Drugs for intraoperative hypotension

Question 1

Sodium nitroprusside

Answer 1

Direct vasodilator. Potent and short acting. Difficult to administer and concerns about cyanide toxicity.

This is presented as a lyophilised reddish-brown powder containing 50 mg of SNP. When reconstituted in 5% dextrose it makes a light orange solution with pH 4.5. If exposed to sunlight it will turn dark brown due to the liberation of cyanide (CN-) ions and so it must be protected with aluminium foil.

The rate of infusion should start at 0.3 μg/kg/min and increase to a maximum of 10 μg/kg/min, titrated to effect. Treatment must be limited to the shortest exposure necessary.

Question 2

Sodium nitroprusside mechanism of action

Answer 2

Inorganic complex- pre drug.
Vasodilates the arteries and veins by producing NO.

Nitroprusside reacts rapidly with oxyhaemoglobin and oxidises the haem ion to its ferric state (methaemoglobin) with the release of NO and cyanide (CN).

The NO diffuses rapidly through the endothelium and activates guanylate cyclase leading to increased cyclic GMP in cells by the conversion of guanosine triphosphate.

The influx of calcium ions into vascular smooth muscle is inhibited, however uptake into smooth endoplasmic reticulum is increased, so cytoplasmic levels fall, which results in vasodilation via smooth muscle relaxation.

Question 3

Sodium nitroprusside effects

Answer 3

Reduced SVR and drop in BP. Reduced preload.
CO maintained by reflex tachycardia (can develop tachyphylaxis).

May inhibit pulmonary hypoxic vasoconstriction and so may need extra oxygen.

Plasma catecholamine and renin levels rise during infusion (rebound hypertension).

Paralytic ileus, N&V, dizziness, abdo pain, muscle twitching.
Cyanide toxicity.

Question 4

Glyceryl Trinitrate

Answer 4

Organic nitrate. Primarily dilates capacitance vessels (venules), arterial vasodilation can occur at higher concentrations.

Question 5

GTN presentation

Answer 5

The recommended concentration for infusion is 100 μg/ml.

GTN is adsorbed onto plastic bags and giving sets (polyvinyl chloride) and so should be infused from a glass bottle or from polyethylene syringes and infusion lines. Although the recommended concentration for infusion is 100 μg/ml diluted with either 0.9% sodium chloride (NaCl) or 5% glucose, it is acceptable to give the 1 mg/ml solution undiluted via a syringe driver.

The dose starts at 2 μg/kg/min (8.4 ml/h of a 1 mg/ml solution for a 70 kg patient) and is titrated up or down as needed. Onset time is very rapid and its maximum effect is seen in 90-120 seconds.

Question 6

GTN mechanism of action

Answer 6

GTN vasodilates veins by the production of NO. GTN is converted to NO in the mitochondria through the action of mitochondrial aldehyde dehydrogenase 2 (mADH2) to produce glyceryl dinitrate (GDN) and NO.

GTN is similar to SNP in that they are both prodrugs working through the metabolite NO, which stimulates GC leading to an increase in cGMP and smooth muscle relaxation.

Question 7

Effects of GTN

Answer 7

Despite a similar mechanism of action to SNP, GTN produces vasodilation mainly in the capacitance vessels (veins), although arteries are dilated to some extent. Thus, GTN reduces preload, venous return, ventricular end-diastolic pressure and wall tension. Myocardial oxygen demand is reduced and coronary blood flow is increased to subendocardial regions (hence the use in angina and cardiac failure).

Question 8

Advantages of GTN

Answer 8

Rapid onset
Easily titrated to effect
Improves coronary blood flow

Question 9

Disadvantages of GTN

Answer 9

Reflex tachycardia
Tachyphylaxis
Rebound hypertension, less pronounced than with SNP
Headache
Very high dose and prolonged administration may cause methaemoglobinaemia

Question 10

What is hydralazine?

Answer 10

Hydralazine is principally an arteriodilator. It is most frequently used as an oral hypotensive agent in the treatment of pre-eclampsia. However, it can also be given IV and, unlike SNP, does not have any toxic metabolites.

Question 11

Hydralazine presentation

Answer 11

Hydralazine is often given in repeated bolus doses, since its duration of action is longer than for the IV nitrates. Slower onset of action: five minutes before the peak effect is seen.

20 mg of dry powder in an ampoule and reconstituted with water to give the required dilution.

IV injection in doses of 2-4 mg and repeated as necessary always bearing in mind the slow onset of action. It can also be given by infusion starting at a rate of 200-300 μg/min, decreasing to maintenance of 50-150 μg/min.

