British Journal of Anaesthesia 94 (5): 556–62 (2005)
doi:10.1093/bja/aei093
Advance Access publication February 18, 2005
REVIEW ARTICLE
Potential value of adenosine 50-triphosphate (ATP) and
adenosine in anaesthesia and intensive care medicine
A. T. P. Skrabanja1*, E. A. C. Bouman2 and P. C. Dagnelie1
1
Department of Epidemiology, NUTRIM, Maastricht University, Maastricht, The Netherlands.
2
Department of Anaesthesiology, University Hospital Maastricht, The Netherlands
*Corresponding author. E-mail: [email protected]
Extracellular adenosine and adenosine triphosphate (ATP) are involved in biological processes
including neurotransmission, muscle contraction, cardiac function, platelet function, vasodilatation, signal transduction and secretion in a variety of cell types. They are released from the
cytoplasm of several cell types and interact with specific purinergic receptors which are present
on the surface of many cells. This review summarizes the evidence on the potential value and
applicability of ATP (not restricted to ATP–MgCl2) and adenosine in the field of anaesthesia
and intensive care medicine. It focuses, in particular, on evidence and roles in treatment of
acute and chronic pain and in sepsis. Based on the evidence from animal and clinical studies
performed during the last 20 years, ATP could provide a valuable addition to the therapeutic
options in anaesthesia and intensive care medicine. It may have particular roles in pain management, modulation of haemodynamics and treatment of shock.
Br J Anaesth 2005; 94: 556–62
Keywords: anaesthesia; nucleotide, adenosine; nucleotide, ATP; complications, sepsis; pain
Extracellular adenosine and adenosine triphosphate (ATP)
are involved in biological processes including neurotransmission, muscle contraction, cardiac function, platelet function, vasodilatation, signal transduction and secretion in a
variety of cell types.31 39 They are released from the cytoplasm of several cell types and interact with specific purinergic receptors which are present on the surface of many
cells. Recently, established and potential clinical applications of adenosine,57 ATP in general3 and ATP–MgCl2 in
intensive care medicine61 have been reviewed separately. In
this review, we summarize the evidence for the potential
value and applicability of ATP (not just ATP–MgCl2) and
adenosine in the field of anaesthesia and intensive care medicine. In particular, we have focused on results and treatment
options for acute and chronic pain and for sepsis. Although a
number of reports from animal and human studies show
potential applications of adenosine and ATP in different
clinical fields, including safety data, the application of
both compounds in clinical practice is still very limited.
Biology of adenosine and ATP
Adenosine 50 -triphosphate (ATP) is the energy source in
living cells. In physiological conditions, the average
concentration varies from 3150 mM in mammalian cells94
to 1500–1900 mM in human blood cells.2 91 Plasma ATP
concentrations ranging between 0.15 and 3.9 mM have
been reported by different groups.42 76 In vivo, ATP is
metabolized rapidly, via adenosine diphosphate (ADP)
and adenosine monophosphate (AMP), to adenosine.42
Reported physiological plasma concentrations of 0.1–1 mM
for these derivatives43 65 are of the same order of magnitude
as for ATP.
A large family of membrane-bound receptors mediates
cell signalling by ATP and adenosine. These purinergic
receptors ultimately determine the variety of effects induced
by extracellular ATP and adenosine. So far, two families of
purinergic receptors have been identified, namely P1 and P2
receptors which respond principally to adenosine and ATP,
respectively.74
P1 receptors are G-protein coupled receptors, of which
four types have been identified so far (A1, A2A, A2B, A3).
Although all the P1 receptor subtypes are primarily activated
by adenosine, each shows a different degree of affinity for its
physiological agonists. Thus, besides adenosine itself, its
breakdown product inosine has also been shown to exert
an agonist action on A1 and A3 receptors, but not on A2
receptors.34 51 However, this agonist action of inosine
appears to have a low efficacy compared with adenosine,
especially at A3 receptors.34
The P2 receptor family is divided in P2X and P2Y receptors, with a number of different subtypes which have varying
# The Board of Management and Trustees of the British Journal of Anaesthesia 2005. All rights reserved. For Permissions, please e-mail: [email protected]
ATP and adenosine in anaesthesia and IC
ATP
P2X
1–7
ADP
AMP
P2Y
1, 2, 4, 6, 11–14
Ligand-gated
ion-channels
Adenosine
P1
A1, A2a, A2b, A3
G-protein coupled receptors
Fig 1 Receptors for ATP and adenosine: schematic overview of the two families of purinergic receptors and their affinities.
affinities for ATP, ADP, uridine triphosphate (UTP), uridine
diphosphate (UDP) and UDP–glucose.
