National Halothane Study: a Study of the Possible Association Between Halothane Anesthesia and Postoperative Hepatic Necrosis; Report. Edited by John P. Bunker [and Others] (1969) / Chapter Skim
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'HISTORICAL BASIS OF THE STUDY'
'HISTORICAL BASIS OF THE STUDY'
Pages 1-46
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From page 1... ...
No data were available on the incidence of hepatic necrosis in patients receiving other anesthetic agents or on the role of pre-existing hepatic disease, viral hepatitis, or prolonged operative shock as etiologic factors in postoperative hepatic failure. For these reasons, preliminary plans for a randomized clinical trial were drawn up and a pilot study was begun in one medical center.
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coded abstracts of the clinical records of all patients who died within 6 weeks of general anesthesia and of those identified in the random sample, including chart number, age, sex, date of discharge or death, whether necropsy was performed, whether massive hepatic necrosis was described at necropsy or given as a clinical diagnosis, cause of death, other clinical diagnoses, anesthetic agents used, physical status (evaluated preoperatively) , duration of anesthesia, operations in the previous 4 years (100 two-digit operation codes were provided for coding operative procedures)
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From page 3... ...
. Therefore, according to the principles that determine the uptake of inert gases by the body, during inhalation of halothane vapor equilibration between the inspired concentration and that in the body should be slower than with anesthetic gases and faster than with other anesthetic vapors.
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Halothane also depresses subcortical structures that regulate somatic and visceral functions. The electroencephalogram during halothane anesthesia shows characteristic changes that correlate with increasing depth of anesthesia (22)
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. Similarly, in man, during halothane anesthesia (1 to 3 percent inspired concentration)
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Metabolism In man given morphine or barbiturate and scopolamine for premedication, oxygen uptake falls to 72 to 87 percent of predicted basal values during halothane anesthesia (1.3 to 1.9 percent inspired concentration in mixture of 75 percent nitrous oxide and 25 percent oxygen)
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Reports of experience in large series of cases have failed to show that the incidence of postpartum hemorrhage is higher with halothane anesthesia, except when operative obstetric procedures were involved (13,72)
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Baldwin. Intracranial pressure and internal carotid blood flow during halothane anesthesia in the dog.
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Oxygen uptake during light halothane anesthesia in man. Anesthesiology 25:627-633, 1964.
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71. Whitteridge, D
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While the National Halothane Study was in progress, a number of retrospective surveys and prospective studies were carried out in an attempt to prove or disprove a causal relationship between halothane and hepatic necrosis and to estimate the incidence of postoperative hepatic complication as related to various anesthetic agents. The following section summarizes the pertinent literature to January 1966.
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From page 12... ...
About 2 percent of patients in both groups revealed preoperative evidence of hepatocellular disease. One patient in each group died of hepatic failure.
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From page 13... ...
The exact incidence cannot be ascertained from these data, but it appears that halothane differs little from other anesthetic agents, even if anesthesia were considered a contributing etiologic factor. From limited experience it may be stated also that halothane is comparable with, and possibly superior to, other anesthetic agents in its safety in the management of patients with hepatic disease or for operation on the biliary tract.
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From page 14... ...
No significant difference between halothane and chloroform 70 Random SGPT Preoperatively; postoperatively, 24 hr 140 140 6 patients in each group had postoperative SGPT higher than 39; study in progress 7 OCT Preoperatively; postoperatively, 2, 4, 6, 8 days 13 3 All values within normal limits 22 Random SGPT Preoperatively; postoperatively, 2 or 6 164 104 No significant difference between preoperative or postoperative values days 23 Liver biopsy, OCT Beginning and end of operation 10 6 No change observed in liver biopsy; all OCT values within normal limit 76 SCOT, SGPT, LDH, MDH Preoperatively; during operation; postoperatively, 24 hr 19 11 No abnormal values observed 50 Matched series Urobilinogen, Cholinesterase, SGPT Preoperatively; postoperatively, 6 and 30 hr SGPT 84 84 Halothane group not different from nonhalothane groups only 51 Matched series SGPT Preoperatively; postoperatively, 6 and 30 hr 50 50 +50* No evidence of hepatic dysfunction after halothane or chloroform 67 BSP retention prothrombin time, guanase, OCT Preoperatively and postoperatively, 1 and 5 days; preoperatively and postoperatively 1 and 3 days 21 21 BSP retention elevated postoperatively; no significant difference between halothane and nonhalothane series 14
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From page 15... ...
