Jaime Betancourt, MD

In less than a year, COVID-19 has infected nearly 100 million people worldwide and caused more than 2 million deaths and counting. Although the infection fatality rate is estimated to be 1% and the case fatality rate between 2% and 3%, COVID-19 has had a disproportionate effect on the older population and those with comorbidities. Some of these findings are mirrored in the US Department of Veterans Affairs (VA) population, which has seen a higher case fatality rate.^1-4

As a respiratory tract infection, the most dreaded presentation is severe pneumonia with acute hypoxemia, which may rapidly deteriorate to acute respiratory distress syndrome (ARDS) and respiratory failure.^5-7 This possibility has led to early intubation strategies aimed at preempting this rapid deterioration and minimizing viral exposure to health care workers. Intubation rates have varied widely with extremes of 6 to 88%.^8,9

However, this early intubation strategy has waned as some of the rationale behind its endorsement has been called into question. Early intubation bypasses alternatives to intubation; high-flow nasal cannula oxygen, noninvasive ventilation, and awake proning are all effective maneuvers in the appropriate patient.^10,11 The use of first-line high-flow nasal cannula oxygen and noninvasive ventilation has been widely reported. Reports of first-line use of high-flow nasal cannula oxygen has not demonstrated inferior outcomes, nor has the timing of intubation, suggesting a significant portion of patients could benefit from a trial of therapy and eventually avoid intubation.^11-14 Other therapies, such as systemic corticosteroids, confer a mortality benefit in those patients with COVID-19 who require oxygen or mechanical ventilation, but their impact on the progression of respiratory failure and need for intubation are undetermined.

There also are reports of patients who report no signs of respiratory distress or dyspnea with their COVID-19 pneumonia despite profound hypoxemia or high oxygen requirements. Various terms, including silent hypoxemia or happy hypoxia, are descriptive of the demeanor of these patients, and treatment has invariably included oxygen.^15,16 Nevertheless, low oxygen measurements have generally prompted higher levels of supplemental oxygen or more invasive therapies.

Treatment rendered may obscure the trajectory of response, which is important to understand to better position options for invasive therapies and other therapeutics. We recently encountered a patient with a course of illness that represented the natural history of COVID-19 pneumonia with low oxygen levels (referred to as hypoxemia for consistency) that highlighted several issues of management.

Case Presentation

A 62-year-old undomiciled woman with morbid obesity, prediabetes mellitus, long-standing schizophrenia, and bipolar disorder presented to our facility for evaluation of dry cough and need for tuberculosis clearance for admittance to a shelter. She appeared comfortable and was afebrile with blood pressure 111/74 mm Hg, heart rate 82 beats per minute. Her respiratory rate was 18 breaths per minute, but the pulse oximetry showed oxygen saturation of 70 to 75% on room air at rest. A chest X-ray showed bibasilar infiltrates (Figure 1), and a rapid COVID-19 nasopharyngeal polymerase chain reaction (PCR) test returned positive, confirmed by a second PCR test. Baseline inflammatory markers were elevated (Figure 2). In addition, the serum interleukin-6 also was elevated to 66.1 pg/mL (normal < 5.0), erythrocyte sedimentation rate elevated to 69 mm/h, but serum procalcitonin was essentially normal (0.22 ng/mL; normal < 20 ng/mL) as was the serum lactate (1.4 mmol/L).

The patient was admitted to the intensive care unit (ICU) for close monitoring in anticipation of the possibility of decompensation based on her age, hypoxia, and elevated inflammatory markers.¹⁷ Besides a subsequent low-grade fever (100.4 oF) and lymphopenia (manual count 550/uL), she remained clinically unchanged. Throughout her hospitalization, she maintained a persistent psychotic delusion that she did not have COVID-19, refusing all medical interventions, including a peripheral IV line and supplemental oxygen for the entire duration. Extensive efforts to identify family or a surrogate decision maker were unsuccessful. After consultation with Psychiatry, Bio-Ethics, and hospital leadership, the patient was deemed to lack decision-making capacity regarding treatment or disposition and was placed on a psychiatric hold. However, since any interventions against her will would require sedation, IV access, and potentially increase the risk of nosocomial COVID-19 transmission, she was allowed to remain untreated and was closely monitored for symptoms of worsening respiratory failure.

 

Over the next 2 weeks, her hypoxemia, inflammatory markers, and the infiltrates on imaging resolved (Figure 2). The lowest daily awake room air pulse oximetry readings are reported, initially with consistent readings in the low 80% range, but on day 12, readings were > 90% and remained > 90% for the remainder of her hospitalization. Therefore, shortly after hospital day 12, she was clinically stable for discharge from acute care to a subacute facility, but this required documentation of the clearance of her viral infection. She refused to undergo a subsequent nasopharyngeal swab but allowed an oropharyngeal COVID-19 PCR swab, which was negative. She remained stable and unchanged for the remainder of her hospitalization, awaiting identification of a receiving facility and was able to be discharged to transitional housing on day 38.

Discussion

The initial reports of COVID-19 pneumonia focused on ARDS and respiratory failure requiring mechanical ventilation with less emphasis on those with lower severity of illness. This was heightened by health care systems that were overwhelmed with large number of patients while faced with limited supplies and equipment. Given the risk to patients and providers of crash intubations, some recommended early intubation strategies.³ However, the natural history of COVID-19 pneumonia and the threshold for intubation of these patients remain poorly defined despite the creation of prognostic tools.¹⁷ This patient’s persistent hypoxemia and elevated inflammatory markers certainly met markers of disease associated with a high risk of progression.

The greatest concern would have been her level of hypoxemia. Acceptable thresholds of hypoxemia vary, but general consensus would classify pulse oximetry < 90% as hypoxemia and a threshold for administering supplemental oxygen. It is important to recognize how pulse oximetry readings translate to partial pressure of oxygen (PaO₂) measurements (Table 1). Pulse oximetry readings of 90% corresponds to a PaO₂ readings of 60 mm Hg in ideal conditions without the influence of acidosis, PaCO₂, or temperature. While lower readings are of concern, these do not represent absolute indications for assisted ventilatory support as lower levels are well tolerated in a variety of conditions. A common example are patients with chronic obstructive pulmonary disease. Long-term mortality benefits of continuous supplemental oxygen are well established in specific populations, but the threshold for correction in the acute setting remains a case-by-case decision. This decision is complex and is based on more than an absolute number or the amount of oxygen required to achieve a threshold level of oxygenation.

The PaO₂/FIO₂ (fraction of inspired oxygen) is a common measure used to address severity of disease and oxygen requirements. It also has been used to define the severity of ARDS, but the ratio is based on intubated and mechanically ventilated patients and may not translate well to those not on assisted ventilation. Treatment with supplemental oxygen also involves entrained air with associated imprecision in oxygen delivery.¹⁸ For this discussion, the patient’s admission PaO₂/FIO₂ on room air would have been between 190 and 260. Coupled with the bilateral infiltrates on imaging, there was justified concern for progression to severe ARDS. Her presentation would have met most of the epidemiologic criteria used in initial case finding for severe COVID-19 cases, including a blood oxygen saturation ≤ 93%, PaO₂/FIO₂ < 300 with infiltrates involving close to if not exceeding 50% of the lung.

With COVID-19 pneumonia, the pathologic injury to the alveoli resembles that of any viral pneumonia with recruitment of predominantly lymphocytic inflammatory cells that fill the alveoli, derangements in ventilation/perfusion mismatch as the core mechanism of hypoxemia with interstitial edema and shuntlike physiology developing at the extremes of involvement. In later stages, the histologic appearance is similar to ARDS, including hyaline membrane formation and thickened alveolar septa with perivascular lymphocytic-plasmocytic infiltration. In addition, there also are findings of organizing pneumonia with fibroblastic proliferation, thrombosis, and diffuse alveolar damage, a constellation of findings similar to that seen in the latter stages of ARDS.²

Although these histologic findings resemble ARDS, many patients with respiratory failure due to COVID-19 have a different physiologic profile compared with those with typical ARDS, with the most striking finding of lungs with low elastance or high compliance. From the critical care standpoint, this meant that the lungs were relatively easy to ventilate with lower peak airway and plateau pressures and low driving pressures. This condition suggested that there was relatively less lung that could be recruited with positive end expiratory pressure; therefore, a somewhat different entity from that associated with ARDS.¹⁹ These findings were often noted early in the course of respiratory failure, and although there is debate about whether this represents a different phenotype or timepoint in the spectrum of disease, it clearly represents a subset that is distinct from that which had been previously encountered.

On the other hand, the clinical features seen in those patients with COVID-19 pneumonia who progressed to advanced respiratory failure were essentially indistinguishable from those patients with traditional ARDS. Other explanations for this respiratory failure have included a disrupted vasoregulatory response to hypoxemia with failed hypoxic vasoconstriction, intravascular microthrombi, and impaired diffusion, all contributing to impaired gas exchange and hypoxemia.^19-21 This can lead to shuntlike conditions that neither respond well to supplemental oxygen nor manifest the type of physiologic response seen with other causes of hypoxemia.

 

The severity of hypoxemia manifested by this patient may have elicited additional findings of respiratory distress, such as dyspnea and tachypnea. However, in patients with severe COVID-19 pneumonia, dyspnea was not a universal finding, reported in the 20 to 60% range of cohorts, higher in those with ARDS and mechanical ventilation, although some report near universal dyspnea in their series.^1,4,8,22,23 Tachypnea is another symptom of interest. Using a threshold of > 24 breaths/min, tachypnea was noted in 16 to 29% of patients with a much greater proportion (63%) in nonsurvivors.^6,24 Several explanations have been proposed for the discordance between the presence and severity of hypoxemia and lack of symptoms of dyspnea and tachypnea. It is important to recognize that misclassification of the severity of hypoxemia can occur due to technical issues and potential errors involving pulse oximetry measurement and shifts in the oxyhemoglobin dissociation curve. However, this is more pertinent for those with mild disease as the severity of hypoxemia in severe pneumonia is beyond what can be attributed to technical issues.

More important, the ventilatory response curve to hypoxemia may not be normal for some patients, blunted by as much as 50% in older patients, especially in those with diabetes mellitus.^7,25,26 In addition, the ventilatory response varies widely even among normal individuals. This would translate to lower levels of minute ventilation (less tachypnea or respiratory effort) with hypoxemia. Hypocapnic hypoxemia also blunts the ventilatory response to hypoxemia. Subjects do not increase their minute ventilation if the PaCO₂ remains low despite oxygen desaturation to < 70%, especially if PaCO₂ < 30 mm Hg or alternatively, increases in minute ventilation are not seen until the PaCO₂ exceeds 39 mm Hg.²⁷ Both scenarios occur in those with COVID-19 pneumonia and provide another explanation for the absence of respiratory symptoms or signs of respiratory distress in some patients.

The observation of more compliant lungs may help in the understanding of the variable presentation of these patients. Compliant lungs do not require the increased pressure needed to achieve a specific tidal volume that, in turn, may increase the work of breathing. This may add to the explanation of seemingly paradoxical silent hypoxemia in those patients where the combination of a blunted ventilatory response, hypocapnia, shunt physiology, and normal respiratory system compliance is represented by the absence of increased breathing effort despite severe hypoxemia.

If not for the patient’s refusal of medical services, this patient quite possibly would have been intubated due to hypoxemia and health care providers’ concern for her risk of deterioration. Reported intubation and mechanical ventilation rates have varied widely from extremes of from < 5 to 88% in severely ill patients.^9,22 About 75% will need oxygen, but many can be treated and recover without the need for intubation and mechanical ventilation.

As previously mentioned, options for treatment include standard and high-flow oxygen delivery, noninvasive ventilation, and awake prone ventilation. Their role in patient management has been recently outlined, and instead of an early intubation strategy, represents gradual escalation of support that may be sufficient to treat hypoxemia and avoid the need for intubation and mechanical ventilation (Table 2).

In addition, the patient’s hospital course was notable for the decline in known markers of active inflammation that mirrored the resolution of her hypoxemia and pneumonia. This included elevated lactate dehydrogenase, D-dimer, ferritin, and C-reactive protein with all but the latter rising and decreasing over 2 weeks. These findings provide additional information of the time for recovery and supports the use of these markers to monitor the course of pneumonia.

The patient declined all intervention, including oxygen, and recovered to her presumed prehospitalization condition. This experiment of nature due to unique circumstances may shed light on the natural time course of untreated hypoxemic COVID-19 pneumonia that has not previously been well appreciated. It is important to recognize that recovery occurred over 2 weeks. This is close to the observed and expected time for recovery that has been reported for those with severe COVID-19 pneumonia.

Conclusions

Since the emergence of the COVID-19, evidence has accumulated for the benefit of several adjunctive therapies in the treatment of this type of pneumonia, with corticosteroids providing a mortality benefit. Although unknown whether this patient’s experience can be generalized to others or whether it represents her unique response, this case provides another perspective for comparison of treatments and reinforces the need for prospective, randomized clinical trials to establish treatment efficacy. The exact nature of silent hypoxemia of COVID-19 remains incompletely understood; however, this case highlights the importance of treating the individual instead of clinical markers and provides a time course for recovery from pneumonia and severe hypoxemia that occurs without oxygen or any other treatment over about 2 weeks.

