Age appropriate use of inotropes

and vasopressors

Walid HABRE, MD, PhD Geneva Children’s Hospital, University of Geneva, Switzerland

November 14th, 2014

Martijn L. et al. Trends in Cardiovascular Medicine, 2010; 20: 164 - 171

Heart development = similarities in all higher vertebrates

Embryonic cardiac chamber maturation: Trabeculation, conduction, and cardiomyocyte proliferation

Samsa LA et al. Am J Med Genet C Semin Med Genet. 2013;163:157-68

Formation of myocardial projections called trabeculae

Establishment of the conduction system

Thickening of the compact myocardium

Left ventricular volume and mass increase early post-natal life in response to changes in workload of left and right ventricules

Am J Med Gen 2013; 163: 157-168

Blood flow (shear stress)

Fluid pressure (cyclic strain)

Inward forces Strains on myocardial &

endothelial cell-cell junctions

Cardiomyocyte proliferation and differentiation due to Growth Factors (acidic fibroblast GF) and catecholamines

Immature neonatal cardiomyocyte Rounded shape

Short Disorganized intracellulary

Less dense myofibrils Situated along the periphery

Primary source of energy: carbohydrate

Mature cardiomyocyte Dense Myofibrils

Aligned in parallell Alternate with mitochondria

Mature mitochondria: energy from long chain fatty acids:

Nassar R et al. Circ Res 1987; 61: 465-483 Price JF Heart Failure in CHD 2011; VI: 21-42

Neonatal myocyte

Adult myocyte

Signaling pathways in cardiac chamber maturation. Several signaling pathways have been identified as key

regulators of cardiac chamber morphogenesis

Samsa LA et al. Am J Med Genet C Semin Med Genet. 2013;163:157-68

Components of the Sarcomere

Spirito P et al. N Engl J Med 1997;336:775-785.

Li S et al. J Physiol 2013;591:5279-5290

SR Ca2+ ATPase (SERCA) and Na+/Ca2+ exchanger (NCX) serve as the main Ca2+ uptake pathways.

Ca++ induced - Ca++ released mechanism is missing

T-tubules

Decrease density of Ca++ channels ?

Potentially decrease myocardial reserve and contractility in the neonatal immature myocardium èNeonatal heart more dependent on extracellular calcium for myocardial contraction ?

Development changes in L-Type Ca++ influx amplitude

Age-dependent density and properties of ion channels ?

Large inter-species variability

Human atrium, calcium channels are in many aspects functionally mature at the time of birth

Age-related changes in calcium current inactivation

Shortened action potential in children

Decrease myocardial reserve and contractility in the neonatal immature myocardium

Calcium current inactivates 2-fold faster in infants than adults

Hatem SN et al. Am J. Physiol 1995; 268: H1195-H1201:

Roca TP et al. Pediatr Res 1996; 40: 462–468

The rate of release of Ca++ increase with age

ì efficiency of Ca++ signaling in more mature myocytes

Camelliti P et al. Cardiovasc Res 2005;65:40-51

•  During early human development, myocyte and connective tissue cell numbers ì at a similar rate until post partum

•  Then, cardiomyocytes remain stable, while the connective tissue cell count rises with cardiac weight at 2 months of age

Immature extracellular matrix: possible impact on myocardial contraction and relaxation

5% fibroblasts in ventricle tissue

50% fibroblasts in sino-atrial node

Composition of Sarcolemna

Less organized and efficient myofibrils

Undeveloped Mitochondria Extracellular

matrix

î Tension per unit cross-sectional area

î Compliance

Friedman WF Prog Cardiovasc Dis 15:87-111

The Frank-Starling curve exists in the neonatal heart but is shifted

Increase preload within physiological range (2-8 mmHg) è Increase stroke volume

Kirkpatrick SE et al. Am J Physiol 1976; 231: 495-500

Thus, ì HR an important mechanism for ì CO

Role of the Autonomous Nervous System

Kimura K et al. Circulation Research. 2012;110:325-336

Innervation RV > LV

Predominantly in the subepicardium

Sympathetic nerve fibers

Project from the base of the heart into the myocardium

Parasympathetic nerve fibers

Both atria and ventricles

> nerve density on the ventricular endocardium, but greater nerve

thickness on the epicardium

High level of sympathetic neurohormonal activity

ì Plasma concentrations of catecholamines in neonates

Limited reserve in contractility in the newborn and î response to endogenous/exogenous catecholamines

