Bryce R.H. Robinson

Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium in Adult Patients in the Intensive Care Unit

Objective:To revise the “Clinical Practice Guidelines for the Sustained Use of Sedatives and Analgesics in the Critically Ill Adult” published in Critical Care Medicine in 2002. Methods:The American College of Critical Care Medicine assembled a 20-person, multidisciplinary, multi-institutional task force with expertise in guideline development, pain, agitation and sedation, delirium management, and associated outcomes in adult critically ill patients. The task force, divided into four subcommittees, collaborated over 6 yr in person, via teleconferences, and via electronic communication. Subcommittees were responsible for developing relevant clinical questions, using the Grading of Recommendations Assessment, Development and Evaluation method (http://www.gradeworkinggroup.org) to review, evaluate, and summarize the literature, and to develop clinical statements (descriptive) and recommendations (actionable). With the help of a professional librarian and Refworks® database software, they developed a Web-based electronic database of over 19,000 references extracted from eight clinical search engines, related to pain and analgesia, agitation and sedation, delirium, and related clinical outcomes in adult ICU patients. The group also used psychometric analyses to evaluate and compare pain, agitation/sedation, and delirium assessment tools. All task force members were allowed to review the literature supporting each statement and recommendation and provided feedback to the subcommittees. Group consensus was achieved for all statements and recommendations using the nominal group technique and the modified Delphi method, with anonymous voting by all task force members using E-Survey (http://www.esurvey.com). All voting was completed in December 2010. Relevant studies published after this date and prior to publication of these guidelines were referenced in the text. The quality of evidence for each statement and recommendation was ranked as high (A), moderate (B), or low/very low (C). The strength of recommendations was ranked as strong (1) or weak (2), and either in favor of (+) or against (–) an intervention. A strong recommendation (either for or against) indicated that the intervention’s desirable effects either clearly outweighed its undesirable effects (risks, burdens, and costs) or it did not. For all strong recommendations, the phrase “We recommend …” is used throughout. A weak recommendation, either for or against an intervention, indicated that the trade-off between desirable and undesirable effects was less clear. For all weak recommendations, the phrase “We suggest …” is used throughout. In the absence of sufficient evidence, or when group consensus could not be achieved, no recommendation (0) was made. Consensus based on expert opinion was not used as a substitute for a lack of evidence. A consistent method for addressing potential conflict of interest was followed if task force members were coauthors of related research. The development of this guideline was independent of any industry funding. Conclusion:These guidelines provide a roadmap for developing integrated, evidence-based, and patient-centered protocols for preventing and treating pain, agitation, and delirium in critically ill patients.

Transfusion of Plasma, Platelets, and Red Blood Cells in a 1:1:1 vs a 1:1:2 Ratio and Mortality in Patients With Severe Trauma: The PROPPR Randomized Clinical Trial

