Free Flap Salvage
Microsurgical risk factors
Prophylaxis
 In 1982, in a world survey of anticoagulation practice used before, during and after
surgery, Davies et al. revealed no consistent protocols and thus concluded that
statistical analysis was impossible. In general, they that found free flaps had equal
outcomes with and without pharmacological intervention, whereas replants had better
outcomes without pharmacological intervention
 In the largest multicenter prospective study of free-tissue transfer, Khouri et al.
reported that only postoperative subcutaneous heparin treatment had a statistically
significant effect on preventing thrombosis. Although they recognize experimental
evidence which shows that heparinized irrigation has a beneficial result in preventing
thrombosis, the data from Khouri et al. have support no benefit to the use of heparin
irrigation or other pharmacological interventions in the practices of 23 different
surgeons.
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Physical factors
1. Moist environment
a. increases flap survival and decreases the depth of tissue loss, presumably by
minimizing dessication of ischaemic tissue
2. Local temperature
a. hypothermia leads to vasoconstriction and increased blood viscosity, with a
resultant decrease in skin blood flow; at 140 C blood flow in flaps has been
shown to cease completely. Warming has the opposite effect.
b. Cooling is beneficial when flaps are ischaemic
3. Stress conditioning
a. animals exposed to supraphysiologic levels of heat synthesize heat shock
proteins which protect the cells from the toxic effects of stress, ie the animal
becomes stress-conditioned.
b. The heat-shock response is also induced by other forms of stress such as
ischaemia, hypoxia, hypoglycaemia and cellular toxins, but once the organism
is stress-conditioned it is also protected against other stress agents.
c. Heat shock and recovery (need 6 to 8 hours before re-stress) has been used
experimentally in rats and found to be effective, possibly by protecting
capillary integrity (heat shock proteins have a strong affinity for capillary
endothelium).
4. Preconditioning
a. muscle flaps subjected to intermittent periods of global ischaemia followed by
reperfusion have been shown to have an increase in flap survival, possibly by
alterations in blood flow, decreased tissue metabolism, decreased levels of
ODFRs, selective loss of certain non-essential cellular functions, and the
release of endothelium-derived relaxing factors which may cause vasodilation
and improved distal blood flow.
5. Hyperbaric O2
a. improves skin flap viability; must be given as soon as possible after surgery.
The beneficial effect is thought to be due to increased superoxide dismutase
activity.
b. effective windows for HBO therapy in free flaps appear to be 18 hours of
normothermic and 72 hours of hypothermic ischaemia.
c. Disadvantage – difficult logistics
6. Cease smoking
a. Smoking decreases capillary blood flow, distal perfusion and flap survival
(more so in small vessel flaps ie finger replant) in a dose- and time-dependent
fashion
Pharmacologic control
Anticoagulants
Dextran (40 or 70)
 heterogeneous polysaccharide synthesized from sucrose by the Leuconostoc
mesenteroides bacterium, is produced as a 40,000 or 70,000 molecular weight polymer
 Mechanisms
1) increasing the electronegativity on platelets and endothelium, thus preventing platelet
aggregation
2) modifying the structure of fibrin, making it more susceptible to degradation
3) inhibiting alpha-2 antiplasmin and subsequently activating plasminogen
4) decreasing factor VIII and von Willebrand factor, thereby decreasing platelet function
5) altering the rheologic properties of blood and acting as a volume expander.
 Use controversial
 a single preoperative bolus of dextran has shown improved patency in the immediate
postoperative period
 should be given as a test dose (less than 5 ml of dilute dextran) with monitoring for a rash
or other adverse sequelae
 Infusion dose – 20ml/hr of Dextran 40
 Complications significant: anaphylactic reaction, bleeding and systemic
 PRS 2003 Cordiero (Sloan-Kettering)
o H&N free flaps using low molecular weight dextran or aspirin
o No difference in free flap loss but dextran use associated with significant systemic
complications (nephrotoxicity, congestive heart failure, myocardial infarction,
pulmonary edema, pleural effusion, and pneumonia) 51 vs 7% for aspirin
·
Heparin
 inactivates the coagulation factors XIIa, XIa, IXa, Xa, and IIa (thrombin)
 inhibition of thrombin and, subsequently, the inhibition of thrombin-induced activation of
factor V and factor VIII are primarily responsible for its anticoagulant effect.
