Antiarrhythmic Drugs and Anaesthesia 1

BJA Education, 23(1): 8e16 (2023)
doi: 10.1016/j.bjae.2022.11.001
Advance Access Publication Date: 5 December 2022
Matrix codes: 1A01,

1A02, 2A03, 3I00
Antiarrhythmic drugs and anaesthesia: part 1.

mechanisms of cardiac arrhythmias
C.J. Kim1,*, N. Lever1,2 and J.O. Cooper1
1
Auckland City Hospital (Te Toka Tumai), Auckland, New Zealand and 2University of Auckland, Auckland,
New Zealand
*Corresponding author: changk@adhb.govt.nz
Keywords: anti-arrhythmic agents; arrhythmias; cardiac; cardiac electrophysiology
Learning objectives Key points

By reading this article you should be able to: The majority of perioperative arrhythmias do not
require treatment with antiarrhythmic drugs.
Describe the normal electrophysiology of the
There are three main mechanisms of arrhyth-
heart and heterogeneity of its electrical activity.
mogenesis: automaticity, triggered rhythm and
Explain the mechanisms of arrhythmogenesis.
re-entry.
Outline factors that increase the risk of devel-
If possible, risk factors for arrhythmias should be
oping perioperative arrhythmias.
corrected before surgery.
Discuss the principles of the perioperative man-
Many drugs used in anaesthesia are potentially
agement of arrhythmias.
arrhythmogenic.
Inappropriate use of antiarrhythmic drugs can
Perioperative arrhythmias are extremely common, usually increase morbidity and mortality.
transient and typically require no intervention. Persistent
arrhythmias with associated haemodynamic instability may
reflect an underlying pathological process. Indeed, the clinical scenario outlined of a patient with sepsis who develops rapid
atrial fibrillation describes a situation that anaesthetists and
intensivists frequently encounter. In some situations, the
primary cause of the arrhythmia may be evident. However, in
Chang Joon Kim FANZCA is a consultant anaesthetist at Auckland many cases the cause is multifactorial, relating to coexisting
City Hospital, Health New Zealand. He routinely provides anaes- disease, acute physiological disturbance, medications or the
thesia care for patients requiring cardiac, thoracic, interventional surgical procedure itself (e.g. cardiac or thoracic surgery).
cardiology procedures including TAVI, catheter ablations and PCIs The principles of perioperative management are based on
and non-cardiac procedures. He is a primary examiner for Austra- maintaining cardiovascular stability through restoration of
lian and New Zealand College of Anaesthetists. sinus rhythm or controlling heart rate. Interventions include
treating the underlying causes(s), haemodynamic support and
Nigel Lever FRACP FCSANZ is a consultant cardiologist at Auckland
electrical cardioversion. Antiarrhythmic drugs are sometimes
City Hospital and associate professor at the University of Auckland,
e but not always e required to successfully manage patients
with clinical expertise in cardiac rhythm disorders and cardiac
with arrhythmias.
ablation procedures. He is involved in translational research with
To understand the mechanism of action of antiarrhythmic
cardiac mapping, heart failure, and novel pacing therapies; and is
drugs, it is necessary to understand normal cardiac electro-
also an examiner for the Royal Australasian College of Physicians.
physiology and the pathophysiology of arrhythmogenesis. In
Jeremy Ormond Cooper FANZCA is a consultant anaesthetist at part one of this two-part series, we focus on normal cardiac
Auckland City Hospital. He has expertise in preoperative patient electrophysiology, arrhythmogenesis and how arrhythmias
assessment, cardiothoracic anaesthesia and an extensive interest are triggered. We discuss the indications for pharmacological
and involvement in education. therapy and outline the factors to consider before initiating
Accepted: 3 November 2022

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Antiarrhythmic drugs and anaesthesia
Electrophysiology of the heart

