Determination of residual antiplatelet activity of clopidogrel before neuraxial injections.

BACKGROUND: Guidelines recommend discontinuation of clopidogrel for 7 days before a neuraxial injection, while other directives suggest that 5 days might be adequate. We examined the time course of antiplatelet activity after clopidogrel discontinuation in patients undergoing epidural injections. METHODS: Thirteen patients were studied at baseline, 3, 5, and 7 days after discontinuation of clopidogrel. P(2)Y(12) determinations were performed using the VerifyNow(®) assay (Accumetrics, San Diego, CA, USA), and clot closure times with stimulation by collagen/epinephrine and collagen/adenosine diphosphate using the PFA-100(®) (Platelet Function Analyzer, Siemens Diagnostics, Deerfield, IL, USA). Repeated-measures ANOVA was used to evaluate P(2)Y(12) platelet reaction units, PFA-100 closure times, and per cent P(2)Y(12) inhibition values. Wilcoxon's signed-rank test was used to compare the frequencies of ≥30%, 11-29%, and ≤10% platelet inhibition between the baseline and subsequent sampling points after discontinuation of clopidogrel. RESULTS: On day 3 after clopidogrel discontinuation, two subjects had ≥30%, seven subjects had 11-29%, and four subjects had ≤10% platelet inhibition; the corresponding numbers were 0, 3, and 10 subjects on day 5 (P=0.04). There were no differences between the ≥30%, 11-29%, and <10% platelet inhibition groups between days 5 and 7 (0, 0, and 13 subjects, P=1.0). PFA-ADP closure times were normal throughout the study period except in one patient. CONCLUSIONS: These findings support the recommendation that discontinuation of clopidogrel for 5 days allows >70% of platelet function and might be adequate before a neuraxial injection is performed.

Activated platelets are the source of elevated levels of soluble CD40 ligand in the circulation of inflammatory bowel disease patients.

BACKGROUND: The CD40/CD40L system, a key regulator and amplifier of immune reactivity, is activated in inflammatory bowel disease (IBD) mucosa. AIMS: To determine whether plasma levels of sCD40L are elevated in Crohn's disease (CD) and ulcerative colitis (UC) patients compared with normal controls, to investigate the cellular source of sCD40L, and to explore CD40L induction mechanisms. PATIENTS: CD, UC, and normal control subjects were studied. METHODS: The concentration of sCD40L in plasma and supernatants of freshly isolated platelets and autologous peripheral blood T cells (PBT) was measured by ELISA. Surface CD40L expression level was measured by flow cytometry in resting and thrombin activated platelets, and unstimulated and CD3/CD28 stimulated PBT before and after coculture with human intestinal microvascular endothelial cells (HIMEC). RESULTS: Compared with normal controls, plasma sCD40L levels were significantly higher in both CD and UC patients and proportional to the extent of mucosal inflammation. Platelets from IBD patients displayed a significantly higher surface CD40L expression than those from control subjects, and released greater amounts of sCD40L than autologous PBT. Contact with IL-1beta activated HIMEC induced significant upregulation of CD40L surface expression and release by platelets. CONCLUSIONS: Elevated levels of sCD40L in the circulation of IBD patients reflect enhanced surface expression and release of CD40L by platelets. This phenomenon translates to an increased platelet activation state apparently induced by passage through an inflamed mucosal microvascular bed, a conclusion supported by the positive correlation of plasma sCD40L levels with the extent of anatomical involvement by IBD. These results suggest that platelet-endothelial interactions critically contribute to activation of the CD40 pathway in IBD.

Treatment of mildly to moderately active ulcerative colitis with a tryptase inhibitor (APC 2059): an open-label pilot study.

BACKGROUND: Mast cells isolated from the colonic mucosa in active ulcerative colitis appear to be partially degranulated, suggesting the release of tryptase. AIM: To investigate the safety and activity of APC 2059, a highly specific tryptase inhibitor, in the treatment of ulcerative colitis. METHODS: This was an open-label, Phase 2, multicentre pilot study in patients with mildly to moderately active ulcerative colitis, with a disease activity index of 6-9 on a 12-point scale. Fifty-six adults received 20 mg APC 2059 subcutaneously twice daily and 53 completed 28 days of treatment. The primary end-point was response, defined as a final disease activity index of < or = 3. Supplementary analyses were also performed. RESULTS: Sixteen (29%) of 56 patients responded. Five (9%) showed complete remission (disease activity index=0). Twenty-seven (49%) improved, with a final disease activity index of < or = 3 or a four-point reduction. Improvement or normalization in each category of the disease activity index was as follows: stool frequency, 64%; bleeding, 64%; endoscopy, 50%; physicians' rating, 63%. There were no significant relationships between outcome and pharmacokinetics. The most common adverse events were related to the injection site (32.1%). CONCLUSIONS: In this pilot study, the tryptase inhibitor APC 2059 was safe and there was evidence of activity in the treatment of ulcerative colitis.

