PHASE 1 CME: FLAP PHYSIOLOGY
BY LAM HUI YUAN
1
Flap Vasculature
2
3
The Microcirculation components
Figure 1 : The Microciculation ( Reference Chapter 30 ,Review of medical physiology , Ganong)
Components Functional Morphology
Arterioles
Function
The walls of arterioles contain less elastic tissue but much more
smooth muscle
Arterioles are mainly
implicated in the
regulation of blood flow
The muscle is innervated by noradrenergic and cholinergic fibres and tissue perfusion
The arterioles divide into smaller muscle walled vessels ‘’
metarterioles ‘’ and in turn feed into capillaries.
Capillaries
It consists of a thin wall which are made up of a single layer of
endothelial cells
capillaries are the site
of oxygen and
nutritional exchange
Small bands of vascular smooth muscle, the precapillary
sphincters, are located at the arterial end of many capillaries and
are responsible for the control of blood flow within the capillaries.
Arteriovenous shunts : Short channels connect arterioles to
venules bypassing the true arteries
Thermoregulation
Figure 2 : Diagramatic representation of microcirculation
AVA Whose radius twice that of capillary would carry 16 times
as much blood per unit length .
Venules
They contain relatively little smooth muscles, but considerable
vasoconstriction is produced by activities in noradrenergic
nerves to vein and circulating vasoconstrictors such as
endothelin
4
Regulation of blood flow
Systemic control
Neural control
vasoconstrictors
o Alpha-adrenergic receptors
Humoral regulation
Mediators of vasoconstriction
o Epinephrine
o Norepinephrine
o Serotonin
o Arachidonicacid
metabolites (Thromboxane A2,
Prostaglandin F2a)
(Reference: The arterial anatomy skin skin flap by Cormack and
lamberty)
vasodilators
o Beta-2 adrenargic receptor
Mediators of vasodilation
o Histamine
o Bradykinin
o Prostaglandin E1
o Prostacyclin/Prostaglandin
I2
5
Regulation of blood flow: Local Factors
▪
a. Metabolic factors
When the metabolic rate of skeletal muscle is
increased by exercise, tissue levels of oxygen
decrease, but those of carbon dioxide, H+, and
K+ increase. Muscle tissue osmolarity also
increases during exercise. All these chemical
alterations cause arteriolar dilation.
Figure 3 .local metabolites hypothesis
adenosine
It is formed from cellular AMP acted upon by 5'-nucleotidase.
The AMP is derived from hydrolysis of intracellular ATP and ADP.
A potent vasodilator, its formation increases during hypoxia and increased oxygen
consumption.
Hypoxia
Hypoxia-induced vasodilation may be
▪ direct: inadequate O2 to sustain smooth muscle contraction.
▪ indirect: via the production of vasodilator metabolites.
Potassium
ion
It is released by contracting cardiac and skeletal muscle.
Small increases in extracellular K+ produces hyperpolarization of vascular smooth muscle and
relaxation through stimulation of the electrogenic Na+/K+-ATPase pump and increasing
membrane conductance to K+ (K+ activated K+ channels).
Reference: Potassium Channels in the Peripheral
Microcirculation by William F. Jackson.
Microcirculation, 12: 113–127, 2005
Carbon
dioxide
Carbon dioxide formation increases during states of increased oxidative metabolism.
6
It readily diffuses from parenchymal cells in which it is produced to the vascular
smooth muscle of blood vessels where it causes vasodilation.
Hydrogen
ion
Hydrogen ion increases when CO2 increases or during states of increased anaerobic
metabolism, which can produce metabolic acidosis.
Like CO2, increased H+ (decreased pH) causes vasodilation
Figure 4 .the partial pressure of carbon dioxide in arterial blood (PaCO2) changes
extracellular pH, which is the initial step leading to changes in vascular smooth muscle
(VSM) intracellular calcium concentration and vascular tone.
Inorganic
phosphate
Inorganic phosphate is released by the hydrolysis of adenine nucleotides. It may
have some vasodilatory activity in contracting skeletal muscle.
b. Physical factors
I. Myogenic factor
II. Local hypothermia
III. Increased blood viscosity
Myogenic
factor
Myogenic reflex, which triggers vasoconstriction in response to distention of isolated
cutaneous vessels and thereby maintains capillary flow at a constant level and control
the amount of fluid filtered out of the capillaries
7
Local
hypothermia
Local
thermoregulation
Central
Thermoregulation
Figure 4 : Overview of thermoregulatory control of skin blood flow
(Mayo Clin Proc. 2003;78:603-612 Skin Blood Flow in Adult Human Thermoregulation: How It Works, When It Does Not, and Why )
1. Local warmimg of the skin causes vasodilation by stimulating local neuropeptide release from sensory nerves
(including calcitonin gene–related peptide [CGRP], substance P [SP], and neurokinin A [NKA]) and by nonneural
local vasodilation caused by nitric oxide (NO).
2. Local cooling of the skin stimulates localized neurotransmission from noradrenergic nerves to cause
vasoconstriction.
3. Mechanisms for reflex control of skin blood flow include sympathetic adrenergic vasoconstrictor nerves and
sympathetic vasodilator nerves, the latter of which are responsible for 80% to 90% of the substantial cutaneous
vasodilation during whole body heat stress.
8
1. Viscosity : A quantity that express the magnitude of the internal frictional
force that arises between adjacent layers of fluid that are in relative motion.
Blood
viscosity
2. The determinants of flow are summarized by the Hagen–Poiseuille
equation:
where: DP is the pressure difference across the tube, r is the radius of the vessel, h
is viscosity and l is the length of the tube.
3. Plasma is 1.8 times as viscous as water ; whole blood is 3-4 times as
viscosu as water .
4. Thus , viscosity depends on hematocrit , i.e. the percentage of the volume
of blood occupied by red blood cells
I.
A lower hematocrit ( < 30 % ) : This do not provide much more advantage
because the curve of viscosity versus haematocrit flattens off markedly.
If the haematocrit falls further, the marginally improved flow characteristics from a
lower viscosity may then be offset by a reduction in oxygen delivery:
9
II.
