Both central and peripheral causes neuromuscular weakness and central nervous system effects might drive respiratory depression.
Respiratory muscle weakness (proximal muscle weakness affecting the diaphragm and respiratory muscles driven by PTH-rp) is considered the underlying driver of respiratory paralysis.
Severe hypercalcemia produces encephalopathy that depresses central ventilatory drive.

Hypophosphatemia associated with hypercalcemia might independently contribute to respiratory muscle dysfunction by ATP depletion and 2,3 DPG depletion, thereby phosphate repletion has been advised along with correction of hypercalcemia of malignancy.

Osteoclast activation and cytokine release leads to release of calcium and inflammatory mediators that directly impair muscle metabolism.
Type ii muscle fiber atrophy and diaphragmatic dysfunction might also be seen.

The distinction from opioid induced respiratory depression might prove to be important. While weakness and reduced respiratory drive might be seen in both, miosis and response to naloxone are seen in opioid related respiratory depression only.

References

Anastasopoulos, D., Kefaliakos, A., & Michalopoulos, A. (2011). Is plasma calcium concentration implicated in the development of critical illness polyneuropathy and myopathy?. Critical care (London, England), 15(5), R247. https://doi.org/10.1186/cc10505

El-Hajj Fuleihan, G., Clines, G. A., Hu, M. I., Marcocci, C., Murad, M. H., Piggott, T., Van Poznak, C., Wu, J. Y., & Drake, M. T. (2023).

Treatment of Hypercalcemia of Malignancy in Adults: An Endocrine Society Clinical Practice Guideline. The Journal of clinical endocrinology and metabolism, 108(3), 507–528. https://doi.org/10.1210/clinem/dgac621

Goltzman D. (2021). Pathophysiology of Hypercalcemia. Endocrinology and metabolism clinics of North America, 50(4), 591–607. https://doi.org/10.1016/j.ecl.2021.07.008

Khan, A., Frazer-Green, L., Amin, R., Wolfe, L., Faulkner, G., Casey, K., Sharma, G., Selim, B., Zielinski, D., Aboussouan, L. S., McKim, D., & Gay, P. (2023). Respiratory Management of Patients With Neuromuscular Weakness: An American College of Chest Physicians Clinical Practice Guideline and Expert Panel Report. Chest, 164(2), 394–413. https://doi.org/10.1016/j.chest.2023.03.011

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Artificial intelligence tools have been employed for evidence synthesis. They do not replace critical scholarship, clinical experience, or editorial judgment. Final responsibility for all interpretations, factual accuracy, originality of synthesis, and the quality of the published material rests entirely with the Founder and Editor.