Specialized palliative care services are associated with improved short - and long-term caregiver outcomes Goals of work The goal of this study was to evaluate , at a population level , the association between specialized palliative care services -LRB- SPCS -RRB- and short - and long-term caregiver outcomes . Introduction In the more than 7,300 specialized palliative-care services -LRB- SPCS -RRB- internationally -LSB- 6 -RSB- , a variety of models of service delivery are in place -LSB- 42 -RSB- . A common model of SPCS relies on trained specialist providers , whose work is largely in palliative care ; in this model , coordination of care occurs wherever the patient is located . To date , evaluation of SPCS has been difficult -LSB- 1 , 28 -RSB- . A recent meta-analysis demonstrated that SPCS had a positive impact on patients ' pain , other symptoms , and caregiver satisfaction . Evidence is lacking for other caregiver outcomes , or for economic benefit to justify the community 's healthcare investment in these services -LSB- 31 -RSB- . Palliative care is person-centered care that focuses on optimizing function and comfort in the setting of life-limiting illness . The patient , family member -LRB- s -RRB- , and informal caregiver -LRB- s -RRB- comprise the `` unit of care . '' SPCS must be judged by their net health impact not only on the patient but also on caregivers including short-term -LRB- while the individual performs the functions of caregiver -RRB- and long-term -LRB- once the role has ceased -RRB- outcomes -LSB- 14 -RSB- . There are extensive demands on informal caregivers serving patients with life-limiting illness ; the caregiver burden encompasses physical , emotional , financial , existential , and social responsibilities -LSB- 2 , 20 , 53 -RSB- . Many caregivers perform a variety of roles , and those with a larger number of roles exhibit greater caregiver strain -LSB- 33 -RSB- . Caregiving may compromise health and is associated with premature mortality long after the death of the patient -LSB- 9 , 47 , 50 , 56 , 58 -RSB- . Depression and restriction of activities are common among caregivers -LSB- 5 , 22 , 66 -RSB- . Caregiver outcomes depend upon a host of variables including gender , age , socioeconomic status , living situation , and the type and quality of relationship between the caregiver and the recipient of care -LSB- 43 -RSB- . In the short term , SPCS coordinate support and services in an attempt to minimize caregiver distress and respond to unmet needs -LSB- 40 , 59 -RSB- . `` Unmet needs '' , defined as needs not being addressed plus needs receiving insufficient attention , can be psychological , social , informational , physical -LRB- activities of daily living and household management -RRB- , existential , legal , or financial -LSB- 40 -RSB- . The experience of caregiving has been described in five domains , each of which carries support needs and outcome repercussions ; these domains are -LRB- 1 -RRB- disrupted schedule , -LRB- 2 -RRB- financial problems , -LRB- 3 -RRB- lack of family support , -LRB- 4 -RRB- loss of physical strength , and -LRB- 5 -RRB- caregiver self-esteem -LSB- 24 , 43 -RSB- . Inadequate support of caregivers may predict financial burden and poorer caregiver health -LSB- 59 -RSB- . A summary measure for differences in caregiver outcomes can be the total number of unmet needs -LSB- 40 , 59 -RSB- . In the intermediate to long term , SPCS programs are designed to facilitate families ' and caregivers ' adjustment to the loss that they have experienced -LSB- 34 -RSB- . High-level long-term caregiver outcomes , with which to evaluate these programs , are poorly developed -LSB- 27 , 28 , 68 -RSB- . One such potential caregiver outcome is `` moving on . '' Inability to `` move on '' has been identified as a marker of a complicated course for caregivers after the death -LSB- 50 , 51 -RSB- . Conversely , caregivers often reflect that they are starting to move on with their life at some point after death . Psychiatric and social-work literature defines moving on as establishing a new caregiver-defined equilibrium after having experienced a period of disequilibrium and integrating the potentially life-changing impact of caregiving into one 's new self-perception and life roles in areas including relationships , intimacy , work , and finances -LSB- 7 , 13 , 17 , 19 , 55 -RSB- . Moving on is not simply `` taking up where one left off '' -LSB- 7 -RSB- ; rather , it implies some degree of re-adjustment and integration of the caregiving and bereavement experiences . It may be characterized as returning to a sense of well-being , `` reframing , '' or `` adapting '' -LSB- 53 , 54 , 65 -RSB- . Despite the widespread use of the concept , a validated instrument for measuring moving on has not yet been developed . Nonetheless , the concept of enabling a caregiver to move on can be a first approximation of the long-term impact of SPCS on caregivers . Historically , efforts to assess SPCS ' influence on short - and long-term caregiver outcomes have been limited because of difficulties in identifying a population of caregivers for people with life-limiting illnesses who do not interact with SPCS -LSB- 2 , 41 , 63 -RSB- . For a population-based assessment of SPCS outcomes , the appropriate denominator must include all caregivers for people with life-limiting illnesses , not only those who are referred to SPCS -LSB- 15 , 48 -RSB- . We have previously described a population-based survey methodology , the South Australian Health Omnibus Survey , for identifying caregivers of people with life-limiting illnesses where SPCS were and were not involved ; we used this methodology again in the current study -LSB- 16 -RSB- . Figure 1 depicts the conceptual model being tested in this study . Its aims are to determine whether : SPCS meet the short-term needs of caregivers at the time they are providing support for someone with a life-limiting illness ; andAn association exists between SPCS use and differences in caregiver-defined long-term outcomes in the years after they have completed their role.Fig . 1Conceptual model of the relationship between caregiving , ` moving on ' , specialized palliative care services -LRB- SPCS -RRB- , and unmet needs The null hypothesis was that SPCS were associated neither with differences in unmet needs nor with caregivers ' ability to move on after bereavement . Methods Setting and subjects South Australia has a population of 1.47 million people -LSB- 4 -RSB- . The South Australian government provides funding for SPCS to support general practitioners and community nurses . The programs offered by SPCS in South Australia reflect service structures in the United Kingdom -LRB- UK -RRB- , United States -LRB- US -RRB- , and elsewhere -LSB- 26 , 28 , 31 , 44 -RSB- . Services delivered include care for inpatients , hospital consultation , outpatient clinics , and community visits . Patients access SPCS through referral from any source . The primary eligibility criterion is a life-limiting illness ; approximately 85 % of people referred to SPCS have cancer . Survey methodology The data for this survey were collected in the South Australian Health Omnibus Survey , a state government-associated face-to-face health survey conducted annually since 1991 with approximately 3,000 randomly selected respondents each year . The full survey methodology has been detailed elsewhere -LSB- 16 , 67 -RSB- . Previously , the content and construct validity in palliative care service planning has been validated -LSB- 16 -RSB- . The survey has Ethics Committee -LRB- aka , Internal Review Board ; IRB -RRB- approval . The survey is revised and piloted annually with 50 people using the planned methods for the main survey -LRB- Fig. 2 -RRB- . Anonymous face-to-face interviews were conducted by trained interviewers in the respondents ' homes annually during September to November in 2001 , 2002 , and 2003 . A total of 13,200 households across these 3 years were selected for the survey . Metropolitan