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Summary: Microvascular endothelial cells (MVEC), which differ from large vessel endothelial cells, have been isolated successfully from lungs of various species, including man. However, contamination by nonendothelial cells remains a major problem in spite of several technical improvements. In view of the organ specificity of MVEC, endothelial cells should be derived from the tissue involved in the diseases one wishes to study. Therefore, to investigate some of the immunopathological mechanisms leading to acute respiratory distress syndrome (ARDS), we have attempted to isolate lung MVEC from patients undergoing thoracic surgery for lung carcinoma and patients dying of ARDS. The method described here includes four main steps: (1) full digestion of pulmonary tissue with trypsin and collagenase, (2) aggregation of MVEC induced by human plasma, (3) Percoll density centrifugation, and (4) selection and transfer of MVEC after local digestion with trypsin/EDTA under light microscopy. Normal and ARDS-derived lung MVEC purified by this technique presented contact inhibition (i.e., grew in monolayer), and expressed classical endothelial markers, including von Willebrand factor (vWF), platelet endothelial cell adhesion molecule 1(PECAM-1, CD31), and transcripts for the angiogensin converting enzyme (ACE). The cells also formed capillarylike structures, took up high levels of acetylated low-density lipoprotein (Ac-LDL), and exhibited ELAM-1 inducibility in response to TNF. Contaminant cells, such as fibroblasts, smooth muscle cells, or pericytes, were easily recognized on the basis of morphology and were eliminated by selection of plasma-aggregated cells under light microscopy. The technique presented here allows one to study the specific involvement and contribution of pulmonary endothelium in various lung diseases

The central nervous and cardiovascular effects of midazolam 0.15 mg kg-1 were studied in 20 healthy, unpremedicated volunteers (10 male and 10 female). No important side-effects were noted and the venous tolerance to midazolam was excellent. Three minutes after injection mean systolic arterial pressure decreased from 121 +/- (SEM) 2 mm Hg to 115 +/- (SEM) 2 mm Hg and diastolic pressure from 78 +/- 2 to 70 +/0 2 mm Hg (P0.05), and these effects persisted for at least 20 min. Heart rate increased from 77 +/- 4 beat min-1 to 90 +/- 3 and 88 +/- 3 beat min-1 and 3 min after the injection (P0.05). Anterograde amnesia (40 +/- 3 min duration) and drowsiness (lasting 128 +/- 23 min) were observed in all subjects. Loss of the eyelash reflex and apnoea were observed more often in the male group than in the female subjects. Midazolam 0.15 mg kg-1 was not sufficient to induce anaesthesia reliably in healthy unpremedicated volunteers.

Supplemental Digital Content is available in the text., Objectives: Hypothermia reduces intracranial hypertension in patients with traumatic brain injury but was associated with harm in the Eurotherm3235Trial. We stratified trial patients by International Mission for Prognosis and Analysis of Clinical Trials in [Traumatic Brain Injury] (IMPACT) extended model sum scores to determine where the balance of risks lay with the intervention. Design: The Eurotherm3235Trial was a randomized controlled trial, with standardized and blinded outcome assessment. Patients in the trial were split into risk tertiles by IMPACT extended model sum scores. A proportional hazard analysis for death between randomization and 6 months was performed by intervention and IMPACT extended model sum scores tertiles in both the intention-to-treat and the per-protocol populations of the Eurotherm3235Trial. Setting: Forty-seven neurologic critical care units in 18 countries. Patients: Adult traumatic brain injury patients admitted to intensive care who had suffered a primary, closed traumatic brain injury; increased intracranial pressure; an initial head injury less than 10 days earlier; a core temperature at least 36°C; and an abnormal brain CT. Intervention: Titrated Hypothermia in the range 32-35°C as the primary intervention to reduce raised intracranial pressure. Measurements and Main Results: Three hundred eighty-six patients were available for analysis in the intention-to-treat and 257 in the per-protocol population. The proportional hazard analysis (intention-to-treat and per-protocol populations) showed that the treatment effect behaves similarly across all risk stratums. However, there is a trend that indicates that patients in the low-risk group could be at greater risk of suffering harm due to hypothermia. Conclusions: Hypothermia as a first line measure to reduce intracranial pressure to less than 20 mm Hg is harmful in patients with a lower severity of injury and no clear benefit exists in patients with more severe injuries.

There is good reason that treatment of the acute respiratory distress syndrome (ARDS) with corticosteroids has been a much-studied subject. In response to a number of serious underlying events, such as sepsis, inhalation of gastric contents, and multiple trauma, the body reacts with acute inflammation of the lung parenchyma — a process that is characterized by increased vascular permeability, extravasation of plasma, and leukocyte infiltration; this combination of events is known as ARDS. This illness has an early acute phase that affects all patients; a variable fraction have a late phase, characterized by pulmonary fibrosis. Management of either phase of . . .

Over the last quarter of a century, intensive care medicine has developed into an established hospital specialty with its own unique identity and characteristics. Significant advances have occurred, mostly in a succession of small steps rather than any dramatic leap, with many being linked to advances in health care across other disciplines. In addition, many changes have resulted from the scientific identification of the detrimental effects of certain traditional practices once thought to be therapeutic. Here, in an attempt to learn from the past and offer guidance for future progress, we detail some of the key changes in various aspects of intensive care medicine including respiratory, cardiovascular, metabolic, and nutritional care, as well as sepsis, polytrauma, organization, and management.