In less than a year, COVID-19 has infected nearly 100 million people worldwide and caused more than 2 million deaths and counting. Although the infection fatality rate is estimated to be 1% and the case fatality rate between 2% and 3%, COVID-19 has had a disproportionate effect on the older population and those with comorbidities. Some of these findings are mirrored in the US Department of Veterans Affairs (VA) population, which has seen a higher case fatality rate.^1-4

As a respiratory tract infection, the most dreaded presentation is severe pneumonia with acute hypoxemia, which may rapidly deteriorate to acute respiratory distress syndrome (ARDS) and respiratory failure.^5-7 This possibility has led to early intubation strategies aimed at preempting this rapid deterioration and minimizing viral exposure to health care workers. Intubation rates have varied widely with extremes of 6 to 88%.^8,9

However, this early intubation strategy has waned as some of the rationale behind its endorsement has been called into question. Early intubation bypasses alternatives to intubation; high-flow nasal cannula oxygen, noninvasive ventilation, and awake proning are all effective maneuvers in the appropriate patient.^10,11 The use of first-line high-flow nasal cannula oxygen and noninvasive ventilation has been widely reported. Reports of first-line use of high-flow nasal cannula oxygen has not demonstrated inferior outcomes, nor has the timing of intubation, suggesting a significant portion of patients could benefit from a trial of therapy and eventually avoid intubation.^11-14 Other therapies, such as systemic corticosteroids, confer a mortality benefit in those patients with COVID-19 who require oxygen or mechanical ventilation, but their impact on the progression of respiratory failure and need for intubation are undetermined.

There also are reports of patients who report no signs of respiratory distress or dyspnea with their COVID-19 pneumonia despite profound hypoxemia or high oxygen requirements. Various terms, including silent hypoxemia or happy hypoxia, are descriptive of the demeanor of these patients, and treatment has invariably included oxygen.^15,16 Nevertheless, low oxygen measurements have generally prompted higher levels of supplemental oxygen or more invasive therapies.

Treatment rendered may obscure the trajectory of response, which is important to understand to better position options for invasive therapies and other therapeutics. We recently encountered a patient with a course of illness that represented the natural history of COVID-19 pneumonia with low oxygen levels (referred to as hypoxemia for consistency) that highlighted several issues of management.

Case Presentation

A 62-year-old undomiciled woman with morbid obesity, prediabetes mellitus, long-standing schizophrenia, and bipolar disorder presented to our facility for evaluation of dry cough and need for tuberculosis clearance for admittance to a shelter. She appeared comfortable and was afebrile with blood pressure 111/74 mm Hg, heart rate 82 beats per minute. Her respiratory rate was 18 breaths per minute, but the pulse oximetry showed oxygen saturation of 70 to 75% on room air at rest. A chest X-ray showed bibasilar infiltrates (Figure 1), and a rapid COVID-19 nasopharyngeal polymerase chain reaction (PCR) test returned positive, confirmed by a second PCR test. Baseline inflammatory markers were elevated (Figure 2). In addition, the serum interleukin-6 also was elevated to 66.1 pg/mL (normal < 5.0), erythrocyte sedimentation rate elevated to 69 mm/h, but serum procalcitonin was essentially normal (0.22 ng/mL; normal < 20 ng/mL) as was the serum lactate (1.4 mmol/L).

The patient was admitted to the intensive care unit (ICU) for close monitoring in anticipation of the possibility of decompensation based on her age, hypoxia, and elevated inflammatory markers.¹⁷ Besides a subsequent low-grade fever (100.4 oF) and lymphopenia (manual count 550/uL), she remained clinically unchanged. Throughout her hospitalization, she maintained a persistent psychotic delusion that she did not have COVID-19, refusing all medical interventions, including a peripheral IV line and supplemental oxygen for the entire duration. Extensive efforts to identify family or a surrogate decision maker were unsuccessful. After consultation with Psychiatry, Bio-Ethics, and hospital leadership, the patient was deemed to lack decision-making capacity regarding treatment or disposition and was placed on a psychiatric hold. However, since any interventions against her will would require sedation, IV access, and potentially increase the risk of nosocomial COVID-19 transmission, she was allowed to remain untreated and was closely monitored for symptoms of worsening respiratory failure.

 

Over the next 2 weeks, her hypoxemia, inflammatory markers, and the infiltrates on imaging resolved (Figure 2). The lowest daily awake room air pulse oximetry readings are reported, initially with consistent readings in the low 80% range, but on day 12, readings were > 90% and remained > 90% for the remainder of her hospitalization. Therefore, shortly after hospital day 12, she was clinically stable for discharge from acute care to a subacute facility, but this required documentation of the clearance of her viral infection. She refused to undergo a subsequent nasopharyngeal swab but allowed an oropharyngeal COVID-19 PCR swab, which was negative. She remained stable and unchanged for the remainder of her hospitalization, awaiting identification of a receiving facility and was able to be discharged to transitional housing on day 38.

Discussion

The initial reports of COVID-19 pneumonia focused on ARDS and respiratory failure requiring mechanical ventilation with less emphasis on those with lower severity of illness. This was heightened by health care systems that were overwhelmed with large number of patients while faced with limited supplies and equipment. Given the risk to patients and providers of crash intubations, some recommended early intubation strategies.³ However, the natural history of COVID-19 pneumonia and the threshold for intubation of these patients remain poorly defined despite the creation of prognostic tools.¹⁷ This patient’s persistent hypoxemia and elevated inflammatory markers certainly met markers of disease associated with a high risk of progression.

The greatest concern would have been her level of hypoxemia. Acceptable thresholds of hypoxemia vary, but general consensus would classify pulse oximetry < 90% as hypoxemia and a threshold for administering supplemental oxygen. It is important to recognize how pulse oximetry readings translate to partial pressure of oxygen (PaO₂) measurements (Table 1). Pulse oximetry readings of 90% corresponds to a PaO₂ readings of 60 mm Hg in ideal conditions without the influence of acidosis, PaCO₂, or temperature. While lower readings are of concern, these do not represent absolute indications for assisted ventilatory support as lower levels are well tolerated in a variety of conditions. A common example are patients with chronic obstructive pulmonary disease. Long-term mortality benefits of continuous supplemental oxygen are well established in specific populations, but the threshold for correction in the acute setting remains a case-by-case decision. This decision is complex and is based on more than an absolute number or the amount of oxygen required to achieve a threshold level of oxygenation.

The PaO₂/FIO₂ (fraction of inspired oxygen) is a common measure used to address severity of disease and oxygen requirements. It also has been used to define the severity of ARDS, but the ratio is based on intubated and mechanically ventilated patients and may not translate well to those not on assisted ventilation. Treatment with supplemental oxygen also involves entrained air with associated imprecision in oxygen delivery.¹⁸ For this discussion, the patient’s admission PaO₂/FIO₂ on room air would have been between 190 and 260. Coupled with the bilateral infiltrates on imaging, there was justified concern for progression to severe ARDS. Her presentation would have met most of the epidemiologic criteria used in initial case finding for severe COVID-19 cases, including a blood oxygen saturation ≤ 93%, PaO₂/FIO₂ < 300 with infiltrates involving close to if not exceeding 50% of the lung.

With COVID-19 pneumonia, the pathologic injury to the alveoli resembles that of any viral pneumonia with recruitment of predominantly lymphocytic inflammatory cells that fill the alveoli, derangements in ventilation/perfusion mismatch as the core mechanism of hypoxemia with interstitial edema and shuntlike physiology developing at the extremes of involvement. In later stages, the histologic appearance is similar to ARDS, including hyaline membrane formation and thickened alveolar septa with perivascular lymphocytic-plasmocytic infiltration. In addition, there also are findings of organizing pneumonia with fibroblastic proliferation, thrombosis, and diffuse alveolar damage, a constellation of findings similar to that seen in the latter stages of ARDS.²

Although these histologic findings resemble ARDS, many patients with respiratory failure due to COVID-19 have a different physiologic profile compared with those with typical ARDS, with the most striking finding of lungs with low elastance or high compliance. From the critical care standpoint, this meant that the lungs were relatively easy to ventilate with lower peak airway and plateau pressures and low driving pressures. This condition suggested that there was relatively less lung that could be recruited with positive end expiratory pressure; therefore, a somewhat different entity from that associated with ARDS.¹⁹ These findings were often noted early in the course of respiratory failure, and although there is debate about whether this represents a different phenotype or timepoint in the spectrum of disease, it clearly represents a subset that is distinct from that which had been previously encountered.

On the other hand, the clinical features seen in those patients with COVID-19 pneumonia who progressed to advanced respiratory failure were essentially indistinguishable from those patients with traditional ARDS. Other explanations for this respiratory failure have included a disrupted vasoregulatory response to hypoxemia with failed hypoxic vasoconstriction, intravascular microthrombi, and impaired diffusion, all contributing to impaired gas exchange and hypoxemia.^19-21 This can lead to shuntlike conditions that neither respond well to supplemental oxygen nor manifest the type of physiologic response seen with other causes of hypoxemia.

 

The severity of hypoxemia manifested by this patient may have elicited additional findings of respiratory distress, such as dyspnea and tachypnea. However, in patients with severe COVID-19 pneumonia, dyspnea was not a universal finding, reported in the 20 to 60% range of cohorts, higher in those with ARDS and mechanical ventilation, although some report near universal dyspnea in their series.^1,4,8,22,23 Tachypnea is another symptom of interest. Using a threshold of > 24 breaths/min, tachypnea was noted in 16 to 29% of patients with a much greater proportion (63%) in nonsurvivors.^6,24 Several explanations have been proposed for the discordance between the presence and severity of hypoxemia and lack of symptoms of dyspnea and tachypnea. It is important to recognize that misclassification of the severity of hypoxemia can occur due to technical issues and potential errors involving pulse oximetry measurement and shifts in the oxyhemoglobin dissociation curve. However, this is more pertinent for those with mild disease as the severity of hypoxemia in severe pneumonia is beyond what can be attributed to technical issues.

More important, the ventilatory response curve to hypoxemia may not be normal for some patients, blunted by as much as 50% in older patients, especially in those with diabetes mellitus.^7,25,26 In addition, the ventilatory response varies widely even among normal individuals. This would translate to lower levels of minute ventilation (less tachypnea or respiratory effort) with hypoxemia. Hypocapnic hypoxemia also blunts the ventilatory response to hypoxemia. Subjects do not increase their minute ventilation if the PaCO₂ remains low despite oxygen desaturation to < 70%, especially if PaCO₂ < 30 mm Hg or alternatively, increases in minute ventilation are not seen until the PaCO₂ exceeds 39 mm Hg.²⁷ Both scenarios occur in those with COVID-19 pneumonia and provide another explanation for the absence of respiratory symptoms or signs of respiratory distress in some patients.

The observation of more compliant lungs may help in the understanding of the variable presentation of these patients. Compliant lungs do not require the increased pressure needed to achieve a specific tidal volume that, in turn, may increase the work of breathing. This may add to the explanation of seemingly paradoxical silent hypoxemia in those patients where the combination of a blunted ventilatory response, hypocapnia, shunt physiology, and normal respiratory system compliance is represented by the absence of increased breathing effort despite severe hypoxemia.

If not for the patient’s refusal of medical services, this patient quite possibly would have been intubated due to hypoxemia and health care providers’ concern for her risk of deterioration. Reported intubation and mechanical ventilation rates have varied widely from extremes of from < 5 to 88% in severely ill patients.^9,22 About 75% will need oxygen, but many can be treated and recover without the need for intubation and mechanical ventilation.

As previously mentioned, options for treatment include standard and high-flow oxygen delivery, noninvasive ventilation, and awake prone ventilation. Their role in patient management has been recently outlined, and instead of an early intubation strategy, represents gradual escalation of support that may be sufficient to treat hypoxemia and avoid the need for intubation and mechanical ventilation (Table 2).

In addition, the patient’s hospital course was notable for the decline in known markers of active inflammation that mirrored the resolution of her hypoxemia and pneumonia. This included elevated lactate dehydrogenase, D-dimer, ferritin, and C-reactive protein with all but the latter rising and decreasing over 2 weeks. These findings provide additional information of the time for recovery and supports the use of these markers to monitor the course of pneumonia.

The patient declined all intervention, including oxygen, and recovered to her presumed prehospitalization condition. This experiment of nature due to unique circumstances may shed light on the natural time course of untreated hypoxemic COVID-19 pneumonia that has not previously been well appreciated. It is important to recognize that recovery occurred over 2 weeks. This is close to the observed and expected time for recovery that has been reported for those with severe COVID-19 pneumonia.

Conclusions

Since the emergence of the COVID-19, evidence has accumulated for the benefit of several adjunctive therapies in the treatment of this type of pneumonia, with corticosteroids providing a mortality benefit. Although unknown whether this patient’s experience can be generalized to others or whether it represents her unique response, this case provides another perspective for comparison of treatments and reinforces the need for prospective, randomized clinical trials to establish treatment efficacy. The exact nature of silent hypoxemia of COVID-19 remains incompletely understood; however, this case highlights the importance of treating the individual instead of clinical markers and provides a time course for recovery from pneumonia and severe hypoxemia that occurs without oxygen or any other treatment over about 2 weeks.

