Efficacy of protocol-based pharmacotherapy management on anticoagulation with warfarin for patients with cardiovascular surgery.

WHAT IS KNOWN AND OBJECTIVE: Anticoagulation therapy with warfarin requires periodic monitoring of prothrombin time-international normalized ratio (PT-INR) and adequate dose adjustments based on the data to minimize the risk of bleeding and thromboembolic events. In our hospital, we have developed protocol-based pharmaceutical care, which we called protocol-based pharmacotherapy management (PBPM), for warfarin therapy. The protocol requires pharmacists to manage timing of blood sampling for measuring PT-INR and warfarin dosage determination based on an algorithm. This study evaluated the efficacy of PBPM in warfarin therapy by comparing to conventional pharmaceutical care. METHODS: From October 2013 to June 2015, a total of 134 hospitalized patients who underwent cardiovascular surgeries received post-operative warfarin therapy. The early series of patients received warfarin therapy as the conventional care (control group, n=77), whereas the latter received warfarin therapy based on the PBPM (PBPM group, n=68). These patients formed the cohort of the present study and were retrospectively analysed. RESULTS: The indications for warfarin included aortic valve replacement (n=56), mitral valve replacement (n=4), mitral valve plasty (n=22) and atrial fibrillation (n=29). There were no differences in patients' characteristics between both groups. The percentage time in therapeutic range in the first 10 days was significantly higher in the PBPM group (47.1%) than that in the control group (34.4%, P<.005). The average time to reach the steady state was significantly (P<.005) shorter in the PBPM group compared to the control group (7.3 vs 8.6 days). WHAT IS NEW AND CONCLUSION: Warfarin therapy based on our novel PBPM was clinically safe and resulted in significantly better anticoagulation control compared to conventional care.

Right and left inverted lobar lung transplantation.

Adult recipients frequently withdraw from living-donor lobar lung transplantation because of the small size of donor grafts. The right lower lobe is 120% larger than the left lower lobe. We developed a novel surgical technique in which an inverted right lower lobe graft can be transplanted into the left thorax. The first patient was a 43-year-old woman with end-stage idiopathic interstitial pneumonia. Her husband was the only eligible donor for living-donor lobar lung transplantation. His right lower lobe was estimated to provide 45% of the recipient's predicted forced vital capacity, which would provide the borderline function required for living-donor lobar lung transplantation. Since lung perfusion scintigraphy of the recipient showed a right-to-left ratio of 64:36, transplanting the right lower lobe graft into the left thorax and sparing the native right lung was considered the only treatment option. We simulated this procedure using three-dimensional models produced by a three-dimensional printer. In living-donor lobar lung transplantation, all anastomoses were performed smoothly as planned preoperatively. Because of the initial success, this procedure was performed successfully in two additional patients. This procedure enables larger grafts to be transplanted, potentially solving critical size matching problems in living-donor lobar lung transplantation.

Sparing Native Upper Lobes in Living-Donor Lobar Lung Transplantation: Five Cases From a Single Center.

Living-donor lobar lung transplantation (LDLLT) is indicated for rapidly deteriorating patients, and the total volume of two lower lobe grafts must be sufficient for the recipient. To rescue patients with small lobar grafts, we performed five LDLLTs sparing native upper lobes. This strategy was used when upper lobes or segments were preoperatively less impaired. There were no hospital deaths. Extracorporeal circulation time and operative time were similar to those of conventional LDLLTs. The length of intensive care unit stay was also similar. Late complications attributed to the spared lungs were airway infection in one recipient and pneumothorax in two but they were successfully managed. All recipients were discharged without supplemental oxygen. The spared lung volumes measured by volumetry did not change after LDLLT. Lung perfusion scintigraphy performed at 1 year showed remaining perfusion in the spared lungs, although much less than in the grafts. These results suggested that the spared lobes kept adequate space in the thoracic cavity and kept functioning to a limited extent. The new lobar-sparing strategy appears feasible and effective in LDLLT using small grafts for selected patients when the upper lobes or segments are less impaired.

[Off-pump coronary artery bypass grafting supported by intra-aortic balloon pumping in a patient with moyamoya disease].

