Magnitude of d-dimer matters for diagnosing pulmonary embolus

Objective

The objective of this study is to determine whether the magnitude of the d-dimer correlates with a higher likelihood of pulmonary embolus (PE).

Methods

We performed an electronic chart review at our academic, tertiary care center, annual emergency department (ED) census greater than 100 000. All patients with a chest computed tomographic (CT) scan with intravenous contrast and an elevated d-dimer level obtained in the ED between January 2001 and July 2008 were identified. Specific, predetermined, predefined data elements including sex, age, d-dimer level, and final ED diagnosis were recorded by a hypothesis-blinded extractor using a preformatted data form. d-dimer level less than 0.58 μg/mL constitutes the normal laboratory reference range for our turbidometric d-dimer assay. Data were analyzed using standard statistical methods, and a linear regression analysis was performed for correlation analysis of d-dimer and diagnosis of PE.

Results

We identified 544 subjects who had both a chest CT scan performed and an elevated d-dimer level obtained in the ED. Fifty-eight subjects (10.7%; mean d-dimer, 4.9 μg/mL) were diagnosed with PE, and 486 (89.3%; mean d-dimer, 2.0) did not have a PE. The percentages of PE diagnoses for d-dimers in the ranges 0.58 to 1.0, 1.0 to 2.0, 2.0 to 5.0, 5.0 to 20.0, and greater than 20.0 (n = 11) were 3.6%, 8.0%, 16.2%, 35.3%, and 45.5%, respectively. The positive predictive value of PE for d-dimer level cutoffs of greater than 0.58, greater than 1.0, greater than 2.0, greater than 5.0, and greater than 20.0 was 10.7%, 14.6%, 22.2%, 37.8%, and 45.5%, respectively. Increasing d-dimer values were strongly correlated with the presence of PE (odds ratio, 1.1685 per stratum; P < .001).

Conclusion

Increasing magnitude of d-dimer correlates with increasing likelihood of PE diagnosed by CT angiography.     

d-dimers as an early marker for oxygenator exchange in extracorporeal membrane oxygenation

Purpose

Early markers of oxygenator dysfunction during prolonged use of extracorporeal membrane oxygenation (ECMO) are important for timely exchange to avoid sudden loss of function due to clot formation within the system. The measurement of d-dimers (DDs) in plasma might be a marker for early diagnosis of thrombus formation and dysfunction of heparin-coated membrane oxygenators (MOs).

Methods

This is a retrospective study on prospectively collected data of 24 adult acute respiratory distress syndrome patients requiring long-term veno-venous ECMO with at least 1 MO exchange. Kinetics of coagulation, inflammation, and oxygenator function were analyzed before and after MO exchange.

Results

Median (interquartile range) support duration is 20 (15-29) days. Thirty-four MOs had to be replaced. Exchange occurred due to visible thrombus formation in the MO (n = 16), worsening gas exchange (n = 11), increased blood flow resistance (n = 1), and activation of coagulation with diffuse bleeding (n = 6). In 15 cases, DDs were continuously elevated and, therefore, not suitable as marker for MO exchange. In the remaining 19 cases, DDs increased significantly within 3 days before exchange from 15 (9-20) to 30 (21-35) mg/dL (P = .002) and declined significantly within 1 day thereafter to 13 (7-17) mg/dL (P = .003).

Conclusions

An increase in plasma DD concentration in absence of other explaining pathology can be helpful in predicting an MO exchange in miniaturized heparin-coated ECMO systems.     

d-dimer is a significant prognostic factor in patients with suspected infection and sepsis

Purpose

The aim of the study was to determine whether C-reactive protein (CRP), procalcitonin (PCT), and d-dimer (DD) are markers of mortality in patients admitted to the emergency department (ED) with suspected infection and sepsis.

Basic Procedures

We conducted a prospective cohort in a university hospital in Medellín, Colombia. Patients were admitted between August 1, 2007, and January 30, 2009. Clinical and demographic data and Acute Physiology and Chronic Health Evaluation II and Sepsis Organ Failure Assessment scores as well as blood samples for CRP, PCT, and DD were collected within the first 24 hours of admission. Survival was determined on day 28 to establish its association with the proposed biomarkers using logistic regression and receiver operating characteristic curves.

