Preston B. Rich

A randomized trial of intermittent lorazepam versus propofol with daily interruption in mechanically ventilated patients.

Objective:To compare duration of mechanical ventilation for patients randomized to receive lorazepam by intermittent bolus administration vs. continuous infusions of propofol using protocols that include scheduled daily interruption of sedation. Design:A randomized open-label trial enrolling patients from October 2001 to March 2004. Setting:Medical intensive care units of two tertiary care medical centers. Patients:Adult patients expected to require mechanical ventilation for >48 hrs and who required ≥10 mg of lorazepam or a continuous infusion of a sedative to achieve adequate sedation. Interventions:Patients were randomized to receive lorazepam by intermittent bolus administration or propofol by continuous infusion to maintain a Ramsay score of 2–3. Sedation was interrupted on a daily basis for both groups. Measurements and Main Results:The primary outcome was median ventilator days. Secondary outcomes included 28-day ventilator-free survival, intensive care unit and hospital length of stay, and hospital mortality. Median ventilator days were significantly lower in the daily interruption propofol group compared with the intermittent bolus lorazepam group (5.8 vs. 8.4, p = .04). The difference was largest for hospital survivors (4.4 vs. 9.0, p = .006). There was a trend toward greater ventilator-free survival for patients in the daily interruption propofol group (median 18.5 days for propofol vs. 10.2 for lorazepam, p = .06). Hospital mortality was not different. Conclusions:For medical patients requiring >48 hrs of mechanical ventilation, sedation with propofol results in significantly fewer ventilator days compared with intermittent lorazepam when sedatives are interrupted daily.

Blood transfusion is an independent predictor of increased mortality in nonoperatively managed blunt hepatic and splenic injuries.

BACKGROUND Management strategies for blunt solid viscus injuries often include blood transfusion. However, transfusion has previously been identified as an independent predictor of mortality in unselected trauma admissions. We hypothesized that transfusion would adversely affect mortality and outcome in patients presenting with blunt hepatic and splenic injuries after controlling for injury severity and degree of shock. METHODS We retrospectively reviewed records from all adults with blunt hepatic and/or splenic injuries admitted to a Level I trauma center over a 4-year period. Demographics, physiologic variables, injury severity, and amount of blood transfused were analyzed. Univariate and multivariate analysis with logistic and linear regression were used to identify predictors of mortality and outcome. RESULTS One hundred forty-three (45%) of 316 patients presenting with blunt hepatic and/or splenic injuries received blood transfusion within the first 24 hours. Two hundred thirty patients (72.8%) were selected for nonoperative management, of whom 75 (33%) required transfusion in the first 24 hours. Transfusion was an independent predictor of mortality in all patients (odds ratio [OR], 4.75; 95% confidence interval [CI], 1.37-16.4; p = 0.014) and in those managed nonoperatively (OR, 8.45; 95% CI, 1.95-36.53; p = 0.0043) after controlling for indices of shock and injury severity. The risk of death increased with each unit of packed red blood cells transfused (OR per unit, 1.16; 95% CI, 1.10-1.24; p < 0.0001). Blood transfusion was also an independent predictor of increased hospital length of stay (coefficient, 5.45; 95% CI, 1.64-9.25; p = 0.005). CONCLUSION Blood transfusion is a strong independent predictor of mortality and hospital length of stay in patients with blunt liver and spleen injuries after controlling for indices of shock and injury severity. Transfusion-associated mortality risk was highest in the subset of patients managed nonoperatively. Prospective examination of transfusion practices in treatment algorithms of blunt hepatic and splenic injuries is warranted.

