Flap physiology

1. Dr.Amit Kr. Choudhary
RIMS,Imphal,India

2.  Introduction
 Physiology of flap
 Pathophysiology of flap failure
 Surgical manipulation for augmentation of pedicle flap
viability
 Pharmacological therapy for augmentation of pedicle
flap viability
 Pharmacological therapy for augmentation of free flap
viability
 Conclusion and future directions

3. WHAT IS A FLAP?
 Flaps are the essence of plastic surgery. The ability to successfully
conceive, design, execute, and manage a flap is what defines a plastic
surgeon.
 What distinguishes a flap from a graft is an intrinsic blood supply that
is responsible for a flap's viability. An intrinsic vascularity confers
tremendous flexibility and potential, allowing a flap to supply critical
vascularized coverage to complex defects and to restore form and
function in nearly unlimited ways.
 Because the viability of a flap depends on its intrinsic vascularity,
fully understanding and being able to optimize the vascular
physiology of a flap can make the difference between success and
failure.

4.  The vascular supply of a flap includes both macrocirculation
and microcirculation components. Both of these are subject to
intrinsic and extrinsic factors that can dramatically influence
perfusion and hence viability.
 The anatomy of the macrocirculation is used to define and
design a flap.
 The major arterial inflow and venous outflow of a flap
constitute the foundation from which the microcirculatory
beds then provide nutrition and oxygen and carry away carbon
dioxide and waste products, thus forming the basis of cellular
metabolism throughout the flap.
 It is at the microcirculatory level-the arterioles, capillaries,
venules, and arteriovenous anastomoses-where this exchange
occurs and where most of the control of perfusion occurs.

5.  Taylor has eloquently demonstrated that the blood supply to
potential flaps involves a continuous three-dimensional network of
vessels not only in the skin but also in all tissue layers. The
anatomic territory of a source artery in the skin and deep tissues, in
most cases, gives rise to what has been described as the angiosome
concept.

6. One of the primary functions of skin is thermoregulation, which is accomplished
through the regulation of skin blood flow. Heat is dissipated by increasing skin
blood flow and is conserved by decreasing skin blood flow.

7.  The primary regulation of blood flow to skin is at the arteriolar level. It is here that sympathetic tone regulates
flow through the precapillary sphincters, arterioles, and arteriovenous anastomoses. When the precapillary
sphincters constrict in response to either local or systemic sympathetic tone, blood flow is forced to bypass the
capillary bed through arteriovenous anastomoses.

8.  In addition, a number of other factors come into play in
regulating flap blood flow. These include the systemic central
blood pressure and cellular factors within the microcirculation
involving the endothelium, platelets, and white blood cells.

9.  The normal blood flow to skin is approximately 20 mL per
100 g of tissue; it is significantly higher for muscle. This is
consistent with the different metabolic demands of skin and
muscle, with muscle having much higher demand for oxygen
and metabolites.
 Because flap viability depends on this critical balance between
blood flow and metabolic demand, it is important to keep the
tissue-specific requirements in mind in designing, executing,
and manipulating blood flow to optimize flap survival.

10.  Because effective microcirculatory perfusion is dependent on its
proximity to the nearest nutrient vessel,flaps that are based on an
axial nutrient vascular system will be much more reliable than flaps
that are not.
 Random flaps are those not based on a dominant nutrient vascular
system but instead are supplied by flow through the subdermal or
subfascial plexus. As a result, random flaps are much less reliable
than axial flaps, and their length is limited to a short distance from
the pedicle origin.

11.  Regulation of cutaneous blood flow occurs at two levels,
systemic and local.
 Systemic control is, in turn, exerted through both neural
regulation and humoral regulation, Of these, neural
regulation is predominant.
 Neural regulation is exerted primarily through sympathetic
fibers and α- adrenergic receptors that induce
vasoconstriction; β-adrenergic receptors, on the other hand,
induce vasodilation.
 .