households were selected in a skip pattern from a randomly selected starting point within 340 Australian Bureau of Statistics collectors ' districts . In nonmetropolitan areas , households were selected using 100 starting points ; all towns with a population greater than 10,000 were included , and towns with a population above 1,000 were randomly selected with probability proportional to size . One interview was conducted per household with the person aged 15 or older who most recently had a birthday . Data were double-punched ; missing responses were followed up by telephone . Supervisors recontacted 5 % of the study population to verify accuracy of the data . Fig. 2All palliative care survey questions embedded in the South Australian Health Omnibus Survey , 2001 -- 2003 Caregiving was defined for the respondent as follows : ``` Care ' includes attention to any of the needs of the person , including hands-on care , overnight care , respite , shopping , collection of medications , taking to appointments , emotional support , bathing , etc. '' To incorporate differing levels of caregiver burden into the analysis , respondents were asked if they provided : `` day-to-day hands-on care '' -LRB- care 5 -- 7 days per week -RRB- ; `` intermittent hands-on care '' -LRB- care 2 -- 4 days per week -RRB- ; or , `` rare hands-on care '' -LRB- care 1 or less days per week -RRB- . While this method does not encompass information on caregivers ' multiple roles -LRB- e.g. , parent , employee , spouse , and caregiver -RRB- , it does stratify respondents along one axis of caregiver burden -- the intensity of care provided . In the 2003 Health Omnibus Survey , a list of response categories was provided to patients to elicit their perceptions of specific unmet needs -LRB- Fig. 2 -RRB- . `` Unmet needs '' were categorized into 14 types of extra support which the respondent felt would have helped him/her as a caregiver ; these were selected based on our clinical experience with patients and caregivers in palliative care , the published literature , and pilot testing of the Health Omnibus Survey -LSB- 40 -RSB- . These categories map to the five domains of caregiver experience described by Given et al. -LSB- 24 -RSB- in the following way : disrupted schedule -LRB- better out-of-hours care , respite care -RRB- ; financial problems -LRB- financial support/financial planning , legal planning -RRB- ; lack of family support -LRB- emotional support for me , emotional support for the person who died , other emotional support , spiritual support , bereavement support -RRB- ; loss of physical strength -LRB- support with the physical care of the person who died -RRB- ; and caregiver self-esteem -LRB- emotional support for me -RRB- . Additionally , the study response categories included informational and medical management needs -LRB- information about what would happen as the illness progressed , information about services available as the illness progressed , assistance with medications , assistance with physical care and control of symptoms -RRB- . Among the 50 pilot respondents in the 2003 survey year , those who answered the respondent-defined moving on question were subsequently asked , `` What does the concept of ` moving on ' mean to you ? '' Responses were incorporated into the categories for the survey -LRB- Fig. 3 -RRB- . Fig. 3Bereaved caregivers ' definitions of ` moving on ' -LRB- n = 24 -RRB- Data analysis The survey respondents were standardized against the population of all South Australia for gender , 10-year age group , socioeconomic status , and region of residence per the 2001 Australian Census -LSB- 4 -RSB- using direct standardization -LSB- 18 -RSB- and macros combining multiple survey years obtained from the South Australian Department of Human Services -LSB- 16 , 67 -RSB- . Each respondent was assigned a standardized weight and only weighted data were analyzed . Annual datasets were compared ; there were no statistically significant differences , before combining the datasets , between the years in response rate , demographics , recency of death , deaths due to cancer , family/friend relationship between the respondent and the deceased , or care provided.Descriptive statistics were used to summarize respondent characteristics and responses . Relationships between categorical variables were tested using the chi-square test or chi-square test for trend , as appropriate . Relationships between continuous variables were tested using the Student 's t test or one-way analysis of variance -LRB- ANOVA -RRB- , as appropriate . Two-tailed p values were reported ; statistical significance was assumed if p < 0.05 . After testing for multi-collinearity -LRB- all tolerances > 0.9266 -RRB- , variables were entered into a multivariable logistic regression model -LRB- PROC LOGISTIC -RRB- to determine the factors accounting for categorical caregiver outcomes , or a linear regression model -LRB- PROC GLM -RRB- with Tukey corrections -LSB- 10 -RSB- to determine the factors accounting for continuous outcomes . The Statistical Analysis Software -LRB- SAS -RRB- statistical package was used for analysis -LRB- The SAS System , release 8.02 , Cary , North Carolina , USA -RRB- . Sample size calculation A sample size requirement was calculated for the comparison of the mean number of unmet needs -LRB- `` extra supports needed '' -RRB- among caregivers where SPCS were used vs. SPCS not used . Assuming that a difference in one unmet need was clinically meaningful and a standard deviation of 2.1 , then a sample size of 94 caregiver respondents was needed for an alpha 0.05 , beta 0.80 , and ratio of cases to controls of 0.6 -LSB- 21 -RSB- . A sample size requirement was also calculated for the dichotomous comparison of the proportion moving on by use of SPCS . If the baseline rate of moving on was 70 % among those who did not use SPCS and an improvement of 10 % with SPCS was deemed clinically meaningful -LRB- i.e. , increased rate of moving on to 80 % when SPCS was used -RRB- , then a sample size of 385 caregiver respondents was needed for an alpha 0.05 , beta 0.80 , and ratio of cases to controls of 0.60 -LSB- 21 -RSB- . Both sample-size expectations were met . Results Response rate Of the 13,200 households approached , the weighted number of respondents was 9,088 . The response rate was 70.7 % after exclusion of 401 uninhabited houses . Of those approached , reasons given for not responding included refusal -LRB- too busy or not interested ; 2,006 , 15.2 % -RRB- , unable to contact -LRB- 1,059 , 8.0 % -RRB- , respondent unable to speak English -LRB- 195 , 1.5 % -RRB- , selected respondent away for duration of survey -LRB- 176 , 1.3 % -RRB- , illness or mental incapacity precluded participation -LRB- 173 , 1.3 % -RRB- , and terminated interview -LRB- 6 , 0.05 % -RRB- . Population affected by a death About 37 % of the population -LRB- 3,340 -RRB- indicated that someone close to them had `` died of a terminal illness like cancer , motor neuron disease , or emphysema '' in the preceding 5 years -LRB- Table 1 -RRB- . Respondents reporting a death of someone close to them were significantly more likely to be older , married , or widowed , in rural settings , working , and finished with school than those who did not report a death -LRB- all p ≤ 0.01 -RRB- . Table 1Characteristics of respondents who reported a death of a loved one due to a terminal illness and bereaved respondents who identified themselves as caregiversCharacteristicAll respondents who reported death of a loved one due to terminal illnessRespondents who identified themselves as caregivers of the deceased individualsRespondents who were not caregivers of the deceased individualsP value between caregivers and noncaregivers of the deceased individualsaN -LRB- % of all respondents -RRB- 3,340 -LRB- 37 -RRB- 949 -LRB- 10 -RRB- 2,391 -LRB- 26 -RRB- Age group -LRB- years -RRB- 15 -- 29692 -LRB- 21 -RRB- 184 -LRB- 19 -RRB- 507 -LRB- 21 -RRB- 0.508730 -- 44946 -LRB- 28 -RRB- 274 -LRB- 