Clinical scenario
An electrical impulse is generated at the sinoatrial (SA) node
A 72-year-old man presented for an elective laparo- at regular intervals with a normal frequency of 60e100 beats
scopic right hemicolectomy for adenocarcinoma of the min1. The electrical impulse travels through the left and right
colon. He had a history of ischaemic heart disease, with atria to the atrioventricular (AV) node where the speed of
previous angioplasty and stenting to the left anterior conduction decreases, providing approximately 0.15 s for the
descending coronary artery. His left ventricular func- atria to fill the ventricles with blood. The impulse then rapidly
tion was mildly impaired and he was taking a loop travels down the His-Purkinje fibre to depolarise the ventricles
diuretic and metoprolol for blood pressure control. in a synchronised fashion, resulting in coordinated ventricu-
Surgery was uneventful, except for occasional ventric- lar contraction.
ular ectopic beats. On the fifth day after surgery, Cardiac action potentials can be broadly classified into two
he developed atrial fibrillation with rapid ventricular distinct types: (i) myocyte action potentials (Fig 1A) and (ii) SA
response, which was associated with severe hypoten- and AV node action potentials (Fig 1B).
sion and required admission to the ICU. Further inves-
tigation revealed an anastomotic leak with peritoneal Myocyte action potentials
sepsis.
The resting membrane potential (RMP), corresponding to
phase 4 in Fig. 1A, is mainly established by the Naþ/Kþ-ATPase
pump and the high permeability of the cell membrane to Kþ.
The cell membrane is much less permeable to Naþ and Ca2þ
drug treatment. In a forthcoming article, we will discuss the
and, therefore, these ions contribute little to the RMP. The Naþ/
classification and clinical pharmacology of antiarrhythmic
Kþ-ATPase pump moves 3 Naþ ions out of the cell and 2 Kþ ions
drugs and provide an overview of managing perioperative
into the cell, resulting in the net outward movement of posi-
arrhythmias.
tive charge. Along with intracellular anionic proteins, the Naþ/
Important concepts and terms are summarised in Table 1.
Kþ-ATPase pump generates a negative electrical potential in-
The ion currents associated with cardiac action potentials are
side the cell and maintains the high intracellular concentra-
shown in Fig 1.
tion of Kþ and the high extracellular concentration of Naþ.
Table 1 Terms and their meanings.
Term Meaning
Resting membrane potential RMP is determined by equilibrium potentials and permeability of various ions across the cell
(RMP) membrane. Kþ is the most important ion because of its high permeability at the resting state. The
RMP is approximately e90 mV, close to the Kþ equilibrium potential. The cell is fully excitable and
capable of generating an action potential.
Hyperpolarisation Repolarisation of cell membrane below the RMP making the potential more negative. This is
mainly caused by efflux of Kþ.
Partial depolarisation A state where the RMP is less negative. Usually associated with pathological conditions such as
myocardial ischaemia.
Depolarisation A change in membrane potential owing to influx of cations (e.g. Naþ and Ca2þ) into the cell
resulting in a less negative or even a positive membrane potential.
Repolarisation A change in membrane potential caused by efflux of Kþ into the cell resulting in a more negative
membrane potential.
Absolute refractory period (ARP) The interval between the beginning of the action potential and when the cell can generate another
action potential. During this period, the cell is not excitable as all Naþ channels are in an
inactivated state and no channels are available to generate a new action potential.
Relative refractory period (RRP) The interval after the absolute refractory period where the cell regains partial excitability. An
action potential can only be generated with a stimulus stronger than one that would normally
elicit an action potential from RMP. Sufficient number of Naþ channels have recovered to generate
an action potential, but not enough to regain full excitability.
Early after depolarisation (EAD) A triggered activity that occurs at the end of the plateau (phase 2) of an action potential. EAD is
associated with a prolonged action potential.
Delayed after depolarisation A triggered activity that occurs near the very end of repolarisation or just after full repolarisation.
(DAD) DAD is associated with increased intracellular Ca2þ concentration.
Transmural dispersion of Dispersion of repolarisation is a phenomenon where repolarisation times are different in different
repolarisation (TDR) parts of the heart. Epicardial cells, endocardial cells, and M-cells in the ventricular wall have
different repolarisation time resulting in different action potential durations across the thickness
of the ventricular wall e termed TDR. This results from different ion channel distribution and
intrinsic differences in activity between different cell types.
þ þ
Na /K ATPase pump ATP-dependent active transport found in the cell membrane. For every ATP molecule hydrolysed,
three Naþ are exported out of the cell and two Kþ are imported into the cell. This keeps
intracellular Kþ and extracellular Naþ concentrations high. The pump is also electrogenic as there
is a net outward movement of a cation.
BJA Education - Volume 23, Number 1, 2023 9
a b
+30 1 +30
2
Voltage (mV)
0 0
Time (ms)
0 3
0 3
–60 4 4
4 4
–90 ARP RRP
250 ms
Repolarising Depolarising
currents
INa If
ICaL ICaT
ICaL
IK1
IK
currents
It0
IKS
IKr
Currents Channels Description