In less than a year, COVID-19 has infected nearly 100 million people worldwide and caused more than 2 million deaths and counting. Although the infection fatality rate is estimated to be 1% and the case fatality rate between 2% and 3%, COVID-19 has had a disproportionate effect on the older population and those with comorbidities. Some of these findings are mirrored in the US Department of Veterans Affairs (VA) population, which has seen a higher case fatality rate.^1-4

As a respiratory tract infection, the most dreaded presentation is severe pneumonia with acute hypoxemia, which may rapidly deteriorate to acute respiratory distress syndrome (ARDS) and respiratory failure.^5-7 This possibility has led to early intubation strategies aimed at preempting this rapid deterioration and minimizing viral exposure to health care workers. Intubation rates have varied widely with extremes of 6 to 88%.^8,9

However, this early intubation strategy has waned as some of the rationale behind its endorsement has been called into question. Early intubation bypasses alternatives to intubation; high-flow nasal cannula oxygen, noninvasive ventilation, and awake proning are all effective maneuvers in the appropriate patient.^10,11 The use of first-line high-flow nasal cannula oxygen and noninvasive ventilation has been widely reported. Reports of first-line use of high-flow nasal cannula oxygen has not demonstrated inferior outcomes, nor has the timing of intubation, suggesting a significant portion of patients could benefit from a trial of therapy and eventually avoid intubation.^11-14 Other therapies, such as systemic corticosteroids, confer a mortality benefit in those patients with COVID-19 who require oxygen or mechanical ventilation, but their impact on the progression of respiratory failure and need for intubation are undetermined.

There also are reports of patients who report no signs of respiratory distress or dyspnea with their COVID-19 pneumonia despite profound hypoxemia or high oxygen requirements. Various terms, including silent hypoxemia or happy hypoxia, are descriptive of the demeanor of these patients, and treatment has invariably included oxygen.^15,16 Nevertheless, low oxygen measurements have generally prompted higher levels of supplemental oxygen or more invasive therapies.

Treatment rendered may obscure the trajectory of response, which is important to understand to better position options for invasive therapies and other therapeutics. We recently encountered a patient with a course of illness that represented the natural history of COVID-19 pneumonia with low oxygen levels (referred to as hypoxemia for consistency) that highlighted several issues of management.

Case Presentation

A 62-year-old undomiciled woman with morbid obesity, prediabetes mellitus, long-standing schizophrenia, and bipolar disorder presented to our facility for evaluation of dry cough and need for tuberculosis clearance for admittance to a shelter. She appeared comfortable and was afebrile with blood pressure 111/74 mm Hg, heart rate 82 beats per minute. Her respiratory rate was 18 breaths per minute, but the pulse oximetry showed oxygen saturation of 70 to 75% on room air at rest. A chest X-ray showed bibasilar infiltrates (Figure 1), and a rapid COVID-19 nasopharyngeal polymerase chain reaction (PCR) test returned positive, confirmed by a second PCR test. Baseline inflammatory markers were elevated (Figure 2). In addition, the serum interleukin-6 also was elevated to 66.1 pg/mL (normal < 5.0), erythrocyte sedimentation rate elevated to 69 mm/h, but serum procalcitonin was essentially normal (0.22 ng/mL; normal < 20 ng/mL) as was the serum lactate (1.4 mmol/L).

The patient was admitted to the intensive care unit (ICU) for close monitoring in anticipation of the possibility of decompensation based on her age, hypoxia, and elevated inflammatory markers.¹⁷ Besides a subsequent low-grade fever (100.4 oF) and lymphopenia (manual count 550/uL), she remained clinically unchanged. Throughout her hospitalization, she maintained a persistent psychotic delusion that she did not have COVID-19, refusing all medical interventions, including a peripheral IV line and supplemental oxygen for the entire duration. Extensive efforts to identify family or a surrogate decision maker were unsuccessful. After consultation with Psychiatry, Bio-Ethics, and hospital leadership, the patient was deemed to lack decision-making capacity regarding treatment or disposition and was placed on a psychiatric hold. However, since any interventions against her will would require sedation, IV access, and potentially increase the risk of nosocomial COVID-19 transmission, she was allowed to remain untreated and was closely monitored for symptoms of worsening respiratory failure.

 

Over the next 2 weeks, her hypoxemia, inflammatory markers, and the infiltrates on imaging resolved (Figure 2). The lowest daily awake room air pulse oximetry readings are reported, initially with consistent readings in the low 80% range, but on day 12, readings were > 90% and remained > 90% for the remainder of her hospitalization. Therefore, shortly after hospital day 12, she was clinically stable for discharge from acute care to a subacute facility, but this required documentation of the clearance of her viral infection. She refused to undergo a subsequent nasopharyngeal swab but allowed an oropharyngeal COVID-19 PCR swab, which was negative. She remained stable and unchanged for the remainder of her hospitalization, awaiting identification of a receiving facility and was able to be discharged to transitional housing on day 38.

Discussion

The initial reports of COVID-19 pneumonia focused on ARDS and respiratory failure requiring mechanical ventilation with less emphasis on those with lower severity of illness. This was heightened by health care systems that were overwhelmed with large number of patients while faced with limited supplies and equipment. Given the risk to patients and providers of crash intubations, some recommended early intubation strategies.³ However, the natural history of COVID-19 pneumonia and the threshold for intubation of these patients remain poorly defined despite the creation of prognostic tools.¹⁷ This patient’s persistent hypoxemia and elevated inflammatory markers certainly met markers of disease associated with a high risk of progression.

The greatest concern would have been her level of hypoxemia. Acceptable thresholds of hypoxemia vary, but general consensus would classify pulse oximetry < 90% as hypoxemia and a threshold for administering supplemental oxygen. It is important to recognize how pulse oximetry readings translate to partial pressure of oxygen (PaO₂) measurements (Table 1). Pulse oximetry readings of 90% corresponds to a PaO₂ readings of 60 mm Hg in ideal conditions without the influence of acidosis, PaCO₂, or temperature. While lower readings are of concern, these do not represent absolute indications for assisted ventilatory support as lower levels are well tolerated in a variety of conditions. A common example are patients with chronic obstructive pulmonary disease. Long-term mortality benefits of continuous supplemental oxygen are well established in specific populations, but the threshold for correction in the acute setting remains a case-by-case decision. This decision is complex and is based on more than an absolute number or the amount of oxygen required to achieve a threshold level of oxygenation.

The PaO₂/FIO₂ (fraction of inspired oxygen) is a common measure used to address severity of disease and oxygen requirements. It also has been used to define the severity of ARDS, but the ratio is based on intubated and mechanically ventilated patients and may not translate well to those not on assisted ventilation. Treatment with supplemental oxygen also involves entrained air with associated imprecision in oxygen delivery.¹⁸ For this discussion, the patient’s admission PaO₂/FIO₂ on room air would have been between 190 and 260. Coupled with the bilateral infiltrates on imaging, there was justified concern for progression to severe ARDS. Her presentation would have met most of the epidemiologic criteria used in initial case finding for severe COVID-19 cases, including a blood oxygen saturation ≤ 93%, PaO₂/FIO₂ < 300 with infiltrates involving close to if not exceeding 50% of the lung.

With COVID-19 pneumonia, the pathologic injury to the alveoli resembles that of any viral pneumonia with recruitment of predominantly lymphocytic inflammatory cells that fill the alveoli, derangements in ventilation/perfusion mismatch as the core mechanism of hypoxemia with interstitial edema and shuntlike physiology developing at the extremes of involvement. In later stages, the histologic appearance is similar to ARDS, including hyaline membrane formation and thickened alveolar septa with perivascular lymphocytic-plasmocytic infiltration. In addition, there also are findings of organizing pneumonia with fibroblastic proliferation, thrombosis, and diffuse alveolar damage, a constellation of findings similar to that seen in the latter stages of ARDS.²

Although these histologic findings resemble ARDS, many patients with respiratory failure due to COVID-19 have a different physiologic profile compared with those with typical ARDS, with the most striking finding of lungs with low elastance or high compliance. From the critical care standpoint, this meant that the lungs were relatively easy to ventilate with lower peak airway and plateau pressures and low driving pressures. This condition suggested that there was relatively less lung that could be recruited with positive end expiratory pressure; therefore, a somewhat different entity from that associated with ARDS.¹⁹ These findings were often noted early in the course of respiratory failure, and although there is debate about whether this represents a different phenotype or timepoint in the spectrum of disease, it clearly represents a subset that is distinct from that which had been previously encountered.

On the other hand, the clinical features seen in those patients with COVID-19 pneumonia who progressed to advanced respiratory failure were essentially indistinguishable from those patients with traditional ARDS. Other explanations for this respiratory failure have included a disrupted vasoregulatory response to hypoxemia with failed hypoxic vasoconstriction, intravascular microthrombi, and impaired diffusion, all contributing to impaired gas exchange and hypoxemia.^19-21 This can lead to shuntlike conditions that neither respond well to supplemental oxygen nor manifest the type of physiologic response seen with other causes of hypoxemia.

 

The severity of hypoxemia manifested by this patient may have elicited additional findings of respiratory distress, such as dyspnea and tachypnea. However, in patients with severe COVID-19 pneumonia, dyspnea was not a universal finding, reported in the 20 to 60% range of cohorts, higher in those with ARDS and mechanical ventilation, although some report near universal dyspnea in their series.^1,4,8,22,23 Tachypnea is another symptom of interest. Using a threshold of > 24 breaths/min, tachypnea was noted in 16 to 29% of patients with a much greater proportion (63%) in nonsurvivors.^6,24 Several explanations have been proposed for the discordance between the presence and severity of hypoxemia and lack of symptoms of dyspnea and tachypnea. It is important to recognize that misclassification of the severity of hypoxemia can occur due to technical issues and potential errors involving pulse oximetry measurement and shifts in the oxyhemoglobin dissociation curve. However, this is more pertinent for those with mild disease as the severity of hypoxemia in severe pneumonia is beyond what can be attributed to technical issues.

More important, the ventilatory response curve to hypoxemia may not be normal for some patients, blunted by as much as 50% in older patients, especially in those with diabetes mellitus.^7,25,26 In addition, the ventilatory response varies widely even among normal individuals. This would translate to lower levels of minute ventilation (less tachypnea or respiratory effort) with hypoxemia. Hypocapnic hypoxemia also blunts the ventilatory response to hypoxemia. Subjects do not increase their minute ventilation if the PaCO₂ remains low despite oxygen desaturation to < 70%, especially if PaCO₂ < 30 mm Hg or alternatively, increases in minute ventilation are not seen until the PaCO₂ exceeds 39 mm Hg.²⁷ Both scenarios occur in those with COVID-19 pneumonia and provide another explanation for the absence of respiratory symptoms or signs of respiratory distress in some patients.

The observation of more compliant lungs may help in the understanding of the variable presentation of these patients. Compliant lungs do not require the increased pressure needed to achieve a specific tidal volume that, in turn, may increase the work of breathing. This may add to the explanation of seemingly paradoxical silent hypoxemia in those patients where the combination of a blunted ventilatory response, hypocapnia, shunt physiology, and normal respiratory system compliance is represented by the absence of increased breathing effort despite severe hypoxemia.

If not for the patient’s refusal of medical services, this patient quite possibly would have been intubated due to hypoxemia and health care providers’ concern for her risk of deterioration. Reported intubation and mechanical ventilation rates have varied widely from extremes of from < 5 to 88% in severely ill patients.^9,22 About 75% will need oxygen, but many can be treated and recover without the need for intubation and mechanical ventilation.

As previously mentioned, options for treatment include standard and high-flow oxygen delivery, noninvasive ventilation, and awake prone ventilation. Their role in patient management has been recently outlined, and instead of an early intubation strategy, represents gradual escalation of support that may be sufficient to treat hypoxemia and avoid the need for intubation and mechanical ventilation (Table 2).

In addition, the patient’s hospital course was notable for the decline in known markers of active inflammation that mirrored the resolution of her hypoxemia and pneumonia. This included elevated lactate dehydrogenase, D-dimer, ferritin, and C-reactive protein with all but the latter rising and decreasing over 2 weeks. These findings provide additional information of the time for recovery and supports the use of these markers to monitor the course of pneumonia.

The patient declined all intervention, including oxygen, and recovered to her presumed prehospitalization condition. This experiment of nature due to unique circumstances may shed light on the natural time course of untreated hypoxemic COVID-19 pneumonia that has not previously been well appreciated. It is important to recognize that recovery occurred over 2 weeks. This is close to the observed and expected time for recovery that has been reported for those with severe COVID-19 pneumonia.

Conclusions

Since the emergence of the COVID-19, evidence has accumulated for the benefit of several adjunctive therapies in the treatment of this type of pneumonia, with corticosteroids providing a mortality benefit. Although unknown whether this patient’s experience can be generalized to others or whether it represents her unique response, this case provides another perspective for comparison of treatments and reinforces the need for prospective, randomized clinical trials to establish treatment efficacy. The exact nature of silent hypoxemia of COVID-19 remains incompletely understood; however, this case highlights the importance of treating the individual instead of clinical markers and provides a time course for recovery from pneumonia and severe hypoxemia that occurs without oxygen or any other treatment over about 2 weeks.

Deep vein thrombosis (DVT) is a frequently encountered medical condition with about 1 in 1,000 adults diagnosed annually.^1,2 Up to one-half of patients who receive a diagnosis will experience long-term complications in the affected limb.¹ Anticoagulation is the treatment of choice for DVT in the absence of any contraindications.³ Thrombolytic therapies (eg, systemic thrombolysis, catheter-directed thrombolysis with or without thrombectomy) historically have been reserved for patients who present with phlegmasia cerulea dolens (PCD), a severe condition involving venous obstruction within the extremities that causes impaired arterial blood supply and cyanosis that can lead to limb loss and death.⁴

The role of thrombolytic therapy is less clear in patients without PCD who present with extensive or symptomatic lower extremity DVT that causes significant pain, edema, and functional disability. Proximal lower extremity DVT (thrombus above the knee and above the popliteal vein) and particularly those involving the iliac or common femoral vein (ie, iliofemoral DVT) carry a significant risk of recurrent thromboembolism as well as postthrombotic syndrome (PTS), a complication of DVT resulting in chronic leg pain, edema, skin discoloration, and venous ulcers.⁵There is a lack of established standards of care for treating severely symptomatic or extensive proximal DVT without PCD. There are currently no specific treatment recommendations in the major guidelines for this subset of patients.

