Managing the 2-week wait for breast patients.

INTRODUCTION: Published data suggest that the 2-week wait system and triple assessment at one fast-track clinic visit is an out-dated method of capturing disease from a referral population. These studies report up to 32% of breast cancer coming from routine referrals. It has been recommended, therefore, that all breast referrals should be seen within 2 weeks. The sheer volume of referrals are likely to prevent this target being achieved. The aim of this study was to analyse the performance of our fast-track system. PATIENTS AND METHODS: The Birmingham Heartlands and Solihull fast-track clinics were set up in 1999 with a prospective audit system. The data from this audit were retrospectively analysed and cross-referenced with the cancer data base to determine the referral origin of breast cancers from November 1999 to February 2005. RESULTS: A total of 14,303 (fast-track, n = 6678; routine referral, n = 7625) patients were seen over a 5-year period. Overall, 1095 cancers (91.8% of the total) came from the fast-track clinics which had a pick-up rate of 16.4% compared with 98 cancers (8.2% of the total) and a pick-up rate of 1.3% for routine referrals (P < 0.001). The appropriateness of fast-track referral was also analysed which showed that 14.4% of cancers were detected if the referral criteria were met compared to 0.55% if they were inappropriate (P < 0.001). CONCLUSIONS: The traditional fast-track, triple assessment breast clinic is an efficient and well-structured way of diagnosing disease. We recommend that the two system referral pattern should continue.

Pharmacological reduction of the systemically damaging effects of local ischaemia.

Many patients with intermittent claudication are encouraged to exercise. However, transient exercise-induced muscle ischaemia results in systemic vascular endothelial injury associated with increased vascular permeability manifest as an increase in urinary albumin excretion. Repetitive systemic vascular endothelial injury leads to accelerated atherogenesis and may explain the high cardiovascular mortality rate of claudicants. Oxpentifylline, a haemorheological agent, has recently been shown to prevent vascular endothelial injury in animal models. A double-blind, placebo-controlled, cross-over trial was undertaken to determine the effect of oxpentifylline on exercise-induced systemic vascular endothelial injury in 20 claudicants. Urinary albumin, expressed as a creatinine ratio (ACR), was measured before and 1 and 2 hours after standardised exercise following 1 week treatment with either active drug or placebo. Oxpentifylline reduced the median (range) 1 hour post exercise increase in ACR from 0.35 (-0.46-12.72) to 0.02 (-6.00-14.10) mg/mmol. (p = 0.030, z = 2.2 Wilcoxon rank sign test). These results confirm that local ischaemia is associated with a potentially deleterious systemic effect and that it may be possible to attenuate this pharmacologically. The clinical significance of this is yet to be determined.

Microproteinuria predicts the severity of systemic effects of reperfusion injury following infrarenal aortic aneurysm surgery.

Noncardiogenic pulmonary dysfunction can be demonstrated in all patients following elective aortic aneurysm repair and is a cause of postoperative morbidity. Aortic clamping and reperfusion initiate a systemic inflammatory response producing endothelial damage and increases in vascular permeability. In the lung this is manifest as pulmonary edema and in the kidney as detectable increases in urinary protein excretion (microproteinuria). Immunoassay of low-level protein excretion appears to provide an index of the systemic effects of local reperfusion injury and may allow early prediction of complications such as pulmonary edema. Hourly urinary albumin and IgG excretion was measured in 40 patients undergoing infrarenal aortic aneurysm repair and expressed as ratios to urinary creatinine (albumin/creatinine ratio [ACR] and IgG/creatinine ratio [IgGCR]). These were compared to clinical outcome. Pulmonary dysfunction was assessed according to PaO2:FiO2 ratios and chest radiography. Within 180 minutes of beginning surgery all patients had significant increases in ACR and IgGCR. Ten patients who manifested respiratory dysfunction had significantly higher ACRs at 4 hours (median 84.8, 95% confidence intervals, range 47.7 to 136) than patients who made uneventful recoveries (median 16.6, 95% confidence intervals, range 7.9 to 31.7). IgGCR increases paralleled that of ACRs. Differences persisted for 24 hours. Urinary protein excretion rises rapidly during aortic surgery. The degree of increase appears to predict development of pulmonary dysfunction. This simple test may provide a rational basis for evaluation of therapeutic modalities to limit reperfusion injury in these patients.

