Phlegmasia Cerulea Dolens: a Sudden Unexpected Death with Hypothesis of Medical Malpractice A

256 A. De Donno, et al.

Case report Clin Ter 2021; 172 (4):256-259 doi: 10.7417/CT.2021.2326

Phlegmasia Cerulea Dolens: a sudden unexpected death with hypothesis of medical malpractice A. De Donno1, M. Favia1, A. Martini1, M. Calvano1, C. Galeandro2, D. Angiletta2

1Department of Legal Medicine, University of Bari, Bari; 2Vascular and Endovascular Surgery Unit, University of Bari, Bari, Italy

Abstract 17-fold within a few hours (1), causing fluid sequestration in the interstitium which may reach volumes of 6 to 10 liters Phlegmasia Cerulea Dolens (PCD) is a severe and rare form of within days (2). venous thrombosis of the lower extremities, caused by a subtotal or The result is the ischemia of the affected area; unlike complete occlusion of venous outflow by a thrombus. PCD should be Phlegmasia Cerulea Dolens, in Phlegmasia Alba Dolens, considered a real medical emergency; complications include necrosis venous thrombosis only affects the deep vessels, thus sparing and gangrene of the affected limb, amputation, massive pulmonary the collateral veins and the superficial venous system through embolism and, in extreme cases, the death of the patient. which the venous outflow can still occur (3). Case Report. A 63-years-old man was admitted to the Emergency The major prevalence in adulthood is mainly due to room with localized pain on the right calf, hyperthermia, cold sweating some risk factors, which play a crucial role in determining and vomiting episodes. Five days prior he developed flu-like symptoms, the onset of disease; they include malignancy, extended joint pain and cold sensation unresponsive to treatment. Ultrasound breastfeeding, hypercoagulable syndrome, heart failure, examination showed a deep venous thrombosis of the lower right limb pregnancy, sepsis, traumas and surgery. In about 10% of with partial occlusion of common iliac and femoral veins. The patient cases, however, the cause remains unknown (4, 5). was treated with low molecular weight heparin given twice daily. He From a clinical point of view, the main symptoms are a began to develop severe hypotension and metabolic acidosis, with characteristics triad which include edema, pain and cyanosis. tachycardia and atrial fibrillation. Despite the treatment, there was Paresthesia, muscle weakness and, in severe and advanced no improvement and he developed severe sinus node dysfunction. He cases, paralysis and shock may also occur. failed to respond to all resuscitative efforts and died. Family members Phlegmasia Cerulea Dolens should be considered a complained Authority, assuming it was a medical error. real medical emergency; complications include necrosis The clinical-forensic investigation is essential to determine the and gangrene of the affected limb, amputation, massive causes and manner of death and to assess medical responsibility and lia- pulmonary embolism and, in extreme cases, the death of bility. Clin Ter 2021; 172 (4):256-259. doi: 10.7417/CT.2021.2326 the patient (6). The main purpose of the treatment of Phlegmasia Cerulea Key words: Phlegmasia Cerulea Dolens, Deep venous thrombosis, Dolens is to restore venous flow and prevent the formation Autopsy, Death, Medical malpractice of additional occlusive thrombi. However, considering the low incidence of this pathology, there is no consensus on treatment of choice.

Introduction Case presentation

Phlegmasia Cerulea Dolens (PCD) is a severe and rare A 63-year-old man with diabetes came to the Emer- form of venous thrombosis of the lower extremities, caused gency Department, complaining of localized pain on the by a subtotal or complete occlusion of venous outflow by right calf accompanied by hyperthermia, cold sweating and a thrombus. vomiting episodes. He presented with a five-day history of Shock and arterial collapse are responsible for the flu-like symptoms, joint pain and cold sensation, for which impairment of arterial circulation. They are caused by a he started to take paracetamol after consulting his primary dramatic increase of hydrostatic pressure, as much as 16- to care physician.