Main Findings

We analyzed 684 patients. The median Acute Physiology and Chronic Health Evaluation II and Sepsis Organ Failure Assessment scores were 10 (interquartile range [IQR], 6-15) and 2 (IQR, 1-4), respectively. The median CRP was 9.6 mg/dL (IQR, 3.5-20.4 mg/dL); PCT, 0.36 ng/mL (IQR, 0.1-3.7 ng/mL); and DD, 1612 ng/mL (IQR, 986-2801 ng/mL). The median DD in survivors was 1475 ng/mL (IQR, 955-2627 ng/mL) vs 2489 ng/mL (IQR, 1698-4573 ng/mL) in nonsurvivors (P = .0001). The discriminatory ability showed area under the curve–receiver operating characteristic for DD, 0.68; CRP, 0.55; and PCT, 0.59. After multivariate analysis, the only biomarker with a linear relation with mortality was DD, with an odds ratio of 2.07 (95% confidence interval, 0.93-4.62) for values more than 1180 and less than 2409 ng/mL and an odds ratio of 3.03 (95% confidence interval, 1.38-6.62) for values more than 2409 ng/mL.

Principal Conclusions

Our results suggest that high levels of DD are associated with 28-day mortality in patients with infection or sepsis identified in the emergency department.     

Enzymatic determination of l-ornithine in serum

Serum l-ornithine was determined enzymatically using ornithine carbamoyltransferase (OCT) from Streptococcus faecalis and measuring the citrulline formed with a diacetyl-thiosemicarbazide reaction after precipitation of proteins with trichloracetic acid. The normal fasting values, 26–92 μmol/1, correlated well with those obtained by Chromatographic methods.     

Enzymic determination of urinary free l-fucose

Conditions necessary for the precise measurement of free l-fucose in urine by an enzymic method using l-fucose dehydrogenase have been studied. The normal urinary levels of l-fucose were 16.4 ± 9.1 μg/ml in children (22.2 ±6.5 μg/mg of creatinine) and 17.7 ± 8.5 μg/ml in adults (16.6 ± 5.7 μg/mg of creatinine). There was a close correlation between the concentration of free l-fucose and that of creatinine. A close correlation was also found between the concentration of free l-fucose and α-l-fucosidase activity. Thus, it was suggested that the free l-fucose in urine reflected the metabolism of l-fucose or l-fucose-containing glycoconjugates.In a preliminary screening test, several urine samples which showed high concentrations of free l-fucose, namely cases of “fucosuria” were found.     

The conversion of d-xylose into d-threitol in patients without liver disease and in patients with portal liver cirrhosis

An oral d-xylose tolerance test was carried out on 12 patients with portal liver cirrhosis, on 7 patients with active fatty liver disease and on 29 subjects without liver diseases. d-Xylose and d-threitol were measured by means of gasliquid chromatography.Fifteen percent of the d-xylose dose excreted in urine within five hours was recovered as d-threitol. The proportion of d-threitol was greater when the collection was extended to 24 h. The d-threitol excretion was markedly diminished in cirrhotic patients, suggesting that a substantial proportion of the d-xylose-d-threitol conversion occurs in the liver. No decrease was detected in patients with fatty liver disease. No significant change in d-xylose excretion was observed in liver cirrhosis or in fatty liver disease.d-Threitol can be regarded as the main end product of d-xylose metabolism in man. The role of the glucuronate pathway in the d-xylose-d-threitol conversion is discussed.     

Hemodynamic Effects of l-Threo-3,4-Dihydroxyphenylserine (Droxidopa) in Hypotensive Individuals With Spinal Cord Injury

Objectives

To determine the effect of an escalating dose of droxidopa (100, 200, and 400mg) compared with placebo on seated blood pressure (BP) in hypotensive individuals with spinal cord injury (SCI). Secondarily, we aimed to determine the effect of droxidopa on (1) supine BP and heart rate, (2) the change in BP and heart rate when these individuals were transferred from the supine to the seated position, and (3) adverse event (AE) reporting.

