Topical application of recombinant activated factor VII during cesarean delivery for placenta previa.

BACKGROUND: During cesarean delivery in patients with placenta previa, hemorrhaging after removal of the placenta is often challenging. In this condition, the extraordinarily high concentration of tissue factor at the placenta site may constitute a principle of treatment as it activates coagulation very effectively. The presumption, however, is that tissue factor is bound to activated factor VII. OBJECTIVE: We hypothesized that topical application of recombinant activated factor VII at the placenta site reduces bleeding without affecting intravascular coagulation. STUDY DESIGN: We included 5 cases with planned cesarean delivery for placenta previa. After removal of the placenta, the surgeon applied a swab soaked in recombinant activated factor VII containing saline (1 mg in 246 mL) to the placenta site for 2 minutes; this treatment was repeated once if the bleeding did not decrease sufficiently. We documented the treatment on video recordings and measured blood loss. Furthermore, we determined hemoglobin concentration, platelet count, international normalized ratio, activated partial thrombin time, fibrinogen (functional), factor VII:clot, and thrombin generation in peripheral blood prior to and 15 minutes after removal of the placenta. We also tested these blood coagulation variables in 5 women with cesarean delivery planned for other reasons. Mann-Whitney test was used for unpaired data. RESULTS: In all 5 cases, the uterotomy was closed under practically dry conditions and the median blood loss was 490 (range 300-800) mL. There were no adverse effects of recombinant activated factor VII and we did not measure factor VII to enter the circulation. Neither did we observe changes in thrombin generation, fibrinogen, activated partial thrombin time, international normalized ratio, and platelet count in the peripheral circulation (all P values >.20). CONCLUSION: This study indicates that in patients with placenta previa, topical recombinant activated factor VII may diminish bleeding from the placenta site without initiation of systemic coagulation.

Local pulmonary administration of factor VIIa (rFVIIa) in diffuse alveolar hemorrhage (DAH) - a review of a new treatment paradigm.

BACKGROUND: Diffuse alveolar hemorrhage (DAH) is a clinical syndrome with typical symptoms dyspnea and hemoptysis. DAH is a complication of specific diseases, in some cases with acute catastrophic hemoptysis, while other patients present low grade alveolar bleeding with a need of chronic transfusion as in pulmonary hemosiderosis. METHODS: Current literature in the PubMed database and other sources was reviewed in order to evaluate the current treatment recommendations, efficacy of this treatment, and finally the risk of complications after off-label use of rFVIIa in respect to DAH. OBJECTIVES: (i) To elucidate the clinical aspects of alveolar hemorrhage, (ii) to develop a simple diagnostic algorithm in order to separate DAH from other important pulmonary diseases with similar clinical picture and comparably high mortality. Such an algorithm has important therapeutic consequences because these diseases: acute lung injury (ALI), acute respiratory distress syndrome (ARDS) and bronchiolitis obliterans organizing pneumonia (BOOP) have different therapies, (iii) to evaluate and discuss whether local pulmonary administration may improve outcome and reduce mortality in DAH, and (iv) to suggest a treatment schedule. RESULTS: Hitherto the diagnosis and treatment of DAH has been based on anecdotal reports. The treatment has relied on different unspecific treatment modalities based on a mixture of treatment of the underlying disease and treatment without evidence targeted to stop the alveolar bleeding. However, recently a number of publications have advocated the use of intrapulmonary rFVIIa. Even in severe bleeding DAH has been shown to respond promptly without thromboembolic complication when FVIIa was administered locally via the air side, because the FVIIa does not penetrate the alveolo-capillary membrane to the blood-side. The incidence of DAH (in the US and Europe is 100,000-150,000, and 50,000 patients annually are at risk of developing DAH following hematopoietic stem cell transplant (HSCT) and autoimmune diseases. Finally 50,000-100,000 patients may be falsely categorized as having acute respiratory distress syndrome/acute lung injury (ARDS/ALI) because DAH and ARDS cannot be separated clinically. A new treatment paradigm of DAH is proposed as no other intervention has been able to ensure pulmonary hemostasis in DAH. The diagnosis of DAH is simple, a series of broncho-alveolar washes which become increasingly bloody. This test should be performed in all patients with pulmonary opacities in order to separate ARDS/ALI from DAH. FVIIa administrated via pulmonary route is "drug of choice", because it stops bleeding in the life-threatening syndrome DAH. Hemostasis is obtained after only one to two small doses of FVIIa (50 µg/kg body weight per dose) and after hemostasis the oxygen transport quickly improves. CONCLUSION: Intrapulmonary administration of rFVIIa is recommended as the treatment of choice for DAH and blast lung injury (BLI) because the treatment has been shown to be successful and uncomplicated in spite of the fact that only a small series of DAH has been documented.

