[tabby title="Overview"]

Overview

Vasopressors and inotropes are cornerstones in the management of shock syndromes. Understanding vasopressors' receptor activity and resultant pharmacological response enables clinicians to select the ideal vasopressor(s) for a patient suffering from shock. The following table outlines common vasopressors/inotropes and their general receptor activity profiles.1,2

Drug

Dose

α1

ß1

ß2

DA

V1

V2

cAMP

Norepinephrine (mcg/kg/min)

0.01 - 3

++++ ++ - - - -

-

Epinephrine (mcg/kg/min)

0.01 – 0.05

+ +++ ++ - - - - > 0.05 ++++ ++ ++ - - -

-

Phenylephrine (mcg/kg/min)

0.4 - 9

++++ - - - - -

-

Dopamine (mcg/kg/min)

1 - 5

- + - ++++ - - -

5 - 10

+ ++ - +++ - - - 10 - 20 +++ ++ - + - -

-

Vasopressin (units/min)

0.03 – 0.04

- - - - ++++ +++

-

Dobutamine (mcg/kg/min)

2 - 20

+ ++++ ++ - - -

-

Milrinone (mcg/kg/min)

0.125 – 0.75

- - - - - -

++++

Isoproterenol (mcg/min)

2 - 20

- ++++ ++++ - - -

-

Clinical efficacy is demonstrated primarily via targeted hemodynamic variables, while application to clinical practice remains variable and driven by expert opinion, patient physiology, and individual preference. The majority of published literature is focused on distributive shock, with physiological application to other shock syndromes. This review addressed the role of vasopressors and inotropes in distributive (septic) and cardiogenic shock. [tabby title="Septic (Distributive) Shock"]

Septic Shock and Other Distributive Shock States

Vasopressors and inotropes demonstrate rather predictable receptor activity; however, patient response may vary considerably based on endogenous sympathetic response, variable end-organ sensitivity, and individual physiology (preload/afterload and right/left ventricular systolic function). Physicians can consider the Surviving Sepsis Guideline expert recommendations during initial therapy selection; however, therapy should be individualized for each patient based on observed response and supporting bedside dynamic monitoring.3 NOREPINEPHRINE

First line vasopressor per Surviving Sepsis Guideline (strong, moderate quality).3
It increases vascular resistance (α1) with variable, but often minimal responses on heart rate and cardiac contractility (β1), particularly at doses < 0.2 mcg/kg/min. Tachycardia may manifest as the dose escalates with a variable impact on cardiac contractility, which is largely dependent upon preload and resultant afterload.1,2
The SOAP II study compared norepinephrine and dopamine in shock. The norepinephrine arm had less incidence of arrhythmias and was associated with lower mortality in the cardiogenic shock subset.4
A meta-analysis found that norepinephrine displayed decreased mortality and was less arrhythmogenic than dopamine.5

VASOPRESSIN

The Surviving Sepsis Guideline recommends adding low dose vasopressin (0.03 units/min) as a norepinephrine sparing measure (weak, low quality).3
At low doses (< 0.04 units/min), it moderately increases vascular resistance (V1) without substantial effects on heart rate and cardiac contractility. It will demonstrate mild fluid retention (V2), but with little expected clinical relevance.1,2
It may serve to restore catecholamine receptor responsiveness, particularly in cases of severe metabolic acidosis.2
The VASST study compared norepinephrine vs norepinephrine + vasopressin in septic shock. The addition of low dose vasopressin to norepinephrine did not result in lower mortality.6
The VANISH study compared norepinephrine vs early vasopressin and the impact on kidney failure in septic shock. The vasopressin arm utilized less renal replacement therapy, but did not reduce the incidence of kidney failure.7

EPINEPHRINE

The Surviving Sepsis Guideline recommends the addition of epinephrine to norepinephrine to achieve targeted MAP (weak, low quality).3
At low doses (< 0.05 mcg/kg/min), it increases heart rate and cardiac contractility (b1) with minimal effect on vascular resistance (α1). As the dose escalates, an increase in vascular resistance is expected with a variable response on cardiac contractility, largely dependent upon preload and resultant afterload.1,2
It may stimulate glycolysis (2), thus increasing serum glucose and lactate production, which may limit the utility in monitoring lactate clearance.1,2
In a prospective, randomized trial, both epinephrine and norepinephrine displayed similar times to achieve perfusion target; however, the epinephrine arm had more metabolic effects.8

