Identification of Clinically Significant Cytokine Signature Clusters in Patients With Septic Shock.

OBJECTIVES: To identify cytokine signature clusters in patients with septic shock. DESIGN: Prospective observational cohort study. SETTING: Single academic center in the United States. PATIENTS: Adult (≥ 18 yr old) patients admitted to the medical ICU with septic shock requiring vasoactive medication support. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: One hundred fourteen patients with septic shock completed cytokine measurement at time of enrollment (t 1 ) and 24 hours later (t 2 ). Unsupervised random forest analysis of the change in cytokines over time, defined as delta (t 2 -t 1 ), identified three clusters with distinct cytokine profiles. Patients in cluster 1 had the lowest initial levels of circulating cytokines that decreased over time. Patients in cluster 2 and cluster 3 had higher initial levels that decreased over time in cluster 2 and increased in cluster 3. Patients in clusters 2 and 3 had higher mortality compared with cluster 1 (clusters 1-3: 11% vs 31%; odds ratio [OR], 3.56 [1.10-14.23] vs 54% OR, 9.23 [2.89-37.22]). Cluster 3 was independently associated with in-hospital mortality (hazard ratio, 5.24; p = 0.005) in multivariable analysis. There were no significant differences in initial clinical severity scoring or steroid use between the clusters. Analysis of either t 1 or t 2 cytokine measurements alone or in combination did not reveal clusters with clear clinical significance. CONCLUSIONS: Longitudinal measurement of cytokine profiles at initiation of vasoactive medications and 24 hours later revealed three distinct cytokine signature clusters that correlated with clinical outcomes.

Bedside estimates of dead space using end-tidal CO2 are independently associated with mortality in ARDS.

PURPOSE: In acute respiratory distress syndrome (ARDS), dead space fraction has been independently associated with mortality. We hypothesized that early measurement of the difference between arterial and end-tidal CO2 (arterial-ET difference), a surrogate for dead space fraction, would predict mortality in mechanically ventilated patients with ARDS. METHODS: We performed two separate exploratory analyses. We first used publicly available databases from the ALTA, EDEN, and OMEGA ARDS Network trials (N = 124) as a derivation cohort to test our hypothesis. We then performed a separate retrospective analysis of patients with ARDS using University of Chicago patients (N = 302) as a validation cohort. RESULTS: The ARDS Network derivation cohort demonstrated arterial-ET difference, vasopressor requirement, age, and APACHE III to be associated with mortality by univariable analysis. By multivariable analysis, only the arterial-ET difference remained significant (P = 0.047). In a separate analysis, the modified Enghoff equation ((PaCO2-PETCO2)/PaCO2) was used in place of the arterial-ET difference and did not alter the results. The University of Chicago cohort found arterial-ET difference, age, ventilator mode, vasopressor requirement, and APACHE II to be associated with mortality in a univariate analysis. By multivariable analysis, the arterial-ET difference continued to be predictive of mortality (P = 0.031). In the validation cohort, substitution of the arterial-ET difference for the modified Enghoff equation showed similar results. CONCLUSION: Arterial to end-tidal CO2 (ETCO2) difference is an independent predictor of mortality in patients with ARDS.

ICU admission body composition: skeletal muscle, bone, and fat effects on mortality and disability at hospital discharge-a prospective, cohort study.

