Enhanced thromboprophylaxis in critically ill patients with COVID-19 infection.

Background: Patients with severe SARS-CoV-2 infection have been shown to have abnormal coagulation parameters and are at increased risk of thromboembolism. The optimal thromboprophylaxis regimen that minimizes thrombosis without increased risk of serious bleeding is uncertain. Objectives: To describe the efficacy and safety of increased intensity (enhanced) thromboprophylaxis in patients with COVID-19 admitted to the medical intensive care unit (MICU). Methods: This is a retrospective cohort analysis of patients with a diagnosis of COVID-19 admitted to the MICU of an urban safety net hospital. With the exception of patients being supported with extracorporeal membrane oxygenation or on chronic anticoagulation who received therapeutic dosing of anticoagulation, thromboprophylaxis was given as either enoxaparin or unfractionated heparin in doses higher than those recommended for standard prophylaxis, but lower than those used for therapeutic anticoagulation. Main results: Of the 120 patients managed with an enhanced thromboprophylaxis protocol, 6 (5%) experienced thromboembolism as a result of their COVID-19 disease (1 pulmonary embolus, 4 deep vein thromboses, and 1 arterial embolism). Four patients experienced major bleeding while receiving therapeutic anticoagulation. Conclusions: In critically ill patients with COVID-19, increased intensity (enhanced) thromboprophylaxis appears to be effective at preventing clinically significant thromboembolic events without an increased risk of serious bleeding.

Computer-assisted versus unassisted analysis of the exercise electrocardiogram in patients without myocardial infarction.

Computer-assisted interpretation of the exercise electrocardiogram has been advocated to improve the accuracy of diagnosing coronary artery disease. Its accuracy was compared with a blinded visual interpretation of exercise-induced ST depression in 271 consecutive subjects without prior myocardial infarction who were referred for coronary angiography. The sensitivity of the visual and computer readings was 0.51 and 0.51, respectively, at a specificity of 0.87. Receiver operating characteristic curves were generated for the visual and computer ST depression in lead V5. Analysis of the areas under these curves showed no significant difference between them, indicating that computer-assisted analysis was not superior to unmodified visual analysis. A similar analysis was applied to two other computer indexes reported to be superior to visual assessments (treadmill exercise score and ST index). These computer indexes were not superior to a conventional visual analysis of leads I, II, V2, V4 and V5 in predicting severe disease (greater than 50% luminal narrowing). These results suggest that computer-assisted interpretation does not improve the accuracy of exercise electrocardiography in diagnosing coronary artery disease in subjects without prior myocardial infarction.

Myocardial infarction and normal coronary arteriography: a 10 year clinical and risk analysis of 74 patients.

Myocardial infarction with normal coronary arteries was identified in 74 patients with a mean age of 43 years (range 19 to 66). A mean follow-up period of 10.5 years after documented myocardial infarction and 8.6 years after cardiac catheterization was obtained. The survival rate was 85% (n = 63). There were no statistical differences in age or clinical risk factor prevalence between survivors and nonsurvivors. Moderate (55%) to severe (27%) left ventricular impairment was more common in nonsurvivors. Nine of 11 deaths were cardiovascular, 6 were sudden and 8 occurred in patients with moderate to severe global left ventricular impairment. Seventy-six percent of survivors were asymptomatic and 86% were fully active at follow-up. Two survivors and three nonsurvivors experienced a second myocardial infarction. The clinical risk factors of the study group (Group I) were compared by age, sex and year of catheterization with risk factors in two matched groups. Group II consisted of 74 patients with coronary occlusive disease and myocardial infarction and Group III consisted of 148 patients with normal arteriograms. Group I differed from Group II in having fewer clinical risk factors (p = 0.01 to less than 0.0001). Cigarette smoking did not differ significantly between Group I (72%) and Group II (69%) but was less common in Group III (45%) (p less than 0.001). Hormone therapy or the peripartum state was more common in women in Group I (34%) than in women in Group III (14%) (p = 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)

Identification of a mouse germ cell-less homologue with conserved activity in Drosophila.