If Funny current Hyperpolarisation- Activated by hyperpolarisation. Inward current of cations
activated cyclic (Na+, K+) initiates spontaneous diastolic depolarisation and
nucleotide-gated produces automaticity.
(HCN) channels
INa Na+ current Volage-gated Na+ Rapid influx of Na+ current resulting in rapid depolarisation
channels producing phase 0.
INaL Late Na+ current Volage-gated Na+ Late component of residual INa after the large peak inflow of
channel Na+. Very small current in normal condition, but may be
large enough to prolong action potential in pathological
conditions such as myocardial ischaemia.
IK1 Inwardly rectifier Inwardly rectifier K+ Outward K+ current responsible for high K+ permeability
current channel during resting membrane potential. The current is greatly
decreased during phase 2 assisting maintenance of plateau.
It0 Transient Voltage-gated K+ Transient outward repolarising K+ current producing a

outward K+ channel notch, phase 1. These channels get inactivated rapidly.
current
IKs Slow delayed Voltage-gated K+ Outward K+ current during plateau and repolarisation
rectifier current channel (phase 2 and 3) of the action potential.
IKr Rapid delayed Human ether-a-go- Outward K+ current during plateau and repolarisation
rectifier current go-related gene (phase 2 and 3) of the action potential. hERG potassium
(hERG) potassium channel blockade can cause acquired long QT interval
channel syndrome.
ICaT T-type Ca2+ Voltage-gated T-type Inward Ca2+ current primarily found in pacemaker, atrial
current Ca2+ channel and Purkinje cells. Responsible for pacemaker potential
bringing the cell mambrane to threshold potential.
ICaL L-type Ca2+ Voltage-gated L-type Inward Ca2+ via L-type channels found all cardiac cell types.
current Ca2+ channel Responsible for maintenance of plateau (phase 2) of the
action potential.
Fig. 1 Action potentials and currents involved in (a) myocyte and (b) sinoatrial and atrioventricular. ARP, absolute refractory period; RRP, relative refractory period.
10 BJA Education - Volume 23, Number 1, 2023
In the resting state, specific Kþ channels are open, allowing reduction of the magnitude and rate of depolarisation and,
þ
K to move down its electrochemical gradient. Movement of therefore, speed of conduction.
Kþ into the cell down its electrical gradient is balanced by
movement of Kþ out of the cell down its chemical gradient. At
Sinoatrial and atrioventricular node action potentials
the equilibrium potential for Kþ, these two opposing forces are
balanced, which is quantified by the Nernst equation: The SA node exhibits pacemaker activity resulting from
þ ! spontaneous diastolic depolarisation (phase 4). Under normal
RT K circumstances, the rate of spontaneous depolarisation in the
EK ¼ loge out (1)
zF Kþin
SA node is higher than in other pacemaker cells (e.g. AV node,
Purkinje fibres), resulting in overdrive suppression of latent
where EK is the equilibrium potential for Kþ, R is the uni- pacemaker cells. When the SA node fails to initiate an im-
versal gas constant, T is the (absolute) temperature in pulse, latent pacemaker cells take over the pacemaker func-
degrees Kelvin, F is the Faraday constant, z is the valency tion of the heart. The intrinsic rate of spontaneous
(1 for Kþ), and loge is the natural logarithm. EK is approx- depolarisation of the SA node and other pacemaker cells is
imately e90 mV, which is close to the RMP. At the RMP e affected by neurohumoral responses, drugs and physiological
which is slightly less negative than EK e there is net out- disturbances (e.g. hypoxaemia).
ward movement of Kþ and this current is called the Spontaneous depolarisation results from inwards current of
inwardly rectifier current (IK1). Owing to its relatively high Naþ and Kþ (referred to as the funny current, If), via
membrane permeability, the extracellular Kþ concentra- hyperpolarisation-activated cyclic nucleotide-gated (HCN)
tion is the main determinant of the RMP. channels.1 At approximately e50 mV, voltage-gated T-type
In the presence of cellular hypoxia, the Naþ/Kþ-ATPase Ca2þ channels allow the influx of Ca2þ (ICaT current), which
pump is unable to maintain the transmembrane potential and brings the membrane to the threshold potential. L-type Ca2þ
the Naþ and Kþ concentration gradients across the cell mem- channels then open, resulting in an increase in ICaL (phase 0). L-
brane are reduced. Consequently, the intracellular Kþ concen- type Ca2þ channels open slowly, resulting in a slow rate of