Extracorporeal life support in pulmonary failure after trauma

OBJECTIVE To present a series of 30 adult trauma patients who received extracorporeal life support (ECLS) for pulmonary failure and to retrospectively review variables related to their outcome. METHODS In a Level I trauma center between 1989 and 1997, ECLS with continuous heparin anticoagulation was instituted in 30 injured patients older than 15 years. Indication was for an estimated mortality risk greater than 80%, defined by a PaO2: FIO2 ratio less than 100 on 100% FIO2, despite pressure-mode inverse ratio ventilation, optimal positive end-expiratory pressure, reasonable diuresis, transfusion, and prone positioning. Retrospective analysis included demographic information (age, gender, Injury Severity Score, injury mechanism), pulmonary physiologic and gas-exchange values (pre-ECLS ventilator days [VENT days], PaO2:FIO2 ratio, mixed venous oxygen saturation [SvO2], and blood gas), pre-ECLS cardiopulmonary resuscitation, complications of ECLS (bleeding, circuit problems, leukopenia, infection, pneumothorax, acute renal failure, and pressors on ECLS), and survival. RESULTS The subjects were 26.3+/-2.1 years old (range, 15-59 years), 50% male, and had blunt injury in 83.3%. Pulmonary recovery sufficient to wean the patient from ECLS occurred in 17 patients (56.7%), and 50% survived to discharge. Fewer VENT days and more normal SvO2 were associated with survival. The presence of acute renal failure and the need for venoarterial support (venoarterial bypass) were more common in the patients who died. Bleeding complications (requiring intervention or additional transfusion) occurred in 58.6% of patients and were not associated with mortality. Early use of ECLS (VENT days < or = 5) was associated with an odds ratio of 7.2 for survival. Fewer VENT days was independently associated with survival in a logistic regression model (p = 0.029). Age, Injury Severity Score, and PaO2:FIO2 ratio were not related to outcome. CONCLUSION ECLS has been safely used in adult trauma patients with multiple injuries and severe pulmonary failure. In our series, early implementation of ECLS was associated with improved survival. Although this may represent selection bias for less intractable forms of acute respiratory distress syndrome, it is our experience that early institution of ECLS may lead to improved oxygen delivery, diminished ventilator-induced lung injury, and improved survival.

Inflammatory cytokine levels in chronic venous insufficiency ulcer tissue before and after compression therapy

OBJECTIVE Elevated inflammatory cytokine levels have been implicated in the pathogenesis of non-healing chronic venous insufficiency (CVI) ulcers. The goal of this study was to determine the protein levels of a wide range of inflammatory cytokines in untreated CVI ulcer tissue before and after 4 weeks of high-strength compression therapy. These levels were compared to cytokines present in healthy tissue. METHODS Thirty limbs with untreated CVI and leg ulceration received therapy for 4 weeks with sustained high-compression bandaging at an ambulatory wound center. Biopsies were obtained from healthy and ulcerated tissue before and after therapy. A multiplexed protein assay was used to measure multiple cytokines in a single sample. Patients were designated as rapid or delayed healers based on ulcer surface area change. RESULTS The majority of pro-inflammatory cytokine protein levels were elevated in ulcer tissue compared to healthy tissue, and compression therapy significantly reduced these cytokines. TGF-beta1 was upregulated in ulcer tissue following compression therapy. Rapid healing ulcers had significantly higher levels of IL-1alpha, IL-1beta, IFN-gamma, IL-12p40, and granulocyte macrophage colony stimulating factor (GM-CSF) before compression therapy, and IL-1 Ra after therapy. IFN-gamma levels significantly decreased following therapy in the rapidly healing patients. CONCLUSION CVI ulcer healing is associated with a pro-inflammatory environment prior to treatment that reflects metabolically active peri-wound tissue that has the potential to heal. Treatment with compression therapy results in healing that is coupled with reduced pro-inflammatory cytokine levels and higher levels of the anti-inflammatory cytokine IL-1 Ra.

Multiplexed analysis of matrix metalloproteinases in leg ulcer tissue of patients with chronic venous insufficiency before and after compression therapy

Elevated matrix metalloproteinases (MMP) levels have been implicated in the pathogenesis of chronic venous insufficiency ulcers. Quantitative measurements of a broad range of MMP proteins in human tissue treated with compression bandaging have not been reported. The goal of this study was to determine the expression of a wide range of proteases in untreated venous leg ulcer tissue and the changes in these levels after 4 weeks of high‐strength compression therapy. Twenty‐nine limbs with new or untreated chronic venous insufficiency and leg ulceration received therapy for 4 weeks with sustained high compression bandaging. Biopsies were obtained from healthy tissue and from ulcerated tissue before and after therapy. A novel multiplexed protein assay was used to measure multiple MMPs in a single sample. MMP protein activity, TIMP protein levels, and gene expression levels were also addressed. MMP1, 2, 3, 8, 9, 12, and 13 protein levels were elevated in ulcer tissue compared with healthy tissue. MMP8 and 9 were highly expressed in ulcer tissue. MMP3, 8, and 9 significantly decreased following treatment. Reduction in the levels of MMP1, 2, and 3 was associated with significantly higher rates of ulcer healing at 4 weeks. We conclude that compression therapy results in a reduction of the pro‐inflammatory environment characterizing chronic venous ulcers, and ulcer healing is associated with resolution of specific elevated levels of protease expression.

