Low-dose fondaparinux in suspected heparin-induced thrombocytopenia in the critically ill.

BACKGROUND: In critically ill patients, heparin-induced thrombocytopenia (HIT) is estimated to account for approximately 1 to 10% of all causes of thrombocytopenia. HIT exerts a strong procoagulant state. In case of suspected HIT, it is an important clinical decision to stop heparin and start treatment with alternative nonheparin anticoagulation, awaiting the results of laboratory testing for the final diagnosis of HIT (bridging therapy). Fondaparinux acts by factor Xa inhibition and expresses no cross-reactivity with HIT antibodies. Excretion of fondaparinux is mainly renal. We describe our early experience with fixed low-dose fondaparinux bridging therapy and monitoring of anticoagulant activity for safety reasons. METHODS: This retrospective cohort study was conducted in a closed format general intensive care unit in a teaching hospital. Consecutive critically ill patients suspected of HIT were treated with fondaparinux after discontinuation of unfractionated heparin or nadroparin. Anti-Xa levels were determined afterwards. RESULTS: Seven patients were treated with fondaparinux 2.5 mg/day for 1.8 to 6.5 days. Anti-Xa levels varied from 0.1 to 0.6 U/ml. A negative correlation was found between creatinine clearance and mean and maximum anti-Xa levels. No thromboembolic complications occurred. Bleeding complications were only minor during fondaparinux treatment. Transfusion requirements did not differ significantly between treatment episodes with fondaparinux or with heparin anticoagulants. CONCLUSION: In this small sample of critically ill patients suspected of HIT, bridging therapy with fixed low-dose fondaparinux resulted in prophylactic and therapeutic anti-Xa levels. Monitoring of anticoagulant activity is advised in patients with renal insufficiency.

Afferent specific role of NMDA receptors for the circuit integration of hippocampal neurogliaform cells.

Appropriate integration of GABAergic interneurons into nascent cortical circuits is critical for ensuring normal information processing within the brain. Network and cognitive deficits associated with neurological disorders, such as schizophrenia, that result from NMDA receptor-hypofunction have been mainly attributed to dysfunction of parvalbumin-expressing interneurons that paradoxically express low levels of synaptic NMDA receptors. Here, we reveal that throughout postnatal development, thalamic, and entorhinal cortical inputs onto hippocampal neurogliaform cells are characterized by a large NMDA receptor-mediated component. This NMDA receptor-signaling is prerequisite for developmental programs ultimately responsible for the appropriate long-range AMPAR-mediated recruitment of neurogliaform cells. In contrast, AMPAR-mediated input at local Schaffer-collateral synapses on neurogliaform cells remains normal following NMDA receptor-ablation. These afferent specific deficits potentially impact neurogliaform cell mediated inhibition within the hippocampus and our findings reveal circuit loci implicating this relatively understudied interneuron subtype in the etiology of neurodevelopmental disorders characterized by NMDA receptor-hypofunction.Proper brain function depends on the correct assembly of excitatory and inhibitory neurons into neural circuits. Here the authors show that during early postnatal development in mice, NMDAR signaling via activity of long-range synaptic inputs onto neurogliaform cells is required for their appropriate integration into the hippocampal circuitry.

Anticoagulation strategies in continuous renal replacement therapy: can the choice be evidence based?

