Evaluation of modified non-overt DIC criteria on the prediction of poor outcome in patients with sepsis

Background

The diagnostic performance of modified criteria for non-overt disseminated intravascular coagulation (DIC) with the addition of antithrombin (AT) levels, protein C (PC) levels, and organ system failure scoring (OSF) to the International Society on Thrombosis and Hemostasis (ISTH) criteria for non-overt DIC was studied to determine the effect on predicting poor outcome in patients with sepsis.

Methods

In total, 135 consecutive patients were studied. Hemostatic markers (platelet count, prothrombin time, D-dimer, AT, PC) were examined on days 0, 1, 2, 3, 4, and 7. ISTH overt and non-overt DIC scoring, OSF, and 28-day mortality were analyzed.

Results

The numbers of patients with overt DIC, non-overt DIC and non-DIC were 42, 17 and 76 respectively. The 28-day mortality rates for ISTH overt DIC, ISTH non-overt DIC, and non-DIC were 47.6, 47.1, and 9.2%, respectively. By adding AT and PC to the ISTH non-overt DIC criteria, the 28-day mortality rate of overt DIC, non-overt DIC, and non-DIC changed to 47.6, 25.0, and 6.7%, respectively. By adding OSF to the ISTH non-overt DIC criteria to predict 28-day mortality in septic patients, receiver operating characteristic (ROC) curve analysis demonstrated that the area under the curve (AUC) of ISTH non-overt DIC (0.777) was significantly increased to 0.878 (P = 0.018). However, neither AT nor PC increased the AUC.

Conclusions

Addition of OSF to the ISTH criteria for non-overt DIC gives a better prediction of poor outcome in patients with sepsis.     

Implementation of the ISTH classification of non-overt DIC in a thromboplastin induced rabbit model

Validation of animal models of disseminated intravascular coagulation (DIC) to human DIC is crucial in order to translate findings in research models to treatment modalities for DIC in humans. ISTH classifications of overt and non-overt human DIC have proven to have a high diagnostic accuracy, but the scoring systems have rarely been applied to animal models of DIC. In this study, we use rabbit brain thromboplastin (thromboplastin) to induce DIC in a rabbit model and test the applicability of the ISTH criteria for standardized diagnosis of DIC.Cardiovascular and haematological parameters from rabbits, either saline-injected or administered 0.625, 1.25, 2.5 or 5 mg thromboplastin/kg as a single bolus, were collected at four timepoints over a 90 minute period. All groups of rabbits were scored at each time point according to the ISTH diagnostic criteria for non-overt DIC.Injection of 5 mg thromboplastin/kg was lethal. For the remaining groups, a dose dependent decrease in blood pressure, platelet count and fibrinogen level together with a dose dependent increase in prothrombin time, activated partial thromboplastin time, level of thrombin-antithrombin complexes, fibrin degradation products and number of thrombi in lung vasculature was seen.The administration of a bolus of 1.25 - 2.5 mg thromboplastin/kg to rabbits induced a reproducible dose dependent model of non-overt DIC according to the ISTH diagnostic criteria. We conclude that the non-overt ISTH score can be applied to evaluate severity and progression of DIC in a standardized manner in this thromboplastin induced rabbit model.     

Prospective comparison of new Japanese Association for Acute Medicine (JAAM) DIC and International Society of Thrombosis and Hemostasis (ISTH) DIC score in critically ill septic patients

Introduction

We prospectively compared the new Japanese Association for Acute Medicine (JAAM) score with the International Society of Thrombosis and Hemostasis (ISTH) score for diagnosis of disseminated intravascular coagulation (DIC) in septic patients admitted in a general critical care intensive care unit.

Material and method

Septic patients with platelet count of < 150 × 10⁹/L were included. Both DIC scores were estimated from day 1 to day 4 along with APACHE II and SOFA scores.