DOPAMINE

The Surviving Sepsis Guideline recommends dopamine as an alternative to norepinephrine if absolute or relative bradycardia (weak, low quality). It is not recommended to use low dose dopamine for renal protection (strong, high quality).3
At low doses (< 5 mcg/kg/min), it is expected to have minimal effect on restoring hemodynamics as affinity for dopamine (DA) receptors predominate. As the dose escalates, an increase in heart rate and cardiac contractility (b1) is expected, with an increased vascular resistance (a1) occurring at the higher end of the dose range.1,2

PHENYLEPHRINE

The Surviving Sepsis Guideline does not make rated recommendations on its use given limited clinical trial data.3
It is increases vascular resistance (α1) with variable, but often an observed decrease in heart rate mediated by the carotid baroreceptor reflex. The cardiac output may vary, largely dependent upon preload and resultant afterload.1,2
It may be a reasonable strategy in patients whom are particularly susceptible to beta-adrenergic generated arrhythmia.3

DOBUTAMINE

Per the Surviving Sepsis Guideline, it should be considered if there is persistent hypoperfusion despite adequate volume status and vasopressor augmentation (weak, low quality).3
It increases heart rate and cardiac contractility (β1), with a variable response on mean arterial pressure, depending upon the degree of concomitant systemic vasodilation (β2).1,2
It may be a reasonable adjunctive agent to norepinephrine in patients with a component of low output heart failure.3

MILRINONE

The use of milrinone is unrated in the Surviving Sepsis Guideline given lack of supporting clinical trial data.3
It increases heart rate and cardiac contractility (cAMP), with a decrease in both systemic and pulmonary vascular resistance (cAMP).1,2
An initial bolus is generally not recommended in any patient population. It is excreted via the kidney (83% unchanged), thus caution must be taken if used in patients with renal impairment to avoid adverse hypotensive effects.

ANGIOTENSIN II (GIAPREZA™)

Manufactured by La Jolla pharmaceuticals, it is the first synthetic human angiotensin II product
Approved by the FDA on December 21, 2017 for use in patients with distributive shock, predominantly septic shock.9
Studied in recently published ATHOS-3 trial10
- Compared patients on 0.2 mcg/kg norepinephrine (or equivalent dose of another vasopressor) receiving either continuous infusion of angiotensin II (n=163) or placebo (n=158).
- Study primary endpoint was response in mean arterial pressure at 3 hours after angiotensin II initiation
  - Response defined as increase from baseline of at least 10 mm Hg or to MAP of at least 75 mm Hg without dose titration of other concomitant vasopressors
- Primary endpoint was achieved in 69.9% of patients receiving angiotensin II infusion as compared to 23.4% of those receiving placebo (OR 7.95; CI [95%] 4.76 – 13.3; P<0.001).
- More patients in angiotensin II arm developed DVTs relative to the placebo arm (3 vs. 0 patients, respectively)
Given increased risk of DVT, the FDA recommends DVT prophylaxis while on Giapreza™. 9
At present, place in therapy is likely as a third line pressor.
Cost considerations are unclear; its manufacturer is anticipating $500 million in U.S. sales.11

[tabby title="Cardiogenic Shock"]

Cardiogenic Shock

Vasopressor and inotrope selection for cardiogenic shock follows similar physiologic principles as septic shock. There is not a single preferred vasoactive therapy, with the strategy dependent upon the etiology (left heart failure, right heart failure, outflow obstruction, aortic stenosis/regurgitation, or mitral stenosis/regurgitation) and clinical presentation. Fluid and vasoactive strategies are often guided by dynamic bedside exam and invasive monitoring devices to enable optimization of preload, afterload, pulmonary vascular resistance, atrioventricular synchrony, and contractility. It is generally recommend to utilize low doses (and often combination vasoactive therapies) to minimize demands on myocardial oxygen consumption, especially in cases of acute ischemia.12 Listed below are considerations for various presentations or conditions: HEMODYNAMIC PHENOTYPES

