Herbert B. Hechtman

Increased Platelet Reactivity and Circulating Monocyte-Platelet Aggregates in Patients with Stable Coronary Artery Disease

OBJECTIVES We sought to examine whether patients with stable coronary artery disease (CAD) have increased platelet reactivity and an enhanced propensity to form monocyte-platelet aggregates. BACKGROUND Platelet-dependent thrombosis and leukocyte infiltration into the vessel wall are characteristic cellular events seen in atherosclerosis. METHODS Anticoagulated peripheral venous blood from 19 patients with stable CAD and 19 normal control subjects was incubated with or without various platelet agonists and analyzed by whole blood flow cytometry. RESULTS Circulating degranulated platelets were increased in patients with CAD compared with control subjects (mean [+/- SEM] percent P-selectin-positive platelets: 2.1 +/- 0.2 vs. 1.5 +/- 0.2, p < 0.01) and were more reactive to stimulation with 1 micromol/liter of adenosine diphosphate (ADP) (28.7 +/- 3.9 vs. 16.1 +/- 2.2, p < 0.01), 1 micromol/liter of ADP/epinephrine (51.4 +/- 4.6 vs. 37.5 +/- 3.8, p < 0.05) or 5 micromol/liter of thrombin receptor agonist peptide (TRAP) (65.7 +/- 6.8 vs. 20.2 +/- 5.1, p < 0.01). Patients with stable CAD also had increased circulating monocyte-platelet aggregates compared with control subjects (percent platelet-positive monocytes: 15.3 +/- 3.0 vs. 6.3 +/- 0.9, p < 0.01). Furthermore, patients with stable CAD formed more monocyte-platelet aggregates than did control subjects when their whole blood was stimulated with 1 micromol/liter of ADP (50.4 +/- 4.5 vs. 28.1 +/- 5.3, p < 0.01), 1 micromol/liter of ADP/epinephrine (60.7 +/- 4.3 vs. 48.0 +/- 4.8, p < 0.05) or 5 micromol/liter of TRAP (67.6 +/- 5.7 vs. 34.3 +/- 7.0, p < 0.01). CONCLUSIONS Patients with stable CAD have circulating activated platelets, circulating monocyte-platelet aggregates, increased platelet reactivity and an increased propensity to form monocyte-platelet aggregates.

Hepatic--portal venous gas in adults: etiology, pathophysiology and clinical significance.

The roentgenographic finding of hepatic-portal venous gas (HPVG) has been reported extensively in the pediatric and radiology literature. The surgical implications and clinical significance have yet to be fully defined. This study reviews the 60 reported cases in the literature and adds four new cases. HPVG appears as a branching radiolucency extending to within 2 cm of the liver capsule. HPVG is associated with necrotic bowel (72%), ulcerative colitis (8%), intra-abdominal abscess (6%), small bowel obstruction (3%), and gastric ulcer (3%). Mucosal damage, bowel distention and sepsis predispose to HPVG. The current mortality rate of 75% represents an improvement from previous experience. Analysis of survivors indicates that the finding of HPVG requires urgent surgical exploration except when it is observed in patients with stable ulcerative colitis.

Consequences of postoperative alterations in respiratory mechanics.

Abstract In patients undergoing extrathoracic surgical procedures, upper abdominal operations led to the most significant reductions in vital capacity, tidal volume, and functional residual capacity. The degree of fall in vital capacity correlated with the development of a clinical pulmonary complication. After upper abdominal surgery there was a delay of sixteen hours prior to a fall in the functional residual capacity. Decrease in surfactant activity is the mechanism proposed for this volume change. In a series of seriously ill patients, changes in the functional residual capacity were related to the degree of arterial hypoxemia. Elevation in the functional residual capacity toward normal resulted in a decrease in the physiologic shunt. Failure to correlate hypoxemia with radiologic evidence of segmental atelectasis is consistent with peripheral alveolar collapse or decrease in alveolar ventilation because of small airway closure.

Neutrophil and nonneutrophil-mediated injury in intestinal ischemia-reperfusion.