Correspondence: Matteo Favia. Tel. +39 0805592563 E-mail: [email protected]

After an initial resolution of symptoms, a new episode A non-specific diagnosis of death by cardiac arrest was of hyperthermia occurred associated with the onset of lower stated. limb pain. Then Novalgin was added to therapy with no According to the patient family, the doctors of the improvement of symptoms; due to the increased pain, he re- Emergency Department did not perform up to the medical quired proper physical examination. Physical exam revealed standard. This led them to a medical malpractice claim. phlebitis and he was treated with analgesics and heparin. Despite this treatment, symptoms did not improve and the patient decided to go to the Emergency Room. Autopsy findings The patient examination revealed a violet discoloration of the right lower limb. In order to carry out an exhaustive forensic investigation, Laboratory data included white blood cell count of 19.31 a complete autopsy was performed to evaluate the existence x 103 / L (v. 4-11) with neutrophilic increase (up to 80.3%); of any professional liability/medical negligence. additionally, blood glucose level was increased by four times The external examination showed the presence of a dif- the reference range, liver and kidney function tests were fuse violet discoloration of the right lower limb, with “skin abnormal (bilirubin, AST, ALT, LDH, CK, creatinine, urea) slippage” phenomenon (Fig. 1-2). and it was found an increase in coagulation parameters: INR The autopsy revealed the occlusion of proximal and = 1.73, aPTT = 38 sec, D-dimers = 2339.19 ng / mL. distal veins of the right limb by clotted blood material with The management of the complex medical condition re- taut consistency and red-grayish color. The popliteal, iliac, quired vascular surgeon. The physical examination revealed and superficial femoral veins were involved (Fig. 3). In blue discoloration of the right lower extremity, which ap- addition, the triceps surae muscles appeared to be modified peared cold and painful; ultrasound examination showed a and reddish gray in color, and their section showed a massive deep venous thrombosis of the lower right limb with partial serous liquid discharge. Specimens were taken from this area occlusion of common iliac and femoral veins, while the arte- in order to perform histological examination: the presence rial flow appeared normal. It also revealed the presence of of interstitial and perivascular neutrophilic infiltrate (predo- fibrocalcific plaques along the examined vessels, resulting minantly granulocytic) with regressive-necrotic phenomena in reduced blood flow in the distal segments of the right leg. of the muscle fibers was observed. For this reason, therapy with low molecular weight heparin The examination of the left lower limb veins and other (Enoxaparin sodium 8000 IU) was administered and the organs didn’t show any significant alteration. involved extremity was elevated. The lungs were examined: the physicians who assisted Five hours after the initial clinical manifestations, the the patient hypothesized that the death could be attributed to patient began to develop severe hypotension and metabolic a secondary embolic event at the inferior DVT. No evidence acidosis, accompanied by tachycardia and atrial fibrilla- of pulmonary embolism was found. tion. Despite the treatment with atropine, bicarbonate and amiodarone, there was no improvement, but dysrhythmia occurred, persisting despite intensive care.

Fig. 1 e Fig. 2. Diffuse violet discoloration of the right lower limb 258 A. De Donno, et al.

