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Venous Insufficiency

Updated : January 19, 2024





Background

Chronic venous insufficiency (CVI) is a term used to describe discomfort brought on by venous hypertension as well as lower extremities edema and skin trophic alterations. In many people, CVI is a common illness. CVI -related disability results in a lower quality of life and reduced productivity at work. Ineffective valves are the main culprit in most situations. Around $500 million is spent on the care of the 150,000 new individuals with CVI who are identified each year.

If CVI is not treated, it frequently progresses and causes venous ulcers and post-phlebitic syndrome. The patient may also have pain, swelling in the legs, pruritus, & skin discoloration in addition to cosmetic loss. Compression stocking use is the cornerstone of treatment; however, compliance rates are low. Surgery is frequently chosen by patients; however, the results can vary.

For the purposes of evaluating & treating CVI, the CEAP classification—which stands for clinical, etiology, anatomy, & pathophysiology—has been devised. The technology has demonstrated the ability to forecast the patient’s symptom severity & quality of life.

Epidemiology

According to estimates, between six and seven million Americans have a severe venous illness and satisfy the diagnostic requirements for CVI. According to research findings, between 1% and 17% of males & 1% – 40% of women in the general population may have CVI. Despite this considerable variation, non-western nations seem to have a lower incidence overall.

Around 1% – 2.7% of people with CVI will get a venous stasis ulcer. Poor outcome is associated with ulcer formation; 40 percent of patients experience recurrence after receiving standard care. About 2% of all healthcare spending in the US goes toward treating CVI.

Anatomy

Pathophysiology

The pathophysiology of chronic venous insufficiency is either brought on by reflux (backward flow) or by blockage of venous blood circulation. The persistent valvular dysfunction of superficial veins, deep veins, or the perforating veins that join them can result in CVI. Venous hypertension in the lower extremities occurs in each and every occurrence. Normal valve congruence is typically prevented by weak or irregularly shaped valves, enlarged venous diameter, or superficial incompetence. The leaky valve is typically seen close to where the larger saphenous vein terminates into the common femoral vein.

In addition to being congenital in some circumstances, valve malfunction can also be brought on by hormone imbalances, prolonged standing, thrombosis, or trauma. The most common cause of deep vein dysfunction is a prior DVT, which causes adhesion and valve scarring, inflammation, & luminal constriction. Failure of the valve system in a perforating vein enables increased pressure to enter the superficial venous system. The superficial veins’ valve cusps cannot properly close due to the following dilatation. The illness will typically also be present in the patients’ superficial veins.

The valve function, outflow obstruction, muscle pump function, and capillary inflow are added to determine the resting venous pressure. Regardless of the reason, lower leg discomfort, edema, & venous microangiopathy may be brought on by continuously high venous hydrostatic pressure. As RBC extravasates into the surrounding skin, some patients experience hemosiderin accumulation that results in permanent skin darkening. Numerous patients with this condition will also develop lipodermatosclerosis, which is epidermal thickening brought on by subcutaneous adipose fibrosis. Ulcers may develop when the condition worsens due to disturbed microcirculation and skin thinning.

The hazards of CVI:

  • Leg injury
  • Usage of oral contraceptives
  • Sedentary lifestyle
  • Deep vein thrombosis history
  • Advanced age

Etiology

Additionally, DVT (deep venous thrombosis) can either be the secondary or primary cause of CVI. Primary chronic venous insufficiency, which is caused by inherent flaws or modifications in the biochemistry of the venous wall, is characterized by clinical manifestation without a precipitating event. According to recent studies, 30% of patients have a secondary illness, & 70percent of patients have basic CVI.

Reduced elastin concentration, enhanced extracellular matrix remodeling, & inflammatory infiltration have all been linked to primary chronic venous insufficiency in studies, which leads to a culmination that compromises the vein’s structural integrity, encouraging dilatation & valvular dysfunction. A DVT causes an inflammatory reaction that damages the vein wall, leading to subsequent CVI.

Chronic venous insufficiency fosters venous hypertension regardless of the exact reason. Female gender & May-Thurner syndrome (non-thrombotic iliac vein blockage) are the most prevalent non-modifiable potential causes. Numerous studies have also suggested that vein wall laxity may have hereditary roots. Smoking, being overweight, being pregnant, staying up too long, DVT, & venous damage are all modifiable factors.

