ANESTHESIA AND ANALGESIA . . . Current Researches VOL.56, No. 4, JULY-AUGUST, 1977
589
Fatal Hepatic Necrosis After Halothane Anesthesia in a Boy with Juvenile Rheumatoid Arthritis: A Case Report ROBERT L. CAMPBELL, DDS* ERNEST W . SMALL, DDS, M S t
HENRY R. LESESNE, MDS KENNETH J. LEVIN, MDS WARREN H. MOORE, MDll Chapel Hill, North Carolina**
Hepatitis from halothane is usually diagnosed by excluding other possible causes. Whether preexisting hepatic damage, which can occur in certain autoimmune disorders, contraindicates the use of halothane has yet to he proven. The
case of a 14-year-old boy with early-onset juvenile rheumatoid arthritis who developed fatal hepatic necrosis 13 days after halothane anesthesia is presented.
H
has been implicated in cases of altered liver function,’ 2 but no evidence has been presented to show that liver disease is an absolute contraindication to the use of halothane. Children under age 10 seem relatively immune to “halothane hepatitis,” only 9 cases 14 of which were subsequently ruled out) having been documented by Carney and Van Dyke,’ in prepubertal children, despite the fact that this age group represents 12 percent of the surgical population in which halothane is the most commonly used agent.
relation between halothane hepatitis and age. Although our patient was 14 years old, he did not have any secondary sex characteristics. The chronic use of salicylates for treatment of his rheumatoid arthritis may have produced a liver more susceptible to hepatic damage.;’,”
Since children seem to be less “allergyprone” than adults,d immunologic immaturity may explain this rarity of halothane hepatitis. However, the nonspecific susceptibility of aging livers to a variety of metabolic insults may be the most important cor-
CASE REPORT A multidisciplinary team including pediatricians, oral surgeons, anesthesiologists, and a hematologist evaluated a patient with early-onset juvenile rheumatoid arthritis ( J R A ) for surgical correction of mandibular
ALOTHANE
An analysis of the death of the patient after temporomandibular surgery for the correction of his severe mandibular ankylosis is presented.
*Clinical Assistant Professor of Oral Surgery; Resident in Anesthesiology, North Carolina Memorial Hospital. -[Professor and Chairman, Department of Oral Surgery. SAssociate Professor, Department of Medicine. SAssociate Professor and Vice Chairman, Department of Anesthesiology. ‘IMediral Intern, T h e Medical College of South Carolina, Charleston, South Carolina. **University of North Carolina School of Medicine. Chapel Hill, North Carolina 27514. Paper received: 8/4/76 Accepted for publication: 10/18/76
590
ANESTHESIAAND ANALGESIA. . . Current Researches VOL.56, No. 4, JULY-AUGUST,1977
ankylosis ( 6 mm mandibular opening) . The patient, 14 years old and small for his age, had no history of heart abnormalities, blood transfusions, allergies, previous operations under general anesthesia, or exposure to persons with hepatitis. Orotracheal intubation being impracticable because of his severe ankylosis of the mandible and cervical vertebrae, he was intubated nasotracheally and anesthetized with halot hane-N 0-0 for the 6-hour bilateral temporomandibular condylectomies with gap arthroplasty. Medications given during this admission included dioctyl sodium sulfosuccinate (Colace@), bisocodyl ( Ducolax@ ) , atropine, occasional acetaminophen, and 2.4 g/day of aspirin postoperatively ( P O ) . For 8 years prior to admission, the patient had been maintained on ASA with serum levels ranging from 12 to 32 mg/100 ml, the latter level prevailing preoperatively. All other preoperative laboratory values were within normal limits. His operative and postoperative course were without incident except for evening chills and fever (38.9" C) 2 days PO. The day before discharge, his SGOT was 39 SF units/ml; bilirubin 0.2 mg/100 ml (indirect), 0.1 mg/100 ml (direct) ; alkaline phosphatase 8.9 npu (nitrophenol units; normal for age, 6 to 12 npu) .
Oral fluid intake and urinary output were normal and he was discharged in good m n dition 7 days PO on a daily maintenance dose of 3 to 5 g ASA. On the 9th postoperative day, the boy was seen by a pediatrician for a rectal temperature of 39.4" C. He felt well, was nontoxic, and was afebrile the next morning. However, 3 days later he awoke with a fever, malaise, anorexia, and jaundice and was readmitted with a tentative diagnosis of "hepatitis of unknown etiology." Liver function and coagulation studies were recorded (table). Physical examination revealed multiple joint ankyloses, including limitation of motion of both ankles and wrists and the left knee and hip and fixation of several ribs and cervical vertebrae, with a fixed flexion of only 15". The liver was palpable 5 cm below the right costal margin and the spleen 2 cm below the left costal margin; both were tender to palpation. There was no ascites, pruritis, or palpable lymphadenopathy. The condition of the patient progressively deteriorated. Two days before death, he became oliguric, responding to treatment with furosemide to produce good urinary output but with gross hematuria. He became comatose within 12 hours. Blood and CSF cultures taken a t this time were negative.