Hematocrit of 30 % -35 % : It apears to be one that offers the best
balance between viscosity and O2-carrying capacity and tissue
perfusion
III.
Hematocrit of 40-60 % : It increases the resistance to blood flow
and thereby increases the work of the heart and impairs organ
perfusion.
Local injury
1. The effects of local injury to a part of the arterial wall can completely
override basal vascular tone and cause spasm even in the absence of
sympathetic innervation.
2. For instance, a pin prick elicits a persistent isolated ring contraction
locally, and extensive crushing or tearing can induce a widespread and
prolonged spasm distantly.
10
SUMMARY : REGULATION OF BLOOD FLOW
NERVOUS
Vasoconstrictors Alpha
adrenergic
HUMORAL
Norepinephrine
METABOLIC
PHYSICAL
Viscosity
Epinephrine
Hypothermia
Serotonin
Myogenic
Prostaglandin F2
reflex
Thromboxane A2
Endothelin
Vasodilators
Beta adrenergic Nitric oxide
Hypoxia
Cholinergic
Bradykinin
Acidosis
Histamine
Hypercarbia
Hyperthermia
Prostacyclin
Adenosine
Diphosphate
Prostaglandin
Thrombin
(Reference : Vedder NB. Flap Physiology, Chapter 20. In Mathes SJ (Ed.). Plastic Surgery,
Volume 1, 2nd edition, 2006: 483-506.)
11
FLAP PHYSIOLOGY
ANATOMIC CHANGES
Impairment of
blood supply
1. This results in a local decrease perfusion pressure to the skin, the
result is that peripheral portions of the flap become acutely ischemic.
“fresh flaps are always both viable and ischemic.”
Myers, B. Understanding flap necrosis
. Plast Reconstr Surg. 1986; 78:813
2. Depending on the degree of ischemia and the amount of time before
recovery of nutrient blood flow, the flap will either die or recover.
3. If flap survive ,
o If the flap is in a favourable recipient site, a fibrin layer forms within
the first 2 days.
o Neovascularization of the flap begins 3 to 7 days after flap
transposition.
12
o Neovascularisation: Direct Ingrowth or inosculation
o
Direct
ingrowth
Inosculation
(Reference : Local Flaps in Facial Reconstruction by Shan R Baker, MD
a. Direct Ingrowth:
1. Ischaemic regions of tissue
release angiogenic cytokines,
2. This cause the breakdown
of the vessel walls of arterioles
and venules, and sprouting of
cells, including pericytes in the
vessel wall.
3. Endothelial cells proliferate
and migrate out of the vessel
into the tissue.
4.They reorganise to form
capillaries which interconnect
(anastomosis) and link to
venules, thereby forming a
new capillary network.
o Angiogenic growth factors can stimulate capillary growth over
distances of 2 to 5 mm.
b. Inosculation:
o capillaries join pre-existing flap vessels.
13
Denervation
1.Both cutaneous and sympathetic nerves are severed in the process of flap
elevation.
A. loss of sensation may limit the usefulness of the flap after transfer.
B. Adrenergic denervation has implications for flap survival
Banbury et al describe a muscle flaps’ triphasic response to sympathectomy
and denervation.
Acute hyperadrenergic
o 0-24 hour
phase
Nonadrenergic phase
o 24-48Hr: Significant vasodilation
o The stored transmitter is depleted
within 24 to 48 hours.
o blood flow increases as the
concentration of norepinephrine
declines.
Sensitised phase
o 2 weeks after denervation
: increased capillary perfusion
: hyperresponsiveness to
vasoactive substances.
Impairment of
Lymphatic
drainage
Reduction of the cutaneous lymphatic drainage results in an increase in
interstitial fluid pressure that is compounded by increased leakage of
intravascular protein associated with inflammation.
The resulting edema can decrease capillary perfusion by increasing the
intravascular resistance.
14
II. The Hemodynamic Changes (Hoopes 1976)
o
decrease circulatory efficiency for the 6 hours.
o
plateau at 6-12 hours
o
marked congestion and oedema during initial 24 hours.
o
oedema is generated by ischemia and inflammation, interstitial pressure increases.
•
0-24 Hrs
Figure 1. Within seconds of hypoxia, levels of ATP begin to
decrease, and cells begin to swell intracellular movement of
sodium and an increase in intracellular osmotic pressure.
Relatively brief periods of ischemia result in a reversible
swelling of the cell. If the ischemic insult is severe and
prolonged, cell lysis and flap necrosis occur.
1-3
Days
3-7
Days
o
Little or no improvement in circulation during initial 48 hrs.
o
increase in number and calibre of longitudinal anastomoses.
o
increase in the number of small vessels in the pedicle.
o
vascular anastomoses between flap and recipient bed present at 2- 3 days
o
it becomes functionally significant in 5-7 days.
o
Increase in size and number of functioning vessels.
o
Reorientation of vessels along the long axis of the flap
o
o
circulatory function well established
pulsatile blood flow approaches preoperative levels
1 week
Pedicle ligation beyond day 6 in rat and day 3 in pig did not produce flap necrosis , indicating
adequate neovascularization for flap survival . Tsur, H., Daniller, A., & Strauch, B. (1980). Neovascularization
of Skin Flaps. Plastic and Reconstructive
Surgery, 66(1), 85–93.
15
7-14
Days
o
o
no further significant increase in vascularization
arterial pattern becomes normal.
o
o
2 weeks: continuous maturation of anastomoses between flap and recipient
3 weeks - flap achieves 90 % of its final circulation.
- Vascular pattern = preoperative state
- Full development of vascular connection with pedicle and recipient site
o
4 weeks: all vessels decreased in diameter.
III. METABOLIC CHANGES
Tissue Oxygen
Tension
Tissue oxygen tensions are significantly higher in musculocutaneous flaps
than in random pattern flaps up to 6 days after elevation.
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
▪
▪
Inflammatory
response
the presence of infection and
provide better bacterial killing function in the setting of infection
The surgical trauma associated with an acutely raised flap results in an
inflammatory response.
Histamine, serotonin, and kinins are released into the extracellular
compartment, increasing the permeability of the microcirculation.
