Update on Novel Shock Treatments and Approach to Utilization

Kayla A. Nichols, BS, PharmD, BCCCP Clinical Pharmacist II, Critical Care Emory University Hospital

Adjunct Clinical Instructor Mercer University College of Pharmacy Atlanta, Georgia

Click to edit Master text styles Disclosures

I 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.

Click to edit Master text styles 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

Click to edit Master text styles Before we tackle the new stuff

Let’s review the old stuff

Click to edit Master text styles 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

ClickJ Environ to edit Sci Master Health text A Tox styles Hazard Subst Environ Eng. 2012;47(7):920-39. Image: https://wesavelives.org/alyson-geller-dear-allstate/ Types of Shock: Cardiogenic

• Reduction in pump function • Ex: myocardial infarction

• Treatment: • Fluid optimization • Inotropes • Vasopressors

ClickJ Environ to edit Sci Master Health text A Tox styles 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/ Types of Shock: Hypovolemic

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

• Treatment: • Fluid resuscitation • Blood • Vasopressors

ClickJ Environ to edit Sci Master Health text A Tox styles Hazard Subst Environ Eng. 2012;47(7):920-39. Image: https://www.kisspng.com/png-red-cell-a-red-blood-cell-311605/ Types of Shock: Obstructive

• Impaired venous return • Decreased cardiac output • Ex: pulmonary embolism

• Treatment: • Vasopressors • Removal of obstruction

ClickJ Environ to edit Sci Master Health text A Tox styles Hazard Subst Environ Eng. 2012;47(7):920-39. Image: https://www.roadtrafficsigns.com/road-closed-signs Types of Shock: Distributive

• Most common form of shock

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

• Treatment: • Fluid resuscitation • Vasopressors

ClickJ Environ to edit Sci Master Health text A Tox styles Hazard Subst Environ Eng. 2012;47(7):920-39. Image: https://pixabay.com/en/pseudomonas-aeruginosa-bacteria-2034320/ Distributive Shock Wheelhouse

Fluids Vasopressors +/- Steroids*

*Individual practice varies

Click to edit Master text styles Improving Blood Pressure: a Review

Vasopressors Inotropes

Epinephrine Vasopressin Dobutamine Norepinephrine Phenylephrine Milrinone Dopamine

Click to edit Master text styles Corticosteroids: a review

Click to edit Master text styles Hypothalamus-Pituitary-Adrenal Cortex Axis

ClickComput to editBiol MasterMed. 2015 text stylesDec 1;67:1-12. Crit Care Med. 2001 Jul;29(7 Suppl):S117-20. Corticosteroids: two mechanisms

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

ClickCrit Care to edit Med. Master 2001 text Jul;29(7 styles Suppl):S117-20. Eur J Pharmacol 1972;20:1–9 The Corticosteroid Controversy

“High dose steroids suppress the sepsis induced inflammatory response”

1970s

ClickCrit Care to edit Resusc. Master 2017 text stylesMar;19(1):3-4. Crit Care Med. 2014 Nov;42(11):2442-3. The Corticosteroid Controversy

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

1970s

1980s

ClickCrit Care to edit Resusc. Master 2017 text stylesMar;19(1):3-4. Crit Care Med. 2014 Nov;42(11):2442-3. The Corticosteroid Controversy

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

1970s 1990s

1980s

ClickCrit Care to edit Resusc. Master 2017 text stylesMar;19(1):3-4. Crit Care Med. 2014 Nov;42(11):2442-3. The Corticosteroid Controversy

New England Journal of Medicine: ADRENAL 2018 APROCCHSS 2018

1970s 1990s

1980s 2018

Click to edit Master text styles Corticosteroids: Prior to 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

Click to edit Master text styles Corticosteroids: 2018 update

Click to edit Master text styles ADRENAL 2018

Objective • 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

ClickN Engl to J edit Med. Master 2018 textMar styles 1;378(9):797-808 ADRENAL 2018

Outcome 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

ClickN Engl to J edit Med. Master 2018 textMar styles 1;378(9):797-808 APROCCHSS 2018

Objective • 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

ClickN Engl to J edit Med. Master 2018 textMar1;378(9):809 styles -818. APROCCHSS 2018

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

ClickN Engl to J edit Med. Master 2018 textMar1;378(9):809 styles -818. Steroids: Role in Therapy

• 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

Click to edit Master text styles What if the steroids aren’t enough?

Click to edit Master text styles Metabolic resuscitation

http://www.hrphysician.com/paulClick to edit Master text styles-e-marik-md/ What is metabolic resuscitation?