Pharmacogenetic variability affects the bioavailability of hydralazine when given orally, but is less important when used intravenously.

Question 12

Hydralazine mechanism of action

Answer 12

The mechanism of action is unknown, but is postulated to involve the activation of guanylate cyclase and increase in intracellular cGMP. This leads to a decrease in intracellular calcium and vasodilation.

Question 13

Advantages of hydralazine

Answer 13

No rebound hypertension on cessation
No toxic metabolites
Unlikely to cause postural hypotension

Question 14

Disadvantages of hydralazine

Answer 14

Slow onset and offset
Tachycardia
Fluid retention and oedema
Nausea and vomiting
Approximately 50% of Caucasians are slow acetylators due to a genetic polymorphism in the gene responsible for N-acetyl transferase-2 enzyme on chromosome 8. This can lead to enhanced hydralazine plasma level and effects
Long-term use is associated with a systemic lupus erythematosus (SLE)-like syndrome

Question 15

Magnesium

Answer 15

Magnesium is the 4th most plentiful cation (after Na, K, Ca) in the body. The ionised fraction is physiologically active. An arteriolar vasodilator with minimal effects on the venous circulation.

Magnesium has proven particularly useful in the management of blood pressure during surgery for phaeochromocytoma

Question 16

Magnesium presentation

Answer 16

2 ml, 5 ml and 10 ml ampoules of of 50% magnesium sulphate are available.

2 ml = 1 g = 4 mmol MgSO4.

A loading dose of 40-60 mg/kg of the sulphate followed by an infusion of 1-2 g/h, is designed to achieve serum magnesium concentrations between 2-4 mmol/L.

Question 17

Magnesium mechanism of action

Answer 17

Magnesium is a physiological antagonist of calcium at the presynaptic adrenergic terminal and in vascular smooth muscle cells.

Question 18

Effects of magnesium

Answer 18

Magnesium exerts a direct depressant effect on myocardial and vascular smooth muscle. It inhibits the release of catecholamines from the adrenal medulla and peripheral adrenergic terminals, and directly blocks catecholamine receptors. As a result, cardiac output and vascular tone are reduced, resulting in hypotension and decreased pulmonary vascular resistance.

Other effects include antiarrhythmic activity, anticonvulsant activity, muscle weakness, bronchodilation, respiratory muscle weakness, reduced uterine tone and impaired platelet activity.

Question 19

Advantages of Mg

Answer 19

Non-toxic
Inexpensive
Stabilises cardiac rhythm

Question 20

Disadvantages of Mg

Answer 20

Impairs atrioventricular conduction
Augments neuromuscular block

Question 21

Phentolamine

Answer 21

The only IV α-adrenoceptor antagonist used for intraoperative hypotension is phentolamine. This imidazolone is a competitive non-selective ɑ-blocker, with an affinity for ɑ1-adrenoreceptors of three times that of ɑ2-adrenoreceptors.

Used in hypertensive crises due to excessive sympathomimetics, MAOI reactions with tyramine and pheochromocytoma, especially during tumour manipulation.

Question 22

Phentolamine mechanism of action

Answer 22

Noradrenaline binds to post-synaptic ɑ1 receptors and, via second messenger, intracellular calcium is increased leading to smooth muscle contraction and vasoconstriction. Phentolamine blocks these receptors causing a marked reduction in systemic vascular resistance.

Advantages: No toxic metabolites

Disadvantages:
Reflex tachycardia
Possible cardiac ischaemia
Marked congestion of nasal mucosa

Question 23

Esmolol

Answer 23

The effects of catecholamines are antagonised by β-blockers. These induce a bradycardia (by prolonging diastolic depolarisation in phase 4), reduce myocardial contractility and prolong AV conduction.

Esmolol is a relatively cardio-selective β-blocker with a rapid onset and offset. Esmolol may be given as a slow IV bolus of 0.5 mg/kg, repeated every 10-15 minutes or as an infusion of up to 300 μg/kg/min titrated to effect.

Esmolol is relatively selective for β1-adrenergic receptors, but β2 antagonism can be seen when large doses are used. It should be used with caution in asthmatics.

Esmolol has a short duration of action because it is an ester and is rapidly hydrolysed by red blood cell esterases. There are no toxic or active metabolites.

It is also important to know that esmolol solution contains propylene glycol, which may cause a metabolic acidosis during prolonged infusions.

Question 24

Labetalol

Answer 24

Labetalol is a competitive antagonist at both β and α1 receptors in a ratio of about 7:1, so it is primarily a β antagonist. It has a slower onset and offset of effect than esmolol. Selective α1 blockade produces peripheral vasodilation while beta blockade prevents reflex tachycardia. The α1 effect of labetalol reduces systemic vascular resistance, which preserves renal blood flow.

