CALCIUM FLUX

The concentration of intracellular ionised calcium is the primary determinant of vascular smooth muscle tone: increases lead to smooth muscle contraction, decreases cause relaxation. Control of calcium influx and efflux is determined by adrenergic receptor occupation and changes in membrane potential, mediated through voltage gated channels (see Chapter 82, Figure 82.2).

ENDOTHELIAL SYSTEM

The endothelium has a central role in blood pressure homeostasis by secreting substances such as nitric oxide, prostacyclin and endothelin.³ These substances are continuously released by the endothelium and are integral in regional autoregulation.⁴

Nitric oxide is synthesised from L-arginine by nitric oxide synthases. It is released under the influence of endothelial agonists such as noradrenaline (norepinephrine), acetylcholine and substance P and in response to mechanical factors such as endothelial shear forces and pulsatile flow. Nitric oxide diffuses into underlying smooth muscle where it activates guanylate cyclase to increase cyclic guanosine monophosphate (cGMP). Subsequent phosphorylation results in relaxation of underlying smooth muscle and vasodilatation.

Prostacyclin is synthesised via the arachidonic pathway and has a minor role in the control of vascular tone.

Endothelin is an endothelium-derived vasoconstrictor peptide that is associated with increases in vascular smooth muscle intracellular calcium. It acts as endogenous ligand to regulate voltage-gated calcium channels, thereby producing vasoconstriction, usually in response to shear stresses, tissue hypoxia, angiotensin II and inflammatory mediators (e.g. interleukin-6 and nuclear factor κB).

RENIN–ANGIOTENSIN–ALDOSTERONE SYSTEM

Angiotensinogen is converted by renin to form angiotensin I, which is subsequently converted to angiotensin II by angiotensin-converting enzyme (ACE). Angiotensin II has a number of effects that are responsible for blood pressure homeostasis. These include release of aldosterone, direct activation of α-adrenergic receptors on vascular smooth muscle and a direct effect in the endothelium. These effects are directed at defending blood pressure and are integral in the stress response. Angiotensin-converting enzyme is also responsible for the inactivation of bradykinins that have predominantly vasodilatory effects, coupled to arachidonic acid synthesis and generation of prostacyclin.

ADRENERGIC SYSTEM

The sympathetic nervous system is integrally involved with all of the above systems, regulating vascular tone at central, ganglionic and local neural levels. Adrenergic stimulation of β-receptors is associated with vasodilatation; α-receptor stimulation results in vasoconstriction. The vascular effects of the catecholamines and vasopressors are discussed in Chapter 82.

Adrenergic stimulation is the predominant system in regulating venous tone.⁵ This is due to endothelial differences in veins resulting in less production of nitric oxide and reduced responsiveness to angiotensin II.

NIFEDIPINE

Nifedipine is a predominant arteriolar vasodilator, with minimal effect on venous capacitance vessels and no direct depressant effect on heart rate conduction.

It may be administered intravenously, orally or sublingually, and has a rapid onset of action (2–5 minutes) and duration of action of 20–30 minutes.

Nifedipine is frequently used to treat angina pectoris, especially that due to coronary artery vasospasm. Peripheral vasodilatation results in decreased systemic blood pressure, often associated with sympathetic stimulation resulting in increased cardiac output and heart rate that may counter the negative inotropic, chronotropic and dromotropic effects of nifedipine. Nevertheless, nifedipine may be associated with profound hypotension in patients with ventricular dysfunction, aortic stenosis and/or concomitant β-blockade. For this reason, the use of sublingual nifedipine as a method of treating hypertensive emergencies is no longer recommended.⁷

Nifedipine and related drugs may cause diuretic-resistant peripheral oedema that is due to redistribution of extracellular fluid rather than sodium and water retention.

NIMODIPINE

Nimodipine is a highly lipid-soluble analogue of nifedipine. High lipid solubility facilitates entrance into the central nervous system where it causes selective cerebral arterial vasodilatation.

It may be used to attenuate cerebral arterial vasospasm following aneurysmal subarachnoid haemorrhage. Improved outcomes have been demonstrated in patients with Grade 1 and 2 subarachnoid haemorrhage.⁸ Systemic hypotension may result from peripheral vasodilatation that may compromise cerebral blood flow in susceptible patients. Similarly, cerebral vasodilatation may increase intracranial pressure in patients with reduced intracranial elastance.