Genetics

Prognostic Factors

The morbidity associated with CVI is extremely high. Without a remedy, the problem is progressive. Venous ulcers are frequent and extremely challenging to treat. Chronic venous ulcers are excruciatingly painful & crippling. Recurrences are frequent if venous hypertension continues, even with therapy.

Phlebitis commonly leads to deep vein thrombosis in more than 50 percent of patients, who acquire it in close to 60% of cases. Severe bleeding can also result from venous insufficiency. Despite the availability of multiple treatments, CVI surgery remains a significant problem. The patient bears a hefty share of the cost of treatment.

Clinical History

Physical Examination

Physical examination

The increasing syndromes of chronic venous stasis & chronic venous hypertension are responsible for the physical symptoms of venous insufficiency that are most frequently observed.

These indicators consist of the following:

  • Ulceration
  • Cutaneous infarction
  • Chronic cellulitis
  • Venous dermatitis
  • Hyperpigmentation
  • Edema

Acute venous blockages, such as deep venous thrombosis or superficial or deep venous reflux, can both cause swelling. Alternatively, edema might not have anything to do with the venous system at all. Pitting edema in the lower extremities is frequent in venous insufficiency patients. Lymphatic edema may indicate inherent lymphatic outflow restriction, or it may be a complication of excessive lymph production brought on by chronic venous hypertension (a so-called endolymphatic syndrome). Skin that is darkened, discolored, or stained may indicate a number of disorders, including venous stasis, arterial insufficiency, persistent infection, past injuries, or other conditions.

These areas are especially vulnerable to venous hypertension because their drainage heavily depends on the competence and patency of the entire great saphenous vein (GSV) as well as the connected perforating veins. If such discoloration is localized along the medial part of the ankle or the medial aspect of the lower leg, it is especially likely to be a sign of chronic venous stasis. Normal veins are typically not visible in the remainder of the leg, but they are usually noticeably enlarged at the foot and ankle and, rarely, in the popliteal fossa.

The regular veins may show up as a bluish subdermal reticular structure on translucent skin. Typically, a dilated vein above the ankle indicates venous disease. Venous insufficiency, either profound or superficial, may cause ulcers that do not heal. The most frequent cause of nonhealing sores on the medial ankle is persistent venous stasis. More frequently than pure venous insufficiency, skin abnormalities or ulcerations that are restricted to the lateral portion of the ankle are caused by previous trauma and arterial insufficiency.

Trendelenburg test

The Trendelenburg test, a staple of the physical examination, can assist distinguish between distal vein congestion brought on by superficial venous reflux resulting from deep venous system valve dysfunction. Elevate the patient’s leg throughout this examination until all of the clogged superficial veins disappear. Direct pressure should be used to occlude the superficial veins below the suspected location of reflux from the deep system into superficial varicosity. The GSV is typically manually blocked at the groin, immediately below the saphenofemoral junction.

Have the patient stand while the occlusion is still in place. Remove the occluding hand and tourniquet as soon as possible if the distal varicosity is empty or fills slowly. If the quick filling that occurs after the occlusion is removed is followed by the gradual filling that was seen with the occlusion, then the main high-pressure point of entry into the superficial system has been appropriately identified. Even after physical occlusion, varicosity immediately refills, which suggests that either the major entry source is still unknown or that there are many reflux pathways at play.

It is possible that the valves in the deep veins between the groin and the level at which the reflux departs the deep system are ineffective if the superficial reflux pathways are blocked despite the extremely quick refilling. The superficial system fills up quickly as a result. Further examinations’ findings that show profound venous insufficiency may substantially restrict the patient’s alternatives for treatment.

Age group

Associated comorbidity

Associated activity

Acuity of presentation

Differential Diagnoses

Differential diagnosis

Varicose veins

Stasis dermatitis

Cellulitis

Lymphedema

Laboratory Studies

Imaging Studies

Procedures

Histologic Findings

Subjective signs that are often uncomfortable early in the disease, less severe in the middle stages, and then deteriorate once more with the advancement of age are frequently reported by patients with venous insufficiency. Small telangiectasias can sometimes be symptoms. More than half of people who initially have telangiectasias with a diameter of less than 1 mm say their symptoms go away after treatment.