Ampoules contain 20 ml of 5 mg/ml of labetalol. It can be given by intermittent bolus dose of 10-20 mg repeated every 5-10 minutes as required or as an infusion at 1-2 mg/kg/h.

Onset is variable, but usually within 5-10 minutes. Unlike esmolol, labetalol is not an ester and undergoes hepatic metabolism with a half-life of 4-6 hours.

Labetalol is the most commonly used hypotensive agent for use in pregnancy. Bronchospasm and Raynaud’s phenomenon may occur less frequently than with esmolol.

Severe hepatocellular damage has been reported after administration.

Question 25

Remifentanil

Answer 25

Pure mu receptor agonist. A synthetic phenylpiperidine derivative of fentanyl with a similar potency.

Remifentanil is presented as a crystalline white powder in glass vials of 1, 2 or 5mg of remifentanil hydrochloride. It also contains glycine and is not licensed for spinal or epidural use.

Question 26

Effects of remifentanil

Answer 26

In addition to its opioid activity reducing sympathetic outflow in response to surgical nociceptive stimulation, remifentanil seems to reduce peripheral vascular tone directly, possibly by calcium antagonism, and also indirectly through an endothelium-dependent mechanism. Its very short duration of action facilitates control of a bradycardic, hypotensive anaesthetic with a good surgical field.

Although remifentanil does not cause myocardial depression, conduction is impaired and complete block can be induced with large doses. Remifentanil has been associated with post-operative shivering and postoperative hyperalgesia, but the clinical significance of postoperative hyperalgesia remains unclear. It is also associated with respiratory depression and chest wall rigidity.

Question 27

Nicardipine

Answer 27

For control intraoperatively, the calcium channel blockers available in IV form may be used. Of these, verapamil has too great an effect on the conducting system of the heart to be used as a deliberate hypotensive agent.

Dihydropyridines are more appropriate. Nicardipine is a dihydropyridine L-type calcium channel blocker that has been used to induce hypotension during anaesthesia, though this practice lies outside its recommended indications, i.e. malignant hypertension, aortic dissection, severe pre-eclampsia and postoperative hypertension. It reduces systemic vascular resistance with little cardiac effect, so heart rate and cardiac output are likely to increase.

A tri-exponential elimination has been demonstrated so the half-life is context-sensitive: initial redistribution t½α 3 minutes, elimination t½β 44 minutes, terminal elimination t½γ 14 hours. Nicardipine is given by infusion. More than 95% is protein bound.

Caution is advised in patients with hepatic impairment because it is metabolised by P450 cytochromes in the liver. Clearance is reduced in the presence of renal impairment, though only tiny amounts appear in urine.

Question 28

Clonidine

Answer 28

Dexmedetomidine and clonidine are imidazole compounds with agonist activity at central imidazole receptors and α-adrenoceptors.

Clonidine is an alpha-agonist with an affinity for α-2 receptors 200 times that for α1 receptors. It is a partial agonist.

It stimulates receptors in the lateral reticular nucleus resulting in reduced central sympathetic outflow, and in the spinal cord where they augment endogenous opioid release and modulate the descending noradrenergic pathways involved in spinal nociceptive processing.

Transmembrane signalling of α2 receptors is coupled to Gi, leading to reduced intracellular cAMP. Potassium channels are also activated.

Rebound hypertension may be seen when stopped abruptly, particular when high doses are used. It also has sedative and analgesia effects.

Elimination half-life is 9-18 hours. 50% is metabolised in the liver to inactive metabolites and 50% excreted unchanged in the urine. The dose should be reduced in renal impairment.

Question 29

Dexmedetomidine

Answer 29

Dexmedetomidine has a mechanism of action similar to that of clonidine, though it is more potent and has a higher affinity for the α2 receptor (α2:α1 ratio 1600:1).

It has an elimination half-time of about 2 hours and is the preferred agent for induced hypotension. During anaesthesia, the observed effect is bradycardia and hypotension (similar to a β-blocker) because the sympathetic outflow is reduced.

Given by infusion, it has been used successfully to induce intraoperative hypotension with similar effects to esmolol but with a slower recovery.

Proponents of dexmedetomidine claim other benefits, including analgesia, anaesthetic sparing effects and possible neurological protection.

Question 30

Volatiles

Answer 30

Hypotension occurs due to both negative inotropy and peripheral vascular dilatation. The relative contribution of these two factors depends on the agent used.

Halothane produces more negative inotropy, whereas sevoflurane, isoflurane and desflurane produce a greater degree of peripheral vascular dilatation and reflex tachycardia. The hypotension produced may be accompanied by loss of autoregulation of blood flow to vital organs, particularly the brain.