It may be given by intravenous infusion or enterally with equal effect.

AMLODOPINE

Amlodipine is an oral preparation that has a similar pharmacodynamic profile to nifedipine. In addition to arteriolar vasodilatory and cardiac effects, amlodipine has been shown to exert specific anti-inflammatory effects in hypertension, diabetic nephropathy and in modulating high-density lipoprotein (HDL) in patients with hypercholesterolaemia.⁹ These effects have seen amlodipine increasingly being used for treatment of hypertension in high-risk patients, and may have a role in stable critically ill patients with associated comorbidities.

VERAPAMIL

The primary effect of verapamil is on the atrioventricular node and this drug is principally used as an antiarrhythmic for the treatment of supraventricular tachyarrhythmias. For this reason, concomitant therapy with β-blockers or digoxin is not recommended.

Verapamil is not as active as nifedipine in its effects on smooth muscle and therefore causes less pronounced decrease in systemic blood pressure and reflex sympathetic activity. It has a limited role as a vasodilator.¹⁰

DILTIAZEM

Diltiazem has a similar cardiovascular profile to verapamil, although its vasodilatory properties are intermediate between nifedipine and verapamil. Diltiazem exerts minimal cardiodepressant effects and is unlikely to potentiate β-blockers.

MAGNESIUM SULPHATE

Magnesium regulates intracellular calcium and potassium levels by activation of membrane pumps and competition with calcium for transmembrane channels. Physiological effects are widespread, affecting cardiovascular, central and peripheral nervous systems and the musculoskeletal junction.¹¹

It acts as a direct arteriolar and venous vasodilator causing reductions in blood pressure. Modulation of centrally mediated and peripheral sympathetic tone results in variable effects on cardiac output and heart rate.

Consequently, it has an established role in the treatment of pre-eclampsia and eclampsia,¹² perioperative management of phaeochromocytoma¹³ and treatment of autonomic dysfunction in tetanus.¹⁴

SODIUM NITROPRUSSIDE

Sodium nitroprusside is a non-selective vasodilator that causes relaxation of arterial and venous smooth muscle. It is compromised of a ferrous ion centre associated with five cyanide moieties and a nitrosyl group. The molecule is 44% cyanide by weight.

It is reconstituted from a powdered form. The solution is light-sensitive requiring protection from exposure to light by wrapping administration sets in aluminium foil. Prolonged exposure to light may be associated with an increase in release of hydrogen cyanide, although this is seldom clinically significant.

When infused intravenously, sodium nitroprusside interacts with oxyhaemoglobin, dissociating immediately to form methaemoglobin while releasing free cyanide and nitric oxide. The latter is responsible for the vasodilatory effect of sodium nitroprusside.

Onset of action is almost immediate with a transient duration, requiring continuous intravenous infusion to maintain a therapeutic effect.

Tachyphylaxis is common, particularly in younger patients. Large doses should not be used if the desired therapeutic effect is not attained, as this may be associated with toxicity.

Sodium nitroprusside produces direct venous and arterial vasodilatation, resulting in a prompt decrease in systemic blood pressure. The effect on cardiac output is variable. Decreases in right atrial pressure reflect pooling of blood in the venous system, which may decrease cardiac output. This may result in reflex tachycardia that may oppose the overall reduction in blood pressure. In patients with left ventricular failure, the effect on cardiac output will depend on initial left ventricular end-diastolic pressure. Sodium nitroprusside has unpredictable effects on calculated systemic vascular resistance. Homeostaticmechanisms in preserving cardiac output may explain tachyphylaxis to prolonged infusions.

Sodium nitroprusside may increase myocardial ischaemia in patients with coronary artery disease by causing an intracoronary steal of blood flow away from ischaemic areas by arteriolar vasodilatation. Secondary tachycardia may also exacerbate myocardial ischaemia.

Due to its non-selectivity, sodium nitroprusside has direct effects on most vascular beds. In the cerebral circulation, sodium nitroprusside is a cerebral vasodilator, leading to increases in cerebral blood flow and blood volume. This may be critical in patients with increased intracranial pressure. Rapid and profound reductions in mean arterial pressure produced by sodium nitroprusside may exceed the autoregulatory capacity of the brain to maintain adequate cerebral blood flow.