12.  In addition, serotonergic receptors, located at arteriovenous
anastomoses, also induce vasoconstriction. Together, these
work to regulate the vascular smooth muscle tone at the level
of the arterioles and arteriovenous anastomoses.

14.  Humoral regulation occurs through the action of systemic
vasoactive substances on their specific receptors, such as that
of epinephrine and norepinephrine on α-adrenergic receptors.
 Other systemic vasoconstrictors include serotonin,
thromboxane A2, and prostaglandin F2α.
 Counteracting vasodilators include prostaglandin E1,
prostaglandin I2 (prostacyclin), histamine, bradykinin, and
leukotrienes C4 and D4.

15.  Metabolic factors that affect skin blood flow at the local level
include hypercapnia, hypoxia, and acidosis, all of which cause
vasodilation.
 Increased tissue perfusion pressure can trigger a "myogenic
reflex," resulting in vasoconstriction in an effort to maintain
constant capillary blood flow, independent of arterial perfusion
pressure.
 Local hypothermia also decreases local blood flow by acting
directly on the vascular smooth muscle to cause
vasoconstriction, whereas local hyperthermia has the opposite
effect.

16.  Rheologic factors can have an effect on flow, but typically
only under abnormal conditions. Profound anemia can
improve rheologic properties and increase flap blood flow; in
some studies, it has been shown to improve distal flap
survival,but other studies have shown little or no effect on flap
survival.
 Abnormally elevated rheologic factors as in polycythemia or
sickle cell disease can, however, seriously compromise
perfusion and viability, especially at the marginal portions of a
flap. It is under conditions and in areas of marginal perfusion
that rheologic factors can play a significant role and may be
amenable to intervention.

17.  The endothelium plays a critical role in the regulation of blood
flow both through the direct release of vasoactive substances
and through its effect on the circulating white blood cells and
platelets.
 The action of elevating a flap produces profound changes and
disrupts the carefully balanced equilibrium that regulates
blood flow to tissue.
 There is an immediate loss of sympathetic innervation that
results in a spontaneous discharge of vasoconstricting
neurotransmitters Combined with the drop in perfusion
pressure from physical removal of inflow vessels, the result is
that peripheral portions of the flap become acutely ischemic.

18.  Banbury et al describe a triphasic, dynamic response in the
peripheral microcirculation of the cremaster muscle flap. An
initial acute hyperadrenergic phase is followed by a
nonadrenergic phase, with significant vasodilatation, then a
sensitized phase, with increased capillary perfusion and
hyperresponsiveness to vasoactive substances.

19.  studies showed that although flow at the base of a pedicle flap
is preserved after elevation, flow at the tip of the flap often
drops to less than 20% of normal, usually within the first 6 to
12 hours. Flow gradually returns to approximately 75% of
normal within 1 to 2 weeks and to 100% by 3 to 4 weeks.
 At the same time that flow is gradually returning to the
ischemic portion of the flap by longitudinal flow from the
pedicle, additional flow is also returning by inosculation and
neovascularization from the bed.This is a significant factor in
very thin flaps.

20.  Musculocutaneous flaps have an
early and continuous increase in
blood flow after elevation, Tissue
oxygen tensions are also
significantly higher in
musculocutaneous flaps than in
random-pattern flaps up to 6 days
after elevation and are higher in the
proximal portions than in the distal
portions in each flap type.
 Differences in patterns of oxygen
delivery to random versus
musculocutaneous flaps may in part
explain the greater reliability of
musculocutaneous flaps when they
are used in the presence of infection.
whereas random skin flaps
have an early decrease.
Random flaps, however,
develop a
subsequent lasting increase in
flow.

21.  Initially, nutrient vessels and sympathetic nerves are severed.
During the first 12 to 18 hours, flow diminishes dramatically, especially in the
distal portion of a flap.
As sympathetic neurotransmitters are depleted during the ensuing 12 to 24 hours,
and as inosculation from the flap bed occurs in 2 to 3 days, flap perfusion is
gradually restored.
However, in distal portions of the flap that are severely ischemic at 6 to 12 hours, the
returning flow only contributes to the reperfusion injury that will ultimately result in
microvascular shutdown and tissue necrosis.

