The following is a list of the most commonly prescribed drugs. It represents an abbreviatedversion of the drug list (formulary) that is at the core of your prescription-drug benefit plan. The list is not all-inclusive and does not guarantee coverage. In addition to using this list,you are encouraged to ask your doctor to prescribe generic drugs whenever appropriate. PLEASE NOTE: The symbol * nex
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Ocr documentAlzheimer's & Dementia 2 (2006) 314-321 Factors associated with use of medications with potential to impair cognition or cholinesterase inhibitors among Alzheimer's Edward D. Huey,*, Joy L. Taylor,C, Pauline Luu, John Oehlert, Jared R. Tinklenberg "Cognitive Neuroscience Section, National Institute of Neurological disorders and Stroke, Building 10, Room 5C205, MSC 1440, National Institutes ~f bStanfordlVA Alzheimer's Center, Palo Alto, CA, USA cSierra-Pacific MIRECC, Palo Alto, CA, USA "Stanjord University Department of Psychiatry, Stanford, CA, USA -------------------------------------------------------------- Background: The aim of this study was to use a signal detection method to examine the prevalence of, and patient characteristics associated with, medication with potential to impair cognition and cholinesterase inhibitor use in patients with Alzheimer's disease. Methods: A cross-sectional study was conducted of 1,954 patients with a diagnosis of probable or possible Alzheimer's disease. Concurrent medications were measured, specifically; (I) a medication with potential to impair cognition or (2) a cholinesterase inhibitor. Predictor variables included age, gender, ethnic group, education, age of symptom onset, number of prescriptions, number of medical diagnoses, Mini-Mental State Examination (MMSE), Blessed-Roth Dementia Rating Scale (BRDRS), probable versus possible AD diagnosis. Results: Fifteen percent of the Alzheimer's disease patients were on a medication with potential to impair cognition, and 44% were on a cholinesterase inhibitor. Patient characteristics associated with the prescription of a medication with potential to impair cognition included total number of prescription medications, low education, low MMSE, older age, reported lack of vitamin use, and more medical diagnoses. Patient characteristics associated with the prescription of a cholinesterase inhibitor included reported use of vitamins, the total number of prescription medications, fewer medical diagnoses, lower age of symptom onset, and higher education. Conclusions: Determining the patient characteristics associated with the prescription of a medi- cation with potential to impair cognition can help clinicians identify patients who are at risk for drug-related morbidity. Patient characteristics unassociated with dementia appear to influence the prescription of cholinesterase inhibitors. Signal detection analysis is well suited to this type of @ 2006 The Alzheimer's Association. All rights reserved. Alzheimer's disease; inappropriate medications; cholinesterase inhibitors; Beers criteria; signal detection; receiver operating characteristic analysis total US population, they consume more than 25% of all prescription medications and can have increased rates of Inappropriate medication use, especially in the elderly, adverse effects [I]. One of the challenges in this area has has been a topic of increasing concern. Although older been to develop criteria for inappropriate medication use.
AmLricans (aged 65 years and older) account for 13% of the Although lists of potentially inappropriate medications can- not capture all of the complex factors that are involved in clinical decision making, they can be useful in gauging potentially inappropriate medication use. The most studied 1552-5260/06/$ -see front matter 11) 2006 The Alzheimer's Association. All rights reserved E. D. Huey et al. / Alzheimer's & Dementia 2 (2006) 314-321 of these is the Beers list of explicit criteria for inappropriate Our second objective was to examine the prevalence of, prescribing in older patients. These criteria, first published and patient characteristics associated with, the prescription in 1991  and updated in 1997  and 2003  were of cholinesterase inhibitors in AD patients. Few studies originally developed for nursing home patients. However, have examined the complex factors involved in the prescrip- they have been used to evaluate patients in board and care tion of a therapeutic agent. During the period of our anal- facilities , outpatient settings [6,7], and home health care ysis, cholinesterase inhibitors were prescribed increasingly.
