Presented by: Sam Cole, Doctor of Pharmacy Candidate, Class of 2023, Husson

University School of Pharmacy

Patient Case Presentation: Hypercalcemia

and Calciphylaxis

11/04/2022

1
Objectives

By the end of this presentation the audience will be able to:

1. Identify signs and symptoms of calciphylaxis in patient CG

2. Understand pathophysiology of calciphylaxis

3. Determine a treatment regimen for a patient with calciphylaxis

11/04/2022 2
Patient Presentation

CC: CG is a 37-year-old male presenting to NL-EMMC Emergency Department for being

unresponsive following a seizure.
PMH: Patient has documented history of HIV, alcohol use disorder, bipolar affective
disorder and depression, and no documented history of seizures.
HPI:
• Upon admission he does not appear to be seizing but does have full body
twitching/aching.
• Patient is altered and unable to provide any history.
• He is tachypneic.
• He has been at Penobscot County Jail for the past 20 days and has been refusing
meds intermittently.

11/04/2022 3
Patient Presentation

Home Medication List (unsure if accurate):

Vitamin B 100 Complex, 1 TAB, PO, Daily
omega-3 polyunsaturated fatty acids(Fish Oil), 1000 mg, PO, With Meals
lamoTRIgine(LaMICtal), 100 mg, PO, Twice Daily
multivitamin, 1 TAB, PO, Daily
traZODone(traZODone), 50 mg, PO, Bedtime, PRN
emtricitabine-tenofovir(Truvada 133 mg-200 mg oral tablet), 1 TAB, PO, Daily
buPROPion(Wellbutrin), 100 mg, PO, Daily
Allergies:
NKDA

11/04/2022 4
Patient Presentation

Surgical History: Vaccination History:

• Excision of condyloma acuminatum • Unknown
(2019)
• Anoscopy (2018)
• Thigh reconstruction (2018)
Social History:
• Former smoker 1/2 ppd for 10 years,
• Buttock lift (2016)
quit 8 years ago
• Excision of skin (2014)
• Unknown alcohol use, patient has
• Repair of digital nerve (2013)
presented to the ED in the past with
• Abdominoplasty (2010)
alcohol intoxication
• Anal fistula operation (2009)
• Incarcerated at Penobscot County Jail
• Laparoscopic cholecystectomy (2009)
• Roux-en-y gastric bypass (2008)
• Laparoscopic appendectomy (2004) Family History:
• Excision of hand lesion (1999) • Paternal grandfather: Diabetes

11/04/2022 5
Patient Presentation

Pertinent Physical Findings on Admission:

General: Unresponsive, severely ill

Eye: Pupils are equal, round and reactive to light, intact accommodation, extraocular Vital Signs on
movements are intact, normal conjunctiva. Admission (prior to
intubation):
Temperature: 39.7 ˚C
Cardiovascular: Tachycardic, Normal peripheral perfusion.
Blood Pressure: 110/78 mmHg
Pulse: 149 BPM
Respiratory: Tachypnea, increased work of breathing SpO2: 99 %
Respiratory Rate: 28 bpm

Neurological: Eyes are open, but patient is unresponsive.

Patient was intubated upon arrival to ED to protect airway and brought to the ICU
11/04/2022 6
Patient Presentation

Pertinent Laboratory Values @ Admission: Normal Lab Value Ranges:

• Na: 174 mEq/L(!) • Na: (135-145 mEq/L)
• K: 4.4 mEq/L • K: (3.5-5 mEq/L)
• CL: 130 mEq/L (H) • Cl: (95-105 mEq/L)
• CO2: 7 mEq/L (!) • CO2: (23-29 mEq/L)
• Anion gap: 37 (H) • Anion gap: (3-10)
• Urea nitrogen: 91 mg/dL (H) • Urea nitrogen: (5-20 mg/dL)
• Creatinine: 5.48 mg/dL (H) • Creatinine: (0.6-1.2 mg/dL)
• CrCl: 18 mL/min • CrCl: (male- 97-137 mL/min)
• Ca: 8.4 mg/dL (L) • Ca: (8.8-10.3 mg/dL)
• Phosphorus: 10.2 mg/dL (!) • Phosphorus: (2.8-4.5 mg/dL)
• CK: 60,200 units/L (!) L = Low • CK: (>1000 units/L)
H = High
! = Critical Low/high 11/04/2022 7
Patient Presentation