Drosophila Germ cell-less (Gcl) has previously been shown to be important in early events during the formation of pole cells, which are the germ cell precursors in the fly. We have isolated a 524 amino acid mouse gene with 32% identity and 49% similarity to Drosophila gcl, termed mgcl-1. Like Drosophila Gcl, mGcl-1 localizes to the nuclear envelope. Ectopic expression of mgcl-1 in Drosophila rescues the gcl-null phenotype, indicating that mGcl-1 is a functional homologue of Gcl. mgcl-1 maps to chromosome 6 at 47.3 cM, and is expressed at low levels at all embryonic stages examined from 8.5 to 18.5 d.p.c. as well as in many adult tissues. Different from Drosophila gcl, mgcl-1 is not highly expressed at the time the primordial germ cells appear in the mouse, but high mgcl-1 expression is found in selected mouse adult male germ cells. The differences in these expression patterns in light of conserved activity between the two genes is discussed.

Vasopressin-resistant nephrogenic diabetes insipidus. A result of amphotericin B therapy.

Polyuria and polydipsia developed in two cases during amphotericin B therapy for deep mycoses. Neither patient could concentrate his urine in response to water deprivation or exogenous vasopressin. Other causes of vasopressin-resistant nephrogenic diabetes insipidus were not present. Three months after amphotericin B therapy had been discontinued, concentrating ability improved toward normal. A third patient was further observed and demonstrated normal diluting capacity but impaired free-water reabsorption, suggesting a distal tubular defect consistent with nephrogenic diabetes insipidus. Four months after discontinuing therapy, renal concentrating ability was normal. Amphotericin B can induce a reversible form of nephrogenic diabetes insipidus.

Alveolar hemorrhage syndromes: diffuse microvascular lung hemorrhage in immune and idiopathic disorders.

We have reviewed the alveolar hemorrhage (AH) syndromes, defined as immune or idiopathic disorders associated with diffuse microvascular hemorrhage into the acinar portion of the lung. The disorders that are most often associated with AH include antibasement membrane antibodies (ABMA) disease, idiopathic pulmonary hemosiderosis, systemic lupus erythematosus, systemic vasculitides, and idiopathic rapidly progressive glomerulonephritis. An approach to the recognition, diagnosis, and treatment of the AH syndromes has been outlined and several illustrative case studies have been presented. Recognition of AH is not usually difficult, but does require a high index of suspicion, since many disease processes may give rise to hemoptysis with infiltrates on chest roentgenogram. Recognition of AH is aided by careful clinical and laboratory assessment for evidence of extrapulmonary disease; simple hematologic studies such as sequential hemoglobins and iron studies; and measurement of carbon monoxide uptake by the lungs. Early recognition of AH may decrease the likelihood of respiratory failure and end-stage renal disease. The specific etiology of AH is usually determined by clinical examination, serologic assay for ABMA, and percutaneous renal biopsy by immunofluorescence. Open-lung biopsy is required in a minority of cases. High-dose pulse methylprednisolone appears to effectively control AH of diverse etiology. Combined plasma exchange and immunosuppression controls AH in ABMA disease and is the treatment of choice in this disorder. Cyclophosphamide is used for Wegener's granulomatosis, and sometimes in systemic necrotizing vasculitis, in an attempt to prevent irreversible damage to the kidneys.

Amyotrophic lateral sclerosis: effects of acute intravenous and chronic subcutaneous administration of thyrotropin-releasing hormone in controlled trials.

