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What is this Adenosine stuff?

Robert Lang MB, BS.
Anaesthetics Registrar (formerly Emergency Medicine Registrar) Adelaide

Australasian Anaesthesia, 1998


* Introduction * Pharmacokinetics
* Physiology of Adenosine * Clinical Uses
* Receptors * Conclusions
* Adenosine receptors * References

Introduction

Adenosine is not a new compound. The physiological effects of adenosine on the heart were first described in 1928. From the 1950’s onwards, in Europe especially, adenosine and adenosine triphosphate (ATP) were used to treat supraventricular tachycardia (SVT). ATP had been incidentally found to be effective for SVT during a trial of ATP for the treatment of rheumatoid arthritis.

Adenosine is a naturally-occuring purine nucleoside, present in all metabolising cells of the body. It is both a metabolite and a precursor of ATP, adenosine diphosphate (ADP) and adenosine monophosphate (AMP). Extracellularly, it has a large number of physiological roles in most organ systems of the body. In particular, it is an important vasodilator in the microcirculation and has potent negative chronotropic, dromotropic and inotropic effects on the heart.

In recent years, adenosine has been marketed as a drug for the emergency treatment of paroxysmal supraventricular tachycardia and is now accepted as the drug of choice for this condition in the Advanced Cardiac Life Support (ACLS) protocols. As experience with adenosine grows, more and more uses are being found. This article discusses these novel applications, with a emphasis on those relevant to anaesthesia.[Top]

Physiology of Adenosine

All metabolically active cells utilise ATP for energy, by progressive dephosphorylation to ADP, AMP and adenosine. Furthermore, the ATP and AMP that escape the cell are broken down to adenosine by ecto-nucleotidases present on endothelial cell walls. ATP is replenished in cells by the uptake of adenosine and phosphorylation, the process requiring oxygen. Itthen follows that those tissues most metabolically active, and those with a relative oxygen deficit, will have the highest concentrations of free adenosine.

This simple principle lies behind adenosine’s importance as a natural negative feedback modulator, or “retaliatory metabolite”. High concentrations of free adenosine signal an imbalance between tissue metabolic rate and oxygen supply, and mediates responses to rectify the imbalance. In the microcirculation, adenosine is thought to be the most important of the mediators of autoregulation. At times of high activity, ATP usage increases, adenosine concentrations rise, causing a compensatory vasodilation, thus increasing oxygen supply to the tissues. In the acutely ischaemic heart, not only does adenosine vasodilate the coronary circulation, but also acts on the sinus node and AV nodes to produce a degree of bradycardia, and has a negative inotropic action on the atria, ultimately decreasing myocardial work.

In the kidney, adenosine constricts the afferent arteriole and dilates the efferent arteriole. This decreases glomerular filtration rate and increases oxygen delivery to the renal medulla. Furthermore, adenosine and ATP are also mediators of cardiovascular function via the autonomic nervous system. Adenosine potentiates the effect of acetylcholine on the heart. Thus, in the presence of vagal tone, adenosine enhaces the bradycardia. It also acts on the carotid body to stimulate respiration and decrease blood pressure and heart rate. Adenosine has actions at a presynaptic level by attenuating the release of noradrenaline. It is also thought to mediate the pain of cardiac ischaemia. There is much evidence to suggest that adenosine is an important mediator of neural transmission in the central nervous system, but its exact role has yet to be clarified.[Top]

Adenosine Receptors 1

Adenosine receptors are a subtype of the family of purinoreceptors. These receptors are distinguished by their differing affinities for purine analogues, their varied physiological actions and more recently, their amino acid sequences. The purinoreceptors are divided into the following categories.

Purinoreceptors - P1 - sensitive to adenosine

further divided into A1, A2A, A2B, A3

P2 - sensitive to ATP

Adenosine A1 receptor

The A1 receptor can be thought of as the cardiac adenosine receptor. Although found in high concentrations in parts of the brain, spinal cord, testis, and kidney, it is in the heart that this receptor has its most obvious clinical effect. In all these tissues, they are tightly coupled to G proteins, and mediate inhibition of adenylyl cyclase, causing a decreased production of cyclic AMP. In atrial and nodal tissues, this has the effect of increasing the outward potassium current, hyperpolarising the cell membrane and making it more resistant to action potential formation. Ultimately, this slows the sinus node, slows AV conduction and has a negative inotropic effect. This effect is very similar to the effect of acetylcholine (ACh) on the heart, independent of the ACh receptor, but coupled to the same second messenger system. The methylxanthines, caffeine and theophylline, are competitive inhibitors of this receptor. The role of the adenosine A1 receptor in the other organ systems of the body is under intense scrutiny.

