Cardiovascular failure, and vasopressors

Introduction the tension in the ventricular wall during nantly affected by extrinsic factors sum- Cardiovascular failure (‘shock’) means that as the fills with blood result- marized in Table 2. tissue is inadequate to meet ing in stretching of fibres. metabolic demands for oxygen and nutri- Stretching the fibres increases the force of Oxygen delivery ents. If uncorrected this can lead to irre- contraction during the subsequent Adequate oxygen delivery is dependent versible tissue hypoxia and cell death. (Frank–Starling mechanism of the heart). on both the and the arte- Cardiovascular failure is a common indica- is the tension in the ventricu- rial oxygen content. Most oxygen trans- tion for admission to the critical care unit. lar wall required to eject blood into the ported in the blood is bound to haemo- The aim of treatment is to support tissue aorta. This will vary depending on the globin. A gram of fully-saturated haemo- perfusion and oxygen delivery which can volume of the , the thickness of globin can carry 1.34 ml of oxygen. be achieved through the use of vasoactive the wall, increased systemic vascular resist- Oxygen will also be dissolved in the drugs (inotropes and vasopressors). ance and the presence of conditions that plasma but the amount is negligible at Inotropes increase cardiac contractility obstruct outflow (e.g. aortic stenosis). normal atmospheric pressures and there- and cardiac output while vasopressors Contractility is the intrinsic ability of fore disregarded. Therefore the arterial cause which increases the heart muscle to contract for a particu- oxygen content and oxygen delivery can . Some vasoactive drugs are lar and afterload. It is predomi- be calculated using the formulae: potent and have deleterious side effects, 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 (beats/min) Number of ventricular contractions per unit time increasingly aggressive treatment of cardio- vascular failure and junior doctors may (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 practical overview of vasoactive drugs and Stroke index (litre/m2) Stroke volume related to the size of the individual cautions against their use outside the criti- cal care setting. Stroke index = stroke volume/body surface area (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 system is to deliver oxygen and nutrients Systemic Resistance to blood flow in the systemic circulation (Dyne s/cm5) to cells to meet their metabolic require- ments and remove waste products. The (mmHg) Mean blood pressure across the use of vasoactive drugs is aimed at main- Mean arterial pressure = diastolic pressure + ( pressure/3) taining this function therefore a thorough and = cardiac output x systemic vascular resistance understanding of cardiovascular physiol- (mmHg) Difference in pressure during systole and diastole ogy and pharmacology is essential for safe Pulse pressure = systolic pressure – diastolic pressure and appropriate use of these drugs. Table 1 summarizes the key physiological parameters. Table 2. Extrinsic factors affecting 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. ), calcium-channel antagonists (e.g. ) 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 (e.g. , )

Correspondence to: Dr J Benham-Hermetz Inotropic drugs ([email protected]) Sympathetic nervous system stimulation (e.g. , surgical stress response, exercise)

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Oxygen content = SaO2 x 1.34 x [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 Oxygen delivery = oxygen content x car- ture to the endogenous catecholamines). are desirable, so patients need to be select- diac output Catecholamines act mainly on ed carefully and the dose of drug titrated Where SaO2= percentage oxygen satura- receptors, which are a family of G protein- cautiously. tion, 1.34 = oxygen content of 1 g satu- coupled receptors that span the extracellu- rated haemoglobin, [Hb] = concentration lar membrane. The action of catecho- Who needs vasoactive drugs? of haemoglobin (g/litre). lamines at these receptors is explained in Not all patients with cardiovascular failure As can be seen from the above formu- Figure 2. Catecholamines are rapidly inac- will need treatment with vasoactive drugs. 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 (also G protein-coupled) as well vasoactive drugs may be considered if there tions will increase blood viscosity and as adrenergic receptors. are continuing signs of inadequate tissue cardiac workload. Inotropes and vaso- The physiological effect of stimulation perfusion or oxygen delivery despite appro- pressors are an effective and controllable depends on the released and priate fluid resuscitation. way of maintaining tissue perfusion and the receptor subtype and location. The In clinical practice mean arterial blood oxygen delivery. 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. The effects on these are summa- presence of and and vasoactive drugs rized in Table 3 and Figure 3. To optimize are often late signs. Blood pressure and The most commonly used inotropes and cardiovascular function drugs are used that vasopressors are catecholamines. The natu- act on receptors which when stimulated Figure 2. Diagram of an . This rally occurring catecholamines (dopamine, improve cardiac function and vascular has seven transmembrane domains. Catecholamine noradrenaline, adrenaline) act as neuro- smooth muscle tone. binds to the receptor extracellularly and causes transmitters and hormones; their synthetic Different catecholamines have varying a change in the intracellular structure that pathway is shown in Figure 1. 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 Dihydroxyphenylalanine (DOPA) often through adenylate cyclase and cyclic AMP. (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