OBJECTIVES: Critical illness increases the tendency to both coagulation and bleeding, complicating anticoagulation for continuous renal replacement therapy (CRRT). We analyzed strategies for anticoagulation in CRRT concerning implementation, efficacy and safety to provide evidence-based recommendations for clinical practice. METHODS: We carried out a systematic review of the literature published before June 2005. Studies were rated at five levels to create recommendation grades from A to E, A being the highest. Grades are labeled with minus if the study design was limited by size or comparability of groups. Data extracted were those on implementation, efficacy (circuit survival), safety (bleeding) and monitoring of anticoagulation. RESULTS: Due to the quality of the studies recommendation grades are low. If bleeding risk is not increased, unfractionated heparin (activated partial thromboplastin time, APTT, 1-1.4 times normal) or low molecular weight heparin (anti-Xa 0.25-0.35 IU/l) are recommended (grade E). If facilities are adequate, regional anticoagulation with citrate may be preferred (grade C). If bleeding risk is increased, anticoagulation with citrate is recommended (grade D(-)). CRRT without anticoagulation can be considered when coagulopathy is present (grade D(-)). If clotting tendency is increased predilution or the addition of prostaglandins to heparin may be helpful (grade C(-)). CONCLUSION: Anticoagulation for CRRT must be tailored to patient characteristics and local facilities. The implementation of regional anticoagulation with citrate is worthwhile to reduce bleeding risk. Future trials should be randomized and should have sufficient power and well defined endpoints to compensate for the complexity of critical illness-related pro- and anticoagulant forces. An international consensus to define clinical endpoints is advocated.

Risk factors for bleeding during treatment of acute venous thromboembolism.

OBJECTIVE: Identification of risk factors for bleeding and prospective evaluation of two bleeding risk scores in the treatment of acute venous thromboembolism. DESIGN: Secondary analysis of a prospective, randomized, assessorblind, multicenter clinical trial. SETTING: One university and 2 regional teaching hospitals. PATIENTS: 188 patients treated with heparin or danaparoid for acute venous thromboembolism. MEASUREMENTS: The presenting clinical features, the doses of the drugs, and the anticoagulant responses were analyzed using univariate and multivariate logistic regression analysis in order to evaluate prognostic factors for bleeding. In addition, the recently developed Utrecht bleeding risk score and Landefeld bleeding risk index were evaluated prospectively. RESULTS: Major bleeding occurred in 4 patients (2.1%) and minor bleeding in 101 patients (53.7%). For all (major and minor combined) bleeding, body surface area < or = 2 m2 (odds ratio 2.3, 95% CI 1.2-4.4; p = 0.01), and malignancy (odds ratio 2.4, 95% CI 1.1-4.9; p = 0.02) were confirmed to be independent risk factors. An increased treatment-related risk of bleeding was observed in patients treated with high doses of heparin, independent of the concomitant activated partial thromboplastin time ratios. Both bleeding risk scores had low diagnostic value for bleeding in this sample of mainly minor bleeders. CONCLUSIONS: A small body surface area and malignancy were associated with a higher frequency of bleeding. The bleeding risk scores merely offer the clinician a general estimation of the risk of bleeding. In patients with a small body surface area or in patients with malignancy, it may be of interest to study whether limited dose reduction of the anticoagulant drug may cause less bleeding without affecting efficacy.

Evaluation of platelet tests for measurement of cell integrity.

Various tests were evaluated for their capacity to differentiate between platelet suspensions with different degrees of cell damage. Those suspensions were prepared by simultaneous isolation of platelets from the same platelet-rich plasma (PRP) using the following procedures: 1. centrifugation at 4 degrees C with EDTA 2. gel filtration in Tangen's buffer 3. gel filtration in Ca2+-free Tyrode's soltuion 4. gel filtration in Ca2+-free Tyrode followed by dehydration against polyethylene glycol 20,000 and 5. albumin density gradient centrifugation. In these suspensions and in the original PRP the following parameters were studied: 1. morphology; 2. aggregability upon ADP addition; 3. platelet factor 3 availability; 4. uptake of 14C-serotonin and 3H-adenine; 5. metabolism of 3H-adenine and adenylate energy charge; 6. endogenous total ATP, ADP and serotonin and 7. lactate dehydrogenase (LDH) activity. Quantitation of pseudopod formation in the light or electron microscope and log dose response studies for ADP-induced aggregation proved to be the most sensitive and reproducible of the tests studied. Additional information could be obtained from measurement of the 3H-label in the ATP and hypoxanthine-inosine fractions and calculation of the adenylate energy charge. Determination of platelet factor 3 availability or uptake studies of 14C-serotonin and 3H-adenine were less suitable for discriminating between cell suspensions. Data for total ATP and serotonin concentrations and LDH activity differed between the cell suspensions but instead of detecting various degrees of cell damage they reflected alterations in platelet population caused by the isolation procedures.

