Associations between enteral nutrition and outcomes in the SUP-ICU trial: Results of exploratory post hoc analyses.

BACKGROUND: Enteral nutrition may affect risks of gastrointestinal bleeding, pneumonia and mortality in critically ill patients and may also modify the effects of pharmacological stress ulcer prophylaxis. We undertook post hoc analyses of the stress ulcer prophylaxis in the intensive care unit trial to assess for any associations and interactions between enteral nutrition and pantoprazole. METHODS: Extended Cox models with time-varying co-variates and competing events were used to assess potential associations, adjusted for baseline severity of illness. Potential interactions between daily enteral nutrition and allocation to pantoprazole on outcomes were similarly assessed. RESULTS: Enteral nutrition was associated with lower risk of clinically important gastrointestinal bleeding (cause-specific hazard ratio [HR]: 0.29, 95% confidence interval: [CI] 0.19-0.44, p < .001), higher risk of pneumonia (HR: 1.44, 95% CI: 1.14-1.82, p = .003), and lower risk of all-cause mortality (HR: 0.22, 95% CI: 0.18-0.27, p < .001). Enteral nutrition with allocation to pantoprazole was associated with a lower risk of mortality (HR: 0.27, 95% CI: 0.21-0.35, p < .001), similar to enteral nutrition with allocation to placebo (HR: 0.17, 95% CI: 0.13-0.23, p < .001). Allocation to pantoprazole with no enteral nutrition had little effect on mortality (HR: 0.83, 95% CI: 0.63-1.09, p = .179), whilst allocation to pantoprazole and receipt of enteral nutrition was mostly compatible with increased all-cause mortality (HR: 1.27, 95% CI: 0.99-1.64, p = .061). The test of interaction between enteral nutrition and pantoprazole treatment allocation for all-cause mortality was statistically significant (p = .024). CONCLUSIONS: Enteral nutrition was associated with an increased risk of pneumonia and a reduced risk of gastrointestinal bleeding. The interaction between pantoprazole and enteral nutrition suggesting an increased risk of mortality requires further study.

Critical care pharmacy workforce: a 2020 re-evaluation of the UK deployment and characteristics.

INTRODUCTION: Critical care pharmacists improve the quality and efficiency of medication therapy whilst reducing treatment costs where they are available. UK critical care pharmacist deployment was described in 2015, highlighting a deficit in numbers, experience level, and critical care access to pharmacy services over the 7-day week. Since then, national workforce standards have been emphasised, quality indicators published, and service commissioning documents produced, reinforced by care quality assessments. Whether these initiatives have resulted in further development of the UK critical care pharmacy workforce is unknown. This evaluation provides a 2020 status update. METHODS: The 2015 electronic data entry tool was updated and circulated for completion by UK critical care pharmacists. The tool captured workforce data disposition as it was just prior to the COVID-19 pandemic, at critical care unit level. MAIN FINDINGS: Data were received for 334 critical care units from 203 organisations (96% of UK critical care units). Overall, 98.2% of UK critical care units had specific clinical pharmacist time dedicated to the unit. The median weekday pharmacist input to each level 3 equivalent bed was 0.066 (0.043-0.088) whole time equivalents, a significant increase from the median position in 2015 (+ 0.021, p < 0.0001). Despite this progress, pharmacist availability remains below national minimum standards (0.1/level 3 equivalent bed). Most units (71.9%) had access to prescribing pharmacists. Geographical variation in pharmacist staffing levels were evident, and weekend services remain extremely limited. CONCLUSIONS: Availability of clinical pharmacists in UK adult critical care units is improving. However, national standards are not routinely met despite widely publicised quality indicators, commissioning specifications, and assessments. Additional measures are needed to address persistent deficits and realise gains in organisational and patient-level outcomes. These measures must include promotion of cross-professional collaborative working, adjusted funding models, and a nationally recognised training pathway for critical care pharmacists.

Associations between enteral nutrition and outcomes in the SUP-ICU trial: Protocol for exploratory post hoc analyses.