Ultrasonographic screening for abdominal aortic aneurysm in an urban community.

As part of the Birmingham Community Aneurysm Screening Project, 3500 men aged 65-75 years from 20 urban general practices were invited for aortic ultrasonographic screening at their own general practitioner's surgery; 2669 (76.3 per cent) attended. Compliance rates varied between catchment areas, from 52.1 per cent for inner-city areas to 89.6 per cent for suburbs. Successful aortic imaging was achieved in 97.3 per cent of scans. Aortic diameter > 29 mm occurred in 219 patients (8.4 per cent) and 79 (3.0 per cent) with a diameter > 40 mm were referred for vascular surgical assessment; 140 patients with an aortic diameter of 29-40 mm are currently undergoing follow-up by serial ultrasonographic examinations at intervals of 3 months at their doctor's surgery. Risk factor analysis revealed ischaemic heart disease in 21.9 per cent of men with aneurysm, compared with 11.6 per cent in those without (P < 0.001); 18.3 per cent of men with aneurysm had had a previous myocardial infarction and 13.2 per cent had peripheral vascular disease, compared with 7.4 per cent (P < 0.001) and 8.0 per cent (P < 0.01) respectively of those without. No association was found between aneurysm and hypertension or diabetes. Community-based aortic screening is an inexpensive, effective method of diagnosis of aneurysm, with high compliance from the at-risk cohort of an urban population. Such screening programmes may help to reduce the mortality rate from aortic aneurysm rupture.

Adjuvant prostanoid treatment during femorodistal reconstruction.

A prospective randomized placebo-controlled trial was conducted to determine the effects of the stable prostacyclin analogue iloprost on early graft patency and hemodynamic parameters during femorodistal reconstruction for critical leg ischemia. Peripheral resistance and graft blood flow were measured using an operative Doppler flowmeter and graft pressure transducer. Postoperative graft surveillance was continued at 1-month and then at 3-month intervals by duplex Doppler ultrasonography, measurement of ankle-brachial pressure indices, and intravenous digital subtraction angiography when indicated. In patients receiving 3000 ng of iloprost (n = 45) infused into the graft on completion there was an immediate mean decrease in peripheral resistance of 44% that persisted to skin closure in comparison with controls (n = 38) in whom no such decrease in resistance occurred (p < 0.001, Wilcoxon test). During the same period, mean graft blood flow increased in iloprost-treated patients by 74.5% compared with controls in whom there was a 6% increase in flow (p < 0.001). Primary cumulative patencies at 1 month were significantly higher in iloprost-treated grafts, 98% compared to 83% for controls (p < 0.05, log-rank test). Cumulative primary patencies at 1 year and secondary patencies at 1 month and 1 year were also greater in the iloprost-treated group (67%, 98%, and 87.6%, respectively) compared to controls (65%, 86%, and 79.3%, respectively), but these did not achieve statistical significance. A single bolus infusion of iloprost has prolonged beneficial effects on graft blood flow and peripheral resistance during femorodistal reconstruction. This is reflected by improved early primary graft patencies.(ABSTRACT TRUNCATED AT 250 WORDS)

Reperfusion plasma contains a neutrophil activator.

