Patient-physician conversations about life-sustaining treatment: Treatment preferences and participant assessments.

OBJECTIVE: In 2019, the Danish parliament issued legislation requiring Danish physicians to clarify and honor seriously ill patients' treatment preferences. The American POLST (Physician Orders for Life-Sustaining Treatment) document could be a valuable model for this process. The aim of the study was to examine patients' preferences for life-sustaining treatment and participant assessment of a Danish POLST form. METHODS: The study is a prospective intervention based on a pilot-tested Danish POLST form. Participant assessments were examined using questionnaire surveys. Patients with serious illness and/or frailty from seven hospital wards, two general practitioners, and four nursing homes were included. The patients and their physicians completed the POLST form based on a process of shared decision-making. RESULTS: A total of 95 patients (aged 41-95) participated. Hereof, 88% declined cardiopulmonary resuscitation, 83% preferred limited medical interventions or comfort care, and 74% did not require artificial nutrition. The preferences were similar within age groups, genders, and locations, but with a tendency toward younger patients being more in favor of full treatment and nursing home residents being more in favor of cardiopulmonary resuscitation. Questionnaire response rates were 69% (66/95) for patients, 79% (22/28) for physicians, and 31% (9/29) for nurses. Hereof, the majority of patients, physicians, and nurses found that the POLST form was usable for conversations and decision-making about life-sustaining treatment to either a high or very high degree. SIGNIFICANCE OF RESULTS: The majority of seriously ill patients did not want a resuscitation attempt and opted for selected treatments. The majority of participants found that the Danish POLST was usable for conversations and decisions about life-sustaining treatment to either a high or a very high degree, and that the POLST form facilitated an opportunity to openly discuss life-sustaining treatment.

Discussing patient preferences for levels of life-sustaining treatment: development and pilot testing of a Danish POLST form.

BACKGROUND: Medically frail and/or chronically ill patients are often admitted to Danish hospitals without documentation of patient preferences. This may lead to inappropriate care. Modelled on the American Physician Orders for Life-Sustaining Treatment (POLST) form, the purpose of the study was to develop and pilot test a Danish POLST form to ensure that patients' preferences for levels of life-sustaining treatment are known and documented. METHODS: The study was a mixed methods study. In the initial phase, a Danish POLST form was developed on the basis of literature and recommendations from the National POLST organisation in the US. A pilot test of the Danish POLST form was conducted in hospital wards, general practitioners' clinics, and nursing homes. Patients were eligible for inclusion if death was assessed as likely within 12 months. The patient and his/her physician engaged in a conversation where patient values, beliefs, goals for care, diagnosis, prognosis, and treatment alternatives were discussed. The POLST form was completed based on the patient's values and preferences. Family members and/or nursing staff could participate. Participants' assessments of the POLST form were evaluated using questionnaires, and in-depth interviews were conducted to explore experiences with the POLST form and the conversation. RESULTS: In total, 25 patients participated, 45 questionnaires were completed and 14 interviews were conducted. Most participants found the POLST form readable and understandable, and 93% found the POLST form usable to a high or very high degree for discussing preferences regarding life-sustaining treatment. Three themes emerged from the interviews: (a) an understandable document is essential for the conversation, (b) handling and discussing wishes, and (c) significance for the future. CONCLUSION: The Danish version of the POLST form is assessed by patients, families, physicians, and nurses as a useful model for obtaining and documenting Danish patients' preferences for life-sustaining treatment. However, this needs to be confirmed in a larger-scale study.

Decision-making conversations for life-sustaining treatment with seriously ill patients using a Danish version of the US POLST: a qualitative study of patient and physician experiences.