The goal of thrombolytic therapy is to prevent thrombus propagation, recurrent thromboembolism, and PTS, in addition to providing more rapid pain relief and improvement in limb function. Catheter-directed thrombolysis is preferred over systemic thrombolysis when used for DVT treatment because it is associated with less major bleeding complications and noninferior clinical outcomes.⁶ Catheter-directed thrombolysis is a minimally invasive endovascular treatment using a wire catheter combination to traverse the thrombus under fluoroscopic guidance through which a thrombolytic drug is infused over a specified duration (usually 24 to 72 hours).⁷

Catheter-directed thrombolysis can be combined with catheter-directed thrombectomy using the same endovascular technique. This combination is called a pharmacomechanical thrombectomy or a pharmacomechanical thromobolysis and can offer more rapid removal of thrombus and decreased infusion times of thrombolytic drug.⁸ Pharmacomechanical thrombolysis is a relatively new technique, so the choice of thrombolytic therapy will depend on procedural expertise and resource availability. Early interventional radiology consultation (or vascular surgery in some centers) can assist in determining appropriate candidates for thrombolytic therapies. Here we present 2 cases of extensive symptomatic DVT successfully treated with catheter-directed pharmacomechanical thrombolysis.

Case 1

A 61-year-old male current smoker with a history of obesity and hypertension presented to the West Los Angeles Veterans Affairs Medical Center emergency department (ED) with 2 days of progressive pain and swelling in the right lower extremity (RLE) after sustaining a calf injury the preceding week. The patient rated pain as 9 on a 10-point scale and reported no other symptoms. He reported no prior history of venous thromboembolism (VTE) or family history of thrombophilia.

A physical examination was notable for stable vital signs and normal cardiopulmonary examination. There was extensive RLE edema below the knee with tenderness to palpation and shiny taut skin. The neurovascular examination of the RLE was normal. Laboratory studies were notable only for a mild leukocytosis. Compression ultrasound with Doppler of the RLE demonstrated an acute thrombus of the right femoral vein extending to the popliteal vein.

The patient was prescribed enoxaparin 90 mg every 12 hours for anticoagulation. After 36 hours of anticoagulation, he continued to experience severe RLE pain and swelling limiting ambulation. Interventional radiology was consulted, and catheter-directed pharmacomechanical thrombolysis of the RLE was pursued given the persistence of significant symptoms. Intraprocedure venogram demonstrated thrombi filling the entirety of the right femoral and popliteal veins (Figure 1A). This was treated with catheter-directed pulse-spray thrombolysis with 12 mg of tissue plasminogen activator (tPA).

 

After a 20-minute incubation period, a thrombectomy was performed several times along the femoral vein and popliteal vein, using an AngioJet device. A follow-up venogram revealed a small amount of residual thrombi in the right suprageniculate popliteal vein and right femoral vein. This entire segment was further treated with angioplasty, and a postintervention venogram demonstrated patency of the right suprageniculate popliteal vein and right femoral vein with minimal residual thrombi and with brisk venous flow (Figure 1B). Immediately after the procedure, the patient’s RLE pain significantly improved. On day 2 postprocedure, the patient’s RLE edema resolved, and the patient was able to resume normal ambulation. There were no bleeding complications. The patient was discharged with oral anticoagulation therapy.

Case 2

A male aged 78 years with a history of hypertension, hyperlipidemia, and benign prostatic hypertrophy presented to the ED with 10 days of progressive pain and swelling in the left lower extremity (LLE). The patient noted decreased mobility over recent months and was using a front wheel walker while recovering from surgical repair of a hamstring tendon injury. He reported taking a transcontinental flight around the same time that his LLE pain began. The patient reported no prior history of VTE or family history of thrombophilia.

A physical examination was notable for stable vital signs with a normal cardiopulmonary examination. There was extensive LLE edema up to the proximal thigh without erythema or cyanosis, and his skin was taut and tender. Neurovascular examination of the LLE was normal. Laboratory studies were unremarkable. Compression ultrasonography with Doppler of the LLE demonstrated an extensive acute occlusive thrombus within the left common femoral, entire left femoral, and left popliteal veins.

After evaluating the patient, the Vascular Surgery service did not feel there was evidence of compartment syndrome nor PCD. The patient received unfractionated heparin anticoagulation therapy and the LLE was elevated continuously. After 24 hours of anticoagulation therapy, the patient continued to have significant pain and was unable to ambulate. The case was presented in a joint Interventional Radiology/Vascular Surgery conference and the decision was made to pursue pharmacomechanic thrombolysis given the significant extent of thrombotic burden.

The patient underwent successful catheter-directed pharmacomechanic thrombolysis via pulse-spray thrombolysis of 15 mg of tPA using the Boston Scientific AngioJet Thrombectomy System, and angioplasty with no immediate complications (Figure 2). The patient noted dramatic improvement in LLE pain and swelling 1 day postprocedure and was able to ambulate. He developed mild asymptomatic hematuria, which resolved within 12 hours and without an associated drop in hemoglobin. The patient was transitioned to oral anticoagulation and discharged to an acute rehabilitation unit on postprocedure day 2.

Discussion

Anticoagulation is the preferred therapy for most patients with acute uncomplicated lower extremity DVT. PCD is the only widely accepted indication for thrombolytic therapy in patients with acute lower extremity DVT. However, in the absence of PCD, management of complicated DVT where there are either significant symptoms, extensive clot burden, or proximal location is less clear due to the paucity of clinical data. For example, in the case of iliofemoral DVT, thrombosis of the iliofemoral region is associated with an increased risk of pulmonary embolism, limb malperfusion, and PTS when compared with other types of DVT.^5,6Furthermore, despite the use of anticoagulant therapy, PTS develops within 2 years in about half of patients with proximal DVT, which can progress to major disability and impaired quality of life.⁹

Earlier retrospective observational studies in patients with acute DVT found that the addition of either systemic thrombolysis or catheter-directed thrombolysis to anticoagulation increased rates of clot lysis but did not lead to a reduction in clinical outcomes such as recurrent thromboembolism, mortality, or the rate of PTS.^10-12 Additionally, both systemic thrombolytic therapy and catheter-directed thrombolytic therapy were associated with higher rates of major bleeding. However, these studies included all patients with acute DVT without selecting for criteria, such as proximal location of DVT, severe symptoms, or extensive clot burden. Because thrombolytic therapy is proven to provide more rapid and immediate clot lysis (whereas conventional anticoagulation prevents thrombus extension and recurrence but does not dissolve the clot), it is reasonable to suggest that a subpopulation of patients with extensive or symptomatic DVT may benefit from immediate clot lysis, thereby restoring limb perfusion and avoiding limb gangrene while preserving venous function and preventing PTS.

 

Mixed Study Results

The 2012 CaVenT study is one of the few randomized controlled trials to assess outcomes comparing conventional anticoagulation alone to anticoagulation with catheter-directed thrombolysis in patients with acute lower extremity DVT.¹³ Study patients did not undergo catheter-directed mechanical thrombectomy. Patients in this study consisted solely of those with first-time iliofemoral DVT. Long-term outcomes at 24-month follow-up showed that additional catheter-directed thrombolysis reduced the risk of PTS when compared with those who were treated with anticoagulation alone (41.1% vs 55.6%, P = .047). The difference in PTS corresponded to an absolute risk reduction of 14.4% (95% CI, 0.2-27.9), and the number needed to treat was 7 (95% CI, 4-502). There was a clinically relevant bleeding complication rate of 8.9% in the thrombolysis group with none leading to a permanently impaired outcome.

These results could not be confirmed by a more recent randomized control trial in 2017 conducted by Vedantham and colleagues.¹⁴ In this trial, patients with acute proximal DVT (femoral and iliofemoral DVT) were randomized to receive either anticoagulation alone or anticoagulation plus pharmacomechanical thrombolysis. In the pharmacomechanic thrombolysis group, the overall incidence of PTS and recurrent VTE was not reduced over the 24-month follow-up period. Those who developed PTS in the pharmacomechanical thrombolysis group had lower severity scores, as there was a significant reduction in moderate-to-severe PTS in this group. There also were more early major bleeds in the pharmacomechanic thrombolysis group (1.7%, with no fatal or intracranial bleeds) when compared with the control group; however, this bleeding complication rate was much less than what was noted in the CaVenT study. Additionally, there was a significant decrease in both lower extremity pain and edema in the pharmacomechanical thrombolysis group at 10 days and 30 days postintervention.

Given the mixed results of these 2 randomized controlled trials, further studies are warranted to clarify the role of thrombolytic therapies in preventing major events such as recurrent VTE and PTS, especially given the increased risk of bleeding observed with thrombolytic therapies. The 2016 American College of Chest Physicians guidelines recommend anticoagulation as monotherapy vs thrombolytics, systemic or catheter-directed thrombolysis as designated treatment modalities.³ These guidelines are rated “Grade 2C”, which reflect a weak recommendation based on low-quality evidence. While these recommendations do not comment on additional considerations, such as DVT clot burden, location, or severity of symptoms, the guidelines do state that patients who attach a high value to the prevention of PTS and a lower value to the risk of bleeding with catheter-directed therapy are likely to choose catheter-directed therapy over anticoagulation alone.

Case Studies Analyses

In our first case presentation, pharma-comechanic thrombolysis was pursued because the patient presented with severesymptoms and did not experience any symptomatic improvement after 36 hours of anticoagulation. It is unclear whether a longer duration of anticoagulation might have improved the severity of his symptoms. When considering the level of pain, edema, and inability to ambulate, thrombolytic therapy was considered the most appropriate choice for treatment. Pharmacomechanic thrombolysis was successful, resulting in complete clot lysis, significant decrease in pain and edema with total recovery of ambulatory abilities, no bleeding complications, and prevention of any potential clinical deterioration, such as phlegmasia cerulea dolens. The patient is now 12 months postprocedure without symptoms of PTS or recurrent thromboembolic events. Continued follow-up that monitors the development of PTS will be necessary for at least 2 years postprocedure.

In the second case, our patient experienced some improvement in pain after 24 hours of anticoagulation alone. However, considering the extensive proximal clot burden involving the entire femoral and common femoral veins, the treatment teams believed it was likely that this patient would experience a prolonged recovery time and increased morbidity on anticoagulant therapy alone. Pharmacomechanic thrombolysis was again successful with almost immediate resolution of pain and edema, and recovery of ambulatory abilities on postprocedure day 1. The patient is now 6 months postprocedure without any symptoms of PTS or recurrent thromboembolic events.

In both case presentations, the presenting symptoms, methods of treatment, and immediate symptomatic improvement postintervention were similar. The patient in Case 2 had more extensive clot burden, a more proximal location of clot, and was classified as having an iliofemoral DVT because the thrombus included the common femoral vein; the decision for intervention in this case was more weighted on clot burden and location rather than on the significant symptoms of severe pain and difficulty with ambulation seen in Case 1. However, it is noteworthy that in Case 2 our patient also experienced significant improvement in pain, swelling, and ambulation postintervention. Complications were minimal and limited to Case 2 where our patient experienced mild asymptomatic hematuria likely related to the catheter-directed tPA that resolved spontaneously within hours and did not cause further complications. Additionally, it is likely that the length of hospital stay was decreased significantly in both cases given the rapid improvement in symptoms and recovery of ambulatory abilities.

High-Risk Patients

Given the successful treatment results in these 2 cases, we believe that there is a subset of higher-risk patients with severe symptomatic proximal DVT but without PCD that may benefit from the addition of thrombolytic therapies to anticoagulation. These patients may present with significant pain, difficulty ambulating, and will likely have extensive proximal clot burden. Immediate thrombolytic intervention can achieve rapid symptom relief, which, in turn, can decrease morbidity by decreasing length of hospitalization, improving ambulation, and possibly decreasing the incidence or severity of future PTS. Positive outcomes may be easier to predict for those with obvious features of pain, edema, and difficulty ambulating, which may be more readily reversed by rapid clot reversal/removal.

 

These patients should be considered on a case-by-case basis. For example, the severity of pain can be balanced against the patient’s risk factors for bleeding because rapid thrombus lysis or immediate thrombus removal will likely reduce the pain. Patients who attach a high value to functional quality (eg, both patients in this case study experienced significant difficulty ambulating), quicker recovery, and decreased hospitalization duration may be more likely to choose the addition of thrombolytic therapies over anticoagulation alone and accept the higher risk of bleed. A scoring system with inclusion/exclusion criteria such as location of clot, bleeding history, age, and pain can create an individualized approach for each patient. Future studies also could consider using a detailed pretreatment symptom-severity score (similar to the Likert pain scale and calf circumference measurements used by Vedantham and colleagues¹⁴) and assess whether higher symptom-severity patients are more likely to benefit from the addition of thrombolytic therapies to anticoagulation. Positive outcomes can be assessed for the short-term such as pain severity, ability to ambulate, and length of hospitalization. Additionally, it would be important to determine whether there is a correlation with severity of pain on presentation and future PTS incidence or severity—a positive correlation would lend further support toward using thrombolytic therapies in those with severe symptomatic DVT.