Sodium nitroprusside is a pulmonary vasodilator and may attenuate hypoxic pulmonary vasoconstriction, resulting in increased intrapulmonary shunting and decreased arterial oxygen tension. This phenomenon may be exacerbated by associated hypotension.

The prolonged use of large doses of sodium nitroprusside may be associated with toxicity related to the production and cyanide and, to a lesser extent, methaemoglobin.¹⁶

Free cyanide produced by the dissociation of sodium nitroprusside reacts with methaemoglobin to form cyanmethaemoglobin, or is metabolised by rhodenase in the liver and kidneys to form thiocyanate. A healthy adult can eliminate cyanide at a rate equivalent to a sodium nitroprusside infusion of 2 μg/kg per min or up to 10 μg/kg per min for 10 minutes, although there is marked inter-individual variability.

Toxicity should be considered in patients who become resistant to sodium nitroprusside despite maximum infusion rates and who develop an unexplained lactic acidosis. In high doses, cyanide may cause seizures.

Treatment of suspected cyanide toxicity is cessation of the infusion and administration of 100% oxygen. Sodium thiosulphate (150 mg/kg) converts cyanide to thiocyanate, which is excreted renally. For severe cyanide toxicity, sodium nitrate may be infused (5 mg/kg) to produce methaemoglobin and subsequently cyanmethaemoglobin. Hydroxocobalamin, which binds cyanide to produce cyanocobalamin, may also be administered (25 mg/hour to maximum of 100 mg).

GLYCERYL TRINITRATE

Glyceryl trinitrate is an organic nitrate that generates nitric oxide through a different mechanism from sodium nitroprusside.

The pharmacokinetics allows glyceryl trinitrate to be given by infusion, with a longer onset and duration of action than sodium nitroprusside. Glyceryl trinitrate may also be administered sublingually, orally or transdermally.

Tachyphylaxis is common with glyceryl trinitrate; doses should not be increased if patients no longer respond to standard doses. Glass bottles or polyethylene administration sets are required as glyceryl trinitrate is absorbed into standard polyvinylchloride sets.

The effects on the peripheral vasculature are dose dependent, acting principally on venous capacitance vessels to produce venous pooling and decreased ventricular afterload. These are important mechanisms in patients with cardiac failure.

Glyceryl trinitrate primarily dilates larger conductance vessels of the coronary circulation, resulting in increased coronary blood flow to ischaemic subendocardial areas, thereby relieving angina pectoris. This is in contrast to sodium nitroprusside that may cause a coronary steal phenomenon.

Reductions in blood pressure are more dependent on blood volume than sodium nitroprusside. Precipitous falls in blood pressure may occur in hypovolaemic patients with small doses of glyceryl trinitrate. In euvolaemic patients, reflex tachycardia is not as pronounced as with sodium nitroprusside. At higher doses, arteriolar vasodilatation occurs without significant changes in calculated systemic vascular resistance.

Glyceryl trinitrate is a cerebral vasodilator and should be used with caution in patients with reduced intracranial elastance. Headache due to this mechanism is a common side-effect in conscious patients.

ISOSORBIDE DINITRATE

Isosorbide dinitrate is the most commonly administered oral nitrate for the prophylaxis of angina pectoris. It has a physiological effect that lasts up to 6 hours in doses of 60–120 mg. The mechanism of action is the same as glyceryl trinitrate. Hypotension may follow acute administration, but tolerance to this develops with chronic therapy.¹⁷

HYDRALAZINE

Hydralazine is a potent, arterioselective, direct-acting vasodilator that acts via stimulation of cGMP and inhibition of smooth muscle myosin light chain kinase.

Following intravenous administration, hydralazine has a rapid onset of action, usually within 5–10 minutes. It may also be administered intramuscularly or orally. The drug is partially metabolised by acetylation, for which there is marked inter-individual variability (35% population are slow acetylators). Whilst this does not have much clinical significance regarding the antihypertensive effects, it is important with respect to toxicity.¹⁷

Hydralazine causes predominantly arteriolar vasodilatation that is widespread but not uniform. It is associated with direct and reflex sympathetic activity, so that cardiac output and heart rate are increased. Prolonged use of hydralazine stimulates renin release and is associated with sodium and water retention. Consequently, hydralazine is frequently administered with β-blockers and/or diuretics.