TABLE Laboratory Data 4 Days Prior to Death Test
N o r m a l value
Actual value
~ _ _ _ _ _
SGPT
SF units/ml 8-35 SF units/ml
Alkaline phosphatase
2-12 npu
SGOT
8-40
2699 4045 21.2
Bilirubin (direct)
0.1-0.2 mg/100 ml
4.8
Bilirubin (indirect)
0.1-1.0 mg/100 ml
9.5
White blood count
5000-9000/cu m m
15,400
Differential Pol ymorphonucleoc ytes
40-605'0
68
Lymphocytes
20-40%
23
Eosinophils
1-37"
0
Monocytes
4-8'/0
5
Bands (metamyeloeytes)
0.5%
4
Prothrombin time
13.8 sec (control)
31.5
P a r t i a l thromboplastin time
48.5 sec (control)
137.0
Sedimentation r a t e
0-20 m m / h r
84
Fatal Hepatic Necrosis . . . Campbell, et a1
Although the temperomandibular surgery now permitted him to open his mouth 23 mm, multiple attempts at tracheal intubation were unsuccessful due to the extreme cervical flexion, and tracheostomy was considered anatomically impossible. A nasogastric tube was placed for suspected gastrointestinal bleeding, during which vomiting and aspiration occurred. Chest x-ray confirmed a chemical pneumonitis. Coagulation studies revealed: PT (prothrombin time) greater than 60 seconds (control, 13.7); YTT (partial thromboplastin time) 162.1 (control, 48) ; TCT (thrombin consumption time) greater than 60 seconds (control, 12.9); and a platelet count of 106,0OO/cu mm. Factor assays included: factor V, 3 percent; factor VII, less than 1 percent: factor VIII, 261 percent; and fibrinogen, 59 mg/100 ml (control 263 mg). Fibrin split products were present at 1/64 dilution. Over his 2 last days, the patient bled almost continuously from the nose and mouth and constant nasopharyngeal suction was necessary to maintain his airway. Placement of anterior and posterior nasal packing failed to control bleeding. Binasal pharyngeal tubes were placed to aid in upper airway management. He received numerous units of whole blood ( 4 ) , packed RBCs ( 6 ) , fresh frozen plasma ( 5 ) , cryoprecipitate ( 3 ) , and platelet-rich plasma (6) but clotting studies did not improve. One day before death, the patient had labored breathing with decreased breath sounds and loud rhonchi. Oxygen (100%) was given by face mask. Arterial blood gases revealed: pH, 7.13; Paco,, 80 torr; and Pao,, 170 torr. The patient had a series of tonic/clonic seizures culminating in terminal cardiopulmonary arrest. Hepatitis B surface antigen (HB,Ag), antimitochondrial antibody (AMA) , antinuclear antibody (ANA), smooth muscle antibody (SMA), and antiparietal cell antibody ( A P A ) assays drawn before death were all negative.
DISCUSSION The incidence of temporomandibular joint dysfunction in JRA has been estimat.ed to be from 5 to 85 per~ent.7.~ A recent study by Grosfeldi of 100 cases of JRA revealed 65 percent with demonstrable changes. Twelve percent of the patients examined had mandibular openings of from 20 to 30 mm, while only 1 patient was limited to a 9-mm opening. Other authors agree that bony ankylosis of the temporomandibular joint as the result of JRA is rare.!)-" When
591
severe ankylosis requires surgical intervention to preserve functional growth and mastication, anesthesia management from the standpoint of airway control and choice of anesthetic agent may pose the greatest obstacle to treatment of these patients. In the absence of surgical infection, fever 9 days PO (7 days before death) may have been due to 3 major cause+an acute exacerbation of JRA, hypersalicylism, or drug (particularly halothane) sensitivity. Diurnal fever is a common symptom in JRA but is usually controlled by salicylates. An acute salicylate overdose can also cause fever. This may be due to excessive sweating, hyperpnea, and dehydration, but the exact mechanism is not known.1.! A febrile episode followed by jaundice (13 days after initial exposure) may indicate halothanerelated hepatic damage.3 1 3 Salicylate therapy is the most commonly accepted drug treatment for JRA and is generally thought to be the safest. Hepatic damage due to salicylates has only recently received significant interest. There have been, however, reports for more than 20 years of abnormal liver function tests in patients receiving salicylates for various disorders. In 1956, Manso's group14 reported an increase in serum enzymes with serum salicylate levels as low as 20 mg/100 ml in patients being treated for rheumatic fever. Recent attention initially indicated that increases in SGOT, SGPT, and alkaline phosphataise in patients with various connectivetissue disorders occurred only at serum levels greater than 25 mg/100 mll'i (therapeutic range, 20 to 25 mg/100 ml) . In all cases the chemical signs of liver damage returned to normal after discontinuance of salicylate therapy and increased again when salicjlate therapy was reinstituted at the previous levels. Massive hepatic necrosis of the type .seen in our patient has not been reported as a consequence of salicylate therapy, but several authors have warned that if salicylates can produce hepatic damage (as evidenced by increased transaminase levels) in some patients, they may certainly have the potential to produce fatal hepatic failure in a susceptible individual. Patients with JRA may well be more susceptible to the adverse effects of aspirin than the general population However, while our patient was at risk for salicylate-induced hepatic damage, there are other, better described, factors that probably explain his hepatic failure.