OBJECTIVE: To explore patients' and physicians' perspectives on a decision-making conversation for life-sustaining treatment, based on the Danish model of the American Physician Orders for Life Sustaining Treatment (POLST) form. DESIGN: Semi-structured interviews following a conversation about preferences for life-sustaining treatment. SETTING: Danish hospitals, nursing homes, and general practitioners' clinics. SUBJECTS: Patients and physicians. MAIN OUTCOME MEASURES: Qualitative analyses of interview data. FINDINGS: After participating in a conversation about life-sustaining treatment using the Danish POLST form, a total of six patients and five physicians representing different settings and age groups participated in an interview about their experience of the process. Within the main research questions, six subthemes were identified: Timing, relatives are key persons, clarifying treatment preferences, documentation across settings, strengthening patient autonomy, and structure influences conversations. Most patients and physicians found having a conversation about levels of life-sustaining treatment valuable but also complicated due to the different levels of knowledge and attending to individual patient needs and medical necessities. Relatives were considered as key persons to ensure the understanding of the treatment trajectory and the ability to advocate for the patient in case of a medical crisis. The majority of participants found that the conversation strengthened patient autonomy. CONCLUSION: Patients and physicians found having a conversation about levels of life-sustaining treatment valuable, especially for strengthening patient autonomy. Relatives were considered key persons. The timing of the conversation and securing sufficient knowledge for shared decision-making were the main perceived challenges.KEY POINTSConversations about preferences for life-sustaining treatment are important, but not performed systematically.When planning a conversation about preferences for life-sustaining treatment, the timing of the conversation and the inclusion of relatives are key elements.Decision-making conversations can help patients feel in charge and less alone, and make it easier for health professionals to provide goal-concordant care.Using a model like the Danish POLST form may help to initiate, conduct and structure conversations about preferences for life-sustaining treatment.

Benefits and harm of paracetamol and ibuprofen in combination for post-operative pain: Pre-planned subgroup analyses of the multicenter, randomized PANSAID trial.

BACKGROUND: The "Paracetamol and Ibuprofen in Combination" (PANSAID) trial showed that combining paracetamol and ibuprofen resulted in lower opioid consumption than each drug alone and we did not find an increase in risk of harm when using ibuprofen vs paracetamol. The aim of this subgroup analysis was to investigate the differences in benefits and harms of the interventions in different subgroups. We hypothesized that the intervention effects would differ in subgroups with different risk of pain or adverse events. METHODS: In these pre-planned subgroup analyses of the PANSAID trial population, we assessed subgroup heterogeneity in intervention effects between (a) subgroups (sex, age, use of analgesics, American Society of Anesthesiologists (ASA) score, and type of anesthesia) and morphine consumption, and (b) subgroups (sex, age, use of non-steroidal anti-inflammatory drugs (NSAIDs), and ASA score) and serious adverse events. RESULTS: Test of interaction between age and the pairwise comparison between paracetamol 1 g vs paracetamol 0.5 g + ibuprofen 200 mg (P = .009) suggested lower morphine consumption in patients >65 years. However, post hoc analyses of related outcomes showed no interaction for this pairwise comparison. All other tests of interaction regarding both benefit and harm were not statistically significant. CONCLUSION: These pre-planned subgroup analyses did not suggest that patients in the investigated subgroups benefitted differently from a basic non-opioid analgesic regimen consisting of paracetamol and ibuprofen. Further, there was no evidence of subgroup heterogeneity regarding harm and use of ibuprofen. Because of reduced statistical power in subgroup analyses, we cannot exclude clinically relevant subgroup heterogeneity.

Changes in End-of-Life Practices in European Intensive Care Units From 1999 to 2016.

