.99Mortality at hospital discharge (%) 39 45 RR 0.86; 0.76-0.98Mortality at 180 days (%) 47 53 RR 0.89; 0.79-0.99Vasopressor-free days at 28 days (days) 17 15 P < 0.001Organ-failure-free days at 28 days (days) 14 12 P = 0.003

Critiques:• Trial conducted using the Surviving Sepsis 2008 Guidelines, which has since

been updated• Patients were generally more ill limiting the generalizability


• Corticosteroids accelerate time to shock resolution and weaning of vasopressors

• To be determined:– Improvement in mortality– Optimal patient population– Optimal timing to initiate– Chronic steroid use and corticosteroids in shock– Adverse effects and risk

Steroids: Role in Therapy


What if the steroids aren’t enough?


Metabolic resuscitation

http://www.hrphysician.com/paul-e-marik-md/

Click to edit Master text stylesChest. 2017 Jun;151(6):1229-1238rationale.Pharmacol Ther. 2018 Apr 21Crit Care Med. 2016Feb;44(2):360-7Image: http://graphics.latimes.com/food-water-footprint/

What is metabolic resuscitation?


What is metabolic resuscitation?Hydrocortisone 50mg IV q6h



Ascorbic acid 1500mg IV q6h



Ascorbic acid 1500mg IV q6h

Thiamine 200mg IV q12h

Click to edit Master text stylesChest. 2017 Jun;151(6):1229-1238

Marik 2017

Objective• To determine if vitamin C, thiamine, and hydrocortisone provides a

mortality benefit in patients with severe sepsis or septic shock

Study Design• Retrospective before-after study• Ascorbic acid + thiamine + hydrocortisone vs. hydrocortisone alone

or no therapy

Population• N = 194• Primary diagnosis of severe sepsis or septic shock• Procalcitonin ≥2


39.141.6

8.5

40.4

0

5

10

15

20

25

30

35

40

45

HC + B1 + Vit C Control

Primary Outcome: In-Hospital Mortality (%)

Predicted Actual

Chest. 2017 Jun;151(6):1229-1238

Marik 2017

P < 0.001

Click to edit Master text stylesChest. 2017 Jun;151(6):1229-1238

Next steps

• The VItamin C, Thiamine And Steroids in Sepsis (VICTAS) Study – Sponsored by Emory University

• Evaluation of Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Septic Shock (HYVITS)– Sponsored by Hamad Medical Corporation


Metabolic Resuscitation: a Summary• Jury is still out on combination

– Marik study demonstrated mortality benefit but does not demonstrate causation

• Several studies underway to evaluate regimen in more elegant way

• Ethics of administering regimen while trials are ongoing?


Enough about steroids and vitamins,

Let’s talk about the drips!


Angiotensin II

Click to edit Master text stylesJ Manag Care Pharm. 2007 Oct;13(8 Suppl B):9-20. Review

Renin Aldosterone-Angiotensin System (RAAS)

• Decrease in renal blood flow causes kidneys to convert prorenin to renin

• Renin converts angiotensinogen to angiotensin I– ACE converts angiotensin I to angiotensin II

• Angiotensin II– Potent vasoconstrictor – Aldosterone stimulator

Click to edit Master text stylesCrit Care Resusc.2017 Mar;19(1):43-49

Angiotensin-II: ATHOS-3Objective

• To determine if angiotensin II improved mean arterial pressure (MAP) compared to placebo

Study Design• Prospective, multicenter, double blind, randomized controlled trial• Angiotensin II and placebo infusions

Population• N = 321• Patients with catecholamine-resistant hypotension (>0.2 mcg/kg/min of

NE or equivalent)• Received at least 25 mL/kg of crystalloid or colloid over the previous 24

hours• Features of distributive shock

Click to edit Master text stylesCrit Care Resusc.2017 Mar;19(1):43-49Giapreza [package insert] La Jolla Pharmaceutical Company, CA; 92121

ATHOS-3Outcome Ang II (n=163) Placebo (n=158) Significance

MAP response (%) 69.9 23.4 OR 7.95; 4.76-13.3

Change in NE-equivalent dose at 3h -0.03 0.03 p<0.001

All cause mortality at 7 days (%) 29 35 OR 0.78; 0.53-1.16

All cause mortality at 28 days (%) 46 54 OR 0.78; 0.57-1.07

Critiques:• Small study size that limited power to detect difference• Titration period may allow for inadvertent un-blinding due to observable MAP

changes

Adverse Event Ang II (n=163) Placebo (n=158)ADRs leading to discontinuation (%) 14.1 21.5

Serious ADRs (%) 60.7 67.1

Deep-vein thrombosis (%) 12.9 5.1


Angiotensin II: Role in Therapy• Opinion on place in therapy is varied between

practitioners– Role in acute kidney injury and liver failure?– How much vasopressor is enough (but not too much)?

