Alexander D. Cornet

The role of heparin and allied compounds in the treatment of sepsis

The crosstalk between coagulation and inflammation and the propensity for microthromboembolic disease during sepsis calls for anticoagulant measures to prevent tissue hypoxygenation and to attenuate organ damage and dysfunction. Only one anticoagulant, recombinant human activated protein C (aPC, drotrecogin-alpha) has a proven survival benefit when used as an adjunctive therapy for human sepsis, partly because of its anti-inflammatory effect. However, heparin (-like compounds) may exert similar beneficial anti-inflammatory actions as aPC, in spite of the relatively narrow therapeutic window for anticoagulation. This narrative review is based on a Medline search of relevant basic and clinical studies published in English and discusses the potential role of heparin in modulating inflammatory responses in the treatment of animal models and human sepsis and its harmful sequelae. In any case, the results of a meta-analysis based on animal data suggest a potentially life-saving effect of heparin (-like compounds) in the treatment of sepsis. Therefore, a prospective randomized clinical trial is called upon to study effects in human sepsis.

The potential harm of oxygen therapy in medical emergencies

In medical emergencies, supplemental oxygen is often administrated routinely. Most paramedics and physicians believe that high concentrations of oxygen are life-saving [1]. Over the last century, however, a plethora of studies point to possible detrimental effects of hyperoxia induced by supplemental oxygen in a variety of medical emergencies. This viewpoint provides a historical overview and questions the safety of routine high-dose oxygen administration and is based on pathophysiology and (pre)clinical findings in various medical emergencies.

Blood transfusion during cardiac surgery is associated with inflammation and coagulation in the lung: a case control study

IntroductionBlood transfusion is associated with increased morbidity and mortality in cardiac surgery patients, but cause-and-effect relations remain unknown. We hypothesized that blood transfusion is associated with changes in pulmonary and systemic inflammation and coagulation occurring in patients who do not meet the clinical diagnosis of transfusion-related acute lung injury (TRALI).MethodsWe performed a case control study in a mixed medical-surgical intensive care unit of a university hospital in the Netherlands. Cardiac surgery patients (n = 45) were grouped as follows: those who received no transfusion, those who received a restrictive transfusion (one two units of blood) or those who received multiple transfusions (at least five units of blood). Nondirected bronchoalveolar lavage fluid (BALF) and blood were obtained within 3 hours postoperatively. Normal distributed data were analyzed using analysis of variance and Dunnetts post hoc test. Nonparametric data were analyzed using the Kruskal-Wallis and Mann-Whitney U tests.ResultsRestrictive transfusion increased BALF levels of interleukin (IL)-1β and D-dimer compared to nontransfused controls (P < 0.05 for all), and IL-1β levels were further enhanced by multiple transfusions (P < 0.01). BALF levels of IL-8, tumor necrosis factor α (TNFα) and thrombin-antithrombin complex (TATc) were increased after multiple transfusions (P < 0.01, P < 0.001 and P < 0.01, respectively) compared to nontransfused controls, but not after restrictive transfusions. Restrictive transfusions were associated with increased pulmonary levels of plasminogen activator inhibitor 1 compared to nontransfused controls with a further increase after multiple transfusions (P < 0.001). Concomitantly, levels of plasminogen activator activity (PAA%) were lower (P < 0.001), indicating impaired fibrinolysis. In the systemic compartment, transfusion was associated with a significant increase in levels of TNFα, TATc and PAA% (P < 0.05).ConclusionsTransfusion during cardiac surgery is associated with activation of inflammation and coagulation in the pulmonary compartment of patients who do not meet TRALI criteria, an effect that was partly dose-dependent, suggesting transfusion as a mediator of acute lung injury. These pulmonary changes were accompanied by systemic derangement of coagulation.

