Optimizing red blood cell transfusion practices in the intensive care unit: a multi-phased health technology reassessment.

BACKGROUND: Health technology reassessment (HTR) is a process to manage existing health technologies to ensure ongoing optimal use. A model to guide HTR was developed; however, there is limited practical experience. This paper addresses this knowledge gap through the completion of a multi-phase HTR of red blood cell (RBC) transfusion practices in the intensive care unit (ICU). OBJECTIVE: The HTR consisted of three phases and here we report on the final phase: the development, implementation, and evaluation of behavior change interventions aimed at addressing inappropriate RBC transfusions in an ICU. METHODS: The interventions, comprised of group education and audit and feedback, were co-designed and implemented with clinical leaders. The intervention was evaluated through a controlled before-and-after pilot feasibility study. The primary outcome was the proportion of potentially inappropriate RBC transfusions (i.e., with a pre-transfusion hemoglobin of 70 g/L or more). RESULTS: There was marked variability in the monthly proportion of potentially inappropriate RBC transfusions. Relative to the pre-intervention phase, there was no significant difference in the proportion of potentially inappropriate RBC transfusions post-intervention. Lessons from this work include the importance of early and meaningful engagement of clinical leaders; tailoring the intervention modalities; and, efficient access to data through an electronic clinical information system. CONCLUSIONS: It was feasible to design, implement, and evaluate a tailored, multi-modal behavior change intervention in this small-scale pilot study. However, early evaluation of the intervention revealed no change in technology use leading to reflection on the important question of how the HTR model needs to be improved.

Exploratory Evaluation of the Relationship Between iNKT Cells and Systemic Cytokine Profiles of Critically Ill Patients with Neurological Injury.

BACKGROUND: Neurological injury can alter the systemic immune system, modifying the functional capacity of immune cells and causing a dysfunctional balance of cytokines, although mechanisms remain incompletely understood. The objective of this study was to assess the temporal relationship between changes in the activation status of circulating invariant natural killer T (iNKT) cells and the balance of plasma cytokines among critically ill patients with neurological injury. METHODS: We conducted an exploratory prospective observational study of adult (18 years or older) intensive care unit (ICU) patients with acute neurological injury (n = 20) compared with ICU patients without neurological injury (n = 22) and healthy controls (n = 10). Blood samples were collected on days 1, 2, 4, 7, 14, and 28 following ICU admission to analyze the activation status of circulating iNKT cells by flow cytometry and the plasma concentration of inflammation-relevant immune mediators, including T helper 1 (TH1) and T helper 2 (TH2) cytokines, by multiplex bead-based assay. RESULTS: Invariant natural killer T cells were activated in both ICU patient groups compared with healthy controls. Neurological patients had decreased levels of multiple immune mediators, including TH1 cytokines (interferon-γ, tumor necrosis factor-α, and interleukin-12p70), indicative of immunosuppression. This led to a greater than twofold increase in the ratio of TH2/TH1 cytokines early after injury (days 1 - 2) compared with healthy controls, a shift that was also observed for ICU controls. Systemic TH2/TH1 cytokine ratios were positively associated with iNKT cell activation in the neurological patients and negatively associated in ICU controls. These relationships were strongest for the CD4+ iNKT cell subset compared with the CD4- iNKT cell subset. The relationships to individual cytokines similarly differed between patient groups. Forty percent of the neurological patients developed an infection; however, differences for the infection subgroup were not identified. CONCLUSIONS: Critically ill patients with neurological injury demonstrated altered systemic immune profiles early after injury, with an association between activated peripheral iNKT cells and elevated systemic TH2/TH1 cytokine ratios. This work provides further support for a brain-immune axis and the ability of neurological injury to have far-reaching effects on the body's immune system.

Continuous Assessment of "Optimal" Cerebral Perfusion Pressure in Traumatic Brain Injury: A Cohort Study of Feasibility, Reliability, and Relation to Outcome.

