Vasodilators and antihypertensives

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 Ch. 90, Fig. 90.2).

Endothelial system

The endothelium plays 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 and diffuses into underlying smooth muscle where it activates guanylate cyclase to increase cyclic guanosine monophosphate (cGMP) resulting 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.

Endothelins are endothelium-derived vasoconstrictor peptides that are associated with increases in vascular smooth muscle intracellular calcium. They bind to endothelin receptors within the vascular smooth muscle and lead to vasoconstriction, usually in response to shear stresses, tissue hypoxia, angiotensin II and inflammatory mediators (e.g. interleukin-6 and nuclear factor-κB (NF-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 alpha-adrenergic (α-adrenergic) receptors on vascular smooth muscle and a direct effect in the endothelium. These effects are directed at maintaining 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 90.

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 can be 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, which 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 beta blockade. For this reason, the use of sublingual nifedipine as a method of treating hypertensive emergencies is no longer recommended.⁸

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.⁹ 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.

The recommended dose following aneurysmal subarachnoid haemorrhage is 60 mg orally 4-hourly, but it can be given at 30 mg 2-hourly to reduce variation in blood pressure. The use of intravenous nimodipine is not recommended owing to its profound effect on blood pressure.

Amlodipine

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.¹⁰ 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 beta blockers or digoxin is not recommended.

Verapamil is not as active as nifedipine in its effects on smooth muscle and it therefore causes less pronounced decrease in systemic blood pressure and is also negatively inotropic. It has a limited role as a vasodilator.¹¹

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 less likely to potentiate beta 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.¹²

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,¹³ perioperative management of phaeochromocytoma¹⁴ and treatment of autonomic dysfunction in tetanus.¹⁵ It has been proposed as a possible agent for the prevention of secondary ischaemia after aneurysmal subarachnoid haemorrhage; however, evidence of a benefit on outcome is still lacking.¹⁶

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 so it requires protection from exposure to light (e.g. 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.

Dosage is from 0.5 µg/kg/min to 8 µg/kg/min, but should always start at a low infusion rate and build up slowly.

Onset of action is almost immediate with a transient duration, requiring continuous intravenous infusion to maintain a therapeutic effect. Tachyphylaxis can occur and 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 may potentially 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.¹⁸

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 of concern 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 nitrite may be infused (5 mg/kg) to produce methaemoglobin and subsequently cyanmethaemoglobin. Hydroxycobalamin, which binds cyanide to produce cyanocobalamin, may also be administered (5 g over 15 minutes, which may be repeated in severe cases).

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. The intravenous dosage can start at 5 µg/min and increase incrementally to 200 µg/min (max dose 400 µg /min). 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 preload. Together with furosemide, glyceryl trinitrate is particularly useful in treating acute cardiac failure and pulmonary oedema.

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, which may cause a coronary steal phenomenon.

Reductions in blood pressure are more dependent on blood volume than with 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. More recently glyceryl trinitrate has been suggested as one approach to improve microcirculatory flow in septic shock, but only after adequate fluid resuscitation.¹⁹

Glyceryl trinitrate is a cerebral vasodilator and should be used with caution in patients with known or suspected raised intracranial pressure. 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.²⁰

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, 5–10 mg intravenously, hydralazine has a rapid onset of action, usually within 5–10 minutes. It can alternatively be given by continuous intravenous infusion, initially 200–300 µg/min and maintenance usually 50–150 µg/min, and may also be administered orally. The drug is partially metabolised by acetylation, for which there is marked inter-individual variability (35% of the population are slow acetylators). Although this does not have much clinical significance regarding the antihypertensive effects, it is important with respect to toxicity.²⁰

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 beta blockers and/or diuretics.

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

Phentolamine

Phentolamine is a non-selective, competitive antagonist at α₁- and α₂-receptors. At low doses, phentolamine causes prejunctional inhibition of norepinephrine (noradrenaline) release (via α₂-receptor inhibition). At higher doses, more complete α-receptor blockade is achieved, with enhancement of effects of beta agonists due to increased local concentration of norepinephrine produced by α₂-blockade (see Ch. 90, Fig. 90.3a).

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. 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 norepinephrine is blocked, thereby potentiating the effects of beta agonists.