The result is an increase in the concentration of proteins and cells within the
extracellular space.
It may have deleterious effects due to the resultant edema formation.
Reperfusion
Injury
The source of Superoxide radicals
o Inadequate tissue oxygenation → conversion from aerobic to
anaerobic metabolism. Superoxide is a byproduct of adenosine
triphosphate production in the mitochondria and other oxidation
reduction reactions.
o Polymorphonuclear cells are a second source of superoxide radicals
that are released in response to bacterial inflammation.
This byproduct of reperfusion can cause damage at both the cellular and
subcellular levels, contributing to postischemic tissue necrosis.
16
III. Pathophysiology of vessel healing following anastomosis.
1. A thin layer of platelets forms at the
anastomotic site immediately after repair.
2. Exposed collagen triggers the platelet
adhesion.
3. Platelets Accumulate over 48-72 hours
before regressing.
If no intima damage..
4. the platelet aggregations disappear
between 24 to 72 hours.
5. pseudo intima forms at the
anastomosis site within 5 days
6. new endothelium covers the
anastomosis site within 1-2 weeks.
If intima damage occurs ,
4. platelet aggregation continues and after
reaching a certain critical mass it will
trigger a cascade of events leading to
thrombus formation in the vessel.
5. The critical period of thrombus formation in
the anastomosis is the first 3-5 days of
healing.
Factors that contribute to intima damage and
anastomotic thrombus
o Rough vessel dissection
o Diathermy close to the vessel
o Use large needles.
o Repeated needle stabs
o Unequal spacing of sutures
o Too many sutures
o Application of vascular clamps with closing
pressure > 30g/mm2
1.
2.
3.
References:
Harris et al. Endothelialization after arterial and venous micro-anastomosis. CAN J PLAST SURG VOL 3 NO 3 FALL 1995.
Lidman et al. The Normal Healing Process of Microvascular Anastomoses. Scandinavian journal of plastic and reconstructive
surgery 15(2):103-10 · February 1981
17
SUMMARY : FLAP PHYSIOLOGY
▪
▪
▪
Impairment of blood
supply
Denervation
Impairment of
lymphatic supply
(Reference: Mathes Textbook of Plastic Surgery)
2.Vessel healing after anastomosis
Immediately
A thin layer of platelets forms at the anastomotic site
48-72 Hours
Platelet accumulation
First 3-5 days
Thrombus formation can occur if intima damage
Within 5 days
Pseudointima occur
1- 2 weeks
New intima covering the anastomotic site
(Reference: Grab and Smith Plastic Surgery 8 th Edition)
18
DISCUSSION : FLAP PHYSIOLOGY
✓ The fear of vasopressor use: stems from the presumption that they can potentially lead to peripheral
vasospasm, thrombosis, reduced flap perfusion, and ultimately flap failure.
o A survey among microsurgeons revealed that 70% of respondents would not permit the use of
vasopressors in nonemergent situations.
o Another survey revealed that almost one-quarter of respondents attributed free flap loss to the
administration of vasopressors.
o Even among anaesthesiologists, norepinephrine uses in free flap surgery was deemed
contraindicated by 46%.
✓ Meta-Analysis of Flap Outcomes: The majority of the studies in this review concluded that.
vasopressors did not have a negative effect on free flap outcomes irrespective of dose, timing of
administration, and method of delivery.
1. vasopressors were associated with significantly less pedicle thrombosis.
✓ These findings have been theorized to be due to the disruption of autonomic nerve fibres following
adventitial stripping and pedicle division during free flap surgery. While chronic sympathetic
denervation is characterized by adrenergic super sensitivity, α-adrenergic-mediated vasoconstriction
is inhibited immediately after surgical adventitectomy.
2. Perioperative use of vasopressor:
✓ General anaesthetic drugs tend to induce systemic hypotension which can result in hypoperfusion of
critical organs and the flap itself.
✓ Large fluid volumes can lead to progressive edema of the flap which may impair flap microcirculation
by mechanical compression of the microvasculature.
✓
Due to the lack of lymphatic drainage and denervation-related decrease in interstitial fluid
reabsorption, free flaps are more prone to graft edema .
✓
Wei FC, Mardini S. Flaps and Reconstructive Surgery. 1st ed. Philadelphia, PA: Saunders (Imprint), Elsevier; 2009
Sigurdsson GH. Perioperative fluid management in microvascular surgery. J Reconstr Microsurg 1995;11(01):57–65
19
3. Few studies have evaluated the use of vasopressors postoperatively.
o
Only postoperative theodrenaline/cafedrine were associated with adverse flap outcomes, possibly
due to α1-mediated vasoconstriction.
o
Postoperative dopamine infusion at 5 to 10 μg/kg/min increased mean arterial pressure without
compromising free flap outcomes.
o
Intraoperative and postoperative use of dobutamine, was not associated with free flap
thromboembolic complications but instead increased head and neck free flap perfusion.
o
In breast reconstruction, dobutamine and dopamine both increased cardiac output and mean
arterial pressure. However, only dobutamine increased blood flow across the free flap pedicle and
was thus recommended over dopamine should vasoactive agents be required in microvascular
surgery.
Dobutamine
Dopamine
systematically increased CO and heart rate while infused at 3 and 12 g/kg/minute increased the
it decreased SVR
CO, increased vasoconstriction at the higher
dose, and had no effect of flap blood flow.
A simultaneous increase in donor and recipient
artery flow was recorded.
Blood flow in the recipient arteries remained
unchanged
Suominen, S., Svartling, N., Silvasti, M., Niemi, T., Kuokkanen, H., & Asko-Seljavaara, S. (2004). The Effect of Intravenous Dopamine
and Dobutamine on Blood Circulation During a Microvascular TRAM Flap Operation. Annals of Plastic Surgery, 53(5), 425–431.
4.there are likely regional differences in terms of microvascular physiology and regulatory.
mechanisms.
✓ Vasoconstrictive medications may preferentially target the peripheral circulation, leading to more
adverse outcomes when involving the extremities as donor or recipient sites.
