A 74-Year-Old Man with Refractory Hypotension in the Setting of COVID-19 Infection

Case Vignette

A 74-year-old man with a medical history significant for monoclonal gammopathy of unclear significance, hypertension, and prior episodes of capillary leak syndrome (CLS) presented to the emergency department with a 24-hour history of nausea and generalized weakness resulting in a mechanical fall without injury. He reported recent exposure to a family member with confirmed coronavirus disease (COVID-19) infection. On examination, the patient appeared lethargic with tachypnea, tachycardia, and hypotension (blood pressure, 67/47 mm Hg). Peripheral edema was noted, along with decreased breath sounds bilaterally.

Laboratory investigations revealed profound hemoconcentration (hematocrit, 69%) despite already receiving intravenous fluids by emergency medical services, hypoproteinemia (serum total protein, 3.4 g/dL), hypoalbuminemia (serum albumin, 1.9 g/dL), and increased creatinine concentration consistent with acute kidney injury (creatinine, 1.76 mg/dL; baseline, 0.8–0.9 mg/dL). Arterial blood gas analysis showed metabolic acidosis with incomplete respiratory compensation (pH 7.27) and hypoxemia (arterial oxygen tension, 58 mm Hg). Electrocardiography showed sinus tachycardia. The initial chest radiograph was clear, without evidence of pneumothorax (Figure 1).

Figure 1.

Evolution of chest imaging from presentation through initial stabilization. Panel 1 shows a radiograph from hospital Day 1, with clear lung fields bilaterally. Panel 2 shows a radiograph from hospital Day 4, with development of bilateral hazy opacities and pleural effusions following aggressive fluid resuscitation.

Nasopharyngeal swab polymerase chain reaction testing confirmed COVID-19 infection (likely an Omicron subvariant; BA.5, BA.2, BA.4.6, and BA.5.2 made up >97% of tested severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] samples at our institution at that time).

The patient was admitted to the intensive care unit and received intravenous fluids, high-dose intravenous hydrocortisone, and vasopressor support for hemodynamic stabilization. Despite initial aggressive supportive measures, the patient exhibited persistent hypotension.

Questions

1. What is the differential diagnosis for shock in this patient with COVID-19?

2. What are the management strategies for CLS?

Clinical Reasoning

The differential diagnosis for shock was broad: hypovolemic shock (reduced oral intake plus insensible losses with fevers and increased cardiometabolic demand), cardiogenic shock (myocardial infarction, myocarditis related to COVID-19), obstructive shock (pulmonary embolism related to COVID-19 hypercoagulability), and distributive shock including septic shock (superimposed bacterial infection or viral septic shock due to COVID-19), anaphylaxis, or CLS. There was no evidence of bleeding, no arrhythmias on monitoring, and no laboratory evidence of acute liver failure. Other conditions to consider in refractory shock include adrenal insufficiency, myxedema coma, toxic shock syndrome, systemic mastocytosis, hemophagocytic histiocytosis, and impaired diastolic filling due to hypertrophic obstructive cardiomyopathy or pericardial effusion causing tamponade.

Hemodynamic support was prioritized, with fluid resuscitation and vasopressors to ensure end-organ perfusion, along with workup for shock etiology. High-dose corticosteroid administration was continued. Assessments of volume status and cardiac function by point-of-care ultrasound argued against cardiogenic and obstructive shock. Formal echocardiography confirmed normal left ventricular ejection fraction and a normal right ventricle, without structural/valvular abnormalities or impaired diastolic filling. Blood and urine cultures were collected. The patient received empiric broad-spectrum antibiotic therapy and recommended COVID-directed treatment (remdesivir).

CLS was ultimately suspected as the cause of shock based on laboratory findings of hemoconcentration and hypoalbuminemia, preexisting history of CLS, and elimination of other potential causes. Lack of improvement in dynamic markers of fluid responsiveness, including central venous pressure, pulse-pressure variation, and point-of-care ultrasound assessments (inferior vena cava distensibility and evidence of hyperdynamic state despite fluid resuscitation), were consistent with a diagnosis of CLS and argued against hypovolemic or cardiogenic shock. Serial superior vena cava oxygen saturation measurements that remained between 60% and 70% provided further evidence against cardiogenic shock. Cultures remained negative.

Acute management for CLS included aggressive fluid resuscitation (11 L crystalloid within 24 h) that was guided by a goal to acutely reduce hematocrit to <60%. Vasopressors and empiric steroids were used for COVID-19 and organ failure. His edema was closely monitored to avoid compartment syndrome. Intravenous immunoglobulin (IVIG) was administered for immunomodulation based on case series data in CLS (1, 2).

On hospital Day 3, his hematocrit level showed a downward trend (Figure 2). By hospital Day 4, hypoxemia had developed, requiring 2 L O₂ via nasal cannula. Imaging revealed bilateral effusions and pulmonary edema (Figure 1). Although the patient was still receiving low-dose vasopressors, diuresis was initiated to combat worsening tissue edema. Vasopressors were discontinued on hospital Day 5.

Figure 2.

Hematocrit trend and fluid resuscitation during hospitalization. The patient had a hematocrit level of 69% on hospital Day 1. Additional fluid resuscitation was administered with the goal of maintaining a hematocrit level <60%. As capillary leak began to improve, the hematocrit level exhibited a downward trend and returned to baseline levels. NE = norepinephrine; IVF = intravenous fluids.