Inflammatory bowel disease and pregnancy.

Most women with inflammatory bowel disease who desire to become pregnant can expect to conceive successfully, carry to term, and deliver a healthy infant. However, the management of inflammatory bowel disease during pregnancy remains challenging, and some women with ulcerative colitis or Crohn's disease will have difficulty becoming pregnant or have increased disease symptoms while pregnant. Control of disease activity before conception and during pregnancy is critical to optimize both maternal and fetal health. The natural history of inflammatory bowel disease during pregnancy will be reviewed and the medical and surgical therapy discussed.

Lung collapse during low tidal volume ventilation in acute respiratory distress syndrome.

BACKGROUND: Current ventilator management for acute respiratory distress syndrome (ARDS) incorporates low tidal volume (V(T)) ventilation in order to limit ventilator-induced lung injury. Low V(T) ventilation in supine patients, without the use of intermittent hyperinflations, may cause small airway closure, progressive atelectasis, and secretion retention. Use of high positive end-expiratory pressure (PEEP) levels with low V(T) ventilation may not counter this effect, because regional differences in intra-abdominal hydrostatic pressure may diminish the volume-stabilizing effects of PEEP. CASE SUMMARY: A 35-year-old man with abdominal compartment syndrome (intra-abdominal pressure > 48 cm H2O developed ARDS and was treated with V(T) of 4.5 mL/kg and PEEP of 20 cm H2O. Despite aggressive fluid therapy, appropriate airway humidification and tracheal suctioning, the patient developed complete bronchial obstruction, involving the entire right lung and left upper lobe. After bronchoscopy the patient was placed on a higher V(T) (7.0 mL/kg). Intermittent PEEP was instituted at 30 cm H2O for 2 breaths every 3 minutes. This intermittently raised the end-inspiratory plateau pressure from 38 cm H2O to 50 cm H2O. With the same airway humidity and tracheal suctioning practices bronchial obstruction did not reoccur. CONCLUSION: Low V(T) ventilation in ARDS may increase the risk of small airway closure and retained secretions. This adverse effect highlights the importance of pulmonary hygiene measures in ARDS during lung-protective ventilation.

New recurring cytogenetic abnormalities and association of blast cell karyotypes with prognosis in childhood T-cell acute lymphoblastic leukemia: a pediatric oncology group report of 343 cases.

To further define the cytogenetic differences between B-cell lineage (B-lineage) acute lymphoblastic leukemia (ALL) and T-cell lineage ALL (T-ALL) and to determine the prognostic value of cytogenetics in childhood T-ALL, the blast cell karyotypes of 343 cases of pediatric T-ALL, the largest series reported to date, were evaluated. Cytogenetics were performed in a single central laboratory, and the children were treated using a single Pediatric Oncology Group protocol. Clear differences between the karyotypic characteristics of B-lineage ALL and T-ALL were confirmed. This study suggests that there may be survival differences associated with some T-ALL blast cell karyotypes. Better survival is associated with only normal karyotypes and with t(10;14) (translocation of chromosomes 10 and 14); worse survival is associated with the presence of any derivative chromosome. Two new recurring chromosome aberrations previously not reported in T-ALL were found: del(1)(p22) and t(8;12)(q13;p13). Ten aberrations found in this series, which were reported only once previously in T-ALL, can now be considered recurring abnormalities in T-ALL. All 12 of these new recurring aberrations are targets for discovery and characterization of new genes that are important in T-cell development and leukemogenesis.

Measuring intra-esophageal pressure to assess transmural pulmonary arterial occlusion pressure in patients with acute lung injury: a case series and review.