IMPORTANCE Severely injured patients experiencing hemorrhagic shock often require massive transfusion. Earlier transfusion with higher blood product ratios (plasma, platelets, and red blood cells), defined as damage control resuscitation, has been associated with improved outcomes; however, there have been no large multicenter clinical trials. OBJECTIVE To determine the effectiveness and safety of transfusing patients with severe trauma and major bleeding using plasma, platelets, and red blood cells in a 1:1:1 ratio compared with a 1:1:2 ratio. DESIGN, SETTING, AND PARTICIPANTS Pragmatic, phase 3, multisite, randomized clinical trial of 680 severely injured patients who arrived at 1 of 12 level I trauma centers in North America directly from the scene and were predicted to require massive transfusion between August 2012 and December 2013. INTERVENTIONS Blood product ratios of 1:1:1 (338 patients) vs 1:1:2 (342 patients) during active resuscitation in addition to all local standard-of-care interventions (uncontrolled). MAIN OUTCOMES AND MEASURES Primary outcomes were 24-hour and 30-day all-cause mortality. Prespecified ancillary outcomes included time to hemostasis, blood product volumes transfused, complications, incidence of surgical procedures, and functional status. RESULTS No significant differences were detected in mortality at 24 hours (12.7% in 1:1:1 group vs 17.0% in 1:1:2 group; difference, -4.2% [95% CI, -9.6% to 1.1%]; P = .12) or at 30 days (22.4% vs 26.1%, respectively; difference, -3.7% [95% CI, -10.2% to 2.7%]; P = .26). Exsanguination, which was the predominant cause of death within the first 24 hours, was significantly decreased in the 1:1:1 group (9.2% vs 14.6% in 1:1:2 group; difference, -5.4% [95% CI, -10.4% to -0.5%]; P = .03). More patients in the 1:1:1 group achieved hemostasis than in the 1:1:2 group (86% vs 78%, respectively; P = .006). Despite the 1:1:1 group receiving more plasma (median of 7 U vs 5 U, P < .001) and platelets (12 U vs 6 U, P < .001) and similar amounts of red blood cells (9 U) over the first 24 hours, no differences between the 2 groups were found for the 23 prespecified complications, including acute respiratory distress syndrome, multiple organ failure, venous thromboembolism, sepsis, and transfusion-related complications. CONCLUSIONS AND RELEVANCE Among patients with severe trauma and major bleeding, early administration of plasma, platelets, and red blood cells in a 1:1:1 ratio compared with a 1:1:2 ratio did not result in significant differences in mortality at 24 hours or at 30 days. However, more patients in the 1:1:1 group achieved hemostasis and fewer experienced death due to exsanguination by 24 hours. Even though there was an increased use of plasma and platelets transfused in the 1:1:1 group, no other safety differences were identified between the 2 groups. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01545232.

An analgesia-delirium-sedation protocol for critically ill trauma patients reduces ventilator days and hospital length of stay.

BACKGROUND Analgesics and sedatives are required to maintain a calm and comfortable mechanically ventilated injured patient. Continuous sedative infusions have been shown to lengthen mechanical ventilation and hospital length of stay. Daily interruption of sedative infusions may reduce both of these variables. Implementation of an Analgesia-Delirium-Sedation (ADS) Protocol using objective assessments with a goal of maintaining an awake and comfortable patient may obviate the need for daily interruption of infusions in critically ill trauma patients. We examined the effects of such a protocol on ventilator duration, intensive care unit (ICU) length of stay, hospital slength of stay, and medication requirements. METHODS A multidisciplinary team designed the protocol. Objective measures of pain (visual/objective pain assessment scale-VAS/OPAS), agitation (Richmond Agitation-Sedation Scale-RASS), and delirium [Confusion Assessment Method {CAM-ICU}] were used. Medications were titrated to a RASS of -1 to +1 and VAS/OPAS <4. Haloperidol was used to treat delirium in CAM-ICU positive patients. Retrospective review of the local Project IMPACT database for a 6-month period in 2004 was compared with the same seasonal period in 2006 in which the ADS protocol was used. All mechanically ventilated trauma patients receiving infusions of narcotic, propofol, or benzodiazepine were included. Age, APACHE II score, Injury Severity Score, ventilator days, ventilator-free days at day 28, ICU length of stay, and hospital length of stay are reported as median values (interquartile range). Medication usage is reported as mean values (+/-SD). Differences in data were analyzed using Wilcoxons rank-sum test or t test, as appropriate. Gender, mortality, and mechanism of injury were analyzed using chi analysis. RESULTS A total of 143 patients were included. Patients who died during their hospitalization were excluded except in the analysis of ventilator-free days at day 28. After exclusions, 61 patients were in the control group and 58 in the protocol group. The median duration of mechanical ventilation in the protocol group was 1.2 days (0.5-3.0) which was significantly reduced compared with 3.2 days (1.0-12.9) in the control group (p = 0.027). Analysis of ventilator-free days at day 28 found that the protocol group had 26.4 ventilator-free days (13.9-27.4) compared with 22.8 days (10.5-26.9) in the control group (p = 0.007). The median ICU length of stay was 5.9 days (2.3-18.2) in the control group and 4.1 days (2.5-8.3) in the protocol group (p = 0.21). Hospital length of stay was 12 days (7-17) in the protocol group in contrast to 18 days (10-27) in the control group (p = 0.036). Opiate equivalents and propofol use per patient was significantly reduced in the protocol group from 2,465 mg (+/-1,242 mg) to 1,641 mg (+/-1,250 mg) and 19,232 mg (+/-22,477 mg) to 10,057 (+/-14,616 mg), respectively (p < 0.001, p = 0.01). CONCLUSION An objective assessment- based ADS protocol without daily interruption of medication infusion decreases ventilator days and hospital length of stay in critically ill trauma patients.

