Neuromuscular effects of ether, cyclopropane, chloroform and Fluo- thane. Whitteridge, D. Effect of anaesthetics on liver in protein-deficient mice. Wollman, H. Cohen, Wilson, K. Halo- P. Chase, E, Melman, and M. G, Behar. Cerebral circulation of man during halo- Anesth. Cleveland , Wingard, D. Davis, and D. Anesthesiology Effects of halothane and chloroform on the , Ngai Columbia University, College of Physicians and Surgeons, and Presbyterian Hospital, New York, New York Soon after halothane was introduced into clinical practice, a number of publications ap- peared describing experiences with it.
The re- ports described series ranging from fewer than to thousands of cases, and were primarily concerned with anesthetic techniques and the patients' responses during and after anesthesia. Few specifically mentioned the possible hepato- toxic effects of halothane. Before , Little e-t aL 55 studied hepatic function in 10 patients before and after halothane anesthesia and compared the results with those in patients anesthetized with cyclopropane or diethyl ether. Transient hepatic dysfunction was observed, but there was no significant difference among these anesthetics.
Stephen et al. Three fatal cases of hepatic necrosis after halothane anesthesia were reported - one after aortic valvuloplasty in a patient with severe congestive heart failure 16 , one after cholecystectomy complicated by episodes of cardiovascular depression during anesthesia 86 , and one after an uncomplicated inguinal hernior- rhaphy These authors suspected halothane of contributing to the deaths, but obviously other factors could have played a role.
Three cases of nonfatal postoperative hepatic complications after halothane anesthesia were also reported, but detailed information on hepatic function was not available 5, A number of case reports of hepatic necro- sis after halothane anesthesia appeared late in and early in 14,15,54,78, These reports raised the question of the safety of this anesthetic agent and served as the impetus for the National Halothane Study.
Since then, addi- tional cases, both fatal and nonfatal, have been reported and many have cast suspicion on or implicated halothane as a hepatotoxin. Such a contention could hardly have been proved because of the multitude of factors leading to hepatic necrosis in patients undergoing operation.
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 halo- thane 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 Table 1 summarizes the total number of cases thus studied and the frequency of use of halothane and other anesthetics associated with fatal and non- fatal hepatic necrosis.
Data were obtained from anesthesia registers, hospital charts, and ne- cropsy records. In some the total number of cases was approximate. Fatal cases were gathered from among those patients who died from 4 weeks to 4 months following anesthesia, although in a number of reports the time was not recorded.
Performance of necropsy varied from 65 to 90 percent. In Table 1 the cases listed under the heading "Nonhalothane" include those involving anesthesia with all commonly used agents: thiopental- nitrous oxide, cyclopropane, diethyl ether, and other halogenated agents trichloroethylene, methoxyflurane, and fluoroxene. Most authors excluded, or considered separately, those cases with preoperative hepatic disease. Detailed description of the liver pathology was not pro- vided in all reports.
Thus, the incidence of hepatic necrosis after anesthesia as estimated from these data must be viewed with caution. It is unlikely that a significant number of patients who died of massive hepatic necrosis were over- looked in these surveys. Rather, the incidence of massive hepatic necrosis may have been over- estimated.
In the series of Slater et al. Additional pertinent information may be gathered from a few of these reports. Kee'ri- Szanto and Lafleur 48 found that, of approxi- mately patients with pre-existing serious hepatic disease, seven died of hepatic complica- tions. Of these, two were given halothane anes- thesia, but that agent was administered to ap- proximately 52 percent of the patients in this selected group.
In another series 46 , pa- tients with cirrhosis of the liver underwent portal-systemic venous anastomosis. Halothane anesthesia was administered to 44 patients and other agents to The over-all mortality rate was Similar results were reported by Benke 8 in a series of patients with pre-existing jaundice of diverse origin, 25 of whom were given halo- thane.
In addition, Dawson et al. TABLE 1. In , diethyl ether was used in patients; in , halothane was used in About 2 percent of patients in both groups re- vealed preoperative evidence of hepatocellular disease. One patient in each group died of hepatic failure. Analysis of postoperative hepatobiliary complications or mortality, from known or un- known causes, revealed no significant difference between the groups.
Thus, from these experiences it would appear that neither pre-existing hepatic disease nor operation on the biliary tract con- traindicates the use of halothane. In addition to the aforementioned studies of postoperative death, Mushin et aL 64 and Henderson and Gordon 38 examined the frequency of postoperative hepatic dysfunction as indicated by abnormal hepatic function tests or jaundice.