P2X receptors are ligand-gated ion channels, of which
currently seven subtypes have been characterized
(P2X1–7).52 62 All are primarily activated by their physiological agonist ATP. P2Y receptors are G-protein coupled
receptors, of which eight subtypes have been identified to
date (P2Y1, 2, 4, 6, 11–14).10 48 96 In contrast with P2X receptors, P2Y receptor subtypes have specific agonist and affinity
profiles. More specifically, P2Y receptors can be subdivided
into two groups based on sequence homology.1 10 Group 1
consists of specific purinergic receptors (P2Y1, P2Y11), specific pyrimidinergic receptors (P2Y4, P2Y6) and receptors of
mixed specificity (P2Y2). Group 2 contains two specific
ADP receptors (P2Y12, P2Y13) and a recently identified
receptor for UDP–glucose (P2Y14).
P1 and P2 receptors are widely distributed in body tissue.
The extent of receptor expression on individual cells or in
specific tissues partially determines the potency of receptormediated effects of ATP and adenosine.
Overall, signalling by P1 and P2 receptors depends on a
wide variety of factors, such as receptor expression, receptor
sensitivity for physiological agonists and extracellular levels
of nucleotides/nucleosides. Purinergic signalling is even
more complex in inflammatory conditions during which it
is subjected to additional modulating factors, including the
release of nucleotides/nucleosides. A schematic overview of
different receptors is given in Figure 1.
Clinical effects of administration of
adenosine and ATP
Continuous i.v. administration of ATP in humans induces a
dose-dependent rise in ATP levels in erythrocytes2 93 and
liver,2 followed by slow release into the plasma compartment. ATP levels in erythrocytes reach plateau levels at 24 h,
and are significantly increased above baseline (more than
50%). At the same time, a significant increase in plasma uric
acid concentration is observed. The mean half-life for the
disappearance of ATP from erythrocytes is 5.9 h.2 Plasma
concentrations are three orders of magnitude lower than
within the erythrocytes, partly due to the rapid breakdown
of ATP; only 1% of ATP is detectable in whole blood 40 s
after bolus injection.73 84
Some of the pharmacological effects observed after ATP
administration in humans are believed to be due to the action
of the degradation products of ATP, especially adenosine
and inosine.
Cardiology
Adenosine has an established clinical application in
cardiology as an anti-arrhythmic agent. It is administered,
usually as an i.v. bolus at doses up to 15 mg,72 to restore
sinus rhythm in patients with supraventricular tachycardia
and for the diagnosis of broad and narrow complex
tachycardia.12 32 40 72 75
I.V. or intracoronary adenosine is also used to achieve
maximal hyperaemia of the coronary microcirculation in the
evaluation of the significance of coronary stenosis.14 The use
of adenosine in ischaemia and reperfusion has gained
increasing interest over the last decade. Adenosine exerts
cardioprotective effects during myocardial ischaemia and
reperfusion. Exogenous administration of adenosine prior
to zero-flow ischaemia has been shown to reduce infarct
size and improve functional recovery. Exogenous administration during low-flow ischaemia can improve functional
recovery and reduce cellular injury, thereby slowing ATP
depletion and delaying ischaemic contracture.88 Nevertheless, because of its haemodynamic side-effects and short
half-life in blood (0.5–1.5 s), adenosine is not routinely
used for the treatment of acute myocardial ischaemia. As
adenosine produces coronary vasodilatation with only minor
effects on the systemic circulation, its use for the prevention
of early occlusion of coronary artery bypass grafts has been
suggested.92
A new application for adenosine is its use in myocardial
contrast echo cardiography.60
Control of arterial pressure
ATP and adenosine have been used experimentally for a
number of years to induce hypotension during anaesthesia
and surgery in patients. In 1951, Davies and colleagues28
demonstrated that an i.v. or intra-arterial bolus injection
of ATP 40 mg induced a moderate fall in arterial pressure
without change in heart rate. The haemodynamic effects of
ATP and adenosine have been investigated in >150 patients
undergoing different types of surgery,36 38 including oral,37
557
Skrabanja et al.