Effect of rate and inspiratory flow on ventilator-induced lung injury.

BACKGROUND We examined the effects of decreasing respiratory rate (RR) at variable inspiratory times (It) and reducing inspiratory flow on the development of ventilator-induced lung injury. METHODS Forty sheep weighing 24.6+/-3.2 kg were ventilated for 6 hours with one of five strategies (FIO2 = 1.0, positive end-expiratory pressure = 5 cm H2O): (1) pressure-controlled ventilation (PCV), RR = 15 breaths/min, peak inspiratory pressure (PIP) = 25 cm H2O, n = 8; (2) PCV, RR = 15 breaths/min, PIP = 50 cm H2O, n = 8; (3) PCV, RR = 5 breaths/min, PIP = 50 cm H2O, It = 6 seconds, n = 8; (4) PCV, RR = 5 breaths/min, PIP = 50 cm H2O, It = 2 seconds, n = 8; and (5) limited inspiratory flow volume-controlled ventilation, RR = 5 breaths/min, pressure-limit = 50 cm H2O, flow = 15 L/min, n = 8. RESULTS Decreasing RR at conventional flows did not reduce injury. However, limiting inspiratory flow rate (LIFR) maintained compliance and resulted in lower Qs/Qt (HiPIP = 38+/-18%, LIFR = 19+/-6%, p < 0.001), reduced histologic injury (HiPIP = 14+/-0.9, LIFR = 2.2+/-0.9, p < 0.05), decreased intra-alveolar neutrophils (HiPIP = 90+/-49, LIFR = 7.6+/-3.8,p = 0.001), and reduced wet-dry lung weight (HiPIP = 87.3+/-8.5%, LIFR = 40.8+/-17.4%,p < 0.001). CONCLUSIONS High-pressure ventilation for 6 hours using conventional flow patterns produces severe lung injury, irrespective of RR or It. Reduction of inspiratory flow at similar PIP provides pulmonary protection.

A prospective comparison of atrio-femoral and femoro-atrial flow in adult venovenous extracorporeal life support

INTRODUCTION In the United States, venovenous extracorporeal life support has traditionally been performed with atrial drainage and femoral reinfusion (atrio-femoral flow). Although flow reversal (femoro-atrial flow) may alter recirculation and extracorporeal flow, no direct comparison of these 2 modes has been undertaken. OBJECTIVE Our goal was to prospectively compare atrio-femoral and femoro-atrial flow in adult venovenous extracorporeal life support for respiratory failure. METHODS A modified bridge enabling conversion between atrio-femoral and femoro-atrial flow was incorporated in the extracorporeal circuit. Bypass was initiated in the direction that provided the highest pulmonary arterial mixed venous oxygen saturation, and the following measurements were taken: (1) maximum extracorporeal flow, (2) highest achievable pulmonary arterial mixed venous oxygen saturation, and (3) flow required to maintain the same pulmonary arterial mixed venous oxygen saturation in both directions. Flow direction was then reversed, and the measurements were repeated. Data were compared with paired t tests and are presented as mean +/- standard deviation. RESULTS Ten patients were studied, and 9 were included in the data analysis. Femoro-atrial bypass provided (1) higher maximal extracorporeal flow (femoro-atrial flow = 55.6 +/- 9.8 mL/kg per minute, atrio-femoral flow = 51.1 +/- 11.1 mL/kg per minute; P = .04) and (2) higher pulmonary arterial mixed venous oxygen saturation (femoroatrial flow = 89.9% +/- 6.6%, atrio-femoral flow = 83.2% +/- 4.2%; P = .006); (3) furthermore, it required less flow to maintain an equivalent pulmonary arterial mixed venous oxygen saturation (femoro-atrial flow = 37.0 +/- 12.2 mL/kg per minute, atrio-femoral flow = 46.4 +/- 8.8 mL/kg per minute; P = .04). CONCLUSIONS During venovenous extracorporeal life support, femoro-atrial bypass provided higher maximal extracorporeal flow, higher pulmonary arterial mixed venous oxygen saturation, and required comparatively less flow to maintain an equivalent mixed venous oxygen saturation than did atrio-femoral bypass.