IMPORTANCE: End-of-life decisions occur daily in intensive care units (ICUs) around the world, and these practices could change over time. OBJECTIVE: To determine the changes in end-of-life practices in European ICUs after 16 years. DESIGN, SETTING, AND PARTICIPANTS: Ethicus-2 was a prospective observational study of 22 European ICUs previously included in the Ethicus-1 study (1999-2000). During a self-selected continuous 6-month period at each ICU, consecutive patients who died or had any limitation of life-sustaining therapy from September 2015 until October 2016 were included. Patients were followed up until death or until 2 months after the first treatment limitation decision. EXPOSURES: Comparison between the 1999-2000 cohort vs 2015-2016 cohort. MAIN OUTCOMES AND MEASURES: End-of-life outcomes were classified into 5 mutually exclusive categories (withholding of life-prolonging therapy, withdrawing of life-prolonging therapy, active shortening of the dying process, failed cardiopulmonary resuscitation [CPR], brain death). The primary outcome was whether patients received any treatment limitations (withholding or withdrawing of life-prolonging therapy or shortening of the dying process). Outcomes were determined by senior intensivists. RESULTS: Of 13 625 patients admitted to participating ICUs during the 2015-2016 study period, 1785 (13.1%) died or had limitations of life-prolonging therapies and were included in the study. Compared with the patients included in the 1999-2000 cohort (n = 2807), the patients in 2015-2016 cohort were significantly older (median age, 70 years [interquartile range {IQR}, 59-79] vs 67 years [IQR, 54-75]; P < .001) and the proportion of female patients was similar (39.6% vs 38.7%; P = .58). Significantly more treatment limitations occurred in the 2015-2016 cohort compared with the 1999-2000 cohort (1601 [89.7%] vs 1918 [68.3%]; difference, 21.4% [95% CI, 19.2% to 23.6%]; P < .001), with more withholding of life-prolonging therapy (892 [50.0%] vs 1143 [40.7%]; difference, 9.3% [95% CI, 6.4% to 12.3%]; P < .001), more withdrawing of life-prolonging therapy (692 [38.8%] vs 695 [24.8%]; difference, 14.0% [95% CI, 11.2% to 16.8%]; P < .001), less failed CPR (110 [6.2%] vs 628 [22.4%]; difference, -16.2% [95% CI, -18.1% to -14.3%]; P < .001), less brain death (74 [4.1%] vs 261 [9.3%]; difference, -5.2% [95% CI, -6.6% to -3.8%]; P < .001) and less active shortening of the dying process (17 [1.0%] vs 80 [2.9%]; difference, -1.9% [95% CI, -2.7% to -1.1%]; P < .001). CONCLUSIONS AND RELEVANCE: Among patients who had treatment limitations or died in 22 European ICUs in 2015-2016, compared with data reported from the same ICUs in 1999-2000, limitations in life-prolonging therapies occurred significantly more frequently and death without limitations in life-prolonging therapies occurred significantly less frequently. These findings suggest a shift in end-of-life practices in European ICUs, but the study is limited in that it excluded patients who survived ICU hospitalization without treatment limitations.

Management and outcome of mechanically ventilated patients after cardiac arrest.

INTRODUCTION: The aim of this study was to describe and compare the changes in ventilator management and complications over time, as well as variables associated with 28-day hospital mortality in patients receiving mechanical ventilation (MV) after cardiac arrest. METHODS: We performed a secondary analysis of three prospective, observational multicenter studies conducted in 1998, 2004 and 2010 in 927 ICUs from 40 countries. We screened 18,302 patients receiving MV for more than 12 hours during a one-month-period. We included 812 patients receiving MV after cardiac arrest. We collected data on demographics, daily ventilator settings, complications during ventilation and outcomes. Multivariate logistic regression analysis was performed to calculate odds ratios, determining which variables within 24 hours of hospital admission were associated with 28-day hospital mortality and occurrence of acute respiratory distress syndrome (ARDS) and pneumonia acquired during ICU stay at 48 hours after admission. RESULTS: Among 812 patients, 100 were included from 1998, 239 from 2004 and 473 from 2010. Ventilatory management changed over time, with decreased tidal volumes (VT) (1998: mean 8.9 (standard deviation (SD) 2) ml/kg actual body weight (ABW), 2010: 6.7 (SD 2) ml/kg ABW; 2004: 9 (SD 2.3) ml/kg predicted body weight (PBW), 2010: 7.95 (SD 1.7) ml/kg PBW) and increased positive end-expiratory pressure (PEEP) (1998: mean 3.5 (SD 3), 2010: 6.5 (SD 3); P <0.001). Patients included from 2010 had more sepsis, cardiovascular dysfunction and neurological failure, but 28-day hospital mortality was similar over time (52% in 1998, 57% in 2004 and 52% in 2010). Variables independently associated with 28-day hospital mortality were: older age, PaO2 <60 mmHg, cardiovascular dysfunction and less use of sedative agents. Higher VT, and plateau pressure with lower PEEP were associated with occurrence of ARDS and pneumonia acquired during ICU stay. CONCLUSIONS: Protective mechanical ventilation with lower VT and higher PEEP is more commonly used after cardiac arrest. The incidence of pulmonary complications decreased, while other non-respiratory organ failures increased with time. The application of protective mechanical ventilation and the prevention of single and multiple organ failure may be considered to improve outcome in patients after cardiac arrest.

Evolution of mortality over time in patients receiving mechanical ventilation.