orthopaedic,24 abdominal aortic aneurysm68 70 and cerebral
aneurysm.24 67 87
I.V. infusion of ATP or adenosine 50–350 mg kg1min1
induced dose-related reductions of 20–43% in arterial pressure. A major decrease in systemic vascular resistance
(36–67%) and an increase in cardiac output (14–42%),
but only a small increase in heart rate (3–16%), occurred
at higher doses. Haemodynamic values returned to their
baseline immediately after stopping the infusion.36 38
No observations of tachyphylaxis and rebound hypertension
have been reported.25 36 38 67–69 87 Other studies25 68 69 79 83 87
have shown no change in arterial pressure during infusion of
adenosine 80 mg kg1min1 in patients undergoing abdominal, breast or shoulder surgery. This is probably due to
differences in dosing of adenosine.
ATP and adenosine (150–300 mg kg1 min1 i.v.) have
been used successfully to antagonize the vasoconstrictive actions of norepinephrine and/or sympathetic nerve
stimulation.5
Pain reduction
Adenosine plays an important role in the perception of pain
in the central and peripheral nervous system. The spinal cord
contains adenosine A1, A2A, A2B and A3 receptors. The A1
receptor plays a key role in spinal antinociception, whereas
the functions of the A2A, A2B and A3 receptors are not
clearly defined. At peripheral sites, A2A and A3 receptors
mediate pain transmission, whereas the A1 receptor seems to
play a central role in antinociception.77
Raising extracellular levels of adenosine through inhibition of adenosine kinase in animal models induced an analgesic effect.26 49 101 Unlike the direct effects of adenosine
receptor agonists, use of adenosine kinase inhibitors does
not have an effect on cardiovascular functions.54 97 The
effects of adenosine are related to peripheral sensitization/
activation of nociceptive afferents79 and influence the need
for anaesthetics.
Adenosine induces release of neurotransmitters in spinal
antinociception, acting both pre- and post-synaptically.
Pre-synaptically it reduces neurotransmitter release, and
post-synaptically it hyperpolarizes the spinal cord neurones
by interaction with ATP-sensitive K+ channels to increase
the conductance.77
Anaesthesia and acute pain
Several double-blind placebo-controlled cross-over studies
in healthy human subjects have shown pain-reducing effects
of i.v. adenosine infusion at doses of 50–70 mg kg1
min1.80 In addition, the effectiveness of adenosine in reducing ischaemic pain (70 mg kg1 min1 i.v. for 30 min) is
comparable to morphine (20 mg kg1 min1 i.v. for 5 min) or
ketamine (20 mg kg1 min1 i.v. for 5 min). Furthermore,
adenosine given in combination with morphine or ketamine
has an additive effect on pain reduction.81 In two doubleblind randomized trials in patients undergoing breast
surgery (75 patients)79 and gynaecological abdominal
surgery (43 patients),82 systemic adenosine infusion
(80 mg kg1 min1 i.v.) significantly reduced perioperative
isoflurane requirements and postoperative pain. In addition,
in both studies, the need for opioids was reduced by
approximately 25% in the adenosine group during the first
postoperative 24 h.82 83 A recent study35 suggested that
adenosine infusion during general anaesthesia for surgery
provided good recovery from anaesthesia associated with
pronounced and sustained postoperative pain relief. In this
study, adenosine (50–500 mg kg1 min1) during surgery
induced pain relief, reduced opioid requirements and
attenuated side-effects such as protracted sedation, cardiorespiratory instability, nausea and vomiting during the
postoperative recovery period. In all these aspects, adenosine
was superior to remifentanil (0.05–0.5 mg kg1 min1). These
results suggest that adenosine acts by inhibiting nociceptive
transmission. This may be mediated by central A1-receptormediated antinociception, and inhibition of peripheral
inflammatory processes via A2A and possibly A3 receptors.
