Computerised tomography for the detection of pulmonary emboli in intensive care patients--a retrospective cohort study.

Pulmonary emboli are frequently considered as a cause for respiratory deterioration in intensive care unit (ICU) patients, however empirical observation suggests that computerised tomographic (CT) angiography is infrequently positive after the first 24 hours. This study aimed to determine the rate and risk factors for detection of pulmonary emboli by CT angiography in ICU patients. All patients undergoing CT angiography > 24 hours after ICU admission for respiratory deterioration from April 2000 until January 2004 were included. The positivity rate for pulmonary emboli was determined and risk factors analysed. Seven (6%) out of 113 CT angiograms were positive for pulmonary emboli. All were found in trauma patients. Comparing positive to negative scans, predefined risk factors including head injury (5/7 positive scans, 71% vs. 23/106 negative scans, 22%, P = 0.005), spine injury with neurological impairment (4/7, 57% vs. 9/106, 8%, P = 0.002) and lower limb injury (3/7, 43% vs. 12/106, 9%, P = 0.039) were significantly more frequent in patients with positive scans. Deep vein thrombosis prophylaxis was employed less frequently prior to a positive scan (in 3/7, 43% patients with positive scans vs. 91/106, 86% patients with negative scans P = 0.015). Only the predefined risk factors were independently associated with positive CT angiography on limited logistic regression (OR 24.7 per risk factor, 95% CI 2.38 to 255.1, P = 0.007). Pulmonary emboli were infrequently diagnosed using CT angiography in ICU patients admitted for more than 24 hours and found only in patients with recognised risk factors.

Effect of haemodilution with diaspirin cross-linked haemoglobin on the oxygen reserve in a rodent model of surgical blood loss.

The efficacy of pre-operative haemodilution is limited by the reduction in haemoglobin concentration. Acellular haemoglobin-based oxygen carriers provide an alternative to colloid as a haemodiluent, potentially extending the safe limits of this procedure. The aim of this investigation was to determine whether haemodilution with a cross-linked haemoglobin solution, diaspirin cross-linked haemoglobin solution (DCLHb), would enhance the oxygen reserve compared to pentastarch. Sprague Dawley rats were placed in a metabolic box to directly measure systemic oxygen consumption (VO2). Rats were randomized to be haemodiluted to a cellular haemoglobin of 80 g L(-1) with either DCLHb or pentastarch. Oxygen reserve was assessed during isovolemic haemorrhage by determining the critical oxygen delivery (DO2crit) and haemoglobin concentration at the point of oxygen supply dependency (OSD). Following haemodilution and for the duration of the experiment, cardiac index (CI) was significantly lower and systemic vascular resistance was significantly higher in the DCLHb than the pentastarch group. The DO2crit (3.2 +/- 0.4 mL minAg(-1) and 3.4 +/- 0.5 mL minAg(-1), DCLHb versus pentastarch) and cellular haemoglobin concentration (51 +/- 9 g L(-1) and 48 +/- 9 g L(-1)), at which rats entered OSD were similar in both groups. Total haemoglobin concentration (cellular and plasma DCLHb) and arterial oxygen content were significantly higher in the DCLHb group (total haemoglobin, 66 +/- 8 g L(-1) and arterial content, 9.2 +/- 1.4 mL dL(-1)) compared to the pentastarch group (total haemoglobin, 48 +/- 9 g L(-1) and arterial content, 7.3 +/- 1.4 mL dL(-1)). Oxygen extraction ratios increased from baseline levels to 0.53 +/- 0.07 and 0.56 +/- 0.1, for the DCLHb and pentastarch groups, respectively, and were not significantly different. The increase in arterial oxygen content from DCLHb in plasma was offset by the decrease in CI observed in this group. Plasma DCLHb did not extend the limits of haemodilution beyond the capacity of the cellular haemoglobin concentration.

Exocrine pancreatic dysfunction in sepsis.