29 -RRB- 673 -LRB- 28 -RRB- 45 -- 59912 -LRB- 27 -RRB- 274 -LRB- 29 -RRB- 638 -LRB- 27 -RRB- 60 -- 74518 -LRB- 15 -RRB- 147 -LRB- 15 -RRB- 371 -LRB- 15 -RRB- 75 and over273 -LRB- 8 -RRB- 70 -LRB- 7 -RRB- 203 -LRB- 8 -RRB- GenderMale1 ,558 -LRB- 47 -RRB- 362 -LRB- 38 -RRB- 1,196 -LRB- 50 -RRB- < 0.0001 Female1 ,782 -LRB- 53 -RRB- 587 -LRB- 62 -RRB- 1,196 -LRB- 50 -RRB- Marital statusMarried or de facto2 ,215 -LRB- 66 -RRB- 603 -LRB- 63 -RRB- 1,612 -LRB- 67 -RRB- < 0.0001 Separated or divorced273 -LRB- 8 -RRB- 62 -LRB- 7 -RRB- 210 -LRB- 9 -RRB- Widowed210 -LRB- 6 -RRB- 111 -LRB- 12 -RRB- 99 -LRB- 4 -RRB- Never married643 -LRB- 19.173 -LRB- 18 -RRB- 470 -LRB- 20 -RRB- Residential locationMetropolitan2 ,270 -LRB- 68 -RRB- 645 -LRB- 68 -RRB- 1,625 -LRB- 68 -RRB- 0.9786 Rural1 ,071 -LRB- 32 -RRB- 304 -LRB- 32 -RRB- 767 -LRB- 32 -RRB- Country of birthEnglish-speaking background2 ,992 -LRB- 90 -RRB- 859 -LRB- 90 -RRB- 2,133 -LRB- 89 -RRB- 0.4447Non-English-speaking background348 -LRB- 10 -RRB- 90 -LRB- 9 -RRB- 258 -LRB- 11 -RRB- Missing1 -LRB- 0 -RRB- 1 -LRB- 0 -RRB- Highest level of educational attainmentDid not complete school , high school or still studying1 ,660 -LRB- 50 -RRB- 479 -LRB- 50 -RRB- 1,182 -LRB- 49 -RRB- 0.6010 Trade qualification , certificate , diploma or higher1 ,680 -LRB- 50 -RRB- 471 -LRB- 50 -RRB- 1,210 -LRB- 51 -RRB- Work statusWork full-time or part-time1 ,852 -LRB- 55 -RRB- 526 -LRB- 55 -RRB- 1,326 -LRB- 55 -RRB- 0.9910 Not working including home duties , student , retired , unemployed and other1 ,488 -LRB- 45 -RRB- 423 -LRB- 44 -RRB- 1,066 -LRB- 45 -RRB- Values are numbers -LRB- percentages -RRB- aChi-square test or chi-square test for trend , as appropriate . Caregivers affected by a death Approximately 10 % -LRB- 949 -RRB- of respondents -LRB- 28.4 % of people bereaved -RRB- identified themselves as caregivers -LRB- Table 1 -RRB- for someone who had died from a life-limiting illness in the past 5 years . When compared to all noncaregivers who reported death of a loved one , caregivers were significantly more likely to be female and widowed -LRB- Table 1 -RRB- . About 905 -LRB- 95.4 % -RRB- caregivers knew if a SPCS was involved in the care of the deceased individual . Caregivers who knew about SPCS usage were more likely to be close family members -LRB- p < 0.0001 ; chi-square test for trend -RRB- but otherwise reported similar patient and caregiver profiles to that of those who `` did not know '' if SPCS were involved . Subsequent analyses describe the 905 caregivers who knew about SPCS usage . About 321 of 905 -LRB- 35.5 % -RRB- individuals provided day-to-day hands-on care for 5 to 7 days per week ; 344 -LRB- 38.0 % -RRB- intermittent hands-on care for 2 to 5 days per week ; and 240 -LRB- 26.5 % -RRB- rare hands-on care for one or less days per week -LRB- Table 2 -RRB- . On average , all caregivers provided care for 22.3 -LRB- SD 37.2 -RRB- months , with day-to-day hands-on caregivers providing care for 24.3 -LRB- SD 39.9 -RRB- months , intermittent caregivers for 23.2 -LRB- SD 38.9 -RRB- months , and rare caregivers for 18.2 -LRB- SD 30.4 -RRB- months -LRB- p = 0.518 ; one-way ANOVA -RRB- . Table 2Relationship between the caregiver and the decreased individual and characteristics of the care providedRelationship between the caregiver and the deceased individualCaregivers -LRB- n -RRB- a905Family relationshipSpouse/partner92 -LRB- 10 -RRB- Child -LRB- of a parent who died -RRB- 209 -LRB- 23 -RRB- Parent -LRB- of a child who died -RRB- 61 -LRB- 7 -RRB- Sibling37 -LRB- 4 -RRB- Other relative303 -LRB- 33 -RRB- Friend175 -LRB- 19 -RRB- Other27 -LRB- 3 -RRB- Close relation -LRB- spouse/parent/child -RRB- 362 -LRB- 40 -RRB- Distant relation or friend543 -LRB- 60 -RRB- Level of care providedDay-to-day hands-on care321 -LRB- 35 -RRB- Intermittent hands-on care344 -LRB- 38 -RRB- Rare hands-on care240 -LRB- 26 -RRB- Duration of care providedbMonths -LSB- mean -LRB- SD -RRB- -RSB- 22.3 -LRB- 37 -RRB- Care for < 1 year134 -LRB- 45 -RRB- Care for ≥ 1 year163 -LRB- 55 -RRB- Values are numbers -LRB- percentages -RRB- except as indicatedaReports are from caregivers who knew if a palliative care service was used -LRB- n = 905 , 95 % of caregivers -RRB- . bReports are from caregivers responding to the 2003 survey only -LRB- n = 314 -RRB- . Use of SPCS Caregivers reported that SPCS provided support in at least 60 % of deaths of terminally-ill people in South Australia -LRB- Table 3 -RRB- and more frequently in people who died of cancer than of noncancer illnesses -LRB- 84.3 vs. 64.7 % , p < 0.0001 ; chi-square test -RRB- . Table 3Characteristics of the deceased individuals and use of specialized palliative care services -LRB- SPCS -RRB- Characteristics of the deceased individualSPCS involved in the care of the deceased individualSPCS not involved in the care of the deceased individualAll deceased individuals cared for by caregiver respondents in this surveyP valueaDeceased individualsb539 -LRB- 60 -RRB- 366 -LRB- 40 -RRB- 905 -LRB- 100 -RRB- Recency of deathMonths -LSB- mean -LRB- SD -RRB- -RSB- 25.3 -LRB- 17 -RRB- 26.0 -LRB- 18 -RRB- 25.6 -LRB- 17.6 -RRB- 0.5578 Cause of deathCancer454 -LRB- 84 -RRB- 235 -LRB- 64 -RRB- 689 -LRB- 76 -RRB- < 0.0001 Noncancer85 -LRB- 16 -RRB- 128 -LRB- 35 -RRB- 213 -LRB- 24 -RRB- Values are numbers -LRB- percentages -RRB- except as indicatedaFrom student t test or chi-square test , as appropriate.bReports are from caregivers who knew if a palliative care service was used -LRB- n = 905 , 95 % of caregivers -RRB- . Unmet needs of caregivers while delivering care and the use of SPCS The relationship between SPCS involvement and additional caregiver supports needed during illness through death was evaluated using the 2003 survey dataset . Approximately 154 -LRB- 48.1 % -RRB- caregivers identified that some type of extra support was needed -- 92 -LRB- 28.8 % -RRB- identified physical support needs , 52 -LRB- 16.3 % -RRB- information needs , 78 -LRB- 24.4 % -RRB- emotional needs , 29 -LRB- 9.1 -RRB- financial needs , and 26 -LRB- 8.1 % -RRB- other needs -- with a mean 1.3 -LRB- SD 2.1 -RRB- extra supports identified per deceased individual . In a linear regression model evaluating the relationship between number of supports needed , level of caregiving , and involvement of a SPCS , involvement of the SPCS helped to predict unmet needs for hands-on caregivers -LRB- Fig. 4 -RRB- . For those without SPCS involvement , the number of extra supports needed increased with the level of caregiving -LRB- t tests for means ; noncaregivers vs rare hands-on caregivers , 0.52 vs. 0.81 , p = 0.2433 ; noncaregivers vs intermittent caregivers , 0.52 vs. 1.56 , p < 0.0001 ; noncaregivers vs day-to-day caregivers , 0.52 vs. 2.35 , p < 0.0001 -RRB- ; this trend was not noted when SPCS were involved , indicating that caregiver gain , in which unmet needs were addressed , occurred in the context of SPCS . Day-to-day caregivers indicated fewer extra support needs when SPCS were involved in the care of the deceased individual -LRB- t tests for means ; no SPCS vs. SPCS , 0.95 vs. 2.3 , p = 0.0031 -RRB- . The frequency of the top five extra support needs of day-to-day caregivers , by SPCS use or not , is presented in Table 4 . Fig. 4Relationship between the number of categories of additional supports needed during the period of the illness through death , level of care provided , and specialized palliative care service -LRB- SPCS -RRB- involvement -LRB- p = 0.0014 for the interaction of level of care and SPCS -RRB- . Data from 2003 survey -LRB- total of 994 respondents and 314 caregiver respondents -RRB- . Linear regression model with Tukey corrections -LRB- PROC GLM -RRB- ; numbers are least squares means of the number of extra support needs identified by respondents . Vertical bars represent 95 % confidence intervalsTable 4Five most frequently identified unmet needs of day-to-day hands-on caregivers -LRB- by percentage of respondents -RRB- Need forPercentage of respondents identifying this