Risk Factors for Post-Intensive Care Syndrome in Family Members (PICS-F) of Adult Patients: A Systematic Review.

Background: Relatives of critically ill patients who either die or survive the intensive care unit (ICU) may develop substantial mental health problems that are collectively dened as Post-Intensive Care Syndrome in Family (PICS-F). It is important to document in a systematic manner all of the possible risk factors associated with the development of the latter. Methods: By using a systematized search strategy we included studies that focused on PICS-F in relatives of adult ICU patients and reported the risk factors associated with its development. The search was conducted within PubMed, Embase, SCOPUS, clinicaltrials.gov and Cochrane Library on the 2nd of May, 2021. PRISMA guidelines were implemented for appropriate reporting. Results: We included 52 papers covering 8293 relatives. The prevalence of PICS-F varied between 2.5-69%. We identied over 70 different risk factors of PICS-F, among which we distinguished patient-related (n=28), relative-related (n=33) and medical staff-related (n=9) risk factors. Among 17 studies with the highest quality we identied the 7 following factors associated with the development of PICS-F: younger age of a patient, death of a patient, depression in relatives during the ICU stay, history of mental disorders in relatives, being a spouse and low satisfaction with communication & care in the ICU. Conclusions: PICS-F is a highly prevalent phenomenon that may be exacerbated by a number of risk factors. Special attention should be paid to proper identication of susceptible relatives in order to prevent PICS.


Introduction
Due to the extensive development in the medical area, short-term outcomes of intensive and critical care patients' have been drastically improving over the last decades. The psychological repercussions in the intensive care unit (ICU) survivors had already been noticed and reported thoroughly in the past century [1,2]. However, the burden of critical illness of the beloved ones is also tremendous for their families. The ICU is possibly the most unfamiliar and intimidating part of the hospital since it requires the most advanced monitoring and involves major medical procedures that may not be understood by unacquainted relatives. The admission to such a ward is usually sudden and unexpected, which causes immense stress and pain for the families. Uncertainty and poor prognoses keep the family members constantly in a precarious position. The relatives usually play the role of caregivers and surrogate decision makers for their spouses, parents, children or siblings. Because of all these reasons, family members of critically ill patients are at high risk of anxiety, depression, post-traumatic stress disorder (PTSD) and other psychiatric disorders [3]. In order to describe this phenomenon, the term PICS-F (Post-Intensive Care Syndrome in Family) was developed [3]. It's occurrence may be devastating for the relatives and should not be belittled. The perseverance of the patient's relatives well-being should be a matter of utmost priority, as the number of ICU admissions is rising together with population aging [4]. It is crucial to determine which factors may increase the risk of PICS-F incidence in order to provide the best care for both patients and their families. Therefore, we decided to collect and analyze all the available data regarding this issue in a systematic manner, according to the PRISMA checklist [5]. A PICO criteria is presented on Table 1.

Protocol and registration
We did not register the protocol of this systematic review.

Eligibility criteria
We included studies that only focused on relatives of adult patients who were hospitalized in the ICU in the past (who were either discharged or died during hospitalization). We primarily focused on the prevalence and risk factors associated with the occurrence of post-intensive care syndrome (de ned as either anxiety, depression, PTSD, complicated grief, burden/overload or activity restriction). We included studies in which full, peer-reviewed reports were published before the day of search (2nd May 2021).
Additionally, the papers had to be published in English, regardless of the year of publication. Qualitative studies, case reports, case series, systematic reviews, meta-analyses and papers that assessed mental health of relatives only during ICU hospitalization were excluded.

Information sources
The search was conducted within PubMed, Embase, clinicaltrials.gov, SCOPUS and Cochrane Library on the 2nd of May, 2021.

Study selection & # 10. Data collections process
After importing all the papers from the initial search using search string, three independent investigators (ZP, NR, KMe) assessed studies by analyzing titles and abstracts (via Mendeley®). The study was processed further if all adjudicators agreed to include the paper for review. If only two reviewers agreed to proceed with the manuscript, the second assessment of the paper was performed by the fourth investigator (ŁJK).

Data items
Authors, year of publication, type of a study, relatives' and patients' characteristics (number of individuals, sex ratio, median or mean age, relationship between patients and relatives, organ failure severity of patients, enrollment criteria), time-point at which mental health assessment of families was performed, mental health assessment tools, any risk factors for the occurrence of PICS-F and prevalence of PICS-F. We analyzed how many times a risk factor appeared in the included papers and how many times a risk factor achieved statistical signi cance. Multivariable analyses took priority over univariable analyses. In order to improve the readability of our article, we decided to move the Table with results of the individual  studies to the Additional le (Table 1,2,3,4 and 5 in Additional le 1) and, instead, designed a table that would more comprehensively grasp the characteristics of all papers. We calculated the range values, the median values and their interquartile ranges for certain variables that were reported by the studies ( Table  2).

Quality assessment
Newcastle-Ottawa scale (NOS) was implemented to assess the quality of cohort studies [6]. A modi cation of NOS was introduced to assess the quality of cross-sectional studies [7]. The total NOS score of each study was converted to Agency for Healthcare Research and Quality standards [8]. Thus, the studies were rated as either good, fair or poor. All authors participated in the quality assessment of the included studies. Any disagreements were resolved by a discussion.