✓ Even with denervation-related insensitivity of the flap pedicle, there is theoretically a risk of overall
reduction in distal flow to the extremity, leading to decreased flap perfusion.
Kotsougiani D, Banz CM, Hundepool CA, et al. Influence of post-Operative vasoactive agent administration on free flap
outcomes.Eur J Plast Surg 2016;39:421–428
5. At present, evidence-based recommendations regarding the use of specific vasopressors in free
flap surgery are limited.
✓
Dobutamine ,dopamine and norepinephrine appear to have beneficial effects on flap blood flow;
hence, their indications and safe dosing limits need to be further clarified.
✓ In contrast,epinephrine can decrease flap flow and should be avoided.
Eley KA, Young JD, Watt-Smith SR. Epinephrine, norepinephrine, dobutamine, and dopexamine effects on free flap skin blood flow.Plast Reconstr
Surg 2012;130(03):564–570
Eley KA, Young JD, Watt-Smith SR. Power spectral analysis of the effects of epinephrine, norepinephrine, dobutamine and dopex- amine on
microcirculation following free tissue transfer. Microsurgery 2013;33(04):275–281
20
1. The Compromised Flap
The 15th principle postulated by Sir Harold Gillies.
‘The after care is as important as the planning’.
‘How futile it is to lose flap or graft for the lack of a little
postoperative care.
If in any doubt about the progress slip your hands out of your
pockets and get down to the haematoma.’
Outline
▪ Causes of a Failing Flap
▪ Pathophysiology of Flap Failure
▪ Management of Flap Failure
21
Flap Failure
Causes of a Failing Flap
Extraluminal
factors
Intraluminal factors
Reference:
Anaesthesia for microvascular free tissue transfer, British Journal of Anaesthesia | Volume 3 Number 2 2003
Chapter 24. Principles and management of microsurgery. Neligen Plastic Surgery 4th edition
Singh, B., Cordeiro, P. G., Santamaria, E., Shaha, A. R., Pfister, D. G., & Shah, J. P. (1999). Factors Associated with Complications in Microvascular
Reconstruction of Head and Neck Defects. Plastic and Reconstructive Surgery, 103(2), 403–411
22
▪ Pathophysiology of Flap Failure
1. Vasospasm
▪
Vasospasm occurs in 5- 10 % of microsurgery procedures ,and plays an important role in pathogenesis of
hypoperfusion ,promoting thrombosis
▪
It may be seen intraoperatively and up to 72 hours postoperatively
▪
The pathophysiology is not clear but it is thought to occur secondary to general and local factors :
I.
General factors:
low core temperature, hypotension and sympathetic response to pain
II.
Local factors:
1
2
3
4
Figure 6 :Vasospasm in the pathogenesis of pedicle and free flap failure (Reference : Chapter 23 Flap
pathophysiology , Neligen 4th Edition
Surgical Trauma
Sympathetic nerve endings release vasoactive compounds
Traumatised
Releases endothelium-derived contracting factors (EDCFS) such as thromboxane a 2 (TXA2),
Vascular
and endothelin-1 (ET-1) which raise vascular tone
Endothelial Cells
23
The rate of endothelial degradation of norepinephrine (Ne )and serotonin (5HT2 )by
catechol-o-methyl transferase and monoamine oxidase, respectively, is reduced in
situations of impaired endothelial function.
The synthesis and release of EDRFs such as PGI2 and NO from the traumatized vascular
endothelium are depressed.
Hematoma
Haemoglobin from haemolyzed red blood cells (e.g., hematoma) is a potent
vasoconstrictor.
✓
The hematoma could stretch
the skin flap and place tension on the
subdermal plexus interfering with
dermal perfusion resulting in
ischemic necrosis.
✓
The released iron in the
hemolysate was found to be a
significant factor in the conversion of
Superoxide (02) to the very toxic
hydroxide (OH-) radical. This free
radical production ultimately
correlated with flap necrosis.
✓
iron bound by deferoxamine
is unable to participate in free radical
mechanisms.
Reference: Diaz, D. D., Freeman, S. B.,
Wilson, J. F., & Parker, G. S.
(1992). Hematoma-Induced Flap Necrosis
and Free Radical Scavengers. Archives of Otolaryngology - Head and Neck Surgery, 118(5), 516–518.
24
Free Radical
Damage of
Vascular Wall
In reperfusion of ischemic blood vessels, superoxide radicals (
) are produced by
platelets, neutrophils, and endothelial cells and these free radicals can damage vascular
walls during reperfusion.
2. Thrombogenesis
(Reference: Peter C. Neligan. Plastic surgery third edition, volume one, 2013. 573-588)
▪
Causes:
a) Changes in intraluminal blood flow
b) Endothelial damage
c) The state of coagulability
a. Changes
in blood
flow
External obstruction:
Internal Obstruction
a
25
I.
a.
b.
c.
d.
II.
External obstruction:
Mechanical compression from bandages,
Closure of the wound under tension,
The weight of the flap,
tension/twisting /vasospasm of the vascular pedicle after the
anastomosis is completed.
Intraluminal turbulence:
a. Irregularities of intima from technical error
b. The result of size mismatch
B. Endothelial
Damaged endothelium produces a highly thrombogenic state, resulting in
damage
platelet aggregation and the initiation of complex clotting cascade.
c.
I.
Hypercoagula
Hypercoagulability state:
Pregnancy, active cancer, and recent trauma
bility
II.
Hypercoagulability disorders :
Activated protein C, hyperfibrinogenaemia , antiphospholipid
syndrome and reactive thrombocytosis
3. Xanthine dehydrogenase/xanthine oxidase enzyme system in pathogenesis of ischemia–
reperfusion injury in free flap surgery
1
2
4
5
3
1. In free flap surgery, skin and muscle are subjected to warm global ischemia under vascular
clamp control during transfer from donor site to recipient site prior to reanastomosis.
26
muscle
skin
2–2.5 hours of warm global ischemia
6–8 hours of warm global ischemia
2. During prolonged ischemia, adenosine triphosphate (ATP) in skin and muscle is catabolized
2+
stepwise to hypoxanthine, with concomitant increase in cytosolic Ca .