 In animal models, heparin increased arterial patency with no effect on venous patencies
o Arterial thrombi more likely to be platelet activated whereas venous thrombi more
likely to be stasis related – fibrin+RBC
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In humans, likely to be useful for both
local irrigant dose of 50-100U/ml helps prevent thrombosis without systemic side effects.
macrovascular surgery literature recommends intraoperative anticoagulation with 100 to
150 U/kg of intravenous heparin before cross clamping, supplemented with 50 U/kg
every 45 to 50 minutes until anastomosis and the reestablishment of flow
Kroll (PRS 1995)
o five groups: no anticoagulation, low-dose IVH, IVH given intraoperatively with
no postoperative anticoagulation, high-dose IVH, and dextran
o hematoma rates for the five groups of patients were 5.3%, 6.7%, 6.5%, 20%, and
9.1%, respectively.
o flap failure rates for these five groups of patients were 4.4%, 1%, 0%, 10%, and
27.2%
Aspirin
 acetylates cyclooxygenase and decreases the products of arachidonic acid metabolism,
including thromboxane, a potent platelet aggregator and vasoconstrictor; and
prostacyclin, a potent vasodilator and inhibitor of platelet aggregation. Thromboxane is
produced by platelet-derived cyclooxygenase, whereas prostacyclin is produced from
endothelial cyclooxygenase.
 Aim is to inhibit thromboxane
 minimal dose for complete suppression of thromboxane in humans is reported at 100 mg
 at low doses (up to 325mg), endothelial prostacyclin is not inhibited – shown to more
effective than high dose in reducing stroke, myocardial infarction, and death
 in rat studies , low dose aspirin inhibits anastomotic venous thrombosis and improves
microcirculatory perfusion
TXA2 synthetase inhibitors
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improved survival in ischaemic flaps
Streptokinase / Urokinase
 Low systemic (non-thrombolytic) doses of both substances given in boluses and
continuous infusion has failed to show improvement in patency rates.
TPA
 continuous infusion over 24hours reduced thrombosis in a rat model with no increase in
bleeding rates.
Leech therapy
 medicinal leeches - Hirudo medicinalis
 used in medicine since ancient times
 used to relieve venous congestion after free tissue transfers and replantations
 exert their effect by injecting hirudin at the site of the bite (hirudin is a naturally
occurring anticoagulant that inhibits the conversion of fibrin to fibrinogen and that, unlike
heparin, does not require antithrombin-III for activation)
 also secrete hyaluronidase (which facilitates spread of the anticoagulant within the
tissues) and a vasodilator which contributes to prolonged bleeding (up to 48 hours)
 has a mechanical action by creating physical channels through which venous drainage can
occur
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Indications - venous congestion where outflow is insufficient or venous channels are
either absent or unsuitable for anastomosis
Contraindications - arterial insufficiency, in which case the leeches will simply not attach
themselves to the flap
Complications
1. Gram negative infection with Aeromonas hydrophilia (the leech enteric organism
responsible for red cell digestion)
2. Anaphylaxis
3. Persistent bleeding
4. Excessive bleeding
Recommendations for antibiotic prophylaxis: ciprofloxacin or (aminoglycoside plus third
generation cephalosporin) – rate of infection of 7- 20% if no antibiotics
successful salvage of tissue with leeches occurs in 70 to 80 percent of cases
Drops to 30% when complicated by infection
Caution when treating immunocompromised patients
Recombinant human tissue factor pathway inhibitor (rhTFPI)
 a naturally occurring protein which combines with tissue factor and factors VIIa and Xa
to retard the coagulation process
 used as a antithrombotic additive to the intraluminal irrigating solution during
microvascular anastomosis
 shown to be as efficacious as heparin for preventing thrombotic complications during and
after the operation (experimental – phase II trials)
Glycoprotein IIb/IIIa antagonists
 Glycoprotein IIb/IIIa is a highly abundant platelet surface receptor that plays a major role
in platelet aggregation by binding platelets to each other through the coagulation factor
fibrinogen.
 Remains experimental (animal studies)
HES - hydroxy-ethyl starch
 also used as a volume expander
 NOT associated with bleeding complications when given at recommended doses
 Main effect is by normovolemic hemodilution as a means to prevent thrombosis
 Experimental (animal models)
Receptor and Axon Blockers
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Antiadrenergic agents have been shown to improve flap survival.