Laboratory value ranges throughout first

11 days of stay:
• Upon admission CG was • Na: (129-174 mEq/L)
found to have multiple • K: (3.4-6.9 mEq/L)
metabolic derangements • Cl: (89-140 mEq/L)
including severe • CO2: (7-25 mEq/L)
hypernatremia, acute kidney • Anion gap: (15-37)
injury, rhabdomyolysis, and • Urea nitrogen: (27-115 mg/dL)
severe metabolic acidosis • Creatinine: (3.69-7.94 mg/dL)
possibly due to severe • CrCl: (13-27 mL/min)
dehydration.
• Ca: (4.4-15.9 mg/dL)
• Phosphorus: (2.5-10.8 mg/dL)
• CK: (2,907-356,520 units/L)
11/04/2022 8
CG’s Stay in the ICU and Hemodialysis

• Upon arrival to the Emergency Department CG was intubated and transferred to the
ICU
• He remained in the ICU under sedation and intubation for 6 total days
• He received hemodialysis for his acute kidney failure on days 2 through 5 while in
the ICU
• On day 6 of his stay, he was extubated and was on room air
• On day 7 of admission, he was then considered stable and transferred to a medical
floor
• He was started on a Tuesday, Thursday, Saturday hemodialysis schedule

11/04/2022 9
 The Battle between Hypocalcemia and Hypercalcemia

Day of Stay Time Calcium Value (mg/dL)

Day 1 1034 8.4 (L)
Normal range 1735 6.9 (L) Started on
serum calcium- Calcium
Day 2 0430 5.6 (!) Gluconate
8.8-10.3 mg/dL
1048 5.1 (!) 1000 mg po
Low (L)- <8.8 mg/dL 1855 5.9 (!) q8h
Critical low (!)- 6.0 2020 5.6 (!)
mg/dL
Day 3 0415 4.4 (!)
High (H)- >10.3 1410 6.1 (L)
Critical high (!)- 2100 5.2 (!)
13.0 mg/dL
Day 4 0350 4.8 (!)
1520 6.4 (L)
Day 5 0406 6.0 (L)

11/04/2022 10
The Battle between Hypocalcemia and Hypercalcemia Cont.

Day of Stay Time Calcium Value (mg/dL)

Day 6 0850 5.8 (!)
1515 6.6 (L)
Day 7 0502 7.5 (L)
Day 8 0504 8.4 (L)
Day 9 1516 11.5 (H)
Stopped
Day 10 0930 13.5 (!) Calcium
Given **Day 11 0720 15.9 (!) Gluconate
Calcitonin
340 units 1742 11.2 (H)
subq Day 12 0457 12.6 (H)

11/04/2022 11
Hypercalcemia5

• Symptoms of hypercalcemia are usually seen when serum calcium levels are more
than 12 mg/dl
• Broad signs and symptoms can be summarized as "groans, bones, stones, moans,
thrones and psychic overtones".
• Groans: Gastrointestinal symptoms like pain, nausea, and vomiting. Hypercalcemia can lead to peptic ulcer
disease and pancreatitis.
• Bones: Bone related complications like bone pain. Hypercalcemia can lead to osteoporosis, osteomalacia,
arthritis and pathological fractures.
• Stones: Renal stones causing pain.
• Moans: Refers to fatigue and malaise.
• Thrones: Polyuria, polydipsia, and constipation (sitting on the toilet as you are sitting on a throne).
• Psychic overtones: Lethargy, confusion, depression and memory loss.

Sadiq NM, Naganathan S, Badireddy M. Hypercalcemia. [Updated 2021 Nov 26].