BACKGROUND: Reduced body weight at the time of intensive care unit (ICU) admission is associated with worse survival, and a paradoxical benefit of obesity has been suggested in critical illness. However, no research has addressed the survival effects of disaggregated body constituents of dry weight such as skeletal muscle, fat, and bone density. METHODS: Single-center, prospective observational cohort study of medical ICU (MICU) patients from an academic institution in the USA. Five hundred and seven patients requiring CT scanning of chest or abdomen within the first 24 h of ICU admission were evaluated with erector spinae muscle (ESM) and subcutaneous adipose tissue (SAT) areas and with bone density determinations at the time of ICU admission, which were correlated with clinical outcomes accounting for potential confounders. RESULTS: Larger admission ESM area was associated with decreased odds of 6-month mortality (OR per cm2, 0.96; 95% CI, 0.94-0.97; p < 0.001) and disability at discharge (OR per cm2, 0.98; 95% CI, 0.96-0.99; p = 0.012). Higher bone density was similarly associated with lower odds of mortality (OR per 100 HU, 0.69; 95% CI, 0.49-0.96; p = 0.027) and disability at discharge (OR per 100 HU, 0.52; 95% CI, 0.37-0.74; p < 0.001). SAT area was not significantly associated with these outcomes' measures. Multivariable modeling indicated that ESM area remained significantly associated with 6-month mortality and survival after adjusting for other covariates including preadmission comorbidities, albumin, functional independence before admission, severity scores, age, and exercise capacity. CONCLUSION: In our cohort, ICU admission skeletal muscle mass measured with ESM area and bone density were associated with survival and disability at discharge, although muscle area was the only component that remained significantly associated with survival after multivariable adjustments. SAT had no association with the analyzed outcome measures.

One-Year Outcomes in Patients With Acute Respiratory Distress Syndrome Enrolled in a Randomized Clinical Trial of Helmet Versus Facemask Noninvasive Ventilation.

OBJECTIVES: Many survivors of acute respiratory distress syndrome have poor long-term outcomes possibly due to supportive care practices during "invasive" mechanical ventilation. Helmet noninvasive ventilation in acute respiratory distress syndrome may reduce intubation rates; however, it is unknown if avoiding intubation with helmet noninvasive ventilation alters the consequences of surviving acute respiratory distress syndrome. DESIGN: Long-term follow-up data from a previously published randomized controlled trial. PATIENTS: Adults patients with acute respiratory distress syndrome enrolled in a previously published clinical trial. SETTING: Adult ICU. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was functional independence at 1 year after hospital discharge defined as independence in activities of daily living and ambulation. At 1 year, patients were surveyed to assess for functional independence, survival, and number of institution-free days, defined as days alive spent living at home. The presence of ICU-acquired weakness and functional independence was also assessed by a blinded therapist on hospital discharge. On hospital discharge, there was a greater prevalence of ICU-acquired weakness (79.5% vs 38.6%; p = 0.0002) and less functional independence (15.4% vs 50%; p = 0.001) in the facemask group. One-year follow-up data were collected for 81 of 83 patients (97.6%). One-year mortality was higher in the facemask group (69.2% vs 43.2%; p = 0.017). At 1 year, patients in the helmet group were more likely to be functionally independent (40.9% vs 15.4%; p = 0.015) and had more institution-free days (median, 268.5 [0-354] vs 0 [0-323]; p = 0.017). CONCLUSIONS: Poor functional recovery after invasive mechanical ventilation for acute respiratory distress syndrome is common. Helmet noninvasive ventilation may be the first intervention that mitigates the long-term complications that plague survivors of acute respiratory distress syndrome managed with noninvasive ventilation.

Distinct T-helper cell responses to Staphylococcus aureus bacteremia reflect immunologic comorbidities and correlate with mortality.

BACKGROUND: The dysregulated host immune response that defines sepsis varies as a function of both the immune status of the host and the distinct nature of the pathogen. The degree to which immunocompromising comorbidities or immunosuppressive medications affect the immune response to infection is poorly understood because these patients are often excluded from studies about septic immunity. The objectives of this study were to determine the immune response to a single pathogen (Staphylococcus aureus) among a diverse case mix of patients and to determine whether comorbidities affect immune and clinical outcomes. METHODS: Blood samples were drawn from 95 adult inpatients at multiple time points after the first positive S. aureus blood culture. Cox proportional hazards modeling was used to determine the associations between admission neutrophil counts, admission lymphocyte counts, cytokine levels, and 90-day mortality. A nested case-control flow cytometric analysis was conducted to determine T-helper type 1 (Th1), Th2, Th17, and regulatory T-cell (Treg) subsets among a subgroup of 28 patients. In a secondary analysis, we categorized patients as either having immunocompromising disorders (human immunodeficiency virus and hematologic malignancies), receiving immunosuppressive medications, or being not immunocompromised. RESULTS: Higher neutrophil-to-lymphocyte count ratios and higher Th17 cytokine responses relative to Th1 cytokine responses early after infection were independently associated with mortality and did not depend on the immune state of the patient (HR 1.93, 95% CI 1.17-3.17, p = 0.01; and HR 1.13, 95% CI 1.01-1.27, p = 0.03, respectively). On the basis of flow cytometric analysis of CD4 T-helper subsets, an increasing Th17/Treg response over the course of the infection was most strongly associated with increased mortality (HR 4.41, 95% CI 1.69-11.5, p < 0.01). This type of immune response was most common among patients who were not immunocompromised. In contrast, among immunocompromised patients who died, a decreasing Th1/Treg response was most common. CONCLUSIONS: The association of both increased Th17 responses and increased neutrophil counts relative to lymphocyte counts with mortality suggests that an overwhelming inflammatory response is detrimental. However, the differential responses of patients according to immune state suggest that immune status is an important clinical indicator that should be accounted for in the management of septic patients, as well as in the development of novel immunomodulatory therapies.

