Forensic Sci Med Pathol (2015) 11:255–261 DOI 10.1007/s12024-015-9664-x
CASE REPORT
Fatal foreign-body granulomatous pulmonary embolization due to microcrystalline cellulose in a patient receiving total parenteral nutrition: all crystals are not what they seem Sarah Strickland • Elena Pena • Alfredo E. Walker
Accepted: 5 February 2015 / Published online: 4 March 2015 Ó Springer Science+Business Media New York 2015
Abstract Pulmonary foreign-body granulomatous embolization has been described secondary to crystal precipitation in total parenteral nutrition (TPN) as well as when pharmaceutical tablets are crushed and injected intravenously. Extensive granulomatous embolization may cause pulmonary hypertension and death due to acute cor pulmonale. We report the case of a 34-year old woman who had been receiving TPN post-operatively secondary to complications of a paraesophageal hernia repair. During and following receiving TPN, she experienced episodes of hypoxia, tachycardia, fever, and hypotension. Computed tomography scans of the thorax showed centrilobular nodules, tree-in-bud and ground-glass opacities, as well as findings of pulmonary hypertension. Following an episode of hypoxia she was found unresponsive and died despite resuscitative efforts. Microscopic examination of the lungs following post-mortem examination revealed occlusive granulomatous inflammation of the pulmonary arterial vasculature by crystalline material. The morphologic and histochemical patterns of the crystals were suggestive of microcrystalline cellulose, a finding that was confirmed by energy dispersive X-spectroscopy and infrared spectroscopy. Ancillary tests did not support that the crystalline material was the result of TPN precipitation. Foreign-body granulomatous embolization leading to acute core pulmonale may occur as a complication of both intravenous
injection of oral medications as well as of TPN crystallization. The source of crystalline material may be difficult to discern based solely on morphological assessment or by histochemical staining. Ancillary studies such as energy dispersive X-spectroscopy or infrared spectroscopy should be performed to definitively discern the two entities.
S. Strickland (&) A. E. Walker Department of Pathology and Laboratory Medicine, The Ottawa Hospital, University of Ottawa, 451 Smyth Road, Room 4155, Ottawa, ON K1H 8M5, Canada e-mail: [email protected]
Case report
E. Pena Departments of Radiology and Medical Imaging, The Ottawa Hospital, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada
Keywords Total parenteral nutrition Pulmonary emboli Granulomas Microcrystalline cellulose Introduction Extensive pulmonary foreign-body granulomatous embolization has been described in patients receiving total parenteral nutrition (TPN) [1–6] as well as in those injecting pharmaceutical tablets intended for oral use [8–15]. In both instances pulmonary hypertension and death due to acute cor pulmonale may occur, however, it may be difficult to discern the cause of embolization as routine histological and histochemical assessments may be insufficient for this purpose. The present case describes a patient who was receiving TPN when she died suddenly, and whose autopsy findings included foreign-body granulomatous pulmonary embolization. It serves to review the literature and describes ancillary tests that may be required to determine the composition of the embolized material.
The decedent was a 34 year old female with a past medical history of gastroesophageal reflux disease (GERD), remote Nissen fundoplication, endometriosis, abdominal trauma requiring multiple surgeries, chronic oral opioid use, pseudoseizures, post-traumatic stress disorder, and anxiety.
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Due to upper gastrointestinal symptoms (dysphagia to solids and liquids) she underwent investigations which revealed a recurrent paraesophageal hernia and a defect in the posterior wrap of her Nissen fundoplication. She underwent laparoscopic paraesophageal hernia repair for surgical management of her symptoms. Post-operatively, she began experiencing dysphagia and epigastric pain on swallowing and was subsequently readmitted to hospital for further investigations. An endoscopy failed to find a mechanical cause for her symptoms and she was started on TPN for nutritional supplementation. She received TPN through a peripherally inserted central catheter (PICC) placed into her right brachial vein. The TPN solution consisted of a standard 7 % amino acid solution with 20 % dextrose, 20 % fat emulsion and sodium, potassium, calcium, magnesium, and phosphate. In total, she received TPN for 14 days, however it was discontinued due to sepsis originating from her PICC site. Following the removal of her right brachial vein PICC, she received a new PICC in her left internal jugular vein and was started on enteral feeding. Beginning 2 days after TPN was started and continuing until her death, the patient experienced repeated episodes of hypoxia, hypotension, tachycardia, and fever. Due to clinical suspicion of pulmonary embolism, computed tomography (CT) pulmonary angiography was performed which excluded pulmonary embolism but demonstrated findings of pulmonary hypertension and patchy areas of ground-glass opacities as well as centrilobular nodules and tree-in-bud opacities