**5. Muscle Pump Function and dysfunction**

Deep veins insufficiency has been suggested to be the consequence of deep veins thrombosis in the majority of cases, i.e., from secondary etiology [59]. However, primary deep venous incompetence is also common (8-22% of the cases [12]) but is usually compensated by a strong muscle [12, 57]. It seems that outflow obstruction and reflux caused by valve damage may cause deep vein thrombosis and these two alterations together increase the probability of the

Deep venous thrombosis may also occur because of an intrinsic venous process, such as a previous deep venous thrombosis episode with inadequate recanalization or venous stenosis, or because of extrinsic compression, as in May-Thurner syndrome [66]. Also, it can be caused by venous agenesis, such as in the Klippel-Trenaunay syndrome, trauma, surgical mishap,

Congenital CVD, in which case the condition is already present at birth, also exist. However, this might be recognized only later in life, such as in the cases of the Klippel-Trenaunay (varicosities and venous malformations, capillary malformation, and limb hypertrophy) [33] and Parkes-Weber (venous and lymphatic malformations, capillary malformations, and arteriove-

CVD is the most common cause of edema with age 50 and over [68]. The venous edema is a very common clinical manifestation of CVD, particularly in C3 to C6 classes [68–72]. The chronic venous edema may blunt the metabolic and immunological capacity of tissues, thus contributing to the risk of venous ulcer [72]. Venous edema occurs when there is an imbalance between vascular filtration and reabsorption and lymphatic reabsorption [19]. About 90% of capillary filtration (proteins, plasma, and other components) is reabsorbed back to the blood, and the remaining 10% is reabsorbed by the lymphatic circulation [20, 73]. In CVD, blood filtration is increased due to the higher intravascular hydrostatic pressure and raised endothelial permeability due to inflammation [19, 73]. In these conditions, venous edema may occur [19, 20]. This is a pitting edema that gets worse through the day and improves during sleeping because of the lying position and leg elevation. Usually, this edema is accompanied by venous symptoms and signs [19, 20]. Clinically, venous edema is perceived as an increase in fluid volume of the skin and subcutaneous tissue, characteristically diminished by pressure [13]. Venous edema usually occurs around the ankle region, but may extend to the leg and

The principal physiological function of the lymphatic circulation is to guarantee homeostasis between the vascular and interstitial fluid compartments [74] and this requires that the lymphatic system compensates the excessive blood filtration at the blood capillary level [19]. Any failure in this process will result in accumulation of a protein rich fluid in the interstitial space, which is associated with an inflammatory reaction, fibrosis, overgrowth of adipose and connective tissue, and other symptoms that characterize the lymphedema [74]. There is

development of post-thrombotic syndrome [12, 61].

and tumors [57].

150 Clinical Physical Therapy

foot [13].

nous fistulas) syndromes [66].

**4. Venous edema and Lymphedema**

The venous return from the periphery to the heart via the venous system is linked to the action of a central pump (heart and respiratory cycle), periphery venous pump, a pressure gradient, and competent veins and/or venous valves [43, 75].

The muscle pump refers to the hemodynamics effect of limb muscles contractions and ambulation on venous circulation, which is twofold: (I) to enhance venous return from the lower extremity, and (II) to stimulate local blood flow and raise muscle perfusion during muscle contractile activity [43, 57]. The calf muscle pump has an important role for the effective venous return and relies on dynamic interaction between the ankle joint, muscle fascia, muscles of the calf and venous valves [43, 57].

During muscle contractions, the venous blood is forced in direction to the heart and the valves prevent reflux during relaxation [27, 48, 76]. As deep veins are tethered to surrounding tissues, muscle relaxation causes the veins to open, lead to a sudden drop in pressure within these vessels [58, 77, 78]. The large pressure gradient caused by the drop in deep veins hydrostatic pressure enhances blood flow from superficial to deep veins trough perforator veins, decreasing superficial venous pressure and enhances arterial inflow [43, 57].

The basic concept of muscle pump operation is that the steep increase in intramuscular pressure that accompanies contraction compresses the deep inner muscle veins and veins in the nearby inter-compartmental spaces, expressing the blood across the unidirectional vein valves. During muscle relaxation, intravascular pressure drops but venous blood backflow is prevented by the rapid closure of vein valves. Vein walls are tethered to the surrounding muscles and, therefore, veins are forced to open during muscle relaxation, resulting in large dropping of hydrostatic pressure inside the deep veins, causing aspiration of the blood flowing the superficial system through the perforator veins. The decreased venous pressure due to the muscle pump action also raises perfusion pressure, thus leading to an increase in blood flow across the limb. Despite the simplicity of this model, the efficacy of the muscle pump relies on multiple factors and shows wide variation even among people free from venous dysfunction [79].

