The current place of aprotinin in the management of bleeding.

There is a considerable difference between the mechanism of action of the lysine analogues, tranexamic acid and epsilon-aminocaproic acid, and the serine protease inhibitor aprotinin. Aprotinin acts to inactivate free plasmin, but with little effect on bound plasmin, whereas the lysine analogues are designed to prevent excessive plasmin formation by fitting into plasminogen's lysine-binding site to prevent the binding of plasminogen to fibrin. Aprotinin is associated with a reduction in bleeding and transfusion requirements following major surgery, and has a dose-response profile, compared with no dose-response effect in the one study investigating tranexamic acid in cardiac surgical patients. Following its withdrawal in 2007, which is explained in detail in this review, the regulators have now licensed aprotinin for myocardial revascularisation only, which is relatively low-risk for bleeding.

Recurring pulmonary hamartomas: cause for concern?

We report the case of a well-controlled female asthmatic who developed 'multiple pulmonary hamartomas' on three separate occasions over a period of 25 years that necessitated surgical resection. To our knowledge, this is the first report of recurrent hamartomas in a single individual necessitating multiple thoracotomies.

"It's just inappropriate": Harassment of dental students by patients.

INTRODUCTION: Harassment is an issue that occurs in all workplaces and institutions. Due to increased exposure to patients, higher rates of harassment are experienced in health care systems. Health care workers need to form a professional relationship with patients to attend to their health care needs; however, harassment by patients can disrupt this relationship and have detrimental physical, mental, and emotional impacts on the health practitioner. OBJECTIVE: The purpose of this study was to examine the prevalence and impact of harassment by patients toward clinical students at a prominent Australasian dental school. METHODS: A 14-item survey was distributed to clinical students. The survey collected basic demographic information and contained Likert-scale closed questions on harassment prevalence and experience and a free text question asking for details of a significant harassment experience. Descriptive statistics and analysis of free text data were performed. RESULTS: The response rate was 67%. About 20% of respondents reported experiencing at least one incident of harassment. Verbal harassment was most commonly reported, followed by sexual and racial harassment. All incidences of sexual harassment were reported by female students, while racial harassment was most frequently reported by students of Asian ethnicity. Most students indicated they were unsure of how to respond to harassment by patients. CONCLUSION: Dental students were exposed to harassment by patients. IMPLICATIONS: Appropriate policies and education on responding to harassment, alongside support for the same, could help ensure the safety and wellbeing of students.

Are we reporting ileal pouch biopsies correctly?

AIM: The accuracy of ileo-anal pouch biopsy reporting was assessed. METHOD: The pathology reports of 100 consecutive pouch biopsies were reviewed to assess the accuracy and consistency with which the St Mark's histological scoring criteria were applied. The quality of pouch biopsy sampling and provision of clinical and endoscopic information on pathology request forms was also assessed. RESULTS: In 27% of cases no relevant endoscopic or clinical information was provided with the pathology request form. Separately labelled biopsies from the prepouch ileum, pouch and columnar cuff were submitted in only 4% of cases. In 32% of pathology reports, no acute or chronic St Mark's score was included. In 2% of cases the St Mark's scoring criteria were applied inappropriately. Twenty per cent of cases histologically diagnosed as pouchitis did not include a numerical score. In 30% of cases diagnosed histologically as pouchitis, an acute inflammatory score of < 4 (i.e. insufficient for this diagnosis) was included in the report. CONCLUSION: Pouchitis is a combined clinical, endoscopic and histological diagnosis. The correct interpretation and application of the St Mark's histological scoring criteria for pouch biopsies is an important part of this diagnostic process.

Outcomes of patients presenting to a dedicated rapid access lung cancer clinic.