592
ANESTHESIA AND ANALGESIA . . . Current Researches VOL.56, No. 4, JULY-AUGUST, 1977
The diagnosis of halothane hepatitis is still largely a “diagnosis of exclusion.” Viral hepatitis is usually the other major consideration. Chronic active hepatitis ( CAH) inflammatory liver disease lasting several months or more-can also have acute exacerbations with massive hepatic necrosis. Negative liver function tests after operation as well as negative antibody assays tend to exclude CAH in this patient. The time and mode of onset of the patient’s fever and jaundice are consistent with those generally described in reports of halothane hepatitis. Of the patients who develop halothane hepatitis, 62 percent do so within the 1st week after exposure, 25 percent in the 2nd week, 9 percent in the 3rd week, and 4 percent in the 4th week:’ l7 Additional clinical criteria for the diagnosis of halothane hepatitis include: ( 1 ) onset of fever 8 to 14 days after anesthesia without previous exposure 11 to 7 days with previous exposure), 12) abrupt rise in serum SGOT levels shortly after the onset of fever and bilirubin elevation 2 to 3 days later, ( 3 absence of HB,Ag, and ( 4 ) prompt recovery or rapid death.17 In 234 collected cases of halothane hepatitis, 30 percent died after a single exposure and 70 percent after multiple exposures, all of which occurred within 3 months of exposure:’ 1: No survivors are reported to have developed a prothrombin time greater than 60 seconds. Factors in our case that tend to exclude other possibilities include: ( 1) the onset of symptoms was too late to be due to a direct hepatotoxin, 12) the onset was too soon for viral (“serum”) hepatitis B and the Hb.Ag assay was negative, and ( 3 ) the onset was slightly before the normal minimum incubation period of viral (“infectious”) hepatitis A. The incubation period of hepatitis A is 3 to 6 weeks and of hepatitis €3, 6 to 16 weeks.’” However, these periods are variable, are not diagnostic for either disease, and are pertinent only if the causative agent was contracted a t the time of operation. It is, of course, possible that the cause of our patient’s hepatic necrosis was an agent contracted in his normal environment. There is no positive evidence for this etiology, but on the other hand, there is only slight negative evidence: no known contact with a jaundiced person, no previous transfusions, etc. In this regard, it is noteworthy that liver enzyme assays of blood drawn 6 days
PO during the patient’s previous hospitalization were normal. Histologic differentiation between the leading possibilities, halothane and viral hepatitis A, is a t best unproven. Light-microscopic changes in this case are consistent with those reported in other cases of alleged halothane hepatitis: massive necrosis, predominately periportal fatty change, portal eosinophilic infiltration, and plasma cell infiltration of the portal areas and parenchyma; but these changes also have all been reported in viral hepatitis and are definitely nonspecific indicators of liver damage. Electron-microscopic changes have been reported which may ultimately allow differentiation in these cases, but a t this time they are not sufficiently reliable. Klion’ has described a segmental loss of the outer membrane and an infolding of the inner one in hepatic cell mitochondria. These are seen in halothane hepatitis but not in viral hepatitis. These findings have been reproduced in experimental animal studies, but the tissue specimens were taken prior to death and were, therefore, less subject to mitochondrial autolysis.’ Suggestive changes were seen in our patient, but the specimen was received 4 hours postmortem, and extensive autolysis was present. Numerous other diagnostic tests are likewise nonspecific. Immunologic tests, another possible means of differentiation in the future, are unreliable a t this time. Lymphocyte transformation tests were not performed, and their interpretation is still controversial.’\ A positive HB,Ag, present in hepatitis B, would have tended to exclude halothane hepatitis.:’ The other antibody assays are often negative in halothane hepatitis. Peripheral eosinophilia is present in some cases but was absent here.
