Oral manifestations and dental management of patients with hereditary angioedema
Jane C. Atkinson^ and Michael M. Frank^ 'Clinical Investigations and Patient Care Branch, National Institute of Dental Research, and 'Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA,
Atkinson ,IC. Frank MM: Oral manifestations and dental managetnent of patients with hereditary angioedema. ,1 Orai Pathol Med 1991; 20: 139 142. Hereditary angioedema (HAEl is a genetic disorder in which alfected individuals develop extensive, .spontaneous angioedema of the extrettiitics, gastroititestinal tract, and oropharynx. Dental treatment of untnedicated patient.s with HAE can trigger life-threatening pharyngeai edetna. Previou.sly, it was demonstrated that the administration of fresh (rozen plasma (FFP) before surgery prevented angioedetna attacks in 6 patietits undergoing dental e.xtractions. The present study examines the long term effectiveness of F'FP in preventing angioedema from developing in 53 patients with UAH undergoing all types of dental treatment over a ten-year period. Only 3 of 45 patients (6.7"o) covered with Fl-'P had a minor angioedetna attack after dental therapy in 10 yr. No attacks of moderate or severe swelling were seen. Attacks occurred independently of the disease activity of the patietit and the tratima c»f the dental procedure. The tise of fresh frozen plastna is effective in preventing attacks of angioedema in HAE patients undergoing all types of dental procedtires.
Hereditary angioedetna (HAH) is a rare, genetic disease, characterized by repeated, often spontaneous swellings of the gastrointestinal tract, extremities, lace, or pharynx (1). Pharytigeal .swelling is particularly dangerous, as it can result in asphyxiation. Dental procedures with local anesthesia have beeti identified as triggers of laryngeal swellings and a subsequent death in these patients (2). Two types of hereditary angioedetna are reeogni/ed. Both are transmitted in an autosotnal, dominant pattern. Itt Type 1, which accounts for 85% of cases, patients have low circulating concentrations of an inhibitor (CI INH) of the first cotnponent of the completrtent cascade (3). In type II HAF, CI INH is present in normal coticentrations but is dysfunctional (4). Therefore, concentrations of CI INH as well as CI INH activity are both necessary for diagtiosis. These results are correlated with a clinical history. Finally, a clinically sintilar acquired angioedetna exists in which patients make ati antibody to CI INH (5, 6). Though the mechanistns differ, the overall defect in all cases is insufficient activity of CI INH, an important regulator of the cotnplement cascade. The serum proteins that cotnprise the completnent cascade are an essential part of the host defense system (7). These proteins participate in lysis and
phagocytosis of cells, viruses, and bacteria, and act as mediators of the imtnune response. The cascade acts in a set order, with one activated protein cleaving the subsequent protein in the sequence. The result is a rapidly escalating inflatnmatory response. To prevent constant activation o( the cotnplement system, there are tnechanistns of control. One important regulator is CI INH (8). This protein prevents activated CI. the first eotnponent of the complement cascade, from cleaving the second completnent cotnponent, C4. When an infection or inllammatory response occurs in normal individuals, levels of activated CI exceed the inhibiting power o l d INH, and the remaining cotnplement cotnponents eventtially becotne functional. The entire completnent cascade of an HAE patietit can be activated spontaneously or secondarily to slight trautna, especially blunt trauma. The result can be an attack of extretne edetna in one or several areas of the body (1,7). Swelling usually peaks in 48 h and takes from hours to days to resolve (I). Though the swollen area is basically painless, abdominal attacks are often aecotnpanied by severe abdominal pain from edema ol the bowel wall. Swelling is not associated with urticaria, which helps differentiate HAF attacks from allergic reactions (I). I-'ever and elevated ervth-
Key words; angioedema,hereditary: complement; dental treatment Jane C, Atkinson, National Institutes of Health, National Institute ot Dental Research, Building 10, Room lN-113. Bethesda, MD 20892, tJSA Accepted for publication October 22, 1990,
rocyte sedimentation rates are not found in attacks. Disease activity varies greatly among the patients, with some experiencing weekly attacks and others going years between attacks. Treattnent of acute attacks of swelling is supportive. If significant pharyngeai swelling occurs before the peak (less than 48 h), intubation can maintain an airway (I). Hoarseness and difficulty swallowing secretions are signs of pharyngeai swelling and a narrowing airway. If the airwa}' becomes too cotistricted for intubation, a tracheostomy tnay be necessary. Medications are only partially suecessful in reducing the swellmg in attacks. These ittclude epinephrine. ().3cc of a 1; 1000 dilution suhcutaneously, narcotics and epsilon amino caproic acid (FACA), an antifibrinolytic agent, .Antihistamines are not universally helpful during attacks, possibly because histamine is not a tnediator of this type of swelling (1, 8). The philosophy for tnanagetnent of HAE is preventing attacks, rather than tnanaging attacks that occur. Anabolic steroids are used to reduce the frequency of attacks. These steroids elevate amounts of CI INH in both patients as well as in normal controls (9), The most popular medications include danazol. stanozolol (lOK and oxymetholone.
