Postoperative respiratory depression caused by iatrogenic hypermagnesaemia

Summary

Hypermagnesaemia is an uncommon electrolyte disorder which can be fatal if not recognised and treated promptly. The signs and symptoms of hypermagnesaemia are non‐specific, making it an under‐diagnosed cause of cardiovascular dysfunction, hypocalcaemia, and neurological and respiratory depression. Since magnesium homeostasis is handled almost exclusively by the kidneys, symptomatic hypermagnesaemia seldom occurs in the context of normal renal function; when it does, it is usually iatrogenic. Here, we report a case of iatrogenic hypermagnesaemia which presented as respiratory depression, preventing weaning from mechanical ventilation following cardiac surgery in a patient in the early stages of chronic kidney disease. On investigation he was found to have isolated severe hypermagnesaemia, following an intravenous bolus of magnesium sulphate administered intra‐operatively to treat tachyarrhythmia. Before administering intravenous magnesium therapeutically, it is important for clinicians to assess renal function and baseline serum magnesium along with other possible risk factors for hypermagnesaemia, and to actively look for signs and symptoms of magnesium toxicity when the patient is receiving therapeutic magnesium.

Introduction

Magnesium is the second most abundant intracellular cation with pleiotropic effects in the body. It acts as a cofactor in over 300 enzymatic reactions. It plays a crucial role in the regulation of cardiac excitability, vasomotor tone, arterial blood pressure, nerve transmission and neuromuscular conduction, muscular contraction and insulin metabolism. Normal serum magnesium levels vary from 0.75 to 0.95 mmol.l⁻¹ [1]. Hypermagnesaemia is usually well tolerated, which is why it is often overlooked. When symptomatic, it has a wide variety of presenting symptoms, often making it a diagnosis by exclusion of the potential causes of cardiorespiratory and neurological depression. Here, we report a case of a patient with early chronic kidney disease (CKD) who received an i.v. bolus of magnesium sulphate for tachyarrhythmia during cardiac surgery without knowledge of the pre‐operative magnesium concentration. This resulted in severe symptomatic hypermagnesaemia requiring haemodialysis. This case highlights the importance of routinely testing serum magnesium values in patients with renal insufficiency before undergoing interventions that might require therapeutic magnesium supplementation.

Report

A 42‐year‐old man was admitted to our institution with heart failure and was diagnosed with rheumatic heart disease manifesting as severe calcific mitral stenosis and severe tricuspid regurgitation complicated by moderate right ventricular systolic dysfunction (tricuspid annular plane systolic excursion 11 mm) and congestive hepatopathy. He had a history of type two diabetes mellitus, stage two CKD with a baseline creatinine of 100 μmol.l⁻¹ and an estimated glomerular filtration rate (eGFR) of 80 ml.min⁻¹. On examination, he was comfortable at rest. His jugular venous pulse was elevated with a prominent v‐wave and he had mild pedal oedema. He had no palpable organomegaly. He received pre‐operative diuretic therapy (furosemide 40 mg i.v. BD) and an infusion of glyceryl trinitrate for heart failure. On the fourth day of his admission, the patient proceeded to mitral valve replacement and tricuspid annuloplasty. Postoperatively he had severe respiratory depression, with a respiratory rate of 6 breaths.min⁻¹. There was no evidence of residual neuromuscular blockade as assessed by train‐of‐four ratio (>0.9, 12 h after muscle relaxant use). At the time of the nephrology consult a few hours postoperatively, he was sedated and on mechanical ventilation. The assessment of his serum electrolytes revealed a magnesium concentration of 3.66 mmol.l⁻¹, which was confirmed on repeat testing. The patient was passing adequate volumes of urine (100–120 ml.h⁻¹) and was haemodynamically stable with no tachy‐ or bradyarrhythmia. His spinal reflexes were normal. While investigating possible causes of acute hypermagnesaemia, it was found that the patient had a single run of ventricular tachyarrhythmia after separation from bypass which cardioverted following 1 g (4 mmol) of i.v. magnesium sulphate heptahydrate 50%, in addition to the 2 g (8 mmol) already given after cross clamp release and before separation from bypass.