settings  as well as nursing homes . The criteria were By identifying the patient variables associated with the developed initially by Beers on the basis of a literature prescription of a relatively new class of medications, we review and evaluated by experts in geriatrics and pharma- hoped to characterize patients who are most likely to receive cology using a modified Delphi method . The patient- new treatments early. These patients provide an interesting based prevalence of potentially inappropriate use of medi- contrast to the patients prescribed a potentially inappropri- cations found in these studies ranges from 14% to 40% with ate medication identified in the first part of this study. higher percentages generally observed in nursing homes and Our third objective was to use an innovative signal de- lower percentages seen in community samples [10,11], al- tection method called a receiver operating characteristic though 2 Canadian studies observed lower rates in nursing curve (ROC) analysis to meet objectives 1 and 2 above. homes than in the community [12,13]. One representative study found that 21% of community-dwelling elderly pa- tients received at least 1 potentially inappropriate medica- 2. Methods
tion . A similar prevalence was found in a European The 1,954 AD patients in this study were seen in 1 of 11 population . The patient characteristics associated with Alzheimer's Disease Research Centers or Alzheimer's Dis- a higher risk of receiving Beers-criteria medications include ease Centers of California. Patients were self-referred or poor overall health [6,10-12], depression , polyphar- refelTed by outside clinicians to one of these centers for macy [6,10-12,14], and possibly female gender [6,10-12].
further evaluation of possible dementia and potential in- Age has had mixed results as a predictive factor, with some volvement in research projects. All patients who presented studies reporting older patients to be at lower risk [12-14] for their first evaluation at one of the sites between Decem- and others at higher risk [10,15,16] of receiving a Beers- ber 31, 1997 and December 31, 2001 and had an initial consensus diagnosis of probable or possible AD by National Psychotropic medications are the most commonly pre- Institute of Neurological and Communicative Disorders and scribed class of Beers-criteria medications in the elderly Stroke and Alzheimer's Disease and Related Disorders As-  (23%,44%, and 51% of potentially inappropriate med- sociation criteria  were included in the study. The pa- ications in long-term care, office-based settings and outpa- tients' capacity to consent to this study was judged by a tient departments, respectively) , with benzodiazepines, multidisciplinary consensus panel. If a patient was judged to amitriptyline, and propoxyphene being the most commonly be incapable of providing informed consent, a surrogate given medications with cognitive adverse effects decision maker was evaluated, and if deemed appropriate [10,11,16]. One study found that 33% of community- and approved by the patient, assigned research durable dwelling elderly who were taking psychotropic drugs re- power of attorney duties. This project was reviewed and ceived medications that were generally inappropriate .
approved by the appropriate institutional review boards.
Although these studies did not target demented patients, The demographic characteristics of the subjects are pre- they were part of the subject population in many of these studies. One report assessed anticholenergic use and poten- Data from the initial evaluation were used to diagnose tial drug-drug interactions in demented and non demented and determine the medications of the patient. Data were populations [ 17]. In this study, we evaluate the amount of retrieved from the Minimum Uniform Data Set (MUDS), medication with potential to impair cognition use in de- which is maintained by the Institute for Health and Aging for the Alzheimer's Disease Research Centers of California.
We had 3 objectives for this study. The first was to This data set includes the conculTent medications recorded evaluate the use of a subset of Beers-criteria medications at the time of the visit as well as other demographic and that can interfere with cognition in patients with possible or probable Alzheimer's disease (AD). The physicians in our We were interested in the subset of the Beers criteria research group reviewed the list of Beers-criteria medica- medications with interference with cognition as a potential tions and defined a subset of medications that can interfere side effect. This included the majority of Beers-criteria with cognition. We are interested in several questions: How medications (15 of 25). The revised list from 1997 was commonly are AD patients on potentially inappropriate used, and only the medications deemed potentially inappro- medications that can interfere with cognition? What patient priate independent of diagnoses were used (Table 2). characteristics CO1Tespond with the prescription of Beers- The 1997, and not the 2003 criteria were used for several criteria medications that can interfere with cognition? reasons: The 2003 criteria were not published until after our E.D Huey et al. / Alzheimer'.s & Dementia 2 (2006} 314-321 --------------------------------------------- On medication with potential to impair cognition ----------------------------------------------------------------------------------------------------------- ~ ----------------------------------------------------------------------------------------------------------- NOTE Numbers in parentheses are one standard deviation for reported means. Percentages in parentheses are percentages of patients with the charaeteristic out of the total number of patients in each column. p value determined from univariate logistie regressions. study was completed, the 2003 criteria rely more heavily Type of medication used in patients taking a medication with potential than the 1997 criteria on diagnosis-specific potentially in- appropriate medications (which is not as well suited to the analysis we used) and to facilitate comparison to the past literature on this topic. In the Beers criteria, benzodiaz- epines included individual medications as being potentially inappropriate if they were above a certain dose. We did not Methocarbamol (Roxabin), carisoprodol (Soma), have records on specific doses of medications, so we were unable to determine if patients were above a certain dose.