Cholinergic innervation and topographical organization of muscarinic binding sites in rat brain: a comparative autoradiographic study.

Employing [3H]hemicholinium-3 ([3H]HC), [3H]pirenzepine([3H]PZ) and [3H]quinuclidinyl benzilate ([3H]QNB), autoradiographic binding studies were performed to identify and quantitate the localization of high-affinity choline carriers, M1-subtype of muscarinic binding sites and a mixed population of M1- and M2-subtypes of muscarinic binding sites, respectively, in 38 anatomically defined areas of rat brain. Labelling of adjacent brain sections with [3H]HC, [3H]PZ and [3H]QNB revealed different topographical binding patterns. [3H]HC binding, which is supposed to reflect cholinergic innervation, was dense in the nucleus accumbens, olfactory tubercle, caudate putamen, basolateral amygdaloid nucleus and the interpeduncular nucleus. Moderate but heterogeneous binding was found in thalamic, hypothalamic, hippocampal and cortical areas. Maximal [3H]PZ binding was observed in the nucleus accumbens, olfactory tubercle and in discrete substructures of the hippocampus, e.g. CA1 and dentate gyrus. Binding to other hippocampal and cortical areas was intermediate, whilst minor binding was found in thalamic, hypothalamic and brain stem areas. The binding of [3H]QNB was more evenly distributed over the brain as compared to that of [3H]PZ. [3H]QNB clearly exceeded the binding of [3H]PZ in the thalamus, hypothalamus and brain stem. A relationship was found between the topography patterns of the [3H]PZ and [3H]QNB binding sites. However, some brain areas showed preference for one of the two ligands, pointing to a distinct localization of M1- and M2-subtypes of muscarinic binding sites. Although M1 sites appeared to predominate in the basal ganglia, hippocampus and cortex, some heterogeneity was observed indicative of the minor occurrence of M2 sites within these structures. There was no relationship between the density of the presumed cholinergic innervation and the binding capacity of either of the muscarinic sites in the various brain areas. However, a relationship was found between M2-selectivity and [3H]HC binding, pointing to a possible presynaptic localization of the M2-sites. In addition, it is suggested that distinct cholinergic cell groups might project their fibres to brain areas containing particular subsets of postsynaptic muscarinic binding sites.

Critical illness onychomadesis.

OBJECTIVE: To present our observation of the development of a rare nail deformity in the prolonged course of disease of a critically ill patient with a pulmonary abscess. DESIGN: Case report. SETTING: Tertiary referral, 16-bed, level I surgical ICU in an academic hospital. PATIENT: A 48-year-old Caucasian male was treated with penicillin for a pneumococcal meningitis and pneumonia. He developed a large pulmonary abscess of the right upper lobe and needed prolonged mechanical ventilation. Extensive surgical treatment was successful eventually. A remarkable feature concerned the occurrence of onycholysis of all finger nails and toe nails resulting in complete shedding of the nails (onychomadesis). This phenomenon can be regarded as an extreme manifestation of Beau's lines precipitated by a severe systemic insult. CONCLUSION: We observed the development of onychomadesis in a critically ill patient with a large pulmonary abscess. This association has not been described before.

Intra-observer variability in APACHE II scoring.

Although the APACHE II score is the most widely used scoring system in intensive care units worldwide, its reliability and variability have not been extensively studied. Differences in case-mix may complicate comparison and interpretation of results. We hypothesised that a degree of variability might be inherent to use of the APACHE II scoring system, and decided to assess intra-observer variability in APACHE II scoring as a potential indicator of inherent score variability. APACHE II scores were assessed twice from the charts of 11 patients by 14 physicians, with a time interval of 4 (range 3.5-4.5) months between the two assessments. Intra-observer was found to be approximately 15%. These findings are in agreement with previous observations regarding inter-observer variability in APACHE II scoring, and strongly suggest that there is an inherent score variability of about 15%.