Discussion

CLS is a rare disorder characterized by episodes of increased vascular permeability leading to severe hypovolemia and end-organ dysfunction (1, 3). The finding of hemoconcentration (seen in 95 of 101 patients analyzed in a systematic review) is necessary but not specific to distinguish CLS from other causes of shock (4). Although CLS pathogenesis remains incompletely understood, various triggers have been implicated (infections, autoimmune diseases, and medications) (3). Monoclonal gammopathies have been associated with CLS (5), but our patient had been diagnosed with CLS several decades before developing monoclonal gammopathy of unclear significance.

CLS poses significant management challenges because of the lack of standardized treatment and variable treatment responses (1). Acute management involves supportive measures to mitigate fluid extravasation, maintain hemodynamic stability, and prevent end-organ dysfunction. Although evidence is limited from randomized controlled trials, various therapies have been proposed based on case reports, small case series, and expert consensus (1, 6).

Fluid resuscitation is crucial initially to restore intravascular volume and tissue perfusion. However, after adequate intravascular volume is achieved, cautious fluid administration and judicious diuretic agent use are warranted to avoid exacerbating fluid extravasation and worsening tissue edema. Targeted reduction in hematocrit with intravenous fluids has been proposed to ensure appropriate intravascular volume and avoid complications. Increasing hematocrit levels suggest worsening capillary leak, whereas declining levels correlate with resolution (4, 7). Complications include blood clots, renal failure, and overresuscitation causing compartment syndrome, rhabdomyolysis, pulmonary edema, and pleural and pericardial effusions (3, 6). Compartment syndrome requiring fasciotomy occured in this patient during a prior episode. With refractory hypotension, vasopressors are used to augment vascular tone and improve blood pressure.

Albumin replacement has been proposed to mitigate hypoalbuminemia and improve intravascular oncotic pressure (6). Efficacy remains controversial, and routine use is not universally recommended. Retrospective data suggest that prophylactic IVIG administration may reduce recurrent CLS episode frequency and severity (1, 2). Further research is needed to elucidate optimal IVIG dosing and timing.

Given the inflammatory nature of CLS, immunomodulatory agents like corticosteroids, interleukin-6 inhibitors, and tumor necrosis factor-α antagonists have been investigated as potential therapies (6, 8, 9). Although some patients experienced improvement with corticosteroids, others experienced no benefit or even exacerbation of symptoms (10). Our patient used oral dexamethasone as needed with onset of CLS symptoms. Similarly, interleukin-6 inhibitors such as tocilizumab have shown promise in cases of COVID-19–associated viral septic shock with cytokine release syndrome, which has overlapping features with CLS. Further studies are needed to assess safety and efficacy in broader CLS populations.

In chronic or recurrent CLS, maintenance therapy with immunosuppressive agents has been proposed to prevent or reduce the frequency of acute exacerbations. However, immunosuppression carries the risks of infection and adverse effects. This patient was undergoing maintenance therapy with chronic terbutaline and theophylline because increased cyclic adenosine monophosphate (cAMP) levels are thought to inhibit capillary leak (5, 11).

In summary, the acute management of CLS remains largely supportive, focusing on fluid resuscitation, hemodynamic support, and prevention of end-organ dysfunction. Although several therapeutic modalities have been proposed (albumin replacement, immunomodulatory agents, long-term immunosuppression, and agents that increase cAMP), efficacy remains uncertain. Additional research is needed to establish optimal treatment strategies and determine if similar mechanisms occur in septic shock associated with viral syndromes.

In the context of the COVID-19 pandemic, growing evidence suggests potential associations between COVID-19 infections and acute exacerbations of CLS (12). Viral-induced cytokine release and endothelial dysfunction are hypothesized to contribute to the pathophysiology of CLS exacerbations. CLS exacerbations following administration of several types of COVID-19 vaccines have also been described. Our case underscores the importance of COVID-19 infection as a potential trigger for acute exacerbations in individuals with underlying CLS. Therapies that have a role in treatment of COVID-19 and CLS, such as steroids and tocilizumab, may be of particular importance in those patients.

Answers

1. What is the differential diagnosis for shock in patients with COVID-19?

   The differential diagnosis for shock in patients with COVID-19 includes cardiogenic shock related to COVID-19 cardiac complications and obstructive shock related to COVID-19 complications such as pulmonary embolism, hypovolemic shock, and distributive shock from a dysregulated host response to infection, anaphylaxis, or CLS.

2. What are the management strategies for CLS?

   Acute CLS management relies on hemodynamic support with adequate yet judicious fluid resuscitation, vasopressors to support end-organ perfusion, mitigation of intravascular fluid losses with IVIG, and immunomodulation; maintenance immunosuppression and agents that increase cAMP may play a role in chronic or recurrent cases of CLS.

Follow-up

The patient’s acute kidney injury improved, and he remained in hemodynamically stable condition during several additional days of diuresis before hospital discharge. He has continued to have episodes of CLS exacerbations (albeit not as severe as this admission with COVID-19 infection), for which he has now started intermittent IVIG infusions.

Insights

• Hemoconcentration with hypoalbuminemia may be a helpful diagnostic clue for CLS to distinguish it from other causes of shock.

• Clinicians should be vigilant for potential triggers of acute exacerbations in patients with underlying CLS, particularly with ongoing COVID-19 infections.

• Early recognition and aggressive management are paramount to improving outcomes in critically ill patients with CLS.

• Further research is needed to elucidate the underlying mechanisms linking COVID-19 infections with shock and CLS exacerbations.