CONCLUSIONS Although the pathogenesis of “halothane hepatitis” has not been elucidated clearly, clinical findings indicate that pediatric patients are relatively immune from this entity. This report of a 14-year-old prepubertal boy with fatal hepatic necrosis following halothane exposure suggests that, rather than the maturation of the child that is important, the relative maturation of the hepatic system may be implicated. This child, with an immunologic disorder combined with a long history of multiple medications, including high doses of salicylates, may
593
Fatal Hepatic Necrosis . . . Campbell, et a1
have “functionally” removed his hepatic system from the pediatric age group. Perhaps halothane anesthesia to pediatric patients of this type is cause for concern.
REFERENCES 1. Klion FM, Schaffner F, Popper H : Hepatitis after exposure to halothane. Ann Intern Med 71: 467-476, 1969
2. Balfrage S, Ahlgren I: Axelson’s halothane hepatitis in a n anesthetist. Lancet 2: 1466-1467, 1966 3. Carney FMT, Van Dyke RA: Halothane hepatitis-a critical review. Anesth Analg 51: 135160, 1972 4. Parker CW: Drug allergy. N Engl J Med 292:732-736, 1975
rheumatoid arthritis. Acta Rheum Scand 13:257274, 1967 10. Franks AS: Temporomandibular joint in adult rheumatoid arthritis. Ann Rheum Dis 28: 139-144, 1969 11. Russel JA, Bayles TB: The temporomandibular joint in rheumatoid arthritis. JADA 28: 533-539, 1941 12. 8-haller J, Wood PH, Calabro JJ: Clinical studies with salicylates, Conference on Effects of Chronic Salicylate Administration. N e w Y o r k , HEW, June 1966, Sec D
13. Clykes MH, Gilbert JP, Schurr PH, et al: A review of the epidemiologic immunologic, and metabolic aspects of the relationship of halothane and the liver. Can J Surg 15:217-238, 1972
5. Lefkovitis AM, Farrow I J : The liver in rheumatoid arthritis. Am Rheum Dis 14:162-168, 1955
14. hlanso C, Taranta A, Nydick I: Effect of aspirin administration on serum glutamic oxaloacetic and glutamic pyruvic transasminases in children. Proc Soc Exp Biol Med 93:84-88, 1956
6. Schaller J, Bechwith B, Wedgewood R J : Hepatic involvement in juvenile rheumatoid arthritis. d Pediat 77:203-210, 1970
15. Scamon WE, Ishak KG, Plotz PH: Aspirininduced hepatotoxicity in patients with systemic lupus erythematosus. Ann Intern Med 8O:l-8,1974
7. Grosfeld 0: Clinical investigations of the temporomandibular joint in children and adolescents with rheumatoid arthritis. Scand J Rheumatol 2: 145-149, 1973
16. Rich RR, Johnson JS: Salicylate hepatotoxicity in patients with juvenile rheumatoid arthritis. AI-thritis Rheum 16:1-9, 1973
8. Goel KM, Shanks RA: Follow-up study of 100 cases of juvenile rheumatoid arthritis. Ann Rheum Dis 33:27-31, 1974 9. Ericksson SE, Lundberg M: Alterations in the temporomandibular joint a t various stages of
17. Mathieu A: Diagnosis of halothane hepatitis. JAMA 224: 1188-1189, 1973 18. I’aronetto F, Popper H: Lymphocyte stimulation induced by halothane in patients with hepatitis following exposure to halothane. N Engl J Med 283:277-280, 1970
PROPRANOLOL WITHDRAWAL. Acute myocardial ischemia following t h e a b r u p t withdrawal of propranolol administration m a y refl’act rebound hypersecretion of catecholamines. To s t u d y this possibility systolic time intervals and u r i n a r y excretion of vanillylmandelic acid (VMA) were studied in heall.hy volunteers receiving 120 t o 160 m g of propranolol f o r 15 days. Acute withdrawal of propranolol did not a l t e r t h e systolic time intervals or VMA excretion in the following 3 to 4 days. These d a t a did not support t h e concept t h a t a rebound hyperinotropic state exists following acute reversal of betaadrenergic blockade. These d a t a f r o m healthy volunteers m a y not, however, reflect changes t h a t occur in patients with coronary atherosclerosis and with chronically elevated circulating catecholamines. (Pantano d A , l’ee Y - C : A b r ~ p tp r o p m n o l o l withdrawal and myoca~dialcontractility. A sttcdy of cfftrrcts in normal man. Arch Intern Med 136:867-871, 1976)
589
Fatal Hepatic Necrosis After Halothane Anesthesia in a Boy with Juvenile Rheumatoid Arthritis: A Case Report ROBERT L. CAMPBELL, DDS* ERNEST W . SMALL, DDS, M S t
HENRY R. LESESNE, MDS KENNETH J. LEVIN, MDS WARREN H. MOORE, MDll Chapel Hill, North Carolina**
Hepatitis from halothane is usually diagnosed by excluding other possible causes. Whether preexisting hepatic damage, which can occur in certain autoimmune disorders, contraindicates the use of halothane has yet to he proven. The
case of a 14-year-old boy with early-onset juvenile rheumatoid arthritis who developed fatal hepatic necrosis 13 days after halothane anesthesia is presented.