Chronic use of hydralazine may be associated with immunological side-effects including a lupus syndrome, vasculitis, haemolytic anaemia and rapidly progressive glomerulonephritis.

DIAZOXIDE

Diazoxide is chemically related to the thiazide diuretics and is a potent, non-selective, direct-acting vasodilator. The mechanism of action is unclear, but it is a predominantly arteriolar vasodilator.¹⁸ Diazoxide is administered intravenously or intramuscularly. It has a rapid onset (3–5 minutes) and prolonged duration of action (1–2 hours), often with precipitous reductions in blood pressure. Diazoxide has similar cardiovascular effects to hydralazine and is associated with significant reflex sympathetic stimulation, resulting in increased cardiac output and heart rate.

It is a useful drug in accelerated hypertension associated with acute renal failure such as glomerulonephritis and has been used in severe pregnancy-induced hypertension and eclampsia. Stimulation of catecholamine release prohibits the use of diazoxide in patients with phaeochromocytoma.

It is associated with metabolic side-effects such as hyperglycaemia and sodium and water retention.

PHENTOLAMINE

Phentolamine is a non-selective, competitive antagonist at α₁– and α₂-receptors. At low doses, phentolamine causes prejunctional inhibition of noradrenaline release (via α₂-receptor inhibition). At higher doses, more complete α-receptor blockade is achieved, with enhancement of effects of β-agonists due to increased local concentration of noradrenaline produced by α₂-blockade (see Chapter 82, Figure 82.3a).

Phentolamine is administered intravenously and may be given intermittently or by infusion. Onset is rapid (within 2 minutes), with a duration of action of 10–15 minutes.

Arteriolar and venous vasodilatation reduces systemic blood pressure, without significant changes in calculated systemic vascular resistance. Effects on cardiac output are variable, and there is modest reflex sympathetic stimulation without significant increases in heart rate.

PHENOXYBENZAMINE

Phenoxybenzamine is a non-selective, non-competitive, α₁– and α₂-receptor antagonist. Blockade is also produced on histamine, serotonin and acetylcholine muscarinic receptors. Reuptake of noradrenaline is blocked, thereby potentiating the effects of β-agonists.

Phenoxybenzamine is usually administered orally, but may also be given intravenously. It has a long onset of action and prolonged duration of action (3–4 days). It causes a gradual reduction in systemic blood pressure, without rapid reflex sympathetic activity.

Prolonged use is associated with increased β-adrenergic effects, predominantly increased heart rate, for which combination therapy with β-blockade is used. Phenoxybenzamine is primarily used in the management of phaeochromocytoma, either preoperatively or long term in inoperable patients. It may also be used to control autonomic hyperreflexia in patients with spinal cord transection.¹⁹

PRAZOSIN

Prazosin is a relatively arterioselective, competitive, α₁-receptor antagonist. It acts postjunctionally and therefore does not inhibit reuptake of noradrenaline. Consequently, it produces less tachycardia for a given reduction in systemic blood pressure.

It is administered orally and usually used for essential or renovascular (hyper-reninaemia) hypertension. It is frequently used in combination with β-blockers and diuretics, particularly in patients with renal dysfunction.

LABETALOL

Labetalol is specific competitive antagonist at α₁-, β₁– and β₂-adrenergic receptors. β-Blockade effects predominate, with a blockade potency approximately 10% of prazosin. Labetalol has partial agonist effects on β₂-receptors. The ratio of α₁:β-receptor blockade is 1:4.

It is administered intravenously, has a rapid onset of action (5–10 minutes) with a duration of 2–6 hours. It may be given by infusion.

Systemic blood pressure and cardiac output are reduced by a combination of negative inotropy, arterial and venous vasodilatation. Reflex tachycardia is attenuated by β-blockade.

Side-effects such as bronchospasm and hyperkalaemia relate predominantly to β-blockade.