It is possible that both central and peripheral mechanisms are
involved. This is in line with the finding that, during surgical
tissue injury and subsequent inflammatory processes, inhibition of both central and peripheral sensitization is necessary to
prevent postoperative pain.99
Chronic pain
Several reports have provided evidence that low doses of
adenosine (50 mg kg1 min1) alleviate neuropathic pain,
hyperalgesia and allodynia without inducing other pain
symptoms.7 86 Adenosine, infused for 45–60 min, induced
improvement of spontaneous or evoked pain in six of seven
patients with peripheral neuropathic pain for periods lasting
from 6 h to 4 days.7 This positive finding was unexpected, as
adenosine is eliminated from the blood within 1–2 min.7 The
effects of adenosine on central hyperexcitability persist
longer than the direct action of adenosine on the receptors.86
A role for adenosine in analgesia is further supported by the
observation of reduced adenosine levels in the blood
and cerebrospinal fluid of patients with neuropathic pain
compared with patients who have nervous system lesions
but no pain.41
It is known that adenosine acts both pre- and postsynaptically. Pre-synaptically it reduces neurotransmitter
release, and post-synaptically it hyperpolarizes the spinal
cord neurones by interaction with ATP-sensitive K+
channels to increase the conductance.77
Recent electrophysiological, behavioural and biochemical studies have shown that ATP is also involved in
nociception by facilitating spinal pain transmission via ionotropic P2X nucleotide receptors.6 30 46 47 77
An animal study by Sawynok and Reid78 provided
evidence in support of a P2X-purinoreceptor-mediated
augmentation of the pain signal by ATP. The pronociceptive
effects of ATP were examined in the low-concentration
558
ATP and adenosine in anaesthesia and IC
formalin model (0.5%) by co-administering ATP, ATP
analogues and antagonists with formalin and determining
the effects on the expression of flinching behaviour.
P2X3 ligand-gated cation channels mediate the excitatory
effects of ATP on sensory neurones.22 56 After nerve injury,
P2X3 receptors are upregulated in dorsal root ganglia.
Activation of P2X3 receptors contributes to the expression
of chronic inflammatory and neuropathic pain states. ATP
acts via P2X3-containing channels as a nociceptive neurotransmitter.47 Unlike P2X receptors, activation of UTPsensitive P2Y receptors produces inhibitory effects on spinal
pain transmission.
Overall, these data demonstrate that activation of P2X3
receptors contributes to the expression of chronic inflammatory and neuropathic pain states. It is possible that relief
from these forms of chronic pain might be achieved by
selective blockade of the expression of P2X3 receptors.
Sepsis and shock
Shock and associated multiple organ failure is still a major
cause of death in critically ill patients. A common feature of
shock is an inadequate circulation leading to diminished
perfusion, hypoxia and tissue injury. The resuscitation
period after shock is also associated with development of
tissue injury and loss of organ function.11 Severe sepsis and
septic shock still have a high mortality, and current therapies
have not had a substantial effect on survival. The recent
development of recombinant activated protein C may hold
more promise;8 9 however, the need for better medication
remains urgent.
In the early 1980s, Chaudry and colleagues20 reported
beneficial effects of ATP–MgCl2 in the treatment of
haemorrhagic shock. Although this was originally attributed to restoration of energy supplies, the total amount of
ATP–MgCl2 applied was minimal in relation to total body
stores of ATP. The discovery of purinergic receptors provided a scientific explanation for the beneficial effects of
ATP–MgCl2, such as improvement of blood flow, microcirculation, energy balance, and cellular and mitochondrial
functions.90 However, some of the effects of ATP–MgCl2
infusion described by Chaudry and colleagues may be due
to magnesium. Magnesium is a cofactor for more than 300
enzymes, some of which catalyse oxidative phosphorylation, activating energy storage and metabolizing ATP.61
Furthermore, magnesium is involved in the regulation of
cell membrane permeability and arteriolar tone, and
enhances the binding of agonists to P1 receptors.64 Paskitti
and Reid71 reported that vanadate may play a role in the
ATP–MgCl2 effect, as the ATP used was derived from
equine muscle and not from bacterial sources and therefore
contained trace amounts of vanadate. Both ATP and
vanadate given alone had a smaller but still significant
effect.
