Home Subcutaneous Magnesium Infusion in Refractory Hypomagnesemia: A Case Report

Abstract

We describe a patient with renal magnesium wasting and prolonged, symptomatic hypomagnesemia that was refractory to oral therapies and intermittent intravenous infusion who achieved near-normal serum magnesium levels with subcutaneous magnesium infusions. A woman in her 40s was seen in nephrology clinic for evaluation and management of severe, chronic hypomagnesemia because of renal magnesium wasting in combination with frequent diarrhea. Clinical manifestations associated with hypomagnesemia included muscle weakness, cognitive impairment, and frequent seizures. Her hypomagnesemia had persisted for more than 20 years despite maximal oral magnesium supplementation and frequent intravenous magnesium infusions. To provide slower delivery of parenteral magnesium, she was prescribed 2 g/d of magnesium sulfate, delivered subcutaneously. This was well tolerated, rapidly normalized her serum magnesium levels, and improved her symptoms. We briefly discuss modalities used for treatment of hypomagnesemia, including shortcomings of intravenous therapy and limited literature discussing efficacy and tolerability of subcutaneous infusions. This case report demonstrates the efficacy and safety of subcutaneous magnesium infusions in a patient with refractory hypomagnesemia and suggests that subcutaneous infusion may be safe and effective for treatment of refractory hypomagnesemia in other patients with urinary magnesium wasting.

Introduction

Magnesium is an abundant mineral in the body and is necessary to maintain normal metabolic function. Its diverse roles include RNA, DNA, and protein synthesis, energy production, regulation of ion transport, and serving as an enzymatic cofactor in numerous biochemical processes.¹ Hypomagnesemia may occur because of impaired gastrointestinal absorption or inappropriate wasting of the kidneys. Manifestations of hypomagnesemia are widespread. Neuromuscular hyperexcitability may present as tremors or tetany, or more severely as seizure, coma, and death. Other clinical manifestations include hypokalemia, hypocalcemia, and cardiac arrythmias. Pharmacologic treatment options of hypomagnesemia include oral magnesium supplementation, adjunctive oral medications to stimulate renal tubular reabsorption of magnesium, and parenteral magnesium supplementation.¹ Magnesium sulfate is the preferred salt for parenteral administration and is commonly used for intravenous electrolyte solutions.² It is approved by the US Food and Drug Administration for replacement because of magnesium deficiency via intravenous or intramuscular routes and has been administered off-label via intraosseous infusion.² Here, we present a case demonstrating the effectiveness and tolerability of off-label subcutaneous magnesium sulfate infusion for treatment of severe hypomagnesemia.

Case Report

A woman in her 40s presented to the nephrology clinic with chronic, refractory hypomagnesemia. At presentation, her serum magnesium level was 1.3 mg/dL (laboratory reference range: 1.6-2.4 mg/dL) and her plasma potassium level was 2.9 mmol/L (3.5-5.1 mmol/L). In association with her electrolyte abnormalities, she experienced muscle cramping, chronic weakness, cognitive impairment, anxiety, depression, and recurrent seizures. Although her serum magnesium levels were only slightly below the laboratory reference range, magnesium depletion was felt likely to be contributing to her symptoms, as even at 1.8 mg/dL, up to 50% of individuals exhibit clinical signs of magnesium deficiency.¹

The patient had been seen by multiple nephrologists for over a 20-year period without significant improvement in laboratory values or symptoms. Evaluation of her hypomagnesemia and hypokalemia had suggested that the cause of these was renal-electrolyte wasting. Twenty four-hour urine volume had revealed elevated excretion of sodium (206 mEq), potassium (89 mEq) and magnesium (59 mg), as well as low calcium excretion (6.0 mg). Urinary wasting of magnesium and potassium were consistent with Gitelman syndrome, although genetic testing for Gitelman syndrome failed to identify known pathologic mutations. Additional contributors to her chronic mineral depletion included frequent diarrhea alternating with constipation. Additional past medical history included chronic kidney disease (estimated glomerular filtration rate 41-54 mL/min/1.73 m², averaging 47 mL/min/1.73 m²), hypotension, gastroesophageal reflux, and gastric ulcers. The cause of her intestinal symptoms was being evaluated by gastroenterology but remained unclear. She was not on a proton pump inhibitor at the time of presentation.