We examined the outcomes of the first 500 patients referred to a dedicated Rapid Access Lung Cancer Clinic. A total of 206 patients (41.2%) were diagnosed with a thoracic malignancy; 179 had primary lung cancer and 27 had secondary or other thoracic cancers. Pulmonary nodules requiring ongoing surveillance were found in a further 79 patients (15.8%). Of those patients found to have primary lung cancer, 24 (13.4%) had Small Cell and 145 (81%) had Non Small Cell Lung Cancer. In patients with Non small cell tumours, 26 (21.1%) were stage 1, 14 (11.4%) stage II, 37 (30.1%) stage III and 46 (37.4%) stage IV at diagnosis. For the 129 patients (72%) in whom the thoracic MDT recommended active treatment, primary therapy was surgical resection in 44 (24.6%), combined chemoradiation in 31 patients (17.3%), chemotherapy alone in 39 (21.8%) and radiation in 15 (8.4%).

Traumatic false aneurysm of the left gastric artery.

We present a patient with a false aneurysm of the left gastric artery, associated with anomalous hepatic artery anatomy, following suspected non-accidental blunt abdominal trauma. We postulate that the anomalous anatomy contributed to the pathogenesis of the lesion by restricting the mobility of the left gastric artery during upward movement of the liver. Trans-catheter embolization of the offending vessel was successful.

Effects of fructose-1,6-diphosphate on endo- and myocardial purine metabolism during coronary artery bypass grafting surgery.

AIM: During ischemia, the glycolytic pathway is up-regulated to anaerobically produce adenosine triphosphate (ATP). However, this is short-lived, due to negative feedback on phosphofructokinase from accumulating lactate. Since fructose-1,6-diphosphate (FDP) enters glycolysis distal to this inhibitory site, exogenously administered FDP may yield ATP-independent lactate accumulation and thus ameliorate ischemic injury. The aim of this prospective randomized study was to investigate whether the improved myocardial preservation by FDP could be attributed to improved intermediary metabolism in patients who underwent coronary artery bypass grafting surgery (CABG). METHODS: Thirty-eight patients scheduled for elective CABG were studied. During operation, aortic and coronary sinus blood were collected at different timepoints and analysed by chromatography. Ten patients received 250 mg/kg FDP and 10 received 5% dextrose (control) as intravenous pretreatment prior to cardiopulmonary bypass. In the second stage, 9 patients received 2.5 mM (1.4 g/L) FDP and 9 patients 5% dextrose with the cardioplegic solution. Myocardial metabolism was quantified by measuring nucleotide catabolites including inosine and hypoxanthine. RESULTS: The release of inosine-hypoxantine was increased in both the FDP and the control groups; however, compared to baseline, inosine-hypoxantine levels were significantly elevated at 0, 1, 5 and 10 minutes following reperfusion in the control group. This was in contrast to the earlier recovery to baseline levels (after 5 minutes following reperfusion) in the FDP group. CONCLUSION: These data suggest that FDP may contribute to myocardial cytoprotection during cardiopulmonary bypass. Moreover, myocardial nucleotide metabolite levels showed no evidence for a protective effect of FDP on nucleotide degradation between the treated and the control groups.

Coronary revascularization in transition from on-pump to off-pump: the effect of the off-pump coronary artery bypass on medium-term outcome.

AIM: We previously reported that early patient outcome, chiefly ischaemic injury, was reduced in patients allocated to off pump coronary artery bypass (OPCAB) surgery. This report concerns the medium-term outcome for this cohort of patients. METHODS: A prospective observational study was carried out in a single cardiothoracic specialty hospital. Forty-four patients scheduled for elective multivessel coronary artery bypass grafting (CABG) surgery using either off pump (OPCAB) (n=21) or on pump (cardiopulmonary bypass, CPB) (n=23) were included in the study. Data on the symptoms, quality of life, need for cardiovascular therapy, and occurrence of cardiovascular events or death among patients at 6- and 12-months after surgery were collected by a patient questionnaire and reviewing the medical charts. RESULTS: Compared with patients who underwent CPB surgery, OPCAB patients required a smaller increase in cardiovascular medication (5.6% versus 47.1%; P=0.007) at the 6-month follow-up and demonstrated a trend toward improved symptoms (dyspnea at 6 months, 0, range 0-4 versus 1, range 0-4; P=0.03) and quality of life (Duke Activity Status Index at 6 months, 20.8+5.6 versus 19+6.8; P=0.13). No differences in the incidence of cardiologic intervention or mortality were observed between groups. CONCLUSIONS: The trend toward improved medium-term outcome variables among patients treated with OPCAB may have owed to the reduced cardiac ischemic injury associated with OPCAB compared with CPB.