tration decreases and the local extracellular Kþ concentration depolarisation and low conduction velocity. Finally, repolar-
increases (interstitial hyperkalaemia). In accordance with the isation occurs as a consequence of the inactivation of Ca2þ
Nernst equation, the RMP becomes less negative (i.e. partially channels and opening of delayed rectifier Kþ channels (phase 3).
depolarised). For instance, at an extracellular Kþ concentration
of 10 mmol L1, the RMP is about e70 mV.1 Physiological heterogeneity of action potentials
When the cell membrane reaches the threshold potential,
There is heterogeneity of action potentials across different
voltage-gated Naþ channels change from a ‘resting’ to an
parts of the heart because of variable expression of ion
‘open’ state, resulting in rapid inflow of Naþ (INa), depolarising
channels.2,3 This heterogeneity has two main consequences.
the membrane to approximately þ30 mV (phase 0). The rate of
First, atrial cells generally have shorter action potentials than
depolarisation largely determines the conduction velocity of
ventricular myocytes because of their larger transient out-
the propagating action potential. Normally, depolarisation
ward Kþ current (It0). Second, repolarisation times in different
lasts approximately 1 ms, after which time Naþ channels as-
parts of the heart vary. Within the ventricles, there are three
sume an ‘inactivated’ state. Although inactivated, Naþ chan-
electrophysiologically distinct cell types: epicardial, endocar-
nels cannot reopen until the channels enter the ‘resting’ state
dial and mid-myocardial cells (M-cells). The action potential is
when the membrane repolarises. In certain pathological
longer in the Purkinje fibres and M-cells, resulting from
conditions (e.g. myocardial ischaemia), a small number of Naþ
decreased Kþ currents and increased late Naþ current (INaL).4
channels remain open during the plateau (phase 2) of the
Differences in ion channel expression cause variability in
action potential, providing a persistent inwards Naþ current
repolarisation times, which is responsible for a phenomenon
(late Naþ current, INaL), prolonging the action potential.
termed transmural dispersion of repolarisation (TDR). It is
After depolarisation, transient outwards Kþ channels
important to understand action potential heterogeneity in
open, creating an outwards repolarising Kþ current (It0) and
order to appreciate the aetiology of arrhythmias and the tar-
forming a notch on the action potential (phase 1). The plateau
gets for pharmacological treatment.
of the action potential (phase 2) is generated by a balance of
opposing currents: an inwards Ca2þ current (ICaL) via L-type
Ca2þ channels and outwards Kþ currents (rapid and slow Mechanism of arrhythmogenesis
delayed rectifier currents, IKr and IKs, respectively). ICaL slowly Arrhythmias are caused by disturbances in impulse genera-
diminishes during phase 2, whereas IKr and IKs increase, tion and conduction. Bradyarrhythmia occurs with failure of
leading to repolarisation. Phase 3 is characterised by a impulse generation from the SA node or failure of action po-
continual decline of ICaL, increase in IKr and IKs, and recovery tential propagation from the atria to the ventricles resulting
of IK1, leading to repolarisation, returning the membrane to from AV block or abnormalities in the His-Purkinje conduc-
the resting state (phase 4). tion system. Tachyarrhythmias arise via three distinct
Although the membrane is depolarised during phase 2 and mechanisms: (i) enhanced automaticity, (ii) triggered auto-
the early part of stage of phase 3, Naþ channels are unavai- maticity and (iii) re-entry.
lable to generate new action potentials. This period is termed
the absolute refractory period. Once Naþ channels begin to
Enhanced automaticity e normal and abnormal
recover to a ‘resting’ state, a premature action potential may
be generated when a strong enough stimulus occurs during Enhanced normal automaticity refers to a rapid regular
phase 3. This period is termed the ‘relative refractory period’. heartbeat originating from the SA node (i.e. sinus tachy-
The number of Naþ channels available during the rela- cardia). Enhanced normal automaticity occurs with b-adren-
tive refractory period is substantially reduced, resulting in ergic or vagolytic stimulation, hypokalaemia or mechanical
(Fig 2B). After propagation of an action potential in the diseased