Raising a flap is thought to lead to a release of norepinephrine that stimulates both α- and
β-receptors, with subsequent vasoconstriction and metabolic stimulation.
1.
reserpine / guanethidine
- deplete norepinephrine stores in nerves
2.
propranolol
- opposes β-mediated metabolic stimulation
3.
phentolamine
- α-blocker / direct smooth muscle relaxant
4.
Other agents include phenoxybenzamine (α-blocker), terbutaline (β2-agonist),
naftidrofuryl (arteriolar vasodilator), trimetazidine, isoxsuprine (vasodilator) and
chlopromazine (α-blocker and direct vasodilator).
Direct smooth muscle relaxants
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topical nitroglycerin
o potent vasodilator with a greater effect on the venous circulation than on arterial
vessels. This may be applied transdermally to improve flap survival.
calcium-channel blockers
1.
eg diltiazem, nifedipine, verapamil, nitrendipine
2.
act on the vascular smooth muscles to cause vasodilation and improve
circulation in the flap
3.
diltiazem also stimulates the release of prostacyclin (PGI2 - a potent vasodilator
and anti-platelet aggregator) from vascular endotheliuim
hydralazine
1.
increases flap survival by increasing intracellular cAMP, which causes
arteriolar smooth muscle relaxation
dimethyl sulfoxide (DMSO) and hyaluronidase improve flap survival
1.
possibly due to a decrease in tissue oedema with resultant improved blood flow
topical lignocaine and pentobarbital
1.
relieve mechanically induced vasospasm, but these effects are circumvented by
microvascular thrombosis
buflomedil (α-blocker)
1.
improves flap survival by increasing red cell deformability, reducing platelet
aggregation, and diminishing leukocyte adhesiveness
Prostaglandins
1.
Exogenous prostacyclin (PGI2) and Iloprost (protacyclin analog)
1. potent vasodilator and inhibitor of platelet aggregation
2. effective if given at time of flap elevation and continued post-operatively
3. IV Iloprost has been used as an infusion to maintain flap patency (BJPS
1996)
2.
Prostaglandin E1
1. causes peripheral vasodilation and platelet disaggregation
2. biphasic response - higher doses result in hypotension and decreased blood
flow to the entire flap
Rheologic agents
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Pentoxifylline
1.
a xanthine derivative
2.
improves flow characteristics by enhancing red cell deformability
3.
also promotes platelet deaggregation.
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Dextran (40 or 70)
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Piracetam
1.
enhances red cell deformability
2.
decreases adherence of the red blood cell to the vascular endothelium
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Flourocarbons
1.
lower the viscosity of blood, thereby improving the microcirculation and
enhancing flap survival
Agents that increased tolerance to ischaemia
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Steroids
1.
effect on flaps is still under debate
2.
mechanisms:
1. vasodilation
2. attenuation of neutrophil infiltration
3. reduction of lipid peroxidation
Free radical scavengers
 Use of scavengers, in particular superoxide dismutase has been shown to improve flap
survival rates in compromised flaps in animal models.
1.
enzymatic systems - superoxide dismutase; catalase; glutathione peroxidase
2.
metal chelators - desferoxamine
3.
antioxidants - caeruloplasmin; vit E; glutathione; betacarotene; vit A; lactoferrin
4.
allopurinol - blocks xanthine oxidase; increased survival
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Salvage following thrombosis
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Arterial thrombosis associated with a much higher salvage rate than venous thrombosis
(40% salvage rate)
 Due to delay in diagnosis and to the microvascular changes, anastomotic revision alone
has been insufficient in the majority of cases as compared with arterial thrombosis.
 It is more often associated with the no-reflow phenomenon.
 2 major theories on the no-reflow phenomenon
1. microemboli
 platelet emboli generated at the arterial anastomosis
 induces microcirculatory changes downstream leading to a disruption of capillary
perfusion
 coupled with low flow prothrombogenic environment this may initiate widespread
thrombosis
2. reperfusion injury
 damage largely due to the formation of cytotoxic oxidants derived from molecular
oxygen ( oxygen-derived free radicals (ODFR))
 Two mechanisms of production of ODFR:
a. hypoxanthine produced during ischaemia With the restoration of normoxia,
the hypoxanthine substrate is combined with oxygen to produce xanthine and
an oxygen radical.
b. Neutrophil accumulation with reperfusion - contains an NADPH oxidase that
reduces molecular oxygen to the superoxide anion.