Determiner la precision de la mesure continue (in vivo) de la saturation veineuse en oxygene du sang mele (Svo2) par catheter a fibres optiques chez les patients en post-circulation extracorporelle (CEC). Nous avons etudie prospectivement 14 patients (âge, 64 ± 8) post-CEC equipes d’un catheter arteriel pulmonaire. Le taux d’hematocrite moyen etait de 30 ± 4 %. Le catheter a ete calibrein vitro etin vivo suivant les recommandations du constructeur. Cinquante-six mesures simultanees de Svo2 continue (CSvo2) et de Svo2 mesuree (MSvo2) par hemoxymetre ont ete effectuees et les valeurs pairees ont ete analysees par regression lineaire. Pour que les deux mesures soient interchangeables, nous avons determine,a priori, une limite maximale de 3% (environ 5% de la mesure) comme difference acceptable entre les deux types de mesures. Toutes les mesures ont ete faites dans les quatre heures suivant la mise en place du catheter. CSvo2 est faiblement correlee a MSvo2 avec un coefficient de correlation r2 = 0,49 (P < 0,001). L’analyse de Bland-Altman objective un biais moyen de 0,8 ± 3% avec 36% des valeurs mesurees en dehors de la zone cliniquement acceptable. Pour des valeurs CSvo2 ± 65%, les mesures ne sont pas correlees (P = NS), le biais est de -2 ± 7% et 56% des valeurs mesurees en dehors de la zone cliniquement acceptable. Nos resultats objectivent que, dans les suites immediates d’une CEC, la mesure continue de la Svo2 et la co-oxymetrie du sang mele ne sont pas interchangeables. D’autres etudes sont necessaires afin de confirmer ces resultats et comprendre les phenomenes physiopathologiques a l’origine de l’absence de concordance entre les deux methodes. To determine the accuracy of continuous (in vivo) measurement of mixed venous oxygen saturation (SvO2), using a fibreoptic catheter, in patients having had cardiopulmonary bypass (CPB). Using a pulmonary arterial catheter, we prospectively studied 14 patients (age 64 ± 8) having had cardiopulmonary bypass. Mean hematocrit was 30 ± 4%. The catheter was calibrated in vitro and in vivo, according to the manufacturer’s instructions. Fifty-six simultaneous measurements of continuous SvO2 (CSvO2) and measured SvO2 (MSvO2) were taken with a co-oxymeter and the paired values were analyzed by the linear regression method. To make the two sets of measurements interchangeable, we established, a priori, a maximum limit of 3% (approximately 5% of the measurement), as being an acceptable difference between the two types of measurements. All the measurements were obtained within four hours of the placement of the catheter. CSvO2 was weakly correlated with MSvO2, with a correlation coefficient of r2 = 0.49 (P < 0.001). The Bland-Altman analysis demonstrates an objective mean bias of 0.8 ± 3%, with 36% of the values measured falling outside clinically acceptable limits. For values of CSvO2 ± 65%, the measurements were not correlated (P = NS). The bias was −2 ± 7%, and 56% of the values measured fell outside clinically acceptable limits. Our results demonstrate that, in the immediate aftermath of cardiopulmonary bypass, the continuous measurement of SvO2 and the co-oxymetry determination of mixed blood is not interchangeable. Other studies will be necessary to confirm these results and enable us to understand the pathophysiological phenomena accounting for the lack of agreement between the two methods.

UNLABELLED A 69-yr-old woman was admitted to the intensive care unit after cardiac surgery. Immediately after the discontinuation of cardiopulmonary bypass, she had a circulatory arrest. A 13-min open-chest cardiac massage was followed by 70 min of cardiopulmonary bypass. Right hemiplegia and right extensor plantar reflex were noted after the patient awakened. She had been included in a prospective study protocol measuring, before and after surgery, cerebral blood flow with transcranial Doppler (TCD). The data were retrospectively analyzed, and it was established that the TCD had recorded cerebral perfusion defects. This is the first case of acute ischemic stroke after cardiac arrest with retrospective documentation of asymmetrical cerebral blood flow by a systematic postoperative TCD recording. IMPLICATIONS Clinical neurological examination is often of limited value in deeply sedated patients. This case report describes the early diagnosis of an ischemic stroke by using transcranial Doppler after cardiac surgery. Thus, transcranial Doppler could be used systematically for cerebral perfusion monitoring in patients who have undergone major hemodynamic instabilities.

To determine whether acute respiratory distress syndrome (ARDS) complicating bacteremic sepsis independently affects mortality in critically ill patients, we conducted a 3-year retrospective cohort study in a surgical intensive care unit. We included all consecutive patients with blood culture-positive sepsis and measured organ dysfunctions and mortality. Among 4,530 admissions, 196 cases of bacteremic sepsis were recorded. ARDS occurred in 31 (16%) of these patients. The case fatality rate was 58% in patients with ARDS compared with 31% in patients without ARDS. Using Cox proportional hazards regression with time-dependent variables, the unadjusted hazard ratio for death was 1.8 (95% confidence interval [CI], 1.0-3.2). After adjusting for comorbid factors that were present before the onset of sepsis, the hazard ratio was 2.2 (95% CI, 1.2-3.9). After further adjustment was made for nonpulmonary organ dysfunctions and microbiologic factors that were independently associated with mortality, the adjusted hazard ratio for ARDS was 0.6 (95% CI, 0.3-1.2). Among critically ill surgical patients, ARDS complicating bacteremic sepsis remains common, but it is not independently associated with short-term mortality, after adjusting for severity of illness and nonpulmonary organ dysfunctions evolving after the onset of sepsis.

Object. There is uncertainty about the efficacy of hypertension, hypervolemia, and hemodilution (triple-H) therapy in reducing the occurrence of delayed ischemic neurological deficits (DINDs) and death after subarachnoid hemorrhage. The authors therefore conducted a systematic review to evaluate the efficacy of triple-H prevention in decreasing the rate of clinical vasospasm, DINDs, and death. Methods. The authors systematically reviewed studies identified based on a MEDLINE, EMBASE, and COCHRANE Register search of articles published between 1966 and 2001, and reference lists of identified articles. An independent assessment of each study's methodological quality, population, intervention, and outcomes (rates of symptomatic vasospasm, DINDs, and death) was performed. Summary relative risk estimates were calculated for the main outcomes using fixed- or random-effect models, as appropriate. Only four prospective, comparative studies with a total of 488 patients were identified. The median internal validity score was 0.5 (range 0–2); the median external validity score was 3 (range 2–6). Compared with no prevention, triple-H therapy was associated with a reduced risk of symptomatic vasospasm (relative risk [RR] 0.45, 95% confidence interval [CI] 0.32–0.65), but not DIND (RR 0.54, 95% CI 0.2–1.49). The risk of death was higher (RR 0.68, 95% CI 0.53–0.87). Sensitivity analyses including only randomized, controlled trials showed no evidence of statistically significant results for these major end points. Conclusions. The paucity of information and important limitations in the design of the studies analyzed preclude evaluation of the efficacy of triple-H prevention and formulation of any recommendations regarding its use for the prevention of cerebral vasospasm.