14(1
ATKINSON & FRANK
Dental treatment ol' patients with hereditars angioedema can result in lifethreatening coniplicatums. Extractions and the placement of restorations with local anesthesia can result in intubation and or tracheostomies. The prophylactic use of fresh frozen plasma (FFP) has dramatically reduced attacks of HA1{ following dental exiraetions (12). This blood produet contains C"l INH, and transfusion ot two units leads to a significant increase in C"l INH levels (12). Plasma is infused 8 h before dental procedures to allow tissue distribution of CI INH. Literature exists concerning dental trciitment of patients with HAF undergoing extractions (12 ]5}, This report sumniarizes the dental findings and details the management of 53 patients with HAE given routine eare at the Dental Clinic of the National Institutes of Health for the last 10 vr.
Methods and materials Patient selection Medical and dental records of 5.^ patients with HAE seen between mT^and 19X9 were examined. Patients were diagnosed with hereditary angioedema by the National Institute of Allergy and Infectious Diseases. Any unusual oral findings were noted. For each dental procedure the follow ing was noted; 1) pretreatment medications, including amount of fresh frozen plasma, type and dosage of medications for control of HAE. and type and dosage of prophylactic antibiotics; 2) anesthesia used for dental procedures: }} type of dental procedure: 4) postoperative swelling and ineidence of HAE attacks within 24 h of the dental appointment: 5) treatment needed to eontrol HAE. attacks following dental treatment: 6) postoperative infections following dental procedures as evidenced by fever and swelling: 7) complications such as post-
operative bleeding that might have related to dental treatment. Nurses notes were made after all inpatient dental proeedures. The only dental procedures done on an outpatient basis were construction ol removable prostheses and final cementation of tlxed appliances.
Results Patient characteristics Patient ages at initial visit ranged from 10 to 7X yr (mean age ."55). Sixteen were men and .17 were women. The patients were maintained on varying doses of danazol C''2). oxymetholone (9). methyltestosterone (4). stanozolol (1). halotestin (1). EACA (1). and 4 were on no medications. The admitting physicians felt three of the patients were inconsistent in their use of medications. In general, patients with all ranges of disease activity were seen, and all patients had hereditary rather than acquired HAE. Ten patients offered a history of extreme facial swelling following dental proeedures. and at least three of these patients required hospitalization (or swelling after dental treatment. Many patients reported muhiple allergies, with three patients reporting allergies to local anesthesia. However, two of these three patients received some loeal anesthesia during inpatient visits at NIH without any complications. Oral e,xaniination,s There was one notable oral finding in this patient group. Four oral cysts that required removal were present in three patients. Two bilateral dentigerous cysts around the maxillary right first premolar (14) and maxillary left second premolar (25) were found in a ten year old girl. The other eysts were an odontogenie cyst with acute indammation from the anterior mandible of a 64 yr old black woman, and a peripheral giant cell
lesion of the mandible from a 4.'5-yr-old white woman. All cysts were removed after the infusion of 2 units of FFP and healed without incident. Denial procedures - Table I summarizes the types of dental treatments patients received in the l()-yr period. The table is divided into two groups; those who had pretreatment fresh frozen plasma and those who did not. Some patients had dental treatment with FTP on one admission, and without FFP at another admission. Patients also had multiple procedures at one visit. Nine patients had an entry in the medical chart on the day of a dental treatment, but there was no reeord of a comprehensive dental examination with radiographs. Therefore, it was only possible to determine whether or not FFP had been given before exatnination for 44 patients. Anglocdana attacks aflcr dental treatment Six incidents of what was considered HAE-type swelling oecurred following dental proeedures in five different patient.s (Table 2). Five of the six attacks were considered minor, and one attack was considered moderate. On three of these occasions, patients had not received FFP before treatment. This decision was made because one patient had normal CI INH levels subsequent to danazol therapy, and the other patient did not use local anesthesia for simple restorative procedures. Fhe specifics for managetnent of the attacks are given in Table 2. No angioedema attack was seen in 12 patients who underwent the most traumatic procedures, surgical removal of cysts and extraction of mandibular third tnolars. All were covered with fresh frozen plasma. Fwo attacks oecurred in patients who had received no local anesthesia, while four attacks were noted after procedures where local anesthesia was used. Only one patient received gen-
Fahie I Dental procedures performed with and without fresh trozeii plasma (FFP) prtsphyUixis Without preop. MF
With pre( ip. FI-1' No. of patients
No. of visits
No, of teeth
No. t)f attacks
No. of patients
I'^xammations l*rophvUivis
4
4
{)
4t)
20
I)
10
Extractions
27
26 .W 52
114
1
1
6*
Resloralions I'jidodontics I'abricalitm t>i removable appliances Occlusal adjustment, or cemciU crown Minor Nalivarv gland biopsies
21
4 1 1) 12
133
1**
5 1
5
!*•
1
0
0 12
0
8 4 0
!••
* inplc{ed in one visit on t)ne paliciit.
