Cases from Oregon Health & Science University

Thrombus-in-transit, serotonin syndrome, leptospirosis, and more.

Case 1: Intracardiac thrombus-in-transit

By Rachel A. Westwood, MD, ACP Resident/Fellow Member, and Kyle Kent, MD, ACP Member

The patient

Figure 1 EKG on admission demonstrating an S wave in lead I and a Q wave with inverted T-wave in lead III suggestive of right-heart strain
Figure 1. EKG on admission demonstrating an S wave in lead I and a Q wave with inverted T-wave in lead III, suggestive of right-heart strain.

A 73-year-old man with history of hypertension presented with one week of progressive dyspnea on exertion, nonproductive cough, and right-sided pleuritic chest pain. He was normotensive, afebrile, and had a new 3-L oxygen requirement. On exam, lungs were clear to auscultation, heart sounds were normal without any appreciated murmurs, and his right calf was 1.5 times larger than his left calf with a negative Homans sign, no tenderness to palpation, and no palpable cord. Labs were significant for a D-dimer level of 3.04 µg/mL (normal range, <0.5 µg/mL) and negative troponin. An electrocardiogram demonstrated S1Q3T3 consistent with right-heart strain (Figure 1). A CT pulmonary angiogram found extensive submassive pulmonary emboli with near occlusion of the right main pulmonary artery. He was started on therapeutic enoxaparin.

Figure 2 CTA of the chest with linear thrombus extending from the right to left atria arrows
Figure 2. CTA of the chest with linear thrombus extending from the right to left atria (arrows).
Figure 3 CTA of the head with occlusion of left MCA at proximal M1
Figure 3. CTA of the head with occlusion of left MCA at proximal M1.
Figure 4 MRI of the brain with polarized light imaging showing large left MCA territory stroke
Figure 4. MRI of the brain with polarized light imaging showing large left MCA territory stroke.

An echocardiogram on hospital day 1 identified a moderately dilated right ventricle, right ventricular systolic pressure (RVSP) of 93 mm Hg, and a 4×1-cm linear echogenic mobile mass traversing the atrial septum and extending into the left ventricle during diastole. Review of the admission chest CT angiogram (CTA) confirmed a thrombus-in-transit through a patent foramen ovale (PFO) (Figure 2). As the risks of systemic thrombolysis or surgical thrombectomy were thought to outweigh the benefits, he was treated with apixaban. On hospital day 3, he developed acute right-sided weakness, facial droop, and global aphasia. A CTA of the head and neck showed a large left middle cerebral artery (MCA) embolic occlusion at the mid-sphenoidal segment artery (M1) (Figure 3). An MRI of the brain showed a large MCA territory stroke (Figure 4). Thrombolytics could not be given due to recent apixaban use, so he underwent emergent thrombectomy with complete MCA reperfusion.

Hypercoagulopathy work-up was negative for antiphospholipid antibodies (lupus anticoagulant, anti-B2 glycoprotein Ab, anticardiolipin Ab), and no malignancy was found on CT of the chest, abdomen, and pelvis. Duplex ultrasound of the lower extremities noted a chronic left tibial deep venous thrombosis (DVT) and an acute DVT extending from the right popliteal to femoral vein. A RVSP of 93 mm Hg without significant right ventricle changes suggested acute-on-chronic thromboembolic pulmonary hypertension. The patient was continued on apixaban indefinitely.

The diagnosis

The patient's diagnosis is a thrombus-in-transit straddling a PFO in the setting of extensive pulmonary emboli and complicated by embolic MCA stroke. An intra-atrial thrombus-in-transit, which is a venous thrombus that travels through a communication in the atria to the arterial system, is an extremely rare event with mortality rates up to 62.5% within the first 24 hours. There is currently no consensus on the optimal treatment strategy; the main options are anticoagulation, systemic thrombolysis, or surgical thrombectomy. Retrospective analyses have found that systemic thrombolysis is linked to the highest 30-day mortality rate at 25%, while surgical thrombectomy has the lowest overall 30-day mortality rate of 10.8% with the possibility for PFO repair. Anticoagulation with a vitamin K antagonist or direct oral anticoagulant is an acceptable alternative if the patient has high surgical risk; however, this raises the danger of continued systemic embolization as illustrated in this case.