Ambulatory venous pressure (AVP) and air plethysmography are gold standard methods for evaluating muscle pump function (usually the foot and calf pumps together) [80, 81]. For ambulatory venous pressure, the conventional procedure measures the intravascular hydrostatic pressure inside a dorsal foot vein, which is then taken as proxy of the pressure in the veins of the lower extremity. The percentage decrease in AVP shows large variability even in healthy control subjects. In a group of CVI participants, AVP decreased by approximately 75% at the end of ten tiptoe exercise compared to basal values, with no differences in the magnitude of AVP decrease between people with different CVI severities [80]. However, compared to healthy groups (CEAP C0 class), CVI groups show a percentage AVP decrease that on average is only approximately 35% in CEAP classes C4…C5, a value that is half of that for participants in C0 class [79]. Surely, the percentage AVP decrease plus the basal venous hydrostatic pressure at foot level determine the ambulatory drop in hydrostatic pressure in dorsal foot veins. In healthy people, the large percentage fall in AVP combines with normal basal hydrostatic venous pressure, so that in such cases mean AVP lowers to around 30 mmHg, contrasting with mean AVP values >55 mmHg in C4-C6 clinical groups [79]. The AVP pressure has a fairly good relationship with venous incompetence, with the risk of ulceration increasing linearly with ambulatory venous hypertension. According to Nicolaides et al. [82], in a cohort of 220 CVI patients the incidence of venous-related ulcers was 0% when AVP levels were <30 mmHg and attained 100% with AVP >90 mmHg.

The magnitude of decrease in AVP is determined by the amount of blood expressed by the muscular contractions but also by the rate of refilling. The time taken to elevate the pressure back to 90% of basal standing levels, a standard measure of recovery time (RT90), is negatively correlated with venous insufficiency severity, being on average >20 s in healthy people and in those with mild venous disease, lowering to approximately 2 s in severe clinical cases [79, 80]. Like for AVP, RT90 values are also predictive of the risk of ulceration [79]. Data obtained with air plethysmography also confirms the presence of muscle pump deficiency in CVI. Standard measures of air plethysmography include the ejection fraction, the venous filling index to 90% of the basal volume, the residual volume fraction, and the venous volume [80, 83][9,12].

These muscle pump function effects have the potential to alleviate symptoms and counteract disability associated with chronic venous disease. The action of the muscle pump in moving venous blood centrally is well described and relies on an imbricate relationship between anatomical and biophysical/physiological factors of at least three separate muscle pumps: the foot, the calf, and the thigh muscle pumps thigh [57, 84]. The calf pump is the most important of the three, as a result of its larger capacitance and highest pressure-generating ability. Together, the foot, calf, and thigh muscle pumps assure near 90% of the venous return in the deep venous system of the leg [85].

#### **5.1. Thigh muscle pump**

The basic concept of muscle pump operation is that the steep increase in intramuscular pressure that accompanies contraction compresses the deep inner muscle veins and veins in the nearby inter-compartmental spaces, expressing the blood across the unidirectional vein valves. During muscle relaxation, intravascular pressure drops but venous blood backflow is prevented by the rapid closure of vein valves. Vein walls are tethered to the surrounding muscles and, therefore, veins are forced to open during muscle relaxation, resulting in large dropping of hydrostatic pressure inside the deep veins, causing aspiration of the blood flowing the superficial system through the perforator veins. The decreased venous pressure due to the muscle pump action also raises perfusion pressure, thus leading to an increase in blood flow across the limb. Despite the simplicity of this model, the efficacy of the muscle pump relies on multiple factors and shows wide variation even among people free from venous