ObjectiveThe role of polymorphonuclear neutrophils (PMN) was examined in local and remote organ injury after intestinal ischemia-reperfusion. Summary Background DataPMN have been found to mediate the local injury in low flow intestinal ischemia-reperfusion. However, in complete intestinal ischemia-reperfusion, prevention of PMN adhesion by monoclonal antibodies to CD11b and CD18 reduces remote but not local intestinal injury. The role of PMN was further investigated in this setting. MethodsIn a rat model of 1-hour complete intestinal ischemia and 4-hour reperfusion, PMN were manipulated in the following four ways: (1) inhibition of oxygen-free radicals using manganese superoxide dismutase and catalase (SOD/CAT), (2) antagonism of PMN elastase using secretory leukocyte protease inhibitor (SLPI), (3) neutropenia using PMN antisera, and (4) inhibition of activation and adhesion using interleukin-1 receptor antagonist (IL-1ra) and tumor necrosis factor binding protein (TNFbp). Lung injury was quantified by the pulmonary permeability index, which is the ratio of bronchoalveolar lavage to blood concentration of radiolabeled bovine serum albumin, and PMN sequestration by myeloperoxidase (MPO) activity. Liver injury was estimated by PMN counts using quantitative histologic examination and by serum glutamic pyruvic transaminase (SGPT). Local injury was quantified by MPO activity and histologic grading. ResultsNeutropenia reduced the pulmonary permeability 80% from 11.0 ± 0.5 X 10−3 with saline treatment to 5.50 ± 0.12 X 10−3; IL-1ra, to 5.62 ± 0.44 X 10−3; and TNFbp, to 4.32 ± 0.18 X 10−3 (all p < 0.05). Pulmonary MPO rose from 0.03 ± 0.01 U/g to 0.25 ± 0.03 U/g (p < 0.05). This was reduced by neutropenia, 0.01 ± 0.003 U/g, but not by inhibition of oxygen-free radicals or PMN elastase. IL-1ra inhibited PMN sequestration, reducing MPO to 0.12 ± 0.01 (p < 0.05). Liver injury was 60% dependent on PMN. Ischemia-reperfusion increased SGPT from 20.3 ± 0.7 IU/L in the sham-treated animals to 97.0 ± 3.1 IU/L in the experimental animals. Neutropenia reduced this to 48.1 ± 3.9 IU/L; IL-1ra, to 44.7 ± 3.7 IU/L; SOD/CAT, to 64.0 ± 3.38 IU/L; and SLPI, to 57.1 ± 3.4 IU/L (p < 0.05 in all cases). Local injury was severe and unaffected by manipulation of the PMN. ConclusionsThese data suggest that PMN and their products mediate most of the lung, part of the liver, and none of the local gut injury after intestinal ischemia-reperfusion.

Aortic aneurysm repair. Reduced operative mortality associated with maintenance of optimal cardiac performance.

Recent advances in the operative management of aortic aneurysms have resulted in a decreased rate of morbidity and mortality. In 1972, we hypothesized that a further reduction in operative mortality might be obtained with controlled perioperative fluid management based on data provided by the thermistor-tipped pulmonary artery balloon catheter. From 1972 to 1979 a flow directed pulmonary artery catheter was inserted in each of 110 consecutive patients prior to elective or urgent repair of nonruptured infrarenal aortic aneurysms. The slope of the left ventricular performance curve was determined preoperatively by incremental infusions of salt-poor albumin and Ringers lactate solution. With each increase in the pulmonary arterial wedge pressure (PAWP), the cardiac index (CI) was measured. The PAWP was then maintained intra- and postoperatively at levels providing optimal left ventricular performance for the individual patient. There were no 30-day operative deaths among the patients in this series and only one in-hospital mortality (0.9%), four months following surgery. The five-year cumulative survival rate for patients in the present series was 84%, a rate which does not differ significantly from that expected for a normal age-corrected population. Since the patient population was unselected and there were no substantial alterations in operative technique during the present period, these improved results support the hypothesis that operative mortality attending the elective or urgent repair of abdominal aortic aneurysm can be minimized by maintenance of optimal cardiac performance with careful attention to fluid therapy during the perioperative period.

Measurement of Cardiac Output by Thermodilution

THE functional assessment of myocardial performance includes a measurement of cardiac output. Such precise diagnostic information is particularly valuable in patients with cardiac disease who are u...