CARVEDILOL

Carvedilol is a non-selective β-blocker with α₁-antagonist activity. Most of the vasodilator activity relates to α₁-antagonism, although at high concentrations it also blocks calcium entry. The ratio of α₁:β-receptor blockade is 1:10.

It is administered orally; no intravenous preparation is available.

Recent studies have demonstrated slowing of progression of congestive cardiac failure and improved mortality, particularly when used in conjunction with ACE inhibitors in patients with mild to moderate cardiac failure.^20,21 It may also be used in patients who cannot be treated with ACE inhibitors.

HALOPERIDOL AND CHLORPROMAZINE

These drugs act as competitive α-receptor antagonists causing non-selective vasodilatation and blockade of noradrenaline reuptake.

These drugs are primarily used as major tranquillisers or antipsychotics; their effect on the peripheral vasculature should be regarded as a side-effect, rather than a specific therapeutic action.

Reduction of systemic blood pressure is variable and may be precipitous, particularly in hypovolaemic patients with high sympathetic drive. These drugs may be useful in neurogenic hypertension, and are not regarded as first-line vasodilators.

PREPARATIONS

Captopril is the prototype and is still widely used. It is administered orally in increasing doses and intervals to a maximum dose of 50 mg 8 hourly. It may be administered sublingually in acute hypertension (5–25 mg), with an onset of action in 20–30 minutes, duration of 4 hours. There are no significant differences in the cardiovascular effects between captopril and other preparations. It is contraindicated in patients with bilateral renal artery stenosis and should be avoided in pregnancy.

Enalapril is a pro-drug, effective by hepatic metabolism to enalaprilat, producing a slower and more controlled action. It is administered orally in 5 mg increments to a total of 20 mg twice daily.

Lisinopril has the advantage of single daily dosing and may be useful in stable critically ill patients.

CARDIOVASCULAR EFFECTS

The cardiovascular effects of ACE inhibition are widespread, with effects that influence the peripheral vasculature, cardiac performance, and salt and water homeostasis. Consequently, ACE inhibitors are not principally regarded as vasodilators, although they have both direct and indirect effects on the peripheral vasculature.

Increased production of endothelial vasodilators such as prostacyclin and decreased production of endothelin by angiotensin result in generalised venous and arteriolar vasodilatation. This occurs in the absence of reflex sympathetic activity or changes in heart rate, due to the modulation of adrenergic stimulation. Systemic blood pressure is reduced without changes in cardiac output or heart rate.

ACE inhibition is associated with improved myocardial performance following acute myocardial infarction due to left ventricular remodelling and improvement in neurohumoral activation. These drugs have been shown to improve survival following myocardial infarction in patients with left ventricular dysfunction.²⁴

‘First-dose hypotension’ is described in patients receiving ACE inhibitors for the first time. This may occur particularly in patients who are salt and water depleted, or those who develop sensitivity to the drug. Drug sensitivity may also present as a sudden decrease in renal function following commencement of the drug (see below).

RENOVASCULAR EFFECTS

ACE inhibitors may cause renal failure, particularly in patients with renovascular disease, hyperreninaemic hypertension and acute renal dysfunction. The renal effects of ACE inhibitors may be potentiated by diuretics, non-steroidal anti-inflammatory agents and β-blockers.

As a rule in intensive care patients, ACE inhibitors are started in suitable patients once renal function has stabilised and the patient no longer requires inotropic support.

SIDE-EFFECTS AND TOXICITY

In addition to renal dysfunction, ACE inhibitors may be associated with a number of side-effects. The most common of these is cough, which is due to the increased production of kinins.²⁵

Severe angioneurotic oedema causing upper-airway obstruction may occur with all ACE inhibitors, although this is less common with enalapril and lisinopril. This is due to increased activation of bradykinins. ACE inhibitors are contraindicated in patients with a history of hereditary or idiopathic angioneurotic oedema.²⁶

Neutropenia and agranulocytosis are uncommon but potentially lethal side-effects in susceptible patients.

CLONIDINE

Clonidine is a centrally acting α₂-agonist which stimulates inhibitory neurones in the vasomotor centre. This results in a reduction in sympathetic outflow from the central nervous system and is associated with negative inotropy and reduction in heart rate. Systemic blood pressure is reduced by this mechanism, with associated arteriolar and venous vasodilatation. Clonidine has centrally acting analgesic properties, which make it a suitable drug in patients with postoperative hypertension.