BACKGROUND: Positive end-expiratory pressure (PEEP) may interfere with accurate assessment of cardiac function. PEEP may decrease left ventricular volume by lowering the transmural gradient between ventricular and pleural surface pressure (P(PL)) around the heart while raising the absolute pulmonary arterial occlusion pressure (PAOP). Clinical formulas used to predict the transmural PAOP (PAOP(TM)) require subtracting 25-50% of the PEEP level from the PAOP. However, both PAOP and P(PL) are influenced by transmitted PEEP and transmitted intra-abdominal pressure (IAP). We compared PAOP(TM) calculated by measuring intra-esophageal pressure (P(ES)) with PAOP(TM) estimated by clinical formulas. METHODS: Twenty-two P(ES) measurements were made with a bedside pulmonary mechanics monitor (BICORE CP-100) on 11 patients with acute lung injury who had an elevated PAOP (mean +/- standard deviation) of 21.1 +/- 6.2 mm Hg and PEEP of 13.0 +/- 3.8 mm Hg. Paired comparisons were made with the Wilcoxon signed-rank test and multiple comparisons were made using one-way analysis of variance (ANOVA) and the Student-Newman-Keuls test. Pearson product-moment correlation coefficients were calculated. A MEDLINE literature search was done to survey the reported range of PEEP transmitted to P(PL). RESULTS: P(ES) (14.6 +/- 5.0 mm Hg) exceeded PEEP; 9 of 11 patients had clinical evidence of increased IAP. PAOP(TM) predicted by clinical formulas were 13.5-17.7 mm Hg, whereas PAOP(TM) calculated by P(ES) was 6.2 +/- 3.6 mm Hg (p < 0.05). Linear regression revealed a moderate correlation between PAOP and PEEP (r = 0.49, p = 0.02). In contrast, there was a strong correlation between PAOP and P(ES) (r = 0.83, p < 0.0001). A review of data derived from the literature did not show a consistent pattern of PEEP transmission. CONCLUSION: PAOP(TM) calculated by P(ES) may reflect transmitted IAP to the pleural surface. Using P(ES) to calculate PAOP(TM) may provide a more accurate assessment of hemodynamic status than predicting PAOP(TM) using clinical formulas based solely on estimated PEEP transmission.

Adverse reactions to isosulfan blue during selective sentinel lymph node dissection in melanoma.

BACKGROUND: Selective sentinel lymph node (SLN) dissection can spare about 80% of patients with primary melanoma from radical lymph node dissection. This procedure identifies the SLN either visually by injecting isosulfan blue dye around the primary melanoma site or by handheld gamma probe after radiocolloid injection. METHODS: During selective SLN mapping, 1 to 5 ml of isosulfan blue was injected intradermally around the primary melanoma. From November 1993, to August 1998, 406 patients underwent intraoperative lymphatic mapping with the use of both isosulfan blue and radiocolloid injection. Three cases of selective SLN dissection, in which adverse reactions to isosulfan blue occurred, were reviewed. RESULTS: We report three cases of anaphylaxis after intradermal injection with isosulfan blue of 406 patients who underwent intraoperative lymphatic mapping by using the procedure as described above. The three cases we report vary in severity from treatable hypotension with urticaria and erythema to severe cardiovascular collapse with or without bronchospasm or urticaria. CONCLUSIONS: In our series, the incidence of anaphylaxis to isosulfan blue was approximately 1%. Anaphylaxis can be fatal if not recognized and treated rapidly. Operating room personnel who participate in intraoperative lymphatic mapping where isosulfan blue is used must be aware of the potential consequences and be prepared to treat anaphylaxis.

Improved flow and pressure capabilities of the Datex-Ohmeda SmartVent anesthesia ventilator.