Aortic aneurysm repair produces inflammatory mediators, neutrophil activation, and remote organ injury. Reperfusion plasma from these patients produces microvascular injury in an ex vivo chemotactic model. This study investigates the mechanism of this injury. Vena caval blood was obtained before and 15 minutes after aortic clamp removal (n = 16) or at laparotomy (n = 10). Plasma or saline solution was introduced into unit dose chambers fixed atop dermabrasions on the back of depilated anesthetized rabbits. Animals were treated with intravenous saline solution (n = 4); made neutropenic with nitrogen mustard (n = 4); pretreated with the xanthine oxidase inhibitor allopurinol (n = 4); or cotreated intravenously with the free radical scavengers superoxide dismutase (SOD) and catalase (n = 4). Three hours later neutrophil counts (polymorphonuclear cells [PMN]/mm3) and activity (free radical production by flow cytometry), protein leakage, and inflammatory mediators (thromboxane [TX] and leukotriene B4 [LTB4]) were measured. In contrast to control plasma in untreated rabbits, reperfusion plasma produced TX and LTB4 generation (1090 +/- 105 and 794 +/- 91 pg/ml, respectively, p < 0.01), PMN accumulation (1636 +/- 210/mm3, p < 0.01) and activation (276 +/- 31 mean fluorescent units), and microvascular permeability (554 +/- 90 micrograms/ml, p < 0.01). Neutropenia (3 +/- 1 PMN/mm3) and cotreatment with SOD and catalase abolished these responses, whereas pretreatment with allopurinol did not. Human reperfusion plasma contains a soluble factor that stimulates free radical generation by rabbit neutrophils to produce a microvascular injury characterized by de novo TX production, neutrophil accumulation and activation, and increased microvascular permeability to protein.

Role of neutrophil adherence receptors (CD 18) in lung permeability following lower torso ischemia.

Ischemia and reperfusion of the lower torso lead to leukotriene- and neutrophil (PMN)-dependent lung injury characterized by lung PMN sequestration, increased permeability, and noncardiogenic edema. It is thought that PMNs require adhesion to endothelium to alter barrier function. This study tests the role of CD 18, the PMN adherence receptor, in mediating lung permeability after lower torso ischemia and reperfusion. Anesthetized rabbits (n = 9) underwent 3 hours of bilateral hind limb ischemia. Ten minutes after the release of the tourniquets, plasma leukotriene B4 levels increased to 395 +/- 85 pg/ml, higher than 129 +/- 35 pg/ml in controls (n = 9, p less than 0.01). At this time there was a reduction in circulating white blood cells (x 10(3)), 3.56 +/- 0.49/mm3 relative to 6.07 +/- 0.61/mm3 in controls (p less than 0.01). PMNs were sequestered in the hind limbs, indicated by increased myeloperoxidase activity of 1.06 +/- 0.19 units/g compared with 0.56 +/- 0.09 units/g in controls (p less than 0.05). Four hours after tourniquet release, PMNs were sequestered in the lungs, 52 +/- 4 PMNs per 10 high-power fields, a value higher than 31.5 +/- 3 PMNs per 10 high-power fields in controls; bronchoalveolar lavage fluid protein content increased to 554 +/- 90 micrograms/ml relative to 277 +/- 46 micrograms/ml in controls; and there was lung edema, measured by increased wet weight-to-dry weight ratios of 5.19 +/- 0.10, higher than 4.29 +/- 0.21 in controls (all p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Lower limb ischaemia and reperfusion alters gut permeability.

The gut may be important in the aetiology of multiple organ failure (MOF) by amplifying of the inflammatory response to trauma. We investigated the effects of the reperfusion of ischaemic lower limbs on gut permeability. Male Wistar rats (n = 30) were randomised to (group 1) controls; (group 2) 3 h bilateral hind-limb ischaemia alone; or 3 h ischaemia followed by (group 3) 15 min reperfusion or (group 4) 2 h reperfusion. Gut permeability and plasma endotoxin were measured prior to tourniquet application, immediately before tourniquet release, and following reperfusion. To evaluate the effect of the hypotension that follows tourniquet release, (group 5) sodium nitroprusside was infused in further controls to maintain mean arterial pressure (MAP) at 75 mmHg for 2 h. Horseradish peroxidase was instilled into the isolated ileo-caecal loop 15 min before the animals were killed to measure permeability of horseradish peroxidase through mucosal intercellular tight junctions by electron microscopy. Mean arterial pressure increased from 105 +/- 5 mmHg to 136 +/- 4 mmHg on tourniquet application and fell to 79 +/- 7 mmHg following reperfusion (p less than 0.05). In group 1 (controls), group 2 (ischaemia alone animals) and group 5 (ischaemia and nitroprusside) one animal out of six demonstrated permeability to horseradish peroxidase. Following reperfusion, horseradish peroxidase permeability had not developed by 15 min (group 3) but was present in all animals by 2h (group 4) (p = 0.015 Fisher's exact test). Plasma endotoxin increased from 21.8 +/- 2.0 pg ml-1 to 30.7 +/- 2.6 pg ml-1 following 2 h reperfusion (p less than 0.05 Scheffe F-test).(ABSTRACT TRUNCATED AT 250 WORDS)

Contribution of canopy leaching to sulphate deposition in a Scots pine forest.