Adenosine A2A receptor

In contrast to the A1 receptor, the A2 receptors mediate stimulation of adenylyl cyclase and, thus, an increase in cyclic AMP within cells. The A2A receptor is found in high concentrations in the dopamine-rich areas of the brain, on endothelial cells, including the coronary circulation, and on platelets. Activation of these receptors is thought to mediate the vasodilation response to adenosine. There is some evidence that this occurs via the formation of nitric oxide in the endothelial cell. In platelets, the stimulation of A2A receptors inhibits aggregation.

Adenosine A2B receptor

The A2B receptor is found in high concentrations in the gastrointestinal tract, where it may mediate chloride secretion by the epithelial cells. It is also found in lower concentrations in many other tissues, including the heart, but its function here is largely unknown.

Adenosine A3 receptor

This is the most recently cloned of the adenosine receptors, and its physiological role awaits clarification.[Top]

Adenosine Pharmacokinetics

Adenosine has the distinction of having the shortest plasma half life of any drug used in medicine. Intravenously administered adenosine is cleared from the circulation with a plasma half life of between 1 and 6 seconds. It is taken up by all cells, particularly endothelial and red cells, via a specific transmembrane nucleoside carrier system. Once inside the cell, adenosine is trapped by phosphorylation to AMP via adenosine kinase, or by deamination to inosine via adenosine deaminase. Uptake is inhibited by dipyridamole (Persantin), which probably explains the action of this drug. While cellular uptake is the primary method of adenosine clearance, intravascular adenosine is also metabolised by cell membrane ecto-nucleotidases.

This extremely rapid clearance from the bloodstream has an important implication for the administration of adenosine. It must be given rapidly for enough of the drug to get to the heart, before it is depleted from the circulation.[Top]

Adenosine Clinical Uses

Adenosine is most commonly used for the conversion of SVT to sinus rhythm. In this role it has largely replaced verapamil, although with some exceptions. It is also commonly used to clarify the diagnosis of particular tachyarrhythmias. Both these applications will be further discussed below.

In recent years, as experience with adenosine has grown, and the understanding of the roles of adenosine receptors becomes clearer, the use of adenosine has been investigated in many other clinical, intraoperative and diagnostic areas, including:

  • adenosine as a vasodilator for intra-operative controlled hypotension;
  • adenosine used to ablate the sympathetic response to intubation;
  • adenosine as an additive to cardioplegia during coronary bypass graft surgery;
  • adenosine to induce asystole to assist in aortic aneurysm stent placement;
  • adenosine as a coronary vasodilator during cardiac catheter studies;
  • adenosine as a diagnostic tool in myocardial perfusion imaging;
  • adenosine as a cardioprotectant following acute myocardial infarction; and,
  • adenosine as an analgesic

Adenosine in SVT 2, 3, 4

Supraventricular tachycardia occurs when there exists a re-entrant circuit involving the AV node of the heart. A “short circuit” can develop through this re-entrant pathway, giving rise to a QRS complex and ventricular contraction with every cycle. This commonly results in a tachycardia at a sustained rate of 150 to 250 beats per minute. Patients often tolerate this rate for long periods, but may decompensate quickly if underlying heart failure of ischaemic heart disease exists, necessitating rapid cardioversion.

There are two forms of re-entry. In the most common (about 90%), the re-entrant pathway is entirely contained within the AV node. In the less common form, known as the Wolff-Parkinson-White (WPW) syndrome, there exists an accessory pathway (the Bundle of Kent) located outside the AV node. In this form, atrio-ventricular conduction can occur through this pathway, and is thus not slowed by the AV node. This manifests as a short PR interval on the ECG and is thus also called a pre-excitation syndrome.

