Clinical predictors of donor antibody titre and correlation with recipient antibody response in a COVID-19 convalescent plasma clinical trial.

BACKGROUND: Convalescent plasma therapy for COVID-19 relies on transfer of anti-viral antibody from donors to recipients via plasma transfusion. The relationship between clinical characteristics and antibody response to COVID-19 is not well defined. We investigated predictors of convalescent antibody production and quantified recipient antibody response in a convalescent plasma therapy clinical trial. METHODS: Multivariable analysis of clinical and serological parameters in 103 confirmed COVID-19 convalescent plasma donors 28 days or more following symptom resolution was performed. Mixed-effects regression models with piecewise linear trends were used to characterize serial antibody responses in 10 convalescent plasma recipients with severe COVID-19. RESULTS: Donor antibody titres ranged from 0 to 1 : 3892 (anti-receptor binding domain (RBD)) and 0 to 1 : 3289 (anti-spike). Higher anti-RBD and anti-spike titres were associated with increased age, hospitalization for COVID-19, fever and absence of myalgia (all P < 0.05). Fatigue was significantly associated with anti-RBD (P = 0.03). In pairwise comparison amongst ABO blood types, AB donors had higher anti-RBD and anti-spike than O donors (P < 0.05). No toxicity was associated with plasma transfusion. Non-ECMO recipient anti-RBD antibody titre increased on average 31% per day during the first three days post-transfusion (P = 0.01) and anti-spike antibody titre by 40.3% (P = 0.02). CONCLUSION: Advanced age, fever, absence of myalgia, fatigue, blood type and hospitalization were associated with higher convalescent antibody titre to COVID-19. Despite variability in donor titre, 80% of convalescent plasma recipients showed significant increase in antibody levels post-transfusion. A more complete understanding of the dose-response effect of plasma transfusion amongst COVID-19-infected patients is needed.

An official American Thoracic Society Clinical Practice guideline: the diagnosis of intensive care unit-acquired weakness in adults

RATIONALE: Profound muscle weakness during and after critical illness is termed intensive care unit-acquired weakness (ICUAW). OBJECTIVES: To develop diagnostic recommendations for ICUAW. METHODS: A multidisciplinary expert committee generated diagnostic questions. A systematic review was performed, and recommendations were developed using the Grading, Recommendations, Assessment, Development, and Evaluation (GRADE) approach. MEASUREMENT AND MAIN RESULTS: Severe sepsis, difficult ventilator liberation, and prolonged mechanical ventilation are associated with ICUAW. Physical rehabilitation improves outcomes in heterogeneous populations of ICU patients. Because it may not be feasible to provide universal physical rehabilitation, an alternative approach is to identify patients most likely to benefit. Patients with ICUAW may be such a group. Our review identified only one case series of patients with ICUAW who received physical therapy. When compared with a case series of patients with ICUAW who did not receive structured physical therapy, evidence suggested those who receive physical rehabilitation were more frequently discharged home rather than to a rehabilitative facility, although confidence intervals included no difference. Other interventions show promise, but fewer data proving patient benefit existed, thus precluding specific comment. Additionally, prior comorbidity was insufficiently defined to determine its influence on outcome, treatment response, or patient preferences for diagnostic efforts. We recommend controlled clinical trials in patients with ICUAW that compare physical rehabilitation with usual care and further research in understanding risk and patient preferences. CONCLUSIONS: Research that identifies treatments that benefit patients with ICUAW is necessary to determine whether the benefits of diagnostic testing for ICUAW outweigh its burdens.(AU)

Prior infections are associated with increased mortality from subsequent blood-stream infections among patients with hematological malignancies.

Many patients who are evaluated and treated for sepsis have histories of recent infections. The prognostic implications of surviving an infectious process are not well understood. We undertook this study to determine the clinical impact of prior infections among patients with hematological malignancies, a population at high risk for developing and dying from sepsis. The medical records of 203 patients with hematological malignancies and blood-stream infections admitted over a 3-year period to an urban teaching hospital were retrospectively reviewed. The 30-day mortality after blood-stream infection in these high-risk patients was 24 %. There were 46 patients (23 %) who had inpatient infections in the 90 days prior to the index blood-stream infection. History of recent infection portended worse prognosis from blood-stream infection under multivariable analysis [odds ratio (OR) 2.60, p = 0.04, 95 % confidence interval (CI) 1.04-6.47]. There were 86 patients (42 %) who had subsequent infections in the first 90 days after the index blood-stream infection. Patients with subsequent infections had greater mortality during days 91-365 than patients without subsequent infections [hazard ratio (HR) 1.97, p = 0.02, 95 % CI 1.13-3.44]. Recent infections prognosticate worse outcomes from subsequent blood-stream infections for this high-risk population. Further research into the clinical and biochemical reasons for this observation may lead to targets for intervention, and, ultimately, improvements in long-term mortality from sepsis.