A prior nephrologist had prescribed oral magnesium oxide, but this was discontinued because of lack of efficacy and exacerbation of diarrhea. Better-absorbed organic magnesium supplements were prohibited by cost because they were not covered by her insurance plan. She was taking magnesium chloride extended release (128 mg, equal to 5.3 mmol, of elemental magnesium by mouth twice daily), potassium chloride (60 mEq by mouth 3 times daily), spironolactone (100 mg by mouth daily), amiloride (5 mg by mouth daily), and table salt (2 tsp, 3 times daily by mouth, for volume depletion and hypotension). (Medications are listed in full in Table 1.) She had been counseled on nutrition and reported trying to consume foods high in magnesium and potassium. She continued to experience severe symptoms and frequent seizures, requiring multiple emergency department visits each month (the exact frequency was unclear, as emergency medical services frequently brought her to different out-of-network hospitals). There, she received intravenous magnesium and potassium supplementation that provided only transient increases in electrolyte levels and seizure relief.

Table 1.

Medications Prescribed to the Patient

Medications	Day -100	Day 0	Day +35
Amiloridea	5 mg oral daily	Unchanged	Unchanged
Ascorbic acid	500 mg oral 3 times daily with magnesium	Unchanged	Unchanged
Buspirone	10 mg oral 3 times daily	Unchanged	Unchanged
Clonazepam	1 mg oral 2 times daily	Unchanged	Unchanged
Cyclobenzaprine	10 mg oral 3 times daily as needed for cramping	Unchanged	Unchanged
Ergocalciferol	50,000 units oral twice weekly	Unchanged	Unchanged
Ferrous sulfate	325 mg oral daily	Unchanged	Unchanged
Lamotrigine	100 mg oral every morning	Unchanged	Unchanged
Lamotrigine	25 mg oral every night	Unchanged	Unchanged
Magnesium chloride extended releasea	128 mg oral twice daily	3 times daily	3 times daily
Ondansetron	100 mg oral every 12 h as needed for nausea	Unchanged	Unchanged
Orphenadrine	100 mg oral 2 times daily	Unchanged	Unchanged
Potassium chloride extended releasea	60 mEq oral 3 times daily	Unchanged	Unchanged
Ranitidine	150 mg oral 2 times daily	Held	Held
Sodium chloride granulesa	1 tsp oral 3 times daily	Unchanged	Held
Spironolactonea	100 mg oral 3 times daily	Unchanged	Held
Buprenorphine/naloxone	8/2 mg sublingual daily	Unchanged	Unchanged
Topiramate	150 mg oral 2 times daily	Unchanged	Unchanged
Vitamin B complex	1 mL subcutaneous weekly	Unchanged	Unchanged
Zinc	25 mg oral daily	Unchanged	Unchanged

Days represent the number of days before or after initiation of subcutaneous magnesium infusion and correspond to the x-axis in Fig 1.

^aMedications likely to influence electrolyte homeostasis.

Given the inefficacy of oral and intravenous supplementation, her outpatient nephrologist contacted a home infusion pharmacy to collaborate in developing a subcutaneous magnesium sulfate prescription that could be well tolerated. Her oral magnesium dosing was increased to 3 times daily while home infusions were arranged. (This change appeared to have little effect on serum magnesium, increasing it from 1.3 to only 1.4 mg/dL before subcutaneous infusions were initiated.) She was prescribed 2 g (8.1 mmol) magnesium sulfate heptahydrate in 100-mL normal saline, to be given subcutaneously. Infusion bags were prepared in a clean room suite and dispensed to the patient while under refrigeration, with directions to use the solutions within 9 days of compounding, in accordance with guidelines from the United States Pharmacopeia.³ Infusions were administered via ambulatory electronic pump every night over 12 hours. The patient and caregiver received in-home training by a registered nurse, after which time the patient and caregiver performed infusions independently with telephone assistance, as needed. The patient was instructed to store bags in the refrigerator until 2-3 hours before use, allowing bags to warm to room temperature prior infusion. The therapy was fully covered by the patient’s medical insurance, with no out-of-pocket cost for medication, supplies, or in-home teaching.

The patient tolerated infusions well, experiencing only mild but tolerable burning over abdominal injection sites and noticeable swelling where the fluid deposited. She reported that infusions were more comfortable when fluid bags were prewarmed to room temperature. Following initiation of the infusions, the patient’s magnesium level abruptly normalized (Fig 1). She reported having clearer thoughts and communication with family members. She reported decreased seizure frequency. She continued to have alternating constipation and diarrhea, so we cannot exclude the possibility that changes in bowel habits influenced her magnesium levels. She remained on her original medication regimen, other than spironolactone (and table salt). This was discontinued because of perceived inefficacy. Her kidney function remained stable, with estimated glomerular filtration rate of 35-53 mL/min/1.73 m² (averaging 46 mL/min/1.73 m²). Unfortunately, approximately 7 weeks after starting infusions, she experienced a series of nonmedical personal events that interfered with medication adherence and follow-up in clinic, and she was subsequently lost to follow-up.