Radioactive sulphate (35SO4) was applied to the soil below a Scots pine forest on 23 June 1989, and its movement into the canopy and into throughfall and stemflow was measured over 4 months. The specific activity, Bq (mg S)(-1), of the canopy increased monotonically; uptake by current-year (1989) expanding needles was initially twice as fast as by older needles or live twigs. By 10 October the canopy average specific activity was 62 Bq (mg S)(-1). The specific activity of net throughfall (throughfall + stemflow - rain), deduced from measurements from six throughfall collectors, six stemflow collectors and two rain collectors, fell rapidly from 12.6 Bq (mg S)(-1) in late July to <1 Bq (mg S)(-1) in mid-August. The results suggest (assuming rapid equilibration of 35S with sulphate in soil) that root-derived sulphate contributed c. 3% of sulphate in net throughfall and that dry deposition of SO2 and sulphate particles contributed c. 97% of the 0.56 g S m(-2) measured in net throughfall over the period. Simultaneous measurements of SO2 at canopy height and of NH3 above and within the canopy gave mean concentrations of 5.9 and 0.86 microg m(-3), respectively, sufficient to account for the sulphate measured in net throughfall only if codeposition of NH3 and SO2 occurred to canopy surfaces. The large values of specific activity observed in July, however, indicate that throughfall composition may be closely related to recent soil input of sulphate, and that equilibrium cannot be safely assumed. The possibility of a significant contribution of soil-derived sulphate to sulphate deposition in net throughfall cannot be ruled out on the basis of this experiment.

Pathophysiology of ischaemia reperfusion injury: central role of the neutrophil.

Ischaemia is a common clinical event leading to local and remote injury. Evidence indicates that tissue damage is largely caused by activated neutrophils which accumulate when the tissue is reperfused. If the area of ischaemic tissue is large, neutrophils also sequester in the lungs, inducing non-cardiogenic pulmonary oedema. Ischaemia reperfusion injury is initiated by production of reactive oxygen species which initially appear responsible for the generation of chemotactic activity for neutrophils. Later, once adherent to endothelium, neutrophils mediate damage by secretion of additional reactive oxygen species as well as proteolytic enzymes, in particular elastase. Therapeutic options for limiting ischaemia reperfusion injury include inhibition of oxygen radical formation, pharmacological prevention of neutrophil activation and chemotaxis, and also the use of monoclonal antibodies which prevent neutrophil-endothelial adhesion, a prerequisite for injury.

Role for tumor necrosis factor as mediator of lung injury following lower torso ischemia.

Ischemia and reperfusion of the ischemic lower torso lead to a neutrophil- (PMN) dependent lung injury characterized by PMN sequestration and permeability edema. This mimics the injury seen after infusion of tumor necrosis factor alpha (TNF), a potent activator of PMN and endothelium. This study tests whether TNF is a mediator of the lung injury after lower torso ischemia. Anesthetized rats underwent 4 h of bilateral hindlimb tourniquet ischemia, followed by reperfusion for 10 min, 30 min, 1, 2, 3, and 4 h (n = 6 for each time point). Quantitative lung histology indicated progressive sequestration of PMN in the lungs, 25 +/- 3 (SE) PMN/10 high-power fields (HPF) 10 min after reperfusion vs. 20 +/- 2 PMN/10 HPF in sham animals (NS), increasing to 53 +/- 5 PMN/10 HPF after 4 h vs. 23 +/- 3 PMN/10 HPF in sham animals (P less than 0.01). There was lung permeability, shown by increasing protein accumulation in bronchoalveolar lavage (BAL) fluid, which 4 h after reperfusion was 599 +/- 91 vs. 214 +/- 35 micrograms/ml in sham animals (P less than 0.01). Similarly, there was edema, shown by the lung wet-to-dry weight ratio, which increased by 4 h to 4.70 +/- 0.12 vs. 4.02 +/- 0.17 in sham animals (P less than 0.01). There was generation of leukotriene B4 in BAL fluid (720 +/- 140 vs. 240 +/- 40 pg/ml, P less than 0.01), and in three of six rats tested at this time TNF was detected in plasma, with a mean value of 167 pg/ml. TNF was not detectable in any sham animal.(ABSTRACT TRUNCATED AT 250 WORDS)