Background Protective ventilatory strategies have resulted in a decreased mortality rate in acute respiratory distress syndrome, but the underlying mechanisms remain unclear. The authors hypothesized that (1) mechanical ventilation modulates activation of polymorphonuclear leukocytes (PMNs), (2) the consequent release of proteinases is correlated with a systemic inflammatory response and with multiple organ dysfunction, and (3) these deleterious effects can be minimized by a protective ventilatory strategy. Methods Human PMNs were incubated with bronchoalveolar lavage fluid obtained from patients at entry or 36 h after randomization to ventilation with either a conventional (control) or a lung-protective strategy. PMN oxidant production and surface expression of adhesion molecules and granule markers, including CD18, CD63, and L-selectin, were measured by flow cytometry. Extracellular elastase activity was quantified using a fluorescent substrate. Results Bronchoalveolar lavage obtained from both groups of patients at entry showed similar effects on PMN oxidant production and expression of surface markers. At 36 h, exposure of PMNs to bronchoalveolar lavage fluid from the control group resulted in increased PMN activation as manifested by a significant increase in oxidant production, CD18, and CD63 surface expression, and shedding of L-selectin. By contrast, these variables were unchanged at 36 h in the lung-protective group. There was a significant correlation between the changes of the variables and changes in interleukin-6 level and the number of failing organs. Conclusions Polymorphonuclear leukocytes can be activated by mechanical ventilation, and the consequent release of elastase was correlated with the degree of systemic inflammatory response and multiple organ failure. This result may possibly explain the decreased mortality in acute respiratory distress syndrome patients treated with a lung-protective strategy.

To evaluate the effect of a norepinephrine-induced differential increase in mean arterial pressure on splanchnic and renal perfusion in a porcine model of volume-resuscitated endotoxic shock.Prospective, controlled, acute interventional study.Animal research laboratory.Fourteen landrace pigs, seven treated with norepinephrine and seven used as endotoxemic controls.In an acute endotoxic shock model, norepinephrine was used to reverse hypotension in seven fluid-resuscitated pigs, anesthetized with alpha-chloralose and equipped with flow probes around the portal vein and renal artery, renal and jejunal mucosal laser Doppler flowmetry, and jejunal tonometry. Mean arterial pressure was increased by 10 and then 20 mm Hg above the shock level with norepinephrine. Seven shocked, fluid-resuscitated only animals served as the comparison group.Measurements were performed before 2-hr endotoxin infusion and at the end of each increased level of mean arterial pressure. Raising mean arterial pressure with norepinephrine by 10 mm Hg significantly increased cardiac output, systemic oxygen extraction, and portal vein blood flow; stabilized metabolic acidosis; and tended to restore renal and jejunal mucosal flows to preshock levels. Increasing mean arterial pressure by 20 mm Hg further increased cardiac output and oxygen delivery but without improving portal vein, renal artery, and jejunal mucosal blood flows.Norepinephrine, administered to increase mean arterial pressure by 10 mm Hg in an acute model of volume-resuscitated endotoxic shock, improved systemic and regional perfusion. The administration of norepinephrine to increase mean arterial pressure 20 mm Hg above shock did not increase renal and splanchnic blood flows, despite an enhanced cardiac output.

Objective: To evaluate the safety of liposomal PGE1 (TLC C-53) in patients with acute respiratory distress syndrome (ARDS), and determine its efficacy in improving oxygenation and reducing ventilator dependency. Design: A multi-centre, randomized, double-blind, placebo-controlled clinical study. Setting: Thirty-one hospitals in six European countries. Patients: One hundred two patients with ARDS. Interventions: Patients were randomized in a 2:1 ratio to receive infusions of either the study drug TLC C-53 or placebo. Infusions were given over 60 min every 6 h for 7 days. The dose of study drug started at 0.6 µg/kg per h, rising over 24 h to a maximum dose of 1.8 µg/kg per h. Measurements and main results: Seventy patients received the study drug and 32 placebo. Sixty-nine patients (47 treatment, 22 placebo) completed the study protocol. Patients were monitored for changes in the PaO2/FIO2 ratio, changes in lung compliance, time to off-ventilator and 28-day mortality, in addition to basic haematological and haemodynamic parameters. There were no significant differences in demographics and baseline characteristics between the two groups. There were no differences in the time to off-ventilation (16 days with treatment, 16.6 days with placebo, p=0.94) or in 28-day mortality (30% with treatment, 28% with placebo, p=0.78). There was a difference in the time to achieve a PaO2/FIO2 ratio above 300 in favour of TLC C-53 (10.3 versus 26.5 days) but this was not statistically significant (p=0.23). Conclusions: TLC C-53 was generally well-tolerated but failed to reduce mortality or duration of mechanical ventilation.

Aneurysmal subarachnoid (SAH) is a serious disease associated with considerable mortality and morbidity: it accounts for 6–10% of all strokes and 22–25% of cerebrovascular deaths (46). The most common causes of death or disability include direct effect of initial bleed and rebleeding (5). Subsequent causes of death include vasospasm (43), hydrocephalus, and surgical and medical complications of SAH treatment. After surgery patients remain at risk of developing secondary neurologic deficits and medical complications for at least 2 to 3 weeks. During this period patients are closely monitored for early detection of onset of delayed ischemic symptoms. As no good evidence exists to support hypertensive and hemodilution therapy to prevent vasospasm, the initial goal should be oriented to maintain euvolemia, considering that patients potentially have pronounced negative fluid balance and then considerable maintenance fluids and sodium must be substituted. However, if symptoms of delayed cerebral ischemia appear, the goals of treatment are immediately converted to hypertensive hypervolemic and hemodilution therapy. Oral, when possible, otherwise intravenous Nimodipine is recommended, its dosage must be adapted to maintain the desired blood pressure.

Cerebral vasospasm remains a devastating medical complication of aneurysmal subarachnoid hemorrhage (SAH). It is associated with high morbidity and mortality rates, even after the aneurysm has been secured surgically or radiologically. A great deal of experimental and clinical research has been conducted in an effort to find ways to prevent this complication. The literature includes extensive coverage of in vivo animal model studies of SAH and vasospasm. These experimental studies have contributed to tremendous advances in the understanding of the mechanisms leading to cerebral vasospasm. Most of the experimental settings, however, have demonstrated varying levels of ability to predict accurately what occurs in human SAH. Therefore, although animal models have been developed to test new therapies, most of the treatment effects have been shown to be less compelling when trials have been conducted in clinical settings. The interpretation of current literature is complicated further by the imprecise estimation of the incidence of cerebral vasospasm, which is due to various degrees of clinical expression, ranging from the absence of symptoms in the presence of increased blood flow velocities at transcranial Doppler or vessel diameter reduction at angiography to neurological manifestations of severe ischemic deficits. In addition, a change over time in the incidence pattern of human SAH and vasospasm, possibly related to improved surgical techniques and overall patient management, may have occurred. This topic review collects the relevant literature on clinical trials investigating prophylactic therapies for cerebral vasospasm in patients with aneurysmal SAH and emphasizes the need for large clinical trials to confirm the results derived from clinical experience. In addition, it points out some experimental therapies that may hold promise in future clinical trials to prevent the occurrence of vasospasm.