Critically ill patients are at risk of gastrointestinal (GI) bleeding. Counter measures to minimise this risk include the use of pharmacological stress ulcer prophylaxis (SUP). The effect of enteral nutrition as SUP on GI bleeding event rates is unknown. There are conflicting data describing the effect of co-administration of enteral nutrition with pharmacological SUP, and there is substantial variation in practice. We aim to conduct an exploratory post hoc analysis to evaluate the association of enteral nutrition with clinically important GI bleed rates in ICU patients included in the SUP-ICU trial, and to explore any interactions between enteral nutrition and pharmacologic SUP on patient outcomes. The SUP-ICU trial dataset will be used to assess if enteral nutrition is associated with the outcomes of interest. Extended Cox models will be used considering relevant competing events, including treatment allocation (SUP or placebo) and enteral nutrition as a daily time-varying covariate, with additional adjustment for severity of illness (SAPS II). Results will be presented as adjusted hazard ratios for treatment allocation and enteral nutrition, and for treatment allocation and enteral nutrition considering potential interactions with the other variable, all with 95% confidence intervals and p-values for the tests of interaction. All results will be considered as exploratory only. This post hoc analysis may yield important insights to guide practice and inform the design of future randomised clinical trial investigating the effect of enteral nutrition on GI bleeding.

Regional citrate anticoagulation versus systemic heparin anticoagulation for continuous kidney replacement therapy in intensive care.

PURPOSE: Many intensive care units (ICUs) have transitioned from systemic heparin anticoagulation (SHA) to regional citrate anticoagulation (RCA) for continuous kidney replacement therapy (CKRT). We evaluated the clinical and health economic impacts of ICU transition to RCA. MATERIALS AND METHODS: We surveyed all adult general ICUs in England and Wales to identify transition dates and conducted a micro-costing study in eight ICUs. We then conducted an interrupted time-series analysis of linked, routinely collected health records. RESULTS: In 69,001 patients who received CKRT (8585 RCA, 60,416 SHA) in 181 ICUs between 2009 and 2017, transition to RCA was not associated with a change in 90-day mortality (adjusted odds ratio 0.98, 95% CI 0.89-1.08) but was associated with step-increases in duration of kidney support (0.53 days, 95% CI 0.28-0.79), advanced cardiovascular support (0.23 days, 95% CI 0.09-0.38) and ICU length of stay (0.86 days, 95% CI 0.24-1.49). The estimated one-year incremental net monetary benefit per patient was £ - 2376 (95% CI £ - 3841-£ - 911), with an estimated likelihood of cost-effectiveness of <0.1%. CONCLUSIONS: Transition to RCA was associated with significant increases in healthcare resource use, without corresponding clinical benefit, and is highly unlikely to be cost-effective over a one-year time horizon.

Renal replacement anticoagulant management: Protocol and analysis plan for an observational comparative effectiveness study of linked data sources.

Acute kidney injury is common in critical illness. In patients with severe acute kidney injury, renal replacement therapy is needed to prevent harm from metabolic and electrolyte disturbances and fluid overload. In the UK, continuous renal replacement therapy (CRRT) is the preferred modality, which requires anticoagulation. Over the last decade, conventional systemic heparin anticoagulation has started being replaced by regional citrate anticoagulation for CRRT, which is now used in approximately 50% of ICUs. This shift towards regional citrate anticoagulation for CRRT is occurring with little evidence of safety or longer term effectiveness. Renal replacement anticoagulant management (RRAM) is an observational comparative effectiveness study, utilising existing data sources to address the clinical and cost-effectiveness of the change to regional citrate anticoagulation for CRRT in UK ICUs. The study will use data from approximately 85,000 patients who were treated in adult, general ICUs participating in the case mix programme national clinical audit between 1 April 2009 and 31 March 2017. A survey of health service providers' anticoagulation practices will be combined with treatment and hospital outcome data from the case mix programme and linked with long-term outcomes from the Civil Registrations (deaths), Hospital Episodes Statistics for England, Patient Episodes Data for Wales, and the UK Renal Registry datasets. The primary clinical effectiveness outcome is all-cause mortality at 90-days. The study will incorporate an economic evaluation with micro-costing of both regional citrate anticoagulation and systemic heparin anticoagulation. Study registration: NCT03545750.

