Pre-liver transplant protocols in dentistryReza Radmand, DMD,a,b Michael Schilsky, MD,c,d,e Simona Jakab, MD,f Mohd Khalaf, DMD,g andDonald A. Falace, DMD, FDS RCSEdh

Yale New Haven Hospital; Yale School of Medicine; Adult Liver Transplant at Yale New Haven Transplantation Center, New Haven, CT, USA;UK College of Dentistry, Lexington, KY, USA; and University of Kentucky College of Dentistry, Lexington, KY, USA

The number of adults with end stage liver disease in the U.S., awaiting liver transplantation, has maintained a steadyupward trend in recent years. Concurrently, the survival rate of liver transplant recipients has also been on the rise. To be ableto safely treat this population, dentists should have familiarity with special management requirements of patients with endstage liver disease. This article reviews the historical background on liver transplantation and provides updated information onindications and evaluation protocols, treatment considerations in end stage liver disease, clinical dental managementprotocols prior to surgical procedures and dental considerations in the pre liver transplant candidates. (Oral Surg Oral MedOral Pathol Oral Radiol 2013;115:426 430)

The rst successful human to human liver transplant inthe U.S. that surpassed 1 year survival was performedby Dr. Thomas Starzl in 1967. It was followed byhistoric milestones in procurement and preservation ofcadaveric organs, understanding the immunologicalcomplexities involved in organ rejection and immuno-suppression regimens, as well as theological and moraldiscussions surrounding organ transplantation and itsinitial high mortality rate, questioning the ethicalparadigms of the concept.1 Currently, post-liver trans-plant survival is around 88% at one year and 72% atve years.2,3 Factors contributing to the increase insuccess rate of transplant survival are improvements inimmunosuppressive therapy, surgical techniques andbetter management of complications.1

In 2008, the number of patients waiting to receivea liver transplant was close to 16,000, but the number ofliver transplants performed was only over 6000. Theannual mortality for patients on the liver transplantwaiting list for the years 2000-2009 was approximately

2000 patients/year.2 The death rate on wait list was 6.6%nationally in 2009, but up to 20% in regions with donorshortage where patients are sicker and have higherMELD (Model for End Stage Liver Disease) score attransplantation.3 The length of time that patients stay onthe transplant list is dependent on the natural history ofthe underlying disease and the rate of its progression, theUnited Network of Organ Sharing (UNOS) region inwhich the patient is located (different organ donationrates and population demands), blood type (longer waittime for blood type O), and if a living donor is available.According to the Organ Procurement and Trans-plantation Network and the Scientic Registry ofTransplant Recipients (OPTN and SRTR), the averagetime to transplant nationally in 2009 was 382 days.3 Thiscould create a dilemma for the dental professionals whoare asked to clear the patient. A dentist could seea patient who will eventually be transplanted after a fewdays or several months. In case of a lower MELD score,or if there is a living donor, there is more time to elec-tively perform needed dental procedures.

INDICATIONS FOR LIVER TRANSPLANTLiver failure occurs when the liver, gradually overa course of years or rapidly in a matter of days, loses itsability to function. If the damage is irreversible, livertransplantation is indicated. The clinical presentation ofliver disease varies based on the underlying conditions(viral, autoimmune, metabolic, etc.). Any patient whohas acute liver failure or chronic liver injury that canlead to end stage liver disease with cirrhosis, hepatic

aSection Chief, Hospital Dentistry, Dental Department, Yale NewHaven Hospital, New Haven, CT, USA.bClinical instructor, Yale School of Medicine, Dental Department,New Haven, CT, USA.cAssociate Professor of Medicine (Digestive Diseases), AdultLiver Transplant at Yale New Haven Transplantation Center, NewHaven, CT, USA.dAssociate Professor of Surgery, Adult Liver Transplant at Yale NewHaven Transplantation Center, New Haven, CT, USA.eMedical Director, Adult Liver Transplant at Yale New HavenTransplantation Center, New Haven, CT, USA.fAssistant Professor of Medicine and Hepatology, Yale School ofMedicine, New Haven, CT, USA.gAssistant Professor of Oral Medicine /Oral Diagnosis, UK College ofDentistry, Lexington, KY, USA.hProfessor Emeritus, Oral Diagnosis and Oral Medicine, University ofKentucky College of Dentistry, Lexington, KY, USA.Received for publication Aug 20, 2012; returned for revision Nov 15,2012; accepted for publication Dec 4, 2012.! 2013 Elsevier Inc. All rights reserved.2212 4403/$ see front matterhttp://dx.doi.org/10.1016/j.oooo.2012.12.006

Statement of Clinical Relevance

The manuscript attempts to familiarize the readerwith organ transplant considerations in patients withend stage liver disease, and dental managementprotocols in the pre-liver transplant candidates.