BACKGROUND: Guidelines recommend maintaining cerebral perfusion pressure (CPP) between 60 and 70 mmHg in patients with severe traumatic brain injury (TBI), but acknowledge that optimal CPP may vary depending on cerebral blood flow autoregulation. Previous retrospective studies suggest that targeting CPP where the pressure reactivity index (PRx) is optimized (CPPopt) may be associated with improved recovery. METHODS: We performed a retrospective cohort study involving TBI patients who underwent PRx monitoring to assess issues of feasibility relevant to future interventional studies: (1) the proportion of time that CPPopt could be detected; (2) inter-observer variability in CPPopt determination; and (3) agreement between manual and automated CPPopt estimates. CPPopt was determined for consecutive 6-h epochs during the first week following TBI. Sixty PRx-CPP tracings were randomly selected and independently reviewed by six critical care professionals. We also assessed whether greater deviation between actual CPP and CPPopt (ΔCPP) was associated with poor outcomes using multivariable models. RESULTS: In 71 patients, CPPopt could be manually determined in 985 of 1173 (84%) epochs. Inter-observer agreement for detectability was moderate (kappa 0.46, 0.23-0.68). In cases where there was consensus that it could be determined, agreement for the specific CPPopt value was excellent (weighted kappa 0.96, 0.91-1.00). Automated CPPopt was within 5 mmHg of manually determined CPPopt in 93% of epochs. Lower PRx was predictive of better recovery, but there was no association between ΔCPP and outcome. Percentage time spent below CPPopt increased over time among patients with poor outcomes (p = 0.03). This effect was magnified in patients with impaired autoregulation (defined as PRx > 0.2; p = 0.003). CONCLUSION: Prospective interventional clinical trials with regular determination of CPPopt and corresponding adjustment of CPP goals are feasible, but measures to maximize consistency in CPPopt determination are necessary. Although we could not confirm a clear association between ΔCPP and outcome, time spent below CPPopt may be particularly harmful, especially when autoregulation is impaired.

Challenges and potential solutions to the evaluation, monitoring, and regulation of surgical innovations.

BACKGROUND: As it may be argued that many surgical interventions provide obvious patient benefits, formal, staged assessment of the efficacy and safety of surgical procedures has historically been and remains uncommon. The majority of innovative surgical procedures have therefore often been developed based on anatomical and pathophysiological principles in an attempt to better manage clinical problems. MAIN BODY: In this manuscript, we sought to review and contrast the models for pharmaceutical and surgical innovation in North America, including their stages of development and methods of evaluation, monitoring, and regulation. We also aimed to review the present structure of academic surgery, the role of methodological experts and funding in conducting surgical research, and the current system of regulation of innovative surgical procedures. Finally, we highlight the influence that evidence and surgical history, education, training, and culture have on elective and emergency surgical decision-making. The above discussion is used to support the argument that the model used for assessment of innovative pharmaceuticals cannot be applied to that for evaluating surgical innovations. It is also used to support our position that although the evaluation and monitoring of innovative surgical procedures requires a rigorous, fit-for-purpose, and formal system of assessment to protect patient safety and prevent unexpected adverse health outcomes, it will only succeed if it is supported and championed by surgical practice leaders and respects surgical history, education, training, and culture. CONCLUSION: We conclude the above debate by providing a recommended approach to the evaluation, monitoring, and regulation of surgical innovations, which we hope may be used as a guide for all stakeholders involved in interpreting and/or conducting future surgical research.

The high cost of critical care unit over-utilization for patients with NSTE ACS.

BACKGROUND: There is substantial variability among hospitals in critical care unit (CCU) utilization for patients admitted with non-ST-Segment Elevation Acute Coronary Syndromes (NSTE ACS). We estimated the potential cost saving if all hospitals adopted low CCU utilization practices for patients with NSTE ACS. METHODS: National hospital claims data were used to identify all patients with a primary diagnosis of NSTE ACS initially admitted to an acute care hospital between 2007 and 2013. Hospital CCU utilization was classified as low (<30%), medium (30-70%), or high (>70%). RESULTS: Among the 270,564 NSTE ACS hospitalizations (71.6% non-ST-segment elevation myocardial infarction; 28.4% unstable angina) admitted to 261 hospitals, 41.9% (inter-hospital range 0.3%-95.1%) were admitted to a CCU. The proportion of patients admitted to a CCU in low, medium and high utilization hospitals was 16.3%, 49.5%, and high 81.1%, respectively. No differences in adjusted inpatient mortality were observed by hospital CCU utilization. The overall inpatient costs of caring for NSTE ACS were $1.1 billion. CCU care accounted for 45.2% of all hospitalization costs including 22.6%, 49.9%, and 69.0% (P < .001) of costs in low, medium and high utilization centers. The national potential direct cost savings of medium and high CCU utilization centers adopting low NSTE ACS CCU utilization practices was $113.4 million over the study period. CONCLUSIONS: In a population-based contemporary cohort, CCU utilization for patients with NSTE ACS varied widely and in-hospital mortality was similar between low, medium and high utilization centers. CCU care accounted for 45% of hospitalization costs; thus, implementing policies and admission practices to align hospital resources with patient care needs have the potential to reduce overall health care costs.