We performed double-blind crossover trials to assess the effects of thyrotropin-releasing hormone (TRH) on amyotrophic lateral sclerosis patients. For acute intravenous trials, 500 mg TRH or placebo with norepinephrine was given at 1-week intervals (16 patients). CSF TRH concentration increased, and clinical side effects appeared with TRH. For chronic studies, 25 mg TRH and a saline placebo were given subcutaneously every day for 3 months (25 patients). CSF TRH level increased 29-fold after a single TRH injection, and mild transient side effects occurred. Vital signs, respiratory function, semiquantitative and quantitative neurologic function, muscle strength by manual and dynamometer testing, and EMG were studied. With daily TRH, 10 patients noted subjective improvement without objective evidence, and 10 patients complained of worsening of the disease with objective decline after TRH was stopped. Statistical analysis, however, showed no beneficial effects from either acute or chronic TRH trials.

Diffuse intrapulmonary hemorrhage and glomerulonephritis unrelated to anti-glomerular basement membrane antibody.

Nine patients with diffuse intrapulmonary hemorrhage and glomerulonephritis not due to anti-glomerular basement membrane (anti-GBM) antibody are described and similar previously reported cases are reviewed. Eight patients were seen during a four-year interval and represented 47 percent of the cases of pulmonary hemorrhage and glomerulonephritis seen during this period. Diagnoses included systemic vasculitis of unspecified type in two patients with seropositive rhematoid arthritis, idiopathic crescentic glomerulonephritis with negative immunofluorescence in two, Wegener's granulomatosis in two, and polyarteritis nodosa, Henoch-Schönlein purpura, and mixed connective tissue disease in one each. Differentiation from anti-GBM antibody-mediated pulmonary hemorrhage and glomerulonephritis by clinical evaluation alone was frequently difficult, emphasizing the importance of both immunopathologic studies and evaluation of serum for anti-GBM antibody in all patients with pulmonary hemorrhage and glomerulonephritis. In eight of nine patients, significant episodes of pulmonary hemorrhage improved markedly within 24 to 72 hours following initiation of high-dose corticosteroid therapy. In contrast, renal function did not improve in the majority of patients.

Children as victims of violence: a national survey.

OBJECTIVE: The goal of this study was to gain a more comprehensive perspective on the scope, variety, and consequences of child victimization, which has been obscured by a fragmentation into specific problems like sexual abuse or kidnapping. METHODS: Two thousand children aged 10 to 16 years were interviewed in a national telephone survey of children. RESULTS: In the previous year, a quarter of the children had experienced a completed victimization, one in eight had experienced an injury, and one in a hundred required medical attention as a result. Nonfamily physical assaults were the most numerous. Contact sexual abuse occurred to 3.2% of girls and 0.6% of boys. There were also substantial numbers of incidents of attempted kidnappings and violence directed to children's genitals. CONCLUSION: The victimization of children occurs to a greater extent than has been previously reported and is poorly represented in official statistics. IMPLICATION: The authors argue for a more comprehensive interest in children's victimization including better national statistics about the problem.

Single night studies in obstructive sleep apnea.

The role of single night studies and the determinants of effective nasal continuous positive airway (CPAP) pressures were determined in 412 consecutive patients between 1984 and 1989. Patients chosen for analysis had an apnea index (AI) of greater than or equal to 20 hr-1 prior to CPAP. The AI was 67 +/- 30 hr-1, the body mass index (BMI) was 36 +/- 9 kg/m2, the age was 51 +/- 13 yr and the lowest oxygen saturation was 72 +/- 14%. Effective CPAP (9 +/- 3 cm H2O) was documented in 320 patients on single night studies and resulted in a 99% reduction in the frequency of obstructive events and improvement in the lowest O2 saturation to 94 +/- 5%. Only 18% of the variability in effective CPAP could be explained by AI and BMI. Single night studies are sufficient to establish effective CPAP in 78% of patients and offer considerable conservation of resources compared to routine multiple night studies. Effective CPAP pressures are variable and must be determined by incremental CPAP trials.

Fever, hyperdynamic shock, and multiple-system organ failure. A pseudo-sepsis syndrome associated with chronic salicylate intoxication.