throughout the lungs bilaterally. Bilateral venous doppler ultrasonography revealed absence of deep vein thrombosis of the legs and a trans-thoracic echocardiogram was within normal limits. Approximately 1 month after ceasing TPN, she was again noted to be hypotensive, tachycardic, and febrile. Blood cultures and a chest X-ray were both negative. After an episode of hypoxia with elevated temperature, she was found unresponsive in her hospital bed and died despite resuscitative efforts. At the time of her death, her prescribed oral medications included hydromorphone, lorazepam, clonazepam, domperidone, docusate sodium, lactulose, ondansetron, lansoprazole, zopiclone, and gabapentin. Notably, the patient had no personal history of intravenous drug use and no concerns were documented pertaining to possible abuse of prescribed medications while in hospital. At autopsy, the absence of thromboembolic disease was confirmed. The right lung weighed 710 g and the left lung 640 g. The upper lobes of both the right and left lungs were abnormal in appearance (diffuse gray color) but without the firmness of bronchopneumonic consolidation. The right middle lobe and the lower lobes of both lungs were slightly firm. Due to the absence of a grossly identifiable cause of
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death, a frozen section of lung tissue was performed at the time of autopsy. This revealed global occlusive foreignbody granulomatous inflammation of all calibers of the pulmonary arterial vasculature, in response to amorphous, rod-shaped polarizable foreign material and unassociated with any similar intra-alveolar foreign-body granulomas to indicate aspiration. Formalin-fixed, paraffin-embedded sections replicated the findings seen in frozen section (Fig. 1). No other organs contained microvascular emboli and the foreign material was brightly birefringent under polarized light (Fig. 1). Special stains of the material revealed that it stained yellow by Movat pentachrome stain, stained red by Congo red, red-violet by periodic-acid Schiff (PAS) stain and stained black by a Gomori methenamine silver (Grocott) stain (Fig. 2). There was no calcium identified by either alizarin red stain or von Kossa stain. Energy dispersive X-spectroscopy in conjunction with electron microscopy revealed that the polarizing material was organic in nature. None of the elemental constituents of TPN including calcium, phosphate, magnesium, potassium, or sodium were identified. Infrared spectroscopy further characterized the material as cellulose-based (Fig. 3). Femoral blood toxicologic analysis revealed a hydromorphone concentration of 22 ng/ mL (±ng/mL) (fatal reference[51 ng/mL) as well as small quantities of substances compatible with her other prescription medications. The cause of death was determined to be occlusive granulomatous foreign-body embolization. The mechanism of death was acute cor pulmonale which resulted from a sudden increase in resistance to blood flow within the pulmonary circulation and lead to acute right heart failure. A cardiothoracic radiologist who was provided with the appropriate clinical history reviewed the decedent’s thoracic CT scans. While hospitalized the decedent had four thoracic CT scans over a period of 44 days, the first of which was performed 3 days post-operatively. One of the four CT scans was performed 2 days after the initiation of TPN while the other three predated this therapy (42, 32, and 16 days prior to the initiation of TPN). All CTs during her admission were compared to a previous CT scan (baseline) which had been performed 5 months earlier. The CT findings as compared to baseline could be divided into pulmonary parenchymal and cardiovascular findings. The parenchymal findings included centrilobular nodules, tree-in-bud and ground-glass opacities. The cardiovascular findings were indicative of pulmonary hypertension and elevated right side cardiac pressures and included enlargement of the pulmonary artery and right cardiac chamber and flattening of the interventricular septum (Figs. 4, 5). Although these findings improved from the first admission CT to the last CT, the lung parenchyma never returned to its normal appearance as seen on the
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Fig. 1 a Hematoxylin and eosin section of right upper lung lobe. There is presence of foreign material within the pulmonary vasculature with accompanying granulomatous response (magnification
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9400). b Foreign material within pulmonary vasculature viewed under polarized light (magnification 9400)
Fig. 2 Foreign material stained with a Movat pentachrome, b periodic-acid Schiff (PAS), c Grocott, and d Congo red (magnification 9400)
baseline CT. The radiological interpretation was therefore that the parenchymal changes had pre-dated the use of TPN.
Discussion TPN is a form of nutritional support for which calories, amino acids, electrolytes, vitamins, minerals, trace elements, lipids, and fluids are provided via a parenteral route for patients who require nutritional supplementation. TPN must be administered via a central venous catheter because the peripheral veins cannot tolerate its high osmotic load [7]. Because of the complexity of TPN formulations, there exists a risk of precipitate and crystal formation [1].