Peripherally, it stimulates prejunctional α₂-receptors, thereby decreasing noradrenaline release, but may also have an effect at postjunctional α₁-receptors causing vasoconstriction. This may present as rebound hypertension following initial reduction of blood pressure, as there is variable duration of the central and peripheral effects.

Clonidine is administered by intravenous injection; it cannot be given by infusion. It has a rapid onset of action (5–10 minutes) and duration of action of 20–30 minutes. It has both central and peripheral effects.

METHYLDOPA

Methyldopa has been used in the treatment of hypertension for 30 years. It acts as a centrally acting ‘false’ transmitter following metabolism to methylnoradrenaline and subsequent stimulation of α₂-receptors, although the precise mechanism is not clear.

It has no direct effect on cardiac or renal function. Cardiac output is maintained without changes in heart rate. Consequently, it may arrest or improve hypertensive nephropathy. It has a limited role in hypertensive emergencies, but is useful in accelerated essential, renovascular and pregnancy-induced hypertension.

It is administered orally in doses of 250 mg to 2 g per day. An intravenous preparation is available.

β-ADRENERGIC ANTAGONISTS

β-Blockers have been used for the treatment of hypertension for over 30 years and have an increasingly important role in the management of cardiac failure.^30–32

In addition to decreasing heart rate and contractility, β-blockers have other neurohumoral effects that affect vascular tone. These relate to inhibition of renin release from juxtaglomerular cells (Figure 83.1) and prejunctional inhibition of noradrenaline that result in reduction in vascular tone and blood pressure. A central effect of β-blockers has also been proposed.

The mode of action has been described in terms of selectivity to blockade of β-adrenergic receptors – β₁ and/or β₂. While this is an appropriate pharmacological distinction, the clinical activity of these drugs is not as predictable due to mixed populations of β₁– and β₂-receptors in most organs and variable receptor responsiveness in physiological and pathophysiological conditions. Consequently,there is marked inter-individual variability in the response to these drugs. In high enough doses, whether intentionally or due to toxicity, all β-blockers will cause generalised antagonism with resultant therapeutic and toxic effects.

Lipid-soluble β-blockers include propranolol and metoprolol that are predominantly excreted by the liver; atenolol and sotalol are predominantly renally excreted, warranting caution with these drugs in patients with renal dysfunction.

β-Blockers may be given orally or intravenously. As there is significant first-pass metabolism, doses for oral and intravenous administration are markedly different.

Esmolol is an intravenous β-blocker that is rapidly metabolised by red cell esterases. Its rapid onset of action and short duration allow infusion of drug, making it a useful drug in patients with acute hypertensive states associated with tachycardia. Labetalol and carvedilol are discussed above.

β-Blockers are frequently used as adjuncts to vasodilators in the treatment of hypertensive emergencies and states, particularly where reflex tachycardia and sympathetic stimulation occurs (e.g. hydralazine, nifedipine and prazosin).

Side-effects and toxicity of β-blockers include bradycardia (which may be profound), hypotension, bronchoconstriction, aggravation of peripheral vascular ischaemia, hyperkalaemia and masking of the sympathetic response to hypoglycaemia.

DIURETICS

As with β-blockers, diuretics have an established place in the management of hypertension. In addition to their effects on salt and water excretion and inhibition of aldosterone, direct vasodilatory effects are associated with diuretics such as furosemide and the thiazides.

These drugs have a rapid venodilatory action, which may be due to inhibition of a noradrenaline-activated chloride channel on veins. Reductions of blood pressure and right atrial pressure may occur following low doses, and may present before an associated diuresis.

All diuretics should be used with caution in patients with renal dysfunction and avoided until a euvolaemic state is achieved.

MONITORING

The principles of haemodynamic monitoring in patients receiving vasoactive drugs is outlined in Chapter 82.

Patients with severe hypertension or those receiving infusions or doses of potent vasodilators such as sodium nitroprusside, glyceryl trinitrate, diazoxide or nifedipine should be monitored via an intra-arterial catheter.

The use of non-invasive measurement devices are not recommended in patients with hypertensive emergencies.