Aprotinin and perioperative complications in cardiac surgery.

AIM: Recently, the clinical significance of aprotinin-induced renal dysfunction and other end-organ complications in patients undergoing cardiac surgery has engendered substantial controversy. Therefore, we assessed the effect of aprotinin on end-organ complications in patients undergoing cardiac surgery. METHODS: Data of 674 patients (mean age 65.4 +/- 11.0 years, 457 males) undergoing cardiac surgery between January 1 and December 31, 2005 at Semmelweis University were used for the analyses. Preoperative, intraoperative and postoperative clinical and surgical variables were recorded. Patients administered aprotinin received the drug either as a low-dose regimen, a loading dose of 1 million kallikrein-inhibitor units (KIU), 1 million KIU in pump, and 1 million KIU post pump (or continuous infusion of 0.25 million KIU per hour); or a high-dose regimen, a loading dose of 2 million KIU, 2 million KIU in pump, and 2 million KIU post pump (or continuous infusion of 0.5 million KIU per hour). The outcomes were renal complications defined as a 25% reduction in postoperative calculated creatinine clearance compared to the preoperative baseline or renal failure requiring dialysis; and the composite of renal, cardiovascular and cerebrovascular complications and all-cause mortality. RESULTS: Patients underwent coronary artery bypass surgery (63%), valvular (27%) or a combination (5%) and surgery on the ascending aorta (5%). There were 550 patients (81.6%) who received aprotinin treatment. In multivariate regression analyses when the relation between high or low dose aprotinin compared to no aprotinin was evaluated, the likelihood of renal complications [high dose: odds ratio (OR)=1.4, 95% confidence interval (CI), 0.6-3.0, P=0.4; low dose: OR=1.2, 95%CI, 0.7-2.3, p=0.5], and the composite outcome variable (high dose: OR=1.6, 95%CI, 0.8-3.4, P=0.2; low dose: OR=1.3, 95%CI, 0.7-2.3, P=0.4) were not significantly increased. CONCLUSION: Our analysis suggests that aprotinin use in either a high or low dose regimen was not associated with an increase in adverse end-organ complications.

Cutaneous lesions, not just skin deep!

BACKGROUND: Cutaneous metastatic disease is not unusual but it may mimic inflammatory lesions. The growth pattern of skin metastases is unpredictable and may differ from that of the primary tumour. Skin metastases may present as rapidly growing, solitary sessile or polypoid vascular nodules that ulcerate or bleed. AIM: To investigate the presenting complaints, surgical treatment and outcome of patients with cutaneous metastatic disease. METHODS: We present three cases of metastatic skin cancer recently seen in our Department and review the clinical and pathological findings. RESULTS: The finding of metastatic skin cancer is associated with a very poor prognosis and suggests widespread disease dissemination. CONCLUSION: The paper emphasizes the importance of excisional biopsy and accurate tissue diagnosis of skin nodules.

Human endocardial innervation and its relationship to the endothelium: an immunohistochemical, histochemical, and quantitative study.