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Xanthine oxidase inhibitors (allupurinol) and free radical scavengers such as
superoxide dismutase has been shown to afford protection in models of reperfusion
injury
The ischaemia-induced reperfusion injury results in:
1. changes in microvascular diameter
2. swelling of endothelial cells
3. impaired red cell deformation
4. enhanced platelet and red blood cell aggregation
5. leakage of macromolecules into the interstitium
Treatment
 In general, all thrombolytic agents act to convert plasminogen to plasmin, which then
degrades clot
 Agents used for salvage are streptokinase, urokinase, and recombinant tissue plasminogen
activator (rt-PA) but there are no randomised trials comparing them
 Higher rates of bleeding complications have been observed in patients treated with
streptokinase and rt-PA when compared with urokinase
 The STILE trial (Surgery versus Thrombolysis for Ischemia of the Lower Extremities)
was a prospective randomized trial that found no difference in the efficacy or safety
between rt-PA and urokinase when used for thrombolysis in ischemic lower extremities.
 At this time, urokinase has been recommended as the agent of choice for thrombolysis in
regard to its clinical effectiveness, cost, and complication rates
Streptokinase
 An indirect activator of plasminogen. It activates the fibrinolytic system by forming a
complex with circulating plasminogen, thereby unmasking a proteolytic site on the
plasminogen component.
 works through a proactivator that converts it to an active form, converting plasminogen to
plasmin
 However, the active streptokinase-plasminogen complex is an indiscriminate protease. It
can degrade numerous circulating proteins, including itself, fibrinogen, and other
coagulation factors. It elicits a systemic lytic state predisposed to bleeding and
characterized by fibrinolysis and an increased concentration of circulating fibrin
degradation products.
 500,000-750,000 units of streptokinase given locally with the venous effluent drained to
prevent systemic effects
 Complications: anaphylaxis and bleeding
Urokinase
 serine protease that converts circulating plasminogen to plasmin in the first order of
action resulting in fibrinolysis. Like streptokinase, urokinase converts both circulating
and fibrinbound plasminogen to plasmin, thus inducing a systemic lytic state
 PRS 1998: Urokinase protocol for free-flap salvage following prolonged venous
thrombosis.
 short half-life – 14 minutes
 Urokinase has not been associated with antibody induction, but with large bolus doses
(>250,000 IU) it has induced shaking chills and tachycardia
 Protocol
a. urgent return to theatre
b.
c.
d.
e.
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expose arterial and venous anastamoses
5000U IV heparin to protect arterial anastamosis
occlude arterial inflow with clamp
venous anastomosis was then resected, and the flap veins were irrigated with
heparinized saline
f. Repeat venous anastamoses
g. 25-gauge butterfly inserted into the recipient artery just proximal to the arterial
anastomosis.
h. 250,000 units of urokinase in 50 cc of saline infused over 30 minutes in small,
intermittent doses.
Other groups leave vein open to prevent systemic effects of the urokinase
rt-PA
 a naturally occurring activator of plasminogen and, unlike streptokinase and urokinase, is
relatively clot selective.
 This property minimizes the risk of inducing a systemic lytic state.
 It binds to fibrin, not fibrinogen, and only in this bound form converts plasminogen to
plasmin Thus clot lysis is initiated only at the site of the clot.
 In replanted digits, direct intravenous infusion is not possible. In such situations, injection
of rt-PA in the pulp soft tissues may result in successful salvage.
Leech Therapy
 Has been used for venous obstruction not considered salvageable by conventional
surgical or thrombolytic therapy (Arch Otolaryngol Head Neck Surg 2002)
 Protocol includes intensive care unit monitoring, antithrombotic pharmacotherapy,
frequent hematologic evaluation, blood transfusions as needed, and antibiotic prophylaxis
for Aeromonas hydrophila
 average of 215 leeches were used per patient, and the average time needed for
inosculation was 6.6 days.
 average duration in the intensive care unit was 9.6 days
 average of 13 U of packed red blood cells per patient was necessary.
 Significant morbidity - with intensive care unit psychosis, prerenal renal failure, and large
transfusion requirements being the most frequent complications.