3. At the same time, a cytosolic protease is activated by intracellular Ca
xanthine dehydrogenase to xanthine oxidase.
4. During reperfusion, the xanthine oxidase generates superoxide (
of molecular oxygen in the presence of hypoxanthine.
5. The unstable
2+
and it converts
) by univalent reduction
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
6. These radicals destroy proteins, membranes, and DNA.
4. Neutrophilic nicotinamide adenine diphosphate (NADPH) and myeloperoxidase (MPO)
enzyme system in pathogenesis of ischemia/reperfusion injury in free flap surgery
Figure 9. Schematic representation of important inflammatory mediators with cytotoxic potential released from activated neutrophils.
O2− indicates superoxide anion; HOCl, hypochlorous acid; H2O2, hydrogen peroxide; MPO, myeloperoxidase; E, elastase; C, collagenase;
LTB4, leukotriene B4; and PAF, platelet-activating factor.
(Reference: Role of neutrophils in ischemia and reperfusion, Circulation. 1995 | Volume 91, Issue 6: 1872– 1885)
1. Polymorphonuclear leukocytes (PMNs) are integrated into the acute inflammatory response to tissue injury and
possess the capacity to produce oxygen-derived free radicals (OFRs) when activated by appropriate stimuli.
2
Activated neutrophils produce:
a. large amounts of
via NADPH oxidase, and these
dismutates yield high concentration of H2O2 and
•
OH , causing tissue damage.
b.
Release of myeloperoxidase (MPO) from the azurophil granules which is unique and abundant in
neutrophils, catalyzes the conversion of H2O2 to hypochlorous acid (HOCl), a potent cytotoxic oxidizing agent
−
+
(H2O2 + Cl + H → HOCl + H2O)
27
5. Intracellular Ca2+ overload in pathogenesis of ischemia–reperfusion injury in free
flap failure
Figure 10 . Cellular effects of ischaemia and reperfusion. The reduced ATP during
ischaemia leads to increased intracellular hydrogen ion and calcium. At
reperfusion the formation of reactive oxygen species (ROS), changing pH and
raised calcium lead to opening of the mitochondrial permeability pore (MPP),
leading to cell death.
(Reference: Kharbanda, R. K. (2010). Cardiac conditioning: a review of evolving
strategies to reduce ischaemia-reperfusion injury. BMJ Journal Heart, 96(15), 1179–
1186.)
1. 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.
2.
+
+
+
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.
+
3. Elevation of intracellular Na concentration causes an increase in intracellular Ca
+
Na /Ca
2+
exchanger causing Ca
2+
influx. If these events continue, the cystolic Ca
2+
2+
by activation of the
will be overloaded, and
2+
significant uptake of Ca from the cytosol to the mitochondria will occur, resulting in mitochondrial Ca
which causes depolarization of mitochondria and impairs ATP synthesis, resulting in cell necrosis.
2+
overload
+
4. At reperfusion, the rapid washout of the extracellular H reactivates the NHE-1, resulting in further extrusion of
+
+
intracellular H , and further accumulation of intracellular Na , causing further cystolic Ca
+
2+
Na /Ca exchange. Again, cytosolic Ca
and resulting in cell death.
2+
overload causes mitochondrial Ca
2+
2+
overload through
overload, impairing ATP synthesis
28
6. Pathogenesis of no-reflow phenomenon in free flap surgery
Three pathogenic mechanisms have been suggested to play
a central role in the development of no-reflow phenomenon in
the skeletal muscle of laboratory animals
Cell membrane damage
2+
allowing Ca influx, resulting in
intracellular overload and lead
to swelling of the endothelial
and parenchymal cell,
narrowing of the capillary
lumen .
Oxygen-derived free radicals
causing damage in the
endothelial and parenchymal
cells;
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.
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.
29
Treatment for failing flap
b
hysical
Interventions
lap
urvival
harmacology
treatment
Experimental
Attempts
Reference: Local flaps in facial reconstruction by Shan R. Baker
30
A. Thrombolytic Agents
History of pharmacology thrombolysis
Indications:
o established extensive clot in either the arterial or the venous system.
o no sufficient restoration of blood flow after blood clot evacuation
o failure to re-establish venous outflow after establishing good arterial inflow.
Contraindications:
o
o
o
o
o
recent stroke or malignancy (particularly if brain metastases are likely)
renal insufficiency
allergy
cardiac thrombus
diabetic retinopathy and coagulopathy
Streptokinase
o Dosage ranging from 50000 – 125000 units
o slowest rate of clot lysis among the three agents
o Stimulates antibody production making retreatment difficult.
o Higher incidence of allergic reaction
urokinase
Urokinase is obtained from human fetal kidney cells.
The advantages of urokinase over streptokinase include:
31
o less antigenicity,
o direct plasminogen activation,
o allowing use in a high concentration as distinguished from
streptokinase, decreased systemic effects reported clinically
Tissue
plasminogen
activator
(t-PA)
o Most flaps were slowly injected in 1 minute via the arterial
pedicle with a dose between 2 and 10mg diluted in saline at a
concentration of 1mg/mL.
o Khansa et al. reported on infusion of up to 40mg of t-PA in some
cases but prevented the thrombolytic drug from entering the
systemic circulation.
o t-PA has several beneficial attributes that include specific affinity
for fibrin-bound plasminogen, enhancement of enzyme activity in
the presence of fibrin, rapid onset of activity, and a short half-life
(range 3.6 - 4.6 minutes).
B. Anticoagulant Agents
Heparin
o The intraoperative use of heparin as a bolus and for irrigation
o A retrospective clinical evaluation of free flap failures demonstrates
safety and efficacy of both intraoperative bolus heparin (5000 IU)
and low dose intravenous standard heparin (2000–3000 IU bolus,
continued by 100–400 IU per hour)
o More frequent haematoma rates were observed when high dose
heparin was given.
S.S. Kroll, M.J. Miller, G.P. Reece, B.J. Baldwin, G.L. Robb, B.P. Bengtson, M.D. Phillips, D. Kim and M.A.