Disseminated tuberculosis, pulmonary aspergillosis and cutaneous herpes simplex infection in a patient with infliximab and methotrexate.

CASE PRESENTATION: Despite chemoprophylaxis with isoniazid a 58-year-old Creole patient with mild rheumatoid arthritis developed disseminated tuberculosis, pulmonary aspergillosis and cutaneous herpes simplex infection during treatment with infliximab and methotrexate. TREATMENT: The patient received antituberculous drugs (ethambutol, isoniazid, pyrazinamide, rifampicin), amphotericin B, flucytosine, and valaciclovir, along with prolonged intensive care treatment and mechanical ventilation. CONCLUSIONS: The present case confirms that isoniazid prophylaxis (300 mg once daily, during 6 months) does not protect against the reactivation and dissemination of latent tuberculosis. It also shows that combined treatment with infliximab and methotrexate may induce severe immunosuppression with prolonged leukocytopenia and depressed cellular immunity, leading to multiple opportunistic infections. Extensive diagnostic testing, early start of antimicrobial therapy and enteral immunonutrition, and further infection prevention with selective decontamination of the digestive tract may have been the key to a good clinical outcome.

Multiple organ dysfunction syndrome induced by whole-body hyperthermia and polychemotherapy in a patient with disseminated leiomyosarcoma of the uterus.

OBJECTIVE: Whole-body hyperthermia (WBH) in combination with chemotherapy is a relatively new promising treatment modality for patients with cancer. The objective of this report is to present the development of an acute systemic inflammatory response syndrome (SIRS) with multiple organ dysfunction syndrome (MODS) following WBH in combination with chemotherapy. Although WBH can also induce cytokine production, MODS has not been described before in association with WBH. DESIGN: Case report. The patient was treated with WBH (core temperature 41.8 degrees C using a radiant heat device (Aquatherm) ) in combination with polychemotherapy (ifosfamide, carboplatin and etoposide (ICE) ) in the context of a clinical trial for metastatic sarcomas. SETTING: Department of medical oncology and intensive care unit of a university hospital. PATIENT: A 58-year-old Caucasian woman treated for disseminated leiomyosarcoma of the uterus, who developed SIRS with brain dysfunction, hypotension, respiratory failure and renal dysfunction following WBH/ICE. INTERVENTIONS: She was successfully treated in the intensive care unit by mechanical ventilation, inotropics and antibiotics. MEASUREMENTS AND RESULTS: There was a remarkable recovery within 2 days: she regained full conciousness, could be extubated, inotropic support was stopped and creatinine levels returned to pre-treatment levels. All cultures remained sterile. After almost complete recovery, 5 days later a second episode of fever during neutropenia occurred and, despite antibiotic treatment, she died of Bacteroides distasonis sepsis. CONCLUSION: WBH should be added as a new cause to the already known list of physical-chemical insults which can result in MODS.

Local cerebral glucose uptake in anatomically defined structures of freely moving rats.

Two limitations of the classical [14C]2-deoxyglucose (DG) method are the severe stress to which the restrained animals are exposed, and the difficulties with the anatomical analysis of the autoradiograms. The present study describes modifications which circumvent these limitations. Firstly, rats are provided with two chronic indwelling cannulas to allow blood sampling under unrestrained conditions. Absence of stress is demonstrated by low plasma corticosterone levels in the cannulated rats at the start of the experiment. The second modification concerns the image analysis system. The image of the autoradiogram is superimposed on the image of the identical histologically stained section in order to improve the accuracy of the structure identification. This approach enables the operator to delineate the anatomical brain structure in the histologically stained section and quantify the glucose uptake in the autoradiogram generated from this section. The reproducibility of the present quantitative measuring system is illustrated by glucose uptake measurements in different laminar zones of the various fields in the dorsal hippocampal formation. It is concluded that the present technical improvements of the classically applied [14C]2-deoxyglucose technique provide favourable conditions for the quantitative study on cerebral glucose uptake in normally behaving animals.

