Mark D. Siegel

Delirium in the Intensive Care Unit: Occurrence and Clinical Course in Older Patients

OBJECTIVES: To describe the occurrence of delirium in a cohort of older medical intensive care unit (ICU) patients and its short‐term duration in the hospital and to determine the association between preexisting dementia and the occurrence of delirium.

Psychiatric illness in the next of kin of patients who die in the intensive care unit.

Objectives:To determine the rates of psychiatric illness in next of kin following the death of a relative in a medical intensive care unit. Design:Cross-sectional survey. Setting:A university teaching hospital, New Haven, CT. Patients:Forty-one next of kin who had served as primary surrogate decision makers before the death of their loved one in the intensive care unit 3–12 months previously. Interventions:Structured Clinical Interviews for DSM-IV and the Inventory of Complicated Grief–Revised were used to determine prevalence of psychiatric illness. Formal questionnaires were used to evaluate key features of the intensive care unit experience. Bivariate statistics were used to identify factors associated with the presence of psychiatric illness. Measurements and Main Results:Following 107 patient deaths, 51 next of kin were successfully contacted and 41 (80%) agreed to study participation. Thirty-four percent (95% confidence interval, 20% to 51%) met criteria for at least one psychiatric illness: major depressive disorder (27%), generalized anxiety disorder (10%), panic disorder (10%), or complicated grief disorder (5%). Disorders were more common in spouses than other kinship relations (63% vs. 16%, p = .002), those experiencing additional stressors after the loss (53% vs. 21%, p = .03), those who said the patient was ill <5 yrs (45% vs. 8%, p = .03), and those who said the patient’s physician was not comforting (71% vs. 23%, p = .02). Conclusions:In a cohort of bereaved next of kin of patients who died in the intensive care unit, we identified a high prevalence of psychiatric illness, particularly major depressive disorder. More work is needed to identify those at risk for psychiatric illness so that appropriate interventions may be targeted.

Randomized Clinical Trial of Activated Protein C for the Treatment of Acute Lung Injury

RATIONALE Microvascular injury, inflammation, and coagulation play critical roles in the pathogenesis of acute lung injury (ALI). Plasma protein C levels are decreased in patients with acute lung injury and are associated with higher mortality and fewer ventilator-free days. OBJECTIVES To test the efficacy of activated protein C (APC) as a therapy for patients with ALI. METHODS Eligible subjects were critically ill patients who met the American/European consensus criteria for ALI. Patients with severe sepsis and an APACHE II score of 25 or more were excluded. Participants were randomized to receive APC (24 microg/kg/h for 96 h) or placebo in a double-blind fashion within 72 hours of the onset of ALI. The primary endpoint was ventilator-free days. MEASUREMENTS AND MAIN RESULTS APC increased plasma protein C levels (P = 0.002) and decreased pulmonary dead space fraction (P = 0.02). However, there was no statistically significant difference between patients receiving placebo (n = 38) or APC (n = 37) in the number of ventilator-free days (median [25-75% interquartile range]: 19 [0-24] vs. 19 [14-22], respectively; P = 0.78) or in 60-day mortality (5/38 vs. 5/37 patients, respectively; P = 1.0). There were no differences in the number of bleeding events between the two groups. CONCLUSIONS APC did not improve outcomes from ALI. The results of this trial do not support a large clinical trial of APC for ALI in the absence of severe sepsis and high disease severity.

Activation of the Interleukin-5 Promoter by cAMP in Murine EL-4 Cells Requires the GATA-3 and CLE0 Elements

Interleukin-5 (IL-5) plays a central role in the growth and differentiation of eosinophils and contributes to several disease states including asthma. Accumulating evidence suggests a role for cAMP as an immunomodulator; agents that increase intracellular cAMP levels have been shown to inhibit production of cytokines predominantly produced by T helper (Th) 1 cells such as IL-2 and interferon (IFN-). In contrast, the production of IL-5, predominantly produced by Th2 cells, is actually enhanced by these agents. In this report, we have performed transient transfection experiments with IL-5 promoter-reporter gene constructs, DNase I footprinting assays, and electrophoretic mobility shift assays to investigate the key regulatory regions necessary for activation of the IL-5 promoter by dibutyryl cAMP and phorbol esters in the mouse thymoma line EL-4. Taken together, our data demonstrate the critical importance of two sequences within the IL-5 5′-flanking region for activation by these agents in EL-4 cells: one, a highly conserved 15-base pair element present in genes expressed by Th2 cells, called the conserved lymphokine element 0 (CLE0; located between −53 and −39 in the IL-5 promoter), and the other, two overlapping binding sites for the transcription factor GATA-3 (but not GATA-4) between −70 and −59. Taken together, our data suggest that activation via the unique sequence combination GATA/CLE0 results in selective expression of the IL-5 gene in response to elevated levels of intracellular cAMP.