Design

Open-label dose titration trial.

Setting

A Veterans Administration Medical Center.

Participants

Participants with SCI (C3-T12) (N=10) were studied during 4 laboratory visits. Subjects visited the laboratory for about 5 hours on each visit, which incorporated a 30-minute seated baseline, a 30- to 60-minute supine, and a 4-hour seated postdrug observation.

Interventions

Placebo on visit 1, droxidopa 100mg on visit 2, droxidopa 200mg on visit 3, and droxidopa 400mg on visit 4.

Main Outcome Measures

BP and heart rate changes from baseline to the postdrug period, orthostatic heart rate and BP responses, and subjective AE reporting.

Results

Seated BP was significantly elevated with 400mg droxidopa compared with placebo and 100mg droxidopa for 3 hours and was elevated for 2 hours compared with 200mg droxidopa. Increase in supine BP was not worsened following droxidopa, and the expected fall in BP when transferred to the seated position was prevented with droxidopa 200 and 400mg. There were no significant differences in the heart rate response or AE reporting among the study visits.

Conclusions

Our preliminary findings suggest that droxidopa, at the doses tested, does not cause excessive increases in supine BP and the 400-mg dose appears to be effective at increasing seated BP for up to 3 hours in persons with SCI.     

d-Dimer in patients with suspected acute mesenteric ischemia

Objectives

The aims of this study were to assess the diagnostic value of d-dimer in patients with suspected acute mesenteric ischemia (AMI) and to evaluate the correlation between d-dimer levels and the severity of bowel necrosis.

Methods

A prospective, noninterventional study of 67 patients with clinical suspicion of AMI was performed. Measurement of d-dimer levels was performed using a latex turbidimetric method.

Results

Acute mesenteric ischemia was diagnosed in 23 patients (34.3%) and non-AMI in 44 patients (65.7%). Median d-dimer levels on admission were 6.24 μg fibrinogen equivalent units (FEU)/mL (range, 0.96-53.48 μg FEU/mL) in patients with AMI and 3.45 μg FEU/mL (range, 0.50-44.69 μg FEU/mL) in non-AMI patients (P = .064). d-Dimer had poor discriminative value to differentiate the presence from the absence of AMI with an area under the receiver operating characteristic curve of 0.64 (95% confidence interval, 0.50-0.78). A serum d-dimer cutoff value of 1.0 μg FEU/mL had a sensitivity of 96%, a specificity of 18%, a positive likelihood ratio of 1.17, and a negative likelihood ratio of 0.24. Among patients with AMI verified at operation, 8 had resectable bowl necrosis and 9 had unresectable bowel necrosis. There was no difference in serum d-dimer levels between resectable and unresectable bowel necrosis (P = .665).

Conclusions

Detection of serum d-dimer could not help to differentiate patient with AMI from those with non-AMI. We did not find a correlation between serum d-dimer levels and the severity of AMI. However, measurement of d-dimer levels can be of value for a small decrease in the likelihood of AMI, when the result is low.     

Anti-tumor drug delivery of pH-sensitive poly(ethylene glycol)-poly(L-histidine-)-poly(L-lactide) nanoparticles

pH-sensitive poly(ethylene glycol)-poly(l-histidine)-poly(L-lactide) (PEG-PH-PLLA) nanoparticles were prepared and used as carriers for anti-tumor drug delivery. The morphology and properties of the nanoparticles such as pH sensitivity, zeta potential and mean diameters were investigated. The cytotoxicity of PEG-PH-PLLA nanoparticles was evaluated. Doxorubicin (DOX) was encapsulated in the nanoparticles to explore the release profile. The drug-loaded nanoparticles were incubated with HepG2 cells to study the in vitro anti-tumor effect. The results showed the sizes of both blank nanoparticles and drug-loaded nanoparticles in pH 7.4 were smaller than those of nanoparticles in pH 5.0, and the mean diameter of drug-loaded nanoparticles was much bigger than that of blank nanoparticles. The PEG-PH-PLLA nanoparticles were nontoxic to both NIH 3T3 fibroblasts and HepG2 cells. The release profile showed that the release of DOX in pH 5.0 was much faster than that in pH 7.4. The in vitro experiments demonstrated that the anti-tumor effect of drug-loaded nanoparticles was preferable to free doxorubicin. The pH-sensitive PEG-PH-PLLA nanoparticles are promising carriers for anti-tumor drug delivery.     