Incomplete cardiac sympathetic innervation in neonates

Gillies M et al. Crit Care 2005; 9:266-279

Guimaräes S et al. Pharmacol Rev 2001; 53(2):319-356

Changes in adrenoreceptors with age

•  Evidence for different response to α-stimulation with increasing V-C with age: Increase of subtype α1A and α1D with age

•  β-adrenoreceptors are present at birth with a

ratio β1/β2 = 4 in children

•  Increase of β2 response up to 1 month of life

•  Troponin I concentration ì in the postnatal period: modulate contractility induced by adrenergic agonists.

Variable response to catecholamines in children

Difference in drug pharmacokinetics

Difference in response to adrenergic receptor agonism Interindividual variability:

enzyme activity

Poor organ perfusion

Duration of perfusion

Developmentally controlled enhancement of phospholambin and troponin I phosphorylation

Reference percentile curves for ventricular volume and masses indexed for BSA for boys and girls.

Sarikouch S et al. Circ Cardiovasc Imaging. 2010;3:65-76

Interindividual variability explained by large variability in ventricular mass

Effect of low cardiac output on adrenergic receptors

î Cardiac Output

ì  Circulating catecholamines ì  DP, EP, NE

ì Sympathetic activity î density of β1-adrenoreceptors

Downregulation of β1-adrenoreceptors

î Inotropic response to β1-agonists

Pharmacokinetics of inotropes in critically ill children

1.  Martinez AM et al. Pediatrics 1992; 89: 47-51 2.  Habib DM et al. Crit Care Med 1992; 20: 601-608 3.  Oualha M et al. Crit Care 2014; 24: 18(1): R23 4.  Oualha M et al. Br J Clin Pharmacol 2014; 78:886-97

Variability of pharmacokinetics in unstable patients Variability of data depending on pharmacokinetic model used Clearance of the 3 inotropes are linearly related

CL (ml/kg/min) T1/2β (min)

Vβ (L/kg)

Dopamine 34.1±16.6 6.9-26 (ì preterm) 1.8-2.9

Dobutamine 35.9±27.8 4-68 0.09-5.6

Epinephrine 29.3±16.1 (2l/kg/h SE 17%)

3 -

Norepinephrine 2 l/kg/hr 0.9 min/10kg 0.08

Majority of hypotensive preterm babies have normal or high CO

Blood Pressure = Cardiac Output x Systemic vascular resistance

Hypotension is due to î SVR Frequent shunts between systemic to pulmonary circulation

(Ductus arteriosus, FO)

Measurements of systemic blood flow (echo) unreliable

Preterm neonates have low Superior Veinous Cava (SVC) flow

Low SVC flows (<41 mL/kg/min) is associated with late P/IVH

Dobutamine > Dopamine ?

ì  SVC flow ì  SBF

ì  organ perfusion

BP below cerebral pressure autoregulation

ì Cerebral hypoperfusion and ischemia

ì Cerebral pressure passivity è Higher sensitivity of Cerebral flow to changes in BP

Hypoperfusion-Reperfusion

ê Cerebral injury

Threshold for hypotension in premature neonates < 30 weeks GA

v MAP less than GA in weeks at birth (Joint Working Group of the British Association of Perinatal Medicin and the Research Unit of the Royal College of Physicians. Arch Dis Child.1992;67 :1221– 1227)

v MAP <10th percentile for birth weight and postnatal day (Watkins AM Early Hum Dev.1989;19 :103– 110)

v MAP < 30 mm Hg (Nuntnarumit P, Clin Perinatol.1999;26 :981– 996)

v MAP < 33 mm Hg (Limperopoulos C et al. Pediatrics 2007; 120:966 -977)

Based on these thresholds is not associated with brain injury in these preterms

Limperopoulos C et al. Pediatrics 2007; 120:966 -977

AUROC around 0.5

Blood pressure management directed on BP thresholds alone

may not prevent brain injury

Controversial issue

Dopamine or Dobutamine for preterms and neonates ?