BACKGROUND: Sepsis in critical illness is associated with the progressive failure of multiple organs. This study aims to establish a correlation between the severity of sepsis and exocrine pancreatic dysfunction. MATERIALS AND METHODS: In a prospective cohort study pancreatic exocrine function was tested by means of a secretin-cholecystokinin test in 21 critically ill, mechanically ventilated patients with sepsis according to criteria of the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Committee (ACCP/SCCM): 11 patients with shock and 10 patients without shock. Data were compared with seven healthy controls. RESULTS: The volume of duodenal fluid was not statistically different in the three groups. Sepsis patients without shock had significantly reduced content of amylase and chymotrypsin in duodenal juice compared with healthy controls (P < 0.01). Secretion of amylase, chymotrypsin, trypsin (P < 0.01 each) and bicarbonate in duodenal fluid (P < 0.05) was impaired in the septic shock patients when compared with the healthy controls. The content of trypsin was different between sepsis patients and septic shock patients (P < 0.05). Spearman correlation analysis was significant between the amylase secretion and the APACHE III and SOFA scores (P < 0.01). The SOFA score was also related to secretion of trypsin (P < 0.05). In patients on pressor therapy, use of norepinephrine was associated with a significant decrease in bicarbonate secretion (P < 0.05). CONCLUSIONS: Sepsis is associated with secretory pancreatic dysfunction that is worse in septic shock than in sepsis without shock. Impaired exocrine function was significantly correlated to the APACHE III and SOFA scores.

From data to evidence: evaluative methods in evidence-based medicine.

The amount of published information is increasing exponentially, and recent technologic advances have created systems whereby mass distribution of this information can occur at an infinite rate. This is particularly true in the broad field of medicine, as the absolute volume of data available to the practicing clinician is creating new challenges in the management of relevant information flow. Evidence-based medicine (EBM) is an information management and learning strategy that seeks to integrate clinical expertise with the best evidence available in order to make effective clinical decisions that will ultimately improve patient care. The systematic approach underlying EBM encourages the clinician to formulate specific and relevant questions, which are answered in an iterative manner through accessing the best available published evidence. The arguments against EBM stem from the idea that there are inherent weaknesses in research methodologies and that emphasis placed on published research may ignore clinical skills and individual patient needs. Despite these arguments, EBM is gaining momentum and is consistently used as a method of learning and improving health care delivery. However, if EBM is to be effective, the clinician needs to have a critical understanding of research methodology in order to judge the value and level of a particular data source. Without critical analysis of research methodology, there is an inherent risk of drawing incorrect conclusions that may affect clinical decision-making. Currently, there is a trend toward using secondary pre-appraised data rather than primary sources as best evidence. We review the qualitative and quantitative methodology commonly used in EBM and argue that it is necessary for the clinician to preferentially use primary rather than secondary sources in making clinically relevant decisions.

Albumin versus hydroxyethyl starch in cardiopulmonary bypass surgery: a meta-analysis of postoperative bleeding.

BACKGROUND: This meta-analysis tested the hypothesis that cumulative blood loss during the first 24 hours after cardiopulmonary bypass is lower in patients exposed to albumin than hydroxyethyl starch (HES). METHODS: Randomized controlled trials comparing albumin and HES in cardiopulmonary bypass patients were identified by bibliographic database searches and other methods. RESULTS: Sixteen trials involving 653 randomized patients were included. In 88% of randomized comparisons, postoperative bleeding was lower in the albumin group, and the standardized mean difference in bleeding favoring albumin across all trials (-0.24; 95% confidence interval, -0.40 to -0.08) was statistically significant. Bleeding differences between albumin and either high or medium molecular weight HES were similar. In trials of adults, the pooled mean blood loss in the albumin group was 693+/-350 mL compared with 789+/-487 mL in the HES group. The estimated proportion of adult albumin group patients with blood loss of more than 1,000 mL was 19% compared with 33% of adult HES group patients. Conclusions. Postoperative blood loss is significantly lower in cardiopulmonary bypass patients exposed to albumin than HES.