A decision analysis to determine a testing threshold for computed tomographic angiography and d-dimer in the evaluation of aortic dissection

Objective

The objective of this study is to determine at what probability of thoracic aortic dissection (TAD) to use a computed tomographic angiography (CTA) or a d-dimer test.

Methods

We used decision analysis software to determine the testing threshold (TT) for 3 hypothetical decisions when evaluating for TAD: (1) no testing vs CTA, (2) no testing vs d-dimer, and (3) CTA vs d-dimer. One- and 2-way sensitivity analyses were performed to determine which variables were drivers of the TTs.

Results

We found TTs of 0.03%, 0.013%, and 0.6% for decisions 1, 2, and 3, respectively. For all 3 decisions, patient age and the annual rate of cancer were major drivers of the TT. In decisions 1 and 2, the probability of acute renal failure requiring renal replacement therapy was a major driver, whereas d-dimer sensitivity was a major driver for decision 3.

Conclusion

The TTs for TAD are low and reflect the large mortality benefit from diagnosis and treatment when compared with the small risks of CTA. However, given the low prevalence of TAD (~ 0.05% among emergency department patients presenting with symptoms previously attributed to TAD), our results suggest that without high-risk features, clinicians should not order a CTA test for TAD. Depending on age, CTA should be considered for those patients with a disease probability greater than 0.3% to 2.1%, whereas d-dimer testing is appropriate in the range of pretest probabilities from 0.01% to 0.6%. Future studies should focus on clinical decision rules that place disease probabilities below, between, and above the calculated TTs.     

N-Methyl-d-aspartate receptor (NMDAR) independent maintenance of inflammatory pain

Following peripheral inflammation, NMDA receptor (NMDAR) activation in spinal cord dorsal horn neurons facilitates the generation of pain in response to low threshold inputs (allodynia) and signals the phosphorylation of protein kinase C (pPKC) and extracellular signal-regulated kinase 2 (pERK2). Intraplantar complete Freund’s adjuvant (CFA) induces inflammatory nociception (allodynic pain) at 24 hours (h) with a concurrent increase in neuronal pPKCγ and pERK2 but not glial pERK2. These effects are attenuated in a spatial knockout of the NMDAR (NR1 KO) confined to SCDH neurons. Although glia and proinflammatory cytokines are implicated in the maintenance of inflammatory pain and neuronal activation, the role of NMDARs and neuronal–glial–cytokine interactions that initiate and maintain inflammatory pain are not well defined. In the maintenance phase of inflammatory pain at 96 h after CFA the NR1 KO mice are no longer protected from allodynia and the SCDH expression of pPKCγ and pERK2 are increased. At 96 h the expression of the proinflammatory cytokine, IL-1β, and pERK2 are increased in astrocytes. Intrathecal IL-1 receptor antagonist (IL-1ra), acting on neuronal IL-1 receptors, completely reverses the allodynia at 96 h after CFA. Deletion of NMDAR-dependent signaling in neurons protects against early CFA-induced allodynia. Subsequent NMDAR-independent signaling that involves neuronal expression of pPKCγ and the induction of pERK2 and IL-1β in activated astrocytes contributes to the emergence of NMDAR-independent inflammatory pain behavior at 96 h after CFA. Effective reduction of the initiation and maintenance of inflammatory pain requires targeting the neuron–astrocyte–cytokine interactions revealed in these studies.     

pH-responsive and charge shielded cationic micelle of poly(l-histidine)-block-short branched PEI for acidic cancer treatment