region, the next antegrade conduction is blocked, as Naþ
a b channels remain inactivated from the previous action poten-
DAD tial. The impulse eventually enters the diseased region from
downstream, propagating retrogradely if sufficient Naþ chan-
nels have recovered. The abnormal electrical region may be
anatomical (e.g. pre-excitation syndrome with an accessory
pathway) or functional, where the membrane is partially
Normal conduction depolarised (e.g. because of ischaemia), resulting in a region of
EAD slow conduction. Tachycardia caused by re-entry can be tran-
Region of sient or sustained, depending on the number of round trips the
slow circuit makes. Multiple re-entry circuits predispose to atrial or
conduction
ventricular fibrillation.
Re-entry
Influence of heterogeneity of electrical activity on
arrhythmia
Fig. 2 (a) Triggered automaticity. Black solid and dotted lines represent the
normal action potential. Red lines represent action potentials triggered by Another important contributor to arrhythmia is increased
delayed afterdepolarisations (DADs) and early afterdepolarisations (EADs). TDR resulting from exaggerated heterogeneity. Drugs that
Note the reduction in the rate of depolarisation of triggered action potentials prolong the QT interval or the presence of localised abnormal
with reduced slope. (b) Re-entry. In the presence of a region where con- cells, preferentially prolong the action potential in M-cells e
duction is slowed, antegrade conduction is blocked from insufficient Naþ
where the action potential is already longer than that in
channel recovery. Retrograde conduction occurs when the antegrade con-
epicardial or endocardial cells e increasing TDR.6 Increased
duction reaches the area from downstream, causing re-entry.
TDR predisposes to arrhythmia because of triggered automa-
ticity (via EADs) and re-entry (Fig 3). Increased TDR is a
precondition for torsade de pointes ventricular tachycardia in
stretch, causing an increased slope of the phase 4 pacemaker patients with long QT syndrome.7,8
action potential and, therefore, an increased pacemaker rate.2
Enhanced abnormal automaticity refers to a situation
where the heartbeat originates from sites other than the SA
node. Myocyte injury can lead to partial depolarisation of the
membrane. Myocytes with a RMP of e60 to e40 mV have an
Intrinsic heterogeneity
increased tendency to spontaneously depolarise, producing
ectopic atrial and ventricular tachycardias.2,5
QT prolonging Local
drugs ischaemia
Triggered automaticity
Triggered arrhythmia describes the occurrence of a prema-
ture action potential occurring before the previous beat is ↓ Outward IKr, IKs and IK1
complete (Fig 2A). There are two main types of triggered ↑ inward ICaL
automaticity: delayed afterdepolarisations (DADs) and early ↑ inward INaL
afterdepolarisations (EADs).
Delayed afterdepolarisations occur during the early stage
of phase 4 and are caused by intracellular Ca2þ overload, such
as occurs in myocardial ischaemia, adrenergic stimulation, or Preferential
EAD-triggered
digoxin toxicity.2 Intracellular Ca2þ overload upregulates ac- APD prolongation
beat
tivity of the electrogenic 3Naþ/Ca2þ exchanger, bringing the in M-cells
membrane to the threshold potential and ‘triggering’ a pre-
mature action potential.
Early afterdepolarisations occur during phase 3 when the
Increased TDR
action potential is prolonged. Prolongation of the action poten-
tial involves an increase in the inwards INaL and ICaL currents and
reduction in the outwards Kþ currents. Any pathology (e.g.
myocardial ischaemia) or use of pharmacological agents that Torsade de Pointes
inhibit Kþ channels also prolong the action potential, which re-entry
manifests as QT prolongation on the ECG. An important clinical
consequence of EADs is torsade de pointes ventricular tachy-
Fig. 3 Arrhythmia caused by heterogeneity of electrical activity. Repolar-
cardia. Purkinje and M cells inherently have a long action po-
isation is delayed owing to a reduction in the net repolarisation current
tential and EADs are more frequently observed in these regions.2 (outwards IKr, IKs and IK1) and an increase in the net depolarising current
(inwards ICaL and INaL) resulting in preferential increase in action potential
Re-entry duration (APD) in M-cells. Exaggerated transmural dispersion of repolar-
isation (TDR) results in the generation of torsade de pointes. EAD, early
Re-entry arrhythmia arises in regions with functional or afterdepolarisation.
structural conduction delay resulting in unidirectional block
Phase 4
Phase 0 Phase 1
Myocyte Resting Phase 2 Phase 3
Rapid Transient
action potential membrane Plateau Repolarisation
