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Hemorrhagic Complications of Anticoagulant Treatment. part 22

Wednesday, October 21st, 2020

Finally, the results of Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries IIa and the Thrombolysis in Myocardial Infarction (TIMI) 9A studies in patients with ischemic coronary syndromes indicated that a 20% increase in the IV heparin dose above the 1,000 U/h that was used in the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries I study increased the risk of intracranial bleeding when combined with thrombolytic therapy.

3.1.2 Relationship between risk of bleeding and method of administering heparin

The evidence for a relationship between the risk of bleeding and the method of administering heparin comes from randomized trials in which UFH was either administered by continuous IV infusion with intermittent IV injection, continuous IV heparin with subcutaneous heparin, continuous IV heparin for approximately 10 days with a shorter course (4 to 5 days), continuous IV heparin and oral anticoagulants compared with oral anticoagulants alone, continuous IV heparin administered on a weight-adjusted basis with a standard clinical approach (5,000-U bolus, 1,000 U/h), and continuous IV heparin monitored using either the APTT or monitored using a heparin assay.

In summary, there was an increased rate of major bleeding with intermittent IV heparin compared with continuous IV infusion. Continuous IV heparin caused less bleeding than intermittent IV heparin; continuous IV heparin and subcutaneous heparin were associated with a similar amount of bleeding; and continuous IV heparin for approximately 10 days and 5 days caused a similar amount of bleeding.

3.1.3 Relationship between the risk of bleeding and patient risk factors

There is good evidence that comorbid conditions, particularly recent surgery or trauma, are very important risk factors for heparin-induced bleeding. This association was demonstrated in the study by Hull and associates in patients with proximal vein thrombosis. Patients without clinical risk factors for bleeding were treated with a starting dose of 40,000 U of heparin by continuous infusion, while those with well-recognized risk factors for bleeding (recent surgery, trauma) received a starting dose of 30,000 U. Bleeding occurred in 1 of 88 low-risk patients (1%) who received 40,000 U initially and 12 of 111 high-risk patients (11%) who received 30,000 U.

The concomitant use of aspirin was identified as a risk factor in early retrospective studies and corroborated by Sethi and associates. In their study in patients undergoing aortocoronary bypass surgery, the preoperative use of aspirin caused excessive operative bleeding in patients who receive very high doses of heparin as part of the routine for bypass procedures. Although the concomitant use of aspirin is associated with heparin-induced bleeding, this combination is used frequently in the initial treatment of acute coronary artery syndromes without serious bleeding.

Hemorrhagic Complications of Anticoagulant Treatment. part 21

Wednesday, October 21st, 2020

3.1 Determinants of bleeding

3.1.1 Relationship between risk of bleeding and heparin dose/response

Since the anticoagulant response to heparin (measured by a test of blood coagulation, eg, the activated partial thromboplastin time [APTT]) is influenced by the heparin dose, it was not possible from reported studies to separate the effects of these two variables (dose and laboratory response) on hemorrhagic rates. To our knowledge, there have been no randomized trials in patients with established VTE directly comparing different doses of heparin. In a study evaluating prophylaxis in patients with recent-onset traumatic spinal cord injuries, the incidence of bleeding was significantly greater in patients randomized to receive heparin adjusted to maintain the APTT at 1.5 times control than compared with heparin, 5,000 U bid. The mean dose of heparin for the adjusted-dose regimen was 13,200 U bid. Bleeding occurred in seven adjusted-dose patients compared with none in the fixed-dose group.

Subgroup analysis of randomized trials and prospective cohort studies provide suggestive evidence for an association between the incidence of bleeding and the anticoagulant response. In the Urokinase Pulmonary Embolism Study, bleeding occurred in 20% of patients assigned to heparin in whom whole-blood clotting time was > 60 min, compared to 5% of those whose whole-blood clotting time was < 60 min (relative risk, 4.0). Norman and Provan reported five major bleeds in 10 patients whose APTT was prolonged to more than twice the upper limit of their therapeutic range for at least 50% of their assays, but in only 1 of 40 patients whose APTT remained therapeutic (relative risk, 20.0). Wilson et al described 80 nonsurgical patients receiving heparin monitored by the whole-blood clotting time. Fifty-six percent who received “excessive heparin” bled, whereas only 16% who did not receive excessive heparin bled (relative risk, 3.5). Anand et al examined the relationship between the APTT and bleeding in 5,058 patients with acute coronary syndrome who received IV heparin in the Organization to Assess Strategies for Ischemic Syndromes-2 trial. For every 10-s increase in the APTT, the major bleeding was increased by 7% (p = 0.0004).

