Bilateral Massive Adrenal Hemorrhage

Introduction Bilateral massive adrenal hemorrhage (BMAH) is a rare catastrophic condition that manifests with acute adrenal insufficiency due to irreversible destruction of the adrenal cortices (19–20). It is uniformly fatal if glucocorticoid treatment is not initiated shortly after onset of the crisis but can be very difficult to diagnose prospectively because of its nonspecific symptoms. Numerous case reports have identified plausible risk factors for the development of this condition, and animal studies lend support to some of them (1, 10, 17, 19, 20, 22, 28). These include advanced age, serious underlying medical illness (such as, congestive heart failure and sepsis), postoperative state (especially cardiovascular or orthopedic surgery, suggested to be due to the common practice of using anticoagulants), significant hypotension, spontaneous or iatrogenic coagulopathies, certain prothrombotic disorders, trauma, adrenocorticotropin (ACTH) administration, vasculitis, adrenal venography, and pheochromocytoma. Anticoagulant use (mainly heparin) has been incriminated in most recent case reports. With heparin use becoming more common, it is useful to identify those at greatest risk for this catastrophic side effect. Since there have been no analytical epidemiologic studies, this case-control study was designed to study the strength of the association between most of these putative risk factors and BMAH. Other exploratory factors were studied, including hypertension, diabetes, cardiovascular disease, atrial fibrillation, radiologic procedures, and smoking. By identifying the profile of a high-risk patient, it becomes feasible to initiate lifesaving glucocorticoid treatment more promptly while awaiting confirmation of BMAH. Methods Design/source of cases and controls This was a multicenter, hospital-based, case-control study comprising case and control patients from acute care hospitals in Kingston (Kingston General Hospital and Hotel Dieu Hospital), Ottawa (Ottawa Civic Hospital and Ottawa General Hospital), Toronto (Sunnybrook Health Science Centre, The Toronto Hospital, and St. Michael’s Hospital), and London (St. Joseph’s Health Centre, LHSC-Victoria Campus, and LHSC-University Campus), Ontario, Canada. All are teaching hospitals providing secondary and tertiary care, with similar record-keeping practices and approaches to patient care. Admission requires a detailed admission note outlining history of the present illness, review of systems, medications, past medical history, and physical examination. We chose to do a hospital-based study not only for convenience and thrift, but also due to the fact that almost all cases of BMAH occur during or shortly after hospitalization for another condition. The critical nature of the condition would not allow for cases in the population to survive undiagnosed for very long. Furthermore, once diagnosed, the condition requires admission for close observation and treatment. In using hospital controls, one can try to answer the question, “what is different about the baseline characteristics and/or hospital exposures in those who eventually become BMAH cases compared with those who do not?” It is reasonable to assume that control patients admitted to the same hospital as the cases belong to the same study base (24). As opposed to using non-hospital controls, one could be better assured that there would be similar quantity and quality of exposure data available for the controls (such as, list of medical conditions and platelet counts). Drawing control patients from all other possible diagnostic admission categories helped eliminate bias should 1 control disease be linked to 1 or more of the study exposures (24). Definition of cases and controls Case definition: The inclusion criteria are listed below (patient must fit all of the criteria): 1) Appearance consistent with bilateral adrenal hemorrhage by radiologic studies (ultrasound, computerized tomography [CT], or magnetic resonance imaging [MRI]), surgery, or autopsy 2) Adrenal insufficiency proven by biochemical criteria (low serum cortisol and/or flat response on rapid ACTH stimulation test) or death 3) Age ≥ 18 years 4) Availability of medical record 5) Admission during the time period 1989–1998 The exclusion criteria are listed below (patient excluded if 1 or more of the following applies): 1) Bilateral adrenal hemorrhage demonstrated to be associated with other bilateral primary adrenal pathology such as tuberculosis, histoplasmosis, amyloid, or neoplasia 2) Adrenal hemorrhage occurring in association with Gram-negative septicemia (Waterhouse-Friderichsen syndrome) 3) Adrenal hemorrhage secondary to adrenal rupture during thoracoabdominal trauma Cases were identified through a computerized search at the Medical Records Departments (1989 and beyond) in each hospital for those with the diagnosis “adrenal hemorrhage.” Since “adrenal hemorrhage” is coded under the same ICD code as undifferentiated adrenal insufficiency, the latter patients first had to be excluded by examination of the medical record. Cases were required to fit the “case definition” defined above. Based on power considerations, 4 control patients per case were randomly chosen from computerized lists of all hospital admissions. There is usually little marginal benefit to including more than this (25). Each control was individually matched to his or her respective case by hospital, year of admission (within 1 year), and age (within 1 year). This matching was felt to be important to avoid bias related to varying quality of record-keeping and changing medical practice over time (such as, anticoagulant use) and between hospitals. It is already known from descriptive studies that most cases of BMAH occur in those past middle age. Because age was not of scientific interest and was a potentially strong confounder (25), it was 1 of the matching criteria for complete control of its potential confounding, possibly improving the efficiency in the estimation of the effect of other exposures (25). Potential controls would be excluded if they had a history of adrenal hemorrhage, bilateral primary adrenal pathology, or adrenalectomy. When there were multiple admissions during the same year, the admission closest in time to that of the case was chosen for data extraction. Data collection Ethics approval was received in each hospital before proceeding with data gathering by way of a retrospective chart review. All volumes of the hospital record for each patient were reviewed to avoid missing pertinent details in the past medical history. An identical database form was filled out for all subjects and the information was gathered by the unblinded principal investigator with the same attention to detail for cases and controls. Data collected for the defined exposure period included demographics, preadmission and admission medications, past and active medical problems, past and recent surgeries or procedures, history of the present illness, course in hospital, and laboratory data. Note that hypertension referred to a prior history of hypertension (BP > 140/90) that may be controlled with medication. Data from the database form were then entered by the same investigator into a computerized data set. “Exposure period” was defined as the 30 days preceding the index hospital admission until the onset of BMAH in cases and until the end of admission in controls. The “latency period” was defined as the duration in days post index admission until the first clear manifestations attributable to BMAH in cases (not until death in some, when it was confirmed at autopsy). Specific details collected and coded in the data set are listed in Table 1.TABLE 1: Data collected and coded for the exposure periodMinor amounts of heparin used in flushes, often not reliably recorded in the medical record, were not noted. The checklist was proofed several times to ensure no misclassifications were made. In the rare situation where incomplete information was sent along from the peripheral hospital upon transfer to the teaching hospital, the pertinent Medical Records Departments were contacted to supply the missing details. Statistical analysis Preliminary analysis of the data was by univariate logistic regression (8, 23). Parameters were estimated by the maximum-likelihood method. A value of p ≤ 0.05 was considered statistically significant and 95% confidence intervals were derived for the odds ratios. Stem and leaf plots were examined for the continuous variables (duration of hospitalization, duration of coumadin, and duration of heparin) without attention to case-control status. Because they were highly skewed in their distributions, they were converted into categorical variables according to quantiles of exposure, and univariate logistic regression was used on these design variables to analyze and derive odds ratios and regression coefficients. The results were scrutinized, including graphically to assess departures from linearity in the logit, and categories were simplified accordingly for further use in the multivariate model. For all variables, both unmatched and matched univariate analyses were performed for comparison. Furthermore, to show that the matching variables were conditionally independent of case-control status given the risk factors (3), average ages and years of admission were compared for cases and controls according to levels of the risk factors appearing to have greatest importance. An unmatched analysis was then deemed appropriate for the multivariate analysis (3) to improve the study’s power and make it more feasible for the investigator. Any bias that may have resulted from using the unmatched analysis would tend to be in the direction of conservatism for estimates of odds ratios. Multivariate modeling by forward stepwise unconditional logistic regression (8, 23) proceeded with those variables felt to be important by previous animal studies and for those of the additional variables that had p < 0.20. Parameters were estimated by the maximum-likelihood method and 95% confidence intervals were derived for the adjusted odds ratios. Once the final model was formed, each excluded variable was individually added into the and the performed and examined to ensure that the variable should be The final model was on for all the variables in the final in to age, were for All analyses were performed by There were cases of BMAH identified that fit the “case definition” as defined cases were from Kingston General Hospital, 1 from Hotel Dieu Hospital, from Ottawa Civic Hospital, from Ottawa General Hospital, 4 from Health Science Centre, from The Toronto Hospital, from St. Michael’s Hospital, from St. Joseph’s Health Centre, from LHSC-Victoria Campus, and from LHSC-University for exclusion of 4 other potential cases included with and with hemorrhage into bilateral adrenal There were no present to potential controls. The cases and the controls on age, hospital, and year of were for complete data collection and The ages for both cases and controls from to with a of The period until clear of BMAH in the cases from to days post admission with a of days patient skewed the results by a admission before cases not have clear until when BMAH was demonstrated at In patients had the of BMAH in but BMAH was already demonstrated in of cases on the of the index admission with BMAH it at and following a recent hospitalization for another As the medical record was for each admissions that the preceding 30 days of the index for cases and controls, were available for data extraction. The duration of hospitalization in the exposure period defined from to days in the cases and 1 to days in the controls Table the results of the univariate analysis the between potential risk factors and development of BMAH. The factors that to be associated with BMAH included hospital heparin and The estimated odds ratios were similar for the matched and unmatched Furthermore, of average ages and years of admission for cases and controls according to levels of the most important exposure variables were similar not of univariate