22. Pathophysiology of
flap failure

24.  Vasospasm and thrombosis
 Xanthine dehydrogenase/xanthine oxidase enzyme system
 Neutrophilic nicotinamide adenine diphosphate (NADPH) and
myeloperoxidase(MPO)
 Intracellular Ca2+
 No-reflow phenomenon

25.  Main pathogenic factors in flap failure.
 Endothelium-derived relaxing factors (EDRFs) such as
prostacyclin (PGI2) and nitric oxide (NO) cause relaxation of
vascular smooth muscle and inhibit platelet aggregation.
 On the other hand, endothelium-derived contracting factors
(EDCFs) such as thromboxane A2 (TXA2), and endothelin-1
(ET-1) raise vascular tone.

26.  Under physiological conditions, a balance of vascular effects
between EDCFs and EDRFs maintains adequate tissue
perfusion.
 However, an imbalance can occur as a result of surgical
trauma, cause vasoconstriction and intravascular platelet
aggregation, especially in the small arteries in the distal portion
of the flap where the perfusion pressure is low and the
concentration of these vasoconstrictive substances is high due
to the downstream effect.

27.  Hemoglobin from hemolyzed red blood cells (e.g., hematoma)
is also a potent vasoconstrictor.
 The histamine released by the mast cells changes the
membrane permeability, resulting in edema formation.
 The synthesis and release of EDRFs such as PGI2 and NO
from the traumatized vascular endothelium are depressed. In
addition, the rate of endothelial degradation of NE and 5HT2
by catechol-O-methyl transferase and monoamine oxidase,
respectively, is reduced in situations of impaired endothelial
function.
 The end result is that there are high local levels of
vasoconstrictive and prothrombotic neurohumoral substances
in surgical trauma and these substances exacerbate vasospasm
and promote thrombosis in flap surgery.

28.  In reperfusion of ischemic blood vessels, superoxide radicals (O2•)
are produced by platelets, neutrophils, and endothelial cells and
these free radicals can damage vascular walls during reperfusion .

29.  Human muscle and skin can withstand 2–2.5 hours and 6–8 hours of
warm global ischemia, respectively.Excessive ischemic insult can
result in ischemia–reperfusion injury caused by energy depletion and
formation of oxygen derived free radicals.
 During prolonged ischemia, adenosine triphosphate (ATP) in skin and
muscle is catabolized stepwise to hypoxanthine, with concomitant
increase in cytosolic Ca2+.

30.  At the same time, a cytosolic protease is activated by
intracellular Ca2+ and it converts xanthine dehydrogenase to
xanthine oxidase. During reperfusion, the xanthine oxidase
generates superoxide (O2•) by univalent reduction of
molecular oxygen in the presence of hypoxanthine.The
unstable O2• forms H2O2 spontaneously by dismutation.
 Furthermore, the unstable O2 • also interacts with H2O2 in the
presence of a transition metal (e.g., iron) to form the most
potent cytotoxic hydroxyl radical (OH•) through the Haber–
Weiss(Fenton) reaction.

31.  Activated neutrophils produce large amounts
of O2 via NADPH oxidase, and these
O2•dismutates yield high concentration of
H2O2 and OH•, causing tissue damage.
 MPO, which is unique and abundant in
neutrophils, catalyzes the conversion ofH2O2
to hypochlorous acid (HOCl), a potent
cytotoxic oxidizing agent (H2O2 + Cl− + H+
→ HOCl + H2O).

33.  In sustained ischemia,
mitochondrial ATP synthesis
ceases and glycolysis ensues,
resulting in a net breakdown of
ATP and an accumulation of
lactate and intracellular H+,
causing intracellular acidosis.
This build-up of intracellular
H+ activates the Na+/H+
exchange isoform-1 (NHE-1)
antiporter, resulting in extrusion
of H+ and accumulation of
intracellular Na+ to restore
intracellular pH.