It was assumed that major hepatic damage oc- curring while the patient was in the hospital would have been observed by the attending clini- cian and that appropriate tests would have been performed. Data were obtained from the records of the biochemical laboratory. Reference to the clinical charts permitted analysis of anesthetic or surgical factors.
Mushin et al. Again, in patients with pre-existing liver disease, halothane did not appear to result in greater degrees of hepatic dysfunction than other anesthetics. Henderson and Gordon 38 found that the incidence of postoperative jaundice defined as a serum bilirubin greater than 1.
These authors attributed the increase to the changing character of surgical practice and to more frequent use of blood transfusions and new therapeutic agents. During , how- ever, when halothane was compared with other anesthetics, there was no difference in abnormal hepatic function tests, the incidence being 4.
Although retrospective surveys of this nature do not ensure identification of all cases of postoperative hepatic dysfunction, it is reasonably certain that most cases with Two other retrospective studies are of interest in that they indicate the relative infre- quency of massive hepatic necrosis associated with anesthesia and operation.
Caravati and Wootton 17 examined all necropsy records in three community hospitals during the year period Total hospital admissions numbered , Massive hepatic necrosis was found in nine of patients who came to ne- cropsy. Only three of these had been subjected to anesthesia and operation soon before the onset of hepatic complications and death. None of these patients received halothane. Rodgers et al. Eighteen instances of massive hepatic necrosis were found among 11, necropsies.
Six of the 18 patients had undergone operation. The primary anesthetics administered were: cyclopropane, three cases; diethyl ether and cyclopropane, one case; and halothane, one case; the remaining patient was operated on without general anes- thesia.
Clinical, laboratory, and necropsy find- ings of these cases are set forth in Tables 3 and 4. Although in some the etiologic factor was not ascertained, it appeared that viral hepatitis, prolonged hypotension treated with vasopressor drugs, septicemia, and reactions to therapeutic agents were causative in most instances. Anes- thesia did not seem to play a role, no matter the agent. The total number of administrations of general anesthesia during the period of survey was not mentioned in either of these reports, but Rodgers et al.
Another form of retrospective survey was carried out by Green and Mungavin 35 , who asked practicing anesthetists in England for information on cases of hepatic complications suspected of having occurred after halothane anesthesia.
More than replies yielded 47 cases, of which 16 were fatalities. It is of interest that, in 10 of the 16 fatal cases, the cause of the hepatic com- plication was "indeterminate. There was no assurance that all pertinent cases were known or reported, and the frequency of use of the anesthetic was not indi- cated.
These authors also searched for cases of fatal hepatic necrosis among necropsy records of six teaching hospitals. The survey was carried out for the years to and covered a cumulative total of 28 years of experience. There were 18 cases associated with halothane anes- thesia and 14 cases in which halothane was not used. Again, the total number of administrations of general anesthesia was not available, although it was estimated that 60 percent of the patients had received halothane.
A number of reports dealt with halothane anesthesia alone and cited the incidence of post- operative hepatic complications or their absence 11,31,32,39,41,44,56,66,71,77, The numbers of cases in the reports ranged from to 12, The incidence of postoperative jaundice ranged from 33 in cases 39 to none in 10, to 12, 31,66, It seems certain that there was little uniformity in the method of case searching; nor can it be assumed that etiologic factors other than anesthesia were not involved.
Nevertheless, the report of Bentel 11 is of interest. Over a period of 4 years, Bentel regularly approximately 20 times per week used halothane, pentolinium Ansolysen , and posture to induce hypotension systolic arterial pressure, 60 to 70 mm Hg for the performance of various surgical procedures. There were only three cases of jaundice that developed 6 months to 1 year after operation, presumably from causes other than anesthesia. From the large numbers of cases in the retrospective surveys, it may be concluded that massive hepatic necrosis after anesthesia and operation is indeed rare.
The exact incidence cannot be ascertained from these data, but it appears that halothane differs little from other anesthetic agents, even if anesthesia were con- sidered a contributing etiologic factor.
From limited experience it may be stated also that halothane is comparable with, and possibly supe- rior to, other anesthetic agents in its safety in the management of patients with hepatic disease or for operation on the biliary tract.
However, the very nature of such studies leaves much to be de- sired. In institutions with large surgical case- loads, it is unlikely that close scrutiny and adequate postoperative examination are afforded all patients. It may also reasonably be assumed that the frequency with which a complication is found is directly related to the index of suspi- cion.