There has been much debate regarding the benefit of PFO closure to prevent recurrent embolic events. The 2011 American Heart Association/American Stroke Association guidelines and a 2015 Cochrane review found that transcatheter device closure (TDC) failed to show significant benefit in reducing risk of recurrent stroke compared to medical therapy with anticoagulants with or without antiplatelets. However, recent randomized controlled trials such as the 2017 CLOSE trial and 2018 DEFENSE-PFO trial suggest that TDC is the most effective treatment to reduce the risk of recurrent stroke, especially in patients with high-risk PFOs, which are defined as a PFO greater than 3 mm, atrial septal aneurysm with greater than 10 mm of septum primum excursion, hypermobility of the septum greater than 15 mm during Valsalva, or a large interatrial right-to-left shunt (>30 microbubbles within three cardiac cycles). The CLOSE trial demonstrated a significant decrease in recurrent nonfatal and fatal ischemic stroke with PFO closure (0%) versus antiplatelets alone (5.9%) (P<0.001). The DEFENSE-PFO trial showed a number needed to treat of 10 to prevent one stroke in two years with PFO closure. Thus, surgical thrombectomy with PFO closure may be the safer and more effective option for secondary prevention of embolic strokes. Contraindications for thrombectomy with TDC closure include active bacteremia, sepsis, intracardiac mass, or intracardiac anatomy that limits safe device delivery.


  • Intracardiac thrombus-in-transit is a rare event with high risk of systemic embolization resulting in significant morbidity and mortality. Retrospective data suggest that surgical thrombectomy, if not contraindicated, may have the lowest 30-day mortality rate.
  • Recent randomized controlled trials support TDC of PFOs for secondary prevention of ischemic strokes as compared with antiplatelet therapy, but if TDC is contraindicated or declined, then anticoagulation is an acceptable alternative to antiplatelets alone.

Case 2: Fentanyl-induced serotonin syndrome

By Matthew O’Donnell, DO, ACP Resident/Fellow Member, and Alan J. Hunter, MD, FACP

The patient

A 42-year-old woman with severe alcohol use disorder and major depression presented to the ED with fever and right-sided back pain for two days. Her medications included sertraline, 150 mg daily, and she reported drinking 1 to 2 L of whiskey per day. In the ED, she was distressed and agitated, exhibiting slurred speech. The patient's temperature was 38.1 °C, blood pressure was 88/53 mm Hg, respiratory rate was 26 breaths/min, and heart rate was 122 beats/min. She exhibited right costovertebral angle tenderness. Her labs were notable for leukocytosis with elevated bands, lactic acidosis, and elevated ethanol level, and a urinalysis was consistent with infection. After vomiting in the ED, she was intubated for airway protection, volume resuscitated, started on ceftriaxone, and transferred to the ICU for treatment of septic shock secondary to suspected pyelonephritis.

In the ICU, she was sedated with IV fentanyl and midazolam. Her sertraline was continued. After 36 hours, she continued to be febrile. Blood cultures returned positive for Escherichia coli, and a CT scan showed perinephric stranding without obstructive calculi or perinephric abscess. At 48 hours, her temperature was 39.4 °C, and she became hypertensive and agitated. Increasing doses of fentanyl and phenobarbital were given for presumed alcohol withdrawal. Four hours later, her exam was notable for diaphoresis, hyperreflexia, and myoclonic jerks. Serotonin syndrome was suspected, and the sertraline and fentanyl were discontinued. Supportive care with cooling blankets, IV lorazepam, and cyproheptadine was initiated, and the patient defervesced and recovered over the next 24 hours.

The diagnosis

The diagnosis is fentanyl-induced serotonin syndrome. This case illustrates the effects of combined serotonergic agents and highlights the importance of promptly managing an uncommon but important cause of pyrexia in the ICU. Despite ongoing fever, only when the patient displayed hypertonia, hyperreflexia, and myoclonus did we suspect serotonin syndrome. Serotonin syndrome is diagnosed using the Hunter criteria, which include use of a serotonergic agent and one of the following: spontaneous clonus, inducible clonus plus agitation or diaphoresis, ocular clonus plus agitation or diaphoresis, tremor plus hyperreflexia, or hypertonia plus temperature above 38 °C plus ocular clonus or inducible clonus. One study published in Neurocritical Care in 2014 found that up to 58% of serotonin syndrome cases in the ICU involve continuation of antidepressants plus addition of serotonergic opioids, principally fentanyl.