Calcium phosphate crystals have been previously recovered from within the pulmonary arterioles of patients who were receiving TPN and experienced sudden cardiorespiratory arrest [2, 3]. Experimental studies have shown that the solubility of calcium and phosphorous is affected by pH, temperature, amino acid formulation and concentration, type of calcium salt, duration of storage, order of mixing, and contact with lipids [2]. There have been case reports of respiratory distress and death in patients receiving TPN [1–6]. The majority of cases occurred in young adults who had been receiving TPN for extended periods of time and began to experience intermittent fever, dyspnea, and chest tightness with a high clinical suspicion of pulmonary embolism [1, 3, 5]. CT imaging findings revealed ground-glass opacities and
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Fig. 3 Infrared spectroscopy of three areas of foreign material isolated from the pulmonary arterioles (a–c) compared to a known reference of cellulose (d)
micronodules throughout the lungs [1, 3, 5]. Transbronchial biopsies in all cases revealed polarizable crystalline material with a surrounding granulomatous reaction [1, 3, 5]. Upon discontinuation of TPN the majority of the patients’ symptoms improved [3, 5] but one patient died at home while still receiving TPN [1]. Other case reports detail two previously healthy young women who were receiving TPN immediately post-operatively and experienced sudden cardiorespiratory arrest. Both women had emboli within their pulmonary capillaries and small arterioles consisting of amorphous birefringent material [2]. In two of the aforementioned series [2, 3] the crystalline material retrieved from transbronchial biopsies or autopsy tissue was analyzed by energy dispersive X-ray analysis and showed either high levels of calcium, potassium, and carbon [3] or calcium phosphate and organic material [2]. One report [3] performed a Movat pentachrome stain which revealed that the crystalline precipitates stained yellow, a finding similar to microcrystalline cellulose. In the other previously described case reports the authors did not perform ancillary investigations to determine the composition of the crystalline material. The intravenous injection of pharmaceutical tablets intended for oral consumption may also cause pulmonary foreign-body granulomatosis [8–15] leading to pulmonary hypertension and cor pulmonale [10, 12–14]. In addition to pharmacologically active ingredients, pharmaceutical tablets may contain a variety of insoluble filler and binder substances such as microcrystalline cellulose, crospovidone, starches, magnesium stearate, silicates, and talc [8]. Morphological features of the crystalline material, birefringence under polarized light, and special staining patterns, may provide clues as to the composition of the material (Table 1) [8, 11, 15].
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Similar to the previously reported cases of crystalline embolization from TPN, the decedent in this case experienced episodes of fever, tachypnea, and dyspnea while receiving TPN with a clinical presentation that was suspicious for pulmonary embolism. The ground-glass opacities seen on thoracic imaging were similar to those in the previously described cases and the histological lung findings from all reported cases were consistent. Also supportive of TPN embolization was the fact that the decedent had no clinical history of intravenous drug use and no concerns were charted regarding the possibility of drug abuse while she was hospitalized. There are several factors, however, which argue against TPN embolization in this case. First and foremost, the decedent had not been receiving TPN until the time of her death (it was discontinued 1 month prior due to PICC line infection). Furthermore on post-mortem review, the CT findings appear to predate the initializing of TPN. The imaging findings of centrilobular nodules, tree-in-bud and ground-glass opacities have been described as findings in foreign-body granulomatosis due to intravenous injection of medications intended for oral use [16–22] and tree-inbud opacities and centrilobular nodules specifically have been described in the context of cellulose granulomatosis [16]. Although these findings improved from the decedent’s first admission CT to the time of her last, the lung parenchyma never returned to its normal appearance as seen on the baseline CT. Ancillary investigations were also not supportive of TPN crystallization. Energy dispersive X-spectroscopy did not reveal presence of calcium or phosphate within the crystallizing material which was isolated in the two cases of TPN embolization that performed crystalline analysis. Other constituents of her TPN solution such as sodium,
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Fig. 4 Contrast-enhanced CT pulmonary angiography comparing a baseline CT (a, c) showing a pulmonary artery of normal size (a) and a normal configuration of the right ventricle and interventricular septum (arrow) (c) with a CT after admission (b, d) which demonstrates an enlarged pulmonary artery (b) and an enlarged right ventricle (d) (line) with flattening of the interventricular septum (arrow), indicating findings of pulmonary hypertension and increased right sided cardiac pressures
potassium, or magnesium were also not identified. Infrared spectroscopy analysis did not reveal any calcium or phosphate containing compounds and found all material analyzed to be cellulose-based. Therefore, although the decedent had been receiving TPN and had no history of intravenous drug use, the imaging findings, morphological features as well as ancillary investigations (including histochemical staining, energy dispersive X-spectroscopy, and infrared spectroscopy) were supportive of microcrystalline cellulose embolization. Interestingly, the scenario of patients receiving TPN who die from cor pulmonale secondary to embolization of intravenous drug fillers has been previously reported.
Ott et al. [23] reported the case of a dyspneic 50 year old man who had been dependent on home TPN for 24 years and was receiving prescription codeine to control his short bowel-induced diarrhea. A thoracic CT demonstrated widespread micronodular parenchymal disease and a transbronchial biopsy identified birefringent crystalline material with associated granulomas. Spectral analysis revealed the material to be organic in nature and, although no further analysis was performed, a diagnosis of microcrystalline cellulose embolization was made. The man admitted to occasionally dissolving and injecting his codeine tablets directly into his PICC line.
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Fig. 5 Contrast-enhanced CT pulmonary angiography in lung windows demonstrating ground-glass opacities (a) and tree-in-bud opacities (b, arrows) as well as centrilobular nodules
Table 1 Previously reported morphological and histochemical staining features of filler materials Crystalline material
Shape
Size (lm)
Birefrin-gence in polarized light
PAS
Congo red
MPS
GMS
Talc
Stacked plates
5–15
?