An intravenous bolus of adenosine terminates the tachycardia by causing a complete but temporary block of the AV node, interrupting the short circuit. As the adenosine is taken up by the cells, normal conduction is re-established, and sinus rhythm restored. Adenosine is effective for the treatment of both nodal re-entrant SVT and that associated with WPW syndrome.

Method of administration of adenosine

The method of administration of adenosine is different to that for any other drug, and many cases of failure to convert the SVT are related to ineffective administration. Because of its extremely short plasma half life, adenosine must be given as a rapid bolus, through a large bore cannula in a large vein, followed by a rapid flush. Giving adenosine through a central line is more reliable. Initially, the recommended dose of adenosine was 3mg, followed by 6mg if the 3mg was ineffective, followed by 12mg, if the 6mg was ineffective. However, several papers showed that the 3mg dose was rarely effective, so the present recommendation is 6mg, followed by 12mg, and 12mg repeated if the previous doses were ineffective. Doses are halved if given through a central line, and for patients taking dipyridamole. They can be doubled for patients taking theophylline.

Adenosine is also the first line pharmacological treatment of SVT in children, where the dose starts at 0.05mg/kg to 0.25mg/kg. It can be given effectively through an intraosseous needle in the emergency situation 5. Adenosine has also been used in pregnant women, but is classed as a category C drug.

Complications of adenosine 6, 7

Adenosine is a safe drug to use. Because of its rapid uptake into cells, any side effects quickly dissipate. However, all patients experience transient symptoms and, rarely, severe complications can develop.

The most common side effect is bradycardia progressing to a transient asystole. This is caused by the AV nodal block and, depending on the dose of adenosine reaching the heart, the ventricular standstill may persist for up to 15 worrying seconds. Occasionally, the patient may have a syncopal episode. Caution should be used in patients taking dipyridamole, and those with known sick sinus syndrome or heart block, as the asystole may be prolonged. Other arrhythmias can also occur. Premature atrial, junctional and ventricular contractions are common, as are a transient sinus tachycardia, and varying degrees of AV block before full sinus rhythm re-establishes itself. There are several case reports of adenosine-induced atrial fibrillation, 1:1 AV conduction during atrial flutter, ventricular tachycardia and one report of torsades de pointes following adenosine.

Awake patients describe several uncomfortable symptoms, including flushing of the face caused by the vasodilation, a sense of respiratory distress, and an ischaemic-type chest pain (but without evidence of actual ischaemia). It is interesting that, physiologically, adenosine probably mediates the pain of cardiac ischaemia, and dyspnoea, via the carotid body chemoreceptor. Adenosine is contraindicated in the asthmatic patient. Patients often get a transitory bronchoconstriction, but there have been two case reports of severe asthma triggered by adenosine, persisting long after the adenosine had been expected to wear off. Only one of these patients was previously known to be asthmatic. Finally, although adenosine achieves close to 100% conversion to sinus rhythm, a significant percentage of patients will relapse into SVT after the effects of the adenosine wear off. This necessitates further doses or the use of a different class of drug to treat recurrent episodes.

Arrhythmias resistant to adenosine

Adenosine is only effective in arrhythmias involving the AV node.

Thus it is ineffective in:

  • atrial flutter;
  • ventricular fibrillation;
  • ventricular tachycardia;
  • heart blocks; and,
  • sick sinus syndrome.

Comparison with verapamil 4,8

There have been many studies comparing adenosine with verapamil for the treatment of SVT. Conversion rates for adenosine vary from 80% to 100%. This wide variation is probably explained by differences in methodology, especially in the mode of administering the adenosine, and the confidence of the original diagnosis of SVT. Overall, conversion rates for both adenosine (up to 4 doses to 12mg) and verapamil in two large multicenter trials were between 91% and 93%, indicating that the efficacy of adenosine is equal to that of verapamil. However, the onset of action of adenosine was much quicker (30 seconds vs up to 15 minutes for verapamil) and the potential for serious complications was less.