OBJECTIVE: The endocardium contains an extensive neural plexus, the composition and function of which are unclear. The aim of this study was to characterise the innervation of the endocardium in terms of the relative density and distribution of its autonomic and sensory nerve subpopulations and to assess the relationship between these nerves and endocardial endothelial cells. METHODS: Immunohistochemical, histochemical, confocal, and quantitative image processing techniques were applied to whole mount preparations of human postmortem endocardium obtained within 24 h of death. RESULTS: The overall distribution of nerve fibres and fascicles was demonstrated using antisera to the general neural marker protein gene product 9.5 (PGP 9.5). Nerves displaying acetylcholinesterase activity represented the main nerve subpopulation, occupying 9-18% of the quantified field area. Neuropeptide Y immunoreactive nerves formed the most numerous peptide containing nerve subpopulation identified, occupying 5-19% and 2-7% of the field area in the ventricle and atrial endocardium respectively and having similar distribution patterns to tyrosine hydroxylase immunoreactive nerves. Nerves showing immunoreactivity for somatostatin, vasoactive intestinal polypeptide, and substance P were detected at a lower density, occurred more frequently in the ventricular than atrial endocardium, and showed a similar distribution in the right and left sides of the heart. Combined peptide immunofluorescence and acetylcholinesterase staining, of the same preparation, indicated that putative sympathetic and sensory nerve subpopulations could be distinguished from presumed parasympathetic, acetylcholinesterase positive, nerves. The relationship between immunostained nerves and endothelial cells was assessed using confocal microscopy. Varicose nerve fibres were detected within 0.2 micron of overlying endothelial cells in the right ventricle and between 0.4-0.6 micron in the left ventricle. CONCLUSIONS: The heterogeneous population of nerve fibres demonstrated in the human endocardium may influence the known interaction between endocardial endothelial cells and the myocardium.

Aprotinin does not inhibit the release of PGI2 or vWF from cultured human endothelial cells.

The release of prostacyclin (PGI2) and von Willebrand factor (vWF) from human umbilical vein endothelial cells (HUVEC) was examined to determine if aprotinin had any effects on these endothelial cell reactions. These end-points were chosen to indicate if this serine protease inhibitor caused alterations in the control of haemostatic function by endothelium, in the light of the improvement in haemostasis seen in patients given aprotinin therapy at the time of open heart surgery. Stimuli used to promote secretion of prostacyclin and vWF were human alpha-thrombin, histamine, protamine sulphate, poly-L-lysine and phorbol myristate acetate. Aprotinin (30 microMs) had no significant effect on the basal or stimulated release of PGI2 or vWF from HUVEC.

Double fluorescent-amplification refractory mutation detection (dF-ARMS) of the factor V Leiden and prothrombin mutations.

Simultaneous fluorescent [F] detection of the factor V Leiden (G1691A) and the prothrombin 3'-untranslated region (G20210A) mutations were performed in a single tube polymerase chain reaction (PCR). Amplification refractory mutation detection system (ARMS) formed the basis of this assay design. Fluorescent-labelled primers incorporated into amplicons during the reaction facilitated detection directly by GeneScan analysis without further manipulation. To test the efficacy of this double [F]-ARMS (dF-ARMS) method, 48 patients with unexplained thrombotic tendencies were investigated for their factor V Leiden and prothrombin genotypes. These results corresponded exactly with data achieved using the more conventional methods of restriction fragment length polymorphism (RFLP)-PCR and direct DNA sequencing. Three out of the 48 patients in this group were found to be compound heterozygotes.

Cardiopulmonary effects of 7.2% saline solution compared with gelatin infusion in the early postoperative period after coronary artery bypass grafting.