One patient with severe preexisting hepatic disease died with diffuse hepatic and kidney necrosis, 15 days after chloroform anesthesia and 22 days after halothane anesthesia for a previous operation. Three patients in each group incurred "minor" hepatic complications.
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From page 16... ...
Nevertheless, in a number of cases hepatic necrosis and dysfunction can probably be explained on the bases of pre-existing hepatic disease, such cardiovascular disturbances as congestive heart failure and shock, prolonged treatment with vasopressor drugs, and overwhelming infection. Because it is not possible to review all reported cases in the same manner as was done for the cases collected in the National Halothane Study, it would not be fruitful or justifiable to render an opinion concerning the probable cause(s)
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Halothane anesthesia as a possible cause of massive hepatic necrosis. Anesthesiology 24:29-37, 1963.
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Postoperative jaundice associated 83. with halothane anesthesia.
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24 Leukemia 34 13 1 4 F 70 Abnormal hepatic function tests Cholecystectomy, liver biopsy H (170) No ~~ " 15 Hepatic failure 20 14 14 F 74 Episodes of dark urine and lightcolored stools Cholecystectomy, choledochotomy, liver biopsy H (180)
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From page 20... ...
» Transfusion Complications Drug therapy Onset of postoperative Jaundice, days Cause and day of death after operation 16 15 F 16 None Repair lacerated wrist H (280) No None No Jaundice Hepatic failure 14 17 15 U Alcoholism (1)
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Oolectomy H (165) Yes None Tetracycline ''trichloryl" 5 Hepatic failure 11 34 53 F 68 -- Cys tec tomy H ~ ~ ~ Not stated Renal failure 14 35 9 F 75 None Gastrectomy, pyloroplasty C Yes -~ 5 Pulmonary infarction 8 36 9 F None Hemicolectomy C Yes None -- No Jaundice Not stated 21 74 37 28 U Alcoholism, cirrhosis (1)
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From page 22... ...
No None Chloramphenicol, neomycin steroids 9 Hepatic failure 24 34 50 74 F None (1) Dressing, for burns V, K Yes None Penicillin (44)
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From page 23... ...
» Transfusion Complications Drug therapy Onset of postoperative Jaundice, days Cause and day of death after operation 60 40 F 45 History of Jaundice (1) ttysterectomy H No (2)
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» Transfusion Complications Drug therapy Onset of postoperative Jaundice, days Cause and day of death after operation 82 79 U 46 None (1)
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SOOT SOFT OF TT thrombin time g % Pathologic findings Author's remarks or conclusions Total Direct 1 44.8 Chronic passive congestion, central lobular necrosis of liver Changes in liver could have resulted from heart failure 2 Clotting time, 3O min. Massive hepatic necrosis, pancreatic necrosis Course and hepatic changes similar to delayed chloroform poisoning 3 3 Urea nitrogen 63 mg *
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Other laboratory findings Pathologic findings Aithor's remarks or conclusions 17 Total Direct BUN, 96 Massive hepatic Strongly suggest that halothane may be responsible mg * necrosis, renal tubular necrosis, coronary occlusion 18 29.5 17 (KA)
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43 24.0 3.8 (B) 4+ 15 sec Massive hepatic Probably viral hepatitis, questionably drug toxicity necrosis, focal periportal mixed cellular Infiltration
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4+ 16 sec Massive hepatic necrosis, moderate mononuclear infiltration Etiology unknown 46 4.2 (B) 3+ 27 Cirrhosis of liver, massive parenchymal necrosis Hepatic necrosis due to prolonged shock and vasopressor therapy, chronic hepatic disease sec 47 38 11.8 (B)
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Alkaline phosphatase, SCOT SOFT CF TT Prothrombln Albuminj « * Other laboratory findings Pathologic findings Author's remarks or conclusions Total Direct units time » 10 (KA)
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From page 30... ...
7000 Massive hepatic necrosis No opinion offered 85 Scattered focal hepatic necrosis, fatty change at periphery of lobules; pulmonary Infarction, atelectaale, and edema Death was due to pulmonary changes; fatty change in liver may be toxic in origin 86 Centrllobular focal hepatic necrosis, diffuse fatty change, cholestasis; meningeal hemorrhage, brain edema Suggesting allergic reaction 87 8.02 Increase Centrllobular fatty change in liver with cholestasis, severe bronchopneumonia, slight toxic nephrosis Compatible with toxic hepatosis 88 in urine urobilinogen Diffuse fatty change, cholestasis, and focal necrosis in liver; Intraabdominal hemorrhage Toxic hepatosis in addition to hemorrhage and shock 89 Dlffuae fatty change, cholestasis, and focal necrosis of liver; herniation of brain stem Death was due to brains tern hern i at ion; toxic hep at os is 30
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From page 31... ...
