Published online August 21, 2006
PEDIATRICS Vol. 118 No. 3 September 2006, pp. e924-e928 (doi:10.1542/10.1542/peds.2006-0085)

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EXPERIENCE & REASON

Intravenous Injection of Pharmaceutical Tablets Presenting as Multiple Pulmonary Nodules and Declining Pulmonary Function in an Adolescent With Cystic Fibrosis

Kelly J. Smith, MD^a, Okan Elidemir, MD^a, Megan K. Dishop, MD^b, Karen W. Eldin, MD^b, Nina Tatevian, MD, PhD^b and Robert H. Moore, MD^a

^a Pediatric Pulmonology
^b Pediatric Pathology, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas

ABSTRACT

Here we present the unusual case of an adolescent with cystic fibrosis presenting with declining pulmonary function and diffuse micronodular pulmonary disease. This case illustrates the radiographic and pathologic findings associated with the intravenous injection and pulmonary arterial embolization of insoluble pharmaceutical-tablet constituents. The number of first-time users reporting nonmedical use of prescription pain relievers is increasing dramatically, especially in adolescents. Recognition of both the diagnostic imaging features and histologic features on lung biopsy are critical steps for early diagnosis, intervention, and potential prevention of sudden death in these at-risk patients.

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Key Words: cystic fibrosis • substance abuse • intravenous • povidone • crospovidone • microcrystalline cellulose • pathology • pulmonary disease • respiratory function tests

Abbreviations: CF, cystic fibrosis • PFT, pulmonary-function test • CT, computed tomography • TIVAD, totally implantable vascular access device

Progressive lung disease is the major cause of morbidity and mortality in patients with cystic fibrosis (CF).¹ Declining pulmonary function is a common diagnostic challenge for physicians caring for children and adults with CF. Exacerbations of CF lung disease are usually caused by recurrent pulmonary infections (bacterial, fungal, and viral), excessive mucus secretion in the lungs, impaired mucociliary clearance, and progressive bronchiectasis.² Pulmonary manifestations of CF on chest imaging commonly include peribronchial thickening, hyperinflation, bronchiectasis, pulmonary infiltrates, and cystic lesions with abscess formation.^3,4 Diffuse bilateral micronodular disease is uncommon in this clinical setting and raises an extended differential diagnosis, including infectious bronchiolitis, diffuse panbronchiolitis, granulomatous infection (mycobacteria, fungi), pneumoconiosis, sarcoidosis, hypersensitivity pneumonitis, Langerhans cell histiocytosis, foreign body–induced necrotizing vasculitis, and metastatic disease.^5,6 Here we present the unusual case of an adolescent with CF presenting with declining pulmonary function and diffuse micronodular pulmonary disease resulting from intravenous injection and pulmonary arterial embolization of pharmaceutical-tablet constituents.

CASE REPORT

An 18-year-old white female with CF, poorly controlled CF-related diabetes mellitus, and a permanent intravenous port presented with a 6-month history of recurrent episodes of increasing cough, decreasing energy, progressive exercise intolerance, worsening hypoxemia, and progressively declining pulmonary-function tests (PFTs) despite aggressive use of inpatient and outpatient intravenous antibiotics, mucolytics, and airway-clearance techniques.

A computed tomography (CT) scan of her chest revealed centrilobular, clustered micronodular opacities and multiple areas of larger patchy opacities (Fig 1A). Mosaic attenuation was present; however, it was unclear whether this was a result of airway disease or vascular disease. There was also moderate, cylindrical bronchiectasis with peribronchial thickening and mucoid impaction consistent with the patient's underlying diagnosis of CF. Transbronchial biopsies and a subsequent open lung biopsy revealed peribronchial foreign body giant-cell reaction to polarizable crystalline material resembling calcium oxalate and a lesser component of lightly basophilic mucoid material. Exogenous inhaled or injected materials were considered, but there was no history of exposure. Despite continued treatment for presumed bronchopneumonia, the patient's PFTs and energy level continued to deteriorate.

View larger version (71K): [in this window] [in a new window]   FIGURE 1 A, Chest CT in October 2004. Centrilobular, clustered micronodular opacities are present bilaterally. Other findings include mosaic attenuation, moderate cylindrical bronchiectasis with peribronchial thickening, and mucoid impaction. B, Chest CT 2 months later. Increased prominence of centrilobular, clustered micronodular opacities can be seen. Multiple areas of larger patchy opacities are present.