To address cancer cell heterogeneity while endowing tumor specificity, the approach of charge shielding/deshielding was tested in vitro and in vivo with a paclitaxel loaded cationic micelle from a block copolymer of poly(l-histidine) (3.7 kDa) and short branched polyethyleneimine (1.8 kDa). The cationic micelle surface was shielded by electrostatically complexing with a negatively charged mPEG (2 kDa)-block-polysulfadimethoxine (4 kDa) (mPEG-b-PSDM) at pH 7.4. Unshielded micelle at pH 7.4 and deshielded micelle at tumor extracellular pH were readily taken up by two wild types of human cancer cell lines, MCF-7 breast adenocarcinoma and SKOV-3 ovarian carcinoma, while the uptake of the shielded micelle at pH 7.4 was minimal. The preliminary in vivo results from a mouse model xenografted with MCF-7 showed significant anticancer therapeutic efficacy and deep penetration of the micelle into tumor tissues after deshielding, supporting the unique pH-responsive mechanism to treat acidic cancer.     

Subthalamic deep brain stimulation versus best medical therapy for l-dopa responsive pain in Parkinson’s disease

Pain is a frequently observed non-motor symptom of patients with Parkinson’s disease. In some patients, Parkinson’s-related pain responds to dopaminergic treatment. In the present study, we aimed to elucidate whether subthalamic deep brain stimulation has a similar beneficial effect on pain in Parkinson’s disease, and whether this effect can be predicted by a pre-operative l-dopa challenge test assessing pain severity. We prospectively analyzed 14 consecutive Parkinson’s patients with severe pain who underwent subthalamic deep brain stimulation. In 8 of these patients, pain severity decreased markedly with high doses of l-dopa, irrespective of the type and localization of the pain symptoms. In these patients, subthalamic deep brain stimulation provided an even higher reduction of pain severity than did dopaminergic treatment, and the majority of this group was pain-free after surgery. This effect lasted for up to 41 months. In the remaining 6 patients, pain was not improved by dopaminergic treatment nor by deep brain stimulation. Thus, we conclude that pain relief following subthalamic deep brain stimulation is superior to that following dopaminergic treatment, and that the response of pain symptoms to deep brain stimulation can be predicted by l-dopa challenge tests assessing pain severity. This diagnostic procedure could contribute to the decision on whether or not a Parkinson’s patient with severe pain should undergo deep brain stimulation for potential pain relief.     

A gas-liquid chromatographic method for the determination of d-glucaric acid in urine

A gas—liquid chromatographic method has been developed for the determination of D-glucaric acid in human and animal urine.The method involved a three stage procedure for the formation of a derivative of D-glucaric acid suitable for gas—liquid chromatography. The urine acidified to 0.1 M HCl was refluxed for 2 h to form an equilibrium mixture of D-glucaric acid and its lactones. The products were then converted to methyl esters with methyl alcohol and acetyl chloride and subsequently reacted with trimethylchlorosilane (TMCS) to form silylated ethers. The gas—liquid chromatographic determination of this derivative of D-glucaro-1:4-lactone gave a measure of the D-glucaric acid content in the urine.The method was found to be specific and unaffected by other likely interfering substances in the urine and capable of estimating 0.1 μg of D-glucaric acid.     

A new simple ultramicromethod for the determination of d-xylose in blood and urine

A simple, rapid and accurate ultramicromethod for the determination of d-xylose in blood and urine, based on Bial reaction, is proposed. The method is well adapted for routine performance in hospital laboratories, and may be especially useful in pediatrie clinics as only 20 μl of blood is required for the determination.     