depolarisation repolarisation
potential
+
Myocardial ischaemia
Partial depolarisation of RMP
↑K+ Increased irritability
Reduced RMP Slow conduction
Increased irritability → re-entry risk
Conduction delay Spont Ca2+ release
and block → ↑ DAD risk
↓Ik→ ↑ AP duration
& EAD risk
Bradycardia
(vagal stimulation/drugs)
Depressed SA node ↓K+, ↓Mg2+, ↓Ca2+
Emergence of latent ↑AP duration and
pacemaker activity QT interval
Increased TDR → EAD risk
↑Sympathetic stimulus
↑If current → ↑automaticity
↑ICaL → ↑DAD risk QT prolonging
↑AP duration drugs
↑EAD risk ↑AP duration and
Faster SA node QT interval
depolarisation → EAD risk
Phase 4 Phase 0
SA/AV node Phase 3
Pacemaker Slow
action potential Repolarisation
potential depolarisation
Fig. 4 Patient-related factors that increase risk of arrhythmia and their mechanisms.
Arrhythmia in the perioperative period the slope of phase 4 of pacemaker cells. Simultaneously,
Ca2þ entry via ICaL also increases, leading to Ca2þ release
If possible, factors that increase the risk of developing
from the sarcoplasmic reticulum, which results in Ca2þ
arrhythmia should be corrected before surgery. Modifiable
overload, predisposing to arrythmia caused by DADs (trig-
causes of arrhythmia include physiological or biochemical
gered automaticity).
disturbances and acute pathological conditions, such as sepsis
and myocardial ischaemia (Fig. 4). Surgery-related oxidative Severe bradycardia
stress, systemic inflammation, autonomic dysfunction and Bradycardia or heart block results from depressed SA node
damage to autonomic fibres are also proposed risk factors.9 activity or severe AV conduction delay, which can occur with
intense vagal stimulation (e.g. during laparoscopic surgery).
Patient-related factors Latent pacemaker cells within the AV node, ventricular
myocytes or Purkinje fibres then take over impulse genera-
Increased sympathetic activity tion. Impulses arising in latent pacemaker cells have a pro-
Any insult to physiological homeostasis, such as hypoxaemia, longed action potential duration relative to the SA node,
hypercarbia, acidosis or pathological processes, can lead to which enhances TDR. Bradycardia exacerbates action poten-
increased sympathetic nervous system activity. Anaesthesia tial heterogeneity between neighbouring cells, creating an
(e.g. laryngoscopy) and surgical (e.g. skin incision) procedures electrical gradient that facilitates ventricular ectopic beats
can induce an intense sympathetic response. Drugs with and re-entry arrhythmia.10
sympathomimetic effects (e.g. ketamine, ephedrine, adrena-
line [epinephrine]) can have similar consequences. Myocardial ischaemia and infarction
Stimulation of b1 receptors leads to the opening of HCN Ischaemic myocardial cells become partially depolarised.
channels with the increased inwards If current steepening In this state, Ca2þ may be spontaneously released from the
sarcoplasmic reticulum, which indirectly triggers increased myocardial depression and bradycardia. The baroreceptor
activity of the 3Naþ/Ca2þ exchanger. The electrogenic inflow reflex is also attenuated, reducing the compensatory re-
of Naþ causes pacemaker-like activity, increasing the risk of sponses to hypotension. Propofol is the i.v. Anaesthetic agent
DADs. In addition, partial membrane depolarisation slows the used most frequently, and has a significant cardiovascular
rate of depolarisation during phase 0, creating an area of slow depressant effect in susceptible patients. Ketamine increases
conduction, predisposing to re-entry. sympathetic activity and prolongs the QT interval (see below),
both of which predispose to arrhythmia.
Electrolyte disturbances
Electrolyte disturbances are an important cause of perioper- Opioids
ative arrythmia. Hypokalaemia with serum Kþ <3.5 mmol L1 Opioids rarely cause marked haemodynamic instability.
(e.g. from diuretic therapy) hyperpolarises the RMP, causing However, large boluses, especially of alfentanil and remi-
depressed automaticity and AV block. Severe hypokalaemia fentanil, are associated with severe sinus bradycardia caused
(<2.5 mmol L1) inhibits delayed rectifier Kþ channels, pro- by a direct parasympathetic effect and blunting of sympathetic
longing the action potential and increasing the risk of devel- tone.15,16 Methadone prolongs the QT interval (see below).
oping EADs and DADs. Atrial fibrillation and flutter are the
most common perioperative arrhythmia associated with Anticholinesterases
hypokalaemia and serum Kþ <3.5 mmol L1 is an indication Anticholinesterases (e.g. neostigmine) increase acetylcholine
for Kþ replacement.11 concentration and stimulate muscarinic receptors. Activation
