BRASH syndrome: an emerging emergency

¹Division of Nephrology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University and Tygerberg Hospital, Cape Town, South Africa, ²Division of General Medicine, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University and Tygerberg Hospital, Cape Town, South Africa

^&Corresponding author
Mogamat-Yazied Chothia, Division of Nephrology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University and Tygerberg Hospital, Cape Town, South Africa

Introduction    

BRASH syndrome (bradycardia, renal failure, atrioventricular nodal (AVN) blockers, shock and hyperkalaemia) is an emerging condition that occurs due to the synergistic effects of hyperkalaemia and AVN blockers on the heart [1]. It was first formally described by Farkas in 2016 where he described an elderly woman with unexplained refractory multiorgan failure and subsequently identified beta-blocker toxicity as the culprit [2]. The syndrome is a distinct entity that lies at the epicenter along a continuum, with isolated hyperkalaemia at one end of the spectrum and AVN blocker toxicity at the other. The typical patient at risk for the syndrome is an elderly patient with underlying heart disease and poor kidney reserve receiving treatment with AVN blocking agents such as beta-blockers (BB), and non-dihydropyridine calcium channel blockers (CCB) such as verapamil and diltiazem [2]. The most common precipitant is thought to be hypovolaemia. A study that investigated consecutive elderly patients requiring urgent transvenous cardiac pacing for bradyarrhythmias reported that it developed more frequently during the summer months and attributed hypovolaemia as the trigger for this phenomenon [3]. Other triggers include increasing doses of blood pressure medication, the addition of or increasing doses of renin-angiotensin aldosterone system inhibitors (RAASi) and any cause of acute kidney injury [1,2]. In clinical practice, it may be difficult to distinguish the syndrome from the isolated effects of hyperkalaemia or AVN blockers. Clues that should raise suspicion of BRASH syndrome include bradycardia in conjunction with hyperkalaemia in the absence of classic electrocardiographic features of hyperkalaemia [1,4] and occasionally, a dramatic response to intravenous calcium [1]. We report on an elderly woman that presented with multiple episodes of syncope and heart failure a few months after restarting BB therapy for paroxysmal atrial fibrillation and was subsequently diagnosed and treated for BRASH syndrome.

Patient and observation     

An 88-year-old woman, known with hypertension, stage 5 chronic kidney disease (not on dialysis) and paroxysmal atrial fibrillation (PAF), presented with a history of four syncopal episodes in the past 2-months and currently had dyspnoea and lethargy for 1-day. Prior to the current presentation, it was noted that the patient presented with bradycardia 4-years ago, which resolved following cessation of atenolol; however, 2-months before this admission, atenolol 50 mg daily was restarted by her local clinic for PAF. Other chronic medication included furosemide 80 mg twice daily, spironolactone 25 mg daily, losartan 50 mg daily, amlodipine 10 mg daily and warfarin.

Clinical examination revealed a blood pressure of 105/60 mmHg (mean arterial pressure of 75 mmHg), a regular pulse with a rate of 31 beats per minute and body temperature was 36.7°C. Hydration status was thought to be normal. She had features suggestive of left-sided heart failure. Pertinent laboratory results were as follows: sodium 136 mmol/L (normal range: 136-145 mmol/L), potassium 6.7 mmol/L (normal range: 3.5-5.5 mmol/L) , urea 25.6 mmol/L (normal range: 2.1-7.1 mmol/L), creatinine 318 μmol/L (normal range: 49-90 μmol/L) (estimated glomerular filtration rate of 11 mL/min/1.73 m²), calcium 2.17 mmol/L (normal range: 2.20-2.55 mmol/L), haemoglobin 10.2 g/dL (normal range: 12-15 g/dL), TSH 1.83 mIU/L (normal range: 0.27-4.20 mIU/L) and high-sensitivity troponin 46 ng/L. Her electrocardiogram indicated a severe sinus bradycardia without any classic features of hyperkalaemia (Figure 1).

The constellation of bradycardia, renal failure, use of a BB, hypotension (shock) and severe hyperkalaemia was diagnostic of BRASH syndrome. The patient was admitted to our high care unit for continuous cardiac telemetry. Her chronic medication was stopped including atenolol. On days 1 to 3, the patient received multiple doses of 10 mL of 10% calcium gluconate intravenously (IV) without any improvement in the heart rate. During the same period, frequent potassium shifting using 10 units of rapid-acting insulin along with 50 mL of 50% glucose were also utilised. One liter of isotonic sodium bicarbonate was administered over 24 hours on day 3 of hospitalisation, along with furosemide 40 mg twice daily IV and oral lactulose 10 mL thrice daily to eliminate potassium from the body. Her kidney function improved with isotonic IV fluids (Figure 2). The patient displayed a good response to treatment (Figure 2). She was advised to avoid future use of any beta-blockers and was discharged 1-week following hospitalisation.