H
has been implicated in cases of altered liver function,’ 2 but no evidence has been presented to show that liver disease is an absolute contraindication to the use of halothane. Children under age 10 seem relatively immune to “halothane hepatitis,” only 9 cases 14 of which were subsequently ruled out) having been documented by Carney and Van Dyke,’ in prepubertal children, despite the fact that this age group represents 12 percent of the surgical population in which halothane is the most commonly used agent.
relation between halothane hepatitis and age. Although our patient was 14 years old, he did not have any secondary sex characteristics. The chronic use of salicylates for treatment of his rheumatoid arthritis may have produced a liver more susceptible to hepatic damage.;’,”
Since children seem to be less “allergyprone” than adults,d immunologic immaturity may explain this rarity of halothane hepatitis. However, the nonspecific susceptibility of aging livers to a variety of metabolic insults may be the most important cor-
CASE REPORT A multidisciplinary team including pediatricians, oral surgeons, anesthesiologists, and a hematologist evaluated a patient with early-onset juvenile rheumatoid arthritis ( J R A ) for surgical correction of mandibular
ALOTHANE
An analysis of the death of the patient after temporomandibular surgery for the correction of his severe mandibular ankylosis is presented.
*Clinical Assistant Professor of Oral Surgery; Resident in Anesthesiology, North Carolina Memorial Hospital. -[Professor and Chairman, Department of Oral Surgery. SAssociate Professor, Department of Medicine. SAssociate Professor and Vice Chairman, Department of Anesthesiology. ‘IMediral Intern, T h e Medical College of South Carolina, Charleston, South Carolina. **University of North Carolina School of Medicine. Chapel Hill, North Carolina 27514. Paper received: 8/4/76 Accepted for publication: 10/18/76
590
ANESTHESIAAND ANALGESIA. . . Current Researches VOL.56, No. 4, JULY-AUGUST,1977
ankylosis ( 6 mm mandibular opening) . The patient, 14 years old and small for his age, had no history of heart abnormalities, blood transfusions, allergies, previous operations under general anesthesia, or exposure to persons with hepatitis. Orotracheal intubation being impracticable because of his severe ankylosis of the mandible and cervical vertebrae, he was intubated nasotracheally and anesthetized with halot hane-N 0-0 for the 6-hour bilateral temporomandibular condylectomies with gap arthroplasty. Medications given during this admission included dioctyl sodium sulfosuccinate (Colace@), bisocodyl ( Ducolax@ ) , atropine, occasional acetaminophen, and 2.4 g/day of aspirin postoperatively ( P O ) . For 8 years prior to admission, the patient had been maintained on ASA with serum levels ranging from 12 to 32 mg/100 ml, the latter level prevailing preoperatively. All other preoperative laboratory values were within normal limits. His operative and postoperative course were without incident except for evening chills and fever (38.9" C) 2 days PO. The day before discharge, his SGOT was 39 SF units/ml; bilirubin 0.2 mg/100 ml (indirect), 0.1 mg/100 ml (direct) ; alkaline phosphatase 8.9 npu (nitrophenol units; normal for age, 6 to 12 npu) .
Oral fluid intake and urinary output were normal and he was discharged in good m n dition 7 days PO on a daily maintenance dose of 3 to 5 g ASA. On the 9th postoperative day, the boy was seen by a pediatrician for a rectal temperature of 39.4" C. He felt well, was nontoxic, and was afebrile the next morning. However, 3 days later he awoke with a fever, malaise, anorexia, and jaundice and was readmitted with a tentative diagnosis of "hepatitis of unknown etiology." Liver function and coagulation studies were recorded (table). Physical examination revealed multiple joint ankyloses, including limitation of motion of both ankles and wrists and the left knee and hip and fixation of several ribs and cervical vertebrae, with a fixed flexion of only 15". The liver was palpable 5 cm below the right costal margin and the spleen 2 cm below the left costal margin; both were tender to palpation. There was no ascites, pruritis, or palpable lymphadenopathy. The condition of the patient progressively deteriorated. Two days before death, he became oliguric, responding to treatment with furosemide to produce good urinary output but with gross hematuria. He became comatose within 12 hours. Blood and CSF cultures taken a t this time were negative.