Wet/Cold (↓CI; ↑SVR; ↑PCWP)
- Most common presentation and accounts for the majority of patients with cardiogenic shock secondary to myocardial infarction.12
- Norepinephrine is preferred if the patient is tachycardic or prone to arrhythmias.12
- Dopamine is preferred in the presence of bradycardia.12
- Upon stabilization, inotropes such as dobutamine or milrinone may be utilized to augment cardiac output.12
Dry/Cold (↓CI; ↑SVR; ↔PCWP)
- It is a common presentation for diuretic-responsive patients with chronic heart failure who present in decompensation. However, this phenotype also accounts for a substantial percentage of patients in cardiogenic shock attributable to myocardial infarction as well.12
- The strategy is largely similar to that of the wet/cold phenotype with the exception of fluid management.12
- Small volume fluid boluses may be considered to maintain and optimize preload.12
Wet/Warm OR Mixed Vasodilatory (↓/↔CI, ↓/↔SVR; ↑ PCWP)
- Characterized as a systemic inflammatory response, often secondary to an insult (e.g. myocardial infarction).12
- Directed by hemodynamic monitoring, norepinephrine may be utilized to improve SVR and cardiac output.12

STRUCTURAL/PHYSIOLOGIC CONDITIONS

Right Ventricular Failure
- Ideally, maintain preload, reduce right ventricular afterload, and prevent bradycardia.12
- Vasopressin increases preload without increasing pulmonary vascular resistance (and RV afterload), unlike norepinephrine.2
- Dopamine is preferred in the presence of bradycardia.12
- Pulmonary vasodilators can be utilized to reduce right ventricular afterload.
- It is important to ensure that vasopressor selection maintains atrioventricular synchrony.12
Aortic Stenosis
- Cardiogenic shock secondary to aortic stenosis is afterload-dependent.
- Accordingly, phenylephrine or vasopressin are commonly utilized to optimize afterload.12
- If left ventricular dysfunction is present, addition of an inotrope following hemodynamic stabilization may be beneficial.12
Aortic Regurgitation
- Dopamine may be preferred to maintain relative tachycardia, a shortened diastolic filling time, and a reduced preload.12
Mitral Stenosis
- Contrary to aortic stenosis, cardiogenic shock secondary to mitral stenosis is pre-load dependent.
- Phenylephrine or vasopressin may be utilized in this setting to enhance preload.12
- Positive chronotropes should be avoided, as they shorten diastolic filling time, thereby reducing preload.12
Mitral Regurgitation
- Norepinephrine or dopamine are preferred for initial hemodynamic stabilization.12
- If left ventricular dysfunction is present, addition of an inotrope following hemodynamic stabilization may be beneficial.12

OTHER CONSIDERATIONS

Bradycardia
- Positive chronotropes (isoproterenol, dopamine, dobutamine or epinephrine) should be utilized to optimize heart rate.12
Milrinone
- May have a larger inotropic role in subsets of cardiogenic shock, especially in patients on aggressive beta-blockade prior to presentation (and not responsive to dobutamine) or those cases benefiting from a reduction in pulmonary vascular resistance.
A recently published meta-analysis compared dopamine versus norepinephrine in the treatment of cardiogenic shock.13 Norepinephrine was associated with decreased 28-day mortality, a lower risk of arrhythmias and less gastrointestinal adverse effects. The impact of norepinephrine on 28-day mortality was not impacted in a subgroup analysis comparing patients with ischemic cardiogenic shock secondary to myocardial infarction.

ISOPROTERENOL

American Heart Association Guideline: consider in cardiogenic shock secondary to bradycardia.12
It increases heart rate and cardiac contractility (β1), with a variable response on mean arterial pressure, depending upon the degree of concomitant systemic vasodilation (β2).1,2
Unfortunately, a recent price increase (~$1500-1800/vial) has introduced a need to consider cost-effectiveness in comparison to significantly cheaper alternative chronotropic agents.

[tabby title="Central Venous Access"]

Central Venous Access

The use of central venous catheters for vasopressor delivery, at least during prolonged administration, has historically been a standard practice to minimize risk of extravasation or tissue ischemia. This remains the standard in a large majority of critical care practice; however, the principle has been challenged, advocating the safety of peripheral administration of vasopressors (for up to 72-hours) when adhering to a strict line management protocol (vein > 4 mm, site other than hand, wrist, or antecubital fossa, ultrasound confirmed placement, 18 or 20-gauge line, and blood return confirmation every 2 hours) and aggressive extravasation treatment (local phentolamine injection and topical nitroglycerin).14,15 The rate of extravasation was 2% (norepinephrine 3.2%, dopamine 2.9%, and phenylephrine 0%) with no cases of tissue ischemia.14