The immunomodulatory effect of inhaled granulocyte-macrophage colony-stimulating factor in cystic fibrosis. A new treatment paradigm.

BACKGROUND: Patients with cystic fibrosis (CF) experience recurrent infections and develop chronically infected lungs, which initiates an altered immunological alveolar environment. End-stage pulmonary dysfunction is a result of a long sequence of complex events in CF, progressing to alveolar macrophage dysfunction via a T-helper 2 (T(H)2) dominated alveolar inflammation with CD20 T-cell activation, induced by the chronic infection and showing a poor prognosis. There is great potential for treatment in transforming the T(H)2 into the more favorable T-helper 1 (T(H)1) response. METHODS: Current literature in the PubMed database and other sources was reviewed in order to evaluate aspects of the innate alveolar host defense mechanisms and the potential impact on the immunoinflammatory response of inhalation of granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with CF. RESULTS: It seems that the cellular host defense, (ie, the alveolar macrophage and neutrocyte function) and the inhaled GM-CSF interact in such a way that the so-called tolerant alveolar environment dominated by the T(H)2 response may be transformed into an active T(H)1 state with a normal pulmonary host defense. The shift of the T(H)2 to the T(H)1 subset dominated by specific and unspecific antibodies may be achieved after the inhalation of GM-CSF. A clinical report has shown promising results with inhalation of GM-CSF in a chronically-infected CF patient treated with several antibacterial and antifungal agents. Inhaled GM-CSF transformed the tolerance toward the Gram-negative infection reflected by the so-called T(H)2 subset into the more acute T(H)1 response characterized by recruitment of the T-cells CD8 and CD16, a condition related to better-preserved lung function. This indicated a transformation from a state of passive bacterial tolerance toward the Gram-negative infecting and colonizing bacteria. This GM-CSF effect cannot be achieved by administering the drug via the IV route because the drug is water-soluble and too large to penetrate the alveolocapillary membrane. CONCLUSIONS: Inhalation of GM-CSF seems to be a novel way to positively modulate the alveolar environment toward an altered immunological state, reflected by a positive change in the pattern of surrogate markers, related to better preservation of pulmonary function and thus improved outcomes in CF patients. It is suggested that future studies examining standard endpoint variables such as number of infections and amount of antibiotics used should be supplemented by surrogate markers, to reveal any positive cellular and cytokine responses reflecting changes in the alveolar compartment after GM-CSF inhalation. The immunological alveolar environment should be monitored by a specific pattern of surrogate markers. Continued research is clearly indicated and the role of inhaled GM-CSF in modulating pulmonary host defense in CF patients should be investigated in a large study.

Acute radiation syndrome (ARS) - treatment of the reduced host defense.

