Critical Limb Ischemia in Covid-19 patients: Early diagnosis can salvage limb and life - Rising Kashmir

Presentations of COVID-19 have ranged from asymptomatic/mild symptoms to severe illness. Common symptoms include sore throat, fever, cough, and shortness of breath.  Other symptoms include fever with chills, difficulty breathing, fatigue, muscle or body aches, headache, loss of taste or smell, congestion or runny nose, nausea or vomiting, diarrhea, neurologic ( headache, altered sensorium) and sudden onset of acute pain in lower limbs.

However, my focus will be on acute onset of lower limb pain or in medical jargon Acute Lower Limb Ischemia (ALLI).

Although ALLI is a rare complication of COVID-19, there has been an increasing number of reports of peripheral arterial thrombosis in COVID-19 patients. Thrombotic complications are emerging as an important issue in patients with COVID-19.

Coagulation defects have been previously described with respiratory viruses including severe acute respiratory syndrome coronavirus 1 (SARS CoV-1), Middle East respiratory syndrome coronavirus [MERS-CoV], and severe acute respiratory virus syndrome coronavirus 2 [SARS-CoV-2.

Findings suggest that endothelial dysfunction, inflammation, cytokine release, hypercoagulability, and hypoxia contribute to thrombosis. Thrombotic complications in patients with coronavirus disease 2019 (COVID-19) present in a variety of ways, most commonly with venous thromboembolism, but also with ischemic complications related to thrombosis of extremity, cerebral, coronary, and visceral arteries.

Early recognition of acute limb ischemia (ALI), which is a sudden decrease in the perfusion to an extremity, and intervention, when possible, can help reduce mortality in these very ill patients and maximize the chance for limb salvage.

Acute lower limb ischemia (ALLI ) is a sudden decrease in limb perfusion that threatens limb viability and represents a major vascular emergency.  It results from arterial thrombotic embolus or situ thrombosis. The most common etiology of ALLI is an arterial embolism, the majority of the emboli originating in the heart. It is one of the   common vascular surgery emergencies with significant rates of mortality and limb loss.

INCIDENCE:

The data available on the incidence and characteristics of arterial thromboembolic complications in patients with COVID-19 come from various case series. The incidence of ALI associated with patients with COVID-19 who require hospitalization ranges from 3 to 15 percent. This corresponds to between 600 and 3000 ALI cases in the United States based on an estimated 20,000 patients presently requiring intensive care  a prevalence of 4 to 21 per 100,000 hospitalized patients with COVID-19 (COVID-19 hospitalization prevalence of 700 per 100,000 population in the United States), an intensive care unit (ICU) rate of 20 percent of hospitalized patients  and an ALI incidence of 3 to 15 percent (all of whom are presumably ICU patients).however no Indian data is available as of now on the incidence and characteristics.

Etiology and anatomic distribution

Coronavirus is a single-stranded, enveloped RNA virus with a helical capsid. It was first considered to cause solely respiratory dysfunction; however, various clinical presentations have shown that COVID-19 is a systemic disease, not restricted to the lungs.  Patients may suffer a number of other problems, such as renal failure, cardiac arrhythmia, myocarditis and coagulative disorders. Thrombotic complications secondary to hypercoagulable state have been reported in which pulmonary embolism (PE) was the commonest reported event. Although arterial thrombosis involving upper and lower extremity is being noted among COVID-19 patients, some studies demonstrated that arterial thrombosis accounts for about 4% of thromboembolic complications due to COVID-19 infection which is a significant number. Any arterial segment can be involved in this condition, there have been reports of arterial thrombosis of brachial artery, radial artery, aorta, iliac and femoral arteries, superior mesenteric artery and even prosthetic vascular grafts as well. The pathophysiology behind this hypercoagulable state is multifactorial.

First, COVID-19 directly attacks vascular endothelial cells causing endothelial damage and activating the coagulation cascade which leads to vessels thrombosis in peripheral arteries and the aorta, and causes major vascular events such as acute arterial ischemia.

Second, the association of COVID-19 with increased levels of pro-inflammatory cytokines (IL-2, IL-6, IL-7, G-CSF, TNF, IP-10, MCP1, MIP1-α, etc.) in patients with a severe disease, which leads to cytokine release syndrome (CRS).Third, the immobility and hypoxia of critically ill patients.

 In patients with COVID-19, ALI is predominantly due to large or medium artery thrombosis and embolism, although other etiologies can also occur. As with ALI in the general population, the lower extremity is affected more commonly than the upper extremity. In the largest case series, with ALI, the distribution of ischemic events included :

●Lower extremity â€" 71 percent

●Upper extremity â€" 14 percent

●Cerebral ischemia â€" 10 percent

●Bowel ischemia â€" 4 percent

●Multiple locations occurred â€" 12 percent

●Concomitant deep vein thrombosis â€" 16 percent

 

Critical Limb Ischemia in Covid-19 patients

Early diagnosis can salvage limb and life

Presentations of COVID-19 have ranged from asymptomatic/mild symptoms to severe illness. Common symptoms include sore throat, fever, cough, and shortness of breath.  Other symptoms include fever with chills, difficulty breathing, fatigue, muscle or body aches, headache, loss of taste or smell, congestion or runny nose, nausea or vomiting, diarrhea, neurologic ( headache, altered sensorium) and sudden onset of acute pain in lower limbs.

