Hypercalcemia of Malignancy in the ED: When to Volume Resuscitate?

CASE

70 year-old female with a past medical history of stage IV inflammatory breast carcinoma complicated by bony metastases, hypertension, and hyperlipidemia presents to the Emergency Department with a one-week history of abdominal pain, constipation, nausea and drowsiness.

• Patient started on a new medication one week ago and believes her symptoms are a result of the medication change. The new medication is Abemaciclib (Verzenio), a non-chemotherapy CDK 4 & 6 inhibitor.

• Recent CT scan demonstrated mixed osteolytic and osteoblastic bony metastases to the vertebrae and pelvis.

• Relevant laboratory results include: Calcium 13.6 mg/dL, Alkaline Phosphatase 297 IU/L, Creatinine 1.48 mg/dL.

• Nursing inquired about the choice of fluids for the patient.

Clinical Question: In the management of hypercalcemia of malignancy in the ED setting, when and how should volume resuscitation be used?

SUMMARY OF EVIDENCE

In the assessment of hypercalcemia severity, ionized calcium is the preferred measurement as it reflects the body’s biologically active calcium (1,2,3). Using ionized calcium, hypercalcemia severity can be categorized as mild (5.6 – 8.0 mg/dL), moderate (8 – 10 mg/dL), or severe (10 – 12 mg/dL), while taking into consideration the patient’s symptoms (4).

Hypercalcemia causes volume depletion and renal vasoconstriction, which can lead to renal insufficiency (4,5). Common symptoms of vomiting and decreased oral intake can further exacerbate volume depletion (5). The decrease in GFR results in impaired calcium clearance and thus, volume replacement is key in management (5).

Normal saline contains excess chloride concentration relative to plasma, which can result in acute kidney injury, metabolic acidosis and coagulopathy (6,7). Many patients with hypercalcemia have pre-existing renal dysfunction and acidosis that makes normal saline sub-optimal (8). Lactated Ringers is also considered sub-optimal as it contains calcium (9). PlasmaLyte does not contain calcium and is therefore an optimal choice of fluid for patients with no pH disorder (10).

RECOMMENDATIONS

The choice of fluid therapy and volume status management in hypercalcemia of malignancy is multifactorial. Assessing the severity of hypercalcemia and the acid-base balance are two important factors in decision-making.

Historically, normal saline has been the fluid of choice for symptomatic hypercalcemia and every patient would receive fluid resuscitation regardless of severity. Based on the latest literature, the following recommendations are made:

1. Patients with mild (ionized calcium level 5.6 – 8.0 mg/dL), asymptomatic hypercalcemia do not require IV fluid resuscitation. Adequate oral hydration (6 – 8 glasses of water per day) is recommended.

2. Patients with moderate to severe, symptomatic hypercalcemia should be treated with IV fluids. The rate of infusion depends on the severity of hypercalcemia, age of patient and comorbid conditions, particularly renal or cardiac disease. In the absence of edema, an infusion rate of 200-300 mL/hour is recommended.

3. The choice of fluids should be in part based upon the pH status of the patient. For patients with metabolic acidosis, isotonic bicarbonate should be used. For patients with metabolic alkalosis, 0.9% normal saline should be used. Lastly, for patients with no pH disorder, PlasmaLyte is preferred over Lactated Ringers.

4. Patients on IV fluids should be monitored for volume overload and only continued on fluids if patient is responding to the fluid infusion with an equal output of urine. Patients with renal insufficiency or heart failure in particular require careful monitoring.

REFERENCES

1. Schenck PA, Chew DJ. Calcium: total or ionized? Vet Clin North Am Small Anim Pract. 2008 May;38(3):497-502, ix. doi: 10.1016/j.cvsm.2008.01.010. PMID: 18402876.

2. Calvi LM, Bushinsky DA. When is appropriate to order an ionized calcium? JASN. 2008 July; 19 (7) 1257-1260; doi: https://doi.org/10.1681/ASN.2007121327.

3. Baird GS. Ionized calcium. Clinica Chimica Acta. 2011 April; 412(9–10): 696-701, 0009-8981, https://doi.org/10.1016/j.cca.2011.01.004.

4. Shane E, Berenson J. Treatment of hypercalcemia. UpToDate. Published April 8, 2022. https://www.uptodate.com/contents/treatment-of-hypercalcemia?search=hypercalcemia&source=search_result&selectedTitle=2~150&usage_type=default&display_rank=2

5. Rosner MH, Dalkin AC. Onco-Nephrology: The Pathophysiology and Treatment of Malignancy-Associated Hypercalcemia. CJASN. 2012 October; 7 (10) 1722-1729; doi: https://doi.org/10.2215/CJN.02470312

6. Hayes W. Ab-normal saline in abnormal kidney function: risks and alternatives. Pediatr Nephrol. 2019 Jul;34(7):1191-1199. doi: 10.1007/s00467-018-4008-1. Epub 2018 Jul 9. PMID: 29987459; PMCID: PMC6531391.

7. Kyaw Hoe K, Gardener S, Dawkins Y, Saint Hoe TH. Normal saline and acute kidney injury in hospitalized patients; more precaution to be taken. J Renal Inj Prev. 2022; 11(2): 22733. doi: 10.34172/jrip.2022.22733.

8. Maier JD, Levine SN. Hypercalcemia in the Intensive Care Unit: A Review of Pathophysiology, Diagnosis, and Modern Therapy. J Intensive Care Med. 2015 Jul;30(5):235-52. doi: 10.1177/0885066613507530. Epub 2013 Oct 15. PMID: 24130250.

9. Singh S, Kerndt CC, Davis D. Ringer's Lactate. [Updated 2022 Jul 6]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK500033/

10. Weinberg L, Collins N, Van Mourik K, Tan C, Bellomo R. Plasma-Lyte 148: A clinical review. World J Crit Care Med. 2016 Nov 4;5(4):235-250. doi: 10.5492/wjccm.v5.i4.235. PMID: 27896148; PMCID: PMC5109922.

11. Asonitis N, Angelousi A, Zafeiris C, Lambrou GI, Dontas I, Kassi E. Diagnosis, Pathophysiology and Management of Hypercalcemia in Malignancy: A Review of the Literature. Horm Metab Res. 2019 Dec;51(12):770-778. doi: 10.1055/a-1049-0647. Epub 2019 Dec 11. PMID: 31826272.