BACKGROUND: The current radiation threat from the Fukushima power plant accident has prompted rethinking of the contingency plan for prophylaxis and treatment of the acute radiation syndrome (ARS). The well-documented effect of the growth factors (granulocyte colony-stimulating factor [G-CSF] and granulocyte-macrophage colony-stimulating factor [GM-CSF]) in acute radiation injury has become standard treatment for ARS in the United States, based on the fact that growth factors increase number and functions of both macrophages and granulocytes. METHODS: Review of the current literature. RESULTS: The lungs have their own host defense system, based on alveolar macrophages. After radiation exposure to the lungs, resting macrophages can no longer be transformed, not even during systemic administration of growth factors because G-CSF/GM-CSF does not penetrate the alveoli. Under normal circumstances, locally-produced GM-CSF receptors transform resting macrophages into fully immunocompetent dendritic cells in the sealed-off pulmonary compartment. However, GM-CSF is not expressed in radiation injured tissue due to defervescence of the macrophages. In order to maintain the macrophage's important role in host defense after radiation exposure, it is hypothesized that it is necessary to administer the drug exogenously in order to uphold the barrier against exogenous and endogenous infections and possibly prevent the potentially lethal systemic infection, which is the main cause of death in ARS. RECOMMENDATION: Preemptive treatment should be initiated after suspected exposure of a radiation dose of at least <2 Gy by prompt dosing of 250-400 µg GM-CSF/m(2) or 5 µg/kg G-CSF administered systemically and concomitant inhalation of GM-CSF < 300 mcg per day for at least 14-21 days. CONCLUSION: The present United States standard for prevention and treatment of ARS standard intervention should consequently be modified into the combined systemic administration of growth factors and inhaled GM-CSF to ensure the sustained systemic and pulmonary host defense and thus prevent pulmonary dysfunction.

[Argatroban treatment of heparin-induced immune-mediated thrombocytopenia]. / Behandling af heparininduceret immunbetinget trombocytopeni med argatroban.

Heparin-induced immune-mediated thrombocytopenia (HIT) is a life-threatening complication of heparin treatment. When HIT is clinically suspected, heparin treatment should immediately be replaced with an alternative, fast-acting, anticoagulant agent, and blood tests should be carried out to verify or to exclude the diagnosis. Argatroban has recently been approved for HIT treatment in Denmark. Recommendations for dosing of argatroban in HIT patients with and without comorbities are presented.

[Mortality and morbidity in surgery for abdominal aortic aneurysm]. / Mortalitet og morbiditet ved operation for rumperet abdominalt aortaaneurisme.

INTRODUCTION: Patients undergoing surgery for ruptured abdominal aortic aneurysm (rAAA) have a mortality of 40-50%. The purpose of the present investigation is to document the mortality and morbidity of such patients at Rigshospitalet (RH) in 2005. The results are compared with the best results published internationally (benchmark) and with predicted mortality. Factors in postoperative intensive therapy that can improve morbidity and mortality are identified. MATERIAL AND METHODS: This is a retrospective calculation and analysis of mortality and morbidity. Data were collected from an Intensive Care Unit's (ICU) Critical Information System, a blood bank and the database of a vascular surgery unit. RESULTS: The perioperative mortality was 8%, ICU mortality 22%, postoperative mortality 33% and 30-day mortality 39%. The ICU mortality for patients with renal failure and septic shock was significantly higher than the overall ICU mortality. The ICU mortality and morbidity increased with the amount of postoperative blood loss. Patients with an initial serum creatinine concentration of <0.100 mmol/l had a 30-day mortality that was lower than that of patients with a higher initial serum creatinine concentration. CONCLUSION: The treatment of patients with rAAA at RH is comparable to leading clinical practice results. Postoperative bleeding, septic shock and renal failure are identified as predictive factors for increased ICU mortality and morbidity, for which reason future monitoring and postoperative rAAA therapy should include improved monitoring and intervention against postoperative bleeding and early identification of signs of sepsis and renal dysfunction.

[Critical care research]. / Forskning i kritisk sygdom.

Critical care research has facilitated the development of clinical guidelines to improve the outcome of critically-ill patients. The high mortality needs to be reduced further, by means of increased research to the benefit of patients, relatives and society. Clinicians, researchers, public officials and politicians at all levels must work together towards this aim.

[Methods for cost-effectiveness evaluation of intensive care]. / Metoder til sundhedsøkonomisk evaluering af intensiv terapi.