Optimal management includes discontinuation of serotonergic medications, supportive care to normalize vital signs, sedation with benzodiazepines, and administration of a serotonin antagonist, such as cyproheptadine. The decision about whether to continue serotonergic medications in the ICU requires weighing the risks of antidepressant discontinuation syndrome (and its variable symptoms, ranging from nausea, dizziness, and headache to delirium and mania) and serotonin syndrome. Either choice requires vigilance. There is no clear evidence addressing this question, but one large systematic review published in Critical Care Medicine in 2017 suggested pausing these medications in acutely ill patients and restarting them in the convalescent phase of illness.


  • Serotonin syndrome in the ICU often results from continuation of antidepressants plus the addition of opioids, principally fentanyl.
  • Clinicians may consider pausing antidepressants in acutely ill patients and restarting them once recovery from critical illness is demonstrated.

Case 3: Leptospirosis from well water

By Asad Arastu, MD, ACP Resident/Fellow Member; Malinda West, MD; and Thomas DeLoughery, MD, MACP

The patient

A 75-year-old man with a history of prostate cancer presented to the ED with one week of progressive weakness, fatigue, diarrhea (multiple loose stools for three days), and dysuria. On arrival, he was afebrile and normotensive. Physical exam was unremarkable and in particular revealed no bruising, petechiae, or purpura. Labs were notable for markedly elevated creatinine level at 4.55 mg/dL (patient baseline, 0.9 mg/dL; reference range, 0.7 to 1.3 mg/dL), a platelet count of 14,000 cells/mm3 (patient baseline, 150,000 cells/mm3; reference range, 150,000 to 400,000 cells/mm3), and leukocytosis with a neutrophil predominance. Fractional excretion of sodium was calculated to be 3%. Immature platelet fraction was 1.3% (reference range, 1% to 5% of total platelet count). Hemolytic labs (lactate dehydrogenase, haptoglobin, fibrinogen, and D-dimer) were all within normal limits.

Figure 5 A blood smear indicating reactive lymphocytes and ballerina skirting
Figure 5. A blood smear indicating reactive lymphocytes and “ballerina skirting.”

A peripheral smear showed no evidence of hemolysis but did find reactive lymphocytes and ballerina skirting (i.e., scalloped margins and indentations by surrounding red blood cells) (Figure 5). Urinalysis and blood cultures yielded no growth. A stool pathogen panel was negative. The patient's kidney function improved with fluid resuscitation, and platelets improved after 1 unit of platelets was transfused.

Given the initial negative workup, further social history was obtained and it was discovered that the water in the patient's home was supplied by a privately owned well. A Leptospira IgM antibody test was sent on hospital day two and was positive. Oral doxycycline was prescribed for seven days. The patient made a full recovery with a return to his baseline kidney function and platelet count.

The diagnosis

The diagnosis is leptospirosis, a bacterial infection caused by a zoonotic pathogen from the genus Leptospira that typically spreads via the urine of infected animals. Symptoms typically present 10 days after exposure. Clinical manifestations of mild disease (anicteric leptospirosis) include high fevers, headache, and myalgias (75% to 100% of patients), nonproductive cough (20% to 57%), conjunctival suffusion (dilation of conjunctival vessels) (28.5% to 99%), diarrhea (50%), and rash (7% to 40%). Approximately 5% to 15% of patients experience the severe form (icterohemorrhagic leptospirosis or Weil's disease) with jaundice, renal failure, and hemorrhage.

Approximately 23% of Oregon residents rely on private wells as their primary water source. Given inadequate testing and poor regulation of privately owned well water in Oregon, a large portion (up to 10%) of groundwater may be contaminated with nitrates, bacteria, viruses, fungi, and parasites. Common pathogens include hepatitis A virus, Giardia, Campylobacter, Escherichia coli, Shigella, Salmonella, Cryptosporidium, and Leptospira. A gastrointestinal pathogen panel and ova and parasite testing capture most of these. However, Leptospira requires antibody or molecular testing as culture is rarely used for it. Serum testing can be performed to detect IgM antibodies (between days 6 and 10 of the disease) or IgG antibodies after two weeks (peak levels occur at three to four weeks). A Leptospira IgM antibody test has 100% sensitivity and 90% specificity compared to indirect hemagglutinin antibody. Molecular testing by polymerase chain reaction should be performed within seven days of illness.

