PubMed Health⌕ Search

Biomedical subjects

W J Sibbald

Publications and source records attributed to W J Sibbald.

At least 73 records · Page 4Linked to original sources

Pulmonary artery catheters in the critically ill. An overview using the methodology of evidence-based medicine.

Evidence-based approaches to assessing the clinical literature are used increasingly in issues relating to critical care medicine. As we discussed previously, this approach attempts to provide a logical and convenient framework from which the quality and relevance of clinical studies may be assessed in an unbiased manner. An evidence-based approach also allows the reader to differentiate between solid evidence and evidence that is based on a presumed mechanism, standard practice, or conventional wisdom. Evidence-based medicine that deemphasizes intuition, unsystemic clinical experience, and pathophysiologic rationale is sufficient grounds for clinical decision making and stresses the examination of evidence from clinical research. Importantly, it is the objective nature by which the evidence-based medicine paradigm approaches the questions of "What are we doing" and "How can we do better," that causes health care providers and funding agencies to increasingly adopt this paradigm as a primary principle. The role of evidence-based medicine, therefore, is not to discount expert opinion but, wherever possible, to require that recommendations be based on the results of rigorous and controlled scientific study. We introduced this article by highlighting the growing imbalance between resources and patient needs in the critical care environment. At the level of diagnostic technology and therapeutic care plans, critical care professionals increasingly are asked to identify strategies to improve efficiencies-approaches with rigorous costs that at the same time promote better patient care. Formalized technology assessment is one of the mechanisms to accomplish this. Using critical appraisal within the context of evidence-based medicine is one of the mechanisms by which data can be synthesized to describe technology assessment. In this example, we used controversies surrounding use of pulmonary artery catheterization in critically ill patients to highlight some of the principles of evidence-based medicine at the bedside. We introduced how a particular case example can be used to ask the question, "What is the evidence that a particular diagnostic technology or therapeutic modality improves outcome?" In the case of PACs, no one would argue that a diagnostic technology a priori leads to improved outcome; rather, we have to presume that given good data, the care provider will apply the most appropriate management strategy. In this case example, however, we demonstrate how the critical appraisal process should identify a search strategy to find the most appropriate evidence to support the questioning process. From this, the evidence can be critically appraised and tabulated. In the case of the PAC, Table 13 demonstrates that there are few data to identify a grade A recommendation that the PAC should be used as part of the care process in critically ill patients. Finding that there is little evidence to support the use of pulmonary artery catheterization in the clinical literature does not mean that this diagnostic technology is neither efficacious nor effective. It might well be that information provided by PACs is important in the care process. However, what this exercise has taught us is that there is little objective evidence to support this conclusion. The challenge to critical care practitioners is not only to apply the evidence-based processes more frequently to our environment but also to use the information to separate out clearly what is fact versus opinion. Where there is little evidence to support a particular clinical practice, as we have demonstrated with the PAC review earlier, the challenge to the clinician should be the design and conduct of clinical trials clarifying debate between opinion and evidence.

Aged↗

Potential savings involved in the purchase of low-cost, high-volume medical commodities as established from a community hospital survey.

Health technology refers to the instruments, equipment, drugs and procedures used in health care delivery, as well as the organizations supporting it. Health technology assessment, which is the process of conducting investigations to establish the criteria for efficacious, effective and efficient patient care, is becoming increasingly important in an era of diminishing resources. This survey of 39 community hospitals in southwestern Ontario found that improved purchasing strategies can result in substantial cost savings which can in turn be used to improve patient care. The study shows that optimizing the price of basic hospital commodities could save an average community hospital as much as $625,000 per year.

Cost Control↗

Evidence based critical care medicine; what is it and what can it do for us? Evidence Based Medicine in Critical Care Group.