Heparin versus citrate anticoagulation for continuous renal replacement therapy in intensive care: the RRAM observational study.

BACKGROUND: In the UK, 10% of admissions to intensive care units receive continuous renal replacement therapy with regional citrate anticoagulation replacing systemic heparin anticoagulation over the last decade. Regional citrate anticoagulation is now used in > 50% of intensive care units, despite little evidence of safety or effectiveness. AIM: The aim of the Renal Replacement Anticoagulant Management study was to evaluate the clinical and health economic impacts of intensive care units moving from systemic heparin anticoagulation to regional citrate anticoagulation for continuous renal replacement therapy. DESIGN: This was an observational comparative effectiveness study. SETTING: The setting was NHS adult general intensive care units in England and Wales. PARTICIPANTS: Participants were adults receiving continuous renal replacement therapy in an intensive care unit participating in the Intensive Care National Audit & Research Centre Case Mix Programme national clinical audit between 1 April 2009 and 31 March 2017. INTERVENTIONS: Exposure - continuous renal replacement therapy in an intensive care unit after completion of transition to regional citrate anticoagulation. Comparator - continuous renal replacement therapy in an intensive care unit before starting transition to regional citrate anticoagulation or had not transitioned. OUTCOME MEASURES: Primary effectiveness - all-cause mortality at 90 days. Primary economic - incremental net monetary benefit at 1 year. Secondary outcomes - mortality at hospital discharge, 30 days and 1 year; days of renal, cardiovascular and advanced respiratory support in intensive care unit; length of stay in intensive care unit and hospital; bleeding and thromboembolic events; prevalence of end-stage renal disease at 1 year; and estimated lifetime incremental net monetary benefit. DATA SOURCES: Individual patient data from the Intensive Care National Audit & Research Centre Case Mix Programme were linked with the UK Renal Registry, Hospital Episode Statistics (for England), Patient Episodes Data for Wales and Civil Registrations (Deaths) data sets, and combined with identified periods of systemic heparin anticoagulation and regional citrate anticoagulation (survey of intensive care units). Staff time and consumables were obtained from micro-costing. Continuous renal replacement therapy system failures were estimated from the Post-Intensive Care Risk-adjusted Alerting and Monitoring data set. EuroQol-3 Dimensions, three-level version, health-related quality of life was obtained from the Intensive Care Outcomes Network study. RESULTS: Out of the 188 (94.9%) units that responded to the survey, 182 (96.8%) use continuous renal replacement therapy. After linkage, data were available from 69,001 patients across 181 intensive care units (60,416 during periods of systemic heparin anticoagulation use and 8585 during regional citrate anticoagulation use). The change to regional citrate anticoagulation was not associated with a step change in 90-day mortality (odds ratio 0.98, 95% confidence interval 0.89 to 1.08). Secondary outcomes showed step increases in days of renal support (difference in means 0.53 days, 95% confidence interval 0.28 to 0.79 days), advanced cardiovascular support (difference in means 0.23 days, 95% confidence interval 0.09 to 0.38 days) and advanced respiratory support (difference in means, 0.53 days, 95% CI 0.03 to 1.03 days) with a trend toward fewer bleeding episodes (odds ratio 0.90, 95% confidence interval 0.76 to 1.06) with transition to regional citrate anticoagulation. The micro-costing study indicated that regional citrate anticoagulation was more expensive and was associated with an estimated incremental net monetary loss (step change) of -£2376 (95% confidence interval -£3841 to -£911). The estimated likelihood of cost-effectiveness at 1 year was less than 0.1%. LIMITATIONS: Lack of patient-level treatment data means that the results represent average effects of changing to regional citrate anticoagulation in intensive care units. Administrative data are subject to variation in data quality over time, which may contribute to observed trends. CONCLUSIONS: The introduction of regional citrate anticoagulation has not improved outcomes for patients and is likely to have substantially increased costs. This study demonstrates the feasibility of evaluating effects of changes in practice using routinely collected data. FUTURE WORK: (1) Prioritise other changes in clinical practice for evaluation and (2) methodological research to understand potential implications of trends in data quality. TRIAL REGISTRATION: This trial is registered as ClinicalTrials.gov NCT03545750. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 13. See the NIHR Journals Library website for further project information.