STUDY OBJECTIVE: To compare the flow and pressure capabilities of the Datex-Ohmeda SmartVent (Ohmeda 7900, Datex-Ohmeda, Madison, WI) to previous Ohmeda (7810 and 7000, Datex-Ohmeda, Madison, WI) anesthesia ventilators. To determine airway pressure and minute ventilation thresholds for intraoperative use of a critical care ventilator. DESIGN: Three anesthesia ventilators and one critical care ventilator (Siemens Servo 900C, Siemens, Solna, Sweden) were studied in a lung model. Retrospective medical record review. SETTING: Research Laboratory and Critical Care Unit of a Level I Trauma Center. PATIENTS: 145 mechanically ventilated patients treated for acute respiratory failure who underwent 200 surgical procedures. INTERVENTIONS: The effect of increasing pressure on mean inspiratory flow was determined by cycling each ventilator through increasing restrictors. Maximum minute ventilation was measured at low compliance (10-30 mL/cm H2O), positive end-expiratory pressure (PEEP) (0-20 cm H2O), and increased airway resistance (approximately 19 and approximately 36 cm H2O/L/sec) in a mechanical lung model. MEASUREMENTS AND MAIN RESULTS: Flow, volume, and pressure were measured with a pulmonary mechanics monitor (BICORE CP-100, Thermo Respiratory Group, Yorba Linda, CA). Preoperative peak airway pressure and minute ventilation (VE) were extracted from the medical record. Mean inspiratory flow declined with increasing pressure in all anesthesia ventilators. The SmartVent and the 7810 produced greater mean inspiratory flow than did the 7000 ventilator. As compliance progressively decreased, the Siemens, the SmartVent, and the 7810 ventilators maintained VE compared to the 7000 ventilator. The Siemens and the SmartVent maintained VE with PEEP, compared to the 7810 and 7000 ventilators. During increased airway resistance, maximal VE was lower for all ventilators. The SmartVent met the ventilation requirements in 90% of the patients compared to 67% of patients with the 7000 ventilator. CONCLUSION: The improved pressure and flow capabilities of the SmartVent increase the threshold for using a critical care ventilator intraoperatively to a peak airway pressure > 65 cm H2O and/or VE > 18 L/min.

Medical and surgical management of severe colitis.

The management of severe ulcerative colitis and Crohn's colitis remains a challenge, despite significant advances in medical and surgical therapy. Optimal management of the patient with severe colitis requires close collaboration between the gastroenterologist and surgeon. All patients with severe colitis should be hospitalized and treated with intravenous corticosteroids. If significant improvement does not occur within 7 to 10 days, then intravenous cyclosporine therapy or surgery is appropriate. Newer medical therapies, including heparin, tacrolimus, and other immunomodulatory agents, show promise for the treatment of severe colitis. When surgery is necessary, a total abdominal colectomy with ileostomy is the appropriate surgical intervention in most cases. In patients presenting with fulminant colitis, toxic megacolon, or perforation, earlier surgical intervention is indicated. The evaluation of and approach to the medical and surgical management of severe colitis will be reviewed.

Catheter probe assisted endoluminal US in inflammatory bowel disease.

BACKGROUND: Use of an echocolonoscope to examine patients with inflammatory bowel disease is technically difficult. Catheter probe assisted endoluminal ultrasonography (US) may be a feasible alternative. METHODS: Determination of demographic information and clinical disease activity was followed by colonoscopy with biopsy. Catheter probe assisted endoluminal US was performed with measurements of thickness of the intestinal wall and evaluation of the structure of the sonographic layers. RESULTS: Twenty-eight patients, 7 with ulcerative colitis, 11 with Crohn's disease, and 10 healthy control subjects participated in a prospective study. Mean colonic wall thickness was 2.2 +/- 0.1 mm (controls) compared with 4. 1 +/- 0.4 mm (ulcerative colitis) (p < 0.001) and 4.4 +/- 0.4 mm (Crohn's disease) (p < 0.001). Among patients with ulcerative colitis, colonic wall thickness correlated with severity of colonoscopic changes (r = 0.84, p = 0.02). Among patients with Crohn's disease, loss of endosonographic layer structure correlated with disease activity score (r = 0.8, p = 0.003), and colonic wall thickness correlated with the severity of histologic changes (r = 0. 62, p = 0.04). CONCLUSIONS: Catheter probe assisted endoluminal US is technically feasible in the care of patients with inflammatory bowel disease. Endosonographic measurements of colonic wall thickness and layer structure provide clinically significant information.

Pathogenesis of inflammatory bowel disease.