OBJECTIVE: We report a clinical study on the use of 7.2%, 2400 mOsm/L, hypertonic saline solution compared with gelatin in early postoperative period after coronary artery bypass surgery. METHODS: Two groups (n = 10 each) received 5 ml/kg of either saline solution or gelatin over 1 hour. Cardiac index, central venous pressure, pulmonary capillary wedge pressure, systemic and pulmonary vascular resistance indices, arterial oxygen tension, plasma osmolarity, electrolytes, and urinary output were recorded before starting the infusion and subsequently at 10, 30, 60, 90, 120, 240 and 600 minutes. Plasma creatinine, urea, electrolytes, urinary volume, and sodium excretion were measured at 12 and 24 hours. RESULTS: There were no significant demographic or operative difference between the groups. Patients receiving saline solution had a larger diuresis at 12 (p = 0.0008) and 24 hours (p = 0.002), with less positive balance at 12 hours (p = 0.0008). The group receiving saline solution had better cardiorespiratory recovery with shorter extubation time (p = 0.033), and earlier increase in cardiac index with a positive correlation between plasma sodium content and cardiac index. Maximum increase in cardiac index (+31%) occurred at 60 minutes (p = 0.025) associated with 8% increase in plasma sodium content (r = 0.51, p = 0.01), without a concomitant rise in pulmonary capillary wedge pressure. The group receiving gelatin had a linear increase in cardiac index with increasing pulmonary capillary wedge pressure, reaching +16% from baseline by 90 minutes. Compared with the gelatin-treated group, patients receiving saline solution had unchanged systemic vascular resistance index but a significantly lower pulmonary vascular resistance index with a negative correlation to plasma sodium content. There was no difference in levels of urea and creatinine. No side-effect attributable to the use of saline solution was observed.

Some short-term effects of changing to lower yield cigarettes.

The rate of clearance from the lung of the hydrophilic tracer molecule 99mTc DTPA was used to investigate the short-term effects on lung epithelial function when smokers switched to cigarettes with lower yields of tobacco smoke constituents. Two separate studies were performed. In the first study, subjects smoked conventional mid- and low-tar cigarettes. The second study used two specially manufactured cigarettes with similar tar and nicotine yields, but differing carbon monoxide yields. Neither study demonstrated any significant improvement in 99mTc DTPA clearance. The yields of carbon monoxide determined under standard machine smoking conditions implied that there would be a 44 percent reduction in exposure to carbon monoxide when subjects switched from smoking conventional mid-tar to low-tar cigarettes. However, measurements of carboxyhemoglobin showed that the smokers compensated for the lower yields and their exposure was reduced by only 11 percent. Similarly, in the second study, the subjects reduced their exposure by 7 percent instead of the expected 44 percent. Urine nicotine/cotinine excretion measurements in this study indicated that there was no complimentary increase in nicotine absorption suggesting the possibility that subjects may be able to regulate their intake of individual components of the cigarette smoke. Thus, the unexpected result from this study was the finding that cigarette smokers could, in some way, regulate their intake of smoke from cigarettes of different composition so as to maintain a constant exposure of smoke constituents.

Effect of aprotinin on vascular reactivity of coronary bypass grafts.

OBJECTIVE: Aprotinin reduces postoperative bleeding and the need for transfusion after cardiopulmonary bypass. The current clinical concern about aprotinin is that it may increase the incidence of postoperative graft thrombosis and thromboembolic phenomena. The fact that the mechanism of action of aprotinin is not completely elucidated and that its effects on the vascular reactivity of bypass conduits are unknown raise doubts regarding its safety. In an attempt to clarify these issues we investigated the vascular reactivity of the human saphenous vein and internal thoracic artery to a range of vasoconstrictor agents in the presence or absence of aprotinin. METHODS: Human saphenous vein was obtained from 24 patients and internal thoracic artery from 7 patients undergoing coronary artery bypass. Vessels were set up in organ baths to record changes in vessel wall tension. RESULTS: Endothelium-dependent relaxations to acetylcholine in saphenous vein rings were unaffected after aprotinin treatment. Contractions to the thromboxane analog U46619 were significantly attenuated after aprotinin treatment in the saphenous vein. Maximum responses were reduced from control values of 88 +/- 7.5 mN to 49.3 +/- 4.8 mN with 1 mumol/L doses of aprotinin (p < 0.05) and 36.6 +/- 4.8 mN with 10 mumol/L doses of 5-hyroxytryptamine or noradrenaline after aprotinin incubations. Furthermore, contractions to U46619 in the internal thoracic artery were unaffected by aprotinin. CONCLUSION: Our data show that there is a preservation of endothelium-dependent responses to acetylcholine and a reduced U46619 vasoconstrictor action on the saphenous vein after aprotinin treatment. Thus the direct effect of aprotinin on the vessel wall could counteract the potential effect of its prothrombotic action on graft patency.