Indicators of intensive care unit capacity strain: a systematic review.

BACKGROUND: Strained intensive care unit (ICU) capacity represents a fundamental supply-demand mismatch in ICU resources. Strain is likely to be influenced by a range of factors; however, there has been no systematic evaluation of the spectrum of measures that may indicate strain on ICU capacity. METHODS: We performed a systematic review to identify indicators of strained capacity. A comprehensive peer-reviewed search of MEDLINE, EMBASE, CINAHL, Cochrane Library, and Web of Science Core Collection was performed along with selected grey literature sources. We included studies published in English after 1990. We included studies that: (1) focused on ICU settings; (2) included description of a quality or performance measure; and (3) described strained capacity. Retrieved studies were screened, selected and extracted in duplicate. Quality was assessed using the Newcastle-Ottawa Quality Assessment Scale (NOS). Analysis was descriptive. RESULTS: Of 5297 studies identified in our search; 51 fulfilled eligibility. Most were cohort studies (n = 39; 76.5%), five (9.8%) were case-control, three (5.8%) were cross-sectional, two (3.9%) were modeling studies, one (2%) was a correlational study, and one (2%) was a quality improvement project. Most observational studies were high quality. Sixteen measures designed to indicate strain were identified 110 times, and classified as structure (n = 4, 25%), process (n = 7, 44%) and outcome (n = 5, 31%) indicators, respectively. The most commonly identified indicators of strain were ICU acuity (n = 21; 19.1% [process]), ICU readmission (n = 18; 16.4% [outcome]), after-hours discharge (n = 15; 13.6% [process]) and ICU census (n = 13; 11.8% [structure]). There was substantial heterogeneity in the operational definitions used to define strain indicators across studies. CONCLUSIONS: We identified and characterized 16 indicators of strained ICU capacity across the spectrum of healthcare quality domains. Future work should aim to evaluate their implementation into practice and assess their value for evaluating strategies to mitigate strain. SYSTEMATIC REVIEW REGISTRATION: This systematic review was registered at PROSPERO (March 27, 2015; CRD42015017931 ).

Association between afterhours admission to the intensive care unit, strained capacity, and mortality: a retrospective cohort study.

BACKGROUND: Admission to the intensive care unit (ICU) outside daytime hours has been shown to be variably associated with increased morbidity and mortality. We aimed to describe the characteristics and outcomes of patients admitted to the ICU afterhours (22:00-06:59 h) in a large Canadian health region. We further hypothesized that the association between afterhours admission and mortality would be modified by indicators of strained ICU capacity. METHODS: This is a population-based cohort study of 12,265 adults admitted to nine ICUs in Alberta from June 2012 to December 2014. We used a path-analysis modeling strategy and mixed-effects multivariate regression analysis to evaluate direct and integrated associations (mediated through Acute Physiology and Chronic Health Evaluation (APACHE) II score) between afterhours admission (22:00-06:59 h) and ICU mortality. Further analysis examined the effects of strained ICU capacity and varied definitions of afterhours and weekend admissions. ICU occupancy ≥ 90% or clustering of admissions (≥ 0.15, defined as number of admissions 2 h before or after the index admission, divided by the number of ICU beds) were used as indicators of strained capacity. RESULTS: Of 12,265 admissions, 34.7% (n = 4251) occurred afterhours. The proportion of afterhours admissions varied amongst ICUs (range 26.7-37.8%). Patients admitted afterhours were younger (median (IQR) 58 (44-70) vs 60 (47-70) years, p < 0.0001), more likely to have a medical diagnosis (75.9% vs 72.1%, p < 0.0001), and had higher APACHE II scores (20.9 (8.6) vs 19.9 (8.3), p < 0.0001). Crude ICU mortality was greater for those admitted afterhours (15.9% vs 14.1%, p = 0.007), but following multivariate adjustment there was no direct or integrated effect on ICU mortality (odds ratio (OR) 1.024; 95% confidence interval (CI) 0.923-1.135, p = 0.658). Furthermore, direct and integrated analysis showed no association of afterhours admission and hospital mortality (p = 0.90) or hospital length of stay (LOS) (p = 0.27), although ICU LOS was shorter (p = 0.049). Early-morning admission (00:00-06:59 h) with ICU occupancy ≥ 90% was associated with short-term (≤ 7 days) and all-cause ICU mortality. CONCLUSIONS: One-third of critically ill patients are admitted to the ICU afterhours. Afterhours ICU admission was not associated with greater mortality risk in most circumstances but was sensitive to strained ICU capacity.