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insufciency and life-threatening complications relatedto portal hypertension, should be considered a candi-date for liver transplantation.

PRE-TRANSPLANT EVALUATIONIn February of 2002, determining priority for organallocation for candidates on the waiting list waschanged to the MELD scoring system (for individualsages 12 and older). The MELD score is calculated byusing a formula that includes three laboratory values:INR, serum bilirubin and serum creatinine. The MELDscore predicts 3-month mortality and thereby theseverity of the patients liver disease.2 The score rangesbetween 6 and 40, where an MELD score of greaterthan 40 translates to a mortality rate of over 71% within3 months, unless the patient receives a liver transplant(Table I). Further renements of the model are ongoingand aim to improve fairness in allocation and sur-vival results. There are certain conditions such ashepatocellular carcinoma, hepatopulmonary syndrome,portopulmonary hypertension or metabolic diseaseswith higher mortality than as reected by the nativeMELD score, when exception MELD points are given.A patient is usually listed for transplantation when theMELD score is 15. When the MELD score is less than15, the one-year mortality post transplant is higher thanthe mortality on the wait list. These patients areconsidered to be too well for transplantation.3

The process of evaluation of transplant candidacy issimilar among liver transplant centers (Table II). Oncethe diagnostic work-up for the prospective candidatesevaluation is completed by the hepatologist, transplantcoordinator and surgeon with consultants in cardiology,pulmonary, anesthesia, and other subspecialties asneeded, the patient is presented to the candidate selec-tion committee (recipient review committee) fora decision about the suitability of the patient fortransplantation. This multidisciplinary committeeconsists of transplant surgeons, hepatologists, trans-plant nursing coordinators, psychiatrists, socialworkers, cardiologists, pulmonologists, anesthesiolo-gists, hospital dentists and, occasionally, the patientsprimary care physician.

DENTAL TREATMENT CONSIDERATIONSThe initial dental consultation is an integral componentof the pretransplantation protocol, aiming to diagnoseand eliminate any sources of existing active infection orpotential for future infection. The evaluation may beperformed either at the bedside, if patient is unable to betransported, or preferably in an outpatient clinicalsetting. After a successful and atraumatic oral surgicalprocedure, the patient can be cleared for liver transplantsurgery in 24-48 h, in the absence of any postoperativecomplications. If the risk of complications outweighs

the benets of dental treatment, it might be best topostpone the oral surgical procedures until after thecoagulopathy has been reversed, typically 1-2 weeksafter a successful liver transplantation.The role of dental professionals trained in manage-

ment of medically complex patients has been recog-nized in the medical community. With respect topatients with chronic liver disease, the complexity oftheir overall condition brings into attention threeessential aspects of their dental treatment: adequatehemostasis, infection control and pain management.Preoperative evaluation of the patients coagulop-

athy is mandatory, irrespective of the type of dentalprocedure that is planned. It should include a completeblood count (for platelet count, but also to evaluatehemoglobin/hematocrit if major blood loss anticipatedor use of general anesthesia), as well as prothrombintime (PT)/international normalized ratio (INR), andpartial thromboplastin time (PTT). Electrolytes andliver function tests (LFTs) should be evaluated ifintravenous sedation or general anesthesia will beused.4 A common volatile general anesthetic gas,sevourane, was shown to increase the peri and post-operative bleeding time.5,6

COAGULOPATHY AND TREATMENTCONSIDERATIONSThe risk of bleeding in patients with chronic liverdisease is the main reason that surgical procedures maybe delayed or canceled. In addition, bleeding in oralcavity after dental procedures may precipitate hepaticcoma it is even more important for these patients tolimit bleeding and use aggressive suction to decreasethe amount of swallowed blood, as well as to monitorthem carefully post procedure.To perform the appropriate dental treatment and

effectively prepare the patient for liver transplant, thedentist must consider a number of factors in order tominimize the associated risks. It is reported that manyphysicians require a platelet count of greater than80,000/mL prior to procedures.7 Studies have shown thatany invasive procedure may be performed in patientswith platelet counts of equal or above 50,000 mL, withvery low risk of bleeding.7

Table I. MELD score and 3-month mortality

MELD score Mortality (%)