Can the clearance of tumor necrosis factor alpha and interleukin 6 be enhanced using an albumin dialysate hemodiafiltration system

Patients with acute hepatic failure (AHF) have elevated levels of inflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6). Recently, we have shown selective hemodiafiltration with albumin dialysis, as an extracorporeal liver support device (ECLVS), to be effective in the clearance of multiple toxins that are elevated in AHF. Our objective was to evaluate whether ECLVS would be effective in the clearance of TNF-alpha and IL-6. An in vitro continuous hemodiafiltration circuit was used with single pass counter-current dialysis. A known amount of recombinant rat TNF-alpha and IL-6 was added to heparinized bovine blood and filtered across a polyalkyl sulfone hemofilter using matched filtration and dialysate flow rates. During 4 hours, the serial TNF-alpha and IL-6 concentrations were measured in the circulating blood, and the content of each cytokine was calculated using mass balance. For each cytokine, clearance was determined for two dialysate groups at constant temperature and pH (group 1: dialysate = 0.9 normal saline, n = 5; group 2: dialysate = albumin 2 gm/dl, n = 5). Analysis of data was performed using ANOVA and Students t-test. There was improved clearance of TNF-alpha and IL-6 when albumin was used in the dialysate (81+/-0.09% of the initial TNF-alpha and 77+/-0.04% of the IL-6 quantities) compared with when 0.9 normal saline was used as the dialysate (58+/-0.14% of the initial TNF-alpha and 56+/-0.18% of the IL-6 quantities); p < 0.03. An ECLVS utilizing hemodiafiltration with albumin dialysis is more effective than conventional hemofiltration in the clearance of TNF-alpha and IL-6 and, therefore, may benefit patients with acute hepatic failure.

Adenosine triphosphate is released during injurious mechanical ventilation and contributes to lung edema.

BACKGROUND Extracellular nucleotides mediate many cellular functions and are released in response to mechanical stress in vitro. It is unknown whether adenosine triphosphate (ATP) is released in vivo during mechanical ventilation (MV). We hypothesized that stress from high-pressure MV would increase airway ATP, contributing to MV-associated lung edema. METHODS Rats were randomized to nonventilated control (n = 6) or 30 minutes of MV with low (15 cm H(2)0, n = 7) or high (40 cm H(2)0, n = 6) pressure. Additional groups received intratracheal ATP (n = 7) or saline (n = 7) before low-pressure MV. RESULTS Low-pressure MV did not affect lung edema or bronchoalveolar lavage (BAL) ATP levels. In contrast, high-pressure MV significantly increased BAL ATP and produced alveolar edema; lactate dehydrogenase was unchanged. Intratracheal ATP administration significantly increased lung water during low-pressure MV. CONCLUSION High-pressure MV increases BAL ATP concentration without altering lactate dehydrogenase, suggesting that release is not from cell lysis. Intratracheal ATP increases lung water, implicating nucleotides in MV-associated lung edema.

Intrapleural tissue plasminogen activator for complicated pleural effusions.

BACKGROUND This study is aimed at evaluating the safety and efficacy of intrapleural tissue plasminogen activator (TPA) for complicated pleural effusions, including posttraumatic hemothorax. METHODS Data were retrospectively collected from hospitalized patients over a 4-year period (1999-2003) who were treated with intrapleural TPA after failing drainage by tube thoracostomy. Pre- and post-TPA imaging studies were reviewed and scored by a blinded radiologist. RESULTS Forty-one consecutive patients with 42 effusions were identified with the following indications: 6 traumatic hemothoraces (14%), 22 loculated pleural effusions (52%), 2 line-associated hemothoraces (5%), and 12 empyemas (29%). Nine patients (22%) required operative drainage including two with posttraumatic hemothoraces. All patients managed nonoperatively demonstrated radiographic improvement after TPA administration. One patient (2.4%) developed hematuria, requiring transfusion. No trauma patient required TPA-related blood transfusion and no deaths were attributable to TPA therapy. CONCLUSION Intrapleural TPA administration appears safe for use in complicated pleural effusions and may decrease the need for operative intervention.