The use of verapamil can be dangerous in particular forms of tachycardia. A patient presenting with an undiagnosed regular broad complex tachycardia may have a supraventricular tachycardia with a conduction defect, or ventricular tachycardia. Giving verapamil in the second instance may cause ventricular depression of an already compromised heart. In this same situation, adenosine will not convert the arrhythmia (it has no effect on VT) but its transitory action will not cause the patient any harm. In a patient with SVT and pre-existing cardiac failure, verapamil may again have hypotensive and negative inotropic effects, which may lead to decompensation despite conversion to a normal sinus rhythm. The same applies to patients already on beta-blockers, who have the risk of complete heart block when given verapamil.

Patients with WPW syndrome deserve special mention. 25% of such patients get episodes of paroxysmal atrial fibrillation. If this is misdiagnosed as SVT and treated with verapamil, there is the risk of the verapamil preferentially blocking the AV node, causing unrestricted conduction of the atrial signals to the ventricles via the accessory pathway. This may result in ventricular rates of up to 300 per minute. While this risk is also present with adenosine (and several cases have been described), it is far less because of the rapid clearing of the drug from the circulation.

Verapamil is probably a safer drug to use than adenosine in asthmatics with SVT. In addition, because of its longer half life, verapamil is probably associated with less relapses of SVT once sinus rhythm is established.

The final difference between verapamil and adenosine relates to the cost. At 1998 prices, a single 5mg ampoule of verapamil costs 25 cents. A 6mg vial of adenosine costs $15, and often three or even five vials are required to convert a patient to sinus rhythm.

Adenosine to aid arrhythmia diagnosis 4,9

There are two situations of ambiguous arrhythmias where adenosine can be a safe and effective means of clarifying the diagnosis.

Broad complex tachycardia

As previously mentioned, a broad complex tachycardia may be SVT with a conduction defect or ventricular tachycardia. Adenosine will convert most cases of the former to sinus rhythm, but have no effect on the latter.

Atrial flutter with block

Atrial flutter often presents with a 2:1 block which may make it look like SVT on an ECG. Adenosine given in this situation will not convert the flutter to sinus rhythm, but by blocking the AV node, increases the ratio of the block, thus revealing the flutter waves. An appropriate drug can then be chosen to treat the flutter.

Adenosine as a hypotensive agent

Induced or controlled hypotension is used in selected types of anaesthesia as a blood conservation technique and to provide the surgeon with a blood-free surgical field. The agents used are vaso- and/or veno- dilators. The ideal agent to produce hypotension would have the following characteristics:

  • an easily controlled dose-dependent response;

  • non-toxic with no accumulation of toxic metabolites;

  • no alteration of blood flow to vital organs;

  • no adverse physiological effects;

  • no tachyphylaxis;

  • be technically easy to administer; and,

  • be inexpensive

Adenosine has been investigated as a vasodilator which has some advantages over previously well-established agents for induced hypotension. It satisfies many, but not all, of the characteristics mentioned.

Characteristics of adenosine as a hypotensive agent 10,11

An intravenous infusion of adenosine acts as a hypotensive agent primarily by its peripheral vasodilating effect, with no effect on the venous capacitance or intrinsic cardiac contractility. Its onset of action is within seconds of commencing the infusion, and its effects disappear within 20-30 seconds of ceasing the infusion. The reduction in blood pressure is titratable and related to the infusion rate. Adenosine is technically easy to administer. In patients undergoing abdominal aortic aneurysm repair under a fentanyl-based anaesthetic, an adenosine infusion rate of 80-100mcg/kg/min achieved a drop in mean arterial blood pressure by about 25% (from 83mmHg to 63mmHg)12. In patients undergoing cerebral aneurysm surgery under neurolept anaesthesia, adenosine infusion rates of 60 to 350mcg/kg/min achieved a more profound drop in mean arterial pressure of 42% (from 79mmHg to 46mmHg 13.

Being an endogenous, rapidly absorbed compound, toxic metabolites do not accumulate, as they do with sodium nitroprusside (SNP). Therefore, the infusion can be continued for very long operative times. Ultimately, adenosine is metabolised to uric acid, and accumulation and renal excretion of urate presents a theoretical limit to its use. Unlike glyceryl trinitrate (GTN), adenosine is not adsorbed by intravenous tubing.