The following are typical signs:

  • Leg fatigue
  • Restless legs
  • Heaviness
  • Aching
  • Cramping
  • Throbbing
  • Swelling
  • Burning

Patients with truncal varices frequently also experience subjective complaints: Nearly 50% of individuals with varicosities complain of episodic symptoms, compared to 18% who report frequent or ongoing problems. Varicose veins are signs of venous hypertension, the most common cause of patient complaints about CVI, in addition to being unsightly. Exercise & prolonged standing cause venous hypertension in the lower leg’s muscles & fascial compartments, which causes the recognizable pain of CVI.

Periodic pain and other superficial venous disease symptoms may be spatially connected to hormonal imbalances that are both physiological & pharmacological. Half of all pregnant women with varicose veins report experiencing pain, & 17% report being unable to stand upright for longer than a few hours at a time due to the pain’s intensity. Nearly all patients with severe system deficiency exhibit symptoms. The most typical subjective symptoms are soreness, heaviness, and hurting in the legs.

Walking or elevating the legs can frequently reduce the discomfort brought on by venous insufficiency. The signs and symptoms of venous insufficiency are frequently made worse by warmth and made better by cold. The pain of venous insufficiency is typically lessened or prevented by compression stockings. Walking and heat make venous blockage pain worse, although elevating the legs helps. Pain from venous blockage is typically reduced by compression stockings.

Around the medial malleolus, where there are numerous big perforating veins, nonhealing ulcers are frequently observed. White blood cells may cause capillary basement membrane destruction, which can lead to leg edema. In capillary proliferation, lower extremities, fat necrosis, & skin fibrosis, & subcutaneous tissues are some of the skin alterations that are typical of lipodermatosclerosis. Hemosiderin from RBC deposits on the skin, turning it brown or reddish.

Staging

Treatment Paradigm

Depending on the degree and kind of disease, patients with CVI should get different treatments. The objectives of treatment include easing pain and swelling, regulating the skin’s look, removing uncomfortable varicose veins, and curing ulcers. Initial conservative care for the majority of patients should include exercise (which enhances the calf muscle pump), leg elevation, weight control, & compression treatment. Only patients who are compliant will benefit over the long run from conservative management. Compression stockings are the recommended treatment if the deep vein system is implicated.

Compression bandaging devices work well for treating ulcers. There is a chance of infection and cancer development (Marjolin ulcer) in chronic venous ulcerations. Patients who also have the peripheral arterial disease should employ compression treatment with caution. Prior to beginning a compression treatment, severe arterial insufficiency should be managed. Patients who get persistent ulcers despite compression therapy may eventually require surgery. It’s critical to realize that sclerosants ARE NOT utilized to treat varicose veins, but rather spider veins.

To collapse varicosity, a significant volume of solution would be needed, which would cause thrombosis, excruciating pain, and irreversible skin discoloration. Endovenous thermal ablation, stripping, or foam sclerotherapy are all effective treatments for superficial vein reflux. Valve transplantation or valve reconstruction are two possible treatments for deep vein reflux. SEPS (Sclerotherapy, endovenous thermal ablation, or subfascial endoscopic perforator surgery) are all options for treating perforator reflux.

However, it should be highlighted that when compression treatment regimens are followed, all types of venous pathology can be effectively treated. Recurrences are typical following all surgical procedures, so far as that is concerned. Additionally, if a minimally damaged saphenous vein is prematurely removed, an important conduit supply is also lost in case a subsequent bypass is required. Some facilities do valvuloplasty, however, the procedure is technically challenging and only sometimes successful.

Surgery-related complications include:

  • Scarring
  • Poor cosmesis
  • Nerve damage (sural and or saphenous nerves)
  • Damage to the vascular system
  • Infection
  • For maximum effectiveness, patients should pair any operation they choose with compression stockings.

by Stage

by Modality

Chemotherapy

Radiation Therapy

 

 

Surgical Interventions

 

 

Hormone Therapy

 

 

Immunotherapy

 

 

Hyperthermia

 

 

Photodynamic Therapy

 

 

Stem Cell Transplant

 

 

Targeted Therapy

 

 

Palliative Care

 

 

Medication

 

 

 

grape seed extract 

Indicated for Chronic Venous insufficiency:

Procyanidin extract: 150-300 mg orally daily
Tablets or Capsules: 75-300 mg orally daily 3 weeks, following 40-80 mg orally daily