analysis and matched variable was in its 4 categories as it was in the was in its categories as the was in a For was also in the logit, the first categories were as the odds ratios were both close to and further analysis of the The categories for to be close to in the graphically and the of was also highly analyses in multivariate analyses as both categorical and continuous the BMAH cases who were to received heparin or received or heparin and received both heparin and or from exposure to heparin was more important in risk of BMAH than other of or There were only subjects in there was exposure to other and in 1 in 1 and in 1 In all of there was additional exposure to heparin and the were to assess independent to platelet included and a patients with or The to BMAH was in the direction to that as there were cases of BMAH in those to platelet The same can be for diabetes, as there were no cases of BMAH in patients with The variables and were excluded from further analysis because of and the of a hypertension and disease association to was In case these were for some other they were included in further multivariate unconditional logistic regression proceeded with those variables in Table that had p < and and/or were felt to be important by previous animal The unconditional was chosen over the matched analysis because the latter was due to as a of the were entered by forward stepwise regression and were for on adjusted coefficients. Table the adjusted odds ratios and 95% confidence intervals for those variables that in the of multivariate analysis logistic of the association between potential risk factors and of to the univariate heparin and were to be associated with risk of BMAH after for the effect of other The for each of these variables in the cases are in Table There not to be significant between the variables in the final model or with age. a risk of BMAH. to heparin for and those for over were about and more to BMAH than those who had than 4 days or no the risk of BMAH radiologic was associated with it as continuous or by categorical design variables, was no of BMAH as it was with heparin and and was on during the stepwise duration of hospitalization its ensure that there was no effect of the excluded variables, they were added in individually to the final model and not to have significant on the estimated of and in analysis suggested that disease was highly development of and hypertension, and diabetes, also may have been of post of variables for other the of disease but not the odds and also not the variables chosen in the final model Table state of adrenal insufficiency becomes once of the adrenal has been The most common is disease, in destruction the other bilateral adrenal is usually associated with a more acute it is to occur in “adrenal of the and in Gram-negative septicemia (Waterhouse-Friderichsen syndrome) it also in the of these conditions and has been bilateral massive adrenal of the adrenal by hemorrhage than the Once a and other radiologic studies have it possible to diagnose BMAH in its course due to for other by BMAH BMAH with nonspecific and it difficult to diagnose cases from the that had case to the of these In the patients present with a of in the or or manifestations (such as, or laboratory include a significant in the of with the of the adrenal and of adrenal insufficiency that often several days to can occur a or after days of but nonspecific those who survive after of glucocorticoid complete and irreversible of adrenal associated with adrenal is almost In autopsy the of adrenal hemorrhage from to of those in autopsy a of of BMAH. bilateral adrenal hemorrhage may more to the of patients than The diagnosis of BMAH can be confirmed in the course by of hemorrhage or and biochemical of adrenal insufficiency (low serum cortisol levels or response on rapid ACTH stimulation both to be often in with the the in and show a in characteristics are with and studies model for development of the adrenal is to adrenal hemorrhage The supply a of through that into a in the This highly into in the by at the a potential the adrenal is only by a further to in adrenal such as that by during or in could the and in hemorrhage into the In the are from the supply and would be to be most to from when the examination in patients following of significant this to be (1, 28). then through the at the time of when is The of the adrenal that are known to platelet and The adrenal is to the of in the and this during times of This could in and of the to as above. As a the can and their into the further In the in the may make it to development of platelet in of and under the of that adrenal hemorrhage and/or can be by and The from massive to or with little or no The usually the adrenal and the is by of and into the and are at the of and there are of secondary time and a in the to between and both and anticoagulant conditions may adrenal hemorrhage by ACTH from the or ACTH in the adrenal in to of 20, 28). show that stimulation with ACTH results in and hemorrhage of the adrenal similar to in from to are to hemorrhage into the adrenal with heparin or the risk of adrenal hemorrhage to in by of through the risk factors defined by case In and other case reports of BMAH (1, 10, 17, putative risk factors identified included advanced age, serious underlying medical illness or congestive heart and postoperative state (especially cardiovascular or orthopedic surgery, suggested to be due to the common practice of using anticoagulants), significant hypotension, spontaneous or iatrogenic time or and anticoagulant certain prothrombotic and and trauma, ACTH administration, with adrenal venography, and with In the case of and disease, the to BMAH could be through the use of of the recent cases of BMAH with heparin or another form of at the time of adrenal hemorrhage spontaneous was not and studies were usually not the is As its is there are multiple reports of BMAH occurring in the of In this condition, are that and in the of usually in and a risk of The state is felt to be due to of and the with