>40 71.330 39 52.620 29 19.610 19 6.0

Presurgical transfusion of appropriate blood products(Table III) may be necessary based on the extent of thedental procedure (i.e., possibility of alveoloplasty,gingival ap manipulation) and the laboratory abnor-malities that are contributing to the coagulopathy. Afterpreoperative transfusion of blood products, a rapiddetermination of platelet count (if platelets were trans-fused) and/or PT/INR (if fresh-frozen plasma wastransfused) should be obtained as close to the surgicalprocedure as possible. In addition to preoperative trans-fusions, transfusion drip is sometimes indicated intra-operatively to obtainmaximum efcacy of hemostasis. Inanemic patients the bleeding time could be abnormalwithan increase in bleeding tendency, which seems to be duein part to an excessive production of nitric oxide, vaso-dilatation of the endothelial lining and inhibition ofplatelet function.8,9 Patients with renal failure may alsoexperience platelet dysfunction resulting from uremia, inwhich case desmopressin or hemodialysis may beeffective in reversing the platelet abnormalities. In somepatients with decompensated liver disease, multi-organdysfunction and extensive coagulopathy, the dental teamand the liver transplant team may decide that dentalsurgery should take place in an operating room setting.Hematology consult may be necessary if there is

alloimmunization limiting the effectiveness of bloodtransfusions, a history of or predisposition to throm-bosis, contraindication to high volume blood productsin a patient with severe uid overload or contraindica-tion to blood transfusions due to religious beliefs. Inpatients with malnutrition, vitamin K should also begiven to correct their nutritional decit.

Alternative local anesthesia such as inltration andintra-ligamental injectionmaybe indicated.Conventionalinferior alveolar nerve blocks may pose an excessive riskof submucosal hematoma in the pterygomandibularspace, in patients with blood dyscrasias.10,11

LOCAL HEMOSTASISThe use of local hemostatic agents in exodontia andsoft tissue surgery is of great value in obtaining im-mediate postoperative hemostasis. In patients withcoagulopathy, the use of local hemostatic agents is anessential part of dental surgical procedures. Either incombination or individually, gel-foam (Pharmacia andUpjohn Company, Kalamazoo, MI) or Surgicel (Ethi-con, San Angelo, TX), 5000 U bovine topical Throm-bin (BioPharm Laboratories, Inc., Bluffdale, Utah), andAvitene microber collagen, (Davol, a Bard Company,Warwick, RI) can be placed in the extraction socket(s)and sutured with resorbable sutures, such as, 4 0 or3 0 chromic gut or Vicryl (Ethicon, San Angelo, TX),preferably with a tapered cutting needle.12 High bri-nolytic activity in oral cavity suggests a role for anti-brinolytics, especially topical epsilon aminocaproicacid 25% oral syrup which has better topical efcacythan the tablet form.

PROPHYLACTIC ANTIBIOTIC COVERAGEAlthough there are no standard guidelines concerningantibiotic prophylaxis in pre-liver transplant patients,preoperative prophylactic antibiotic coverage may beconsidered to reduce the incidence of postoperativeinfection, based on the extent of the procedure and the

Table II. Transplant evaluation process

Event Description

Referral To transplant center or hepatologistFinancial screening Secure approval for evaluationMedical evaluation: lab testing Assess hepatic synthetic function, electrolytes, renal function, viral serologies, markers of other causes

of liver disease, tumor markers, ABO Rh blood typing; insulin clearance or 24 h urine for creatinineclearance; urinalysis and urine drug screen

Hepatic imaging Ultrasonography with Doppler to document portal vein patency and tumor screening, triple phasecomputed tomography or gadolinium magnetic resonance imaging for tumor screening

General health assessment Chest x ray, prostate specic antigen level (males), Pap smear and mammogram (females), colonoscopyif age 50 years or older or Primary sclerosing cholangitis

Transplant surgery evaluation Assess technical issues and discuss risks of procedureAnesthesia evaluation Assess perioperative riskPsychiatry or psychology evaluation If prior history of substance abuse, psychiatric illness, or adjustment difcultiesSocial work evaluation Address potential psychosocial issues and possible impact of transplantation on patients personal and

social systemFinancial counseling Itemize costs of transplant and post transplant care, help develop nancial management plansDental evaluation To diagnose and eliminate any sources of existing active infection or potential for future infection.

Educate the patient on the importance of maintaining optimal oral care during the long term posttransplant immunosuppression state

Pre/post transplant education Transplant coordinators facilitate the evaluation process and education of patients about liver diseaseand transplantation

Nutritional support Assess nutritional status and patient educationPharmacy support Review of medications and potential drug interaction

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severity of the liver disease. Transient bacteremia inpatient with ascites may lead to spontaneous bacterialperitonitis with additional increase in mortality rate.13

Ampicillin or amoxicillin clavulanic acid or third-generation cephalosporins may be used before dentalprocedures in patients with refractory ascites and hypo-albuminemia/severe synthetic dysfunction, although thisis not an ofcial recommendation.

