palliative sedation is considered as one of the last resorts to relieve the refractory symptoms among dying cancer patients .
the prevalence of refractory symptoms in advanced cancer is high ( 50 - 84% ) with the number of individual refractory symptoms ranging from 1 to 27 .
although majority of the refractory symptoms can be controlled , some may remain refractory and uncontrolled till the end and may remain unrelieved despite administering all possible treatments that are available .
palliative sedation is found to be one of the few options to relieve these intractable sufferings at the end of life .
the first ever reported study , on palliative sedation at home settings published in 1990 , found that more than 50% of patients die with uncontrolled physical symptoms that can be controlled only by means of sedation when other means of treatments fail to relieve the suffering .
is it ethical to make the patient sleep and be unaware of one 's surroundings at the time of death ? is palliative sedation a modified form of euthanasia ?
in addition to these , there has always been a concern whether palliative sedation shortens the life span of advanced cancer patients .
although some studies report a shortening of life span following palliative sedation , others show evidence to the contrary .
the variation in results appears to be related to the sample studied , method of palliative sedation used as well as the way in which survival times have been calculated .
this systematic review intends to study the available evidence regarding the effect of palliative sedation on survival time among adult terminally ill cancer patients and answers to the question : does palliative sedation shorten survival time ?
a systematic literature search was done in the following databases : medline , embase , psycinfo , the cochrane central register of controlled trials ( central ) , cinahl , and scopus to identify papers that investigated the effect of survival time in terminally ill cancer patients receiving palliative sedation .
the publications were restricted to 1980 onwards and to papers published in the english language only .
the following key words were used in combinations : conscious sedation , palliative sedation , terminal sedation , continuous deep sedation , carcinoma , neoplasm , life span , survival , end of life care , palliative care , terminal care , and refractory symptoms .
in addition , a thorough hand search of the references of relevant papers was done .
the authors of reputed articles on palliative sedation in different countries were contacted and requested to share their research .
letters to editor , case studies , case series , reviews , and descriptive articles were excluded it was quite evident from earlier search that there were no randomized controlled trials ( rct ) available on this topic .
therefore , it was decided to include two types of studies : prospective trials with adequate control / comparative group which studied mean survival time ( mst ) as an outcome of palliative sedation.retrospective studies with comparative group and mst as an outcome .
prospective trials with adequate control / comparative group which studied mean survival time ( mst ) as an outcome of palliative sedation .
days or hours from the start of palliative sedation to the time of death ( or)the time between the last admission and time of death . days or hours from the start of palliative sedation to the time of death ( or ) the time between the last admission and time of death .
we decided to use the second definition time between the last admission and time of death ) in this review because the first definition would not allow us to use a comparative group ( comparative group is a group which was comparable to the index group but did not receive palliative sedation ) .
data were extracted using a specifically designated data collection form and the following were recorded : first author , year of publication , sample size , type of study ( prospective and retrospective ) , study setting ( hospice , hospital , and home care ) , number of patients sedated , indications for sedation , drugs used for sedation with dosage , mode of sedation ( intermittent / continuous and mild / deep ) , mean and/or median length of sedative use ( days / hours ) , and mean and/or median of overall survival ( days / hours ) .
two researchers independently screened the abstracts of all the studies that were identified by the electronic database searches and hand search .
the inclusion criteria included : adult cancer patients with one or more physical refractory symptoms , palliative sedation given with any sedative , dose , or frequency , presence of a comparative group , andmst measured in hours or days from the start of last admission until death .
adult cancer patients with one or more physical refractory symptoms , palliative sedation given with any sedative , dose , or frequency , presence of a comparative group , and mst measured in hours or days from the start of last admission until death .
exclusion criteria included : studies in which more than 50% of study population had a non - malignant condition and where mst was not available for the non - sedated group .
studies which met the inclusion criteria were assessed for their methodological robustness independently by both researchers according to the criteria developed by hawker 's et al .
as this systematic review included both prospective and retrospective studies , hawker 's criteria were found most suitable to assess the quality of the included studies .
though the first publication of hawker 's criteria had nine items , subsequent publication included ten items , where item six was split into two ( ethics and bias ) .
these criteria assess each part of the study as good , fair , poor , and very poor based on the clarity and relevance of data presented .