• High cost medication with 24 hour expiration

• Restricted at Emory University Hospital to:– High output shock with adequate volume resuscitation– Norepinephrine 0.2 mcg/kg/min + vasopressin or

equivalent


Angiotensin II: TitrationNE equivalent (mcg/kg/min) Vasopressin (units/min) Angiotensin II

(ng/kg/min)

0.10 – 0.15 0.03 0

0.16 – 0.20 0.03 5

0.20 – 0.25 0.03 10

0.25 – 0.30 0.03 15

0.30 – 0.35 0.03 20

0.35 – 0.40 0.03 25

0.40 – 0.45 0.03 30

0.45 – 0.50 0.03 35

> 0.50 0.03 40


Methylene Blue


Inhibit NO synthase

[NO] decreases

Inhibits guanylate cyclase

[cGMP] decreases

Methylene Blue: Two Mechanisms

AM J Med Sci 2005;349(1):80-88Ann Thorac Surg 2014;97:1785-6Am J Med Sci 2015;349(1):80–88.

• cGMP causes myosin de-phosphorylation which prevents actin and myosin interaction

• Decreasing cGMP allows this interaction to occur, raising vascular tone

NO: nitric oxidecGMP: cyclic guanosine monophosphate[X]: concentration of X

1 2


Levin 2004

Objective

• Evaluate effect of intravenous methylene blue on mortality in post-operative vasoplegic patients

Study design

• Multicenter study (probably not blinded)• 1.5 mg/kg intravenous methylene blue over 1 hour or placebo

Population

• N = 56 (8.8% of 638 total patients evaluated)• Elective cardiac surgery patients with presence of “vasoplegic

syndrome”Ann Thorac Surg. 2004 Feb;77(2):496-9


Levin 2004

• Critiques– Small sample size– No power calculation– Vasoplegia resolution not defined– Incidence of vasoplegia half of anticipated– Length of follow up not defined

Ann Thorac Surg. 2004 Feb;77(2):496-9

Outcome Methylene Blue (n = 28)

Placebo (n = 28) Significance

Mortality, all-cause (%) 0 (0) 6 (21.4) p = 0.01


Methylene Blue: Role in Therapy• Dose: 1.5 – 2 mg/kg bolus over 1 hour

• Continuous drip if bolus is successful

• When to use: • Vasoplegia after cardiac bypass• Other reversible causes of distributive shock

• Concerns:• Monoamine oxidase inhibitor (MAOI) properties• Glucose-6-phosphate dehydrogenase (G6PD) metabolism • Blue-green discoloration

AM J Med Sci 2005;349(1):80-88Ann Thorac Surg 2014;97:1785-6Pharmacotherapy. 2010 Mar;30(3):323.Image: www.medline.com/product/Methylene-Blue-Injection/Z05-PF92283


Methylene Blue: Role in Therapy• Dose: 1.5 – 2 mg/kg bolus over 1 hour

• Continuous drip if bolus is successful

• When to use: • Vasoplegia after cardiac bypass• Other reversible causes of distributive shock

• Concerns:• Monoamine oxidase inhibitor (MAOI) properties• Glucose-6-phosphate dehydrogenase (G6PD) metabolism • Blue-green discoloration

AM J Med Sci 2005;349(1):80-88Ann Thorac Surg 2014;97:1785-6Pharmacotherapy. 2010 Mar;30(3):323.Image: www.medline.com/product/Methylene-Blue-Injection/Z05-PF92283

*Not removed by CVVHDF?


Hydroxocobalamin


Shapeton 2018• Literature review for using hydroxocobalamin for

treatment of vasoplegia

• 14 articles reviewed, 1 excluded– 7 case reports

• Only 2 did not use concomitant methylene blue– 4 case series

• Largest (n = 33) also used methylene blue in half of patients

J Cardiothorac Vasc Anesth. 2018 Aug 11


Hydroxocobalamin: Case Reports

Ann Thorac Surg 2014;97:1785-6Can J Anaesth. 2017 Jun;64(6):673-674.J Cardiothorac Vasc Anesth. 2018 Aug 11

Case Report Age (Sex) Procedure Vasoplegia

resolved? Comments

Roderique 2014 71 (M) Valve repair Yes Citalopram as home med

Warmer et al 2017 82 (M)Abdominalaortic stent

graftYes Experienced

chromaturia


Hydroxocobalamin• Mechanism of action unknown

– Likely related to NO sequestering in vascular endothelium

• Available only in Cyanokits – 5g IV in NS 200mL over 15 minutes

• Concerns– Red color– Erythema– Rash– Infusion site reactions– Blood leak false alarm in dialysis patients– Hypokalemia in megaloblastic anemia

