CURRENT OPTIONS IN PHARMACOLOGICAL INTERVENTIONS FOR MICROVASCULAR ANASTOMOSIS PATENCY: REVIEW

^INTRODUCTION

The scope of reconstructive techniques using microsurgical anastomosis continues to expand. The surgical approach and materials were mostly standardized. Nevertheless, the patency of microvascular anastomosis and prevention of thrombosis of peripheral vessels of the flap remain the key points of a successful reconstruction. Although most specialists agree that the surgeon’s experience, quality operative techniques and well-chosen and prepared patient lead to major reduction of ischemic complications in the first place, and some authors consider this to be the only relevant factor, there are still various drugs applied to prevent clot formation in the anastomosis site and inside the flap.

Despite the long history of microvascular reconstructive procedures, no consensus on a single perioperative pharmacological approach exists between the authors. The literature offers mostly retrospective studies, presentation of individual experiences or laboratory experiments. Strong factors influencing potential research are interindividual differences in vessel quality and individual coagulation status among patients. Most protocols are based on the creation of iatrogenic hypocoagulation or hypoaggregation condition in perioperative care for prevention of thrombotic complications, yet the used doses of drugs differ. Minority of protocols use spasmolytics, promote faster epithelization and minimize expression of pro-inflammatory and pro-coagulative factors in the anastomose site.

^{PHARMACOLOGICALLY INFLUENCEABLE CAUSES OF FLAP ISCHEMIA}

Beginning with general conditions, flap could be ischemic due to the alteration of blood circulation, which can be caused by low cardiac output, hypotension, hypothermia or low haematocrit, high blood viscosity or excessive blood loss. Locally may occur peripheral vasoconstriction or in 5–10% cases spasm of flap nutrition vessel¹. Low blood flow with damaged endothelium and hypercoagulopathy lead potentially to thrombus formation².

Blood clot in anastomosis site is the most frequent local event resulting in flap failure³. That is the reason why increased effort is necessary during perioperative period to prevent this condition and also microthrombotisation of peripheral flap vessels. Venous thrombus is more frequent than arterial. 90% of arterial thrombi are formed usually within the first 24 hours. Conversely, the venous thrombus occurs mostly between the first 24–48 hours after surgery⁴. Other unfavourable local conditions as vessel kinking, strangulation or compression by haematoma should be eliminated by proper surgical technique.

^{PERIOPERATIVE FLUID AND PHARMACOLOGICAL MANAGEMENT}

Former recommendations aimed at prevention of the flap vessels spasm by administering vasodilators and usage of peripheral vasoconstrictors for mean arterial pressure (MAP) stabilisation was considered risky⁵. MAP around 100mmHg is now recommended and considered appropriate for sufficient perfusion of the flap. Recent studies have not demonstrated that administration or omission of peripheral vasoconstrictors e.g. phenylephrine, ephedrine, dopamine, dobutamine, noradrenalin in perioperative period is important for flap survival⁶. Some studies differentiate between drugs influencing blood pressure and circulation; for example Suominen prefers usage of Dobutamine that increases stroke volume and decreases systemic vascular resistance more than dopamine, which only increases stroke volume⁷. German society for microsurgery of peripheral nerves and vessels recommends to use norepinephrine rather than dobutamine⁸. Mokatef reported better flap perfusion with norepinephrine or dobutamine⁹. (Figure 1.)

It is recommended to maintain normal partial pressure of O₂ a CO₂ during general anaesthesia (GA). Hyperoxemia and hypokapnia as well as hypothermia and insufficient postoperative pain control can lead to peripheral vasoconstriction⁵. Drugs used in GA often lead to systemic hypotension. Sevoflurane is the most commonly used volatile anaesthetic agent. It has documented protection for endothelium against ischemic damage, it promotes healing of vessels and in comparison with Propofol it decreases capillary filtration coeficient⁹. As prevention of hypotension during GA, it is recommended to reduce doses of anaesthetics and to increase circulating fluid volume. It is necessary to balance pros and cons. The benefit is elevation of MAP, but it may cause oedema of tissues within the flap, worsening of microcirculation, haemodilutive coagulopathy or heart failure¹⁰.

Ševčíková found that 20–30% haemodilution by crystalloids can lead to hypercoagulative condition, caused by dilution of coagulation inhibitors and by lowering threshold for positive feedback, which is a component of coagulation cascade¹¹. Administration of more that 130 ml/kg crystalloids per day or more that 7 litres during the operation correlates significantly with perioperative complications including thrombosis and flap loss. The recommended dose of crystalloids in the first perioperative 24 hours is 3.5 to 6.0 ml/kg per hour⁹.