After surgery, critically ill patients in the intensive care unit (ICU) may acquire infections which differ from those acquired elsewhere with regard to the anatomical site involved and the causative micro-organisms. Specific risk factors for infection in the ICU have been shown to be associated with exposure to invasive devices and the use of broad-spectrum antibiotic treatment. Control of infection depends on the timely suspicion of its presence and the identification of the potential anatomical source of infection. Furthermore, the collection of adequate fluid samples for cultures before any anti-microbial treatment is introduced is paramount in order to identify responsible microbes correctly and to re-adjust therapy subsequently. It should be stressed that, when empirical anti-microbial therapy is started before micro-organism identification, the initial treatment will be appropriate only in half of the cases. Gram-negative bacteria of the Pseudomonas aeruginosa and Enterobacter cloaca strains remain the leading cause of nosocomial infection in the ICU. Other pathogens which have caused concern in ICU patients over the past decade are Staphylococcus aureus and fungal infection mainly of the Candida spp. This chapter reviews the more common infections encountered in the high-risk surgical patients in the ICU according to the anatomical localization of the infection, i.e. respiratory, abdominal, urinary, wound and bloodstream infections.

Department of Anaesthesiology, Pharmacology and Surgical Intensive Care, University Medical Center, University of Geneva, Switzerland. lucas@cmu.unige.chThe conditions under which tumor necrosis factor-alpha (TNF) induces apoptosis in primary microvascular endothelial cells (MVEC) were investigated. In the absence of sensitizing agents, TNF induced apoptosis after 3 days of incubation in confluent MVEC. In contrast, upon addition of the transcriptional inhibitor actinomycin D (Act. D), confluence was no longer required and apoptosis occurred already after 16 h. To assess the role of either TNF receptor (TNFR) type in apoptosis, MVEC isolated from mice genetically deficient in TNFR1 (Tnfr1o mice) or TNFR2 (Tnfr2o mice) were incubated with TNF in the presence or absence of Act. D. Under sensitized conditions, Tnfr2o MVEC were lysed like controls, whereas Tnfr1o MVEC were completely resistant, indicating an exclusive role for TNFR1. In contrast, in the absence of Act. D, confluent monolayers of wild-type cells were lysed by TNF, but both Tnfr1o and Tnfr2o MVEC were resistant to TNF-mediated toxicity, indicating a requirement for both TNFR types. Overexpression of the anti-apoptotic protein bcl-xL in MVEC led to a protection against the direct, but not the sensitized cytotoxicity of TNF. In conclusion, in pathophysiologically relevant conditions, both TNFR appear to be required for TNF-induced apoptosis in MVEC.

Objectives: To review the problems associated with pulmonary artery catheter use in the intensive care unit; to discuss the need for clinical trials to assess its benefits; and to present original data on the use of the pulmonary artery catheter in European countries. Data Sources: Selected relevant articles from the literature and data from a recent multicenter European study. Data Extraction and Synthesis: It has recently been suggested that pulmonary artery catheter use increases mortality. As a result, some have recommended placing a moratorium on pulmonary catheter use or suggested conducting large multicenter trials to assess the positive and negative effects of pulmonary catheter use. Although there is limited evidence showing an improved outcome with pulmonary artery catheter use, many leaders in intensive care medicine feel that the pulmonary catheter is a useful tool, when used correctly. We believe that misuse of the pulmonary artery catheter is common. The incidence of complications is low and, with improved training of insertion techniques, the frequency of complication would decrease further. The pulmonary artery catheter is a monitoring tool and, as such, is only as good as the interpretation of the data it generates. Clinical trials on such an accepted technique are difficult to conduct and their cost/benefit ratio is debatable. Conclusions: A moratorium on pulmonary artery catheter use is not necessary and clinical trials in heterogeneous ICU populations are not warranted. Improved training in the insertion, interpretation, and implementation of the pulmonary artery catheter and the data it generates is required. As an alternative to expensive clinical trials on the pulmonary artery catheter, we propose that our limited financial resources for clinical investigation be invested in the development of innovative techniques that may reduce the need for pulmonary artery catheter in the future.

Purpose: Intravenous N-acetylcysteine (NAC) has been reported to improve systemic oxygenation and reduce the need for ventilatory support in patients with an acute lung injury. In the more serious form, namely established adult respiratory distress syndrome (ARDS) (Pao2/Fio2 ≤ 200 mm Hg), we tested the hypothesis that treatment with intravenous NAC may be beneficial. Materials and Methods: Respiratory dysfunction was graded daily according to the need for mechanical ventilation and Fio2 and to the evolution of the lung injury score (LIS) and the Pao2/Fi02 ratio in 42 patients with established ARDS receiving either NAC 190 mg/kg/day or placebo as a continuous intravenous infusion over the first 3 days of their clinical course. Results: NAC and placebo groups (22 and 20 patients, respectively) were comparable for demographic characteristics, ARDS categories, severity of illness (simplified acute physiology score [SAPS II]) LIS and Pao2/Fio2 ratio. Mortality rate was 32% for the NAC and 25% for the placebo group (difference not significant). At admission (day 1), 91% of patients in the NAC and 95% in the placebo group required ventilatory support; at days 2, 3, 5, and 7 after admission, the percentage of patients receiving ventilatory support was not significantly reduced for both groups in comparison with day 1. Moreover, there were no differences between the two groups at the same observation days. In both groups, the Fio2 was significantly lower and the Pao2/Fio2 ratio was significantly higher than the initial values during the evolution (Fio2 at day 3, P < .01 for NAC and P < .05 for placebo; Pao2/Fio2 at day 3: P < .01 for NAC and P < .02 for placebo), but this improvement was similar for both groups and, moreover, the between-group comparison was never significantly different at the various collection days. The LIS decreased significantly in NAC group between days 1 and 3 (2.23 ± 0.62 v 1.76 ± 0.17; P < .05), whereas no changes were observed in the placebo group; at day 5, there was a significant difference between the two groups (1.53 ± 0.21 for the NAC v 2.15 ± 0.19 for the placebo group; P < .05). In the prevalent sepsis category (10 patients in the NAC and 9 in the placebo group), the mortality rate, the need of ventilatory support, the intensive care unit stay, and the Pao2/Fio2 evolution did not differ significantly in both subgroups. Conclusions: In this relatively small group of patients presenting with an established ARDS subsequent to a variety of underlying diseases, intravenous NAC treatment during 72 hours neither improved systemic oxygenation nor reduced the need for ventilatory support oxygenation nor reduced the need for ventilatory support.