Thus, bias on the part of the observer can- not be discounted. Although cases of serious and fatal hepatic necrosis are not likely to be missed in retrospective studies, the incidence of milder forms of hepatic dysfunction after halothane or other anesthetic agents would be generally unknown. Furthermore, choice of anesthetic agent may have been dictated not only by clinical circumstances but by the personal preference of the anesthetist.
These variables are important in the final results, but are not apparent in statistical analyses such as those de- scribed above. TABLE 2. A well-designed prospective study may eliminate some of these discrepancies, but certain criteria must be considered. Depending on the incidence of postoperative hepatic com- plications, the size of the sample must be ade- quate to permit statistical analysis.
Patients must be selected on a broad basis, with respect to age, sex, physical status, and type of opera- tion. If one anesthetic agent is to be compared with another without bias, patients must be randomly assigned to each group. Appropriate laboratory tests must be performed at the proper time to detect hepatic dysfunction. It may be difficult to execute such a study properly because of practical and ethical problems.
Table 2 summarizes the results of published prospective studies comparing the effect of halothane and other anesthetic agents on hepatic functions. These studies vary considerably in the size of samples, the liver function tests applied, and the time of application of these tests postoperatively. With few exceptions, the samples were small. Only three studies randomly as- signed the anesthetic agent to be administered.
In some, postanesthetic alterations in hepatic function were not followed beyond 30 hr. Despite these limitations, the general conclusion has been that there is no significant difference among halothane and other agents in their effects on the liver.
Transient abnormalities, presumably attributable to the operation, were found with equal frequency. A number of reports have dealt with the effect of halothane alone.
Lorentz and Henneberg 57 measured serum lactic dehy- drogenase in 16 patients 24 and 48 hr after halothane anesthesia for major surgical pro- cedures; there was no change of significance. Tracy and Heyman 81 , Urso et al. Hepatic func- tion tests included sulfobromophthalein retention, serum transaminase levels, bilirubin concen- tration, flocculation, and alkaline phosphatase.
Although transient abnormal values were ob- served in some patients, the role of pre-existing disease, concurrent drug therapy, and the opera- tive procedure was unknown.
No comparable series of cases with other anesthetic agents were available for comparison. Keeri-Szantd 47 reported a prospective study involving surgical patients anesthetized with halothane, methoxyflurane, or neuroleptanal- gesic mixtures.
He observed a greater intra- operative sulfobromophthalein retention with halothane than with methoxyflurane. In another patients, the degree of abnormal BSP reten- tion 5 days postoperatively was greater in those who received higher concentrations of halothane 2 percent for induction than in those who re- ceived 1 percent of halothane.
The possible significance of these results is obscure. McReynoldset al.. Distribu- tion of patients according to age, physical status, and site of operation was approximately the same for both groups.
The over-all mortality rate was 3. One patient with severe pre- existing 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.
The authors concluded that halothane and On the basis of its data-retrieval system and the sorting of a total of , references, a list of publications was compiled to include all papers pertaining to anesthesia, halothane, toxicologic reports, jaundice, hepatic disease, hepatitis, hepatic necrosis, and postoperative complications.
In addition, the medical library of the Ayerst Laboratories kindly provided a complete bibliography on halothane for to These lists were screened and all perti- nent references perused for case histories of hepatic complications after anesthesia and operation. This process yielded cases of post- operative death due to hepatic necrosis or asso- ciated with some degree of pathologic change in the liver but not necessarily massive necrosis.
An additional cases were selected in which evidence of postoperative hepatic dysfunction was presented. This evidence included clinical jaundice, abnormal hepatic function tests, and biopsies. Relevant clinical histories and labora- tory and pathologic findings, where available, are presented in Tables 3 and 4 fatal cases and 5 and 6 nonfatal cases. Most but not all of the fatal cases mentioned in the section on retro- spective studies are included.
In the retrospec- tive studies of Kee'ri-Szanto and Lafleur 48 , Allen and Metcalf 2 , and Henderson and Gordon 38 , 11 patients incurred hepatic necrosis; of these, seven had received halothane anesthesia.
The survey of Green and Mungavin 35 of six hospitals in England yielded 32 cases of hepatic necrosis, 18 associated with halothane and 14 with other agents. None of these 43 cases is included in Tables 3 and 4, because of lack of details.
Slater et al. A subsequent publication by the same authors 29 provided additional information on nine patients who showed evidence of acute parenchymatous hepatic disease at necrospy. Overlaps in re- porting are apparent in these publications, as well as in those by Virtue and Payne 86 , Ging- rich and Virtue 33 , Lindenbaum and Leifer 54 , and Blackburn et al. Obvious duplications are omitted from Tables 3 through 6.