We also do not have information on as needed versus scheduled use. However, we felt that benzodiazepines were an important class of medications to analyze and so we Amitriptyline (Elavil), chlordiazepoxide amitriptyline (Limbitrol), and perphenazine included these medications in our analyses irrespective of The entire MUDS was reviewed, and variables that were judged as clinically significant were included in the analy- sis. These variables were age, gender, ethnic group, educa- alprazolam (Xanax), temazepam (Restoril), tion, age of symptom onset, number of prescriptions, num- Chlordiazepoxide (Librium), chlordiazepoxide ber of medical diagnoses, MMSE , BRDRS , and probable versus possible AD diagnosis. Data from the initial patient evaluation were used in the analysis. Two families of multivariate statistical methods are used Dicyclomine (Bentyl), hyoscyamine (Lev sin, Levsinex), propantheline (Pro-Banthine), commonly to identify subgroups of individuals at elevated belladonna alkaloids Donnatal and others, risk for a particular outcome. Linear models, including logistic regression analysis, are most commonly used. The Antihistamines including chlorpheniramine other family, recursive partitioning, includes classification and regression trees (CART), y automatic interaction de- (Benadry1), hydroxyzine (Visaril, Atarax), cyproheptadine (Periactin), promethazine tection, and signal detection methods  .In this study, we chose to use a signal detection method, rather than logistic regression analysis, for several reasons. First, although lo- gistic regression analysis is preferred for the testing of a priori hypotheses, signal detection techniques are designed NOTE Because some patients were taking more than I medication with for exploratory, hypothesis-generating studies such as this potential to impair cognition, the total percentage sums to greater than 100%. E'. D. Huey et al. / A Izheimer'.I. & Dementia 2 (2006} 314-321 Of \ \ 38 patients on < 5 medications, 98 (9'/,) Of 480 patients on > or = 5 medications, 90 Of 206 patients on < 9 medications, 55 (27%) Of 130 patients on > or = 9 medications. 53 on med with potential to impair cognition are on med with potential to impair cognition (4 J %) are on med with potential to impair Of 869 patients with MMSE Of 198 patients with MMSE Fig I. ROC analysis of medications with potential to impair cognition. one. The recursive partitioning process of signal detection cance of p < 0.01, or the subgroup to be analyzed has 10 or techniques automatically and systematically examines a se- fewer subjects, or after the program has reached 3 levels of ries of interactions  .In contrast, stepwise forward re- analysis (i.e., creating a maximum of 8 subgroups). For gression requires that the investigator enter alllower-order continuous predictor variables (e.g., age), the procedure interaction terms before considering higher-order interac- calculates ROC curves first for the lowest value in the data tions  .These explicit decisions can affect the magnitude set, then for the lowest value plus 1, then plus 2, and so on, of the estimated weights and thus the identified predictors and ultimately selects the value with the best sensitivity and . Second, if there are reasons to believe that predictors specificity. The ROC procedure can be set to differentially are collinear (as in this study), signal detection may be weight the analysis for sensitivity and specificity. Our anal- preferred to logistic regression, because collinear predictors yses were set to equally weigh sensitivity and specificity can substantially bias the estimated weights for the predic- thereby achieving both maximum sensitivity and maximum tors in all-in logistic regression, independent of the actual specificity. The ROC analysis software was developed at the relationship between predictor and outcome [21,23,24].
Sierra-Pacific MIRECC at the Palo Alto Veterans Affairs Third, in stepwise-forward logistic regression, the main hospital. The program is public domain and may be ac- effect terms making up an interaction must be entered be- cessed at http://mirecc.stanford. edu. fore the interaction term itself, which lowers statistical power to detect interaction terms [21,25]. The specific signal detection analysis we used is called a 3. Results
"receiver operating characteristic curve (ROC) analysis" because it calculates ROC curves to identify subgroups of a 3.1. Potentially inappropriate medication use population at higher or lower risk for a dichotomous out- come of interest (in our case, use of a potentially inappro- In Fig. 1 at the top of the analysis, we can see that priate medication and the use of a cholinesterase inhibitor) overall, 15% of patients were prescribed a potentially inap- propriate medication that could interfere with cognition.