The microvascular endothelial cell (MVEC) is a major target of inflammatory cytokines overproduced in conditions such as sepsis and infectious diseases. We addressed the direct and indirect effects of tumor necrosis factor (TNF) on endothelial cells that can be relevant for the pathogenesis of septic shock, with particular attention to the acute respiratory distress syndrome (ARDS) and to cerebral malaria (CM). To identify functional and phenotypical changes occurring in MVEC during sepsis, we isolated these cells from the lungs of patients who died of ARDS. The constitutive expression of ICAM-1 and, to a lesser extent, VCAM-1, CD14, and TNFR2 were significantly increased on MVEC isolated from ARDS patients compared with control MVEC, whereas ELAM-1 and TNFR1 were not increased. We found that lung MVEC from ARDS patients present a procoagulant profile and a higher production capacity of interleukin-6 (IL-6) and IL-8 when compared with those from controls. As in pulmonary MVEC derived from ARDS patients, the only TNFR type found upregulated in brain microvessels during CM was TNFR2. This increase in TNFR2 expression only occurred in CM-susceptible mice at the onset of the neurological syndrome. We therefore investigated the role of TNFR2 in the development of this brain pathology by comparing the incidence of CM in wild-type and TNF receptor knock-out mice. Unexpectedly, the genetic deficiency in TNFR2, but not in TNFR1, conferred protection against CM and its associated mortality. No ICAM-1 upregulation was detected in the brain of Tnfr2° mice, indicating a close correlation between protection against CM-associated brain damage, absence of TNFR2, and absence of ICAM-1 upregulation in the brain. Our results in ARDS and CM indicate a specific upregulation of TNFR2, but not of TNFR1, on lung and brain MVEC, respectively. This increased expression leads to a reduced sensitivity toward TNFR1-mediated phenomena, such as the sensitized TNF cytolytic activity on lung MVEC. In contrast, the sensitivity toward TNFR2-mediated effects, such as ICAM-1 induction by membrane-bound TNF, is increased on brain and lung MVEC expressing increased levels of TNFR2. Therefore, the ICAM-1-inducing effect, rather than the direct cytotoxicity of inflammatory cytokines, such as TNF, appears to be crucial in ARDS and CM-induced endothelial damage, and TNFR2 seems to play an important role in this activity in vivo.

To investigate the implication of extracellular matrix proteinases in acute respiratory distress syndrome (ARDS), we determined 92 kD gelatinase (92 G'ase) and its natural antagonist, the tissue inhibitor of metalloproteinases-1 (TIMP) in bronchoalveolar lavage fluid (BALF) and plasma of 33 intensive care unit (ICU) patients presenting with trauma or septic shock. Eleven of these patients developed short-course ARDS, nine developed prolonged ARDS, and 13 did not progress to ARDS. Ten non-ICU patients served as controls. During the early phase of disease, 92 G'ase in BALF of ICU patients was higher than in controls, but plasma levels were not different. TIMP was increased in BALF and plasma in ARDS as compared with those of patients at risk. The 92 G'ase/TIMP ratio in BALF remained elevated in late phases of prolonged ARDS. The high intrapulmonary levels of 92 G'ase in patients at risk and with ARDS may reflect increased turnover of extracellular matrix in acute lung injury. Increased TIMP may interfere with tissue repair and fibrosis by its inhibition of 92 G'ase. Interleukin-6 (IL-6) could be involved in enhanced local synthesis of TIMP. The balance between 92 G'ase and TIMP may play an important role in lung remodeling, which is characteristic of ARDS.

The aims of this study were: a) to evaluate plasma concentrations of cytokines and their soluble receptors, as well as antioxidant substances in patients at high risk of developing multiple organ failure; b) to investigate early change: and c) to examine the possible prognostic value of these elements.Prospective analysis.Surgical intensive care unit (ICU) of a university hospital.sixteen patients at risk for multiple organ failure.Ten patients developed multiple organ failure and five of them died. Whereas tumor necrosis factor-alpha (TNF-alpha) plasma concentrations were only borderline higher in patients developing multiple organ failure, TNF-soluble receptors 55 and 75 were significantly increased during all ICU days compared with patients not going into organ failure. Interleukin-6 plasma concentrations were higher in patients developing multiple organ failure during the first 2 days after ICU admission. The antioxidant vitamin C was significantly decreased in patients going into multiple organ failure during all ICU days. Other biochemical markers of antioxidant activity, such as vitamin E, copper, and zinc plasma concentrations, did not differ between the two groups.Our data suggest that there is a marked increase in anti-TNF activity and a decrease of antioxidant defense in patients at risk of developing multiple organ failure. The predictive value of plasma concentrations of circulating TNF-soluble receptors and vitamin C in this type of patient needs further evaluation.

The prognosis in patients with sepsis depends on severity of acute illness, underlying chronic diseases, and complications associated with infection. Adjusting for these factors is essential for evaluation of new therapies. The purpose of the present study was to determine variables readily identifiable at the bedside that predict mortality in intensive care unit (ICU) patients with sepsis and positive blood cultures. For a 5-yr period, all patients of a surgical ICU presenting with positive blood cultures and sepsis were systematically analyzed for clinical variables and organ dysfunctions at the day of onset of sepsis and bacteremia and during the subsequent clinical course. The prognostic value of these variables was determined using logistic regression procedures. Of the 5,457 admissions to the ICU, 176 patients developed sepsis with positive blood cultures (3.2 per 100 admissions). The fatality rate was 35% at 28 days after the onset of sepsis; in-hospital mortality was 43%. Independent predictors of mortality at onset of sepsis were previous antibiotic therapy (odds ratio [OR], 2.40; 95% confidence interval [CI95], 1.59 to 3.62; p = 0.034), hypothermia (OR, 1.43; CI95, 1.04 to 2.44; p = 0.030), requirement for mechanical ventilation (OR, 2.97; CI95, 1.96 to 4.51; p = 0.009), and onset-of-sepsis APACHE II score (OR, 1.21; CI95, 1.13 to 1.29; p < 0.001). Vital organ dysfunctions developing after the onset of sepsis influenced outcome markedly. The best two independent prognostic factors were the APACHE II score at the onset of sepsis (OR, 1.13 per unit; CI95, 1.08 to 1.17; p = 0.0016) and the number of organ dysfunctions developing thereafter (OR, 2.39; CI95, 2.02 to 2.82; p < 0.001). In ICU patients with sepsis and positive blood cultures, outcome can be predicted by the severity of illness at onset of sepsis and the number of vital organ dysfunctions developing subsequently. These variables are easily assessed at the bedside and should be included in the evaluation of new therapeutic strategies.