Schusterman, Anticoagulants and hematomas in free flap surgery, Plast. Reconstr. Surg. 96 (1995), 643–647
Aspirin
o Aspirin is an inhibitor of both prostaglandin synthesis and platelet
aggregation.
o It was also reported that a low oral dose of aspirin (325 mg/day) did
not cause postoperative hematoma formation in clinical free flaps.
o One retrospective clinical study aims at aspirin treatment and free
flaps survival in head and neck reconstruction.
o
In this trial, oral aspirin (325 mg daily) was found to be safe and
equivalent compared with subcutaneous heparin (5000 IU bid).
32
Dextran
o Dextran is a heterogeneous polysaccharide used in clinical
hemorheology as a volume expander.
o
It is effective as an antithrombotic agent, as well, by decreasing
factor VIII and von-Willebrand-factor activity and by inhibiting
platelet function.
o Dextran 40 is the most popular dextran used to decrease platelet
aggregation and to improve blood flow in free flap surgery.
o However, dextran 40 also has undesirable side-effects such as
anaphylaxis, pulmonary and cerebral edema, and renal failure.
o
clinical evidence is accumulating to indicate that pre- or
postoperative low-molecular-weight dextran treatment may not be
effective in augmenting free flap viability
C. Antispasmodic agents
1.Local
2.Calcium
Channel
Blocker
anesthesia
3.Alpha
Antagonist
4.phosphodiest
erase inhibitors
Direct
Vasodilators
In general, antispasmodic agents can be classified into five pharmacologic categories based on their
primary mechanisms.
Fig. 11 Mechanisms of topical vasodilation.
33
Drug class
Example
characteristics
phosphodiesterase
Papaverine,
Papaverine
inhibitors
pentoxifylline
o
time to effect with papaverine was less, between 1 and 5
minutes after topical application.
Advantages.
o
it is one of the most studied drugs to treat microvascular
vasospasm.
o
it is an effective spasmolytic agent with a quick onset and a
reasonable duration of effect.
Disadvantages:
o
Of note, available papaverine solutions are typically quite
acidic (pH, 3 to 4.5) and can be caustic to the vascular
endothelium, inducing apoptosis of vascular endothelial and
smooth muscle cells in animal investigations.
o
For this reason, systemic administration is contraindicated,
and use of papaverine as an intraluminal irrigate has been
questioned.
Local anaesthetics
Lidocaine,
o
bupivacaine
The precise mechanism by which lidocaine exerts its local
vasoactive properties is unclear.
o
Some authors have postulated that vasodilation may result
from inhibition of voltage gated sodium channels, producing
a decrease in intracellular sodium and calcium concentration
within vascular smooth muscle cells.
o
Doses Evaluated: 1%, 2%, 4%, 8%, 10%, 12%, 20%
o
The ideal concentration of lidocaine to resolve microvascular
vasoconstriction has been reported to be 12% because this
dose was as effective as, but less toxic than, 20% lidocaine in
a rat tail artery study that evaluated ergotamine-induced
vasospasm.
34
o
However, the safetyand efficacy of lidocaine greater than 2%
have not been systematically examined.
o
For humans, the safety of doses in excess of 2% has not been
conclusively established.
o
Calcium channel
Nicardipine,
Calcium channel blockers work by blocking transmembrane
blockers
nifedipine,
voltage-gated calcium channels, effectively decreasing the
verapamil,
intracellular calcium concentration in vascular smooth
magnesium
muscle cells and ultimately producing vasodilation.
sulfate
o
Advantages:
o
Extraluminal verapamil and papaverine were demonstrated
to be effective antispasmodic agents following NE
vasoconstriction, but verapamil showed higher flow rates
across the porcine gastroepiploic artery (GEA) compared
with papaverine
o
Verapamil was a found superior to 2% lidocaine at preventing
flap marginal necrosis in a rat abdominal wall skin flap model
following injection adjacent to the arterial anastomosis
Direct vasodilators
o
Disadvantages: Insufficient study in humans
Nitroprusside,
o
Advantages: Non apparent
prostaglandin
o
Disadvantages: insufficient study in humans
E1 ,
o
Major systemic side effects: Hypotension, tachycardia
o
Mechanism of Vasodilation: Alpha-1 receptor antagonist
o
Advantages: Encouraging in vivo results
o
Disadvantages: Insufficient study in humans
o
Major systemic effects: Reflex tachycardia
nitroglycerin,
hydralazine
Alpha antagonists
Phentolamine,
chlorpromazine
(Reference: Vargas, Christina R.; Iorio, Matthew L.; Lee, Bernard T. (2015). A Systematic Review of Topical Vasodilators for the
Treatment of Intraoperative Vasospasm in Reconstructive Microsurgery. Plastic and Reconstructive Surgery, 136(2), 411–422.)
35
Which is the preference among plastic surgeons?
Between May and August 2008, an email questionnaire was sent to all 281 consultants in the 49 ‘main’
Plastic Surgery Units listed in the BAPRAS Members & Associates 2008 Booklet.
36
1. The choice of agent and dose to use is often institution- or surgeon-specific and there is no clear consensus
regarding the optimum drug or dose.
2. Based on the studies examined, CCBs (nicardipine/nifedipine/GTN-verapamil) appear to have the greatest efficacy
in preventing vasospasm and inducing vasodilation following microsurgical anastomosis compared with other
agents
3. Future studies need to further compare various CCBs, both topically and systemically, to identify the most effective
antispasmodic agent in this class
D. Free Radical Scavengers
Superoxide
dismutase
Hawkes, Young, and Cleland note anaphylactic reactions in a pig model associated
with the use of superoxide dismutase.
iron chelator
deferoxamine
● Fe2+ + H2O2 → e3+ + OH− + •OH (Haber-Weiss reaction).
● Inhibit hydroxyl radical (OH) formation.
Reduces haematoma-related flap necrosis.
These benefits, however, occur with significant toxicity that can be ameliorated (in
pigs) by the conjugated form, deferoxamine-hespan (DFO-H). DFO-H has a longer
half-life, but with reduced efficacy in augmenting flap survival.
This was postulated to decrease its ability to reach the intracellular oxygen free
radicals.
Allopurinol
Elevated levels of xanthine oxidase have been noted to be elevated in ischaemic flap
tissue in animals.