The effects of exogenous l-carnitine on lipid peroxidation and tissue damage in an experimental warm hepatic ischemia-reperfusion injury model

Background:l-Carnitine is the essential endogenous factor for the transport of long-chain fatty acids from the cytoplasm to within the mitochondrion where the β-oxidation process takes place. l-Carnitine is a superoxide scavenger and an antioxidant that possesses an anti-ischemic action and a stabilizing effect on cell membranes. It may be of help in liver ischemia reperfusion injury. Results regarding the effects of l-carnitine on liver ischemia and reperfusion injury are few and conflicting.Objective: The aim of this study was to investigate the efficacy of exogenous l-carnitine on lipid peroxidation and protecting liver at different stages of experimental total warm hepatic ischemia-reperfusion (TWHIR) procedure in rats.Methods: This experimental study in healthy, weanling, male Wistar rats (weighing 180-200 g) was conducted at the Experimental Animal Research Laboratory of the Faculty of Medicine of Mersin University, Mersin, Turkey. Rats were randomly divided into 5 groups: (A) Control group; (B) TWHIR procedure only; (C) l-carnitine administered 2 hours before the TWHIR procedure; (D) l-carnitine administered just before the TWHIR procedure; and (E) l-carnitine administered after total warm hepatic ischemia but just before the reperfusion procedure. Total warm hepatic ischemia (via the Pringle maneuver) and reperfusion were performed for 45 and 30 minutes, respectively. l-Carnitine (200 mg/kg) was administered intravenously. At the end of each procedure a blood sample was drawn and total hepatectomy was performed following reperfusion. Malondialdehyde (MDA) and myeloperoxidase (MPO) levels of both plasma and liver tissue, total antioxidant capacity (TAOC), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in plasma, and histopathologic examination were analyzed to assess lipid peroxidation and damage in liver tissue.Results: Thirty-four rats (mean [SD]age, 59.26 [1.2]days; mean [SD] weight, 194.1 [5.1] g) were used in the study. There was a significant difference observed between groups A (n = 5) and B (n = 5) for all evaluation parameters. The TWHIR procedure performed in group B was associated with significant increases versus baseline in ALT, AST, MDA, and MPO in plasma, and MDA and MPO in liver tissue, but a significant decrease of TAOC in plasma. ALT, AST, serum and liver MDA, and MPO levels of group B were significantly higher than all groups administered l-carnitine. l-Carnitine administration between total warm hepatic ischemia and reperfusion was associated with a significant attenuation in all parameters. The liver MDA levels of groups C (n = 8) and D (n = 8) were significantly lower than that of group E (n = 8) (mean [SD]: C, 16.53 [3.32] and D, 18.28 [1.67] vs E, 23.05 [3.52]; P = 0.001 and P = 0.016, respectively). The mean (SD) liver MPO level of group C (1.09 [0.16]) was significantly lower than that of groups D (2.12 [0.25]) and E (2.11 [0.28]) (both, P = 0.001). The TAOC of group B (0.77 [0.12]) was significantly lower than that of groups C (1.34 [0.19]) and D (1.08 [0.20]) (P = 0.001 and P = 0.015, respectively). The TAOC of group C was significantly higher than that of the other l-carnitine groups (E, 0.94 [0.13]) (P = 0.023 vs group D; and P = 0.001 vs group E). Histopathologic scores of groups A, C, and E were significantly lower than that of group B, but the difference between groups B and D was not statistically significant.Conclusions: In this experimental study, administration of exogenous l-carnitine was associated with significantly decreased lipid peroxidation in plasma and liver tissue when administered prior to a TWHIR procedure. In addition, l-carnitine seemed to be more effective with regard to decreasing lipid peroxidation in liver tissue when administered before warm hepatic ischemia. l-Carnitine was associated with significantly decreased leukocyte sequestration in plasma and liver tissue. A significant increase in TAOC was associated with l-carnitine administered prior to ischemia. These observations suggest that l-carnitine might have a protective effect against ischemia-reperfusion injury in rat liver tissue.     

Luminal concentrations of L- and D-lactate in the rectum may relate to severity of disease and outcome in septic patients

Introduction  

Little is known about the condition of the large bowel in patients with sepsis. We have previously demonstrated increased concentrations of L-lactate in the rectal lumen in patients with abdominal septic shock. The present study was undertaken to assess the concentrations of L- and D-lactate in rectal lumen and plasma in septic patients including the possible relation to site of infection, severity of disease, and outcome.