è  Blood pressure or end organ perfusion? è  Long-term effects

Osborn D et al. J Pediatr 2002; 140: 183 - 191

Randomized trial of dobutamine versus dopamine in preterm infants with low systemic blood flow

Trend for dobutamine to produce a greater increase in SVC flow

Osborn D A et al. Pediatrics 2007;120:372-380

Follow-up assessments at corrected ages of 1 & 3 yrs

DOBUTAMINE n/N (%) 22

DOPAMINE n/N (%) 20

Pneumothorax 1 (5) 1 (5)

Pulm hemorrhage 2 (9) 3 (15)

Creatinine level>120 µmol/l 3 (14) 5 (25)

Any PIVH 10 (45) 9 (45)

PIVH grade 3 or 4 3 (14) 7 (35)

Late PIVH 5 (23) 8 (40)

Late grade 3 or 4 PIVH 1 (5) 7 (35)*

Necrotizing enterocolitis 3 (14) 1 (5)

Died before discharge 14 (64) 9 (45)

Periventricular leukomalacia 3/13 (14) 0/11 (0)

Chronic lung disease at 28 days 6/12 (50) 10/11 (91)

Chronic lung disease at 36 wk 3/8 (38) 5/11 (45)

Any retinopathy of prematurity 4/10 (40) 5/10 (50)

Retinopathy of prematurity grade 3 or 4 2/10 (20) 4/10 (40)

Dopamine or Dobutamine for hypotensive preterm infants

•  Five RCT’s

•  No evidence of a significant difference between dopamine and dobutamine in terms of:

- Neonatal mortality

- Incidence of periventricular leukomalacia

- Severe periventricular haemorrhage

•  Dopamine > dobutamine in treating systemic hypotension, with fewer infants having treatment failure (NNT = 4.4, 95% CI 2.9 to 7.7)

Subhedar NV et al. Cochrane Database Syst Rev. 2003;(3):CD001242.

There is little evidence that Dobutamine is better than dopamine at increasing and maintaining systemic blood flow

Disability at 3 years

Peri/intraventricular haemorrhage grade 3 or 4

Late Peri/intraventricular haemorrhage

Osborn DA et al. Cochrane Database Syst Rev. 2007 Jan 24;(1):CD005090.

2  

Inotropic Therapy for Right Ventricular Failure in Newborn Piglets

Hyldebrandt J et al. Pediatr Crit Care Med 2014; 15(7):e327-e333

Dobutamine

Nonsustained effect on RV failure

î Contractility

DM > EM > Dobu

Prem < 32 w. MBP < GA at least 60 min

2.5-5-7.5-10 µg/kg/min 0.125-0.250-0.375-0.5 µg/kg/min

Pellicer A et al. Pediatrics 2005;115:1501-1512

Is epinephrine better in preterm neonates ?

Effect on cerebral perfusion:

NIRS assessment

Pattern of inotrope-induced changes in MBP and HR is not related to gestational age but to the drug

Pellicer A et al. Pediatrics 2005;115:1501-1512 ΔCBV = K · ΔTHb/H

Higher HR with EP

Both drugs increased CBV No difference between DP and EP

The safety profile of NAD has not been studied in neonates

•  Indication in PPHN-induced cardiac dysfunction?

ä Pulm vasc resistance

Right-Left shunt through DA

ä RV afterload +

ä  venous return

Severe Hypoxemia

Myocardial dysfunction

NAD î the pulmonary/systemic artery pressure ratio and ì cardiac performance

Tourneux P. et al. J Pediatr 2008; 153: 345-349

NAD î basal pulm vascular tone and ì PBF through α2-receptors and NO release NAD: systemic VC and reverses the shunt through the Ductus Arteriosis

Effects of inotropic therapy on intracellular calcium handling in cardiomyocytes

Stevenson L W Circulation. 2003;108:367-372 Phosphorylation effect of PKA: ì release of Ca++ from SR and faster relaxation

Pharmacokinetics of milrinone

< 1 year 1-13 years Adults Post CPB1 Vβ (L/kg) 0.9 ± 0.4 0.7± 0.2 0.3 ± 0.1

CL (ml/kg/min) 3.8±1 5.9±2 2±0.7

T1/2β (h) 3.15±2 1.86±2 1.69±0.18

Septic Schok2 CL (ml/kg/min) 10.6±5.3

T1/2β (h) 1.47 (0.62-10.9)

Post CPB3 CL (ml/min) 2.5 x Wt x (1+0.058 x age)

1.  Ramamoorthy C et al. Anesth Analg 1998; 86(2):283-289 2.  Lindsay CA et al. J Pediatr 1998; 132: 329-334 3.  Bailey JM et al. Anesthesiology 1999; 90: 1012-1018