Neutrophil elastase and oxygen radicals: synergism in lung injury after hindlimb ischemia.

Hindlimb ischemia and reperfusion lead to lung injury dependent on activated polymorphonuclear neutrophils (PMN) adherence. This study tests whether elastase and oxygen radicals participate in PMN-induced injury once they have become sequestered in lungs. Anesthetized rats treated with saline (n = 9) or the specific elastase inhibitor methoxysuccinyl-L-Ala-L-Ala-L-Pro-L-Val-chloromethylketone (MAAPV, n = 6) underwent 4 h of bilateral hindlimb tourniquet ischemia followed by 4 h of reperfusion. At this time, in saline-treated rats, PMN were sequestered in lungs as assayed by myeloperoxidase activity [(MPO) 51 +/- 5 U/g tissue], higher than MPO in saline-treated sham rats (n = 9; 18 +/- 3 U/g MPO; P less than 0.01); bronchoalveolar lavage (BAL) fluid leukotriene (LT) B4 levels increased to 594 +/- 46 relative to 200 +/- 38 pg/ml in shams (P less than 0.01); increased permeability was documented by BAL fluid protein content of 599 +/- 91 compared with 214 +/- 35 micrograms/ml in sham animals (P less than 0.01); and edema was shown by increase in lung wet-to-dry weight ratio of 4.77 +/- 0.14 relative to 4.00 +/- 0.09 in sham rats (P less than 0.01). In MAAPV-treated animals, lung neutrophil sequestration (62 +/- 9 U/g MPO) and rise of LTB4 in BAL fluid (780 +/- 244 pg/ml) were not affected, but both BAL fluid protein (335 +/- 32 micrograms/ml) and lung wet-to-dry weight ratio (4.21 +/- 0.17) were reduced (both P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Interleukin-2-induced lung injury is mediated by oxygen free radicals.

Interleukin-2 therapy leads to respiratory dysfunction caused by increased vascular permeability. This study examines the role of oxygen-derived free radicals (OFR). Sheep (n = 6) with chronic lung lymph fistulae were given interleukin-2, 10(5) units/kg, as an intravenous bolus. The mean pulmonary artery pressure rose from 13 to 23 mm Hg (p less than 0.05) at 1 hour and remained elevated for 4 hours, although the pulmonary artery wedge pressure was unchanged at 4 mm Hg. Arterial oxygen tension fell from 88 to 77 mm Hg (p less than 0.05). Lung lymph flow rose from 2.2 to 6.4 ml/30 min (p less than 0.05) at 3 hours. This rise coincided with an increase in the lymph/plasma protein ratio from 0.67 to 0.77 (p less than 0.05) and lymph protein clearance from 1.5 to 4.4 ml/30 min (p less than 0.05), indicating increased lung microvascular permeability. Interleukin-2 led to transient increases in plasma thromboxane B2 from 168 to 388 pg/ml (p less than 0.05) and lung lymph thromboxane B2 from 235 to 694 pg/ml (p less than 0.05). The leukocyte count fell from 8156 to 4375/mm3 (p less than 0.05) primarily caused by a 78% drop in lymphocyte count. Platelet count declined from 292 to 184 X 10(3)/mm3 (p less than 0.05). Pretreatment with the hydroxyl radical scavenger dimethylthiourea, 1 gm/kg, intravenously, (n = 6) prevented the interleukin-2-induced increase in mean pulmonary artery pressure, lung lymph flow, lymph/plasma protein ration, lymph protein clearance, and thromboxane B2 levels in plasma and lung lymph. The arterial oxygen tension decreased from 85 to 80 mm Hg (p less than 0.05). The leukocyte count declined from 7854 to 6229/mm3 (p less than 0.05), but this was not as low nor as prolonged as the interleukin-2 group. Further, the decrease in platelet count was prevented (p less than 0.05). Interleukin-2 incubated with sheep or human leukocytes led to a dose-dependent increase in intracellular hydrogen peroxide production by neutrophils as measured by flow cytometry of dichlorofluorescein oxidation. These data indicate that interleukin-2 stimulates OFR generation and that OFR moderate the interleukin-2-induced increased lung permeability.

