Cool and Comfortable: How to manage vasopressors and sedation ...

Cool and Comfortable: How to manage vasopressors and sedation ...

Cool and Comfortable: How to manage vasopressors and sedation with therapeutic hypothermia Keliana OMara, PharmD FN3 Annual Conference July 13, 2019 Objectives Review the pathophysiology of hypotension Discuss the role of vasopressors and ionotropes in neonates with hypotension Review sedation choices in neonates with HIE

Pathophysiology-Based Approach Blood Pressure Component Vascular tone Heart rate Contractility Preload Afterload Role in Hypotension Vasodilation most common cause of shock Neonates more dependent on HR to maintain BP (tachycardia, bradycardia)

Systolic dysfunction most often seen with asphyxia Insensible water losses, capillary leak, mechanical Elevated with pulmonary hypertension, worsens cardiac output Cardiovascular Effects TH alone is not associated with increased risk of hypotension Normal or slightly increased BP related to hypothermia-induced vasoconstriction Reduction in heart rate after TH leads to 60-70% decrease in LV output compared to normothermic controls Often sufficient because of decreased metabolic activity Sinus bradycardia Slowed diastolic repolarization in SA node

Diminished influence of sympathetic autonomous nervous system on heart rate Normal heart rate despite low temperature may reflect subclinical systemic hypoperfusion and contribute to ongoing brain injury Pulmonary Vascular Effects Severity of brain injury may be associated with dysregulation of vascular tone in pulmonary vascular bed Concurrent HIE and pulmonary hypertension more likely to have abnormal brain MRI despite TH Greater disease severity-severe/prolonged hypoxia increases risk of impaired transition, persistent pulmonary hypertension Pulmonary Vascular Effects on CNS

Reduced pulmonary blood flow Lower preductal cardiac aoutput + systemic hypotension = worsened ischemic insult Use of rapidly-acting pulmonary vasodilators (iNO) Increased pulmonary venous return + augmentation of preductal cardiac output = reperfusion injury Clinical Considerations/Confounders Variables Change Seen Pathophysiology

Heart rate Sinus bradycardia Decreased SA node repolarization Increased DBP Systemic vasoconstriction Decreased SBP Decreased cardiac output

Color Pallor Decreased skin perfusion Capillary refill time Prolongation Decreased skin perfusion Lactate

Lactic acidosis Lactate washout after initiation insult, sequestering Blood gas Metabolic acidosis Residual perinatal acidosis Urinary output

Oliguria or Anuria Acute renal injury Blood pressure Effects of Rewarming Augmentation of cardiac output and systolic blood pressure + concurrent decrease in systemic vascular resistance and DBP Overall reduction in mean BP by ~8 mmHg Changes in drug volume of distribution, metabolism, and clearance High Vd medications mobilized from sequestered tissue and can have exaggerated effects during rewarming

Adjustment of cardiovascular medications CNS hemorrhage during rewarming associated with greater degree of hemodynamic instability Avoid iatrogenic hypertension and excessive unregulated cerebral blood flow Pharmacology of Hypotension Vasopressor Increases vascular tone Peripheral action: vasoconstriction via alpha-1 adrenergic and vasopressin receptors Inotrope: Increases myocardial contractility Example: dobutamine

Vasopressor-inotrope Mixed effects, dose-dependent Examples: dopamine, epinephrine Phosphodiesterase inhibitors Example: milrinone Vasoactive Medications Treatment of Hypotension with HIE HIE: Hypovolemia Hypotension Aggressive volume resuscitation should be avoided Association between increased cerebral blood flow and poor outcome

Exception: direct evidence of acute hypovolemia Blood transfusions for anemia + pulmonary hypertension Increased oxygen carrying capacity Normal Saline Bolus Useful when hypovolemia is present Increased intravascular volume, increased CO 10 mL/kg NS = 1.54 mEq/kg of normal saline Limited efficacy when pathophysiology is not related to hypovolemia HIE: Isolated Hypotension Presentation