TABLE Laboratory Data 4 Days Prior to Death Test
N o r m a l value
Actual value
~ _ _ _ _ _
SGPT
SF units/ml 8-35 SF units/ml
Alkaline phosphatase
2-12 npu
SGOT
8-40
2699 4045 21.2
Bilirubin (direct)
0.1-0.2 mg/100 ml
4.8
Bilirubin (indirect)
0.1-1.0 mg/100 ml
9.5
White blood count
5000-9000/cu m m
15,400
Differential Pol ymorphonucleoc ytes
40-605'0
68
Lymphocytes
20-40%
23
Eosinophils
1-37"
0
Monocytes
4-8'/0
5
Bands (metamyeloeytes)
0.5%
4
Prothrombin time
13.8 sec (control)
31.5
P a r t i a l thromboplastin time
48.5 sec (control)
137.0
Sedimentation r a t e
0-20 m m / h r
84
Fatal Hepatic Necrosis . . . Campbell, et a1
Although the temperomandibular surgery now permitted him to open his mouth 23 mm, multiple attempts at tracheal intubation were unsuccessful due to the extreme cervical flexion, and tracheostomy was considered anatomically impossible. A nasogastric tube was placed for suspected gastrointestinal bleeding, during which vomiting and aspiration occurred. Chest x-ray confirmed a chemical pneumonitis. Coagulation studies revealed: PT (prothrombin time) greater than 60 seconds (control, 13.7); YTT (partial thromboplastin time) 162.1 (control, 48) ; TCT (thrombin consumption time) greater than 60 seconds (control, 12.9); and a platelet count of 106,0OO/cu mm. Factor assays included: factor V, 3 percent; factor VII, less than 1 percent: factor VIII, 261 percent; and fibrinogen, 59 mg/100 ml (control 263 mg). Fibrin split products were present at 1/64 dilution. Over his 2 last days, the patient bled almost continuously from the nose and mouth and constant nasopharyngeal suction was necessary to maintain his airway. Placement of anterior and posterior nasal packing failed to control bleeding. Binasal pharyngeal tubes were placed to aid in upper airway management. He received numerous units of whole blood ( 4 ) , packed RBCs ( 6 ) , fresh frozen plasma ( 5 ) , cryoprecipitate ( 3 ) , and platelet-rich plasma (6) but clotting studies did not improve. One day before death, the patient had labored breathing with decreased breath sounds and loud rhonchi. Oxygen (100%) was given by face mask. Arterial blood gases revealed: pH, 7.13; Paco,, 80 torr; and Pao,, 170 torr. The patient had a series of tonic/clonic seizures culminating in terminal cardiopulmonary arrest. Hepatitis B surface antigen (HB,Ag), antimitochondrial antibody (AMA) , antinuclear antibody (ANA), smooth muscle antibody (SMA), and antiparietal cell antibody ( A P A ) assays drawn before death were all negative.
DISCUSSION The incidence of temporomandibular joint dysfunction in JRA has been estimat.ed to be from 5 to 85 per~ent.7.~ A recent study by Grosfeldi of 100 cases of JRA revealed 65 percent with demonstrable changes. Twelve percent of the patients examined had mandibular openings of from 20 to 30 mm, while only 1 patient was limited to a 9-mm opening. Other authors agree that bony ankylosis of the temporomandibular joint as the result of JRA is rare.!)-" When
591
severe ankylosis requires surgical intervention to preserve functional growth and mastication, anesthesia management from the standpoint of airway control and choice of anesthetic agent may pose the greatest obstacle to treatment of these patients. In the absence of surgical infection, fever 9 days PO (7 days before death) may have been due to 3 major cause+an acute exacerbation of JRA, hypersalicylism, or drug (particularly halothane) sensitivity. Diurnal fever is a common symptom in JRA but is usually controlled by salicylates. An acute salicylate overdose can also cause fever. This may be due to excessive sweating, hyperpnea, and dehydration, but the exact mechanism is not known.1.! A febrile episode followed by jaundice (13 days after initial exposure) may indicate halothanerelated hepatic damage.3 1 3 Salicylate therapy is the most commonly accepted drug treatment for JRA and is generally thought to be the safest. Hepatic damage due to salicylates has only recently received significant interest. There have been, however, reports for more than 20 years of abnormal liver function tests in patients receiving salicylates for various disorders. In 1956, Manso's group14 reported an increase in serum enzymes with serum salicylate levels as low as 20 mg/100 ml in patients being treated for rheumatic fever. Recent attention initially indicated that increases in SGOT, SGPT, and alkaline phosphataise in patients with various connectivetissue disorders occurred only at serum levels greater than 25 mg/100 mll'i (therapeutic range, 20 to 25 mg/100 ml) . In all cases the chemical signs of liver damage returned to normal after discontinuance of salicylate therapy and increased again when salicjlate therapy was reinstituted at the previous levels. Massive hepatic necrosis of the type .seen in our patient has not been reported as a consequence of salicylate therapy, but several authors have warned that if salicylates can produce hepatic damage (as evidenced by increased transaminase levels) in some patients, they may certainly have the potential to produce fatal hepatic failure in a susceptible individual. Patients with JRA may well be more susceptible to the adverse effects of aspirin than the general population However, while our patient was at risk for salicylate-induced hepatic damage, there are other, better described, factors that probably explain his hepatic failure.