Hyperkalaemia (>5.0e6.0 mmol L1) initially shortens of M2 receptors within the heart causes bradycardia and AV
the action potential duration and the absolute refractory conduction delay. To prevent severe bradycardia, anticholin-
period. However, as hyperkalaemia worsens (>7.0 mmol ergic drugs (atropine, glycopyrrolate) should be given together
L1), the RMP becomes partially depolarised, inducing with neostigmine.
postrepolarisation refractoriness and prolonging the abso-
lute refractory period. As the number of Naþ channels Vasoconstrictors
available for depolarisation is reduced, the rate of phase Vasoconstrictors (phenylephrine, metaraminol, noradrena-
0 depolarisation decreases along with the conduction ve- line [norepinephrine]) have no direct proarrhythmic effects.
locity. Severe hyperkalaemia is associated with conduction However, these agents can cause hypertension, which in turn
block (e.g. left bundle branch block, right bundle branch activate carotid baroreceptors, leading to reflex bradycardia.
block, AV block), asystole, ventricular tachycardia and The effect is typically short-lived and does not usually require
ventricular fibrillation.12 intervention.
Hypocalcaemia (ionised Ca2þ <1.17 mmol L1) prolongs the
action potential and is associated with EADs, predisposing to
Drugs that prolong the QT interval
torsade de pointes ventricular tachycardia. Hypocalcaemia also
Several drugs commonly given during the perioperative
exacerbates the pro-arrhythmia effect of hyperkalaemia.13
period can prolong the QT interval (Table 2). It is postulated
Hypercalcaemia (ionised Ca2þ >1.4 mmol L1) shortens the
that drugs that cause torsade de pointes ventricular tachycardia
action potential but is not associated with clinically important
preferentially prolong the QT interval of M-cells and Purkinje
arrhythmia.
fibres, thereby worsening TDR and increasing the risk of
Hypomagnesaemia (<0.74 mmol L1) commonly coexists
ventricular arrhythmia.
with hypokalaemia and hypocalcaemia, as a consequence of
Numerous anaesthetic drugs increase the QT interval but
diuretic therapy.14 Reduced Mg2þ concentration leads to a
do not increase the risk of torsade de pointes ventricular
decrease in Naþ/Kþ-ATPase activity, rendering the RMP less
tachycardia owing to their limited effect on TDR. Such agents
negative. This in turn slows the rate of depolarisation and
include volatile anaesthetics, thiopentone, midazolam and
decreases the outwards Kþ current, prolonging the QT interval,
etomidate. Therefore, these drugs are safe for use in patients
thereby increasing the risk of ventricular ectopic beats and
with a prolonged QT interval. However, ketamine and meth-
torsade de pointes ventricular tachycardia. Although moderate
adone do increase TDR and are associated with torsade de
hypermagnesaemia has no known clinically important effects
pointes ventricular tachycardia and should be avoided in pa-
on cardiac rhythm, severe hypermagnesaemia (>4 mmol L1)
tients with a prolonged QT interval.
exerts a calcium antagonist effect and may cause conduction
Patients with a corrected QT (QTc) >450 ms (males) and
defects, bradycardia and hypotension.
>460 ms (females) are at risk of developing ventricular
When combined with other risk factors, electrolyte dis-
arrhythmia.
turbances substantially increase the risk of developing clini-
cally important arrhythmias.
Management of perioperative arrhythmia
Metabolic and respiratory abnormalities
Assessment before surgery
Metabolic and respiratory abnormalities, such as hypoxaemia,
hypercarbia and acidebase disturbances, can increase sym- An ECG should be obtained in all patients with known car-
pathetic nervous system activity, leading to arrhythmia. diovascular disease. The following abnormalities should be
specifically sought: ischaemia, previous myocardial infarc-
tion, ventricular hypertrophy or strain, prolonged QTc, bundle
Pharmacological factors
branch block and arrhythmias. Acute or unexpected abnor-
Intravenous anaesthetic agents malities should be evaluated with an echocardiogram to
Most agents used for inducing general anaesthesia reduce identify functional or structural heart disease. Accurate
sympathetic nervous system activity, potentially leading to diagnosis of arrhythmia and its cause can be difficult in the
Intraoperative management
Table 2 Drugs that increase the QT interval and the risk of
inducing torsade de pointes.7,8 *Adrenergic drugs should be When arrhythmia is encountered, the following general steps
avoided unless necessary; metaraminol and phenylephrine should be considered before starting pharmacological
can be used safely. yNeostigmine-glycopyrrolate prolongs the therapy:
QT interval and thus should be avoided if possible. zAlthough
Identify and eliminate the cause(s).
5HT3 antagonists should be avoided, ondansetron has been
Establish an accurate diagnosis.
used without any issues. ¶Ketamine should be avoided
Evaluate the presence of underlying structural or func-
because of the increased sympathetic activity. Other intra-
tional heart disease, especially congestive heart failure or
venous anaesthetic agents are safe.
ischaemic heart disease. Few antiarrhythmic drugs have
Adrenergic drugs* Adrenaline an established safety profile in these settings.17
Dobutamine Once the decision is made to use an antiarrhythmic drug,
Dopamine the adverse effect profile and patient-specific contraindi-
Ephedrine cations should be considered. For example, amiodarone in
Noradrenaline patients with severe pulmonary disease, b-blockers in pa-
Salbutamol
tients with asthma, and calcium channel blockers in pa-
Antiarrhythmic agents Class Ia and class III drugs
Antibiotics Azithromycin tients with acute decompensated heart failure.5,10
Clarithromycin
Erythromycin Management after surgery
Anticholinergic agentsy Atropine
Glycopyrrolate Patients with arrhythmias that are self-limiting can usually
Antiemetic agents Chlorpromazine follow a routine postoperative care pathway. Arrhythmias
Droperidol such as sinus bradycardia, first-degree heart block, junctional
Domperidone rhythm, sinus tachycardia and premature ventricular con-
Metoclopramide
tractions are common and rarely require further management.
Ondansetronz
Intravenous anaesthetic Ketamine Clinically significant arrhythmias, such as new onset atrial
agents¶ fibrillation, second-degree or complete AV block and persis-
Neuromuscular blocking Pancuronium tent ventricular arrhythmias, require continuous ECG moni-
agents Suxamethonium toring and evaluation by a cardiologist. If there is
Opioids Methadone haemodynamic instability, admission to the high dependency
Sufentanil
unit or ICU is appropriate.
Oxytocic agents Oxytocin
Conclusions
short window before surgery and an opinion from a cardiol- Perioperative arrhythmias are common and are attributable to
ogist can be useful when unexpected arrhythmias are iden- a multitude of factors including the drugs used for anaes-
tified. Arrhythmias that may warrant postponing surgery thesia, electrolyte disorders and patient pathologies (sepsis,
include trifascicular block, second degree heart block, com- myocardial ischaemia). The majority of perioperative cardiac
plete heart block, or new onset left bundle branch block, atrial arrhythmias do not require intervention other than general
fibrillation, atrial flutter, supraventricular tachycardia or supportive care. Treatment of the underlying cause of the
sustained ventricular arrhythmia. arrhythmia is crucial. Before an antiarrhythmic drug is given,
the potential benefits and risks should be considered care-
Indications for antiarrhythmic drug therapy fully, as inappropriate use can lead to increased morbidity and
mortality.
Antiarrhythmic drugs may be indicated in the following set-
tings: alleviation of symptoms, to improve cardiac function
when dysfunction is a result of tachycardia or dyssynchrony, Declaration of Interest
to prevent progression into a life-threatening arrhythmia, and The authors declare that they have no conflicts of interest.
to reduce the need for electrical cardioversion.17
The benefit of symptom relief in patients with chronic
arrhythmia is controversial, as adverse effects may negate MCQs
any benefit from symptomatic relief. Many antiarrhythmic The associated MCQs (to support CME/CPD activity) will be
drugs have a narrow therapeutic window and exhibit inter- accessible at www.bjaed.org/cme/home by subscribers to BJA
patient variability in efficacy. Several trials, including the Education.
Cardiac Arrhythmia Suppression Trial (CAST), Survival with
Oral D-sotalol (SWORD), and Atrial Fibrillation Follow-up
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BJA Education, 23(1): 8e16 (2023)

Matrix codes: 1A01,

Antiarrhythmic drugs and anaesthesia: part 1.

Keywords: anti-arrhythmic agents; arrhythmias; cardiac; cardiac electrophysiology

Learning objectives Key points

Accepted: 3 November 2022

Electrophysiology of the heart

Table 1 Terms and their meanings.

BJA Education - Volume 23, Number 1, 2023 9

Currents Channels Description

It0 Transient Voltage-gated K+ Transient outward repolarising K+ current producing a

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(Fig 2B). After propagation of an action potential in the diseased

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