An Official ATS/AACN/ACCP/ESICM/SCCM Policy Statement: Responding to Requests for Potentially Inappropriate Treatments in Intensive Care Units.

BACKGROUND: There is controversy about how to manage requests by patients or surrogates for treatments that clinicians believe should not be administered. PURPOSE: This multisociety statement provides recommendations to prevent and manage intractable disagreements about the use of such treatments in intensive care units. METHODS: The recommendations were developed using an iterative consensus process, including expert committee development and peer review by designated committees of each of the participating professional societies (American Thoracic Society, American Association for Critical Care Nurses, American College of Chest Physicians, European Society for Intensive Care Medicine, and Society of Critical Care). MAIN RESULTS: The committee recommends: (1) Institutions should implement strategies to prevent intractable treatment conflicts, including proactive communication and early involvement of expert consultants. (2) The term "potentially inappropriate" should be used, rather than futile, to describe treatments that have at least some chance of accomplishing the effect sought by the patient, but clinicians believe that competing ethical considerations justify not providing them. Clinicians should explain and advocate for the treatment plan they believe is appropriate. Conflicts regarding potentially inappropriate treatments that remain intractable despite intensive communication and negotiation should be managed by a fair process of conflict resolution; this process should include hospital review, attempts to find a willing provider at another institution, and opportunity for external review of decisions. When time pressures make it infeasible to complete all steps of the conflict-resolution process and clinicians have a high degree of certainty that the requested treatment is outside accepted practice, they should seek procedural oversight to the extent allowed by the clinical situation and need not provide the requested treatment. (3) Use of the term "futile" should be restricted to the rare situations in which surrogates request interventions that simply cannot accomplish their intended physiologic goal. Clinicians should not provide futile interventions. (4) The medical profession should lead public engagement efforts and advocate for policies and legislation about when life-prolonging technologies should not be used. CONCLUSIONS: The multisociety statement on responding to requests for potentially inappropriate treatments in intensive care units provides guidance for clinicians to prevent and manage disputes in patients with advanced critical illness.

Effect of Noninvasive Ventilation Delivered by Helmet vs Face Mask on the Rate of Endotracheal Intubation in Patients With Acute Respiratory Distress Syndrome: A Randomized Clinical Trial.