History of the Innovation of Damage Control for Management of Trauma Patients: 1902-2016.

OBJECTIVE: To review the history of the innovation of damage control (DC) for management of trauma patients. BACKGROUND: DC is an important development in trauma care that provides a valuable case study in surgical innovation. METHODS: We searched bibliographic databases (1950-2015), conference abstracts (2009-2013), Web sites, textbooks, and bibliographies for articles relating to trauma DC. The innovation of DC was then classified according to the Innovation, Development, Exploration, Assessment, and Long-term study model of surgical innovation. RESULTS: The "innovation" of DC originated from the use of therapeutic liver packing, a practice that had previously been abandoned after World War II because of adverse events. It then "developed" into abbreviated laparotomy using "rapid conservative operative techniques." Subsequent "exploration" resulted in the application of DC to increasingly complex abdominal injuries and thoracic, peripheral vascular, and orthopedic injuries. Increasing use of DC laparotomy was followed by growing reports of postinjury abdominal compartment syndrome and prophylactic use of the open abdomen to prevent intra-abdominal hypertension after DC laparotomy. By the year 2000, DC surgery had been widely adopted and was recommended for use in surgical journals, textbooks, and teaching courses ("assessment" stage of innovation). "Long-term study" of DC is raising questions about whether the procedure should be used more selectively in the context of improving resuscitation practices. CONCLUSIONS: The history of the innovation of DC illustrates how a previously abandoned surgical technique was adapted and readopted in response to an increased understanding of trauma patient physiology and changing injury patterns and trauma resuscitation practices.

Healthcare Provider Perceptions of Causes and Consequences of ICU Capacity Strain in a Large Publicly Funded Integrated Health Region: A Qualitative Study.

OBJECTIVES: Discrepancy in the supply-demand relationship for critical care services precipitates a strain on ICU capacity. Strain can lead to suboptimal quality of care and burnout among providers and contribute to inefficient health resource utilization. We engaged interprofessional healthcare providers to explore their perceptions of the sources, impact, and strategies to manage capacity strain. DESIGN: Qualitative study using a conventional thematic analysis. SETTING: Nine ICUs across Alberta, Canada. SUBJECTS: Nineteen focus groups (n = 122 participants). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Participants' perspectives on strain on ICU capacity and its perceived impact on providers, families, and patient care were explored. Participants defined "capacity strain" as a discrepancy between the availability of ICU beds, providers, and ICU resources (supply) and the need to admit and provide care for critically ill patients (demand). Four interrelated themes of contributors to strain were characterized (each with subthemes): patient/family related, provider related, resource related, and health system related. Patient/family-related subthemes were "increasing patient complexity/acuity," along with patient-provider communication issues ("paucity of advance care planning and goals-of-care designation," "mismatches between patient/family and provider expectations," and "timeliness of end-of-life care planning"). Provider-related factor subthemes were nursing workforce related ("nurse attrition," "inexperienced workforce," "limited mentoring opportunities," and "high patient-to-nurse ratios") and physician related ("frequent turnover/handover" and "variations in care plan"). Resource-related subthemes were "reduced service capability after hours" and "physical bed shortages." Health system-related subthemes were "variable ICU utilization," "preferential "bed" priority for other services," and "high ward bed occupancy." Participants perceived that strain had negative implications for patients ("reduced quality and safety of care" and "disrupted opportunities for patient- and family-centered care"), providers ("increased workload," "moral distress," and "burnout"), and the health system ("unnecessary, excessive, and inefficient resource utilization"). CONCLUSIONS: Engagement with frontline critical care providers is essential for understanding their experiences and perspectives regarding strained capacity and for the development of sustainable strategies for improvement.

Indications for Use of Damage Control Surgery in Civilian Trauma Patients: A Content Analysis and Expert Appropriateness Rating Study.