However, my focus will be on acute onset of lower limb pain or in medical jargon Acute Lower Limb Ischemia (ALLI).

Although ALLI is a rare complication of COVID-19, there has been an increasing number of reports of peripheral arterial thrombosis in COVID-19 patients. Thrombotic complications are emerging as an important issue in patients with COVID-19.

Coagulation defects have been previously described with respiratory viruses including severe acute respiratory syndrome coronavirus 1 (SARS CoV-1), Middle East respiratory syndrome coronavirus [MERS-CoV], and severe acute respiratory virus syndrome coronavirus 2 [SARS-CoV-2.

Findings suggest that endothelial dysfunction, inflammation, cytokine release, hypercoagulability, and hypoxia contribute to thrombosis. Thrombotic complications in patients with coronavirus disease 2019 (COVID-19) present in a variety of ways, most commonly with venous thromboembolism, but also with ischemic complications related to thrombosis of extremity, cerebral, coronary, and visceral arteries.

Early recognition of acute limb ischemia (ALI), which is a sudden decrease in the perfusion to an extremity, and intervention, when possible, can help reduce mortality in these very ill patients and maximize the chance for limb salvage.

Acute lower limb ischemia (ALLI ) is a sudden decrease in limb perfusion that threatens limb viability and represents a major vascular emergency.  It results from arterial thrombotic embolus or situ thrombosis. The most common etiology of ALLI is an arterial embolism, the majority of the emboli originating in the heart. It is one of the   common vascular surgery emergencies with significant rates of mortality and limb loss.

INCIDENCE:

The data available on the incidence and characteristics of arterial thromboembolic complications in patients with COVID-19 come from various case series. The incidence of ALI associated with patients with COVID-19 who require hospitalization ranges from 3 to 15 percent. This corresponds to between 600 and 3000 ALI cases in the United States based on an estimated 20,000 patients presently requiring intensive care  a prevalence of 4 to 21 per 100,000 hospitalized patients with COVID-19 (COVID-19 hospitalization prevalence of 700 per 100,000 population in the United States), an intensive care unit (ICU) rate of 20 percent of hospitalized patients  and an ALI incidence of 3 to 15 percent (all of whom are presumably ICU patients).however no Indian data is available as of now on the incidence and characteristics.

Etiology and anatomic distribution

Coronavirus is a single-stranded, enveloped RNA virus with a helical capsid. It was first considered to cause solely respiratory dysfunction; however, various clinical presentations have shown that COVID-19 is a systemic disease, not restricted to the lungs.  Patients may suffer a number of other problems, such as renal failure, cardiac arrhythmia, myocarditis and coagulative disorders. Thrombotic complications secondary to hypercoagulable state have been reported in which pulmonary embolism (PE) was the commonest reported event. Although arterial thrombosis involving upper and lower extremity is being noted among COVID-19 patients, some studies demonstrated that arterial thrombosis accounts for about 4% of thromboembolic complications due to COVID-19 infection which is a significant number. Any arterial segment can be involved in this condition, there have been reports of arterial thrombosis of brachial artery, radial artery, aorta, iliac and femoral arteries, superior mesenteric artery and even prosthetic vascular grafts as well. The pathophysiology behind this hypercoagulable state is multifactorial.

First, COVID-19 directly attacks vascular endothelial cells causing endothelial damage and activating the coagulation cascade which leads to vessels thrombosis in peripheral arteries and the aorta, and causes major vascular events such as acute arterial ischemia.

Second, the association of COVID-19 with increased levels of pro-inflammatory cytokines (IL-2, IL-6, IL-7, G-CSF, TNF, IP-10, MCP1, MIP1-α, etc.) in patients with a severe disease, which leads to cytokine release syndrome (CRS).Third, the immobility and hypoxia of critically ill patients.

 In patients with COVID-19, ALI is predominantly due to large or medium artery thrombosis and embolism, although other etiologies can also occur. As with ALI in the general population, the lower extremity is affected more commonly than the upper extremity. In the largest case series, with ALI, the distribution of ischemic events included :

●Lower extremity â€" 71 percent

●Upper extremity â€" 14 percent

●Cerebral ischemia â€" 10 percent

●Bowel ischemia â€" 4 percent

●Multiple locations occurred â€" 12 percent

●Concomitant deep vein thrombosis â€" 16 percent

 

Clinical presentations and diagnosis:  

Arterial occlusion results in a sudden cessation of blood supply and nutrients to the tissues in the distribution of the vessel, including skin, muscle, and nerves. The clinical presentation of acute arterial occlusion depends upon the time course of vessel occlusion; the location of the affected vessels, ranging from proximal large vessel occlusion resulting in ischemia of the entire extremity to distal small vessel occlusion resulting in digital ischemia; whether there is underlying vascular disease; and the ability to recruit collateral channels to provide flow around the occlusion. Symptoms can develop over a period of hours to days and can range from new or worsening claudication to relatively sudden paralysis of the affected limb

A careful examination of all extremities is necessary to detect signs of ischemia. The level of arterial obstruction is usually one joint above the line of demarcation between the normal and ischemic tissue.