Phenoxybenzamine is usually administered orally, but may also be given intravenously (taking care to avoid extravasation as it is irritant to tissues). 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 beta-adrenergic effects, predominantly increased heart rate, for which combination therapy with beta 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.²¹

Prazosin

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

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

Labetalol

Labetalol is specific competitive antagonist at α₁-, β₁- and β₂-adrenergic receptors. Beta blockade effects predominate, with a approximate ratio of α₁ : β-receptor blockade of 1 : 4–7. Labetalol has partial agonist effects on β₂-receptors.

It is administered intravenously (typically 10–50 mg), has a rapid onset of action (5–10 minutes) with a duration of 2–6 hours. It may be given by infusion (usually 15–180 mg/h).

Systemic blood pressure and cardiac output are reduced by a combination of negative inotropy, arterial and venous vasodilatation. Reflex tachycardia is attenuated by beta blockade. These properties make labetalol particularly useful in controlled hypotension during anaesthesia and surgery to reduce bleeding.

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

Carvedilol

Carvedilol is a non-selective beta 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.^22,23 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 norepinephrine 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 has a short half-life and therefore may be useful for initiating treatment within the ICU. 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, and duration of 4 hours. There are no significant differences in the cardiovascular effects between captopril and other preparations.

Enalapril is a prodrug, 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.²⁶

‘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 kidney injury. The renal effects of ACE inhibitors may be potentiated by diuretics, non-steroidal anti-inflammatory drugs and beta blockers. ACE inhibitors are contraindicated in patients with bilateral renal artery stenosis.

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. Initial doses should be low and increased as tolerated.

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.²⁷

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 oedema²⁸ and should be avoided in pregnancy.

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

Clonidine

Clonidine is a centrally acting α₂-agonist that stimulates inhibitory neurons 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 norepinephrine 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 can be administered orally (50–100 µg 8-hourly) or by intravenous injection (25–150 µg) or by infusion (maximum 750 µg in 24 hours). It has a rapid onset of action (5–10 minutes) and duration of action of 20–30 minutes.

Methyldopa

Methyldopa acts as a centrally acting ‘false’ transmitter following metabolism to methylnorepinephrine and subsequent stimulation of α₂-receptors leading to reduced sympathetic outflow, although the precise mechanism is not clear.

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 3 g per day although side-effects (abnormal function, depression) may be minimised if the daily dose is <1 g. It may lead to a positive direct Coombs test in 20% of patients.

Beta-adrenergic antagonists

Beta 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.^32–34 Although no longer recommended as first-step treatment of hypertension they may be used if ACE inhibitors are poorly tolerated.⁷

In addition to decreasing heart rate and contractility, beta blockers have other neurohumoral effects that affect vascular tone. These relate to inhibition of renin release from juxtaglomerular cells (see Fig. 91.1) and prejunctional inhibition of norepinephrine that result in reduction in vascular tone and blood pressure. A central effect of beta blockers has also been proposed.

The mode of action has been described in terms of selectivity to blockade of beta-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 beta blockers will cause generalised antagonism with resultant therapeutic and toxic effects.

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

Beta 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 beta blocker that is rapidly metabolised by red cell esterases and is therefore not dependent on renal or hepatic function. 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.

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

Side-effects and toxicity of beta blockers include bradycardia (which may be profound), hypotension, bronchoconstriction (caution in patients who have asthma), aggravation of peripheral vascular ischaemia, hyperkalaemia and masking of the sympathetic response to hypoglycaemia.

Diuretics

As with beta 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 norepinephrine-activated chloride channels 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 if hypovolaemia is present or suspected.

Pulmonary Vasodilators

Pulmonary vasodilators may be used in the ICU mainly to treat acute right-sided heart failure commonly after cardiac surgery/transplantation. Many of the systemic vasodilators detailed above (namely calcium channel blockers, sodium nitroprusside and nitrates) will also have vasodilatory effects within the pulmonary circulation. Specific pulmonary vasodilators may be inhaled or administered intravenously.

Nitric Oxide

As detailed above, nitric oxide (NO) is an endogenous vasodilator. When inhaled it leads to vasodilation in only the ventilated areas of the lung, and rapid combination with haemoglobin prevents systemic vasodilation. This may improve ventilation–perfusion mismatch resulting in an improved oxygenation but controlled trials have not demonstrated any beneficial effect on outcomes in severe acute lung injury and it may have an adverse effect on kidney function.³⁵ Its use is now mainly confined to treatment of acute pulmonary hypertension post cardiac surgery.

NO is oxidated to NO₂ particularly in a high-oxygen environment and therefore NO₂ levels should be carefully monitored. Similarly appropriate scavenging systems must be employed.