unmet needSPCS involved in the care of the deceased individual -LRB- n = 120 -RRB- More help with the physical care of the person22 % More information about what to expect as the illness progressed13 % Better emotional support for the caregiver13 % Better emotional support for the person who had the life-limiting illness13 % More information about services that could be accessed12 % SPCS not involved in the care of the deceased individual -LRB- n = 88 -RRB- Better emotional support for the caregiver30 % Better emotional support for the person who had the life-limiting illness23 % More information about services that could be accessed22 % More help with the physical care of the person21 % Better symptom control19 % Impact of SPCS on long-term caregiver outcomes When SPCS were involved in care , caregivers were significantly more likely to be able to move on with their lives after the death -LRB- Table 5 ; 86.4 vs 77.2 % , p for trend = 0.0016 -RRB- . More than 80 % of people who used SPCS were able to move on by 1 year , whereas it took 2 years for 80 % of people who did not use SPCS to move on -LRB- Fig. 5 -RRB- . About 3 years after the death , 10 -- 14 % of all caregivers still had not been able to move on . Fig. 5Relationship between time and the ability to `` move on '' with life for those with and without involvement from a specialized palliative-care service -LRB- SPCS -RRB- . Chi-square tests were used at each timepoint -LRB- likelihood of moving on by use of SPCS -RRB- Table 5Impact of specialized palliative care services -LRB- SPCS -RRB- on caregiver outcomesOutcomeSPCS involved in the care of the deceased individualSPCS not involved in the care of the deceased individualP value for trendaN537364Ability to `` move on '' with life `` I have been able to move on with my life '' 464 -LRB- 86 -RRB- 281 -LRB- 77 -RRB- 0.0016 `` I am starting to move on with my life '' 60 -LRB- 11 -RRB- 67 -LRB- 18 -RRB- `` I have not been able to move on with my life '' 13 -LRB- 2 -RRB- 16 -LRB- 4 -RRB- Experience vs. expectations Better than expected97 -LRB- 18 -RRB- 55 -LRB- 15 -RRB- 0.6310 As expected172 -LRB- 32 -RRB- 121 -LRB- 33 -RRB- Worse than expected240 -LRB- 45 -RRB- 163 -LRB- 45 -RRB- I did n't know what to expect27 -LRB- 5 -RRB- 22 -LRB- 6 -RRB- Values are numbers -LRB- percentages -RRB- aChi-square test for trend . Predictors of caregivers ' ability to move on In a multivariable logistic regression model , use of SPCS was positively associated with an ability for caregivers to move on -LSB- odds ratio -LRB- OR -RRB- 0.54 , CI 0.36 -- 0.80 ; Table 6 -RSB- . This translates to a 46 % improvement on the ability to move on when a SPCS is involved . No other factors in the model positively influenced ability to move on . Table 6Multivariable logistic regression model -LRB- PROC LOGISTIC -RRB- predicting caregivers unlikely to `` move on '' with lifeVariablesOdds-ratios -LRB- 95 % confidence interval -RRB- Age -LRB- years -RRB- 0.99 -LRB- 0.98 , 1.01 -RRB- Gender -LRB- reference : female -RRB- Male0 .87 -LRB- 0.58 , 1.32 -RRB- Marital status -LRB- reference : married -RRB- Separated or divorced1 .25 -LRB- 0.58 , 2.79 -RRB- Widowed1 .75 -LRB- 0.93 , 3.29 -RRB- Never married1 .25 -LRB- 0.67 , 2.32 -RRB- Residential location -LRB- reference : metropolitan -RRB- Rural0 .87 -LRB- 0.57 , 1.33 -RRB- Country of birth -LRB- reference English-speaking background -RRB- Non-English-speaking background1 .23 -LRB- 0.65 , 2.31 -RRB- Highest level of educational attainment -LRB- reference : trade qualification , certificate , diploma , or higher -RRB- Did n't complete school or still studying0 .96 -LRB- 0.63 , 1.45 -RRB- Work status -LRB- reference : Work full or part time -RRB- Not working , home duties or other1 .43 -LRB- 0.90 , 2.25 -RRB- Recency of death -LRB- reference : death > 2 years ago -RRB- Death in past 2 years2 .58 -LRB- 1.68 , 3.97 -RRB- Cause of death -LRB- reference : cancer -RRB- Noncancer0 .77 -LRB- 0.47 , 1.25 -RRB- Family relationship -LRB- reference : distant relation or friend -RRB- Close relation -LRB- spouse/parent/child -RRB- 3.34 -LRB- 2.13 , 5.23 -RRB- Level of care provided -LRB- reference : rare hands-on care -RRB- Day to day hands-on care3 .72 -LRB- 1.93 , 7.16 -RRB- Intermittent hands-on care2 .42 -LRB- 1.25 , 4.69 -RRB- Expectations vs experience -LRB- reference : Better than expected -RRB- As expected1 .33 -LRB- 0.63 , 2.78 -RRB- Worse than expected/I did n't know what to expect3 .43 -LRB- 1.76 , 6.68 -RRB- Specialized palliative care service -LRB- SPCS -RRB- involvement -LRB- reference : No SPCS involvement -RRB- SPCS involved in the care of the deceased individual0 .54 -LRB- 0.36 , 0.80 -RRB- Unlikely to `` move on '' with life is defined as `` I am starting to move on or I have not moved on with my life '' since the death of the individual Predictors of caregivers inability to move on In a multivariable logistic regression model , caregivers who were unlikely to have `` moved on '' were significantly more likely to have : had a worse-than-expected experience between diagnosis and death -LRB- OR 3.43 , CI 1.76 -- 6.68 ; Table 5 -RRB- ; provided day-to-day or intermittent hands-on care -LRB- OR 3.72 , CI 1.93 -- 7.16 , and OR 2.42 , CI 1.25 -- 4.69 -RRB- ; been in a close family relationship with the deceased -LRB- OR 3.34 , CI 2.13 -- 5.23 -RRB- ; and been bereaved in the preceding 2 years -LRB- OR 2.58 , CI 1.68 -- 3.97 -RRB- . Discussion SPCS are a significant health-system investment . For 30 years , researchers have been working to define the improved outcomes associated with SPCS use -LSB- 2 , 12 , 25 , 30 , 31 , 45 , 46 , 48 , 49 , 61 , 64 -RSB- . The Health Omnibus data support that SPCS are associated with better meeting of needs for day-to-day hands-on caregivers while in the caregiving role and that SPCS have a subsequent long-term impact in improving a caregiver-defined outcome , moving on . Finding the whole caregiver population -LRB- rather than only those referred to services -RRB- has been the dominant challenge in establishing caregiver benefits from SPCS involvement -LSB- 41 -RSB- . By using a population-level method -LSB- 16 -RSB- , this study avoided the bias introduced in studies which only access caregivers through clinicians , case note audits , or registries -LRB- clinical or death -RRB- . Impact of SPCS on caregivers while in the role Our study builds on evidence that caregivers providing constant care who accessed SPCS had fewer unmet needs than did an otherwise identical population who did not access SPCS -LSB- 31 -RSB- . Considering the five domains of the caregiving experience described by Given et al. -LSB- 24 -RSB- , family support was the main domain identified as a source of unmet need ; the proportion of respondents who identified unmet needs in this domain decreased when SPCS were involved . An additional category of unmet needs important to the caregivers in this study pertained to information needs and help with physical and medical aspects of caring . The largest proportion of identified unmet needs reported were in this category ; fewer needs in this category were reported by caregivers of deceased individuals who had SPCS involvement . Impact of SPCS on caregiver long-term outcomes SPCS need proactively to minimize the health risks associated with caregiving -LSB- 23 -RSB- . Other population approaches have shown associations of benefit with SPCS use in caregiver morbidity and mortality -LSB- 63 -RSB- . Christakis and Iwashyna -LSB- 15 -RSB- analyzed 31,000 spousal survivors of someone who died from 1 of 13 frequent causes of expected death vs. propensity-matched to controls from the same US Medicare data set . Mortality rates for the surviving spouses were compared 18 months after the death . There was decreased mortality in the group who used SPCS for 24,721 female caregivers -LRB- 5.4 vs 4.9 % , OR 0.92 , CI 0.84 -- 0.99 -RRB- and 6,117 male caregivers -LRB- 13.7 vs 13.2 % , OR 0.95 , CI 0.84 -- 1.06 -RRB- . The Omnibus study adds to the work of