OBJECTIVE: To describe a sepsis-like syndrome associated with chronic salicylate intoxication. DESIGN: Retrospective clinical study. SETTING: University-affiliated county hospital. PATIENTS: Five patients who became accidentally intoxicated while ingesting salicylates on a long-term daily basis. RESULTS OF DATA ANALYSIS: All five salicylate-intoxicated patients had clinical and laboratory features that were highly suggestive of sepsis, but no bacteriologic or pathologic evidence of infection could be documented. Features included fever, leukocytosis with increased band forms, hypotension with a reduced SVR and multiple system organ failure (ARDS, encephalopathy, renal failure, and DIC). A diagnosis of salicylate intoxication was made at the time of admission to the hospital in only one case. In the other four cases, the presumptive diagnosis was sepsis; a correct diagnosis of salicylate intoxication was not established until between 16 h and 10 days after admission in these four cases. Two patients died, one patient required permanent hemodialysis, and two patients recovered fully only after prolonged and complicated hospitalizations. The pathogenesis of this syndrome is uncertain. In two cases, serum levels of TNF-alpha, IL-1 beta and IL-6 were measured by ELISA. In both cases serum IL-6 was markedly increased, and in one case serum TNF-alpha was also elevated. CONCLUSION: Occult salicylate intoxication should be considered when apparent sepsis syndrome occurs without a readily easily identifiable source of infection.

Right ventricular end-diastolic volume as a predictor of the hemodynamic response to a fluid challenge.

OBJECTIVE: To compare thermodilution right ventricular end-diastolic volume index (RVEDVI) and pulmonary artery occlusion pressure (Ppao) as predictors of the hemodynamic response to a fluid challenge. DESIGN: Prospective cohort study. SETTING: Medical ICU of a university-affiliated county hospital and medical-surgical ICU of a community hospital. PATIENTS: Twenty-five critically ill patients who had one or more clinical conditions that suggested the possibility of inadequate preload. INTERVENTIONS: Thirty-six fluid challenges. Fluid (saline or colloid) was administered rapidly until the Ppao rose by at least 3 mm Hg. When a patient underwent more than one fluid challenge, these were given on separate days and for different clinical indications. MEASUREMENTS AND RESULTS: Responders (n=20; > or = 10% increase in stroke volume [SV]) and nonresponders (n=16; <10% increase in SV) differed with respect to baseline Ppao (10.0+/-3.4 vs 14.2+/-3.6 mm Hg; p=0.001), but not with respect to baseline RVEDVI (105+/-31 vs 119+/-33 mL/m2; p=0.22). There was a moderate correlation between RVEDVI and fluid-induced change in SV (r=0.44); the relationship between Ppao and change in SV was stronger (r=0.58). A positive response to fluid was observed in 4 of 9 cases in which RVEDVI exceeded 138 mL/m2, a threshold value that has been suggested to reliably predict a poor response to fluid. CONCLUSION: RVEDVI was not a reliable predictor of the response to fluid. As a predictor of fluid responsiveness, Ppao was superior to RVEDVI. In an individual patient, adequacy of preload is best assessed by an empiric fluid challenge.

Tidal volume reduction in ARDS. Effect on cardiac output and arterial oxygenation.