592
ANESTHESIA AND ANALGESIA . . . Current Researches VOL.56, No. 4, JULY-AUGUST, 1977
The diagnosis of halothane hepatitis is still largely a “diagnosis of exclusion.” Viral hepatitis is usually the other major consideration. Chronic active hepatitis ( CAH) inflammatory liver disease lasting several months or more-can also have acute exacerbations with massive hepatic necrosis. Negative liver function tests after operation as well as negative antibody assays tend to exclude CAH in this patient. The time and mode of onset of the patient’s fever and jaundice are consistent with those generally described in reports of halothane hepatitis. Of the patients who develop halothane hepatitis, 62 percent do so within the 1st week after exposure, 25 percent in the 2nd week, 9 percent in the 3rd week, and 4 percent in the 4th week:’ l7 Additional clinical criteria for the diagnosis of halothane hepatitis include: ( 1 ) onset of fever 8 to 14 days after anesthesia without previous exposure 11 to 7 days with previous exposure), 12) abrupt rise in serum SGOT levels shortly after the onset of fever and bilirubin elevation 2 to 3 days later, ( 3 absence of HB,Ag, and ( 4 ) prompt recovery or rapid death.17 In 234 collected cases of halothane hepatitis, 30 percent died after a single exposure and 70 percent after multiple exposures, all of which occurred within 3 months of exposure:’ 1: No survivors are reported to have developed a prothrombin time greater than 60 seconds. Factors in our case that tend to exclude other possibilities include: ( 1) the onset of symptoms was too late to be due to a direct hepatotoxin, 12) the onset was too soon for viral (“serum”) hepatitis B and the Hb.Ag assay was negative, and ( 3 ) the onset was slightly before the normal minimum incubation period of viral (“infectious”) hepatitis A. The incubation period of hepatitis A is 3 to 6 weeks and of hepatitis €3, 6 to 16 weeks.’” However, these periods are variable, are not diagnostic for either disease, and are pertinent only if the causative agent was contracted a t the time of operation. It is, of course, possible that the cause of our patient’s hepatic necrosis was an agent contracted in his normal environment. There is no positive evidence for this etiology, but on the other hand, there is only slight negative evidence: no known contact with a jaundiced person, no previous transfusions, etc. In this regard, it is noteworthy that liver enzyme assays of blood drawn 6 days
PO during the patient’s previous hospitalization were normal. Histologic differentiation between the leading possibilities, halothane and viral hepatitis A, is a t best unproven. Light-microscopic changes in this case are consistent with those reported in other cases of alleged halothane hepatitis: massive necrosis, predominately periportal fatty change, portal eosinophilic infiltration, and plasma cell infiltration of the portal areas and parenchyma; but these changes also have all been reported in viral hepatitis and are definitely nonspecific indicators of liver damage. Electron-microscopic changes have been reported which may ultimately allow differentiation in these cases, but a t this time they are not sufficiently reliable. Klion’ has described a segmental loss of the outer membrane and an infolding of the inner one in hepatic cell mitochondria. These are seen in halothane hepatitis but not in viral hepatitis. These findings have been reproduced in experimental animal studies, but the tissue specimens were taken prior to death and were, therefore, less subject to mitochondrial autolysis.’ Suggestive changes were seen in our patient, but the specimen was received 4 hours postmortem, and extensive autolysis was present. Numerous other diagnostic tests are likewise nonspecific. Immunologic tests, another possible means of differentiation in the future, are unreliable a t this time. Lymphocyte transformation tests were not performed, and their interpretation is still controversial.’\ A positive HB,Ag, present in hepatitis B, would have tended to exclude halothane hepatitis.:’ The other antibody assays are often negative in halothane hepatitis. Peripheral eosinophilia is present in some cases but was absent here.