Low systolic BP and evidence of end organ hypoperfusion Treatment goals Increase stroke volume and cardiac output Treatment options Epinephrine Dobutamine Dobutamine Indications: Hypotension/hypoperfusion related to myocardial dysfunction Severe sepsis/shock in full term neonates unresponsive to fluid resuscitation

Dosing: 2 to 20 mcg/kg/min (max 25 mcg/kg/min) Monitoring: heart rate, BP Toxicity: hypotension, tachycardia, vasodilation Epinephrine Dose-dependent stimulation of alpha and beta adrenergic receptors Low dose (0.01 to 0.1 mcg/kg/min) Stimulates cardiac and vascular beta 1 and 2 receptors Increased inotropy, chronotrophy, peripheral vasodilation Higher dose (>0.1 mcg/kg/min) Stimulates vascular and cardiac alpha 1 receptors Vasoconstriction, increased inotropy

Net effect: increased blood pressure, systemic blood flow via drug-induced increases in SVR and cardiac output Epinephrine Compared to dopamine Similar efficacy in improving blood pressure and increasing cerebral blood flow Epi group more likely to develop increased serum lactate levels, hyperglycemia requiring insulin Clinical considerations Beta-2 stimulation in liver and muscle causes decreased insulin release and increased glycogenolysis (elevates lactate) May be unable to use serum lactate as clinically useful marker of overall perfusion Insulin infusion may be necessary

Most useful with low vascular resistance with or without myocardial contractility impairment Epinephrine Dosing Information Low-dose: 0.01-0.1 mcg/kg/min High dose: >0.1 mcg/kg/min No documented true maximum dose Dose-limiting side effects: tachycardia, peripheral ischemia, lactic acidosis, hyperglycemia Titration: 0.01-0.02 mcg/kg/min every 3 to 5 minutes Monitoring: MAP, heart rate, glucose, lactates Administration: NEVER through arterial access, central venous access preferred

Hypotension + Increased Afterload Presentation Low pulmonary blood flow, impaired oxygenation, low cardiac output Treatment goals Sedation, +/- muscle relaxation, ventilation, iNO Avoid excessive mean airway pressurefurther impairment of pulmonary venous return Treatment options

Dobutamine Milrinone Vasopressin Norepinephrine Milrinone Selective phosphodiesterase-III inhibitor Exerts cardiovascular effects through preventing breakdown of cAMP Enhances myocardial contractility, promotes myocardial relaxation, decreases vascular tone in systemic and pulmonary vascular beds Disease states Post-operative cardiac repair, PPHN as an adjunct to iNO

Post PDA-ligation to prevent hemodynamic instability in 24 hours after procedure Milrinone-PPHN In cases unresponsive to iNO, oxygenation may be improved with addition of milrinone Exogenous NO upregulates PDE-III in smooth muscle cells of pulmonary vasculature Decrease or loss of cAMP-dependent vasodilation Addition of milrinone to iNO restores pulmonary vasodilation mechanisms dependent of cAMP Increased pulmonary vasodilation, improved oxygenation

Milrinone Dosing Information Dosing range: 0.25-0.99 mcg/kg/min Dose reduce for renal impairment Titration: 0.2-0.4 mcg/kg/min every 2-4 hours Monitoring: MAP: can initially decrease, usually returns to baseline within 1-2 hours Heart rate: can initially decrease, may increase if bolus used (not recommended) UOP: improved

Oxygen saturations: improved Vasopressin Primary physiologic role is extracellular osmolarity Vascular effects mediated by stimulation of vasopressin 1A and 2 receptors in the cardiovascular system V1A: vasoconstriction V2: vasodilation Most useful with vasodilatory shock, deficiency of endogenous vasopressin production with septic shock, infants after cardiac surgery Vasopressin Clinical Considerations Increases MAP, SVR

