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An 85-year-old woman presented to the emergency department with drowsiness on a background of functional decline of two weeks’ duration. Her medical history was significant for hypertension and hyperlipidaemia, for which she was on regular follow-up. Medications included amlodipine 10 mg OM (every morning), atenolol 100 mg OM, atorvastatin 20 mg ON, frusemide 40 mg OM, prazosin 0.5 mg BD (twice daily) and valsartan 160 mg OM. The patient was drowsy with Kussmaul breathing prior to a transient period of asystole noted on the cardiac monitor. Immediate resuscitation was performed with return of spontaneous circulation after 10 seconds.
Initial investigations showed decompensated metabolic acidosis (pH 7.14, partial pressure of carbon dioxide 24 mmHg, bicarbonate 8.4mmol/L) with hyperkalaemia (6.9 mmol/L), for which she was treated with calcium gluconate, insulin and dextrose. What did her admission electrocardiogram (ECG) show (
Case 1: Initial ECG on admission performed after resuscitation.
Case 1: Rhythm strip on ECG shows transcutaneous pacing, with arrows indicating pacing spikes.
The patient’s hypotensive and bradycardic episodes persisted following resuscitation despite initiation and titration of intravenous dopamine to 20 mcg/kg/min. Further investigations revealed acute kidney injury, with an elevated creatinine level of 853 mmol/L from a baseline of 65 mmol/L. The patient was then intubated for airway protection, started on inotropic support and administered intravenous glucagon. She was also commenced on transcutaneous pacing (TCP) at 70 beats per minute (bpm) (
The patient’s intrinsic cardiac rhythm improved following two days of CRRT, with an improvement in her heart rate. The TCP backup pacing and inotropes were gradually weaned and stopped after four days, and the patient became haemodynamically stable without support. Atenolol was also stopped since admission.
A 53-year-old man with a significant medical history of Type 2 diabetes mellitus, hypertension, hyperlipidaemia, chronic kidney disease and ischaemic heart disease presented with non-ST elevation myocardial infarction on a background of septic shock and acute-on-chronic kidney injury/disease (AoCKD). His medications included aspirin 100 mg OM, clopidogrel 75 mg OM, carvedilol 6.25 mg BD, atorvastatin 40 mg ON and frusemide 80 mg TDS (three times a day). The patient developed haemodynamically significant bradycardia despite being administered intravenous dopamine of 20 mcg/kg/min. What does the ECG (
Case 2: ECG at the onset of clinical deterioration.
Case 2: Electrocardiogram after transvenous pacing.
Case 2: Chest radiograph after transvenous pacing.
The patient remained haemodynamically unstable on intravenous infusion of dopamine of 20 mcg/kg/min and was started on TCP. This resulted in improvement of haemodynamics. Laboratory investigations revealed progression of AoCKD. Review of drug charts also revealed that the patient had been consistently administered carvedilol 6.25 mg BD during his inpatient stay. A diagnosis of haemodynamically significant bradycardia secondary to carvedilol retention on a background of poor renal clearance owing to AoCKD was established. The patient was sent to the coronary care unit for immediate TVP to augment cardiac output.
BBs are commonly used in general practice for a variety of medical conditions. Major society guidelines have indicated the use of BBs for the management of stable ischaemic heart disease, acute coronary syndrome,(1-3) atrial fibrillation,(4) atrial flutter,(4) supraventricular tachycardia,(5) ventricular tachycardia,(6) hypertrophic cardiomyopathy(7) and heart failure.(8)
The pharmacokinetic properties of BBs can be broadly divided into lipophilic and hydrophilic drugs. Lipophilic drugs (e.g. metoprolol, propranolol and timolol) are absorbed from the enteral route but undergo extensive hepatic first-pass metabolism, leading to low oral bioavailability (10%–30%). Hence, these drugs may accumulate in patients with reduced hepatic perfusion (e.g. elderly patients, or those with congestive cardiac failure or liver cirrhosis) (
Pharmacokinetics of some commonly used beta-blockers.(10)
Conversely, hydrophilic drugs (e.g. atenolol and esmolol) are absorbed in their entirety from the gastrointestinal tract and are renally excreted unchanged or as active metabolites. These drugs do not readily cross the blood-brain barrier and have longer elimination half-lives (6–24 hours), which are further prolonged in case of a reduction in glomerular filtration rate (GFR) (i.e. elderly individuals, patients with renal insufficiency) (
Properties of beta-blockers in relation to renal function.(10)
BBs such as bisoprolol exhibit equal hepatic and renal clearance (balanced clearance),(9) while carvedilol has a low oral bioavailability owing to its extensive first-pass metabolism. It binds to plasma proteins and is eliminated hepatically.(11)
Adverse events related to beta-blocker use
In general, beta-adrenergic inhibitors are well tolerated. However, serious adverse events may still occur, especially when BBs are used in large doses,(9) as briefly mentioned below.