Effects on cardiac output and coronary flow 11, 12, 14

In a study on patients undergoing aortic aneurysm repair, infusions of adenosine and SNP had different effects on myocardial performance. At doses producing satisfactory hypotension, cardiac index remained unchanged with both vasodilators. Heart rate increased with SNP infusion, but remained unchanged with adenosine. Left ventricular stroke work index and myocardial oxygen consumption decreased with the SNP infusion, but were unchanged with adenosine. Coronary sinus flow increased with adenosine, indicating coronary vasodilation, and decreased with SNP. Coronary sinus oxygen content also increased with adenosine and was unaffected with SNP. A second study13 supported these findings, but also showed an increase in cardiac index of 18% with adenosine, presumably secondary to reduced afterload, with no increase in heart rate. Myocardial lactate and oxygen consumption were also monitored and found not to increase.

Effects on cerebral circulation

Cerebral blood flow and cerebral oxygen metabolism during adenosine-induced hypotension was investigated in ten patients undergoing anaesthesia for cerebral aneurysm surgery 14. These patients received a neurolept anaesthetic with controlled ventilation, without volatile agents. The dose of adenosine was titrated to achieve a mean arterial pressure of 46mmHg. No significant change in cerebral blood flow was found. Also, the cerebral AV difference of oxygen decreased by 16% and cerebral AV difference of lactate did not change. The study concluded that, at this level of hypotension, adenosine did not adversely affect cerebral perfusion or oxygenation and may provide a protective effect.

A study on pigs anaesthetised with fentanyl, with controlled ventilation, looked at cerebral blood flow and the ablation of autoregulation by adenosine-induced hypotension15. Once the hypotension was achieved, two formal tests of autoregulation were performed. In the first, angiotensin was infused to elevate mean arterial pressure and, in the second, myocardial filling pressure reduced by caval pressure. The study found that while adenosine-induced hypotension maintains cerebral blood flow, autoregulation is decreased at light hypotension and completely abolished at moderate hypotension.

Effect on the renal circulation

Two common phenomena in other hypotensive agents are tachyphylaxis and rebound hypertension. These are thought to be due to increasing stimulation of the renin-angiotensin-aldosterone system during the period of hypotension, requiring gradually increasing doses of hypotensive agent and resulting in exaggerated hypertension once the hypotensive agent is ceased. In contrast to the other hypotensive agents, adenosine vasoconstricts the renal afferent arteriole causing a dramatic drop in the glomerular filtration rate and urine flow, and inhibiting renin release. Thus the renin-angiotensin-aldosterone system is not turned on, and the dose of adenosine required to maintain the hypotension stays stable. Furthermore, rebound hypertension does not occur on ceasing the infusion 16.

Effect on the hepatic circulation

Adenosine is a powerful vasodilator of the splanchnic circulation. In a study in rats, awake and anaesthetised with halothane and sevoflurane, adenosine-induced hypotension was shown to increase portal and hepatic arterial blood flows in the awake rats, to counteract the decrease in blood flows caused by halothane, and to improve portal blood flows in the sevoflurane group 17. The investigators concluded that the vasodilating effects of adenosine on the hepatic circulation predominate over those of the volatile anaesthetics, and provide a protective effect.

Cost of adenosine infusion

Despite its advantages, the cost of adenosine as an infusion for hypotension remains prohibitive. At $15 for a 6mg vial, running at just 100mcg/kg/min, the cost in a 60kg patient is $15 per minute.

Adenosine and intubation

Laryngoscopy and intubation often provoke a dramatic sympathetic response manifesting as tachycardia, hypertension and even arrhythmias. While this response is usually tolerated well, in those patients with serious cardiovascular disease or those undergoing surgery for cerebral aneurysms, this response may be harmful. Many different pharmacological agents have been investigated and shown to be effective to various extents at ablating this sympathetic response to intubation. These agents include lignocaine, both topical and intravenous, fentanyl, alpha - and beta - blocking agents, and vasodilators such as SNP, GTN, isosorbide dinitrate and prostaglandin E1.

