William Sibbald

Hemoglobin solutions—not just red blood cell substitutes

ObjectiveTo review current knowledge about cell-free hemoglobin solutions. Data SourcesAll studies involving cell-free hemoglobin were retrieved from a computerized MEDLINE search from 1980 to 1998. We also reviewed the reference lists of all available review articles and primary studies to identify references not found in the computerized search. Study SelectionClinical and experimental studies in which cell-free hemoglobin solutions were studied. Data ExtractionFrom the selected studies, information was obtained regarding the experimental model or the study population in which cell-free hemoglobin solutions were investigated, the type of cell-free hemoglobin solution, their deleterious or beneficial effects, and their possible indications. Data SynthesisIn many studies, hemoglobin solutions were considered as efficient resuscitative agents and good alternatives to red blood cell transfusion, because of their marked vasopressor effect coupled with their capacity to improve the microcirculation and quickly restore metabolic parameters. Nevertheless, potential problems include an increased susceptibility to infection, immunosuppression, oxidative damage, excessive pulmonary and systemic vasoconstriction, and platelet activation. ConclusionsHemoglobin solutions are more than mere blood substitutes. Promising effects on oxygen transport and the microcirculation need to be confirmed, and the results of continuing research are eagerly awaited.

Real-time automated paging and decision support for critical laboratory abnormalities

Background For patients with critical laboratory abnormalities, timely clinical alerts with decision support could improve management and reduce adverse events. Methods The authors developed a real-time clinical alerting system for critical laboratory abnormalities. The system sent alerts to physicians as text messages to a smartphone or alphanumeric pager. Decision support was available via smartphone or hospital intranet. The authors evaluated the system in a prospective controlled stepped-wedge study with blinded outcome assessment in general internal medicine units at two academic hospitals. The outcomes were the proportion of potential clinical actions that were actually completed in response to the alert, and adverse events (worsening of condition or complications related to treatment of the condition). Results The authors evaluated 498 laboratory conditions on 271 patients. Overall, only 50% of potential clinical actions were carried out, and there were adverse clinical events within 48 h for 36% of the laboratory conditions. The median (IQR) proportion of potential clinical actions that were actually completed was 50% (33–75%) with alerting system on and 50% (33–100%) with alerting system off (p=0.94, Wilcoxon rank sum test). When the alerting system was on (n=164 alerts) there were 67 adverse events within 48 h of the alerts (42%). When the alerting system was off (n=334 alerts), there were 112 adverse events within 48 h (33%; difference: 9% higher with alerting system on, p=0.06). Conclusions The provision of real-time clinical alerts and decision support for critical laboratory abnormalities did not improve clinical management or decrease adverse events.

Doctors' perceptions of the effects of interventions tested in prospective, randomised, controlled, clinical trials: results of a survey of ICU physicians

Abstract.Objectives: To establish a list of therapeutic interventions considered by intensive care unit (ICU) physicians to have been tested by prospective, randomised, controlled clinical trials (RCTs) in critically ill patients, and to survey the perceptions of the same physicians on the therapeutic effect of these interventions as evaluated by RCT. Designandsetting: Self- applied questionnaire in an International Symposium of Intensive Care and Emergency Medicine, Brussels, Belgium. Participants: All 3250 registrants at the symposium. Measurementsandresults: There were 527 questionnaires completed, and 446 were suitable for analysis. Respondents were asked to list the therapeutic interventions used in intensive care medicine which they believed have been shown by RCTs to improve survival. Using a 5-point Likert scale, respondents were then asked to rate their assessment of the effectiveness of each intervention they listed and, using a 3-point scale, to select their level of confidence in those assessments. A total of 512 interventions were identified by the respondents as having been tested by RCT. Analysing the 42 interventions quoted more than 12 times, 31 were believed by the respondents to have been shown to have a beneficial effect, and 11 to have a harmful effect. Many of the interventions noted have not in fact been subjected to RCT. Conclusions: Many interventions that have not been tested by RCT were believed to have been tested; conversely, some interventions actually tested by RCT were not mentioned. Few interventions used in the ICU have actually been shown by RCT to have a positive effect on outcome.

Endotoxin induces a dose-dependent myocardial cross-tolerance to ischemia-reperfusion injury.

Objective: To test whether or not endotoxin induces a dose‐dependent reduction of myocardial contractile dysfunction after a standardized period of myocardial ischemia and reperfusion and whether nitric oxide is involved in this form of myocardial protection. Design: Prospective, randomized, controlled animal study. Setting: University research laboratory. Subjects: Twenty‐five male Sprague‐Dawley rats. Interventions: After anesthesia, the left carotid artery was cannulated under sterile conditions and animals were allowed to recover from surgery for 12 hrs. Sterile saline or increasing doses (2.5, 5, or 10 mg/kg body weight) of endotoxin (Escherichia coli 026:B6; Sigma, Mississauga, Ontario, Canada) were given intravenously (1 mL over 5 mins). In some rats, diaspirin‐crosslinked hemoglobin (200 mg/kg) was infused 6 hrs and 60 min before endotoxin infusion (10 mg/kg). Hearts were rapidly excised for retrograde perfusion through the ascending aorta (Langendorff apparatus) 6 hrs later. After baseline data collection, hearts were subjected to global ischemia (30 mins, 37°C [98.6°F]), followed by 30 mins of reperfusion. Measurements and Main Results: Physiologic variables were recorded 6 hrs after saline and endotoxin infusion. Baseline myocardial systolic contractility and diastolic compliance were assessed, respectively, by left ventricular developed pressure (LVDP) and left ventricular (LV) volume‐preload relationships. After 30 min of reperfusion, LVDP recovery and left ventricular end‐diastolic pressure were measured. Endotoxin induced LV systolic contractile depression, irrespective of the dose of endotoxin administered. LV diastolic dysfunction varied between different doses of endotoxin administered. On reperfusion, endotoxin produced a dose‐dependent improvement of postischemic LVDP recovery: 30 ± 6% in sham, 78 ± 9% in 2.5 mg/kg, 93 ± 8% in 5 mg/kg, and 107 ± 10% in 10 mg/kg endotoxin heart. In rats treated with 10 mg/kg endotoxin, diaspirin‐crosslinked hemoglobin pretreatment abrogated endotoxin‐induced postischemic LVDP recovery improvement (105 ± 10% vs. 43 ± 7%, p = .01). Conclusion: Sublethal doses of endotoxin induce in a dose‐dependent manner a delayed form of myocardial protection against ischemia. Although free‐cell hemoglobin solution abrogates this endotoxin‐induced cross‐tolerance, we propose that possible mechanisms involved in this form of myocardial protection include nitric oxide pathway activation.