Acute kidney injury, which prevents kidneys from working properly, is common in critically ill patients being treated in an intensive care unit. Patients with acute kidney injury are treated with a machine that takes over kidney functions, a process called continuous renal replacement therapy. Traditionally, as part of continuous renal replacement therapy, heparin (an anticoagulant that stops the blood from clotting) is added to the blood as it enters the continuous renal replacement therapy machine. Recently, citrate anticoagulation (an alternative to heparin) has been increasingly used in intensive care units in the UK. However, the increased use of citrate is happening without evidence that this is better for patients and cost-effective for the NHS. We aimed to find out whether or not changing to citrate anticoagulation for continuous renal replacement therapy is more beneficial than heparin anticoagulation for patients with acute kidney injury treated in an intensive care unit. We also looked at whether or not changing to citrate is cost-effective for the NHS. We used routinely collected data from the Intensive Care National Audit & Research Centre Case Mix Programme national clinical audit to identify 69,001 patients who received continuous renal replacement therapy in an intensive care unit in England or Wales between 1 April 2009 and 31 March 2017. To get a more comprehensive view of the long-term effects of changing to citrate, we 'linked' data from the 69,001 patients together with other routinely collected data sets to get information on their hospital admissions, longer-term kidney problems and survival after leaving the intensive care unit. We combined this information with a survey of anticoagulant use in intensive care units in England and Wales to compare patients who received continuous renal replacement therapy with heparin and citrate. We found that the change to citrate was not associated with a significant change in the death rate at 90 days, but that it was more expensive for hospitals. Our findings suggest that the change to citrate-based anticoagulation may have been premature and should cause clinicians in intensive care units that are still using systemic heparin anticoagulation to pause before making this change.

Current anthelmintic and antibiotic use in UK organic farming systems.

INTRODUCTION: The use of anthelmintic and antibiotic medicines is imperative to prevent the suffering of diseased stock in organic farming. However, their use must be minimised to comply with low input ideals and prevent the spread of resistance. Reducing such inputs first requires determining their current use, but information is lacking. The objective of this study was to benchmark the current use of anthelmintics and antibiotics in UK organic livestock farming. METHODS: Data were gathered by conducting a national survey of organic livestock farmers in the UK and by analysing records of requests for allopathic medicines. RESULTS: Key findings include (i) anthelmintics used in sheep constitute the greatest input of veterinary medicines in organic systems, (ii) farmers are incorporating alternative/support tools in helminth control to reduce anthelmintic requirements, (iii) the use of antibiotics is targeting individual animals, whereas the use of anthelmintics is targeting groups of animals. CONCLUSION: This study provides the first benchmark on the use of anthelmintics and antibiotics in UK organic livestock.

The National Institute for Health Research Critical Care Research Priority Setting Survey 2018.

INTRODUCTION: Defining research priorities in intensive care is key to determining appropriate allocation of funding. Several topics were identified from the 2014 James Lind Alliance priority setting exercise conducted with the Intensive Care Society. The James Lind Alliance process included significant (and vital) patient/public contribution, but excluded professionals without a bedside role. As a result it may have failed to identify potential early-stage translational research topics, which are more likely identified by medical and/or academic members of relevant specialist basic science groups. The objective of the present project was to complement the James Lind Alliance project by generating an updated list of research priorities by facilitating academic research input. METHOD: A survey was conducted by the National Institute for Health Research (NIHR) to identify the key research priorities from intensive care clinicians, including allied health professionals and academics, along with any evolving themes arising from translational research. Feasibility of all identified topics were then discussed and allocated to themes by a joint clinical academics/NIHR focus group. RESULTS: The survey was completed by 94 intensive care clinicians (including subspecialists), academics and allied health professions. In total, 203 research questions were identified, with the top five themes focusing on: appropriate case selection (e.g. who and when to treat; 24%), ventilation (7%), sepsis (6%), delirium (5%) and rehabilitation (5%). DISCUSSION: Utilising a methodology distinct from that employed by the James Lind Alliance process, from a broad spectrum of intensive care clinicians/scientists, enabled identification of a variety of priority research areas. These topics can now inform not only the investigator-led research agenda, but will also be considered in due course by the NIHR for potential future funding calls.

