JAMA Surgery

Ottinger, Leslie W.

doi: 10.1001/archsurg.134.4.354pmid: 10199306

Coady, Michael A.; Davies, Ryan R.; Roberts, Michele; Goldstein, Lee J.; Rogalski, Matthew J.; Rizzo, John A.; Hammond, Graeme L.; Kopf, Gary S.; Elefteriades, John A.

doi: 10.1001/archsurg.134.4.361pmid: 10199307

HypothesisTo provide evidence that genetic factors contribute to the development of thoracic aortic aneurysms (TAA) by demonstrating familial patterns of the disease.DesignRetrospective review.SettingUniversity hospital.Patients and MethodsWe sought to identify familial patterns of TAA from a database of 598 patients evaluated or treated for TAA at the Yale Center for Thoracic Aortic Disease, New Haven, Conn, from January 1985 to August 1998. Of the 598 patients, 45 patients had a diagnosis of Marfan syndrome and 553 patients had no known history of any collagen vascular disorder. Of the 553 patients in the latter category, 398 patients had confirmed TAA, 66 had TAA with concomitant aortic dissections, and 89 had aortic dissections. From the group of 464 patients with TAA with or without concomitant aortic dissections, 2 interviewers attempted to contact 150 randomly selected patients for telephone screening to determine the presence of familial patterns of aortic disease. Fifteen of these patients were lost to follow-up. Complete medical and family histories of the remaining 135 patients (85 men, 50 women) were reviewed. Of the 135 individuals screened, 26 (18 men, 8 women) (19.3%) were found to belong to multiplex pedigrees. These 26 patients with familial nonsyndromic TAA were compared with the remaining 109 patients with sporadic TAA and the 45 patients with Marfan syndrome–associated TAA.Main Outcome MeasuresGroups were examined for statistical differences in age and aortic size at the time of diagnosis, growth rates of TAA, and rates of concomitant diseases. Nonsyndromic family pedigrees were analyzed and potential modes of inheritance were determined.ResultsThe mean age at presentation for patients with familial nonsyndromic TAA (56.8 years) was significantly younger than the mean age of presentation in sporadic cases (64.3 years, P≤.03), and significantly older than that of patients with Marfan syndrome (24.8 years, P≤.001). Patients with a family history of aortic aneurysms had faster growth rates (0.22 cm/y) compared with patients with sporadic TAA (0.03 cm/y) (P≤.001) and patients with Marfan syndrome (0.10 cm/y) (P≤.04). Familial nonsyndromic TAA in patients with a concomitant aortic dissection had a growth rate of 0.33 cm/y, which was greater than that of patients with sporadic TAA (0.10 cm/y) and patients with Marfan syndrome (0.08 cm/y) with associated aortic dissection. This growth of 0.33 cm/y was significantly faster than the overall growth rate estimate of aneurysms in patients with aortic dissection (0.14 cm/y) (P≤.05). Ten pedigrees (38.5%) showed direct father to son transmission, consistent with an autosomal dominant mode of inheritance. Six family pedigrees (23.1%) suggested an autosomal dominant or X-linked mode of inheritance. Seven pedigrees (26.9%) suggested a recessive mode of inheritance; 2 an autosomal recessive mode, and 5 an X-linked recessive or autosomal recessive mode. The remaining 3 pedigrees displayed more complex modes of inheritance.ConclusionsThis study supports the role of genetic factors influencing familial aggregation of TAA. Thoracic aortic aneurysms in association with multiplex pedigrees represent a new risk factor for aneurysm growth. Pedigree analysis suggests genetic heterogeneity. The primary mode of inheritance seems to be autosomal dominant, but X-linked dominant and recessive modes are also evident.THORACIC AORTIC aneurysms (TAA) of any cause involve a structural weakness in the aortic wall, resulting in progressive dilatation in accord with the relationships expressed in LaPlace's law. The manifestations of aneurysmal disease result in considerable morbidity and mortality for affected individuals. Understanding familial aggregation patterns and recognition of high-risk groups may lead to earlier detection and treatment and to the isolation of genetic factors contributing to the development and growth of thoracic aortic aneurysms.Although abdominal aortic aneurysms (AAA) have been well characterized in terms of familial clustering, risk factors, growth rates, and possible modes of inheritance, less is known about TAA. Aneurysms affecting the thoracic aorta in patients with Marfan syndrome behave more aggressively than TAA in patients without Marfan syndrome; however, the natural history of TAA in patients who do not have Marfan syndrome but who demonstrate a family history that is positive for aortic aneurysms has not been not well-described.We sought to identify familial patterns of TAA from a database of 553 patients evaluated or treated for diseases of the thoracic aorta at the Yale Center for Thoracic Aortic Disease, New Haven, Conn. One hundred thirty-five patients selected at random were interviewed, and both medical and family histories were obtained. Age and sex distributions, risk factors, and aneurysm growth rates are reported. These factors are compared for sporadic, familial nonsyndromic, and Marfan syndrome–associated TAA. The prevalence of aortic aneurysms among relatives of patients in our database is evaluated, and possible modes of inheritance are discussed.PATIENTS AND METHODSSeveral sources were used for identification of patients with TAA evaluated or treated at Yale University between January 1985 and August 1998. The computerized records of the Yale Center for Thoracic Aortic Disease were searched. This database stores longitudinal information (mean follow-up of 32 months) on 598 patients evaluated or treated for diseases of the thoracic aorta. In addition, the computerized database of the Department of Diagnostic Imaging at Yale University was searched for patients who underwent computed tomography, magnetic resonance imaging, angiography, and ultrasound studies of the thoracic aorta. Records of all patients undergoing operations of the thoracic aorta were reviewed. Autopsy records of all patients who died of aortic disease were examined. These sources identified 598 patients with TAA, and 1529 multiple imaging studies on most patients (computed tomography, magnetic resonance imaging, angiography, transesophageal echocardiography, and transthoracic echocardiography). Data recovered from hospital records and computer files were cross-checked with hospital discharge abstract data monitored by the Connecticut Hospital Association and Connecticut State Mortality Records, Wallingford, Conn.Of the 598 patients, 45 patients had a diagnosis of Marfan syndrome, and 553 patients had no history of Marfan syndrome or any other collagen vascular disorder. From the 553 patients in the latter category, 398 patients had confirmed TAA, 66 had TAA with concomitant aortic dissections, and 89 had aortic dissections. From the group of 464 patients with TAA with or without concomitant aortic dissections, 2 interviewers (M.A.C. and M.J.R.) attempted to contact 150 randomly selected patients for telephone screening to determine the presence of familial patterns of aortic disease. Fifteen of these patients were lost to follow-up. Complete medical and family histories of the remaining 135 patients (85 men, 50 women) were reviewed. All telephone screening was carried out consistently by 2 trained interviewers. Responses were recorded on standardized forms. Pedigree analysis was performed on families in which more than one member had an aortic aneurysm.We defined familial nonsyndromic TAA as those occurring in patients having 1 or more first-generation relatives with an aortic aneurysm and no history of Marfan syndrome or any other collagen vascular disorder. Sporadic cases of thoracic aneurysms are defined as those with no family history of aneurysmal disease and no history of Marfan syndrome or any other collagen vascular disorder. Patients with a diagnosis of Marfan syndrome met the revised criteria for the diagnosis outlined by DePaepe et alin 1996.Risk factors for vascular diseases were assessed (tobacco use, diabetes mellitus, hypertension, lipid profile, cardiac disease, and renal dysfunction), and were graded as mild, moderate, or severe according to the suggested standards for reports pertaining to lower extremity ischemia as formulated by the Ad Hoc Committee on Reporting Standards of the Society of Vascular Surgery and the International Society of Cardiovascular Surgery North America.Statistical methods were used to compare 3 categories of TAA: familial nonsyndromic TAA, sporadic TAA, and Marfan syndrome–associated TAA. Univariate analyses were performed using a commercial software program (SAS, version 6.12; SAS Institute Inc, Cary, NC). Analysis of variance was performed to compare means between familial nonsyndromic patients, sporadic patients, and patients with Marfan syndrome. The Bonferroni technique was performed to test for differences between means in multiple groups.Dinsmore et alreported an extremely high correlation among magnetic resonance imaging, computed tomography scans, and ultrasound studies in TAA measurement. In this study, these 3 modalities were used for growth rate measurement. Serial information on aneurysm size was available for 18 patients in the familial nonsyndromic group, 45 patients in the sporadic group, and 39 patients in the Marfan syndrome group. Mean follow-up time for the 3 categories of TAA was 52.9 months (range, 0.07-304 months) for patients with familial nonsyndromic TAA, 31.6 months (range, 0.3-174 months) for sporadic TAA, and 58.3 months (range, 0.03-220 months) for Marfan syndrome–associated TAA.Once patients underwent surgical repair, their subsequent imaging measurements were excluded from growth rate estimates. Serial imaging studies for the 3 categories of TAA were performed at mean (±SD) intervals of 9.75 ± 14.5 months for patients with familial nonsyndromic TAA, 11.14 ± 16.4 months for sporadic TAA, and 9.06 ± 12.5 months for Marfan syndrome–associated TAA.Growth rate estimates were performed as we have reported previously, using multivariable regression analysis in which aneurysm growth follows an exponential path.Specifically, an instrumental variables regression-based estimation technique was employed that is designed to mitigate measurement errors, yielding more stable and less biased estimates of aneurysm growth.This approach correlates the change in aneurysm size with a variable, which, unlike aneurysm size, has little measurement error. The natural logarithm of the last measured size to the first measured size was related to the interval between the 2 tests and interactions between this time variable and risk factors.This relationship is then estimated by ordinary least squares regression analysis, yielding an estimate that relates the interval between diagnostic imaging tests to aneurysm growth.Importantly, the estimate will only be correlated with the true variation in aneurysm growth, not with the measurement error terms.The overall growth rate estimates of aneurysms were calculated by examining all patients in our database for whom serial imaging measurements were available (n=258). Initial risk factors for aortic growth were analyzed and included chronic dissection, aneurysm location (ascending or arch vs descending or thoracoabdominal), age, smoking history, hypertension (diastolic blood pressure >95 mm Hg), and sex.RESULTSDEMOGRAPHICS AND CLINICAL CHARACTERISTICSOne hundred thirty-five patients were interviewed, and information was collected regarding 1014 first-degree relatives, 510 of whom were men (50.3%) and 504 of whom were women (49.7%). Of the 135 patients interviewed, 26 patients (18 men, 8 women) (19.3%) with TAA were found to have at least 1 first-degree relative with an aortic aneurysm; the remaining 109 patients were considered sporadic cases. Table 1summarizes the demographic and clinical features of these 26 familial nonsyndromic patients. The mean age at presentation (56.8 years) was significantly younger than the mean age of presentation in sporadic cases (64.3 years, P≤.03), and significantly older than that of patients with Marfan syndrome (24.8 years, P≤.001) (Table 2).Table 1. Demographics and Clinical Characteristics of Patients With Familial Nonsyndromic Thoracic Aortic Aneurysms&ast;PedigreeAge, y/SexTobacco UseDMHTNLipid StatusCardiac DiseaseRenal DysfunctionCTMRITEEAGTTEInitial Aortic Size, cmSiteDissectionP00745/MMildNoneModerateMildMildNone+−+−+4.2Desc_P02728/MNoneNoneMildNoneNoneNone++−−+5.0Asc_P04258/MSevereNoneModerateSevereMildNone−−−−+3.9Arch_P14152/MMildNoneMildSevereSevereNone++−−−4.7Asc_P14533/MNoneNoneNoneNoneNoneNone+−−++4.8Asc_P16757/FSevereMildMildNoneNoneMild++−−+9.8TA_P18474/FModerateNoneModerateSevereModerateNone+−+++6.0Asc_P18859/MNoneNoneMildNoneModerateNone+−−+−4.5Asc_P27174/MSevereNoneNoneNoneNoneNone−−−−+4.0Asc_P28437/MNoneNoneNoneNoneNoneNone+−−++6.3Asc_P28665/FSevereMildMildNoneMildNone+−−−+3.3TA_P33014/FNoneNoneNoneNoneNoneNone−+−−+6.0Asc_P42245/MMildNoneModerateNoneNoneNone−+−++4.5Asc_P47058/MNoneNoneSevereNoneMildMild+−−++4.9Desc_P51164/MNoneNoneNoneNoneNoneNone+++−−3.3DescType BP51878/FNoneNoneMildMildNoneNone++−−−5.0Asc_P54669/MNoneNoneSevereNoneNoneNone+−−+−4.0AscType AP54776/MMildNoneMildNoneMildNone+++−+5.5Asc_P55779/MNoneNoneMildNoneSevereNone+++−+4.2DescType BP56372/FNoneMildMildNoneModerateNone+−−−−7.0DescType BP56570/MNoneNoneSevereNoneNoneNone+−−++4.1AscType AP57175/MMildMildSevereSevereModerateMild++−−+5.0Asc−P57261/MMildNoneMildNoneMildNone−+−−−3.3AscType AP58046/FModerateNoneMildNoneMildNone+−−−−4.0Desc_P58553/FModerateNoneNoneNoneNoneMild+−−−−4.1Desc−P58849/MNoneNoneNoneNoneNoneNone+−−−−5.4Asc−&ast;DM indicates diabetes mellitus; HTN, hypertension; CT, computed tomography; MRI, magnetic resonance imaging; TEE, transesophageal echocardiography; AG, angiography; TTE, transthoracic echocardiography; +, study was performed for either diagnosis or follow-up; −, study not performed; Desc, descending aorta; Asc, ascending aorta; and TA, thoracoabdominal aorta. Risk factors are graded as per the "Patients and Methods" section.Table 2. Comparison of Patients With Familial Nonsyndromic, Sporadic, and Marfan Syndrome–Associated Thoracic Aortic Aneurysms&ast;VariableFamilial NonsyndromicSporadicMarfan Syndrome AssociatedNo. of patients (sex)26 (18 M, 8 F)109 (67 M, 42 F)45 (29 M, 16 F)Age, y56.8 ± 18.2†‡64.3 ± 14.0†‡24.8 ± 17.1‡Initial aortic diameter, cm4.87 ± 1.35.25 ± 1.3‡4.02 ± 1.1‡Associated hypertension, %73‡75‡16‡Growth rate, cm/y0.22 (0.14 to 0.31)§&par;0.03 (−0.04 to 0.10)§0.10 (0.05 to 0.15)&par;&ast;Values are given as mean ± SD. The Bonferroni test for differences between means was used in the analysis of variance procedure.†P≤.03.‡P≤.001.§P≤.0012.&par;P≤.04.Sixteen (61.5%) of 26 patients with TAA and family history positive for nonsyndromic aortic aneurysms had an aneurysm located in the ascending aorta; the remaining 10 patients (38.5%) had an aneurysm located in the descending aorta (Table 1). Six patients (26.0%) had concomitant aortic dissections, 3 in the ascending aorta and 3 in the descending aorta.Accompanying medical problems were common among the 26 patients (Table 1), particularly, tobacco use (13 patients, 50.0%), diabetes mellitus (4 patients, 15.4%), hypertension (19 patients, 73.1%), hypercholesterolemia (6 patients, 23.1%), cardiac disease (13 patients, 50.0%), and renal dysfunction (4 patients, 15.4%). Hypertension was associated more frequently with patients with familial nonsyndromic TAA and sporadic TAA (73% and 75%, respectively) than with Marfan syndrome–associated TAA (16%) (P≤.001) (Table 2).Several different imaging studies were used in the diagnosis of TAA and in the follow-up of these patients (Table 1). One or more methods were used for every patient, and size measurements over time were used in growth rate calculations. Computed tomography, the most commonly used imaging modality, was used in 22 cases (84.6%). In addition, magnetic resonance imaging was performed in 11 patients (42.3%), angiography in 8 patients (30.7%), transesophageal echocardiography in 5 patients (19.2%), and transthoracic echocardiography in 16 patients (61.5%).ANEURYSMAL GROWTH RATESThe initial aortic diameter at the time of diagnosis was similar for patients with familial nonsyndromic TAA and patients with sporadic TAA (means, 4.87 cm and 5.25 cm, respectively) (Table 2). Patients with Marfan syndrome–associated TAA tended to have smaller aortic aneurysm diameters at the time of diagnosis (mean ± SD, 4.02 cm ± 1.1 cm) compared with familial cases (4.87 cm ± 1.3 cm), and a statistically significant difference compared with patients with sporadic TAA (5.25 cm ± 1.3 cm) (P≤.001).Aortic aneurysm growth rates for familial nonsyndromic, sporadic, and Marfan syndrome–associated TAA are displayed in Table 2and Table 3. Patients with a family history of aortic aneurysms had faster growth rates (0.22 cm/y) compared with patients with sporadic TAA (0.03 cm/y) (P≤.001) and patients with Marfan syndrome–associated TAA (0.10 cm/y) (P≤.04). This is depicted graphically in Figure 1. The presence of a dissection also increased aortic growth. Familial nonsyndromic TAA in patients with a concomitant aortic dissection had a growth rate of 0.33 cm/y, which was greater than in patients with sporadic TAA (0.10 cm/y) and in patients with Marfan syndrome–associated TAA (0.08 cm/y). This growth of 0.33 cm/y was significantly faster than the overall growth rate estimate of aneurysms in patients with aortic dissection (P≤.05) (Table 3).Table 3. Comparison of Aortic Growth Rate According to Dissection Status in Patients With Familial Nonsyndromic, Sporadic, and Marfan Syndrome–Associated Thoracic Aortic Aneurysms (TAA)&ast;Type of TAAAortic Dissection, cm/yNo Dissection, cm/yFamilial nonsyndromic0.33 (0.07 to 0.60)†0.20 (0.10 to 0.30)(n = 5)(n = 8)Sporadic0.10 (0.00 to 0.20)0.01 (−0.01 to −0.10)(n = 18)(n = 13)Marfan syndrome associated0.08 (−0.08 to 0.24)0.09 (0.04 to 0.14)(n = 39)(n = 27)Overall0.14 (0.07 to 0.21)†0.09 (0.06 to 0.13)(n = 90)(n = 168)&ast;Values indicate aortic growth rate based on regression analysis for patients with serial imaging studies, both with and without aortic dissection. They are expressed as mean (±SD).†P<.05.Figure 1.Mean growth rates for thoracic aortic aneurysms. For the familial nonsyndromic group, P≤.04.PEDIGREE ANALYSISFigure 2displays the family pedigrees of the 26 patients and their first-order relatives.Figure 2.Nonsyndromic thoracic aortic aneurysm family pedigree. Squares represent the men and circles, the women. An arrow indicates the proband with a thoracic aortic aneurysm. Blackened squares or circles represent affected patients with aortic aneurysms.Ten pedigrees (38.5%) display direct father to son transmission (P007, P145, P284, P470, P511, P547, P565, P572, P585, and P588) consistent with an autosomal dominant mode of inheritance. Six family pedigrees (23.1%) suggest an autosomal dominant or X-linked mode of inheritance (P027, P141, P167, P184, P557, and P580). Seven pedigrees (26.9%) suggest a recessive mode of inheritance; 2 autosomal recessive (P286 and P518), and 5 X-linked recessive or autosomal recessive (P042, P188, P271, P546, and P571).The final 3 pedigrees represent more complex modes of inheritance. In P330, the proband and her mother have an aortic aneurysm and her sister does not have an aneurysm. This situation may represent an autosomal dominant or X-linked dominant transmission. However, the paternal grandfather is also affected. The contribution of this on the proband is unclear.In P422, the proband and his 2 brothers are affected. The paternal aunt is also affected. If the proband's father were affected and the gene was not penetrant, this might represent an autosomal transmission. Autosomal recessive transmission is less likely.Finally, in P563 the proband and her paternal aunt are affected. Considerations include autosomal or X-linked dominant transmission with incomplete penetrance.COMMENTMost of what is known about the genetic factors involved in aortic aneurysms is derived from studies of patients with AAA. In 1977, Cliftonwas the first to note a familial aggregation of AAA, describing a family of 3 male siblings who underwent surgery for ruptured aneurysms. Tilson and Seashorelater reported on 50 families with 1 or more first-degree relatives with AAA. Studies involving the familial nature of AAA have considered almost every possible genetic model (Table 4).These studies confirm that AAA is one of the most common familial diseases, with at least 18% of patients with AAA having a first-degree relative with an aortic aneurysm.For most patients, however, the cause of the aortic aneurysm remains unknown.Table 4. Familial Studies of Abdominal Aortic AneurysmsSource, yProposed Genetic ModelsTilson and Seashore, 1984X-linkedTilson and Seashore,1984Autosomal dominantBowers and Cave, 1985Autosomal recessiveTilson and Seashore, 1984MultifactorialPowell and Greengalgh, 1987MultifactorialMajumder et al,1991Autosomal recessive, diallelic locusAlthough AAA has been studied extensively, less is known regarding TAA. Biddinger et alin 1997 confirmed the familial aggregation of TAA. Similar to that study, our data support a genetic predisposition to the development of TAA in 19% of patients. We have demonstrated that patients with familial nonsyndromic TAA are younger at the time of diagnosis (56.8 years) than are patients with sporadic TAA (64.3 years) (P≤.03), but are older than patients with Marfan syndrome (24.8 years) (Table 2). Ascertainment bias may be a contributing factor in both familial nonsyndromic TAA and Marfan syndrome–associated TAA. Patients who have a close relative with an aneurysm may seek medical attention earlier than patients with sporadic TAA. Patients with Marfan syndrome are screened for asymptomatic aortic disease. The relative contribution of these factors remains to be elucidated.Our data are similar to data presented by Biddinger et al; hypertension is strongly associated with both familial nonsyndromic and sporadic cases (73% and 75%, respectively) (Table 2). Although it is well known that hypertension is associated with aortic aneurysms, aneurysm formation cannot simply be ascribed to elevated blood pressure alone.Interestingly, hypertension was found in only 16% of the patients with Marfan syndrome in our study. Thus, the inherent vessel weakness due to the genetic defect in the fibrillin gene may represent the greatest influence on aneurysm formation in these patients. In addition, patients may have different genetic predispositions to respond to hypertensive stresses imposed on their aortas. This may be reflected by our findings of an increased aneurysmal growth rate in the absence of a disparity in rates of hypertension between familial nonsyndromic and sporadic TAA.We recently reported the overall growth rate for TAA to be 0.10 cm/y.In this study, we have demonstrated that the growth rate of aortic aneurysms in familial nonsyndromic TAA is 0.22 cm/y (Table 2). Thus, the current study defines a new risk factor for aneurysm growth, namely, probands belonging to multiplex pedigrees. The aneurysmal growth rate of 0.22 cm/y is significantly faster than the growth rate of aneurysms in patients belonging to the sporadic (0.03 cm/y, P≤.001) or Marfan syndrome groups (0.10 cm/y, P≤.04) (Table 2, Figure 1).We have also recently reported that the presence of an aortic dissection significantly increases the aneurysm growth rate.This study demonstrates that patients with familial nonsyndromic aneurysms and superimposed aortic dissections also display a faster rate of aneurysmal growth (0.33 cm/y, P≤.05) when compared with the overall growth rate of aortic dissections alone. The reasons for faster growth rates in patients exhibiting familial patterns and with concomitant aortic dissections are not clear, but may reflect a compounded environmental insult on a genetically weakened aortic wall. There are likely to be additional contributing factors affecting aortic growth that have not been clarified.Pedigree analysis (Figure 2) demonstrates more than 1 possible mode of transmission of aortic aneurysms. In this study, most seem to be autosomal dominant (38.5%), and an additional 23.1%, autosomal dominant or X-linked dominant. Twenty-seven percent represented a recessive mode of transmission. The current literature supports our findings that there may be more than 1 genetic model (Table 4).This suggests that genetic heterogeneity (ie, more than 1 gene causing a single phenotype) may play an important role in aortic aneurysm formation.One point that warrants discussion is the possibility of noninclusion of asymptomatic aneurysms in our pedigree analysis. It is possible that there are additional family members who have undetected TAA or AAA. Likewise, a relative may have died before an aneurysm developed. It is also possible that there may be undiagnosed familial clustering of aneurysms incorrectly placed in the sporadic category. With the small number of pedigrees and the limited number of generations, our pedigree analysis may be affected by these potential pitfalls. It is also necessary to make a disclaimer for the incomplete accuracy of family history data acquired by interview. Errors including inaccurate or incomplete memory, lack of confirmation of diagnosis, and misinformation may have occurred. We made efforts to maximize consistency during data acquisition by maintaining 2 trained interviewers and confirming diagnoses whenever possible.To avoid noninclusion of asymptomatic family members, we have begun to screen by ultrasound all first-generation family members of our 26 pedigrees to identify additional patients with previously undetected aneurysms and to confirm or refute absence of aortic disease in other family members. Screening the general population for TAA would not be cost effective. In a theoretical screening model for AAA of a population of 100,000 individuals, it has been proposed that 1500 lives could be saved at a cost of $78,000 per life saved.Most of the aneurysms detected by screening are small, with few aneurysms detected that were 6 cm in diameter or larger. Screening selective populations is far more cost effective. For instance, in 561 patients with peripheral vascular disease, almost all of whom were cigarette smokers, aneurysms 3 cm in diameter or larger were found in 14%.Screening brothers of patients with aneurysms renders an incidence of aneurysms of 20% to 29%.Therefore, we expect that ultrasound screening of the 26 families with familial nonsyndromic TAA will find additional affected patients and permit more accurate pedigree analysis.The genetic basis of aortic aneurysms was reviewed by Kuivaniemi et alin 1991. The major determining factor in the appearance of aortic aneurysms may be an inborn defect of collagen type III or of another component of the connective tissue matrix. In patients with Ehlers-Danlos syndrome, defects in the type III collagen gene (COL3A1) have been implicated.The mutations associated with collagen diseases such as Ehlers-Danlos syndrome and osteogenesis imperfecta are heterogeneous, and a similar situation may exist for aortic aneurysms.The gene for Marfan syndrome has recently been identified, and there is optimism that this will provide a basis for preventative medicine.The gene has been linked to markers in or near the fibrillin-1 gene in chromosome band 15q21.1.Interestingly, the Gly1127Ser mutation in an EGF domain of the fibrilllin-1 gene has been shown to be a risk factor for ascending aortic aneurysms and dissections.A mutation in the COL3A1gene resulting in an amino acid substitution was identified in a family with a strong history of AAA.Although this mutation was not detected in any of 140 other patients with AAA, variants of the COL3A1gene are thought to predispose to aneurysm formation in the presence of other components of a multifactorial process.Mutations of the FBN1and COL3A1genes may produce a spectrum of connective-tissue disorders responsible for abnormal or reduced matrix deposition in the aorta and subsequent aneurysm development.As mentioned previously, we are supplementing the present pedigrees by ultrasound screening of families. Patients are examined and peripheral blood is drawn on both affected and unaffected family members. We are presently employing mutation and linkage analysis in an effort to isolate candidate gene(s) causing TAA. The latter approach employs markers that have been mapped to a particular locus on the genome, and is used to test whether the marker is coinherited with aortic aneurysms in families.In summary, clarifying the genetic basis for the development of TAA is a complex and challenging endeavor. We have confirmed that familial clustering of TAA does occur. The current study defines a new risk factor for aneurysm growth, namely, probands belonging to multiplex pedigrees. The aneurysmal growth rate of patients with familial nonsyndromic TAA is significantly faster than the growth rate of aneurysms in patients with sporadic or Marfan-associated TAA. 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New York, NY: Macmillan Publishing Co Inc; 1994.REDinsmoreRRLiberthsonGLWismerMagnetic resonance imaging of thoracic aortic aneurysms.Am J Radiol.1986;146:309-314.MACoadyJARizzoGLHammondGSKopfJAElefteriadesSurgical intervention criteria for thoracic aortic aneurysms.Ann Thorac Surg.In press.JARizzoMACoadyJAElefteriadesProcedures for estimating growth rates in thoracic aortic aneurysms.J Clin Epidemiol.1998;51:747-754.YHiroseSHamadaMTakamiyaPredicting the growth of aortic aneurysms: a comparison of linear vs exponential models.Angiology.1995;46:413-419.CHsiaoAnalysis of Panel Data.New York, NY; Cambridge University Press: 1989.MACliftonFamilial abdominal aortic aneurysms.Br J Surg.1977;64:765.MDTilsonMRSeashoreFifty families with abdominal aortic aneurysm in two or more first-order relatives.Am J Surg.1984;147:551-553.DBowersWSCaveAneurysm of the abdominal aorta: a 20-year study.J R Soc Med.1985;78:812-820.JTPowellRMGreengalghMultifactorial inheritance of abdominal aortic aneurysm.Eur J Surg.1987;1:29-31.RRMajumderPSt JeanREFerrellMWWebsterDLSteedOn the inheritance of abdominal aortic aneurysm.Am J Hum Genet.1991;48:164-170.KJohansenTKoepsellFamilial tendency for abdominal aortic aneurysms.JAMA.1986;256;1934-1936.ABiddingerMRocklinJCoselliDMMilewiczFamilial thoracic aortic dilatations and dissections: a case control study.J Vasc Surg.1997;25:506-511.DSQuillMPColganDSSumnerUltrasonic screening for the detection of abdominal aortic aneurysms.Surg Clin North Am.1989;69:713.RBGallandMJSimmonsEPHTorriePrevalence of abdominal aortic aneurysm in patients with occlusive peripheral vascular disease.Br J Surg.1991;78:1259.JAdamsonJTPowellRMGreenhalghSelection for screening for familial aortic aneurysms.Br J Surg.1992;79:897.HKuivaniemiGTrompDJProckopGenetic causes of aortic aneurysms.J Clin Invest.1991;88:1441-1444.HKuivaniemiGTrompHKuivaniemiA mutation in collagen genes: causes of rare and some common diseases in humans.FASEB J.1991;5:2025.IYoungUnderstanding Marfan syndrome.Br Med J.1991;30:1414-1415.KKainulainenLPulkkinenASavolainenIKaitilaLPeltonenLocation on chromosome 15 of the gene defect causing Marfan syndrome.N Engl J Med.1990;323:935-939.UFranckeMABergKTynanA Gly1127Ser mutation in an EGF-like domain of the fibrillin-1 gene is a risk factor for ascending aortic aneurysm and dissection.Am J Hum Genet.1995;56:1287-1296.SKontusaariGTrompHKuivaneimoA mutation in the gene for type III collagen (COL3A1) in a family with aortic aneurysms.J Clin Invest.1990;86:1465.DJProckopMutations in collagen genes as a cause of connective tissue diseases.N Engl J Med.1992;326:540.GTrompKuivaniemiDNA sequencing as a method to identify mutations in patients with familial forms of aneurysms.J Vasc Surg.1992;15:928-930.Richard Cambria, MD, Boston, Mass:Congratulations to Dr Coady on a very nice presentation and we've heard this afternoon the latest installment in a series of enlightening publications referable to thoracic aortic disease from Dr Elefteriades' group at Yale. The authors sought to establish the presence of familial clustering of thoracic aortic aneurysms. This information was previously available in only a single report in the literature for aneurysm disease north of the diaphragm, but as alluded to in the presentation, firmly established for the more commonly encountered AAA. Using telephone inquiry of 150 patients selected at random from their sizable registry, they recorded a 19.3% rate of familial clustering of thoracic aneurysms, that is, patients with a first-blood-order relative afflicted with the disease. In comparing familial with sporadic thoracic aneurysm patients, they noted younger age at treatment and significantly faster growth rates in familial cases. The latter discovery, of course, has potentially important clinical implications. They report a variety of inheritance modes and the frustration they note in attempting to clarify simple or uniform modes of inheritance is exactly paralleled in the literature referable to AAA.My knowledge of genetics is limited to the fact that I know a fellow named Mendel who grew peas. We do, however, have complete demographic data on some 230 patients treated for thoracoabdominal aortic aneurysm with familial clustering noted in some 10% of these patients. I've recently had the opportunity to review the available data on the natural history of thoracic and thoracoabdominal aneurysms. I can assure you the information we heard today is a valuable addition to the literature.Approximately 10 years ago, our group, under the leadership of Clem Darling, published a sizable series of 550 abdominal aneurysm repairs designed to answer many of the questions that Dr Coady asked today. Is there familial clustering; if so, are there characteristics of these familial aneurysms that are clinically important?In this series we noted familial clustering in 15.1% of patients, a figure almost identical to that reported today. While AAA growth rates were not available from our studies since they were all operated cases, we did note that familial aneurysm patients were more likely in women and when such a familial aneurysm occurred in women, there was a significantly increased risk of presentation with rupture. Thus, our data is consistent with that from the Yale group, ie, familial cases seem to be more prone to expansion and rupture. Furthermore, in our vascular registry, the male-female sex ratio for abdominal aneurysms is the typically reported 5 to 6 to 1, but in our thoracoabdominal aneurysm cohort, the sex predilection is 1 to 1. This introduces my first question. Dr Coady, do you have information from your registry on sex distribution for degenerative vs chronic dissection aneurysms in the thoracic aorta?My other questions relate to the issue of aneurysm growth rates, which the authors have emphasized as among their most important findings. Apparently, part of the significance they've assigned to the growth rates of familial cases relates to the comparison to an extremely low, 0.03 cm/y, rate of expansion assigned to sporadic cases. This latter figure is approximately 10 times lower than my understanding of the available literature on this topic, and indeed lower than the information from your own registry. Could you comment on possible explanations for the apparent minuscule expansion rate in sporadic cases? Is it fair or logical to group growth rates in different regions of the thoracic aorta, namely ascending, arch, descending, and thoracoabdominal together, since the pathology may be different (dissection vs degenerative aneurysm) and it is well known that the lamellar architecture of the aorta is different in the ascending as opposed to the descending aorta.Michael Coady, MD:Dr Cambria, thank you very much. I'll answer each of your questions in series. The first question addresses the interesting observation by Dr Darling made in 1989 (J Vasc Surg. 1989;10:39-43). Dr Darling, in a 9-year prospective study, noted an increased prevalence of female patients in a group of familial abdominal aortic aneurysms. He also studied the association between sex and the risk of aortic rupture. Dr Darling found that those families with AAA and a female member with an aneurysm had a strong correlation with aneurysm rupture. The term "black widow syndrome" was employed to describe the female member belonging to this group of familial AAA, as she served as a marker for families which were at significant risk for having at least 1 member of their family experience an aneurysm rupture. In our present series, we have not observed any sex predilection for aortic aneurysm rupture. Currently, the number of patients who had a ruptured aneurysm in these familial, sporadic, and Marfan groups is too small to make any meaningful observations regarding sex distribution. In our larger aneurysm registry, we have not identified any differences in the sex distribution for degenerative or chronic dissecting aneurysms of the thoracic aorta.Regarding your second question on the growth rate, our sporadic group had a very small growth rate of 0.03 cm/y. While this is certainly much slower in comparison to the overall growth rate estimate of 0.12 cm/y that we published last year in a larger series, this is the first time we have attempted to segregate the groups of aneurysms into familial nonsyndromic, sporadic, and Marfan syndrome associated. While sample size may be affecting the growth rate estimates in all groups, I suspect that there may be true differences in growth that may directly relate to the genetic defect in the aortic wall. When segregated, familial and Marfan-associated aneurysms grow faster than sporadic aneurysms. Growth rate estimates for these groups have not been well studied. As we increase our sample size we hope to continue to achieve more accurate estimates.Your last question addresses whether it is logical to analyze growth rates in different regions of the thoracic aorta. Our group has analyzed aneurysm growth rates at various aortic locations because it has been well documented that the growth rate varies by location. Descending and thoracoabdominal aortic aneurysms, for instance, may actually grow faster than ascending and arch aneurysms. Using regression techniques, we have previously shown that descending and thoracoabdominal aortic aneurysms grow 0.29 cm/y (J Thorac Cardiovasc Surg. 1997;113:476-491), which closely approximates the growth rate estimates reported by Dapunt et al (J Thorac Cardiovasc Surg. 1994;107:1323-1333) for aneurysms in this location. In this study, we have chosen to measure overall growth rates for the 3 groups primarily because the sample size did not permit more sophisticated analysis of aneurysm growth rates by location. As we continue to expand our database, we hope to refine further statistically-based growth rate estimates.This work was funded by Grant-in-Aid CT-BP97-GR-45 from the American Heart Association, Dallas, Tex.Presented at the 79th Annual Meeting of the New England Surgical Society, Toronto, Ontario, September 25, 1998.Corresponding author: John A. Elefteriades, MD, Section of Cardiothoracic Surgery, Yale University School of Medicine, 333 Cedar St, New Haven, CT 06510 (e-mail: john [email protected]).