Milrinone has larger volume of distribution and a faster clearance in infants than in adults

Loading dose of 50 µg/kg + Infusion 0.5 µg/kg/min

Bailey J et al. Anesthesiology 1999;90:1012-1018

Predicted concentration of Milrinone in Pediatric Patients after Cardiac Surgery

Loading dose of 50 µg/kg + Infusion 3.5 µg/kg/min for 30 minutes then, 0.5 µg/kg/min

Simulation studies predicted a loading infusion (0.75 microg/kg/min for 3 h) followed by maintenance infusion (0.2 microg/kg/min until 18 h of age)

Preterm Infants:

Paradisis M et al. Arch Dis Child Fetal Neonatal Ed, 2007; 92: F204–F209

Primacorp study: RCT for LCOS in infants (>36 GA)

Hoffman T M et al. Circulation. 2003;107:996-1002

25 µg/kg bolus over 60’ 0.25 µg/kg/min for 35h

75 µg/kg bolus over 60’ 0.75 µg/kg/min for 35h

Primary outcome: LCOS and Death

8.3±15 mths 5.9±10 mths 8.6±16.5 mths

Reduction of LCOS By 48% with high dose

Levosimendan: new insight into the cardiomyocyte

Tamargo J Curr Med Chem. 2010;17(4):363-90

N-terminal domain of TnC

ì myofilament Ca++ sensitivity & contractility (without changes in [Ca2+]i or MVO2)

Opening of K+ channels [ATP-dependent (KATP) and voltage-dependent channels (Kv)]

Inhibition of PDE III activity (at high concentrations)

Stabilizes Ca++-TnC complex

Systemic and Coronary vasodilation

Pharmacokinetics of Levosimendan in children

3-6 months > 6 months

Post CPB1 Vβ (L/kg) 0.43 0.35 ± 0.21

CL (ml/kg/min) 3.8 3.6 ± 1.3

T1/2β (h) 2.3 1.6±0.79

Maila T et al. Pediatr Crit Care Med 2004; 5:457-462

- Pharmacokinetic profile after bolus 12 mcg/kg (over 10 min) - Mean volume of distribution 2x higher in children than adults - Lower elimination in infants less than 6 months

Little evidence that Levosimendan is as efficacious as milrinone in neonates and infants after CPB

Momeni M et al. JCTVA 2010; 25: 419-424

Levosimendan 0.05 mcg/kg/min

Milrinone 0.4 mcg/kg/min

Started at onset of CPB + epinephrine 0.02 mcg/kg/hr

Rate-pressure index (HR x SBP) lower with Levosimendan: less myocardial oxygen demand

Exclusion: Wt < 3kg, GA < 36 wks Preop renal failure TOF

Levosimendan versus milrinone in neonates and infants after corrective open-heart surgery

Lechner E et al. Pediatr Crit Care Med 2012; 13:542-548

Levosimendan 0.1 mcg/kg/min

Milrinone 0.5 mcg/kg/min

Age: 78.4 ± 80.5 Weight: 4.08±1.45 Aristotle score: 10.0±2.09

Age: 63.9 ± 81.3 Weight: 4.28±1.24 Aristotle score: 10.2±2.04

No bolus and similar CPB and Aortic cross-clamp time

Lechner E et al. Pediatr Crit Care Med 2012; 13:542-548

Little evidence that CI increases with time with Levosimendan

V1 receptor: high density on vascular smooth muscle

Vasoconstriction by ì intracellular calcium

Vasopressine

PurinoRp on cardiomyocytes

Cardiac effect?

Indications of vasopressin in neonates

•  AVP and its analogue, terlipressin used as rescue therapy:

–  for hypotension refractory to high-dose catecholamine and corticosteroids in neonates with sepsis

–  cardiogenic shock

–  necrotizing enterocolitis

– SIRS following surgery

There is insufficient evidence to recommend or refute the use of vasopressin or its analogues in the

treatment of refractory hypotension in neonates

Shivanna B et al. Cochrane Database Syst Rev. 2013 Mar 28;3:CD009171

No clinical benefit of vasopressin for pediatric vasodilatory shock

(n:33) (n:32)

Low dose of AVP 0.0005-0.002 U/kg/min in addition to Open-Label vasoactive agents

Tendency for increased mortality

Choong K et al. Am J Respir Crit Care Med 2009; 180:632–639

Hypotension in preterm infants

Relative or absolute adrenocortical insufficiency

Limited ability to increase cortisol

Low cortisol concentrations

when inotropes given

Role of Corticosteroids: pressor agents in preterms?