No. of ViSilS
9X 16 -) 17*
I 2t) 4 (I
N o . of lecth
No. of attacks (I
9 37*
1
1 0 1
1 0
0 t)
Dental nianagcmciit of hereditary angioedema
141
Table 2. Swelling incidenls alter dental procedures Patient
Dental procedure
I
3
Danazol Pulpeetomy (1st cndodontie a| pointment) Hygiene Dana/ol Minor salivary gland biopsy oi 2 units FFP lower hp. endodonties. 2 posterior amalgams 2 anterior resins Dana/ol
4
3 posterior amalgams
2 units Ff"P
5
I-.xtraetion of No. 27. No, 36
2 unils FI-T
1 2
Preop. eoverage
eral anesthesia for the removal of a cyst, and she did not have an attack. F'our of the five patients with poorly controlled disease haci extractions after administration of FFI' and had no abnormal swelling. Eight patients receiving EFT were also treated a subsequent day (approximately 36 h after FFP was given) with no difficulty. If only the visits for extractions, restorative procedures, endodonties, biopsies, and cyst removal are examined (procedttres associated with potential trauma), a total of 45 patients were treated with prophylactic El^'P on 97 separate visits. Three of these patients had a minor attack following a dental visit (3,/45 or 6.7%). Only 9 patients were treated for these procedures without FFP coverage on 22 visits, and two of the patients had an attack. Other contpltcations following dcniitt procedures There was no note of increased hemorrhage in any patient who had extractions. Sutures were used only when clinically indicated for soft tissue closure. One patient on a single occasion had fever after a restoration was placed. However, the dental record indicates that the tooth that was restored required no further treatment in 6 yr. Antibiotics were prescribed twice when there were signs of active dental infection. Two other patients were given pen-
Fidoeaine
Severity
Treatment
Y
Moderate faeial swelling
None
N
Onlv abdominal pain Swelling of the lower lip
None 0.3 ce epinephrine suheutaneousH
Swelling o\ upper hp
0.3 ec epmephruie subeutaneousK None
Mild faeial swelling and hoarseness Mild abdominal swellinc
icillin prophylactically for mitral valve prolapse.
Discussion Only 6.7"(> of the patients in this series who received pretreatment tVesh frozen plastna suffered angioedema attacks folUnving dental treatment. Nine of these patients (20"-o) had a history of extreme swelling after dental treatment. Infusion of fresh frozen plasma is extremely effective in preventing major post treattnent angioedema attacks and mitigating attacks that do occur. None of the three patients covered with fresh frozen plasma who had an HAE attack after dental treatment experienced a severe attack. The effectiveness of FFP was not inOuenced by the patient's disease activity, type of dental procedure, nor the number of dental procedures pertbrmed per visit. Too few patients were treated without ITT' to draw meaningful conclusions about the effeetiveness of danazol or other tnedications in preventing H.AF attacks after traumatic dental treatment. Four of the .seven patients who had restorations placed without FFP eoverage did not have loeal anesthesia. There are other facti)rs to consider when treating an H.'\F, patient. These patients reported multiple allergies, in-
None
cluding three who claimed to be allergie to local anesthesia. It is very likely an HAF attack in the past was confused with an allergic reaction. The delivery of intraoral local anesthesia is felt to be a trigger of angioedema attaeks (2). Some patients expressed extreme l"ear of the dentist because of previous angioedema attacks, necessitating intravenous sedation before extractions. This was considered prudent care, since anxiety can trigger attacks (1). General anesthesia for extractions also should be avoided to eliminate the trauma of nasotrachcal intubation (16). Patient compliance with medication usage was a probletn in a few patients. All androgens have reported side effects, including tnasculinization of females and gynecomastia in males, weight gain, hepatic dysfunction, and hematuria (It), 17). Another medication problem in certain patients was narcotic dependence. Demerol and other Schedule II narcotics are frequently used to control the pain of abdominal attaeks. Patients in this group were generally given only acetamint)phen and codeine or other Schedule III narcotics to manage dental pain to tninimize their use of stronger nareoties. The high number of cysts seen in this patient group may be coincidental. It does, however, suggest that periodic pa-
Table 3. Recommendations for denial treatment Dental Procedure
Recommended pre-therap> alterations
Intraoral fixam Obtaining radiographs Crown ceinentatioii Suture removal Gentle prophylaxis Placement of minor restorations without loeal anesthesia Taking impressions for removable applianees and subsequent steps lo fabrieate partial and full dentures Plaeemenl of restorations with loeal anesthesia Extractions Surgery with general anesthesia or inlraoral biopsies
None None None None None if primary care physieian feels patient is well controlled None il primary care physieian feels patient is well controlled None, but eonsullation wilh phssieian is reeonimended before beginning Ihe first eonstruelion visit 2 units of fresh frozen plasma the day or exening before procedure 2 units of fresh frozen plasma the evening before proeedure 2 units of fresh frozen pl.isnia the evening before procedure.