Performance of pulmonary scintigraphy (PS) for suspected pulmonary embolism (PE) in ICU patients normally involves the added risk of transporting unstable patients to the nuclear medicine unit (NMU) and poses technical difficulties in ventilating intubated patients. This retrospective study addresses the feasibility of performing PS as the bedside.During a 2-year period, all ICU patients with suspected PE underwent PS at the bedside, performed with a mobile gamma-camera. 99mTc-labelled albumin macroaggregates were used for the perfusion studies. Gasified 99mTc or 81mKr gas was administered by an adapting technique in intubated patients.45 patients were studied, 29 (64%) of whom were intubated and 21 (47%) of whom were in shock. PE was confirmed or excluded by PS in 49% of patients. Angiography was performed in 4 patients (8%). In the rest, a combination of low clinical and low or very low PS probabilities rendered PE highly unlikely. There was no evidence of PE in the subsequent follow-up.In ICU patients with suspected PE, PS can be performed at the bedside with a mobile gamma-camera. The risk of transporting unstable patients can thus be avoided.

The most adequate anticoagulation regimen during extracorporeal renal replacement therapy can be difficult to define. Two hundred fifty-five critically ill patients with a mean age (#x00B1;SD) of 58.2 #x00B1; 16.3 years were treated by continuous venovenous hemofiltration (CVVH) between 1986 and 1992 in our intensive care units. Blood was circulated through hemofilters, either polyacrylonitrile (AN 69; Hospal, Lyon, France) or polyamide (FH 66; Gambro, Lund, Sweden), using a roller pump and an air safety system. The patients were classified into three subgroups according to the amount of heparin needed to achieve an adequate anticoagulation (ie, prevention of extracorporeal circuit clotting without inducing a patient's bleeding tendency): group 1, 37 patients who received no heparin (14.5%); group 2, 189 patients who received 100 to 700 IU/hr of heparin (74.1%); and group 3: 29 patients who received more than 700 IU/hr of heparin (11.4%). We analyzed the filter survival, the routine coagulation parameters, and the evolution of the patients for each group. Median duration of treatment was 144 hours (range, 4 to 1,152 hours). There were no differences in requirement of heparin among the two types of membrane: AN 69 (mean #x00B1; SD), 393 #x00B1; 106 IU/hr v FH 66, 374 #x00B1; 35.3 IU/hr (range, 0 to 2,000 IU/hr). There were no relationships between the amount of heparin the patients received and the mean survival of the filters (group 1, 22.1 #x00B1; 14.8 hr; group 2, 24.7 #x00B1; 13.2 hr; group 3, 23 #x00B1; 9.6 hr). The only routine coagulation parameter that differed significantly between each of the three groups was the initial platelet counts (group 1,42,000/μL; group 2,141,730/μL; group 3, 211,000/μL; ANOVA P = 0.001). The initial prothrombin time was lower in group 1 (45.5%) than in groups 2 (60.6%) and 3 (60.9%). The initial partial thromboplastin time was prolonged in all groups. During CVVH, the platelet count decreased significantly from 141,730/μL to 113,735/μL in group 2 and from 211,000/μL to 122,000/μL in group 3, in contrast to group 1, in which platelet counts remained stable. The highest mortality rate was found in group 1 (73%) compared with groups 2 (51.4%) and 3 (69%). Four deaths were attributed to bleeding in group 1 (14.8%), seven in group 2 (7.2%), and two in group 3 (10%). In conclusion, the majority of patients had an adequate anticoagulation with low-dose heparin, and in the presence of initial low platelet count, CVVH can be conducted without anticoagulation. Furthermore, during CVVH, platelet counts significantly decrease in patients receiving a high or normal dose of heparin, but not in patients who started with low platelet counts and who were not given heparin.

Objective To determine the effects of intravenous N-acetylcysteine (NAC) on the development of severe adult respiratory distress syndrome (ARDS) and mortality rate in patients with mild-to-moderate acute lung injury and to analyze the duration of ventilatory support and FIo 2 required as well as the evolution of the lung injury score. Setting Three university hospital ICUs and one regional ICU in Switzerland. Patients Sixty-one adult patients presenting with mild-to-moderate acute lung injury and various predisposing factors for ARDS received either NAC, 40 mg/kg/d, or placebo intravenously for 3 days. Measurements Respiratory dysfunction was assessed daily according to the need for mechanical ventilation and FIO 2 , the evolution of the lung injury score, and the PaO 2 /FIo 2 ratio. The cardiovascular state, liver function, and kidney function were also monitored. Data were collected at admission (day 0), during the first 3 days, and on the day of discharge from the ICU. Results The NAC and placebo groups (32 and 29 patients, respectively) were comparable at ICU admission for severity of illness assessed by the simplified acute physiology score (SAPS) (10.8 ± 4.6 vs 10.9 ± 4.8) and lung injury score (LIS) (1.39 ± 0.95 vs 1.11 ± 1.08) (mean ± SD). Three patients in each group developed ARDS. The 1-month mortality rate was 22 percent for the NAC group and 35 percent for the placebo group (difference not statistically significant). At admission, 22 of 32 patients (69 percent) in the NAC group were mechanically ventilated compared with 22 of 29 (76 percent) in the placebo group. At the end of the treatment period (day 3), 5 of 29 (17 percent) in the NAC group and 12 of 25 (48 percent) in the placebo group were still receiving ventilatory support (p = 0.01), The FIo 2 was 0.37 less than admission value (day 0) in the NAC group, and 0.20 less in the placebo group (p 2 /FIo 2 ) improved significantly (p Conclusions Intravenous NAC treatment during 72 h improved systemic oxygenation and reduced the need for ventilatory support in patients presenting with mild-to-moderate acute lung injury subsequent to a variety of underlying diseases. Development of ARDS and mortality were not reduced significantly by this therapy.

