Inotropes, Vasopressors, and Cardiovascular Medications

Populational-based blood pressure by EPIQ-CNN

Calculator here: https://neopeds.academy/bp/ 

Treatment of “isolated hypotension” of the very low birth weight (VLBW) infant is controversial as some studies indicate increase intraventricular hemorrhage (IVH) and no change in mortality (Dempsey et al. 2009). HIP trial (Dempsey et al. 2021) did not show any difference with the use dopamine but was terminated prematurely. As such, to avoid iatrogenic and without any indication that this leads to tissue ischemia, we do not recommend active interventions, but rather watchful assessments of ongoing perfusion.

Figure on cardiovascular medications (English)

Figure sur les médications cardiovasculaires (français)

Hemodynamic Considerations in Prematurity

Cardiovascular Medications in Prematurity

A big thanks to Louis Chartier - Pharmacist at the Montreal Children's Hospital for contributing his expertise in reviewing the half-life of each medications in the literature. 

Please find in french some references here regarding pharmacology in the NICU: Guide pratique des médicaments en néonatologie au CHU Sainte-Justine

Infusion rates

How to prepare certain dilutions

Adrenergic receptors (G-protein coupled)

• α1: Located on arterial and venous smooth muscle cells, cardiac myocytes. Smooth muscle (vascular) contraction leading to vasoconstriction (increasing calcium entry), increases contractility (inotrope), decreases insulin relase, increases gluconeogenesis.

• α2:  Sympathetic nerves and central nervous system. Blocks norepinerphine release, inhibits sympathetic output and leads to vascular smooth muscle relaxation. 

• β1: Sino atrial and atrio-ventricular node, atrial and ventricular muscle, conduction cells (Purkinje, sinoatrial, AV node). Increases heart rate (chronotropy) by acting on the SA node, increases conduction velocity by acting on the AV node, increases contractility and increases renin secretion. 

• β2: Arterial / venous smooth muscle cells, bronchial smooth muscle cells. Leads to smooth muscle relaxation (vasodilation), bronchial relaxation, increases heart rate and contractility, decreased intestinal motility, induces glycogenolysis, increases insulin secretion. 

Physiology reminders

• Blood pressure = Cardiac Output (Flow) x Vascular resistance 

• Cardiac Output = Heart rate x Stroke Volume

• Cardiac output = Systemic Blood pressure / Total peripheral vascular resistance

• Stroke volume is dependent on the preload, afterload and contractility

  • Preload: depends on volume in ventricle at end of diastole (impacted by blood volume, venous tone, intrapleural pressure, atrial contractility and capacity to fill - diastolic function)

  • Afterload: depends on resistance/pressure that ventricle confronts during contraction. Determined by the end diastolic aortic/pulmonary pressure and aortic/pulmonary resistance. 

  • Stroke volume = End diastolic volume - End systolic volume of the ventricle (volume ejected from the respective ventricle). 

• Stroke work = Work performed by the ventricle during a heartbeat leading to a rise in blood pressure = Stroke Volume x Mean Arterial Pressure.

• Frank Starling: Heart may adapt to different volumes (preload) - as the muscle is stretched with increasing amount of volume, there is increased forced in the contraction to pump extra blood. 

• Poiseuille´s law: The resistance of a vessel (R) is directly proportional to its length (L) and to the blood viscosity (η), and inversely proportional to the radius to the fourth power (r4).