Ischemia-induced neutrophil activation and diapedesis is lipoxygenase dependent.

Ischemia and reperfusion lead to eicosanoid- and neutrophil (PMN)-dependent injury. This study tests the role of ischemia-induced lipoxygenase activity in mediating PMN activation and diapedesis. Anesthetized rabbits (n = 8) underwent 3 hours of bilateral hindlimb ischemia. At 10 minutes of reperfusion, leukotriene B4 (LTB4) levels in femoral venous effluent were 0.49 +/- 0.05 ng/ml compared with 0.04 +/- 0.07 ng/ml in sham-treated animals (n = 10) (p less than 0.05). Intracellular H2O2 production of circulating PMNs assayed flow cytometrically by dichlorofluorescein (DCF) oxidation, increased from a preischemic value of 74 +/- 14 femtomoles DCF/cell to 135 +/- 8 fmol DCF/cell (p less than 0.05). PMNs were treated with phorbol myristate acetate (PMA), 10(-7) mol/L. In contrast to a 162% increase in H2O2 production before ischemia, PMNs at 10 minutes of reperfusion had an enhanced response to PMA of 336% (p less than 0.05). Addition of authentic LTB4 (0.5 ng/ml) to PMN from sham-treated animals led to their activation, manifest by an oxidative burst, 127 +/- 12 fmol DCF/cell, and an enhanced response of 337% to PMA stimulation. To study diapedesis, plasma collected at 10 minutes of reperfusion was introduced into plastic chambers taped atop skin abrasions in rabbits (n = 8). After 3 hours, 1610 +/- 246 PMN/mm3 accumulated and LTB4 levels in blister fluid were 0.83 +/- 0.03 ng/ml, higher than values of 44 +/- 23 PMN/mm3 (p less than 0.05) and 0.04 +/- 0.03 ng LTB4/ml (p less than 0.05) with saline solution and 68 +/- 16 PMN/mm3 (p less than 0.05) and 0.19 +/- 0.02 ng/ml (p less than 0.05) with nonischemic plasma. The introduction of LTB4, 3.3 ng/ml, into the chambers resulted in an accumulation of 536 +/- 352 PMN/mm3 (p less than 0.05). Pretreatment of animals before hindlimb ischemia (n = 5) with the lipoxygenase inhibitor diethylcarbamazine abolished PMN activation (51 +/- 12 fmol DCF/cell) and ischemic plasma-induced diapedesis into the plastic chamber (38 +/- 18 PMN/mm3). Pretreatment of nonischemic animals (n = 13) used for the dermabrasion bioassay with diethylcarbamazine abolished diapedesis into the plastic chambers induced by ischemic plasma (n = 5) (32 +/- 24 PMN/mm3) or LTB4 (n = 3) (36 +/- 28 PMN/mm3). These data indicate that PMN activation after reperfusion of ischemic tissue is mediated by a lipoxygenase product, perhaps LTB4, and that both reperfusion plasma and authentic LTB4 induce diapedesis by stimulating de novo lipoxygenase activity.

Ischemia activates neutrophils but inhibits their local and remote diapedesis.