OBJECTIVES: To characterize and evaluate indications for use of damage control (DC) surgery in civilian trauma patients. BACKGROUND: Although DC surgery may improve survival in select, severely injured patients, the procedure is associated with significant morbidity, suggesting that it should be used only when appropriately indicated. METHODS: Two investigators used an abbreviated grounded theory method to synthesize indications for DC surgery reported in peer-reviewed articles between 1983 and 2014 into a reduced number of named, content-characteristic codes representing unique indications. An international panel of trauma surgery experts (n = 9) then rated the appropriateness (expected benefit-to-harm ratio) of the coded indications for use in surgical practice. RESULTS: The 1107 indications identified in the literature were synthesized into 123 unique pre- (n = 36) and intraoperative (n = 87) indications. The panel assessed 101 (82.1%) of these indications to be appropriate. The indications most commonly reported and assessed to be appropriate included pre- and intraoperative hypothermia (median temperature <34°C), acidosis (median pH <7.2), and/or coagulopathy. Others included 5 different injury patterns, inability to control bleeding by conventional methods, administration of a large volume of packed red blood cells (median >10 units), inability to close the abdominal wall without tension, development of abdominal compartment syndrome during attempted abdominal wall closure, and need to reassess extent of bowel viability. CONCLUSIONS: This study identified a comprehensive list of candidate indications for use of DC surgery. These indications provide a practical foundation to guide surgical practice while studies are conducted to evaluate their impact on patient care and outcomes.

Decompressive Craniectomy in Patients with Traumatic Brain Injury: Are the Usual Indications Congruent with Those Evaluated in Clinical Trials?

BACKGROUND: In patients with traumatic brain injury (TBI), multicenter randomized controlled trials have assessed decompressive craniectomy (DC) exclusively as treatment for refractory elevation of intracranial pressure (ICP). DC reliably lowers ICP but does not necessarily improve outcomes. However, some patients undergo DC as treatment for impending or established transtentorial herniation, irrespective of ICP. METHODS: We performed a population-based cohort study assessing consecutive patients with moderate-severe TBI. Indications for DC were compared with enrollment criteria for the DECRA and RESCUE-ICP trials. RESULTS: Of 644 consecutive patients, 51 (8 %) were treated with DC. All patients undergoing DC had compressed basal cisterns, 82 % had at least temporary preoperative loss of ≥1 pupillary light reflex (PLR), and 80 % had >5 mm of midline shift. Most DC procedures (67 %) were "primary," having been performed concomitantly with evacuation of a space-occupying lesion. ICP measurements influenced the decision to perform DC in 18 % of patients. Only 10 and 16 % of patients, respectively, would have been eligible for the DECRA and RESCUE-ICP trials. DC improved basal cistern compression in 76 %, and midline shift in 94 % of patients. Among patients with ≥1 absent PLR at admission, DC was associated with lower mortality (46 vs. 68 %, p = 0.03), especially when the admission Marshall CT score was 3-4 (p = 0.0005). No patients treated with DC progressed to brain death. Variables predictive of poor outcome following DC included loss of PLR(s), poor motor score, midline shift ≥11 mm, and development of perioperative cerebral infarcts. CONCLUSIONS: DC is most often performed for clinical and radiographic evidence of herniation, rather than for refractory ICP elevation. Results of previously completed randomized trials do not directly apply to a large proportion of patients undergoing DC in practice.

Evidence-based design in an intensive care unit: end-user perceptions.

BACKGROUND: The objective of this study was to describe end-user impressions and experiences in a new intensive care unit built using evidence-based design. METHODS: This qualitative study was comprised of early (2-3 months after opening) and late (12-15 months after opening) phase individual interviews with end-users (healthcare providers, support staff, and patient family members) of the newly constructed Foothills Medical Centre intensive care unit in Calgary, Canada. The study unit was the recipient of the Society of Critical Care Medicine Design Citation award in 2012. RESULTS: We conducted interviews with thirty-nine ICU end-users, twenty-four in the early phase and fifteen in the late phase. We identified four themes (eleven sub-themes): atmosphere (abundant natural light and low noise levels), physical spaces (single occupancy rooms, rooms clustered into clinical pods, medication rooms, and tradeoffs of larger spaces), family participation in care (family support areas and social networks), and equipment (usability, storage, and providers connectivity). Abundant natural light was the design feature most frequently associated with a pleasant atmosphere. Participants emphasized the tradeoffs of size and space, and reported that the benefits of additional space (e.g., fewer interruptions due to less noise) out-weighed the disadvantages (e.g., greater distances between patients, families and providers). End-users advised that local patient care policies (e.g., number of visitors allowed at a time) and staffing needed to be updated to reflect the characteristics of the new facility design. CONCLUSIONS: End-users identified design elements for creating a pleasant atmosphere, attention to the tradeoffs of space and size, designing family support areas to encourage family participation in care, and updating patient care policies and staffing to reflect the new physical space as important aspects to consider when building intensive care units. Evidence-based design may optimize ICU structure for patients, patient families and providers.

Association Between Nighttime Discharge from the Intensive Care Unit and Hospital Mortality: A Multi-Center Retrospective Cohort Study.