OR

360 mg or720 mg orally daily



troxerutin 

Indicated for chronic venous insufficiency
The recommend dose is 600 mg to 1200 mg orally every day



 
 

Media Gallary

References

https://www.ncbi.nlm.nih.gov/books/NBK430975/

https://emedicine.medscape.com/article/1085412-clinical

Venous Insufficiency

Updated : January 19, 2024




Chronic venous insufficiency (CVI) is a term used to describe discomfort brought on by venous hypertension as well as lower extremities edema and skin trophic alterations. In many people, CVI is a common illness. CVI -related disability results in a lower quality of life and reduced productivity at work. Ineffective valves are the main culprit in most situations. Around $500 million is spent on the care of the 150,000 new individuals with CVI who are identified each year.

If CVI is not treated, it frequently progresses and causes venous ulcers and post-phlebitic syndrome. The patient may also have pain, swelling in the legs, pruritus, & skin discoloration in addition to cosmetic loss. Compression stocking use is the cornerstone of treatment; however, compliance rates are low. Surgery is frequently chosen by patients; however, the results can vary.

For the purposes of evaluating & treating CVI, the CEAP classification—which stands for clinical, etiology, anatomy, & pathophysiology—has been devised. The technology has demonstrated the ability to forecast the patient’s symptom severity & quality of life.

According to estimates, between six and seven million Americans have a severe venous illness and satisfy the diagnostic requirements for CVI. According to research findings, between 1% and 17% of males & 1% – 40% of women in the general population may have CVI. Despite this considerable variation, non-western nations seem to have a lower incidence overall.

Around 1% – 2.7% of people with CVI will get a venous stasis ulcer. Poor outcome is associated with ulcer formation; 40 percent of patients experience recurrence after receiving standard care. About 2% of all healthcare spending in the US goes toward treating CVI.

The pathophysiology of chronic venous insufficiency is either brought on by reflux (backward flow) or by blockage of venous blood circulation. The persistent valvular dysfunction of superficial veins, deep veins, or the perforating veins that join them can result in CVI. Venous hypertension in the lower extremities occurs in each and every occurrence. Normal valve congruence is typically prevented by weak or irregularly shaped valves, enlarged venous diameter, or superficial incompetence. The leaky valve is typically seen close to where the larger saphenous vein terminates into the common femoral vein.

In addition to being congenital in some circumstances, valve malfunction can also be brought on by hormone imbalances, prolonged standing, thrombosis, or trauma. The most common cause of deep vein dysfunction is a prior DVT, which causes adhesion and valve scarring, inflammation, & luminal constriction. Failure of the valve system in a perforating vein enables increased pressure to enter the superficial venous system. The superficial veins’ valve cusps cannot properly close due to the following dilatation. The illness will typically also be present in the patients’ superficial veins.

The valve function, outflow obstruction, muscle pump function, and capillary inflow are added to determine the resting venous pressure. Regardless of the reason, lower leg discomfort, edema, & venous microangiopathy may be brought on by continuously high venous hydrostatic pressure. As RBC extravasates into the surrounding skin, some patients experience hemosiderin accumulation that results in permanent skin darkening. Numerous patients with this condition will also develop lipodermatosclerosis, which is epidermal thickening brought on by subcutaneous adipose fibrosis. Ulcers may develop when the condition worsens due to disturbed microcirculation and skin thinning.

The hazards of CVI:

  • Leg injury
  • Usage of oral contraceptives
  • Sedentary lifestyle
  • Deep vein thrombosis history
  • Advanced age

Additionally, DVT (deep venous thrombosis) can either be the secondary or primary cause of CVI. Primary chronic venous insufficiency, which is caused by inherent flaws or modifications in the biochemistry of the venous wall, is characterized by clinical manifestation without a precipitating event. According to recent studies, 30% of patients have a secondary illness, & 70percent of patients have basic CVI.

Reduced elastin concentration, enhanced extracellular matrix remodeling, & inflammatory infiltration have all been linked to primary chronic venous insufficiency in studies, which leads to a culmination that compromises the vein’s structural integrity, encouraging dilatation & valvular dysfunction. A DVT causes an inflammatory reaction that damages the vein wall, leading to subsequent CVI.