In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022
11/04/2022 12
Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK430714/
Underlying Hand Issues

• On day 6 of admission, it was noted that the patient had discoloration on his right
hand that was tender to palpation and Plastics and Hand Surgery Service was
consulted

• Plastics and Hand Surgery saw the patient later in the day on day 6
• He noted that there was edema in both the left and right hands. On the right hand there was a large patch of
well-demarcated irregularly bordered area of ecchymosis with subtle cap refill. He also noted that on the
right forearm, there is a 2nd area of dark ecchymosis with well-demarcated borders.

• It was decided that CG had right hand intravenous infiltration with calcium chloride
• He was given hyaluronidase injection into the right hand, as well as topical Silvadene cream.

11/04/2022 13
Hand Issues Cont.

• Despite treatment with topical Silvadene cream and analgesics, CG regularly

complained of pain in his right hand and forearm that was not improving.
• On day 13 CG had a CT w/ contrast of the right arm, and the theory then was that it
was either cellulitis or some other soft tissue infection
• It was also hypothesized that there was a rare chance due to his decline in renal function it was calciphylaxis.
• On day 14 of admission a punch biopsy was done of the affected area on the
forearm
• The cultures from the biopsy came back on day 18 of admission and CG was
diagnosed with calciphylaxis.

11/04/2022 14
What is Calciphylaxis?

11/04/2022 15
Presentation1

• Calciphylaxis (calcific uremic arteriolopathy) is

a rare but potentially devastating condition
most often observed in patients with end-
stage renal disease, although it does
occasionally develop in patients without renal
failure or in acute renal failure.
• Characterized by cutaneous arteriolar
calcification and subsequent tissue ischemia
and causes painful skin lesions.

Westphal SG, Plumb T. Calciphylaxis. [Updated 2022 May 2]. In: StatPearls [Internet].
Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: 11/04/2022 16
https://www.ncbi.nlm.nih.gov/books/NBK519020/
Epidemiology1,2

• Although calciphylaxis can develop in the absence of kidney disease, most cases
occur in patients with advanced renal failure.

• The Incidence of calciphylaxis in dialysis patients ranges from 0.04% to 4%

• The incidence outside of dialysis patients is largely unknown

• Calciphylaxis is associated with increased morbidity due to severe pain, nonhealing

wounds, and frequent hospitalizations.
• It is a highly fatal condition with 1-year mortality rates greater than 50%, most often due to sepsis.

Westphal SG, Plumb T. Calciphylaxis. [Updated 2022 May 2]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available
from: https://www.ncbi.nlm.nih.gov/books/NBK519020/
Yerram P, Chaudhary K. Calcific uremic arteriolopathy in end stage renal disease: pathophysiology and management. Ochsner J. 2014 Fall;14(3):380- 11/04/2022 17
5. PMID: 25249804; PMCID: PMC4171796.
What Does Calcification Mean?2

• Calcification is defined as, “the

hardening of tissue or other material
by the deposition of or conversion into
calcium carbonate or some other
insoluble calcium compounds.”
• Calcification typically normally occurs
in the formation of bone, but calcium
can be deposited abnormally in soft
tissue, causing it to harden
• Calciphylaxis occurs when calcium is
deposited in the soft tissue

Yerram P, Chaudhary K. Calcific uremic arteriolopathy in end stage renal disease: pathophysiology 11/04/2022 18
and management. Ochsner J. 2014 Fall;14(3):380-5. PMID: 25249804; PMCID: PMC4171796.
Pathophysiology of Calciphylaxis1,2

• The cause and mechanisms that cause calciphylaxis are poorly understood
• Development is dependent on multiple factors that then lead to the calcification of
arterioles.
• Elevated calcium or phosphate, increased parathyroid hormone levels, and administration of activated
vitamin D have been associated with the development of calciphylaxis.
• However, abnormalities of these parameters are typically not sufficient to cause calciphylaxis on their own in
most patients
• Calciphylaxis can develop even if parathyroid hormone, phosphorus, and calcium levels are normal.
• Deficiency of vascular calcification inhibitors such as fetuin-A, osteoprotegerin, and
matrix G1a protein may play a role in the development of calciphylaxis.
• Fetuin-A is a glycoprotein that binds calcium and phosphorus and may help to prevent calcification of vessels
and soft tissue. Fetuin-A is downregulated in dialysis patients.