Treatment depends on disease severity. Mild disease can be treated symptomatically or with antibiotics (doxycycline, 100 mg twice a day for seven days, or azithromycin, 500 mg once a day for three days). Severe disease may require hospitalization and IV antibiotics for seven days.


  • Leptospirosis does not always present as Weil's disease (jaundice, renal failure, and hemorrhage), and the diagnosis requires a thorough history and Leptospira-specific testing.
  • Leptospirosis is typically treated with antibiotics, oral doxycycline or azithromycin for mild cases and IV antibiotics for more severe disease.

Case 4: Dialysis graft-associated heart failure

By R. Logan Jones, MD, and Thomas J. Prendergast, MD

The patient

A 51-year-old man with a history of type 2 diabetes mellitus, hypertension, severe untreated obstructive sleep apnea, congestive heart failure, mild pulmonary hypertension thought to be World Health Organization type II, and end-stage renal disease on hemodialysis presented with worsening fatigue and hypoxia. Nine months previously he had had an arteriovenous (AV) fistula placed, which failed due to partial occlusion. He then had an AV graft placed and developed subacute progressive exertional dyspnea a few days later. Three months before the current presentation, he had been taking regular two-mile hikes, but he was now limited to walking about 20 feet with a new 3-L oxygen requirement.

The patient's condition had been evaluated prior to his current presentation at the hospital. Pulmonary function tests had revealed a mild restrictive pattern. He had a low probability for pulmonary embolus on a ventilation-perfusion scan, normal left ventricular ejection fraction (LVEF) on echocardiography, and a chest CT showing mild pulmonary edema with trace pleural effusions.

Upon examination, he was normotensive and normoxic. He had an elevated jugular venous pressure of 13 cm H2O with positive Kussmaul's sign, an S4 gallop, clear lungs with dullness and scant inspiratory crackles at both posterior bases, no peripheral edema, and a thrill over a left-arm AV graft. Arterial blood gas measurement on room air did not show resting hypercarbia or hypoxia.

Given the temporal relationship between symptom onset and AV graft placement, the patient underwent a right-heart catheterization to evaluate for high-output heart failure. It showed elevated pulmonary capillary wedge pressure and a cardiac index of 6.7 L/min/m2 (reference range, 2.5 to 4.0 L/min/m2), consistent with high-output heart failure. He was referred for graft ligation, but he opted to monitor symptoms over time. Six months later, he is no longer oxygen dependent but is still functionally limited to short walks.

The diagnosis

The diagnosis in this case is high-output heart failure, which is defined by clinical heart failure and a documented cardiac index greater than or equal to 4 L/min/m2. Classic causes of high-output heart failure include wet beriberi, Paget's disease, severe anemia, and thyrotoxicosis. However, as our patient populations change overtime, so too does the risk profile for this condition. In a contemporary case series of 120 U.S patients undergoing right-heart catheterization for suspected high-output heart failure in 2000 to 2014, the causative processes identified were obesity (31%), liver disease (23%), AV shunts (23%), lung disease (16%), and myeloproliferative disorders (8%). This same case series, published by the Journal of the American College of Cardiology in 2016, showed that five-year survival among various subgroups ranged from 81% (obesity-associated high-output heart failure) to 41% (liver disease).

The common physiologic mechanism among the conditions causing high-output heart failure is decreased systemic vascular resistance, whether through macrovascular shunting from an AV shunt or secondary to a systemic disease causing vasodilation. Thus, it is important to recognize these risk factors associated with high-output heart failure to ensure prompt completion of hemodynamic studies, expedited diagnostic evaluation, and referral for surgical revision of the fistula or graft.


  • For patients with end-stage renal disease on hemodialysis presenting with new or worsening clinical heart failure, temporal correlation between AV fistula/graft placement and symptom onset should raise concern for possible high-output heart failure.
  • Classic causes of high-output heart failure include wet beriberi, Paget's disease, severe anemia, and thyrotoxicosis, but obesity, liver disease, and AV shunts are commonly found in patients with the condition today.

Other cases in this issue