IMPORTANCE: Noninvasive ventilation (NIV) with a face mask is relatively ineffective at preventing endotracheal intubation in patients with acute respiratory distress syndrome (ARDS). Delivery of NIV with a helmet may be a superior strategy for these patients. OBJECTIVE: To determine whether NIV delivered by helmet improves intubation rate among patients with ARDS. DESIGN, SETTING, AND PARTICIPANTS: Single-center randomized clinical trial of 83 patients with ARDS requiring NIV delivered by face mask for at least 8 hours while in the medical intensive care unit at the University of Chicago between October 3, 2012, through September 21, 2015. INTERVENTIONS: Patients were randomly assigned to continue face mask NIV or switch to a helmet for NIV support for a planned enrollment of 206 patients (103 patients per group). The helmet is a transparent hood that covers the entire head of the patient and has a rubber collar neck seal. Early trial termination resulted in 44 patients randomized to the helmet group and 39 to the face mask group. MAIN OUTCOMES AND MEASURES: The primary outcome was the proportion of patients who required endotracheal intubation. Secondary outcomes included 28-day invasive ventilator-free days (ie, days alive without mechanical ventilation), duration of ICU and hospital length of stay, and hospital and 90-day mortality. RESULTS: Eighty-three patients (45% women; median age, 59 years; median Acute Physiology and Chronic Health Evaluation [APACHE] II score, 26) were included in the analysis after the trial was stopped early based on predefined criteria for efficacy. The intubation rate was 61.5% (n = 24) for the face mask group and 18.2% (n = 8) for the helmet group (absolute difference, -43.3%; 95% CI, -62.4% to -24.3%; P < .001). The number of ventilator-free days was significantly higher in the helmet group (28 vs 12.5, P < .001). At 90 days, 15 patients (34.1%) in the helmet group died compared with 22 patients (56.4%) in the face mask group (absolute difference, -22.3%; 95% CI, -43.3 to -1.4; P = .02). Adverse events included 3 interface-related skin ulcers for each group (ie, 7.6% in the face mask group had nose ulcers and 6.8% in the helmet group had neck ulcers). CONCLUSIONS AND RELEVANCE: Among patients with ARDS, treatment with helmet NIV resulted in a significant reduction of intubation rates. There was also a statistically significant reduction in 90-day mortality with helmet NIV. Multicenter studies are needed to replicate these findings. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01680783.

Rapidly reversible, sedation-related delirium versus persistent delirium in the intensive care unit.

RATIONALE: Intensive care unit (ICU) delirium is associated with ventilator, ICU, and hospital days; discharge functional status; and mortality. Whether rapidly reversible, sedation-related delirium (delirium that abates shortly after sedative interruption) occurs with the same frequency and portends the same prognosis as persistent delirium (delirium that persists despite a short period of sedative interruption) is unknown. OBJECTIVES: To compare rapidly reversible, sedation-related delirium and persistent delirium. METHODS: This was a prospective cohort study of 102 adult, intubated medical ICU subjects in a tertiary care teaching hospital. Confusion Assessment Method for the ICU evaluation was performed before and after daily interruption of continuous sedation (DIS). Investigators were blinded to each other's assessments and as to whether evaluations were before or after DIS. The primary outcome was proportion of days with no delirium versus rapidly reversible, sedation-related delirium versus persistent delirium. Secondary outcomes were ventilator, ICU, and hospital days; discharge disposition; and 1-year mortality. MEASUREMENTS AND MAIN RESULTS: The median proportion of ICU days with delirium was 0.57 before versus 0.50 after DIS (P < 0.001). The Confusion Assessment Method for the ICU indicated patients are 10.5 times more likely to have delirium before DIS versus after (P < 0.001). Rapidly reversible, sedation-related delirium showed fewer ventilator (P < 0.001), ICU (P = 0.001), and hospital days (P < 0.001) than persistent delirium. Subjects with no delirium and rapidly reversible, sedation-related delirium were more likely to be discharged home (P < 0.001). Patients with persistent delirium had increased 1-year mortality versus those with no delirium and rapidly reversible, sedation-related delirium (P < 0.001). CONCLUSIONS: Rapidly reversible, sedation-related delirium does not signify the same poor prognosis as persistent delirium. Degree of sedation should be considered in delirium assessments. Coordinating delirium assessments with daily sedative interruption will improve such assessments' ability to prognosticate ICU delirium outcomes. Clinical trial registered with www.clinicaltrials.gov (NCT 00919698).

Psychometric comparison of three behavioural scales for the assessment of pain in critically ill patients unable to self-report.