Catania, Robert A.; Schwacha, Martin G.; Cioffi, William G.; Bland, Kirby I.; Chaudry, Irshad H.

doi: 10.1001/archsurg.134.4.368pmid: 10199308

HypothesisUninjured skin contributes to the elevation in circulating levels of proinflammatory cytokines seen following severe injury.DesignMale C3H/HeN mice underwent trauma, trauma-hemorrhage and resuscitation, or closed long-bone fracture. Serum, skin, and liver samples were harvested at designated times after experimental treatment.Main Outcome MeasuresLevels of interleukin (IL) 1β, IL-6, and tumor necrosis factor α (TNF-α) were determined in serum and skin cultures at 1, 8, and 24 hours after trauma-hemorrhage. The RNA was isolated from liver and skin samples at 1, 2, 4, 8, and 24 hours from all 3 experimental groups, and gene expression of the cytokines was determined.ResultsRemote (nontraumatized) skin from trauma-hemorrhage animals released significantly more IL-6 and TNF-α into culture supernatants at 1 and 24 hours and significantly more IL-1β at 1, 8, and 24 hours than did skin from sham animals. Serum levels of all 3 cytokines were significantly elevated at 1 and 24 hours after trauma-hemorrhage relative to sham animals. Gene expression of all 3 cytokines was detected in skin and liver following trauma-hemorrhage. Furthermore, gene expression of all 3 cytokines was detected in uninjured skin after soft tissue trauma and closed long-bone fracture.ConclusionsProinflammatory cytokine gene expression is up-regulated in uninjured skin following trauma, trauma-hemorrhage, and long-bone fracture. This increase in gene expression correlates with increased cytokine production by cultured skin as well as increased circulating cytokine levels. These results suggest that uninjured skin may also contribute to the rise in circulating cytokine levels seen after injury.SEVERE INJURY, particularly with concomitant hemorrhagic shock, predisposes patients to the development of infectious complications and multiple organ failure.In particular, hypotension induces a decline in cell-mediated immunity that is more profound in the presence of concurrent soft tissue traumaor long-bone fracture.Our laboratory has previously demonstrated that Kupffer cells are primed following hemorrhagic shock, and that unlike other macrophage populations, they produce increased amounts of proinflammatory cytokines under those conditions.In combination with activation of neutrophils,the systemic release of inflammatory mediators such as interleukin (IL) 1, IL-6, and tumor necrosis factor α (TNF-α) is believed to have a negative impact on the function of many organ systems.The body's largest immune organ, the skin, is composed of multiple cell types that are also capable of producing cytokines.Specifically, keratinocytes, fibroblasts, dermal endothelial cells, Langerhans cells, dendritic cells, and inflammatory cells infiltrating the skin are able to release cytokines under various conditions.Previous investigations have established that thermally injured skin produces detectable levels of several cytokines, including IL-1,IL-6,and TNF.Since early burn wound excision has been shown to restore the depressed cellular immune response seen after thermal injury,this suggests that skin-derived mediators are capable of modulating systemic immune function. Interestingly, cytokines produced by the skin in response to topical irritants have been shown to be measurable in draining lymph,indicating that skin-derived cytokines can reach the systemic circulation.Direct injury to the skin is known to incite a vigorous immune response associated with wound healing.Furthermore, after the onset of severe shock, the skin is known to be one of the first organs from which blood is shunted to preserve central perfusion.Given the known ability of skin to produce cytokines in response to topical injury, and given the sustained cutaneous hypoperfusion that occurs during hemorrhagic shock, it seems plausible that skin contributes to the systemic elevation in proinflammatory cytokines following trauma and hemorrhage. Our aim, therefore, was to determine if proinflammatory cytokine expression was up-regulated after trauma-hemorrhage and resuscitation. Furthermore, the effect of remote soft tissue trauma and fracture on skin cytokine production was investigated.MATERIALS AND METHODSEXPERIMENTAL MODELWe used inbred male C3H/HeN mice (Charles River Laboratories, Wilmington, Mass), 7 weeks of age. Mice in the trauma-hemorrhage groups were lightly anesthetized with methoxyflurane and restrained in a supine position, and a 2.5-cm midline laparotomy (ie, trauma induction) was performed. The incision was then closed aseptically using 6-0 monofilament nylon (Ethilon; Ethicon Inc, Somerville, NJ) sutures. Next, both femoral arteries were aseptically cannulated with polyethylene-10 tubing (Clay-Adams, Parsippany, NJ). Blood pressure was constantly monitored using a commerically available arterial blood pressure analyzer (Digi-Med; Micro-Med Inc, Louisville, Ky). On awakening, the animals were bled rapidly through the other catheter to a mean (±SEM) arterial blood pressure of 35±5 mm Hg (prehemorrhage mean [±SEM] arterial blood pressure, 95±5 mm Hg), which was maintained for 90 minutes. After hemorrhage, the animals were resuscitated with lactated Ringer solution (4 times the shed blood volume for 30 minutes), the catheters were removed, the vessels were ligated, and the groin incisions were closed. Animals undergoing sham operation (sham animals, control group for trauma-hemorrhage) underwent anesthesia and the same groin dissection, which included ligation of both femoral arteries, but no hemorrhage or fluid resuscitation. Mice in the trauma group underwent anesthesia and midline laparotomy as described above; mice in the fracture group underwent anesthesia and had a unilateral closed tibial fracture induced as described previously.In the fracture group, the fractured limb was splinted to prevent further soft tissue injury or conversion to an open fracture. Control animals for the trauma and fracture groups underwent anesthesia and restraint (sham trauma) or splinting (sham fracture). Animals were killed at 1, 2, 4, 8, or 24 hours for RNA isolation or 1, 8, or 24 hours for skin culture.Different groups of animals were used for the experiments involving RNA isolation and skin culture. There was no mortality in any group within the 24 hours. All procedures were performed in accordance with the guidelines set forth in the Animal Welfare Act and the Guide for the Care and Use of Laboratory Animals by the National Institutes of Health. This project was approved by the Institutional Animal Care and Use Committee of Rhode Island Hospital and Brown University, Providence.RNA ISOLATIONAnimals were killed with an overdose of methoxyflurane, and skin and liver samples were harvested. The tissues were homogenized in thiocyanate and phenol in monophase solution (Tri-Reagent; Sigma-Aldrich Corporation, St Louis, Mo) using a Dounce homogenizer. To clarify the samples, they were centrifuged at 10,000gfor 10 minutes, and the liquid phase was used. Chloroform was added, and the samples were shaken vigorously for 15 seconds and then allowed to stand at room temperature for 15 minutes. The samples were centrifuged at 12,000gfor 15 minutes at 4°C, and the aqueous phase was transferred to a fresh tube to which isopropanol was added. The samples were again shaken and allowed to stand overnight at −20°C. Following centrifugation at 12,000gfor 10 minutes at 4°C, the pellets were washed in 75% ethanol. The resultant pellets were resuspended in a minimal volume of diethylpyrocarbonate (DEPC)–treated water. The RNA was run on a 1% agarose gel using morphololinopropanesulfonic (MOPS) running buffer to ensure there was no RNA degradation or contaminating genomic DNA.REVERSE TRANSCRIPTASE–POLYMERASE CHAIN REACTIONA commercially available kit (RETROscript; Ambion, Austin, Tex) was used for the reverse transcriptase (RT) reaction as described by the manufacturer. Briefly, 2 µg of RNA was added to the supplied deoxynucleotidetriphosphate (dNTP) mix and first-strand primers (Random Decamers; Ambion) in a final volume of 20 mL. The cocktail was heated to 85°C for 3 minutes and placed on ice. To this, 10× RT–polymerase chain reaction (PCR) buffer, placental RNAse inhibitor, and Moloney-murine leukemia virus RT were added and incubated at 42°C for 1 hour. The mixture was incubated at 92°C for 10 minutes to inactivate the RT, and the resultant complementary DNA was used in the PCR. A DNA Taq polymerase kit (SuperTaq; Ambion) was used to perform PCR as described by the manufacturer. Briefly, 4 mL of RT product was added to the reaction master mix (containing 10× reaction buffer and magnesium chloride, dNTP mix, and 5‘-, and 3‘-primers) in a final volume of 24 mL. The mixture was vortexed and heated to 95°C for 5 minutes, followed by 58°C for 5 minutes. Samples were then placed at 72°C, and 1 mL (0.5 U) of SuperTaq enzyme was added. The samples were run through a 30-cycle amplification on a programmable thermocycler gradient 96 (RoboCycler; Stratagene, La Jolla, Calif) set up as follows: 95°C for 1.5 minutes, 58°C for 2.5 minutes, and 72°C for 3 minutes. The primers for murine IL-1, IL-6, and TNF-α were obtained from Clontech, Palo Alto, Calif, and used according to the manufacturer's specifications. To control for RT activity and ensure uniform sample concentration, a control primer (S15 rRNA) was run with all samples. Resultant amplified DNA was run on a 2% agarose gel containing ethidium bromide, and the gels were photographed using commercially available film (Polaroid ISO 3000/36; Polaroid Corp, Cambridge, Mass). Images were captured using commercially available image analysis software (Mocha; Jandel Scientific, San Rafael, Calif). Results shown represent repeated experiments (n=4).SKIN CULTUREAt the appropriate time after the experimental procedure, animals were killed using methoxyflurane overdose. The dorsal surface of the animal was shaved and rinsed with 70% ethanol. A 2×2-cm sample of skin was dissected free from the underlying fascia and minced using surgical scissors. The tissue was placed in 2 mL of RPMI 1640 media supplemented with 10% fetal bovine serum, 10-mg/mL gentamycin, and 100-U/mL penicillin. The samples were incubated under standard tissue culture conditions (37°C, 5% carbon dioxide, and 85% humidity) for 8 hours. Following incubation, the supernatants were harvested and centrifuged at 10,000gand frozen at −80°C until assayed for cytokine concentration.SKIN SUPERNATANT CYTOKINE PRODUCTIONThe levels of IL-1β, IL-6, and TNF-α present in skin culture supernatants was determined using commercially available murine enzyme-linked immunosorbent assay (ELISA) kits. Six animals were included for each time. The IL-1β and TNF-α ELISA kits (DuoSet) were obtained from Genzyme Diagnostics (Cambridge, Mass). The IL-6 ELISA kit (OptEIA) was obtained from PharMingen (San Diego, Calif). The kits were used as described by the manufacturer.CIRCULATING CYTOKINE LEVELSWhole blood samples were obtained from sham and trauma-hemorrhage groups by cardiac puncture (n=6) at the appropriate time after experimental treatment and methoxyflurane overdose. The samples were centrifuged at 10,000gfor 10 minutes in serum separator tubes (Microtainer; Becton Dickinson, Franklin Lakes, NJ). The serum was removed and frozen at −80°C until assayed for cytokine concentration. Cytokine levels were determined using the ELISA kits described above.STATISTICSDifferences between experimental groups were considered to be statistically significant if P<.05 as determined using 1-way analysis of variance and Tukey test.RESULTSGENE EXPRESSION FROM UNINJURED SKIN AND LIVER FOLLOWING TRAUMA-HEMORRHAGEThe results shown in Figure 1demonstrate expression of IL-1β, IL-6, and TNF-α in uninjured skin and liver samples harvested following trauma-hemorrhage and resuscitation. Skin samples (Figure 1, A) were obtained from dorsal uninjured skin that was remote from the site of laparotomy. Proinflammatory gene expression was also noted in the liver (Figure 1, B).Figure 1.Proinflammatory cytokine gene expression following trauma-hemorrhage and resuscitation. Expression of interleukin (IL) 1β, IL-6, tumor necrosis factor α (TNF-α), and S15 rRNA (positive control for RNA quality) was determined in animals undergoing sham operation (sham animals) and trauma-hemorrhage (trauma-hemorrhage animals) using reverse transcriptase–polymerase chain reaction with RNA isolated from uninjured skin (A) and liver (B). Samples were harvested 1, 2, 4, 8, or 24 hours after completion of resuscitation. Sham animals underwent anesthesia, groin dissection, and bilateral femoral artery ligation, and the time of harvest was adjusted to be comparable to the time of harvest in the trauma-hemorrhage animals. The lane at the far right (plus sign) is a positive control, indicating molecular weight of the amplified polymerase chain reaction product.PROINFLAMMATORY CYTOKINE PRODUCTION IN ISOLATED SKINThe results presented in Figure 2demonstrate release of IL-1β, IL-6, and TNF-α from skin placed in culture media following trauma-hemorrhage and resuscitation. Production of IL-1β by skin was significantly greater in trauma-hemorrhage animals relative to sham animals at all times assayed. Production of IL-6, although greater in trauma-hemorrhage animals at all times, was only found to be elevated to a significant degree at 1 and 24 hours after resuscitation. Production of TNF-α similarly was elevated in trauma-hemorrhage animals relative to sham animals at all times; however, statistically significant increases were seen only at 1 and 24 hours.Figure 2.Proinflammatory cytokine production by cultured skin following trauma-hemorrhage and resuscitation (trauma-hemorrhage animals). Culture supernatant levels of interleukin (IL) 1β (A), IL-6 (B), and tumor necrosis factor α (TNF-α) (C) were determined using enzyme-linked immunosorbent assay at 1, 8, and 24 hours after completion of resuscitation. Data are represented as mean±SEM and compared using 1-way analysis of variance and Tukey test. Asterisk indicates P<.05 compared with animals undergoing sham operation (sham animals).CIRCULATING LEVELS OF PROINFLAMMATORY CYTOKINESSerum levels of IL-1β, IL-6, and TNF-α were elevated in trauma-hemorrhage animals relative to sham animals at 1 and 24 hours. Maximal circulating levels were seen at 1 hour for all 3 cytokines. These results are presented in Table 1.Circulating Levels of Proinflammatory Cytokines After Trauma-Hemorrhage and Resuscitation&ast;Time of Harvest, hAnimal GroupsIL-1β, pg/mLIL-6, pg/mLTNF-α, pg/mLShamTrauma-HemorrhageShamTrauma-HemorrhageShamTrauma-Hemorrhage143.6 ± 13.4129.6 ± 18.4†16.5 ± 16.5830.5 ± 150.1†0365.9 ± 49.7†838.4 ± 9.375.4 ± 27.024.8 ± 15.7172.6 ± 67.9088.8 ± 51.32420.3 ± 9.593.6 ± 20.0†50.8 ± 18.8457.1 ± 181.2†8.4 ± 8.4127.2 ± 59.4†&ast;IL indicates interleukin; TNF, tumor necrosis factor. Serum levels of IL-1β, IL-6, and TNF-α were determined using enzyme-linked immunosorbent assay at 1, 8, and 24 hours after completion of resuscitation. Data are represented as mean ± SEM and compared using 1-way analysis of variance and Tukey test.†P<.05, animals undergoing trauma-hemorrhage vs animals undergoing sham operation.GENE EXPRESSION FROM INJURED AND UNINJURED SKIN FOLLOWING SOFT TISSUE TRAUMAThe results in Figure 3A, demonstrate that IL-1β, IL-6, and TNF-α gene expression is up-regulated in injured and uninjured skin following laparotomy (ie, soft tissue trauma) alone, in the absence of hemorrhagic shock. Figure 3B, also demonstrates proinflammatory cytokine gene expression in uninjured remote skin following unilateral closed tibial fracture.Figure 3.Proinflammatory cytokine gene expression after soft tissue trauma (A) and closed long-bone fracture (B). Expression of interleukin (IL) 1β, IL-6, tumor necrosis factor α (TNF-α), and S15 rRNA (positive control for RNA quality) was determined using reverse transcriptase–polymerase chain reaction with RNA isolated from injured and uninjured skin (A) or remote, uninjured skin (B). Samples were harvested 1, 2, 4, 8, or 24 hours after injury. The sham control (S) corresponds to 1 hour. The lane at the far right (plus sign) is a positive control indicating molecular weight of the amplified polymerase chain reaction product.COMMENTInvestigators have long sought the mechanisms responsible for the depression in organ function noted after injuries. The discovery and characterization of soluble mediators of inflammation, including cytokines and prostanoids, has greatly facilitated this study. Specifically, the proinflammatory cytokines IL-1β, IL-6, and TNF-α have been implicated in the mediation of organ dysfunction following hemorrhage and/or injury. The prevailing hypothesis regarding cytokine production following trauma and hemorrhage holds that the liver is the organ responsible for elaboration of these mediators. Ayala et aldemonstrated that production of Kupffer cell IL-1 and TNF was significantly increased following trauma and hemorrhage. Furthermore, O'Neill et alreported that hepatic Kupffer cells were responsible for IL-6 release following trauma-hemorrhage and resuscitation and that depleting or inhibiting Kupffer cells with gadolinium chloride reduced the circulating levels of IL-6 by 80%. The effect of gadolinium chloride on the skin cytokine expression remains unknown, as does the effect of gadolinium chloride treatment on IL-1 and TNF production; thus it is not clear whether the liver is the sole organ affected by gadolinium chloride treatment. Using a model of hemorrhagic shock in rats, Deitch et alfound that portal vein levels of IL-1 and TNF were significantly higher than the concentration of these cytokines in cardiac (ie, systemic) blood, allowing them to conclude that the gut becomes a cytokine-liberating organ following hemorrhagic shock as well.Our results indicate that proinflammatory gene expression is induced in the liver following trauma and hemorrhage. We also report an increase in IL-1β, IL-6, and TNF-α gene expression in uninjured skin following trauma-hemorrhage and resuscitation. Skin from trauma-hemorrhage animals released significantly more IL-1β, IL-6, and TNF-α at 1 and 24 hours after resuscitation, indicating that the increase in gene expression correlates with an increased elaboration of these cytokines. Since the skin is the largest immune organ in the body, and since it is capable of producing proinflammatory cytokines following trauma-hemorrhage, we suggest that skin may be another important source of circulating cytokines following injury. Evidence supporting the ability of skin to produce systemic elevations in cytokine levels is present in the literature. Skin injured by UV radiation is known to release histamine, kinins, cytokines, and cyclooxygenase- and lipoxygenase-derived products of arachidonic acid metabolism,with these agents mediating the local inflammatory reaction evident histopathologically as sunburn. It has also been demonstrated that circulating levels of TNF-α are elevated in subjects with severe sunburn.Furthermore, patients with primary cold urticaria, a skin condition in which a shocklike response occurs after cold exposure, have been found to have elevated levels of TNF-α in efferent venous blood from hands immersed in cold water.Clearly, then, the literature supports the notion that skin is able to produce cytokines that enter the systemic circulation.Our data support the additional hypothesis that after distant injury, uninjured skin is able to up-regulate proinflammatory genes. Cytokine expression was detectable using RT-PCR after laparotomy (ie, soft tissue injury) and unilateral closed tibial fracture. As anticipated, there was also a profound up-regulation of cytokine expression noted in injured skin. Previous investigators have found that following thermal injury, unburned skin produces TNF, IL-6, and IL-8 at the messenger RNA (mRNA) and protein levels.In addition, Wichmann et alhave shown immune function to be more compromised after closed bone fracture and hemorrhagic shock than hemorrhage alone, suggesting that bone fracture induces the release of mediators that inhibit immune function. Thus, evidence suggests that soft tissue injury and long-bone fracture induce cytokine production in uninjured skin, and that the ability to induce cytokine gene expression in remote skin may account for the elevation in circulating cytokine levels associated with such injuries.The mechanism mediating the up-regulation of cytokine gene expression in skin remains unknown. It is tempting to speculate that under conditions of hypoperfusion and regional hypoxia, skin cells respond with the production of proinflammatory cytokines. Previous studies from our laboratory have shown that hypoxemia, in the absence of hypotension or blood loss, is sufficient stimulus to induce the production of IL-1, IL-6, and TNF from Kupffer cells.However, this does not explain the expression of cytokines in truly uninjured tissue (ie, that obtained following simple laparotomy or distant long-bone fracture). We propose that humoral factors are released at the site of injury and then travel through the circulation to the skin, or that impulses are transmitted via the central nervous system and ultimately act to up-regulate proinflammatory cytokine gene expression. To further elucidate these mechanisms, pretreatment of animals with anti-inflammatory drugs or nerve blocks would be illustrative.Although this study provides evidence that the skin may be an important source of elevated cytokine levels following multiple types of injuries, many questions remain unanswered. We have not demonstrated the cellular source of cytokine expression in skin. As previously noted, skin contains numerous different cell populations known to produce cytokines. We propose that this question may be answered by using the technique of in situ hybridization. Despite the evidence that cytokines are spontaneously released from cultured skin after trauma-hemorrhage, we have not demonstrated that these cytokines in fact reach the circulation. In addition, the time course of gene expression and cytokine release from the tissue differed somewhat. Although IL-1β and TNF-α gene expression was elevated as early as 1 hour and as late as 24 hours after completion of resuscitation, IL-6 gene expression was limited to earlier times (1 and 2 hours). This is in contrast to tissue IL-6 release, which was elevated as late as 24 hours. Finally, circulating levels of IL-6, although elevated 24 hours after injury, were much higher at 1 hour, whereas IL-6 production in tissue culture remained elevated through 24 hours. Taken together, this suggests that skin is not the principal source of circulating IL-6 after injury.Our study demonstrates that circulating proinflammatory cytokine levels are elevated following trauma-hemorrhage, and that this elevation correlates with enhanced gene expression and tissue culture production of these cytokines from uninjured skin. Furthermore, gene expression of IL-1β, IL-6, and TNF-α are up-regulated in uninjured skin after soft tissue trauma and closed bone fracture. Given the known deleterious effects of circulating proinflammatory cytokines on organ function after severe injury, therapies aimed at reducing or eliminating skin production of cytokines may be beneficial to the care of the trauma patient. Although extrapolation of these results to the human system is premature, given the accessibility of skin, reproduction of this study in humans should be possible.Statement of Clinical RelevanceSepsis syndrome and multiple organ failure are the leading causes of death after hemorrhagic shock. The postulated mechanism responsible for this is an uncontrolled systemic inflammatory response. Circulating levels of proinflammatory cytokines are elevated after injury and hemorrhagic shock, and the gut and liver have been postulated to be the organ systems responsible for releasing these soluble mediators. Clinical trials aimed at reducing the systemic inflammatory response using anti-cytokine antibodies have shown promise in the experimental setting, yet they have been disappointing in human clinical trials. A better understanding of the mechanisms responsible for the up-regulation of proinflammatory cytokine production may allow us to tailor our therapy to prevent their release. Our data indicate that injured and uninjured skin are potential sources of circulating cytokines following hemorrhagic shock and severe injury. Further study aimed at elucidating the signals responsible for up-regulating skin cytokine production may allow us ultimately to block the production of proinflammatory cytokines after hemorrhagic shock, thus reducing the morbidity and mortality associated with severe injury.IHChaudryAAyalaImmunological Aspects of Hemorrhage.Austin, Tex: Medical Intelligence Unit, RG Landes Co; 1992.RZellwegerAAyalaCMDeMasoIHChaudryTrauma-hemorrhage causes prolonged depression in cellular immunity.Shock.1995;4:149-153.HNaraharaJMJohnstonEffects of endotoxins and cytokines on the secretion of platelet-activating factor acetylhydrolase by human decidual macrophages.Am J Obstet Gynecol.1993;169:531-537.AAyalaMMPerrinWErtelIHChaudryDifferential effects of haemorrhage on Kupffer cells: decreased antigen presentation despite increased inflammatory cytokine (IL-1, IL-6 and TNF) release.Cytokine.1992;4:66-75.RSimpsonRAlonLKobzikCRValeriDSheproHBHechtmanNeutrophil and non-neutrophil-mediated injury in intestinal ischemia-reperfusion.Ann Surg.1993;218:444-453.JDBosThe skin as an organ of immunity.Clin Exp Immunol.1997;107:3-5.PPaquetGEPierardInterleukin-6 and the skin.Int Arch Allergy Immunol.1996;109:308-317.HGattoJViacMCharveronDSchmittEffects of thermal shock on interleukin-1 levels and heat shock protein 72 (HSP72) expression in normal human keratinocytes.Arch Dermatol Res.1992;284:414-417.TSKupperEADeitchCCBakerWCWongThe human burn wound as a primary source of interleukin-1 activity.Surgery.1986;100:409-415.JLRodriguezCGMillerWLGarnerCorrelation of the local and systemic cytokine response with clinical outcome following thermal injury.J Trauma.1993;34:684-694.HOhaztoMMondenKYoshizakiSystemic production of interleukin-6 following acute inflammation.Biochem Biophys Res Comm.1993;197:1556-1562.OCetinkaleKMUlualpFAyanMDurenOCizmeciAPusaneEarly wound excision and skin grafting restores cellular immunity after severe burn trauma.Br J Surg.1993;80:1296-1298.MRHollidayRJDearmanECorsiniDABasketterIKimberSelective stimulation of cutaneous interleukin 6 expression by skin allergens.J Appl Toxicol.1996;16:65-70.JCHopeRJDearmanIKimberSJHopkinsThe kinetics of cytokine production by draining lymph node cells following primary exposure of mice to chemical allergens.Immunology.1994;83:250-255.PMartinWound healing: aiming for perfect skin regeneration.Science.1997;276:75-81.ABPeitzmanTBBilliarBGHarbrechtAOUdekwuEKellyRLSimmonsHemorrhagic shock.Curr Probl Surg.1995;32:925-1002.AAyalaMMPerrinPWangWErtelIHChaudryHemorrhage induces enhanced Kupffer cell cytotoxicity while decreasing peritoneal or splenic macrophage capacity: involvement of cell-associated TNF and reactive nitrogen.J Immunol.1991;147:4147-4154.PJO'NeillAAyalaPWangRole of Kupffer cells in interleukin-6 release following trauma-hemorrhage and resuscitation.Shock.1994;1:43-47.EADeitchDXuLFrankoAAyalaIHChaudryEvidence favoring the role of the gut as a cytokine-generating organ in rats subjected to hemorrhagic shock.Shock.1994;1:141-146.NASoterAcute effects of ultraviolet radiation on the skin.Semin Dermatol.1990;9:11-15.AKockTSchwarzRKirnbauerHuman keratinocytes are a source for tumor necrosis factor α: evidence for synthesis and release upon stimulation with endotoxin or ultraviolet light.J Exp Med.1990;172:1609-1614.ITillie-LeblondPGossetAJaninTumor necrosis factor-α release during systemic reaction in cold urticaria.J Allergy Clin Immunol.1994;93:501-509.MWWichmannRZellwegerCMDeMasoAAyalaCWilliamsIHChaudryImmune function is more compromised after closed bone fracture and hemorrhagic shock than hemorrhage alone.Arch Surg.1996;131:995-1000.WErtelMHMorrisonAAyalaIHChaudryHypoxemia in the absence of blood loss or significant hypotension causes inflammatory cytokine release.Am J Physiol.1995;269:R160-R166.Herbert B. Hechtman, MD, Boston, Mass:These are superb testable hypotheses with crisp data, giving us the nicely presented results. Drs Catania and Chaudry have continued to educate us at these meetings with regard to the mechanisms of inflammation following trauma. The subject matter, that is, cytokines, is in step with their recent emphasis on Kupffer cells that we heard about last year.There are 3 separate models that are presented, each of which stimulates cytokine production by skin. Following hemorrhage and resuscitation, one might argue that the cytokine response is secondary to the generalized as well as local stimulus of ischemia and reperfusion. Of equal interest is the observation that the so-called sham group, those animals that had only their femoral arteries ligated, also expressed cytokine mRNA.I had the opportunity of seeing the manuscript and studying the blots which are presented there, but might have escaped your scrutiny during this presentation. This is fascinating to me. Would the authors think that this rise in mRNA could be a remote tissue response to hind-limb ischemia and reperfusion much as occurs remotely in other organs that they've described, such as the liver and the lungs?Positive findings in another sham group are more perplexing. That a sham incision leads to message expression for TNF-α indicates that multiple variables may be operative. Is there any information available regarding the role of changes in skin temperature on cytokine production?Your observation of the importance of a simple laparotomy incision in provoking remote cytokine gene expression was really unexpected. It's reminiscent of our experience in patients of prominent systemic prostacycline synthesis accompanied by a slight but significant fall in blood pressure following simple laparotomy. Could you speculate about the mechanism of your observation? You imply that circulating mediators are of primary importance, and I certainly agree.Dr Catania:There are quite a few questions to answer. In terms of the up-regulation of IL-1 that was evident in the sham group, I agree with you there is something occurring during the sham procedure. Whether it is related to the hind-limb ischemia, which could result from our bilateral catheterization of the femoral arteries, or in the case of shams, tying off the femoral arteries, or whether it is due to the incision itself, I'm not entirely sure. What is clear is that in animals that undergo no surgical procedure, there is no up-regulation of IL-1 in skin, so there is some component to the sham procedure which does elevate gene expression.In terms of the elevated TNF in sham incisions, TNF was a rather interesting gene to work with, both in the liver and in the skin. We did see TNF expression variably in our sham animals, usually at very low levels. Whether this has something to do with the change in tissue temperature, or whether it has something to do with the actual procedure of anesthesia and restraint which the sham animals all undergo, I'm not exactly sure.I agree with you that the findings following simple laparotomy were somewhat unexpected. When we designed this experiment, we actually thought that laparotomy would be a negative control. We believed that the main driving force behind cytokine expression in skin following trauma-hemorrhage would be hypotension and tissue hypoxia or hypoperfusion. There are a few experiments we would like to perform to further elucidate the mechanisms responsible for this up-regulation in gene expression. A soluble factor, such as prostanoid, may mediate this effect, and pretreatment with either ibuprofin or indomethacin to block these pathways would be interesting to determine if this is the mechanism which regulates skin gene expression. However, given the fact that this up-regulation occurs so rapidly, I also think that there is a fair chance the central nervous system is playing a role, and as we all know, the skin is very densely innervated. We would like to try to denervate the area where we perform our laparotomy and see if that has any effect on gene expression.Mark Callery, MD, Worcester, Mass:I'd like you to just talk to us about nature for a second if you would. It seems that nature put 2 of the largest macrophage populations in the body conveniently at an environmental interface, namely, the macrophages of the skin (air) and the macrophages of the liver (gut). So my question to you is whether this response is a protective response that nature has provided, or is it wrong just because you're saying it's producing cytokines in response to an injury?Dr Catania:I would be hesitant to ever criticize nature on evolution, which seems to have done a pretty good job in most cases. In the case following trauma and hemorrhage, however, I don't know that we were necessarily meant to survive some of the injuries that we now routinely survive, thanks to medical intervention. Whether or not a less vigorous response would be protective in a less significant injury, I can only assume that it would be. This is why we're always hesitant to tinker with the cytokine release, because clearly if it didn't have some beneficial role it would have evolved away. Exactly what constitutes a good response and what constitutes an overactive response remains to be determined.Brad Patterson, MD, Weybridge, Vt:For those of us who are not very familiar with cytokine levels, could you make some comment about whether these are important at a systemic level, the kind of thing we're used to hearing about as side effects of cytokines?Dr Catania:I believe most cytokines function in a microenvironment. When we start seeing high levels of cytokines systemically, that's usually when the cytokines are implicated in having a negative role. What the levels of the cytokines are in the microcirculation around the area of injury is probably the important factor in things like wound healing. Clearly the levels of cytokines in a healing wound are well in excess of the systemic levels we see here. However, when systemic cytokines levels do increase significantly, their action becomes less predictable. Their influence on neutrophil function following gut ischemia, for example, has been fairly well described by Dr Hechtman's group. Based on previous research, we presume that systemic elevations in cytokine levels have a detrimental effect.This investigation was supported by grant R01 GM 37127 from the National Institutes of Health, Bethesda, Md (Dr Chaudry).Presented at the 79th Annual Meeting of the New England Surgical Society, Toronto, Ontario, September 25, 1998.Reprints: Irshad H. Chaudry, PhD, Center for Surgical Research, Rhode Island Hospital, Middle House II, 593 Eddy St, Providence, RI 02903 (e-mail: [email protected]).