Red-violet
Negative
Negative or light blue
MCC
Rod-like
25–200
?
Red-violet
Red
Yellow or yellow-green
Gray–black
Crospovidone
Rod-like
\100
-
Blue-gray
Red-brown
Yellow-orange or blue-green
Brown–gray
Starch
Maltese-cross
10–100
?
Red-violet
Un-stained
MCC microcrystalline cellulose, PAS periodic-acid Schiff, MPS Movat pentachrome stain, GMS Gomori methenamine silver
In a review of embolized crospovidone in the lungs of intravenous drug users, Ganesan et al. [8] examined three cases of fatal hydromorphone toxicity with suspected thoracic embolized crospovidone. One of the cases was a 38 year old woman receiving TPN after an extensive small bowel resection who had no clinical history of intravenous drug use. Infrared spectroscopy analysis of the crystalline material within her pulmonary arterioles revealed only crospovidone and microcrystalline cellulose.
polarizable occlusive foreign-body granulomatous inflammation in the pulmonary arterial vasculature. As the clinical presentation, diagnostic imaging findings and microscopy findings can be similar in both entities; ancillary investigations such as energy dispersive X-spectroscopy and infrared spectroscopy should be performed to establish a definitive cause of death.
Key points Conclusion In summary, this case presents the first case report of a patient receiving TPN who died of acute cor pulmonale secondary to extensive foreign-body granulomatous embolization and who had extensive relevant ancillary investigations performed. In both TPN crystallization and injection of pharmaceutical tablets the clinical presentation may include intermittent episodes of hypoxia, hypotension, tachycardia, and fever and the pulmonary CT findings may include centrilobular nodules, and tree-in-bud and ground-glass opacities. The histological findings in both entities include
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1.
2.
3. 4.
Foreign-body granulomatous pulmonary emboli can occur both from crystallization of TPN as well as from injection of pharmaceutical tablets intended for oral use. Both entities can be fatal due to acute cor pulmonale and autopsy findings include occlusive foreign-body granulomatous inflammation in the pulmonary arterial vasculature. CT findings of both entities include centrilobular nodules, tree-in-bud and ground-glass opacities. Ancillary investigations such as dispersive X-spectroscopy and infrared spectroscopy may be required to distinguish the two causes of crystallization.
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References 1. Reedy JS, Kuhlman JE, Voytovich M. Microvascular pulmonary emboli secondary to precipitated crystals in a patient receiving total parenteral nutrition: a case report and description of the high-resolution CT findings. Chest. 1999;115(3):892–5. 2. Hill SE, Heldman LS, Goo EDH, Whippo PE, Perkinson JC. Fatal microvascular pulmonary emboli from precipitation of a total nutrient admixture solution. JPEN J Parenter Enteral Nutr. 1996;20(1):81–7. 3. McNearney T, Bajaj C, Boyars M, Cottingham J, Haque A. Total parenteral nutrition associated crystalline precipitates resulting in pulmonary artery occlusions and alveolar granulomas. Dig Dis Sci. 2003;48(7):1352–4. 4. Hammar SP, Williams MG, Dodson RF. Pulmonary granulomatous vasculitis induced by insoluble particulates: a case report. Ultrastruct Pathol. 2003;27(6):439–49. 5. Knowles JB, Cusson G, Smith M, Sitrin MD. Pulmonary deposition of calcium phosphate crystals as a complication of home total parenteral nutrition. JPEN J Parenter Enteral Nutr. 1989;13(2):209–13. 6. Shay DK, Fann LM, Jarvis WR. Respiratory distress and sudden death associated with receipt of a peripheral parenteral nutrition admixture. Infect Control Hosp Epidemiol. 1997;18(12):814–7. 7. Kuwahara T, Asanami S, Tamura T, Kaneda S. Effects of pH and osmolality on phlebitic potential of infusion solutions for peripheral parenteral nutrition. J Toxicol Sci. 1998;23:77. 8. Ganesan S, Felo J, Saldana M, Kalasinsky V, Lewin-Smith M, Tomashefski J. Embolized crospovidone (poly[N-vinyl-2pyrrolidone]) in the lungs of intravenous drug users. Mod Pathol. 2003;16(4):286–92. 9. Tomashefski J, Hirsch C. The pulmonary vascular lesions of intravenous drug abuse. Hum Pathol. 1980;11:133–45. 10. Tomashefski J, Hirsch C, Jolly P. Microcrystalline cellulose pulmonary embolism and granulomatosis. A complication of illicit intravenous injections of pentazocine tablets. Arch Pathol Lab Med. 1981;105:89–93. 11. Kingsholm B, Christoffersen P. The nature and the occurrence of birefringent material in different organs in fatal drug addiction. Forensic Sci Int. 1987;34:53–62. 12. Zeltner T, Nussbaumer U, Zimmermann R. Unusual pulmonary vascular lesions after intravenous injections of microcrystalline