in the usually are not and and may be the in BMAH. can be by or of of but to be more common after of or The risk of after of heparin but may for about a after exposure As the risk factors for BMAH by descriptive studies have a by about the and and from animal It is usually possible to from the record the time of onset of adrenal by of acute (such as, or that is a days by a in the and/or radiologic of adrenal hemorrhage to the The and usually would not have been prospectively as due to BMAH because of the nonspecific nature of the and the of the condition. the of the most appropriate way to the strength of the association between the putative risk factors and BMAH was by of a case-control factors at that could be linked through or included hypertension, diabetes, cardiovascular disease, atrial fibrillation, radiologic and smoking. study The case-control study demonstrated that the of and exposure to heparin are and associated with development of BMAH in These are in with suggested by descriptive studies and animal The of in and very odds ratios for each of these variables a There not to be significant these variables, the may have a By plausible risk factors and in of the the nature of the multivariate analysis the out of from independent risk factors and variables in the duration of hospitalization not in the multivariate that there were no other exposures associated with hospitalization that were not As multiple variables were with one another important in the univariate their in the multivariate of this include and other with heparin and with heparin exposure and hypotension, highly important in the animal studies and in the univariate was no significant after for other of the detailed case suggested that the response in and it is also a to in It may be that was by only because of these to the of disease, hypertension and diabetes, was associated with development of BMAH. The only plausible that is that of these patients were and other may development of such as by in in the case of post of these variables into the multivariate analysis not have on the odds ratios. from the epidemiologic it can be that these were a of bias by the use of hospital controls because patients are more to have other medical conditions that them to admitted (24). In other a association is between these and case-control status because of the of admission to hospital for and exposure characteristics in the This has been demonstrated For the situation where the case disease has a very of hospitalization as compared with the control disease, as is the case with exposure or characteristics can be associated with the control In effect in more it that heparin use must days to risk of BMAH. This is with about duration of heparin exposure for development of in most this association was with the included in the model. the be to for all of the association It may be that the anticoagulant heparin the side effect during It that of heparin was not as important as and case exposures included both and the was to a of risk between An is that the as a of of the association of heparin and BMAH this has a case of acute bilateral adrenal in a patient with confirmed due to This that anticoagulant effect is not a for the of bilateral adrenal and cases of adrenal may have been by this As the adrenal on the of in this confirmed primary adrenal insufficiency, this the in a case-control study on adrenal The greatest to this study is the may have resulted in or It also resulted in confidence for the odds ratios. Furthermore, multiple were the risk of for the risk factors heparin exposure, and sepsis), the results were to be of a This study the about a retrospective but were to similar quality of data. The fact that all of the data gathering was by the same investigator and at teaching of the about bias in between and between study Furthermore, the medical from all was of similar quality and of similar attention to detail for data gathering for cases and controls, could that was in the It was not feasible in this study to randomly to to this Furthermore, has been as a possible for the association with disease and possibly and hypertension, could be as as in the in this the of the other variables examined not conditions or exposures risk of hospitalization, and were of exposures for the most Because this was a hospital-based the odds ratios be to the population in This may not be very important most cases of BMAH in bias may have resulted from patients of BMAH and not autopsy of In this were to the effect of on risk of BMAH because it was not in a is usually by the and of the examined and of hypotension, and there are no with ACTH is the of greatest of (duration of was examined and not to be important while the of the other variables were Case reports and case have identified putative risk factors for the development of bilateral massive adrenal hemorrhage (BMAH) in The and of the adrenal allow development of a model to fit the these risk these risk factors were not using analytical epidemiologic A case-control study was using of cases and controls from multiple teaching hospitals in Ontario, Canada. The results of multivariate logistic regression that 95% confidence intervals p < heparin exposure of or days > p < and p were most and associated with development of BMAH. association included radiologic p or duration of hospitalization were independent risk disease and possibly and hypertension to be for risk of this may be a of bias by using hospital controls as the effect was not by a effect of a of the high-risk patient should include a patient who has been with heparin or days and has had (not by heparin) during the course of the or or or disorders, should not to with lifesaving while awaiting results of The of the Medical Records at the following hospitals was Kingston General Hospital, Hotel Dieu Hospital Ottawa Civic Hospital, Ottawa General Hospital, Health Science The Toronto Hospital, St. Michael’s Hospital St. Joseph’s Health LHSC-Victoria and LHSC-University

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