Results

Out of the 148 blood samples drawn from 42 patients (28 male & 14 female) the JAAM and ISTH DIC scores had an overall significant agreement (k = 0.246, p < 0.001) in 83 samples. JAAM score had higher diagnostic rates on all four days. Significant (p ≤ 0.001) day wise variation existed in JAAM and ISTH DIC scores. Correlation between JAAM DIC and ISTH DIC scores on day 1 (r = 0.631) & day 4 (r = 0.609) was significant (p < 0.001). Pneumonia was the predominant cause of sepsis. Twenty seven (64.3%) patients died during their stay in ICU. Amongst DIC patients both severity scores (SOFA/APACHE II) and DIC scores (JAAM/ISTH) did not discriminate between survivors and non-survivors. Health care associated infection (p = 0.040), high lactate levels (p = 0.020) on day 1 and high procalcitonin levels (p = 0.036) were found to have significant discriminating ability between survivors and non-survivors. Significantly shorter length of stay was observed amongst non-survivors (p = 0.002).

Conclusions

In sepsis the JAAM DIC score identified most of the patients diagnosed by the overt ISTH criteria, but failed to discriminate between survivors and non-survivors amongst DIC patients.     

Cerebral venous thrombosis treated with enoxaparin in an IUGR neonate with DIC

Background  The case of a term IUGR newborn who presented a cerebral vein thrombosis diagnosed by routine ultrasound brain scan, and confirmed by magnetic resonance imaging and magnetic resonance venography, is reported. A thrombosis of cortical cerebral veins and intracerebral haemorrhage in the right frontal paramedian region was observed. Methods  Treatment with enoxaparin was started at the initial dose of 0.5 mg/kg subcutaneously every 12 h and then at 1.25 mg/kg per 12 h in order to obtain anti-factor Xa levels between 0.5 and 1.0 U/ml. After hospital discharge, enoxaparin was continued for 2 months with a lower dose (1.8 mg/kg/die). Conclusion  Treatment with enoxaparin was effective as demonstrated by a complete “restitutio ad integrum”.     

Efficacy of a short-term psychoeducational intervention for persistent non-organic insomnia in severely mentally ill patients. A pilot study.

Insomnia in psychiatric patients is frequently underestimated in clinical practice. Usually drugs are prescribed for the treatment of this disorder but non-pharmacological intervention can be successfully used. The present study aimed at evaluating the efficacy of a two-session psychoeducational intervention in improving persistent non-organic insomnia and reducing the administration of PRN therapy in severely mentally ill patients. A pre-post study was performed on 36 psychiatric patients admitted to a residential psychiatric unit. The Nocturnal Sleep Onset Scale (NSOS) and Daytime Sleepiness Scale (DSS), the sleep onset latency, the time awake after sleep onset and the numbers of awakenings were gathered 2 weeks before the intervention (T0), immediately prior the intervention (T1), 2 weeks after the last session of the intervention (T2) and a 3-month follow-up (T3). The total number of administrations of PRN therapy from T0 to T1 and from T1 to T2 were also examined. A significant reduction was shown on the NSOS, the sleep onset latency and in the time awake after sleep onset from T1 to T2 and from T1 to T3, while no significant difference was found between T0 and T1. A significant decrease on the mean number of administrations of PRN therapy was also found between 15 days before the intervention (T0-T1) and 15 days after intervention (T1-T2). The initial results of this study seems to suggest the possible efficacy of a short-term psychoeducational intervention on improving persistent non-organic insomnia in severely mentally ill patients. Further control studies are necessary to confirm these findings.     

Prostacyclin in aortocoronary bypass surgery: a double-blind, placebo-controlled study

In a double-blind, placebo-controlled trial of 40 patients requiring aortocoronary vene transplant surgery, prostacyclin (PGI2) was infused in a dose of 8 ng/kg/min throughout cardiopulmonary bypass. When compared with the placebo-group, the patients treated with PGI2 were found to have significantly higher platelet counts 60(2) and 90 minutes after onset of extra-corporeal circulation (EC). Although this platelet preservation by PGI2 was accompanied by less degranulation of alpha-granula, total antithrombin III (AT III) as well as active AT III and factor Xa inhibitory activity did show comparable results in both treatment groups. In the early phase of EC coagulation factors (fibrinogen, prothrombin and factor VII) exhibited a trend in favour of higher plasma levels in the PGI2-treated group. The same results were found for plasminogen. F VIII-related antigen and complement factors (C3, C4, C3 activator) did not show any difference between the two treatment groups. Bleeding times, blood loss and renal function also did not exhibit any significant differences between the two groups of patients. Except for one control (60 minutes after onset of EC) hemodynamic parameters were not significantly different between the two patient groups. Whether the trend in favour of a lower mortality in PGI2-treated patients can be confirmed, will be up to further studies with greater numbers of patients.     