• Great resource for Pressure-Volume Loop and relationship between Pressure-Volume-ECG, Frank-Starling Curve, Cardiac Work

Epinephrine 

α1 and β1 (slight β2)) - Vasoconstriction (α); Inotropy (β)

Side effects: Induces hyperglycemia (insulin suppression, ↑ glycogenolysis and in gluconeogenesis) and hyperlactatemia (increase in oxygen consumption)

In piglets: epinephine ↑ cardiac index with no effect on systolic arterial pressure or systemic vascular resistance

• Starting dose: 0.05 à 0.1 mcg/kg/min

• Range of treatment: 0.01 à 1 mcg/kg/min

• Continuous IV or intraosseous infusion: Initial: 0.02 to 0.1 mcg/kg/minute (usual range: 0.05 to 0.5 mcg/kg/minute); maximum recommended dose: 1 mcg/kg/minute; doses up to 2.6 mcg/kg/minute have been reported

  • Davis AL, Carcillo JA, Aneja RK, et al. American College of Critical Care Medicine clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock. Crit Care Med. 2017;45(6):1061-1093.doi: 10.1097/CCM.0000000000002425. [PubMed 28509730] 

  • Domonoske C. Appendix A: Common neonatal intensive care unit (NICU) medication guidelines. In: Eichenwald EC, Hansen AR, Martin CR, Stark AR. Cloherty and Stark's Manual of Neonatal Care. 8th edition. Lippincott Williams & Wilkins; 2017. 

  • Heckmann M, Trotter A, Pohlandt F, Lindner W. Epinephrine treatment of hypotension in very low birthweight infants. Acta Paediatr. 2002;91(5):566-570. [PubMed 12113327]

Biventricular dysfunction before Epinephrine initiation:

Significant improvement after epinephrine initiation:

Dopamine

No neonatal data showing different dosages have different cardiovascular impact in newborns.

• DA1 receptors (theoretical vasodilation at renal, mesenteric, cerebral and coronary level)

• β1 (chronotropy, inotropy)

• α1 (peripheral vasoconstriction)

Adrenergic by degradation in Norepinephrine and Epinephrine (in adrenal medulla – can be immature in premature or injured in those with asphyxia).

Theoretical impact on thyroid hormonal secretion. May increase pulmonary vascular resistance.

Initial dosage : 5-10 mcg/kg/min; Usual range: 1 à 20 mcg/kg/min

• Increases pulmonary vascular resistance

• Increased Pulmonary/Systemic pressure ratio

• β1 (slightly β2): Inotropy and chronotropy (arrhythmias / tachycardia).

• Meta-analysis have been done on dopamine in the context of HIE and did not find any differences in mortality or neurodevelopmental outcomes

• Dopamine associated in observational studies with a rise in BP numbers, but no link with improved outcomes

• Few animal studies done: Apoptotic cell death ↓ in cerebral white matter of (dopamine treated fetal sheep) brains vs NS.

• Dopamine dose-dependent effect unproven in the newborn. Theoretically, has been described to have, at low doses (<5 mcg/kg/minute), increase renal blood flow and urine output effect; at intermediate doses (5 to 15 mcg/kg/minute) increase renal blood flow, heart rate, cardiac contractility, cardiac output, and blood pressure; and high doses (>15 mcg/kg/minute) leads to vasoconstriction and increased blood pressure. However, these effects have largely not been proven in the neonate. There are concerns regarding its effect on the brain (dopamine receptors) and in the pulmonary vasculature (increase PVR). 

Dobutamine

• Synthetic agonist of β1 (slightly β2): Inotropy and chronotropy (may induce arrhythmias).

• Theoretical benefit in cardiogenic shock but can disturb diastolic function as heart rate increases (less filling time)

  • ↑ cardiac O2 consumption. Can induce tachycardia and eventually arrhytmias. 

• Initial dosage : 5-10 mcg/kg/min

• Usual range: 1 à 20 mcg/kg/min (we locally rarely go above 15). 

  • Dempsey E, Rabe H. The use of cardiotonic drugs in neonates. Clin Perinatol. 2019;46(2):273-290. doi:10.1016/j.clp.2019.02.010 [PubMed 31010560] 

  • Domonoske C. Appendix A: Common neonatal intensive care unit (NICU) medication guidelines. In: Eichenwald EC, Hansen AR, Martin CR, Stark AR. Cloherty and Stark's Manual of Neonatal Care. 8th ed. Lippincott Williams & Wilkins; 2017. 