Study selection
By using the search string within various medical databases (look at Information sources) we identi ed 4608 articles in total. After removing duplicates (n = 1079) we screened the remaining papers by evaluating titles and abstracts (n = 3529). By using the PICO criteria and the inclusion and the exclusion criteria, we distinguished 340 papers for the full-text read assessment. After excluding the articles for numerous reasons, the nal 52 papers were included in the systematic review. We identi ed 40 [49] from which we extracted all the relevant data. Study selection process is presented on a owchart (Fig. 1).

Study characteristics
The majority of studies were conducted in either North America (n = 22) or Europe (n = 20). Nearly half of the studies (n = 25) explored more than one PICS-F area. The total number of patients and relatives included across the studies was 7448 and 8102 respectively. The summary of included studies is presented on Table 2.

Risk factors for PICS-F
We distinguished several subgroups of risk factors. In total, 70 potential risk factors for PICS-F were identi ed, among which the most common were relative-related risk factors (n = 33), followed by patientrelated (n = 28) and medical-staff-related (n = 9) factors. The highest number of risk factors associated with development of anxiety, depression, PTSD and complicated grief were variables involving the relatives, while the presence of caregiver burden was rather connected with worse condition and lower level of patient's activity after ICU stay. The complicated grief was considerably determined by factors regarding the patient's death. The most prevalent (identi ed by at least 3 studies) risk factors for particular outcomes were the following: for anxiety: medical history of mental disorders among the relatives; for PTSD and depression: death and worse condition of a patient, female sex of the relative, being a spouse, as well as mental disorders of the relative in medical history or during patient's ICU stay.
The risk factors related to each outcome and their occurrence are listed in Table 3.

Discussion
In this systematic review, we focused on identifying risk factors associated with the development of PICS-F. The majority of participants consisted of women below 65 years who were spouses of the ICU patients.
We described over 70 potential risk factors, among which, younger age of a patient, death of a patient, depression in relatives during the ICU stay, history of mental disorders in relatives, being a spouse and low satisfaction with communication & care in the ICU seem to be most well-documented. Secondly, the prevalence of PICS-F is high and seems to depend on its subtype (e.g. complicated grief/caregiver burden possibly occurring more frequently than anxiety, depression or PTSD). Importantly, the majority of included studies presented poor quality and substantial heterogeneity, therefore, we failed to conduct meta-analysis.
The majority of studies were conducted in Western countries (n = 45). Noteworthily, there was a considerable difference in terms of healthcare, income, culture, and structure of societies between these countries and other parts of the world. This divergence could in uence the way the risk factors shape the development of PICS-F. For instance, as developed countries may exhibit higher ICU-survival rates, the importance of certain outcomes, e.g. caregiver burden may be markedly different for countries with higher mortality rates, where, in contrast, complicated grief may be expressed more strongly.
The heterogeneity among the studies was noticeable in terms of selection of the participants, representativeness of patient populations, mental health screening-tools and assessment of the outcomes (outcome de ned as either continuous change in psychiatric scores or as a presence of clinically signi cant PICS-F). It is important to note that the majority of the outcomes were reported by the participants and not diagnosed by specialists in psychiatry and psychology. This introduces a signi cant limitation in terms of either prevalence of PICS-F or the association between certain risk factors and PICS-F. Moreover, a number of studies did not implement multivariable analyses to assess the signi cance of risk factors. Lastly, we observed a considerable proportion of studies with loss-to-follow-up exceeding 20% which also introduces bias to our analysis ( Table 2).
In order to assess the power of certain risk factors, we analyzed what frequency a given risk factor was statistically signi cantly associated with PICS-F in regards to all studies that examined that factor (Table 3 and Additional le 1: Tables 7 & 8). For instance, "mental disorders during an ICU stay" (Table 3, depression) was reported to be signi cant in 4 out of 6 studies that explored this risk factor. In contrast, "lower level of education" was reported only in 1 out of 10 studies (Table 3, anxiety). The above mentioned proportions could shape the way we interpret every risk factor. Importantly, death of a patient was not always identi ed as a signi cant risk factor for PICS-F (5/16). This nding could suggest that a fraction of patients who survive the ICU may require excessive care and their quality of life may be signi cantly reduced. This would result in relatives experiencing higher burden, higher stress and lifestyle disturbances that promote the occurrence of PICS-F in a similar fashion as would the death of a patient.
To summarize, although we de ned over 70 risk factors, it is possible that a number of them are rather controversial and should be con rmed in further studies, particularly because many of those factors were explored just once across the literature.

Conclusions
There are a plethora of possible risk factors associated with the development of PICS-F that also seem to depend on its subtype. Among others, younger age of a patient, death of a patient, depression in relatives during the ICU stay, history of mental disorders in relatives, being a spouse and low satisfaction with communication & care in the ICU are associated with the development of PICS-F. Therefore, special attention should be paid to relatives who represent the above mentioned factors. The de nitive conclusions are considerably limited by the quality and heterogeneity of the included studies.

Availability of data and materials
Not applicable.

Competing interests
The authors declare that they have no competing interests.