Finally, additional studies involving variations in methodology should be examined, including whether pharmacomechanic thrombolysis may be safer in terms of bleeding than catheter-directed thrombolysis alone, as suggested by the lower bleeding rates seen in the pharmacomechanic study by Vedantham and colleagues when compared with the CaVenT study.^13,14 Patients in the CaVenT study received an infusion of 20 mg of alteplase over a maximum of 96 hours. Patients in the pharmacomechanic study by Vedanthem and colleagues received either a rapid pulsed delivery of alteplase over a single procedural session (as in our 2 cases) or a maximum of 30 hours of alteplase infusion (total alteplase dose < 35 mg) followed by thrombus removal. It is possible that the lower incidence of major bleeds observed in the study by Vedanthem and colleagues is a result of the decreased exposure to thrombolytic agents.

Conclusions

There is a relative lack of high-quality data examining thrombolytic therapies in the setting of acute lower extremity DVT. Recent studies have prioritized evaluation of the posttreatment incidence of PTS, recurrent thromboembolism, and risk of bleeding caused by thrombolytic therapies. Results are mixed thus far, and further studies are necessary to clarify a more definitive role for thrombolytic therapies, particularly in established higher-risk populations with proximal DVT. In this case series, we highlighted 2 patients with extensive proximal DVT burden with significant symptoms who experienced almost complete resolution of symptoms immediately following thrombolytic therapies. We postulate that even in the absence of PCD, there is a subset of patients with severe symptoms in the setting of acute proximal lower extremity DVT that clearly benefit from thrombolytic therapies.

Deep vein thrombosis (DVT) is a frequently encountered medical condition with about 1 in 1,000 adults diagnosed annually.^1,2 Up to one-half of patients who receive a diagnosis will experience long-term complications in the affected limb.¹ Anticoagulation is the treatment of choice for DVT in the absence of any contraindications.³ Thrombolytic therapies (eg, systemic thrombolysis, catheter-directed thrombolysis with or without thrombectomy) historically have been reserved for patients who present with phlegmasia cerulea dolens (PCD), a severe condition involving venous obstruction within the extremities that causes impaired arterial blood supply and cyanosis that can lead to limb loss and death.⁴

The role of thrombolytic therapy is less clear in patients without PCD who present with extensive or symptomatic lower extremity DVT that causes significant pain, edema, and functional disability. Proximal lower extremity DVT (thrombus above the knee and above the popliteal vein) and particularly those involving the iliac or common femoral vein (ie, iliofemoral DVT) carry a significant risk of recurrent thromboembolism as well as postthrombotic syndrome (PTS), a complication of DVT resulting in chronic leg pain, edema, skin discoloration, and venous ulcers.⁵There is a lack of established standards of care for treating severely symptomatic or extensive proximal DVT without PCD. There are currently no specific treatment recommendations in the major guidelines for this subset of patients.

The goal of thrombolytic therapy is to prevent thrombus propagation, recurrent thromboembolism, and PTS, in addition to providing more rapid pain relief and improvement in limb function. Catheter-directed thrombolysis is preferred over systemic thrombolysis when used for DVT treatment because it is associated with less major bleeding complications and noninferior clinical outcomes.⁶ Catheter-directed thrombolysis is a minimally invasive endovascular treatment using a wire catheter combination to traverse the thrombus under fluoroscopic guidance through which a thrombolytic drug is infused over a specified duration (usually 24 to 72 hours).⁷

Catheter-directed thrombolysis can be combined with catheter-directed thrombectomy using the same endovascular technique. This combination is called a pharmacomechanical thrombectomy or a pharmacomechanical thromobolysis and can offer more rapid removal of thrombus and decreased infusion times of thrombolytic drug.⁸ Pharmacomechanical thrombolysis is a relatively new technique, so the choice of thrombolytic therapy will depend on procedural expertise and resource availability. Early interventional radiology consultation (or vascular surgery in some centers) can assist in determining appropriate candidates for thrombolytic therapies. Here we present 2 cases of extensive symptomatic DVT successfully treated with catheter-directed pharmacomechanical thrombolysis.

Case 1

A 61-year-old male current smoker with a history of obesity and hypertension presented to the West Los Angeles Veterans Affairs Medical Center emergency department (ED) with 2 days of progressive pain and swelling in the right lower extremity (RLE) after sustaining a calf injury the preceding week. The patient rated pain as 9 on a 10-point scale and reported no other symptoms. He reported no prior history of venous thromboembolism (VTE) or family history of thrombophilia.

A physical examination was notable for stable vital signs and normal cardiopulmonary examination. There was extensive RLE edema below the knee with tenderness to palpation and shiny taut skin. The neurovascular examination of the RLE was normal. Laboratory studies were notable only for a mild leukocytosis. Compression ultrasound with Doppler of the RLE demonstrated an acute thrombus of the right femoral vein extending to the popliteal vein.

The patient was prescribed enoxaparin 90 mg every 12 hours for anticoagulation. After 36 hours of anticoagulation, he continued to experience severe RLE pain and swelling limiting ambulation. Interventional radiology was consulted, and catheter-directed pharmacomechanical thrombolysis of the RLE was pursued given the persistence of significant symptoms. Intraprocedure venogram demonstrated thrombi filling the entirety of the right femoral and popliteal veins (Figure 1A). This was treated with catheter-directed pulse-spray thrombolysis with 12 mg of tissue plasminogen activator (tPA).

 

After a 20-minute incubation period, a thrombectomy was performed several times along the femoral vein and popliteal vein, using an AngioJet device. A follow-up venogram revealed a small amount of residual thrombi in the right suprageniculate popliteal vein and right femoral vein. This entire segment was further treated with angioplasty, and a postintervention venogram demonstrated patency of the right suprageniculate popliteal vein and right femoral vein with minimal residual thrombi and with brisk venous flow (Figure 1B). Immediately after the procedure, the patient’s RLE pain significantly improved. On day 2 postprocedure, the patient’s RLE edema resolved, and the patient was able to resume normal ambulation. There were no bleeding complications. The patient was discharged with oral anticoagulation therapy.

Case 2

A male aged 78 years with a history of hypertension, hyperlipidemia, and benign prostatic hypertrophy presented to the ED with 10 days of progressive pain and swelling in the left lower extremity (LLE). The patient noted decreased mobility over recent months and was using a front wheel walker while recovering from surgical repair of a hamstring tendon injury. He reported taking a transcontinental flight around the same time that his LLE pain began. The patient reported no prior history of VTE or family history of thrombophilia.

A physical examination was notable for stable vital signs with a normal cardiopulmonary examination. There was extensive LLE edema up to the proximal thigh without erythema or cyanosis, and his skin was taut and tender. Neurovascular examination of the LLE was normal. Laboratory studies were unremarkable. Compression ultrasonography with Doppler of the LLE demonstrated an extensive acute occlusive thrombus within the left common femoral, entire left femoral, and left popliteal veins.

After evaluating the patient, the Vascular Surgery service did not feel there was evidence of compartment syndrome nor PCD. The patient received unfractionated heparin anticoagulation therapy and the LLE was elevated continuously. After 24 hours of anticoagulation therapy, the patient continued to have significant pain and was unable to ambulate. The case was presented in a joint Interventional Radiology/Vascular Surgery conference and the decision was made to pursue pharmacomechanic thrombolysis given the significant extent of thrombotic burden.

The patient underwent successful catheter-directed pharmacomechanic thrombolysis via pulse-spray thrombolysis of 15 mg of tPA using the Boston Scientific AngioJet Thrombectomy System, and angioplasty with no immediate complications (Figure 2). The patient noted dramatic improvement in LLE pain and swelling 1 day postprocedure and was able to ambulate. He developed mild asymptomatic hematuria, which resolved within 12 hours and without an associated drop in hemoglobin. The patient was transitioned to oral anticoagulation and discharged to an acute rehabilitation unit on postprocedure day 2.

Discussion

Anticoagulation is the preferred therapy for most patients with acute uncomplicated lower extremity DVT. PCD is the only widely accepted indication for thrombolytic therapy in patients with acute lower extremity DVT. However, in the absence of PCD, management of complicated DVT where there are either significant symptoms, extensive clot burden, or proximal location is less clear due to the paucity of clinical data. For example, in the case of iliofemoral DVT, thrombosis of the iliofemoral region is associated with an increased risk of pulmonary embolism, limb malperfusion, and PTS when compared with other types of DVT.^5,6Furthermore, despite the use of anticoagulant therapy, PTS develops within 2 years in about half of patients with proximal DVT, which can progress to major disability and impaired quality of life.⁹

Earlier retrospective observational studies in patients with acute DVT found that the addition of either systemic thrombolysis or catheter-directed thrombolysis to anticoagulation increased rates of clot lysis but did not lead to a reduction in clinical outcomes such as recurrent thromboembolism, mortality, or the rate of PTS.^10-12 Additionally, both systemic thrombolytic therapy and catheter-directed thrombolytic therapy were associated with higher rates of major bleeding. However, these studies included all patients with acute DVT without selecting for criteria, such as proximal location of DVT, severe symptoms, or extensive clot burden. Because thrombolytic therapy is proven to provide more rapid and immediate clot lysis (whereas conventional anticoagulation prevents thrombus extension and recurrence but does not dissolve the clot), it is reasonable to suggest that a subpopulation of patients with extensive or symptomatic DVT may benefit from immediate clot lysis, thereby restoring limb perfusion and avoiding limb gangrene while preserving venous function and preventing PTS.

 

Mixed Study Results

The 2012 CaVenT study is one of the few randomized controlled trials to assess outcomes comparing conventional anticoagulation alone to anticoagulation with catheter-directed thrombolysis in patients with acute lower extremity DVT.¹³ Study patients did not undergo catheter-directed mechanical thrombectomy. Patients in this study consisted solely of those with first-time iliofemoral DVT. Long-term outcomes at 24-month follow-up showed that additional catheter-directed thrombolysis reduced the risk of PTS when compared with those who were treated with anticoagulation alone (41.1% vs 55.6%, P = .047). The difference in PTS corresponded to an absolute risk reduction of 14.4% (95% CI, 0.2-27.9), and the number needed to treat was 7 (95% CI, 4-502). There was a clinically relevant bleeding complication rate of 8.9% in the thrombolysis group with none leading to a permanently impaired outcome.

These results could not be confirmed by a more recent randomized control trial in 2017 conducted by Vedantham and colleagues.¹⁴ In this trial, patients with acute proximal DVT (femoral and iliofemoral DVT) were randomized to receive either anticoagulation alone or anticoagulation plus pharmacomechanical thrombolysis. In the pharmacomechanic thrombolysis group, the overall incidence of PTS and recurrent VTE was not reduced over the 24-month follow-up period. Those who developed PTS in the pharmacomechanical thrombolysis group had lower severity scores, as there was a significant reduction in moderate-to-severe PTS in this group. There also were more early major bleeds in the pharmacomechanic thrombolysis group (1.7%, with no fatal or intracranial bleeds) when compared with the control group; however, this bleeding complication rate was much less than what was noted in the CaVenT study. Additionally, there was a significant decrease in both lower extremity pain and edema in the pharmacomechanical thrombolysis group at 10 days and 30 days postintervention.

Given the mixed results of these 2 randomized controlled trials, further studies are warranted to clarify the role of thrombolytic therapies in preventing major events such as recurrent VTE and PTS, especially given the increased risk of bleeding observed with thrombolytic therapies. The 2016 American College of Chest Physicians guidelines recommend anticoagulation as monotherapy vs thrombolytics, systemic or catheter-directed thrombolysis as designated treatment modalities.³ These guidelines are rated “Grade 2C”, which reflect a weak recommendation based on low-quality evidence. While these recommendations do not comment on additional considerations, such as DVT clot burden, location, or severity of symptoms, the guidelines do state that patients who attach a high value to the prevention of PTS and a lower value to the risk of bleeding with catheter-directed therapy are likely to choose catheter-directed therapy over anticoagulation alone.

Case Studies Analyses

In our first case presentation, pharma-comechanic thrombolysis was pursued because the patient presented with severesymptoms and did not experience any symptomatic improvement after 36 hours of anticoagulation. It is unclear whether a longer duration of anticoagulation might have improved the severity of his symptoms. When considering the level of pain, edema, and inability to ambulate, thrombolytic therapy was considered the most appropriate choice for treatment. Pharmacomechanic thrombolysis was successful, resulting in complete clot lysis, significant decrease in pain and edema with total recovery of ambulatory abilities, no bleeding complications, and prevention of any potential clinical deterioration, such as phlegmasia cerulea dolens. The patient is now 12 months postprocedure without symptoms of PTS or recurrent thromboembolic events. Continued follow-up that monitors the development of PTS will be necessary for at least 2 years postprocedure.

In the second case, our patient experienced some improvement in pain after 24 hours of anticoagulation alone. However, considering the extensive proximal clot burden involving the entire femoral and common femoral veins, the treatment teams believed it was likely that this patient would experience a prolonged recovery time and increased morbidity on anticoagulant therapy alone. Pharmacomechanic thrombolysis was again successful with almost immediate resolution of pain and edema, and recovery of ambulatory abilities on postprocedure day 1. The patient is now 6 months postprocedure without any symptoms of PTS or recurrent thromboembolic events.

