Gregory A. Schmidt

Early physical and occupational therapy in mechanically ventilated, critically ill patients: a randomised controlled trial.

BACKGROUND Long-term complications of critical illness include intensive care unit (ICU)-acquired weakness and neuropsychiatric disease. Immobilisation secondary to sedation might potentiate these problems. We assessed the efficacy of combining daily interruption of sedation with physical and occupational therapy on functional outcomes in patients receiving mechanical ventilation in intensive care. METHODS Sedated adults (>/=18 years of age) in the ICU who had been on mechanical ventilation for less than 72 h, were expected to continue for at least 24 h, and who met criteria for baseline functional independence were eligible for enrolment in this randomised controlled trial at two university hospitals. We randomly assigned 104 patients by computer-generated, permuted block randomisation to early exercise and mobilisation (physical and occupational therapy) during periods of daily interruption of sedation (intervention; n=49) or to daily interruption of sedation with therapy as ordered by the primary care team (control; n=55). The primary endpoint-the number of patients returning to independent functional status at hospital discharge-was defined as the ability to perform six activities of daily living and the ability to walk independently. Therapists who undertook patient assessments were blinded to treatment assignment. Secondary endpoints included duration of delirium and ventilator-free days during the first 28 days of hospital stay. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00322010. FINDINGS All 104 patients were included in the analysis. Return to independent functional status at hospital discharge occurred in 29 (59%) patients in the intervention group compared with 19 (35%) patients in the control group (p=0.02; odds ratio 2.7 [95% CI 1.2-6.1]). Patients in the intervention group had shorter duration of delirium (median 2.0 days, IQR 0.0-6.0 vs 4.0 days, 2.0-8.0; p=0.02), and more ventilator-free days (23.5 days, 7.4-25.6 vs 21.1 days, 0.0-23.8; p=0.05) during the 28-day follow-up period than did controls. There was one serious adverse event in 498 therapy sessions (desaturation less than 80%). Discontinuation of therapy as a result of patient instability occurred in 19 (4%) of all sessions, most commonly for perceived patient-ventilator asynchrony. INTERPRETATION A strategy for whole-body rehabilitation-consisting of interruption of sedation and physical and occupational therapy in the earliest days of critical illness-was safe and well tolerated, and resulted in better functional outcomes at hospital discharge, a shorter duration of delirium, and more ventilator-free days compared with standard care. FUNDING None.

Feasibility, efficacy, and safety of antipsychotics for intensive care unit delirium: The MIND randomized, placebo-controlled trial

Objective: To demonstrate the feasibility of a placebo-controlled trial of antipsychotics for delirium in the intensive care unit and to test the hypothesis that antipsychotics would improve days alive without delirium or coma. Design: Randomized, double-blind, placebo-controlled trial. Setting: Six tertiary care medical centers in the US. Patients: One hundred one mechanically ventilated medical and surgical intensive care unit patients. Intervention: Patients were randomly assigned to receive haloperidol or ziprasidone or placebo every 6 hrs for up to 14 days. Twice each day, frequency of study drug administration was adjusted according to delirium status, level of sedation, and side effects. Measurements and Main Outcomes: The primary end point was the number of days patients were alive without delirium or coma. During the 21-day study period, patients in the haloperidol group spent a similar number days alive without delirium or coma (median [interquartile range], 14.0 [6.0–18.0] days) as did patients in the ziprasidone (15.0 [9.1–18.0] days) and placebo groups (12.5 [1.2–17.2] days; p = 0.66). No differences were found in secondary clinical outcomes, including ventilator-free days (p = .25), hospital length of stay (p = .68), and mortality (p = .81). Ten (29%) patients in the haloperidol group reported symptoms consistent with akathisia, compared with six (20%) patients in the ziprasidone group and seven (19%) patients in the placebo group (p = .60), and a global measure of extrapyramidal symptoms was similar between treatment groups (p = .46). Conclusions: A randomized, placebo-controlled trial of antipsychotics for delirium in mechanically ventilated intensive care unit patients is feasible. Treatment with antipsychotics in this limited pilot trial did not improve the number of days alive without delirium or coma, nor did it increase adverse outcomes. Thus, a large trial is needed to determine whether use of antipsychotics for intensive care unit delirium is appropriate. Trial Registration: ClinicalTrials.gov, number NCT00096863.

Feasibility of physical and occupational therapy beginning from initiation of mechanical ventilation.