Rebound pulmonary hypertension may occur and so NO therapy should be slowly weaned rather than abruptly stopped.

Prostacyclin

Inhaled epoprostenol or iloprost (a prostacyclin derivative) can be used as alternatives to NO. Care should be taken to avoid systemic hypotension.

Sildenafil

Sildenafil is a phosphodiesterase type 5 inhibitor used in the management of chronic pulmonary hypertension, as well as erectile dysfunction. There are reports of its use for acute pulmonary hypertension within the ICU and that it can improve haemodynamics, however, by increasing shunt fraction it might worsen oxygenation when used in acute lung injury.³⁶

Monitoring

The principles of haemodynamic monitoring in patients receiving vasoactive drugs are outlined in Chapter 90.

Patients with severe hypertension or those receiving infusions or doses of potent vasodilators such as sodium nitroprusside and glyceryl trinitrate must be monitored via an intra-arterial catheter. Non-invasive measurement devices are not rapid or accurate enough and are not recommended in patients with hypertensive emergencies.

As peripheral vasodilators have significant effects on both the arterial and venous systems, assessment 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. Common drug doses are shown in Table 91.1.

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 beta blockers. The majority of instances of acute hypertension in the ICU will respond to simple measures addressing the above.³⁸

Sustained hypertension may be treated acutely with incremental doses or infusions of short-acting drugs such as glyceryl trinitrate, sodium nitroprusside, labetalol, 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 beta 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 and it may be the rate of increase of blood pressure that is more important than the absolute value. It may present as confusion, visual disturbances, blindness, seizures or stroke. Uncontrolled hypertension is one of the causes of the posterior reversible encephalopathy syndrome (PRES), along with pre-eclampsia, immunosuppressant drugs and sepsis. If not adequately treated, hypertensive encephalopathy may result in intracerebral haemorrhage, coma or death.³⁹

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. It is also important to rule out other causes of neurological deterioration that may also present with hypertension (e.g. stroke, intracranial haemorrhage or space-occupying lesion).

There is no evidence from randomised controlled trials to conclude one therapy is superior to another at improving outcomes. 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. Assuming there are no absolute contraindications to beta blockers, labetalol and esmolol are ideal drugs to use. Sodium nitroprusside can be used although it may increase intracranial pressure and reduce cerebral blood flow. Phentolamine may be equally effective.^8,36

Other agents that are useful in controlling severe hypertension include hydralazine, clonidine and ACE inhibitors (although these must be used cautiously in patients with associated renal dysfunction). Severe drops in blood pressure that might compromise end-organ perfusion have been reported after the use of nifedipine and therefore its use in the emergency setting is not recommended.⁸ Combination therapy is often 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.⁴⁰

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 brain is vulnerable to critical reductions in cerebral blood flow, while excessive mean arterial pressure may increase the risk of cerebral haemorrhage.⁴¹

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. The aim of medical treatment is to control blood pressure and left ventricular ejection velocity to minimise propagation of the dissection. Blood pressure should be decreased as rapidly as possible to a normal or slightly hypotensive level. 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.⁴²

This is best achieved initially by use of opioid analgesia, intravenous beta blockers (e.g. esmolol, labetalol or atenolol), and possibly adding a vasodilator 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. Verapamil or diltiazem are suitable alternatives for patients who have a contraindication to beta blockade.

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 beta 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.⁴³

Acute hypertensive crises associated with phaeochromocytoma are managed with incremental doses or infusions of phentolamine. Untreated patients may be significantly hypovolaemic and may require judicious volume replacement. Beta blockers should not be used in the acute setting as these will potentiate unopposed alpha-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 beta-adrenergic effects are treated with beta blockers only after sufficient alpha blockade with phenoxybenzamine.²¹

Magnesium sulphate is useful in the perioperative management of phaeochromocytoma. It is given by infusion at 2–4 g/hour.¹⁴

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 channel blockers, 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.⁴⁴

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 encephalopathy¹³). The recommended drugs for the treatment of severe hypertension in critically ill women during pregnancy or soon after birth include labetalol, hydralazine and nifedipine.⁴⁵

ACE inhibitors and angiotensin receptor blockers are contraindicated in pregnancy. This is discussed in Chapter 63.

Drug interactions

Severe rebound hypertension may result following abrupt cessation of antihypertensive treatment. Drugs associated with this discontinuation syndrome include clonidine, methyldopa, beta 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 to 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 alpha and/or beta blockers.

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