Masiakos, Peter T.; Islam, Saleem; Doody, Daniel P.; Schnitzer, Jay J.; Ryan, Daniel P.

doi: 10.1001/archsurg.134.4.375pmid: 10199309

HypothesisExtracorporeal membrane oxygenation (ECMO) is effective in nonneonatal acute respiratory failure under certain circumstances.DesignRetrospective medical record review.SettingThe intensive care unit of a tertiary care hospital.PatientsThirty-four nonneonatal patients (mean age, 22 years; range, 8 days to 56 years), with ratios of the PaO2to the fraction of inspired oxygen persistently below 70, who were treated with ECMO after maximal ventilator therapy had failed (mean time of ventilator therapy, 6.9 days; range, 1-41 days). The mean ECMO duration was 304 hours (range, 56-934 hours). Patients were grouped into 7 categories based on their diagnosis: sepsis or sepsis syndrome (n=3), bacterial or fungal pneumonia (n=10), viral pneumonia (n=5), trauma or burn (n=2), inhalation injury without burn (n=1), immunocompromised state (due to transplantation or chemotherapy) (n=8), and acute respiratory failure of unknown origin (n=5).Main Outcome MeasureSurvival to hospital discharge following ECMO therapy.ResultsOverall survival was 53% (18 patients). All 6 patients (100%) with viral pneumonias or isolated inhalation injuries survived. Of 13 patients with bacterial pneumonia, sepsis, or sepsis syndrome not complicated by multiorgan failure, 10 (77%) survived. In contrast, all but 1 of the immunocompromised patients died. Survival in patients who were intubated for less than 9 days before ECMO was 64%, whereas survival fell precipitously to 22% for patients who experienced mechanical ventilation for 9 or more days before the implementation of ECMO. Finally, the proportion of patients who died while receiving ECMO therapy was greater when the ECMO duration exceeded 300 hours (62% vs 38%; P<.05).ConclusionsNonneonatal survival with ECMO therapy is strongly dependent on the diagnosis. Pre-ECMO intubation for less than 9 days had little effect on survival. Survival rates decreased when the length of time of receiving ECMO exceeded 300 hours.ACUTE RESPIRATORY failure (ARF) in nonneonatal patients is an infrequent occurrence with devastating consequences. Although fewer than 2% of all admissions to intensive care units are complicated by severe ARF, mortality rates reported in the pediatric and adult literatureexceed 80%. Conventional mechanical ventilatory support is designed to improve gas exchange without worsening the underlying lung injury. The support these critically ill patients require, however, often exceeds the supplemental oxygen, positive end-expiratory pressure (PEEP), and positive pressure ventilation limits that have been shown to cause irreversible damage and fibrosis of the lung parenchyma.Extracorporeal membrane oxygenation (ECMO), introduced successfully in 1972,has been most commonly used as a means of cardiopulmonary support for patients with recoverable pulmonary insufficiency in whom maximal conventional therapies were exhausted. Generally accepted as an alternative method of ventilatory support in neonates, it has only recently begun to attract advocates of its use in nonneonatal, noncardiac patients.Most recently, in a retrospective review, Green et alshowed an ECMO-dependent improvement in survival for 331 pediatric patients aged 13 days to 18 years from 32 hospitals. Still, many criticsargue that ECMO remains a futile or expensive technology that extends intensive care unit admissions but offers little more for outcome than current optimal therapies do. The controversy has spurred the users of ECMO technology to review current management schemes frequently and to provide evidence for changing them based on experience. These reviews have also provided further insight into identifying when ECMO has ceased to be beneficial for the subset of patients described here.The purpose of this retrospective study is to report the results of the ECMO experience in nonneonatal patients with severe ARF. In addition, the data presented here provide confirmatory evidence that ECMO can be beneficial in this patient population. Finally, this report may aid in the design of more appropriate selection criteria for critically ill patients with ARF for whom conventional therapy has failed.PATIENTS AND METHODSBetween February 1, 1990, and April 30, 1998, 34 patients aged 8 days to 56 years with refractory ARF were consecutively treated with venoarterial or venovenous extracorporeal lung support in the neonatal, pediatric, and adult intensive care units at the Massachusetts General Hospital, Boston. Patients were identified retrospectively by reviewing office records from the pediatric surgical service ECMO database. The hospital medical record for each patient was reviewed, and pertinent information was recorded. A favorable outcome was defined as patient survival and discharge from the hospital.Patients were considered for enrollment using a modification of Extracorporeal Life Support Organization criteria; all patients were treated with ECMO after severe ARF developed and maximal ventilator therapy that required prolonged oxygenation with 100% oxygen failed. The patients had mean±SD ratios of PaO2to the fraction of inspired oxygen of 85.0±22.9 for survivors and 56.9±4.8 (P=.27) for nonsurvivors. They were considered for ECMO therapy only after all septic foci had been drained, pulmonary air leaks were managed with thoracostomy tubes, and all identified infections were treated with appropriate antibiotic therapy.Patients were separated into 2 groups: survivors (n=18) and nonsurvivors (n=16). The characteristics for these patients—age, the duration of ECMO therapy, ventilatory support variables before ECMO therapy, and laboratory values—are shown in Table 1.Table 1. Patient Characteristics, Arterial Blood Gas Values, and Laboratory Values&ast;VariableSurvivors (n = 18)Nonsurvivors (n = 16)PAge, y19.8 ± 3.924.6 ± 4.3.46Time on ECMO therapy, h250.0 ± 42.1366.0 ± 72.7.16Pre-ECMO ventilationVentilatory support, d4.8 ± 2.59.3 ± 0.8.08Peak inspiratory pressure (PIP), cm H2O46.4 ± 3.053.8 ± 4.7.18Positive end-expiratory pressure (PEEP), cm H2O13.6 ± 1.115.8 ± 1.2.19FIO2>0.9, h32.3 ± 9.774.3 ± 43.8.33PIP >40 cm H2O, h37.7 ± 9.7134.5 ± 55.9.08PEEP >8 cm H2O, h42.7 ± 6.6177.8 ± 58.4.02Pre-ECMO arterial blood gas valuespH7.30 ± 0.027.32 ± 0.03.57PaO2, mm Hg78.8 ± 20.453.9 ± 3.5.26PaCO2, mm Hg61.4 ± 5.560.8 ± 5.7.94Alveolar-arterial gradient531 ± 30559 ± 21.46PaO2/FIO2ratio85 ± 2357 ± 5.27Laboratory valuesPre-ECMO PRBC transfusion, U2.3 ± 0.99.6 ± 3.2.03PRBC transfusions on ECMO therapy, U15.5 ± 4.641.7 ± 9.6.02Pre-ECMO WBC count, × 109/L18.0 ± 1.915.7 ± 3.7.57Pre-ECMO hematocrit, %34.0 ± 1.333.7 ± 1.6.87Pre-ECMO platelet count, × 109/L215 ± 40170 ± 37.42Pre-ECMO serum creatinine, µmol/L (mg/dL)66.0 ± 8.8 (0.8 ± 0.1)97.2 ± 17.7 (1.1 ± 0.2).09&ast;Data are given as mean ± SEM. ECMO indicates extracorporeal membrane oxygenation; FIO2, fraction of inspired oxygen; PRBC, packed red blood cell; and WBC, white blood cell.Ventilator management while receiving ECMO was directed at limiting airway pressures by maintaining peak inspiratory pressures of less than 30 cm H2O and PEEP between 20 and 24 cm H2O. Large air leaks were treated with no PEEP and minimal ventilation until they resolved. Anticoagulation maintained activated clotting times at 180±20 (mean±SD) seconds for all patients.Statistical analyses on the data presented in Table 1were performed using the Student ttest. To determine whether age was a significant predictor of outcome, analysis of variance was performed.RESULTSThirty-four nonneonatal patients received ECMO support during the 8 years that were reviewed. The male-to-female ratio was 5:9 for the survivors and 13:3 for the nonsurvivors. Of the 34 patients with ARF, 21 (62%) recovered lung function and were weaned from extracorporeal support. Of these, 18 patients (53%) survived and were discharged from the hospital. Of patients who were weaned from ECMO and subsequently died, 1 patient died of complications from an underlying congenital heart lesion, and 2 patients who were previously treated with bleomycin sulfate had gradually progressive respiratory failure. The mean age for the group as a whole was 22 years (range, 8 days to 56 years). The age of the patients in the survivor group ranged from 8 days to 53 years (mean, 19.8 years) compared with the patients in the nonsurvivor group, whose age ranged from 2 months to 56 years (mean, 24.6 years). The mean of the 2 groups did not differ significantly; however, a bimodal distribution was observed when patient age was plotted against the frequency of survival (Figure 1). Furthermore, there was a significant increase in survival of patients in the later peak (P<.05) as the ECMO experience progressed through the 8 years (Figure 2).Figure 1.Patient survival (percentage) by age. The Massachusetts General Hospital (MGH), Boston, experience was compared with the Extracorporeal Life Support Organization (ELSO) database.Figure 2.Survival by year of extracorporeal membrane oxygenation (ECMO) therapy and age of patient. Each circle represents a patient who survived therapy with ECMO and was discharged from the hospital.The total number of days during which the patients were treated with assisted ventilation before ECMO therapy varied from 1 to 41 days (mean, 6.9 days). The duration of ECMO ranged from 56 to 934 hours (mean, 304 hours). The proportion of patients who died while receiving ECMO was greater when the ECMO duration exceeded 300 hours (8/13 [62%] vs 8/21 [38%]; P<.05). Survival by the duration of mechanical ventilation preceding ECMO is shown in Figure 3. Patients who received ventilatory support for fewer than 9 days had a significantly better outcome (P<.05).Figure 3.Patient survival (percentage) by duration of mechanical ventilation. A significant difference (P<.05) in survival after extracorporeal membrane oxygenation (ECMO) therapy was observed when mechanical ventilation before ECMO exceeded 8 days.For all categories, differences between the survivors and nonsurvivors were not significant, with the exception of the number of hours that PEEP exceeded 8 cm H2O and the number of units of packed red blood cells transfused before and during the implementation of ECMO. Patients were grouped into 7 categories based on their primary discharge diagnosis: sepsis or sepsis syndrome (n=3), bacterial or fungal pneumonia (n=10), viral pneumonia (n=5), trauma or burn (n=2), inhalation injury without burn (n=1), immunocompromised state (due to transplantation or chemotherapy) (n=8), and ARF, unknown origin (n=5). Survival for each group is shown in Table 2.Table 2. Cause of Acute Respiratory Failure and OutcomeDiagnosisNo. of Patients (n = 34)Survival, No. (%)Sepsis or sepsis syndrome33 (100)Bacterial or fungal pneumonia104 (40)Viral pneumonia55 (100)Trauma or burn20 (0)Inhalation injury without burn11 (100)Immunocompromised state&ast;81 (12)Unknown etiology54 (80)&ast;Transplantation or chemotherapy.COMMENTRespiratory insufficiency in nonneonatal patients is usually self-limiting. In the few patients in whom fulminant respiratory failure develops, however, reported mortality exceeds 50%. If pulmonary failure progresses in this group, and conventional management schemes are exhausted, mortality rates approach 90%.Experimental modelssuggest that the irreversible progression to death in nonneonatal patients is caused in part by the iatrogenic damage of the lung occurring with prolonged positive-pressure mechanical ventilation needed to overcome the ventilation-perfusion mismatches resulting from parenchymal shunting. Management strategies have been designedto improve oxygenation and minimize the mechanical damage associated with high alveolar pressure. These include low-volume and high-frequency ventilation, reversed inhalation to exhalation ratios, pressure-controlled ventilation to maintain peak inspiratory pressures under 40 cm H2O, permissive hypercapnia, and inhaled nitric oxide. All strategies are designed to promote optimal ventilation and perfusion, to minimize positive pressure–related parenchymal damage, and to afford the greatest capacity for recovery of the already-insulted lung.Still, the mortality of the patients not responding to these therapies exceeds 50%, and alternative methods of support have been studied.Poor survival in adults was initially reported by Zapol et alafter an ambitious multicenter, randomized ECMO trial. Subsequently, the application of ECMO in this population was forestalled. At the same time, however, Bartlett et alshowed dramatic successes in the treatment of refractory neonatal ARF by ECMO. There is little debate regarding its efficacy in these patients, as it has been shownto improve survival rates to 80% in patients with a predicted mortality of 90%. Soon thereafter, Gattinoni et alreported improved survival for adults with ARF using extracorporeal removal of carbon dioxide. The Extracorporeal Life Support Organization and its registry, as well as others,have since reported a combined survival for the nonneonatal, noncardiac group of patients of greater than 50%. The growing neonatal experience, together with reports of successes in adults, has led to an expanded use in patients other than neonates. In addition to longer treatment periods, the improvement in survival is thought to have been most influenced by the development of newer technologies, management strategies, and a better understanding of which patients may benefit from these technologies. Guidelines have been established to aid in the selection of patients who would be the most appropriate candidates for ECMO. These were defined as those who had "severe but reversible" ARF.Despite changes in protocols and improvement in outcomes, several controversies remain as to how ECMO should be implemented so that risks are outweighed by benefits and outcomes are better than they would be if conventional therapies were applied.Recently, several investigatorshave studied the outcomes for nonneonatal patients with ARF based on the cause of their respiratory failure. Similarly, we reviewed our patient base and placed each into 1 of 7 categories based on their discharge diagnosis (see "Results" section). As other groups have suggested, we observe that several disease states portend better outcomes, whereas the course of others is unchanged by ECMO therapy. Overall survival in our institution was 53% (18 patients). More interestingly, survival in patients presenting with isolated viral pneumonias, isolated inhalation injuries, or with sepsis or sepsis syndrome with ARF but not complicated by multiorgan failure was 100% (9 patients). In contrast, 1 (12%) of the 8 patients who were immunocompromised either as a result of chemotherapy for the treatment of cancer or by immunosuppression for organ transplantation survived to hospital discharge. Although 2 of the 7 nonsurvivors were weaned from extracorporeal support and the cannula removed, they subsequently died of a progressive respiratory failure thought to be related to their past bleomycin therapy. Therefore, as many have thought, these patients may not be suitable candidates for ECMO therapy. Similarly poor outcomes were seen for patients with ARF complicated by multiorgan failure or precipitated by trauma or burns. In this series, the disease process appeared to be significantly effective in identifying those patients with "reversible" lung injury in whom ECMO may be of benefit.Most authors agree that limiting lung injury before and during ECMO is of paramount importance when considering whether a patient is capable of survival. Identifying patients earlier in their "reversible" disease progression, and thereby limiting the well-characterized pre-ECMO ventilatory insult, should improve survival. Pranikoff et alshowed that pre-ECMO mechanical ventilation exceeding 5 days was a poor prognostic indicator in adults. Our data suggest that there is no significant difference in survival in those patients who had had up to 9 days of pre-ECMO ventilatory support and that a lesser but substantial percentage of patients who receive mechanical ventilation for longer than 9 days will survive to discharge after ECMO therapy.Early in the ECMO experience, Zapol et alconsidered the appropriate duration of ECMO therapy in adults to be equivalent to that seen by investigators treating neonates. Most authors at that time failed to take into account any possible differences in the resilience of the damaged lung parenchyma that may be expected in the nonneonates compared with neonates. The results reported by Zapol et al, therefore, as many have come to realize, came early in the ECMO learning curve and underestimated the time necessary for the return of lung function in the nonneonatal group. The centers that participated in the National Institutes of Health–sponsored adult trial allowed only 5 days of ECMO, and if no improvement was seen, it was considered futile and discontinued. Since then, the average time of extracorporeal support in nonneonatal patients has been better defined, the mean±SD duration of ECMO for these patients now being reported as 10.3±6.8 days.The cannulation time for our patients ranged from 2.3 to 38.9 days (mean, 12.6 days). More important, the difference in the mean cannulation time of the survivors (10.4 days) from that of the nonsurvivors (15.3 days) is apparently not significant. The proportion of patients who died while receiving ECMO, however, was greater when the ECMO duration exceeded 12.5 days (8/13 [62%] vs 8/21 [38%]; P<.05). Still, 5 of the 18 patients in the survivor group had ECMO durations exceeding 300 hours.When considering a patient with ARF of unknown origin, age may prove to be a useful prognostic indicator. When the age of the patients in this series was plotted as a function of survival, a bimodal distribution resulted. The survivors tended to cluster between 8 days and 9 years of age and then again between 29 and 38 years of age (Figure 1). Patients who were older than 38 years had poorer outcomes. Meyer and Jepsonmade a similar observation for their group of patients. We first thought that this phenomenon was a reflection of the small number of patients in our series. When all available data from the Extracorporeal Life Support Organization database for the nonneonatal, noncardiac patients was accumulated and plotted in the same way, however, this distribution was confirmed (Figure 1). Although we cannot conclusively identify the reason for this observation, a likely explanation may be, as Meyer and Jepson suggest, that diseases (viral or bacterial pneumonias) that cluster in certain age groups may result in more easily reversible pulmonary dysfunction. The Extracorporal Life Support Organization database should be reviewed to compare the underlying diseases in the various age groups.CONCLUSIONSImprovements in ECMO technology and the reevaluation of criteria for patient selection for extracorporeal support have greatly improved survival. We provide additional data that may be helpful when deciding whether a patient with ARF might benefit from the lung rest that is afforded by ECMO. Still, many questions remain unanswered. A multicenter, randomized trial would be appropriate to better define the population of patients who would most benefit by this therapeutic option.RARiveraWButtFShannPredictors of mortality in children with respiratory failure: possible indications for ECMO.Anaesth Intensive Care.1990;18:385-389.WMZapolMJFrikkerHPontoppidanThe adult respiratory distress syndrome at Massachusetts General Hospital.In: Zapol WM, Lemaire F, eds. Adult Respiratory Distress Syndrome.New York, NY: Marcel Dekker Inc; 1991:367-380.TKolobowMPMorettiRFumagalliSevere impairment in lung function induced by high peak airway pressure during mechanical ventilation: an experimental study.Am Rev Respir Dis.1987;135:312-315.DDreyfussGBassetPSolerGSaumonIntermittent positive-pressure hyperventilation with high inflation pressures produces pulmonary microvascular injury in rats.Am Rev Respir Dis.1985;132:880-884.JDHillTGO'BrienJJMurrayProlonged extracorporeal oxygenation for acute post-traumatic respiratory failure (shock-lung syndrome): use of the Bramson membrane lung.N Engl J Med.1972;286:629-634.DMMeyerMEJepsonResults of extracorporeal membrane oxygenation in children with sepsis: the Extracorporeal Life Support Organization.Ann Thorac Surg.1997;63:756-761.MMachaBPGriffithRKeenanECMO support for adult patients with acute respiratory failure.ASAIO J.1996;42:M841-M844.DPRyanDPDoodyTreatment of acute pulmonary failure with extracorporeal support: 100% survival in a pediatric population.J Pediatr Surg.1992;27:1111-1117.TPGreenODTimmonsJCFacklerFWMolerAEThompsonMFSweeneyThe impact of extracorporeal membrane oxygenation on survival in pediatric patients with acute respiratory failure: Pediatric Critical Care Study Group.Crit Care Med.1996;24:323-329.AHMorrisCJWallaceKLMenloveRandomized clinical trial of pressure-controlled inverse ratio ventilation and extracorporeal CO2removal for adult respiratory distress syndrome.Am J Respir Care Med.1994;149(2 pt 1):295-305.JRCusterJFacklerECLS for children with acute respiratory distress syndrome.In: Zwischenberger JB, Bartlett RH, eds. ECMO: Extracorporeal Cardiopulmonary Support in Critical Care.Ann Arbor, Mich: Extracorporeal Life Support Organization; 1995:chap 20.MRSuchytaTPClemmerJFOrme JrAHMorrisCGElliottIncreased survival of ARDS patients with severe hypoxemia (ECMO criteria).Chest.1991;99:951-955.GJPeekAWSosnowskiExtracorporeal membrane oxygenation for pediatric respiratory failure.Br Med Bull.1997;53:745-756.KGHicklingSJHendersonRJacksonLow mortality associated with low volume pressure limited ventilation with permissive hypercapnia in severe adult respiratory distress syndrome.Intensive Care Med.1990;16:372-377.ABidaniAETzouanakisVJCardenas JrJBZwischenbergerPermissive hypercapnia in acute respiratory failure.JAMA.1994;272:957-962.WMZapolMTSniderJDHillExtracorporeal membrane oxygenation in severe acute respiratory failure: a randomized prospective study.JAMA.1979;242:2193-2196.RHBartlettAFAndrewsJMToomasianNJHaiducABGazzanigaExtracorporeal membrane oxygenation for newborn respiratory failure: forty-five cases.Surgery.1982;92:425-433.EMRosenbergJHSeguinSelection criteria for use of ECLS in neonates.In: Zwischenberger JB, Bartlett RH, eds. ECMO: Extracorporeal Cardiopulmonary Support in Critical Care.Ann Arbor, Mich: Extracorporeal Life Support Organization; 1995.LGattinoniAPesentiGPRossiTreatment of acute respiratory failure with low-frequency positive-pressure ventilation and extracorporeal removal of CO2.Lancet.1980;2:292-294.TPranikoffRBHirschlCNSteimleHLAnderson IIIRHBartlettMortality is directly related to the duration of mechanical ventilation before the initiation of extracorporeal life support for severe respiratory failure.Crit Care Med.1997;25:28-32.GRBernardAArtigasKLBrighamThe American-European Consensus Conference on ARDS: definitions, mechanisms, relevant outcomes, and clinical trial coordination.Am J Respir Crit Care Med.1994;149(pt 1):818-824.FWMolerJRCusterRHBartlettExtracorporeal life support for severe pediatric respiratory failure: an updated experience, 1991-1993.J Pediatr.1994;124:875-880.Hardy Hendren, MD, Boston, Mass:The work in each of these ECMO patients, for those of you who have not witnessed it, is absolutely enormous. Yesterday I asked the authors to estimate how many hours they would spend each day at the bedside of 1 of these patients. It is conservatively about 6 hours. A little calculation—6 hours a day for 1 of the 300-hour ECMO-support patients, which is 13 days—indicates that this is roughly the equivalent of doing 20 open heart operations or 10 to 15 Whipple operations, depending on the speed of the operator.The authors have shown us that a survival of 53% can be achieved in this group of desperately ill patients, for whom the predicted mortality would be 80% otherwise, so this is a significant salvage. They have shown us that multiorgan failure and an immunocompromised state are bad predictors for these patients and that short-term support, that is, less than 13 days, is more apt to result in success than long-term support, that is, more than 300 hours.I would like to ask the authors 3 questions: First, you've shown that patients younger than 10 years and those in their 30s had a higher likelihood of survival. What's the problem with being in the 10- to 30-year age group?The second question is, you've shown us that single-organ failure, that is, the lung, and short-term patients do best. Do you have absolute contraindications to the use of ECMO? And how about age? Are about two thirds of the people in this audience beyond the age limit and would you write us off or would you give us a chance with ECMO in the final analysis if it were a single-organ lung failure?The third question is, when you cross that threshold of 300 hours or 13 days, when and how do you decide to turn off the ECMO?Pardon Kenney, MD, Boston:Your survival data are obviously impressive. I have a quality-of-life question. How many of your survivors required permanent ventilators, and how many of them actually ended up in a chronic care hospital? How many of these patients have been referred? Are they all based at the Massachusetts General Hospital originally? Can these patients be transported for ECMO, and when would you do that?Dr Masiakos:To answer Dr Hendren's questions, we find that these diseases cluster by ages, and we suspect that they cluster because of disease predispositions. The group that you speak of, the 10- to 30-year-olds, contains the sickest patients. They are the ones who have fungal sepsis, are immunocompromised after their lung transplants, and are most likely to present with multiorgan failure after trauma. They typically do the worst.To your second question about the absolute contraindications: The first contraindication is head injury. Children or adults who present with head trauma or intracranial hemorrhage are refused. Irreversible lung damage, as seen by biopsy with indications of pulmonary fibrosis, is also a contraindication. Finally, a patient with an underlying fatal disease like metastatic cancer or end-stage acquired immunodeficiency syndrome would be refused as well.Age is not an absolute contraindication, and I know you all hate me for saying that, however, it's a patient by patient evaluation and we assume enrollment criteria based on what we find on their lung pathology report.To your last question, the 300-hour threshold: There's no good way to tell a patient's parents or family members that their life support is going to be withheld or withdrawn. We observe the patients day to day, and if there's no evidence of lung recovery after the second or third week, the patients are offered a lung biopsy. If fibrosis is seen on lung biopsy, we consider that to mean irreversible lung damage, and at that point, we suggest that ECMO be discontinued.The quality-of-life issues: None of the patients who were survivors after receiving ECMO therapy had poor quality of life, none of them were institutionalized, and none continued to need ventilation therapy for their disease. After they recovered, they would be terminated from ECMO and then subsequently be terminated from ventilator support.To your question about ECMO referrals, it's imperative to understand that lung damage predisposes these patients to poor outcomes. We suggest that the patients be transferred to an institution where ECMO can be provided if in a short amount of time the patient is deemed not recoverable by the current conventional therapies. To get a patient there promptly results in fewer problems in the transfer than when the patient decompensates later.Presented at the 79th Annual Meeting of the New England Surgical Society, Toronto, Ontario, September 26, 1998.We would like to thank the respiratory therapists; neonatal, pediatric, and adult intensive care unit nursing staff; and our colleagues in pediatric and adult intensive care medicine who cared for these patients during their most critical hours. We also thank Steve Conrad, MD, PhD, of Louisiana State University, Baton Rouge, and Peter Rycus, MPH, of the University of Michigan, Ann Arbor, and the Extracorporeal Life Support Organization registry for generously providing us with the current registry data.Corresponding author: Daniel P. Ryan, MD, Department of Surgery, Pediatric Surgical Service, Massachusetts General Hospital, Harvard Medical School, 40 Fruit St, WRN 1131, Boston, MA 02114.