Chaudry and colleagues15 17–21 reported that ATP–MgCl2
infusion was beneficial for the survival of rats and mini-pigs
after haemorrhagic shock, sepsis and peritonitis. ATP–
MgCl2 accelerated the recovery of renal function after
ischaemia. However, bolus administration of ATP–MgCl2
had profound circulatory effects, and was suggested as a
cause of shock.
The short-lived response to i.v. ATP–MgCl2 infusion in
a clinically relevant hypoxic–hypotensive rat model confirmed the necessity of prolonged continuous infusion of
ATP–MgCl2.73 84 In vivo animal studies indicate that
infusion of ATP–MgCl2 after haemorrhagic shock has a
favourable effect on survival.15 16 23 33 44 45 63 100 Other
studies suggest that ATP and adenosine have protective
effects on tissue injury following reperfusion after a period
of ischaemia. The beneficial effect of ATP–MgCl2 in shock
could be due to provision of energy directly to tissue with
low levels of ATP.21 ATP–MgCl2 has been shown to
improve the function of rat kidney,21 66 rat liver,18 dog
heart,53 58 rabbit lung50 and rat gut85 after a period of ischaemia. The use of i.m. ATP–MgCl2 was also protective in
rats with burns.100
Another animal study98 indicated that administration of
ATP–MgCl2 early after the onset of sepsis attenuated the
impaired endothelium-dependent vascular relaxation. In this
way, ATP may be effective in maintaining endothelial cell
function during the hyperdynamic stage of sepsis.
A mouse model of sepsis was used to investigate the
influence of ATP–MgCl2 infusion on high-energy phosphate
stores and immune function in lymphocytes.59 Treatment
with ATP–MgCl2 at the onset of sepsis significantly
increased lymphocyte ATP levels and the proliferation
response to mitogenic stimuli. Moreover, improved lymphocyte function in this group correlated with a significant
increase in overall survival of the animals. It was suggested
that decreased lymphocyte ATP levels might be the cause of
defective lymphocyte proliferation capacity in late sepsis. In
a porcine model, it was shown that ATP–MgCl2 normalized
the lipopolysaccharide-induced rise in the ileal–mucosal
PCO2 gap and attenuated hepatic lactate clearance.4
ATP production by mitochondrial oxidative phosphorylation accounts for more than 90% of total oxygen
consumption. Brealey and colleagues13 postulated that
mitochondrial dysfunction results in organ failure, possibly because of production of nitric oxide which is
known to inhibit mitochondrial respiration in vitro and
is produced in excess in sepsis. In a group of 28 critically
ill septic patients, these authors showed that skeletal muscle concentrations of ATP were significantly lower in
the12 patients who subsequently died (7.6 nmol mg1
dry weight) compared with both the 16 patients who survived (15.8 nmol mg1) and controls (12.5 nmol mg1).
In septic patients, an association was found between
nitric oxide overproduction, antioxidant depletion, mitochondrial dysfunction and decreased intracellular ATP
concentrations. Addition of extracellular ATP may replace
this deficit. The repletion of intracellular ATP pools
during ATP infusion in humans has been observed
559
Skrabanja et al.
using 31P magnetic resonance spectroscopy in patients
with cancer cachexia.27 55
In the light of these findings, studies to evaluate the use of
ATP infusions in relation to sepsis61 have been proposed.
A particular target is the treatment of impaired microcirculation29 95 where ATP or adenosine could provide a
valuable alternative to the current use of vasopressor
medication to increase arterial pressure.89 After restoring
volume depletion, the combined ATP effects of vasodilation
and increased cardiac output could be used to improve
microcirculation and tissue perfusion, and to increase oxygen delivery/extraction.
Conclusion
Based on the evidence from both animal and clinical studies
performed during the last 20 years, ATP could provide a
valuable addition to the therapeutic options in anaesthesia
and intensive care medicine. In particular, its use in pain
management, modulation of haemodynamics and treatment
of shock seems promising. Further research is required,
particularly on the issue of ATP–MgCl2, to clarify the
exact role of ATP, magnesium and the combined compound.
Acknowledgements
The authors would like to thank Professor Dr M. E. Durieux for valuable
comments on earlier versions of the review.
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