The Southwestern Ontario Joint Replacement Pilot Project: electronic point-of-care data collection. Southwestern Ontario Study Group.

OBJECTIVE: To pilot a provincial joint replacement registry using electronic point-of-care data collection. DESIGN: Data collection study. SETTING: Southwestern Ontario, which has a population base of 3.5 million people. PARTICIPANTS: Eighteen orthopedic surgeons. METHOD: Information on total hip and knee replacements was obtained by the orthopedic surgeons over a 6-month period. Information was obtained in paper form and electronically on hand-held computers. MAIN OUTCOME MEASURES: Patient demographics, waiting times from referral to operation, patient satisfaction and relevance and value of electronic records compared with paper records. MAIN RESULTS: Data were collected on 815 total hip and knee arthroplasties. A slightly greater number of hips required revision than knees. The majority of patients were in the 60 to 90-year age range. With respect to the waiting time from referral to operation 10% of patients waited less than 5 weeks, 50% waited less than 30 weeks, and 90% waited less than 59 weeks. There was a high level of patient satisfaction with the operation and with hospital care received. Most surgeons found that the gathering and use of data electronically was relevant and easy. The electronic data were more timely, accurate and complete than paper records. CONCLUSION: Electronic point-of-care data collection is appropriate, particularly in high-volume, high-cost surgical interventions such as total joint replacements.

Endothelial E- and P-selectin expression in iNOS- deficient mice exposed to polymicrobial sepsis.

In vitro, nitric oxide (NO) decreases leukocyte adhesion to endothelium by attenuating endothelial adhesion molecule expression. In vivo, lipopolysaccharide-induced leukocyte rolling and adhesion was greater in inducible NO synthase (iNOS)-/- mice than in wild-type mice. The objective of this study was to assess E- and P-selectin expression in the microvasculature of iNOS-/- and wild-type mice subjected to acute peritonitis by cecal ligation and perforation (CLP). E- and P-selectin expression were increased in various organs within the peritoneum of wild-type animals after CLP. This CLP-induced upregulation of E- and P-selectin was substantially reduced in iNOS-/- mice. Tissue myeloperoxidase (MPO) activity was increased to a greater extent in the gut of wild-type than in iNOS-/- mice subjected to CLP. In the lung, the reduced expression of E-selectin in iNOS-/- mice was not associated with a decrease in MPO. Our findings indicate that NO derived from iNOS plays an important role in sepsis-induced increase in selectin expression in the systemic and pulmonary circulation. However, in iNOS-/- mice, sepsis-induced leukocyte accumulation is affected in the gut but not in the lungs.

Development of the continuous quality improvement questionnaire (CQIQ).

PURPOSE: Increasingly, hospitals are engaging in continuous quality improvement (CQI) endeavors, aimed at optimizing patient care. Physician involvement is critical to the success of such initiatives. Little is known about any mediating factors that affect physician participation in these projects, though such knowledge may be potentially important for targeting approaches to maximize physician involvement. The purpose of this study was to develop a reliable and valid instrument to assess physicians' knowledge of and attitudes toward CQI. MATERIALS AND METHODS: Items for the questionnaire were generated by using interviews and literature re-view and covered areas of knowledge, attitude, and facilitators and barriers to involvement in CQI projects. Five physicians participated in the interviews, 64 participated in the survey, and 9 participated in the assessment of test-retest reliability. Main outcomes were reliability and validity. RESULTS: The CQI questionnaire (CQIQ) had acceptable internal consistency and Cronbach's alpha correlation coefficient exceeded.70 for all scales. Item-total correlation ranged from.30 to.63 for all scales except for 1 item. Pearson's correlation coefficient for test-retest reliability was 0.85 (P =.02). A 76% response rate was achieved. CONCLUSIONS: There appears to be complex interactions among psychologic and environmental mediators that influence physician participation in hospital quality initiatives. The CQIQ shows reasonable measurement properties and our findings should be generalizable to physicians in other academic institutions. The CQIQ provides additional information on the implementation of programs and processes that should be validated in other institutional settings to enhance the interpretability of the instrument.