Gadd, Michele A.; Cosimi, A. Benedict; Yu, Jeanne; Duncan, Lyn M.; Yu, Lawrence; Flotte, Thomas J.; Souba, Wiley W.; Ott, Mark J.; Wong, Lisa S.; Sober, Arthur J.; Mihm, Martin C.; Haluska, Frank G.; Tanabe, Kenneth K.

Ott, Mark J.; Tanabe, Kenneth K.; Gadd, Michele A.; Stark, Paul; Smith, Barbara L.; Finkelstein, Dianne M.; Souba, Wiley W.

doi: 10.1001/archsurg.134.4.388pmid: 10199311

HypothesisMerkel cell carcinoma is a rare dermal neuroendocrine carcinoma whose optimal treatment and prognostic factors are poorly defined. We hypothesize that high-risk patients with Merkel cell carcinoma are best treated with multimodality therapy.DesignA retrospective review of all patients (N = 33) with Merkel cell carcinoma treated at the Massachusetts General Hospital from January 1, 1980, to August 24, 1997. Median follow-up time was 37 months (range, 6-157 months).PatientsAdequate data for evaluation were available for 31 patients. Male to female distribution was 14 men and 17 women, with a median patient age of 68 years.Main Outcome MeasureStage at presentation; factors associated with recurrence; and the effects of surgery, radiation therapy (XRT), and chemotherapy on recurrence, salvage, and survival rates.ResultsThere were 12 extremity, 11 head and neck, and 8 truncal tumors. There were 22 isolated primary tumors, 8 with additional clinically positive lymph nodes, and 1 with distant disease. Therapy was local excision with or without XRT in 19 patients, local resection and lymphadenectomy with or without XRT in 8 patients, and XRT alone in 4 patients with head and neck tumors. Fifteen patients developed recurrences (7 local, 8 nodal, and 10 distant). Median time to recurrence was 8 months (range, 3-48 months). There were 7 tumor-related deaths, 6 of which were associated with truncal lesions (P<.001). No locoregional recurrences occurred in patients with margins of resection of 2 cm or greater or adequate XRT. A multivariate analysis selected truncal location (P= .005) and nodal disease (P= .05) as predictors of mortality. Remission was possible in 5 patients with locoregional and 2 patients with distant recurrences.ConclusionsMerkel cell carcinoma is an aggressive dermal cancer with frequent nodal metastases; truncal tumors have the worst prognosis. Locoregional recurrence correlates with inadequate margins and lack of XRT, but remission is possible with multimodality therapy.MERKEL CELL carcinoma (MCC), a neuroendocrine carcinoma of the dermis, is an extremely rare and aggressive malignant neoplasm. This tumor has a high propensity for local recurrence (20%-75%), regional nodal metastases (31%-80%), and distant metastases (26%-75%).Approximately one third of patients eventually die of their disease.Tokerfirst described MCC in 1972, and the first published series appeared in 1982.Since that time, slightly over 600 cases have been reported in the literature. Merkel cell carcinoma has a distinctive appearance, presenting clinically as a red to violaceous intradermal nodule. The lesion typically increases rapidly in size over a few weeks to months. Recommended management has usually been surgical excision of the primary lesion, with wide margins (1-3 cm) advocated by most authors.In addition, some have recommended a prophylactic lymphadenectomy due to the propensity for early occult spread to regional nodes.More recently, sentinel lymph-node mapping has been used in MCC to detect the presence of regional nodal metastases. This technique allows one to perform selective lymph-node dissection.Most authors have recommended adjuvant radiation therapy (XRT) for local control, but a survival benefit has not been demonstrated. Meeuwissen et aldemonstrated a substantial benefit in both time to recurrence and disease-free survival when XRT was used. While MCC is sensitive to multiple chemotherapy agents (cisplatin, doxorubicin hydrochloride, vindesine sulfate, and fluorouracil), the experience of most authorities is that the response has been short-lived. Owing to the rarity of this tumor and the lack of a standardized approach to treatment, it has been difficult to adequately evaluate the proper role and regimen for chemotherapy.The purpose of this study was to analyze our experience with MCC and determine which factors in patient presentation affected outcome and to help clarify the optimal treatment of these patients.SUBJECTS AND METHODSThe medical records of 33 patients identified through the cancer data registry with MCC treated at the Massachusetts General Hospital, Boston, from January 1, 1980, to August 24, 1997, were reviewed. Median follow-up was 37 months (range, 6-157 months). Adequate data for evaluation were available for 31 patients (94%). Demographic data were collected and clinical outcomes recorded. Individual physicians were contacted when necessary to complete follow-up data. We determined location and stage at presentation; the incidence of other malignant neoplasms; factors associated with recurrence; and the effects of surgery, XRT, and chemotherapy on recurrence, salvage, and survival rates.Disease-free survival curves were estimated using the Kaplan-Meier method.Patients who were alive and disease free at the most recent follow-up were treated as censored for this analysis. Factors associated with outcome were compared using a univariate log-rank test Cox regression. An optimal multivariate model was selected using a forward and backward selection procedure. A 2-tailed Fisher exact test was used for analysis of local and regional recurrence.RESULTSPREDICTORS OF DISEASE-FREE SURVIVAL RATESThe median patient age was 68 years (range, 34-81 years). There were 14 men and 17 women and all patients were white. Thirteen patients (42%) had a total of 17 previously treated or coexisting malignant neoplasms (Table 1). The size of the primary lesions varied from 0.5 to 15 cm (median, 2 cm) and did not affect the outcome. Demographic data, tumor location, regional nodal status, and effect of treatment on outcome are presented in Table 2. While the incidence of MCC was roughly equal between the sexes, there was a trend for female patients to have a better outcome by univariate analysis (P= .09). Twenty-two patients (71%) presented with stage I disease, 8 patients (26%) presented with stage II disease (clinically positive nodes), and only 1 patient (3%) presented with distant disease (stage III) at diagnosis. Primary treatment included local excision with or without XRT in 19 patients, local resection and lymphadenectomy with or without XRT in 8 patients, and XRT alone in 4 patients with head and neck tumors. Fifteen patients (48%) developed recurrences (7 local, 8 nodal, and 10 distant).Table 1. Other Malignant Neoplasms in Patients With Merkel Cell CarcinomaMalignant NeoplasmsNo. of OccurrencesSquamous cell carcinoma of the skin3Breast cancer3Endometrial cancer2Colon cancer2Prostate cancer2Chronic lymphocytic leukemia2Ovarian clear cell carcinoma1Bladder cancer1Squamous cell carcinoma of the vocal cord1Table 2. Prognostic, Demographic, and Treatment VariablesCharacteristicsNo. of PatientsNo. of DeathsPUnivariateMultivariateSexMale145.09Female172Age, y≥55264.002<5553Site of tumorExtremity120<.001.005Head and neck111Trunk86Nodal statusPositive84.002.05Negative233Radiotherapy, Gy≥4590.08<45227ChemotherapyYes63.02No254Tumor margin, cm≥272.69<2245Univariate, statistically significant predictors of disease-free survival were location of the lesion (P<.001), age 55 years or older (P= .002), and regional nodal status at the time of diagnosis (P= .002). A multivariate survival model selected only truncal location (P= .005) and nodal disease (P= .05) as statistically significant, independent predictors of survival. With these variables in the model, there were no additional clinical treatments or demographic variables that independently predicted mortality at a significant level. Lesions occurring on the trunk had an extremely poor prognosis (Figure 1), with 6 of the 7 deaths occurring in this group and only 2 of the 8 patients with truncal lesions surviving free of disease (at 96 months and 12 months). Both of these patients underwent wide excision of their lesions, with XRT of 45 Gy or more to the tumor bed and regional nodes and adjuvant chemotherapy. Of the 8 patients with clinically positive regional nodes at the time of presentation, only 4 survived (Figure 2). Two of these 4 survivors received XRT to the nodal bed, 1 received XRT and a therapeutic lymph-node dissection, and 1 only received a therapeutic lymph-node dissection. Of the 4 patients with positive nodes at the time of diagnosis who did not survive, none received adequate XRT to the nodal bed in the immediate postoperative period. Of the 23 patients who had clinically negative regional nodes at presentation, only 2 subsequently developed nodal disease.Figure 1.The effect of tumor location on outcome in patients with Merkel cell carcinoma, using Kaplan-Meier life-table multivariate analysis (P= .005).Figure 2.The effect of regional nodal status on outcome in patients with Merkel cell carcinoma, using Kaplan-Meier life-table multivariate analysis (P= .05).TREATMENTRadiation therapy of 45 Gy or more to the primary site and/or regional nodes appeared to confer a benefit (P= .08), with no treatment failures among the 9 patients who received this dose (Figure 3). Within this group, 4 patients had head and neck lesions (4.5 cm on the right cheek, 1.7 cm on the right eyebrow, 1.2 cm on the left upper eyelid [39 Gy], and 3 cm on the left cheek) whose margins were either positive (3 patients) or within 1 mm (1 patient). Due to the limits of resection, XRT was the primary treatment modality in these patients. All of these patients were alive and free of disease at 8, 33, 60, and 92 months, respectively.Figure 3.The effect of perioperative external beam radiation therapy on outcome in patients with Merkel cell carcinoma, using Kaplan-Meier life-table univariate analysis (P= .08).Three of 6 patients who received chemotherapy survived, compared with 21 of 25 patients who did not receive chemotherapy. Thus, the administration of chemotherapy was associated with a worse outcome by univariate analysis (P= .02). This difference disappeared in multivariate analysis since many of these patients had truncal lesions and positive regional nodes, and that was the main determinant of their outcome. There were in fact 2 patients with distant metastases who were treated with chemotherapy and were free of disease at 33 and 96 months, respectively.Seven patients had margins of resection of 2 cm or larger. None of these patients experienced a local recurrence, compared with 7 local recurrences in 24 patients with margins of resection less than 2 cm (P= .16). Two of the 7 patients with wide excisions subsequently died of distant disease. As a result, a margin of resection of 2 cm or larger vs less than 2 cm did not significantly affect the survival rate. Median time to recurrence for the entire series was 8 months (range, 3-48 months).Recurrence developed locally in 4 patients and in regional nodes only in 1 patient. All 5 of these patients were curable with XRT and/or reexcision (mean disease-free survival, 40 months).COMMENTThe rarity of Merkel cell carcinoma has contributed to its undertreatment. From both our series of patients and the previously reported combined experience in the literature, it is clear that MCC is an aggressive but also curable lesion. Understaging combined with undertreatment leads to local recurrence and distant failure. Shaw and Rumballpoint out that, in many respects, MCC is similar to aggressive melanoma. Both skin tumors are of neural tissue origin and found almost exclusively in whites. They both tend to follow a predictable pattern of spread to the regional lymph nodes followed by systemic disease. The occurrence or spread of MCC may reflect a predisposition to developing cancer. Thirteen patients (42%) had previous malignant neoplasms. Four of these patients had experienced 2 prior separate malignant neoplasms. This is a higher multiple cancer rate for this age group than even the expected single cancer rate of 1 in 3 for male and 1 in 4 for female patients. This study represents the first documentation of an increased malignant neoplasm rate among patients with MCC.WHAT DETERMINES outcome in patients with MCC? In our series, the tumor size had no effect on survival rates, similar to the findings of Victor et al.Six patients with large tumors (4-10 cm) were disease free at 8, 12, 24, 37, 96, and 113 months. By contrast, 3 of the 7 deaths occurred in patients with primary tumors smaller than 2 cm. There was a trend for women to have a better prognosis than men, similar to melanoma.A more favorable prognosis for women with MCC has also been found by other authors.Figure 1andFigure 2demonstrate that location and nodal status at presentation are correlated with outcome. Again this is similar to melanoma, for which truncal lesions and positive lymph nodes are poor prognostic factors; however, this is the first time truncal location has been shown to carry such a poor prognosis for MCC. Truncal location resulted in mortality in 6 (75%) of 8 patients, compared with no deaths among the 12 patients with extremity lesions and 1 death among the 11 patients with head and neck lesions. The poor outcome of patients with truncal tumors may reflect a wider potential array of lymphatic basins for dissemination relative to extremity and head and neck lesions; it may also be due to earlier systemic spread. Our observation that the 2 truncal lesion survivors received more aggressive therapy than the nonsurvivors suggests that multimodality treatment does make a difference. Both survivors received wide excision and XRT to the tumor bed and regional nodes in excess of 45 Gy, and 1 patient also received chemotherapy. By contrast, of the 6 nonsurvivors, only 1 patient had an optimal wide excision and none received optimal XRT in the perioperative period.Due to the propensity for early nodal spread and the significant negative impact nodal disease has on outcome, many have felt that prophylactic lymph-node dissection is warranted.These authors demonstrate improved locoregional control but no impact on survival. No comment is made about complications of the lymph-node dissection (edema, infection, and pain), so it is not clear at what cost this local benefit was obtained. Our study confirms the findings of the previous studies. Although the 8 patients in our series who underwent lymphadenectomy did not develop nodal recurrences, there was no survival benefit. None of these patients experienced any significant complications from the nodal dissection. At the very least, the information on nodal status may be useful in selecting patients for further adjuvant therapy. In this regard, the report by Messina et alemploying the sentinel node technique is promising, with no false negatives, although the follow-up is limited (median, 10.5 months).Since a truncal location of tumor and node positivity have a significant negative impact on survival, what is the optimal treatment of these high-risk patients as well as all patients with MCC? Almost all authors advocate wide local excision, and we strongly agree with this. This reduces the incidence of local recurrence but does not improve survival. Our findings confirm this and indicate that a 2-cm margin, when possible, is the appropriate width of excision to obtain local control. None of the 7 patients with margins of resection of 2 cm or larger experienced a local recurrence, whereas one third of patients with narrower margins did. In anatomical locations where wide margins cannot technically be obtained, XRT has been useful in local control with long-term survival rates. Our 4 patients with facial lesions treated primarily by XRT suggest that this is a reasonable alternative, although the sample size does not allow a satisfactory statistical analysis.Radiation therapy is an important component in the treatment of MCC. All 9 patients who received XRT of 45 Gy or greater to the primary tumor bed and to the regional nodal bed were alive and free of disease at the time of this report (Figure 3). This result, in conjunction with the 4 disease-free head and neck primary tumors that were treated primarily with XRT, supports the benefit of XRT for outcome. This is the first time that XRT as the only therapy for MCC has been shown to have a curative role. With a larger sample size, it is likely that the benefit of XRT for survival (P= .08) would have achieved statistical significance. While most studies have demonstrated the benefit of XRT for local control, the study by Meeuwissen et aland our study are the only studies also confirming the benefit for survival.The use of chemotherapy is unproven but advisable for high-risk patients (ie, truncal lesions or nodal disease). Multiple agents have been demonstrated to be active against MCC.Although the administration of chemotherapy was associated with a worse outcome in our series, this clearly reflects a selection bias, as demonstrated by the multivariate analysis. The fact that 2 patients with distant metastatic disease were alive and free of disease at 32 and 96 months may suggest that some lasting benefit is gained from chemotherapy. Given the extremely low incidence of this tumor, it is unlikely that anything more than anecdotal treatment reports will appear in the literature.When treatments fails with either local recurrence or nodal disease, patient should undergo resection, followed by XRT greater than 45 Gy to the site. At the time of this report, we had 5 such patients, with mean disease-free survival of 40 months. This is in agreement with the 50% to 60% success rate reported by Meland and Jackson.Our recommendations for the treatment of MCC are based on its aggressive behavior, which requires an aggressive treatment plan. To minimize local recurrence, lesions should, whenever anatomically possible, be widely excised with a 2-cm margin. They should also receive postoperative XRT to the primary site if wide margins have not been obtained or if the primary lesion is located on the trunk. At the time of the resection the status of the draining lymph nodes should be ascertained. Results using the sentinel-node mapping technique suggest that this is as applicable here as it has been shown to be in patients with melanoma. Patients with positive lymph nodes should undergo formal lymph-node dissection, followed by XRT to the nodal bed. Patients who choose not to have a complete lymph-node dissection should probably undergo XRT to the regional nodes, especially if they have a truncal lesion. Patients with truncal lesions or positive nodes are at high risk for distant metastatic disease, and systemic chemotherapy should be seriously considered. When lesions recur, a combined modality approach of reexcision, lymphadenectomy, XRT, and chemotherapy should be used, unless contraindicated. The combination of wide local excision, regional lymphadenectomy, and postoperative XRT has the potential to achieve cure in greater than 90% of patients.ACotlarJGatesFGibbsMerkel cell carcinoma: combined surgery and radiation therapy.Am J Surg.1986;52:159-164.CLHitchcockKIBlandRGLaneyFDaisyBHarrisEMCopelandNeuroendocrine (Merkel cell) carcinoma of the skin: its natural history, diagnosis, and treatment.Ann Surg.1988;207:201-207.MKrollCTokerTrabecular carcinoma of the skin: further clinicopathologic and morphologic study.Arch Pathol Lab Med.1982;106:404-408.RXMurphy JrJKLiFKMincerBStrauchTrabecular (neuroendocrine) carcinoma of the skin: report of 4 cases and review of the literature.N Y State J Med.1990;90:35-38.NMelandIJacksonMerkel cell tumor: diagnosis, prognosis, and treatment.Plast Reconstr Surg.1986;77:632-638.JHRaafCUrmacherWKKnapperMShiuEChengTrabecular (Merkel cell) carcinoma of the skin: treatment of primary, recurrent, and metastatic disease.Cancer.1986;57:178-182.RBSchackRMBartonJDelozierRReesJLynchIs aggressive surgical management justified in the treatment of Merkel cell carcinoma?Plast Reconstr Surg.1994;94:970-974.RKSibleyLPDehnerJRosaiPrimary neuroendocrine (Merkel cell?) carcinoma of the skin: a clinicopathologic and ultrastructural study of 43 cases.Am J Surg Pathol.1985;9:95-108.ASzadowskaLWozniakJLasotaBMireckaHWolskaNeuroendocrine (Merkel cell) carcinoma of the skin: a clinico-morphological study of 13 cases.Histopathology.1989;15:483-493.SKAl-GhazalDSAroraHWSimpsonPSaxbyMerkel cell carcinoma of the skin.Br J Plast Surg.1996;49:491-496.CTokerTrabecular carcinoma of the skin.Arch Dermatol.1972;105:107-110.PQueiroloMGipponiAPeressiniMerkel cell carcinoma of the skin: treatment of primary, recurrent, and metastatic disease: review of clinical cases.Anticancer Res.1997;17:673-678.SAMarendaRAOttaAdnexal carcinoma of the skin.Otolaryngol Clin North Am.1993;26:87-116.NSVictorBMortonJWSmithMerkel cell cancer: is prophylactic lymph node dissection indicated?Am Surg.1996;62:879-882.DESmithSBielamowiczARKaganPJAndersonAVPeddadaCutaneous neuroendocrine (Merkel cell) carcinoma.Am J Clin Oncol.1995;18:199-204.JLMessinaDSReintgenCWCruseSelective lymphadenectomy in patients with Merkel cell (cutaneous neuroendocrine) carcinoma.Ann Surg Oncol.1997;4:389-395.JAMeeuwissenRGBourneJHKearsleyThe importance of perioperative radiation therapy in the treatment of Merkel cell carcinoma.Int J Radiat Oncol Biol Phys.1995;31:325-331.ELKaplanPMeierNonparametric estimation from incomplete observations.J Am Stat Assoc.1958;53:457-481.JHShawERumballMerkel cell tumour: clinical behavior and treatment.Br J Surg.1991;78:138-142.TBFitzpatrickGWMiltonCMBalchHMShawWHMcCarthyAJSoberClinical characteristics.In: Balch CM, Houghton AN, Milton GW, Saber AJ, Soong SJ, eds. Cutaneous Melanoma.2nd ed. Philadelphia, Pa: Lippincott-Raven Publishers; 1992:228.MPitaleRBSesionsSHusainAn analysis of prognostic factors in cutaneous neuroendocrine carcinoma.Laryngoscope.1992;102:244-249.KKrasagakisBAlmond-RoeslerCCZouboulisMerkel cell carcinoma: report of 10 cases with emphasis on clinical course, treatment, and in vitro drug sensitivity.J Am Acad Dermatol.1997;36:727-732.Richard Swanson, MD, Worcester, Mass:I congratulate Dr Ott and his colleagues at the Massachusetts General Hospital for doing an excellent job analyzing data regarding this rare tumor so they they can help us with treatment guidelines. The rarity of this tumor is clear from the fact that only 2 cases per year were seen at the Massachusetts General Hospital over 17 or 18 years. At our own institution, the University of Massachusetts Memorial Health Care Cancer Center, we have seen 5 cases over 7 years. This represents less than 0.1% of all cancer cases seen during this period. Obviously with such a rare tumor it would difficult to conduct a randomized prospective trial to definitively answer questions regarding optimal treatment. Thus, we need to formulate treatment decisions from retrospective analysis such as that presented today.From your data you've made recommendations about . . . treatment regarding aggressive surgery and radiotherapy. Your suggestions are similar to those found in the literature. From our own small experience, and from my reading of the literature, I'm impressed by the radio-responsiveness of these tumors. This leads me to wonder whether aggressive surgery is necessary if radiotherapy will be used.Specifically, from your data you recommended . . . excision when possible with postoperative radiotherapy. If all patients receive 45 Gy to the primary, do we need the 2-cm margin? You state that 4 who've had neck cancers were treated primarily with radiotherapy without a wide excision and all are alive without disease. You also stated that 9 patients who had over 45 Gy radiotherapy enjoyed disease-free survival. Other than the 4 head and neck cancer patients, did any of these 9 patients have less than 2-cm margins? Perhaps radiotherapy alone or radiotherapy after a simple excision of the primary without regard to achieving wide margins would be sufficient. I'd appreciate your comments about that point.You recommended sentinel lymph-node biopsy, or suggest a sentinel lymph-node biopsy would be helpful in determining positive nodes, and then you recommend a formal lymph-node dissection and radiotherapy to the nodal region for positive nodes. I agree that a sentinel-node biopsy is reasonable to identify positive nodes, and I agree that patients with positive nodes should have treatment of those nodes; the question is, what is necessary to treat the sentinel node–positive but clinically negative nodal basin? From your data and the literature I suspect that over 45 Gy in radiotherapy to the nodal region would be sufficient, and dissection would not be necessary. Do you have specific data that argue for the addition of node dissection to radiotherapy in the subset?In summary, can we treat patients with MCC with excision of the gross tumor without concern about margins followed by sentinel-node biopsy and radiation therapy to the primary and to the node region for positive nodes without formal node dissection?Peter Deckers, MD, Farmington, Conn:I'd like to speak to just the opposite of what Dr Swanson spoke about. Let me put it this way. I think all of us who have done lymphadenectomies, either in the groin or the axilla, over the years have been impressed with the fact that if you add radiotherapy to well-done axillary dissections or well-done groin dissections, then you don't really gain anything by that from the point of view of survival or local control, but you do significantly increase the morbidity, ie, lymphedema of the arm or lymphedema of the leg. So what I'm asking is can you give me solid evidence that the radiotherapy after an adequate groin dissection or an adequate axillary dissection for clinically positive disease makes a real difference?Charles Shoemaker, MD, Newport, RI:Just a few observations. One, we reviewed this entity at the New England cancer meeting a couple of years ago, and it's a very rare lesion. I heard the comment, "What does it look like?" Our experience was you took the lesion out, then you found out it was MCC and it was too late to get a picture. Histologically, the lesion starts in the deep layers of the skin, so the top layer of skin may not be involved, so it's just a heaping up of the skin, and looking back at notes, it's sort of pink in color.The other part of our review supports your last comment—be very aggressive about the recurrences, because some patients are salvageable.The third comment relates to Dr Deckers' comment. Surgeons from Memorial Sloan-Kettering are very aggressive about doing lymph-node dissection for lesions arising in the head and neck, but do not employ postoperative radiation.William Cook, MD, North Andover, Mass:It just happens that 2 days ago I had a call from one of our local oncologists, who had an MCC tumor patient they thought was controlled over the past 4 or 5 years and that patient has presented with a solitary nodule in the lung. Dr Ott, would you comment on the nature of your distant metastases as to how often you see, or might expect to see, a solitary pulmonary nodule as an expression of recurrence, or whether I should be thinking about this being a different kind of tumor; obviously, I'll find out. If it turns out to be a recurrence of the MCC tumor, what would you propose besides resection of the lesion as far as additional therapy?Dougald MacGillivray, MD, Portland, Me: I have 2 questions. One is the method of detection of distant metastases. Have you used octreotide scans in evaluating these patients? We recently had a patient who had an unsuspected distant metastasis detected this way. This patient was on immunosuppression after having a renal transplantation and had very rapid progression of disease. In my review of the literature there have been anecdotal reports of these tumors associated with immunosuppression. Were any of your patients on immunosuppression?Dr Ott:Thank you very much, Dr Swanson. In terms of the several issues, I'll work back a little bit in reverse order. Several of these patients did have immunosuppressed states. As I said, there was a high incidence of associated malignancies in these patients, and several of them were actually undergoing chemotherapy prior to the development of their MCC. I do think that there probably is some immunosuppression involved with development of this tumor. Certainly, octreotide scans have been reported in the literature as being used clinically to detect metastases. I'm aware of one positive scan similar to yours as well. These do have somatostatin receptors. The octreotide scan is said to be 80% to 85% sensitive in detecting neuroendocrine tumors, and MCC is a neuroendocrine tumor. Only 1 patient in our series had the scan, and it was positive.In terms of Dr Cook's questions and his patient with the lung metastases, his patient is almost identical to one of the patients in our series. Our patient developed an isolated lung metastasis 26 months after resection of the initial skin lesion. The patient underwent chemotherapy with cisplatin and Adriamycin and is presently at 33 months disease free. The patient did not have resection of that isolated lesion as part of the patient's treatment.Merkel cell cancer, when it's looked at by a pathologist, looks exactly like small cell carcinoma lung. In fact, when a skin lesion is detected, it's very important to make sure that the patient does not have a primary somewhere else and that the skin lesion is not a metastasis. Neuroendocrine tumors of the gut and small cell of the lung can metastasize to the skin, so it is important to exclude these other tumors.In terms of the metastatic pattern, we've had metastases to the lung. We've had them to the bone. We've had them to other areas of the skin, to the liver, to the small bowel, to the kidney, to the brain, and to nodes. So in a sense it behaves very similar to an aggressive melanoma, and it can basically show up anywhere.Dr Shoemaker's comments about the lesion's appearance on the skin: Yes, it's an intradermal lesion. The Merkel cell receptor is located at the base of the hair follicle, and it's believed to arise in that area, and it does cause a heaping up of the skin with sort of a reddish/purple discoloration. The vast majority of times, the lesion is excised, believing that it's a benign intradermal process. When it ultimately comes back as MCC, it is usually a surprise. So you're right; it's very uncommon to have a great photograph of an MCC until it's in the pathology lab.In terms of the whole question of surgery and radiation therapy, this is an extremely radiosensitive tumor. In the 4 cases of the head and neck lesions, 2 of those cases had clinically positive neck nodes, and all of those cases received radiation to the primary as well as to the neck on that side. All 4 patients had regression of the primary or nodal disease. All 4 patients are now alive at 8, 33, 60, and 92 months out and are free of disease. I think there is certainly room for treating these patients with radiation as the primary form of therapy. There was 1 patient who had a positive single lymph-node biopsy in the groin and then received subsequent radiation to that area without surgical resection and is among the patients who are disease free 3 to 4 years out from their initial treatment. Certainly this is a radiosensitive tumor, but due to the small numbers, it is difficult to test whether surgery vs radiotherapy is better or whether they should be combined.As to my own opinion of using both surgery and radiation therapy, yes, there is a higher incidence of lymphedema and morbidity from that combined approach. And, yes, there are patients in our series who had just lymphadenectomy without radiation therapy and are free of disease at 3 to 4 years. I can think of 2 in our series of survivors who did not have radiation. Having reviewed the data, my point is that more of these patients could have been cured. Due to the rarity of this disease, we're never going to know how little we can get away with. We are therefore stuck with erring on the side of being more aggressive and combining therapies. That was the basis of this entire paper. That applies particularly to the nodal disease. To Dr Swanson's question about whether it is adequate just to simply excise the primary and give radiation therapy to control the primary, I think the answer to that is probably yes. All of us here are surgeons, and we would feel much more comfortable doing a wide excision of 2 cm which will also cure the primary. Certainly curative surgery is preferable to surgery and radiation when possible in treating the primary tumor. It is nice to have a tumor which gives one both options.Presented at the 79th Annual Meeting of the New England Surgical Society, Toronto, Ontario, September 26, 1998.Corresponding author: Mark J. Ott, MD, Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital, 626 Cox Bldg, 100 Blossom St, Boston, MA 02114 (e-mail: [email protected]).