Decreases PVR, oxygenation index, iNO requirement, vasopressor requirement At high doses, increased SVR may impair cardiac contractility Vasopressin Dosing Information Low dose: 0.17 -0.7 milli-units/kg/min Decreased in catecholamine requirement High dose: 1-20 milli-units/kg/min Effective for reducing catecholamine requirement, but more side effects Titration: 0.05-0.1 milli-units/kg/min every 15-30 minutes Monitoring: Blood pressure, serum sodium (hyponatremia), weight gain, urine output (decreases), liver enzymes

Norepinephrine Endogenous catecholamine that activates alpha 1,2 and beta 1 receptors Increases systemic vascular resistance>>pulmonary vascular resistance Increases cardiac output by increasing contractility via beta 1 receptors First-line treatment for septic shock in adult patients Neonatal data Sepsis: increased MAP, decreased oxygen requirement, improved tissue perfusion PPHN: produced pulmonary vasodilation, decreased oxygen requirement, increased cardiac output, improved blood flow to lungs without evidence of peripheral ischemia Norepinephrine Dosing Information Dosing range: 0.05-0.7 mcg/kg/min

Max: 3.3 mcg/kg/min Titration: 0.05-0.1 mcg/kg/min every 5-10 minutes Monitoring: MAP, oxygen saturations, tissue perfusion Administration: NEVER through arterial line, central venous access preferred Refractory Hypotension Adrenal insufficiency can occur independently or in combination with other causes of hypotension Refractory Persistent hypotension despite catecholamine therapy Hypoglycemia, hyponatremia Adrenal injury

Treatment Hydrocortisone Hydrocortisone Decreases breakdown of catecholamines, increases calcium in myocardial cells, upregulate adrenergic receptors Delayed onset of action for hypotension Inferior as first-line treatment to dopamine Relative adrenal insufficiency in premature infants may play a role in need for supplementation Timing Prophylactic: prevents adrenal insufficiency, subsequent complications of uninhibited inflammation

Refractory hypotension: effectively increases BP and reduces catecholamine requirement What about Dopamine? Most commonly used cardiovascular medication in the NICU Dose-dependent stimulation of alpha, beta, and dopaminergic receptors Low (<0.5 mcg/kg/min) Vascular dopaminergic receptors selectively expressed Renal, mesenteric, coronary circulations Moderate (2-4 mcg/kg/min) Alpha receptor activation-vasoconstriction, inotropy High (> 4 8 mcg/kg/min) Beta receptor activation-inotropy, chronotropy, peripheral vasodilation

Can increase pulmonary vascular resistance (worsen PPHN) Decreased contractility/excessive increase in SVR Dopamine Dosing Information Usual dosing range: 5-20 mcg/kg/min Titration: 2.5-5 mcg/kg/min every 5-10 minutes Monitoring: MAPs, oxygen saturations, urine output Concerns: worsening pulmonary status when used in patients with pulmonary hypertension (i.e. PDA with right-to-left flow)

Administration: NEVER through arterial line, central venous access preferred Approach to Cardiovascular Care Consider pathophysiology, phase of intervention, and impact of concomitant treatments For HIE patients, weigh impact of treatment against consequences of reperfusion injury Sedation Management in HIE Need for treatment Treatment options Monitoring/Assessment

Neonatal Response to Stress Physiologic Response to HypoxiaIschemia Pre and postnatal asphyxia increase HPA axis stimulation Response correlates to gestational age and severity of hypoxia-ischemia Elevated cortisol/adrenal response may interfere with protective effect of hypothermia via activation of glucocorticoid pathways TH does not attenuate the HPA axis response to hypoxic-ischemic stress Mild Hypothermia in Unsedated Newborn Pigs-Pediatric Res 2001 Known information

3 to 12 hours of mild TH started after HI is neuroprotective in anesthesized piglets Study purpose Determine if neuroprotection maintained in non-sedated piglets Study design 39 piglets (36=HI, 3=no HI) Normothermia = 18 Hypothermia x 24 hr = 21 + 3 no HI Mild Hypothermia in Unsedated Newborn Pigs-Pediatric Res 2001