Measurement temperature plays a pivotal role in the distribution of erythrocyte deformability after LPS.

Reductions in red blood cell membrane deformability (RBC(D)) may perturb microcirculatory blood flow and impair tissue O(2)-availability. We investigated the effect of assay temperature on the distribution of RBC(D) in endotoxin (LPS) incubated and control RBCs. Fresh blood from healthy rats was incubated with and without the presence of LPS for 6 hrs. An index of red blood cell membrane deformability, delta, was measured via the micropipette aspiration technique at 25 degrees C and 37 degrees C at 0, 2 and 6 hrs of incubation. The ATP content of RBC was measured by the luciferin-luciferase technique. At 25 degrees C, LPS caused a significant decrease in mean delta after 2 and 6 hours incubation compared to controls (-10.0%, p=0.03 and -24.0%, p=0.03, respectively) characterized by a left shift in the distribution (skewness: -1.4). However, at 37 degrees C a significant decrease in delta was only detected after 6 hrs of LPS incubation (-13.8%, p=0.01, compared to -5.1%, p=0.7 at 2 hours) and lacked the left shifted distribution (skewness: 0.2). No significant difference in ATP content of RBCs was observed between groups. We have shown that LPS incubation results in a significant decrease in RBC(D) and that room temperature measurement of physical membrane properties may exaggerate the differences between normal and perturbed RBCs.

Coma mimicking brain death following baclofen overdose.

Baclofen toxicity can be a cause of profound coma with brainstem dysfunction mimicking brain death, and is mainly a clinical diagnosis. Measuring plasma levels is not always possible and may be misleading. Imaging results are usually normal. Electroencephalography may show a pattern of burst suppression. At present no effective specific therapy is available. However, as demonstrated in our case, the prognosis can be good even in severe cases, provided it is recognized early enough, and appropriate supportive measures are instituted.

Diaspirin cross-linked Hb and norepinephrine prevent the sepsis-induced increase in critical O(2) delivery.

We hypothesized that support of arterial perfusion pressure with diaspirin cross-linked Hb (DCLHb) would prevent the sepsis-induced attenuation in the systemic O(2) delivery-O(2) uptake relationship. Awake septic rats were treated with a chronic infusion of DCLHb or a reference treatment [norepinephrine (NE)] to increase mean arterial pressure by 10-20% over 18 h. Septic and sham control groups received normal saline. Isovolemic hemodilution to create anemic hypoxia was then performed in a metabolic box during continuous measurement of systemic O(2) uptake. O(2) delivery was calculated from hemodynamic variables, and the critical point of O(2) delivery (DO(2 crit)) was determined using piecewise regression analysis of the O(2) delivery-O(2) uptake relationship. Sepsis increased DO(2 crit) from 4.99 +/- 0.17 to 6.69 +/- 0.42 ml x min(-1) x 100 g(-1) (P < 0.01), while O(2) extraction capacity was decreased (P < 0.05). DCLHb and NE infusion prevented the sepsis-induced increase in DO(2 crit) [4.56 +/- 0.42 ml x min(-1) x 100 g(-1) (P < 0.01) and 5.04 +/- 0.56 ml x min(-1) x 100 g(-1) (P < 0.05), respectively]. This was explained by a 59% increase in O(2) extraction capacity in the DCLHb group compared with septic controls (P < 0.05), whereas NE treatment decreased systemic O(2) uptake in anemic hypoxia (1.51 +/- 0.08 vs. 1.87 +/- 0.1 ml x min(-1) x 100 g(-1) in septic controls, P < 0.05). We conclude that DCLHb ameliorated O(2) extraction capacity in the septic microcirculation, whereas NE decreased the metabolic demands of the tissues.

Roundtable conference on tissue oxygenation in acute medicine, Brussels, Belgium, 14-16 March 1998.