Intensive care costs are a challenge to the health care system. Because of a political strategy aiming at competition as well as the documentation of treatment quality, cost-effectiveness evaluations are important in order to clarify the association between quality and the costs of treating critically-ill patients. The context of cost-effect analyses is important. Most studies apply the hospital's perspective based on surrogate markers such as organ failure and length of stay as a replacement for health status evaluation in the context of society. The treatment of critically-ill patients aims at improved health. Cost-effectiveness analyses should therefore include quality variables in that the healthcare system is an integral and inseparable part of society.

Inhalation of activated protein C: A possible new adjunctive intervention in acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is a potential lethal disease. At present time no evidence based intervention reduces mortality. The pathophysiology of ARDS include intraalveolar fibrin deposition, hyperinflammation and reduced cellular host defense in the airspace. The normal lung activates protein C (PC) to activated protein C (APC), in contrast to the ARDS lung where the PC-APC axis is disrupted. The lungs have targets for inhaled APC as illustrated by a patient case with ARDS, unresponsive to conventional therapy. After inhalation of 190 mug/kg of APC (Drotrecogin alpha activated) three times a day for seven days, a clear reduction in infiltrates on chest X-ray and a 138% increase in oxygenation capacity as reflected by the PaO(2)/FiO(2) ratio was brought about. The patient, however, died later after cardiac arrest after suspected recurrence of the T-cell lymphoma. No local or systemic adverse effects was found related to the iAPC, during, after or at the time of death. It is suggested based on existing studies and the presented case that inhaled APC is a new treatment option in patients with ARDS - a hypothesis which should be substantiated in a larger series of ARDS patients.

Successful pulmonary administration of activated recombinant factor VII in diffuse alveolar hemorrhage.

INTRODUCTION: Diffuse alveolar hemorrhage (DAH) is a serious pulmonary complication seen in patients with autoimmune disorders and patients treated with chemotherapy or after hematopoietic stem cell transplantation. The clinical management of DAH is complex and the condition has a high mortality rate. Tissue factor is expressed in the lung alveoli during inflammation and therefore pulmonary administration of human recombinant activated factor VIIa (rFVIIa) could be a rational treatment option. METHODS: Six patients with acute, bronchoscopically confirmed DAH from a single intensive care unit university hospital center were included in the study of acute DAH in critically ill patients. The patients were treated with intrapulmonary administration of 50 microg/kg rFVIIa in 50 ml of sodium chloride by bronchoalveolar lavage (BAL) with 25 ml in each of the main bronchi, which was repeated after 24 hours in case of treatment failure. RESULTS: An excellent response, defined as complete and sustained hemostasis after a single dose of rFVIIa, was seen in three patients. A good response, meaning that sustained hemostasis was achieved by a repeated rFVIIa administration, was seen in the remaining three patients. In one of these patients, the BAL treatment was repeated twice; in another patient, the second dose of rFVIIa was administered by nebulizer after extubation after the initial BAL. The hemostatic effect was statistically significant (p = 0.031). The oxygenation capacity, as reflected by the PaO2/FiO2 (arterial oxygen pressure/inspiratory fractional oxygen content) ratio, increased significantly (p = 0.024) in all six patients following the local rFVIIa therapy. CONCLUSION: Symptomatic therapy of DAH after intrapulmonary administration of one or more doses of rFVIIa was found to have a good to excellent hemostatic effect in six consecutive patients with DAH. The intrapulmonary administration of rFVIIa seemed to have a high benefit-to-risk ratio. Larger series should confirm the safety of this approach.

Procalcitonin increase in early identification of critically ill patients at high risk of mortality.