each item is scored on a four - point scale ( one being very poor and four being good ) .
descriptive data were used to measure the mst in days which was the primary outcome of this review . because of the divergent study design and marked variability among the nature of participants , interventions , and outcomes of the included studies , it was not possible to combine the data and perform meta - analysis .
a systematic literature search was done in the following databases : medline , embase , psycinfo , the cochrane central register of controlled trials ( central ) , cinahl , and scopus to identify papers that investigated the effect of survival time in terminally ill cancer patients receiving palliative sedation .
the publications were restricted to 1980 onwards and to papers published in the english language only .
the following key words were used in combinations : conscious sedation , palliative sedation , terminal sedation , continuous deep sedation , carcinoma , neoplasm , life span , survival , end of life care , palliative care , terminal care , and refractory symptoms .
in addition , a thorough hand search of the references of relevant papers was done .
the authors of reputed articles on palliative sedation in different countries were contacted and requested to share their research .
letters to editor , case studies , case series , reviews , and descriptive articles were excluded it was quite evident from earlier search that there were no randomized controlled trials ( rct ) available on this topic .
therefore , it was decided to include two types of studies : prospective trials with adequate control / comparative group which studied mean survival time ( mst ) as an outcome of palliative sedation.retrospective studies with comparative group and mst as an outcome .
prospective trials with adequate control / comparative group which studied mean survival time ( mst ) as an outcome of palliative sedation .
days or hours from the start of palliative sedation to the time of death ( or)the time between the last admission and time of death . days or hours from the start of palliative sedation to the time of death ( or ) the time between the last admission and time of death .
we decided to use the second definition time between the last admission and time of death ) in this review because the first definition would not allow us to use a comparative group ( comparative group is a group which was comparable to the index group but did not receive palliative sedation ) .
data were extracted using a specifically designated data collection form and the following were recorded : first author , year of publication , sample size , type of study ( prospective and retrospective ) , study setting ( hospice , hospital , and home care ) , number of patients sedated , indications for sedation , drugs used for sedation with dosage , mode of sedation ( intermittent / continuous and mild / deep ) , mean and/or median length of sedative use ( days / hours ) , and mean and/or median of overall survival ( days / hours ) .
two researchers independently screened the abstracts of all the studies that were identified by the electronic database searches and hand search .
the inclusion criteria included : adult cancer patients with one or more physical refractory symptoms , palliative sedation given with any sedative , dose , or frequency , presence of a comparative group , andmst measured in hours or days from the start of last admission until death .
adult cancer patients with one or more physical refractory symptoms , palliative sedation given with any sedative , dose , or frequency , presence of a comparative group , and mst measured in hours or days from the start of last admission until death .
exclusion criteria included : studies in which more than 50% of study population had a non - malignant condition and where mst was not available for the non - sedated group .
studies which met the inclusion criteria were assessed for their methodological robustness independently by both researchers according to the criteria developed by hawker 's et al .
as this systematic review included both prospective and retrospective studies , hawker 's criteria were found most suitable to assess the quality of the included studies .
though the first publication of hawker 's criteria had nine items , subsequent publication included ten items , where item six was split into two ( ethics and bias ) .
these criteria assess each part of the study as good , fair , poor , and very poor based on the clarity and relevance of data presented .
each item is scored on a four - point scale ( one being very poor and four being good ) .
descriptive data were used to measure the mst in days which was the primary outcome of this review . because of the divergent study design and marked variability among the nature of participants , interventions , and outcomes of the included studies , it was not possible to combine the data and perform meta - analysis .
a total of 442 studies were identified from the search and 421 articles were excluded on the basis of title and abstract [ figure 1 ] .
twenty - one studies were scrutinized and of which nine studies were excluded as they did not meet the inclusion criteria . refer table 2 for details .
details of excluded studies of the remaining 12 studies , one study was excluded as it had poor score when the quality appraisal tool was applied .
four studies were conducted in hospital , four in hospice , two studies were conducted in home care , and one study in both hospital and hospice .
intermittent and continuous sedation were used in combination in six studies , whereas one study used continuous sedation alone .
the level of sedation varied from mild to deep . of the three studies that mentioned the level of sedation , one study used both deep and mild sedation , whereas the other study used only deep sedation .
haloperidol , levomepromazine , lorazepam , phenobarbitone , chlorpromazine , and promethazine were the other sedatives used .