34.  There is a further increase in intracellular Na+
accumulation because Na+ extrusion is limited by
inactivation of the energy-dependent Na+-K+-ATPase
pump.Elevation of intracellular Na+ concentration causes
an increase in intracellular Ca2+ by activation of the Na+/
Ca2+ exchanger causing Ca2+ influx.

 The cystolic Ca2+ will be overloaded, and significant
uptake of Ca2+ from the cytosol to the mitochondria will
occur, resulting in mitochondrial Ca2+ overload which
causes depolarization of mitochondria and impairs ATP
synthesis, resulting in cell necrosis

35.  Rabbit island epigastric skin free flaps were used to study the
pathogenesis of the no-reflow phenomenon in free flap
surgery. It was observed that ischemia induced swelling of the
endothelial and parenchymal cell, narrowing of the capillary
lumen, intravascular aggregation of blood cells, and leakage of
intravascular fluid into the interstitial space to form edema.
 This pathology increased with the increase in length of
ischemic time from 1 to 8 hours and the obstruction of blood
flow reached a point of irreversibility after 12 hours of
ischemia, leading to no reflow and ultimate death of the flap.

36. Three pathogenic mechanisms have been suggested to play a central
role in the development of no-reflow phenomenon :
(1) oxygen-derived free radicals causing damage in the endothelial
and parenchymal cells;
(2) this cell membrane damage allowing Ca2+ influx, resulting in
intracellular overload; and
(3) change in arachidonic acid metabolism resulting in synthesis of
less vasodilating and antithrombotic PGI2 by the endothelium and
increased synthesis of vasoconstricting and thrombotic TXA2 by
platelets.

37. Surgical manipulation for
augmentation of pedicle flap
viability

38.  Flap design
 Surgical delay
 Vascular delay

39.  One of the misleading principles in plastic surgery is that the viable
length of a skin flap depends on the width of the pedicle.
 Milton was the first to disprove this principle,Using a random-
pattern skin flap model in the pig, it was demonstrated that the
ultimate surviving length of a pedicle flap is determined by the
balance between perfusion pressure and vascular resistance.

40.  Increasing the width of pedicle flaps merely adds additional vessels of
the same type and the same perfusion pressure and thus cannot
increase the length of flap viability .
 However, in other locations of the body, increasing the width of the
pedicle may increase the chance of including a large artery.
 Therefore,one of the surgical manipulations to augment flap viability is
the conversion of a random-pattern skin flap to an arterialized skin flap
by incorporating a direct artery or a larger perforator.

41.  It takes two to three stages in surgical delay of pedicle skin flaps
in order to augment flap viability. Specifically, a skin flap is
mapped out on the donor site and incised on its two longitudinal
sides. The flap is then undermined to form a bipedicle flap and is
sutured back to the donor site.

42.  Two to three weeks after construction of the bipedicle
flap, the third side (distal end) is cut in one or two
stages at 2–3 days apart. At the end of this stage, a
single pedicle flap is completely raised and the distal
portion of the flap is moved to the recipient site for
wound coverage without skin necrosis.
 Studies with pig random pattern skin flaps showed
that surgical delay increased skin flap capillary blood
flow between 2 and 7 days of delay. This increase in
capillary blood flow was mainly in the distal random
portion of the delayed skin flaps.

43.  Division of perforators or one
or two dominant arteries that
supply blood to the rectus
abdominis muscle 2–3 weeks
before flap surgery
significantly augmented
viability in TRAM flaps in rats
and augmented skin and
muscle blood flow and
viability in TRAM flaps in
pigs.

44.  In human patients, ligation of the deep inferior
epigastric arteries 2–4 weeks before flap surgery
augmented skin blood supply and viability in TRAM
flaps.