Benzodiazepines were the most commonly prescribed class We used an ROC analysis to identify patient character- of medications. Looking at the first cutpoint in the ROC istics associated with prescription of either a potentially analysis, the number of prescriptions ("RxCount") ;::: or less inappropriate medication or of a cholinesterase inhibitor.
than 7 medications best separates patients who are and are The procedure constructs ROC curves for each potential not prescribed a medication with potential to impair cogni- predictor variable and determines which variable best sep- tion (32% vs. 12%). After another split by number of pre- arates the larger group into 2 subgroups with the greatest scriptions, those patients with education less than 4 years or purity of the dichotomous outcome of interest (i.e., the patients with a MMSE score less than 12 were more likely largest difference of prevalence) [21,23]. Each splitting to receive a medication with potential to impair cognition.
variable must achieve a level of statistical significance of p Taking the extreme categories from Fig. I, a patient on 7 or < 0.01 or lower. After a split has been made, the program 8 medications and who had less than 4 years of education repeats the analysis on each of the subgroups to further was 10 times more likely to be on a medication with po- divide the sample into subgroups having improved purity tential to impair cognition as a patient on less than 5 med- for the outcome of interest. The process repeats until the ications with a MMSE score of 12 or greater (62% vs. 6%). program can not identify a predictor that achieves signifi The number of prescriptions was an important variable at E.D. Huey et al / Alzheimer's & Dementia 2 (2006} 314-321 Of 1844 patients wilh age < 89,265 (14%) Of 100 patienls with age > or = 89, 30 on med with potential to impair cognition Of 1536 patients with MMSE > or = 10.204 on med with potcntial to impair cognition Of 1393 patients with < 4 medical diagnoses, Of 143 patients with > or = 4 medical Of91 patientson>or= 1 vitamin. 1) (12%) Of 106 paticnts on 0 vitamins, 31 (29%) on 175 (13%) on med with potential to impair diagnoses, 29 (20%) on med with potential to on med with potcntial to impair cognition Fig 2. ROC analysis of medications with potential to impair cognition excluding number of prescriptions. 3.2. Cholinesterase inhibitor use several steps in the analysis, as we expected based on the results of previous studies and because our outcome vari- able affects this variable. (Because we are looking at the Forty-four percent of the patients were on a cholinester- possibility of being prescribed a certain medication, being ase inhibitor at the time of their initial evaluation (Fig. 3).
prescribed one of these medications will affect the total The greatest predictor of whether a patient was on a cho- number of prescriptions.) We therefore wanted to reanalyze linesterase inhibitor was whether the patient was taking the data without the influence of prescription number and so vitamins. Vitamin takers were more likely to be prescribed Fig. 2 is the same analysis as Fig. 1, excluding the number a cholinesterase inhibitor. Total number of prescriptions also predicted who was on a cholinesterase inhibitor. If we If we drop the number of prescriptions from the analysis look at the ROC analysis without the inclusion of number of (Fig. 2), age, with patient age greater than or equal to 89 prescriptions (Fig. 4), we see that additional predictors of years, is the most predictive of which patients were more being on a cholinesterase inhibitor are fewer medical diag- likely to receive a medication with potential to impair cog- noses, lower age of symptom onset, and education ~14 nition (30% vs. 14%). Among the patients less than 89 years. Looking at the most widely separated groups in Fig.
years, prescription of a medication with potential to impair 4, we see that a patient on vitamins, with fewer than 2 cognition was more likely if they had a MMSE score less medical diagnoses and with symptom onset at less than 74 than 10 and were not taking vitamins. In patients with an years old, was almost 3 times as likely to be on a cholines- MMSE score ~ 10, ~4 medical diagnoses was associated terase inhibitor than a patient not on vitamins, with less than with prescription of a medication with potential to impair 14 years of education, with age of symptom onset at 80 Of 530 pnticnts OIJ > or ~ 4 medicat;Jns, 120 (29"10) on cholinc,tcrasc inhibitor Fig 3. ROC analysis of cholinesterase inhibitor use. E. D. Huey et al. / Alzheimer's & Dementia 2 (2006) 314--321 Of 553 patients with < 2 medical diagnoses.