* Nutritional tissue perfusion and tissue metabolic demand are heterogeneously distributed. * Oxygen diffusion occurs preferentially at the precapillary arteriolar level. * Determination of adequacy of tissue oxygenation requires local organ measurements. * While there remains considerable variability in individual RBC transfusion practices, a recent clinical trial questioned the efficacy of RBC transfusion to hemoglobin concentrations greater than 80 gm/l in patients without heart disease [63]. * RBC substitutes, including cell-free hemoglobin solutions and PFC solutions are efficacious, yet may exhibit a number of direct vascular effects.

Endotoxin promotes adhesion of human erythrocytes to human vascular endothelial cells under conditions of flow.

OBJECTIVE: To investigate the effects of endotoxin on adhesion of human red blood cells to human vascular endothelial cells under conditions of flow. DESIGN: Prospective, randomized, controlled in vitro study. SETTINGS: University-affiliated cell biology laboratory. SUBJECTS: Human erythrocytes and human vascular endothelial cells. INTERVENTIONS: Fresh human erythrocytes and human vascular endothelial cells grown as monolayers were incubated with either saline or endotoxin. After incubation, endothelial monolayers were superfused with erythrocytes, and the number of erythrocytes adhering to the endothelial monolayer was quantified. MEASUREMENTS AND MAIN RESULTS: Adhesion of erythrocytes to vascular endothelium was measured under conditions of continuous flow in different settings: a) exposure of both endothelial cells and erythrocytes to saline; b) incubation of both erythrocytes and endothelial cells with endotoxin; c) exposure of erythrocytes only to endotoxin; d) incubation of endothelial cells only to endotoxin; and e) both the endothelial cells and erythrocytes incubated with different concentrations of endotoxin. Erythrocyte adhesion in the saline control group was 71 +/- 8 cells/mm2. Incubation of both components with endotoxin increased the number of adhesive erythrocytes to 172 +/- 9 cells/mm2 (p < .05). When only the endothelial cells were treated with endotoxin, 142 +/- 8 cells/mm2 adhered to the endothelial monolayer, whereas the incubation of the erythrocytes only to endotoxin resulted in adhesion of 102 +/- 3 cells/mm2. Decreasing concentrations of endotoxin reduced adhesion from 172 +/- 9 cells/mm2 (endotoxin, 75 microg/mL) to 165 +/- 9 cells/mm2 (endotoxin, 25 microg/mL), 153 +/- 4 cells/mm2 (endotoxin, 1 microg/mL), and 146 +/- 6.1 cells/mm2 (endotoxin, 5 ng/mL). CONCLUSIONS: Exposure of human erythrocytes and human venous vascular endothelial cells to an inflammatory stimulus such as endotoxin promotes a dose-dependent adhesion of erythrocytes to endothelium in a dynamic environment. These adhesive erythrocyte-endothelium interactions can be produced by exposure of either red blood cells or endothelial cells to endotoxin, with a higher degree of adhesion after activation of the endothelial cell component.

Noninvasive positive pressure ventilation in the setting of severe, acute exacerbations of chronic obstructive pulmonary disease: more effective and less expensive.