è Glucocorticoids

ì β-adrenergic Rp expression

ì responsiveness to catecholamines

Increase vascular tone Increase myocardial contractility

Corticosteroids for treating hypotension in preterm infants

•  4 RCT’s with total of 123 babies

•  Dopamine > hydrocortisone as primary treatment

•  Hydrocortisone > Placebo for refractory hypotension (NNT 2.1 95%CI 1.47, 3.8)

Ibrahim H et al. Cochrane Database Syst Rev. 2011; 7:CD003662

è Long Term Safety and/or benefit in unknown è  Direct toxic effect of corticosteroids on the developing CNS ? è  Early postnatal CS treatment for prevention of preterm CLD may be associated with an increase in neurodevelopmental impairment

Halliday HL et al. Cochrane Database Syst Rev. 2010; 20:CD001146

Evidence-based? Or Expert-Based recommendations ?

Large variability in drug usage for prevention and treatment of LCOS in children: EuLoCOS-Paed

•  LCOS with high SVR: –  milrinone (34%)

–  epinephrine (24%)

–  Epineph./levosim. (22%)

•  LCOS with low SVR: dopamine (20%) epinephrine (29%) norepinephrine (24%)

•  LCOS with high PVR: –  milrinone (17%)

–  inhaled nitric oxide (20%)

–  prostacyclin deriv. (22%)

•  24 different regimens: –  Milrinone

–  Dopamine

–  Epinephrine

–  Dobutamine

–  Levosimendan

•  Milrinone in 70% of all regimens:

•  dopamine 20% in combination

PREVENTION TREATMENT

Vogt W et al. Arch Dis Child 2011;96:1180-86 Vogt W et al. Pediatr Anesth 2011;21:1176-84

86%

Clinical Application In Children 1st Line Agent 2nd Line Agent Septic Shock Norepinephrine Vasopressin Dopamine Epinephrine Heart Failure Dopamine Milrinone Epinephrine Cardiogenic Shock Norepinephrine Levosimendan Dobutamine/Epinephrine Anaphylactic Shock Epinephrine Vasopressin Neurogenic Shock Phenylephrine Norepinephrine

Hypotension Anesthesia-induced Ephedrine/Phenylephrine Dopamine

Following CABG Epinephrine-Milrinone Levosimendan

PALS algorithm: can we apply it independent of age?

Push 5ml/kg neonate, 20 ml/kg isotonic saline or colloid boluses Correct hypoglycemia and hypocalcemia

Begin Dopamine therapy

Fluid refractory-dopamine resistant shock

Cold shock Warm shock

Titrate Epinephrine Titrate Norepinephrine

Dopamine or norepinephrine as first-line for shock in children ? : SOAP-II trial

De Backer D et al. N Engl J Med 2010;362:779-789.

Peripheral line

DOPAMINE 3 mcg/kg/min

β: ì HR & contractility: ì CO & SBP δ1: vasodilation of capillary beds increases renal perfusion

Central line

NOREPINEPHRINE 0.01 mcg/kg/min

Titrate up to 7 mcg/kg/min Get a central venous line

and an arterial line

α1 : V-C and ì SVR β1 : some: ì inotropisme

Expert based recommendations in children? For perioperative use

Adrenaline 0.01 mcg/kg/min

β1 & α1

ìHR, SV, CO ì SVR

Milrrinone 0.5 mcg/kg/min (Optimal bolus)

IPDE

î SVR, PVR ìEF, CO

Tachyarrhythmia and ì myocardial oxygen consumption

To consider in case of LCOS: combination of E-M ì ventriculovascular coupling

Levosimendan 0.1 mcg/kg/min

Ca++ sensitizer

ìSV, CO

Conclusion

Optimal dosing and combination of inotropes in the newborn cannot be extrapolated from studies in older children and adults

î responsive to catecholamines î responsive β-Rp – AC – cAMP pathway

îcontractile reserve îmyocardial compliance

We lack evidence-based data on strategies and efficacy of inotropes-vasopressors in the padiatric population