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CTD_C74_C77_inotropes.indd 75 30/04/2012 11:21 heart rate can give an indication of cardio- Once patients with cardiovascular fail- carefully monitored and adjusted. This is vascular status but there are many other ure (shock) are identified it is important only possible with an infusion. Inotropes parameters that affect cardiac output and to determine the underlying cause to and vasopressors must be administered via oxygen delivery (Table 1). enable treatment. Shock is commonly central access because there is a risk of Clinical assessment facilitates recogni- classified by its underlying mechanism skin necrosis if they extravasate. Invasive tion of subtle indicators of poor per- which is summarized in Table 6. Inotropes monitoring is required because rapid fusion. The exact findings will vary are used to improve contractility and car- changes in blood pressure and arrhythmi- depending on the underlying cause of diac output. Vasopressors are used where as can occur during the administration of shock. Inadequate perfusion will impact the problem is a low systemic vascular these drugs. Therefore beat-to-beat moni- on the function of vital organs, for exam- resistance. toring of arterial pressure via an arterial ple reduced renal perfusion will reduce line is mandatory. Other invasive moni- renal output and poor brain perfusion Practicalities toring systems can be used, such as may manifest as confusion. Table 5 sum- Catecholamines are given as continuous oesophageal Doppler, LiDCO and marizes some of the key findings in a infusions because of their short half-life. PiCCO systems, which enable measure- compromised circulation and provides a Further their effects on the cardiovascular ment of cardiovascular parameters to cal- checklist for examination. system are potent and dosing must be culate cardiac output and stroke volume.

Table 4. Receptor actions of catecholamines Dose range Drug Receptor affinity Action (mg/kg/min) Side effects Noradrenaline Mainly α1 agonist, Vasoconstriction increasing systemic 0.03–0.2 Reduced renal perfusion as a result of vasoconstriction, some β1 agonist action vascular resistance increased afterload will reduce stroke volume and increase myocardial oxygen demand Adrenaline Low doses: β1 agonist Increased heart rate, stroke volume 0.01–0.15* Tachycardia and tachyarrhythmia, increased myocardial and cardiac output oxygen demand High doses: α1 agonist Vasoconstriction at higher doses increasing 0.01–0.15* High concentrations can cause reduced cardiac output systemic vascular resistance Dobutamine β1 agonist Increased heart rate, increased cardiac output 2.5–25 Tachyarrhythmia, increased myocardial oxygen consumption β2 agonist Vasodilatation and reduced systemic 2.5–25 Risk of hypotension vascular resistance Dopamine Low dose: dopamine Vasodilatation of capillary beds, reduced systemic 1–3 Risk of tachyarrhythmia receptor agonist vascular resistance and increased cardiac output Medium dose: Increases contractility, stroke volume 3–10 Previously used at low (‘renal’) doses to maintain renal β1 agonist and cardiac output perfusion and function High dose: α1 agonist Vasoconstriction increasing afterload, peripheral >10 No longer used as any benefit on renal outcome is caused resistance and mean arterial pressure by the increased cardiac output * there is no strict cut off between high and low dose so dose range applies to both

Table 5. Evidence of inadequate Table 6. Classification and mechanisms of shock tissue perfusion Mechanism Causes Oliguria or anuria Cardiogenic Pump failure: ↓ contractility, ↓ cardiac output Myocardial infarction, arrhythmias, decompensated Confusion or agitation cardiac failure Cool and clammy skin (although skin warm and Hypovolaemia Fluid loss: ↓ preload, ↓ stroke volume and ↓cardiac output Haemorrhage, dehydration sweaty in sepsis) Sepsis Peripheral vasodilatation, extravasation of fluid: ↓ systemic Bacterial infection, e.g. Weak or thready vascular resistance; normal or increased cardiac output with Streptococcus pneumoniae, Slow capillary refill time reduced capillary blood flow as a result of microcirculatory Escherichia coli Tachypnoea shunt; mitochondrial dysfunction with reduced oxygen extraction Tachycardia Neurogenic Peripheral vasodilatation: ↓ systemic vascular resistance Spinal cord transection, brainstem injury Hypotension Anaphylaxis Vasodilatation and pump failure: ↓ systemic vascular resistance Drug or food allergens Metabolic acidosis (negative base excess) and ↓ cardiac output