Objective:Physical and occupational therapy are possible immediately after intubation in mechanically ventilated medical intensive care unit patients. The objective of this study was to describe a protocol of daily sedative interruption and early physical and occupational therapy and to specify details of intensive care unit-based therapy, including neurocognitive state, potential barriers, and adverse events related to this intervention. Design and Patients:Detailed descriptive study of the intervention arm of a trial of mechanically ventilated patients receiving early physical and occupational therapy. Setting:Two tertiary care academic medical centers participating in a randomized controlled trial. Intervention:Patients underwent daily sedative interruption followed by physical and occupational therapy every hospital day until achieving independent functional status. Therapy began with active range of motion and progressed to activities of daily living, sitting, standing, and walking as tolerated. Measurements and Main Results:Forty-nine mechanically ventilated patients received early physical and occupational therapy occurring a median of 1.5 days (range, 1.0–2.1 days) after intubation. Therapy was provided on 90% of MICU days during mechanical ventilation. While endotracheally intubated, subjects sat at the edge of the bed in 69% of all physical and occupational therapy sessions, transferred from bed to chair in 33%, stood in 33%, and ambulated during 15% (n = 26 of 168) of all physical and occupational therapy sessions (median distance of 15 feet; range, 15–20 feet). At least one potential barrier to mobilization during mechanical ventilation (acute lung injury, vasoactive medication administration, delirium, renal replacement therapy, or body mass index ≥30 kg/m2) was present in 89% of patient encounters. Therapy was interrupted prematurely in 4% of all sessions, most commonly for patient-ventilator asynchrony and agitation. Conclusion:Early physical and occupational therapy is feasible from the onset of mechanical ventilation despite high illness acuity and presence of life support devices. Adverse events are uncommon, even in this high-risk group.

Inhaled helium-oxygen revisited: Effect of inhaled helium-oxygen during the treatment of status asthmaticus in children

OBJECTIVES To assess the effects of breathing a low-density gas mixture on dyspnea and the pulsus paradoxus in children with status asthmaticus. DESIGN In an urban academic tertiary referral center, 18 patients, aged 16 months to 16 years, who were being treated for status asthmaticus with continuously inhaled beta-agonist and intravenously administered methylprednisolone and had a pulsus paradoxus of greater than 15 mm Hg received either an 80%:20% helium-oxygen gas mixture (HELIOX patients) or room air (control patients) at 10 L/min by nonrebreathing face mask in a double-blind, randomized, controlled trial. In all patients, baseline data, including pulsus paradoxus (determined by sphygmomanometer or arterial catheter blood pressure readings), respiratory rate, heart rate, investigator-scored dyspnea index, and oxygen saturation, were compared with values obtained 15 minutes during and after intervention. In a subset of patients, peak flows before and after breathing HELIOX or room air were measured. When clinically indicated, arterial blood gases were obtained. RESULTS The pulsus paradoxus (in millimeters of mercury) fell significantly from an initial mean value of 23.3 +/- 6.8 to 10.6 +/- 2.8 with HELIOX breathing (p < 0.001) and increased again to 18.5 +/- 7.3 after cessation of HELIOX. Peak flow increased 69.4% +/- 12.8% during HELIOX breathing (p < 0.05). The dyspnea index decreased from an initial mean value of 5.7 +/- 1.3 to 1.9 +/- 1.7 with HELIOX breathing (p < 0.0002) and increased again to 4.0 +/- 0.5 after cessation of HELIOX breathing. In control patients, there was no significant difference in pulsus paradoxus or dyspnea index at any time during the study period. Mechanical ventilation was averted in three patients in whom dyspnea lessened dramatically during breathing of HELIOX. CONCLUSION During acute status asthmaticus, inhaled HELIOX significantly lowered the pulsus paradoxus, increased peak flow, and lessened the dyspnea index. Moreover, HELIOX spared three patients a planned intubation and caused no apparent side effects. Thus HELIOX reduces the work of breathing and may forestall respiratory failure in children with status asthmaticus, thus preventing the need for mechanical ventilation.

Fluid Therapy in Resuscitated Sepsis: Less Is More

Fluid infusion may be lifesaving in patients with severe sepsis, especially in the earliest phases of treatment. Following initial resuscitation, however, fluid boluses often fail to augment perfusion and may be harmful. In this review, we seek to compare and contrast the impact of fluids in early and later sepsis; show that much fluid therapy is clinically ineffective in patients with severe sepsis; explore the detrimental aspects of excessive volume infusion; examine how clinicians assess the intravascular volume state; appraise the potential for dynamic indexes to predict fluid responsiveness; and recommend a clinical approach.

