Inotropes and vasopressores - Cardiff PICU

Definition of ShockInadequate oxygen delivery totissues to meet demand becauseof circulatory failure

PhysiologyO 2 delivery = (1.34 × Hb × O 2 sats) + (PO 2 × 0.023) × COAdults = 600ml/min/m 2Neonate = 665 – 1000ml/min/m 2

Physiology◦ Adult Oxygen demand 120 – 220ml/min/m 2◦ Neonatal oxygen demand 180 – 280ml/min/m 2◦ Neonates cardiac output near maximaleven at rest• Vulnerable to increase in demand• Vulnerable to decrease in supply

Physiology – fluid filled circuit andOhm’s Law◦ I = V/R◦ Flow = Pressure Difference/Resistance◦ Perfusion pressure = Cardiac output× Resistance

Compensation◦ Increase cardiac output• CO = SV × HR◦ HR dependent in infants◦ Relatively little capacity in neonates toincrease HR◦ Redistribute blood flow• Peripheral/ splanchnic vasoconstriction

Flow needs to be adequate forPerfusion pressureCritical point

Pathophysiology of Sepsis◦ Endothelial disease• Capillary leak◦ Hypovolaemia – hypovolaemic shock◦ ARDS – impaired oxygenation◦ Myocardial depression• IL-6 – cardiogenic shock◦ Abnormal vascular tone• High or low SVR – impaired organperfusion

Treatment goals◦ Improve oxygenation◦ Restore circulating volume◦ Improve cardiac contractility◦ Achieve effective organ perfusionpressures

A brief history of septic shock treatment

Outcome?U of M 1969 Medicine 48: 307-3297% Mortality G-ve sepsis

The search for a magic bulletFew Randomised studies◦ 3 Dengue Fever◦ 2 endotoxin antagonist (no effect)◦ APC no effect◦ Immunoglobulin 1989-91 (Saudi, Taiwan,Turkey India)◦ I small Polish Neonatal◦ 2 GM-CSF neonatal◦ HAS vs. saline Malaria

Efficacy variable Placebo N=235 ∗ DrotAA N=239 ∗ P ValueInfection site, % (n):LungBloodCNSIntra-abdominalOther21/86 (24.4)10/77 (13.0)2/17 (11.8)4/27 (14.8)4/28 (14.3)18/89 (20.2)7/74 (9.5)5/21 (23.8)6/17 (35.3)5/38 (13.2)0.36

esolve 28-day MortalityAdditional SubgroupsnDrotA(a)PlaceboAbsoluteRiskReductionresolve Overall47417.15%17.45%0.3DICNo DIC20318314.4%18.1%22.2%11.2%7.8-6.90.5 0.6 0.7 0.8 0.9 1 1.25 1.67 2Relative Risk of Death (Point Estimate and 95% CI)

Fluid resuscitation

Shock:GastroenteritisAbdo obstructionsepticaemia

Severe sepsis – Outcomes (9625 cases, US 1995)R Scott Watson AJRCCM 14 Nov 2002

Role of early fluid resuscitation in pediatricseptic shock.Carcillo JA, Davis AL, Zaritsky A. JAMA 1991 4;266(9):1242-5All children with septic shock to ER over 6 yearsPA catheter by 6 hours.Three groups based on fluid volume in the first hour:group 1, less than 20 mL/kg;group 2, 20 to 40 mL/kg; andgroup 3, more than 40 mL/kg.

RESULTS.34 patients (median age, 13.5 months)mL/kg (mean +/- SD)1 hour 6 hoursgroup 1 (n =14) 11 +/-6 71 +/-29group 2 (n=11) 32 +/-5 108 +/-54group 3 (n=9) 69 +/-19 117 +/-29

RESULTS.34 patients (median age, 13.5 months)DeathsmL/kg (mean +/- SD)1 hour 6 hoursgroup 1 (6/14) 57% 11 +/-6 71 +/-29group 2 (7/11) 63% 32 +/-5 108 +/-54group 3 (1/9) 11%* 69 +/-19 117 +/-29

CONCLUSIONRapid fluid resuscitation in excess of 40 mL/kg in the firsthour following emergency department presentationwas associated with:◦ improved survival◦ no increase in the risk of cardiogenicpulmonary edema or ARDS

7000 critically ill adults

Figure 3. Type of fluid administered before and after arrival of the PICU teama. Before arrival of PICU transfer teamb. After arrival of PICU transfer teamSalineGelofusinHASRBCFFPPltsOther

Inotropes and pressors

Inotropes and pressors◦ Advantages• Improve pumpfunction• Increase SVRimprovingperfusion pressure• Increase diastolicBP improvingcoronary arteryperfusion◦ Disadvantages• May increaseafterload• Increasemyocardial oxygendemand• Arrythmia• Extravasationdanger – should gocentrally

When to start inotropes◦ Sepsis – failure to respond to40ml/kg fluid in first hour◦ Will need adequate monitoring◦ Invasive BP if possible

Available inotropes and pressors◦ Natural catecholamines• Adrenaline• Noradrenaline• Dopamine◦ Synthetic catecholamines• Dobutamine◦ Phosphodiesterase inhibitors• Milrinone, enoximone◦ Pure pressors• Vasopressin, Terlipressin

Choice of inotrope◦ Personal preference◦ No RCT to rely on◦ Prejudices common – rememberthese are based on class 4evidence.◦ Watch the bottom line◦ ‘Warm’ shock with good CO and lowSVR less common in children◦ ‘Cold’ shock with low CO and highSVR more common – some usevasodilators