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cellulose. Virchows Arch A Pathol Anat Histol. 1982;395(2): 207–16. Arnett E, Battle W, Russo J, Roberts W. Intravenous injection of talc-containing drugs intended for oral use. A cause of pulmonary granulomatosis and pulmonary hypertension. Am J Med. 1976; 60:711–8. Dettmeyer R, Verhoff M, Bruckel B, Walter D. Widespread pulmonary granulomatosis following long time intravenous drug abuse—a case report. Forensic Sci Int. 2010;197:e27–30. Sigdel S, Gemind T, Tomashefski J. The Movat pentachrome stain as a means of identifying cellulose among other particulates found in lung tissue. Arch Pathol Lab Med. 2011;135:249–54. Bendeck SE, Leung AN, Berry GJ, Daniel D, Ruoss SJ. Cellulose granulomatosis presenting as centrilobular nodules: CT and histologic findings. AJR Am J Roentgenol. 2001;177:1151–3. Nguyen ET, Silva CI, Souza CA, Muller NL. Pulmonary complications of illicit drug use: differential diagnosis based on CT findings. J Thorac Imaging. 2007;22:199–206. Schmidt RA, Glenny RW, Godwin JD, Hampson NB, Cantino ME, Reichenbach DD. Panlobular emphysema in young intravenous Ritalin abusers. Am Rev Respir Dis. 1991;143:649–56. Stern EJ, Frank MS, Schmutz JF, Glenny RW, Schmidt RA, Godwin JD. Panlobular pulmonary emphysema caused by i.v. injection of methylphenidate (Ritalin): findings on chest radiographs and CT scans. AJR Am J Roentgenol. 1994;162:555–60. Ward S, Heyneman LE, Reittner P, Kazerooni EA, Godwin JD, Muller NL. Talcosis associated with IV abuse of oral medications: CT findings. AJR Am J Roentgenol. 2000;174:789–93. Diaz-Ruiz MJ, Gallardo X, Castaner E, Mata JM, Catala J, Ferreres JC. Cellulose granulomatosis of the lungs. Eur Radiol. 1999;9:1203–4. Smith KJ, Elidemir O, Dishop MK, Eldin KW, Tatevian N, Moore RH. Intravenous injection of pharmaceutical tablets presenting as multiple pulmonary nodules and declining pulmonary function in an adolescent with cystic fibrosis. Pediatrics. 2006;118:e924–8. Ott M, Khoor A, Scolapio J, Leventhal J. Pulmonary microcrystalline cellulose deposition from intravenous injection of orgal medication in a patient receiving total parenteral nutrition. JPEN J Parenter Enteral Nutr. 2003;27:91–3.
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CASE REPORT
Fatal foreign-body granulomatous pulmonary embolization due to microcrystalline cellulose in a patient receiving total parenteral nutrition: all crystals are not what they seem Sarah Strickland • Elena Pena • Alfredo E. Walker
Accepted: 5 February 2015 / Published online: 4 March 2015 Ó Springer Science+Business Media New York 2015
Abstract Pulmonary foreign-body granulomatous embolization has been described secondary to crystal precipitation in total parenteral nutrition (TPN) as well as when pharmaceutical tablets are crushed and injected intravenously. Extensive granulomatous embolization may cause pulmonary hypertension and death due to acute cor pulmonale. We report the case of a 34-year old woman who had been receiving TPN post-operatively secondary to complications of a paraesophageal hernia repair. During and following receiving TPN, she experienced episodes of hypoxia, tachycardia, fever, and hypotension. Computed tomography scans of the thorax showed centrilobular nodules, tree-in-bud and ground-glass opacities, as well as findings of pulmonary hypertension. Following an episode of hypoxia she was found unresponsive and died despite resuscitative efforts. Microscopic examination of the lungs following post-mortem examination revealed occlusive granulomatous inflammation of the pulmonary arterial vasculature by crystalline material. The morphologic and histochemical patterns of the crystals were suggestive of microcrystalline cellulose, a finding that was confirmed by energy dispersive X-spectroscopy and infrared spectroscopy. Ancillary tests did not support that the crystalline material was the result of TPN precipitation. Foreign-body granulomatous embolization leading to acute core pulmonale may occur as a complication of both intravenous
injection of oral medications as well as of TPN crystallization. The source of crystalline material may be difficult to discern based solely on morphological assessment or by histochemical staining. Ancillary studies such as energy dispersive X-spectroscopy or infrared spectroscopy should be performed to definitively discern the two entities.