education, 130 (43'Yo) on cb"lin inbibitor Of 162 patients witb age at Of 410 patients with age at Fig 4, ROC analysis of cholinesterase inhibitor use excluding number of prescriptions. 3.3. Variables chosen for analysis several reasons: We were only looking at a subset of the Beers criteria medications, dementia patients are hopefully Univariate logistic regressions were performed on all of less likely than non-demented patients to receive a medica- the independent variables that we selected for our analysis tion that may interfere with cognition, and the patient pop- (Table 1). With the exception of one split on the basis of ulation we analyzed is a research population that is likely vitamin use at the third level of analysis of Fig. 2, all of the highly motivated and more closely monitored compared to independent variables identified in the ROC analysis were the general population. However, as previously noted, a significant in univariate logistic regressions. Note that this significant proportion of subjects in previous studies on this minor discrepancy does not mean that the ROC analysis was topic suffered from dementia. We were unable to remove incorrect in this instance. Within the subgroup defined by low dose benzodiazepines from our analysis as specified in the previous 2 splits, and removing the effect of number of the Beers criteria , and so 15 % may be an overestima- prescriptions, the third level split on the basis of vitamin use tion, especially since benzodiazepines were the most com- in Fig. 2 was statistically significant at p < 0.0 1 in the ROC monly prescribed class of Beers criteria medications in our sample. This is a serious limitation as benzodiazepines were the largest category of medications with potential to impair cognition prescribed. 7% of the patients were on both a To test whether assessment center had an effect on our medication with potential to impair cognition and a cho- outcomes of interest, we reperformed with ROC analyses linesterase inhibitor. Note that we use the term "potential to discussed above with the inclusion of assessment center as impair cognition." The Beers criteria are guidelines and a variable. There were no differences on the 2 analyses on there may be instances where the best choice for an indi- prescription of a medication with potential to impair cog- vidual patient is a Beers criteria "potentially inappropriate" nition (Figs. I and 2) in the reanalysis. There was an effect of center on cholinesterase inhibitor use, but the effect was Our results agree with previous studies that the strongest minor (at the third and final split level of the analysis).
single predictor for a patient being on a medication with Patients not on vitamins with 4 or more prescriptions were potential to impair cognition is being on a high number of more likely to be on a cholinesterase inhibitor if they were medications. Being on 7 or more medications almost tripled seen at the Martinez, Caljfornia sjte. Patients not on vita- mins who had less than 14 years of education were more a patient's chance of being on a medication with potential to likely to be on a cholinesterase inhibitor if they were seen at impair cognition. Our results also support previous papers the Martinez, California site. Otherwise, the analyses with that have reported older age and more medical diagnoses as and without assessment center were identical. significant predictors of being on a medication with poten- tial to impair cognition. Lower education and lower MMSE have not been as consistently reported. It appears that older, 4. Discussion
sicker, less-educated dementia patients are at particular risk for receiving a medication that can impair cognition. Not Overall, 15% of patients were prescribed a potentially taking vitamins is also a predictor of being on a medication inappropriate medication that could interfere wjth cogni- with potential to impair cognition. This has not, to our tion. This is on the low end of the range reported in previous knowledge, been reported. This information could help cli- studies of outpatient and nursing home elderly (14% to nicians involved in quality improvement projects. For ex- 40%) [10,11]. However, we would expect the number found ample, if a pharmacy wanted to assess whether patients with in our study to be lower than that of previous studies for E.D. Huey et ul. / Alzheimer.s & Dementia 2 (2006) 314-.'121 dementia are on medications with potential to impair cog- cation use were the opposite of those associated with cho- nition, they could prioritize resources to patients identified linesterase inhibitor use. The research on this topic demon- in this study at particularly high risk for being on such a strates the complexity of medical care delivery to the elderly, the continuing need for highly trained prescribing The patient characteristics that predicted cholinesterase physicians, and the need to develop new statistical methods inhibitor treatment are quite different than those that pre- to investigate the complex factors that influence medication dicted medication with potential to impair cognition use.