Clinical toxicity of reserpine in hospitalized patients: a report from the Boston Collaborative Drug Surveillance Program.

Adverse reactions to reserpine were studied in 231 hospitalized medical patients who received the drug. Reserpine was administered specifically for hypertension in 91.3 percent of patients; 35.5 per cent of patients received the drug by intramuscular (IM) injection. The IM route of administration was associated with higher mean daily doses (1.28 +/- 0.14 mg/day) than was oral administration (0.37 +/- 0.02 mg/day). Adverse reactions to reserpine were reported in 26 patients (11.3 per cent), but only three of these reactions were considered life-threatening and no deaths were attributed to the drug. Central nervous system (CNS) disturbances, reported in 12 patients, were the most common unwanted effects. Gastrointestinal disturbances were reported in six patients, and hypotension in six. Toxicity occurred more frequently in those who received IM, and therefore high-dose, reserpine. Adverse reactions also were more common in patients who had not received rauwolfia derivatives prior to admission; however, this group of patients also received IM reserpine more frequently. Finally, reserpine toxicity, in particular central nervous system (CNS) disturbances, was reported more frequently in patients also receiving barbiturates, suggesting additive CNS effects.

Mondor's disease as first thrombotic event in hereditary protein C deficiency and anticardiolipin antibodies.

A 45-year-old Caucasian woman presented with superficial thrombophlebitis of the right arm and right anterior thoracic wall after bilateral breast surgery followed by spontaneous left anterior thoracic vein thrombophlebitis 3 months later. Besides breast surgery and use of oral contraceptives, hereditary protein C deficiency and anticardiolipin antibodies were found as causes for this bilateral Mondor's disease.

Severe maternal respiratory distress due to the amniotic fluid embolism syndrome in a twin pregnancy.

A 28-year-old female with a twin pregnancy at 29 6/7 weeks who was having premature uterine contractions developed acute respiratory failure due to sudden pulmonary oedema requiring mechanical ventilation. No evidence for venous thromboembolism, pulmonary infection or myocardial infarction was found. Subsequently a mild coagulopathy and foetal distress developed. Ultrasonography revealed oligohydramnios of one of the foetuses. A Caesarean section was performed and postoperatively mother and babies had an uneventful clinical course. By exclusion of other causes, we diagnosed severe maternal acute respiratory distress due to the amniotic fluid embolism syndrome in a twin pregnancy.

Wobble board training after partial sprains of the lateral ligaments of the ankle: a prospective randomized study.

Ankle sprains are often complicated by functional instability and repeated sprains. Rehabilitation with wobble boards in patients with functional instability has been tested, and significant improvement has been found compared to no training. The aim of this study was to investigate whether the number of patients with residual symptoms following ankle sprains could be reduced by training on a wobble board during 12-week recovery period. In addition, the influence of training in the time course reduction of edema was investigated. We performed a prospective study including 61 patients, all active in sports for more than 2 hours a week with primary ankle sprains. The effect of a 12-week training program with wobble board was compared with no training. Forty-eight patients completed the study. In the follow-up period (mean X = 230 days), we found significantly fewer recurrent sprains, and significantly fewer patients in the training group had functional instability of the ankle compared with the no training group. There were no differences in the two groups in the time which elapsed before patients were painless at walking, during running, or at sports. Volumetric measurements revealed no difference in the speed of reduction of hematoma and edema of the ankle and foot between the two groups. We conclude that training on a wobble board early after primary stage 2 ankle sprains is effective in reducing residual symptoms following this lesion and that training does not seem to affect the time course reduction in edema.

Recognizing and treating the patient with somatic manifestations of depression.