The preponderance in Tables 3 through 6 of cases associated with halothane reflected the current interest in this problem. The degree of suspicion that each author held certainly played an important role in these reports. Thus, the majority of cases involving anesthetic agents other than halothane were reported in connection with retrospective surveys when the total experi- ence in a given institution was scrutinized. When this was done, the incidence of hepatic necrosis or dysfunction associated with halothane usually did not differ significantly from that associated with other agents cf.
Case reports cited herein varied con- siderably in details of clinical histories, particu- larly regarding circulatory status during and after operation, transfusion, and concurrent drug therapy. Descriptions of pathologic changes in the liver were not always given in sufficient detail. For these reasons, no attempt will be made to discuss individual cases.
Nevertheless, in a number of cases hepatic necrosis and dysfunc- tion 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 con- cerning the probable cause s of hepatic necrosis in any of the reported cases.
The possibility of coincidental viral infection was repeatedly men- tioned, but this must remain conjectural, as shall be the contention of many other authors who implicated halothane.
Thus, it appears that, even with such a large series of patients who incurred postoperative hepatic damage, any conclusion based on case reports concerning the causal relationship be- tween halothane and hepatic necrosis would be unwarranted.
These reports cannot be taken to prove that halothane is or is not hepatotoxic. Affolter, H. Hartmann, V. Kapfhammer, and S. Akute Massennekrose der Leber nach mehrmaliger Halothane- Narkose.
Allen, H. A search for halothane liver complications. Armstrong, C. Fatal jaundice after halothane. Ashton, J. O'Connor, and G. Jaundice after halothane and radiotherapy. Barton, J. Jaundice and halothane. Beddard, J. Belgeri, R. Comportamento della ornitina carbamil transferasi OCT del siero dopo narcosi con Fluothane in ostetricia e ginecologia. Benke, A. Uber einige Ursachen des Coma hepaticum.
Bennike, K. Cyclo- propane hepatitis: A Danish disease? Hagelsten, and E. Leberstorungen nach Halothane- narkose--post oder propter?
Bentel, H. Halothane and liver damage. Birt, R. Post-operative jaundice: A case history. Blackburn, W. Ngai, and J. Linden- baum. Morphologic changes in hepatic necrosis following halothane anesthesia in man. Brody, G. Halothane anesthesia as a possible cause of massive hepatic necrosis.
Bunker, J. Liver necrosis after halothane anesthesia. Cause or coincidence? New Eng. Burnap, T. Galla, and L. Anesthetic, circulatory and respiratory effects of Fluothane. Caravati, C. Acute mas- sive hepatic necrosis with fatal liver failure.
Southern Med. Chadwick, D. Massive hepatic necrosis associated with halothane anaesthesia. Chamberlain, G. Liver damage after halothane anaesthesia. Chambers, J. Sewell, and H. Jaundice after halothane and radio- therapy. Clements en, H. Wolff, and W. Die Funktionsveranderungen des E. Anaes- thesist , Collins, W. Transam- inase studies following anesthesia. Costa, J. Contribuicao ao estudo da toxicidade hepatica do halotano.
Davies, C. Jaundice following halothane anaesthesia a case report. Dawson, B. Jones, N. Schnelle, V. Hartridge, J. Paulson, M. Adson, and W. Halothane and ether anesthesia in gallbladder and bile duct surgery: A retrospective study into mor- tality and hepatobiliary complications. Deacon, A. Liver damage after halothane. DeBacker, L. Pros- pective and retrospective searches for liver necrosis following halothane anesthesia. Serum enzyme study and case report.
Defalque, R. Hepatic failure after halothane. Dykes, M. Walzer, E. Slater, J. Gibson, and D. Acute paren- chymatous hepatic disease following general anesthesia: Clinical appraisal of hepatotoxi- city following administration of halothane.
Fono, R. Fluothane ikterus gyermekkorban. Frey, R. Halothan und Leberschaden. Calvin, H. Liver damage and halothane. Irish J. Gingrich, T. Post- operative liver damage: Is anesthesia in- volved? Surgery , Gordon, J. Jaundice associated with halothane anaesthesia. Green, K. Halothane and the liver: Retrospective studies. Griffiths, H. Effects of chloroform and halothane anaesthesia on liver function in man.