Myocardial depression during sepsis

The cardiac response to volume loading was evaluated in fifty severely septic patients. After a rapid infusion of albumin or whole blood the cardiac index (CI) and left ventricular stroke work index (LVSWI) were recorded as the pulmonary arterial wedge pressure (PAWP) increased. Initial values of PAWP, CI, and LVSWI were similar in both the nineteen surviving and thirty-one nonsurviving patients. Surviving patients, however, demonstrated greater increases in CI and LVSWI as PAWP rose. Nearly half of both patient groups developed decreases in CI and LVSWI as the PAWP continued to increase. These downslopes occurred at relatively low PAWP and are taken as evidence of an abnormality of myocardial function in both survivors and nonsurvivors. The lower upslope of the performance curves in nonsurvivors indicates myocardial depression or a negative inotropic effect. Cardiac ischemia, acute respiratory failure, and high affinity red cells were found to diminish the cardiac response to volume loading, whereas hepatic and renal failure were associated with a good CI and LVSWI response.

Lower torso ischemia-induced lung injury is leukocyte dependent.

Lower torso ischemia leads on reperfusion to sequestration of polymorphonuclear leukocytes (PMN) in the lungs and increased permeability. This study tests the role of circulating leukocytes (WBC) in mediating this lung injury. Anesthetized sheep prepared with chronic lung lymph fistulae underwent 2 hours of bilateral hind limb tourniquet ischemia. In untreated controls (n = 7), 1 minute after reperfusion there were transient increases in mean pulmonary arterial pressure (MPAP) from 13 to 38 mmHg (p less than 0.05) and pulmonary microvascular pressure (Pmv) from 7 to 18 mmHg (p less than 0.05), changes temporally related to a rise in plasma thromboxane (Tx) B2 levels from 211 to 735 pg/ml (p less than 0.05). Lung lymph TxB2 levels rose from 400 to 1005 pg/ml at 30 minutes (p less than 0.05), and remained elevated longer than plasma levels. Lung lymph flow (QL) rose from 4.3 to 8.3 ml/30 minutes (p less than 0.05) after 30 minutes of reperfusion and remained elevated for 2 hours. The lymph/plasma (L/P) protein ratio was unchanged from 0.6, while the lymph protein clearance increased from 2.6 to 4.6 ml/30 minutes (p less than 0.05), suggesting increased microvascular permeability. WBC counts decreased within the first hour of reperfusion from 6853 to 3796/mm3 (p less than 0.05), and lung histology after 2 hours showed proteinaceous exudates and leukosequestration of 62 PMN/10 high-powered fields (HPF), higher than the 22 PMN/10 HPF (p less than 0.05) in sham animals (n = 3). Recruitment of the pulmonary vasculature by left atrial balloon inflation (n = 3) resulted in a rise in MPAP to 20 mmHg. After 3 hours of balloon inflation, QL stabilized at 9.8 ml/15 minutes, and a pressure-independent L/P protein ratio of 0.3 was achieved. During reperfusion, QL increased further to 11.2 ml/15 minutes, the L/P ratio rose to 0.56 and the calculated osmotic reflection coefficient decreased from 0.70 to 0.44, documenting an increase in lung microvascular permeability. In contrast to these untreated ischemic controls, sheep (n = 7) rendered leukopenic with hydroxyurea or nitrogen mustard and having a total WBC count of 760/mm3 and PMN count of 150/mm3 did not manifest reperfusion-induced increases in MPAP, Pmv, QL, lymph protein clearance, or lung lymph. TxB2 level (p less than 0.05). Plasma TxB2 levels rose slightly at 30 minutes from 199 to 288 pg/ml (p less than 0.05). Lung histology was normal. These data indicate that WBC mediate the ischemia-induced increase in pulmonary microvascular permeability.

Noncardiogenic pulmonary edema after abdominal aortic aneurysm surgery.