RATIONALE: Baseline characteristics and management have changed over time in patients requiring mechanical ventilation; however, the impact of these changes on patient outcomes is unclear. OBJECTIVES: To estimate whether mortality in mechanically ventilated patients has changed over time. METHODS: Prospective cohort studies conducted in 1998, 2004, and 2010, including patients receiving mechanical ventilation for more than 12 hours in a 1-month period, from 927 units in 40 countries. To examine effects over time on mortality in intensive care units, we performed generalized estimating equation models. MEASUREMENTS AND MAIN RESULTS: We included 18,302 patients. The reasons for initiating mechanical ventilation varied significantly among cohorts. Ventilatory management changed over time (P < 0.001), with increased use of noninvasive positive-pressure ventilation (5% in 1998 to 14% in 2010), a decrease in tidal volume (mean 8.8 ml/kg actual body weight [SD = 2.1] in 1998 to 6.9 ml/kg [SD = 1.9] in 2010), and an increase in applied positive end-expiratory pressure (mean 4.2 cm H2O [SD = 3.8] in 1998 to 7.0 cm of H2O [SD = 3.0] in 2010). Crude mortality in the intensive care unit decreased in 2010 compared with 1998 (28 versus 31%; odds ratio, 0.87; 95% confidence interval, 0.80-0.94), despite a similar complication rate. Hospital mortality decreased similarly. After adjusting for baseline and management variables, this difference remained significant (odds ratio, 0.78; 95% confidence interval, 0.67-0.92). CONCLUSIONS: Patient characteristics and ventilation practices have changed over time, and outcomes of mechanically ventilated patients have improved. Clinical trials registered with www.clinicaltrials.gov (NCT01093482).

In-hospital cardiac arrest: characteristics and outcome after implementation of systematic practice-oriented training.

Survival after in-hospital cardiac arrest (CA) has been reported to be surprisingly low without any major improvement during the last decade. Cardiopulmonary resuscitation (CPR) quality affects survival after CA, and specific education is necessary for health care professionals participating in CPR. Decisions regarding CPR and do not attempt resuscitation (DNAR) orders remain demanding, as does including patients in the process. Addressed training regarding CPR/DNAR orders is necessary to improve the CPR/DNAR decision process used by physicians. The aim of this retrospective study is to evaluate the clinical impact (return of spontaneous circulation and 21-day survival after CA) of an intervention within one single hospital, including a systematic education of all health care professionals in CPR. In total, there were 33 in-hospital CAs before (12 months) and 176 after (36 months) the intervention. No significant difference was found between the 2 calendar periods.

The impact of religion on changes in end-of-life practices in European intensive care units: a comparative analysis over 16 years.

PURPOSE: Religious beliefs affect end-of-life practices in intensive care units (ICUs). Changes over time in end-of-life practices were not investigated regarding religions. METHODS: Twenty-two European ICUs (3 regions: Northern, Central, and Southern Europe) participated in both Ethicus-1 (years 1999-2000) and Ethicus-2 studies (years 2015-2016). Data of ICU patients who died or had limitations of life-sustaining therapy were analysed regarding changes in end-of-life practices and patient/physician religious affiliations. Frequencies, timing of decision-making, and religious affiliations of physicians/patients were compared using the same definitions. RESULTS: In total, 4592 adult ICU patients (n = 2807 Ethicus-1, n = 1785 Ethicus-2) were analysed. In both studies, patient and physician religious affiliations were mostly Catholic, Greek Orthodox, Jewish, Protestant, or unknown. Treating physicians (but not patients) commonly reported no religious affiliation (18%). Distribution of end-of-life practices with respect to religion and geographical regions were comparable between the two studies. Withholding [n = 1143 (40.7%) Ethicus-1 and n = 892 (50%) Ethicus-2] and withdrawing [n = 695 (24.8%) Ethicus-1 and n = 692 (38.8%) Ethicus-2] were most commonly decided. No significant changes in end-of-life practices were observed for any religion over 16 years. The number of end-of-life discussions with patients/ families/ physicians increased, while mortality and time until first decision decreased. CONCLUSIONS: Changes in end-of-life practices observed over 16 years appear unrelated to religious affiliations of ICU patients or their treating physicians, but the effects of religiosity and/or culture could not be assessed. Shorter time until decision in the ICU and increased numbers of patient and family discussions may indicate increased awareness of the importance of end-of-life decision-making in the ICU.

Global Comparison of Communication of End-of-Life Decisions in the ICU.