One study investigated the effect of giving ATP, the phosphorylated form of adenosine, at intubation to ablate this sympathetic response.18 The study was performed in two parts. In the first part, 20 patients of ASA status 1 were given a standardised anaesthetic and intubated without ATP. After heart rate and blood pressure had stabilised, they were given an ATP bolus of either 0.05mg/kg or 0.1mg/kg and the effect was monitored. The fall in mean arterial pressure began 30 seconds after administration of ATP and was maximal at 45 seconds. The drop in mean pressure was from 90mmHg to 80mmHg in the first group and to 68mmHg in the second group. In both groups, mean arterial pressures returned to baseline after 1.5 to 4 minutes. The changes in heart rate were not significant. In the second part, 30 patients of ASA status 1 again received a standardised anaesthetic but also were given a bolus of either saline or ATP at 0.05mg/kg or 0.1mg/kg at the commencement of laryngoscopy. Mean arterial pressures increased from a baseline of 92mmHg to 130mmHg in the saline group, to 120mmHg in the 0.05mg/kg ATP group and to 110mmHg in the 0.1mg/kg ATP group. Heart rates increased from 78 beats per minute to 110 beats per minute with all groups and were not statistically different. No arrhythmias were noted and no patient required vasopressors to restore blood pressure.

The study concluded that a single bolus of ATP given at the commencement of larygoscopy is a safe and effective means of decreasing the pressor response to intubation in this group of patients. There was no attempt to compare this effect with those of the other agents mentioned, nor was there any attempt to recreate these findings in patients other than ASA status 1.

Adenosine to induce asystole in aortic stenting

Endoluminal aortic stent grafting was first described in 1991 and has become a common way of treating abdominal aortic aneurysms in many centres. More recently, thoracic aortic aneurysms have also been treated this way. The stent is usually introduced in a contracted state via the femoral artery, carefully positioned under radiological guidance and then expanded to fix the stent in place. Various methods of expanding the stent include a spring-loaded mechanism, a heat-sensitive metal that expands in warmth, and balloon expansion.

Positioning the stent is critical and, once expanded, it is usually very difficult to move. Previously, this procedure has been performed under general anaesthetic with induced hypotension and, occasionally, with cardiopulmonary bypass. The hypotension is necessary to prevent displacement of the stent and strain on the myocardium. At the time that the balloon is expanded, the pressure of blood in the aorta may force the balloon and stent distally. Also, the acute rise in afterload may strain the heart and and the resulting pressure rise may trigger an aortic rupture or dissection.

A study at the Royal Prince Alfred Hospital in Sydney 19 describes three cases of endoluminal thoracic aortic surgery without cardiopulmonary bypass, using a bolus of adenosine to cause transient asystole long enough to expand the balloon and stent. All patients had a general anaesthetic, were heparinised and the dose of adenosine required to produce an asystole of the the required time of 20-30 seconds was determined by giving graded trial doses before the stent had been placed in the critical position. In all three cases, asystole of long enough duration to deploy the stents was produced, and normal sinus rhythm re-established spontaneously. The dose of adenosine required varied from 12mg via a pulmonary artery catheter to 45mg via a peripheral cannula. There were no adverse complications from the procedure or the adenosine in these patients. The study concluded that the use of adenosine enhanced the ease of placement and deployment of the grafts and has the advantage of a transient controlled hypotension with cardioprotective and cerebroprotective effects.

Adenosine in cardioplegic solutions

“Myocardial stunning” refers to the reduced cardiac function in the immediate post bypass period following coronary artery bypass surgery. The role of various cardioplegic solutions in this phenomenon is debated. A recent study looked at the safety, tolerance and efficacy of adenosine as a cardioplegic additive for patients undergoing coronary artery bypass surgery 20. In the study, 61 patients were randomised to standard cold blood cardioplegia or cold blood cardioplegia with varying concentrations of adenosine additive. Cardiac function post bypass was evaluated by assessing the amount of vasoactive drugs required postoperatively and by measuring left ventricular ejection fractions both pre- and postoperatively. The study found that the use of high dose adenosine additive to the cardioplegic solution was associated with a much decreased dopamine and SNP requirement postoperatively, and with improved regional cardiac wall movement and ejection fraction seven days postoperatively. Despite concerns about adenosine induced hypotension during the bypass period, adenosine cardioplegia was found to be well tolerated.

Uses of adenosine in ischaemic heart disease

Adenosine is now being used during myocardial thallium perfusion imaging as a coronary vasodilator, in those patients who are unable to tolerate exercise ECG testing for ischaemic heart disease. Adenosine has an advantage over dipyridamole (Persantin), which was previously used for this purpose, as it has a very short half life and a shorter period of potential side effects such as hypotension and coronary steal.