Pre‐operative serum magnesium was unavailable. Serum potassium, calcium, creatine kinase and lactate dehydrogenase levels were within normal limits eliminating rhabdomyolysis and haemolysis, hyperparathyroidism or hypercalcaemia‐induced magnesium absorption in the renal tubules. Urine calcium to creatinine ratio was within normal range ruling out familial hypercalciuric hypocalcaemia. Thyroid function was normal, ruling out hypothyroidism. He had no manifestations of cortico‐adrenal insufficiency. The patient had no pre‐existing bowel conditions that could increase magnesium absorption. There was no history of intake of lithium‐based psychotropic drugs that could impede urinary excretion of magnesium. Magnesium‐based antacids or proton pump inhibitors were not administered. In the absence of any other obvious cause, a diagnosis of iatrogenic hypermagnesaemia was made.

The patient was managed initially with i.v. calcium gluconate (1.5 g bolus followed by an infusion of 1 g over 6 h), i.v. sodium chloride 0.9% (titrated according to urine output and volume status) and loop diuretics (furosemide infusion at 2 mg.h⁻¹) while closely monitoring his ECG, haemodynamic state, conscious state and two hourly examination of motor power and patellar reflexes. Serum magnesium and calcium levels were monitored two hourly for 6 h after which the decision to commence haemodialysis was made as his respiratory depression had not improved despite a slight decrease in serum magnesium values and a Glasgow Coma Scale score of 15 (Fig. 1). One session of haemodialysis was performed with a dialysate containing magnesium < 0.5 mmol.l⁻¹, calcium 1.75 mmol.l⁻¹ and potassium 2 mmol.l⁻¹.

Figure 1.

Graph representing variations in serum magnesium (blue), calcium (orange) and potassium (grey) after the cardiac surgery. Red arrow indicates the time of haemodialysis.

After dialysis, the serum magnesium concentration was 2.35 mmol.l⁻¹ and the respiratory function improved, permitting extubation of the patient’s trachea. He was maintained on i.v. furosemide and normal saline (titrated according to daily urine output and volume status). The serum magnesium returned to within the normal range (0.62 mmol.l⁻¹) on the sixth postoperative day. There were no further complications, and the patient was discharged on the ninth postoperative day with a serum creatinine of 97 μmol.l⁻¹.

Discussion

Respiratory depression following surgery is not uncommon but requires timely recognition and intervention. The most common cause is opioid‐induced respiratory depression. Other causes are residual anaesthesia or muscle relaxant, concurrent use of other sedatives, deranged electrolytes, obstructive sleep apnoea and diaphragmatic splinting from inadequate pain control [2]. Hypermagnesaemia is generally well tolerated and is thus often overlooked. However, this case highlights that even a single dose of i.v. magnesium sulphate can cause high serum levels especially in patients with CKD. Magnesium acts as a physiological calcium blocker and high levels can lead to substantial electrophysiological and haemodynamic effects. It causes cardiac conduction delay and hypotension, mainly by blocking myocardial calcium channels and by blocking the potassium channels needed for repolarisation. Magnesium also decreases the amount of acetylcholine liberated by motor nerve impulses, and decreases the sensitivity of the endplate to the depolarising action of acetylcholine and the direct excitability of muscle fibres [3]. This effective neuromuscular blockade results in flaccid paralysis of muscles and respiratory depression. The clinical manifestations of hypermagnesaemia are described in Table 1.

Table 1.

Clinical manifestations of hypermagnesaemia according to serum magnesium levels.

Serum magnesium (mmol.l−1)	Clinical manifestations
<1.6	Asymptomatic or pauci‐symptomatic
1.6–2.3	Weakness, nausea, dizziness and confusion
2.3‐–5	Drowsiness, worsening confusional states, decreased reflexes, bladder paralysis, flushing, headache, constipation, a slight reduction in blood pressure and blurred vision caused by diminished accommodation and convergence
>5	Muscle paralysis, paralytic ileus, decreased respiratory rate, low blood pressure, ECG changes including increased PR and QRS interval with sinus bradycardia and atrioventricular block
>6.2	Coma and cardiac arrest

Factors other than renal insufficiency that increase the risk of hypermagnesaemia include malnourishment, alcoholism, lithium‐based psychotropic drugs, proton pump inhibitors, hypothyroidism, cortico‐adrenal insufficiency, hyperparathyroidism, familial hypocalciuric hypercalcemia, alterations in calcium metabolism, underlying bowel conditions and excessive oral intake of magnesium‐rich foods. A thorough history including drug history should be taken, with laboratory assessment of electrolytes, and kidney, thyroid and cortico‐adrenal function tests performed to assess the risk [4].