Plasma level of stromal derived factor-1 (SDF-1) is increased in disseminated intravascular coagulation patients who have poor outcomes: in vitro effect of SDF-1 on coagulopathy

Stromal cell-derived factor-1 (SDF-1) is a CXC chemokine that activates and directs the migration of leukocytes that have CXCR4, which is the unique receptor for SDF-1. Although SDF-1/CXCR4 interaction has been implicated in various inflammatory conditions, its role in modulating coagulation has not been determined. We studied the plasma SDF-1 levels in 90 patients with suspected disseminated intravascular coagulation (DIC) and we found that circulating SDF-1 was significantly increased in the overt DIC patients and was also increased in overt DIC patients who have a poor outcome. We then tested in vitro whether SDF-1 can affect the expression of monocyte tissue factor (TF) and endothelial thrombomodulin (TM), and both of these play important roles in coagulopathy. SDF-1 did not affect the expression of surface TF protein and its function and the TF mRNA level in both monocytes and the monocytic leukemia cell line THP-1. SDF-1 also did not change the surface TM expression of endothelial cells. SDF-1 could enhance low-dose ADP induced platelet aggregation, although it failed by itself to induce aggregation. These findings suggest that plasma SDF-1 might be closely associated with hypercoagulability though its action as a platelet activator.     

Antithrombin III in patients with acute deep vein thrombosis during heparin treatment (subcutaneous and intravenous) and during and after treatment with oral coumarins

The antithrombin III (AT-III) concentration was studied in 98 patients with symptomatic acute deep-vein thrombosis. All patients were initially treated with heparin randomly by subcutaneous injections or by continuous infusions. Then the patients were treated with coumarins during one or six months. The AT-III concentration was estimated daily during heparin treatment and repeatedly during the first year. The mean AT-III concentration decreased progressively 25% during 5 days of heparin treatment regardless of whether heparin was given intravenously or subcutaneously. The mean AT-III concentration during coumarin treatment was higher than after coumarin treatment. Eleven patients developed recurrent thromboembolic episodes during the follow-up period. The mean AT-III concentration in these patients was not lower than in the patients without recurrences.     

Efficacy of antithrombin in the prevention of microvascular thrombosis during endotoxemia: an intravital microscopic study

INTRODUCTION: The KyberSept trial in septic patients showed that antithrombin (AT) reduced 90-day mortality significantly in a subgroup of patients not receiving concomitant heparin for thrombosis prophylaxis. Microvascular thrombosis is a key pathophysiologic mechanism during sepsis, ischemia/reperfusion and disseminated intravascular coagulation (DIC). Therefore, this study investigated the antithrombotic property of AT as potential monotherapy in an experimental endotoxemia model in order to omit concomitant heparin. MATERIALS AND METHODS: Using a light/dye injury model in the ear and the cremaster muscle preparation of mice, we quantitatively assessed microvascular thrombus formation in a total of 30 endotoxemic mice by means of intravital fluorescence microscopy. Before thrombus induction animals received a single i.v. bolus of AT (100 or 250 IU/kg), heparin (100 IU/kg) or saline (NaCl). RESULTS: In NaCl-treated endotoxemic animals, light/dye exposure led to complete thrombotic occlusion in arterioles and venules within <450 s in the ear model. Heparin delayed thrombotic vessel occlusion by more than 50%. AT significantly prolonged times until thrombotic vessel occlusion in a dose-dependent manner and more effectively than heparin (p<0.05 vs. NaCl and heparin). This anti-coagulative effect of AT was especially pronounced in arterioles. Upon light/dye exposure to cremaster muscle preparations in endotoxemic mice AT also caused a 4-fold delay in microvascular thrombus growth with 827+/-77 s until complete thrombotic occlusion. CONCLUSIONS: We could characterize for the first time AT-mediated antithrombotic activity during endotoxemia in two models of phototoxicity-induced microvascular thrombosis. Our results clearly demonstrate an additional AT mechanism of action that may be responsible for beneficial effects observed during endotoxemia and DIC. This AT profile may allow future high-dose AT application without giving heparin for thrombosis prophylaxis, an intriguing strategy that is to be tested under clinical conditions.     