details of sedatives used mst was calculated from the time of last admission until death . for those studies which were conducted at home care settings ,
mst was measured from the onset of home care until death . in this review ,
mst ranged from 8 to 63.9 days in the sedated group . in the non - sedated group , it ranged from 6 to 63.3 days . in two studies ,
mst was of longer duration in studies conducted in home settings compared to those conducted in hospital and hospice .
two studies which were conducted at home settings reported mst of 25 and 63.9 days , respectively . however , all the 11 studies stated that the difference between the sedated and non - sedated groups was not statistically significant .
the comparison of mean survival time between sedated and non - sedated group although this was not the primary outcome of this review , eight studies reported mean duration of sedation in addition to mst .
mst was calculated from the time of last admission until death . for those studies which were conducted at home care settings ,
mst was measured from the onset of home care until death . in this review ,
mst ranged from 8 to 63.9 days in the sedated group . in the non - sedated group , it ranged from 6 to 63.3 days . in two studies ,
mst was of longer duration in studies conducted in home settings compared to those conducted in hospital and hospice .
two studies which were conducted at home settings reported mst of 25 and 63.9 days , respectively . however , all the 11 studies stated that the difference between the sedated and non - sedated groups was not statistically significant .
although this was not the primary outcome of this review , eight studies reported mean duration of sedation in addition to mst .
the main goal of palliative care is to provide symptom relief for patients who are suffering from multiple physical symptoms .
when all possible medical treatments fail to relieve the intractable suffering in dying patients , palliative sedation is chosen to provide relief from suffering rather than to hasten death .
a previous review found that the effect of palliative sedation on life span in advanced cancer patients is inconsistent between the studies .
however , this review had also included studies which did not have a comparative group .
another review that explored the feasibility of palliative sedation at home settings showed palliative sedation as a feasible option of treatment for patients who were dying at home .
this review analyzed six studies out of which four did not have a comparative group .
mst in our review is not comparable with these two reviews as the definition chosen for mst is from the time of last admission until death .
this wide range could be due to inclusion of studies in home care settings , wherein mst was measured from the day of enrollment until death . at home setting , patients enrolled under home care program may not be as terminally ill at the time of enrollment compared with patients in hospice or hospital settings
. their condition may be less serious and co - morbidity may be considerably less .
in addition to this finding , this review found that the mst in sedated group is similar or higher compared with the non - sedated groups .
this is consistent with the findings of a review conducted in home care settings . among the studies which are included in the review , those studies that do not have a comparison group reported the mean duration of sedation as survival time
the mean duration of sedation ranged from a low of 2.5 days to a high of 4.3 days .
de graeff et al . in a review , that was intending to set standards on palliative sedation , do not recommend opioids as a suitable sedative for palliative sedation .
it further states that even very high doses of opioids could not induce sedation in terminally ill cancer patients . however , two studies in our systematic review used morphine as a sedative .
stated that the mean dose of morphine used for sedation was 41.2 mg / day .
however , this study did not report any adverse effect of morphine or its association with mst .
chiu et al . mentioned the use of morphine but did not state the dose used for sedation or its association with mst .
both the studies did not mention whether morphine was effective in inducing sedation compared with other sedatives used in their study .
palliative sedation can cause non - serious side effects such as decreased level of consciousness that results in reduced communication capacity . of the eleven included studies ,
. found no difference in the level of consciousness until 3 days before death between sedated and non - sedated groups .
used an ad hoc scale to measure level of consciousness and found sedated patients became more drowsy and unresponsive 3 days prior to death .
found that the level of consciousness became low as the midazolam dose increased during the last days .
however , this review could not find any serious side effects of palliative sedation in terminal cancer patients such as respiratory suppression without arrest , aspiration , paradoxical reaction , fatal respiratory , and circulatory suppression .
three of the included studies reported the level of symptom relief achieved through palliative sedation as one of the outcomes .
reported good symptom control in sedated group ( 68% and 58% , respectively ) and 34% and 40% in non - sedated groups , respectively .
chiu et al . reported that overall 71.4% of the study population achieved symptom relief .
although sedation is mainly indicated for intractable and refractory physical symptoms , literature supports that sedation can be given for psycho - existential issues .