Catecholamine synthesis

Receptor2 ndmessengerActionsα 1IP 3, 1-2 DAG Vasoconstrictionα 2↓ cAMP Vasodilation, -vechronotropeβ 1↑ cAMP +ve inotrope &chronotropeβ 2↑cAMP Vasodilation,bronchodilationDA 1↑cAMP VasodilationDA 2↓cAMP Inhibits PLN & β-endorphin secretion

Dopamine◦ Precursor of noradrenaline.◦ α 1 , β 1 , β 2 , DA 1 , DA 2 receptors.◦ 5 – 15 mcg/kg/min β1 effectsdominate◦ > 15α1 becomeimportant◦ > 25α1 dominates◦ ‘Renal dose’ concept obsolete

Adrenaline◦ α 1 , β 1 , β 2 .◦ 0.05 – 0.3 µg/kg/min β 1, 2 > α 1 ,• β 2 effects may cause balanced effect on SVR.◦ 0.3 – 1 µg/kg/min β 1, 2 = α 1◦ > 1 µg/kg/min β 1, 2< α 1◦ Disadvantage - increase in myocardial O 2 demandand arrythmias

Noradrenaline◦ α1 and β1, with dominant α1effects.◦ β1

Dobutamine◦ Synthetic mixture of two stereo-isomers.◦ One isomer has β effects, the other α 1 .◦ 5 – 20 µg/kg/min β 1,2◦ Increases contractility◦ May ‘unmask’ hypovolaemia◦ SVR decreases. Direct coronaryvasodilatory effect.◦ >20 µg/kg/minα 1 dominates

Phosphodiesterase inhibitors◦ Enoximone and milrinone – bipyridine PDE3inhibitors.◦ PDE3 specific to myocardium.◦ Increases myocardial contractility, enhancesvascular smooth muscle relaxation - lusiotropic.◦ Decreases preload and afterload, reduce LVEDPand RVEDP improves diastolic dysfunction.◦ Heart rate and myocardial oxygen consumptionrelatively unchanged.◦ They are not generally first line agents, but areuseful in situations with β receptor downregulation.◦ Commonly used post cardio-pulmonary bypass.

Phosphodiesterase inhibitors◦ Enoximone – causes thrombocytopaenia.Available orally. Crystallises easily insolution.◦ Milrinone – shorter half-life, more proarrythmogenic.Accumulates in renalimpairment.◦ Commonly used in post-cardiac bypasscases◦ Ongoing MCRCT◦ May be useful in septic shock resistant toinotropes with increased SVR.

Vasopressin◦ Initially high endogenousvasopressin in septic shock andhaemorrhagic shock◦ Secretion normally stimulated byhypovolaemia and hypotension◦ Prolonged hypotension or septicshock levels decrease

Vasopressin◦ Injection in humans with normal BP – no effectunless very high doses used◦ Injection of physiological doses in hypovolaemia –vasoconstrcition◦ Enhances sensitivity to catecholamines◦ Coronary, Pulmonary and cerebral vasodilator atphysiological doses.◦ Clinical studies – 0.01 – 0.04U/min improve BPand responsiveness to catecholamines in septicand vasodilatory shock◦ Higher doses cause pulmonary, coronary andrenal vasoconstriction◦ RCT in adults shows improved CI, BP and fewerarrythmias if used with norad compared withnorad alone

Which inotropes when?

Goal targeted treatment

Benefit from individualised resuscitation to more detailed goalsdo the basics very well vs. doing basics wellSearch for cryptic shockVenous desaturation

Largest mortality benefit of any sepsis study

Shock should be clinically diagnosed,before hypotension occurs, by:hypothermia or hyperthermia,altered mental status,with peripheral vasodilationor cool extremities with capillary refill > 2 seconds

Does it work?

A Comparison of ACCM-PALS Guidelines to Standard Care on Outcomefrom Pediatric Septic ShockA Randomized Control Trial (C Oliveira et al 2008)102 Septic ShockPatientsGoal normal perfusion Goal O 2 sat > 70%28 day Mortality20/51 (39.2%)28 day Mortality6/51(11.8%)OR 0.2 95% CI 0.07-0.57

Mortality associated with CV O 2sat < 70% was averted with intervention(C Oliveira et al)Mortality rate ifBaselineControl groupCV O 2 sat < 70%CV O 2 sat > 70%68.8 %21.7 %Intervention groupCV O 2 sat < 70% 13.3 %

◦ Case control study of fatal vs. nonfatalmeningococcal disease 1997-1999◦ 145 cases; 355 controls◦ Factors associated with death• Not under care of paediatrician• Failure of supervision by a consultant• Failure in administration of inotropes

Pitfalls

Common errors (1)◦ Failure to establishsecure access◦ Ventilation delayeduntil arrest

Common errors (1)◦ Failure to establishsecure access◦ -Intra-Osseousneedle after 90 secin shocked child◦ Ventilation delayeduntil arrest• Recognise severediseaselow WCCcoagulopathyextensive rash

Common errors (2)◦ Inadequate fluidadmin◦ Myocardialdepressant drugsadministered forinduction ofanaesthesia

Common errors (2)◦ Inadequate fluidadmin◦ 20mls/kg and rpt200mls/kg notunusual◦ Myocardialdepressant drugsadministered forinduction ofanaesthesiaFentanyl (+/- ketamine)Pancuronium/Suxnotthiopentonemidazolampropofol

Common errors (3)◦ KCl boluses◦ Large ET leak◦ Nasal intubation◦ dobutamine used alone

Common errors (3)◦ KCl boluses◦ Large ET leak◦ Total Body K + normal or high,anticipate acidosis◦ high pressure leak only◦ Nasal intubation◦ dobutamine used alone◦ Avoid in coagulopathy◦ AVOID dobutamineIf no CVL thenIO dopamine/adrenaline

Summary◦ Volume◦ Inotropes◦ Aggressive early treatment