Figure 1.

Initiation of subcutaneous magnesium sulfate was associated with improvement in the patient’s serum magnesium levels. Y-axis represents clinically determined serum magnesium level. Yellow represents the normal reference range for magnesium (1.6-2.4 mg/dL). X-axis represents days before (negative values) and after (positive values) initiation of subcutaneous magnesium infusion. Note the scale change at day 0.

Discussion

Oral magnesium supplements are considered first-line pharmacologic treatment of chronic hypomagnesemia in the outpatient setting.² Although magnesium oxide is least costly and is frequently prescribed, chloride or organic magnesium salts are better absorbed.^4,5 The effectiveness of oral magnesium supplements may be limited by gastrointestinal symptoms, including nausea, diarrhea, and abdominal cramping. Adjunctive agents, such as potassium-sparing diuretics and type 2 sodium/glucose cotransporter inhibitors, enhance renal tubular magnesium reabsorption and increase blood magnesium, at least in some patients.6, 7, 8, 9, 10 Amiloride and spironolactone were both used in this case but were minimally effective. When oral replacement and adjunctive therapy fail to adequately treat hypomagnesemia, parental therapy may be indicated.¹ Although intravenous replacement in the outpatient setting is available, placement and maintenance of intravenous catheters can be associated with adverse effects, including infection or venous thrombosis.¹¹ Additionally, intravenous infusions stimulate renal magnesium excretion and often only transiently increase circulating magnesium.¹

Subcutaneous infusions represent a viable alternative to intravenous infusion. This infusion modality provides lower risk of infection, thrombosis, and catheter occlusion than intravenous therapy. Critically, slower absorption associated with drugs infused subcutaneously provides more sustained delivery.¹² We turned to subcutaneous infusions in this patient in the hopes that slower absorption would provide a more sustained increase in circulating magnesium levels, considering our patient’s underlying urinary magnesium wasting.

Few published manuscripts address the viability of subcutaneous magnesium infusion. One case series and associated review describes subcutaneous magnesium infusions predominantly in patients with severe gastrointestinal malabsorption, which is often related to short gut syndrome following intestinal resection.¹³ The present case report demonstrates that subcutaneous magnesium infusion may also be effective in cases of hypomagnesemia because of urinary magnesium wasting.

Several parameters were considered in designing our patient’s infusion prescription, including magnesium dose and infusate volume, tonicity, infusion time, and additives. Clearly, minimal infusate volume is desired. Some reports have employed sufficiently small infusion volumes to allow the use of an insulin pump for the infusion. However, lower infusion volumes necessitate higher infusate tonicity. Published studies do not provide clear guidance as to the maximum safe or tolerable infusion tonicity. However, pharmacists on the team estimated that the maximum safe osmolarity would be approximately 600 mOsm/L. This would allow 4 g of magnesium sulfate to be dissolved in as little as 100 mL of normal saline. Treatment was initiated with 2 g magnesium sulfate per 100 mL of normal saline. Although we had planned to increase the concentration to 4 g magnesium sulfate if this were well tolerated, the satisfactory increase in serum magnesium made this unnecessary. An infusion time of 12 hours was initially chosen to minimize discomfort. More rapid infusions may also be well tolerated.

Some reports have described the use of lidocaine to avoid burning with infusion.¹³ This may have been required because of the much higher concentration of magnesium sulfate they employed (sometimes 50 g/dL), although it is not clear whether infusion was first attempted without lidocaine. Our patient experienced minimal burning with infusions, and lidocaine was not required.

Overall, the subcutaneous infusions were well tolerated in our patient. Other case reports describe infrequent adverse effects limited to mild cellulitis at the infusion site, localized edema, or leakage of fluid.¹³ Because follow-up was limited, it is possible that adverse effects may have occurred in our patient with longer therapy, but our patient reported that adverse effects were mild and tolerable over the follow-up period described.

Although it appears clear that serum magnesium levels improved in association with subcutaneous magnesium infusion, limitations in interpretation of this case stem from the possibility that gastrointestinal magnesium absorption changed during the observation period, the fact that oral magnesium supplements were not held constant, and the possibility that medication adherence may have improved when a caregiver was participating in daily magnesium infusions. Nevertheless, the observations here are consistent with improved serum magnesium as a result of subcutaneous infusion.

In conclusion, our case report provides evidence that subcutaneous magnesium sulfate appears to be well tolerated and effective in normalizing serum magnesium in patients with chronic, severe hypomagnesemia in the context of hypermagnesuria. Because randomized, controlled trials addressing the efficacy and safety of this approach are not likely to be feasible, future “n-of-1” trials may provide the most thorough possible assessment of efficacy moving forward.¹⁴