Cardiovascular failure, inotropes and vasopressors Introduction thetensionintheventricularwallduring nantly affected by extrinsic factors sum- Cardiovascularfailure(‘shock’)meansthat diastoleastheheartfillswithbloodresult- marizedinTable 2. tissue perfusion is inadequate to meet inginstretchingofcardiacmusclefibres. metabolicdemandsforoxygenandnutri- Stretchingthefibresincreasestheforceof Oxygen delivery ents.Ifuncorrectedthiscanleadtoirre- contractionduringthesubsequentsystole Adequate oxygen delivery is dependent versible tissue hypoxia and cell death. (Frank–Starlingmechanismoftheheart). onboththecardiacoutputandthearte- Cardiovascularfailureisacommonindica- Afterloadisthetensionintheventricu- rial oxygen content. Most oxygen trans- tionforadmissiontothecriticalcareunit. lar wall required to eject blood into the portedinthebloodisboundtohaemo- Theaimoftreatmentistosupporttissue aorta. This will vary depending on the globin.Agramoffully-saturatedhaemo- perfusionandoxygendeliverywhichcan volume of the ventricle, the thickness of globin can carry 1.34ml of oxygen. beachievedthroughtheuseofvasoactive thewall,increasedsystemicvascularresist- Oxygen will also be dissolved in the drugs(inotropesandvasopressors). ance and the presence of conditions that plasma but the amount is negligible at Inotropes increase cardiac contractility obstructoutflow(e.g.aorticstenosis). normalatmosphericpressuresandthere- and cardiac output while vasopressors Contractility is the intrinsic ability of fore disregarded. Therefore the arterial cause vasoconstriction which increases theheartmuscletocontractforaparticu- oxygencontentandoxygendeliverycan bloodpressure.Somevasoactivedrugsare lar preload and afterload. It is predomi- becalculatedusingtheformulae: potentandhavedeleterioussideeffects,so they must only be used on critical care Table 1. Definitions of key parameters in cardiovascular physiology units where appropriate monitoring is available. Advances in therapeutics and Parameter (units) Definition monitoring have contributed to the Heart rate (beats/min) Number of ventricular contractions per unit time increasinglyaggressivetreatmentofcardio- vascular failure and junior doctors may Stroke volume (ml) Volume of blood ejected from the left ventricle with each contraction regularly encounter patients treated with Cardiac output (litre/min) Volume of blood ejected from the left ventricle over unit time vasoactive drugs. This article provides a Cardiac output = stroke volume x heart rate practicaloverviewofvasoactivedrugsand Stroke index (litre/m2) Stroke volume related to the size of the individual cautionsagainsttheiruseoutsidethecriti- calcaresetting. Stroke index = stroke volume/body surface area Cardiac index (litre/min/m2) Cardiac output related to the size of the individual Cardiovascular physiology Cardiac index = cardiac output/body surface area The main function of the cardiovascular systemistodeliveroxygenandnutrients Systemic vascular resistance Resistance to blood flow in the systemic circulation (Dyne s/cm5) to cells to meet their metabolic require- ments and remove waste products. The Mean arterial pressure (mmHg) Mean blood pressure across the cardiac cycle useofvasoactivedrugsisaimedatmain- Mean arterial pressure = diastolic pressure + (pulse pressure/3) tainingthisfunctionthereforeathorough and = cardiac output x systemic vascular resistance understanding of cardiovascular physiol- Pulse pressure (mmHg) Difference in pressure during systole and diastole ogyandpharmacologyisessentialforsafe Pulse pressure = systolic pressure – diastolic pressure andappropriateuseofthesedrugs.Table 1 summarizes the key physiological parameters. Table 2. Extrinsic factors affecting myocardial contractility Preload, afterload and contractility determine the stroke volume. Preload is Decreased contractility Acidosis and alkalosis Dr Julia Benham-Hermetz is CT1 in Cardiac disease (e.g. ischaemic heart disease, cardiomyopathy) Anaesthetics and Dr Mark Lambert is Drugs – β blockers (e.g. metoprolol), calcium-channel antagonists (e.g. verapamil) a Specialist Registrar in Anaesthetics in the Anaesthetics Department, The Royal Electrolyte disturbance, e.g. hyperkalaemia, hypocalcaemia Free Hospital, London NW3 2QG, and Hypoxaemia and hypercapnia Dr Robert CM Stephens is Consultant Parasympathetic nervous system stimulation Anaesthetist, UCL Hospitals, London Increased contractility Catecholamines (e.g. adrenaline, dopamine) Correspondence to: Dr J Benham-Hermetz Inotropic drugs ([email protected]) Sympathetic nervous system stimulation (e.g. sepsis, surgical stress response, exercise) C74 BritishJournalofHospitalMedicine,May2012,Vol73,No5 CTD_C74_C77_inotropes.indd 74 30/04/2012 11:21 Tips From The shop Floor Oxygencontent=SaO2x1.34x[Hb] and dopexamine