BBs may cause haemodynamically significant bradycardia and AV block via their negative chronotropic and inotropic properties. Further, BBs may reduce peripheral tissue perfusion owing to unopposed stimulation of vascular alpha-adrenoceptors because of blockade of vascular beta-adrenoceptors, leading to peripheral vasoconstriction, Raynaud’s phenomenon, impotence and deterioration of symptoms in patients with severe peripheral vascular disease. These side effects may be mitigated via the selection of agents with beta1-selectivity. BBs may also cause coronary vasospasm and ischaemia via their effect on increasing coronary vasomotor tone, again owing to unopposed alpha-adrenergic-mediated vasoconstriction.(9,11) Finally, abrupt discontinuation of BBs following long-term therapy may lead to rebound symptoms such as arrhythmias and angina.(12)
In patients with diabetes mellitus, non-selective BBs may hide manifestations of hypoglycaemia such as tremor and tachycardia. Hence, beta1-selective agents are preferred in this vulnerable patient population.
Beta2-adrenoceptors are responsible for bronchodilation of the pulmonary tree, and BBs may cause life-threatening bronchoconstriction, hyper-reactivity and increased airway resistance. As a result, BBs are relatively contraindicated in patients with asthma and bronchospastic chronic obstructive pulmonary disease.(13)
Effects on the central nervous system
Lipophilic BBs can cross the blood-brain barrier, leading to central nervous system (CNS) side effects such as fatigue, headache, insomnia, vivid dreams and depression. Clinicians may consider switching patients who experience these symptoms to a hydrophilic BB, where CNS penetration and side effects are markedly reduced.(14)
Management of symptomatic and/or haemodynamically unstable bradycardia
While sinus and junctional bradycardia are generally benign, extreme bradycardia from asystole or prolonged sinus arrest or AV blocks may render a patient symptomatic and/or lead to haemodynamic instability, which warrants acute management.
Pharmacological therapy can be immediately started with agents that increase the sinus heart rate or the escape rhythm, such as atropine, isoprenaline, dopamine, dobutamine and adrenaline.(15)
TCP is an effective but underused modality owing to the discomfort it causes to the patient. It is suitable as an emergency life-saving therapy or as backup for infrequent pacing. In Case 1, TCP was initiated for haemodynamically significant bradycardia despite using the maximal dose of intravenous dopamine infusion. We opted for TCP instead of TVP, as the bradycardia of the patient was reversible with dialysis, thus avoiding the potential complications of TVP.
Temporary TVP is an alternative to TCP but risks potentially serious complications such as infection, myocardial perforation and tamponade. The 2013 European Society of Cardiology guidelines on pacing suggest that TVP be used only when pharmacological therapy fails and that it be limited to cases of high-degree AV block without escape rhythm, life-threatening bradyarrhythmias or in acute settings (acute myocardial infarction, drug toxicity or concomitant systemic infection).(16) In Case 2, a transvenous pacing wire was inserted into the RV apex, as the patient remained haemodynamically compromised despite receiving the maximal dose of intravenous infusion of dopamine.
Lastly, haemodialysis may be considered when patients have been haemodynamically stabilised and if there is a dialysable culprit drug leading to bradycardia. In Case 1, the patient was initiated on CRRT immediately upon stabilisation of her clinical parameters. It is of utmost importance to identify any potentially reversible causes of an unstable bradycardia and address them, as evidenced by Case 1, where patients could be weaned off TCP following clearance of supratherapeutic levels of atenolol.
In conclusion, despite the vast therapeutic indications of BBs, their use is associated with potentially life-threatening risks. Prompt recognition of the signs and symptoms as well as the predisposing factor of BB-related toxicities and instituting appropriate emergency medical therapy are of utmost importance in the face of an ageing population with multiple comorbidities and polypharmacy.
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