As peripheral vasodilators have significant effects on both the arterial and venous systems, measurement of volume status is important. In the majority of patients, establishing a euvolaemic state is essential before commencing a vasodilator.

DOSAGES AND DRUG ADMINISTRATION

Vasodilators administered via infusion are delivered through a dedicated central venous catheter using infusion pumps or syringe drivers and titrated to achieve a target mean arterial pressure.

Infusion lines should be free of injection portals and clearly marked with identifying labels.

Concentrations of infusions should be standardised in accordance with individual unit protocols. Suggested infusion concentrations and common drug doses are shown in Table 83.1.

Table 83.1 Dose and infusion concentrations of commonly used vasodilators and antihypertensives in intensive care

ACUTE HYPERTENSION

The most common cause of hypertension in intensive care patients is pain or agitation, particularly in postoperative patients. It is important that patients have adequate analgesia and sedation before antihypertensives or vasodilators are used.

Other common causes of hypertension include hypothermia, urinary retention, positional discomfort and omission of pre-admission antihypertensives, particularly β-blockers.

The majority of instances of acute hypertension in the ICU will respond to simple measures addressing the above.³⁴

Sustained hypertension may be treated acutely with incremental doses or infusions of short-acting drugs such as glyceryl trinitrate, sodium nitroprusside, phentolamine, hydralazine, nifedipine or clonidine. Infusions of vasodilators may be required if hypertension persists, or if the patient in unable to take longer acting oral agents such as prazosin or amlodipine. Hypertension associated with tachycardia may be treated with β-blockers.

HYPERTENSIVE ENCEPHALOPATHY

Hypertensive encephalopathy is defined as an acute organic brain syndrome occurring as a result of failure of cerebrovascular autoregulation. There may be differences in the degree of hypertension that cause encephalopathy. It may present as confusion, visual disturbances, blindness, seizures or stroke. If not adequately treated, hypertensive encephalopathy may result in intracerebral haemorrhage, coma or death.³⁵

Hypertensive encephalopathy may occur in patients with untreated or undertreated hypertension or in association with other diseases such as renal disease (e.g. glomerulonephritis, renovascular disease), thrombotic thrombocytopenic purpura, immunosuppressive therapy, collagen vascular diseases or eclampsia. Consequently, drug treatment will depend on the context in which it occurs.

The aim of drug therapy in these patients is to reduce blood pressure in a controlled, predictable and safe way. Acutely, short-acting, titratable parenteral drugs are suitable in emergency situations. Sodium nitroprusside can be used safely in most circumstances. Although sodium nitroprusside may increase intracranial pressure, associated reductions in mean arterial pressure offset this effect. Phentolamine is equally effective. Esmolol may be useful as an adjunctive agent.³⁶

Other agents that are useful in controlling severe hypertension include hydralazine, diazoxide, nifedipine, clonidine and ACE inhibitors (although these must be used cautiously in patients with associated renal dysfunction). Combination therapy is usually required, although this should be done with caution to minimise additive effects with resultant hypotension.

Patients with hypertensive emergencies are frequently hypovolaemic due to excessive sympathetic stimulation. In the absence of left ventricular failure, judicious fluid replacement may reduce blood pressure and improve renal function, thereby minimising precipitous hypotension that may result following administration of some drugs. Diuretics are generally avoided in these conditions unless there is evidence of left ventricular failure.³⁶

ACUTE STROKE

Acute stroke syndromes frequently occur in the setting of severe hypertension. The reduction of mean arterial pressure must be balanced by the maintenance of adequate cerebral perfusion pressure and cerebral blood flow. Ischaemic or infarcted brain is vulnerable to critical reductions in cerebral blood flow, while excessive mean arterial pressure may increase the risk of cerebral haemorrhage.³⁷

Acutely, blood pressure should be maintained in a normal range until intracranial pathology has been identified by CT scan. Aggressive reduction in blood pressure is not recommended in patients with ischaemic stroke, whilst hypertension in patients with aneurysmal subarachnoid haemorrhage or intracranial haemorrhage may be managed by drugs outlined above.