Christakis by suggesting not only that caregivers who interact with SPCS might have an association with less post-role mortality , but that they may adjust more rapidly to their new life after having been a caregiver . Like Christakis ' work , this current study can not attribute a cause-and-effect relationship , although it can demonstrate strength of association . Those willing to access services may have had a better outcome because of problem-focused coping strategies -LSB- 53 -RSB- . McCorkle et al. -LSB- 37 -RSB- conducted a randomized controlled trial -LRB- RCT -RRB- evaluating a home nursing intervention to support palliative caregivers . Despite initial improvement in psychological morbidity of bereaved caregivers in the intervention group , differences that were clinically and statistically significant at 6 and 13 months were no longer apparent by 25 months . Zisook and Shuchter -LSB- 69 -RSB- demonstrated that caregivers ' self-rated `` adjustment '' on a categorical scale showed progressive reductions in the first year . Such patterns are mirrored by our data . In the McCorkle , Zisook , and Omnibus studies , there is a sizeable group of caregivers who still could not move on after several years . The fact that caregiver distress can last for so long after the death of the person for whom they have cared means that the measurement of service impact demands longitudinal approaches -LSB- 32 , 48 , 60 -RSB- . An RCT from Norway randomized access to SPCS by whole populations in a setting comparable to the current study -LSB- 54 -RSB- . The primary outcome for `` close family members '' -LRB- whose level of caring was not clear -RRB- was the intensity of grief reactions as measured in the second part of the Texas Revised Inventory of Grief . There was no difference in grief reactions at 13 months in the 183 family members of the 434 patients who were originally enrolled in the study . By contrast , the higher level question , `` Have you been able to ` move on ' ? '' in our study elicited a substantial difference over time between people who did and did not access SPCS . Although moving on constitutes only part of the definition for complicated grief -LSB- 51 -RSB- -LRB- or prolonged grief reaction -RRB- , the measured rates of complicated grief in similar populations in the literature appear to be of the same order of magnitude , and at the same time after the death of the care recipient , as the findings from the Omnibus study -LSB- 11 , 39 , 52 -RSB- . Other predictors of caregiver outcomes Our study supports other broad population-based observations that the intensity of the level of care provided directly correlates with longer-term caregiver outcomes including burden , health , and mortality -LSB- 57 , 59 -RSB- . The level of caregiving helped to predict both unmet needs and the ability to move on . One of the strongest predictors of an inability to move on was if the experience from diagnosis to death was `` worse than expected ; '' this finding is consistent with other work in the area -LSB- 8 , 29 -RSB- . The discrepancy between expectations and what actually happens can amplify feelings of lack of control over a situation . Conversely , a perceived sense of control is known to be related to overall wellbeing -LSB- 36 -RSB- , and may contribute to an ability to move on . Limitations to the study Analysis was limited to the information collected by the South Australian Health Omnibus Survey , a retrospective population-based approach which is dependent upon recollections of bereaved respondents . Methodologically , a prospective study would have been preferable in order to establish potential causal relationships between SPCS and short - and long-term caregiver outcomes ; however , it would not be practically feasible to conduct such a prospective controlled research study among caregivers at a population level . Because the area of caregiving is a relative newcomer to the realm of clinical research , a paucity of robust assessment measures is , as yet , a major limitation of studies in this population . In assessment of short-term caregiver outcomes , we developed a variable to indicate level of intensity of caregiving , which we could link to caregiver strain . We could not encompass in this variable other factors not provided by the 2001 -- 2003 Omnibus dataset , such as roles that caregivers might have been simultaneously performing.Thus , within our measure of caregiver strain defined by intensity of caregiving , we were unable to differentiate those caregivers who performed multiple roles from those who were solely caregivers . With respect to long-term caregiver outcomes , as noted above , a validated instrument to measure moving on has not yet been developed ; in the absence of such a measure , we acknowledge the respondent-defined nature of the concept as utilized in this study . As a first step toward defining this construct , we asked the 50 respondents for the 2003 annual Health Omnibus Survey pilot for input regarding what the concept of moving on meant to them . Results appear in Fig. 3 and provide some initial parameters for development of a measure of this construct . People who live in remote South Australia and those without caregivers were not represented , and people from some cultural backgrounds may not be seen in these data . All results were based upon the recall of the respondent , which is a validated approach -LSB- 35 , 38 , 62 -RSB- . Caregiver-derived information about the uptake of SPCS is directly derived from first-hand knowledge . Other limitations of the approach have been outlined previously -LSB- 16 -RSB- . The programs offered through SPCS and their funding varies widely across the world , making global assessments of the impact of SPCS difficult -LSB- 3 , 15 , 42 -RSB- . This study reflects a variety of palliative care service types ranging from single-nurse-led rural services to large regional metropolitan interdisciplinary programs . These results can be generalized to similar health settings internationally . Future directions The relationship between fewer unmet needs and SPCS suggests that SPCS do provide substantial support in helping to plan care and identify contingencies in future care . An understanding of the specific attributes of SPCS that make the most difference in meeting caregivers ' needs will be pursued through future work using similar methods . Moving on was defined by respondents of a single year of the Health Omnibus Survey ; broader validation is planned . Subsequent information will enable evaluation of whether moving on , as a measurable outcome , can be improved . An interesting line of inquiry , which would be made possible by inclusion of a baseline question in a future Health Omnibus Survey , is whether respondents who accessed SPCS were further along in the trajectory of psychological acceptance than were respondents who had not accessed SPCS . A positive correlation might indicate a self-selection bias in which respondents who had used SPCS and who had succeeded in moving on had a predisposition to move on , in comparison to respondents who had not chosen to access SPCS . While of academic interest , this information would not impact the utility of the finding that SPCS facilitated moving on among those individuals who accessed services . The methodological strength of the approach used in this study , in which we probed data collected via the Health Omnibus Survey to answer a health services question on the population level , could be improved by favorable comparison of data from the Omnibus on caregiver assessment to data collected using a validated caregiver assessment instrument . This step represents a possible future avenue of study but is not yet possible due to the lack of such an instrument . The relationship between caregivers ' expectations -LRB- diagnosis through death -RRB- and outcomes will be explored with two subsequent years of data . All results need to be confirmed in other health-delivery systems .