BACKGROUND: Prolonging life in the ICU increasingly is possible, so decisions to limit life-sustaining therapies frequently are made and communicated to patients and families or surrogates. Little is known about worldwide communication practices and influencing factors. RESEARCH QUESTION: Are there regional differences in end-of-life communication practices in ICUs worldwide? STUDY DESIGN AND METHODS: This analysis of data from a prospective, international study specifically addressed end-of-life communications in consecutive patients who died or had limitation of life-sustaining therapy over 6 months in 199 ICUs in 36 countries, grouped regionally. End-of-life decisions were recorded for each patient and ethical practice was assessed retrospectively for each ICU using a 12-point questionnaire developed previously. RESULTS: Of 87,951 patients admitted, 12,850 died or experienced a limitation of therapy (14.6%). Of these, 1,199 patients (9.3%) were known to have an advance directive, and wishes were elicited from 6,456 patients (50.2%). Limitations of life-sustaining therapy were implemented for 10,401 patients (80.9%), 1,970 (19.1%) of whom had mental capacity at the time, and were discussed with 1,507 patients (14.5%) and 8,461 families (81.3%). Where no discussions with patients occurred (n = 8,710), this primarily was because of a lack of mental capacity in 8,114 patients (93.2%), and where none occurred with families (n = 1,622), this primarily was because of unavailability (n = 720 [44.4%]). Regional variation was noted for all end points. In generalized estimating equation (GEE) analyses, the odds for discussions with the patient or family increased by 30% (OR, 1.30; 95% CI, 1.18-1.44; P < .001) for every one-point increase in the Ethical Practice Score and by 92% (OR, 1.92; 95% CI, 1.28-2.89; P = .002) in the presence of an advance directive. INTERPRETATION: End-of-life communication with patients and families or surrogates varies markedly in different global regions. GEE analysis supports the hypothesis that communication may increase with ethical practice and an advance directive. Greater effort is needed to align treatment with patients' wishes.

Treatment limitations in intensive care units.

INTRODUCTION: Patients in intensive care units (ICUs) have treatment limited or withdrawn if further treatment is considered futile. This multicentre prospective observational study was part of a European study of patterns of limitations. METHODS: In the first six months of 2016, all patients admitted to three Danish ICUs were screened and those with treatment limitations or death in the ICU were included. End-of-life outcomes were classified into five mutually exclusive categories: withholding, withdrawing, shortening of dying process, failed cardio-pulmonary resuscitation and brain death. This sub-study compared interdepartmental variation in limitation patterns among Danish ICUs. RESULTS: A total of 1,132 ICU patients were admitted, and 264 (23.3%) had limitations to their treatment and/or died and were therefore included. Mortality among these patients was 71.5%, with interdepartmental differences of 52-85% in mortality, but no difference in overall mortality. Specifically, eight different limitations were described with distinct differences amongst departments, most likely due to case mix differences. A total of 96% of patients with limitations suffered from one or more chronic conditions, and 15-48% of the patients with limitations survived to ICU discharge. CONCLUSION: Many Danish ICU patients have limitations imposed on therapy during their ICU stay, but large interdepartmental differences are primarily based on case mix differences. Although a large proportion of patients with limitations ultimately die, limitations do not portend imminent death. FUNDING: None. TRIAL REGISTRATION: Not relevant.

Variations in end-of-life practices in intensive care units worldwide (Ethicus-2): a prospective observational study.