Although none of the studies were designed to compare the effects on bleeding of either different doses of heparin or different levels of heparin response, there is a suggestion that bleeding is more likely to occur when an in vitro test of coagulation is prolonged excessively, but this evidence is by no means definitive. In addition, there is good evidence that serious bleeding during heparin treatment can occur when the anticoagulant response is in the therapeutic range.

Hemorrhagic Complications of Anticoagulant Treatment. part 20

Wednesday, October 21st, 2020

There were no major bleeds in the ximelagatran group and one in the warfarin group. In the SPORTIF III trial, 3,407 patients with nonvalvular atrial fibrillation received ximelagatran, 36 mg bid, or warfarin (INR, 2.0 to 3.0). The rates of major bleeding were 1.3% and 1.8%, respectively. This difference was not statistically significant.

Oral direct thrombin inhibition with ximelagatran at doses of 24 mg, 36 mg, 48 mg, or 60 mg bid plus 160 mg/d of aspirin was compared to 160 mg/d of aspirin alone in a recent multicenter blinded trial for secondary prevention of myocardial infarction. There were 1,883 patients followed up for a 6-month treatment period. The rates of major bleeding did not differ between treatment groups (1% for aspirin alone vs 2% for combined ximelagatran doses), but patients in the combined ximelagatran groups were three times more likely to stop therapy due to bleeding (hazard ratio, 3.35; 95% CI, 1.87 to 6.01). In addition, any bleeding (major and minor) was more frequent in the combined ximelagatran group (22%) compared to the aspirin-alone group (13%) [hazard ratio, 1.76; 95% CI, 1.38 to 2.25].

Ximelagatran has been evaluated for both short-term and long-term treatment of VTE (Thrombin Inhibitors in Venous Thromboembolism studies). In the shortterm treatment study, 2,491 patients with acute DVT were treated for 6 months with ximelagatran, 36 mg bid, or LMWH followed by vitamin K antagonist therapy (INR, 2.0    to 3.0), using a blinded design. An “on-treatment” analysis suggested less major bleeding with ximelagatran (1.3% vs 2.2%; 95% CI for difference, -2.0 to + 0.2%); intention-to-treat analyses have not been reported for bleeding.

In a long-term treatment study, 18 months of ximel-agatran, 24 mg bid, was compared with placebo in 1,224 patients with DVT or pulmonary embolism who had completed 6 months of initial treatment with vitamin K antagonists. There was no apparent increase of major bleeding with ximelagatran (0.7%/yr; hazard ratio, 1.2; 95% CI, 0.4 to 3.8).

3.0    Heparins

Heparin is usually administered in low doses by subcutaneous injection to prevent venous thrombosis (prophylactic heparin), in higher doses to treat patients with acute VTE or with acute coronary syndromes (therapeutic heparin), and in very high doses in patients during open-heart surgery. In this chapter, we will discuss only bleeding associated with therapeutic heparin (see the chapter by Geerts et al for a discussion of bleeding associated with prophylactic heparin). Heparin has the potential to induce bleeding by inhibiting blood coagulation, by impairing platelet function, and by increasing capillary permeabil-ity. Heparin can also produce thrombocytopenia, but this is rarely an important cause of bleeding.

The Relationship of Asthma Impairment Determined by Psychometric Tools to Future Asthma Exacerbations

Saturday, October 10th, 2020

Methods: Two thousand six hundred eighty patients with persistent asthma completed a survey that included the Asthma Control Test (ACT), mini-Asthma Quality of Life Questionnaire (mAQLQ), and Asthma Impact Survey (AIS-6), as well as a history of exacerbations in the prior 12 months. An exploratory factor analysis was performed using the questions of the three tools, and individual patient factor scores were calculated. Independent relationships between predictors (tools and factors) and exacerbations the following year captured from administrative data were evaluated.

Results: Each tool was significantly related (P < .0001) to future exacerbations above and beyond the risk conferred by prior exacerbations (relative risk [RR] = 1.3). When prior exacerbations were included in the model, the three impairment tools provided similar and overlapping information, such that only the mAQLQ entered the model (RR = 1.3; 95% CI, 1.1-1.5). Factor analysis revealed three factors (symptoms, activity, and bother) that were each significantly associated (P < .0001) with future asthma exacerbations. However, only the activity factor was independently related to future exacerbations.