Microparticles from Stored Red Blood Cells Activate Neutrophils and Cause Lung Injury after Hemorrhage and Resuscitation

BACKGROUND Transfusion of stored blood is associated with increased complications. Microparticles (MPs) are small vesicles released from RBCs that can induce cellular dysfunction, but the role of RBC-derived MPs in resuscitation from hemorrhagic shock is unknown. In the current study, we examined the effects of RBC-derived MPs on the host response to hemorrhage and resuscitation. STUDY DESIGN MPs were isolated from murine packed RBC units, quantified using flow cytometry, and injected into healthy mice. Separate groups of mice underwent hemorrhage and resuscitation with and without packed RBC-derived MPs. Lungs were harvested for histology and neutrophil accumulation and assessed by myeloperoxidase content. Human neutrophils were treated with human RBC-derived MPs and CD11b expression, superoxide production, and phagocytic activity were determined. RESULTS Stored murine packed RBC units contained increased numbers of RBC-derived MPs compared with fresh units. Hemorrhaged mice resuscitated with MPs demonstrated substantially increased pulmonary neutrophil accumulation and altered lung histology compared with mice resuscitated without MPs. Intravenous injection of MPs into normal mice resulted in neutrophil priming, evidenced by increased neutrophil CD11b expression. Human neutrophils treated with RBC-derived MPs demonstrated increased CD11b expression, increased superoxide production, and enhanced phagocytic ability compared with untreated neutrophils. CONCLUSIONS Stored packed RBC units contain increased numbers of RBC-derived MPs. These MPs appear to contribute to neutrophil priming and activation. The presence of MPs in stored units can be associated with adverse effects, including lung injury, after transfusion.

All massive transfusion criteria are not created equal: defining the predictive value of individual transfusion triggers to better determine who benefits from blood.

BACKGROUND As familiarity with military massive transfusion (MT) triggers has increased, there is a growing interest in applying these in the civilian population to initiate MT protocols (MTP) earlier. We hypothesize that these triggers do not have equal predictability for MT and understanding the contribution of each would improve our ability to initiate the MTP earlier. METHODS All patients presenting to a Level I trauma center from October 2007 to September 2008 requiring immediate operation were included in this study. Emergency department records, operative logs, and blood transfusion data from arrival to procedure end were analyzed using multivariate regression techniques. Triggers included systolic blood pressure (SBP) <90 mm Hg, hemoglobin <11 g/dL, temperature <35.5°C, International normalized ratio (INR) >1.5, and base deficit ≥6. RESULTS One hundred seventy patients required immediate operation with an overall survival of 91%. Transfusion of packed red blood cells was noted in 45% (77 of 170) with the mean number of transfused units highest in those meeting SBP (12.9 Units) or INR (12.3 Units) triggers. The triggers do not contribute equal predictive value for the need for transfusion with INR being the most predictive (odds ratio, 16.7; 95% confidence interval, 2-137) for any transfusion and highly predictive for the need for MT (odds ratio, 11.3; 95% confidence interval, 3-47). In fact, if patients met either INR or SBP triggers alone, they were likely to receive MT (p = 0.018 and 0.003, respectively). CONCLUSION Triggers have differential predictive values for need for transfusion. Defining the individual utility of each criterion will help to identify those most likely to benefit from an early initiation of the MTP.