BACKGROUND: We aimed to determine the impact of nighttime discharge from the intensive care unit (ICU) to the ward on hospital mortality and readmission rates in consecutive critically ill patients admitted to five Canadian ICUs. We hypothesized that hospital mortality and readmission rates would be higher for patients discharged after hours compared with discharge during the day. METHODS: A multi-center retrospective cohort study was carried out at five hospitals in Edmonton, Canada, between July 2002 and December 2009. Nighttime discharge was defined as discharge from the ICU occurring between 07:00 pm and 07:59 am. Logistic regression analysis was used to explore the associations between nighttime discharge and outcomes. RESULTS: Of 19,622 patients discharged alive from the ICU, 3,505 (17.9%) discharges occurred during nighttime. Nighttime discharge occurred more commonly among medical than surgical patients (19.9% vs. 13.8%, P < 0.001) and among those with more comorbid conditions, compared with daytime discharged patients. Crude hospital mortality (11.8% versus 8.8%, P < 0.001) was greater for nighttime discharged as compared to daytime discharged patients. In a multivariable analysis, after adjustment for comorbidities, diagnosis and source of admission, nighttime discharge remains associated with higher mortality (odds ratio [OR] 1.29; 95% CI, 1.14 to 1.46, P < 0.001). This finding was robust in two sensitivity analyses examining discharges occurring between 00:00 am and 04:59 am (OR 1.28; 1.12-1.47; P < 0.001) and for those who died within 48 h of ICU discharge without readmission (OR 1.24; 1.07-1.42, P = 0.002). There was no difference in ICU readmission for nighttime compared with daytime discharges (7.4% vs. 6.9 %, p = 0.26). However, rates were higher for nighttime discharges in community compared with tertiary hospitals (7.7% vs. 5.7%, P = 0.023). CONCLUSIONS: In a large integrated health region, 1 in 5 ICU patients are discharged at nighttime, a factor with increasing occurrence during our study and shown to be independently associated with higher hospital mortality.

Pharmacokinetics and Pharmacodynamics of Tissue Plasminogen Activator Administered Through an External Ventricular Drain.

BACKGROUND: Intraventricular hemorrhage (IVH) frequently complicates spontaneous intracerebral or subarachnoid hemorrhage (SAH). Administration of intraventricular tissue plasminogen activator (TPA) accelerates blood clearance, but optimal dosing has not been clarified. Using a standardized TPA dose, we assessed peak cerebrospinal fluid (CSF) TPA concentrations, the rate at which TPA clears, and the relationship between TPA concentration and biological activity. METHODS: Twelve patients with aneurysmal SAH and IVH, treated with endovascular coiling and ventricular drainage, were randomized to receive either 2 mg intraventricular TPA or placebo every 12 h (five doses). CT scans were performed 12, 48, and 72 h after initial administration, and blood was quantified using the SAH Sum and IVH Scores. CSF TPA and fibrin degradation product (D-dimer) concentrations were measured at baseline and 1, 6, and 12 h after the first dose using ELISA assays. RESULTS: Median CSF TPA concentrations in seven TPA-treated patients were 525 (IQR 352-2129), 323 (233-413), and 47 (29-283) ng/ml, respectively, at 1, 6, and 12 h after drug administration. Peak concentrations varied markedly (401-8398 ng/ml). Two patients still had slightly elevated levels (283-285 ng/ml) when the second dose was due after 12 h. There was no significant correlation between the magnitude of CSF TPA elevation and the rate of blood clearance or degree of D-dimer elevation. D-dimer peaked at 6 h, had declined by 12 h, and correlated strongly with radiographic IVH clearance (r = 0.82, p = 0.02). CONCLUSIONS: The pharmacokinetics of intraventricular TPA administration varies between individual patients. TPA dose does not need to exceed 2 mg. The optimal administration interval is every 8-12 h.

Neurocritical care: why does it make a difference?

PURPOSE OF REVIEW: The care of critically ill brain-injured patients is complex and requires careful balancing of cerebral and systemic treatment priorities. A growing number of studies have reported improved outcomes when patients are admitted to dedicated neurocritical care units (NCCUs). The reasons for this observation have not been definitively clarified. RECENT FINDINGS: When recently published articles are combined with older literature, there have been more than 40 000 patients assessed in observational studies that compare neurological and general ICUs. Although results are heterogeneous, admission to NCCUs is associated with lower mortality and a greater chance of favorable recovery. These findings are remarkable considering that there are few interventions in neurocritical care that have been demonstrated to be efficacious in randomized trials. Whether the relationship is causal is still being elucidated but potential explanations include higher patient volume and, in turn, greater clinician experience; more emphasis on and adherence to protocols to avoid secondary brain injury; practice differences related to prognostication and withdrawal of life-sustaining interventions; and differences in the use and interpretation of neuroimaging and neuromonitoring data. SUMMARY: Neurocritical care is an evolving field that is associated with improvements in outcomes over the past decade. Further research is required to determine how monitoring and treatment protocols can be optimized.