Wang, Ping; Ba, Zheng F.; Jarrar, Doraid; Cioffi, William G.; Bland, Kirby I.; Chaudry, Irshad H.

doi: 10.1001/archsurg.134.4.394pmid: 10199312

BackgroundAlthough adrenal insufficiency may not occur with moderate hypotension, it does occur with severe hemorrhage. Since hepatocellular function is depressed following severe hemorrhage, it remains unknown whether the liver plays any role in regulating adrenal function after trauma and hemorrhagic shock.HypothesisHepatic 11β-hydroxysteroid dehydrogenase (11β-HSD), a microsomal enzyme responsible for the degradation of bioactive corticosterone, plays a major role in the development of adrenal insufficiency following trauma and severe hemorrhage.Design, Interventions, and Main Outcome MeasuresMale rats underwent laparotomy to induce trauma before hemorrhage. They were then bled to and maintained at a blood pressure of 40 mm Hg until 40% of the maximal bleed-out volume was returned in the form of Ringer lactate. The rats were then resuscitated with 4 times the volume of maximal bleed-out with Ringer lactate during a 60-minute period. Plasma levels of corticosterone and corticotropin were measured at various intervals. In additional groups, corticotropin-induced corticosterone release, adrenal contents of corticosterone and cyclic adenosine monophosphate (cAMP), hepatic 11β-HSD activity, and plasma levels of corticosterone-binding globulin were determined at 1.5 hours after resuscitation. Moreover, a model of moderate hypotension (blood pressure, 80 mm Hg) was used to determine whether adrenal function is depressed under such conditions.ResultsAt the time of maximal bleed-out, plasma corticosterone and corticotropin levels increased by 245% (P<.001) and 293% (P<.001), respectively. Despite corticotropin levels being similar to those of the animals undergoing sham operation after resuscitation, corticosterone levels in hemorrhaged animals remained elevated up to 4 hours after resuscitation (by 158%-207%; P<.001). In addition, corticotropin-induced corticosterone release decreased by 78% at 1.5 hours after resuscitation (P=.009). In contrast, moderate hypotension did not reduce corticotropin-induced corticosterone release. Adrenal corticosterone content and cAMP levels (ie, the second messenger of corticotropin action) decreased by 55% (P<.001) and 25% (P=.03), respectively. Hepatic 11β-HSD activity decreased significantly at 1.5 hours after resuscitation (P<.001).ConclusionsSustained increase in plasma corticosterone levels following hemorrhage and resuscitation may be, in part, due to the decreased hepatic 11β-HSD activity. The high level of corticosterone negatively regulates corticotropin release, further reducing adrenal responsiveness to corticotropin stimulation. Thus, the liver appears to play an important role in regulating adrenal function following trauma and severe hemorrhage.DESPITE MAJOR advances in the management of trauma, a large number of trauma patients subsequently die of the ensuing sepsis, septic shock, and multiple organ failure.Although early and rapid fluid resuscitation remains the cornerstone of the treatment of trauma victims, studies have indicated that hepatocellular dysfunction (ie, the depressed clearance of indocyanine green), which occurs early after hemorrhage, persists despite crystalloid resuscitation.In addition, circulating levels of liver enzymes (alanine aminotransferase and aspartate aminotransferase) increase significantly following trauma and hemorrhagic shock,indicating hepatocyte damage under such conditions. Although adrenal insufficiency occurs frequently during sepsis and septic shock,and although administration of hydrocortisone in patients with sepsis has been reported to reverse the altered hemodynamics during late septic shock,it is a common notion that adrenal insufficiency occurs rarely after trauma and surgery.However, recent studies by Barquist and Kirtonhave indicated that although the overall incidence of adrenal insufficiency was less than 1% in surgical intensive care units, 11% of the patients older than 55 years and with intensive care unit stays of 14 days or longer were found to have adrenal insufficiency. It is also reported that postoperative adrenal insufficiency is more common in patients than currently recognized.Thus, investigation of the mechanism responsible for adrenal insufficiency following trauma and hemorrhage is important for improved management of severe trauma.The enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD) is expressed extensively in the liverand catalyzes the conversion of 11β-hydroxysteroids—cortisol in humans and corticosterone (the main glucocorticoid in rodents) in the rat—into their inactive forms, cortisone and 11-dehydrocorticosterone, respectively.Although previous studies have demonstrated that hepatocellular dysfunction occurs early after the onset of hemorrhage and persists even after fluid resuscitation,it remains unknown whether the depressed hepatocellular function is associated with a decrease in 11β-HSD activity. Our aim, therefore, was to determine whether hepatic 11β-HSD activity is reduced following hemorrhage and resuscitation and, if so, whether the decreased 11β-HSD activities are associated with adrenal insufficiency under such conditions.MATERIALS AND METHODSANIMAL MODEL OF TRAUMA AND SEVERE HEMORRHAGEWe used a nonheparinized model of trauma-hemorrhage and resuscitation in the rat, as described previously,with minor modifications. Briefly, male Sprague-Dawley rats (Charles River Laboratory, Wilmington, Mass) weighing 275 to 325 g were not fed for 16 hours before the experiment but were allowed water ad libitum. The animals were anesthetized using methoxyflurane inhalation; they underwent a 5-cm ventral midline laparotomy to induce tissue trauma before the onset of hemorrhage. The abdominal incision was then closed in layers. Both femoral arteries were cannulated using polyethylene-50 tubing for bleeding or monitoring of mean arterial pressure. All incisions were then closed and bathed with 1% lidocaine hydrochloride to provide analgesia throughout the experiment. The animals were then bled to a mean arterial pressure of 40 mm Hg (ie, severe hypotension) within 10 minutes. The blood pressure of 40 mm Hg was maintained by removing more blood until the animal was no longer able to maintain its blood pressure at that level (ie, maximal bleed-out). At that point, the blood pressure was further maintained by returning fluid in the form of Ringer lactate solution (RL) intravenously until 40% of the shed blood volume was returned in that form. Following this, the animals were resuscitated with RL at 4 times the volume of maximal bleed-out during a period of 60 minutes. Animals undergoing sham operation (hereafter referred to as sham animals) underwent the same surgical procedure but were not bled or resuscitated. The time required for maximal bleed-out was approximately 45 minutes, the volume of maximal bleed-out was approximately 60% of the calculated circulating blood volume,and the total hemorrhage time was approximately 90 minutes. Blood samples were collected at various time points for measurement of plasma corticosterone and adrenocorticotropic hormone (corticotropin) levels. In additional groups of animals, adrenal glands were harvested at 1.5 hours after the completion of hemorrhage and resuscitation for determination of tissue corticosterone and corticotropin levels. Moreover, corticotropin-induced release of corticosterone was assessed at 1.5 hours after resuscitation in separate groups of animals. There were 6 to 8 rats in each group at each time, and the rats were killed using an overdose of intravenous pentobarbital sodium at the end of each experiment. The experiments described herein were performed in adherence to the National Institutes of Health guidelines for the use of experimental animals. This project was approved by the Institutional Animal Care and Use Committee of Rhode Island Hospital, Providence.EXPERIMENTAL MODEL OF MODERATE HYPOTENSIONTo determine whether adrenal insufficiency occurs only following severe hemorrhagic shock, a model of moderate hypotension was also used in additional groups of animals. Briefly, male Sprague-Dawley rats (275-325 g) were not fed overnight before the experiment but were allowed water ad libitum. The rats were anesthetized using methoxyflurane inhalation before the induction of trauma (ie, 5-cm midline laparotomy). Following cannulation of various blood vessels, the rats were bled to and maintained at a mean arterial pressure of 80 mm Hg for 90 minutes (moderate hypotension). The animals were then resuscitated using RL at 4 times the volume of the withdrawn blood (5.46±0.45 mL/rat; approximately 30% of the calculated blood volume) during a 60-minute period. Blood samples were taken at various times for measuring corticosterone and corticotropin levels. At 1.5 hours after resuscitation, corticotropin-induced corticosterone release was determined in additional groups of animals. There were 5 to 8 rats in each group at each time.DETERMINATION OF CORTICOSTERONE AND CORTICOTROPIN LEVELSBlood samples for corticosterone and corticotropin assays were collected at 2 to 4 PM, when plasma levels were similar to the 24-hour average.Plasma levels of corticosterone and corticosterone contents in the adrenal tissues were determined using a commercially available double-antibody radioimmunoassay kit specifically for rat corticosterone (Immuchem; ICN Biomedicals Inc, Costa Mesa, Calif). Plasma samples (10 µL each) were assayed in duplicates. The cross-reactivity of the radioimmunoassay for rat corticosterone was 100%. For other steroids, the cross-reactivity was as follows: desoxycorticosterone, 0.34%; testosterone, 0.10%; cortisol, 0.05%; aldosterone, 0.03%; progesterone, 0.03%; and all other tested steroids, less than 0.01%. Plasma levels of corticotropin were measured using a specific radioimmunoassay kit from Peninsula Labs (Belmont, Calif). Briefly, a 1.5-mL blood sample was collected into a polypropylene tube containing ethylenediaminetetraacetic acid (1 mg/mL) and aprotinin (500 KIU/mL) at various times during and after hemorrhage, and plasma was separated. The extraction of corticotropin was performed using columns packed with C18 sorbent. The corticotropin was eluted with 60% acetonitrile and 1% trifluoroacetic acid. Eluates were evaporated to dryness using a centrifugal concentrator. Rat corticotropin assay has less than 0.1% cross-reactivity with other tested peptides.CORTICOTROPIN-STIMULATED RELEASE OF CORTICOSTERONEAt 1.5 hours after the completion of hemorrhage and resuscitation or a corresponding time in the sham animals, 100 µg of porcine corticotropin (1-39; 90 IU/mg; Sigma-Aldrich Corporation, St Louis, Mo) in 0.2-mL isotonic sodium chloride solution vehicles was injected intravenously.Blood samples were taken before and 30 minutes after corticotropin administration for corticosterone assays, as described. Studies have indicated that the plasma concentrations of corticosterone increased rapidly following corticotropin administration, reaching a peak at 15 to 30 minutes and returning to basal levels by 90 minutes.Our preliminary experiments indicated that plasma corticosterone levels reached a peak 30 minutes after intravenous injection of porcine corticotropin in sham animals (data not shown).MEASUREMENT OF CYCLIC ADENOSINE MONOPHOSPHATE LEVELSTo determine the levels of cyclic adenosine monophosphate (cAMP) in the adrenal tissue, both adrenal glands were homogenized at 4°C with isotonic sodium chloride solution (1 mL of homogenate). The cAMP levels were determined radioimmunologically according to the manufacturer's instructions (a nonacetylated-procedure, cAMP radioimmunoassay kit; Du Pont/NEN, Boston, Mass), as described previously.DETERMINATION OF HEPATIC 11β-HSD ACTIVITYHepatic 11β-HSD activity was determined by assessing the rate of conversion of cortisol to cortisone.Briefly, approximately 0.2 g of hepatic tissue was homogenized in 4 mL of ice-cold sodium phosphate buffer (10 mmol/L; pH, 7.0) containing 0.25-mol/L sucrose. Each assay tube contains approximately 150,000 counts per minute tritiated cortisol (Du Pont/NEN), 1.0 µmol/L nonradioactive cortisol, and 250-µmol/L β-nicotinamide adenine dinucleotide phosphate. Sodium phosphate buffer (0.1 mol/L) was added to bring the volume up to 0.4 mL. After 10-minute incubation at 37°C, 100 µL hepatic homogenate containing 1.0 mg of protein was added. After further incubation for 30 minutes, the reaction was arrested by rapidly transferring the tubes onto ice. The steroids were then extracted with 4 mL ethyl acetate containing a 40-µg mixture of nonradioactive cortisol and cortisone as carrier steroids. The extracts were dried, and the residues were resuspended in 100 µL of methanol. A fraction of the resuspension was spotted on a thin layer chromatography plate, which was developed in chloroform-methanol (volume-volume ratio, 9:1). The bands containing the labeled cortisol and cortisone were identified by UV light of the cold carriers, cut out into scintillation vials, and counted. The conversion rate of cortisol to cortisone was calculated from the specific activity of the labeled cortisol and the radioactivity of cortisone, and the results are expressed as the amount of cortisone (picomoles) formed per milligram of protein in 30 minutes.DETERMINATION OF CORTICOSTERONE-BINDING GLOBULIN AND PLASMA PROTEIN LEVELSPlasma levels of corticosterone-binding globulin (CBG) were assayed by using a saturation analysis.Briefly, endogenous steroids were removed from the samples by dilution (1:100) in a slurry of dextran-coated charcoal (DCC). After the centrifugation to remove DCC, aliquots (100 µL) of the supernatant were incubated with 10-nmol/L tritiated cortisol (Du Pont/NEN) in the presence or absence of 2-µmol/L unlabeled cortisol. Separation of CBG-bound steroid was achieved by incubation for 10 minutes at 0°C with 600 µL of DCC, followed by centrifugation. The supernatants were subjected to liquid scintillation counting. Plasma levels of protein were measured according to the method of Lowry et al.STATISTICAL ANALYSISOne-way analysis of variance and Tukey test or Student ttest were used, and the differences were considered significant at P≤.05. Results are presented as mean±SEM.RESULTSALTERATIONS IN PLASMA LEVELS OF CORTICOSTERONE AND CORTICOTROPINAs shown in Figure 1, plasma levels of corticosterone increased by 245% (P<.001) at the time of maximal bleed-out. The significantly increased levels of corticosterone persisted after fluid resuscitation, ie, 158% to 207% at 0 to 4 hours after the completion of fluid resuscitation (P<.001) (Figure 1). Similar to the changes in plasma corticosterone levels, corticotropin levels increased by 293% (P<.001) at the time of maximal bleed-out (Figure 2). However, circulating levels of corticotropin decreased by 52% to 58% (P<.001) at 0 to 4 hours after the completion of fluid resuscitation, compared with the levels at the time of maximal bleed-out (Figure 2). In addition, these levels were not significantly different from the values in sham animals (Figure 2).Figure 1.Alterations in plasma levels of corticosterone in animals undergoing sham operation (sham animals), at the time of the maximal bleed-out, and 0, 1.5, and 4 hours after the completion of fluid resuscitation. Data are presented as mean±SEM and compared using 1-way analysis of variance and Tukey test. Asterisk indicates P<.05 vs sham animals.Figure 2.Alterations in plasma levels of adrenocorticotropic hormone (corticotropin) in animals undergoing sham operation (sham animals), at the time of the maximal bleed-out, and 0, 1.5, and 4 hours after the completion of fluid resuscitation. Data are presented as mean±SEM and compared using 1-way analysis of variance and Tukey test. Asterisk indicates P<.05 vs sham animals; dagger, P<.05 vs time of maximal bleed-out.CORTICOTROPIN-INDUCED CORTICOSTERONE RELEASE AND ADRENAL CONTENTS OF CORTICOSTERONE AND cAMPAt 30 minutes after the intravenous administration of porcine corticotropin, plasma levels of corticosterone increased by 101% in sham animals (from 4.31±0.70 to 8.68±0.98 ng/mg protein; P=.005) (Figure 3). At 1.5 hours after hemorrhage and resuscitation, however, corticotropin-induced release of corticosterone only increased by 8% (from 12.36±0.96 to 13.34±0.59 ng/mg protein; P=.41) (Figure 3). Thus, corticotropin-induced net increase of corticosterone levels was reduced by 78% from 4.37±0.73 to 0.98±0.75 ng/mg protein (P=.009). In addition, adrenal corticosterone levels decreased by 55% at 1.5 hours after hemorrhage and resuscitation (P<.001) (Figure 4, top). Similarly, the basal cAMP levels in the adrenal tissue decreased significantly following hemorrhage and resuscitation (Figure 4, bottom).Figure 3.Alterations in corticotropin-stimulated increase in plasma corticosterone levels in animals undergoing sham operation (sham animals) and at 1.5 hours after the completion of hemorrhage and resuscitation. Data are presented as mean±SEM and compared using 1-way analysis of variance and Tukey test. Asterisk indicates P<.05 vs the respective corticosterone level before corticotropin administration.Figure 4.Alterations in adrenal corticosterone contents (top) and adrenal cyclic adenosine monophosphate (cAMP) levels (bottom) in animals undergoing sham operation (sham animals) and at 1.5 hours after the completion of hemorrhage and resuscitation. Data are presented as mean±SEM and compared using unpaired Student ttest. Asterisk indicates P<.05 vs sham animals.ALTERATIONS IN HEPATIC 11β-HSD ACTIVITYAs shown in Figure 5, hepatic 11β-HSD activity was 81.3±2.6 pmol/mg protein in 30 minutes in sham animals. At 1.5 hours after the completion of hemorrhage and resuscitation, however, hepatic 11β-HSD levels decreased by 31% (P<.001) (Figure 5).Figure 5.Alterations in hepatic 11β-hydroxysteroid dehydrogenase (11β-HSD) activity in animals undergoing sham operation (sham animals) and at 1.5 hours after the completion of hemorrhage and resuscitation. Data are presented as mean±SEM and compared using unpaired Student ttest. Asterisk indicates P<.05 vs sham animals.ALTERATIONS IN PLASMA CGB LEVELSThe plasma levels of CGB were found to be 30.25±2.76 pmol/mL in sham animals. Although plasma CBG levels increased to 45.50±6.74 pmol/mL at 1.5 hours after the completion of hemorrhage and resuscitation, such an increase was not statistically significant (6 animals per group; P=.06).ADRENAL RESPONSES AFTER MODERATE HYPOTENSIONSimilar to the severe hemorrhage, plasma levels of corticosterone in moderate hypotension increased significantly during the hemorrhage period and persisted at 0 and 1.5 hours after the completion of fluid resuscitation (Table 1). However, the increased corticosterone levels were not statistically different from those of the sham animals at 4 hours after resuscitation (Table 1). Plasma levels of corticotropin were also significantly elevated during hemorrhage and at 4 hours after resuscitation (Table 1). Despite the similarity in the responses of corticosterone and corticotropin after moderate hypotension vs after severe hemorrhage, corticotropin induced a significant increase in corticosterone release in sham (P=.014) and hemorrhaged animals (P<.001) (Figure 6). The corticotropin-induced net increase of corticosterone levels was 3.81±0.98 ng/mg protein in sham animals and 2.76±0.32 ng/mg protein in hemorrhaged animals (reduced by 28%) (P=.34).Alterations in Plasma Levels of Corticosterone and Corticotropin During and After Moderate Hypotension&ast;Corticosterone, ng/mg ProteinCorticotropin, pg/mg ProteinAfter sham operation3.57 ± 1.111.54 ± 0.16During 45-min hemorrhage8.22 ± 0.30†2.39 ± 0.13†After resuscitation, h06.63 ± 0.39†1.67 ± 0.131.56.25 ± 0.52†1.58 ± 0.1245.81 ± 0.472.44 ± 0.24†&ast;Data are presented as mean ± SEM and compared using 1-way analyses of variance and Tukey test. Moderate hypotension indicates mean arterial pressure of 80 mm Hg for 90 minutes.†P<.05 vs sham values.Figure 6.Alterations in corticotropin-stimulated increase in plasma corticosterone levels in animals undergoing sham operation (sham animals) and at 1.5 hours after the completion of hemorrhage and resuscitation in a model of moderate hypotension. Data are presented as mean±SEM and compared using 1-way analysis of variance and Tukey test. Asterisk indicates P<.05 vs the respective corticosterone level before corticotropin administration.COMMENTA number of studies have demonstrated that circulating levels of corticosterone increase following trauma, hemorrhage, and other adverse circulatory conditions.Although it remains controversial whether administration of corticosteroids in trauma victims or patients with sepsis and septic shock is beneficial, recent studies by Bollaert et alindicated that administration of modest doses of hydrocortisone in the setting of pressor-dependent septic shock for 4 days resulted in a significant improvement in hemodynamics and a beneficial effect on survival. Despite the possibility that the beneficial effects of hydrocortisone may not be directly related to the improvement in adrenocortical insufficiency,it has been demonstrated that the incidence of adrenal insufficiency increases in critically ill patients at the surgical intensive care unit.Furthermore, adrenal insufficiency appears to occur during the progression of multiple organ failure in trauma victims. Although adrenal insufficiency occurs after various adverse circulatory conditions such as septic shock and severe trauma or major surgery,and although it has been clearly demonstrated that hepatocellular dysfunction and hepatic failure occur under such conditions,it remains unknown whether there is any correlation between adrenal insufficiency and hepatocellular dysfunction following trauma-hemorrhage and resuscitation. Our aim, therefore, was to determine whether the hepatocellular dysfunction observed following hemorrhagic shock plays any role in the development of adrenal insufficiency.Our results indicate that at the time of maximal bleed-out, plasma levels of corticosterone and corticotropin increased significantly. However, despite the fact that corticotropin levels decreased to levels similar to those of sham animals after resuscitation, plasma corticosterone levels remained significantly elevated up to 4 hours after resuscitation. The lack of the sustained high levels of corticotropin may be due to the negative feedback of the high levels of plasma corticosterone. Hepatic 11β-HSD is responsible for the degradation of circulating corticosterone in the rat. Thus, the reduced 11β-HSD activity may play a partial role in producing the sustained levels of plasma corticosterone after resuscitation. Since our results demonstrate that hepatic 11β-HSD activity was decreased significantly after hemorrhage and resuscitation, the reduction of hepatic 11β-HSD activity may be responsible for the increased levels of plasma corticosterone. The increased corticosterone levels, therefore, decreased the levels of corticotropin after resuscitation compared with the levels at the time of maximal bleed-out, through a negative feedback mechanism. Moreover, adrenal insufficiency occurred at 1.5 hours after fluid resuscitation in hemorrhaged animals, as evidenced by the decrease of corticotropin-induced corticosterone release by 78%. In addition, adrenal corticosterone content and cAMP levels (ie, the second messenger of the corticotropin action) decreased by 55% and 25%, respectively. These results, taken together, suggest that the sustained increase in plasma corticosterone levels following resuscitation may be due to the decreased hepatic 11β-HSD activity. The high level of corticosterone negatively regulates corticotropin release,further reducing adrenal responsiveness to corticotropin stimulation. Thus, the liver appears to play an important role in regulating adrenal function following trauma and severe hemorrhagic shock.Under normal conditions, corticotropin is secreted by the anterior pituitary gland following the stimulation of corticotropin-releasing hormone, a peptide secreted from the hypothalamus. Corticotropin then stimulates the secretion of glucocorticoid hormones, which by a negative feedback mechanism regulate release of corticotropin-releasing hormone and corticotropin.The short-term effect of corticotropin on the release of corticosterone from the adrenal cortex is due to the rapid mobilization of cholesterol by binding to the membrane receptors, activating adenylate cyclase, and elevating intracellular cAMP levels. As a result, cholesterol is liberated and penetrates into the P-450 system of the inner mitochondrial membrane, thus providing more substrate for steroidogenesis within minutes.In the long term (hours), corticotropin regulates the activity of the adrenal steroid hydroxylase system by elevating intracellular cAMP levels.However, the corticotropin-induced corticosterone release test, which we used, appears to assess the short-term effects of corticotropin on the adrenal cortex.Our results indicate that the basal level of adrenal cAMP decreased significantly after severe hemorrhage and fluid resuscitation. Although it remains unknown whether corticotropin-stimulated cAMP accumulation is also reduced under such conditions, our findings that corticotropin-stimulated release of corticosteroid and basal cAMP levels in adrenal tissue decreased significantly suggest that corticotropin-stimulated cAMP accumulation may have decreased. Further studies are needed to determine whether corticotropin-stimulated cAMP accumulation indeed decreases after trauma and hemorrhagic shock and, if so, whether this is due to down-regulation of corticotropin receptors, decrease of levels of adenylate cyclase and/or G proteins in the adrenal tissues, or reduction in adrenal adenosine triphosphate levels. It could be argued that the elevated levels of plasma corticosterone following severe hemorrhage may not reflect adrenal insufficiency, since a maximal corticosterone response may have been achieved without the stimulation of exogenous corticotropin. Although our study cannot rule out this possibility, other studies have clearly indicated that adrenal insufficiency occurs in combination with the elevated levels of circulating corticosterone.In our study, the adrenal insufficiency observed after severe hemorrhage is characterized by not only the reduced corticotropin-stimulated release of corticosterone, but also the decreased adrenal contents of its second messenger, cAMP, and reduced adrenal levels of corticosterone. In addition, the occurrence of adrenal insufficiency suggests that the adrenal glands may not meet the demands for further increasing corticosterone release when a second hit (eg, sepsis) develops following trauma and hemorrhagic shock. In contrast to severe hemorrhage, adrenal insufficiency did not occur following moderate hypotension, despite significantly increased plasma levels of corticosterone under those conditions. Since 11β-HSD is responsible for degradation of circulating corticosterone, and since its activity in the hepatic tissue is reduced following trauma-hemorrhage and resuscitation, it is most likely that the reduced hepatic 11β-HSD activity is, in part, responsible for producing the elevated levels of plasma corticosterone under such conditions. In this regard, we propose that the reduced hepatic 11β-HSD activity plays an important role in maintaining the sustained high level of plasma corticosterone. The increased levels of corticosterone thus negatively regulate corticotropin-releasing hormone release from the hypothalamus and corticotropin release from the anterior pituitary gland, thereby reducing the circulating levels of corticotropin. The combination of the decreased levels of plasma corticotropin, adrenal corticosterone, and cAMP contents reduces adrenal function (ie, adrenal corticotropin responsiveness) following trauma and hemorrhagic shock. Thus, the reduced hepatic 11β-HSD activity, as the result of hepatocellular dysfunction following trauma and hemorrhagic shock, appears to have an important impact on adrenal function. Also, β-glycyrrhetinic acid is a potent inhibitor of 11β-HSD activity.To further confirm the role of 11β-HSD in producing adrenal insufficiency following severe hemorrhage, β-glycyrrhetinic acid should be administered to healthy animals to determine whether the inhibition of 11β-HSD results in an elevated level of corticosterone and reduced corticotropin-induced corticosterone release.More than 75% of the circulating corticosterone is bound to CBG under normal conditions.Although it is unknown whether the ratio between bound and unbound corticosterone changes following adverse circulatory conditions in which plasma levels of corticosterone increase markedly, studies have indicated that plasma levels of CBG decrease significantly during sepsis and septic shock, but do not decrease in patients without sepsis.In line with that study, we did not find plasma levels of CBG to be reduced following trauma-hemorrhage and fluid resuscitation. In contrast, the plasma CBG level was approximately 50% higher than that in sham animals, although such an increase was not statistically significant. It is possible that the elevated plasma CBG levels represent a compensatory mechanism that attempts to reduce the unbound corticosterone levels in the circulation. Because the measured plasma levels of corticosterone represent both bound and unbound portions of corticosterone, it remains unknown whether the increased CBG levels alter the ratio of bound and free corticosterone following trauma and hemorrhagic shock.Our results suggest that the sustained increase in plasma corticosterone levels following resuscitation may be, in part, due to the decreased hepatic 11β-HSD activity. The high level of corticosterone negatively regulates corticotropin release, further reducing adrenal responsiveness to corticotropin stimulation. Thus, the liver appears to play an important role in regulating adrenal function following trauma and severe hemorrhagic shock.Statement of Clinical RelevanceDespite advances in the understanding of the mechanisms responsible for cell and organ dysfunction and failure following trauma and hemorrhagic shock, a large number of trauma victims subsequently die of sepsis, septic shock, and ensuing multiple organ failure. Although adrenal insufficiency may not occur with mild trauma and moderate hypotension, it does occur following severe trauma, hemorrhagic shock, and/or major surgery. Since hepatocellular function is depressed early after hemorrhage and persists after fluid resuscitation, it is important to determine whether the depressed hepatocellular function under such conditions plays any role in the development of adrenal insufficiency. In this regard, our results indicate that the sustained increase in plasma corticosterone levels following resuscitation may be partially due to the decreased hepatic 11β-HSD activity observed under such conditions. The high level of corticosterone negatively regulates corticotropin release, further reducing adrenal responsiveness to corticotropin stimulation. Thus, the liver appears to play an important role in regulating adrenal function following trauma and severe hemorrhage. In view of this, we propose that maintenance of hepatocellular function (thereby preventing the reduction in hepatic 11β-HSD activity) may reverse the negative feedback mechanism and thereby improve adrenal corticotropin responsiveness.AEBaueRDurhamEFaistSystemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), multiple organ failure (MOF): are we winning the battle?Shock.1998;10:79-89.EADeitchMultiple organ failure: pathophysiology and potential future therapy.Ann Surg.1992;216:117-134.HBHechtmanDSheproLung metabolism and systemic organ function.Circ Shock.1982;9:457-467.PWangJGHauptmanIHChaudryHepatocellular dysfunction occurs early after hemorrhage and persists despite fluid resuscitation.J Surg Res.1990;48:464-470.PWangGSinghMWRanaZFBaIHChaudryPreheparinization improves organ function after hemorrhage and resuscitation.Am J Physiol.1990;259:R645-R650.PWangZFBaMZhouSMTaitIHChaudryPentoxifylline restores cardiac output and tissue perfusion following trauma-hemorrhage and decreases susceptibility to sepsis.Surgery.1993;114:352-359.BAygenMInanMDoganayFKelestimurAdrenal functions in patients with sepsis.Exp Clin Endocrinol Diabetes.1997;105:182-186.DECarlsonAdrenocorticotropin correlates strongly with endotoxemia after intravenous but not after intraperitoneal inoculations of E coli.Shock. 1997;7:65-69.JBriegelGSchellingMHallerWMrazHForstKPeterA comparison of the adrenocortical response during septic shock and after complete recovery.Intensive Care Med.1996;22:894-899.PEBollaertCCharpentierBLevyMDebouverieGAudibertALarcanReversal of late septic shock with supraphysiologic doses of hydrocortisone.Crit Care Med.1998;26:645-650.MSClaussenJLandercasperTHCogbillAcute adrenal insufficiency presenting as shock after trauma and surgery: three cases and review of the literature.J Trauma.1992;32:94-100.JFMurphyGFPurdueJLHuntAcute adrenal insufficiency in the patient with burns.J Burn Care Rehabil.1993;14:155-157.EBarquistOKirtonAdrenal insufficiency in the surgical intensive care unit patient.J Trauma.1997;42:27-31.WHMerryRHCaplanGGWickusPostoperative acute adrenal failure caused by transient corticotropin deficiency.Surgery.1994;116:1095-1100.KHierholzerHBuhlerMetabolism of cortical steroid hormones and their general mode of action.In: Greger R, Windhorst U, eds. Comprehensive Human Physiology.Vol 1. New York, NY: Springer-Verlag NY Inc; 1996:403-429.FMujasoGNeriCTortorellaGMazzocchiGGNussdorferIntra-adrenal 11 β-hydroxysteroid dehydrogenase plays a role in the regulation of corticosteroid secretion: an in vitro study in the rat.Life Sci.1996;59:1401-1406.PWangZFBaM-CLuAAyalaJMHarkemaIHChaudryMeasurement of circulating blood volume in vivo after trauma-hemorrhage and hemodilution.Am J Physiol.1994;266:R368-R374.CDPutnamDWBrannVBMaheshAcute activation of the adrenocorticotropic-adrenal axis: effect on gonadotropin and prolactin secretion in the female rat.Endocrinology.1991;128:2558-2566.SCavallaroAKorneyevAGuidottiECostaDiazepam-binding inhibitor (DBI)–processing products, acting at the mitochondrial DBI receptor, mediate adrenocorticotropic hormone-induced steroidogenesis in rat adrenal gland.Proc Natl Acad Sci U S A.1992;89:10598-10602.PWangSMTaitZFBaIHChaudryATP-MgCl2administration normalizes macrophage cyclic AMP and β-adrenergic receptors after hemorrhage and resuscitation.Am J Physiol.1994;267:G52-G58.KYangETMBerduscoJRGChallisOpposite effects of glucocorticoid on hepatic 11 β-hydroxysteroid dehydrogenase mRNA and activity in fetal and adult sheep.J Endocrinol.1994;143:121-126.GLHammondPLALähteenmäkiA versatile method for the determination of serum cortisol binding globulin and sex hormone binding globulin binding capacities.Clin Chim Acta.1983;132:101-110.OHLowryNJRosebroughALFarrRJRandallProtein measurement with the Folin phenol reagents.J Biol Chem.1951;193:265-275.DECarlsonJKBabusNNguyuzaHMelhem-StancofskiBJEastridgeRole of endotoxin in the response to experimentally induced bacteremia in chronically prepared rats.Am J Physiol.1997;272:R1562-R1570.MWWichmannRZellwegerCMDeMasoAAyalaIHChaudryMelatonin administration attenuates depressed immune functions after trauma-hemorrhage.J Surg Res.1996;63:256-262.RLHaugerKVThrivikramanPMPlotskyAge-related alterations of hypothalmic-pituitary-adrenal axis function in male Fischer 344 rats.Endocrinology.1994;134:1528-1536.ACSharmaHBBosmannSJMotewKHHalesDBHalesJLFergusonSteroid hormone alterations following induction of chronic intraperitoneal sepsis in male rats.Shock.1996;6:150-154.JBWebsterKRBellPrimary adrenal insufficiency following traumatic brain injury: a case report and review of the literature.Arch Phys Med Rehabil.1997;78:314-318.DNDarlingtonCABarracloughDSGannHypotensive hemorrhage elevates corticotropin-releasing hormone messenger ribonucleic acid (mRNA) but not vasopressin mRNA in the rat hypothalamus.Endocrinology.1992;130:1281-1288.GKomakiPEGottschallASomogyvari-VighITatsunoTYatohgoAArimuraRapid increase in plasma IL-6 after hemorrhage, and posthemorrhage reduction of the IL-6 response to LPS, in conscious rats: interrelation with plasma corticosterone.Neuroimmunomodulation.1994;1:127-134.MPLillyDSGannThe hypothalamic-pituitary-adrenal-immune axis: a critical assessment.Arch Surg.1992;127:1463-1474.CRivierWValeDiminished responsiveness of the hypothalmic-pituitary-adrenal axis of the rat during exposure to prolonged stress: a pituitary-mediated mechanism.Endocrinology.1987;121:1320-1328.MPLillyEffect of surgery on the pituitary-adrenal response to repeated hemorrhage.Am J Physiol.1994;266:R1976-R1984.DPerrotABonnetonHDechaudJMotinMPugeatHypercortisolism in septic shock is not suppressible by dexamethasone infusion.Crit Care Med.1993;21:396-401.Herbert Hechtman, MD, Boston, Mass:The authors have revisited the question of adrenal insufficiency following trauma and hemorrhage. The data are intriguing but fall a little short of supporting a definitive conclusion. The main issue is the need to prove causality with regard to the approximately 30% decline of the hepatic dehydrogenase as a mechanism of the 3- to 4-fold rise in corticosterone. These percentage changes do not appear to be in synchrony. What would be the effect of partial or complete hepatectomy therapy, removing all or part of liver dehydrogenase activity, on adrenal function? Is the significance of corticosterone a negative regulator in the setting of trauma and hemorrhage? In sham animals, would an infusion of corticosterone, sufficient to raise circulating levels 3 to 4 times normal, not lead to a reduction of corticotropin below normal values? In contrast, corticotropin levels in your severe hemorrhage animals remain elevated to 2 times baseline.The fascinating question is why the elevated corticosterone levels following trauma and hemorrhage lead to adrenal unresponsiveness to corticotropin in only 112hours. Have you shown the same phenomena by a corticosterone infusion to mimic levels seen following trauma?Finally, you might reconsider the confusing description of these data as adrenal insufficiency, since there are high levels of adrenal hormone.Armour Forse, MD, Boston:This is indeed an interesting paper, but a few questions are important to make it clear what degree of shock you are dealing with in this model. The model you used, particularly the severe shock, has a mortality of 50% or 60%. Could you provide us with some information about the cardiovascular parameters in this animal model? I am particularly concerned that the models not only reflect shock but also severe anemia, as the animals were resuscitated with RL. Could you give us some indication of what the hematocrit was in these animals?Are you hypothesizing that one cause for the results was changes in hepatic function? Could you give us more information about the liver? Did you measure liver function parameters? Do you have any liver histology? Finally, did you perform any histology on the adrenal gland? This would be important in interpreting your results.Dr Wang:In his opening remarks, Dr Hechtman questioned whether there is a cause-and-effect relationship between the decreased hepatic 11β-HSD activity and adrenal insufficiency following trauma and hemorrhagic shock. I would like to point out that the primary aim of this study was not to examine the cause-and-effect relationship, but to determine whether hepatic 11β-HSD activity is reduced following hemorrhagic shock, and, if so, whether the decreased hepatic 11β-HSD is associated with adrenal insufficiency. Our data have clearly indicated that hepatic 11β-HSD activity decreases significantly following trauma-hemorrhage and fluid resuscitation, which is associated with adrenal insufficiency. Additional studies are, however, needed to determine whether inhibition of hepatic 11β-HSD by its inhibitors, such as β-glycyrrhetinic acid, in normal animals, produces adrenal insufficiency.Dr Hechtman suggested that we should examine the effects of partial or complete hepatectomy (ie, partial or complete removal of hepatic 11β-HSD) on adrenal function. Although studies utilizing models of partial or complete hepatectomy may provide some mechanistic insights into the role of hepatic 11β-HSD in producing adrenal insufficiency, the inhibition of 11β-HSD activity by β-glycyrrhetinic acid may be a better approach, since hepatectomy in itself will significantly affect systemic metabolisms and host defense mechanisms.Another question of Dr Hechtman's was whether or not administration of corticosterone in normal animals reduces plasma corticotropin below normal values. Although it has been well documented that the synthesis and release of corticotropin are negatively regulated by circulating levels of corticosterone, it remains unknown whether plasma corticotropin decreases below the basal level when plasma corticosterone increases 3 to 4 times higher than the basal level. The fact that plasma corticotropin decreased significantly after fluid resuscitation as compared to the levels at the time of maximal bleed-out would suggest that the sustained high levels of plasma corticosterone negatively regulate corticotropin synthesis/release following hemorrhage and resuscitation.Dr Hechtman also raised the issue that adrenal unresponsiveness to corticotropin stimulation occurs as early as 1.5 hours after the completion of hemorrhage and resuscitation. Since hemorrhage time was approximately 90 minutes, and the time required for fluid resuscitation was 60 minutes, 1.5 hours after resuscitation represents approximately 4 hours from the onset of hemorrhage. With regard to the reduced adrenal responsiveness to corticotropin after hemorrhage, we propose this is probably due to a combination of the decrease in corticotropin receptor number and/or affinity, uncoupling between corticotropin receptor and adenylate cyclase, decrease in intracellular levels of cAMP, and reduction in the adrenal corticosterone levels. However, it remains to be determined whether administration of corticosterone in normal animals can mimic the reduced adrenal responsiveness to corticotropin which is observed following trauma and hemorrhage.With regard to Dr Hechtman's last question, adrenal insufficiency is defined as a condition in which corticotropin-induced release of corticosterone is significantly reduced. In this study, although plasma levels of corticosterone remained significantly elevated, corticotropin-induced corticosterone release decreased by 78% at 1.5 hours after the completion of hemorrhage and resuscitation. Thus, the occurrence of adrenal insufficiency suggests that the adrenal glands will not meet the demands for further increasing corticosterone release when a second hit (eg, sepsis) develops following trauma and hemorrhagic shock.Dr Forse's question dealt with cardiovascular and hepatic responses following trauma-hemorrhage and resuscitation. We have indeed performed various studies to determine alterations in cardiovascular and hepatocellular functions in the hemorrhage model used in this study. Our results indicate that cardiac performance, cardiac output, and organ blood flow decrease significantly after hemorrhage, despite crystalloid resuscitation. In addition, hepatocellular function, as determined by indocyanine green clearance, decreases during hemorrhage and persists following resuscitation. Our preliminary results also indicate that oxygen delivery decreases significantly following hemorrhage and resuscitation. The systemic hematocrit decreases by more than 50% following fluid resuscitation in the hemorrhaged animals. Thus, tissue hypoxia may occur in this model of hemorrhage. Although liver histology shows focal necrosis and neutrophil infiltration, we have not examined adrenal histology after trauma-hemorrhage and resuscitation.This investigation was supported by grant RO1 GM 39519 (Dr Chaudry) and Independent Scientist Award KO2 AI 01461 (Dr Wang), National Institutes of Health, Bethesda, Md.Presented at the 79th Annual Meeting of the New England Surgical Society, Toronto, Ontario, September 27, 1998.Reprints: Ping Wang, MD, Center for Surgical Research, Rhode Island Hospital, Middle House II, 593 Eddy St, Providence, RI 02903 (e-mail: [email protected]).

Scholl, Frank G.; Coady, Michael A.; Davies, Ryan; Rizzo, John A.; Hammond, Graeme L.; Kopf, Gary S.; Elefteriades, John A.