In both case presentations, the presenting symptoms, methods of treatment, and immediate symptomatic improvement postintervention were similar. The patient in Case 2 had more extensive clot burden, a more proximal location of clot, and was classified as having an iliofemoral DVT because the thrombus included the common femoral vein; the decision for intervention in this case was more weighted on clot burden and location rather than on the significant symptoms of severe pain and difficulty with ambulation seen in Case 1. However, it is noteworthy that in Case 2 our patient also experienced significant improvement in pain, swelling, and ambulation postintervention. Complications were minimal and limited to Case 2 where our patient experienced mild asymptomatic hematuria likely related to the catheter-directed tPA that resolved spontaneously within hours and did not cause further complications. Additionally, it is likely that the length of hospital stay was decreased significantly in both cases given the rapid improvement in symptoms and recovery of ambulatory abilities.

High-Risk Patients

Given the successful treatment results in these 2 cases, we believe that there is a subset of higher-risk patients with severe symptomatic proximal DVT but without PCD that may benefit from the addition of thrombolytic therapies to anticoagulation. These patients may present with significant pain, difficulty ambulating, and will likely have extensive proximal clot burden. Immediate thrombolytic intervention can achieve rapid symptom relief, which, in turn, can decrease morbidity by decreasing length of hospitalization, improving ambulation, and possibly decreasing the incidence or severity of future PTS. Positive outcomes may be easier to predict for those with obvious features of pain, edema, and difficulty ambulating, which may be more readily reversed by rapid clot reversal/removal.

 

These patients should be considered on a case-by-case basis. For example, the severity of pain can be balanced against the patient’s risk factors for bleeding because rapid thrombus lysis or immediate thrombus removal will likely reduce the pain. Patients who attach a high value to functional quality (eg, both patients in this case study experienced significant difficulty ambulating), quicker recovery, and decreased hospitalization duration may be more likely to choose the addition of thrombolytic therapies over anticoagulation alone and accept the higher risk of bleed. A scoring system with inclusion/exclusion criteria such as location of clot, bleeding history, age, and pain can create an individualized approach for each patient. Future studies also could consider using a detailed pretreatment symptom-severity score (similar to the Likert pain scale and calf circumference measurements used by Vedantham and colleagues¹⁴) and assess whether higher symptom-severity patients are more likely to benefit from the addition of thrombolytic therapies to anticoagulation. Positive outcomes can be assessed for the short-term such as pain severity, ability to ambulate, and length of hospitalization. Additionally, it would be important to determine whether there is a correlation with severity of pain on presentation and future PTS incidence or severity—a positive correlation would lend further support toward using thrombolytic therapies in those with severe symptomatic DVT.

Finally, additional studies involving variations in methodology should be examined, including whether pharmacomechanic thrombolysis may be safer in terms of bleeding than catheter-directed thrombolysis alone, as suggested by the lower bleeding rates seen in the pharmacomechanic study by Vedantham and colleagues when compared with the CaVenT study.^13,14 Patients in the CaVenT study received an infusion of 20 mg of alteplase over a maximum of 96 hours. Patients in the pharmacomechanic study by Vedanthem and colleagues received either a rapid pulsed delivery of alteplase over a single procedural session (as in our 2 cases) or a maximum of 30 hours of alteplase infusion (total alteplase dose < 35 mg) followed by thrombus removal. It is possible that the lower incidence of major bleeds observed in the study by Vedanthem and colleagues is a result of the decreased exposure to thrombolytic agents.

Conclusions

There is a relative lack of high-quality data examining thrombolytic therapies in the setting of acute lower extremity DVT. Recent studies have prioritized evaluation of the posttreatment incidence of PTS, recurrent thromboembolism, and risk of bleeding caused by thrombolytic therapies. Results are mixed thus far, and further studies are necessary to clarify a more definitive role for thrombolytic therapies, particularly in established higher-risk populations with proximal DVT. In this case series, we highlighted 2 patients with extensive proximal DVT burden with significant symptoms who experienced almost complete resolution of symptoms immediately following thrombolytic therapies. We postulate that even in the absence of PCD, there is a subset of patients with severe symptoms in the setting of acute proximal lower extremity DVT that clearly benefit from thrombolytic therapies.

Deep vein thrombosis (DVT) is a frequently encountered medical condition with about 1 in 1,000 adults diagnosed annually.^1,2 Up to one-half of patients who receive a diagnosis will experience long-term complications in the affected limb.¹ Anticoagulation is the treatment of choice for DVT in the absence of any contraindications.³ Thrombolytic therapies (eg, systemic thrombolysis, catheter-directed thrombolysis with or without thrombectomy) historically have been reserved for patients who present with phlegmasia cerulea dolens (PCD), a severe condition involving venous obstruction within the extremities that causes impaired arterial blood supply and cyanosis that can lead to limb loss and death.⁴

The role of thrombolytic therapy is less clear in patients without PCD who present with extensive or symptomatic lower extremity DVT that causes significant pain, edema, and functional disability. Proximal lower extremity DVT (thrombus above the knee and above the popliteal vein) and particularly those involving the iliac or common femoral vein (ie, iliofemoral DVT) carry a significant risk of recurrent thromboembolism as well as postthrombotic syndrome (PTS), a complication of DVT resulting in chronic leg pain, edema, skin discoloration, and venous ulcers.⁵There is a lack of established standards of care for treating severely symptomatic or extensive proximal DVT without PCD. There are currently no specific treatment recommendations in the major guidelines for this subset of patients.

The goal of thrombolytic therapy is to prevent thrombus propagation, recurrent thromboembolism, and PTS, in addition to providing more rapid pain relief and improvement in limb function. Catheter-directed thrombolysis is preferred over systemic thrombolysis when used for DVT treatment because it is associated with less major bleeding complications and noninferior clinical outcomes.⁶ Catheter-directed thrombolysis is a minimally invasive endovascular treatment using a wire catheter combination to traverse the thrombus under fluoroscopic guidance through which a thrombolytic drug is infused over a specified duration (usually 24 to 72 hours).⁷

Catheter-directed thrombolysis can be combined with catheter-directed thrombectomy using the same endovascular technique. This combination is called a pharmacomechanical thrombectomy or a pharmacomechanical thromobolysis and can offer more rapid removal of thrombus and decreased infusion times of thrombolytic drug.⁸ Pharmacomechanical thrombolysis is a relatively new technique, so the choice of thrombolytic therapy will depend on procedural expertise and resource availability. Early interventional radiology consultation (or vascular surgery in some centers) can assist in determining appropriate candidates for thrombolytic therapies. Here we present 2 cases of extensive symptomatic DVT successfully treated with catheter-directed pharmacomechanical thrombolysis.

Case 1

A 61-year-old male current smoker with a history of obesity and hypertension presented to the West Los Angeles Veterans Affairs Medical Center emergency department (ED) with 2 days of progressive pain and swelling in the right lower extremity (RLE) after sustaining a calf injury the preceding week. The patient rated pain as 9 on a 10-point scale and reported no other symptoms. He reported no prior history of venous thromboembolism (VTE) or family history of thrombophilia.

A physical examination was notable for stable vital signs and normal cardiopulmonary examination. There was extensive RLE edema below the knee with tenderness to palpation and shiny taut skin. The neurovascular examination of the RLE was normal. Laboratory studies were notable only for a mild leukocytosis. Compression ultrasound with Doppler of the RLE demonstrated an acute thrombus of the right femoral vein extending to the popliteal vein.

The patient was prescribed enoxaparin 90 mg every 12 hours for anticoagulation. After 36 hours of anticoagulation, he continued to experience severe RLE pain and swelling limiting ambulation. Interventional radiology was consulted, and catheter-directed pharmacomechanical thrombolysis of the RLE was pursued given the persistence of significant symptoms. Intraprocedure venogram demonstrated thrombi filling the entirety of the right femoral and popliteal veins (Figure 1A). This was treated with catheter-directed pulse-spray thrombolysis with 12 mg of tissue plasminogen activator (tPA).

 

After a 20-minute incubation period, a thrombectomy was performed several times along the femoral vein and popliteal vein, using an AngioJet device. A follow-up venogram revealed a small amount of residual thrombi in the right suprageniculate popliteal vein and right femoral vein. This entire segment was further treated with angioplasty, and a postintervention venogram demonstrated patency of the right suprageniculate popliteal vein and right femoral vein with minimal residual thrombi and with brisk venous flow (Figure 1B). Immediately after the procedure, the patient’s RLE pain significantly improved. On day 2 postprocedure, the patient’s RLE edema resolved, and the patient was able to resume normal ambulation. There were no bleeding complications. The patient was discharged with oral anticoagulation therapy.

Case 2

A male aged 78 years with a history of hypertension, hyperlipidemia, and benign prostatic hypertrophy presented to the ED with 10 days of progressive pain and swelling in the left lower extremity (LLE). The patient noted decreased mobility over recent months and was using a front wheel walker while recovering from surgical repair of a hamstring tendon injury. He reported taking a transcontinental flight around the same time that his LLE pain began. The patient reported no prior history of VTE or family history of thrombophilia.

A physical examination was notable for stable vital signs with a normal cardiopulmonary examination. There was extensive LLE edema up to the proximal thigh without erythema or cyanosis, and his skin was taut and tender. Neurovascular examination of the LLE was normal. Laboratory studies were unremarkable. Compression ultrasonography with Doppler of the LLE demonstrated an extensive acute occlusive thrombus within the left common femoral, entire left femoral, and left popliteal veins.

After evaluating the patient, the Vascular Surgery service did not feel there was evidence of compartment syndrome nor PCD. The patient received unfractionated heparin anticoagulation therapy and the LLE was elevated continuously. After 24 hours of anticoagulation therapy, the patient continued to have significant pain and was unable to ambulate. The case was presented in a joint Interventional Radiology/Vascular Surgery conference and the decision was made to pursue pharmacomechanic thrombolysis given the significant extent of thrombotic burden.

The patient underwent successful catheter-directed pharmacomechanic thrombolysis via pulse-spray thrombolysis of 15 mg of tPA using the Boston Scientific AngioJet Thrombectomy System, and angioplasty with no immediate complications (Figure 2). The patient noted dramatic improvement in LLE pain and swelling 1 day postprocedure and was able to ambulate. He developed mild asymptomatic hematuria, which resolved within 12 hours and without an associated drop in hemoglobin. The patient was transitioned to oral anticoagulation and discharged to an acute rehabilitation unit on postprocedure day 2.

Discussion

Anticoagulation is the preferred therapy for most patients with acute uncomplicated lower extremity DVT. PCD is the only widely accepted indication for thrombolytic therapy in patients with acute lower extremity DVT. However, in the absence of PCD, management of complicated DVT where there are either significant symptoms, extensive clot burden, or proximal location is less clear due to the paucity of clinical data. For example, in the case of iliofemoral DVT, thrombosis of the iliofemoral region is associated with an increased risk of pulmonary embolism, limb malperfusion, and PTS when compared with other types of DVT.^5,6Furthermore, despite the use of anticoagulant therapy, PTS develops within 2 years in about half of patients with proximal DVT, which can progress to major disability and impaired quality of life.⁹

Earlier retrospective observational studies in patients with acute DVT found that the addition of either systemic thrombolysis or catheter-directed thrombolysis to anticoagulation increased rates of clot lysis but did not lead to a reduction in clinical outcomes such as recurrent thromboembolism, mortality, or the rate of PTS.^10-12 Additionally, both systemic thrombolytic therapy and catheter-directed thrombolytic therapy were associated with higher rates of major bleeding. However, these studies included all patients with acute DVT without selecting for criteria, such as proximal location of DVT, severe symptoms, or extensive clot burden. Because thrombolytic therapy is proven to provide more rapid and immediate clot lysis (whereas conventional anticoagulation prevents thrombus extension and recurrence but does not dissolve the clot), it is reasonable to suggest that a subpopulation of patients with extensive or symptomatic DVT may benefit from immediate clot lysis, thereby restoring limb perfusion and avoiding limb gangrene while preserving venous function and preventing PTS.

 

Mixed Study Results

The 2012 CaVenT study is one of the few randomized controlled trials to assess outcomes comparing conventional anticoagulation alone to anticoagulation with catheter-directed thrombolysis in patients with acute lower extremity DVT.¹³ Study patients did not undergo catheter-directed mechanical thrombectomy. Patients in this study consisted solely of those with first-time iliofemoral DVT. Long-term outcomes at 24-month follow-up showed that additional catheter-directed thrombolysis reduced the risk of PTS when compared with those who were treated with anticoagulation alone (41.1% vs 55.6%, P = .047). The difference in PTS corresponded to an absolute risk reduction of 14.4% (95% CI, 0.2-27.9), and the number needed to treat was 7 (95% CI, 4-502). There was a clinically relevant bleeding complication rate of 8.9% in the thrombolysis group with none leading to a permanently impaired outcome.

These results could not be confirmed by a more recent randomized control trial in 2017 conducted by Vedantham and colleagues.¹⁴ In this trial, patients with acute proximal DVT (femoral and iliofemoral DVT) were randomized to receive either anticoagulation alone or anticoagulation plus pharmacomechanical thrombolysis. In the pharmacomechanic thrombolysis group, the overall incidence of PTS and recurrent VTE was not reduced over the 24-month follow-up period. Those who developed PTS in the pharmacomechanical thrombolysis group had lower severity scores, as there was a significant reduction in moderate-to-severe PTS in this group. There also were more early major bleeds in the pharmacomechanic thrombolysis group (1.7%, with no fatal or intracranial bleeds) when compared with the control group; however, this bleeding complication rate was much less than what was noted in the CaVenT study. Additionally, there was a significant decrease in both lower extremity pain and edema in the pharmacomechanical thrombolysis group at 10 days and 30 days postintervention.