The neurologic examination should assess sensation and muscle strength. The quality and character of the peripheral pulses in the affected extremity, as well as the contralateral extremity, are evaluated and compared. The vascular examination should include palpation of all pulses, including the femoral, popliteal, dorsalis pedis, and posterior tibial pulses as well as the upper extremity pulses (ie, subclavian, axillary, brachial, radial, and ulnar). Since the quality of the pulse examination can vary, a handheld Doppler should be used to confirm the presence of distal pulses (eg, dorsalis pedis, posterior tibial Doppler signals). The operator should listen for arterial and venous signals.

If Doppler signals are present, the ankle-brachial index (ABI) should be obtained. In general, the absence of any distal Doppler signals (arterial and venous) indicates severe ischemia. For the  extremity, although the ABI may vary significantly depending upon the location of the thrombus or embolus, a value 0>

The classic presentation of limb ischemia is known as the "six Ps," pallor, pain, paresthesia, paralysis, pulselessness, and poikilothermia. These clinical manifestations can occur anywhere distal to the occlusion. Most patients initially present with pain, pallor, pulselessness, and poikilothermia. Pain is often localized and less severe when the limb is in the dependent position. As the ischemia prolongs, paresthesia replaces pain, and the final stages of injury cause paralysis. Patients with embolic occlusion tend to have an abrupt onset with more severe symptoms, as collateralization of the vasculature has not occurred at this point. It is important to realize that symptoms can develop over the course of hours to days and present as new or recurring.

 A diagnosis of acute extremity ischemia can generally be made based upon the history and physical examination, including assessment of the ankle-brachial index bilaterally. The suspected cause and severity of ischemia determines whether or not to proceed with additional diagnostic testing and keep in mind while examining that COVID-19 can have dermatologic changes   that have been associated with COVID-19 related to alteration in coagulation COVID-19 has been associated with a variety of dermatologic manifestations, including a viral exanthem, livedo reticularis, urticaria, petechial rashes, and acral pernio-like lesions . The last of these are patches of erythematous-to-violaceous skin, which can affect the feet and toes  hands/fingers, or other locations. The lesions may correspond to focal areas of vascular occlusion. The mechanism is unknown but it does not appear to be related to macrovascular occlusive disease or embolism. Microscopic intravascular thrombi have been seen on biopsy of lesions in critically ill patients.

Some have speculated that the dermatologic lesions may be a clinical sign of systemic hypercoagulability. However, acral lesions have also been reported in asymptomatic individuals and those with a mild case of COVID-19.

Vascular imaging

The type of vascular imaging chosen weighs the availability of a specific imaging modality and the time required to perform and interpret the study against the urgency and possible methods of revascularization (eg, endovascular, open surgery) . Patients with viable or marginally threatened limbs are usually candidates for urgent vascular imaging (typically computed tomographic [CT] angiography, or catheter-based arteriography) to evaluate arterial anatomy and to potentially institute thrombolytic therapy. However, patients with an immediately threatened extremity should preferentially undergo further evaluation and treatment in a surgical suite

 

While ALI is a complication of hospitalized patients with severe COVID-19, it is also being recognized that it can occur in patients with mild symptoms of COVID-19, and moreover that ALI can be the initial presenting symptom of COVID-19 even in the absence of respiratory symptoms. Infected patients with minimal or no symptoms of COVID-19 can develop a prothrombotic state, and several reports have described patients complaining predominantly of acute extremity pain that was associated with mild respiratory symptoms or other symptoms associated with COVID-19, but in some cases ALI has been the sole clinical manifestation of COVID-19 . ALI has also been described following recovery from a mild infection.

Treatment:

Cases of limb-threatening ischemia require emergent vascular surgery consultation. The surgical approach is directed at the reperfusion of the affected extremity. This can be accomplished by the surgical bypass, endarterectomy, or embolectomy. Results are variable and will ultimately depend on the duration of the ischemia and the extent of occlusion. Patients presenting with profound paralysis and absent pain with inaudible arterial and venous pulses are considered to have irreversible damage and will require amputation. While the patient waits for surgical treatment, initial therapy should include fluid resuscitation, pain control, and administration of unfractionated heparin to minimize thrombus propagation. The general goal of anticoagulation is to achieve an increase in partial thromboplastin by a factor of 2.0 to 2.5 above baseline. Management after revascularization requires close and frequent observation. Prolonged ischemia of greater than 4 hours increases the risk of compartment syndrome and must be monitored with hourly neurovascular checks.

So, early recognition of acute limb ischemia (ALI), and intervention is the key which will  help in reducing  mortality in these very ill patients and maximize the chance for limb salvage.

Dr Farooq Ahmed Ganie

Assistant Professor Cardiovascular Thoracic Surgery SKIMS Srinagar

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