Chronic venous insufficiency fosters venous hypertension regardless of the exact reason. Female gender & May-Thurner syndrome (non-thrombotic iliac vein blockage) are the most prevalent non-modifiable potential causes. Numerous studies have also suggested that vein wall laxity may have hereditary roots. Smoking, being overweight, being pregnant, staying up too long, DVT, & venous damage are all modifiable factors.

The morbidity associated with CVI is extremely high. Without a remedy, the problem is progressive. Venous ulcers are frequent and extremely challenging to treat. Chronic venous ulcers are excruciatingly painful & crippling. Recurrences are frequent if venous hypertension continues, even with therapy.

Phlebitis commonly leads to deep vein thrombosis in more than 50 percent of patients, who acquire it in close to 60% of cases. Severe bleeding can also result from venous insufficiency. Despite the availability of multiple treatments, CVI surgery remains a significant problem. The patient bears a hefty share of the cost of treatment.

Physical examination

The increasing syndromes of chronic venous stasis & chronic venous hypertension are responsible for the physical symptoms of venous insufficiency that are most frequently observed.

These indicators consist of the following:

  • Ulceration
  • Cutaneous infarction
  • Chronic cellulitis
  • Venous dermatitis
  • Hyperpigmentation
  • Edema

Acute venous blockages, such as deep venous thrombosis or superficial or deep venous reflux, can both cause swelling. Alternatively, edema might not have anything to do with the venous system at all. Pitting edema in the lower extremities is frequent in venous insufficiency patients. Lymphatic edema may indicate inherent lymphatic outflow restriction, or it may be a complication of excessive lymph production brought on by chronic venous hypertension (a so-called endolymphatic syndrome). Skin that is darkened, discolored, or stained may indicate a number of disorders, including venous stasis, arterial insufficiency, persistent infection, past injuries, or other conditions.

These areas are especially vulnerable to venous hypertension because their drainage heavily depends on the competence and patency of the entire great saphenous vein (GSV) as well as the connected perforating veins. If such discoloration is localized along the medial part of the ankle or the medial aspect of the lower leg, it is especially likely to be a sign of chronic venous stasis. Normal veins are typically not visible in the remainder of the leg, but they are usually noticeably enlarged at the foot and ankle and, rarely, in the popliteal fossa.

The regular veins may show up as a bluish subdermal reticular structure on translucent skin. Typically, a dilated vein above the ankle indicates venous disease. Venous insufficiency, either profound or superficial, may cause ulcers that do not heal. The most frequent cause of nonhealing sores on the medial ankle is persistent venous stasis. More frequently than pure venous insufficiency, skin abnormalities or ulcerations that are restricted to the lateral portion of the ankle are caused by previous trauma and arterial insufficiency.

Trendelenburg test

The Trendelenburg test, a staple of the physical examination, can assist distinguish between distal vein congestion brought on by superficial venous reflux resulting from deep venous system valve dysfunction. Elevate the patient’s leg throughout this examination until all of the clogged superficial veins disappear. Direct pressure should be used to occlude the superficial veins below the suspected location of reflux from the deep system into superficial varicosity. The GSV is typically manually blocked at the groin, immediately below the saphenofemoral junction.

Have the patient stand while the occlusion is still in place. Remove the occluding hand and tourniquet as soon as possible if the distal varicosity is empty or fills slowly. If the quick filling that occurs after the occlusion is removed is followed by the gradual filling that was seen with the occlusion, then the main high-pressure point of entry into the superficial system has been appropriately identified. Even after physical occlusion, varicosity immediately refills, which suggests that either the major entry source is still unknown or that there are many reflux pathways at play.

It is possible that the valves in the deep veins between the groin and the level at which the reflux departs the deep system are ineffective if the superficial reflux pathways are blocked despite the extremely quick refilling. The superficial system fills up quickly as a result. Further examinations’ findings that show profound venous insufficiency may substantially restrict the patient’s alternatives for treatment.

Differential diagnosis

Varicose veins

Stasis dermatitis

Cellulitis

Lymphedema

Subjective signs that are often uncomfortable early in the disease, less severe in the middle stages, and then deteriorate once more with the advancement of age are frequently reported by patients with venous insufficiency. Small telangiectasias can sometimes be symptoms. More than half of people who initially have telangiectasias with a diameter of less than 1 mm say their symptoms go away after treatment.