Westphal SG, Plumb T. Calciphylaxis. [Updated 2022 May 2]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022
Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK519020/
Yerram P, Chaudhary K. Calcific uremic arteriolopathy in end stage renal disease: pathophysiology and management. Ochsner J. 2014
11/04/2022 19
Fall;14(3):380-5. PMID: 25249804; PMCID: PMC4171796.
Assessment and Diagnosis

• No specific laboratory findings in patients with calciphylaxis.

• In some patients, increases in calcium parathyroid hormone (PTH), and phosphorus may be observed, but
not always
• A biopsy of the affected skin is needed to make the diagnosis of calciphylaxis.
• Often a CT is done of the affected area to see the extent of the calcification in the soft tissue
• Calcification of small to medium-sized blood vessels are seen. The intimal layer of
blood vessels is most commonly fibrosed and intravascular thrombi may be seen.
• Characteristic feature of calciphylaxis is the diffuse calcification of the small
capillaries in the adipose tissue of the area.

11/04/2022 20
Treatment Options1,2,3

• Currently there is no approved treatment for calciphylaxis

• Treatment revolves around analgesia, wound care, and mitigation of risk factors
• There are also no evidence-based clinical practice guidelines for the prevention and
treatment of calciphylaxis, there exists only expert opinions that are derived from
the very limited literature.
• A meta-analysis and systemic review conducted by Udomkarnjananun et al. in
February 2019 reviewed the 5 most common treatment modalities for calciphylaxis
• These include sodium thiosulfate, surgical parathyroidectomy, hyperbaric oxygen therapy, cinacalcet, and
bisphosphonates.
• The review found that all 5 treatments failed to demonstrate a mortality benefit in the pooled cohort studies.
However, they ruled the results as inconclusive, as they are not derived from randomized controlled trials,
but their potential benefit cannot be ruled out.

Westphal SG, Plumb T. Calciphylaxis. [Updated 2022 May 2]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from:
https://www.ncbi.nlm.nih.gov/books/NBK519020/
Yerram P, Chaudhary K. Calcific uremic arteriolopathy in end stage renal disease: pathophysiology and management. Ochsner J. 2014 Fall;14(3):380-5. PMID: 25249804; PMCID: PMC4171796.
Udomkarnjananun S, Kongnatthasate K, Praditpornsilpa K, Eiam-Ong S, Jaber BL, Susantitaphong P. Treatment of Calciphylaxis in CKD: A Systematic Review and Meta-analysis. Kidney Int Rep. 11/04/2022 21
2018 Oct 9;4(2):231-244. doi: 10.1016/j.ekir.2018.10.002. PMID: 30775620; PMCID: PMC6365410.
Bisphosphonates and Cinacalcet7

• Bisphosphonates have been shown to be effective in animal models of calciphylaxis.

The mechanism of action is hypothesized to be due to the inhibition of macrophages
and local proinflammatory cytokines and binding to calcified vascular smooth
muscle cells to inhibit further arterial calcification.

• Cinacalcet increases the sensitivity of the parathyroid gland receptor for calcium,
thereby decreasing serum calcium. Hypothesized to help with calciphylaxis by
decreasing calcium levels in the serum meaning that there is less calcium to cause
calcium buildup in the small vessels.

11/04/2022 22
Treatment Options

• Wound care and pain control are critical aspects of the management of calciphylaxis.
• Opioid analgesics are often required to control pain associated with calciphylaxis.
• Patients typically need more analgesics and aggressive wound care after debridement.

• Wound infection is a common complication of calciphylaxis that may present as

increased pain, swelling, and/or purulent discharge at the site of the wound.
• Clinicians should suspect and be on the lookout for any signs of infection during the entire disease course.
• The treatment of suspected wound infections includes antimicrobial therapy and surgical debridement
• In patients with calciphylaxis, it is typically not possible to identify a specific culprit organism, empiric
antibiotic therapy for suspected wound infections should include drugs with activity against streptococci,
methicillin-resistant Staphylococcus aureus, aerobic Gram-negative bacilli, and anaerobes.