BACKGROUND: End-of-life practices vary among intensive care units (ICUs) worldwide. Differences can result in variable use of disproportionate or non-beneficial life-sustaining interventions across diverse world regions. This study investigated global disparities in end-of-life practices. METHODS: In this prospective, multinational, observational study, consecutive adult ICU patients who died or had a limitation of life-sustaining treatment (withholding or withdrawing life-sustaining therapy and active shortening of the dying process) during a 6-month period between Sept 1, 2015, and Sept 30, 2016, were recruited from 199 ICUs in 36 countries. The primary outcome was the end-of-life practice as defined by the end-of-life categories: withholding or withdrawing life-sustaining therapy, active shortening of the dying process, or failed cardiopulmonary resuscitation (CPR). Patients with brain death were included in a separate predefined end-of-life category. Data collection included patient characteristics, diagnoses, end-of-life decisions and their timing related to admission and discharge, or death, with comparisons across different regions. Patients were studied until death or 2 months from the first limitation decision. FINDINGS: Of 87 951 patients admitted to ICU, 12 850 (14·6%) were included in the study population. The number of patients categorised into each of the different end-of-life categories were significantly different for each region (p<0·001). Limitation of life-sustaining treatment occurred in 10 401 patients (11·8% of 87 951 ICU admissions and 80·9% of 12 850 in the study population). The most common limitation was withholding life-sustaining treatment (5661 [44·1%]), followed by withdrawing life-sustaining treatment (4680 [36·4%]). More treatment withdrawing was observed in Northern Europe (1217 [52·8%] of 2305) and Australia/New Zealand (247 [45·7%] of 541) than in Latin America (33 [5·8%] of 571) and Africa (21 [13·0%] of 162). Shortening of the dying process was uncommon across all regions (60 [0·5%]). One in five patients with treatment limitations survived hospitalisation. Death due to failed CPR occurred in 1799 (14%) of the study population, and brain death occurred in 650 (5·1%). Failure of CPR occurred less frequently in Northern Europe (85 [3·7%] of 2305), Australia/New Zealand (23 [4·3%] of 541), and North America (78 [8·5%] of 918) than in Africa (106 [65·4%] of 162), Latin America (160 [28·0%] of 571), and Southern Europe (590 [22·5%] of 2622). Factors associated with treatment limitations were region, age, and diagnoses (acute and chronic), and country end-of-life legislation. INTERPRETATION: Limitation of life-sustaining therapies is common worldwide with regional variability. Withholding treatment is more common than withdrawing treatment. Variations in type, frequency, and timing of end-of-life decisions were observed. Recognising regional differences and the reasons behind these differences might help improve end-of-life care worldwide. FUNDING: None.

Relieving suffering or intentionally hastening death: where do you draw the line?

OBJECTIVE: End-of-life practices vary worldwide. The objective was to demonstrate that there is no clear-cut distinction between treatments administered to relieve pain and suffering and those intended to shorten the dying process. DESIGN: Secondary analysis of a prospective, observational study. SETTING: Thirty-seven intensive care units in 17 European countries. PATIENTS: Consecutive patients dying or with any limitation of therapy. INTERVENTIONS: Evaluation of the type of end-of-life category; dates and times of intensive care unit admission, death, or discharge; and decisions to limit therapy, medication, and doses used for active shortening of the dying process and the intent of the doctors prescribing the medication. MEASUREMENTS AND MAIN RESULTS: Limitation of life-sustaining therapy occurred in 3,086 (72.6%) of 4,248 patients, and 94 (2.2%) underwent active shortening of the dying process. Medication for active shortening of the dying process included administration of opiates (morphine to 71 patients) or benzodiazepines (diazepam to 54 patients) alone or in combination. The median dosage for morphine was 25.0 mg/hr and for diazepam 20.8 mg/hr. Doses of opiates and benzodiazepines were no higher than mean doses used with withdrawal in previous studies in 20 of 66 patients and were within the ranges of doses used in all but one patient. Doctors considered that medications for active shortening of the dying process definitely led to the patient's death in 72 patients (77%), probably led to the patient's death in 11 (12%), and were unlikely to have led to death in 11 (12%) patients. CONCLUSIONS: There is a gray area in end-of-life care between treatments administered to relieve pain and suffering and those intended to shorten the dying process.

The world's major religions' points of view on end-of-life decisions in the intensive care unit.

OBJECTIVE: Recent research has shown that the religious affiliation of both physicians and patients markedly influences end-of-life decisions in the intensive care unit in the Western world. The world's major religions' standings on withholding and withdrawing of therapy, on hastening of the death process when providing pain relief (double effect) and on euthanasia are described. This review also discusses whether nutrition should be provided to patients in a permanent vegetative state, and the issues of brain death and organ donation. DESIGN: The review is based on literature research and a description of the legislature in countries where religious rulings do influence secular law. RESULTS: Not all religions have distinct rulings on all the above-mentioned issues, but it is pointed out that all religions will probably have to develop rulings on these questions. The importance of patient autonomy in the Western (Christian) world is not necessarily an issue among other ethnic and religious groups, and guidelines are presented with methods to uncover and deal with different ethnic and religious views. CONCLUSION: Many religious groupings are now spread world-wide (most notably Muslims), and with increasing globalization it is important that health-care systems take into account the religious beliefs of a wide variety of ethnic and religious groups when contemplating end-of-life decisions.