Magnesium can potentiate the effect of depolarising and non‐depolarising neuromuscular blocking agents [5], especially vecuronium. In a patient receiving a magnesium sulphate infusion, one‐half to one third of the usual dose of non‐depolarising agent should be used to maintain relaxation and carefully titrated to twitch response with a peripheral nerve stimulator. Pre‐treatment with a small dose of non‐depolarising neuromuscular blocking agent to decrease fasciculations and myalgia is contraindicated as it may cause significant paralysis [6].

Magnesium haemostasis is almost entirely handled by the kidneys, which can maintain magnesium equilibrium until the creatinine clearance falls below 20 ml.min⁻¹. Though our patient had an eGFR of 82 ml.min⁻¹.1.73 m⁻² making him low risk for developing hypermagnesaemia, his impaired renal function is likely to have played a role, considering that the rise in serum magnesium value was very rapid [7]. Additionally, serum magnesium levels do not reflect the total magnesium content of the body, and it is the tissue magnesium levels which influence the clinical sequelae rather than that measurable in serum [8]. As a result, the serum magnesium value and clinical symptoms may not always correlate [7].

Although we are unable to report the pre‐operative serum magnesium level, we believe that this was a case of iatrogenic hypermagnesaemia. One of the most common causes of iatrogenic hypermagnesaemia in clinical practice is magnesium sulphate therapy for pre‐eclamptic toxaemia or eclampsia, where it is given to decrease central nervous system irritability and thereby prevent or treat seizures [6]. In this context, routine measurements of serum magnesium levels are often not performed and accidental overdoses with serum levels as high as 7.82 mmol.l⁻¹ have been reported [9]. In patients who are at the risk of developing hypermagnesaemia, a baseline value will be useful in guiding therapy. Postoperative serum magnesium levels can be performed according to need, and neurological, respiratory and cardiac parameters should be monitored.

Treatment depends on the severity of symptoms and renal function. In mild, non‐emergent cases with normal renal function, removing the causative medication is usually sufficient. The elimination half‐time of magnesium is 28 h. In moderate‐to‐severe cases with normal renal function, mild‐to‐moderate renal insufficiency or non‐oliguric acute kidney injury, loop diuretic therapy with furosemide (1 mg.kg⁻¹) with high‐volume saline diuresis 0.9% (up to 150 ml.h⁻¹) can be given. Loop diuretics inhibit the tubular reabsorption of magnesium in the thick ascending limb of the loop of Henle, enhancing renal excretion. If the patient has chronic kidney disease with an eGFR < 15 ml.min⁻¹ or anuric acute kidney injury, haemodialysis using magnesium‐free dialysate is the only way to rapidly remove magnesium [10]. In emergency situations, an i.v. calcium preparation (e.g. 10 ml of calcium gluconate 10% i.v. over 2–5 min, repeated if required after 5–10 min) and loop diuretic should be commenced immediately until haemodialysis is available. In patients with normal renal function or mild renal dysfunction, high‐volume saline diuresis (administering 200–300 ml.h⁻¹ of i.v. normal saline to achieve urine output rates of 6 ml.kg⁻¹.h⁻¹) should also be considered. The amount of acetylcholine released by a motor nerve volley is a function of the relative amounts of the calcium and magnesium ions present [3], and an increase in calcium concentration can reverse the effects of magnesium on the neuromuscular junction.

An aggressive use of haemodialysis can achieve a 50% reduction in serum magnesium in around 4 h, and thereby reduce the risk of morbidity and mortality. Clinicians must closely monitor the ECG, blood pressure, neuromuscular function, and serum calcium and magnesium. Dialysis can cause hypocalcaemia which can worsen the signs and symptoms of hypermagnesaemia. A transient rebound in the serum magnesium after haemodialysis should be anticipated as most bodily magnesium is intracellular.

In conclusion, the risk of hypermagnesaemia should be considered in patients with renal insufficiency receiving therapeutic magnesium. In patients with a high risk of developing hypermagnesaemia undergoing cardiac surgery, or any procedure which might necessitate magnesium infusion, serum magnesium should be measured pre‐operatively. The need for serial assessment of serum magnesium concentration can be decided based on regular examination for the signs and symptoms of early toxicity. In severe symptomatic cases with renal insufficiency, haemodialysis is the only effective means to acutely decrease serum levels.