Airway clearance techniques and use of mucoactive agents for adult critically ill patients with acute respiratory failure: a qualitative study exploring UK physiotherapy practice.

OBJECTIVES: To explore and describe current UK physiotherapy practice relating to airway clearance techniques and mucoactive agents in critically ill adult patients with acute respiratory failure in the intensive care unit. DESIGN: A descriptive, qualitative study using focus group interviews. Focus groups were audio-recorded, independently transcribed, and data analysed thematically. Participants Senior, experienced physiotherapists, clinically active in critical care. RESULTS: Fifteen physiotherapists participated in four interview sessions. Five themes emerged describing airway clearance techniques: 'Repertoire of airway clearance techniques', 'Staffing and skillset', 'Commencing respiratory physiotherapy', 'Technique selection', and 'Determining effectiveness' were themes related to airway clearance techniques. Five themes were also identified in relation to mucoactive agents: 'Use in clinical practice', 'Decision to commence', 'Selection of agent', 'Stopping mucoactive agents', and 'Determining effectiveness'. A summary of key features of standard practice was developed. CONCLUSIONS: Standard UK physiotherapy practice of airway clearance techniques is variable, but patient-centred and targeted to individual need, with adjunctive use of mucoactive agents to enhance and optimise patient management if required. Based on this study, key features of airway clearance techniques have been summarised to help capture standard care, which could be used in future trials involving ACT as part of usual care.

Mucoactive agents for acute respiratory failure in the critically ill: a systematic review and meta-analysis.

PURPOSE: Acute respiratory failure (ARF) is a common cause of admission to intensive care units (ICUs). Mucoactive agents are medications that promote mucus clearance and are frequently administered in patients with ARF, despite a lack of evidence to underpin clinical decision making. The aim of this systematic review was to determine if the use of mucoactive agents in patients with ARF improves clinical outcomes. METHODS: We searched electronic and grey literature (January 2020). Two reviewers independently screened, selected, extracted data and quality assessed studies. We included trials of adults receiving ventilatory support for ARF and involving at least one mucoactive agent compared with placebo or standard care. Outcomes included duration of mechanical ventilation. Meta-analysis was undertaken using random-effects modelling and certainty of the evidence was assessed using Grades of Recommendation, Assessment, Development and Evaluation. RESULTS: Thirteen randomised controlled trials were included (1712 patients), investigating four different mucoactive agents. Mucoactive agents showed no effect on duration of mechanical ventilation (seven trials, mean difference (MD) -1.34, 95% CI -2.97 to 0.29, I2=82%, very low certainty) or mortality, hospital stay and ventilator-free days. There was an effect on reducing ICU length of stay in the mucoactive agent groups (10 trials, MD -3.22, 95% CI -5.49 to -0.96, I2=89%, very low certainty). CONCLUSION: Our findings do not support the use of mucoactive agents in critically ill patients with ARF. The existing evidence is of low quality. High-quality randomised controlled trials are needed to determine the role of specific mucoactive agents in critically ill patients with ARF. PROSPERO REGISTRATION NUMBER: CRD42018095408.

Mucoactive agent use in adult UK Critical Care Units: a survey of health care professionals' perception, pharmacists' description of practice, and point prevalence of mucoactive use in invasively mechanically ventilated patients.