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.

Cost considerations in sedation, analgesia, and neuromuscular blockade in the intensive care unit.

Sedation of critically ill patients is a costly endeavor. Costs of commonly used intensive care unit (ICU) sedatives range from pennies to more than $500 per day. Although the agents account for some of this expense, complications related to the use of these drugs in the ICU produce even greater costs. Prolongation of mechanical ventilation and length of stay are some of the common complications resulting from non-ideal use of these drugs. Sedative agents also impair neurological evaluation in many critically ill patients, which may mask detection of acute delirium resulting from intercurrent illness or intracranial catastrophes and can lead to excessive diagnostic testing. Opiates may result in gastrointestinal dysfunction with resulting malnutrition and perhaps bacterial translocation and sepsis. Neuromuscular blocking agents may cause prolonged paralysis and disability in critically ill patients who receive them. Simple dosing strategies based on pharmacological principles may decrease the incidence of these costly problems.

Acute respiratory distress syndrome: adjuncts to lung-protective ventilation.

Despite recent advances in understanding, the management of acute respiratory distress syndrome (ARDS) remains a challenging clinical problem. Optimization of gas exchange and preventing the iatrogenic propagation of lung injury are cornerstones of its clinical management. A number of novel approaches and adjuncts to mechanical ventilation have been described over the past decade to help achieve these goals, and some have been widely implemented with varying degrees of success. This chapter will review the rationale and evidence supporting the use of such adjunctive strategies.

Outcomes of critically ill patients denied consideration for liver transplantation.

Patients with advanced liver disease (ALD) leading to admission to the ICU are often evaluated for possible orthotopic liver transplantation (OLT). Those deemed ineligible for listing for OLT must be managed by medical therapy. The number of patients not eligible for OLT listing will likely increase given the current organ transplant shortage. We performed a retrospective multivariate analysis of mortality predictors for patients denied listing for OLT. One hundred and eighty-three patients denied OLT listing were evaluated over a 3(1)/(2)-yr period, beginning in 1994. Overall mortality was 56% for those not listed versus 12% for those listed for OLT (p < 0.001). Independent predictors of increased mortality among those not listed were APACHE II score (p = 0.001; OR 1.11), sepsis (p = 0.04; OR 2.41), and the need for mechanical ventilation (p = 0.001; OR 3.71). Gastrointestinal (GI) bleeding was associated with decreased mortality (p = 0.02; OR 0.44). We conclude that critically ill patients with ALD denied OLT listing have substantially higher mortality than those listed for OLT. APACHE II score, sepsis, and the need for mechanical ventilation predict increased mortality in this group. Conversely, GI bleeding predicts decreased mortality; therefore, aggressive resuscitative measures seem merited in these patients.

Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation.

BACKGROUND: Conous infusions of sedative drugs in the intensive care unit may prolong the duration of mechanical ventilation, prolong the length of stay in the intensive care unit and the hospital, impede efforts to perform daily neurologic examinations, and increase the need for tests to assess alterations in mental status. Whether regular interruption of such infusions might accelerate recovery is not known. METHODS: We conducted a randomized, controlled trial involving 128 adult patients who were receiving mechanical ventilation and continuous infusions of sedative drugs in a medical intensive care unit. In the intervention group, the sedative infusions were interrupted until the patients were awake, on a daily basis; in the control group, the infusions were interrupted only at the discretion of the clinicians in the intensive care unit. RESULTS: The median duration of mechanical ventilation was 4.9 days in the intervention group, as compared with 7.3 days in the control group (P=0.004), and the median length of stay in the intensive care unit was 6.4 days as compared with 9.9 days, respectively (P=0.02). Six of the patients in the intervention group (9 percent) underwent diagnostic testing to assess changes in mental status, as compared with 16 of the patients in the control group (27 percent, P=0.02). Complications (e.g., removal of the endotracheal tube by the patient) occurred in three of the patients in the intervention group (4 percent) and four of the patients in the control group (7 percent, P=0.88). CONCLUSIONS: In patients who are receiving mechanical ventilation, daily interruption of sedative-drug infusions decreases the duration of mechanical ventilation and the length of stay in the intensive care unit.