Ann Thorac Surg 2014;97:1785-6Can J Anaesth. 2017 Jun;64(6):673-674.J Cardiothorac Vasc Anesth. 2018 Aug 11

Click to edit Master text stylesAnn Thorac Surg 2014;97:1785-6Can J Anaesth. 2017 Jun;64(6):673-674.J Cardiothorac Vasc Anesth. 2018 Aug 11

Hydroxocobalamin• Mechanism of action unknown

– Likely related to NO sequestering in vascular endothelium

• Available only in Cyanokits – 5g IV in NS 200mL over 15 minutes

• Concerns– Red color– Erythemia– Rash– Infusion site reactions– Blood leak false alarm in dialysis patients– Hypokalemia in megaloblastic anemia

Before hydroxocobalamin After hydroxocobalamin


Hydroxocobalamin: Role in Therapy

J Cardiothorac Vasc Anesth. 2018 Aug 11 epub.

Diagnosis of vasoplegia refractory to

vasopressors

Are there contraindications for methylene blue?

-Risk of Serotonin syndrome?-G6PD deficiency?

Yes

Consider hydroxocobalamin

No

Consider methylene blue


Next Steps• Hemodynamic Effects of Methylene Blue vs.

Hydroxocobolamin In Patients At Risk of Vasoplegia During Cardiac Surgery– Sponsored by Dartmouth-Hitchcock Medical Center

• Study will be using either agent prophylactically in patients at risk of vasoplegia

J Cardiothoracic Vasc Anesth. 2017 Jun;31(3):1012-14CClin Kidney J. 2017 Jun;10(3):357-362


Lets put it all together

With some examples


LM: 58 year old male• Presented to the dentist with a presumed abscess and a

mass that has been increasing in pain for the past month

• Later diagnosed with head and neck cancer and had esophagectomy.

• POD 2 patient develops hypotension and is started on broad spectrum antibiotics and vasopressors.


LM: 58 year old male• Vitals

– BP: 70/40 mmHg – HR: 130 bpm– RR: 29 breaths per minute– Temp: 38.5°C– Lactate: 5 mMol/L

130

4.1

115

25

58

2.8995

0.8 677.5

23.4What are our options?


LM: 58 year old maleRaise your hand for the option you would consider in this patient

1. Hydrocortisone2. Metabolic resuscitation3. Angiotensin II4. Methylene blue5. Hydroxocobalamin


LM: 58 year old maleRaise your hand for the option you would consider in this patient

1. Hydrocortisone2. Metabolic resuscitation3. Angiotensin II4. Methylene blue5. Hydroxocobalamin

Could argue that all of these are correct in appropriate order


LM: 58 year old male

NE at 0.1 mcg/kg/min


Vasopressors continue to

escalate

Hydrocortisone +metabolic

resuscitation






escalate


resuscitation

Angiotensin II






escalate


resuscitation

Angiotensin II

Methylene blue or hydroxocobalamin


Next patient


PM: 85 year old female• Significant PMH including dementia, failure to thrive, and

multiple CABGs now in unit for shock – Suspect cardiogenic or septic

• Patient has reached 0.3 NE equivalents + vasopressin

• Should we start angiotensin II?


PM: 85 year old female• Significant PMH including dementia, failure to thrive, and

multiple CABGs now in unit for shock – Suspect cardiogenic or septic

• Patient has reached 0.3 mcg/kg/min NE + vasopressin

• Should we start angiotensin II?

Technically we couldBut I vote no


Next patient


BA: 31 year old female• Newly diagnosed HIV patient presenting with

generalized weakness to ED

• Now on vasopressors with presumed septic shock

• PMH:– ESRD on HD– Depression on Cymbalta


BA: 31 year old female• Now on escalating vasopressors despite hydrocortisone,

vitamin C, thiamine, and angiotensin II

• Team approaches you regarding selection of methylene blue or hydroxocobalamin for refractory shock

• Which do you choose?


BA: 31 year old female• Now on escalating vasopressors despite hydrocortisone,

vitamin C, thiamine, and angiotensin II

• Team approaches you regarding selection of methylene blue or hydroxocobalamin for refractory shock

• Which do you choose?

Hydroxocobalamin


Thank you!

• Peter Moran, PharmD, MSPS

• Aaron Morton, MMSc, PA-C, ATC, FAPACVS


Update on Novel Shock Treatments and Approach to Utilization

Kayla A. Nichols, BS, PharmD, BCCCPClinical Pharmacist II, Critical Care

Emory University Hospital

Adjunct Clinical InstructorMercer University College of Pharmacy

Atlanta, Georgia

[email protected]

update on novel shock treatments and approach to utilization...corticus: no difference in responders...

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