Given the mixed results of these 2 randomized controlled trials, further studies are warranted to clarify the role of thrombolytic therapies in preventing major events such as recurrent VTE and PTS, especially given the increased risk of bleeding observed with thrombolytic therapies. The 2016 American College of Chest Physicians guidelines recommend anticoagulation as monotherapy vs thrombolytics, systemic or catheter-directed thrombolysis as designated treatment modalities.³ These guidelines are rated “Grade 2C”, which reflect a weak recommendation based on low-quality evidence. While these recommendations do not comment on additional considerations, such as DVT clot burden, location, or severity of symptoms, the guidelines do state that patients who attach a high value to the prevention of PTS and a lower value to the risk of bleeding with catheter-directed therapy are likely to choose catheter-directed therapy over anticoagulation alone.

Case Studies Analyses

In our first case presentation, pharma-comechanic thrombolysis was pursued because the patient presented with severesymptoms and did not experience any symptomatic improvement after 36 hours of anticoagulation. It is unclear whether a longer duration of anticoagulation might have improved the severity of his symptoms. When considering the level of pain, edema, and inability to ambulate, thrombolytic therapy was considered the most appropriate choice for treatment. Pharmacomechanic thrombolysis was successful, resulting in complete clot lysis, significant decrease in pain and edema with total recovery of ambulatory abilities, no bleeding complications, and prevention of any potential clinical deterioration, such as phlegmasia cerulea dolens. The patient is now 12 months postprocedure without symptoms of PTS or recurrent thromboembolic events. Continued follow-up that monitors the development of PTS will be necessary for at least 2 years postprocedure.

In the second case, our patient experienced some improvement in pain after 24 hours of anticoagulation alone. However, considering the extensive proximal clot burden involving the entire femoral and common femoral veins, the treatment teams believed it was likely that this patient would experience a prolonged recovery time and increased morbidity on anticoagulant therapy alone. Pharmacomechanic thrombolysis was again successful with almost immediate resolution of pain and edema, and recovery of ambulatory abilities on postprocedure day 1. The patient is now 6 months postprocedure without any symptoms of PTS or recurrent thromboembolic events.

In both case presentations, the presenting symptoms, methods of treatment, and immediate symptomatic improvement postintervention were similar. The patient in Case 2 had more extensive clot burden, a more proximal location of clot, and was classified as having an iliofemoral DVT because the thrombus included the common femoral vein; the decision for intervention in this case was more weighted on clot burden and location rather than on the significant symptoms of severe pain and difficulty with ambulation seen in Case 1. However, it is noteworthy that in Case 2 our patient also experienced significant improvement in pain, swelling, and ambulation postintervention. Complications were minimal and limited to Case 2 where our patient experienced mild asymptomatic hematuria likely related to the catheter-directed tPA that resolved spontaneously within hours and did not cause further complications. Additionally, it is likely that the length of hospital stay was decreased significantly in both cases given the rapid improvement in symptoms and recovery of ambulatory abilities.

High-Risk Patients

Given the successful treatment results in these 2 cases, we believe that there is a subset of higher-risk patients with severe symptomatic proximal DVT but without PCD that may benefit from the addition of thrombolytic therapies to anticoagulation. These patients may present with significant pain, difficulty ambulating, and will likely have extensive proximal clot burden. Immediate thrombolytic intervention can achieve rapid symptom relief, which, in turn, can decrease morbidity by decreasing length of hospitalization, improving ambulation, and possibly decreasing the incidence or severity of future PTS. Positive outcomes may be easier to predict for those with obvious features of pain, edema, and difficulty ambulating, which may be more readily reversed by rapid clot reversal/removal.

 

These patients should be considered on a case-by-case basis. For example, the severity of pain can be balanced against the patient’s risk factors for bleeding because rapid thrombus lysis or immediate thrombus removal will likely reduce the pain. Patients who attach a high value to functional quality (eg, both patients in this case study experienced significant difficulty ambulating), quicker recovery, and decreased hospitalization duration may be more likely to choose the addition of thrombolytic therapies over anticoagulation alone and accept the higher risk of bleed. A scoring system with inclusion/exclusion criteria such as location of clot, bleeding history, age, and pain can create an individualized approach for each patient. Future studies also could consider using a detailed pretreatment symptom-severity score (similar to the Likert pain scale and calf circumference measurements used by Vedantham and colleagues¹⁴) and assess whether higher symptom-severity patients are more likely to benefit from the addition of thrombolytic therapies to anticoagulation. Positive outcomes can be assessed for the short-term such as pain severity, ability to ambulate, and length of hospitalization. Additionally, it would be important to determine whether there is a correlation with severity of pain on presentation and future PTS incidence or severity—a positive correlation would lend further support toward using thrombolytic therapies in those with severe symptomatic DVT.

Finally, additional studies involving variations in methodology should be examined, including whether pharmacomechanic thrombolysis may be safer in terms of bleeding than catheter-directed thrombolysis alone, as suggested by the lower bleeding rates seen in the pharmacomechanic study by Vedantham and colleagues when compared with the CaVenT study.^13,14 Patients in the CaVenT study received an infusion of 20 mg of alteplase over a maximum of 96 hours. Patients in the pharmacomechanic study by Vedanthem and colleagues received either a rapid pulsed delivery of alteplase over a single procedural session (as in our 2 cases) or a maximum of 30 hours of alteplase infusion (total alteplase dose < 35 mg) followed by thrombus removal. It is possible that the lower incidence of major bleeds observed in the study by Vedanthem and colleagues is a result of the decreased exposure to thrombolytic agents.

Conclusions

There is a relative lack of high-quality data examining thrombolytic therapies in the setting of acute lower extremity DVT. Recent studies have prioritized evaluation of the posttreatment incidence of PTS, recurrent thromboembolism, and risk of bleeding caused by thrombolytic therapies. Results are mixed thus far, and further studies are necessary to clarify a more definitive role for thrombolytic therapies, particularly in established higher-risk populations with proximal DVT. In this case series, we highlighted 2 patients with extensive proximal DVT burden with significant symptoms who experienced almost complete resolution of symptoms immediately following thrombolytic therapies. We postulate that even in the absence of PCD, there is a subset of patients with severe symptoms in the setting of acute proximal lower extremity DVT that clearly benefit from thrombolytic therapies.

First described in 2000 in a case series of 15 patients, nephrogenic systemic fibrosis (NSF) is a rare scleroderma-like fibrosing skin condition associated with gadolinium exposure in end stage renal disease (ESRD).¹ Patients with advanced chronic kidney disease (CKD) or ESRD are at the highest risk for this condition when exposed to gadolinium-based contrast dyes.

Nephrogenic systemic fibrosis is a devastating and rapidly progressive condition, making its prevention in at-risk populations of utmost importance. In this article, the authors describe a case of a patient who developed NSF in the setting of gadolinium exposure and multiple inflammatory dermatologic conditions. This case illustrates the possible role of a pro-inflammatory state in predisposing to NSF, which may help further elucidate its mechanism of action.

Case Presentation

A 61-year-old Hispanic male with a history of IV heroin use with ESRD secondary to membranous glomerulonephritis on hemodialysis and chronic hepatitis C infection presented to the West Los Angeles VAMC with fevers and night sweats that had persisted for 2 weeks. His physical examination was notable for diffuse tender palpable purpura and petechiae (including his palms and soles), altered mental status, and diffuse myoclonic jerks, which necessitated endotracheal intubation and mechanical ventilation for airway protection. Blood cultures were positive for methicillin-sensitive Staphylococcus aureus (MSSA). Laboratory results were notable for an elevated sedimentation rate of 53 mm/h (0-10 mm/h), C-reactive protein of 19.8 mg/L (< 0.744 mg/dL), and albumin of 1.2 g/dL (3.2-4.8 g/dL). An extensive rheumatologic workup was unrevealing, and a lumbar puncture was unremarkable. A biopsy of his skin lesions was consistent with leukocytoclastic vasculitis.

The patient’s prior hemodialysis access, a tunneled dialysis catheter in the right subclavian vein, was removed given concern for line infection and replaced with an internal jugular temporary hemodialysis line. Given his altered mental status and myoclonic jerks, the decision was made to pursue a magnetic resonance imaging (MRI) scan of the brain and spine with gadolinium contrast to evaluate for cerebral vasculitis and/or septic emboli to the brain.

The patient received 15 mL of gadoversetamide contrast in accordance with hospital imaging protocol. The MRI revealed only chronic ischemic changes. The patient underwent hemodialysis about 18 hours later. The patient was treated with a 6-week course of IV penicillin G. His altered mental status and myoclonic jerks resolved without intervention, and he was then discharged to an acute rehabilitation unit.

Eight weeks after his initial presentation the patient developed a purulent wound on his right forearm (Figure 1) 

and was readmitted for workup. A biopsy of this wound was consistent with pyoderma gangrenosum, and he was started on high-dose steroids. He then developed thickening and induration of his bilateral forearm skin with the characteristic peau d’orange appearance of NSF. He developed contractures of his upper and lower extremities over several days, which caused him to become wheelchair-bound. Nephrogenic systemic fibrosis was confirmed by a skin biopsy that showed characteristic diffuse dermal fibrosis (Figures 2 and 3).

The patient was discharged to continue physical and occupational therapy to preserve his functional mobility, as no other treatment options were available. 

At the 3-month dermatology clinic follow-up appointment, the patient continued to have significant contractures of his upper extremities and remained dependent on his family for multiple activities of daily living.

Discussion

Nephrogenic systemic fibrosis is a poorly understood inflammatory condition that produces diffuse fibrosis of the skin. Typically, the disease begins with progressive skin induration of the extremities. Systemic involvement may occur, leading to fibrosis of skeletal muscle, fascia, and multiple organs. Flexion contractures may develop that limit physical function. Fibrosis can become apparent within days to months after exposure to gadolinium contrast.

Beyond renal insufficiency, it is unclear what other risk factors predispose patients to developing this condition. Only a minority of patients with CKD stages 1 through 4 will develop NSF on exposure to gadolinium contrast. However, the incidence of NSF among patients with CKD stage 5 who are exposed to gadolinium has been estimated to be about 13.4% in a prospective study involving 18 patients.²

In a 2015 meta-analysis by Zhang and colleagues, the only clear risk factor identified for the development of NSF, aside from gadolinium exposure, was severe renal insufficiency with a glomerular filtration rate of < 30 mL/min/1.75m².³ Due to the limited number of patients identified with this disease, it is difficult to identify other risk factors associated with the development of NSF. Based on in vitro studies, it has been postulated that a pro-inflammatory state predisposes patients to develop NSF.^4,5 The proposed mechanism for NSF involves extravasation of gadolinium in the setting of vascular endothelial permeability.^5,6 Gadolinium then interacts with tissue macrophages, which induce the release of inflammatory cytokines and the secretion of smooth muscle actin by dermal fibroblasts.^6,7

Treatment of NSF has been largely unsuccessful. Multiple modalities of treatment that included topical and oral steroids, immunosuppression, plasmapheresis, and ultraviolent therapy have been attempted, none of which have been proven to consistently limit progression of the disease.⁸ The most effective intervention is early physical therapy to preserve functionality and prevent contracture formation. For patients who are eligible, early renal transplantation may offer the best chance of improved mobility. In a case series review by Cuffy and colleagues, 5 of 6 patients who underwent renal transplantation after the development of NSF experienced softening of the involved skin, and 2 patients had improved mobility of joints.⁹

 

Conclusion

The case presented here illustrates a possible association between a pro-inflammatory state and the development of NSF. This patient had multiple inflammatory conditions, including MSSA bacteremia, leukocytoclastic vasculitis, and pyoderma gangrenosum (the latter 2 conditions were thought to be associated with his underlying chronic hepatitis C infection), which the authors believe predisposed him to endothelial permeability and risk for developing NSF. The risk of developing NSF in at-risk patients with each episode of gadolinium exposure is estimated around 2.4%, or an incidence of 4.3 cases per 1,000 patient-years, leading the American College of Radiologists to recommend against the administration of gadolinium-based contrast except in cases in which benefits clearly outweigh risks.¹⁰ However, an MRI with gadolinium contrast can offer high diagnostic yield in cases such as the one presented here in which a diagnosis remains elusive. Moreover, the use of linear gadolinium-based contrast agents such as gadoversetamide, as in this case, has been reported to be associated with higher incidence of NSF.⁵ Since this case, the West Los Angeles VAMC has switched to gadobutrol contrast for its MRI protocol, which has been purported to be a lower risk agent compared with that of linear gadolinium-based contrast agents (although several cases of NSF have been reported with gadobutrol in the literature).¹¹

Providers weighing the decision to administer gadolinium contrast to patients with ESRD should discuss the risks and benefits thoroughly, especially in patients with preexisting inflammatory conditions. In addition, although it has not been shown to effectively reduce the risk of NSF after administration of gadolinium, hemodialysis is recommended 2 hours after contrast administration for individuals at risk (the study patient received hemodialysis approximately 18 hours after).¹² Given the lack of effective treatment options for NSF, prevention is key. A deeper understanding of the pathophysiology of NSF and identification of its risk factors is paramount to the prevention of this devastating disease.

First described in 2000 in a case series of 15 patients, nephrogenic systemic fibrosis (NSF) is a rare scleroderma-like fibrosing skin condition associated with gadolinium exposure in end stage renal disease (ESRD).¹ Patients with advanced chronic kidney disease (CKD) or ESRD are at the highest risk for this condition when exposed to gadolinium-based contrast dyes.