Defining when to initiate massive transfusion: A validation study of individual massive transfusion triggers in PROMMTT patients

BACKGROUND Early predictors of massive transfusion (MT) would prevent undertriage of patients likely to require MT. This study validates triggers using the Prospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study. METHODS All enrolled patients in PROMMTT were analyzed. The initial emergency department value for each trigger (international normalized ratio [INR], systolic blood pressure, hemoglobin, base deficit, positive result for Focused Assessment for the Sonography of Trauma examination, heart rate, temperature, and penetrating injury mechanism) was compared for patients receiving MT (≥10 U of packed red blood cells in 24 hours) versus no MT. Adjusted odds ratios (ORs) for MT are reported using multiple logistic regression. If all triggers were known, a Massive Transfusion Score (MTS) was created, with 1 point assigned for each met trigger. RESULTS A total of 1,245 patients were prospectively enrolled with 297 receiving an MT. Data were available for all triggers in 66% of the patients including 67% of the MTs (199 of 297). INR was known in 87% (1,081 of 1,245). All triggers except penetrating injury mechanism and heart rate were valid individual predictors of MT, with INR as the most predictive (adjusted OR, 2.5; 95% confidence interval, 1.7–3.7). For those with all triggers known, a positive INR trigger was seen in 49% receiving MT. Patients with an MTS of less than 2 were unlikely to receive MT (negative predictive value, 89%). If any two triggers were present (MTS ≥ 2), sensitivity for predicting MT was 85%. MT was present in 33% with an MTS of 2 greater compared with 11% of those with MTS of less than 2 (OR, 3.9; 95% confidence interval, 2.6–5.8; p < 0.0005). CONCLUSION Parameters that can be obtained early in the initial emergency department evaluation are valid predictors for determining the likelihood of MT. LEVEL OF EVIDENCE Diagnostic, level II.

Psychometric analysis of subjective sedation scales in critically ill adults.

Objective:To describe and analyze the development and psychometric properties of subjective sedation scales developed for critically ill adult patients. Data Sources:PubMed, MEDLINE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, CINAHL, Scopus, ISI Web of Science, and the International Pharmaceutical Abstracts. Study Selection:English-only publications through December 2012 with at least 30 patients older than 18 years, which included the key words of adult, critically ill, subjective sedation scale, sedation scale, validity, and reliability. Data Extraction:Two independent reviewers evaluated the psychometric properties using a standardized sedation scale psychometric scoring system. Data Synthesis:Among the 19,000+ citations extracted for the 2013 Society of Critical Care Medicine’s Clinical Practice Guidelines for the Management of Pain, Agitation and Delirium and from December 2010 to 2012, 36 articles were identified compassing 11 sedation scales. The scale development process, psychometric properties, feasibility, and implementation of sedation scales were analyzed using a 0–20 scoring system. Two scales demonstrated scores indicating “very good” published psychometric properties: Richmond Agitation-Sedation Scale (19.5) and the Sedation-Agitation Scale (19). Scores with “moderate” properties include the Vancouver Interaction and Calmness Scale (14.3), Adaptation to the Intensive Care Environment (13.7), Ramsay Sedation Scale (13.2), Minnesota Sedation Assessment Tool (13), and the Nursing Instrument for the Communication of Sedation (12.8). Scales with “low” properties included the Motor Activity Assessment Scale (11.5) and the Sedation Intensive Care Score (10.5). The New Sheffield Sedation Scale (8.5) and the Observer’s Assessment of Alertness/Sedation Scale (3.7) demonstrated “very low” published properties. Conclusions:Based on the current literature, and using a predetermined psychometric scoring system, the Richmond Agitation-Sedation Scale and the Sedation-Agitation Scale are the most valid and reliable subjective sedation scales for use in critically ill adult patients.

Human microparticles generated during sepsis in patients with critical illness are neutrophil-derived and modulate the immune response.