OBJECTIVE: To describe the philosophy and approach to patient care called evidence based medicine, and to highlight how it can enhance the practice of intensive care. DATA SOURCES: We searched MEDLINE, reference lists, and our personal files to identify relevant literature. STUDY SELECTION: Articles on intensive care practice, critical appraisal, clinical research, and healthcare delivery were selected for discussion. DATA SYNTHESIS: We summarize the rationale for evidence based medicine, its applications and future developments, and suggest several methods for intensivists to use evidence based medicine in their practice and teaching. CONCLUSIONS: Evidence based medicine can complement other foundation disciplines in intensive care. This is the first article in a series entitled "Evidence Based Critical Care Medicine" which will demonstrate how this approach can be used at the bedside.

Clinical Competence↗

Introducing Critical Appraisal to studies of animal models investigating novel therapies in sepsis.

OBJECTIVES: To discuss theoretical and practical aspects relating to the design of animal studies investigating the efficacy of novel therapeutic agents for the treatment of sepsis, and to make explicit the process whereby these studies can be evaluated for the purpose of designing clinical trials in humans. DATA SOURCES: Relevant articles from the pertinent literature were reviewed. STUDY SELECTION: Studies relevant to an evidence-based assessment of clinical studies on therapeutic efficacy, and studies relevant to the design of animal models of sepsis were selected. DATA EXTRACTION: Concepts relevant to an evidence-based assessment of the animal literature were extracted. DATA SYNTHESIS: Articles were reviewed and an evidence-based framework for the assessment of animal studies was developed. In this process, we discuss the steps that are necessary to assess the internal validity of an individual study and review topics relevant to the application of animal data to the design of clinical trials. CONCLUSIONS: The success of clinical trials of sepsis therapies is predicated on the generation and interpretation of sound preclinical data. In this review, we have attempted to outline an evidence-based approach to the assessment of preclinical animal studies evaluating novel therapeutic interventions in sepsis.

Animals↗

Circulatory sequelae of administering CPAP in hyperdynamic sepsis are time dependent.

Evidence questions the circulation's ability to acutely compensate for abrupt changes in O2 delivery (Qo2). Because both sepsis and continuous positive airway pressure (CPAP) may alter the metabolic regulation of tissue oxygenation, we designed an experiment to determine the interaction, if any, between sepsis and time on circulatory homeostasis after the application of CPAP. Twenty-four sheep were randomized to cecal ligation and perforation (CLP) or sham procedure (Sham) and then rerandomized to receive either CPAP (10 mmHg) or no CPAP (No CPAP; CLP/CPAP, n = 8; CLP/No CPAP, n = 8; Sham/CPAP, n = 4; Sham/No CPAP, n = 4). Forty-eight hours later, CLP animals demonstrated an elevated cardiac index (+63%), systemic Qo2 (+49%), and systemic O2 uptake (+28%). Organ blood flow, measured with radiolabeled microspheres, was augmented to the heart and depressed in organs comprising the splanchnic circulation. Compared with the CLP/No CPAP group and both Sham groups, myocardial Qo2 in the CLP/ CPAP group was significantly elevated when measured both 2 and 8 h after CPAP. These changes were unrelated to differences in mean heart work between the study groups. Simultaneously, QO2 to all of the small gut, large gut, pancreas, and kidney in the CLP/CPAP group was elevated during the 2-h study yet reverted to levels not different from baseline by the 8-h study. These data demonstrate 1) a unique sepsis x time interaction with the use of 10 mmHg of CPAP, particularly in the "nonvital" circulations, and 2) CPAP effects on the septic coronary circulation, which were unexplained by changes in external determinants of myocardial O2 need.

Animals↗

Sepsis depresses the metabolic oxygen reserve of the coronary circulation in mature sheep.