S. Strickland (&) A. E. Walker Department of Pathology and Laboratory Medicine, The Ottawa Hospital, University of Ottawa, 451 Smyth Road, Room 4155, Ottawa, ON K1H 8M5, Canada e-mail: [email protected]
Case report
E. Pena Departments of Radiology and Medical Imaging, The Ottawa Hospital, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada
Keywords Total parenteral nutrition Pulmonary emboli Granulomas Microcrystalline cellulose Introduction Extensive pulmonary foreign-body granulomatous embolization has been described in patients receiving total parenteral nutrition (TPN) [1–6] as well as in those injecting pharmaceutical tablets intended for oral use [8–15]. In both instances pulmonary hypertension and death due to acute cor pulmonale may occur, however, it may be difficult to discern the cause of embolization as routine histological and histochemical assessments may be insufficient for this purpose. The present case describes a patient who was receiving TPN when she died suddenly, and whose autopsy findings included foreign-body granulomatous pulmonary embolization. It serves to review the literature and describes ancillary tests that may be required to determine the composition of the embolized material.
The decedent was a 34 year old female with a past medical history of gastroesophageal reflux disease (GERD), remote Nissen fundoplication, endometriosis, abdominal trauma requiring multiple surgeries, chronic oral opioid use, pseudoseizures, post-traumatic stress disorder, and anxiety.
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Due to upper gastrointestinal symptoms (dysphagia to solids and liquids) she underwent investigations which revealed a recurrent paraesophageal hernia and a defect in the posterior wrap of her Nissen fundoplication. She underwent laparoscopic paraesophageal hernia repair for surgical management of her symptoms. Post-operatively, she began experiencing dysphagia and epigastric pain on swallowing and was subsequently readmitted to hospital for further investigations. An endoscopy failed to find a mechanical cause for her symptoms and she was started on TPN for nutritional supplementation. She received TPN through a peripherally inserted central catheter (PICC) placed into her right brachial vein. The TPN solution consisted of a standard 7 % amino acid solution with 20 % dextrose, 20 % fat emulsion and sodium, potassium, calcium, magnesium, and phosphate. In total, she received TPN for 14 days, however it was discontinued due to sepsis originating from her PICC site. Following the removal of her right brachial vein PICC, she received a new PICC in her left internal jugular vein and was started on enteral feeding. Beginning 2 days after TPN was started and continuing until her death, the patient experienced repeated episodes of hypoxia, hypotension, tachycardia, and fever. Due to clinical suspicion of pulmonary embolism, computed tomography (CT) pulmonary angiography was performed which excluded pulmonary embolism but demonstrated findings of pulmonary hypertension and patchy areas of ground-glass opacities as well as centrilobular nodules and tree-in-bud opacities throughout the lungs bilaterally. Bilateral venous doppler ultrasonography revealed absence of deep vein thrombosis of the legs and a trans-thoracic echocardiogram was within normal limits. Approximately 1 month after ceasing TPN, she was again noted to be hypotensive, tachycardic, and febrile. Blood cultures and a chest X-ray were both negative. After an episode of hypoxia with elevated temperature, she was found unresponsive in her hospital bed and died despite resuscitative efforts. At the time of her death, her prescribed oral medications included hydromorphone, lorazepam, clonazepam, domperidone, docusate sodium, lactulose, ondansetron, lansoprazole, zopiclone, and gabapentin. Notably, the patient had no personal history of intravenous drug use and no concerns were documented pertaining to possible abuse of prescribed medications while in hospital. At autopsy, the absence of thromboembolic disease was confirmed. The right lung weighed 710 g and the left lung 640 g. The upper lobes of both the right and left lungs were abnormal in appearance (diffuse gray color) but without the firmness of bronchopneumonic consolidation. The right middle lobe and the lower lobes of both lungs were slightly firm. Due to the absence of a grossly identifiable cause of
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death, a frozen section of lung tissue was performed at the time of autopsy. This revealed global occlusive foreignbody granulomatous inflammation of all calibers of the pulmonary arterial vasculature, in response to amorphous, rod-shaped polarizable foreign material and unassociated with any similar intra-alveolar foreign-body granulomas to indicate aspiration. Formalin-fixed, paraffin-embedded sections replicated the findings seen in frozen section (Fig. 1). No other organs contained microvascular emboli and the foreign material was brightly birefringent under polarized light (Fig. 1). Special stains of the material revealed that it stained yellow by Movat pentachrome stain, stained red by Congo red, red-violet by periodic-acid Schiff (PAS) stain and stained black by a Gomori methenamine silver (Grocott) stain (Fig. 2). There was no calcium identified by either alizarin red stain or von Kossa stain. Energy dispersive X-spectroscopy in conjunction with electron microscopy revealed that the polarizing material was organic in nature. None of the elemental constituents of TPN including calcium, phosphate, magnesium, potassium, or sodium were identified. Infrared spectroscopy further characterized the material as cellulose-based (Fig. 3). Femoral blood toxicologic analysis revealed a hydromorphone concentration of 22 ng/ mL (±ng/mL) (fatal reference[51 ng/mL) as well as small quantities of substances compatible with her other prescription medications. The cause of death was determined to be occlusive granulomatous foreign-body embolization. The mechanism of death was acute cor pulmonale which resulted from a sudden increase in resistance to blood flow within the pulmonary circulation and lead to acute right heart failure. A cardiothoracic radiologist who was provided with the appropriate clinical history reviewed the decedent’s thoracic CT scans. While hospitalized the decedent had four thoracic CT scans over a period of 44 days, the first of which was performed 3 days post-operatively. One of the four CT scans was performed 2 days after the initiation of TPN while the other three predated this therapy (42, 32, and 16 days prior to the initiation of TPN). All CTs during her admission were compared to a previous CT scan (baseline) which had been performed 5 months earlier. The CT findings as compared to baseline could be divided into pulmonary parenchymal and cardiovascular findings. The parenchymal findings included centrilobular nodules, tree-in-bud and ground-glass opacities. The cardiovascular findings were indicative of pulmonary hypertension and elevated right side cardiac pressures and included enlargement of the pulmonary artery and right cardiac chamber and flattening of the interventricular septum (Figs. 4, 5). Although these findings improved from the first admission CT to the last CT, the lung parenchyma never returned to its normal appearance as seen on the
Forensic Sci Med Pathol (2015) 11:255–261
Fig. 1 a Hematoxylin and eosin section of right upper lung lobe. There is presence of foreign material within the pulmonary vasculature with accompanying granulomatous response (magnification
257
9400). b Foreign material within pulmonary vasculature viewed under polarized light (magnification 9400)
Fig. 2 Foreign material stained with a Movat pentachrome, b periodic-acid Schiff (PAS), c Grocott, and d Congo red (magnification 9400)
baseline CT. The radiological interpretation was therefore that the parenchymal changes had pre-dated the use of TPN.