Ambulatory venous pressure (AVP) and air plethysmography are gold standard methods for evaluating muscle pump function (usually the foot and calf pumps together) [80, 81]. For ambulatory venous pressure, the conventional procedure measures the intravascular hydrostatic pressure inside a dorsal foot vein, which is then taken as proxy of the pressure in the veins of the lower extremity. The percentage decrease in AVP shows large variability even in healthy control subjects. In a group of CVI participants, AVP decreased by approximately 75% at the end of ten tiptoe exercise compared to basal values, with no differences in the magnitude of AVP decrease between people with different CVI severities [80]. However, compared to healthy groups (CEAP C0 class), CVI groups show a percentage AVP decrease that on average is only approximately 35% in CEAP classes C4…C5, a value that is half of that for participants in C0 class [79]. Surely, the percentage AVP decrease plus the basal venous hydrostatic pressure at foot level determine the ambulatory drop in hydrostatic pressure in dorsal foot veins. In healthy people, the large percentage fall in AVP combines with normal basal hydrostatic venous pressure, so that in such cases mean AVP lowers to around 30 mmHg, contrasting with mean AVP values >55 mmHg in C4-C6 clinical groups [79]. The AVP pressure has a fairly good relationship with venous incompetence, with the risk of ulceration increasing linearly with ambulatory venous hypertension. According to Nicolaides et al. [82], in a cohort of 220 CVI patients the incidence of venous-related ulcers was 0% when AVP levels were <30

The magnitude of decrease in AVP is determined by the amount of blood expressed by the muscular contractions but also by the rate of refilling. The time taken to elevate the pressure back to 90% of basal standing levels, a standard measure of recovery time (RT90), is negatively correlated with venous insufficiency severity, being on average >20 s in healthy people and in those with mild venous disease, lowering to approximately 2 s in severe clinical cases [79, 80]. Like for AVP, RT90 values are also predictive of the risk of ulceration [79]. Data obtained with air plethysmography also confirms the presence of muscle pump deficiency in CVI. Standard measures of air plethysmography include the ejection fraction, the venous filling index to 90% of the basal volume, the residual volume fraction, and the venous volume [80, 83][9,12]. These muscle pump function effects have the potential to alleviate symptoms and counteract disability associated with chronic venous disease. The action of the muscle pump in moving

dysfunction [79].

152 Clinical Physical Therapy

mmHg and attained 100% with AVP >90 mmHg.

The calf muscles, and possibly the thigh muscles, act as a pump, also called as "peripheral heart", which can generate pressures of up to 300 mm Hg during exercise [86]. Nevertheless, it has been suggested that thigh muscle pump has a minor effect in venous return, compared to calf muscle pump [43, 57, 84].

The thigh muscle pump may be separated in a posterior division that includes mostly the semimembranous muscle, and an anterior division made up by veins from the quadriceps femoris muscle [32]. The veins inside the semimembranous muscle form longitudinal plexus that are connected in the lower part of the muscle with the popliteal vein and with the deep femoral vein upwards. The quadriceps femoris' veins drain into a large trunk that often join the deep femoral vein to end into the common femoral vein near the root of the thigh. The venous valves of thigh veins may not be entirely competent thus allowing variations in the volume of the thigh venous reservoir to occur with posture changes [84].

#### **5.2. Calf muscle pump**

The calf muscle pump is in sequence with the foot pump is the most important muscle pump in the human circulatory system [27, 87]. The calf muscle pump is associated with the strong triceps surae muscle and can be separated in two units: a first unit that includes the soleus muscle (leg pump) and its veins, and a second unit situated in the upper leg region and composed by the gastrocnemius muscle and respective veins (popliteal pump) [88]. The veins in the soleus are organized in a lateral larger group and in a medial one. The lateral veins are larger, run vertically and drain into the fibular veins near the superior border of the soleus muscle. The majority of the medial veins drain horizontally into the posterior tibial veins at different heights of the leg but few course vertically and laterally to join the fibular veins. The gastrocnemius veins take their origin from the calf perforators at the lower part of the muscle then giving origin to a number of pedicles that run upwards through the calf to terminate in a single collector draining into the popliteal vein. Through this collector the gastrocnemius pump powerfully ejects the blood into the popliteal vein, and anatomical variations in this collector are linked to differences in calf pump efficacy [88]. Calf muscles contraction can elevate the pressure to approximately 140 mm Hg and increase venous blood flow through the popliteal and the femoral veins [32]. In competent veins, the centrifugal component during muscle relaxation lasts approximately 200 to 300 milliseconds and represents the physiological reflux, in incompetent veins the duration exceeds 500 milliseconds [32].

Less efficient calf muscle pump function (CMPF) (involving especially the gastrocnemius and soleus muscles) has also been related with muscle inflammation, reduced muscle oxygen supply, muscle necrosis, myofibril atrophy (muscle fibers type I and II) and muscle denervation [28, 29]. A study by Araki et al. [89] concluded that venous insufficiency cannot fully explain venous ulceration, pointing to deficient calf muscle pump as a primary factor in CVD-related skin and tissue damage. Several studies show that early treatment, by exercising the muscle pump, can prevent the most severe forms of CVD [14, 90]. The important role of CMPF on the progression of CVD is well established, but in many individual cases impaired calf pump function may go undetected until most severe changes become evident [91]. Therefore, assessable, accurate and non-invasive methods to evaluate CMPF are needed [30, 59, 90–92].