This study was undertaken to describe the metabolic O2 reserve of the coronary circulation in an awake sheep model of hyperdynamic sepsis. Forty-eight hours after sheep were randomized to either a SHAM group (n = 8) or a cecal ligation and perforation (CLP) group (n = 8), we measured hemodynamics, organ blood flows, and systemic and myocardial O2 metabolism variables at baseline and through four stages of progressive hypoxia. A significant elevation in arterial lactate levels occurred at a higher O2 delivery in the CLP group (527 +/- 55 ml/min/m2) than in the SHAM group (357 +/- 29 ml/min/m2, p < 0.05). The heart's metabolic O2 reserve (difference in circulatory determinants of O2 availability between baseline and where O2 uptake could not be sustained) was exhausted at an O2 content of 56.9 +/- 4.2 ml O2/L in SHAM sheep and 79.6 +/- 7.2 ml O2/L (p < 0.05) in CLP sheep. An increase in coronary blood flow was three times greater in SHAM than in CLP animals. Myocardial O2 extraction increased in hypoxia in SHAM sheep (0.78 +/- 0.03 to 0.88 +/- 0.02, p < 0.05), but not in CLP sheep (0.79 +/- 0.02 to 0.80 +/- 0.04). We conclude that the metabolic O2 reserve of the coronary circulation is depressed in this model of hyperdynamic sepsis as the ability to increase both coronary blood flows and myocardial O2 extraction was significantly limited.

Animals↗

Microcirculatory changes in rat skeletal muscle in sepsis.

The aim of this study was to confirm that microvascular perfusion was abnormal during the early phases of normotensive sepsis and to determine whether these changes were due to the development of tissue edema. Skeletal muscle red blood cell (RBC) flow was studied in rats made septic by cecal ligation and perforation (CLP). After anesthesia with halothane, arterial and venous cannulae were inserted and, in the treatment group, a CLP performed. At 6, 24, and 48 h after entry into the study, the incidence of microcirculatory absence of flow in the extensor digitorum longus muscle (EDL) was examined with intravital microscopy. The number of capillaries containing RBCs were counted over a 60-s interval, and the flow status of each capillary was recorded. A significant increase in the number of stopped-flow capillaries was observed in the CLP group (p < 0.01) as compared with time-matched controls. In both groups the number of capillaries with stopped flow was greater than in naive animals. The severity of absence of flow was negatively correlated with the systemic hemoglobin concentration. These changes were not associated with an increase in tissue wet/dry weight ratio or albumin flux. This study shows that sepsis was associated with increased RBC flow heterogeneity. These changes, which occur within 24 h of the septic insult, are a persistent feature of the evolving septic process in the absence of tissue edema. These observations support the view that extrinsic compression of the microcirculation by tissue edema is not the primary cause of alterations in microcirculatory flow in sepsis.

Animals↗

Sepsis reduces isoflurane MAC in a normotensive animal model of sepsis.

Patients with sepsis often require anaesthesia for surgical procedures. Anaesthesia can be unpredictable and the most haemodynamically stable agents are used. No data are available for the minimum alveolar concentration (MAC) requirements in such patients or in animal models of sepsis. We have characterized the effect of sepsis on the MAC of isoflurane in a normotensive rodent model of sepsis. The minimum inhibitory concentration (MIC) of isoflurane to an identical stimulus was determined for rodents subjected to caecal ligation and perforation (CLP n = 8), or sham laparotomy (n = 7). The calculated MAC of isoflurane was reduced in the septic animals compared with the sham animals (MAC of isoflurane, CLP = 0.8%, sham = 1.4% P < 0.003). No statistical differences were found in the haemodynamic variables measured in either group. Isoflurane leads to haemodynamic stability during anaesthesia in this animal model of sepsis. However, the MAC requirement for isoflurane is reduced by sepsis.

Anesthetics, Inhalation↗

Pentoxifylline does not prevent microvascular injury in normotensive, septic rats.