european association for palliative care recommend that the decision to sedate for psycho - existential issues needs to be taken only after consulting with experts in the field .
only one study in our review described how the decision to sedate for psycho - existential suffering was taken .
it stated that psychologist with expertise in palliative care was consulted before the decision to start sedation .
of the eleven studies included in this review , six of them described psycho - existential reasons as one of the indications for sedation and two studies showed a higher percentage of psycho - existential distress .
mentioned that 6% of patients were sedated for psycho - existential suffering alone and 18% were sedated for both refractory physical and psycho - existential issues .
muller - busch et al . , in a retrospective study , found that 40% required sedation for psycho - existential issues and the need for sedation for psycho - existential issues had been showing an increasing trend over the 7 year study period .
the author explains that this could be because of well - controlled physical symptoms due to accessible palliative care over the years in germany , which probably led to less requirement of sedation for refractory physical symptoms and more for psycho - existential issues .
the strengths of this review include the use of different search engines , namely medline , psycinfo , embase , cinahl , cochrane central , and scopus .
the search was done in large database such as medline , scopus , and cochrane central so as to cover the large number of journal articles .
embase which is a database for pharmacological agents was searched as this review involves sedatives .
the database cinahl was searched to find the journals published in nursing care as palliative sedation is one of the therapeutic measures of last days of dying patients .
the authors of reputed articles on palliative sedation in different countries were sent letters and were requested to share their research .
all palliative care physicians in india , the editor of indian journal of palliative care , and the secretary of the indian association of palliative care were e - mailed to share their researches , thesis , and articles waiting to be published .
though every attempt was made to acquire studies that were not published , we might have missed dissertation , published , and other unpublished works .
the major limitation of this review is inclusion of more retrospective studies as there was a paucity of well - conducted prospective studies in this topic .
therefore , studies which investigated the mst as a secondary outcome have also been included in this review .
there are no rct that has been conducted on this area of research so far , as per our search .
the prospective studies did not use blinding , so there could be bias in the outcome measurement . also performing quality control of selected articles
was a difficult task , as there are limited tools available to assess the quality of observational studies .
the quality of evidence used according to this tool is poor as this has included only observational studies .
the findings of results could not be combined because of divergent study design of the included studies and the heterogeneity of data prevented us from performing a meta - analysis .
mst was not statistically different between sedated and non - sedated groups in any of the included studies in this review .
however , the finding that in all studies regardless of setting , patient group , and different types of palliative sedation , the mst that did not differ from the comparison group is an important finding .
however , this conclusion needs to be taken with consideration of the methodology , study design , and population studied of the included studies in this review . although it is ideal that the systematic review includes only methodologically sound prospective studies , in a situation where a new and a rare intervention is being studied , an initial systematic review needs to consider including retrospective studies as well
. this might pave the way for design and conduct of appropriate prospective studies that will provide valid results to conduct a systematic review on this topic in future .
pragmatic trials yield results that are more useful for the clinician in situations that require different treatment options that can often not be controlled .
so conducting pragmatic trials methods might be a better solution for answering the question of survival times in palliative sedation and larger multicentric pragmatic trials may be the way forward .
 background : patients with advanced cancer often suffer from multiple refractory symptoms in the terminal phase of their life . 
 palliative sedation is one of the few ways to relieve this refractory suffering.objectives:this systematic review investigated the effect of palliative sedation on survival time in terminally ill cancer patients.materials and methods : six electronic databases were searched for both prospective and retrospective studies which evaluated the effect of palliative sedation on survival time . 
 only those studies which had a comparison group that did not receive palliative sedation were selected for the review . 
 abstracts of all retrieved studies were screened to include the most relevant studies and only studies which met inclusion criteria were selected . 
 references of all retrieved studies were also screened for relevant studies . 
 selected studies were assessed for quality and data extraction was done using the structured data extraction form.results:eleven studies including four prospective and seven retrospective studies were identified . 
 mean survival time ( mst ) was measured as the time from last admission until death . 
 a careful analysis of the results of all the 11 studies indicated that mst of sedated and non - sedated group was not statistically different in any of the studies.conclusion:this systematic review supports the fact that palliative sedation does not shorten survival in terminally ill cancer patients . 
 however , this conclusion needs to be taken with consideration of the methodology , study design , and the population studied of the included studies in this review . 