During continuous positive pressure ventilation (CPPV), mean airway pressure and lung volume will be influenced both by the tidal volume (VT) employed and the amount of positive end-expiratory pressure (PEEP). The effect of varying levels of CPPV on PaO2 and cardiac output (Q) has been previously assessed by adjusting the level of PEEP at constant VT. This study examined the influence of a 200-ml reduction in VT, at a constant PEEP of 15 cm H2O, on the PaO2 and Q of 21 patients with adult respiratory distress syndrome (ARDS). The relationship between change in Q and change in total respiratory system compliance (Cst) after VT reduction was also examined. VT reduction from 14.1 +/- 0.8 ml/kg to 11.2 +/- 0.9 ml/kg yielded an increase in Q (+ 15 +/- 12 percent, p less than 0.01) without a significant change in PaO2 (-6.3 +/- 15.0 mm Hg, p = 0.08). Cst increased with VT reduction (+ 3.1 +/- 1.8 ml/cm H2O). There was only a modest correlation (r = +0.42, p = 0.06) between delta Q percent and delta Cst following VT reduction. VT reduction at high level PEEP may yield a significant improvement in Q and net O2 delivery, but the degree of hemodynamic improvement is variable and is not reliably predicted noninvasively by measurement of Cst.

Interpretation of the pulmonary artery occlusion pressure in mechanically ventilated patients with large respiratory excursions in intrathoracic pressure.

OBJECTIVE: To assess the reliability of the pulmonary artery occlusion pressure (Ppao) when respiratory excursions in intrathoracic pressure are prominent. DESIGN: We studied 24 critically ill patients who had 15 mm Hg or more of respiratory excursion in their Ppao tracing. Large respiratory excursions resulted from respiratory muscle activity that persisted despite sedation and mechanical ventilation in the assist-control mode. From the Ppao tracing, the end-expiratory and mid-point values were recorded; the latter was measured halfway between end-expiration and the nadir due to inspiratory triggering. The Ppao was then re-measured after administration of a non-depolarizing muscle relaxant. SETTING: Medical intensive care unit of a university-affiliated teaching hospital. MEASUREMENTS AND RESULTS: The difference between the pre-relaxation end-expiratory Ppao and the relaxed Ppao was larger than the difference between the pre-relaxation mid-point Ppao and the relaxed Ppao (11 +/- 5 vs 3 +/- 3 mm Hg, p < 0.01). In 21 of 24 (88%) cases, the relaxed Ppao was more closely approximated by the mid-point Ppao than by the end-expiratory Ppao. The difference between the end-expiratory Ppao and the relaxed Ppao increased as the amount of respiratory excursion increased (r = 0.51; p < 0.01). CONCLUSIONS: In mechanically ventilated patients whose respiratory muscles produce large excursions in the Ppao, the end-expiratory Ppao is often much higher than the Ppao measured after muscle relaxation. The pre-relaxation mid-point Ppao and the relaxed Ppao are usually similar, but this may not be true in individual patients. In this setting, the Ppao measured after muscle relaxation probably provides the most clinically reliable estimate of left heart filling pressure.

Effect of hypoxia on brainstem concentration of biogenic amines in postnatal rabbits.

The effects of hypoxia FiO2 = 0.10 on concentration of biogenic amines in specific brainstem nuclear groups were investigated in 3-and 21-day-old rabbits. The rabbit pups were confined to temperature-controlled water-jacketed chambers and exposed to 6h of 21% O2 or to one of 3 combinations of 21% O2 and 10% O2. These 3 combinations were either intermittent hypoxia, or 4 h of normoxia followed by 2 h constant hypoxia, or 2 h of hypoxia followed by recovery for 4 h in normoxia. Radioenzymatic assays were used to determine the concentration of dopamine, norepinephrine and serotonin in the following brainstem nuclei: substantia nigra, locus coeruleus, dorsal raphe and the nucleus reticularis pontis oralis. Compared with control, hypoxia did not affect dopamine levels at either age. The concentration of norepinephrine was inconsistently affected by hypoxia at either age. In contrast, in the 3-day-old rabbits serotonin was consistently reduced in each of the nuclei. In the 21-day-old rabbits, serotonin was either unchanged or increased following hypoxia. Our results show that hypoxia alters the concentration of serotonin in an age-specific manner. This change in serotonin concentration may reflect altered serotonin metabolism and suggests a possible mechanism by which hypoxia disrupts physiologic homeostasis in newborns.

Development of methionine-enkephalin in microdissected areas of the rabbit brain.