Limb ischemia in experimental animals leads to white blood cell (WBC) and thromboxane (Tx)A2 dependent pulmonary dysfunction. This study examines the pulmonary sequelae of lower torso ischemia in 20 consecutive patients aged 63 +/- 5 years (mean +/- SEM) who underwent elective abdominal aortic aneurysm surgery. After 30 minutes of aortic cross-clamping, plasma TxB2 levels had risen from 77 +/- 26 pg/ml to 359 +/- 165 pg/ml (p less than 0.01) and was temporally related to increases in mean pulmonary artery pressure (MPAP) from 18 +/- 1 to 23 +/- 3 mmHg (p less than 0.01), as well as to increases in pulmonary vascular resistance (PVR) from 0.07 +/- 0.02 to 0.12 +/- 0.02 mmHg sec/ml (p less than 0.01). Each time that the aortic clamp was repositioned and with final declamping, after 83 +/- 10 minutes, there were further increases in MPAP to a peak of 32 +/- 2 mmHg (p less than 0.01) and in PVR to 0.26 +/- 0.030 mmHg sec/ml (p less than 0.01), corresponding to a plasma TxB2 level of 406 +/- 177 pg/ml (p less than 0.01). MPAP and PVR returned to baseline values within 30 minutes of declamping. Ten minutes after removal of the aortic clamp, platelet levels had fallen from 180 +/- 41 to 97 +/- 17 X 10(3)/mm3 (p less than 0.01) and WBC levels from 8900 +/- 1100 to 4700 +/- 400/mm3 (p less than 0.01). Both platelets and WBC returned towards normal levels, but at 24 hours, while WBC was elevated at 13000 +/- 900/mm3 (p less than 0.01), platelets were 44% of baseline at 135 +/- 14 X 10(3)/mm3 (p less than 0.01). Four to 8 hours after surgery, pulmonary dysfunction was manifest by increases in physiologic shunt from 9 +/- 2% to 16 +/- 2% (p less than 0.01), and peak inspiratory pressure (PIP) from 23 +/- 2 to 33 +/- 2 cmH2O (p less than 0.01). Chest radiography demonstrated interstitial pulmonary edema in all patients, whereas pulmonary artery wedge pressure was 12 +/- 2 mmHg, excluding the possibility of left ventricular failure. After 24 hours, pulmonary edema had resolved, and the PIP and PaO2 had both returned to baseline. These data indicate that reperfusion of the ischemic lower torso leads to the synthesis of TxA2, an event temporally related to pulmonary hypertension and transient leukopenia with subsequent pulmonary microvascular injury manifest by interstitial edema.

Tumor Necrosis Factor-α Mediates Acid Aspiration-induced Systemic Organ Injury

Acid aspiration-induced systemic organ injury is mediated by the sequestration of activated neutrophils (PMN). In other settings cytokines have been shown to increase neutrophil-endothelial adhesion, a requisite for injury. This study tests whether the systemic leukosequestration and permeability following localized aspiration is mediated by tumor necrosis factor (TNF)-alpha-induced synthesis of an adhesion protein. Anesthetized rats underwent tracheostomy and insertion of a fine-bore cannula into the anterior segment of the left lung. This was followed by the instillation of either 0.1 mL 0.1 N HCI (n = 18) or 0.1 mL saline in control rats (n = 18). Localized aspiration induced generalized pulmonary leukosequestration with 95 PMN/10 high-power fields (HPF) in the aspirated lung and 46 PMN/10 HPF in the nonaspirated lung, higher than control values of 7 PMN/10 HPF and 5 PMN/10 HPF in saline- and nonsaline-aspirated sides, respectively (p less than 0.05). The leukosequestration was associated with permeability edema shown by increased protein concentrations in bronchoalveolar lavage (BAL) of 3900 micrograms/mL in the aspirated and 2680 micrograms/mL in the nonaspirated side, higher than saline with 482 micrograms/mL and 411 micrograms/mL, respectively (p less than 0.05). There was generalized pulmonary edema following aspiration measured by increase in wet-to-dry weight ratios (w/d) of 6.6 in the aspirated and 5.1 in the nonaspirated lung, higher than control values of 3.5 and 3.4, respectively (p less than 0.05). Localized aspiration led to systemic leukosequestration documented by increases in myeloperoxidase activity (units/g tissue) of 2.2 and 1.7 in heart and kidney, higher than control values of 0.3 and 0.4, respectively (p less than 0.05). This event was associated with edema of these organs with w/d ratios of 4.6 and 4.3, relative to control values of 3.0 and 3.4 (p less than 0.05). Treatment of animals (n = 18) 20 minutes after aspiration with anti-TNF-alpha antiserum (rabbit anti-murine) but not normal rabbit serum (n = 18) reduced lung leukosequestration in the aspirated and nonaspirated segments (61 and 32 PMN/10HPF), BAL protein concentration (1490 and 840 micrograms/mL), and w/d ratio (4.3 and 3.7) (all p less than 0.05). In the heart and kidney there were reductions in myeloperoxidase activity (0.7 and 0.6) and w/d ratio (3.5 and 3.6) (both p less than 0.05). Treatment of rabbits (n = 18) with the protein synthesis inhibitor cycloheximide, 0.2 mg/kg/hr was as effective as TNF-alpha antiserum in modifying aspiration injury.(ABSTRACT TRUNCATED AT 400 WORDS)