  • Joynt C, Cheung PY. Treating hypotension in preterm neonates with vasoactive medications. Front Pediatr. 2018;6:86. doi:10.3389/fped.2018.00086 [PubMed 29707527]

• Some data from animal models: dose-dependent increase in cardiac index by ↑ in HR, with no effect on stroke volume. SVR ↓ but not PVR

Norepinephrine

• Mostly vasoconstriction: α>β1>β2

• May lead to mesenteric / cutaneous ischemia by vasoconstriction.

• ↑ afterload (beware if poor LV function).

• Observational animal and human: may have some advantageous effect in pulmonary hypertension (observational studies). Better Pulmonary to Systemic pressure ratio. To consider in acute pulmonary hypertension by decreasing the Pulmonary:Systemic ratio. Some inotropic effect but mostly vasoconstrictive. 

• To consider in severe diabetic hypertrophic cardiomyopathy with septal hypertrophy to stent the left ventricular outflow tract. To avoir too much chronotropic effect (which decreases filling time), one may also consider phenylephrine (pure alpha-agonist). Some infants with this disease may need beta-blocker (such as Esmolol, which has a rapid half-life and easy to titrate), in order to promote filling time by decreasing heart rate when the infant is tachycardic. 

• Often use in the context of vasoplegic septic shock / NEC (with release of LPS leading to systemic vasodilation and hypotension - "warm shock"). 

• Dose: Usual initial dose: 0.02 to 0.1 mcg/kg/minute; titrate to desired effect; usual maximum dose: 1 to 3 mcg/kg/minute

  • Ref: Dempsey E, Rabe H. The use of cardiotonic drugs in neonates. Clin Perinatol. 2019;46(2):273-290. doi:10.1016/j.clp.2019.02.010 [PubMed 31010560]; 

  • Domonoske C. Appendix A: Common neonatal intensive care unit (NICU) medication guidelines. In: Eichenwald EC, Hansen AR, Martin CR, Stark AR. Cloherty and Stark's Manual of Neonatal Care. 8th edition. Lippincott Williams & Wilkins; 2017.

  • Sasse S, Kribs A, Vierzig A, Roth B. A staged protocol for the treatment of persistent pulmonary hypertension of the newborn. Klin Padiatr. 1997;209(5):301-307. doi:10.1055/s-2008-1043968 [PubMed 9342718] 

  • Tourneux P, Rakza T, Bouissou A, Krim G, Storme L. Pulmonary circulatory effects of norepinephrine in newborn infants with persistent pulmonary hypertension. J Pediatr. 2008b;153(3):345-349. [PubMed 18534241]

Hydrocortisone

• Appropriate glucocorticoid response to stress is essential for maintenance of hemodynamic stability.

• Glucocorticosteroids improve adrenergic receptors in smooth muscles, inhibits NO synthase expression and ↓ reuptake of norepinephrine leading to an increase in vascular tone and support of myocardial function.

• Effective in increasing BP and decreasing inotropic support.

• No study showing improved clinical outcomes with steroids in newborn shock

• Hydrocortisone normalizes PDE-5 activity in pulmonary artery smooth muscle cells from lambs with PPHN (Perez, M., Wedgwood, S., Lakshminrusimha, S., Farrow, K. N., & Steinhorn, R. H. (2014). Hydrocortisone normalizes phosphodiesterase-5 activity in pulmonary artery smooth muscle cells from lambs with persistent pulmonary hypertension of the newborn. Pulmonary circulation, 4(1), 71-81.)

Vasopressin

• Patient started on Vasopressin – up to 0.3 milliunits/kg/minute with good response in BP and presence of adequate urine output.

• Usual dosage: 0.1 to 0.3 milliunits/kg/min, to increase by steps of 0.1 to 0.2 milliunits/kg/min q60 min (avoid increasing faster than q20minutes). Beware of the units. 