POST PROCEDURE ANALGESIAAs the liver plays a crucial role in drug metabolism,patients with liver disease are expected to have a signif-icantly diminished capacity to break down and eliminatedrugs. The metabolism of most common analgesics isthrough the hepatic route. For patients with chronic liverdisease, alterations in drug dosage and/or administrationintervals need to be made.Acute or chronic use of acetaminophen in doses less

than 2 g/day is safe in a wide range of liver diseases,14

and acetaminophen should be the rst line analgesic forthese patients. Patients and medical providers tend tooverestimate the risk of acetaminophen-related hepa-totoxicity in the context of underlying liver disease.

Although the half-life of acetaminophen in end stageliver disease patients is prolonged relative to that ofhealthy subjects, the cytochrome P-450 activity is notincreased in those taking the recommended doses of upto 2 g/day.14 The daily dose needs to take into accountcombination analgesics that include acetaminophen toavoid therapeutic misadventures.The use of non-steroidal anti-inammatory drugs

(NSAIDs) is generally contraindicated given their poten-tial for gastrointestinal bleeding and renal complicationsin patients with cirrhosis.For patients with more severe pain, use of narcotics

could be considered, but narcotics may precipitatehepatic encephalopathy. A better alternative than nar-cotics for the relief of moderate to severe postoperativepain in cirrhotic patients is a different class of analge-sics called synthetic opioid agonists such as tramadol.According to the United States Food and DrugAdministration, in adult patients with liver insufciencythe recommended dose of tramadol is lower, 50 mgevery 12 h, as needed. Cautious use of narcotics isaccepted in cirrhotic patients if acetaminophen and/ortramadol is not enough.

Table III. Blood products and synthetic anti-brinolytic agents

Blood products Product description and indication Cost

Platelets A unit of pooled platelets in adults is a compilation of approximately 5 units of plateletconcentrates from random donors. In a non alloimmunized patient, this amount couldproduce approximately 10,000 platelets/mL, with an approximately 66% efcacycompared to freshly collected platelets.16 Alloimmunization, may lead to refractorinessresulting from drug administration such as Vancomycin and Ibuprofen.17 Patients withlow efcacious platelet counts after two or more transfusions, will be classied as havingthe diagnosis of refractoriness to transfusion. The etiology of refractoriness should beinvestigated in order to identify an immunologic cause due to a non compatible donor.18,19

$400/U of pooledplatelets

FFP Fresh frozen plasma: will help to restore coagulation factors and will be administered if INRis excessively high. A reduction in INR and PTT values on repeat testing is expected. Ifthe volume necessary to achieve correction of INR is contraindicated, DDAVP (SanoAventis, Bridgewater, NJ) and/or recombinant factor VII may be considered (see below).18

$70 90/U of FFP

RBC Red blood cells: in patients with moderate to severe anemia (approximate average for maleand female adults,

CONCLUSIONLiver transplantation is the most effective treatment formany patients with acute or chronic liver failure. Becauseof scarcity of organ donors, candidates have to undergoa rigorous evaluation protocol. A comprehensive dentalevaluation and treatment is an essential part of this processand poses careful considerations, given the signicantcomplications that can occur when performing variousdental procedures. Despite the concerns for such compli-cations, there is very little evidence in the literature tosupport the correlation between dental disease and relatedpost-organ transplant complications or rejections.15 In thecase of end stage liver disease, we can therefore suggestthat if the risk of pre-transplant excessive or uncontrolledbleeding outweighs the benets of extractions, it might bebest to postpone the oral surgical procedure until after thecoagulopathy has been reversed, typically soon aftera successful liver transplantation.

The data and analyses reported in the 2010 Annual DataReport of the US Organ Procurement and TransplantationNetwork and the Scientic Registry of Transplant Recipientshave been supplied by UNOS and the Minneapolis MedicalResearch Foundation under contract with HHS/HRSA. Theauthors alone are responsible for reporting and interpretingthese data; the views expressed herein are those of the authorsand not necessarily those of the US Government.

REFERENCES1. Starzl TE, Fung JJ. Themes of liver transplantation. Hepatology.

2010;51:1869-1884.2. OPTN/SRTR 2010 Annual Data Report. HHS/HRSA/HSB/DOT.3. Thuluvatha PJ, Guidingerc MK, Funge JJ, Johnson LB,

Rayhillf SC, Pelletierc SJ. Liver transplantation in the UnitedStates, 1999-2008. Am J Transplant. 2010;10:1003-1019.