ClickChest. to 2017 edit MasterJun;151(6):1229 text styles-1238 rationale.Pharmacol Ther. 2018 Apr 21 Crit Care Med. 2016Feb;44(2):360-7 Image: http://graphics.latimes.com/food-water-footprint/ What is metabolic resuscitation?

Hydrocortisone 50mg IV q6h

Hydrocortisone 50mg IV q6h Ascorbic acid 1500mg IV q6h

Thiamine 200mg IV q12h

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

ClickChest. to 2017 edit MasterJun;151(6):1229 text styles-1238 Marik 2017

Primary Outcome: In-Hospital Mortality (%) 45 41.6 40.4 40 39.1

25 P < 0.001 20

10 8.5

0 HC + B1 + Vit C Control Predicted Actual

ClickChest. to 2017 edit MasterJun;151(6):1229 text styles-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

ClickChest. to 2017 edit MasterJun;151(6):1229 text styles-1238 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?

Click to edit Master text styles Enough about steroids and vitamins,

Let’s talk about the drips!

Click to edit Master text styles Angiotensin II

Click to edit Master text styles 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

ClickJ Manag to edit Care Master Pharm. text 2007 styles Oct;13(8 Suppl B):9-20. Review Angiotensin-II: ATHOS-3

Objective • 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 ClickCrit Care to edit Resusc.2017 Master text Mar;19(1):43 styles -49 ATHOS-3

Outcome 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

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

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

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

Click to edit Master text styles Angiotensin II: Titration

NE equivalent Angiotensin II Vasopressin (units/min) (mcg/kg/min) (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

Click to edit0.45 Master– text0.50 styles 0.03 35

> 0.50 0.03 40 Methylene Blue

Click to edit Master text styles Methylene Blue: Two Mechanisms

1 2

Inhibits Inhibit NO [NO] [cGMP] guanylate synthase decreases decreases cyclase

• cGMP causes myosin de-phosphorylation which prevents actin and myosin interaction • Decreasing cGMP allows this interaction to occur, raising vascular tone

NO: nitric oxide cGMP: cyclic guanosine monophosphate [X]: concentration of X

Click to edit Master text styles AM J Med Sci 2005;349(1):80-88 Ann Thorac Surg 2014;97:1785-6 Am J Med Sci 2015;349(1):80–88. 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”

ClickAnn Thorac to edit Surg.Master 2004 text Feb;77(2):496styles -9 Levin 2004

Methylene Blue Placebo Outcome Significance (n = 28) (n = 28) Mortality, all-cause (%) 0 (0) 6 (21.4) p = 0.01

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

ClickAnn Thorac to edit Surg.Master 2004 text Feb;77(2):496styles -9 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

ClickAM J toMed edit Sci Master 2005;349(1):80 text styles-88 Ann Thorac Surg 2014;97:1785-6 Pharmacotherapy. 2010 Mar;30(3):323. Image: www.medline.com/product/Methylene-Blue-Injection/Z05-PF92283 Methylene*Not Blue: removed byRole CVVHDF? 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

Click to edit Master text styles 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

ClickJ Cardiothorac to edit Master Vasc text Anesth. styles 2018 Aug 11 Hydroxocobalamin: Case Reports

Age Vasoplegia Case Report Procedure Comments (Sex) resolved?

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

Abdominal Experienced Warmer et al 2017 82 (M) aortic stent Yes chromaturia graft

ClickAnn Thorac to edit SurgMaster 2014;97:1785 text styles -6 Can 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 – Erythema – Rash – Infusion site reactions – Blood leak false alarm in dialysis patients – Hypokalemia in megaloblastic anemia

ClickAnn Thorac to edit SurgMaster 2014;97:1785 text styles -6 Can J Anaesth. 2017 Jun;64(6):673-674. J Cardiothorac Vasc Anesth. 2018 Aug 11 Hydroxocobalamin • Mechanism of action unknown Before– Likely hydroxocobalamin related to NO sequestering inAfter vascular hydroxocobalamin 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

ClickAnn Thorac to edit SurgMaster 2014;97:1785 text styles -6 Can J Anaesth. 2017 Jun;64(6):673-674. J Cardiothorac Vasc Anesth. 2018 Aug 11 Hydroxocobalamin: Role in Therapy

Diagnosis of vasoplegia refractory to vasopressors

Are there contraindications for methylene blue? -Risk of Serotonin syndrome? -G6PD deficiency?

No Yes

Consider Consider methylene blue hydroxocobalamin

ClickJ Cardiothorac to edit Master Vasc text Anesth. styles 2018 Aug 11 epub. 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

ClickJ Cardiothoracic to edit Master Vasc text Anesth. styles 2017 Jun;31(3):1012-14 CClin Kidney J. 2017 Jun;10(3):357-362 Lets put it all together

With some examples