Infusion of colloids as hydroxyethyl starch or gelatine can help to maintain reasonable MAP, and also cause mild prolongation of activated partial thromboplastin time (aPTT) and prothrombin time (PT). Five percent human albumin influences coagulation less than starch solutions⁹.

No data support dependency of haematocrit level on the flap loss¹⁶. Also, an association between blood transfusion administration and more surgical complications and flap failure is disapproved. Complications occur more often with more administered transfusions, but increased frequency of complications depends more on polymorbidity of the patient.

Although corticosteroids promote pro-coagulative state and release of platelets, their administration is supported as an anti-swelling agent and for prevention of postoperative nausea and vomiting⁸. Surgical complications were observed more frequently with longer duration of GA¹².

Pentoxifylline increases red blood cells deformability and lowers blood viscosity. Vasodilation effect was observed too¹. Statins prevent endothelial dysfunction, release of nitrogen monoxide (NO) from endothelium, and reduce inflammatory response and by that act anti-thrombotically. Some studies on animals also support vasodilatation^1,13.

^{SYSTEMIC ANTICOAGULATION AND ANTIAGGREGATING}

The most common way how to minimize the risk of thrombus formation is to create hypocoagulation or hypoaggregation of blood. The most commonly used drugs are heparin, low molecular weight heparins (LMWH) and acetylsalicylic acid¹⁴.

Heparin is an anticoagulant and it prevents both arterial and venous thrombosis acting on various systems: it inactivates or reduces activation of coagulation factors¹⁵, lowers the recruitment of platelets and fibrin deposition and in higher doses increases vasodilation probably by releasing NO from endothelium³. Effect of Heparin is measurable by activated Partial Thromboplastin Time (aPTT), the normal range of which is 22–35 s². Measurement with thromboelastography (TEG) is more dynamic, but aPTT is considered the standard¹⁶. As heparin cannot dissolve an existing clot, it should be administered systemically preoperatively in a bolus, or before the division of flap vessels in the harvest site. Some protocols recommend administration before clamp release after suturing the anastomosis¹⁷. However, flap is not presaturated with heparin in these cases. Heparin medication is often prolonged after surgery.

Heparin can also be used locally, when anastomosing vessels are irrigated by heparin solution, or flap is totally flushed with heparin solution. Pressure of irrigation solution should not be more than 100mmHg, because of the risk of intimal damage⁴.

The use of heparin can lead to complications. The most common is haematoma formation and bleeding, less commonly heparin induced thrombocytopenia may occur¹⁸.

Low molecular weight heparin (LMWH) is a derivate of heparin, with more specific effect on factor X. Easier administration is the major benefit as well as higher biological availability and lower risk of thrombocytopenia¹⁷. However, monitoring of the activity of LMWH with anti-Xa is not as precise as in heparin with aPTT and the effect on arterial thrombosis prevention is doubtfull³.

Acetylsalicylic acid (ASA) irreversibly inhibits cyclooxygenase in platelets. By this, the transformation of arachidonic acid to thromboxane and prostacyclin is blocked¹³. Thromboxane is a vasoconstrictor and platelet aggregator; the effect of prostacyclin is the opposite. ASA also interferes with thrombin formation¹³. ASA is commonly used in vascular surgery. Dosage and time of administration is important. The vessel patency is better if ASA is administrated 10 hours before a surgery. The dose of 5mg/kg sufficiently blocks synthesis of thromboxane and maintains synthesis of prostaglandins^4,17. ASA is usually used in combination with heparin or LMWH. Most common complication is higher risk of perioperative bleeding and haematoma formation, renal dysfunction and bleeding from the gastrointestinal tract¹⁹. Because of relevant interindividual pharmacokinetic differences and inhibition of only external path of coagulation cascade, warfarin is not used in free flap surgery. Also, usage of ticlopidine and clopidogrel is only experimental in free flap surgery²⁰.

Dextrans as plasmaexpanders lower blood viscosity and improve rheology of blood and act antithrombotically by increasing electronegativity of red blood cells, platelets and endothelium¹³. Anaphylactic reaction, acute respiratory distress syndrome, risk of heart failure and kidney damage can occur as a negative complication^3,4. In prospective randomized studies dextran does not have an effect on flap survival in comparison with the group without any antithrombotic medication. Systemic complications were observed in both cases⁹.

Zhou pointed out in 2018 in a prospective randomized double-blinded controlled clinical trial that the use of antithrombotic agents in head and neck microvascular surgery does not decrease the risk of thrombosis formation and may increase the risk of haematoma formation. He also summarized that postoperative antithrombotic agents should not be used routinely, but administration should be based on an individual risk assessment²¹.