O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B I O O O O O O O O O O O B O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

outcome assessment (health care)
health services needs and demands


` No Time to be Lost ! ' Severe Traumatic Brain Injury -LRB- TBI -RRB- remains a major cause of death and disability afflicting mostly young adult males and elderly people , resulting in high economic costs to society . Therapeutic approaches focus on reducing the risk on secondary brain injury . Specific ethical issues pertaining in clinical testing of pharmacological neuroprotective agents in TBI include the emergency nature of the research , the incapacity of the patients to informed consent before inclusion , short therapeutic time windows , and a risk-benefit ratio based on concept that in relation to the severity of the trauma , significant adverse side effects may be acceptable for possible beneficial treatments . Randomized controlled phase III trials investigating the safety and efficacy of agents in TBI with promising benefit , conducted in acute emergency situations with short therapeutic time windows , should allow randomization under deferred consent or waiver of consent . Making progress in knowledge of treatment in acute neurological and other intensive care conditions is only possible if national regulations and legislations allow waiver of consent or deferred consent for clinical trials . Introduction Severe Traumatic Brain Injury -LRB- TBI -RRB- remains a major cause of death and disability afflicting mostly young adult males and elderly people , resulting in high economic costs to society -LSB- 1 -RSB- . Road traffic accidents , domestic and work-related falls and assaults are the main causes of TBI in Europe . The fatality rate for severe TBI is about 30 % and a significant disability in 35 -- 40 % in unselected series . The primary injury initiates a complex sequence of events resulting in secondary brain damage , which can be exacerbated by systemic insults , such as hypotension and hypoxia . Therapeutic approaches focus on reducing the risk on secondary brain injury . Pharmacological neuroprotective agents aim to limit secondary brain damage after the primary acute injury and aim to improve overall outcome . Various neuroprotective agents , mainly targeting specific pathophysiologic mechanisms , have been tested in TBI , but convincing benefit has not been shown -LSB- 2 -RSB- . These data signify an ethical imperative to develop and test new therapeutic strategies and neuroprotective pharmacological agents in the field of TBI . The most important ethical issues pertaining to clinical pharmacological trials in severe TBI are : emergency nature of the researchincapacity of the patients to consentshort therapeutic time windowsrisk/benefit ratio based on the concept that in relation to the seriousness of the injury , significant adverse side effects may be acceptable for treatments with possible benefit . The importance of implications of these issues is not fully recognized outside , and even within , the expert field of treatment of severe TBI . Therapeutic trials to evaluate the efficacy and safety of pharmacological agents are subject to the ethical and juridical principles of Good Clinical Practice , national legislation and European and international regulations . The guiding ethical principles underlying these investigations of treatment are respect for autonomy of the subjects , protection against discomfort , harm , risk and exploitation and the prospect of benefit . The prospect of benefit is almost always complicated by the equipoise underpinning the statistical null hypothesis of pharmacological trials : the hope that an individual patient will benefit , but that this is not more certain than the chance of non benefit . Countries in the European Union are amending legislation to comply with the European Union Directive 2001/20/EC -LSB- 3 -RSB- . In this European legislation , emergency research under deferred or waiver of consent is however not permitted . This will impede or even obviate emergency research phase III trials in TBI in the European countries -LSB- 4 -- 6 -RSB- . The European Clinical trial Directive 2001/20/EC was originally aimed as a European-wide harmonization of the provisions concerning clinical pharmacological trials , with a focus at the facilitation of multi-national clinical research . Since the publication in 2001 , several articles drew attention to the serious threat to the development of evidence-based critical care and emergency research within the European Union -LRB- EU -RRB- posed by the Directive 2001/20/EC which requires prior informed written consent before subjects can be recruited to clinical trials of medicinal products -LSB- 7 -- 19 -RSB- . The Directive made no direct exception for emergency and critical care situations , and therefore threatened to prevent all emergency trials involving patients with acute catastrophic illness causing loss of decision-making capacity and facing -LRB- very -RRB- short therapeutic time windows , such as severe shock , circulatory arrest , acute myocardial infarction , severe stroke and other acute neurological conditions , and moderate and severe traumatic brain injury . Implementation by all EU countries was required by May 2004 . The wording of the Directive permitted some flexibility so that variations were expected that might impact on emergency research -LSB- 20 -RSB- . Lemaire et al. -LSB- 9 -RSB- have described the variations in national legislative responses to the Directive within Europe ; they called on legislators to permit waivers of informed consent for emergency and critical care research , to clarify terms and definitions , and to remove the artificial distinction between interventional and observational research . Concerning practice in The Netherlands , the requirements as described in the Directive have been transposed into the revision of the Medical Research in Human Subjects Act -LRB- WMO -RRB- and Medicine law -LRB- WOG -RRB- -LSB- 21 -RSB- . The amended WMO will change the rules governing drugs studies in The Netherlands . There will be little , if any , change to non-drug research . The Dutch Parliament has accepted the amended WMO for the implementation -LRB- amended WMO -RRB- at November 22 , 2005 and the revised Act became effective in The Netherlands on March 1 , 2006 . The Directive was conceived in part to ensure that participants enrolled in research projects are given adequate information about the nature of the trials and the associated risks . Legislation to protect the interests of patients was necessary and timely . The research community welcomed most of the Articles in the Directive ; they offer guidance and will help to maintain confidence in the probity of medical research . Unfortunately , however , neither those responsible for the Directive , nor many who drafted enabling legislation within Member States , considered the special problems relating to research in emergency nor critical care situations , where consent can not be obtained from subjects and where the need for emergency treatment does not allow time for contact with relatives or other legal representatives . Moreover , in the United States , in 1996 , the FDA had published a waiver of informed consent for certain types of emergency and critical care research after earlier strict provisions had brought to a halt important progress in some critical clinical situations . This shortcoming and the variable response within European Member States to the requirements of the Directive , prompted an expert meeting to be convened in Vienna , Austria on 30 May 2005 -LRB- ` Vienna Initiative to save European Research ' -LSB- VISEAR -RSB- -RRB- . A final report was presented in December 2005 and full reports appeared in the Wiener Klinische Wochenschrift in 2006 . The initiative to the meeting was supported by the Department for Ethics in Medical Research of the Vienna Medical University , in cooperation with the European Forum for Good Clinical Practice -LRB- EFGCP -RRB- , the European Clinical Research Infrastructures Network -LRB- ECRIN -RRB- , and the Vienna School of Clinical Research . One of the six working groups aimed at ` clinical trials including patients who are not able to consent ; the concept of individual direct benefit from research and informed consent in case of the temporarily incapacitated patient ' Their recommendations were published in 2006 -LSB- 6 -RSB- . Consent Procedures Informed consent in TBI victims can , due to the severity of the brain injury , never be obtained from the patients . Proxies or an independent physician must give consent for inclusion in research , or consent must be deferred or waived . Most ethical committees in European countries consider consent by legal representatives -LRB- proxy consent -RRB- valid . The moral basis for proxy consent is restricted to the substituted judgment about the inclusion into the trial . The proxy is supposed to act as the patient , if competent , would have decided . The question remains if the patient wants to be represented by relatives for inclusion in a trial . Roupie et al. -LSB- 22 -RSB- found that only 40.6 % of 1,089 patients would want their spouse/partner to be their surrogate , 28 % want to be represented by the physician in charge of their care . Coppolino and Ackerson -LSB- 23 -RSB- concluded that surrogate decision makers for critical care research resulted in false-positive consent rates in up to 20 % . In the study by Sulmasy et al. -LSB- 24 -RSB- , agreement between patients and proxies varied between 57 % and 81 % , depending on whether previous discussions had taken place on similar situations . It is very unlikely that such existential discussions occur frequently in the target population prone to TBI -LRB- young adult males -RRB- , resulting in lack of evidence as to what their relative would have wanted in case of severe TBI . Most proxies seem to make decisions in emergency situations based on what they hope that will happen -LRB- survival of the patient -RRB- , rather than what is likely to happen -LRB- possible death or -LSB- severe -RSB- disability -RRB- ; this will bias decision-making towards possible therapeutic benefit , however small the chance will be -LSB- 12 -RSB- . In some European countries consent for randomization may be given by an independent physician . Different perceptives on consent by a physician are reflected in conflicting reports . In one study , 84 % of patients with myocardial infarction felt that the physician could independently decide on inclusion , if the patient was unable to consent for himself -LSB- 25 -RSB- . In the field of neonatology only 11 % of parents believe that physicians should decide regarding research participation -LSB- 26 -RSB- . With deferred -LRB- proxy -RRB- consent patients are included into the research without prior consent . After inclusion , the patient -LRB- deferred consent -RRB- or his/her representatives -LRB- deferred proxy consent -RRB- should be informed as soon as possible and subsequent informed consent should be requested . With waiver of consent , all consent is waived . Emergency research without prior consent -LRB- deferred consent or waiver of consent -RRB- can morally be accepted on the principles of fairness , justice and beneficence -LSB- 27 -RSB- . As severe TBI mostly occur outside the domestic situation -LRB- road traffic accidents -RRB- , proxies are rarely available during the first hours after TBI -LSB- 28 -RSB- . This prompted investigators to use deferred -LRB- proxy -RRB- consent and waiver of consent in emergency research facing very short therapeutic time windows . In the National Acute Brain Injury Study : Hypothermia -LRB- NABIS-H -RRB- resulted the adoption of waiver of consent in a higher enrolment and reduced the time between injury and treatment by approximately 45 min -LSB- 27 -RSB- . In this study , relatives of only 11 out of 113 patients arrived within 6 h of the injury . In a septic shock trial the investigators could not contact the proxies within the inclusion time in 74 % of the cases , and these were included under waiver of consent -LSB- 19 -RSB- . In the CRASH trial , mean time to randomization was significantly longer in those hospitals where consent was required compared with those it was not -LRB- 4.4 h -LSB- SE = 0.21 -RSB- vs. 3.2 h -LSB- SE = 0.16 -RSB- -RRB- , the difference in the mean time to randomization was 1.2 h -LSB- 95 % CI 0.7 to 1.8 h -RSB- -LSB- 29 -RSB- . In our series in the dexanabinol trial only 174 out of 6,303 -LRB- 2.7 % -RRB- were excluded for reason that proxy consent could not be obtained within 6 h after injury -LSB- 30 -RSB- . Even when proxies are available , many do not know what the patient 's wishes are -LSB- 31 -RSB- . Surrogate decision makers for critical-care research resulted in false-positive consent rates of 16 -- 20.3 % -LSB- 23 -RSB- . The emotional nature of an emergency situation limited the reliability of proxy consent for clinical research -LSB- 26 , 31 , 32 -RSB- . Only 48 % of 79 representatives of European Brain Injury Consortium -LRB- EBIC -RRB- associated neuro-trauma centers in 19 European countries feel that relatives can make a balanced decision in an emergency situation , 72 % believed that a consent procedure forms a significant factor causing decrease in enrolment rate in a TBI study , and 83 % believed that prior consent is a significant factor causing delay in initiation of study treatment -LSB- 12 -RSB- . Under emergency circumstances , proxy consent does not seem to secure proper patient/subject protection . To our experience the validity of informed consent and proxy consent given in an emergency situation is at least troubling . When consent for clinical research is sought during an emergency situation , comprehension is generally less than optimal -LSB- 33 -- 35 -RSB- . A small minority realized that pharmacological trials are designed to assess not only efficacy but safety as well -LSB- 36 -RSB- . One study searching for public views on emergency exception to informed consent found that most -LRB- 88 % -RRB- of 530 people believed that research subjects should be informed prior to being enrolled , while 49 % believed enrolling patients without prior consent in an emergency situation would be acceptable and 70 % -LRB- 369 -RRB- would not object to being entered into such a study without providing prospective informed consent -LSB- 37 -RSB- . In another study 11 of 12 stroke patients stated that , if the patient of family was not able to consent , then the treating physician should make the decision for inclusion in an emergency trial -LSB- 38 -RSB- . The requirement for all patients to give written informed -LRB- proxy -RRB- consent before enrolment can result in major selection biases , such that registry patients were not representative of the typical patient -LSB- 39 -RSB- . The Emergency Nature of Research in TBI Traumatic Brain Injury is by definition an acute condition . The emergency nature of pharmacological research in TBI is reflected by the fact that experimental and clinical studies have shown that patho-physiological cascades are initiated within minutes to hours following primary injury . Time windows for treatment modalities are therefore considered to be short . Experimental studies have shown the efficacy of many neuroprotective agents , if these were administered before , or within 15 min after injury ; others have shown a window of efficacy of 3 -- 6 h . In the most recent international pharmacological trial in TBI , a phase III randomized , placebo-controlled clinical trial investigating the efficacy and safety of a single dose Dexanabinol -LSB- 40 -RSB- , the experimental data have consistently shown better protection the sooner the agent is administered after TBI -LSB- 41 -RSB- . In the animal model for TBI , this agent given up to 3 h after TBI was protective against breakdown of the blood -- brain barrier and reduced formation of edema and resulted in less severe neurological symptoms -LSB- 42 -RSB- . Administered between 4 h and 6 h after injury , no significant reduction of cerebral edema was noticed , nevertheless neurological symptoms improved . Based on these findings , it may be concluded that in the experimental model the patho-physiologic endpoint can be determined at 3 h . If this time window also form the clinical therapeutic border in patients with severe TBI remains however uncertain . Time windows as applied to clinical trials in TBI have rarely been based on experimental evidence , but were rather determined by organizational and logistical considerations as to the time window within which investigators expected that a considerable number of patients could be enrolled . This was also the case in the recent Dexanabinol trial . One of the inclusion criteria in this trial was ` sustained TBI within the past 6 h -LSB- 40 -RSB- Informed consent could , seen the severity of the brain injury , not be obtained from the patients . Proxy consent was accepted in all participating countries . Deferred patient or proxy consent was only allowed in Australia , Austria , Finland , France and Germany and consent by an independent physician was allowed in Israel , Italy , Spain and the United Kingdom . In all cases of deferred consent , subsequent written assent by patient or proxy was obtained . As coordinating quality control and assurance center for this trial , we had the opportunity to study time windows in more detail -LSB- 43 -RSB- . We defined for this analysis four different time windows : the time between injury and admission in a neuro-trauma center ; the time between admission in a neuro-trauma center and first head CT scan ; the time between the first head CT scan and proxy consent for inclusion in the trial ; the time between proxy consent and study drug administration . For analysis of these four time windows we selected 631 patients . The only selection criterion was that the study drug was administered after written proxy consent . Patients included in the trial under deferred consent were excluded from our analysis . Furthermore , we only included patients from Europe and Israel , excluding patients from Australia and the United States for other reasons -LSB- 44 -RSB- . The time between injury and admission at the neuro-trauma center was for all selected patients between 1 h , 16 h and 2.35 h -LRB- Table 1 , Fig. 1 -RRB- . 