The following are typical signs:

  • Leg fatigue
  • Restless legs
  • Heaviness
  • Aching
  • Cramping
  • Throbbing
  • Swelling
  • Burning

Patients with truncal varices frequently also experience subjective complaints: Nearly 50% of individuals with varicosities complain of episodic symptoms, compared to 18% who report frequent or ongoing problems. Varicose veins are signs of venous hypertension, the most common cause of patient complaints about CVI, in addition to being unsightly. Exercise & prolonged standing cause venous hypertension in the lower leg’s muscles & fascial compartments, which causes the recognizable pain of CVI.

Periodic pain and other superficial venous disease symptoms may be spatially connected to hormonal imbalances that are both physiological & pharmacological. Half of all pregnant women with varicose veins report experiencing pain, & 17% report being unable to stand upright for longer than a few hours at a time due to the pain’s intensity. Nearly all patients with severe system deficiency exhibit symptoms. The most typical subjective symptoms are soreness, heaviness, and hurting in the legs.

Walking or elevating the legs can frequently reduce the discomfort brought on by venous insufficiency. The signs and symptoms of venous insufficiency are frequently made worse by warmth and made better by cold. The pain of venous insufficiency is typically lessened or prevented by compression stockings. Walking and heat make venous blockage pain worse, although elevating the legs helps. Pain from venous blockage is typically reduced by compression stockings.

Around the medial malleolus, where there are numerous big perforating veins, nonhealing ulcers are frequently observed. White blood cells may cause capillary basement membrane destruction, which can lead to leg edema. In capillary proliferation, lower extremities, fat necrosis, & skin fibrosis, & subcutaneous tissues are some of the skin alterations that are typical of lipodermatosclerosis. Hemosiderin from RBC deposits on the skin, turning it brown or reddish.

Depending on the degree and kind of disease, patients with CVI should get different treatments. The objectives of treatment include easing pain and swelling, regulating the skin’s look, removing uncomfortable varicose veins, and curing ulcers. Initial conservative care for the majority of patients should include exercise (which enhances the calf muscle pump), leg elevation, weight control, & compression treatment. Only patients who are compliant will benefit over the long run from conservative management. Compression stockings are the recommended treatment if the deep vein system is implicated.

Compression bandaging devices work well for treating ulcers. There is a chance of infection and cancer development (Marjolin ulcer) in chronic venous ulcerations. Patients who also have the peripheral arterial disease should employ compression treatment with caution. Prior to beginning a compression treatment, severe arterial insufficiency should be managed. Patients who get persistent ulcers despite compression therapy may eventually require surgery. It’s critical to realize that sclerosants ARE NOT utilized to treat varicose veins, but rather spider veins.

To collapse varicosity, a significant volume of solution would be needed, which would cause thrombosis, excruciating pain, and irreversible skin discoloration. Endovenous thermal ablation, stripping, or foam sclerotherapy are all effective treatments for superficial vein reflux. Valve transplantation or valve reconstruction are two possible treatments for deep vein reflux. SEPS (Sclerotherapy, endovenous thermal ablation, or subfascial endoscopic perforator surgery) are all options for treating perforator reflux.

However, it should be highlighted that when compression treatment regimens are followed, all types of venous pathology can be effectively treated. Recurrences are typical following all surgical procedures, so far as that is concerned. Additionally, if a minimally damaged saphenous vein is prematurely removed, an important conduit supply is also lost in case a subsequent bypass is required. Some facilities do valvuloplasty, however, the procedure is technically challenging and only sometimes successful.

Surgery-related complications include:

  • Scarring
  • Poor cosmesis
  • Nerve damage (sural and or saphenous nerves)
  • Damage to the vascular system
  • Infection
  • For maximum effectiveness, patients should pair any operation they choose with compression stockings.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

grape seed extract 

Indicated for Chronic Venous insufficiency:

Procyanidin extract: 150-300 mg orally daily
Tablets or Capsules: 75-300 mg orally daily 3 weeks, following 40-80 mg orally daily

OR

360 mg or720 mg orally daily



troxerutin 

Indicated for chronic venous insufficiency
The recommend dose is 600 mg to 1200 mg orally every day



 

 

https://www.ncbi.nlm.nih.gov/books/NBK430975/

https://emedicine.medscape.com/article/1085412-clinical