Intraventricular tissue plasminogen activator in subarachnoid hemorrhage patients: a prospective, randomized, placebo-controlled pilot trial.

BACKGROUND: The quantity of subarachnoid (SAH) and intraventricular hemorrhage (IVH) occurring in the setting of a ruptured cerebral aneurysm is strongly associated with subsequent complications and poor outcomes. METHODS: We randomly allocated aneurysmal SAH patients with a modified Fisher score of 4, who had been treated with endovascular coil embolization and ventricular drainage, to receive either 2 mg intraventricular tissue plasminogen activator (TPA) every 12 h (maximum 10 mg) or placebo. Computed tomography scans were performed 12, 48, and 72 h after administration. Primary outcomes included feasibility (enrollment and consent rates), safety (assessed by prospectively screening for complications), and rate of intracranial blood clearance (measured using sequential IVH, modified Graeb, and SAH sum scores). Secondary outcomes included angiographic vasospasm, delayed cerebral ischemia, need for ventriculoperitoneal shunting, and 6-month neurological outcomes. RESULTS: Seventy-seven patients were screened, 17 were eligible, and 12 were randomized. The consent rate was 87 %. There were no cases of new intracranial hemorrhage complicating use of TPA. Models fit using generalized estimating equations demonstrated more rapid reduction in IVH volume (p = 0.009), modified Graeb score (p < 0.001), and SAH sum score (p < 0.001) among patients treated with TPA. SAH clearance at 48 h was enhanced by earlier drug administration (p = 0.02). There were no differences in secondary outcomes. CONCLUSIONS: Intraventricular TPA accelerates clearance of SAH and IVH, especially when administered early. A larger-scale clinical trial of intraventricular TPA is feasible, will need to be conducted at multiple centers, and is required to determine whether this practice reduces complications and improves outcomes.

Multicentre implementation of a quality improvement initiative to reduce delirium in adult intensive care units: An interrupted time series analysis.

PURPOSE: The ABCDEF bundle may improve delirium outcomes among intensive care unit (ICU) patients, however population-based studies are lacking. In this study we evaluated effects of a quality improvement initiative based on the ABCDEF bundle in adult ICUs in Alberta, Canada. MATERIAL AND METHODS: We conducted a pre-post, registry-based clinical trial, analysed using interrupted time series methodology. Outcomes were examined via segmented linear regression using mixed effects models. The main data source was a population-based electronic health record. RESULTS: 44,405 consecutive admissions (38,400 unique patients) admitted to 15 general medical/surgical and/or neurologic adult ICUs between 2014 and 2019 were included. The proportion of delirium days per ICU increased from 30.24% to 35.31% during the pre-intervention period. After intervention implementation it decreased significantly (bimonthly decrease of 0.34%, 95%CI 0.18-0.50%, p < 0.01) from 33.48% (95%CI 29.64-37.31%) in 2017 to 28.74% (95%CI 25.22-32.26%) in 2019. The proportion of sedation days using midazolam demonstrated an immediate decrease of 7.58% (95%CI 4.00-11.16%). There were no significant changes in duration of invasive ventilation, proportion of partial coma days, ICU mortality, or potential adverse events. CONCLUSIONS: An ABCDEF delirium initiative was implemented on a population-basis within adult ICUs and was successful at reducing the prevalence of delirium.

Diagnostic accuracy of computed tomographic angiography for blunt cerebrovascular injury detection in trauma patients: a systematic review and meta-analysis.