Zotepine loading in acute and severely manic patients: a pilot study

OBJECTIVES: In clinical practice patients with severe mania (agitation, insomnia and aggressive behaviour) still receive effective, but often not well tolerated typical antipsychotics. The aim of this study was to test the first-generation atypical antipsychotic zotepine regarding its antimanic efficacy, tolerability and to find an adequate dosage for a loading strategy. METHOD: Twelve patients (seven male) with an acute and severe manic episode, according to DSM-IV, received zotepine loading in individual dosages (up to 600 mg/day) over a maximum period of 3 weeks. Clinical efficacy was measured using the Young-Mania Rating Scale (Y-MRS) total score. Response was defined as a 50% reduction in the Y-MRS score. Safety was assessed by systematic collection of data on side effects and weight; Hamilton Rating Scale for Depression (HAM-D) scores were used to detect a switch into depression. RESULTS: Two patients dropped out of the study after 2 days. Nine of ten patients (baseline mean Y-MRS: 45 +/- 7) were classified as responders, with five of them responding within 4 days. One patient did not respond sufficiently. No switch into a depressive episode occurred. CONCLUSIONS: This open pilot study suggests that zotepine with a median daily dosage of 250 mg/day is effective with a rapid therapeutic effect in severely manic patients. In general, patients tolerated the drug well; dose-dependent extrapyramidal side effects, an increase in weight and autonomic side effects occurred to a lesser degree. This is the first study assessing zotepine monotherapy in manic patients. Controlled studies are warranted.     

Citalopram-lithium combination treatment of elderly depressed patients: A pilot study

Fourteen elderly depressive patients (age 67-88 yr), phenotyped with dextromethorphan and mephenytoin before and during the trial, were treated for 4 weeks with citalopram (final dose 20-30 mg/day, except one patient 60 mg/day). The clinical state of the patients was recorded weekly using the Hamilton Depression Rating Scale, the CGI (psychopathology) scale, the VAS and the UKU scale for side-effects. As assessed by the Hamilton Depression Rating Scale, nine patients improved by more than 50% and continued with their citalopram treatment. The treatment of the five non-responders was then continued for another 2 weeks by addition of lithium (target plasma levels 0.4-0.8 mmol/l) to the ongoing citalopram medication. After 1 week, one patient had to be withdrawn for non-response, three were responders, while the fifth patient was a responder only after 2 weeks of lithium addition. Due to side-effects, the lithium dose had to be decreased in one patient who had responded to the combination therapy. Plasma levels of citalopram were within 145-459 nmol/l after 4 weeks of citalopram treatment. All patients were extensive metabolizers of dextromethorphan, and all but possibly one also of mephenytoin. After 4 weeks of citalopram, there was a highly significant correlation between the ratios of S/R-mephenytoin in urine and citalopram/desmethylcitalopram in plasma, which suggests a common mechanism in the metabolism of these drugs. The preliminary finding that a citalopram-Li combination therapy may be useful in elderly depressive patients resistant to citalopram alone needs to be replicated by a controlled double-blind study.     

A pilot study of standardized treatment in geriatric bipolar disorder.

OBJECTIVE: The authors sought to determine the feasibility of treating elderly adults with bipolar disorder under standardized-treatment conditions. METHODS: Thirty-one patients age 60 and older with bipolar disorder were treated in standardized pathways. Mood state was checked at each study visit with the Hamilton Rating Scale for Depression-17 item (Ham-D-17) and the Young Mania Rating Scale (YMRS). RESULTS: Defining "well days" as both Ham-D and YMRS scores of 相似文献   

Distant visual acuity in chronic psychiatric patients. A pilot study

Background: There is a paucity of systematically collected data on visual impairment in patients with chronic psychiatric disorders. The aim of this pilot study was to estimate the magnitude of impairment of distant visual acuity (DVA) including refractive and non-refractive errors in institutionalized psychiatric patients awaiting resettlement in the community in Hong Kong. Method: DVA was tested using the Snellen method in a randomly selected cohort of 428 institutionalized psychiatric patients from the four long-stay rehabilitation units in Hong Kong. The pinhole method was employed to differentiate between refractive and non-refractive impairment of DVA. Results: Seventy-five percent of the sample had impaired DVA; 39 % of the subjects had refractive error (myopia). Only a small percentage of patients wore spectacles and had adequately corrected vision. Patients with impaired DVA were significantly older than those with normal DVA. Conclusion: While the frequency of myopia corresponds to that found in the general population in Hong Kong, the nature of non-refractive impairment needs further investigation including systematic eye examination, and examination of medication and life-style factors. Periodical eye examinations should be part of comprehensive health assessment for chronic psychiatric patients. Accepted: 27 May 2002     