45.  Surgical delay procedure reduces arteriovenous (AV) shunt
flow
 Surgical delay procedure depletes vasoconstriction and
prothrombotic substances in the skin flap
 Surgical delay procedure induces vascular territory expansion
by opening existing choke arteries
 Surgical delay procedure induces angiogenesis

46.  In acute skin flap surgery, distal ischemic necrosis is caused by
opening of AV shunt flow as a result of sympathetic
denervation,flow in the proximal areas is sufficient to supply
both the AV and capillary (nutrient) blood flow, but the
shunting became lethal in the distal areas of the skin flap
where the total blood flow was low.
 In surgical delay, the bipedicle skin flap provided sufficient
blood supply during the early period of sympathetic
denervation and opening of AV shunts.

47.  Local tissue content of vasoconstricting and
prothrombotic substances are known to be elevated by
surgical trauma.
 Surgical delay procedure reduces local production and
also allows time to deplete the vasoconstricting and
prothrombic substances before converting the bipedicle
flap to single-pedicle flaps.

48.  The capillary blood flow increased
significantly within 2 days of delay and a
maximum increase in skin flap capillary
blood flow occurred between 2 and 3
days of delay, and remained unchanged
between 4 and 14 days of delay without
an increase in density of arteries
(arteriogenesis). This increase in
capillary blood flow occurred mainly in
the distal portion of the skin flap.
 This phenomenon is vascular territory
expansion by recruitment (opening) of
existing arteries as angiosome territory
expansion by opening of existing choke
blood vessels.

49.  Vascular delay was associated with a significant increase in
gene expression of vascular endothelial growth factor (VEGF)
and basic fibroblast growth factor (FGF) in the skin paddle of
the rat TRAM flaps within 12 hours of vascular delay.

50. Pharmacological therapy for
augmentation of pedicle flap
viability

51.  The categories of drugs included:
1. α-adrenoreceptor antagonists
2. Drugs causing depletion of catecholamine in nerve terminals
3. Drugs preventing catecholamine release from the nerve terminal
4. β-adrenoreceptor agonists
5. Direct vasodilators
6. calcium channel blockers
7. Hemorrheological drugs; vasodilating eicosanoids and their
synthesis inhibitors
8. Anti-inflammatory drugs
9. Drugs inhibiting adherence and accumulation of neutrophils
Free radical scavengers.

52.  Angiogenic cytokines such as VEGF, FGF, and platelet derived
growth factors (PDGF) are known to induce an increase in
capillary density (angiogenesis).
 For example, improved viability was observed following local
subdermal injection of VEGF immediately after elevation of rat
dorsal random-pattern skin flaps;

53. Pharmacological therapy
for augmentation of free
flap viability
Vasospasm, thrombosis, and ischemia–reperfusion
injury are the main causes of free flap failure.

54.  These drugs can be classified into three
categories-
(1) Anticoagulant agents
(2) Thrombolytic agents
(3) Antispasmodic agents

55.  Heparin, aspirin, and dextran are the three common
anticoagulants used in microsurgery.
 Intravenous heparin treatment reduced the incidence of
anastomotic thrombosis when given before the
restoration of blood flow
 Some surgeons recommend an intraoperative bolus
injection of 100–150 units/kg of intravenous heparin
before cross-clamping and a supplement injection of 50
units/kg of heparin every 45–50 minutes until re-
establishment of blood flow after anastomosis.

56.  In humans, low-dose aspirin (40–325 mg) was observed to
inhibit platelet cyclooxygenase production of TXA2 with
minimal inhibition of endothelium-derived production of PGI2
,more than 24 hours are required to achieve maximal
cyclooxygenation inhibition.
 The low-molecular-weight dextran 40 (MW 40 000) and
dextran 70 (MW 70 000) are known to have blood volume
expansion and antithrombogenic effects in human.
 Dextran 40 is the most popular dextran used to decrease
platelet aggregation and to improve blood flow in free flap
surgery. However, dextran 40 also has undesirable side-effects
such as anaphylaxis, pulmonaryand cerebral edema, and renal
failure.