OBJECTIVE: To determine if treatment with pentoxifylline would decrease the tissue injury that occurs in a normotensive model of sepsis. DESIGN: Random assignment to control, cecal ligation-perforation, or cecal ligation-perforation plus pentoxifylline groups for a 24-hr study. SETTING: Animal laboratory. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: Sepsis was induced by cecal ligation-perforation with aggressive fluid resuscitation (normal saline 10 mL/kg/hr). Pentoxifylline was administered as a 2-mg/kg bolus, followed by a continuous infusion of 6 mg/kg/hr. MEASUREMENTS AND MAIN RESULTS: Compared with controls, rats in the cecal ligation-perforation group had an increased heart rate (432 +/- 12 vs. 399 +/- 10 beats/min) and respiratory rate (129 +/- 6 vs. 94 +/- 7 breaths/min). Blood pressure was slightly decreased (104 +/- 4 vs. 125 +/- 5 mm Hg), while cardiac index was not significantly different (50.1 +/- 5.7 vs. 40.7 +/- 3.9 mL/min/100 g). Blood pressure (103 +/- 4 mm Hg) was the only parameter that was significantly different in the cecal ligation-perforation plus pentoxifylline group compared with controls. When compared with controls, tissue wet/dry weight ratios were increased in the diaphragm of the cecal ligation-perforation group and in the liver, pancreas, small bowel, and large bowel of the cecal ligation-perforation, and the cecal ligation-perforation plus pentoxifylline groups. Tissue/plasma albumin ratios were increased in the diaphragm of the cecal ligation-perforation group and in the liver, pancreas, and large bowel of the cecal ligation-perforation and the cecal ligation-perforation plus pentoxifylline groups. There were no significant differences between the cecal ligation-perforation and the cecal ligation-perforation plus pentoxifylline groups. CONCLUSIONS: Normotensive sepsis is accompanied by increased vascular permeability in the diaphragm and intra-abdominal organs. Pentoxifylline appears to attenuate some of the systemic manifestations of sepsis. However, pentoxifylline did not prevent the development of protein-rich tissue edema.

Animals↗

Round table conference on clinical trials for the treatment of sepsis.

OBJECTIVES: Using an evidence-based approach for a round table conference, to discuss sepsis according to its current epidemiology and clinical management, lessons which we feel can be learned by investigators from the design and conduct of previous clinical trials of drug therapy, and to describe the "optimum" clinical trials design for treatments of this syndrome. DATA SOURCES: Experts in the field of sepsis were selected and requested to apply an "evidence-based" approach to the published literature, from which recommendations would be synthesized and rated according to levels of evidence. These experts undertook a review of appropriate literature, primarily focusing on evidence presented by clinical trials. Applicable articles were searched for by individual experts, using a variety of on-line search strategies (i.e., MEDLINE, Current Contents; Clinical Medicine). DATA EXTRACTION AND REVIEW: Presentation at the round table conference was followed by agreement by consensus amongst participants as to the grade of recommendation. Individual presentations and arguments for grading of levels of evidence will be published independently. Where possible, recommendations on individual topics were ranked according to the level of evidence presented. Levels I to V were used to rank randomized, controlled trials through case series, respectively. Grade A recommendation is supported by Level I evidence, Grade B recommendation is supported by Level II evidence, and Grade C recommendation is supported by Levels III, IV or V evidence. CONCLUSION: Recommendations for the design, conduct and analysis of future trials of sepsis therapies were summarized.

Clinical Trials as Topic↗

Multiple organ dysfunction score: a reliable descriptor of a complex clinical outcome.