adenocarcinoma, thyroid cancer and cholangiocarcinoma (8-10). The differential diagnosis includes venous gangrene, lymphatic obstruction, acute cellulitis, Phlegmasia Alba Dolens (PAD) and acute arterial occlusion. Diagnosis of PCD can be made clinically. Doppler ultrasound can identify occlusion in both arteries and veins of the lower extremities, this means that among all the imaging tools it is the first choice. Usually, sonography is the only imaging modality required, with no need for magnetic resonance venography or arteriography. Catheter venography and arteriography remain the gold standard and can be therapeutic (11). From a clinical point of view, Phlegmasia Cerulea Dolens Fig. 3. Occlusion of proximal and distal veins of the right limb by is characterized by intense pain, edema and cyanosis; these clotted blood material. are also associated with lack of arterial pulse and cold lower extremity. The presence of cyanosis differentiates PCD from pure arterial ischemia and PAD. In the latter condition the skin appears pale (the so called “milk leg”). Based on the clinical picture and typical symptom triad, diagnostic suspect is generally confirmed by using Doppler Discussion ultrasound which is a non-invasive and easy-to-use method that allows doctors to detect the presence of proximal venous After the post mortem examination, a sudden death by thrombosis and evaluate the extent of thrombosis (12). PCD was suspected. The clinical-forensic investigation was carried out to Considering Phlegmasia Cerulea Dolens, the main etio- verify the possibility of medical malpractice and liability. pathogenetic mechanisms responsible for death are pulmo- According to the Italian Law, the physician’s responsibil- nary embolism and hypovolemic heart failure secondary to ity could be related to: massive fluid sequestration in the interstitium. - failure to meet one’s duty of care; In the presented case, autopsy findings and the following - breach of duties; histological analysis (microscopic evaluation) serve to rule - misapplication of the diagnostic-therapeutic procedures out the first hypothesis, thus concluding that the patient’s that result in a patient’s injury. death was due to a terminal shock secondary to heart failure In this specific case, the post-mortem examination was associated with metabolic and kidney failure caused by carried out to assess the possibility of negligence, imperfec- rhabdomyolysis. tion, imprudence by the medical staff. In particular, the second hypothesis is supported by the There is no definite therapy for PCD, but the goal of results of the examinations performed in the emergency room management is clear: prevent thrombus propagation, reduce (increased CK, altered ABG suggesting severe metabolic aci- venous hypertension and preserve the collateral circulation dosis associated with hyperkalemia and hypocalcemia), and and tissue viability. The therapeutic strategy depends largely by the histological analysis (nonspecific renal inflammation on the clinical picture and experience of the surgeon, and secondary to rhabdomyolysis). All these findings allow the it should be more aggressive with greater extent of tissue post-mortem diagnosis of PCD. ischemia and venous gangrene (13). The goal of treatment In cases of PCD, a massive thrombus occludes both in PCD is thrombus removal to improve venous patency deep and superficial veins, obstructing the capillary outflow and valve function, while decreasing risk of recurrence and and then it causes the elevation of hydrostatic pressure, post-thrombotic syndrome. leading to fluid shift into the interstitial space and causing The treatment in PCD has many modalities that include substantial tissue edema. When the thrombosis extends to conservative treatment, systemic or local thrombolysis, the collateral veins, massive fluid sequestration and more pharmacomechanical thrombolysis (PMT), and surgical significant edema ensue. thrombectomy (14). The extreme venous hypertension with massive tissue According to literature, once the disease has been dia- edema impedes the arterial inflow, compromises the tissue gnosed, the goal of therapy is to halt thrombus propagation perfusion, and ultimately results in venous gangrene, limb and prevent the formation of additional barriers to the loss and death. venous outflow. A literature review from the past 30 years identifies about First-line treatment consists in absolute rest, elevation 200 published cases of Phlegmasia Cerulea Dolens. Of these, of the affected limb and intravenous administration of he- one third is characterized by a history of malignancy while parin (15). 50% of patients show other risk factors, including throm- The overall mortality rate of PCD is 20-40% (18) and bophilia, venous stasis, oral contraceptives, traumas and secondary pulmonary embolism accounts for 30% of deaths surgical procedures (7). Specifically, cases of PCD-induced in PCD patients (16). Amputation rate can reach 68% and neoplasia have been reported in patients with testicular tu- additionally, postphlebitic sequelae can be found in more mors, pancreatic tumors, bronchial adenocarcinoma, ovarian than 60% of the surviving patients (17). Phlegmasia Cerulea Dolens: a sudden unexpected death 259