Outcomes of critically ill cancer patients in a university hospital setting.

Critically ill cancer patients constitute a large percentage of admissions to tertiary care medical intensive care units (ICUs). We sought to describe outcomes of such patients, and to evaluate how conditions commonly seen in these patients impact mortality. A total of 348 consecutive medical ICU cancer patients were evaluated. Subgroup comparisons included the three most common cancer types (leukemia, lymphoma, lung cancer), as well as three different treatments/conditions (bone marrow transplant [BMT] versus non-BMT, mechanical ventilation [MV] versus non-MV, neutropenic versus non-neutropenic). There were no mortality differences between patients with leukemia, lymphoma, or lung cancer. By logistic regression, mortality predictors were: MV, hepatic failure, and cardiovascular failure for the group as a whole (41% overall mortality); MV and allogeneic (as compared with autologous) BMT for the BMT group (39% overall mortality); hepatic failure, cardiovascular failure, and persistent acute respiratory distress syndrome (ARDS) for the MV group (67% overall mortality); and MV for the neutropenic group (53% overall mortality). Neutropenia showed no independent association with mortality in the group as a whole or any subgroup analyzed. We conclude that respiratory, hepatic, and cardiovascular failure predict mortality, whereas neutropenia does not. Additionally, we have noted an encouraging improvement in survival in many groups of critically ill cancer patients.

The impact of morbid obesity on oxygen cost of breathing (VO(2RESP)) at rest.

Oxygen consumption dedicated to respiratory work (V O(2RESP)) during quiet breathing is small in normal patients. In the morbidly obese, at high minute ventilations, VO(2RESP) is greater than in normal patients, but VO(2RESP) during quiet breathing in these patients is not known. We postulated that such patients have increased VO(2RESP) at rest which may predispose them to respiratory failure when additional respiratory workloads are imposed. We measured baseline VO(2) in morbidly obese patients immediately prior to gastric bypass surgery and again after intubation, mechanical ventilation, and paralysis, and compared their change in VO(2) to nonobese patients scheduled for elective abdominal surgery. Baseline VO(2) was higher in the obese patients compared with control patients (354.6 versus 221.4 ml/min; p = 0.0001) and the change in VO(2) from spontaneous breathing to mechanical ventilation was significant in the obese patients (354.6 versus 297.2 ml/min; p = 0.0002) but not the control patients (221.4 versus 219.8 ml/min; p = 0.86). We conclude that morbidly obese patients dedicate a disproportionately high percentage of total VO(2) to conduct respiratory work, even during quiet breathing. This relative inefficiency suggests a decreased ventilatory reserve and a predisposition to respiratory failure in the setting of even mild pulmonary or systemic insults.

Determination of hemoglobin saturation in patients with acute sickle chest syndrome: a comparison of arterial blood gases and pulse oximetry.

STUDY OBJECTIVES: To evaluate three different methods of measuring oxygen saturation in patients suffering from acute sickle chest syndrome. DESIGN: A prospective, descriptive study of 9 months' duration. SETTING: A tertiary care university hospital. PATIENTS: Adult patients with acute sickle chest syndrome scheduled to undergo RBC exchange transfusion. INTERVENTIONS: None. MEASUREMENTS: Baseline hemoglobin oxygen saturation was determined simultaneously by (1) calculation based on PaO2 and an oxyhemoglobin dissociation curve algorithm, (2) co-oximetry, and (3) pulse oximetry. These same measures were repeated after exchange transfusion. Baseline and postexchange hemoglobin electrophoresis was performed in all patients. RESULTS: Baseline calculated saturation overestimated true saturation (determined by co-oximetry) with a baseline mean bias (co-oximetry minus calculated saturation) of -6.78 +/- 2.63% (95% confidence interval for bias: -8.37% to -5.19%). Pulse oximetry was not different than co-oximetry at baseline with a baseline bias of +1.86 +/- 3.25% (95% confidence interval: -0.1% to 3.82%). After exchange transfusion, there was no bias between either co-oximetry and calculated saturation (mean difference: -0.17 +/- 1.31% [95% confidence interval: -0.95% to 0.61%]), or co-oximetry and pulse oximetry (mean difference: +0.3 +/- 1.53% [95% confidence interval: -0.62% to 1.22%]). CONCLUSIONS: Calculated saturation overestimates true saturation during acute sickle chest syndrome. This discrepancy abates after exchange transfusion. Pulse oximetry more closely follows co-oximetry than does calculated saturation during acute sickle chest syndrome.