INTRODUCTION: Pain assessment is associated with important outcomes in ICU patients but remains challenging, particularly in non-communicative patients. Use of a reliable tool is paramount to allow any implementation of sedation/analgesia protocols in a multidisciplinary team. This study compared psychometric properties (inter-rater agreement primarily; validity, responsiveness and feasibility secondarily) of three pain scales: Behavioural Pain Scale (BPS/BPS-NI, that is BPS for Non-Intubated patients), Critical Care Pain Observation Tool (CPOT) and Non-verbal Pain Scale (NVPS), the pain tool routinely used in this 16-bed medical ICU. METHODS: Pain was assessed by at least one of four investigators and one of the 20 bedside nurses before, during and 10 minutes after routine care procedures in non-comatose patients (Richmond Agitation Sedation Scale ≥ -3) who were unable to self-report their pain intensity. The Confusion Assessment Method for the ICU was used to assess delirium. Non-parametric tests were used for statistical analysis. Quantitative data are presented as median (25th to 75th). RESULTS: A total of 258 paired assessments of pain were performed in 30 patients (43% lightly sedated, 57% with delirium, 63% mechanically ventilated). All three scales demonstrated good psychometric properties. However, BPS and CPOT exhibited the best inter-rater reliability (weighted-κ 0.81 for BPS and CPOT) and the best internal consistency (Cronbach-α 0.80 for BPS, 0.81 for CPOT), which were higher than for NVPS (weighted-κ 0.71, P <0.05; Cronbach-α 0.76, P <0.01). Responsiveness was significantly higher for BPS compared to CPOT and for CPOT compared to NVPS. For feasibility, BPS was rated as the easiest scale to remember but there was no significant difference in regards to users' preference. CONCLUSIONS: BPS and CPOT demonstrate similar psychometric properties in non-communicative intubated and non-intubated ICU patients.

Impact of ventilator adjustment and sedation-analgesia practices on severe asynchrony in patients ventilated in assist-control mode.

OBJECTIVES: Breath-stacking asynchrony during assist-control-mode ventilation may be associated with increased tidal volume and alveolar pressure that could contribute to ventilator-induced lung injury. Methods to reduce breath stacking have not been well studied. The objective of this investigation was to evaluate 1) which interventions were used by managing clinicians to address severe breath stacking; and 2) how effective these measures were. SETTING: Sixteen-bed medical ICU. PATIENTS AND INTERVENTIONS: Physiological study in consecutively admitted patients without severe brain injury, who had severe breath stacking defined as an asynchrony index greater than or equal to 10% of total breaths. During 30 minutes before (baseline) and after any intervention employed by the managing clinician, the ventilator flow, airway pressure, and volume/time waveforms were continuously recorded and analyzed to detect normal and stacked breaths. The initial approach taken was assigned to one of three categories: no intervention, increase of sedation-analgesia, or change of ventilator setting. Nonparametric Wilcoxon-Mann-Whitney tests and multiple regression were used for statistical analysis. Quantitative data are presented as median [25-75]. MAIN RESULTS: Sixty-six of 254 (26%) mechanically ventilated patients exhibited severe breath-stacking asynchrony. A total of 100 30-minute sequences were recorded and analyzed in 30 patients before and after 50 clinical decisions for ongoing management (no intervention, n=8; increasing sedation/analgesia, n=16; ventilator adjustment, n=26). Breath-stacking asynchrony index was 44 [27-87]% at baseline. Compared with baseline, the decrease of asynchrony index was greater after changing the ventilator setting (-99 [-92, -100]%) than after increasing the sedation-analgesia (-41 [-66, 7]%, p<0.001) or deciding to tolerate the asynchrony (4 [-4, 12]%, p<0.001). Pressure-support ventilation and increased inspiratory time were independently associated with the reduction of asynchrony index. CONCLUSIONS: Compared with increasing sedation-analgesia, adapting the ventilator to patient breathing effort reduces breath-stacking asynchrony significantly and often dramatically. These results support an algorithm beginning with ventilator adjustment to rationalize the management of severe breath-stacking asynchrony in ICU patients.

A comparison of initial monotherapy with norepinephrine versus vasopressin for resuscitation in septic shock.