142
ATKrN.SON & l-'RANK
nographie radiographs are beneficial lor this patient group. Based on the dental experiences at this clmie. the guidelines in Table 3 were formulated. Ihe patient's primary care physieian must be consulted before any dental procedure is scheduled except for examinations. Fhe physician should be questioned about the frequency of attaeks, compliance with medications, use of narcotics, and stability of the patient's disease. Treatment can be delayed until several restorations are indicated. Future studies are needed before danazol alone ean be recommended m plaee of fresh frozen plastna as prophylaxis before dental treatment. There is one report of dana/ol only being used to provent an HAF attack during surgical extraction of four wi.sdom teeth (15). This treatment would be desirable because it would decrease the cost lor dental proeedures and eliminate the possibility of patients acquiring an infection from the fresh fro/en plasma. However, some patients continue lo have full tlare attacks while taking dana/ol. while it is rare to see a true HAF attack within 24 h t>f infusing fresh fro/en plasma. ,iiknimlediiments The authors «ish to thank Ms, DIBRA Bi:RMri)i/ tor hcrcxecllent research assistance, ami Drs. PHUJF f. I'bx and iNt.RiD VALDI / lor their editorial help.
References 1, l-RASK MM, CIijj-AM) JA. ATKINSON JP. Hereditary angioedema: the clinical sviidrome and its management, ,-inn Intern Med 1976: 84: 58t) 93. 2, DONALDSON VH. I'AANS RR,
A hio-
eheniical abnormality in hereditary angioedema, \, C ase reports and a review oC Ihe literature, ./ Atteriiv 1962: 33: 316-29. 3, Cic ,,\Ri>i Vrr. kiARASiii T. ROSIN I S . DAVIS 111 AF. Molecular basis lor the deCieiency ot complement 1 inhibitor in type I heredilary angioneurotic edema, / Ctiii ImeM 1987: 79: 698 702. 4, ROSIN
I'S.
.Ai.i'iR
CA.
PINSKY
J.
KiiMi'tRiR MR. DONALDSON VII. Cie-
netieaily determined heterogeneity ol the CI esterase inhibitor in patients with hereditary angioneurotic edema, ./ (7m bnesi 1971: 50: 2143 9, 5, Cii:i.iANi) JA, Boss C'lR, CoNLrY C L. Ri.iNtiART R. FRANK MM. Acquired C"l esterase inhibitor denciency and angioedema: a review. Medieine (Baltimore) 1979: 58: 321 X, 6, C»i:nA RS. QriNTi I. AI;STI,N KI-. CI(AKDi M. ROSIN I'S, Acquired CI eslerase inhibitor defieieney associated with antiitliotypie antibody to monoelonal immunoglobulins, .V Eni>t ,1 Med 1985; 312: 5.M 40. 7, F'RANK MM, The complement system. In: SAMTKR M . lALMAiKit; DW. FRANK
MM.
ArsTi:N K1-, CLAMAN UN. eds,
bnmunolojiieal diseiises. 4th ed. Boston loronto: Little. Brown and Co.. 19X8: 203 12,
X, DAVIS A F . CI inhibitor and hereditary angioneurotic edema. Ann Rev hnnnmot 19X8: 6: .s95 62X, 9. CJI LI AND JA. SlILRlNS RJ, AlllNIi DW, I'RANK MM, Treatment of hereditary angioedema with ilana/ol. Reversal of elinieal and biochemical abnormalities. /V Eiiat ,t Med 1976: 295: 1444 8, It). SmiiFR AL. liARON f)T. .AUSTI:N KF-. Hereditary angioedema: a decade ot management with stano/olol. ./ ,4ttergy Clin Immwiot 1987: 80: 85.*; 60. 11. DONALDSON V S , ROSLN F.S. Hereditary
angioneurotie edema: a elinieal survey. I'ediairies 1966: 37: 1017 27. 12. JAIM CJ. ArKlNSON JI', Cil.LlANI) JA. I-RANK MM. Hereditary angioedema: the use of fresh iVo/en plasma for prophylaxis in patients undergoing oral surgery, J Allergy Ctin Immwwt 1975: 55: 3X6 93. 13. PHILLIPS KM. (ii.K K M . COHI;N S(i. He-
reditary angioedema: report ot ease. Spee Care Deni I')X9: 9: 23 6. 14. MACRO JV. MLYROWIT/ MR, LK ARI G .
JANKOWSKI R. Hereditary angioneurotic edema: clinical management and ease report. ./ Am Deni Assov 19X2: 104: 641 3, 15. S n Rin KA, BLA.STAI i RH, (iRisit s RJ.