Supplemental Oxygen Therapy in Medical Emergencies: More Harm Than Benefit?

mendation and rationale. Ann Intern Med. 2002;137(2):129-131. 6. O’Connell JB, Maggard MA, Liu JH, Etzioni DA, Livingston EH, Ko CY. Rates of colon and rectal cancers are increasing in young adults. Am Surg. 2003; 69(10):866-872. 7. Bleyer A. CAUTION! Consider cancer: common symptoms and signs for early detection of cancer in young adults. Semin Oncol. 2009;36(3):207-212. 8. US Census Bureau. Income, Poverty, and Health Insurance Coverage in the United States. 2006. http://www.census.gov/hhes/www/income/income.html. Accessed April 31, 2011.

Recombinant human activated protein C in the treatment of acute respiratory distress syndrome : A randomized clinical trial

Rationale Pulmonary coagulopathy may play a pathogenetic role in acute respiratory distress syndrome (ARDS), by contributing to alveolocapillary inflammation and increased permeability. Recombinant human activated protein C (rh-APC) may inhibit this process and thereby improve patient outcome. Methods A prospective randomized, saline-controlled, single-blinded clinical trial was performed in the intensive care units of two university hospitals, and patients with ARDS were included within 24 h after meeting inclusion criteria. Intervention A 4-day course of intravenous rh-APC (24 mcg/kg/h) (n = 33) versus saline (n = 38). Outcomes The primary outcome parameter was the pulmonary leak index (PLI) of 67Gallium-transferrin as a measure of alveolocapillary permeability and secondary outcomes were disease severity scores and ventilator-free days, among others. Results Baseline characteristics were similar; in 87% of patients the PLI was above normal and in 90% mechanical or non-invasive ventilation was instituted at a median lung injury score of 2.5. There was no evidence that Rh-APC treatment affected the PLI or attenuated lung injury and sequential organ failure assessment scores. Mean ventilator-free days amounted to 14 (rh-APC) and 12 days (saline, P = 0.35). 28-day mortality was 6% in rh-APC- and 18% in saline-treated patients (P = 0.12). There was no difference in bleeding events. The study was prematurely discontinued because rh-APC was withdrawn from the market. Conclusion There is no evidence that treatment with intravenous rh-APC during 4 days for infectious or inflammatory ARDS ameliorates increased alveolocapillary permeability or the clinical course of ARDS patients. We cannot exclude underpowering. Trial Registration Nederlands Trial Register ISRCTN 52566874

Activated protein C attenuates pulmonary coagulopathy in patients with acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) frequently complicates critical illness. We hypothesized that an infusion of recombinant human activated protein C (rh‐APC), a natural anticoagulant, would attenuate pulmonary coagulopathy and injury.

Activated protein C in the treatment of acute lung injury and acute respiratory distress syndrome

Background: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) frequently necessitate mechanical ventilation in the intensive care unit. The syndromes have a high mortality rate and there is at present no treatment specifically directed at the underlying pathogenesis. Central in the pathophysiology of ALI/ARDS is alveolocapillary inflammation leading to permeability edema. As a result of the crosstalk between inflammation and coagulation, activation of proinflammatory and procoagulant/antifibrinolytic pathways contributes to disruption of the endothelial barrier. Protein C (PC) plays a central role in maintaining the equilibrium between coagulation and inflammation. Additionally, natural anticoagulants, such as PC, are depleted, both in blood as well as in the lung. Therefore, the PC system is of interest as a therapeutic target in patients with ALI/ARDS. Method: This review is based on a Medline search of relevant basic and clinical studies. Objective: It discusses the potential role of activated PC in modulating the proinflammatory/procoagulant state for enhancing endothelial barrier function in animal models and human ALI/ARDS.

Letter by Cornet et al Regarding Article, “Relationship Between Supranormal Oxygen Tension and Outcome After Resuscitation From Cardiac Arrest”

To the Editor: We read with great interest the article by Kilgannon and coworkers1 demonstrating a dose-dependent linear relationship between supranormal oxygen tension after resuscitation from cardiac arrest and in-hospital death. This observation is important and merits further …

Cervical lump? The clue is in the hotspot.

Presenting symptoms include cervical masses (76%), nasal dysfunction (73%), tinnitus and deafness (62%), headache (35%), and weight loss (7%). 4 On physical examination, cervical masses (75%) and cerebral nerve palsy (20%) are often found. 4