BACKGROUND Microparticles (MPs) are 0.3 &mgr;m to 1.0 &mgr;m vesicles generated after cell activation or apoptosis that may play a role in the pathophysiology of sepsis. We sought to elucidate the role of MPs in patients with critical illness and hypothesized that MPs are generated at the site of inflammation and can modulate the immune response. METHODS Surgical patients with critical illness with ongoing sepsis were enrolled from the intensive care unit of an urban, Level I trauma center from March to June 2011. Abdominal washings and bronchoalveolar lavage fluid were collected from sites of inflammation. MPs were isolated using differential centrifugation, then characterized by flow cytometry. Immunologic assays were conducted by incubating neutrophil-derived MPs (NDMPs) with a human monocytic cell line (THP-1). A p value ⩽0.05 was considered significant. RESULTS MPs were absent in noninflamed foci in patients, whereas NDMPs were present in locations of inflammation. NDMPs were added to cultured THP-1 cells to quantify immunomodulatory effects. THP-1 cells were able to phagocytose NDMPs. Cells that ingested NDMPs demonstrated increased activation. In contrast, bystander THP-1 cells without ingested NDMPs demonstrated decreased activation. CONCLUSION NDMPs are generated at the site of inflammation in patients with critical illness during sepsis. They have a divergent effect on the immune response by activating phagocytic cells and deactivating bystander cells. NDMPs may play an important role in regulating the inflammatory response to sepsis in patients with critical illness. LEVEL OF EVIDENCE Prognostic/epidemiologic study, level III.

Asynchrony and dyspnea.

Patient-ventilator synchrony and patient comfort are assumed to go hand in hand, yet few studies provide support for this common sense idea. In reality, synchrony between the patient and ventilator is complex and can be affected by the ventilator settings, type of ventilator, patient-ventilator interface, and sedation. Inspections of airway pressure and flow waveforms are reliable methods for detecting asynchrony, and automated detection seems accurate. A number of types of asynchronies have been defined, and asynchrony during invasive and noninvasive ventilation have different calling cards. There is a clear association between asynchrony, ventilator-induced diaphragmatic dysfunction, and duration of mechanical ventilation. Whether these are cause and effect or simply associated remains to be determined.

Application of the Berlin definition in PROMMTT patients: The impact of resuscitation on the incidence of hypoxemia

BACKGROUND Acute lung injury following trauma resuscitation remains a concern despite recent advances. With the use of the PROMMTT study population, the risk of hypoxemia and potential modifiable risk factors are studied. METHODS Patients with survival for 24 hours or greater with at least one intensive care unit day were included in the analysis. Hypoxemia was categorized using the Berlin definition for adult respiratory distress syndrome: none (PaO2-to-FIO2 ratio [P/F] > 300 mm Hg), mild (P/F, 201–300 mm Hg), moderate (P/F, 101–200 mm Hg) or severe (P/F ⩽ 100 mm Hg). The cohort was dichotomized into those with none or mild hypoxemia and those with moderate or severe injury. Early resuscitation was defined as that occurring 0 hour to 6 hours from arrival; late resuscitation was defined as that occurring 7 hours to 24 hours. Multivariate logistic regression models were developed controlling for age, sex, mechanisms of injury, arrival physiology, individual Abbreviated Injury Scale (AIS) scores, blood transfusions, and crystalloid administration. RESULTS Of the patients 58.7% (731 of 1,245) met inclusion criteria. Hypoxemia occurred in 69% (mild, 24%; moderate, 28%; severe, 17%). Mortality was highest (24%) in the severe group. During early resuscitation (0–6 h), logistic regression revealed age (odd ratio [OR], 1.02; 95% confidence interval [CI], 1.00–1.04), chest AIS score (OR, 1.31; 95% CI, 1.10–1.57), and intravenously administered crystalloid fluids given in 500 mL increments (OR, 1.12; 95% CI, 1.01–1.25) as predictive of moderate or severe hypoxemia. During late resuscitation, age (OR, 1.02; 95% CI, 1.00–1.04), chest AIS score (OR, 1.33; 95% CI, 1.11–1.59), and crystalloids given during this period (OR, 1.05; 95% CI, 1.01–1.10) were also predictive of moderate-to-severe hypoxemia. Red blood cell, plasma, and platelet transfusions (whether received during early or late resuscitation) failed to demonstrate an increased risk of developing moderate/severe hypoxemia. CONCLUSION Severe chest injury, increasing age, and crystalloid-based resuscitation, but not blood transfusions, were associated with increased risk of developing moderate-to-severe hypoxemia following injury. LEVEL OF EVIDENCE Epidemiologic/prognostic study, level III.