OBJECTIVE: To develop an objective scale to measure the severity of the multiple organ dysfunction syndrome as an outcome in critical illness. DESIGN: Systematic literature review; prospective cohort study. SETTING: Surgical intensive care unit (ICU) of a tertiary-level teaching hospital. PATIENTS: All patients (n = 692) admitted for > 24 hrs between May 1988 and March 1990. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Computerized database review of MEDLINE identified clinical studies of multiple organ failure that were published between 1969 and 1993. Variables from these studies were evaluated for construct and content validity to identify optimal descriptors of organ dysfunction. Clinical and laboratory data were collected daily to evaluate the performance of these variables individually and in aggregate as an organ dysfunction score. Seven systems defined the multiple organ dysfunction syndrome in more than half of the 30 published reports reviewed. Descriptors meeting criteria for construct and content validity could be identified for five of these seven systems: a) the respiratory system (Po2/FIO2 ratio); b) the renal system (serum creatinine concentration); c) the hepatic system (serum bilirubin concentration); d) the hematologic system (platelet count); and e) the central nervous system (Glasgow Coma Scale). In the absence of an adequate descriptor of cardiovascular dysfunction, we developed a new variable, the pressure-adjusted heart rate, which is calculated as the product of the heart rate and the ratio of central venous pressure to mean arterial pressure. These candidate descriptors of organ dysfunction were then evaluated for criterion validity (ICU mortality rate) using the clinical database. From the first half of the database (the development set), intervals for the most abnormal value of each variable were constructed on a scale from 0 to 4 so that a value of 0 represented essentially normal function and was associated with an ICU mortality rate of < 5%, whereas a value of 4 represented marked functional derangement and an ICU mortality rate of > or = 50%. These intervals were then tested on the second half of the data set (the validation set). Maximal scores for each variable were summed to yield a Multiple Organ Dysfunction Score (maximum of 24). This score correlated in a graded fashion with the ICU mortality rate, both when applied on the first day of ICU admission as a prognostic indicator and when calculated over the ICU stay as an outcome measure. For the latter, ICU mortality was approximately 25% at 9 to 12 points, 50% at 13 to 16 points, 75% at 17 to 20 points, and 100% at levels of > 20 points. The score showed excellent discrimination, as reflected in areas under the receiver operating characteristic curve of 0.936 in the development set and 0.928 in the validation set. The incremental increase in scores over the course of the ICU stay (calculated as the difference between maximal scores and those scores obtained on the first day [i.e., the delta Multiple Organ Dysfunction Score]) also demonstrated a strong correlation with the ICU mortality rate. In a logistic regression model, this incremental increase in scores accounted for more of the explanatory power than admission severity indices. CONCLUSIONS: This multiple organ dysfunction score, constructed using simple physiologic measures of dysfunction in six organ systems, mirrors organ dysfunction as the intensivist sees it and correlates strongly with the ultimate risk of ICU mortality and hospital mortality. The variable, delta Multiple Organ Dysfunction Score, reflects organ dysfunction developing during the ICU stay, which therefore is potentially amenable to therapeutic manipulation. (ABSTRACT TRUNCATED)

Humans↗

Hematocrit modifies the circulatory control of systemic and myocardial oxygen utilization in septic sheep.

OBJECTIVE: To describe the relationship between hematocrit and oxygen utilization before and after the onset of a hyperdynamic septic state. DESIGN: Prospective, observational study. SETTING: Laboratory of a large university-affiliated medical school. SUBJECTS: Thirty mature sheep, each weighing 30 to 40 kg (0.9 to 1.1 m2 body surface area). INTERVENTIONS: After baseline measurements, cecal ligation and perforation were used to establish an intra-abdominal source of infection. The abdominal wound was closed and animals were studied on the second postoperative day. An increase in cardiac output of > or = 30% was used to arbitrarily define the onset of sepsis. Repeat measurements were performed and the animal was killed. RESULTS: The circulatory response to this septic insult included an increase in both cardiac index (change, baseline to sepsis, delta +2.24 +/- 0.75 L/min/m2; p < .01) and myocardial blood flows (delta +76.4 +/- 56 mL/100 g/min; p < .01). We found a negative correlation between the hematocrit and cardiac index (r2 = .21; p < .01) during the septic study, and noted that the amount (p < .01) of this correlation was significantly greater in the septic than the nonseptic study. Concurrently, the negative correlation observed between hematocrit and whole-body oxygen extraction (r2 = .21; p < .01) was significantly lower (p < .01) across the range of hematocrit values examined during the septic study vs. the similar relationship in the nonseptic study (r2 = .27; p < .01). The increase in myocardial oxygen consumption paralleled the relationship between cardiac work and hematocrit in the septic study, and was accompanied by increases in both myocardial blood flows (r2 = .25; p < .01) and myocardial oxygen extraction (r2 = .35; p < .01). CONCLUSIONS: The normal circulatory compensation to anemia in hyperdynamic sepsis includes increases in cardiac index and whole-body oxygen extraction, although greater reliance is likely placed on the use of systemic flow reserve to maintain tissue oxygen uptake in septic vs. healthy study conditions. Furthermore, increased reliance on myocardial oxygen extraction in sepsis suggests that the normal flow-reserve supporting myocardial oxygen availability may be limited in this syndrome.