doi: 10.1001/archsurg.134.4.402pmid: 10199313

HypothesisSelected patients with acute type A (ascending) aortic dissection who are treated with delayed operation or nonoperative therapy may have better early and short-term outcomes than was previously expected.Design and SettingRetrospective cohort at a university hospital.SubjectsData on 75 patients with acute or chronic type A aortic dissection treated at one institution from January 1, 1985, to November 30, 1997, were analyzed. Of these 75 patients, 34 (21 male and 13 female, with a mean age of 65.5 years) did not undergo initial operative treatment, and 15 (10 male and 5 female, with a mean age of 72.6 years) never underwent surgery. For the 19 patients who underwent delayed surgery, the mean period between aortic dissection and intervention was 11.4±4.83 days. The follow-up period ranged from 0.27 to 149 months, with a mean of 20.2 months.Main Outcome MeasuresVascular complications, hospital mortality, and early survival.ResultsReasons for interval delay in surgical treatment included initial misdiagnosis or delay in diagnosis (13 [68%] of 19), need to address significant comorbidity (4 [21%] of 19), and initial refusal of operative intervention (2 [11%] of 19). For the 15 patients treated entirely by medical therapy, reasons for electing nonoperative management included extensive comorbidity (5 [33%] of 15), refusal of surgical intervention (6 [40%] of 15), and misdiagnosis or long delay in diagnosis (4 [27%] of 15). Of the 34 patients, 15 (44%) presented with moderate or severe aortic insufficiency, 5 (14%) had evidence of pericardial effusion, 6 (21%) had evidence of concomitant coronary ischemia on electrocardiogram, and 8 (24%) had extension of the dissection into the descending aorta. Four patients (11.8%) died while in the hospital. Of the 34 patients, 30 (88%) who underwent either delayed or no surgery received aggressive medical treatment (β-adrenergic blocking agents and afterload-reducing agents) and were discharged from the hospital. All patients who were operative candidates in the interval treatment group survived to reach definitive operation. There was no statistically significant difference in short-term survival between the group of patients undergoing delayed surgery or medical treatment only and the group of 41 patients undergoing early operation (P=.42).ConclusionsImmediate surgical therapy is still recommended for acceptable operative candidates with acute type A aortic dissection who seek immediate treatment. However, this study permits the following 2 conclusions: (1) patients with type A aortic dissection who are referred or whose conditions are diagnosed several days after presentation have survived the early dangerous period and can safely undergo surgery semielectively (rather than emergently); and (2) selected patients who are not considered operative candidates and who survive the initial type A aortic dissection without complication may be treated with aggressive medical therapy and achieve acceptable early and short-term outcomes, which is better than previously expected.EARLY EXPERIENCEindicated an extremely high immediate mortality from acute ascending (type A) aortic dissection. Accordingly, acute type A aortic dissection is generally considered a surgical emergency. The results of surgical treatment have shown significant improvement during recent years,and, now, patients with acute type A aortic dissection usually undergo urgent surgical repair.Because of the urgent surgical treatment, the natural history of acute type A aortic dissection treated with nonsurgical therapy in the current era is not well known. Current medical management with aggressive anti-impulse therapy and blood pressure control may influence significantly the early morbidity and mortality of type A aortic dissection treated with nonoperative therapy. The patient who survives an initial episode of aortic dissection may be at lower risk of death than previously thought if aggressive medical treatment is begun.We examined the outcome of patients at our institution with acute type A aortic dissection who, because of a variety of reasons, did not undergo standard early operative treatment and had delayed surgical intervention or nonoperative treatment of the aortic dissection. The purpose of this study is to determine the clinical outcome of this group of patients and to form clinical correlates regarding appropriate management.PATIENTS AND METHODSA computerized database is maintained as part of ongoing studies at the Yale Center for Thoracic Aortic Disease, New Haven, Conn.This database currently includes 1962 imaging studies in 598 patients with diseases of the thoracic aorta. From this database, 75 patients with acute and chronic type A aortic dissection treated from January 1, 1985, to November 30, 1997, were identified. Forty-one patients were treated by immediate surgical intervention. Of these patients, 34 (21 male and 13 female) were treated with early medical therapy without initial operative treatment. Of these patients, 15 (10 male and 5 female) never underwent surgical intervention, while 19 patients (11 male and 8 female) underwent interval operation more than 48 hours after the aortic dissection. The time and date of onset of the acute aortic dissection were assumed to be coincident with the onset of pain.The medical regimen for anti-impulse therapy included intravenous β-adrenergic blocking agents (or calcium antagonists when β-adrenergic blocking agents were contraindicated) as well as afterload-reducing agents. The regimen was administered until the patient had a target heart rate less than 60 beats/min and systolic blood pressure less than 100 mm Hg, unless oliguria or evidence of organ ischemia occurred. Oral medications were used after 48 hours of treatment.Follow-up was obtained via telephone conversations with patients, physicians, or family members and through office and hospital chart review and was available in 99% (74 of 75) of patients. The overall mean follow-up was 20.2 months, with a range of 0.27 to 149 months.RESULTSPatients treated nonoperatively were older as a group than those treated with either delayed operative treatment or with initial surgery. Demographic data are shown in Table 1. The reasons for electing either nonoperative treatment or delayed surgical treatment are listed in Table 2. Major reasons for nonoperative treatment included delay in diagnosis, usually at an outside institution, patient's or family's refusal of surgery, and significant comorbidity. The 34 patients treated without initial operation sought treatment a mean of 4.2 days (range, 2-20) after the initial aortic dissection. In the patients who underwent interval operation, the mean time from aortic dissection to surgical intervention was 11.4±4.83 days.Table 1. Patient Demographics&ast;CharacteristicInitial Surgical TreatmentInitial Nonoperative TreatmentInterval Operative TreatmentMedical Treatment OnlyPatients (M/F)41 (28/13)19 (11/8)15 (10/5)Age, mean ± SD, y59.49 ± 15.8458.33 ± 22.4072.64 ± 15.49†Interval from aortic dissection until surgical intervention, mean ± SD<24 h11.4 ± 4.8 d. . .&ast;Ellipses indicate not applicable.†Significant difference in age (P= .01).Table 2. Reasons for Nonoperative or Delayed Operative Management&ast;ReasonNo. (%) of PatientsInterval Operative Treatment (n = 19)Medical Treatment (n = 15)Extensive comorbidity4 (21)5 (33)ARF/encephalopathy. . .1 (7)Severe COPD2 (11)3 (20)CHF2 (11)1 (7)Refusal of operation2 (11)6 (40)Initial misdiagnosis or delay in diagnosis13 (68)4 (27)&ast;ARF indicates acute renal failure; COPD, chronic obstructive pulmonary disease; CHF, congestive heart failure, which was historical and not a consequence of aortic dissection; and ellipses, not applicable.Of the 34 patients, 15 (44%) had moderate or severe aortic insufficiency, 5 (14%) had evidence of pericardial effusion, 6 (21%) had evidence of concomitant coronary ischemia on an electrocardiogram, and 8 (24%) had extension of the dissection into the descending aorta.An outcome flow diagram for the study is presented in Figure 1. The hospital mortality rate for the patients treated with delayed surgical intervention was 5.2% (1/19). The cause of death was disseminated intravascular coagulation and massive hemorrhage at the time of operation. All patients who were operative candidates in the interval treatment group survived to reach definitive operation. For patients undergoing medical therapy exclusively, the hospital mortality rate was 20% (3 /15). The causes of death were extension of the aortic dissection with cardiac tamponade in 2 patients and acute renal failure and ongoing cardiac ischemia in 1 patient. For the patients undergoing immediate surgical treatment, the hospital mortality rate was 19.5% (8/41). These mortality rates are not statistically different (P=.84; χ2=0.33). The short-term survival rate (Figure 2) after hospital discharge as determined by the log-rank test did not show a significant difference between the 41 patients treated with initial operative intervention and the 34 patients treated with either interval operation or medical treatment alone. The 1- and 2-year actuarial survival rates for the patients treated with initial operation are 82%. Actuarial survival is 74% at 1 and 2 years for those treated without initial operation (P=.42). Only 1 medically treated patient died following discharge from the hospital during the follow-up period; the cause of death was a suspected extension of the aortic dissection.Figure 1.Outcome of all patients treated for acute type A aortic dissection. COPD indicates chronic obstructive pulmonary disease; ARF, acute renal failure.Figure 2.Kaplan-Meier actuarial survival curve from date of initial presentation and treatment. Comparision made using log-rank test (P=.44).COMMENTMost patients with type A aortic dissection are brought to the operating room for urgent surgical correction. This course of treatment is the standard policy at our institution. We continue to recommend such immediate surgical intervention for suitable operative candidates presenting early following type A aortic dissection. This report focuses on those patients presenting later in the course of acute type A aortic dissection and those patients who, for other reasons, are not suitable operative candidates.The well-known complications of acute type A aortic dissection, for example, intrapericardial rupture, acute aortic valve insufficiency, coronary ischemia, and branch vessel occlusion, are often lethal without prompt surgical intervention. This report is not intended to refute in any way the conventional wisdom that acute type A aortic dissection represents a surgical emergency.This retrospective review is intended to provide a snapshot of 2 distinct groups of patients: those who seek medical attention or whose conditions are diagnosed several days after the onset of acute type A aortic dissection and those who are not appropriate for surgical correction secondary to advanced age, debility, or comorbidity. Scant information is available in the literature regarding these specific subgroups of patients with type A aortic dissection.The subgroup profile of patients in this report should not be interpreted to reflect general patterns of this disease, because there is likely a selection bias inherent in the referral pattern of a tertiary referral center serving a broad geographic area. Specifically, the patients presented in this report are those who have survived long enough to have their conditions diagnosed and be referred and transported. Thus, the relative size of the group of patients who did not undergo initial operation may be exaggerated by this selection bias.The decision about the timing of surgery when a patient with acute type A aortic dissection is referred 2 days into the disease course is difficult. Usually, the decision revolves around whether the patient should be taken to the operating room at night or undergo operation semielectively the next day when a full complement of staff can assist in the challenging procedure. This report suggests that after 48 hours the aortic dissection may have passed the most critical phase and can be aggressively managed with anti-impulse therapy and operated on semielectively. The absence of mortality prior to operation in the subgroup of patients undergoing interval operation supports this reasoning. The low operative mortality in this subgroup (5.2%) likely represents both self-selection of a more stable group of patients and the benefits of a semielective optimal operative environment.Because most patients with acute type A aortic dissection undergo urgent surgical management, few current data are available regarding the group of patients treated solely with medical therapy. The group of medically treated patients in this report is different from patients with chronic type A aortic dissection who present months or years after the acute event. These patients' conditions were all diagnosed during the acute phase of the aortic dissection shortly after the initial event. The data in this series show that the outlook for these patients, at least in the short term, may be better than previously expected both during hospitalization and after discharge from the hospital. This conclusion is consistent with data from Masuda and colleagues,who reported that survival of medically treated patients with acute type A aortic dissection who survived the first week did not differ from the survival of patients with medically treated type B (descending) aortic dissection. Again, these patients may have passed the critical phase of the aortic dissection and proved their ability to survive the initial dangerous period. Since the acutely lethal consequences of type A aortic dissection, such as rupture with tamponade, acute aortic insufficiency, and coronary ischemia, are usually early events, it is not unreasonable to conclude that the natural history after the first week may resemble that of type B aortic dissection.This is a retrospective review of a highly selected group of patients and is subject to the errors inherent in such a design. The groupings were made based on retrospective chart review and not in advance or during the course of treatment. Additionally, although the number of patients in this report may be adequate considering the highly selected subgroups of interval and permanent medical management, these results and suggestions must be viewed as preliminary. It is the intent of this article to add some insight into the relative void of information on this complex topic.CONCLUSIONSAcute type A aortic dissection is an indication for urgent operation and we advocate prompt surgical treatment for patients with acute type A aortic dissection. However, the results of the current study suggest the following: (1) patients with type A aortic dissection who present for treatment several days after initial aortic dissection have survived the initial dangerous period and can safely undergo surgery semielectively rather than emergently; and (2) those patients who are not operative candidates due to age, overwhelming comorbidity, or refusal may be treated with anti-impulse therapy and achieve reasonable early and short-term outcomes, which is better than previously expected.TShennanDissecting Aneurysms.London, England: Medical Research Council; 1934. Special Report Series No. 193.AJHirstVJJohns JrSWKime JrDissecting aneurysms of the aorta: a review of 505 cases.Medicine (Baltimore).1958;37:217-279.LGSvenssonESCrawfordKRHessDissection of the aorta and dissecting aortic aneurysms: improving early and long-term surgical results.Circulation.1990;82(suppl 5):IV24-IV38.DCMillerRSMitchellPEOyerEBStinsonSWJamiesonNEShumwayIndependent determinants of operative mortality for patients with aortic dissections.Circulation.1984;70(3, pt 2):I153-I164.NTKouchoukosTHWareingSFMurphyJBPerrilloSixteen-year experience with aortic root replacement: results of 172 operations.Ann Surg.1991;214:308-318.MCoadyJRizzoGHammondWhat is the appropriate size criterion for resection of thoracic aortic aneurysm?J Thorac Cardivasc Surg.1997;113:476-491.MErginRGrieppDissections of the aorta.In: Baue AE, Geha AS, Hammond GL, Laks H, Nawnheim KS, eds. Glenn's Thoracic and Cardiovascular Surgery.East Norwalk, Conn: Appleton & Lange; 1996.CStoneHBorstDissecting aortic aneurysm.In: Edmunds LJ, ed. Cardiac Surgery.New York, NY: McGraw-Hill Book Co; 1997.YMasudaZYamadaNMorookaSWatanabeYInagakiPrognosis of patients with medically treated aortic dissections.Circulation.1991;84(suppl 5):III7-III13.Alan Hilgenberg, MD, Boston, Mass:Patients with aortic dissections are divided into acute and chronic types, depending upon the timing of their presentation. Patients with acute aortic dissection are traditionally defined as those presenting within 2 weeks of the onset of symptoms; the logic of this definition is derived from the fact that most of the mortality associated with acute aortic dissection involving the ascending aorta occurs within the first 2 weeks. In untreated patients, the mortality rate is about 70%, with death most commonly due to intrapericardial aortic rupture. The typical patient experiences acute pain, presents to an emergency room, the diagnosis is confirmed by transesophageal echocardiography, and an emergency operation is usually done to replace the ascending aorta, generally without preoperative angiography. The authors of this paper are to be commended for focusing attention on a group of patients who still fit into the definition of acute aortic dissection but who have survived the initial few days of their disease without benefit of diagnosis or treatment. Thus, there has been some biologic selection so that they probably are not representative of the entire population of patients with acute aortic dissection. In this study, the hospital mortality and 2-year survival rates were not statistically different for 3 groups of patients: those treated with emergency surgery, delayed surgery, or medical treatment. The 3 deaths in the medically treated patients were due to predictable causes: aortic rupture, extension of dissection, and renal failure.Our experience at the Massachusetts General Hospital is somewhat different, with hospital mortality lower for surgically treated patients then for a small group of medically treated patients. During a recent 3-year period, 1995 to 1997, we treated 45 patients with acute type A dissections. Forty of them had emergency surgery, usually within 1 hour of diagnosis, and there were 3 deaths, a 7.5% mortality rate. Five had medical treatment with 2 hospital deaths, a 40% mortality rate.I have a few questions. What is the advantage to the patient or to the surgeon in delaying operation more than just a few hours or perhaps 1 day after diagnosis in those patients who are to undergo delayed surgery?Were the operative procedures in the delayed patients different from those in the immediate surgery group? For example, was one group more likely to need aortic valve replacement or composite aortic root replacement, as opposed to just simply an ascending aortic graft? Was bleeding less in the delayed patients, perhaps because the aortic tissue was more substantial? And finally, based on this retrospective study, do you plan to make any changes in your future management strategy of these patients who present several days after the onset of symptoms?Once again I commend the authors for bringing this rather unusual and very interesting and important material to our attention.Arun Singh, MD, Providence, RI:All acute dissection does not need to be operated on, if the patients present in stable condition. Our experience is similar; we had 32 patients with acute dissection, operated on in the last 3 years with a mortality of 8%. Five patients had delayed presentation. Three of them were followed up for 2 years and are still alive and doing well. Two of the patients subsequently operated on have survived and done well.This series goes back to 1985 to 1995, so what was the long-term follow-up of the medically treated patients, because your data show survival up to only 2 years?Dr Scholl:I'd like to thank Dr Hilgenberg and Dr Singh for their excellent comments.With regards to your initial question, Dr Hilgenberg, the advantages to the patients in delaying the operation, we find that once some of these patients are admitted to the hospital, the dissection occurred some time ago and they have been hemodynamically stable without evidence of end-organ ischemia. If we then treat them with aggressive medical therapy, the operation can be safely delayed until such time as they can be operated on in a semielective fashion, with a fresh operative team and all available resources on hand to assist in their care. Also, this allows time for more accurate and sometimes multiple diagnostic studies of these complex patients.However, the fact is, as you mentioned in your comments, that these patients have biologically self-selected themselves by the simple fact that they are hemodynamically stable and have withstood the initial dissection without significant end-organ injury. We also have no way of knowing how many of these patients died before arriving at the hospitalRegarding your question as to the types of operations required, the acutely operated-on patients tended to require more valve replacements due to the fact that some of them were brought to the operating room with significant aortic insufficiency or very proximal dissection with tamponade.As far as the future management of patients with ascending aortic dissections, we continue to advocate prompt surgical treatment for all patients who present with acute type A dissection. We feel that the patients with acute type A dissections who present at a later time and who are hemodynamically stable without signs of end-organ damage can be safely managed with aggressive anti-impulse therapy and semielective operation as the operating room schedule permits. We will continue to follow this group of patients, as well as the group treated with medical therapy alone, and critically evaluate their long-term outcomes.In response to Dr Singh's comments, the majority of the medically treated patients were treated more recently, thus follow-up on this group is relatively short; in addition we have a few patients lost to follow-up. Thus, we don't yet have a good idea of the long-term prognosis of these medically treated patients as the number of patients who are out at the longer follow-up intervals is quite small. We will be looking at these patients closely over the next few years to see if they succumb to complications of their dissection.Presented at the 79th Annual Meeting of the New England Surgical Society, Toronto, Ontario, September 27, 1998.Reprints: John A. Elefteriades, MD, Section of Cardiothoracic Surgery, Yale University School of Medicine, 333 Cedar St, New Haven, CT 06510.

Gedaly, Roberto; Pomposelli, James J.; Pomfret, Elizabeth A.; Lewis, W. David; Jenkins, Roger L.

doi: 10.1001/archsurg.134.4.407pmid: 10199314