OATIS (iW. Hereditary angioedema eontrolled with
Jane C. Atkinson^ and Michael M. Frank^ 'Clinical Investigations and Patient Care Branch, National Institute of Dental Research, and 'Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA,
Atkinson ,IC. Frank MM: Oral manifestations and dental managetnent of patients with hereditary angioedema. ,1 Orai Pathol Med 1991; 20: 139 142. Hereditary angioedema (HAEl is a genetic disorder in which alfected individuals develop extensive, .spontaneous angioedema of the extrettiitics, gastroititestinal tract, and oropharynx. Dental treatment of untnedicated patient.s with HAE can trigger life-threatening pharyngeai edetna. Previou.sly, it was demonstrated that the administration of fresh (rozen plasma (FFP) before surgery prevented angioedetna attacks in 6 patietits undergoing dental e.xtractions. The present study examines the long term effectiveness of F'FP in preventing angioedema from developing in 53 patients with UAH undergoing all types of dental treatment over a ten-year period. Only 3 of 45 patients (6.7"o) covered with Fl-'P had a minor angioedetna attack after dental therapy in 10 yr. No attacks of moderate or severe swelling were seen. Attacks occurred independently of the disease activity of the patietit and the tratima c»f the dental procedure. The tise of fresh frozen plastna is effective in preventing attacks of angioedema in HAE patients undergoing all types of dental procedtires.
Hereditary angioedetna (HAH) is a rare, genetic disease, characterized by repeated, often spontaneous swellings of the gastrointestinal tract, extremities, lace, or pharynx (1). Pharytigeal .swelling is particularly dangerous, as it can result in asphyxiation. Dental procedures with local anesthesia have beeti identified as triggers of laryngeal swellings and a subsequent death in these patients (2). Two types of hereditary angioedetna are reeogni/ed. Both are transmitted in an autosotnal, dominant pattern. Itt Type 1, which accounts for 85% of cases, patients have low circulating concentrations of an inhibitor (CI INH) of the first cotnponent of the completrtent cascade (3). In type II HAF, CI INH is present in normal coticentrations but is dysfunctional (4). Therefore, concentrations of CI INH as well as CI INH activity are both necessary for diagtiosis. These results are correlated with a clinical history. Finally, a clinically sintilar acquired angioedetna exists in which patients make ati antibody to CI INH (5, 6). Though the mechanistns differ, the overall defect in all cases is insufficient activity of CI INH, an important regulator of the cotnplement cascade. The serum proteins that cotnprise the completnent cascade are an essential part of the host defense system (7). These proteins participate in lysis and
phagocytosis of cells, viruses, and bacteria, and act as mediators of the imtnune response. The cascade acts in a set order, with one activated protein cleaving the subsequent protein in the sequence. The result is a rapidly escalating inflatnmatory response. To prevent constant activation o( the cotnplement system, there are tnechanistns of control. One important regulator is CI INH (8). This protein prevents activated CI. the first eotnponent of the complement cascade, from cleaving the second completnent cotnponent, C4. When an infection or inllammatory response occurs in normal individuals, levels of activated CI exceed the inhibiting power o l d INH, and the remaining cotnplement cotnponents eventtially becotne functional. The entire completnent cascade of an HAE patietit can be activated spontaneously or secondarily to slight trautna, especially blunt trauma. The result can be an attack of extretne edetna in one or several areas of the body (1,7). Swelling usually peaks in 48 h and takes from hours to days to resolve (I). Though the swollen area is basically painless, abdominal attacks are often aecotnpanied by severe abdominal pain from edema ol the bowel wall. Swelling is not associated with urticaria, which helps differentiate HAF attacks from allergic reactions (I). I-'ever and elevated ervth-
Key words; angioedema,hereditary: complement; dental treatment Jane C, Atkinson, National Institutes of Health, National Institute ot Dental Research, Building 10, Room lN-113. Bethesda, MD 20892, tJSA Accepted for publication October 22, 1990,
rocyte sedimentation rates are not found in attacks. Disease activity varies greatly among the patients, with some experiencing weekly attacks and others going years between attacks. Treattnent of acute attacks of swelling is supportive. If significant pharyngeai swelling occurs before the peak (less than 48 h), intubation can maintain an airway (I). Hoarseness and difficulty swallowing secretions are signs of pharyngeai swelling and a narrowing airway. If the airwa}' becomes too cotistricted for intubation, a tracheostomy tnay be necessary. Medications are only partially suecessful in reducing the swellmg in attacks. These ittclude epinephrine. ().3cc of a 1; 1000 dilution suhcutaneously, narcotics and epsilon amino caproic acid (FACA), an antifibrinolytic agent, .Antihistamines are not universally helpful during attacks, possibly because histamine is not a tnediator of this type of swelling (1, 8). The philosophy for tnanagetnent of HAE is preventing attacks, rather than tnanaging attacks that occur. Anabolic steroids are used to reduce the frequency of attacks. These steroids elevate amounts of CI INH in both patients as well as in normal controls (9), The most popular medications include danazol. stanozolol (lOK and oxymetholone.