Elevated serum angiopoietin 2 levels are associated with increased mortality in sepsis.

The vascular growth factor angiopoietin 2 (Ang-2) is known to promote inflammation and endothelial dysfunction, but its prognostic capacity and relationship to outcomes in human sepsis are unknown. This is a prospective observational cohort study of 66 patients newly admitted to a tertiary care medical intensive care unit (ICU), which included ICU patients with no sepsis (n = 20) as well as those with sepsis (n = 10), severe sepsis (n = 12), and septic shock (n = 24). Clinical data were collected until hospital discharge, and Ang-2 and IL-6 levels were determined on specimens obtained after ICU admission. Serum Ang-2 correlated with IL-6 and severity-of-illness scores. In the septic cohort, circulating Ang-2 levels were significantly higher (P = 0.01) in those who died (24.9 ng/mL; interquartile range, 21.5-38.0 ng/mL) compared with those who survived (13.5 ng/mL; interquartile range, 8.1-21.6 ng/mL). Elevated circulating serum Ang-2 levels are associated with increased hospital mortality in patients with sepsis.

Acute inhalation injury

Recent events have underscored the importance of proper diagnosis and management of patients with inhalation injury. Clinicians who care for individuals who have sustained inhalation damage to their respiratory tract need to take a careful exposure history and be alert to possibilities of delayed effects and clinical deterioration. Although supportive care and prevention remain the cornerstone of current approaches to this condition, better understanding of the mechanisms of cellular injury and repair may lead to improved treatments in the future.

Pathogenetic and predictive value of biomarkers in patients with ALI and lower severity of illness: results from two clinical trials

Plasma and bronchoalveolar lavage (BAL) biomarkers related to the pathogenesis of acute lung injury (ALI) have previously been associated with poorer clinical outcomes and increased disease severity among patients with ALI. Whether these biomarkers have predictive value in a less severely ill population that excludes septic patients with high APACHE II scores is currently unknown. We tested the association of plasma and BAL biomarkers with physiological markers of ALI severity or clinically relevant outcomes in a secondary analysis of a clinical trial of activated protein C for the treatment of ALI. Plasma plasminogen activator inhibitor-1 (PAI-1) and mini-BAL protein were both significantly associated with increased oxygenation index (P = 0.02 and 0.01, respectively), whereas there was a trend toward an association between IL-6 and oxygenation index (P = 0.057). High plasma IL-6, thrombomodulin, and mini-BAL protein were all significantly associated with fewer ventilator-free days (VFDs) (P = 0.01, 0.01, and 0.05, respectively); no markers were associated with mortality, but we hypothesized that this was due to the small size of our cohort and the low death rate. To confirm these associations in a larger sample, we identified a restricted cohort of patients from the ARDS Network ALVEOLI study with similar baseline characteristics. We retested the associations of the significant biomarkers with markers of severity and clinical outcomes and studied IL-8 as an additional biomarker given its important predictive value in prior studies. In this restricted cohort, IL-6 was significantly associated with oxygenation index (P = 0.02). Both IL-6 and IL-8 were associated with decreased VFDs and increased 28-day mortality. Future studies should be focused on examining larger numbers of patients with less severe ALI to further test the relative predictive value of plasma and mini-BAL biomarkers for clinically relevant outcomes, including VFDs and mortality, and for their prospective utility in risk stratification for future clinical trials.