 
A repeat CT scan of the chest showed an acute worsening of her multinodular lung disease compared with the CT scan obtained 2 months earlier (Fig 1B). While in the bathroom alone 1 day after hospital discharge following a prolonged hospitalization for treatment of Pseudomonas bronchopneumonia, she developed chest pain, dizziness, anxiety, and shortness of breath. She walked into the adjacent room, told her parents about these symptoms, and then collapsed. She was unable to be resuscitated and died. A postmortem chest radiograph showed no evidence of pneumothorax but did demonstrate a significant increase in the micronodular pattern, especially in the lower lung fields, when compared with a chest radiograph performed 3 days earlier.

PATHOLOGY

At autopsy, the lungs showed a "sandpaper" texture with diffuse fine gritty cut surfaces without clearly defined nodules. In addition to mild bronchiolectasis and mucus plugging typical of CF, microscopic examination revealed a peribronchial foreign body giant-cell reaction to refractile crystalline material and a lesser component of lightly basophilic mucicarmine-positive material, similar to the previous lung biopsies. With the prominent vascular distribution, embolized material from intravenous injection was given greater consideration. The branching "coral-like" morphology of the basophilic material was a diagnostic clue used to identify this component as crospovidone (or povidone), an insoluble polymer used as a disintegrant in pharmaceutical tablets (Fig 2). The refractile material had typical histochemical and ultrastructural characteristics of microcrystalline cellulose, an insoluble filler material commonly used in pharmaceutical tablets (Fig 3).

View larger version (129K): [in this window] [in a new window]   FIGURE 2 Light microscopy (A, hematoxylin and eosin; B, Movat pentachrome). Embolized foreign material adjacent to and within the pulmonary arteries elicits a giant-cell reaction. Microcrystalline cellulose is the pale-yellow refractile crystalline material, and the crospovidone is variable dense basophilic material, which forms branching "coral-like" structures in some areas (arrows).

 

View larger version (134K): [in this window] [in a new window]   FIGURE 3 Electron microscopy. Ultrastructural examination of the microcrystalline cellulose demonstrates variably dense crystalline particles (A) with delicate fibrillar structure (B).

 
Prescription records showed that she had filled 4 prescriptions for acetaminophen/hydrocodone (Vicodin; Abbott Pharmaceuticals, Abbott Park, IL) during the previous 16 months for postoperative sinus surgery pain, renal colic, and postoperative pain after open thoracotomy. Interestingly, the time points at which the first and third acetaminophen/hydrocodone prescriptions were filled correlated closely with rapid, significant declines in her PFTs (Fig 4). A similar decline in her PFTs had occurred 4 months after the second prescription was filled. In addition, the most recent prescription was filled the day before her death. Microscopic evaluation of a crushed Vicodin tablet in aqueous solution revealed materials with characteristics similar to that seen in the lung biopsy and autopsy tissue.

View larger version (21K): [in this window] [in a new window]   FIGURE 4 PFT timeline. The arrows indicate dates on which prescriptions for acetaminophen/hydrocodone were filled.

 

DISCUSSION

Nonmedical use of prescription medications has become a common form of drug abuse in this country in the last 2 decades, second only to marijuana use. The number of first-time users reporting nonmedical use of prescription pain relievers increased dramatically from 600000 individuals in 1990 to >2 million in 2001, with the highest rate among adolescents and young adults (aged 12–25 years).⁷ From 1998 to 2000, adolescents (aged 12–17 years) outnumbered young adults (aged 18–25 years) in first-time use of pain relievers for nonmedical purposes.⁸ One form of such abuse is the intravenous injection of an aqueous solution of crushed pain-reliever tablets. In addition to the active ingredients, pharmaceutical drugs intended for oral consumption are composed of a variety of inactive filler substances (excipients) used as a vehicle for the drug and having binding or disintegrant properties. These filler compounds commonly include microcrystalline cellulose, povidone, talc, and cornstarch. Although the insoluble excipients are harmless if ingested, intravenous injection results in embolization of these compounds to the pulmonary arterial circulation causing occlusion, thrombosis, and inflammation of the artery branches and microvasculature.^9–14

Pharmaceutical agents used in this manner have included acetaminophen/hydrocodone, codeine, hydromorphone, propoxyphene, methadone, tripelennamine, methylphenidate, and pentazocine.^10,13–16 An all-inclusive list of drugs with a high likelihood for abuse and the excipients they contain is outside the scope of this brief case report. However, Micromedex Healthcare Series Online,¹⁷ an on-line drug database, is a useful resource that lists the excipients for many drugs, as reported by the manufacturers. Various formulations of the same medication can contain different excipients, even if made by the same manufacturer. In addition, some drugs with a similar name but different ingredients are produced and marketed by different manufacturers.