Allopurinol is a xanthine oxidase inhibitor, reduce SOR production.
A beneficial effect has yet to be shown in humans.
PicardAmi and colleagues, however, note that xanthine oxidase levels in human
tissue are 1/40th of those in rats, casting doubt on XO as a major source of free
radicals responsible for tissue injury and flap necrosis in human skin.
37
B. Physical
Moist
diminished the depth of tissue loss and increased flap survival, presumably by
minimizing desiccation of ischemic tissue. (McGrath in 1981)
Warm
Warming of the flap prevent vasoconstriction and prevent increased blood viscosity,
with resultant increase in skin blood flow
Surgical
Delay
The delay procedure
is a preliminary surgical intervention wherein a portion of the vascular supply to a flap is
divided before the definitive elevation and transfer of the flap.
The resulting benefit, termed the delay phenomenon, is extension of the longitudinal
reach of a flap’s vascular pedicle, creating a greater flap area due to the survival of a
more extended random cutaneous component distally.
Purpose:
1. Increase the surviving length of a flap.
2. Improve the circulation of a flap to diminish the insult of transfer.
Mechanism of delay phenomenon: 2 school of thoughts
1. Delay conditions tissue to ischaemia, allowing it to survive on less nutrient blood flow
than normally needed.
2. Delay improves or increases vascularity.
*Most likely a combination of both mechanisms.
Theories have been proposed to explain delay phenomenon:
1.Increased axiality of blood flow
▪ Removal of blood flow from the periphery of a random flap promotes
development of an axial blood supply from its base.
▪ Axial flaps have improved survival compared to random flaps.
38
2.Tolerance to ischaemia
• Cells become accustomed to hypoxia after the initial delay procedure.
• Less tissue necrosis therefore occurs after the second operation.
(Reference: Dhar, S. C., & Taylor, G. I. (1999). The Delay Phenomenon: The Story Unfolds. Plastic and Reconstructive
Surgery, 104(7), 2079–2091)
3.Sympathectomy vasodilatation theory
39
• Dividing sympathetic fibres at the borders of a flap results in vasodilatation and
improved blood supply.
Figure : Active dilatation of choke vessels due to relaxation of the sympathetic tone on the
vascular smooth muscle . choke vessels reorient themselves and increase blood flow
Reference : Ghali S, Butler P EM, Tepper O M, Gurtner G C. Vascular delay revisited. Plast Reconstr Surg. 2007;119(6):1735–1744.
4.Intraflap shunting hypothesis
• Postulates that sympathectomy dilates AVAs, resulting in an increase in non-nutritive
blood flow bypassing the capillary bed.
• A greater length of flap will survive at the second stage as there are fewer
sympathetic fibres to cut and therefore less of a reduction in nutritive blood flow.
5.Hyperadrenergic state
Figure :Biphasic response to sympathetic nerve division
(Pearl, R. M. (1981). A Unifying Theory of the Delay Phenomenon– Recovery from the Hyperadrenergic
State. Annals of Plastic Surgery, 7(2), 102–112.)
• Surgery results in increased tissue concentrations of vasoconstrictors, such as
epinephrine and norepinephrine.
• After the initial delay procedure, the resultant reduction in blood supply is not sufficient
to produce tissue necrosis.
40
∘ The level of vasoconstrictor substances returns to normal before the second
procedure.
• The second procedure produces another rise in the concentration of vasoconstrictor
substances.
∘ This rise is said to be smaller than it would be if the flap were elevated without a prior
Delay -- The flap is therefore less likely to undergo distal necrosis after a delay
procedure.
Leeches
Background:
The word ‘leech’ is supposed to be derived from an old English word for
physician,laece
1500 BC: Leeches were used for treatment in Egypt- treat ailments, like nosebleeds
and gout.
1981: They have been shown to be useful in distal digital replantation (Foucher et al.,
1981) and in the replantation of other tissues (Henderson et al., 1983).
July 2004: the FDA approved leeches as a medical device in the area of plastic and
reconstructive surgery
Mechanism:
• Mechanical- Blood suction following a bite will temporarily improve tissue
perfusion by actively draining blood from congested tissue (mechanism
demonstrated by laser Doppler analysis by Knobloch et al)
•
Biological effects-Once active suction is complete, passive blood loss will
occur. Anticoagulants, inhibitors of platelet aggregation, and other vasodilators
produced by leeches will allow blood flow at the bite site to continue even after
the leech is detached.
Side effects:
• Excessive blood loss may necessitate a blood transfusion.
• Allergic responses, including anaphylaxis.
• bacterial infection from the gram-negative rod Aeromonas hydrophilia (which is
the leech enteric organism responsible for red cell digestion)
-Infections can arise 2 to 11 days after therapy begins and can result in
abscesses and cellulitis
- Prophylactic antibiotics are usually recommended: double coverage (two
antibiotics) during therapy and single coverage (one antibiotic) for two weeks
afterward [
41
Limitations:
1. flap volume.
The success rate falls to around 30% for high-volume flaps.
such as TRAM or DIEP
2. Studies on hirudotherapy have a relatively low-level evidence.
42
3. FLAP MONITORING
o The goal of postoperative free flap monitoring is to detect microvascular complications before permanent injury.
o The ultimate success of microsurgical free-tissue transfer rests on optimizing the ability to identify and salvage a failing free flap
o When thrombosis does occur, success of salvage is highly dependent on early clinical detection, with free flap salvage rates dropping from
62.2 to 21.4% if recognized after 16 h ( Young 2007)
o Creech and Miller outlined essential criteria for an ideal monitoring technique should be:
– Simple, and harmless to the patient and free flap
– Rapid, repeatable, reliable, recordable, and rapidly responsive
– Accurate and inexpensive
– Objective and applicable to all kinds of flaps
– Equipped with a simple display that could alert relatively inexperienced personnel to the development of circulatory impairment.