#### **5.3. Foot muscle pump**

The deep venous system of the foot forms a venous plexus that is composed by a lateral vein, a medial vein, and a deep plantar arch. The lateral and medial plantar veins are usually doubled and course either intramuscularly or in between the plantar muscles from a lateral position distally to a medial position near the ankle, where they drain into the paired posterior tibial veins [93]. The deep plantar arch and the lateral and medial plantar veins receive blood from superficial veins located in the sole of the foot and from the metatarsal veins [85, 93]. The plantar deep venous system is connected with the superficial veins on the dorsum of the foot via several perforator veins. The link between these two venous systems is specially well developed between the medial plantar vein and the medial marginal vein , forming what has been named the "medial functional unit", which possesses the unique feature of blood flow being directed from deep to superficial vessels [85, 94].

The physiology of the foot pump is still not totally clear. The anatomical design of the deep plantar system, characterized by the presence of paired veins flanking an artery and joined together by connective tissue, and by the close relation between these veins, the plantar muscles and the metatarsophalangeal joints, is well suited to enhance venous blood flow during weight bearing and ambulation. These imply that the foot pump expels the blood through a double mechanism: contact of the foot with the ground, resulting in extension of the tarsal arch and metatarsophalangeal joints associated with compression of the deep veins and the calcaneous plexus, and by contraction of the plantar muscles surrounding the blood reservoir of the deep venous system [88, 93–95]. The foot pump empties during the stance phase of the gait, as a result of weight-bearing, and pushing off action, and refills during the swing phase, when the foot is cleared from ground contact. Through its mechanisms, this pump moves 25–30 mL of blood, equal to the capacity of the deep medial and lateral plantar veins [94]. Individual differences in plantar support and in the pattern of the foot muscles contraction during the stance phase of the gait cycle have the potential to modify the efficacy of the foot pump [96].

These two mechanisms (weight bearing and muscle contraction), however, do not work synchronously, with plantar compression acting first then followed by the action of the muscle contractions at the foot [93]. These two different foot pump mechanisms may both be present during the stance phase of the gait cycle, but would be active ats [93]. Also, certain clinical conditions of CVD could be explained by a conflict between the mechanisms of the foot pump and the leg pumps [97]. The knowledge about the interaction of the lower limb muscle pumps during contraction/relaxation as a mechanism for venous return is still quite poor [57].

#### **5.4. Impairment of calf muscle pump and functional capacity**

Less efficient calf muscle pump function (CMPF) (involving especially the gastrocnemius and soleus muscles) has also been related with muscle inflammation, reduced muscle oxygen supply, muscle necrosis, myofibril atrophy (muscle fibers type I and II) and muscle denervation [28, 29]. A study by Araki et al. [89] concluded that venous insufficiency cannot fully explain venous ulceration, pointing to deficient calf muscle pump as a primary factor in CVD-related skin and tissue damage. Several studies show that early treatment, by exercising the muscle pump, can prevent the most severe forms of CVD [14, 90]. The important role of CMPF on the progression of CVD is well established, but in many individual cases impaired calf pump function may go undetected until most severe changes become evident [91]. Therefore, assessable, accurate and non-invasive methods to evaluate CMPF are needed [30, 59, 90–92].

The deep venous system of the foot forms a venous plexus that is composed by a lateral vein, a medial vein, and a deep plantar arch. The lateral and medial plantar veins are usually doubled and course either intramuscularly or in between the plantar muscles from a lateral position distally to a medial position near the ankle, where they drain into the paired posterior tibial veins [93]. The deep plantar arch and the lateral and medial plantar veins receive blood from superficial veins located in the sole of the foot and from the metatarsal veins [85, 93]. The plantar deep venous system is connected with the superficial veins on the dorsum of the foot via several perforator veins. The link between these two venous systems is specially well developed between the medial plantar vein and the medial marginal vein , forming what has been named the "medial functional unit", which possesses the unique feature of blood