OBJECTIVE: To determine admission characteristics associated with the outcome of septicemia in critically ill patients and more specifically assess the prognostic value of pre-existing co-morbidities. DESIGN: 5 year-retrospective cohort study. SETTING: Surgical Intensive Care Unit (ICU-20 beds) in a 1600 bed-tertiary care center. PATIENTS: Among 5457 patients admitted to the ICU between 1984 and 1988, 176 (3.2%) met prospectively-defined criteria for blood culture-proven septicemia (8.77 per 1000 patient-days). Overall septicemic patients had a 5-fold increased risk of death compared to non-septicemic patients (relative risk 5.03, 95% confidence intervals 4.17-6.07, p < 0.0001), and this estimate persisted after stratification according to age, sex, primary diagnosis and conditions of admission to the ICU (emergency/elective). RESULTS: Prognostic factors recorded on admission to ICU that were associated with mortality from septicemia among 173 patients were older age, higher admission Apache II score, gastrointestinal surgery, ultimately and rapidly fatal diseases and the number of co-morbidities in addition to the principal diagnosis (active smoking, alcohol abuse, non-cured malignancy, diabetes mellitus, splenectomy, recent antibiotic therapy, major surgery, or major cardiac event). In the multivariate analysis with logistic regression procedures, Apache II and co-morbidities were identified as the two independent predictors of mortality. CONCLUSIONS: Pre-existing co-morbidities assessed at the admission to the ICU significantly improved the prediction of mortality from septicemia compared to Apache II score alone.

During the last two decades, severe group A beta-haemolytic streptococcal infections have been defined as the "toxic strep syndrome", and have been reported not only in immunocompromised or elderly people, but also occasionally in previously healthy patients. We describe 4 patients presenting with the toxic strep syndrome, requiring surgery and intensive care, and briefly review the related literature. Fatigue, localized pain and other nonspecific symptoms were associated with the onset of the disease, followed by septic shock with multiple organ failure. Early diagnosis and surgical intervention, if necessary, are mandatory. Subsequently, appropriate supportive treatment of vital organ dysfunction and penicillin as the antibiotic of choice represent the cornerstones of the management of this syndrome.

Objective To determine the pharmacokinetics of continuously infused midazolam in patients during intensive care. Design Descriptive trial. Setting General ICU in a Swiss hospital. Subjects Eight critically ill patients requiring mechanical ventilation. Interventions To achieve an appropriate level of long-term sedation, the rate of iv infusion of midazolam in ICU patients was adjusted individually to between 6 and 15 mg/hr. Blood samples were taken during and after the continuous infusion of midazolam. Measurements Measurements included plasma concentration time profiles of midazolam and pharmacokinetic parameters, such as elimination half-life, clearance, and volume of distribution. Results The elimination half-life was prolonged (mean 5.4 vs. 2.3 hrs) and the volume of distribution was larger (3.1 vs. 0.9 L/kg) in patients vs. healthy volunteers. The clearance did not differ between groups (6.3 vs. 4.9 mL/min/kg in patients vs. volunteers, respectively). Conclusions The increased volume of distribution in our critically ill patients is the major determinant for the observed slower elimination of midazolam. It is unlikely that the hepatic metabolism of midazolam was impaired in these patients. (Crit Care Med 1992; 20:1123–1126)

OBJECTIVES To analyze the impact of the position of the thoracic external electrodes on the values of cardiac output measured by electrical bioimpedance and to compare the results obtained by bioimpedance with those values determined by thermodilution in critically ill patients. DESIGN Open, prospective, comparative trial. SETTING ICU of a teaching hospital. PATIENTS Twenty healthy volunteers and ten critically ill patients. INTERVENTIONS Measurements of cardiac output by bioimpedance at rest and after physical activity in normal volunteers and after changing the neck or xiphoid electrodes. Comparisons of cardiac output obtained by thermodilution and bioimpedance with internal and external electrodes in patients. MEASUREMENTS AND MAIN RESULTS Mean +/- SD values are presented. Cardiac output values at rest and after exercise were 6.7 +/- 1.3 and 10.8 +/- 2.6 L/min at rest and after exercise, respectively (p less than .001). Displacement of the xiphoid electrodes 3 cm in the caudal direction was accompanied by a decrease of the mean cardiac output from 7.1 +/- 1.2 to 5.8 +/- 1.3 L/min (p less than .001) and displacement 3 and 6 cm cranially was accompanied by increases in cardiac output from 7.1 +/- 1.2 to 8.1 +/- 1.4 L/min (p less than .001) and 8.6 +/- 1.5 L/min (p less than .001), respectively. In the ten patients, cardiac output measurements were virtually identical when results obtained by thermodilution (6.7 +/- 3.1 L/min) were compared with those results obtained by bioimpedance using internal esophageal (6.6 +/- 3.1 L/min), but not external (4.7 +/- 1.6 L/min) electrodes. CONCLUSIONS a) The values of cardiac output derived from measurements obtained by bioimpedance using internal electrodes were comparable with those values derived from thermodilution. b) Values of cardiac output from bioimpedance studies with external electrodes were dependent on the position of the xiphoid electrodes.

Substantial efforts have been devoted to improving the means for early and accurate diagnosis of ventilator-associated (VA) pneumonia in intensive care unit (ICU) patients because of its high incidence and mortality. A good diagnostic yield has been reported from quantitative cultures of bronchoalveolar lavage (BAL) fluid or a protected specimen brush, both obtained by fiberoptic bronchoscopy. As bronchoscopy requires specific skills and is costly, we evaluated a simpler method to obtain BAL fluid, that is, by a catheter introduced blindly into the bronchial tree. Quantitative cultures from bronchoscopically sampled BAL (B-BAL) and blindly nonbronchoscopically collected BAL (NB-BAL) were assessed for sensitivity, specificity, and predictive value for the diagnosis of VA pneumonia. A total of 40 pairs of samples were examined in 28 patients requiring prolonged mechanical ventilation and presenting a high risk of developing pneumonia. For comparison with bacteriologic data we defined a clinical score for pneumonia ranging from zero to 12 using the following variables: body temperature, leukocyte count, volume and character of tracheal secretions, arterial oxygenation, chest X-ray, Gram stain, and culture of tracheal aspirate. To quantify the bacteria in BAL the bacterial index (BI) was used, defined as the sum of the logarithm of the number of bacteria cultured per milliliter of BAL fluid. A good correlation between clinical score and quantitative bacteriology was observed (r = 0.84 for B-BAL and 0.76 for NB-BAL; p less than 0.0001). Similar to studies in baboons, patients with pulmonary infection could be distinguished by a BI greater than or equal to 5 with a sensitivity of 93% and a specificity of 100% (B-BAL).(ABSTRACT TRUNCATED AT 250 WORDS)