Non-invasive
Invasive
Clinical assessment (gold standard)
Implantable Doppler/ venous coupler
Acoustic cutaneous Doppler
Oxygen tension monitoring
Color Doppler sonography
Tissue pH monitoring
Laser Doppler flowmetry
Microdialysis
Microlight-guided spectrophotometry
Technetium-99m sestamibi scintigraphy
Surface temperature monitoring
Contrast-enhanced Doppler
Tissue oximetry
Biochemical markers from free-flap blood (e.g., glucose,
lactate)
Fluorescence imaging
Perfusion-weighted MRI
43
▪ Non-Invasive Monitoring
Technique
Description
Gold standard –
Clinical
Assessment
Advantages
Disadvantages
1. Standard technique
May be unreliable, impossible
for some flaps
2.cheap (cost)
3. The effectiveness of clinical
monitoring is high:
one meta-analysis found flap
success rates with clinical
assessment alone to range.
from 85 to 95%
Handheld
doppler
An 8 MHz hand-held Doppler probe is used to perform
periodic detection of venous and arterial Doppler signals
cheap and portable
not possible in buried flaps and
flaps with difficult access e.g.,
the oropharynx.
Colour Duplex
Ultrasonography
o
This is a combination of b -mode ultrasound and bidirectional Doppler imaging.
o
It can be useful in the
assessment of buried flaps.
o
US$30,000 to US$225,000
=~ 2 x Honda city car
o
Colour duplex sonography combines the recording of blood
flow velocity with the recording of blood flow direction.
o
Excellent positive and negative
predictive values
o
Combined colour flow and spectral Doppler imaging within
both flap and recipient vessels enables accurate assessment
of
anastomotic patency
o
Requires for an ultrasound
technician, radiologist, and
44
the microvascular surgeon
to each be present to
perform and interpret the
examination.
Laser Doppler
Flowmetry
o
LDF measurements are relative and measured in blood
perfusion units which is proportional to the velocity and
concentration of RBCs within the tissues studied.
o
Using this technique, a laser light is emitted onto a tissue
surface. The light penetrates to a depth of 1-2 mm causing its
wavelength to shift by moving particles.
o
Moving red cells contribute to more than 99.9% of the total
amount of moving cells within a blood vessel (Doppler
effect). The shifted and un-shifted light is returned to photo
detectors where it is processed and amplified.
o
Easy to use for surface flaps.
o
o
The probe can be attached to
the skin by using double-sided
adhesive rings; sutures can also
be used when a firmer
attachment is required.
Difficult to use in buried
flaps, probe can be fragile
and easily damaged.
o
The price of the laser
Doppler flowmeter
ranges upward from $5460,
o
the price of the probe
ranges upwards from $1015.
The probe can be used for at
least 10 cases or half a year
before it needs to be
replaced
45
Surface
temperature
Monitoring
o
o
o
a reduction of 3°C in the centre of the flap indicated arterial
occlusion.
a reduction of 1°C to 2°C venous compromise
The temperature can be monitored using:
a) touch
b) temperature probes
c) temperature-sensitive tape
o
Simple
o
Not suitable for most oral or
pharyngeal reconstruction
o
Kaufman’s study of muscle
flaps suggested that
temperature monitoring
was not a reliable indicator
of flap perfusion unless all
environmental influences
were monitored and kept
absolutely constant so that
perfusion was the only
variable
d) infrared thermometry
46
ii. INVASIVE MONITORING
Implantable
Doppler
(Cook- Swartz
Doppler )
o
o
The use of an implantable Doppler probe as a method for free-flap
monitoring was first described in 1988 by Swartz; the device is
commonly referred to as a Cook–Swartz Doppler.
o
Excellent positive and
negative predictive
values
o
A recent systematic
review comparing the
implantable Doppler to
clinical monitoring—for
head and neck,
breast, and extremity
reconstruction—found
that overall,
the implantable
Doppler was associated
with significantly
greater flap salvage
rates and overall flap
success rates.
The device consists of a piezoelectric crystal mounted on a silicon
cuff that is wrapped around the anastomosed blood vessel—
either artery, vein, or both— with wires extending to the surgical
wound where they are connected to the equivalent of a
cutaneous acoustic Doppler.
o
o
By this means, the implantable Doppler provides continuous
information about intravascular flow through the anastomosed
vessel(s). Vascular compromise can therefore be detected
instantaneously, allowing, in theory, a more prompt return to the
operating room and better chances at flap salvage.
o
o
Learning curve, difficulty
detaching lead
£1500-£2000 for monitor
and £200-£300 for probe
47
o
Microdialysis
Micro dialysis involves insertion of a
semipermeable micro dialysis catheter
Excellent positive and
negative predictive
values
o
Labour intensive
o
Cost: £35,000.00 for the
analyzer/monitor plus
£350.00 per case for
reagents and
consumables.
o
= 2x
into the flap (fat or muscle) intraoperatively.
48
o
This is perfused using Ringers Solution at a constant rate using a batteryoperated pump to monitor the metabolism of a flap.
o
The analysis of each sample takes about 15 min and needs a minimum of
0.5_L of sample fluid and 15_L of reagent.
o
The perfusate is normally collected every hour so flap monitoring is not
continuous. Ischaemia can be detected by monitoring the changes in
glucose, lactate, and pyruvate levels in the interstitial fluid of monitored
tissue.
Fluorescein
angiography
o
Fluorescein angiography was first described in 1977 to evaluate the
viability of arterialized flaps after harvest.
o
Newer trials have employed indocyanine green (ICG) dye instead of
fluorescein, stating its low side-effect profile and lack of vascular
extravasation (compared with fluorescein which does not remain
strictly intravascular)
o
Fluobeam™ system set-up to explore perforator vessels of the thigh
o
The technique is
relatively
straightforward and
inexpensive
o
require additional
investigation (larger
trials, randomized headto-head comparisons,
and cost analyses) to
determine whether or
not they truly provide
any additional benefit
over the traditional
monitoring techniques
discussed previously.
49
Summary
Clinical monitoring remains the gold standard method of postoperative free-flap evaluation.
Other adjuncts can prove useful to the surgeon and allied health team, but no definite consensus exists regarding their proper use.
As with many postoperative regimens, free-flap monitoring techniques are surgeon-dependent and can vary significantly from institution to institution.
Thank You.
50