CONCLUSIONS Although the pathogenesis of “halothane hepatitis” has not been elucidated clearly, clinical findings indicate that pediatric patients are relatively immune from this entity. This report of a 14-year-old prepubertal boy with fatal hepatic necrosis following halothane exposure suggests that, rather than the maturation of the child that is important, the relative maturation of the hepatic system may be implicated. This child, with an immunologic disorder combined with a long history of multiple medications, including high doses of salicylates, may
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have “functionally” removed his hepatic system from the pediatric age group. Perhaps halothane anesthesia to pediatric patients of this type is cause for concern.
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2. Balfrage S, Ahlgren I: Axelson’s halothane hepatitis in a n anesthetist. Lancet 2: 1466-1467, 1966 3. Carney FMT, Van Dyke RA: Halothane hepatitis-a critical review. Anesth Analg 51: 135160, 1972 4. Parker CW: Drug allergy. N Engl J Med 292:732-736, 1975
rheumatoid arthritis. Acta Rheum Scand 13:257274, 1967 10. Franks AS: Temporomandibular joint in adult rheumatoid arthritis. Ann Rheum Dis 28: 139-144, 1969 11. Russel JA, Bayles TB: The temporomandibular joint in rheumatoid arthritis. JADA 28: 533-539, 1941 12. 8-haller J, Wood PH, Calabro JJ: Clinical studies with salicylates, Conference on Effects of Chronic Salicylate Administration. N e w Y o r k , HEW, June 1966, Sec D
13. Clykes MH, Gilbert JP, Schurr PH, et al: A review of the epidemiologic immunologic, and metabolic aspects of the relationship of halothane and the liver. Can J Surg 15:217-238, 1972
5. Lefkovitis AM, Farrow I J : The liver in rheumatoid arthritis. Am Rheum Dis 14:162-168, 1955
14. hlanso C, Taranta A, Nydick I: Effect of aspirin administration on serum glutamic oxaloacetic and glutamic pyruvic transasminases in children. Proc Soc Exp Biol Med 93:84-88, 1956
6. Schaller J, Bechwith B, Wedgewood R J : Hepatic involvement in juvenile rheumatoid arthritis. d Pediat 77:203-210, 1970
15. Scamon WE, Ishak KG, Plotz PH: Aspirininduced hepatotoxicity in patients with systemic lupus erythematosus. Ann Intern Med 8O:l-8,1974
7. Grosfeld 0: Clinical investigations of the temporomandibular joint in children and adolescents with rheumatoid arthritis. Scand J Rheumatol 2: 145-149, 1973
16. Rich RR, Johnson JS: Salicylate hepatotoxicity in patients with juvenile rheumatoid arthritis. AI-thritis Rheum 16:1-9, 1973
8. Goel KM, Shanks RA: Follow-up study of 100 cases of juvenile rheumatoid arthritis. Ann Rheum Dis 33:27-31, 1974 9. Ericksson SE, Lundberg M: Alterations in the temporomandibular joint a t various stages of
17. Mathieu A: Diagnosis of halothane hepatitis. JAMA 224: 1188-1189, 1973 18. I’aronetto F, Popper H: Lymphocyte stimulation induced by halothane in patients with hepatitis following exposure to halothane. N Engl J Med 283:277-280, 1970
PROPRANOLOL WITHDRAWAL. Acute myocardial ischemia following t h e a b r u p t withdrawal of propranolol administration m a y refl’act rebound hypersecretion of catecholamines. To s t u d y this possibility systolic time intervals and u r i n a r y excretion of vanillylmandelic acid (VMA) were studied in heall.hy volunteers receiving 120 t o 160 m g of propranolol f o r 15 days. Acute withdrawal of propranolol did not a l t e r t h e systolic time intervals or VMA excretion in the following 3 to 4 days. These d a t a did not support t h e concept t h a t a rebound hyperinotropic state exists following acute reversal of betaadrenergic blockade. These d a t a f r o m healthy volunteers m a y not, however, reflect changes t h a t occur in patients with coronary atherosclerosis and with chronically elevated circulating catecholamines. (Pantano d A , l’ee Y - C : A b r ~ p tp r o p m n o l o l withdrawal and myoca~dialcontractility. A sttcdy of cfftrrcts in normal man. Arch Intern Med 136:867-871, 1976)