The physiology of the foot pump is still not totally clear. The anatomical design of the deep plantar system, characterized by the presence of paired veins flanking an artery and joined together by connective tissue, and by the close relation between these veins, the plantar muscles and the metatarsophalangeal joints, is well suited to enhance venous blood flow during weight bearing and ambulation. These imply that the foot pump expels the blood through a double mechanism: contact of the foot with the ground, resulting in extension of the tarsal arch and metatarsophalangeal joints associated with compression of the deep veins and the calcaneous plexus, and by contraction of the plantar muscles surrounding the blood reservoir of the deep venous system [88, 93–95]. The foot pump empties during the stance phase of the gait, as a result of weight-bearing, and pushing off action, and refills during the swing phase, when the foot is cleared from ground contact. Through its mechanisms, this pump moves 25–30 mL of blood, equal to the capacity of the deep medial and lateral plantar veins [94]. Individual differences in plantar support and in the pattern of the foot muscles contraction during the stance phase of the gait cycle have the potential to modify the efficacy of the foot

These two mechanisms (weight bearing and muscle contraction), however, do not work synchronously, with plantar compression acting first then followed by the action of the muscle contractions at the foot [93]. These two different foot pump mechanisms may both be present

flow being directed from deep to superficial vessels [85, 94].

**5.3. Foot muscle pump**

154 Clinical Physical Therapy

pump [96].

Calf muscle pump dysfunction might be caused by weakness of calf muscles but may also be related to decreased range of motion around the ankle joint during walking and other movements [30, 75, 78, 98], neuropathy, muscle denervation or muscle atrophy, or gait abnormalities [29, 36, 43].

Ankle function plays an important role in mobility [36]. Distal leg muscles may exhibit reductions in strength and power with aging, and these affects walking, balance, and increases the risk of falling [99]. Impaired ankle muscles strength has been associated with falls [100]. The power output by dorsiflexion muscles has been found to be closely associated with function in community-dwelling older women in terms of their ability to get up from and sit down on a chair and climb stairs [100]. Plantarflexion strength has been shown to be positively related to both preferred gait speed and fast gait speed [100].

Patients with CVD present limited ankle range of motion [36, 45, 47, 78, 98]. Diminished ankle mobility tends to aggravate as CVD progresses and in parallel with increasing severity of symptoms, thus further contributing to a poor CMPF [78, 98]. Together with decreased ankle range of motion, there is also decreased muscle strength of dorsi and plantarflexors [30, 75], with decreased peak torque, power ability [36], muscle resistance (number of heel rises) [45], and total work performed by the ankle plantarflexors [75]. Other functional alterations associated with CVD include decreased gait speed [36, 45], decreased number of steps per week (in venous ulcer patients) [101], and generally impaired functional capacity and mobility [36]. Also, changes in ankle function alters foot pressure distribution during gait that becomes higher at the midfoot and lower at the toes [43].

These functional alterations, specially the decreased strength of the calf muscles and reduced ambulation, contribute to venous hypertension [30, 43, 46, 47, 57, 98]. Dysfunction of the muscle pumps leads to venous blood not being effectively emptied out of the distal extremity [30]. This rarely occurs as a "primary" disorder in neuromuscular conditions or muscle wasting syndromes; however, clinically significant muscle pump dysfunction often occurs in severe reflux or obstruction [92]. Muscle pump dysfunction appears to be a major mechanism for the development of superficial venous incompetence and its complications, such as venous ulcers, and around 70% of patients with venous ulcer present calf muscle pump dysfunction [48, 66, 89, 91, 102].

Venous blood flow increases during calf muscle contractions in individuals with or without CVD. Popliteal peak flow volume is maximal during the first contraction of the tip-toe set of ten repetitions when the venous reservoir is full [103]. In the CVD patients, but not in the healthy subjects, venous flow augmentation was seen to diminish during the ten tip-toe exercise [104]. Such apparent calf pump dysfunction might be related to weak calf muscles in CVD patients [29, 30] and is compatible with a lower ejection volume, such as has been measured before in this population with air-plethysmography [92]. In addition, abnormal venous blood reflux from deep to superficial venous system through incompetent perforator veins may blunt blood flow through the popliteal vein [104].

Nonetheless, it seems that calf muscle size is not a strong indicator of the efficacy of muscles to pump venous blood during contractions in patients with venous ulcer [105]. Also, gastrocnemius thickness and some other muscle architectural features, like pennation angle, are similar in patients with low to moderate CVD severity and healthy participants, and seem unrelated with the severity of CVD [104]. Despite this fact, for the medial gastrocnemius, a few morphological parameters (like higher muscle fascicle length, and pennation angle) are associated with the degree of increase in peak flow velocity in the popliteal vein during tip-toe movement [104].