In spite of expanding knowledge of cellular and molecular mechanisms of intestinal inflammation, the etiology and pathogenesis of inflammatory bowel disease (IBD) remain obscure. The link between the environment and IBD is still circumstantial, but definite progress is occurring in defining genetic susceptibility loci for Crohn's disease (CD) and ulcerative colitis (UC). The notion that normal enteric flora play a role in initiating or maintaining IBD is gaining momentum. Some components of the flora may act as noxious agents, whereas others (probiotics) seem to have a protective effect. The importance of the mucosal immune system to IBD is established, and evidence is accumulating that nonimmune components, such as epithelial, mesenchymal, and endothelial cells, also contribute to gut inflammation. The effect of cytokines in intestinal immunity is being elucidated by studies on their molecular mechanism, particularly the activation of nuclear factor (NF)-kappaB. Finally, the beneficial effects of cytoprotective prostaglandins and cell adhesion molecule (CAM) blockade promise novel therapeutic opportunities derived from an improved understanding of IBD pathogenesis.

The influence of human endotoxemia on CD95-induced apoptosis.

BACKGROUND: The responses of monocyte and neutrophil tumor necrosis factor receptor type 1 (TNFR-1) and TNFR-2 during systemic inflammation have been described previously. Several other members of the TNFR superfamily also appear to have regulatory roles in immunocyte function, including apoptosis. However, the response of these other receptor members, such as CD95, to systemic inflammation is unclear. OBJECTIVES: To compare the response of CD95 with that of TNFR during systemic inflammation and to assess the influence of the inflammatory milieu on CD95 function. SETTING: Adult clinical research center of a university hospital. SUBJECTS AND METHODS: Five healthy male subjects were administered intravenous endotoxin (2 ng/kg), and systemic response was measured by cytokine analysis and receptor expression assays during a 48-hour period. CD95 function during systemic inflammation was assessed using a Jurkat cell bioassay for degree of apoptosis. RESULTS: Monocyte and neutrophil CD95 expression exhibited changes parallel to that of TNFR following endotoxin injection. In contrast to soluble TNFR, which was transiently elevated during endotoxemia, soluble CD95 levels remained unchanged from baseline. Jurkat cells incubated in normal and post-endotoxin serum samples equally exhibited less than 10% spontaneous apoptosis. No soluble CD95 ligand was detectable in experimental human endotoxemia. CONCLUSIONS: Cell-associated CD95 exhibited changes parallel to its receptor family member TNFR following endotoxin administration. Soluble CD95 is present in human serum samples, but the levels remained unchanged following endotoxin administration. No soluble CD95 ligand activity was detectable by enzyme-linked immunosorbent assay or by functional assay. The potential protective role of soluble CD95 in human serum samples against CD95 ligand-induced apoptosis remains to be defined.

Sympathetic blockade does not enhance tissue warming during isolated heated limb perfusion.

UNLABELLED: Isolated, heated limb perfusion is used for the treatment of locally recurrent melanoma, intransit metastases, and acral lentiginous melanomas. Tissue warming during this procedure requires adequate perfusion within the isolated extremity. At our institution, spinal or epidural anesthesia was used to produce sympathetic blockade and vasodilation for lower extremity procedures. More recently, we began using mild systemic hyperthermia to produce active thermoregulatory vasodilation. In the presence of heat stress, sympathetic blockade may actually decrease skin blood flow because active cutaneous vasodilation, which is associated with sweating, is dependent on intact sympathetic innervation. We therefore investigated whether the continued use of neuraxial blockade was justified. Twenty patients undergoing lower extremity perfusions were alternately assigned to receive either combined general and spinal anesthesia or general anesthesia alone. All were aggressively warmed using forced air and circulating water. There were no significant differences in tissue temperatures (measured at four sites in the isolated limb) between groups at any time before or after the start of perfusion. Similarly, pump flow (715 +/- 211 mL/min versus 965 +/- 514 mL/min) and the time required to achieve an average tissue temperature of 39 degrees C (43 +/- 16 vs 34 +/- 13 min) were not different between groups (spinal versus no spinal). Sweating was observed in all but three patients at esophageal temperatures of 37.9 +/- 0.6 degrees C. We conclude that sympathetic blockade confers no added benefit for tissue warming during isolated limb perfusions in the presence of induced mild systemic hyperthermia. IMPLICATIONS: Sympathetic blockade prevents adrenergic vasoconstriction, but also inhibits active, neurally mediated cutaneous vasodilation (a normal thermoregulatory response to heat). In slightly hyperthermic patients, we demonstrated that spinal anesthesia does not improve convective tissue warming during isolated, heated limb perfusion. Mild systemic hyperthermia may promote greater vasodilation than sympathetic blockade.