Nephrogenic systemic fibrosis is a devastating and rapidly progressive condition, making its prevention in at-risk populations of utmost importance. In this article, the authors describe a case of a patient who developed NSF in the setting of gadolinium exposure and multiple inflammatory dermatologic conditions. This case illustrates the possible role of a pro-inflammatory state in predisposing to NSF, which may help further elucidate its mechanism of action.

Case Presentation

A 61-year-old Hispanic male with a history of IV heroin use with ESRD secondary to membranous glomerulonephritis on hemodialysis and chronic hepatitis C infection presented to the West Los Angeles VAMC with fevers and night sweats that had persisted for 2 weeks. His physical examination was notable for diffuse tender palpable purpura and petechiae (including his palms and soles), altered mental status, and diffuse myoclonic jerks, which necessitated endotracheal intubation and mechanical ventilation for airway protection. Blood cultures were positive for methicillin-sensitive Staphylococcus aureus (MSSA). Laboratory results were notable for an elevated sedimentation rate of 53 mm/h (0-10 mm/h), C-reactive protein of 19.8 mg/L (< 0.744 mg/dL), and albumin of 1.2 g/dL (3.2-4.8 g/dL). An extensive rheumatologic workup was unrevealing, and a lumbar puncture was unremarkable. A biopsy of his skin lesions was consistent with leukocytoclastic vasculitis.

The patient’s prior hemodialysis access, a tunneled dialysis catheter in the right subclavian vein, was removed given concern for line infection and replaced with an internal jugular temporary hemodialysis line. Given his altered mental status and myoclonic jerks, the decision was made to pursue a magnetic resonance imaging (MRI) scan of the brain and spine with gadolinium contrast to evaluate for cerebral vasculitis and/or septic emboli to the brain.

The patient received 15 mL of gadoversetamide contrast in accordance with hospital imaging protocol. The MRI revealed only chronic ischemic changes. The patient underwent hemodialysis about 18 hours later. The patient was treated with a 6-week course of IV penicillin G. His altered mental status and myoclonic jerks resolved without intervention, and he was then discharged to an acute rehabilitation unit.

Eight weeks after his initial presentation the patient developed a purulent wound on his right forearm (Figure 1) 

and was readmitted for workup. A biopsy of this wound was consistent with pyoderma gangrenosum, and he was started on high-dose steroids. He then developed thickening and induration of his bilateral forearm skin with the characteristic peau d’orange appearance of NSF. He developed contractures of his upper and lower extremities over several days, which caused him to become wheelchair-bound. Nephrogenic systemic fibrosis was confirmed by a skin biopsy that showed characteristic diffuse dermal fibrosis (Figures 2 and 3).

The patient was discharged to continue physical and occupational therapy to preserve his functional mobility, as no other treatment options were available. 

At the 3-month dermatology clinic follow-up appointment, the patient continued to have significant contractures of his upper extremities and remained dependent on his family for multiple activities of daily living.

Discussion

Nephrogenic systemic fibrosis is a poorly understood inflammatory condition that produces diffuse fibrosis of the skin. Typically, the disease begins with progressive skin induration of the extremities. Systemic involvement may occur, leading to fibrosis of skeletal muscle, fascia, and multiple organs. Flexion contractures may develop that limit physical function. Fibrosis can become apparent within days to months after exposure to gadolinium contrast.

Beyond renal insufficiency, it is unclear what other risk factors predispose patients to developing this condition. Only a minority of patients with CKD stages 1 through 4 will develop NSF on exposure to gadolinium contrast. However, the incidence of NSF among patients with CKD stage 5 who are exposed to gadolinium has been estimated to be about 13.4% in a prospective study involving 18 patients.²

In a 2015 meta-analysis by Zhang and colleagues, the only clear risk factor identified for the development of NSF, aside from gadolinium exposure, was severe renal insufficiency with a glomerular filtration rate of < 30 mL/min/1.75m².³ Due to the limited number of patients identified with this disease, it is difficult to identify other risk factors associated with the development of NSF. Based on in vitro studies, it has been postulated that a pro-inflammatory state predisposes patients to develop NSF.^4,5 The proposed mechanism for NSF involves extravasation of gadolinium in the setting of vascular endothelial permeability.^5,6 Gadolinium then interacts with tissue macrophages, which induce the release of inflammatory cytokines and the secretion of smooth muscle actin by dermal fibroblasts.^6,7

Treatment of NSF has been largely unsuccessful. Multiple modalities of treatment that included topical and oral steroids, immunosuppression, plasmapheresis, and ultraviolent therapy have been attempted, none of which have been proven to consistently limit progression of the disease.⁸ The most effective intervention is early physical therapy to preserve functionality and prevent contracture formation. For patients who are eligible, early renal transplantation may offer the best chance of improved mobility. In a case series review by Cuffy and colleagues, 5 of 6 patients who underwent renal transplantation after the development of NSF experienced softening of the involved skin, and 2 patients had improved mobility of joints.⁹

 

Conclusion

The case presented here illustrates a possible association between a pro-inflammatory state and the development of NSF. This patient had multiple inflammatory conditions, including MSSA bacteremia, leukocytoclastic vasculitis, and pyoderma gangrenosum (the latter 2 conditions were thought to be associated with his underlying chronic hepatitis C infection), which the authors believe predisposed him to endothelial permeability and risk for developing NSF. The risk of developing NSF in at-risk patients with each episode of gadolinium exposure is estimated around 2.4%, or an incidence of 4.3 cases per 1,000 patient-years, leading the American College of Radiologists to recommend against the administration of gadolinium-based contrast except in cases in which benefits clearly outweigh risks.¹⁰ However, an MRI with gadolinium contrast can offer high diagnostic yield in cases such as the one presented here in which a diagnosis remains elusive. Moreover, the use of linear gadolinium-based contrast agents such as gadoversetamide, as in this case, has been reported to be associated with higher incidence of NSF.⁵ Since this case, the West Los Angeles VAMC has switched to gadobutrol contrast for its MRI protocol, which has been purported to be a lower risk agent compared with that of linear gadolinium-based contrast agents (although several cases of NSF have been reported with gadobutrol in the literature).¹¹

Providers weighing the decision to administer gadolinium contrast to patients with ESRD should discuss the risks and benefits thoroughly, especially in patients with preexisting inflammatory conditions. In addition, although it has not been shown to effectively reduce the risk of NSF after administration of gadolinium, hemodialysis is recommended 2 hours after contrast administration for individuals at risk (the study patient received hemodialysis approximately 18 hours after).¹² Given the lack of effective treatment options for NSF, prevention is key. A deeper understanding of the pathophysiology of NSF and identification of its risk factors is paramount to the prevention of this devastating disease.

First described in 2000 in a case series of 15 patients, nephrogenic systemic fibrosis (NSF) is a rare scleroderma-like fibrosing skin condition associated with gadolinium exposure in end stage renal disease (ESRD).¹ Patients with advanced chronic kidney disease (CKD) or ESRD are at the highest risk for this condition when exposed to gadolinium-based contrast dyes.

Nephrogenic systemic fibrosis is a devastating and rapidly progressive condition, making its prevention in at-risk populations of utmost importance. In this article, the authors describe a case of a patient who developed NSF in the setting of gadolinium exposure and multiple inflammatory dermatologic conditions. This case illustrates the possible role of a pro-inflammatory state in predisposing to NSF, which may help further elucidate its mechanism of action.

Case Presentation

A 61-year-old Hispanic male with a history of IV heroin use with ESRD secondary to membranous glomerulonephritis on hemodialysis and chronic hepatitis C infection presented to the West Los Angeles VAMC with fevers and night sweats that had persisted for 2 weeks. His physical examination was notable for diffuse tender palpable purpura and petechiae (including his palms and soles), altered mental status, and diffuse myoclonic jerks, which necessitated endotracheal intubation and mechanical ventilation for airway protection. Blood cultures were positive for methicillin-sensitive Staphylococcus aureus (MSSA). Laboratory results were notable for an elevated sedimentation rate of 53 mm/h (0-10 mm/h), C-reactive protein of 19.8 mg/L (< 0.744 mg/dL), and albumin of 1.2 g/dL (3.2-4.8 g/dL). An extensive rheumatologic workup was unrevealing, and a lumbar puncture was unremarkable. A biopsy of his skin lesions was consistent with leukocytoclastic vasculitis.

The patient’s prior hemodialysis access, a tunneled dialysis catheter in the right subclavian vein, was removed given concern for line infection and replaced with an internal jugular temporary hemodialysis line. Given his altered mental status and myoclonic jerks, the decision was made to pursue a magnetic resonance imaging (MRI) scan of the brain and spine with gadolinium contrast to evaluate for cerebral vasculitis and/or septic emboli to the brain.

The patient received 15 mL of gadoversetamide contrast in accordance with hospital imaging protocol. The MRI revealed only chronic ischemic changes. The patient underwent hemodialysis about 18 hours later. The patient was treated with a 6-week course of IV penicillin G. His altered mental status and myoclonic jerks resolved without intervention, and he was then discharged to an acute rehabilitation unit.

Eight weeks after his initial presentation the patient developed a purulent wound on his right forearm (Figure 1) 

and was readmitted for workup. A biopsy of this wound was consistent with pyoderma gangrenosum, and he was started on high-dose steroids. He then developed thickening and induration of his bilateral forearm skin with the characteristic peau d’orange appearance of NSF. He developed contractures of his upper and lower extremities over several days, which caused him to become wheelchair-bound. Nephrogenic systemic fibrosis was confirmed by a skin biopsy that showed characteristic diffuse dermal fibrosis (Figures 2 and 3).

The patient was discharged to continue physical and occupational therapy to preserve his functional mobility, as no other treatment options were available. 

At the 3-month dermatology clinic follow-up appointment, the patient continued to have significant contractures of his upper extremities and remained dependent on his family for multiple activities of daily living.

Discussion

Nephrogenic systemic fibrosis is a poorly understood inflammatory condition that produces diffuse fibrosis of the skin. Typically, the disease begins with progressive skin induration of the extremities. Systemic involvement may occur, leading to fibrosis of skeletal muscle, fascia, and multiple organs. Flexion contractures may develop that limit physical function. Fibrosis can become apparent within days to months after exposure to gadolinium contrast.

Beyond renal insufficiency, it is unclear what other risk factors predispose patients to developing this condition. Only a minority of patients with CKD stages 1 through 4 will develop NSF on exposure to gadolinium contrast. However, the incidence of NSF among patients with CKD stage 5 who are exposed to gadolinium has been estimated to be about 13.4% in a prospective study involving 18 patients.²

In a 2015 meta-analysis by Zhang and colleagues, the only clear risk factor identified for the development of NSF, aside from gadolinium exposure, was severe renal insufficiency with a glomerular filtration rate of < 30 mL/min/1.75m².³ Due to the limited number of patients identified with this disease, it is difficult to identify other risk factors associated with the development of NSF. Based on in vitro studies, it has been postulated that a pro-inflammatory state predisposes patients to develop NSF.^4,5 The proposed mechanism for NSF involves extravasation of gadolinium in the setting of vascular endothelial permeability.^5,6 Gadolinium then interacts with tissue macrophages, which induce the release of inflammatory cytokines and the secretion of smooth muscle actin by dermal fibroblasts.^6,7

Treatment of NSF has been largely unsuccessful. Multiple modalities of treatment that included topical and oral steroids, immunosuppression, plasmapheresis, and ultraviolent therapy have been attempted, none of which have been proven to consistently limit progression of the disease.⁸ The most effective intervention is early physical therapy to preserve functionality and prevent contracture formation. For patients who are eligible, early renal transplantation may offer the best chance of improved mobility. In a case series review by Cuffy and colleagues, 5 of 6 patients who underwent renal transplantation after the development of NSF experienced softening of the involved skin, and 2 patients had improved mobility of joints.⁹

 

Conclusion

The case presented here illustrates a possible association between a pro-inflammatory state and the development of NSF. This patient had multiple inflammatory conditions, including MSSA bacteremia, leukocytoclastic vasculitis, and pyoderma gangrenosum (the latter 2 conditions were thought to be associated with his underlying chronic hepatitis C infection), which the authors believe predisposed him to endothelial permeability and risk for developing NSF. The risk of developing NSF in at-risk patients with each episode of gadolinium exposure is estimated around 2.4%, or an incidence of 4.3 cases per 1,000 patient-years, leading the American College of Radiologists to recommend against the administration of gadolinium-based contrast except in cases in which benefits clearly outweigh risks.¹⁰ However, an MRI with gadolinium contrast can offer high diagnostic yield in cases such as the one presented here in which a diagnosis remains elusive. Moreover, the use of linear gadolinium-based contrast agents such as gadoversetamide, as in this case, has been reported to be associated with higher incidence of NSF.⁵ Since this case, the West Los Angeles VAMC has switched to gadobutrol contrast for its MRI protocol, which has been purported to be a lower risk agent compared with that of linear gadolinium-based contrast agents (although several cases of NSF have been reported with gadobutrol in the literature).¹¹

Providers weighing the decision to administer gadolinium contrast to patients with ESRD should discuss the risks and benefits thoroughly, especially in patients with preexisting inflammatory conditions. In addition, although it has not been shown to effectively reduce the risk of NSF after administration of gadolinium, hemodialysis is recommended 2 hours after contrast administration for individuals at risk (the study patient received hemodialysis approximately 18 hours after).¹² Given the lack of effective treatment options for NSF, prevention is key. A deeper understanding of the pathophysiology of NSF and identification of its risk factors is paramount to the prevention of this devastating disease.