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Table 7. Non-catecholamine vasoactive drugs

Drug Mechanism Action , Phosphodiesterase III (PDE III) inhibitor, prevent hydrolysis of intracellular cyclic AMP, Increased cardiac contractility and stroke volume, augmenting its effects. Many isoenzymes of phosphodiesterase – PDE III is the target vasodilatation for inotropic actions Calcium sensitizer. Increases the sensitivity of myocardial troponin to intracellular calcium, Increased cardiac contractility without increasing possible inhibition of PDE III myocardial oxygen demand, effect on mortality unclear Vasopressin Endogenous hormone, also called antidiuretic hormone, V1 receptor activity in vascular Vasoconstriction increasing systemic vascular smooth muscle increasing intracellular calcium resistance and blood pressure See further reading for more information

For all these reasons treatment with ino- mechanism and actions of some more mechanism of action and principles of tropes and vasopressors necessitates care commonly used drugs of this type. management when using these drugs can by an expert on a high dependency unit. guide clinical practice. BJHM It is important to regularly re-assess Conclusions fluid balance. Patients should be ade- Inotropes and vasopressors are often used Conflict of interest: none. quately fluid resuscitated (or this should in the management of shock. Doctors Further reading be in progress) before starting vasoactive working in the acute setting need knowl- Feneck R (2007) Phosphodiesterase inhibitors and drugs. Using inotropes or vasopressors edge of the pathophysiology of shock and the cardiovascular system. Contin Educ Anaesth Crit Care Pain 7(6): 203–7 when patients are fluid depleted can wors- the pharmacology of vasoactive drugs to Overgaard CB, Dzavík V (2008) Inotropes and en perfusion. enable them to identify and refer patients vasopressors: review of physiology and clinical use Inotropes and vasopressors should be who would benefit from their use on in cardiovascular disease. Circulation 118(10): 1047–56 titrated to ensure the minimum amount of critical care. There is no definitive evi- Sharman A, Low J (2008) Vasopressin and its role in drug is used to maintain adequate tissue dence as to which vasoactive drug should critical care. Contin Educ Anaesth Crit Care Pain perfusion without causing adverse effects. be first line for a particular cause of shock, 8(4): 134–7 Singer M, Webb AR (2009) Oxford Handbook of The aim is not to maintain a specific blood so drug choice varies between different Critical Care. 3rd edn. Oxford University Press, pressure but to achieve satisfactory end- critical care units. Understanding the Oxford: 161–93 organ perfusion, which can be assessed clinically or with measured markers of organ perfusion. Key Points Vasoactive drugs are only supportive: n Cardiovascular failure and shock occur when tissue oxygen delivery is inadequate to meet tissue they do not reverse the underlying cause of oxygen demand. cardiovascular failure which must be n Early recognition of the signs of shock is difficult. addressed. Prolonged treatment with n Early treatment of shock is crucial to avoid irreversible cellular hypoxia. vasoactive drugs is undesirable because overstimulation of receptors will also result n Cardiac output and arterial oxygen content must be optimized before commencing vasoactive in tachyphylaxis, i.e. tolerance develops as therapies. a result of downregulation of membrane n Inotropes increase myocardial contraction and cardiac output. receptors, and cardiac oxygen demands n Vasopressors increase systemic vascular resistance. increase and may induce ischaemia and damage to cardiac myocytes. n Patients on inotropes and vasopressors should be managed on a critical care unit. Dose ranges for common inotropes and vasopressors are listed in Table 4. However, given the potency of the drugs, infusions should be started cautiously and titrated to Top tips use the lowest dose for the required n Regularly reassess patients for improvement in cardiovascular parameters and side effects of response. vasoactive drugs. n Monitor biochemistry for derangement in electrolytes and glucose. Adrenaline in particular can cause Other vasoactive drugs hyperglycaemia, increased lactate levels and metabolic acidosis. There are a number of other vasoactive n Check local guidelines – different critical care units will have their own preferred drugs, preparations drugs that do not act directly on catecho- and dose regimens. lamine receptors. These are used in clinical practice but none are considered first line n Check patient drug history for potential drug interactions, for example tricyclic and and there is no definite evidence that they monoamine oxidase inhibitors can produce exaggerated responses to catecholamines. improve outcomes. Table 7 summarizes the

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