Discussion TPN is a form of nutritional support for which calories, amino acids, electrolytes, vitamins, minerals, trace elements, lipids, and fluids are provided via a parenteral route for patients who require nutritional supplementation. TPN must be administered via a central venous catheter because the peripheral veins cannot tolerate its high osmotic load [7]. Because of the complexity of TPN formulations, there exists a risk of precipitate and crystal formation [1].
Calcium phosphate crystals have been previously recovered from within the pulmonary arterioles of patients who were receiving TPN and experienced sudden cardiorespiratory arrest [2, 3]. Experimental studies have shown that the solubility of calcium and phosphorous is affected by pH, temperature, amino acid formulation and concentration, type of calcium salt, duration of storage, order of mixing, and contact with lipids [2]. There have been case reports of respiratory distress and death in patients receiving TPN [1–6]. The majority of cases occurred in young adults who had been receiving TPN for extended periods of time and began to experience intermittent fever, dyspnea, and chest tightness with a high clinical suspicion of pulmonary embolism [1, 3, 5]. CT imaging findings revealed ground-glass opacities and
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Fig. 3 Infrared spectroscopy of three areas of foreign material isolated from the pulmonary arterioles (a–c) compared to a known reference of cellulose (d)
micronodules throughout the lungs [1, 3, 5]. Transbronchial biopsies in all cases revealed polarizable crystalline material with a surrounding granulomatous reaction [1, 3, 5]. Upon discontinuation of TPN the majority of the patients’ symptoms improved [3, 5] but one patient died at home while still receiving TPN [1]. Other case reports detail two previously healthy young women who were receiving TPN immediately post-operatively and experienced sudden cardiorespiratory arrest. Both women had emboli within their pulmonary capillaries and small arterioles consisting of amorphous birefringent material [2]. In two of the aforementioned series [2, 3] the crystalline material retrieved from transbronchial biopsies or autopsy tissue was analyzed by energy dispersive X-ray analysis and showed either high levels of calcium, potassium, and carbon [3] or calcium phosphate and organic material [2]. One report [3] performed a Movat pentachrome stain which revealed that the crystalline precipitates stained yellow, a finding similar to microcrystalline cellulose. In the other previously described case reports the authors did not perform ancillary investigations to determine the composition of the crystalline material. The intravenous injection of pharmaceutical tablets intended for oral consumption may also cause pulmonary foreign-body granulomatosis [8–15] leading to pulmonary hypertension and cor pulmonale [10, 12–14]. In addition to pharmacologically active ingredients, pharmaceutical tablets may contain a variety of insoluble filler and binder substances such as microcrystalline cellulose, crospovidone, starches, magnesium stearate, silicates, and talc [8]. Morphological features of the crystalline material, birefringence under polarized light, and special staining patterns, may provide clues as to the composition of the material (Table 1) [8, 11, 15].