» Transfusion Complications Drug therapy Onset of postoperative Jaundice, days Remarks 1 16 U None Frontal ainusotomy H No Hypotension during operation -?
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« Transfusion Complications Drug therapy Onset of postoperative Jaundice, days Remarks 13 37 U 57 None (1) Hemiorrhaphy H (120)
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* Transfusion Complications Drug therapy Onset of postoperative Jaundice, days Remarks 27 62 F 57 None (l)
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» Transfusion Complications Drug therapy Onset of postoperative Jaundice, days Remarks years 48 64 F 29 -- Colectomy Non-H Yea -Chlorpromazine, neomycin, phthalylsulfathiazole 1 49 39 U -Herniorrhaphy H (40) -- ~ -- 1 (mild)
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« Transfusion Complications Drug therapy Onset of postoperative Jaundice, days Remarks 76 39 F 15 -Appendectomy H (50) -2 (mild)
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From page 36... ...
» Onset of postoperative Jaundice, days Case Reference and age, years Operation Transfusion Complications Drug therapy Remarks 96 85 F 60 None (1) Radium implantation H No None (2)
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* Transfusion Complications Drug therapy Onset of postoperative Jaundice, days Remarks 115 29 None Laminectomy N (180)
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From page 38... ...
Alkaline phosphatase, units ProAlbumin, If Other laboratory findings Pathologic findings Author's remarks or conclusions Case Total Direct SOOT SGPT CF TT thrombln time 1 Postnecrotic cirrhosis ? Natural progression of pre-existing liver disease 2 3 4 13.3 7.0 18 (KA)
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From page 39... ...
Viral hepatitis 15 5.9 450 1000 Wondering If combination of halothane and radium therapy is responsible for hepatic damage 16 Wondering if combination of halothane and radium therapy is responsible for hepatic damage 17 21 310 Wondering if combination of halothane and radium therapy is responsible for hepatic damage IS 4.1 0.9 -19 7.6 1.6 -20 3.5 1.5 -21 1.9 0.3 17 (U) 4+ 4 3.7 Probably viral hepatitis 22 3 2.4 20.8 (?
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From page 40... ...
) 100 88 Centrilobular cholestasis, diffuse fatty change Difficult to Judge cause of hepatic damage 30 1.4 10.4 (?
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From page 41... ...
Other laboratory findings Pathologic findings Author's remarks or conclusions Total Direct 53 23 101 76 ~ 54 1.0 23 16 55 1.1 8 11 -56 1.7 75 60 -57 2.0 703 250 -58 3.3 -59 0.4 -60 2.8 35 38 -61 1.0 -62 1.1 -63 2.2 -64 1.4 44 28 -65 1.3 -66 1.2 67 0.8 83 45 -68 1.8 50 95 -69 1.8 50 95 -70 0.4 50 38 71 2.5 121 170 72 1.0 60 23 73 1.2 -74 2.8 113 234 ~ 75 1.4 ~ 76 0.9 48 8 -- 77 1.0 -- 78 4.8 370 601 -- 79 9.2 2174 3629 -- 80 1.4 23 15 -- 81 6.6 249 556 -- 82 5.4 3.3 19 (?
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From page 42... ...
31 21 15.3 (KA) >60 >60 Zinc turbidity, 10 units 91 2.3 1025 1630 Suggest causal relationship between halothane and Jaundice 92 3.0 590 Suggest causal relationship between halothane and Jaundice 93 1.5 710 520 Variable degrees of eosinophilic degeneration of hepatic cells, diffuse inflammation Viral hepatitis 94 6 1420 860 Suggest causal relationship between halothane and Jaundice 95 6 t 210 200 Neg Neg ..
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From page 43... ...
Alkaline phoephatase, units SCOT SGPT CF TT Prothraabin time Albumin, g% Other laboratory findings Pathologic findings Author's remarks or conclusions Total Direct 113 5.3 8.6 (B) 73 + Recognition of etiologic factors is conjectural 114 2.9 13.0 (B)
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