14(1
ATKINSON & FRANK
Dental treatment ol' patients with hereditars angioedema can result in lifethreatening coniplicatums. Extractions and the placement of restorations with local anesthesia can result in intubation and or tracheostomies. The prophylactic use of fresh frozen plasma (FFP) has dramatically reduced attacks of HA1{ following dental exiraetions (12). This blood produet contains C"l INH, and transfusion ot two units leads to a significant increase in C"l INH levels (12). Plasma is infused 8 h before dental procedures to allow tissue distribution of CI INH. Literature exists concerning dental trciitment of patients with HAF undergoing extractions (12 ]5}, This report sumniarizes the dental findings and details the management of 53 patients with HAE given routine eare at the Dental Clinic of the National Institutes of Health for the last 10 vr.
Methods and materials Patient selection Medical and dental records of 5.^ patients with HAE seen between mT^and 19X9 were examined. Patients were diagnosed with hereditary angioedema by the National Institute of Allergy and Infectious Diseases. Any unusual oral findings were noted. For each dental procedure the follow ing was noted; 1) pretreatment medications, including amount of fresh frozen plasma, type and dosage of medications for control of HAE. and type and dosage of prophylactic antibiotics; 2) anesthesia used for dental procedures: }} type of dental procedure: 4) postoperative swelling and ineidence of HAE attacks within 24 h of the dental appointment: 5) treatment needed to eontrol HAE. attacks following dental treatment: 6) postoperative infections following dental procedures as evidenced by fever and swelling: 7) complications such as post-
operative bleeding that might have related to dental treatment. Nurses notes were made after all inpatient dental proeedures. The only dental procedures done on an outpatient basis were construction ol removable prostheses and final cementation of tlxed appliances.
Results Patient characteristics Patient ages at initial visit ranged from 10 to 7X yr (mean age ."55). Sixteen were men and .17 were women. The patients were maintained on varying doses of danazol C''2). oxymetholone (9). methyltestosterone (4). stanozolol (1). halotestin (1). EACA (1). and 4 were on no medications. The admitting physicians felt three of the patients were inconsistent in their use of medications. In general, patients with all ranges of disease activity were seen, and all patients had hereditary rather than acquired HAE. Ten patients offered a history of extreme facial swelling following dental proeedures. and at least three of these patients required hospitalization (or swelling after dental treatment. Many patients reported muhiple allergies, with three patients reporting allergies to local anesthesia. However, two of these three patients received some loeal anesthesia during inpatient visits at NIH without any complications. Oral e,xaniination,s There was one notable oral finding in this patient group. Four oral cysts that required removal were present in three patients. Two bilateral dentigerous cysts around the maxillary right first premolar (14) and maxillary left second premolar (25) were found in a ten year old girl. The other eysts were an odontogenie cyst with acute indammation from the anterior mandible of a 64 yr old black woman, and a peripheral giant cell
lesion of the mandible from a 4.'5-yr-old white woman. All cysts were removed after the infusion of 2 units of FFP and healed without incident. Denial procedures - Table I summarizes the types of dental treatments patients received in the l()-yr period. The table is divided into two groups; those who had pretreatment fresh frozen plasma and those who did not. Some patients had dental treatment with FTP on one admission, and without FFP at another admission. Patients also had multiple procedures at one visit. Nine patients had an entry in the medical chart on the day of a dental treatment, but there was no reeord of a comprehensive dental examination with radiographs. Therefore, it was only possible to determine whether or not FFP had been given before exatnination for 44 patients. Anglocdana attacks aflcr dental treatment Six incidents of what was considered HAE-type swelling oecurred following dental proeedures in five different patient.s (Table 2). Five of the six attacks were considered minor, and one attack was considered moderate. On three of these occasions, patients had not received FFP before treatment. This decision was made because one patient had normal CI INH levels subsequent to danazol therapy, and the other patient did not use local anesthesia for simple restorative procedures. Fhe specifics for managetnent of the attacks are given in Table 2. No angioedema attack was seen in 12 patients who underwent the most traumatic procedures, surgical removal of cysts and extraction of mandibular third tnolars. All were covered with fresh frozen plasma. Fwo attacks oecurred in patients who had received no local anesthesia, while four attacks were noted after procedures where local anesthesia was used. Only one patient received gen-
Fahie I Dental procedures performed with and without fresh trozeii plasma (FFP) prtsphyUixis Without preop. MF
With pre( ip. FI-1' No. of patients
No. of visits
No, of teeth
No. t)f attacks
No. of patients
I'^xammations l*rophvUivis
4
4
{)
4t)
20
I)
10
Extractions
27
26 .W 52
114
1
1
6*
Resloralions I'jidodontics I'abricalitm t>i removable appliances Occlusal adjustment, or cemciU crown Minor Nalivarv gland biopsies
21
4 1 1) 12
133
1**
5 1
5
!*•
1
0
0 12
0
8 4 0
!••
* inplc{ed in one visit on t)ne paliciit.