OBJECTIVE: The use of noninvasive ventilation for patients with acute respiratory failure has become increasingly popular over the last decade. Although the literature provides good evidence for the effectiveness of noninvasive ventilation in addition to standard therapy compared with standard therapy alone in patients with chronic obstructive pulmonary disease (avoiding intubation and improving hospital mortality), the associated costs have not been rigorously measured. Adding noninvasive positive pressure ventilation (NPPV) to standard therapy in the setting of a severe, acute exacerbation of chronic obstructive pulmonary disease (COPD) in patients with respiratory acidosis who are at high risk of requiring endotracheal intubation is both more effective and less expensive. DESIGN: Economic evaluation based on theoretical model. SETTING: This analysis base case was modeled for a tertiary care, teaching hospital. PATIENTS OR OTHER PARTICIPANTS: Carefully selected patients with severe exacerbations of COPD. INTERVENTION: The two alternative therapies compared were standard therapy (oxygen, bronchodilators, steroids, and antibiotics) and standard therapy plus NPPV. MEASUREMENTS AND MAIN RESULTS: As the hypothesis was dominance, the main outcomes modeled and calculated were costs, mortality rate, and rates of intubation between the two interventions. To determine clinical effectiveness, we used a meta-analysis of randomized trials evaluating the impact of NPPV on hospital survival. A decision tree was constructed and probabilities were applied at each chance node using research evidence and a comprehensive regional database. To provide data for this economic evaluation, MEDLINE literature searches were conducted. Bibliographies of relevant articles were reviewed, as were personal files. To estimate the costs of the alternative therapeutic approaches, eight types of hospitalization days were costed using the London Health Sciences Center costing data. Sensitivity analyses were performed, varying all assumptions made. The meta-analysis yielded an odds ratio for hospital mortality in the NPPV arm, compared with standard therapy, of 0.22 (95% confidence interval, 0.10-0.66). By using baseline case assumptions, we found a cost savings of $3,244 (1996, Canadian), per patient admission, if NPPV were adopted in favor of standard therapy. These findings present a scenario of clear dominance for treatment with NPPV. Sensitivity analyses did not alter the results appreciably. CONCLUSIONS: We conclude that from a hospital's perspective, NPPV and standard therapy for carefully selected patients with acute, severe exacerbations of COPD are more effective and less expensive than standard therapy alone.

The Critical Care Research Network: a partnership in community-based research and research transfer.

The objectives of this study were to present a short history of the Critical Care Research Network (CCR-Net), describe its approach to health services research and to summarize completed and current research projects. In doing this, we explored the question is this research network accomplishing its goals? We reviewed the medical literature to identify studies on similar types of Networks and also the evidence supporting the methodology used by CCR-Net to conduct research using MEDLINE, HEALTHSTAR, CINAHL and the keywords network and health care or healthcare, benchmarking and health care or healthcare, and research transfer or research utilization. We also reviewed the bibliographies of retrieved articles and our personal files. In addition, we summarized the results of studies conducted by CCR-Net and outlined those currently in progress. A review of the literature identified studies on two similar networks that appeared to be succeeding. In addition, the literature was also supportive of the general process used by CCR-Net, although the level of evidence varied. Finally, the studies conducted to date within CCR-Net follow the suggested methodology. At the time of this preliminary communication CCR-Net appears to have adopted a valid approach to health services research within the area of Critical Care Medicine. Further direct evidence is required and appropriate studies are planned.

Sedation in the intensive care unit: a systematic review.

CONTEXT: Sedation has become an integral part of critical care practice in minimizing patient discomfort; however, sedatives have adverse effects and the potential to prolong mechanical ventilation, which may increase health care costs. OBJECTIVE: To determine which form of sedation is associated with optimal sedation, the shortest time to extubation, and length of intensive care unit (ICU) stay. DATA SOURCES: A key word search of MEDLINE, EMBASE, and the Cochrane Collaboration databases and hand searches of 6 anesthesiology journals from 1980 to June 1998. Experts and industry representatives were contacted, personal files were searched, and reference lists of relevant primary and review articles were reviewed. STUDY SELECTION: Studies included were randomized controlled trials enrolling adult patients receiving mechanical ventilation and requiring short-term or long-term sedation. At least 2 sedative agents had to be compared and the quality of sedation, time to extubation, or length of ICU stay analyzed. DATA EXTRACTION: Data on population, intervention, outcome, and methodological quality were extracted in duplicate by 2 of 3 investigators using 8 validity criteria. DATA SYNTHESIS: Of 49 identified randomized controlled trials, 32 met our selection criteria; 20 studied short-term sedation and 14, long-term sedation. Of these, 20 compared propofol with midazolam. Most trials were not double-blind and did not report or standardize important cointerventions. Propofol provides at least as effective sedation as midazolam and results in a faster time to extubation, with an increased risk of hypotension and higher cost. Insufficient data exist to determine effect on length of stay in the ICU. Isoflurane demonstrated some advantages over midazolam, and ketamine had a more favorable hemodynamic profile than fentanyl in patients with head injuries. CONCLUSION: Considering the widespread use of sedation for critically ill patients, more large, high-quality, randomized controlled trials of the effectiveness of different agents for short-term and long-term sedation are warranted.