are synthetic catecho- types and therefore produce different and lamines (having a similar chemical struc- effects (Table 4). Not all of these effects Oxygendelivery=oxygencontentxcar- ture to the endogenous catecholamines). aredesirable,sopatientsneedtobeselect- diacoutput Catecholamines act mainly on adrenergic edcarefullyandthedoseofdrugtitrated WhereSaO2=percentageoxygensatura- receptors,whichareafamilyofGprotein- cautiously. tion, 1.34 = oxygen content of 1g satu- coupledreceptorsthatspantheextracellu- ratedhaemoglobin,[Hb]=concentration lar membrane. The action of catecho- Who needs vasoactive drugs? ofhaemoglobin(g/litre). lamines at these receptors is explained in Notallpatientswithcardiovascularfailure Ascanbeseenfromtheaboveformu- Figure 2.Catecholaminesarerapidlyinac- willneedtreatmentwithvasoactivedrugs. lae, optimization of oxygen saturation tivated by re-uptake at the presynaptic Correction of fluid balance can improve and cardiac output improves oxygen nerve and so have a short half-life. cardiovascular parameters, increasing per- delivery. Excessive transfusion to Dopamine can activate both dopamine fusion and oxygen delivery. However, supranormal haemoglobin concentra- receptors(alsoGprotein-coupled)aswell vasoactivedrugsmaybeconsideredifthere tions will increase blood viscosity and asadrenergicreceptors. are continuing signs of inadequate tissue cardiac workload. Inotropes and vaso- The physiological effect of stimulation perfusionoroxygendeliverydespiteappro- pressorsareaneffectiveandcontrollable dependsonthecatecholaminereleasedand priatefluidresuscitation. wayofmaintainingtissueperfusionand the receptor subtype and location. The In clinical practice mean arterial blood oxygendelivery. important receptors in the cardiovascular pressure and heart rate are measured system are the α1, β1 and β2 adrenergic because this can be done easily, but the Cardiovascular pharmacology receptors.Theeffectsonthesearesumma- presence of tachycardia and hypotension and vasoactive drugs rizedinTable 3andFigure 3.Tooptimize are often late signs. Blood pressure and The most commonly used inotropes and cardiovascularfunctiondrugsareusedthat vasopressorsarecatecholamines.Thenatu- act on receptors which when stimulated Figure 2. Diagram of an adrenergic receptor. This rallyoccurringcatecholamines(dopamine, improve cardiac function and vascular has seven transmembrane domains. Catecholamine noradrenaline, adrenaline) act as neuro- smoothmuscletone. binds to the receptor extracellularly and causes transmittersandhormones;theirsynthetic Different catecholamines have varying a change in the intracellular structure that pathwayisshowninFigure 1.Dobutamine affinity for the adrenergic receptor sub- enables it to activate a G protein. The activated G protein triggers a secondary messenger Figure 1. Catecholamine synthesis. cascade. For adrenergic receptors this is most Phenylalanine Dihydroxyphenylalanine (DOPA) often through adenylate cyclase and cyclic AMP. Tyrosine (essential dietary The other principal signalling pathway is through amino acid) Catechol group Amino group phospholipase and inositol triphosphate and { { diacylglycerol. N terminus OH Dopamine OH CH2 CH2 NH2 OH Noradrenaline OH CH CH2 NH2 OH Intracellular G protein Adrenaline OH C terminus CH OH CH2 NH CH2 Figure 3. Locations and effect of stimulation of catecholamine receptors. Table 3. Adrenergic receptors and the cardiovascular system β1 Inotropy and Receptor Location Effect of stimulation chronotropy α1 adrenergic Vascular smooth muscle (peripheral, Vasoconstriction (increasing systemic vascular resistance) renal and coronary circulation) Peripheral β1 adrenergic Heart Increased heart rate and increased contractility vasculature (increasing cardiac output) β2 adrenergic Vascular smooth muscle Vasodilatation (reducing systemic vascular resistance) β2 α1 Vasodilatation (peripheral and renal circulation) Vasoconstriction BritishJournalofHospitalMedicine,May2012,Vol73,No5 C75 CTD_C74_C77_inotropes.indd 75 30/04/2012 11:21 heartratecangiveanindicationofcardio- Once patients with cardiovascular fail- carefullymonitoredandadjusted.Thisis vascular status but there are many other ure(shock)areidentifieditisimportant onlypossiblewithaninfusion.Inotropes parameters that affect cardiac output and to determine the underlying cause to andvasopressorsmustbeadministeredvia oxygendelivery(Table 1). enable treatment. Shock is commonly central access because there is a risk of Clinical assessment facilitates recogni- classified by its underlying mechanism skinnecrosisiftheyextravasate.Invasive tion of subtle indicators of poor per- whichissummarizedinTable 6.Inotropes monitoring is required because rapid fusion. The exact findings will vary areusedtoimprovecontractilityandcar-