Clinical examination reliably detects intrinsic positive end-expiratory pressure in critically ill, mechanically ventilated patients.

Critically ill patients requiring mechanical ventilation often develop intrinsic positive end-expiratory pressure (PEEPi). Methods for its detection include an expiratory flow waveform display (not always available), an esophageal pressure transducer (invasive), or a relaxed or paralyzed patient. We sought to determine the accuracy of clinical examination for detecting PEEPi. Examiners blinded to waveform analysis assessed patients for the presence of PEEPi by inspection/palpation and auscultation. If either inspection/palpation or auscultation demonstrated PEEPi, it was said to be present by clinical exam. Clinicians with various levels of experience (attending, resident, student) made 503 observations of 71 patients. Sensitivity (SENS), specificity (SPEC), positive predictive value (PPV), negative predictive value (NPV), and likelihood ratios were determined for inspection/palpation, auscultation, and clinical exam. PEEPi was present during 69.8% of observations. SENS, SPEC, and PPV of clinical exam were 0.72, 0.91, and 0.95 respectively for the examiners as a whole. Likelihood ratio for PEEPi detection by clinical exam was 8.35. Attending intensivists displayed SPEC and PPV of 1.0. NPV was only 0.58 (likelihood ratio 0.31). We conclude that the clinical exam is very good for detecting PEEPi at all experience levels; and further, that the clinical exam is only modestly useful for ruling out PEEPi, therefore, other tests should be used if PEEPi is not detected by clinical exam.

Sedation of critically ill patients during mechanical ventilation. A comparison of propofol and midazolam.

Propofol (P) and midazolam (M) are frequently given by continuous infusion for sedation in critically ill, mechanically ventilated patients. We compared these drugs with regard to: (1) time-to-awaken; (2) reproducibility of bedside assessments of level of sedation; (3) time-to-sedation; and (4) change in oxygen consumption (V O2) from awake to sedated state. Seventy-three patients were prospectively randomized to receive either P (n=37) or M (n=36). Wake-up times after stopping the drug were assessed by blinded and unblinded observers, by asking patients to perform simple tasks. Times to sedate were assessed by consensus agreement among nurses and investigators. Demographics and APACHE II scores were not different between P and M. The P group had a significantly narrower range of wake-up times with a higher likelihood of waking in less than 60 min. Blinded versus unblinded observations had excellent correlation. Average time to sedate and decrease in V O2 were not different. We conclude that in this patient population: (1) both P and M achieved optimal sedation in a large fraction of patients when administered by specified dosing protocols; (2) P had a faster, more reliable, wake-up time; (3) assessments of time-to-awaken were objective and reproducible; (4) time to sedation was not significantly different; (5) V O2 decreased similarly with both.

[Major agitated-anxious versus blunted-retarded depression: differential effects of fluoxetine]. / Dépressions majeures agitées-anxieuses versus émoussées-ralenties: effets différentiels de la fluoxétine.

A multi-centre study was designed to evaluate the efficacy and tolerance of fluoxetine in two groups of major depression: "agitated-anxious" and "blunted-retarded". The study included 50 patients presenting a major depressive episode (following DSM III-R criteria and score > or = 20 on MADRS): 26 in "agitated-anxious" group (score > or = 15 on Hamilton anxiety scale and > or = 10 on Tyrer anxiety brief scale) and 24 in the "blunted-retarded" group (score > or = 15 on Widlöcher retardation scale and > or = 10 on Abrams-Taylor blunted affect scale). After one week period on placebo, all patients were treated in an open design with fluoxetine at a fixed daily dose of 20 mg and followed on a period of 6 weeks with active treatment. In spite of a significant antidepressant efficacy of fluoxetine in the two groups, better results were observed in the "agitated-anxious" depressed group: marked improvement on MADRS total score at day 42 (76% decrease vs 62% in the "blunted-retarded" group, p = 0.012), greater number of "responders" defined by a decrease > or = 50% on MADRS total score and a total score < or = 12 (95% vs 63%, p = 0.04), better patient's global impression on efficacy (54% of "excellent efficacy" vs 18%, p = 0.012), more improvement on HSCL-58 total score (mean decrease of 69% vs 39%, p = 0.016), higher improvement on "hostility/interpersonal hypersensitivity" score (mean decrease of 74% vs 37%, p = 0.001) and on "anger attacks/irritability" sub-score (mean decrease of 73% vs 30%, p = 0.0002).(ABSTRACT TRUNCATED AT 250 WORDS)