Diaspirin cross-linked hemoglobin improves mucosal perfusion in the ileum of septic rats.

OBJECTIVE: To determine the effect of a bolus infusion of diaspirin cross-linked hemoglobin (DCLHb or hemoglobin crosfumaril) on the ileal mucosal microcirculation in septic rats. DESIGN: Prospective, randomized, single-blinded study. SETTING: University-affiliated animal research laboratory. SUBJECTS: Twenty-four male Sprague-Dawley rats, weighing 320-380 g. INTERVENTIONS: Under inhalational anesthesia, arterial and venous catheters were inserted and sepsis was created by cecal ligation and perforation (CLP). Twenty-four hours later, animals were reanesthetized and ventilated. Via midline abdominal incision, the ileum was mobilized and prepared for intravital microscopy. Post-CLP hemodynamic values were obtained, and videomicroscopy was performed on four to ten villi. Animals were then randomized to receive 2 mL of DCLHb solution (100 mg/mL; n = 12) or pentastarch (n = 12) intravenously, and measurements were repeated after 20 mins. Rats treated with DCLHb then received nitroprusside to restore mean arterial pressure to post-CLP levels, and final measurements were obtained 15 mins later. MEASUREMENTS AND MAIN RESULTS: Cardiac index increased with both treatments (p < .001), whereas systemic vascular resistance index and mean arterial blood pressure were augmented only with DCLHb (p < .0001 compared with pentastarch). Intercapillary areas (ICA; inversely related to capillary density) were determined using computerized image analysis. ICA size decreased after treatment, from 974 +/- 79 to 791 +/- 106 microm2 with DCLHb and from 1044 +/- 90 to 840 +/- 82 microm2 with pentastarch (both p < .05). Red blood cell velocity in terminal arterioles, as assessed by velocimetry from the recorded images, increased by 15% with both treatments (p < .05). Restoration of mean arterial pressure to post-CLP levels in DCLHb animals by nitroprusside infusion abolished the effects of the hemoglobin solution on ICA size and red blood cell velocity. CONCLUSION: Both DCLHb and pentastarch infusion improved microcirculatory perfusion in the ileum of septic rats. In addition, DCLHb also exhibited vasopressor properties, which in combination with improved perfusion may be particularly useful in the treatment of sepsis.

An alternative pathway for preclinical research in fluid management.

Recent meta-analyses have created uncertainties regarding the appropriate clinical role of colloid resuscitation fluids in critically ill patients and prompted changes in fluid management practice. Such changes may not be justified in view of methodological limitations inherent in the meta-analyses. Further research is nevertheless needed to resolve the questions raised concerning the relationship between choice of resuscitation fluid and patient outcome. Animal studies can play an important part by reliably indicating whether particular fluids are likely to prove effective and safe in clinical trials. It is important to avoid costly large-scale clinical trials that fail to demonstrate the clinical utility of the tested therapy, as resources expended in failed trials raise overall development costs and thereby restrict the range of therapies meeting criteria of commercial feasibility. Promising therapies may thus not be pursued, even though an urgent clinical need may exist. An alternative pathway of preclinical research may be of value in avoiding some of the major clinical trial failures of recent years, particularly in the area of sepsis. This alternative pathway commences with the formulation of hypotheses by therapeutics developers. Independent preclinical investigators are challenged, by means of a competitive request for proposals, to test the hypotheses in rigorous randomized studies employing clinically relevant animal models. Promising proposals would then be selected for further development with the aid of peer review. The results of the randomized animal studies, along with other preclinical data, could also be evaluated using accepted principles of 'critical appraisal' commonly applied to clinical trial results. This critical appraisal might, where appropriate, include meta-analysis of animal study findings. This alternative preclinical pathway to new product evaluation should be completed before the commencement of large-scale clinical trials.