BACKGROUND: Mechanical ventilation for acute respiratory failure is one of the most common indications for admission to intensive care units (ICUs). Airway mucus clearance is impaired in these patients medication, impaired mucociliary motility, increased mucus production etc. and mucoactive agents have the potential to improve outcomes. However, studies to date have provided inconclusive results. Despite this uncertainty, mucoactives are used in adult ICUs, although the extent of use and perceptions about place in therapy are not known. AIMS AND OBJECTIVES: We aim to describe the use of mucoactive agents in mechanically ventilated patients in UK adult critical care units. Specifically, our objectives are to describe clinicians perceptions about the use of mucoactive agents, understand the indications and anticipated benefits, and describe the prevalence and type of mucoactive agents in use. METHODS: We conducted three surveys. Firstly, a practitioner-level survey aimed at nurses, physiotherapists and doctors to elucidate individual practitioners perceptions about the use of mucoactive agents. Secondly, a critical care unit-level survey aimed at pharmacists to understand how these perceptions translate into practice. Thirdly, a point prevalence survey to describe the extent of prescribing and range of products in use. The practitioner-level survey was disseminated through the UK Intensive Care Society for completion by a multi-professional membership. The unit-level and point prevalence surveys were disseminated cthrough the UK Clinical Pharmacy Association for completion by pharmacists. RESULTS: The individual practitioners survey ranked 'thick secretions' as the main reason for commencing mucoactive agents determined using clinical assessment. The highest ranked perceived benefit for patient centred outcomes was the duration of ventilation. Of these respondents, 79% stated that further research was important and 87% expressed support for a clinical trial. The unit-level survey found that mucoactive agents were used in 83% of units. The most highly ranked indication was again 'thick secretions' and the most highly ranked expected patient centred clinical benefit being improved gas exchange and reduced ventilation time. Only five critical care units provided guidelines to direct the use of mucoactive agents (4%). In the point prevalence survey, 411/993 (41%) of mechanically ventilated patients received at least one mucoactive agent. The most commonly administered mucoactives were inhaled sodium chloride 0.9% (235/993, 24%), systemic carbocisteine (161/993, 16%) and inhaled hypertonic sodium cloride (127/993, 13%). CONCLUSIONS: Mucoactive agents are used extensively in mechanically ventilated adult patients in UK ICUs to manage 'thick secretions', with a key aim to reduce the duration of ventilation. There is widespread support for clinical trials to determine the optimal use of mucoactive agent therapy in this patient population.

Measuring sleep in the intensive care unit: Electroencephalogram, actigraphy, or questionnaire?

BACKGROUND: Studies consistently report deranged sleep in patients admitted to intensive care unit. Poor sleep has harmful physical and cognitive effects, and an evidence-based intervention to improve sleep is needed. It is, however, difficult to measure sleep in the intensive care unit. 'Gold standard' monitoring (polysomnography) is unsuitable for usual care. METHODS: We collected concurrent sleep data from electroencephalograph recordings, activity monitoring, and nurse- and patient-completed Richards-Campbell Sleep Questionnaires (RCSQ). RESULTS: Electroencephalograph data (n = 34) confirm poor sleep. Individual bouts last approximately 1 min and around 2 h of sleep overnight is common. Correlation between electroencephalograph, self-report, nurse-report, actigraphy and overall activity score is low (ρ = 0.123 (n = 24), 0.127 (n = 22), and 0.402 and - 0.201 (n = 13), respectively). Correlation between nurse and patient assessment is limited (ρ = 0.537 (n = 444)). CONCLUSIONS: No current method of sleep monitoring seems suitable in the intensive care unit. However, to facilitate comparison across studies, the patient-completed RCSQ seems the most meaningful measure.

Co-administration of multiple intravenous medicines: Intensive care nurses' views and perspectives.

BACKGROUND: Co-administration of multiple intravenous (IV) medicines down the same lumen of an IV catheter is often necessary in the intensive care unit (ICU) while ensuring medicine compatibility. AIMS AND OBJECTIVES: This study explores ICU nurses' views on the everyday practice surrounding co-administration of multiple IV medicines down the same lumen. DESIGN: Qualitative study using focus group interviews. METHODS: Three focus groups were conducted with 20 ICU nurses across two hospitals in the Thames Valley Critical Care Network, England. Participants' experience of co-administration down the same lumen and means of assessing compatibility were explored. All focus groups were recorded, transcribed verbatim, and analysed using thematic analysis. Functional Resonance Analysis Method was used to provide a visual representation of the co-administration process. RESULTS: Two key themes were identified as essential during the process of co-administration, namely, venous access and resources. Most nurses described insufficient venous access and lack of compatibility data for commonly used medicines (eg, analgesics and antibiotics) as particular challenges. Strategies such as obtaining additional venous access, prioritizing infusions, and swapping line of infusion were used to manage IV administration problems where medicines were incompatible, or of unknown or variable compatibility. CONCLUSIONS: Nurses use several workarounds to manage commonly encountered medication compatibility problems that may lead to delays in therapy. Organizations should review and tailor compatibility resources towards commonly administered medicines using an interdisciplinary approach. Developing a clinical decision-making pathway to minimise variability while promoting safe co-administration practice should be prioritised. RELEVANCE TO CLINICAL PRACTICE: This study highlights several ways ICU nurses are able to manage challenges associated with co-administration and the need for the development of a more robust and comprehensive compatibility resource that is relevant to everyday practice through collaboration between nurses and pharmacists.