Taking vitamins was the single best predictor of a patient taking a cholinesterase inhibitor. Other predictors included fewer medical diagnoses, earlier symptom onset, and higher Acknowledgment
education. These characteristics are likely markers for healthier, health-literate patients who may be more likely to The authors thank Helena C KI-aemer for statistical con- request a new medication from their physician. The process sultation, Art Noda for his assistance with the ROC analy- of the prescription of therapeutic medications is an under- sis, Elizabeth C. Lindenberger for her assistance with manu- script preparation, the investigators at the Alzheimer's Overall, 44% of our patients were taking a cholinest- Disease Research Centers of California, the staff at the erase inhibitor. This is, however, a group of dementia StanfordN A Alzheimer's Center, and all of the patients and patients referred to a research clinic during the years their families who were involved in this study. 1998 to 200 1 , and as such it represents a particular group This project was funded by the State of California DHS of patients during a specific period. Preceding and during Alzheimer's Disease Program, Grant Agreement No. 03- this period, more cholinesterase inhibitors were made 75273; NIA-AG 17824; and the Sierra-Pacific Mental Il1ness available (tacrine in 1993, donepezil in 1996, rivastig- Research, Education and Clinical Center (MlRECC). Work mine in 2000, and galantamine in 2001 ), and the pre- was performed at the Palo Alto, California Veteran's Affairs scription of this class of medications gained acceptance in the medical community. We do not know how many patients during this period were on cholinesterase inhib- itors in a general community sample or how the prescrip- References
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 Lane CJ, Bronskill SE, Sykora K, Dhalla IA, Anderson OM, Mam-  Folstein MF, Fo!stein SE, MeHugh PR. "Mini-mental state:' A prac- dani MM, et al. Potentially inappropriate prescribing in Ontario tical method for grading the cognitive !;tate of patients for the clini- community-dwelling older adults and nursing home residents. J Am cian. J Psychiatr Res 1975;]2(3):189-98.  Blessed a, Tomlinson BE. Roth M. The association between quan-  Dhalla IA, Anderson OM, Mamdani MM, Bronskill SE, Sykora K, titative measures of dementia and of senile change in the cerebra] Rochon PA. Inappropriate prescribing before and after nursing home grey matter of elderly subjects. Br J Psychiatry 1968; 114(512)-797- admission. J Am aeriatr Soc 2002;50(6);995-l000.  Fialova D, Topinkova E, aambassi a, Finne-Soveri H, Jonsson PV,  Kiernan M, Kraemer HC, Winkleby MA, King AC. Taylor CB. Do Carpenter I, et al, Potentially inappropriate medication use among logistic regression and signal detection identify different subgroups at elderly home care patients in Europe. JAMA 2005;293(1 I): 1348-58. risk? Implications for the design of tailored interventions Psychol  Mort JR, Aparasu RR. Prescribing potentially inappropriate psycho- tropic medications to the ambulatory elderly. Arch Intern Med 2000;  Hosrner OW Jr, Lemeshow S. Applied logistic regression, New York. [ 16] Aparasu RR, Mort JR. Prevalence, conelates, and associated outcomes of potentially inappropriate psychotropic use in the con1lnunity-  Kraemer H. Evaluating medical tests objective and quantitative dwelling elderly. Am J aeriatr Pharmacother 2004;2(2):102-11 guidelines. Newbury Park, CA. Sage Publications, 1992  airon MS, Wang HX, Bernsten C, Thorslund M. Winblad B, Fastbom  Mcaee D, Reed D, Yano K. The results of logistic analyses when the J. The appropriateness of drug use in an older nondemented and variables are highly conelated. an empirical example using diet and demented population. J Am aeriatr Soc 2001;49(3).277-83. CHD incidence. J Chronic Dis 1984;37(9-10):713-9.  8] McKIlann a, Drachman D, Folstein M, Katzman R, Price O, Stadlan  Cohen J. Statistical power analysis for the behavioral sciences. 2nd ed EM. Clinieal diagnosis of Alzheimer's disease. report of the
P27 Post-partum haemorrhage admissions to critical care: completing the audit cycle A D Evans, L Rees, R E Collis Department ofAnaesthetics, University Hospital of Wales, Cardiff, UK Introduction: Post -partum haemorrhage (PPH) remains a common cause of obstetric admissions to critical care in the UK. Our audit (May 2004 association with carboprost (HaemobateTM) and pulmon