Diagnosis and Management of Life-Threatening Pulmonary Embolism

Pulmonary embolus (PE) is estimated to cause 200 000 to 300 000 deaths annually. Many deaths occur in hemodynamically unstable patients and the estimated mortality for inpatients with hemodynamic instability is between 15% and 25%. The diagnosis of PE in the critically ill is often challenging because the presentation is nonspecific. Computed tomographic pulmonary angiography appears to be the most useful study for diagnosis of PE in the critically ill. For patients with renal insufficiency and contrast allergy, the ventilation perfusion scan provides an alternative. For patients too unstable to travel, echocardiography (especially transesophageal echocardiography) is another option. A positive result on lower extremity Doppler ultrasound can also aid in the decision to treat. The choice of treatment in PE depends on the estimated risk of poor outcome. The presence of hypotension is the most significant predictor of poor outcome and defines those with massive PE. Normotensive patients with evidence of right ventricular (RV) dysfunction, as assessed by echocardiography, comprise the sub-massive category and are at intermediate risk of poor outcomes. Clinically, those with sub-massive PE are difficult to distinguish from those with low-risk PE. Cardiac troponin, brain natriuretic peptide, and computed tomographic pulmonary angiography can raise the suspicion that a patient has sub-massive PE, but the echocardiogram remains the primary means of identifying RV dysfunction. The initial therapy for patients with PE is anticoagulation. Use of vasopressors, inotropes, pulmonary artery (PA) vasodilators and mechanical ventilation can stabilize critically ill patients. The recommended definitive treatment for patients with massive PE is thrombolysis (in addition to anticoagulation). In massive PE, thrombolytics reduce the risk of recurrent PE, cause rapid improvement in hemodynamics, and probably reduce mortality compared with anticoagulation alone. For patients with a contraindication to anticoagulation and thrombolytic therapy, surgical embolectomy and catheter-based therapies are options. Thrombolytic therapy in sub-massive PE results in improved pulmonary perfusion, reduced PA pressures, and a less complicated hospital course. No survival benefit has been documented, however. If one is considering the use of thrombolytic therapy in sub-massive PE, the limited documented benefit must be weighed against the increased risk of life-threatening hemorrhage. The role of surgical embolectomy and catheter-based therapies in this population is unclear. Evidence suggests that sub-massive PE is a heterogeneous group with respect to risk. It is possible that those at highest risk may benefit from thrombolysis, but existing studies do not identify subgroups within the sub-massive category. The role of inferior vena cava (IVC) filters, catheter-based interventions, and surgical embolectomy in life-threatening PE has yet to be completely defined.

Safe initiation of oral diets in hospitalized patients based on passing a 3-ounce (90 cc) water swallow challenge protocol

BACKGROUND Safe and timely oral alimentation is crucial for optimum patient care. OBJECTIVE To determine the short-term success of recommending specific oral diets, including drinking thin liquids, to acute care hospitalized patients at risk for dysphagia based on passing a 3-ounce water swallow challenge protocol. DESIGN Prospective single group consecutively referred case series. SETTING Large, urban, tertiary care, teaching hospital. PARTICIPANTS 1000 hospitalized patients. INTERVENTION 3-ounce (90 cc) water swallow challenge protocol. MEASUREMENTS Specific diet recommendations and volume (in cc) of liquid ingested at the next days meal 12-24 h after passing a 3-ounce challenge protocol were accessed electronically from oral intake information entered on each participants daily care logs. Eating and drinking success, clinically evident aspiration events and compliance with ordering the recommended diet were recorded. Care providers were blinded to the studys purpose. RESULTS Of 1000 patients, 907 met the inclusion criteria of stable medical, surgical or neurological conditions 12-24 h after passing a 3-ounce water swallow challenge protocol. All 907 were both eating and drinking thin liquids successfully and without overt signs of dysphagia. Median volume of liquid ingested was 340 cc [interquartile range (IQR), 240-460]. Specific diet recommendations were followed with 100% accuracy. CONCLUSION A 3-ounce water swallow challenge protocol successfully identified patients who can be safely advanced to an oral diet without subsequent identification of overt signs of aspiration within 12-24 h of testing. Importantly, when a clinical 3-ounce challenge protocol administered by a trained provider is passed, specific diet recommendations, including drinking thin liquids, can be made safely and without the need for additional instrumental dysphagia testing.

MECHANICAL VENTILATION IN CHRONIC OBSTRUCTIVE LUNG DISEASE

Exacerbations of COPD are a leading indication for MV in the intensive care unit. A thorough understanding of the pathophysiology of AVF in COPD is critical for physicians caring for these patients. In particular, physicians should understand DHI and use the ventilator and ancillary techniques to minimize its impact. Noninvasive positive-pressure ventilation should be considered strongly in relatively stable patients with an adequate mental status and manageable secretions. Once AVF resolves, patients should be removed from the ventilator as soon as is safe to do so to minimize the adverse effects of prolonged MV. An organized approach to weaning and identifying patients capable of independent breathing is crucial. Most patients with COPD and AVF benefit from MV and generally return to or approach their premorbid functional status. A significant subset, however, will not benefit from, or choose not to undergo, MV. Deciding upon appropriate therapeutic options for these patients relies heavily on effective communication between physician and patient. Comprehensive discussions before the development of AVF can assist decision-making after respiratory failure develops.