Shock: Ultrasound to Guide Diagnosis and Therapy

The availability of portable ultrasound devices is changing the approach to the diagnosis and management of shock by offering timely diagnosis and acting to guide therapy. Goal-directed echocardiography (GDE) can be performed well by noncardiologists and consists of a limited number of standard cardiac views: parasternal long axis, parasternal short axis, apical four chamber, subcostal long axis, and inferior vena cava long axis. GDE allows the intensivist to assess left and right ventricular pump function, pericardial effusion, septal dynamics, valvular morphology, major valve failure, and fluid responsiveness. Here, we review the questions involved in a systematic approach to the patient in shock, employing GDE: (1) Is there an imminently life-threatening cause for the shock? (2) Is the shock state likely to be fluid responsive? (3) Is there evidence of pump failure? (4) Is there more than one cause for the shock state? (5) Is the cause of the shock state other than cardiac in origin? In contrast to formal echocardiography, GDE is qualitative, can be performed in a few minutes, is interpreted immediately, can be repeated as often as needed, and is always integrated with other elements of the intensivists assessment to arrive at an understanding of the basis for the shock and a rational treatment plan. An important part of using GDE is recognizing its limitations and judging when to proceed to a comprehensive echocardiography examination. Competence in GDE has become an essential skill for the practicing intensivist.

Liberation From Mechanical Ventilation in Critically Ill Adults: An Official American College of Chest Physicians/American Thoracic Society Clinical Practice Guideline: Inspiratory Pressure Augmentation During Spontaneous Breathing Trials, Protocols Minimizing Sedation, and Noninvasive Ventilation Immediately After Extubation.

Background An update of evidence‐based guidelines concerning liberation from mechanical ventilation is needed as new evidence has become available. The American College of Chest Physicians (CHEST) and the American Thoracic Society (ATS) have collaborated to provide recommendations to clinicians concerning liberation from the ventilator. Methods Comprehensive evidence syntheses, including meta‐analyses, were performed to summarize all available evidence relevant to the guideline panel’s questions. The evidence was appraised using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach, and the results were summarized in evidence profiles. The evidence syntheses were discussed and recommendations developed and approved by a multidisciplinary committee of experts in mechanical ventilation. Results Recommendations for three population, intervention, comparator, outcome (PICO) questions concerning ventilator liberation are presented in this document. The guideline panel considered the balance of desirable (benefits) and undesirable (burdens, adverse effects, costs) consequences, quality of evidence, feasibility, and acceptability of various interventions with respect to the selected questions. Conditional (weak) recommendations were made to use inspiratory pressure augmentation in the initial spontaneous breathing trial (SBT) and to use protocols to minimize sedation for patients ventilated for more than 24 h. A strong recommendation was made to use preventive noninvasive ventilation (NIV) for high‐risk patients ventilated for more than 24 h immediately after extubation to improve selected outcomes. The recommendations were limited by the quality of the available evidence. Conclusions The guideline panel provided recommendations for inspiratory pressure augmentation during an initial SBT, protocols minimizing sedation, and preventative NIV, in relation to ventilator liberation.

Diabetes mellitus increases risk of unsuccessful graft preparation in Descemet membrane endothelial keratoplasty: a multicenter study.

Purpose: The aim of this study was to evaluate preparation outcomes of tissue prepared for Descemet membrane endothelial keratoplasty (DMEK) from diabetic and nondiabetic donors. Methods: In this nonrandomized, consecutive case series, DMEK grafts were prepared from diabetic and nondiabetic donors by experienced technicians in 2 eye banks using slightly different, modified submerged manual preparation techniques to achieve “prestripped” graft tissue. Graft preparation results were analyzed retrospectively. The main outcome measure was the rate of unsuccessful (failed) DMEK graft preparations, defined as tears through the graft area that prevent tissue use. Results: A total of 359 corneas prepared from 290 donors (114 diabetic and 245 nondiabetic) were included in the statistical analysis of graft preparation failure. There were no significant differences between diabetic and nondiabetic donor tissue characteristics with respect to donor age, death to preservation time, death to preparation time, endothelial cell density, percent hexagonality, or coefficient of variation. DMEK tissue preparation was unsuccessful in 19 (5.3%) cases. There was a significant difference in the site-adjusted rate of DMEK preparation failure between diabetic [15.3%; 95% confidence interval (CI), 9.0–25.0] and nondiabetic donors (1.9%; 95% CI, 0.8–4.8), and the corresponding site-adjusted odds ratio of DMEK graft preparation failure in diabetic donor tissue versus nondiabetic donor tissue was 9.20 (95% CI, 2.89–29.32; P = 0.001). Conclusions: Diabetes may be a risk factor for unsuccessful preparation of donor tissue for DMEK. We recommend caution in the use of diabetic tissue for DMEK graft preparation. Further study is needed to identify what subset of diabetic donors is at risk for unsuccessful DMEK graft preparation.