Heidenberg, W. Halothane hepatitis. Henderson, J. The in- cidence of postoperative jaundice with special reference to halothane. Henke, D. Zur Frage der Hepatotoxizitat von Fluothane aus klinischer Sicht. Bruns1 Beitr. Herber, R. Liver necrosis following anesthesia. Hilscher, A. Noch einmal: Akute Massen- nekrose der Leber nach mehrmaliger Halothanenarkose. Holmes, A. Torgerson, and W. The acute effects of anesthesia with halothane on liver function in man.
Gastro- enterology , Howard, E. Hutchinson, B. Halothane in closed circuit anaesthesia. New Zeal. Johnson, C. Hepatitis associated with halothane. Northwest Med. Jones, R. Dawson, M. Halothane and nori- halogenated anesthetic agents in patients with cirrhosis of the liver: Mortality and morbidity following portal-systemic venous anastomoses.
Clin N. Keeri-SzinW, M. Halothane and the liver. Kee'ri-Szantd, M. Postanes- thetic liver complications in a general hospital: A statistical study. Kerbel, N. Halothane hepatotoxicity. Kirwan, M. Dundee, R. Clarke, Mitchell, and D. Halothane hepatotoxicity; an investigation of the effects of short exposure. Dundee, and D. A comparison of the effects of chloroform and halothane on liver function. Klinge, O. Toxische Hepatose bei Halothan- Lehner, T.
Systemic candidiasis and renal involvement. Lindenbaum, J. Hepatic necrosis associated with halothane anes- thesia. Little, D. Barbour, and J. Trying to learn the entire history of the world is not only impossible, it feels too hard and reduces our enthusiasm for history. In-depth study of a few important events gives us a chance to understand the many sides of a story. We can always add new facts.
History is hands-on work. Learning history is best done in the same way we learn to use a new language, or to play basketball: we do it as well as read about it. Doing history means asking questions about events and characters; searching our towns for signs of its history; talking with others about current events and issues; writing our own stories about the past.
There is no final word on history. There are good storytellers and less good storytellers. And there are many stories. But very rarely does any one storyteller "get it right," or one story say it all. A good student of history will always look for other points of view, knowing that our understanding of history changes over time.
Your children do well to ask "So What? We should invite them to clear up doubts they have about the reasons for remembering certain things, getting the facts right, getting facts right, and collecting and judging evidence.
At each step, asking "so what? Asking Questions At the end of each activity in this book, you will find a series of questions that can help develop the critical thinking skills children need to participate well in society, learn history, and learn from history.
The questions help them know the difference between what is real, fantasy, and ideal, and make the activity more fun. Critical thinking is judging the value of historical evidence; judging claims about what is true or good; deciding what information is important to have; looking at a topic from different points of view; being curious enough to look further into an event or topic; being skeptical enough to look for more than one account of an event or life; and being aware that our vision and thinking are often limited by our biases and opinions.
There is no explanation of why the Mexicas lost. Many individuals believe that history is about telling stories, but most historians also want answers to questions like why did the Mexicas lose? To answer these questions, historians turn to primary sources, sources that were written at the time of the event, in this case written from in Mexico.
These would be firsthand accounts. Unfortunately, in the case of the conquest of Mexico, there is only one genuine primary source written from Other sources are conventionally used as primary sources, although they were written long after the conquest. Other accounts consist of Mexica and other Nahua stories and traditions about the conquest of Mexico from their point of view. Historians then use these sources to make arguments, which could possibly be refuted by different interpretations of the same evidence or the discovery of new sources.
For example, the Bentley and Ziegler textbook make several arguments on page about why the Spaniards won:. Ideally, under each of these "thesis statements," that is, each of these arguments about why the Mexicas were defeated, the authors will give some examples of information that backs up their "thesis. Since the Bentley and Ziegler book does not provide any evidence to back up their main arguments, you can easily use the material available here to provide evidence to support your claim that any one of the above arguments is better than the others.
To become a critical reader, to empower yourself to "own your own history," you should think carefully about whether the evidence the authors provide does in fact support their theses. Since the Bentley and Ziegler book provides only conclusions and not much evidence to back up their main points, you may want to explore your class notes on the topic and then examine the primary sources included on the Conquest of Mexico on this web site.
There are several ways to make this a successful assignment. First, you might take any of the theses presented in the book and use information from primary sources to disprove it—the "trash the book" approach. Or, if your professor has said something in class that you are not sure about, find material to disprove it—the "trash the prof" approach and, yes, it is really okay if you have the evidence.
Another approach is to include new information that the authors ignored. For example, the authors say nothing about omens. If one analyzes omens in the conquest, will it change the theses or interpretations presented in the textbook? Or, can one really present a Spanish or Mexica perspective?
Another approach is to make your own thesis, i.
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