Neuroendocrine investigation of depression in mentally retarded patients. A pilot study

As part of a pilot study, eight adults with severe mental retardation were screened for the presence of endogenous depression by the standard 1-mg overnight dexamethasone suppression test (DST). The eight had been rigorously screened to rule out potential for false-positive DST. Two of the eight patients demonstrated nonsuppression, and a third had borderline results. Of these three, two manifested behavioral disturbances that could be attributed to major depressive disorder. The authors discuss the results, the difficulty diagnosing psychiatric disorders in severely retarded persons, and the proposed utility of the DST in this area.     

Efficacy of concomitant and adjuvant temozolomide in glioblastoma treatment. A multicentre randomized study

Background and purposeThe common treatment in patients with newly diagnosed glioblastoma multiforme is the ultimately radical surgical removal of the tumour combined with radiotherapy. This study compared safety and efficacy of radiotherapy alone with radiotherapy combined with temozolomide (TMZ) given before, during, and after radiotherapy.Material and methodsThe patients operated on for glioblastoma multiforme during the first 21 postoperative days were randomly assigned to the group treated with radiotherapy alone (involved-field radiotherapy in 2 Gy fractions daily five times a week up to the total of 60 Gy over 6 weeks of treatment) or to the group treated with radiotherapy and TMZ, initially in the dose of 200 mg/m² during 5 postoperative days and after 23 days followed by 75 mg/m² of body surface area daily, 7 days a week (from the first to the last day of radiotherapy). On completion of radiotherapy, five complementary courses of TMZ were introduced (150–200 mg/m² for 5 days, repeated every 28 days). The primary outcome measure was overall survival.ResultsFifty-eight patients from 3 centres were included in the study. The mean age of patients was 55 years and all the patients underwent a surgical procedure of glioblastoma removal. The mean overall survival in the group treated with TMZ was 16.0 months, whereas in the group with radiotherapy alone the overall survival reached 12.5 months. 24-month survival reached 23% in patients treated with TMZ and 6.7% in those who received radiotherapy only. Haematological complications of third or fourth degree were present in 10% of patients treated with radiotherapy and TMZ.ConclusionsThe introduction of TMZ before, during and after radiotherapy for newly diagnosed glioblastoma multiforme gives clinically and statistically significant improvement of survival with unremarkably increased toxicity of the treatment.     

Disseminated intravascular coagulation (DIC) diagnosed based on the Japanese Association for Acute Medicine criteria is a dependent continuum to overt DIC in patients with sepsis

Introduction

Sepsis is the most common disease associated with disseminated intravascular coagulation (DIC). To test the hypothesis that DIC diagnosed by the Japanese Association for Acute Medicine (JAAM) DIC scoring system (JAAM DIC) constitutes a dependent continuum to overt DIC diagnosed by the International Society on Thrombosis and Haemostasis (ISTH) overt DIC scoring system (ISTH overt DIC) in patients with sepsis, we conducted a retrospective study.

Materials and Methods

The databases from two prospective, multicenter clinical investigations were analyzed. The inclusion criteria comprised patients with sepsis-related DIC, who met the JAAM DIC criteria.

Results

The present study enrolled 166 patients, of whom 67 met the ISTH overt DIC criteria. All patients with sepsis who developed to overt DIC during the study period could be identified by the JAAM DIC diagnostic criteria in the first study. While the overall 28-day mortality was 31.3%, mortality (40.3%, p = 0.0040) and the incidence of multiple organ dysfunction syndrome (70.1%, p = 0.008) of the patients with the ISTH overt DIC was approximately one and a half times that of the patients associated with only the JAAM DIC. A stepwise increase in the ISTH overt DIC scores and the incidence of the ISTH overt DIC were also observed in accordance with the increase in the JAAM DIC scores.

Conclusion

DIC diagnosed based on the JAAM DIC diagnostic criteria exists in a dependent continuum to the ISTH overt DIC in patients with sepsis, thus enabling them to receive early treatment.