Peripheral infusion of vasopressors (norepinephrine, dopamine, phenylephrine, epinephrine) is commonly and safely employed as a temporizing measure or in patients with successful hemodynamic restoration utilizing a single vasoactive medication.14,15
If peripheral infusion is utilized, a strict management protocol (as detailed above) is imperative to minimize complications.
Norepinephrine may have a greater risk of extravasation and tissue injury given its degree of vasoconstrictive (α1) potency, lack of concomitant dermal vasodilation (β2) activity, and level of acidity (pH 3 – 4.5).14,15

Vasopressor Extravasation Extravasation and tissue injury is a defined complication, but should be minimized if adhering to proper line insertion and management principles. If it does happen to occur, one should be aware of management strategies to minimize tissue damage.16

Extravasation treatment may contribute to worsening hemodynamic instability, thus vasopressors via an alternative site catheter may be necessary.
Stop the vasoactive peripheral infusion, aspirate residual medication, and remove the catheter.
Demarcate the extravasation margins.
Elevate the extravasation site and apply warm compresses proximally.
Consider phentolamine 5 mg/5 mL normal saline, 0.5 – 1 mL local aliquot injections around leading edge of extravasation margins.
Consider nitroglycerin paste (2.5 cm) applied to extravasation area.

[tabby title="Authors"]

Authors

Chris Donaldson, PharmD; Ron R Neyens, PharmD, BCPS [tabby title="References"]

References

Hollenberg SM. Vasoactive Drugs in Circulatory Shock. Am J Respir Crit Care Med. 2011; 183:847-855.
Overgaard CB, Dzavik V. Inotropes and Vasopressors. Circulation. 2008; 118:1047-1056.
Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Crit Care Med. 2017; 45:486-552.
De Backer D, Biston P, Devriendt J, et al. Comparison of Dopamine and Norepinephrine in the Treatment of Shock. N Engl J Med. 2010; 362:779-789.
Avni T, Lador A, Lev S, et al. Vasopressors for the Treatment of Septic Shock: Systematic Review and Meta-Analysis. PLoS One. 2015; 10:1-17.
Russell JA, Walley KR, Singer J, et al. Vasopressin versus Norepinephrine Infusion in Patients with Septic Shock. N Engl J Med. 2008; 358:877-887.
Gordon AC, Mason AJ, Thirunavukkarasu N, et al. Effect of Early Vasopressin vs Norepinephrine on Kidney Failure in Patients with Septic Shock. JAMA. 2016; 316:509-518.
Myburgh JA, Higgins A, Jovanovska A, et al. A Comparison of Epinephrine and Norepinephrine in Critically Ill Patients. Intensive Care Med. 2008; 34:2226-2234.
S. Food and Drug Administration. FDA approves drug to treat dangerously low blood pressure. U.S. Food and Drug Administration. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm590249.htm. Published December 21, 2017. Accessed December 30, 2017.
Khanna A, English SW, Wang XS, et al. Angiotensin II for the Treatment of Vasodilatory Shock. N Engl J Med. 2017 Aug 3;377(5):419-430.
Sagonowsky E. With La Jolla's $500M Giapreza nod, FDA breaks a high-water mark for approvals. FiercePharma. https://www.fiercepharma.com/regulatory/as-la-jolla-s-giapreza-wins-approval-fda-passes-recent-high-water-mark. Published December 22, 2017. Accessed December 30, 2017.
Van Diepen S, Katz JN, Albert NM, et al. Contemporary Management of Cardiogenic Shock: A Scientific Statement from the American Heart Association. Circulation. 2017; 136:e232-e268.
Rui Q, Jiang Y, Chen M, et al. Dopamine versus norepinephrine in the treatment of cardiogenic shock: A PRISMA-compliant meta-analysis. Medicine. 2017; 96:e8402.
Cardenas-Garcia J, Schaub KF, Belchikov YG, et al. Safety of Peripheral Intravenous Administration of Vasoactive Medication. J Hosp Med. 2015; 10:581-585.
Loubani OM, Green RS. A Systematic Review of Extravasation and Local Tissue Injury from Administration of Vasopressors through Peripheral Intravenous Catheters and Central Venous Catheters. J Crit Care. 2015; 30:e9-e17.
Reynolds PM, MacLaren R, Mueller SW, et al. Management of Extravasation Injuries: A Focused Evaluation of Noncytotoxic Medications. Pharmacotherapy. 2014; 34:617-632.

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Vasopressors and Inotropes for Shock…

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