The definitive treatment can be both medical or surgical. 4. Cohen D, Briggs R, Head H, et al. Phlegmasia cerulea dolens There are three possibilities: and its association with hypercoagulable states: case reports. - anticoagulant therapy with low molecular weight hepa- Angiology 1989; 40:498–508 rin; 5. Lorimer JW, Semelhago LC, Barber GG. Review Venous - systemic thrombolysis (administration of t-PA or uro- gangrene of the extremities. Can J Surg. 1994 Oct; 37(5):379- chinase) or regional catheterization; 84 - surgical thrombectomy; it is an alternative treatment for 6. Perkins JM, Magee TR, Galland RB. Review Phlegmasia patients who cannot undergo thrombolysis because of caerulea dolens and venous gangrene. Br J Surg. 1996 Jan; contraindications or in case of failure of anticoagulant 83(1):19-23 7. Chang G, Yeh JJ. Fulminant phlegmasia cerulea dolens with therapy (18-20). concurrent cholangiocarcinoma and a lupus anticoagulant: The patient was treated with low molecular weight he- a case report and review of the literature. Blood Coagul parin (Enoxaparin sodium) and with atropine, bicarbonate Fibrinolysis. 2014; 25:507-11 and amiodarone when severe hypotension and metabolic 8. Mulatero C, Brogan G, Oliver R. Advanced testicular cancer acidosis occurred. According to literature, the high rate of presenting with phlegmasia cerulea dolens. Postgrad Med J complications due to the disease cannot be attributed to 2000; 76:234–236 medical malpractice and it was possible to conclude that 9. Demers C, Ginsberg J, Brill-Edwards P, et al. Rapid anticoa- the treatment was appropriate. gulation using ancrod for heparin-induced thrombocytopenia. Blood 1991; 78:2194–2197. 10. Cooper R, Hayat S. Phlegmasia cerulea dolens, a rare com- Conclusion plication of deep vein thrombosis. BMJ Case Reports 2009 11. Bazan HA, Reiner E, Sumpio B. Management of bilateral All the investigations point to lack of evidence of medical phlegmasia cerulea dolens in a patient with subacute splenic malpractice. In fact, the medical treatment was adequate: laceration. Ann Vasc Dis 2008; 1:45-8 when thrombophlebitis was clinically evident, both the 12. Hill SL, Martin D, McDannald ER Jr, et al. Early diagnosis diagnostic and therapeutic strategies were appropriate, ac- of iliofemoral venous thrombosis by Doppler examination. cording to the guidelines for the treatment of DVT. Am J Surg. 1988 Jul;156(1):11-5 The cause of death could be ascribed to the severity and 13 Chinsakchai K, Ten Duis K, Moll FL, et al. Trends in manage- rapid evolution of PCD and its systemic consequences. A ment of phlegmasia cerulea dolens. Vasc Endovascular Surg post-mortem diagnosis of PCD was performed and all the 2011; 45:5-14 hypotheses of medical malpractice were excluded. 14. Weaver F, Meacham P, Adkins R, et al. Phlegmasia cerulea dolens: therapeutic considerations. South Med J 1988; 81:306–312 Acknowledgement: The authors would like to thank 15. Suwanabol PA, Tefera G, Schwarze ML. Syndromes associ- Dr Francesca Addante for constructive criticism and her ated with the deep veins: phlegmasia cerulea dolens, May- contribution to this manuscript. Thurner syndrome, and nutcracker syndrome. Perspect Vasc Surg Endovasc Ther 2010; 22:223–30 The authors received no specific funding for this work. 16. Bhatt S, Wehbe C, Dogra VS. Phlegmasia cerulea dolens. J There are not conflict of interest to disclosure. Clin Ultrasound. 2007 Sep; 35(7):401-4 17. Tran J, Rafique Z. Phlegmasia Cerulea Dolens In The Pedi- atric Population: A Life-Threatening Condition, The Journal References of Emergency Medicine, 2015; 49(4):e111–e114 18. Patel NH, Plorde JJ, Meissner M. Catheter-directed throm- 1. Snyder MA, Adams JT, Schwartz SI. Hemodynamics of bolysis in the treatment of phlegmasia cerulea dolens. Ann phlegmasia cerulean dolens. Surg Gynecol Obstet. 1967; Vasc Surg 1998;12(5):471–5 125:342–346 19. Chaer RA, Dayal R, Lin SC, et al. Multimodal therapy for 2. Haller JA. Jr. Effects of deep femoral thrombophlebitis on acute and chronic venous thrombotic and occlusive disease. the circulation of the lower extremities. Circulation. 1963; Vasc Endovascular Surg 2005; 39(5):375–80 27:693–698. doi: 10.1161/01.CIR.27.4.693 20. Venous thromboembolic diseases: diagnosis, management 3. La Gregoire R. La Phlebite bleue (Phlegmasia Cerulea Do- and thrombophilia testing, NICE Clinical guideline (CG144) lens) Presse Med. 1938; 48:1313–1315 Published date: June 2012 Last updated: November 2015