BACKGROUND: Early goal-directed therapy is a time-sensitive therapeutic algorithm with a tiered approach to target hypoperfusion and cardiovascular collapse within the first 6 hours of septic shock. The Surviving Sepsis Campaign guidelines recommend norepinephrine or dopamine as the initial vasoactive agent for resuscitation in septic shock, reserving the administration of vasopressin as adjunctive therapy. OBJECTIVE: To determine whether vasopressin was noninferior to norepinephrine as the initial vasopressor to achieve a mean arterial pressure (MAP) goal in the first 6 hours of shock onset. METHODS: This retrospective cohort study evaluated adults who received monotherapy with either norepinephrine or vasopressin as initial vasoactive therapy for the management of septic shock. Patients were excluded if the treatment arm was not monotherapy, if they were admitted to a cardiology or cardiothoracic surgery service, or if they lacked a comparator-based 1:1 frequency matching. RESULTS: A total of 130 patients were included, 65 in each treatment arm. The proportion of patients who achieved a goal MAP in the vasopressin group was 63% (95% CI 51%-75%) and was 67.7% (95% CI 56%-79%) in the norepinephrine group. This observed difference between goal MAP attainment did not exceed the predefined noninferiority margin of -25% (CI for 4.7% difference -21.2% to 12%), suggesting noninferiority of vasopressin. No significant difference was identified between vasopressin and norepinephrine for final mean (SD) MAP achieved (75 [9.6] and 76.0 [8.2] mm Hg, respectively; p = 0.06) or the mean total change from baseline MAP to goal (14.1 [8.4] and 15.1 [9.1] mm Hg, respectively; p = 0.6). CONCLUSIONS: Vasopressin was noninferior to norepinephrine for the achievement of a MAP goal in the first 6 hours from onset of septic shock. Further prospective analysis is warranted; however, the results are useful for consideration of alternative vasopressors in the setting of drug shortages.

Recommendations to limit life support: a national survey of critical care physicians.

RATIONALE: There is debate about whether physicians should routinely provide patient surrogates with recommendations about limiting life support. OBJECTIVES: To explore physicians' self-reported practices and attitudes. METHODS: A cross-sectional, stratified survey of 1,000 randomly selected US critical care physicians was mailed. We included a vignette to experimentally examine how surrogate desire for a recommendation and physician agreement with the surrogate modified whether physicians would provide a recommendation. MEASUREMENTS AND MAIN RESULTS: Proportion of respondents reporting they routinely provide surrogates with a recommendation and how responses varied based on vignette characteristics. A total of 608 (66%) of 922 eligible physicians participated. Approximately one (22%) in five reported always providing surrogates with a recommendation, whereas 1 (11%) in 10 reported rarely or never doing so. Almost all respondents reported comfort making recommendations (92%) and viewed them as appropriate (93%). Most also viewed recommendations as a critical care physician's duty (87%) and did not view them as unduly influential (80%). Approximately two-fifths (41%) believed recommendations were only appropriate if sought by surrogates. In response to the vignettes, nearly all respondents (91%) provided a recommendation when the surrogate requested a recommendation and the physician agreed with the surrogate's likely decision. Physicians were less likely to provide an unwanted recommendation, both when physicians agreed (29%) and disagreed with the surrogate's likely decision (44%). CONCLUSIONS: There is substantial variation among physicians' self-reported use of recommendations to surrogates of critically ill adults. Surrogates' desires for recommendations and physicians' agreement with surrogates' likely decisions may have important influence on whether recommendations are provided.

Perioperative physiotherapy.

PURPOSE OF REVIEW: Physiotherapy in the perioperative period is emerging as an important component of postoperative recovery. This review highlights recent advances in the implementation of physiotherapy in the perioperative period and its enhancement of postsurgical outcomes. RECENT FINDINGS: Physical therapy in the preoperative period can improve physical deconditioning and potentially affect subsequent postsurgical outcomes. Fast-track surgical programs have highlighted the importance of early ambulation in the postoperative period. Incorporation of this multimodal, evidenced-based approach has been shown to reduce postoperative pulmonary complications and shorten hospital length of stay. Physiotherapy is feasible and well tolerated in patients who remain intubated and mechanically ventilated in the postoperative period. This approach also improves duration of mechanical ventilation and return to functional independence at hospital discharge. SUMMARY: Timely and early physiotherapy in the perioperative period improves surgical recovery and reduces postoperative complications.