Reasons, considerations, difficulties and documentation of end-of-life decisions in European intensive care units: the ETHICUS Study.

OBJECTIVE: To evaluate physicians' reasoning, considerations and possible difficulties in end-of-life decision-making for patients in European intensive care units (ICUs). DESIGN: A prospective observational study. SETTING: Thirty-seven ICUs in 17 European countries. PATIENTS AND PARTICIPANTS: A total of 3,086 patients for whom an end-of-life decision was taken between January 1999 and June 2000. The dataset excludes patients who died after attempts at cardiopulmonary resuscitation and brain-dead patients. MEASUREMENTS AND RESULTS: Physicians indicated which of a pre-determined set of reasons for, considerations in, and difficulties with end-of-life decision-making was germane in each case as it arose. Overall, 2,134 (69%) of the decisions were documented in the medical record, with inter-regional differences in documentation practice. Primary reasons given by physicians for the decision mostly concerned the patient's medical condition (79%), especially unresponsive to therapy (46%), while chronic disease (12%), quality of life (4%), age (2%) and patient or family request (2%) were infrequent. Good medical practice (66%) and best interests (29%) were the commonest primary considerations reported, while resource allocation issues such as cost effectiveness (1%) and need for an ICU bed (0%) were uncommon. Living wills were considered in only 1% of cases. Physicians in central Europe reported no significant difficulty in 81% of cases, while in northern and southern regions there was no difficulty in 92-93% of cases. CONCLUSIONS: European ICU physicians do not experience difficulties with end-of-life decisions in most cases. Allocation of limited resources is a minor consideration and autonomous choices by patient or family remain unusual. Inter-regional differences were found.

The importance of religious affiliation and culture on end-of-life decisions in European intensive care units.

OBJECTIVE: To determine the influence of religious affiliation and culture on end-of-life decisions in European intensive care units (ICUs). DESIGN AND SETTING: A prospective, observational study of European ICUs was performed on consecutive patients with any limitation of therapy. Prospectively defined end-of-life practices in 37 ICUs in 17 European countries studied from 1 January 1999 to 30 June 2000 were compared for frequencies, patterns, timing, and communication by religious affiliation of physicians and patients and regions. RESULTS: Of the 31,417 patients 3,086 had limitations. Withholding occurred more often than withdrawing if the physician was Jewish (81%), Greek Orthodox (78%), or Moslem (63%). Withdrawing occurred more often for physicians who were Catholic (53%), Protestant (49%), or had no religious affiliation (47%). End-of-life decisions differed for physicians between regions and who had any religious affiliation vs. no religious affiliation in all three geographical regions. Median time from ICU admission to first limitation of therapy was 3.2 days but varied by religious affiliation; from 1.6 days for Protestant to 7.6 days for Greek Orthodox physicians. Median times from limitations to death also varied by physician's religious affiliation. Decisions were discussed with the families more often if the physician was Protestant (80%), Catholic (70%), had no religious affiliation (66%) or was Jewish (63%). CONCLUSIONS: Significant differences associated with religious affiliation and culture were observed for the type of end of life decision, the times to therapy limitation and death, and discussion of decisions with patient families.

PANSAID - PAracetamol and NSAID in combination: study protocol for a randomised trial.