4. Kujovich JL. Hemostatic defects in end stage liver disease. CritCare Clin. 2005;21:563-587.

5. Matsuoka H, Watanabe Y, Isshiki A, Quock RM. Increasedproduction of nitric oxide metabolites in the hippocampusunder isourane anaesthesia in rats. Eur J Anaesthesiol. 1999;16:216-224.

6. Apuhan T, Yildirim YS, Aksoy F, Borcin O, Ozturan O. Theeffects of desurane and sevourane on the peri- and post-operative bleeding of adenotonsillectomy patients. Int J PediatrOtorhinolaryngol. 2011;75:790-792.

7. Afdhal N, McHutchison J, Brown R, et al. Thrombocytopeniaassociated with chronic liver disease. J Hepatol. 2008;48:1000-1007.

8. Valeri RC, Khuri S, Ragno G. Nonsurgical bleeding diathesis inanemia thrombocytopenic patients: role of temperature, red blood

cells, platelets, and plasma clotting proteins. Transfusion. 2007;47:206-248.

9. Radomski MW, Palmer RM, Moncada S. Endogenous nitricoxide inhibits human platelet adhesion to vascular endothelium.Lancet. 1987;2:1057-1058.

10. Spuller RL. Use of the periodontal ligament injection in dentalcare of the patient with hemophiliada clinical evaluation. SpecCare Dentistry J. 1988;8:28-29.

11. Claudio I, Galdames S, Gonzalo M, Lpez C, Alejandra D,Matamala Z. Inferior alveolar nerve block anesthesia via theretromolar triangle, an alternative for patients with blooddyscrasias. Med Oral Patol Oral Cir Bucal. 2008;13:43-47.

12. Hill RC, Kalantarian B, Jones DR. Use of microbrillar collagenhemostat (Avitene) and thrombin to achieve hemostasis aftermediansternotomy. J Thorac Cardiovasc Surg. 1994;108:1151-1152.

13. Runyon BA. AASLD Practice Guidelines Committee. Manage-ment of adult patients with ascites due to cirrhosis: an update.Hepatology. 2009;49:2087-2107.

14. Benson GD, Koff RS, Tolman KG. The therapeutic use of acet-aminophen in patients with liver disease. Am J Ther. 2005;12:133-141.

15. Guggenheimer J, Eghtesad B, Stock DJ. Dental management ofthe (solid) organ transplant patient. Oral Surg Oral Med OralPathol Endod. 2003;95:383-389.

16. http://www.wadsworth.org/labcert/blood_tissue/pdf/pltadmin.pdf.17. McFarland JG. Laboratory investigation of drug-induced immune

thrombocytopenia. Transfus Med. 1993;4:275-287.18. British Committee for Standards in Haematology, Working Party

of the Blood Transfusion Task Force. Guidelines for the use offresh frozen plasma. Transfus Med. 1992;2:57-63.

19. Hod E, Schwartz J. Platelet transfusion refractoriness. Br JHaematol. 2008;142:348.

20. Practice guidelines for blood component therapy: a report by theAmerican society of anesthesiologists task force on bloodcomponent therapy. Anesthesiology. 1996;84:732-747.

21. Chowdhury P, Saayman AG, Paulus U, Findlay GP, Collins PW.Efcacy of standard dose and 30 ml/kg fresh frozen plasma incorrecting laboratory parameters of haemostasis in critically illpatients. Br J Haematol. 2004;125:69-73.

22. Leslie SD, Toy PT. Laboratory hemostatic abnormalities inmassively transfused patients given red blood cells and crystal-loid. Am J Clin Pathol. 1991;96:770-773.

23. Mannucci PM. Desmopressin (DDAVP) in the treatment ofbleeding disorders: the rst 20 years. Blood. 1997;90:2515-2521.

24. Dunn CJ, Goa KL. Tranexamic acid: a review of its use in surgeryand other indications. Drugs. 1999;57:1005-1032.

25. Stepfanini M, Dameshek W, eds. The Hemorrhagic Disorders.New York: Grune and Stratton; 1962:510-514.

Reprint requests:

Reza Radmand, DMDYale New Haven HospitalDental DepartmentT 231, New Haven, CT 06519, USArradmand@gmail.com

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Pre-liver transplant protocols in dentistryINDICATIONS FOR LIVER TRANSPLANTPRE-TRANSPLANT EVALUATIONDENTAL TREATMENT CONSIDERATIONSCOAGULOPATHY AND TREATMENT CONSIDERATIONSLOCAL HEMOSTASISPROPHYLACTIC ANTIBIOTIC COVERAGEPOST PROCEDURE ANALGESIACONCLUSIONREFERENCES