PROTEINURIA IS ASSOCIATED WITH

ACUTE RESPIRATORY DISTRESS SYNDROME IN PATIENTS WITH METASTATIC

PHEOCHROMOCYTOMA OR PARAGANGLIOMA

PROTEINURIA IS ASSOCIATED WITH

ACUTE RESPIRATORY DISTRESS SYNDROME IN PATIENTS WITH METASTATIC

PHEOCHROMOCYTOMA OR PARAGANGLIOMA

University of California, San Francisco Departments of Medicine1, Pediatrics2, and Nuclear Medicine3

BackgroundResults

Design and Method

Discussion• Catecholamines increase pulmonary artery pressure and

the risk of pulmonary edema. However we found no statistically significant association between ARDS and secretions of catecholamines or metanephrines.

• The underlying etiology of the association between proteinuria and ARDS in patients with pheochromocytoma is unknown.

• Pheochromocytomas and paragangliomas produce tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) (ref tong, Kontogeorgos).

• Increased levels of TNF-α have been associated with proteinuria and may predispose to pulmonary edema (ref yang, dm)

• The occurrence of ARDS following ¹³¹I-MIBG treatment may due to an increased release of these cytokines or an increased sensitivity to them following the early concentration ¹³¹I-MIBG in the lungs immediately following its administration (ref I 123).

Conclusions

Objective

Porzig A1, Matthay KK2, Dubois S2, Pampaloni M3, Damon L1, Hawkins R3, Goldsby R2, Hollinger F2, Fitzgerald P1

Acute Respiratory Distress Syndrome (ARDS) is an acute onset, hypoxic respiratory failure with bilateral infiltrates on chest radiograph without left atrial hypertension. ARDS is frequently fatal.

• ARDS has been reported rarely in patients with pheochromocytoma, occurring both spontaneously or after ¹³¹I-meta-iodobenzylguanidine therapy (¹³¹I-MIBG).

• ARDS has been reported in four pregnant women with pheochromocytomas and proteinuria.

• ARDS has also been reported in one non-pregnant woman and one man with pheochromocytomas and proteinuria.

¹³¹I-MIBG is currently used in the treatment of patients with metastatic neuroblastoma, paraganglioma & pheochromocytoma.

There have been two prior case reports of patients developing ARDS following MIBG therapy for metastatic paraganglioma.

There are no case reports of ARDS following ¹³¹I-MIBG therapy for patients with metastatic neuroblastoma.

Our objective was to determine whether proteinuria in patients with metastatic pheochromocytoma or paraganglioma treated with ¹³¹I-MIBG predicts an increased risk of ARDS.

A retrospective analysis of a prospective cohort study of 64 patients with metastatic pheochromocytoma or paraganglioma treated with ¹³¹I-MIBG on institutional protocols.

• Median age is 45 years (range 10-71 years).

• Nine patients received multiple administrations of ¹³¹I-MIBG.

• The median dose of ¹³¹I-MIBG was 808 mCi (30 GBq)

with range of 386-1160 mCi (14-43 GBq).

Definitions:

• Proteinuria was defined as at least one urinalysis positive for at least trace protein within one month prior to ¹³¹I-MIBG. For cases in which ARDS developed more than four months after ¹³¹I-MIBG, urine analysis was also examined within one month prior to ARDS.

• Secretory was defined as elevation in metanephrines or catecholamines beyond the upper limit of normal for that lab.

Statistical Analysis:• Proportions were compared using Fisher’s exact

test.• Means were compared using the t-test.

• Urinalyses within the defined time period were available for 48 patients, 8 of whom had proteinuria prior to ¹³¹I-MIBG.

• Of 8 patients with proteinuria, 5 developed ARDS.

• Of these 5 patients with proteinuria and ARDS, • three patients developed ARDS within 10 days following

¹³¹I-MIBG, • two patients developed ARDS six months after ¹³¹I-MIBG.

• One of these two with later onset of ARDS had a previous history of ARDS three months prior to his ¹³¹I-MIBG treatment.

• Both patients with later onset of ARDS had proteinuria within one month before ARDS and had proteinuria within one month prior to at least one ¹³¹I-MIBG administration.

• None of the 40 patients whose urinalyses were all negative for protein within one month of ¹³¹I-MIBG developed ARDS.

• None of the 16 patients with missing urinalyses developed ARDS.

• Patients with proteinuria were more likely to develop ARDS than those without proteinuria (63% vs. 0%; p <0.0001).

• The following variables were not significantly associated with ARDS: • Age, gender, hypertension, • Dosage of¹³¹I-MIBG, • Number of ¹³¹I-MIBG administrations, • Creatinine, metanephrine, normetanephrine, epinephrine

and norepinephrine.

Proteinuria in patients with metastatic pheochromocytoma or paraganglioma appears to increase the risk of ARDS. In these patients, ARDS may occur spontaneously or following ¹³¹I-MIBG therapy.

No Proteinuria

N (%)

Proteinuria

N (%)

P-value

Men

Women

19 (51)

18 (49)

4 (50)

4 (50)1.0

No Hypertension

Hypertension

16 (43)

21 (57)

2 (25)

6 (75)0.45

Non-secretory

Secretory

10 (25)

30 (75)

0

7 (100)0.32

Normal Creatinine

Elevated Creatinine

33 (89)

4 (11)

4 (50)

4 (50)0.02

Chest CT of a 24 year old woman with metastatic paraganglioma and proteinuria who developed ARDS following ¹³¹I-MIBG therapy.

Characteristics of Patient Population

No ARDSN (%)

ARDSN (%)

P-value

No Hypertension

Hypertension

24 (43)31 (53)

1 (20)4 (80)

0.39

Non-secretory

Secretory

14 (24)44 (76)

05 (100)

0.58

Normal CreatinineElevated Creatinine

45 (88)6 (12)

3 (60)2 (40)

0.14

No Proteinuria Proteinuria

40 (93)3 (7)

05 (100)

<0.0001

There were no statistically significant association between proteinuria and gender, hypertension, or secretions. There was as statistically association between proteinuria and creatinine elevation.

None of the patients without proteinuria developed ARDS, but 63% of the patients with proteinuria developed ARDS (p<0.0001).

References:

MatthayAlmog, et al Acta Obstet Gynec Scand 2000; Feldman Journal of Surgical Oncology 2005, Golshevsky et al Anesthesia and Intensive Care 2007, Hudsmith et al International Journal of Obstrestic Anesthesia 2006 Ford, Canadian Medical Association Journal 1997; O’Hickey Thorax 1987; Scully, NEJM 1989; Yoshida T Am J Emerg Med. 2009 GoniasFitzgerald Ann N Y Acad Sci.2006 TongKontogeogosYang

Patient characteristics and ARDS

Box Plot: The central box demonstrates the 25th to 75th percentile.  The horizontal line within the center box marks the median fold elevation.  The individual dots represent outliers.  For example, the blue dot in the left top corner represents the metanephrine level that were 300 times higher than the upper limit of normal in one patient without ARDS. The blue box on the lower left shows that 75% of patients without ARDS had metanephrines between normal and 1.9 times the upper limit of normal. Most patients had normal epinephrine levels.