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Similar to the previously reported cases of crystalline embolization from TPN, the decedent in this case experienced episodes of fever, tachypnea, and dyspnea while receiving TPN with a clinical presentation that was suspicious for pulmonary embolism. The ground-glass opacities seen on thoracic imaging were similar to those in the previously described cases and the histological lung findings from all reported cases were consistent. Also supportive of TPN embolization was the fact that the decedent had no clinical history of intravenous drug use and no concerns were charted regarding the possibility of drug abuse while she was hospitalized. There are several factors, however, which argue against TPN embolization in this case. First and foremost, the decedent had not been receiving TPN until the time of her death (it was discontinued 1 month prior due to PICC line infection). Furthermore on post-mortem review, the CT findings appear to predate the initializing of TPN. The imaging findings of centrilobular nodules, tree-in-bud and ground-glass opacities have been described as findings in foreign-body granulomatosis due to intravenous injection of medications intended for oral use [16–22] and tree-inbud opacities and centrilobular nodules specifically have been described in the context of cellulose granulomatosis [16]. Although these findings improved from the decedent’s first admission CT to the time of her last, the lung parenchyma never returned to its normal appearance as seen on the baseline CT. Ancillary investigations were also not supportive of TPN crystallization. Energy dispersive X-spectroscopy did not reveal presence of calcium or phosphate within the crystallizing material which was isolated in the two cases of TPN embolization that performed crystalline analysis. Other constituents of her TPN solution such as sodium,
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Fig. 4 Contrast-enhanced CT pulmonary angiography comparing a baseline CT (a, c) showing a pulmonary artery of normal size (a) and a normal configuration of the right ventricle and interventricular septum (arrow) (c) with a CT after admission (b, d) which demonstrates an enlarged pulmonary artery (b) and an enlarged right ventricle (d) (line) with flattening of the interventricular septum (arrow), indicating findings of pulmonary hypertension and increased right sided cardiac pressures
potassium, or magnesium were also not identified. Infrared spectroscopy analysis did not reveal any calcium or phosphate containing compounds and found all material analyzed to be cellulose-based. Therefore, although the decedent had been receiving TPN and had no history of intravenous drug use, the imaging findings, morphological features as well as ancillary investigations (including histochemical staining, energy dispersive X-spectroscopy, and infrared spectroscopy) were supportive of microcrystalline cellulose embolization. Interestingly, the scenario of patients receiving TPN who die from cor pulmonale secondary to embolization of intravenous drug fillers has been previously reported.
Ott et al. [23] reported the case of a dyspneic 50 year old man who had been dependent on home TPN for 24 years and was receiving prescription codeine to control his short bowel-induced diarrhea. A thoracic CT demonstrated widespread micronodular parenchymal disease and a transbronchial biopsy identified birefringent crystalline material with associated granulomas. Spectral analysis revealed the material to be organic in nature and, although no further analysis was performed, a diagnosis of microcrystalline cellulose embolization was made. The man admitted to occasionally dissolving and injecting his codeine tablets directly into his PICC line.
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Fig. 5 Contrast-enhanced CT pulmonary angiography in lung windows demonstrating ground-glass opacities (a) and tree-in-bud opacities (b, arrows) as well as centrilobular nodules
Table 1 Previously reported morphological and histochemical staining features of filler materials Crystalline material
Shape
Size (lm)
Birefrin-gence in polarized light
PAS
Congo red
MPS
GMS
Talc
Stacked plates
5–15
?
Red-violet
Negative
Negative or light blue
MCC
Rod-like
25–200
?
Red-violet
Red
Yellow or yellow-green
Gray–black
Crospovidone
Rod-like
\100
-
Blue-gray
Red-brown
Yellow-orange or blue-green
Brown–gray
Starch
Maltese-cross
10–100
?
Red-violet
Un-stained
MCC microcrystalline cellulose, PAS periodic-acid Schiff, MPS Movat pentachrome stain, GMS Gomori methenamine silver
In a review of embolized crospovidone in the lungs of intravenous drug users, Ganesan et al. [8] examined three cases of fatal hydromorphone toxicity with suspected thoracic embolized crospovidone. One of the cases was a 38 year old woman receiving TPN after an extensive small bowel resection who had no clinical history of intravenous drug use. Infrared spectroscopy analysis of the crystalline material within her pulmonary arterioles revealed only crospovidone and microcrystalline cellulose.
polarizable occlusive foreign-body granulomatous inflammation in the pulmonary arterial vasculature. As the clinical presentation, diagnostic imaging findings and microscopy findings can be similar in both entities; ancillary investigations such as energy dispersive X-spectroscopy and infrared spectroscopy should be performed to establish a definitive cause of death.
Key points Conclusion In summary, this case presents the first case report of a patient receiving TPN who died of acute cor pulmonale secondary to extensive foreign-body granulomatous embolization and who had extensive relevant ancillary investigations performed. In both TPN crystallization and injection of pharmaceutical tablets the clinical presentation may include intermittent episodes of hypoxia, hypotension, tachycardia, and fever and the pulmonary CT findings may include centrilobular nodules, and tree-in-bud and ground-glass opacities. The histological findings in both entities include
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1.
2.
3. 4.
Foreign-body granulomatous pulmonary emboli can occur both from crystallization of TPN as well as from injection of pharmaceutical tablets intended for oral use. Both entities can be fatal due to acute cor pulmonale and autopsy findings include occlusive foreign-body granulomatous inflammation in the pulmonary arterial vasculature. CT findings of both entities include centrilobular nodules, tree-in-bud and ground-glass opacities. Ancillary investigations such as dispersive X-spectroscopy and infrared spectroscopy may be required to distinguish the two causes of crystallization.
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