The effect of nicotine on pulmonary epithelial permeability in man.

We examined the effect of nicotine on pulmonary epithelial permeability in man. Nicotine was administered from a chewing gum base given over a seven-day period. An index of pulmonary permeability was derived from the rate of clearance from the lung into the blood of 99mTcDTPA (diethylenetriamine pentacetate). In five nonsmoking volunteers there was no change in permeability for the seven-day study period. This lack of effect of nicotine alone was in striking contrast to the increase in epithelial permeability observed in five nonsmoking subjects who took up cigarette smoking.

Reduction in blood loss and blood use after cardiopulmonary bypass with high dose aprotinin (Trasylol).

The effect of high dose aprotinin (Trasylol) was evaluated in three groups of patients undergoing cardiopulmonary bypass. In a prospective, placebo-controlled, double-blind study, 80 patients having primary aorta-coronary bypass grafting received aprotinin (700 mg approximately) or saline placebo from the beginning of the procedure until skin closure. Standardized anesthetic, perfusion, and surgical techniques were used. The total loss from the thoracic drains was significantly reduced in the aprotinin group as compared with the loss in the placebo group (309 +/- 133 ml versus 573 +/- 166 ml, p less than 0.01; mean +/- standard deviation). There was a threefold difference in the total hemoglobin loss into the chest drains (aprotinin 12.0 +/- 12.6 gm versus placebo 37.7 +/- 18.3 gm). Patients of the aprotinin group received remarkably less bank blood postoperatively: 13 units total compared with 75 units. Of the 40 patients in the aprotinin group, 32 received no bank blood compared with 2 of 37 patients in the placebo group. Venous hemoglobin levels preoperatively, on day 1, and on day 7 postoperatively did not differ between the groups. At day 7 the values were 13.1 +/- 1.4 gm/dl versus 12.5 +/- 1.2 gm/dl in the aprotinin group and the placebo group, respectively. Platelet counts determined at fixed times perioperatively did not differ between the two groups. In contrast, template bleeding time measured in 32 study patients was distinctly different between groups, with a postoperative rise of 6.2 +/- 2.1 minutes in the placebo group opposed to only 1.5 +/- 1.1 minutes in the aprotinin group.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased production of peroxidation products associated with cardiac operations. Evidence for free radical generation.

We investigated the degree and time course of neutrophil sequestration into human lungs during cardiac operations. At the same time, measurement of the concentration of peroxidation products in the plasma was used as an index of oxidant free radical activity. The study was performed in two groups of patients. Group A (n = 11) had studies extending over the entire operative period and showed a highly significant sequestration of neutrophils into the lung, together with a highly significant (p less than 0.001) rise in peroxidation products from 2.8 +/- 0.12 nmol/ml(mean +/- standard error of the mean)before bypass to a peak of 5.05 +/- 0.13 nmol/ml at the end of bypass. As these changes occurred only during the time after release of the aortic cross-clamp, we investigated this period in more detail in a second group of patients (Group B, n = 7). Results from this group showed that significant release of peroxidation products occurred at the same time as pulmonary neutrophil sequestration. This study has produced evidence of increased oxidant activity in the lung associated with cardiac operations. Nevertheless, it is not known whether the neutrophils sequestered into the lung alone induced the increased activity. Similarly, whether neutrophil-derived oxidant species are the sole cause of lung tissue injury remains unproved.