OBJECTIVE: To compare the diagnostic accuracy of computed tomographic angiography (CTA) with digital subtraction angiography (DSA) for blunt cerebrovascular injury (BCVI) detection in trauma patients. BACKGROUND: Controversy exists as to whether the diagnostic performance of CTA compares favorably with the reference-standard, DSA. METHODS: We searched electronic databases (1950 to May 22, 2012), article bibliographies, conference proceedings (2008-2011), and clinical trial registries for studies comparing the accuracy of CTA with DSA for BCVI detection in trauma patients. Pooled estimates of sensitivity, specificity, and positive and negative likelihood ratios were calculated using bivariate random effects models. RESULTS: Eight studies that examined 5704 carotid or vertebral arteries in 1426 trauma patients met inclusion criteria. The pooled sensitivity and specificity for BCVI detection with CTA versus DSA was 66% (95% CI, 49%-79%; I = 80.4%) and 97% (95% CI, 91%-99%; I = 94.6%), respectively. Corresponding pooled positive and negative likelihood ratios were 20.0 (95% CI, 6.9-58.4; I = 87.7%) and 0.35 (95% CI, 0.22-0.56; I = 74.9%), respectively. Although pooled sensitivity varied with the number of available CT slices, the training of interpreting radiologists, and in a pattern suggestive of differences in diagnostic threshold for judging CTA positivity, it remained 80% or less among studies that used scanners with 16 or more slices per rotation and where the CTA was read by neuroradiologists. CONCLUSIONS: Existing evidence suggests that the diagnostic performance of CTA varies considerably across studies, likely due to an implicit variation in diagnostic threshold across trauma centers. Moreover, although CTA appears to lack sensitivity to adequately rule out BCVI, it may be useful to rule in BCVI among trauma patients with a high pretest probability of injury.

Determination of neurologic prognosis and clinical decision making in adult patients with severe traumatic brain injury: a survey of Canadian intensivists, neurosurgeons, and neurologists.

OBJECTIVES: Accurate prognostic information in patients with severe traumatic brain injury remains limited, but mortality following the withdrawal of life-sustaining therapies is high and variable across centers. We designed a survey to understand attitudes of physicians caring for patients with severe traumatic brain injury toward the determination of prognosis and clinical decision making on the level of care. DESIGN, SETTING, AND PARTICIPANTS: We conducted a cross-sectional study of intensivists, neurosurgeons, and neurologists that participate in the care of patients with severe traumatic brain injury at all Canadian level 1 and level 2 trauma centers. INTERVENTION: None. MEASUREMENTS: The main outcome measure was physicians' perceptions of prognosis and recommendations on the level of care. MAIN RESULTS: Our response rate was 64% (455/712). Most respondents (65%) reported that an accurate prediction of prognosis would be most helpful during the first 7 days. Most respondents (>80%) identified bedside monitoring, clinical exam, and imaging to be useful for evaluating prognosis, whereas fewer considered electrophysiology tests (<60%) and biomarkers (<15%). In a case-based scenario, approximately one-third of respondents agreed, one-third were neutral, and one-third disagreed that the patient prognosis would be unfavorable at one year. About 10% were comfortable recommending withdrawal of life-sustaining therapies. CONCLUSIONS: A significant variation in perceptions of neurologic prognosis and in clinical decision making on the level of care was found among Canadian intensivists, neurosurgeons, and neurologists. Improved understanding of the factors that can accurately predict prognosis for patients with traumatic brain injury is urgently needed.

Incidence of neurologic death among patients with brain injury: a cohort study in a Canadian health region.

BACKGROUND: Hospital mortality has decreased over time for critically ill patients with various forms of brain injury. We hypothesized that the proportion of patients who progress to neurologic death may have also decreased. METHODS: We performed a prospective cohort study involving consecutive adult patients with traumatic brain injury, subarachnoid hemorrhage, intracerebral hemorrhage or anoxic brain injury admitted to regional intensive care units in southern Alberta over a 10.5-year period. We used multivariable logistic regression to adjust for patient age and score on the Glasgow Coma Scale at admission, and to assess whether the proportion of patients who progress to neurologic death has changed over time. RESULTS: The cohort consisted of 2788 patients. The proportion of patients who progressed to neurologic death was 8.1% at the start of the study period, and the adjusted odds of progressing to neurologic death decreased over the study period (odds ratio [OR] per yr 0.92, 95% confidence interval [CI] 0.87-0.98, p = 0.006). This change was most pronounced among patients with traumatic brain injury (OR per yr 0.87, 95% CI 0.78-0.96, p = 0.005); there was no change among patients with anoxic injury (OR per yr 0.96, 95% CI 0.85-1.09, p = 0.6). A review of the medical records suggests that missed cases of neurologic death were rare (≤ 0.5% of deaths). INTERPRETATION: The proportion of patients with brain injury who progress to neurologic death has decreased over time, especially among those with head trauma. This finding may reflect positive developments in the prevention and care of brain injury. However, organ donation after neurologic death represents the major source of organs for transplantation. Thus, these findings may help explain the relatively stagnant rates of deceased organ donation in some regions of Canada, which in turn has important implications for the care of patients with end-stage organ failure.