Mild Hypothermia in Unsedated Newborn Pigs-Pediatric Res 2001 Conclusions NO neuroprotection seen in piglets undergoing TH without sedation Only study in pigliets to directly evaluate TH in the absence of sedation Previous studies by same group used sedation and saw decreases in HR/MAP, demonstrated neuroprotection Theory: stress from being awake during HT negates the neuroprotective effect of TH Cytokines in Perinatal AsphyxiaInflamm Res 2013 Stress Response to

Therapeutic Hypothermia (TH) Induction of stress response in non-sedated patients In adult patients, lack of sedation during TH resulted in increased plasma levels of norepinephrine and cortisol, increased shivering Increased basal metabolic rate may limit protective effect of HT Non-sedated and conscious subjects being cooled with try to maintain temperature by increasing metabolic activity Fentanyl vs. Morphine-J Peds 1999 Evaluated the effect of fentanyl and morphine on plasma catecholamines in neonates undergoing mechanical ventilation after birth Fentanyl: 10.5 mcg/kg bolus followed by 1.5 mcg/kg/hr continuous infusion

Morphine: 140 mcg/kg bolus followed by 20 mcg/kg/hr continuous infusion Fentanyl vs. Morphine-J Peds 1999 Fentanyl and morphine both effective for lowering noradrenaline and adrenaline levels in neonates undergoing mechanical ventilation Only fentanyl reduced beta endorphin Fentanyl and morphine displayed similar analgesic effects No notable respiratory depression in either group Neonatal Response to Asphyxia Uncontrolled pain may potentiate the effect of hypoxia Exposure to untreated repetitive pain and stress causes prolonged C-fiber firing Glutamate-induced NMDA receptor activation

Augmentation of hypoxia-induced glutamate release End result: neuronal injury/death Opioid Effect on Neuroimaging Retrospective evaluation of 52 infants with some degree of birth asphyxia Received opioid = 17 No opioid = 35 Opioid: Morphine (intermittent bolus or infusion) Fentanyl (intermittent bolus or infusion) First week of life

Opioid Effect on Neuroimaging Opioid-treated infants were more critically ill, worse clinical markers of asphyxia at baseline Better MRI findings Improved long term neurologic examination findings at 12-8 months Potential for neuroprotection in hypoxic-ischemic brains Endogenous and exogenous opioids can protect cortical neurons from hypoxia-induced apoptosis Induce ischemic tolerance in cerebellar Purkinje cells subject to ischemiareperfusion conditions Sedation in Early

Trials Study Intervention (N) Sedation Azzopardi et al. Pediatrics 2000 Whole body hypothermia Pilot study (n=16, 10 TH, 6 NT) Morphine infusion 10-40 mcg/kg/hr

(ventilated) Chloral hydrate 2550 mg/kg (nonventilated) Outcomes 6/10 cooled infants had minor neurologic abnormalities or normal f/u exams Thoresen, Whitelaw CV changes during Pediatrics 2000 mild TH (n=9)

Midazolam 100 mcg/kg bolus then 30-60 mcg/kg/hr Marked reduction in spontaneous muscle activity, rectal temp Roka et al. Pediatrics 2008 Morphine infusion

Elevated morphine concentrations in HT compared to NT patients Serum morphine concentration in HT and NT infants (n=16) What we know Unaddressed pain and stress in the neonate is bad Asphyxiated neonates seems to be particularly sensitive to pain and stress Hypothermia may worsen these responses

Use of opioids in asphyxiated neonates (without TH) associated with improved neurodevelopmental outcomes Providing sedation/analgesia during hypothermia is probably the most ethical approach to treatment Standard of care in every other patient population who undergoes TH Most studies outcomes include patients who received sedation The benefit seen with hypothermia includes the effect of having sedation on board Opioid Controversy Some data (mostly animal) suggest that opioids may have deleterious effects on neurodevelopmental outcomes Preterm infants