Hindlimb ischemia and reperfusion results in local limb and distant lung injury. This study tests whether the mechanism of injury is by ischemia mediated polymorphonuclear leukocyte (PMN) activation and diapedesis. Anesthetized rabbits were subjected to three hours of hindlimb ischemia (n = 8) or sham ischemia (n = 4). PMN derived solely from the reperfused ischemic limb and assayed flow cytometrically displayed an oxidative burst of 135 /- 8 fentamoles dichlorofluorescein (fmDCF)/cell compared to preischemc levels of 74 +/- 14 fmDCF/cell (p less than 0.05). Additional aliquots of isolated neutrophils were treated with phorbol myristate acetate (PMA) 10(-7) M. In contrast to a 162% increase in oxidative burst before ischemia, neutrophils at ten minutes of reperfusion had an enhanced response to PMA of 336% (p less than 0.05). Plasma collected from the ischemic hindlimb at ten minutes of reperfusion when introduced into an abraded skin chamber or intratracheally induced diapedesis in nonischemic animals. PMN accumulations in the skin chamber were 1636 +/- 258 PMN/mm3 after three hours (n = 8) compared to 63 +/- 18 PMN/mm3 induced by sham plasma (n = 4, p less than 0.05). Introduction of ischemic plasma intratracheally into a lobar bronchus (n = 4) induced PMN accumulations after three hours, measured by bronchoalveolar lavage fluid of 19 +/- 2 X 10(4) PMN/mm3 compared to 5 +/- 1 X 10(4) PMN/mm3 with sham plasma (n = 4, p less than 0.05). Diapedesis was completely prevented (0-3 PMN/mm3, p less than 0.05) by introducing ischemic plasma into skin chambers in animals whose hindlimbs had been made ischemic (n = 6) or into chambers located on skin regions that had been previously made ischemic (n = 6). Similarly after hindlimb ischemia, lavage of the lung with ischemic plasma yielded few PMN 0-3/mm3 (p less than 0.05). These data indicate that ischemia and reperfusion lead to generation of a circulating component in plasma that causes an oxidative burst in PMN and inhibits their diapedesis but promotes diapedesis when applied extravascularly to a naive animal.

Pulmonary edema after aneurysm surgery is modified by mannitol.

Abdominal aortic aneurysmectomy (AAA) results in thromboxane (Tx)A2 generation, a rise in mean pulmonary artery pressure (MPAP), leukopenia, and noncardiogenic pulmonary edema. This study tests whether mannitol, a hydroxyl radical scavenger, modifies these events. Patients received mannitol 0.2 g/kg (n = 14) or saline (n = 12) intravenously before infrarenal aortic clamping. With saline, 30 minutes after clamping, plasma TxB2 levels rose from 124 to 290 pg/mL (p less than 0.01), and MPAP rose from 19 to 27 mmHg (p less than 0.01). Aortic clamp release led to further increases in plasma TxB2 to 378 pg/mL (p less than 0.01) and MPAP to 34 mmHg (p less than 0.01). The white blood count (WBC) fell from 9800 to 4400/mm3 (p less than 0.01). Four to eight hours after surgery, physiologic shunting (Q[sc]S[xsc]/Q[sc]T[xsc]) rose from 9% to 20% (p less than 0.01) and peak inspiratory pressure (PIP) increased from 22 to 32 cmH2O (p less than 0.01). Chest radiography demonstrated pulmonary edema while the pulmonary wedge pressure was 12 mmHg, excluding left ventricular failure. By 24 hours pulmonary edema resolved and the PIP and PaO2 returned to baseline. Mannitol treatment relative to saline, during and after aortic clamping reduced plasma TxB2 levels to 155 and 198 pg/mL, respectively (p less than 0.01); MPAP to 21 and 26 mmHg (p less than 0.01); minimized the decline in WBC to 5850/mm3 (p less than 0.01), and the postoperative rise in Q[sc]S[xsc]/Q[sc]T[xsc] to 12%, and PIP to 28 cmH2O (both p less than 0.01). Chest radiography showed no pulmonary edema. Finally in vitro studies documented that mannitol 1 to 10(-4)M, but not dextrose, in a dose-dependent manner inhibited Tx synthesis by ADP-activated platelets. These data indicate that mannitol maintains pulmonary function after AAA by limiting ischemia-induced thromboxane synthesis.