  • Hypotension - range: 0.17 to 0.67 milliunits/kg/minute (0.01 to 0.04 units/kg/hour); initiated at low end and titrated q20 minutes in 0.17 milliunits/kg/minute (0.01 units/kg/hour) increments. Reference: Rios DR, Moffett BS, Kaiser JR. Trends in pharmacotherapy for neonatal hypotension. J Pediatr. 2014;165(4):697-701. [PubMed 25039051]

  • Persistent pulmonary hypertension of the newborn (PPHN): Initial: 0.1 milliunits/kg/minute, increase in 0.1 milliunits/kg/minute increments every hour as needed for clinical response to a maximum dose of 1.2 milliunits/kg/minute. Reference: Mohamed A, Nasef N, Shah V, McNamara PJ. Vasopressin as a rescue therapy for refractory pulmonary hypertension in neonates: case series. Pediatr Crit Care Med. 2014;15(2):148-154. [PubMed 24141655]

• In animal model: vasopressin increases BP numbers. Act by increasing systemic vascular resistance (vasoconstriction). Does not have inotropic effect on the ventricles.

• Will increase LV afterload - to avoid if there are signs of significant LV dysfunction

• More evidence in context of acute PH with great response. To consider if significant PPHN with adequate LV function since it seems to decreases the Pulmonary:Systemic pressure ratio

• Beware of Syndrome of inappropriate antidiuretic hormone secretion (SiADH), often present in HIE or with hyponatremia - vasopressin may lead to significant hyponatremia if no adequate urine output. May also be associated with natriuresis and require Na supplementation. 

• One advantage is that adrenergic medications are sensitive to pH. Vasopressin seem to act regardless of underlying pH (such as in profound acidosis) 

• Reference on Vasopressin in the newborn

Milrinone

• PDE3 inhibitor leads to ↑ intra-cellular calcium in myocardial muscle.

• Theoretical effect: Inotropic, lusitropic (promotes filling), ↓ systemic and pulmonary vascular resistance, ↓ afterload of LV and/or RV to promote forward flow. May lead to significant hypotension. Excreted by kidneys and neonates may be intoxicated with no urine output. 

• Usual initial dosage : 0.2 to 0.5 mcg/kg/min (usually starts at 0.3 mcg/kg/min)

• Very limited neonatal data

• 9 cases described with early improvements in O2 with milrinone infusion after iNO

• BEWARE in HIE: renally excreted and can accumulate in blood, vasodilation and can induce distributive shock à refractory hypotension

• Can lead to V/Q mismatch (beware in meconium aspiration).

References:

Dietrichs ES, Kondratiev T, Tveita T. Milrinone ameliorates cardiac mechanical dysfunction after hypothermia in an intact rat model. Cryobiology. 2014;69(3):361-6.

McNamara PJ, Laique F, Muang-In S, Whyte HE. Milrinone improves oxygenation in neonates with severe persistent pulmonary hypertension of the newborn. Journal of critical care. 2006;21(2):217-22.

Tveita T, Sieck GC. Effects of milrinone on left ventricular cardiac function during cooling in an intact animal model. Cryobiology. 2012;65(1):27-32.

Dietrichs ES, Kondratiev T, Tveita T. Milrinone ameliorates cardiac mechanical dysfunction after hypothermia in an intact rat model. Cryobiology. 2014;69(3):361-6.

Hemodynamic instability in HIE

From: Ruoss JL, McPherson C, DiNardo J. Inotrope and vasopressor support in neonates. NeoReviews. 2015;16(6):e351-e61.

From: Giesinger RE, McNamara PJ. Hemodynamic instability in the critically ill neonate: An approach to cardiovascular support based on disease pathophysiology. Semin Perinatol. 2016 Apr;40(3):174-88. doi: 10.1053/j.semperi.2015.12.005. Epub 2016 Jan 14. PMID: 26778235.

Presentation on Approach to hypotension by Dr Carolina Macias Michel

Anti-Hypertensive Medications

Presentation at PAS 2024 - TARGET Shock - Targeted Agents Reducing Global hypoperfusion in Extreme preTerms