We follow the procedure to measure the actual aPTT, PT, red blood cells and platelets just before the flap division and administer usually 10,000 IU bolus of heparin systemically. Since the end of surgery, we administer an infusion of 1000ml of normal saline + 10ml of 1% Mesocain + 10ml of 10% MgSO₄ + 5ml of pentoxifylline (Agapurin) continually for 24 hours. Heparin is administered continually with an effort to maintain aPTT between 42–45s for the following week.

^{TOPICAL AND LOCAL DRUGS}

The idea of the vasodilator administration locally onto or into the sutured vessel as a prevention of spasm and subsequent prevention of systemic effect have led to local administration of drugs. A survey of plastic surgeons in the United Kingdom revealed that although 94 percent routinely used vasodilators intraoperatively, 99 percent of surgeons used them topically, with 19 percent additionally irrigating the vessel lumen¹. There are two major ways to smooth muscle relaxation: increase of NO synthesis and blockage of Ca²⁺ channels. Well documented effect and simple application has lidocaine as a local anaesthetic. Increased release of NO, blockage of Na²⁺ channels and sympathetic innervation of vessel produces vasodilatation^1,22. Lidocaine is administered topically and intraluminary onto the sutured vessel in 4% concentration^4,9,23. Vasospasm was observed in the concentration of 1% or less. Although the total dose administered this way exceeded DMS, no signs of intoxication were observed²⁴. Hyža proved vasodilatation effect of 
1% trimecaine and 10% MgSO₄²⁵.

Other drugs for local administration such as pentoxifylline, calcium channel blockers, papaverine, sodium nitroprusside, amrinone, phenolamin, chlorpromazine, botulotoxin, vascular endothelial growth factor (VEGF) and prostaglandins are documented mostly in vitro and on animal models^{1,15, 26, 27, 28, 29}. Use of a blunt endodontic cannula with side hole has showed in our practice as a smart solution for internal irrigation of sutured vessels. We irrigate vessels topically and intraluminary during suturing using a solution consisting of mesocain, Agapurin, MgSO₄ and heparin. (Figure 2, 3.)

^MONITORING

The following techniques should be mentioned as standard methods of flap assessment: visual inspection of skin or mucous island colour, flap temperature, invasive blood pressure (IBP) with MAP, Doppler ultrasound for flap vessel blood flow detection, pin-prick test in soft tissue flaps with fresh bleeding up to 5 seconds. Promising seems to be near infrared spectroscopy (NIRS) for continual monitoring of flap perfusion. In case of patients with artificially altered coagulation or aggregation, it is possible to use thromboelastography/metry (TEG/ROTEM) besides the standard measurements of aPTT and antiXa. (Figure 4, 5.)

^{SALAVGE PROCEDURES}

Beside revisional surgery, medical leeches can be applied on a venostatic flap also after successful revision of anastomosis. Venostasis can be reduced by bleeding and by hirudin released in tissues. Infection of a wound by bacteria from leeches’ digestive tract can occur as a major complication³.

Thrombolytics such as streptokinase, urokinase, t-PA are enzymes dissolving a thrombus. Their use is experimental in anastomosis revisions and in replantation surgery because of a serious risk of bleeding⁴.

^CONCLUSION

Despite the wide range of drugs in investigation, mainly heparin, LMWH, acetylsalicylic acid and various local agents are in fact used nowadays. Other drugs have a potential for future research rather than for an actual daily administration in free flap surgery. Moreover, recent well-documented studies do not justify routine use of antithrombotic agents in head and neck free flap surgery. Good message is the dismissed concern of blood transfusions and vasoconstrictor administration and also more options for perioperative monitoring. The perioperative pharmacological management evolves from special interventions based on theoretic pathophysiology to less complex care similar to other comparable surgical procedures as a result of research. Nevertheless, surgeon should definitely stay focused on a meticulous operative technique.

List of abbreviations

MAP – mean arterial pressure

GA – general anaesthesia

aPTT – activated partial thromboplastin time

PT – prothrombin time

NO – nitrogen monoxide

TEG – thromboelastography

LMWH – low molecular weight heparin

ASA – acetylsalicylic acid

VEGF – vascular endothelial growth factor

MgSO₄ – magnesium sulphate

Role of authors: Štěpán Pohanka, MDDr – research, assessment of publications and writing of manuscript, corresponding author. Jiří Šimek, MD, PhD – consultant of resources and final manuscript.

Conflict of interest: Authors declare no conflict of interest.

Disclosure: We declare that this study has received no financial support. All procedures performed in this study involving human participants were in accordance with ethical standards of the institutional and/or national research committee and with the Helsinki declaration and its later amendments or comparable ethical standards.

Corresponding author:

Štěpán Pohanka, MDDr

Department of Oral and Maxillofacial Surgery

Tomas Bata Regional Hospital

Havlíčkovo nábřeží 600

762 75 Zlín, Czech Republic

E-mail: stepan.pohanka@seznam.cz