HypothesisPatient outcome and the development of major intra-abdominal postoperative complications following removal of cavernous hemangiomas of the liver are affected by methods of resection.DesignCase-control study.SettingHepatobiliary surgery and liver transplantation unit in a tertiary care referral medical center.PatientsBetween December 1, 1987, and December 1, 1997, 28 patients underwent the surgical removal of cavernous hemangioma either by hepatic resection or enucleation. Indications for the operation were pain, enlarging tumors, uncertain diagnosis, or rupture.Main Outcome MeasuresThe technique of tumor removal, hospital course, and the development of intra-abdominal complications. Independent factors influencing the development of complications were ascertained by multivariate analysis.ResultsTwenty-four female and 4 male patients (age, 47.5±12.4 [mean±SD] years) underwent either enucleation (n=23) or liver resection (n=5). Lesions ranged from 2 to 16 cm in their postresection diameter. No surgical (30-day) mortality was observed. Four major intra-abdominal complications were found: 1 episode of intraoperative bleeding requiring abdominal packing and 3 intra-abdominal fluid collections requiring percutaneous drainage. Enucleation was the only independent factor found by univariate and multivariate analyses to be associated with a reduction in the number of intra-abdominal complications (P=.04).ConclusionsCavernous hemangiomas of the liver can be removed safely by either hepatic resection or enucleation. Enucleation is associated with fewer intra-abdominal complications and should be the technique of choice when tumor location and technical factors favor enucleation.CAVERNOUS hemangiomas represent the most common benign tumor of the liver.These lesions consist of large vascular spaces lined by a monolayer of endothelial cells. Because most of these tumors are asymptomatic, the diagnosis is most commonly made by ultrasonography, computed tomographic (CT) scan, or during laparotomy for other intra-abdominal disease.Occasionally, patients present with abdominal pain, early satiety, or a sensation of an abdominal mass. Rarely, a patient may present with consumptive coagulopathy (Kasabach-Merritt syndrome) resulting from sequestration and the destruction of platelets related to giant hemangiomas.For most patients, the natural history of cavernous hemangiomas in the liver remains uneventful, and surgical intervention can be avoided. The observation of asymptomatic lesions with routine follow-up with CT scan or ultrasonography is often sufficient.Indications for the surgical removal of hemangioma may include the development of pain, especially in patients with rupture, rapidly enlarging lesions, profound thrombocytopenia, or an uncertain diagnosis of a liver mass.In this study, we evaluated the outcome of patients who underwent the surgical removal of cavernous hemangioma and assessed factors affecting major complications postoperatively.PATIENTS AND METHODSPATIENTSBetween December 1, 1987, and December 1, 1997, 28 patients (24 women and 4 men) underwent surgical removal of a hepatic cavernous hemangioma in the Hepatobiliary Surgery and Liver Transplantation Unit at the Beth Israel Deaconess Medical Center, Boston, Mass. Patients underwent surgical removal by either anatomic resection (n=5) or enucleation (n=23). Patient medical records were reviewed for demographics, characteristics of the tumor (location and size), indication for the operation, the technique of removal (resection or enucleation), operative variables (operation time, amount of blood loss, transfusion requirement, and inflow occlusion time), hospital length of stay, and postoperative complications. Indications for the operation included pain, rapidly enlarging mass, uncertain diagnosis, and hemorrhage. No patient in the current series presented with coagulopathy associated with Kasabach-Merritt syndrome.Methods for diagnosis included ultrasonography, CT scan, magnetic resonance imaging (MRI) scan, or combinations of more than 1 technique. Scanning using erythrocytes labeled with technetium Tc 99m was done in 4 patients to assist with the preoperative pathological diagnosis. Our current diagnostic preference is ultrasonography and dynamic CT scanning, followed by MRI, if necessary.For patients who underwent anatomic resection, the following definitions are used for consistency: right hepatic lobectomyincludes the resection of Couinaud segments5, 6, 7, and 8, whereas left hepatic lobectomyrefers to the resection of segments 2, 3, and 4. Extended left hepatic lobectomyrefers to the resection of segments 2, 3, and 4 and portions of segments 5 and 8, whereas extended right hepatic lobectomyrefers to the resection of segments 5, 6, 7, and 8 and portions of segment 4. Left lateral segmentectomyis limited to the resection of segments 2 and 3.Enucleationrefers to the creation of a plane between the normal liver parenchyma and the hemangioma without the removal of any normal hepatic parenchyma. Major intra-abdominal complicationswere defined as intra-abdominal infection, hemorrhage requiring reoperation and packing, and major bile leakage.OPERATIVE TECHNIQUEEnucleationA right subcostal incision is used, with extension to the left side as needed. After the abdominal cavity is explored, the liver is fully mobilized by dividing the suspensory ligaments. Intraoperative ultrasonography is frequently used to assist with the identification of the lesion and its relations to intraparenchymal venous structures. Following the initial assessment of the location of the lesion, a 2.5-cm Penrose drain is placed around the hepatoduodenal ligament to provide inflow occlusion as indicated (Pringle maneuver). The capsule of the liver is coagulated with cautery to demarcate the extent of the resection and to initiate the development of a plane between the tumor and the hepatic parenchyma. The tumor is progressively separated from the parenchyma with a finger or a blunt instrument. Small bridging vessels are divided with the cautery, and the relatively few larger vessels are controlled with silk ligatures. After the hemangioma is removed, the residual cavity is manually compressed for several minutes to facilitate hemostasis. Residual bleeding points are controlled with suture ligatures, electrocautery, or argon-beam coagulation. For large defects, omentum can be placed in the bed of the cavity. A closed suction drain is placed to monitor for bile leaks and bleeding.Hepatic ResectionAnatomic resection is performed using standard resection techniques. We prefer complete mobilization of the liver and the routine use of intraoperative ultrasonography to identify portal and hepatic venous structures. This is especially useful during right hepatic lobe resections, when large inferior right hepatic veins can be easily identified.Once the extent of resection is decided, dissection of the porta hepatis is carried out. Generally, the portal vein and hepatic artery on the affected side are divided before bile duct division. This minimizes the risk of injury to the bile duct on the contralateral side. After the inflow vessels are divided, we generally prefer to control the hepatic veins at their level of entry into the inferior vena cava before hepatic parenchyma division. This reduces blood loss considerably and may obviate the need for total inflow occlusion (Pringle maneuver).After the hepatic parenchyma is removed, manual compression of the cut surface is used to facilitate hemostasis. Residual bleeding sites are controlled with simple sutures, electrocautery, or argon-beam coagulation. We do not use large transhepatic compression sutures to avoid ischemic injury to the remaining segments.STATISTICAL ANALYSISResults are expressed as mean±SD. Continuous variables were compared by the Student ttest. Univariate analysis was performed using the Fisher exact test for dichotomized variables. Multivariate analysis using logistic regression was performed to identify independent factors affecting abdominal complications. Differences were considered significant at P<.05 in all cases.RESULTSIn 17 patients (61%), the tumor was located in the right lobe and, in 9 patients (32%), in the left lobe. Bilobar location was found in 2 patients (7%). Indications for surgical resection were pain alone in 16 patients (57%), pain and tumor growth in 3 patients (11%), uncertain diagnosis in 7 patients (25%), and rupture in 2 patients (7%).The surgical removal of the tumors was by enucleation in 23 patients and anatomic liver resection in 5 patients. In the group undergoing anatomic resection, 2 patients had right hepatic lobectomies, 1 patient had extended right hepatic lobectomy, 1 patient had extended left hepatic lobectomy, and 1 patient had left lateral segmentectomy. The lesions ranged from 2 to 16 cm as measured after resection. Given the propensity for these vascular lesions to empty of blood during resection, the diameter of the lesions before resection was always much greater, with the largest lesion having a radiologically measured diameter of 45 cm.Vascular inflow occlusion (Pringle maneuver) was used in 11 (48%) of 23 patients in the group having enucleation, for a mean of 14.7 minutes (range, 0-50 minutes), and in 3 (60%) of 5 patients in the group having resection, for a mean of 19.2 minutes (range, 0-45 minutes). Transfusion requirement, operative time, and length of hospital stay are summarized in the following tabulation. Packed red blood cells (PRBC) were administered to 10 patients, and 3 patients received only autologous blood.CourseMean ± SD (Range)PRBC transfused, U1.29 ± 2.88 (0-14)Autologous blood, U1.46 ± 3.47 (0-17)Operative time, h3.58 ± 1.31 (1.6-6.8)Hospital stay, d8.39 ± 3.65 (5-21)As shown in Table 1, demographics, characteristics of the tumor, and indications for surgical resection were similar in the group of patients undergoing enucleation compared with those undergoing anatomic resection. Perioperative variables like amount of blood loss, transfusions, operative time, time of vascular inflow occlusion, and hospital stay between these 2 groups demonstrated that blood loss was significantly greater in the group undergoing anatomic resection than in the group undergoing enucleation (P=.04). Table 2demonstrates the tendency of a longer operative time, greater blood product usage, and prolonged vascular inflow occlusion and hospital stays in the group of patients treated with anatomic resection, without showing statistical significance.Table 1. Tumor Characteristics and Indications for Surgery Between the Group Undergoing Enucleation (n = 23) and the Group Undergoing Anatomic Resection (n = 5)&ast;VariableEnucleationResectionAge, mean ± SD, y47.6 ± 13.4†47.2 ± 7.2†Tumor size, mean ± SD, cm6.0 ± 3.7†8.6 ± 5.4†LocationRight lobe14 (61)3 (60)Left lobe8 (35)1 (20)Bilateral extension1 (4)1 (20)IndicationsPain13 (56)3 (60)Uncertain diagnosis6 (26)1 (20)Rapid growth3 (13)0Rupture1 (4)1 (20)&ast;Data are given as number (percentage) of patients except as noted.†Values are not statistically different by Student ttest.Table 2. Operative and Hospital Course in the Group Undergoing Enucleation (n = 23) and the Group Undergoing Anatomic Resection (n = 5)&ast;CourseEnucleationResectionBlood loss, mL922.7 ± 1032.5†2080.0 ± 1138.9†Blood transfusion, U1.2 ± 3.62.6 ± 2.8Operative time, h3.4 ± 1.24.3 ± 1.5Time of vascular control, min14.1 ± 17.819.2 ± 19.5Hospital stay, d8.2 ± 3.99.4 ± 2.2&ast;Data are given as mean ± SD.†Blood loss statistically significant by Student ttest, P= .04.Four major intra-abdominal complications were encountered. These included 1 case of persistent intraoperative bleeding that required packing and reoperation 24 hours later for pack removal; 2 patients in whom infected intra-abdominal fluid collections developed that were treated by percutaneous drainage under CT guidance, and 1 patient with a biloma in whom a bronchobiliary fistula eventually developed, requiring reoperation. There was no operative (30-day) mortality. Other significant complications included 1 nonfatal case of pulmonary embolus, 3 cases of atelectasis, 1 of urinary tract infection, 1 of postoperative ileus, 1 of antibiotic reaction resulting in anaphylaxis, and 1 of wound infection.UNIVARIATE AND MULTIVARIATE ANALYSISUnivariate analysis revealed that enucleation of hemangiomas was associated with significantly fewer intra-abdominal complications compared with anatomic resection (Table 3). Enucleation was the only independent risk factor found by multivariate analysis to be associated with fewer intra-abdominal complications (P=.04). Although there was a strong trend for blood loss of greater than 1500 mL to be associated with a higher complication rate, this did not reach statistical significance (P=.06).Table 3. Univariate Analysis of Variables Predicting Major Complications After Surgical Removal of Hepatic HemangiomasParameter&ast;POperative time, h≥3.6.12<3.6Blood loss, mL≥1565.06<1565Resection vs enucleation.01†Vascular control time, min‡>15.30≤15TransfusionsYes.32NoVascular control usedYes.20No&ast;The mean value was used as the threshold value for operative time, blood loss, and time of vascular control.†Type of surgical resection significant by Fisher exact test, P<.05.‡Vascular control time refers to minutes with inflow occlusion (Pringle maneuver).COMMENTHepatic hemangiomas are common tumors and have an incidence of 0.4% to 7.0% in the general population.For most persons, these tumors remain asymptomatic and are discovered incidentally during a surgical procedure or imaging studies for unrelated problems. When symptomatic, abdominal pain, early satiety, and distention are most common.Rarely, platelet sequestration with thrombocytopenia or spontaneous rupture with intraperitoneal or intrahepatic hemorrhage can occur and can be life-threatening.In this study, 2 patients (7%) presented with severe pain and intrahepatic hemorrhage due to rupture.The strategic approach to diagnose these lesions varies among institutions, with ultrasonography, CT scan, erythrocyte scanning, and MRI scanning used alone or in combination.Rarely is arteriography necessary to ascertain the diagnosis or resectability. The precise diagnostic criteria for cavernous hemangiomas of the liver vary with each diagnostic procedure. For lesions found on ultrasonography, small hemangiomas are described as hyperechoic homogeneous masses.Large or massive hemangiomas have heterogeneous areas interspersed within the hyperechoic mass on ultrasonography.With contrast-enhanced CT scans, a peripheral nodular pattern of enhancement with a hypodense center is often seen(Figure 1). Scintigraphic studies using red blood cells tagged with technetium Tc 99m show delayed filling from the periphery of the lesion, whereas a hyperintense signal is seen during T2-weighted MRI scanning.A computed tomographic scan showing a nodular peripheral enhancement with hypodense center after the administration of contrast medium, typically seen in hepatic hemangiomas.The diagnostic algorithm used in our institution has been to focus on ultrasonography to assess initial tumor characteristics, followed by dynamic CT scanning to better identify anatomic relationships. We generally restrict the use of MRI to adjunctive use if the diagnosis is in doubt or if a more complete delineation of the tumor's relationship to hepatic venous structures is desired. Scanning with technetium-labeled erythrocytes has been used less extensively in recent years because improved CT and MRI scanning techniques have evolved. Core biopsy and fine-needle aspiration are reportedly safe but may be associated with pain or bleeding, and we do not recommend them for diagnosis.Because most patients with cavernous hepatic hemangiomas remain asymptomatic, the decision to remove these lesions surgically has been a point of controversy in previous reports.In this series, only hemangiomas causing severe abdominal pain or those with an indeterminate diagnosis or hemorrhage were removed. In these patients, the benefit of palliating pain, excluding the diagnosis of a possible malignant tumor, or controlling life-threatening hemorrhage, justifies the risk of surgery. In an asymptomatic patient with a secure diagnosis of a cavernous hemangioma, surgical resection cannot be justified.Once the decision to remove a symptomatic hemangioma has been made, an important surgical management issue relates to the technique of removal. Both anatomic resection and enucleation can be effective in removing the lesion. In this study, enucleation was found to be associated with fewer complications postoperatively compared with anatomic resection. Occasionally, the tumor location precludes safe enucleation, and anatomic resection can be performed more expeditiously. Given the potential for life-threatening intraoperative and postoperative complications, the surgical treatment of hepatic cavernous hemangiomas should be performed by surgeons comfortable with their removal using a variety of techniques, which will ensure a low rate of morbidity and mortality.LBelliLDe CarlisCBeatiGRondinaraVSansaloneGBrambillaSurgical treatment of symptomatic giant hemangiomas of the liver.Surg Gynecol Obstet.1992;174:474-478.AWeimannBRingeJKlempnauerBenign liver tumors: differential diagnosis and indications for surgery.World J Surg.1997;21:983-991.NIqbalASaleemHepatic hemangioma: a review.Tex Med.1997;93:48-50.ECLarsenWHZinkhamJCEgglestonBJZitelliKasabach-Merritt syndrome: therapeutic considerations.Pediatrics.1987;79:971-980.TMewesHMoldenhauerJPfeiferJPapenbergThe Kasabach-Merritt syndrome: severe bleeding disorder caused by celiac arteriography: reversal by heparin treatment.Am J Gastroenterol.1989;84:965-971.AMoreno EgeaMDel Pozo RodriguezMVicente CanteroJAbellan AtenzaIndications for surgery in the treatment of hepatic hemangioma.Hepatogastroenterology.1996;43:422-426.RAnderssonSBengmarkSurgical treatment of cavernous hemangioma of the liver.Acta Chir Scand.1988;154:577-579.PCKuoWDLewisRLJenkinsTreatment of giant hemangiomas of the liver by enucleation.J Am Coll Surg.1994;178:49-53.SMStrasbergTerminology of liver anatomy and liver resections: coming to grips with hepatic Babel [published erratum appears in J Am Coll Surg.1997;185:309].J Am Coll Surg.1997;184:413-434.CCouinadLobes et seqments hepatiques: note sur l'architecture anatomique et chirurgicale du foie.Press Med.1954;63:709.SISchwartzWCHusserCavernous hemangioma of the liver: a single institution report of 16 resections.Ann Surg.1987;205:456-465.RLJenkinsLBJohnsonWDLewisSurgical approach to benign liver tumors.Semin Liver Dis.1994;14:178-189.JTFerrucciLiver tumor imaging: current concepts.AJR Am J Roentgenol.1990;155:473-484.TKEgglinERummenyDDStarkJWittenbergSSainiJTFerrucciHepatic tumors: quantitative tissue characterization with MR imaging.Radiology.1990;176:107-110.JGaaSSainiJTFerrucciPerfusion characteristics of hepatic cavernous hemangioma using intravenous CT angiography (IVCTA).Eur J Radiol.1991;12:228-233.SASamadAMaimunahAZulfiqarMZaharahUltrasound (US) and computed tomographic (CT) appearances of large (giant) hepatic cavernous hemangiomas.Med J Malaysia.1995;50:82-86.RSirisriroEEKimDAPodoloffRadioimmunoscintigraphy in the differential diagnosis of hepatic mass lesion.Eur J Nucl Med.1995;22:385-388.MLiseGFeltrinPPDa PianGiant cavernous hemangiomas: diagnosis and surgical strategies.World J Surg.1992;16:516-520.DFLeslieCDJohnsonCMJohnsonDMIlstrupWSHarmsenDistinction between cavernous hemangiomas of the liver and hepatic metastases on CT: value of contrast enhancement patterns.AJR Am J Roentgenol.1995;164:625-629.MMoinuddinJRAllisonJHMontgomeryJFRockettJMMcMurrayScintigraphic diagnosis of hepatic hemangioma: its role in the management of hepatic mass lesions.AJR Am J Roentgenol.1985;145:223-228.GATungJJCronanPercutaneous needle biopsy of hepatic cavernous hemangioma.J Clin Gastroenterol.1993;16:117-122.MTaavitsainenTAiraksinenJKreulaMPaivansaloFine-needle aspiration biopsy of liver hemangioma.Acta Radiol.1990;31:69-71.JJCronanAREsparzaGSDorfmanMSRidlenLPPaolellaCavernous hemangioma of the liver: role of percutaneous biopsy.Radiology.1988;166:135-138.OFargesSDaradkehHBismuthCavernous hemangiomas of the liver: are there any indications for resection?World J Surg.1995;19:19-24.Giles Whalen, MD, Farmington, Conn:Dr Gedaly and colleagues focused their gaze on this rather uncommon problem. It is the most common benign liver tumor, but it is an uncommon clinical problem, as indicated by only 28 patients during a 10-year period. It is even more uncommonly operated on. The reason is that these are often large tumors. They are bloody, may be awkwardly situated, and, perhaps most important, their natural history is not as worrisome as used to be thought. It is clear that these generally do not go on to rupture, which was previously a fear. Interestingly, you have 2 patients in this series who did appear to have rupture. Because the usual precipitating event, at least in most of the literature, has been a biopsy, or mucking around with it in some way, I would be interested in knowing whether or not those patients who had presented with a rupture, in fact, had had a previous biopsy, or were they being watched? As is expected, the most common indication for operating on 1 of these tumors is pain. I would like to hear how much pain did the patients need to be in to have an operation? Some of the pain is perhaps due to thrombosis of the vessels. The natural history of the tumor in patients with pain is not entirely clear, and it can be a difficult call. You performed these operations with your expected success and excellence, a 14% major abdominal morbidity rate and no mortality. These are large operations with large incisions, and you have demonstrated how well the technique of enucleation works. The rest of my questions go directly to your central claim: Why do you think enucleation is a better technique for these operations? Even though there is a nice univariate and multivariate analysis, I feel a bit statistically challenged. Five of the operations are resections, and there are only 4 complications. I wonder whether the operations that were resections were performed for an emergency rupture, in which case one might expect to find a higher morbidity.The other question is, if it is such a wonderful technique, are there times when you would not use it? Are there particular circumstances when you feel that it is not indicated? If you have embarked on it and have encountered some technical difficulties, do you have any tricks that you would like to impart as to how to get out of trouble while enucleating the tumor?Mark Callery, MD, Worcester, Mass:Dr Whalen makes some important points in this mysterious lesion. My question pivots on your patient selection. How much pain do they have to have for you to operate on them? And what are your results from relieving the pain? How do you know which patients are probably going to have a good result?Robert Beazley, MD, Boston, Mass:I have grown up with the fear that hemangiomas may rupture, but I have never heard of one or seen one that has ruptured. These are the first 2 cases I have heard reported. Would you give us some background on the cause of the rupture, whether they were iatrogenic, steering wheel, or what?My other question is more of a philosophical one. I think enucleation is a major advance in the management of these tumors because it is so much better than a resectional approach, so much easier and less bloody. I question whether you might know if anyone has started to do these laparoscopically?Richard Swanson, MD, Worcester:One question on the indications. You talked about pain. Do you use size alone as an indication, or a change in size? Was that 45-cm tumor operated on purely because of the size?Dougald MacGillivray, MD, South Portland, Me:If uncertainty in the diagnosis was the reason for operation, did you approach these lesions with plans for enucleation, or were those the patients who had resection?Dr Gedaly:I had 2 questions concerning rupture as the cause of the surgical intervention. We have 2 patients in our series with this rare and unusual complication, representing 7% of our patients. I have found only 29 other cases of spontaneous rupture of these tumors that have been reported in the literature. Most cases of hemorrhage from hemangiomas are iatrogenic, associated with biopsies or trauma, as described in previous studies.Another important issue is, how much pain do patients have to have to need surgery and is there any way to anticipate good results in these patients? Let me answer the second part of the question first. It is essential that the surgeon rule out other important causes of pain in the right upper quadrant, even in those patients with giant tumors that obviously seem to be the source of their symptoms. This should be performed to have a certain amount of confidence that the hemangioma is the cause of pain and to subsequently optimize the results. Some authors have described the pain as severe or incapacitating to justify surgery. Yes, we think that enucleation is an excellent operation for benign tumors, not just because it was associated with a low rate of intra-abdominal complications compared with anatomic resection in both univariate and multivariate analyses in this series. We have demonstrated that this procedure can be performed with a low major morbidity rate and no mortality, with excellent results in terms of the resolution of the symptoms.As I said in the conclusions, both anatomic resection and enucleation can be effective in removing these tumors, and enucleation should be considered the technique of choice. In some patients, however, the location of the tumor and technical aspects preclude safe enucleation. A good example may be total lobar replacement by the hemangioma or nearly total replacement of 1 lobe in a patient with a suggestion of a malignant neoplasm in which the only way to get adequate margins is to perform a right or left hepatic lobectomy. In these circumstances, anatomic resection is a reasonable alternative, but each case should be evaluated individually.Changing to the next question regarding laparoscopic resection of hepatic hemangiomas, I have found only a few reports of laparoscopic removal of these tumors in studies regarding laparoscopic resection of hepatic tumors. The last question was in respect to the size as an indication of surgery. Size itself is not an indication. Rapid growth may increase the suspicion that you are dealing with a hepatic cancer. In this case, uncertainty of diagnosis is the real indication for surgical exploration. I want to be clear in this particular point: indications for surgery are severe abdominal pain, uncertain diagnosis, rupture, and profound thrombocytopenia and coagulopathy associated with Kasabach-Merritt syndrome.Dr Jenkins:The important thing is to make sure that you take your time doing this. You cannot push with your fingers very much, but it really is extraordinarily easy to develop this plane and skeletonize everything so that when you look down at the end of it with a large tumor, you have a view of the vena cava, hepatic veins, and biliary radicals. Obviously, if you get into a difficult situation, you might have to do a major hepatic resection, but this is much easier. I get calls every year from surgeons who have cut across a hemangioma at the base of it as they were doing a liver resection. They call me from the operating room and say, "What shall we do now? The patient's bleeding to death." Enucleation is a much safer way to do this.Presented at the 79th Annual Meeting of the New England Surgical Society, Toronto, Ontario, September 27, 1998.Corresponding author: Roger L. Jenkins, MD, Division of Hepatobiliary Surgery and Liver Transplantation, Beth Israel Deaconess Medical Center, 110 Francis St, Suite 8C, Boston, MA 02215.