Depressed patients often present to their family physicians with physical complaints that mimic other medical diseases rather than the classic symptoms of sadness, hopelessness, or loss of pleasure in usual activities. These somatic presentations of depression can include gastrointestinal disturbances, complaints of chronic pain, fatigue, and/or an extensive history of unexplained medical illness. Depression and other psychiatric disorders occurring in the somatic patient can often be identified through the use of a routine and noninvasive questionnaire administered at the initial physician encounter. Regardless of its presentation, however, major depression should be treated vigorously, with full therapeutic doses of antidepressants administered for at least 6 weeks to determine response, and followed by at least 6 months to ensure full remission utilizing antidepressants whose side-effect profile may help ameliorate the patient's somatic complaints while avoiding those that might exacerbate them. Effectively diagnosing and treating the somatic patient's depression will improve his or her quality of life and may reduce their current excessive use of healthcare resources.

[Acute tumor lysis syndrome due to mono-therapy with a corticosteroid in a patient with non-Hodgkin lymphoma]. / Acuut tumorlysissyndroom door monotherapie met een corticosteroïd bij een patiënt met non-Hodgkin-lymfoom.

A 20-year-old man was hospitalised because he nearly suffocated when lying on his back. After bronchoscopy which revealed severe external compression of the airways, suddenly respiratory insufficiency developed. Because a malignant lymphoma was suspected chemotherapy was started, using monotherapy with prednisolone as the risk of acute tumour lysis syndrome (ATLS) is high with polychemotherapy of bulky tumours. Nevertheless ATLS developed, for which haemodialysis had to be applied. The tumour, a T-cell lymphoblastic non-Hodgkin lymphoma with high grade malignancy, was treated successfully with cyclophosphamide, doxorubicin, vincristine en prednisone. ATLS is characterized by hyperkalaemia, hyperuricaemia, hyperphosphataemia, hypocalcaemia, lactate acidosis and acute renal failure. It can occur in the course of aggressive cytoreductive therapy in rapidly growing lymphoproliferative malignancies with large tumour size, due to massive tumour cel lysis. Corticosteroid monotherapy is a very rare cause of ATLS.

[Recombinant factor VIIa (eptacog alfa): a new therapeutic option for patients with severe bleeding disorder due to inhibitory antibodies against a coagulation factor]. / Recombinantfactor VIIa (eptacog alfa): nieuwe therapeutische optie bij patiënten met een ernstige bloeding door antistoffen tegen een stollingsfactor.

In 2 patients with severe haemorrhage (a 63-year-old man with haemophilia A (the factor VIII level was 29%) and a 44-year-old woman), of an inhibitory antibody against factor VIII was diagnosed. The development of recombinant factor VIIa (eptacog alpha) has made available a new therapeutic option for patients with an inhibitory antibody against a coagulation factor. Both patients were treated successfully with the new factor after other forms of treatment had failed. The new concept of the coagulation cascade on which the treatment with eptacog alpha is based assumes that the lack of an amplifying loop in the coagulation which takes place via factor IX (in combination with factor VIII) can be compensated by extra stimulation of the principal route (tissue factor-factor VIIa --> factor X) by pharmacological amounts of factor VIIa.

Rethinking inpatient treatment of borderline clients.

A number of clinical and financial advantages exist when clients diagnosed with borderline personality disorder are placed in an unlocked milieu-oriented treatment unit during hospitalization. The author describes the transition from a locked inpatient unit to an unlocked unit, the effects of this change on staff and clients' attitudes toward treatment, and the impact of this transition on client functioning.

[Bilateral rupture of the quadriceps tendon in a healthy individual]. / Bilateral quadricepsseneruptur hos et rask individ.

A case of bilateral rupture of the quadriceps tendons in a 59 year-old man without any known systemic disease is presented. The ruptures occurred while he was descending a staircase, after which he fell. Repetitive microtrauma was suspected as the etiological reason for rupture.