Outcomes of Prophylactic Pantoprazole in Adult Intensive Care Unit Patients Receiving Dialysis: Results of a Randomized Trial.

BACKGROUND: Intensive care unit (ICU) patients with acute kidney injury requiring renal replacement therapy (RRT) are considered at high risk of gastrointestinal (GI) bleeding and stress ulcer prophylaxis (SUP) is often prescribed. We aimed to assess the incidence of GI bleeding and effects of SUP in these patients. METHODS: We assessed GI bleeding in ICU patients receiving RRT at baseline (and at any time in the ICU) and effects of prophylactic pantoprazole versus placebo in the international SUP in the ICU (SUP-ICU) trial. All analyses were conducted according to a published protocol and statistical analysis plan. RESULTS: Data of 3,291 acutely admitted adult ICU patients with one or more risk factors for GI bleeding randomized to pantoprazole or placebo intravenously once daily during ICU stay (until ICU discharge, death, or a maximum of 90 days) were analyzed. Some 20 out of 258 (7.8%, 95% CI 4.5-11.1%) and 52 out of 568 (9.2%, 95% CI 6.8-11.6%) of the patients receiving RRT at baseline and at any time in ICU, respectively, developed clinically important GI bleeding in the ICU. We did not observe statistically significant differences in the intervention effect (pantoprazole vs. placebo) in the proportion of patients with clinically important GI bleeding, clinically important events, infectious adverse events, use of interventions to stop GI bleeding, or 90-day mortality in patients with versus without RRT at baseline. CONCLUSIONS: In adult ICU patients receiving RRT at baseline, we observed high incidences of clinically important GI bleeding, but did not observe effects of pantoprazole versus placebo in this subgroup.

Time to onset of gastrointestinal bleeding in the SUP-ICU trial: A pre-planned substudy.

BACKGROUND: The aetiology and risk factors for clinically important gastrointestinal bleeding (CIB) in adult ICU patients may differ according to the onset of CIB, which could affect the balance between benefits and harms of stress ulcer prophylaxis (SUP). METHODS: We assessed the time to CIB in the Stress Ulcer Prophylaxis in the Intensive Care Unit (SUP-ICU) trial. We assessed if associations between baseline characteristics including allocation to SUP and CIB changed during time in the ICU, specifically in the later (after day 2) compared to the earlier (first 2 days) period, using Cox models adjusted for SAPS II and allocation to SUP. Additionally, we described baseline characteristics and CIB episodes stratified by earlier/later/no CIB and 90-day mortality status. RESULTS: Clinically important gastrointestinal bleeding occurred in 110/3291 (3.3%) patients after a median of 6 (interquartile range 2-13) days; 25.5% of the episodes occurred early. Higher SAPS II was consistently associated with increased risk of CIB (hazard ratio (HR) 1.03, 95% confidence interval (CI) 1.01-1.05 in the earlier period vs HR 1.02, 95% CI 1.01-1.03 in the later period; P = .37); university hospital admission was associated with decreased risk of earlier CIB (HR 0.30, 95% CI 0.14-0.63); this significantly increased in the later period (to HR 0.85, 95% CI 0.53-1.37; P = .02). Patients with later compared to earlier CIB received more transfusions and had more diagnostic/therapeutic procedures for CIB. CONCLUSIONS: Clinically important gastrointestinal bleeding mostly occurred more than 2 days after randomization. University hospital admission was associated with significantly decreased risk of CIB in the earlier period only.