Renin-angiotensin system activation correlates with microvascular dysfunction in a prospective cohort study of clinical sepsis

IntroductionMicrovascular dysregulation characterized by hyporesponsive vessels and heterogeneous bloodflow is implicated in the pathogenesis of organ failure in sepsis. The renin-angiotensin system (RAS) affects the microvasculature, yet the relationships between RAS and organ injury in clinical sepsis remain unclear. We tested our hypothesis that systemic RAS mediators are associated with dysregulation of the microvasculature and with organ failure in clinical severe sepsis.MethodsWe studied 30 subjects with severe sepsis, and 10 healthy control subjects. Plasma was analyzed for plasma renin activity (PRA) and angiotensin II concentration (Ang II). Using near-infrared spectroscopy, we measured the rate of increase in the oxygen saturation of thenar microvascular hemoglobin after five minutes of induced forearm ischemia. In so doing, we assessed bulk microvascular hemoglobin influx to the tissue during reactive hyperemia. We studied all subjects 24 hours after the development of organ failure. We studied a subset of 12 subjects at an additional timepoint, eight hours after recognition of organ failure (early sepsis).ResultsAfter 24 hours of resuscitation to clinically-defined endpoints of preload and arterial pressure, Ang II and PRA were elevated in septic subjects and the degree of elevation correlated negatively with the rate of microvascular reoxygenation during reactive hyperemia. Early RAS mediators correlated with microvascular dysfunction. Early Ang II also correlated with the extent of organ failure realized during the first day of sepsis.ConclusionsRAS is activated in clinical severe sepsis. Systemic RAS mediators correlate with measures of microvascular dysregulation and with organ failure.

A retrospective observational study of drotrecogin alfa (activated) in adults with severe sepsis: comparison with a controlled clinical trial.

Objective:To compare characteristics and outcomes of patients treated with drotrecogin alfa (activated) (DrotAA) in clinical practice to those treated in a phase III randomized controlled trial (PROWESS). Design:Observational data were collected retrospectively from patients who received DrotAA as part of physician-directed treatment. Setting:Intensive care units of five teaching institutions. Patients:Patients were ≥18 yrs old, had severe sepsis (confirmed/suspected infection with one or more sepsis-induced organ dysfunctions), and received DrotAA. Interventions:None. Measurements and Main Results:Baseline demographics, severity of illness, time from organ dysfunction onset to DrotAA treatment, daily assessment of organ dysfunction, serious bleeding events, and in-hospital mortality were reported. Timing from severe sepsis documentation to start of DrotAA infusion was categorized: day 0 (same calendar day); day 1 (next calendar day); and day ≥2 (second calendar day or later). Clinical practice patients (n = 274) were younger, had more comorbidities, had higher severity of illness (as measured by organ dysfunction or greater vasopressor/ventilator use), and received DrotAA later than PROWESS patients (all p < .05). Overall hospital mortality for clinical practice patients was 42%, compared with 37% for DrotAA-treated PROWESS patients with Acute Physiology and Chronic Health Evaluation II score ≥25. Mortality for day 0, day 1, and day ≥2 groups was 33%, 40%, and 52%, respectively. In PROWESS, the vast majority were treated on day 0 or day 1. Serious bleeding events during infusion were noted in 4.0% of clinical practice patients compared with 2.2% of PROWESS DrotAA-treated patients with Acute Physiology and Chronic Health Evaluation II score ≥25. Conclusions:Patients treated in clinical practice differed from those in PROWESS. Patients were younger, had more comorbidities, had greater severity of illness, and had longer mean time from severe sepsis onset to the start of DrotAA. Hospital mortality for patients treated within 1 day of severe sepsis onset was similar to DrotAA-treated PROWESS patients. While the low number of serious bleeding events precludes a definitive assessment, the observed incidence of serious bleeding events in clinical practice patients was numerically higher than in DrotAA-treated PROWESS patients.