No. of ViSilS
9X 16 -) 17*
I 2t) 4 (I
N o . of lecth
No. of attacks (I
9 37*
1
1 0 1
1 0
0 t)
Dental nianagcmciit of hereditary angioedema
141
Table 2. Swelling incidenls alter dental procedures Patient
Dental procedure
I
3
Danazol Pulpeetomy (1st cndodontie a| pointment) Hygiene Dana/ol Minor salivary gland biopsy oi 2 units FFP lower hp. endodonties. 2 posterior amalgams 2 anterior resins Dana/ol
4
3 posterior amalgams
2 units Ff"P
5
I-.xtraetion of No. 27. No, 36
2 unils FI-T
1 2
Preop. eoverage
eral anesthesia for the removal of a cyst, and she did not have an attack. F'our of the five patients with poorly controlled disease haci extractions after administration of FFI' and had no abnormal swelling. Eight patients receiving EFT were also treated a subsequent day (approximately 36 h after FFP was given) with no difficulty. If only the visits for extractions, restorative procedures, endodonties, biopsies, and cyst removal are examined (procedttres associated with potential trauma), a total of 45 patients were treated with prophylactic El^'P on 97 separate visits. Three of these patients had a minor attack following a dental visit (3,/45 or 6.7%). Only 9 patients were treated for these procedures without FFP coverage on 22 visits, and two of the patients had an attack. Other contpltcations following dcniitt procedures There was no note of increased hemorrhage in any patient who had extractions. Sutures were used only when clinically indicated for soft tissue closure. One patient on a single occasion had fever after a restoration was placed. However, the dental record indicates that the tooth that was restored required no further treatment in 6 yr. Antibiotics were prescribed twice when there were signs of active dental infection. Two other patients were given pen-
Fidoeaine
Severity
Treatment
Y
Moderate faeial swelling
None
N
Onlv abdominal pain Swelling of the lower lip
None 0.3 ce epinephrine suheutaneousH
Swelling o\ upper hp
0.3 ec epmephruie subeutaneousK None
Mild faeial swelling and hoarseness Mild abdominal swellinc
icillin prophylactically for mitral valve prolapse.
Discussion Only 6.7"(> of the patients in this series who received pretreatment tVesh frozen plastna suffered angioedema attacks folUnving dental treatment. Nine of these patients (20"-o) had a history of extreme swelling after dental treatment. Infusion of fresh frozen plasma is extremely effective in preventing major post treattnent angioedema attacks and mitigating attacks that do occur. None of the three patients covered with fresh frozen plasma who had an HAE attack after dental treatment experienced a severe attack. The effectiveness of FFP was not inOuenced by the patient's disease activity, type of dental procedure, nor the number of dental procedures pertbrmed per visit. Too few patients were treated without ITT' to draw meaningful conclusions about the effeetiveness of danazol or other tnedications in preventing H.AF attacks after traumatic dental treatment. Four of the .seven patients who had restorations placed without FFP eoverage did not have loeal anesthesia. There are other facti)rs to consider when treating an H.'\F, patient. These patients reported multiple allergies, in-
None
cluding three who claimed to be allergie to local anesthesia. It is very likely an HAF attack in the past was confused with an allergic reaction. The delivery of intraoral local anesthesia is felt to be a trigger of angioedema attaeks (2). Some patients expressed extreme l"ear of the dentist because of previous angioedema attacks, necessitating intravenous sedation before extractions. This was considered prudent care, since anxiety can trigger attacks (1). General anesthesia for extractions also should be avoided to eliminate the trauma of nasotrachcal intubation (16). Patient compliance with medication usage was a probletn in a few patients. All androgens have reported side effects, including tnasculinization of females and gynecomastia in males, weight gain, hepatic dysfunction, and hematuria (It), 17). Another medication problem in certain patients was narcotic dependence. Demerol and other Schedule II narcotics are frequently used to control the pain of abdominal attaeks. Patients in this group were generally given only acetamint)phen and codeine or other Schedule III narcotics to manage dental pain to tninimize their use of stronger nareoties. The high number of cysts seen in this patient group may be coincidental. It does, however, suggest that periodic pa-
Table 3. Recommendations for denial treatment Dental Procedure
Recommended pre-therap> alterations
Intraoral fixam Obtaining radiographs Crown ceinentatioii Suture removal Gentle prophylaxis Placement of minor restorations without loeal anesthesia Taking impressions for removable applianees and subsequent steps lo fabrieate partial and full dentures Plaeemenl of restorations with loeal anesthesia Extractions Surgery with general anesthesia or inlraoral biopsies
None None None None None if primary care physieian feels patient is well controlled None il primary care physieian feels patient is well controlled None, but eonsullation wilh phssieian is reeonimended before beginning Ihe first eonstruelion visit 2 units of fresh frozen plasma the day or exening before procedure 2 units of fresh frozen plasma the evening before proeedure 2 units of fresh frozen pl.isnia the evening before procedure.