BACKGROUND: Effective postoperative pain management is essential for the rehabilitation of the surgical patient. No 'gold standard' exists after total hip arthroplasty (THA) and combinations of different nonopioid medications are used with virtually no evidence for additional analgesic efficacy compared to monotherapy. The objective of this trial is to investigate the analgesic effects and safety of paracetamol and ibuprofen alone and in combination in different dosages after THA. METHODS: PANSAID is a placebo-controlled, parallel four-group, multicentre trial with centralised computer-generated allocation sequence and allocation concealment and with varying block size and stratification by site. Blinding of assessor, investigator, caregivers, patients and statisticians. Patients are randomised to four groups: (A) paracetamol 1 g × 4 and ibuprofen 400 mg × 4, (B) paracetamol 1 g × 4 and placebo, (C) placebo and ibuprofen 400 mg × 4 and (D) paracetamol 0.5 g × 4 and ibuprofen 200 mg. The two co-primary outcomes are 24-h consumption of morphine and number of patients with one or more serious adverse events within 90 days after surgery. Secondary outcomes are pain scores during mobilisation and at rest at 6 and 24 h postoperatively, and number of patients with one or more adverse events within 24 h postoperatively. Inclusion criteria are patients scheduled for unilateral, primary THA; age above 18 years; ASA status 1-3; BMI >18 and <40 kg/m2; women must not be pregnant; and provision of informed consent. Exclusion criteria are patients who cannot cooperate with the trial; participation in another trial; patients who cannot understand/speak Danish; daily use of strong opioids; allergy against trial medication; contraindications against ibuprofen; alcohol and/or drug abuse. A total of 556 eligible patients are needed to detect a difference of 10 mg morphine i.v. the first 24 h postoperatively with a standard deviation of 20 mg and a family wise type 1 error rate of 0.025 (two-sided) and a type 2 error rate of 0.10 for the six possible comparisons of the four intervention groups. DISCUSSION: We started recruiting patients in December 2015 and expect to finish in September 2017. Data analysis will be from September 2017 to October 2017 and manuscript submission ultimo 2017. TRIAL REGISTRATION: EudraCT: 2015-002239-16 (12/8-15); ClinicalTrials.gov: NCT02571361 . Registered on 7 October 2015.

PANSAID-PAracetamol and NSAID in combination: detailed statistical analysis plan for a randomised, blinded, parallel, four-group multicentre clinical trial.

BACKGROUND: Effective postoperative pain management is essential for the rehabilitation of the surgical patient. The PANSAID trial evaluates the analgesic effects and safety of the combination of paracetamol and ibuprofen. This paper describes in detail the statistical analysis plan for the primary publication to prevent outcome reporting bias and data-driven analysis results. METHODS/DESIGN: The PANSAID trial is a multicentre, randomised, controlled, parallel, four-group clinical trial comparing the beneficial and harmful effects of different doses and combinations of paracetamol and ibuprofen in patients having total hip arthroplastic surgery. Patients, caregivers, physicians, investigators, and statisticians are blinded to the intervention. The two co-primary outcomes are 24-h consumption of morphine and proportion of patients with one or more serious adverse events within 90 days after surgery. Secondary outcomes are pain scores during mobilisation and at rest at 6 and 24 h postoperatively, and the proportion of patients with one or more adverse events within 24 h postoperatively. DISCUSSION: PANSAID will provide a large trial with low risk of bias regarding benefits and harms of the combination of paracetamol and ibuprofen used in a perioperative setting. TRIAL REGISTRATION: ClinicalTrials.org identifier: NCT02571361 . Registered on 7 October 2015.

Severe hypercapnia and outcome of mechanically ventilated patients with moderate or severe acute respiratory distress syndrome.

PURPOSE: To analyze the relationship between hypercapnia developing within the first 48 h after the start of mechanical ventilation and outcome in patients with acute respiratory distress syndrome (ARDS). PATIENTS AND METHODS: We performed a secondary analysis of three prospective non-interventional cohort studies focusing on ARDS patients from 927 intensive care units (ICUs) in 40 countries. These patients received mechanical ventilation for more than 12 h during 1-month periods in 1998, 2004, and 2010. We used multivariable logistic regression and a propensity score analysis to examine the association between hypercapnia and ICU mortality. MAIN OUTCOMES: We included 1899 patients with ARDS in this study. The relationship between maximum PaCO2 in the first 48 h and mortality suggests higher mortality at or above PaCO2 of ≥50 mmHg. Patients with severe hypercapnia (PaCO2 ≥50 mmHg) had higher complication rates, more organ failures, and worse outcomes. After adjusting for age, SAPS II score, respiratory rate, positive end-expiratory pressure, PaO2/FiO2 ratio, driving pressure, pressure/volume limitation strategy (PLS), corrected minute ventilation, and presence of acidosis, severe hypercapnia was associated with increased risk of ICU mortality [odds ratio (OR) 1.93, 95% confidence interval (CI) 1.32 to 2.81; p = 0.001]. In patients with severe hypercapnia matched for all other variables, ventilation with PLS was associated with higher ICU mortality (OR 1.58, CI 95% 1.04-2.41; p = 0.032). CONCLUSIONS: Severe hypercapnia appears to be independently associated with higher ICU mortality in patients with ARDS. TRIAL REGISTRATION: Clinicaltrials.gov identifier, NCT01093482.