Pantoprazole in ICU patients at risk for gastrointestinal bleeding-1-year mortality in the SUP-ICU trial.

BACKGROUND: The long-term effects of stress ulcer prophylaxis with pantoprazole are unknown in ICU patients. We report 1-year mortality outcome in the Stress Ulcer Prophylaxis in the Intensive Care Unit (SUP-ICU) trial. METHODS: In the SUP-ICU trial, acutely admitted adult ICU patients at risk of gastrointestinal bleeding were randomised to intravenous pantoprazole 40 mg vs placebo (saline) once daily during their ICU stay. We assessed mortality at 1 year and did sensitivity analyses according to the trial protocol and statistical analysis plan. RESULTS: A total of 3261 of the 3291 patients with available data (99.1%) were followed up at 1 year after randomisation; 1635 were allocated to pantoprazole and 1626 to placebo. At 1 year after randomisation, 610 of 1635 patients (37.3%) had died in the pantoprazole group as compared with 601 of 1626 (37.0%) in the placebo group (relative risk, 1.01; 95% confidence interval 0.92-1.10). The results were consistent in the sensitivity analysis adjusted for baseline risk factors and in those of the per-protocol population. We did not observe heterogeneity in the effect of pantoprazole vs placebo on 1-year mortality in the predefined subgroups, that is, patients with and without shock, mechanical ventilation, liver disease, coagulopathy, high disease severity (SAPS II > 53) or in medical vs surgical ICU patients. CONCLUSION: We did not observe a difference in 1-year mortality among acutely admitted adult ICU patients with risk factors for gastrointestinal bleeding allocated to stress ulcer prophylaxis with pantoprazole or placebo during the ICU stay. (The SUP-ICU trial was funded by Innovation Fund Denmark and others; ClinicalTrials.gov number, NCT02467621).

The role of the pharmacist in the intensive care unit.

The use of medication to support patients and optimise outcomes is a fundamental strand of care. Pharmacists provide a key role managing medication within the complexity of various routes of administration, severe and rapidly shifting pharmacokinetic and dynamic parameters, and extremes of physiology in critical illness. Pharmacists intercept and resolve medication errors, optimise medication therapy and undertake broader professional activities within the job role that contribute to the smooth running of ICU. These activities are associated with improved quality, reduced mortality and reduced costs.

Pantoprazole prophylaxis in ICU patients with high severity of disease: a post hoc analysis of the placebo-controlled SUP-ICU trial.

PURPOSE: In the subgroup of patients with Simplified Acute Physiology Score (SAPS) II > 53 in the Stress Ulcer Prophylaxis in Intensive Care Unit (SUP-ICU) trial, there was interaction (P = 0.049) suggesting increased mortality in patients allocated to pantoprazole as compared with placebo. We aimed to explore this further. METHODS: The SUP-ICU trial allocated acutely admitted adults at risk of gastrointestinal bleeding to pantoprazole vs placebo. In this post hoc study, we repeated all the preplanned analyses of SUP-ICU in patients with baseline SAPS II > 53. RESULTS: A total of 1140 patients had a complete SAPS II > 53 and were included. At 90 days, 272/579 patients (47%) assigned to pantoprazole had died, as compared with 229/558 patients (41%) assigned to placebo [relative risk 1.13; 95% confidence interval (CI) 1.00-1.29]. This was supported by sensitivity analyses adjusted for risk factors and those in the per-protocol population. When accounting for patients with incomplete SAPS II in two additional analyses, the relative risk was 1.08; 95% CI 0.96-1.22 and 1.10; 95% CI 0.97-1.25. This was also observed for the secondary outcome days alive without life support. There were no differences between the intervention groups in the other secondary outcomes. CONCLUSIONS: In this post hoc analysis of patients with high disease severity included in the SUP-ICU trial, we observed higher 90-day mortality and fewer days alive without life support with pantoprazole vs placebo. Some of this may have been explained by missing SAPS II data, but further research is needed to draw firm conclusions. CLINICALTRIALS.GOV: ClinicalTrials.gov No. NCT02467621.