During cardiac catheter studies of coronary stenosis, adenosine is being used as a coronary vasodilator to assess the functional significance of specific stenoses. Normal resting coronary flow is little affected by a stenosis of up to 85% diameter. Adenosine is perfused through the catheter to induce a hyperaemic state in the vessel distal to the stenosis and flow reassessed. Hyperaemic flow may begin to decrease with a 50-60% diameter stenosis. Thus, the degree of coronary flow reserve can be determined.

Finally, adenosine is being investigated for use as a myocardial protectant following acute myocardial infarction. Following reperfusion by thrombolysis or angioplasty, the myocardium is at risk of reperfusion injury. There are early indications that an infusion of adenosine post-reperfusion may limit the degree of reperfusion injury. This is analogous to the role of adenosine in cardioplegia during cardiopulmonary bypass.

Adenosine as a novel analgesic

Most of the work investigating the analgesic effects of adenosine has been done by Sollevi and coworkers. In the peripheral nervous system, infusions of adenosine at a rate greater than 70mcg/kg/min are associated with pain symptoms from various parts of the body. In particular, an ischemic-type chest pain is often elicited. In the central nervous system, the role of adenosine is not clear. It is thought that central adenosine A1 receptors are associated with a modulatory effect on pain transmission at the spinal cord level.

An infusion of adenosine at less than 70mcg/kg/min was shown to alleviate the pain of experimentally induced limb ischemic pain in healthy volunteers 21. This effect was as effective as IV morphine or ketamine at 0.1mg/kg. Furthermore, in a study on patients undergoing anaesthesia with isoflurane and spontaneously breathing, an infusion of adenosine at80mcg/kg/min was shown to decrease isoflurane requirements by 20-50%22. Narcotic administration was not required during the anaesthesia and the first 24 hour postoperative narcotic requirement was reduced by 18-27%, despite the adenosine infusion being terminated early in the post-operative period. The study concluded that adenosine is an alternative to narcotic during spontaneously breathing isoflurane anaesthesia and had no respiratory depressant effect.

In a placebo-controlled double crossover trial of adenosine in two patients with severe neuropathic pain, adenosine infusion was shown to alleviate both the spontaneous pain and tactile allodynia 23. The effect lasted for several hours after the infusion was terminated.

Finally, intrathecal adenosine has also been investigated and used for the treatment of chronic pain 24. In one case report, a single intrathecal injection of adenosine in a patient with severe chronic allodynia of the foot resulted in total pain relief for months. There are two multicenter trials currently under way looking at the role of intrathecal adenosine in acute surgical pain and in chronic neuropathic pain patients.[Top]

Conclusion

Although adenosine is not a new drug, it has recently become more easily available for the treatment of tachyarrhythmias. In this role, it is a safe, effective and simple drug to use. As experience with its use grows, more and more applications are being found for it. It is too early to say which of these will become accepted medical practice in the future. Certainly, the cost of adenosine at present is prohibitive for commonplace use, however this may soon change. Anaesthetists need to be aware of the existence of adenosine and its indications and method of use. It is anticipated that, at least in some areas, adenosine itself will be a commonplace drug, and in others, adenosine agonists will have a greater role.[Top]

References

1. Shryock JC, Belardinalli L. Adenosine and adenosine receptors in the cardiovascular system: Biochemistry, physiology, and pharmacology. Am J Cardiol 1997; 79(12A): 2-10

2. Wilbur SL, Marchlinski FE. Adenosine as an antiarrhythmic agent. Am J Cardiol 1997; 79 (12A): 30-37

3. Lowenstein SR, Halperin BD, Reiter MJ. Paroxysmal supraventricular tachycardias. J Emerg Med 1996; 14(1): 39-51

4. DiMarco JP, Miles W, Akhtar M et al Adenosine for paroxysmal supraventricular tachycardia: dose ranging and comparison with verapamil. Ann Int Med 1990; 113:104-110

5. Friedman FD. Intraosseous adenosine for the termination of supraventricular tachycardia in an infant. Ann Emerg Med 1996; 28:356-358