Animals↗

Compared with crystalloid, colloid therapy slows progression of extrapulmonary tissue injury in septic sheep.

We tested the hypothesis that the type of fluid infused to chronically maintain intravascular volumes would modify both microvascular integrity and cellular structure in extrapulmonary organs in hyperdynamic sepsis. After cecal ligation and perforation, awake sheep were treated for 48 h with 10% pentastarch (n = 9), 10% pentafraction (Du Pont Critical Care; n = 8), or Ringer lactate (n = 8) titrated to maintain a constant left atrial pressure. After 48 h of fluid therapy, biopsy samples were taken from the left ventricle and gastrocnemius for electron microscopy. At this time, all groups demonstrated a similar hyperdynamic circulatory response, increased systemic O2 utilization and organ blood flows, measured by radioactive microsphere injection. However, greater capillary luminal areas with less endothelial swelling and less parenchymal injury were found in septic sheep treated with pentastarch vs. Ringer lactate infusion in both muscle types. Pentafraction showed few benefits in study end points over pentastarch. Thus, we conclude that chronic intravascular volume resuscitation of hyperdynamic sepsis with pentastarch ameliorated the progression of both microvascular and parenchymal injury. These findings indicate that microvascular surface area for tissue O2 exchange in sepsis may be better preserved with chronically infused colloid, resulting in less parenchymal injury.

Animals↗

Modulation of hemodynamics and organ blood flow by nitric oxide synthase inhibition is not altered in normotensive, septic rats.

Hyperdynamic sepsis is associated with a redistribution of organ blood flow. We hypothesized that increased nitric oxide (NO) production could mediate this process. The objective of this study was to determine the effect of a NO synthesis inhibitor on systemic and organ blood flows in vivo in septic and in normal rats. Rats were instrumented for hemodynamic monitoring and randomized to undergo cecal ligation and perforation (CLP) or control laparotomy. Cardiac output and organ blood flow were measured by thermodilution and radioactive microspheres, respectively. Baseline values were obtained at 24 h after CLP or control laparotomy and after the administration of L-nitro-arginine methyl ester (L-NAME) at 2, 4, 8, and 16 mg/kg intravenously. All studies were performed in awake, unrestrained animals. Septic animals were normotensive and hyperdynamic. L-NAME decreased cardiac index and increased systemic vascular resistance and mean arterial blood pressure to an equivalent degree in control and in CLP animals. CLP was associated with significantly increased relative blood flow to the small bowel and portal circulation. Although cardiac output decreased with L-NAME, blood flow to the diaphragm, liver, and brain was relatively well preserved. Absolute blood flow to other organs, including small bowel, decreased in parallel to the cardiac output. The effect of L-NAME on organ blood flow was comparable in control and in CLP animals. We conclude that the influence of NO on organ blood flows appears to vary between organs, but that NO does not explain the redistribution of blood flow observed in hyperdynamic sepsis.

Amino Acid Oxidoreductases↗