Inability to predict pharmacokinetic changes during hypothermia can lead to supra-therapeutic opioid concentrations Potential for adverse effects (prolonged sedation, cardiovascular compromise) Potential Future Therapies Alpha agonists appear to exert a neuroprotective effect in neonatal animal models of perinatal asphyxia Clonidine Dexmedetomidine (8 x more specific to alpha 2 receptor) Provide analgesia, sedation, and anxiolysis Synergistic effect when used with other classes of analgesics/sedatives Minimal effect on respiratory drive, gastrointestinal function

Bradycardia, hypo/hypertension Neuroprotection? Alpha Agonists in Neonatal Asphyxia Laudenbach et al. Anesth 2002 In vivo concentration-dependent cortex and white matter lesion In vitro decreased number of neurons damaged by NMDA exposure Paris et al. Anesth Analg 2006 Neonatal rat model Reduced mean lesion size by 44-49% Dexmedetomidine in Hypothermia

PK study in piglet model of HIE with cooling Decreased clearance/increased plasma levels of dexmedetomidine Did not evaluate potential neuroprotection DEX in hypothermia neonatal rats Prolonged exposure was not associated with renal or brain pathology or indices of gliosis, macrophage activation, or apoptosis Plasma and brain concentrations tightly correlated Reduced cranial temp from 32-30 C within 30 min in cooled rats Dexmedetomidine for Sedation with

TH Retrospective analysis of 19 patients Dexmedetomidine for Sedation with TH Dexmedetomidine for Sedation with TH NPASS Scores NPASS Considerations Treatment ranges/goals

Pain assessment: 0-10 points Treat for scores>3 Sedation assessment: Light sedation: -5 to -2 Deep sedation: -10 to -5 Limitations No ability to differentiate between pain and agitation Lack of correlation between pain severity and expected scores No recommendations for treatment based on score NPASS Considerations in HIE Behavioral indicators may be confounded by neuro-irritability from

underlying pathophysiology Extremities assessment may be inaccurate Vital signs may also be difficult to interpret when infant is undergoing therapeutic hypothermia NPASS Scores in HIE Patient Characteristic Gestational age (wk) Birth weight (kg) Sarnat score, n (%) 1 2 3 Seizures

Sedation, n (%) Fentanyl infusion Dexmedetomidine infusion Both N=23 38.6 3.22 0 (0) 15 (65.3) 8 (34.7) 4 (17.4) 8 (34.7) 10 (43.5)

5 (21.8) NPASS Scores in HIE 1.5 1 0.5 0 -0.5 -1

-1.5 Baseline 12 hour 24 hour 48 hour 72 hour 96 hour

NPASS Scores by Sedation Type 3 2 NPASS 1 0 -1 -2

-3 Hours Fentanyl Precedex Combo Time Fentanyl Precedex Combo

p value 0 0.8 1.4 0.4 0.72 1

-0.4 2.5 -1 0.03 2 1 2.5

-1.4 0.02 3 -0.9 1.7 -1.4 0.06

4 -1 1.6 -2.2 0.01 5 -1.6

1 -2.2 0.09 6 -2.5 1.3 -1.8

0.006 7 -0.25 0.4 -0.6 0.8 8

-0.5 0.3 -1.6 0.4 9 0.1 0.5

-1 0.6 10 -1.1 1.5 -1 0.1

11 -1.2 1.5 0.2 0.06 12 0.4

0.9 1.2 0.7 13 0.4 1.4 1.8

0.14 14 0.9 0.4 1 0.5 15

1.4 0.4 0.8 0.3 Unanswered Questions Lack of strong data specifically assessing use of sedation and neurologic outcomes with hypothermia

What med is best? When should it be started? How should it be dosed? How long should it be continued? Does it provide extra neuroprotection? Is there risk of increased neuronal apoptosis as premature neonatal animal models suggest? Questions?

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