Purpose The response to inhaled nitric oxide (iNO) is inconsistent in patients with acute respiratory distress syndrome (ARDS). We sought to determine whether the response to iNO, defined as 20% Pa o 2/F io 2 increase from baseline, depends on the level of cardiac natriuretic peptides. Materials and methods This is a prospective cohort study including 11 consecutive patients with ARDS who were eligible to receive iNO. Measurements of plasma concentrations of atrial natriuretic peptide (ANP), N-Terminal-Pro-B-Type Natriuretic Peptide (NT-pro-BNP) and 3′,5′-cyclic guanosine monophosphate were obtained before initiating iNO and 30 minutes later during iNO. Baseline cardiac peptides, oxygenation, and hemodynamic variables and their change during iNO were compared among responders and nonreponders to iNO. Results Baseline ANP and NT-pro-BNP concentrations were higher in patients that responded to iNO and tended to decrease during iNO in responders only. 3′,5′-Cyclic guanosine monophosphate concentrations were not different among responders and nonresponders and were unchanged during iNO. Baseline ANP was strongly correlated with change in intrapulmonary shunt, and baseline NT-pro-BNP and its change were correlated with the change in cardiac output. Conclusions High ANP and NT-pro-BNP concentrations are associated with the response to iNO. These data suggest that cardiac peptides have the potential to identify a subgroup of patients with ARDS who might derive clinical benefit from iNO.

Attenuation of ventilator-synchronous pressure fluctuations of intracranial pressure has been demonstrated during high frequency ventilation in animal and human studies, but the consequences of this effect on cerebral blood flow have not been investigated in man. We compared the effects of high frequency jet ventilation and intermittent positive pressure ventilation on CBF in 24 patients investigated three hours after completion of open-heart surgery. The patients were investigated during three consecutive periods with standard sedation (morphine, pancuronium): a. IPPV; b. HFJV; c. IPPV. Partial pressure of arterial CO, (PaCO 2 :4.5–5.5 kPa) and rectal temperature (35.5 to 37.5°C) were maintained constant during the study. The CBF was measured by intravenous 133 Xe washout technique. The following variables were derived from the cerebral clearance of 133 Xe: the rapid compartment flow, the initial slope index, ie , a combination of the rapid and the slow compartment flows, and the ratio of fast compartment flow over total CBF (FF). Compared to IPPV, HFJV applied to result in the same mean airway pressure did not produce any change in pulmonary gas exchange, mean systemic arterial pressure, and cardiac index. Similarly, CBF was not significantly altered by HFJV. However, important variations of CBF values were observed in three patients, although the classic main determinants of CBF (PaCO 2 , cerebral perfusion pressure, Paw, temperature) remained unchanged. Our results suggest that in patients with normal systemic hemodynamics, the effects of HFJV and BPPV on CBF are comparable at identical levels of mean airway pressure. (Chest 1990; 97:420–24)

Over the last quarter of a century, intensive care medicine has developed into an established hospital specialty with its own unique identity and characteristics. Significant advances have occurred, mostly in a succession of small steps rather than any dramatic leap, with many being linked to advances in health care across other disciplines. In addition, many changes have resulted from the scientific identification of the detrimental effects of certain traditional practices once thought to be therapeutic. Here, in an attempt to learn from the past and offer guidance for future progress, we detail some of the key changes in various aspects of intensive care medicine including respiratory, cardiovascular, metabolic, and nutritional care, as well as sepsis, polytrauma, organization, and management.

Setting the Stage Setting the Scene (J.L. Vincent).- Managing and Leading in Critical Care (W.J. Sibbald).- Critical Care from 50,000 Feet (D.C. Angus).- Expectations around Intensive Care - 10 Years on (K. Hillman).- The Safety and Quality Agenda in Critical Care Medicine (T. Dorman).- The Challenge of Emerging Infections and Progressive Antibiotic Resistance (S.M. Opal).- Health Technology Assessment (J. Bakker and P. Verboom).- Trends in Pediatric and Neonatal Critical Care in the next 10 Years (R.C. Tasker).- Diagnostic, Therapeutic and Information Technologies Ten Years from Now The Patient Process as the Basis for the Design of an ICU (B. Regli and J. Takala).- Information Technology (G.D. Martich, D. Van Pelt and D. Lovasik).- Diagnostic Technologies to Assess Tissue Perfusion and Cardiorespiratory Performance (M.R. Pinsky).- Microcirculatory Distress in Critically Ill Patients: Meaning and Future (C. Ince).- Managing Infection: From Agar Plate to Genome Scan (J. Cohen).- Immunological Monitoring, Functional Genomics and Proteomics (E. Abraham).- Improving Organ Function (M. Singer).- The Profile and Management of Acute Respiratory Distress Syndrome (L. Gattinoni, P. Caironi and E. Carlesso).- The Ventilator of Tomorrow (L. Brochard, M. Dojat and F. Lellouche).- My NeuroICU 10 Years from Now (D.K. Menon).- Disaster Medicine (P.E. Pepe, K.J. Rinnert and J.G. Wigginton).- How Might Critical Care Medicine be Organized and Regulated? Hospital and Medical School Organization of Critical Care Services (P. Fink).- Physician Staffing in the ICU 10 Years from Now (J.A. Russell and A. Sutherland).- ICU Research - One Decade from Now (J.J. Marini and D.J. Dries).- Organizing Clinical Critical Care Research and Implementing the Results(D. Cook and S. Finfer).- Funding Models and Accountability Relationships (P.M. Suter).- Measuring Performance (G.D. Rubenfeld).- Ethics and End-of-Life Care (J.R. Curtis).- Rationing in the ICU: Fear, Fiction and Fact (M.M. Levy) Training Training Pathways - Physician and Non-Physician (J. Bion, H. Barrett, and T. Clutton-Brock).- Simulation Training in Critical Care Medicine (P.B. Angood).- The Critical Care 'Agenda' The Agenda for the Intensivist (V.M. Ranieri and G.L. Rosboch).- Transforming Adult Critical Care Service Delivery in Ontario (H. MacLeod).- Index