In comparison with infusions of more specific hypotensive agents, control of blood pressure is less predictable.

Question 31

Propofol

Answer 31

Propofol reduces systemic vascular resistance as well as having a small depressant effect on the myocardium. Propofol also depresses the autonomic-mediated baroreceptor reflex. Propofol alone is as crude a hypotensive agent as deep volatile anaesthesia.

Question 32

Ganglion blockers

Answer 32

Ganglion blockers are no longer available in the UK but they have been used extensively in the past.

They are competitive antagonists at the nicotinic acetylcholine receptors in autonomic ganglia, both sympathetic and parasympathetic. Loss of sympathetic tone in arterioles results in hypotension with minimal reflex tachycardia as the parasympathetic cardiac ganglia are also blocked.

Pentolinium was usually given as multiple small boluses, each lasting 20-40 minutes. Trimetaphan, known as trimethaphan in the US, was given by infusion and the hypotensive effect was augmented by histamine release.

Prolonged use was associated with neuromuscular blockade.

Question 33

Phaeochromocytoma

Answer 33

Phaeochromocytomas are neoplasms of chromaffin tissue that synthesise catecholamines. Symptoms include the classic triad of headache, palpitations, and sweating. Hypertension is present in around 90% of cases, although it is paroxysmal in 35-50% of these.

Preoperative medical therapy focused on reducing the physiological impact of excess circulating catecholamines.

There is no universally accepted regimen and clinical practice varies. Combined α- and Β-adrenergic blockade is the most commonly implemented strategy.

Question 34

Alpha blockade in phaeochromocytoma

Answer 34

Several different α-adrenergic blocking medications may be administered preoperatively for phaeochromocytoma resection and none is clearly superior to others. This was demonstrated by the PRESCRIPT trial. These medications prevent or mitigate hypertension during surgery prior to clamping of the effluent venous drainage from the tumour, but they can cause hypotension after that point, when catecholamine secretion drops precipitously.

Question 35

Phenoxybenzamine in phaeochromocytoma

Answer 35

Phenoxybenzamine is an irreversible, long-acting, nonspecific α-adrenergic blocking agent. It effectively prevents intraoperative hypertension but its long duration of action means the return of normal adrenal function can be delayed. Blood pressure support may therefore be required in the postoperative period. It should be stopped 24-48 hours before surgery.

Question 36

Doxazosin in phaeochromocytoma

Answer 36

In contrast to phenoxybenzamine, selective α1 blockers, e.g. doxazosin, prazosin, terazosin, are reversible and are shorter-acting. Doxazosin does not cause tachycardia or sedation and some studies suggest a reduced incidence of postoperative hypotension, making it a good alternative to phenoxybenzamine.

Question 37

Beta blockade in phaeochromocytoma

Answer 37

For patients with tachycardia or arrhythmias, beta blockade is typically added cautiously several days before surgery. The Β-adrenergic blocker should never be started before the α blocker as further elevation in blood pressure and even cardiac failure can be precipitated by blockade of vasodilatory peripheral Β2-adrenergic receptors with unopposed α-adrenergic stimulation.

Β blockade is especially important for patients presenting with tachyarrhythmias, due to high adrenaline secretion from the tumour.

Β blockade is started at a low dose using short-acting oral medication, e.g. metoprolol. If tolerated, longer-acting and higher-dose medication is added.

Complications may occur in patients with asthma or congestive heart failure.

Patients with occult catecholamine-induced cardiomyopathy are at risk of congestive heart failure and pulmonary oedema.

Question 38

CCBs in phaeochromocytoma

Answer 38

e.g. nicardipine, are sometimes used to supplement combined alpha and beta blockade

Calcium channel blockers inhibit noradrenaline-induced calcium influx and have been utilised for haemodynamic control before surgery, mainly as an additional drug class to further improve control in those already α-blocked.

They are not recommended for monotherapy unless patients have very mild hypertension or develop severe orthostatic hypotension with α-blockers.

Sustained-release nicardipine 30 mg twice daily is a commonly used preparation.

Question 39

Intraoperative immediate control of BP in phaeochromocytoma

Answer 39

Patients with phaeochromocytoma may demonstrate profound blood pressure lability. Risk factors include high pre-induction plasma noradrenaline levels, large tumour size, profound postural drop after commencement of α-blockade and a pre-induction mean arterial pressure (MAP) above 100 mmHg.

Prevention: Mg, remi, dexmedetomidine

Immediate:
GTN, nicardipine or esmolol, sodium nitroprusside