Microdissected areas of the rabbit brain were isolated at prenatal day E-29, postnatal days P-3, 7, 14, 21, 2 months and adults. Methionine-enkephalin (ME) was assayed by RIA and ME concentration [ME] was expressed relative to the protein content of the extracted brain tissues. In brain nuclei with important roles in respiratory control [ME] was higher in prenatal and early postnatal life than in adults. In contrast, the prenatal and early postnatal [ME] levels in other nuclei were lower than or equal to adult values. These data suggest an important and changing role for ME in respiratory control throughout development. Early high [ME] levels within brainstem respiratory control nuclei may contribute to the newborn's increased susceptibility to respiratory depression.

Expression of syndecan-3 and tenascin-C: possible involvement in periosteum development.

The development of cartilaginous elements of long bone during embryogenesis and postnatal bone repair processes is a complex process that involves skeletal cells and surrounding mesenchymal periosteal cells. Relatively little is known of the mechanisms underlying these processes. Previous studies from this and other laboratories have suggested that the extracellular matrix protein tenascin-C is involved in skeletogenesis. Using in situ hybridization and immunofluorescence, we extended those studies by comparing the expression of tenascin-C with that of syndecan-3, which belongs to a family of cell surface receptors with which tenascins are known to interact. We found that syndecan-3 transcripts at first were very abundant in the presumptive periosteum surrounding the diaphysis of early chondrocytic skeletal elements in chick limb. As the elements developed further, syndecan-3 gene expression decreased in the diaphyseal periosteum, whereas it became stronger around the early epiphysis and within the forming articular cells. However, as the diaphyseal periosteum initiated osteogenesis and gave rise to the intramembranous bone collar, syndecan-3 gene expression increased again. At early stages of skeletogenesis: the tenascin-C gene exhibited patterns of expression that were similar to and temporally followed, those of the syndecan-3 gene. At later stages, however, tenascin-C gene expression was markedly reduced during intramembranous osteogenesis around the diaphysis. In addition, although syndecan-3 gene expression was low in osteoblasts and osteocytes located deep into trabecular bone, tenascin-C gene expression remained strong. Thus, tenascin-C and syndecan-3 display distinct temporal and spatial patterns of expression in periosteum and during the development of long bone. Given their multidomain structure and specific patterns of expression, these macromolecules may regulate site-specific skeletal processes, including interactions between developing periosteum and chondrocytes and delineation of the early cartilaginous skeletal elements.

Life-threatening asthma.

This article focuses on various issues related to acute, life-threatening episodes of asthma. The areas discussed include epidemiology, clinical assessment, pharmacologic treatment with bronchodilators and anti-inflammatory agents, endotracheal intubation, mechanical ventilation, adjunctive and nonconventional therapy used in the management of the mechanically ventilated asthmatic, and the prognosis of patients who require mechanical ventilation, including both short-term morbidity and long-term outlook.

Mechanical ventilation in obstructive lung disease.

This article reviews selected topics relevant to the use of mechanical ventilation in patients with severe airflow obstruction. Areas discussed include the bedside assessment of respiratory system mechanics, the ventilatory determinants of dynamic pulmonary hyperinflation, the role of controlled hypoventilation with permissive hypercapnia, and the delivery of bronchodilators during mechanical ventilation.

Victimization of children.

Children suffer more victimizations than do adults, including more conventional crimes, more family violence, and some forms virtually unique to children, such as family abduction. On the basis of national statistics, these victimizations can be grouped into three broad categories: the pandemic, such as sibling assault, affecting most children; the acute, such as physical abuse, affecting a fractional but significant percentage; and the extraordinary, such as homicide, affecting a very small group. They can also be differentiated by the degree to which they result from the unique dependency status of children. A field called the victimology of childhood should be defined that adopts a developmental approach to understanding children's vulnerability to different types of victimizations and their different effects.