11/04/2022 23
Primary Literature4

• A 2013 retrospective study conducted by Nigwekar et al. found that in 172 patients
undergoing maintenance hemodialysis between August 2006 and June 2009 at
Fresenius Medical Care North America who had calciphylaxis (CUA) and were
treated with sodium thiosulfate (STS)
Complete resolution of CUA 26.4%
Marked improvement in CUA 18.9%
Improvement in CUA 28.3
Did not improve 5.7%
Unknown response 20.8%

• While these results are by no means definitive, it does paint a good picture for using
STS in patients with CUA

Nigwekar SU, Brunelli SM, Meade D, Wang W, Hymes J, Lacson E Jr. Sodium thiosulfate therapy for calcific
uremic arteriolopathy. Clin J Am Soc Nephrol. 2013 Jul;8(7):1162-70. doi: 10.2215/CJN.09880912. Epub 2013 11/04/2022 24
Mar 21. PMID: 23520041; PMCID: PMC3700696
Sodium Thiosulfate6

• Indicated use is as an alternative treatment for cyanide poisoning

• Off label uses include: Calciphylaxis, Management of mechlorethamine extravasation, Management of
delayed calcium extravasation (calcinosis cutis), Management of concentrated cisplatin (≥0.4 mg/mL)
extravasation
• Mechanism of action in extravasation management: Neutralizes the reactive species
and reduces the formation of hydroxyl radicals which cause tissue injury
• Adverse events:
• Cardiovascular: Hypotension
• Central nervous system: Disorientation, flushing sensation, headache, salty taste
• Gastrointestinal: Nausea, vomiting
• Hematologic & oncologic: Prolonged bleeding time

11/04/2022 25
Conclusion of Patient Case

11/04/2022 26
What Happened to CG?

• Unfortunately, no happy ending…

• Sodium thiosulfate was added to dialysis medications every Tuesday, Thursday, and
Saturday

• Increased pain regimen was added to CGs medication list

• Topical Silvadene was continued as needed

• The rest is to be continued…

11/04/2022 27
References

1. Westphal SG, Plumb T. Calciphylaxis. [Updated 2022 May 2]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available
from: https://www.ncbi.nlm.nih.gov/books/NBK519020/

2. Yerram P, Chaudhary K. Calcific uremic arteriolopathy in end stage renal disease: pathophysiology and management. Ochsner J. 2014 Fall;14(3):380-5.
PMID: 25249804; PMCID: PMC4171796.

3. Udomkarnjananun S, Kongnatthasate K, Praditpornsilpa K, Eiam-Ong S, Jaber BL, Susantitaphong P. Treatment of Calciphylaxis in CKD: A Systematic
Review and Meta-analysis. Kidney Int Rep. 2018 Oct 9;4(2):231-244. doi: 10.1016/j.ekir.2018.10.002. PMID: 30775620; PMCID: PMC6365410.

4. Nigwekar SU, Brunelli SM, Meade D, Wang W, Hymes J, Lacson E Jr. Sodium thiosulfate therapy for calcific uremic arteriolopathy. Clin J Am Soc Nephrol.
2013 Jul;8(7):1162-70. doi: 10.2215/CJN.09880912. Epub 2013 Mar 21. PMID: 23520041; PMCID: PMC3700696.

5. Sadiq NM, Naganathan S, Badireddy M. Hypercalcemia. [Updated 2021 Nov 26]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing;
2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK430714/

6. Generali JA, Cada DJ. Sodium Thiosulfate: Calciphylaxis. Hosp Pharm. 2015 Nov;50(11):975-7. doi: 10.1310/hpj5011-975. Epub 2015 Nov 24. PMID:
27621504; PMCID: PMC4750847.

7. Sensipar (cinacalcet) [prescribing information]. Thousand Oaks, CA: Amgen Inc; December 2019.

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