Clinically, individuals who crush oral medications and inject them intravenously (or through a central port, as in this case) can develop a multinodular pattern on chest radiograph and chest CT that can be associated with a progressive decline in PFTs.^15,18,19 Repeated insults can lead to dyspnea, pulmonary hypertension, and death.^14,16 Proving this diagnosis may be a challenge in a patient who is legitimately prescribed narcotics for pain but adamantly denies intravenous drug abuse. Although crystalline material has been reported from precipitation of total parenteral nutrition fluid components,²⁰ recognition of characteristic histologic features of oral-tablet constituents such as microcrystalline cellulose and povidone on a lung biopsy specimen leads to a definitive diagnosis. We believe that this patient's death was directly attributable to vascular occlusion, inflammation, and pulmonary arterial hypertension secondary to the intravenous injection of pharmaceutical-tablet excipients.

Injection and resulting embolism of tablet constituents was facilitated in this case by the presence of a central venous catheter. Although indwelling central venous catheters are generally safe and reliable, a number of complications have been reported in patients with CF. Munck et al²¹ performed the largest retrospective multicenter study to date by evaluating 452 totally implantable vascular access devices (TIVADs) in 315 patients with CF (mean age: 12.3 years at the time of initial implantation) from 36 CF centers during a 9-year period. Immediate complications such as hematoma, pneumothorax, hemothorax, or wound infection occurred in 4% of the cases. Long-term complications occurred with 42% of the devices and included catheter occlusion (21%), infection (8.6%), and vascular thrombosis (4.7%). Blood sampling via the TIVAD (versus nonuse) and polyurethane TIVAD devices (as opposed to silicone devices) was associated with a twofold increase each in the relative risk of device removal for any reason. Two other retrospective studies in patients with CF reported similar types of complications.^22,23 Other reported complications include superior vena cava syndrome, air embolism, paradoxical cerebral embolism, and life-threatening pulmonary embolism.^22,24–26 Given the risk of venous thrombosis, some authors suggest that it may be helpful to include a hemostatic evaluation before TIVAD insertion.²⁷ In addition, the possibility of a patent foramen ovale should be considered before placement of an indwelling central catheter because of an increased risk of stroke.²⁴

CONCLUSIONS

Intravenous injection of aqueous pharmaceutical drugs results in a diffuse micronodular pattern on chest imaging as a result of pulmonary arterial embolization of tablet constituents. Intravenous drug use should be considered and evaluated in patients with this pattern of disease. We believe that adolescent and young-adult patients with chronic illness, including CF, sickle cell disease, inflammatory bowel disease, and malignancy, may be at higher risk than the general population, because these patients often have central venous access ports or peripherally inserted central catheter lines used for total parenteral nutrition or administration of antibiotics, analgesics, or chemotherapy. In some cases, these patients also have access to prescription pain medications and access to syringes. The rising incidence of pharmaceutical drug abuse in recent years among the general population of adolescents and young adults compounds the concern for potential abuse among peer groups with similar chronic illnesses. Recognition of both the diagnostic imaging features and histologic features on lung biopsy are critical steps for early diagnosis, intervention, and potential prevention of sudden death in these at-risk patients.

ACKNOWLEDGMENTS

We thank R. Paul Guillerman, MD (Department of Diagnostic Imaging, Texas Children's Hospital), for insightful radiographic interpretations.

FOOTNOTES

Accepted Mar 28, 2006.

Address correspondence to Kelly J. Smith, MD, Pulmonary Medicine Service, Texas Children's Hospital, 6621 Fannin, CC1040.00, Houston, TX 77030. E-mail: kjsmith{at}texaschildrenshospital.org

The authors have indicated they have no financial relationships relevant to this article to disclose.

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PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics

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