142
ATKrN.SON & l-'RANK
nographie radiographs are beneficial lor this patient group. Based on the dental experiences at this clmie. the guidelines in Table 3 were formulated. Ihe patient's primary care physieian must be consulted before any dental procedure is scheduled except for examinations. Fhe physician should be questioned about the frequency of attaeks, compliance with medications, use of narcotics, and stability of the patient's disease. Treatment can be delayed until several restorations are indicated. Future studies are needed before danazol alone ean be recommended m plaee of fresh frozen plastna as prophylaxis before dental treatment. There is one report of dana/ol only being used to provent an HAF attack during surgical extraction of four wi.sdom teeth (15). This treatment would be desirable because it would decrease the cost lor dental proeedures and eliminate the possibility of patients acquiring an infection from the fresh fro/en plasma. However, some patients continue lo have full tlare attacks while taking dana/ol. while it is rare to see a true HAF attack within 24 h t>f infusing fresh fro/en plasma. ,iiknimlediiments The authors «ish to thank Ms, DIBRA Bi:RMri)i/ tor hcrcxecllent research assistance, ami Drs. PHUJF f. I'bx and iNt.RiD VALDI / lor their editorial help.
References 1, l-RASK MM, CIijj-AM) JA. ATKINSON JP. Hereditary angioedema: the clinical sviidrome and its management, ,-inn Intern Med 1976: 84: 58t) 93. 2, DONALDSON VH. I'AANS RR,
A hio-
eheniical abnormality in hereditary angioedema, \, C ase reports and a review oC Ihe literature, ./ Atteriiv 1962: 33: 316-29. 3, Cic ,,\Ri>i Vrr. kiARASiii T. ROSIN I S . DAVIS 111 AF. Molecular basis lor the deCieiency ot complement 1 inhibitor in type I heredilary angioneurotic edema, / Ctiii ImeM 1987: 79: 698 702. 4, ROSIN
I'S.
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CA.
PINSKY
J.
KiiMi'tRiR MR. DONALDSON VII. Cie-
netieaily determined heterogeneity ol the CI esterase inhibitor in patients with hereditary angioneurotic edema, ./ (7m bnesi 1971: 50: 2143 9, 5, Cii:i.iANi) JA, Boss C'lR, CoNLrY C L. Ri.iNtiART R. FRANK MM. Acquired C"l esterase inhibitor denciency and angioedema: a review. Medieine (Baltimore) 1979: 58: 321 X, 6, C»i:nA RS. QriNTi I. AI;STI,N KI-. CI(AKDi M. ROSIN I'S, Acquired CI eslerase inhibitor defieieney associated with antiitliotypie antibody to monoelonal immunoglobulins, .V Eni>t ,1 Med 1985; 312: 5.M 40. 7, F'RANK MM, The complement system. In: SAMTKR M . lALMAiKit; DW. FRANK
MM.
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bnmunolojiieal diseiises. 4th ed. Boston loronto: Little. Brown and Co.. 19X8: 203 12,
X, DAVIS A F . CI inhibitor and hereditary angioneurotic edema. Ann Rev hnnnmot 19X8: 6: .s95 62X, 9. CJI LI AND JA. SlILRlNS RJ, AlllNIi DW, I'RANK MM, Treatment of hereditary angioedema with ilana/ol. Reversal of elinieal and biochemical abnormalities. /V Eiiat ,t Med 1976: 295: 1444 8, It). SmiiFR AL. liARON f)T. .AUSTI:N KF-. Hereditary angioedema: a decade ot management with stano/olol. ./ ,4ttergy Clin Immwiot 1987: 80: 85.*; 60. 11. DONALDSON V S , ROSLN F.S. Hereditary
angioneurotie edema: a elinieal survey. I'ediairies 1966: 37: 1017 27. 12. JAIM CJ. ArKlNSON JI', Cil.LlANI) JA. I-RANK MM. Hereditary angioedema: the use of fresh iVo/en plasma for prophylaxis in patients undergoing oral surgery, J Allergy Ctin Immwwt 1975: 55: 3X6 93. 13. PHILLIPS KM. (ii.K K M . COHI;N S(i. He-
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JANKOWSKI R. Hereditary angioneurotic edema: clinical management and ease report. ./ Am Deni Assov 19X2: 104: 641 3, 15. S n Rin KA, BLA.STAI i RH, (iRisit s RJ.
OATIS (iW. Hereditary angioedema eontrolled with