57.  While early detection and re-exploration are crucial for
salvaging failing free flaps, those flaps unresponsive to
standard interventions may benefit from the selective use of
thrombolytics for lysing formed thrombi.
 Ex.-streptokinase, and recombinant tissue plasminogen
activator.

58.  Papaverine, nifedipine, and lidocaine are the most common
topical antispasmodic drugs used in clinical microsurgery.
 Papaverine is an opiate alkaloid, which relaxes vascular
smooth muscle, especially during spasms. It inhibits
phosphodiesterase, the enzyme involved in the breakdown of
cyclic adenosine monophosphate (cAMP), resulting in
accumulation of cAMP, causing vasodilation.

59.  Nifedipine is a calcium channel blocker. The
mechanism of action is inhibition of calcium influx
into the arterial smooth-muscle cells, thus causing
smooth-muscle cell relaxation.
 Lidocaine, the result of its effect on the Na+/Ca2+
ion exchanger pump causing a reduction in
intracellular calcium content, resulting in
vasodilation.

60. Preischemic and postischemic
pharmacological conditioning against
ischemia–reperfusion injury in free
flap surgery

61.  Three cycles of 10 minutes’ occlusion/reperfusion in pig latissimus
dorsi muscle flaps with a vascular clamp reduced the muscle
infarction by 40–50% when these muscle flaps were subsequently
subjected to 4 hours of warm ischemia and 48 hours of reperfusion.
 Local preischemic conditioning also augmented ischemia–
reperfusion injury tolerance in rat skeletal muscle,and in the skin of
cutaneous and musculocutaneous flaps in the rat.
 Martou et al. demonstrated the efficacy of preischemic conditioning
against ischemia–reperfusion injury in ex vivo human rectus
abdominis muscle strips.

62.  10-minute cycle of occlusion and reperfusion in a hind limb by
tourniquet application preconditioned the heart against reperfusion
tachyarrhythmia in the rat.This is known as remote preischemic
conditioning.
 Three cycles of 10 minutes of occlusion/ reperfusion in a hind limb of
the pig by tourniquet application (~300 mmHg) under general
anesthesia protected multiple skeletal muscles at various distant
locations from infarction when these muscles were subsequently
subjected to 4 hours of ischemia and 48 hours of reperfusion.

63.  Local intra-arterial infusion of the NO donor SIN-1 to pig
latissimus dorsi myocutaenous flaps and buttock cutaneous
flaps by means of a catheter for 18 hours after 6 hours of
ischemia was effective in salvaging the ischemic skin and
muscle from reperfusion injury.
 McAllister et al. reported that instigation of four cycles of 30-
second reperfusion/reocclusion at the onset of reperfusion after
4 hours of ischemia reduced pig latissimus dorsi muscle flap
infarction by ~50%, assessed at 48 hours of reperfusion.
 This phenomenon is known as postischemic conditioning.

64.  Surgical and vascular delay is the only proven clinical technique for
augmenting skin and muscle flap viability.
 However, surgical manipulations are time consuming and costly.
Similarly, preischemic and postischemic conditioning are effective in
protecting free flaps from ischemia–reperfusion injury in laboratory
animals, but surgeons are reticent to conduct clinical tests on the
efficacy of ischemic conditioning against ischemia–reperfusion injury
in free flap surgery because these techniques are invasive and/or time-
consuming.
 Therefore, there is the need to continue to search for pharmacological
therapy to increase skin and muscle blood flow and distal perfusion in
pedicle flaps and to protect skin and muscle from ischemia–reperfusion
injury in free flap and replant surgery.

65.  The angiogenic cytokine VEGF is known to cause
vasodilation and increase in capillary density (angiogenesis),
resulting in augmentation of skin viability in random-pattern
skin flaps in the rat.
 Angiopoietin-2 is known to induce arteriogenesis in mouse
ischemic hind limb. Future studies are recommended to
investigate if combined local VEGF and angiopoietin-2
protein or gene therapy will synergistically increase capillary
and arteriole density, resulting in maximizing skin viability in
random-pattern skin flaps.