Discussion     

Patients with BRASH syndrome may present along a spectrum, from a coincidental finding of bradycardia to multiorgan failure [1]. Our patient presented with a history of 4 syncopal episodes and heart failure. Syncope seems to be the most common initial symptom of BRASH syndrome. A recent clinical review found that 13 of 23 patients (56.5%) presented with either presyncope or syncope, while the remaining patients presented with dyspnoea, diaphoresis, chest pain, weakness or lethargy in isolation or in combination with presyncope/syncope [1].

Little is known regarding its epidemiology; however, older age, poor kidney function, use of AVN blockers such as BBs and CCBs, as well as RAASi´s are common findings in a recent review of 23 cases [1]. In the latter series [5-21], the average age was 67.5 years (range 24 - 97 years). Thirteen patients were using CCBs and/or BBs in combination with RAASi´s, while 10 patients were using CCBs or BBs in isolation. Clinically, the average heart rate was 32 beats per minute (range 20 - 56 beats per minute) and the average mean arterial pressure was 62 mmHg (range 40 - 131 mmHg). For the laboratory findings, the average serum potassium concentration was 6.9 mmol/L (range 5.6 - 10.1 mmol/L) and the average serum creatinine was 260 μmol/L (range 115 - 751 μmol/L). The creatinine concentration was not reported in 4 patients because they were receiving dialysis. All these findings were present in our patient. Since elderly patients are more likely to be hypertensive, and have underlying heart and/or kidney disease, it is not surprising that BRASH syndrome is more likely to develop in this group of patients. The latter risk factors along with the prescription of antihypertensives (CCBs, BBs and RAASi´s), anti-heart failure (BBs and RAASi´s) and renoprotective drugs (RAASi´s), creates the perfect storm.

Regarding the pathogenesis, preceding renal hypoperfusion due to volume depletion from any cause, leads to kidney failure or exacerbates existing kidney disease [22]. This causes reduced renal elimination of both AVN blockers as well as potassium. Bradycardia develops due to the ensuing hyperkalaemia as well as the toxic effect of drugs on the AV node [1]. The bradycardia in turn further reduces kidney perfusion due to a reduction in cardiac output, resulting in a vicious cycle. Although kidney failure may prolong the half-life of AVN blockers that are renally eliminated, this mechanism along with RAASi are contributary and are not required for the syndrome to develop. Since volume status was thought to be normal in our patient, the negative inotropic and chronotropic effects of the BB was thought to decrease the effective arterial blood volume, reducing kidney perfusion resulting in acute-on-chronic kidney failure. The latter reducing the kidney´s ability to eliminate both the BB and potassium.

A common mistake is focusing on a single aspect of the syndrome, rather than addressing all the factors involved the pathogenesis. The key to management is a multipronged approach which includes stopping the offending agent/s such as BBs and/or CCBs, instituting general principles for the management of hyperkalaemia, management of the bradycardia and fluid resuscitation [1]. Specifically, repeated doses of intravenous calcium salts, beta-2 agonist nebulisations and isotonic sodium bicarbonate should be considered for the management of hyperkalaemia. As alluded to previously, there may be a dramatic response to IV calcium with improvement of the bradycardia as well as cardiac inotropy. Repeated doses of IV calcium should be administered until a chronotropic response occurs. However, in the absence of a response, there should be a low threshold for intravenous adrenaline [1]. This has the advantage of increasing the heart rate, as well as shifting potassium intracellularly. Since hypovolaemia plays a pivotal role, isotonic sodium bicarbonate will improve volume status and therefore kidney perfusion, while simultaneously improving metabolic acidosis and hyperkalaemia. Most patients respond well to these general management principles without the need for more aggressive therapies. If these measures are not successful, then more advanced therapies should be considered. These include haemodialysis, IV lipid emulsions, IV glucagon and high-dose insulin and glucose, and transdermal or transvenous cardiac pacing [1,23]. Although our patient did not respond to repeated doses of IV calcium, she remained haemodynamically stable, and a decision was made not to use adrenaline. The hyperkalaemia as well as the acute kidney injury responded well to multiple doses of IV insulin and glucose, as well as the isotonic fluids including isotonic sodium bicarbonate.

Conclusion     

In patients with syncope, BRASH syndrome should be considered when bradycardia is associated with hyperkalaemia, without classic ECG changes, along with a history of AVN blocker use. It is important to recognise so that appropriate therapy can be instituted that addresses all the elements of the syndrome, rather than focusing on a single component.

Competing interests     

The authors declare no competing interests.

Authors' contributions     

MYC was involved the clinical management of the patient and drafted the first version of the manuscript. MYC and MRD revised and approved the final version of the manuscript. All authors have read and agreed to the final manuscript.

Figures     

Figure 1: the electrocardiogram at admission showing sinus bradycardia without classic features of hyperkalaemia

Figure 2: the average daily heart rate, serum creatinine and potassium concentration during admission. D, day

References