501 -LRB- 79.4 % -RRB- patients were directly admitted to the neuro-trauma center , 130 cases -LRB- 20.6 % -RRB- concerns secondary referrals . In all patients the window between admission and the first diagnostic CT scan remains within 1 h. With exception of France , in all countries the median time between injury and completion of the CT scan remained within the 3 h -LRB- Table 1 -RRB- . The longest time window was found between the first diagnostic CT scan and obtaining the required proxy consent -LRB- between 1.71 h and 2.74 h -RRB- . The median time between injury and obtained proxy consent was between 3.75 h and 5.00 h -LRB- IQR 2.75 -- 5.38 h -RRB- -LRB- Table 1 -RRB- . After proxy consent was given , almost all patients subsequently received the study drug within one hour -LRB- Table 1 , Fig. 1 -RRB- . In 85.3 % of all cases the time between injury and study drug administration was longer than 4 h , in 60 % of the cases even longer than 5 h. Table 1Time windows per country -LRB- median + IQR -RRB- Country -LRB- N -RRB- Hours between injury and admission NTC median -LRB- IQR -RRB- Hours between injury and CT scan median -LRB- IQR -RRB- Hours between injury and obtained consent median -LRB- IQR -RRB- Hours between injury and SDA median -LRB- IQR -RRB- Belgium -LRB- 23 -RRB- 0.93 -LRB- 0.65 -- 1.27 -RRB- 1.80 -LRB- 1.28 -- 2.27 -RRB- 3.75 -LRB- 2.75 -- 4.75 -RRB- 4.60 -LRB- 3.98 -- 5.42 -RRB- Netherlands -LRB- 73 -RRB- 1.00 -LRB- 0.75 -- 1.33 -RRB- 1.65 -LRB- 1.32 -- 2.00 -RRB- 4.53 -LRB- 3.95 -- 5.05 -RRB- 5.53 -LRB- 5.07 -- 5.75 -RRB- Israel -LRB- 116 -RRB- 0.93 -LRB- 0.72 -- 1.40 -RRB- 1.91 -LRB- 1.58 -- 2.47 -RRB- 4.01 -LRB- 3.20 -- 4.83 -RRB- 4.67 -LRB- 4.00 -- 5.33 -RRB- Spain -LRB- 75 -RRB- 1.33 -LRB- 0.97 -- 1.67 -RRB- 2.07 -LRB- 1.65 -- 2.53 -RRB- 4.17 -LRB- 3.33 -- 5.00 -RRB- 5.17 -LRB- 4.30 -- 5.58 -RRB- Germany -LRB- 109 -RRB- 1.20 -LRB- 0.88 -- 2.00 -RRB- 1.65 -LRB- 1.30 -- 2.13 -RRB- 4.08 -LRB- 3.42 -- 4.98 -RRB- 5.25 -LRB- 4.25 -- 5.67 -RRB- Italy -LRB- 146 -RRB- 1.25 -LRB- 0.83 -- 2.60 -RRB- 1.77 -LRB- 1.40 -- 2.35 -RRB- 4.92 -LRB- 4.08 -- 5.28 -RRB- 5.50 -LRB- 4.98 -- 5.75 -RRB- France -LRB- 34 -RRB- 2.17 -LRB- 1.42 -- 3.00 -RRB- 3.08 -LRB- 1.97 -- 3.53 -RRB- 5.00 -LRB- 4.50 -- 5.38 -RRB- 5.75 -LRB- 5.17 -- 5.83 -RRB- Other countries * -LRB- 55 -RRB- 1.47 -LRB- 1.00 -- 2.67 -RRB- 1.82 -LRB- 1.33 -- 2.50 -RRB- 4.00 -LRB- 3.08 -- 4.75 -RRB- 5.25 -LRB- 4.33 -- 5.75 -RRB- * Countries with small patient populations -LRB- United Kingdom , Denmark , Austria , Poland , and Turkey -RRB- were combinedFig . 1Time between injury and admission neurotrauma center , time between admission and first CT scan , time between first CT scan and informed consent for inclusion in trial and time between consent and start study drug admission -LRB- from Ref . 43 -RRB- Dexanabinol was one of the promising new pharmaceuticals in the treatment of TBI , but it shown to be safe but not effective in the treatment of severe TBI -LSB- 40 -RSB- . Nevertheless , one can conclude that chances of efficacy increase if treatment is provided earlier . Fact is that in almost all of the studied cases the time between injury and completion of the primary diagnostic CT scan remains within 3 h post injury , which is shown to be the therapeutic time window in the animal model . In 60 % of the cases the time between injury and study drug administration was however longer than 5 h , and in 85.3 % of all cases longer than 4 h -LRB- Fig. 1 -RRB- . Our data provide the empirical proof for considering deferred consent or waiver of consent in trials with a very short therapeutic time window . Risk-Benefit Ratio To my opinion the balance between risk and benefit should be the guiding principle in emergency research in severe TBI . This also applies to the nature and the type of consent procedures . The ethical principle of respect for the autonomy of the patient underpinning the informed consent procedures is not valid for acutely incapacitated patients as TBI victims . Significant concerns has been raised on the validity and ethics of proxy consent in acute emergency situations , and the required written consent cause a significant delay in treatment initiation , as we have shown with our analysis of the time windows . The possible therapeutic benefit , as has been shown in experimental models , form the moral justification for randomizing patients under deferred consent or waiver of consent within a sufficient period of time . The risks should however be acceptable in relation to the severity of the disease or injury . For trials under deferred consent or waiver of consent in acute emergency situations we would constrain the institution of an independent safety committee , under the auspices of regulatory authorities . The obligation to such a committee is based on the experience of a dramatically harmful outcome in some trials under waiver of consent in other fields of medicine -LSB- 45 , 46 -RSB- . Conclusions Specific ethical issues pertaining in clinical testing of pharmacological neuroprotective agents in TBI include the emergency nature of the research , the incapacity of the patients to informed consent before inclusion , short therapeutic time windows , and a risk-benefit ratio based on concept that in relation to the severity of the trauma , significant adverse side effects may be acceptable for treatments with possible benefit . Time windows as applied to randomized controlled clinical trials in TBI have rarely been based on experimental evidence , but were rather determined by organizational and logistical considerations as to a time window within which investigators expected that a considerable number of patients could be enrolled -LSB- 12 -RSB- . The main determinant is now formed by the informed -LRB- proxy -RRB- consent procedures , as also has been compelled in the new European Union Directive 2001/20/EC -LSB- 3 , 6 -RSB- . These requirements assume that relatives are available in emergency situations , and that these relatives can be fully informed and given sufficient time to make a balanced decision in a relatively short time period . The conflict between the desire for early initiation of experimental treatment versus the time required for following consent procedures and the conflict between the desire for following consent procedures requiring prior consent and the doubts about the validity of proxy consent in acute situations are the most problematic aspects of emergency research in TBI . Clinical research in emergency situations without prospective informed or proxy consent is ethically challenging . Severe TBI is without doubt an emergent and life-threatening condition and existing therapy is unsatisfactory seen the high morbidity and mortality in a mostly young group of patients . This should qualify severe TBI for emergency exception form informed consent for randomized clinical controlled trials with pharmacological agents with promising therapeutic benefit facing short therapeutic time windows . Randomized controlled investigations are necessary to determine the safety and effectiveness of new developed agents in these conditions . We have proved that the requirement of previous written proxy consent causes a significant delay till study drug administration in a trial with a neuroprotective agent in TBI . With waiver of consent or deferred -LRB- proxy -RRB- consent the first dose of the experimental drug can be administered directly after completion of the first diagnostic CT scan , which is very close to the experimental therapeutic time window . Randomized controlled phase III trials investigating the safety and efficacy of agents with promising benefit , conducted in acute emergency situations with short therapeutic time windows , should allow randomization under deferred -LRB- proxy -RRB- consent or waiver of consent . Making progress in knowledge of treatment in acute neurological and other intensive care conditions is only possible if national regulations and legislations allow waiver of consent or deferred -LRB- proxy -RRB- consent for clinical trials -LSB- 15 -RSB- . As two of us have said before : ` treat first , ask later ' seems ethically defendable in acute care research -LSB- 4 -RSB- .

O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O B I I O O O O O O O O O O O O O O O O O O O O O O O O B I I O B I O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O B I O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O B I O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

proxy consent
waiver of consent
deferred consent
traumatic brain injury
pharmacological trial