Conclusions: Asthma impairment is significantly related to the risk of future exacerbations, but the ACT, mAQLQ, and AIS-6 do not provide independent information from each other in this regard. Interference with activities is the primary subjective component of asthma impairment that is related to the risk of future exacerbations.

Abbreviations: ACT = Asthma Control Test; AIS-6 = Asthma Impact Survey; mAQLQ = mini-Asthma Quality of Life Questionnaire; PPV = positive predictive value

Asthma causes a spectrum of morbidity, ranging from symptoms to functional impairment to exacerbations. Factor analysis studies have suggested that asthma exacerbations represent a separate dimension from symptoms, quality of life, and pulmonary function. Partly in response to these data, the new National Asthma Education and Prevention Program Expert Panel 3 guidelines divide asthma severity and control into two domains: impairment and risk.

Long-term Disease-Free Survival of a Patient With Synchronous Bilateral Lung Adenocarcinoma Displaying Different EGFR and C-MYC Molecular Characteristics

Saturday, October 10th, 2020

The second interaction to consider is the potential effect of the airway edema on subsequent bronchoconstriction. Thickening of the airway wall has been hypothesized to be one of the mechanisms contributing to airway hyperresponsiveness in asthma. Acute changes in thickness can occur from inflammation or from local edema caused by vascular leakage in the wall. Such acute airway wall thickening secondary to edema formation has been proposed as a possible cause of wheezing in patients with congestive heart disease in left ventricular failure. As the heart failure improves, pulmonary function also improves. Although it cannot be ruled out that airway edema led to bronchocon-striction, given the clinical scenario it remains more likely that in this case the bronchoconstriction indeed came first, perhaps even generating a “downward spiral” of edema, airway narrowing, and bronchoconstriction.

The main difficulty with multiple lung tumors is distinguishing synchronous and metachronous lesions from second independent primary tumors, particularly when dealing with the same histologic type. Challenging diagnostic hurdles may explain, at least in part, the extremely variable (0%-79%) 5-year survival rate. We present a case report of a patient with synchronous primary adenocarcinoma treated with surgery that exhibited different EGFR gene status, with an exon 19 mutation in the adenocarcinoma of the left upper lobe that was absent in the right upper lobe. Further, specific EGFR and C-MYC amplification events were associated only with the EGFR-mutated lesion. According to an independent evolution theory, these events were classified as early stage, and the patient is still alive and free of disease 70 months after surgery. Molecular evaluation was an important tool to support the diagnosis of synchronous primary adenocarcinoma, which had not been possible with the application of Martini-Melamed criteria.

Background: Impairment and risk are considered separate domains of asthma control, but relationships between them are not completely understood. We compared three validated questionnaires reflecting asthma impairment in their ability to predict future exacerbations.

We suspect that NPPE after bronchospasm may occur more frequently

Saturday, October 10th, 2020

Noninvasive positive-pressure ventilation was started with 6 cm H2O of pressure support over 8 cm H2O of positive end expiratory pressure. Consequently, the patient rapidly improved in the PACU, and noninvasive positive pressure ventilation was terminated after 5 h. The following morning the patient was transferred to the gynecology ward and went on to make a full recovery over the next 24 h.


We suspect that NPPE after bronchospasm may occur more frequently than reported but goes unrecognized because pulmonary edema after bronchospasm can often be attributed to other factors, such as aspiration, volume overload, or atelectasis. Many patients require oxygen therapy in the PACU, chest radiographs are not routinely obtained, and often NPPE resolves quickly with conservative measures.

The interaction between airway edema and bronchocon-striction raises many issues. The first is whether broncho-constriction could be the root cause of the NPPE. There have been a few theories as to this possibility. Large negative pleural pressures have been measured in children with acute asthma, and this has been shown to be correlated with fluid accumulation in the lungs of dogs. However, asthma is a very heterogeneous disease and bronchoconstric-tion is not uniform in either location or extent. It is possible to close even large central cartilaginous airways with a large enough stimulus, but whether this can happen under clinical conditions is unclear. Although narrowing of large airways occurs in asthma, it is generally believed that it is the additional closure of hundreds or even thousands of small airways leading to air trapping and hyperinflation that causes the clinical signs and symptoms of asthma (Fig 2).

This patient had severe pulmonary disease, a recent decrease in her oral steroid dose, and significant stimulation of her trachea during extubation. This constellation of events could have lead to significant conducting airway narrowing with inadequate airflow during strong inspiratory efforts, leading to the resultant NPPE. A mucus plug could be another inciting factor for the development of her NPPE.