6. Strickberger SA, Man KC, Daoud EG et al Adenosine-induced atrial arrhythmias: a prospective analysis. Ann Int Med 1997; 127: 417-422

7. Brodsky MA, Hwang C, Hunter D et al Life-threatening alterations in heart rate after the use of adenosine in atrial flutter. Am Heart J 1995; 130: 564-571

8. Rankin AC, Rae AP, Oldroyd KG, Cobbe SM. Verapamil or adenosine for the immediate treatment of supraventricular tachycardia.Q J Med 1990; 74: 203-8

9. Griffith MJ, Linker NJ, Ward DE, Camm AJ. Adenosine in the diagnosis of broad complex tachycardia. Lancet 1988 Mar 26: 672-5

10. Bulley SR, Wittnich C. Adenosine infusion: a rational approach towards induced hypotension. Can J Cardiol 1995; 11: 327-334

11. Kien ND, White DA, Reitan JA, Eisele JH. Cardiovascular function during controlled hypotension induced by adenosine triphosphate or sodium nitroprusside in the anesthetised dog. Anesth Analg 1987; 66: 103-110

12. Owall A, Sollevi A. Myocardial effects of adenosine and sodium nitroprusside-induced hypotension: a comparitive study in patients anaesthetised for abdominal aortic aneurysm Surgery. Acta Anaes Scand 1991; 35: 216-220

13. Lagerkranser M, Bergstrand G, Gordon E, Irestedt L, Lindquist C, Stange K, Sollevi A Cerebral blood flow and metabolism during adenosine-induced hypotension in patients undergoing cerebral aneurysm surgery. Acta Anaes Scand 1989; 33: 15-20

14. Owall A, Jarnberg PO, Brodin LA, Sollevi A. Effects of adenosine-induced hypotension on myocardial hemodynamics and metabolism in fentanyl anesthetised patients with peripheral vascular disease. Anesthesiology 1988; 68: 416-421

15. Stange K, Lagerkranser M, Sollevi A. Effect of adenosine-induced hypotension on the cerebral autoregulation in the anaesthetized pig. Acta Anaes Scand 1989; 33: 450-457

16. Zall S, Eden E, Winso I, Volkmann R, Sollevi A, Ricksten SE. Controlled hypotension with adenosine or sodium nitroprusside during cerebral aneurysm surgery: Effects on renal hemodynamics, excretory function, and renin release. Anesth Analg 1990; 71: 631-636

17. Crawford MW, Lerman J, Saldivia V, Orrego H, Carmichael FJ. The effect of adenosine -induced hypotension on systemic and splanchnic hemodynamics during halothane or sevoflurane anesthesia in the rat. Anesthesiology 1994; 80:159-167

18. Mikawa K, Maekawa N, Kaetsu H, Goto R, Yaku H. Effects of adenosine triphosphate on the cardiovascular response to tracheal intubation. Br J Anaesth 1991; 67: 410-415

19. Baker AB, Bookallil MJ, Lloyd G. Intentional asystole during endoluminal thoracic aortic surgery without cardiopulmonary bypass. Br J Anaesth 1997; 78: 444-448

20. Mentzer RM, Rahko PS, Molina-Viamonte V et al Safety, Tolerance, and efficacy of adenosine as an additive to blood cardioplegia in humans during coronary artery bypass surgery. Am J Cardiol 1997; 79(12A): 38-43

21. Segerdahl M, Ekblom A, Sollevi A. The influence of adenosine, ketamine and morphine on experimentally induced ischemic pain in healthy volunteers. Anesth Analg 1994; 79: 787-791

22. Segerdahl M, Ekblom A, Sandelin K et al Peroperative adenosine infusion reduces requirements of isoflurane and postoperative analgesics. Anesth Analg 1995:80: 1145-1149

23. Belfrage M, Sollevi A, Segerdahl M. Systemic adenosine infusion alleviates spontaneous and stimulus evoked pain in patients with peripheral neuropathic pain. Anesth Analg 1995: 81: 713-717

24. Karlsten R, Gordh T. An A1 selective adenosine agonist abolishes allodynia elicited by vibration and touch after intrathecal injection. Anesth Analg 1995: 80: 844-847[Top]


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