Hamdan, Allen D.; Pomposelli, Jr, Frank B.; Gibbons, Gary W.; Campbell, David R.; LoGerfo, Frank W.

doi: 10.1001/archsurg.134.4.412pmid: 10199315

HypothesisThat alternative methods of cerebral protection, especially routine shunting of all patients undergoing general anesthesia or shunting on the basis of neurologic assessment with the patient awake under cervical plexus block, result in outcomes of carotid endarterectomy comparable with those reported using electroencephalographic monitoring.DesignRetrospective review of cases from a vascular registry established in 1990.SettingTertiary care center.PatientsConsecutive sample of 1001 patients who underwent carotid endarterectomy.InterventionsCarotid endarterectomy procedures were performed without electroencephalographic monitoring, using general anesthesia with routine shunting or using regional anesthesia.Main Outcome MeasuresOverall stroke and mortality rates and cause and consequence of the postoperative strokes.ResultsThere were 14 nonfatal strokes (1.4%) and 2 deaths (0.2%), for a combined stroke and death rate of 1.6%. Nine (64%) of the 14 strokes appeared to result from a technical error during the endarterectomy. Mild deficits were noted after 7 strokes (50%), with the remainder resulting in deficits that required inpatient rehabilitation. Twelve patients with strokes (86%) eventually returned home without need for assistance.ConclusionsMost postoperative strokes in this series were due to technical errors. Overall, even in patients with strokes initially requiring inpatient rehabilitation, there was good recovery of function. Low stroke and mortality rates can be achieved in carotid endarterectomy without the use of electroencephalographic monitoring.WITH THE results of 2 major, randomized prospective trials reporting the expected benefits of carotid endarterectomy (CEA) vs medical management for symptomatic and asymptomatic carotid stenosis,the number of patients undergoing this procedure has increased. For the benefits of surgery to be realized, however, the operation must be performed with a low complication rate in regard to stroke and mortality.Since it is likely that in some instances placement of an indwelling shunt will prevent the development of postoperative stroke, the method of cerebral protection or cerebral monitoring is a topic of interest. Cerebral monitoring in general is conducted with an electroencephalogram (EEG) or use of regional anesthesia in an awake patient.Carotid artery stump pressures also have been used to determine the need for shunt placement based on predetermined thresholds.The rationale for monitoring is to identify a subgroup of patients most likely to benefit from shunt placement. Some patients will demonstrate significant cerebral hypoperfusion, as measured by EEG changes, on carotid clamping. The presumption is that in the absence of a shunt, a small number of these patients will have a postoperative neurologic deficit. Electroencephalographic monitoring, however, requires additional equipment and expertise and generates a cost. Another method, which abrogates the need for cerebral monitoring, is the use of general anesthesia with routine shunting. At our institution, we have used regional anesthesia with shunting based on a neurologic change during the procedure, but we now perform CEA with general anesthesia and routine shunting almost exclusively. We reviewed 1001 consecutive CEAs performed during a 7-year period without the use of EEG. In addition, an attempt was made to characterize the cause of perioperative stroke as well as the resultant deficits.PATIENTS, MATERIALS, AND METHODSA computerized vascular registry was established in January 1990. Data from all patients who have undergone vascular procedures at the West Campus of the Beth Israel Deaconess Medical Center (formerly The New England Deaconess Hospital), Boston, Mass, were prospectively entered. We reviewed all consecutive patients who underwent CEA from January 1, 1990, through August 31, 1997. Patients who underwent combined procedures (coronary artery bypass grafting), aortic arch procedures, or operations for recurrent carotid stenosis were not included in this review. The 1001 CEAs were performed during these 7 years by 4 of the 5 of us (F.B.P., G.W.G., D.R.C., and F.W.L.) at our hospital. Patients who underwent bilateral CEAs during the study interval had their risk factors and results entered separately at the time of each operation. Most patients underwent general anesthesia with routine shunting. Proper function of the shunt was confirmed using a hand-held continuous-wave doppler. Some CEAs were performed under regional anesthesia with shunting on the basis of continuous neurologic assessment. A patch closure was used at the discretion of the individual surgeons based on the diameter of the internal carotid artery. Recently, all arteries are patched, most commonly with collagen-impregnated Dacron fabric. Typically, postoperative patients recovered overnight in the postanesthesia care unit or the vascular intensive care unit (a specialized vascular ward for stable, unintubated patients) and then were discharged to home or transferred to the floor.Patient demographics and preoperative risk factors were also evaluated, including history of coronary artery disease or congestive heart failure and presence of diabetes mellitus. Data were obtained by registry review and additional review of hospital records in certain cases. Indications for CEA were classified as asymptomatic, symptomatic (which included transient ischemic attacks [TIAs] and amaurosis fugax), or completed stroke. We characterized patients who presented with unclear or nonlateralizing symptoms as asymptomatic.Categorization of the extent of disability due to a postoperative stroke was as follows: mild indicates deficit limited to 1 extremity, requiring no inpatient rehabilitation or in-home assistance; moderate, deficits requiring inpatient rehabilitation for motor skills or speech; or severe, profound deficits requiring skilled nursing facilities, including ventilatory and nutrition support. Other complications tracked include congestive heart failure, myocardial infarction, arrhythmia, hyperperfusion syndrome, and severe cranial nerve injuries (requiring rehabilitation). The number of minor cranial nerve injuries was not present in the current database. The average length of hospital stay (LOS) includes all postoperative days, including those incurred during a second consecutive procedure after a CEA such as a peripheral bypass.RESULTSPATIENTSMean age of patients was 70.5 years (range, 39-94). Other overall characteristics of the 1001 patients with regard to preoperative risk factors are listed in the following tabulation: Characteristics% of PatientsMale61Female39Diabetes38Hypertension70Congestive heart failure10Previous coronary artery bypass graft22Overt coronary artery disease46Indications for CEAAsymptomatic42.6Symptomatic49Completed stroke8.4LENGTH OF HOSPITAL STAYFor the whole group, the average LOS was 3.1 days (range, 0-62 days). Six hundred seventy-seven (67.7%) of the patients were discharged by postoperative day 2.COMPLICATIONS AND MORBIDITYComplications are given in the following tabulation: ComplicationNo. (%) of PatientsNonfatal strokes14 (1.4)Death2 (0.2)TIA4 (0.4)Myocardial infarction5 (0.5)Congestive heart failure8 (0.8)Arrhythmia8 (0.8)Hyperperfusion syndrome3 (0.3)Severe cranial nerve injury1 (0.1)Overall, 14 strokes and 4 TIAs totaled 18 neurologic complications (1.8%).Transient Ischemic AttacksTwo of the 4 patients with TIAs presented with symptomatic stenosis, 2 were asymptomatic, and all underwent CEA with an indwelling shunt. On reexploration, an intimal dissection was noted in 2 patients, no abnormality in one patient, and only an occluded external carotid artery in the other.StrokesEleven (79%) of the 14 patients who suffered a postoperative stroke presented with a symptomatic stenosis, yielding stroke rates for asymptomatic and symptomatic patients of 0.7% and 1.9%, respectively. General endotracheal anesthesia with shunting was used in 11 patients (79%), with regional anesthesia used in the remainder. None of the strokes in the regional group was preceded by intraoperative clinical changes, and therefore the patients did not undergo shunting.In those patients who underwent reexploration for ipsilateral postoperative neurologic deficits, several causes of the strokes were noted. In 5 patients, there was internal carotid artery thrombosis or the presence of fresh clot without an intimal flap. In 2 patients, a distal intimal flap with clot was apparent. In 1 patient, a distal kink with obstruction of flow was found, and, in another, the stroke resulted from an embolus or hypoperfusion, since no operative defect was identified, and since the patient did not undergo shunting.The other 5 patients did not undergo reexploration, but some information was available. Heparin-induced thrombocytopenia and complete thrombosis of the internal carotid artery developed in 1 patient after a subsequent peripheral bypass graft 14 days after CEA. There was 1 intracerebral bleed noted on postoperative day 8. Emboli or hypoperfusion was presumed to be the cause of strokes in the other 3 patients, since all had patent internal carotid arteries radiologically. Thus, of the 14 postoperative strokes, 9 (64.3%) were likely due to technical errors during the endarterectomy and closure, since these patients had intimal flaps or presence of clot.The initial manifestations of the strokes were as follows: 7 mild deficits (50%) that did not require any inpatient rehabilitation but prolonged the LOS to 6.3 days; 2 moderate deficits (14%) that required an LOS of 14 days and a subsequent period of inpatient rehabilitation; and 5 severe deficits (36%) that required intensive rehabilitation and, in 2 patients (14%), tracheostomy and gastrostomy tube placement. Their average LOS was 12.2 days before transfer to a skilled nursing facility. In the mild deficit category, all 7 patients showed continued recovery of motor or speech deficits, with 2 patients eventually having no recognizable deficit. In 1 patient, however, occlusion of his carotid repair developed, and he died of multiple-system organ failure as a complication of sepsis and renal failure 4 months after surgery. In the moderate deficit group, 1 patient showed some recovery of motor and speech loss and, although she eventually went home, she was still significantly debilitated. The other patient experienced a full recovery. In the severe deficit group, 1 patient suffered a subsequent ipsilateral TIA and, despite occlusion of the operative repair, the paresis improved and she did not require inpatient rehabilitation. Two patients were able to return home in less than 1 month and recovered most function except the ability to write in 1 patient and some speech disability in the other. Of the 2 patients who required tracheostomy and gastrostomy, 1 patient now lives at home with assistance from a health aide, whereas the other died at the rehabilitation center 2 months after surgery.DeathThere were 2 deaths within 30 days after surgery. One patient with severe renal insufficiency died in the recovery room from a suture line bleed, resulting in a respiratory arrest. The other patient died 8 days after surgery from complications of a myocardial infarction.TYPE OF ANESTHESIA OR SHUNTEleven patients (79%) underwent general anesthesia; the remainder underwent regional anesthesia. Stroke rates for both groups were 1.5% and 1.2%, respectively. Six (43%) of 14 patients underwent patching.COMMENTOur report presents data on 1001 CEAs performed without using EEG as a cerebral monitoring technique. Most of the operations were performed under general anesthesia with routine shunting, but some were performed under regional anesthesia. The stroke rate was 1.4%; the combined stroke and death rate, 1.6%. These results were very similar to those of the Asymptomatic Carotid Atherosclerosis Study,in which all patients were asymptomatic, and to those of the Cleveland Clinic report on 1924 CEAs,in which most were performed with routine shunting. The stroke rates reported in these series, including ours, represent clinically apparent strokes, since it is not standard practice to obtain preoperative and postoperative computed tomographic or magnetic resonance imaging scans in all patients. In 1 study, this practice increased the infarct rate from 2% to 12%.The significance of asymptomatic strokes is not exactly clear, but when comparing results between series, one must realize that the so-called silent stroke rate may vary considerably.Results of series in which selective shunting was used based on EEG changes reveal combined stroke and mortality rates ranging from 1.4% to 2.7%.However, it is clear in these series and others that EEG is not 100% sensitive for predicting postoperative strokes.Also, EEG changes do not always occur immediately on clamping, but can happen several minutes later, which can cause technical problems if it occurs during the actual endarterectomy. In addition, it is clear from series exclusively using regional anesthesia that some patients will not show signs of cerebral ischemia during CEA but still suffer a perioperative stroke.Accordingly, these patients would not undergo shunting during the procedure. This occurred in 3 patients who suffered postoperative strokes after CEA performed under regional anesthesia in our study. The causes of the strokes in the regional group, however, were similar to those noted in the routine shunting group.Overall, the data suggest that although only a small number of patients will benefit from shunting, there is no preoperative clinical factor or intraoperative technique, including close observation under regional anesthesia, that reliably identifies those patients. Based on this, our current practice is to use general endotracheal anesthesia with routine shunting in most cases. Since it is also evident that series using different techniques have similarly low morbidity rates, we do not believe that routine shunting is the only acceptable method. However, since all patients receiving general anesthesia undergo shunting, we concentrate on widely exposing the distal internal carotid artery to avoid the potentially dangerous situation of having to urgently insert a shunt in an environment with inadequate distal exposure. Some of the technical errors were possibly contributed to by the shunt itself, but the rate is extremely low.Another observation that can be made from these data is that, as noted by Riles et al,a number of the strokes were due to a technical error with the endarterectomy or the distal end point. Thus, the already low stroke rates may be even lower.In conclusion, performing CEA without EEG monitoring is a safe and reliable method. The results are likely due in part to the fact that CEAs were performed at a tertiary care center with a high volume of carotid procedures and reflect a multidisciplinary approach, including experienced nurses and anesthesiologists. However, technical errors still account for a large proportion of postoperative strokes after CEA, emphasizing the need for technical precision. Accordingly, more attention should be directed toward performing a precise endarterectomy and less to the method of cerebral monitoring. When strokes do occur, most patients can be expected to make a reasonable recovery and return to a level of function where they can live at home.Executive Committee for the Asymptomatic Carotid Atherosclerosis StudyEndarterectomy for asymptomatic carotid artery stenosis.JAMA.1995;273:1421-1428.North American Symptomatic Carotid Endarterectomy Trial CollaboratorsBeneficial effect of carotid endarterectomy in symptomatic patients with high-grade stenosis.N Engl J Med.1991;325:445-453.WSMooreHJMBarnettHGBeebeGuidelines for carotid endarterectomy.Stroke.1995;26:188-201.ADWhittemoreJLKaufmanTRKohlerJAMannickRoutine electroencephalographic (EEG) monitoring during carotid endarterectomy.Ann Surg.1982;197:707-713.MEBenjaminMBSilva JrCWattAwake patient monitoring to determine the need for shunting during carotid endarterectomy.Surgery.1993;114:673-681.RNHaradaAJComerotaGMGoodStump pressure, electroencephalographic changes and the contralateral carotid artery.Am J Surg.1995;170:148-153.NRHertzerPJO'HaraEJMaschaEarly outcome assessment for 2228 consecutive carotid endarterectomy procedures.J Vasc Surg.1997;26:1-10.RBerguerMYSieggreenMLazoBAHodakowskiThe silent brain infarct in carotid surgery.J Vasc Surg.1986;3:442-447.RMGreenWJMessickJJRicottaBenefits, shortcomings and costs of EEG monitoring.Ann Surg.1985;201:785-792.WJMcCarthyAEParkEKoushanpourCarotid endarterectomy.Ann Surg.1996;224:297-307.PFLawrenceJCAlvesDJJichaIncidence, timing, and causes of cerebral ischemia during carotid endarterectomy with regional anesthesia.J Vasc Surg.1998;27:329-337.TSRilesAMImparatoGRJacobowitzThe cause of perioperative stroke after carotid endarterectomy.J Vasc Surg.1994;19:206-216.Jack Huse, MD, Meriden, Conn:The North American Symptomatic Carotid Endarterectomy Trial (NASCET) and the Asymptomatic Carotid Atherosclerosis Study (ACAS) have verified what surgeons have intuitively believed for decades, namely, that properly selected patients with high-grade carotid stenosis, regardless of symptoms, have a longer stroke-free survival with operative vs nonoperative therapy. This concept is valid only when surgical management results in a stroke and combined stroke and death rate of 1% to 3%. The maintenance of optimal cerebral profusion is generally regarded as the critical factor for the successful carotid endarterectomy outcomes. How to best monitor this optimal cerebral profusion has been the topic of countless articles in the surgical literature. Moore and Hall, in 1969, proposed the use of internal carotid artery stump pressure as an index of collateral cerebral circulation during carotid clamping. Since that time, other authors have championed transcranial doppler ultrasonography (TCD) to monitor blood flow in the basal cerebral arteries. Pertinent to this morning's paper, the EEG has been shown to be an exquisitely sensitive measure of cerebral blood flow. Despite its sensitivity, the value of an EEG interoperatively to reduce CEA complication rates is rightfully being called into question.Dr Hamdan and his colleagues from the Beth Israel Deaconess Medical Center have provided a meticulous analysis of over 1000 cases of CEAs safely performed without the use of intraoperative EEG monitoring. Unfortunately, the sensitivity of an EEG to predict a postoperative stroke is not 100%. In fact, there are a number of papers documenting minimal or no evidence of intraoperative EEG changes in patients who have demonstrated significant neurologic deficits postoperatively. Conversely, there are papers documenting patients with substantial intraoperative EEG changes who did not develop any postoperative neurologic deficits. When faced with this mind-boggling dilemma (before having had the opportunity to read Dr Hamdan's paper), I did what all good scientists do, I asked my colleagues in Connecticut what they were doing referable to EEG monitoring. I'm pleased to report, at least on this issue, Massachusetts and Connecticut agree. The routine use of EEG monitoring in the operating room is not currently utilized in Hartford, New Haven, New Britain, or, I suspect, in other hospitals within the state that I failed to contact.Cost-effectiveness is certainly important to all of this in this day and age, but patient safety and excellence of outcomes has always been our goal. It is therefore important we document the efficacy of CEA, without the added expense of intraoperative EEG monitoring. I believe this paper has successfully defended that position.I have several questions for the authors. When you reviewed the technical errors that contributed to the incidence of postoperative neurologic deficits, did you discover any features which might be helpful in reducing future technical problems? And secondly, do you have any experience with the use of high-dose thiopental anesthesia as a method of cerebral protection during CEA?Padiath Aslam, MD, Augusta, Me:I'd like to know if the same uniform technique was used with a classical longitudinal incision, or eversion endarterectomy had been done in later cases, as it is becoming popular? And also, whether any intraoperative arteriogram or intraoperative duplex scanning has been employed to see the adequacy of the endarterectomy?Dr Hamdan:As for the technical errors that we identified, the most common one was a problem with the distal end point. One thing that we have discovered, especially when you are using a patch, is to extend the initial arteriotomy beyond the distal end point so that when you are sewing in the patch, or starting your primary closure, you are not closing directly over the area of concern. Other than that, I don't have other tips on avoiding technical errors except for being as precise with the endarterectomy and closure as possible.As far as use of thiopental anesthesia, I apologize, but I'm not really familiar with that technique, and we don't have any experience with that at our institution.To answer the second group of questions, this is a standard endarterectomy with a longitudinal arteriotomy. We don't perform eversion endarterectomies, although that has been shown to be a very successful technique.We do not routinely evaluate the adequacy of our repair and closure with intraoperative duplex scan or arteriography. We do use a handheld continuous wave doppler at the end of the procedure. When there is a concern about the repair, we will perform an intraoperative arteriogram. However, this has been the case in only a small percentage of our patients.Presented at the 79th Annual Meeting of the New England Surgical Society, Toronto, Ontario, September 27, 1998.Reprints: Frank B. Pomposelli, Jr, MD, Harvard Medical School, Department of Vascular Surgery, Beth Israel Deaconess Medical Center, West Campus, 110 Francis St, Suite 5B, Boston MA, 02215 (e-mail: [email protected]).