AORTIC DISSECTION

Aortic dissection is the most dramatic and most rapidly fatal complication of severe hypertension. Blood pressure should be decreased as rapidly as possible to normal or slightly hypotensive levels. Titrations are usually made to achieve systolic blood pressures of 100–110 mmHg or mean arterial pressure of 55–65 mmHg. This will depend on the patient’s premorbid blood pressure and the accuracy of blood pressure measurement. It is important to maintain blood pressure at levels compatible with adequate cerebral and renal perfusion.³⁸

This is best achieved initially by a combination of β-blockers (e.g. esmolol, labetalol or atenolol), then in combination with vasodilators such as sodium nitroprusside or glyceryl trinitrate. Tachycardia must be avoided as this is a significant determinant of aortic shear force that may exacerbate the dissection.

Aortic dissection distal to the left subclavian artery is managed conservatively with antihypertensive therapy. Proximal dissections are managed surgically after acute control of blood pressure.

ACUTE MYOCARDIAL ISCHAEMIA

Myocardial ischaemia in the absence of obstructive coronary atherosclerosis may be precipitated by severe hypertension. This occurs by increased left ventricular wall stress, reduced preload, tachycardia and increased myocardial metabolic demand. Severe ischaemia may result in acute left ventricular failure.

Intravenous glyceryl trinitrate is useful in this situation and may be used in combination with β-blockers such as esmolol, labetalol or carvedilol.

ACE inhibitors may be used in the acute situation and may be required for longer term treatment.

PHAEOCHROMOCYTOMA

Tumours of the adrenal medulla secrete catecholamines that result in initial paroxysmal, then sustained, severe hypertension. They may present to the ICU as a hypertensive emergency or perioperatively for surgical ablation.³⁹

Acute hypertensive crises associated with phaeochromocytoma are managed with incremental doses orinfusions of phentolamine. Untreated patients may be significantly hypovolaemic and may require judicious volume replacement. β-Blockers should not be used in the acute stage as these will potentiate unopposed α-adrenergic stimulation.

Phenoxybenzamine forms the mainstay of treatment and preparation for surgery. This is commenced in 20–30 mg increments and continued until blood pressure is controlled. Excessive β-adrenergic effects are treated with β-blockers after sufficient α-blockade with phenoxybenzamine.¹⁹

Magnesium sulphate is useful in the perioperative management of phaeochromocytoma. It is given by infusion at 2–4 g/hour.¹³

RENAL FAILURE

Renal insufficiency may be a cause or consequence of a hypertensive emergency. Patients on haemodialysis (particularly those receiving erythropoietin therapy) and renal transplant patients (especially those receiving ciclosporin or corticosteroids) commonly present with severe hypertension. In patients with new onset renal failure accompanying severe hypertension, blood pressure must be controlled without potentiating renal dysfunction. Drugs such as calcium antagonists, phentolamine or prazosin may preserve renal blood flow and are appropriate in these patients. ACE inhibitors and diuretics should be used with caution until renal function has stabilised or improved.

Patients in the recovery phase of acute renal failure are usually hypertensive. This is a normal physiological response and should not be treated unless there is associated myocardial or cerebral ischaemia.⁴⁰

PRE-ECLAMPSIA AND ECLAMPSIA

In addition to delivery of the baby and placenta, parenteral magnesium sulphate is the treatment of choice to prevent the evolution of pre-eclampsia to eclampsia (seizures and deteriorating encephalopathy¹²). Other parenteral drugs that have been used for many years for pregnancy-induced hypertensive states include hydralazine, phentolamine, diazoxide and labetalol.⁴¹

ACE inhibitors and angiotensin receptor blockers are contraindicated in pregnancy. This is discussed in Chapter 55.

DRUG INTERACTIONS

Severe rebound hypertension may result following abrupt cessation of antihypertensive treatment. Drugs associated with this discontinuation syndrome include clonidine, methyldopa, β-blockers, guanethidine and diuretics. The degree of rebound depends on the rapidity of drug withdrawal, dosage, renovascular and cardiac function. Antihypertensives should be reintroduced according the status of the patient and the degree of hypertension managed accordingly.

Interaction with monoamine oxidase inhibitors and drugs such as indirect sympathomimetics, narcotics and tyramine-containing foods may result in a hypertensive emergency. This is best managed acutely with α- and/or β-blockers.