OBJECTIVE: To investigate day-by-day changes in procalcitonin and maximum obtained levels as predictors of mortality in critically ill patients. DESIGN: Prospective observational cohort study. SETTING: : Multidisciplinary intensive care unit at Rigshospitalet, Copenhagen University Hospital, a tertiary reference hospital in Denmark. PATIENTS: Four hundred seventy-two patients with diverse comorbidity and age admitted to this intensive care unit. INTERVENTIONS: Equal in all patient groups: antimicrobial treatment adjusted according to the procalcitonin level. MEASUREMENTS AND MAIN RESULTS: Daily procalcitonin measurements were carried out during the study period as well as measurements of white blood cell count and C-reactive protein and registration of comorbidity. The primary end point was all-cause mortality in a 90-day follow-up period. Secondary end points were mortality during the stay in the intensive care unit and in a 30-day follow-up period. A total of 3,642 procalcitonin measurements were evaluated in 472 critically ill patients. We found that a high maximum procalcitonin level and a procalcitonin increase for 1 day were independent predictors of 90-day all-cause mortality in the multivariate Cox regression analysis model. C-reactive protein and leukocyte increases did not show these qualities. The adjusted hazard ratio for procalcitonin increase for 1 day was 1.8 (95% confidence interval 1.3-2.7). The relative risk for mortality in the intensive care unit for patients with an increasing procalcitonin was as follows: after 1 day increase, 1.8 (95% confidence interval 1.4-2.4); after 2 days increase, 2.2 (95% confidence interval 1.6-3.0); and after 3 days increase: 2.8 (95% confidence interval 2.0-3.8). CONCLUSIONS: A high maximum procalcitonin level and a procalcitonin increase for 1 day are early independent predictors of all-cause mortality in a 90-day follow-up period after intensive care unit admission. Mortality risk increases for every day that procalcitonin increases. Levels or increases of C-reactive protein and white blood cell count do not seem to predict mortality.

Factors influencing the in vitro deposition of tobramycin aerosol: a comparison of an ultrasonic nebulizer and a high-frequency vibrating mesh nebulizer.

The aim of the study was to elaborate recommendations for inhalation during mechanical ventilation that could optimize delivery. Delivery of aerosols in vitro from nebulizers during mechanical ventilation is dependent on the dimensions of the ventilator circuit, the nebulizer type, and the ventilator settings. A review of the literature shows that some ventilator settings have a larger influence on the amount of aerosol delivered than others. It has been shown in an in vitro model that the factors influencing delivered aerosol are the ventilator flow rate, the diameter of the endotracheal tube, and the time spent in inspiration (all p < 0.05). Two different nebulizer types were used in the study: an ultrasonic nebulizer (SUN 345) and a high-frequency vibrating mesh nebulizer (Aeroneb Pro). No difference in the amount delivered was seen with different nebulizer types (p = 0.215). For optimizing the amount delivered, the largest possible flow, endotracheal tube, and time spent in inspiration should be used.

Amphotericin B and caspofungin resistance in Candida glabrata isolates recovered from a critically ill patient.

BACKGROUND: Consecutive Candida glabrata isolates recovered from a patient in an intensive care unit were resistant to amphotericin B (minimum inhibitory concentration, up to 32 mu g/mL; determined by Etest [AB Biodisk]). Analyses at the national reference laboratory showed that some isolates were also resistant to azoles and caspofungin. In this study, 4 isolates were studied thoroughly using susceptibility assays and a mouse model and to determine clonality. METHODS: Different broth microdilution tests, Etests, and time-kill studies for antifungals were performed in different media. Three of the 4 isolates were examined in an in vivo experiment, in which mice were challenged intravenously with 1 of 3 isolates and treated daily with amphotericin B, caspofungin, or saline. For the clonality studies, arbitrarily primed polymerase chain reaction (PCR) was performed with the 4 isolates, 8 isolates obtained from nonrelated patients, and a reference strain. RESULTS: The murine model indicated that 1 isolate was resistant to amphotericin B, 1 had intermediate susceptibility, and 1 was fully susceptible. Two of the 3 isolates were resistant to caspofungin. Microdilution methods did not reliably differentiate between amphotericin B-susceptible and -resistant isolates. All assays identified caspofungin-susceptible and -resistant isolates. Arbitrarily primed PCR showed that the 4 isolates probably were of clonal origin. CONCLUSIONS: We have documented the emergence of amphotericin B-resistant and caspofungin-resistant C. glabrata isolates during treatment of a critically ill liver transplant recipient. Only the Etest predicted amphotericin B resistance in the isolates. We recommend that important fungal strains recovered from patients who are receiving antifungal therapy should be tested for susceptibility to the antifungal drug used, because resistance can be present initially or may occur during treatment.