A 48-year-old woman was admitted to the hospital for coronary artery bypass grafting (CABG) of ischemic coronary disease, including left main trunk disease. She had a history of moyamoya disease with bilateral internal carotid artery occlusion. Her cerebral blood flow and cerebral vascular reactivity were evaluated by single photon emission computed tomography. Her collateral blood flow and cerebral vascular reserve were the lower limit of normal. We performed off-pump CABG supported by intra-aortic ballon pumping to maintain appropriate cerebral blood flow intraoperatively. Moreover, during operation, systolic blood pressure and blood Paco2 level were constantly maintained above 100 mmHg and 40 mmHg. Her postoperative course was uneventful without transient ischemic attacks or stroke.

Denatured hemoglobin in sickle erythrocytes.

To study the nature of numerous inclusion bodies seen in red cells from patients with sickle cell disease (Hb SS), we have prepared red cell ghosts free of oxyhemoglobin and analyzed them by spectrophotometric and heme extraction methods. The absorption spectrum in the visible region of the ghost suspensions was typical of hemichromes. The spectrum was similar to that of denatured hemoglobin repared by treatment of oxyhemoglobin S with mechanical shaking or heat. Similar treatment of cells containing only normal hemoglobin (Hb AA) showed a very small amount of denatured hemoglobin, approximately one-fifth of the amount in Hb SS cells. The amount of denatured hemoglobin determined after solution of membrane with 2.5% sodium dodecyl sulfate was 0.158+/-0.070% (1 SD) of the total cellular heme in Hb SS patients. In controls, the amount was 0.030+/-0.016%. Persons with Hb AA and reticulocytosis did not have an elevated amount of membrane-associated heme. In patients with hereditary spherocytosis and autoimmune hemolytic anemia, denatured stromal hemoglobin was normal or slightly elevated before and after splenectomy. The increased amount of denatured hemoglobin in Hb SS red cells may be related to the instability of sickle oxyhemoglobin.

Spin-label studies of membrane-associated denatured hemoglobin in normal and sickle cells.

A maleimide spin label (N-(1-oxyl-2,2,5,5-tetramethylpyrrolidinyl)-maleimide) was reacted with oxyhemoglobin-free cell stromata of normal and sickle cells. The EPR spectrum of spin-labeled red cell membranes showed that the spin labels are attached to at least two different binding sites. There was a major signal, A, which characterized a strongly immobilized environment and a minor signal, B, which characterized a weakly immobilized environment. Quantitative EPR measurements using equal amounts of Hb AA and Hb SS red blood cells demonstrated that Hb SS red cell membranes had an approximately four times higher EPR signal intensity than Hb AA red cell membranes ((7.98 +/- 1.14 . 10(5) and (2.2 +/- 1.2) . 10(5) spin labels/cell, respectively). Moreover, the ratio of signal intensities A and B are different in these cells. Comparative spectrophotometric studies of membrane-associated denatured hemoglobins of Hb AA and Hb SS red cell membranes suggested that the EPR signal A is derived from spin labels attached to membrane-associated denatured hemoglobin, while signal B is mainly from spin labels attached to membranes. The combination of EPR spectrum of Hb AA membranes pretreated with N-ethylmaleimide and that of spin-labeled precipitated hemoglobin further strengthened this conclusion.

Identification of full-sized forms of salivary (S-type) cystatins (cystatin SN, cystatin SA, cystatin S, and two phosphorylated forms of cystatin S) in human whole saliva and determination of phosphorylation sites of cystatin S.

Our recent work on the gene structures for human salivary (S-type) cystatins [Saitoh, E. et al. (1987) Gene 61, 329-338] has suggested that the structures of cystatins which we determined previously at the protein level lack N-terminal peptide portions of the full-sized intact forms. In the present study, attempts were made to isolate full-sized S-type cystatins by introducing methanol fractionation into the purification steps to suppress the enzymatic activity present in saliva. Full-sized cystatin SN and two phosphorylated forms of full-sized cystatin S were thus isolated. Analysis of one fraction indicated that this was a mixture of full-sized cystatin SA and non-phosphorylated cystatin S. The phosphorylation sites of cystatin S were determined to be Ser-Ser-Ser1(P)-Lys-Glu-Glu- for monophosphorylated cystatin S and Ser1(P)-Ser-Ser3(P)-Lys-Glu-Glu- for diphosphorylated cystatin S. Immunoblotting analysis with anti-cystatin S antiserum revealed that tears and seminal plasma also contained S-type cystatins, but diphosphorylated cystatin S was detected neither in tears nor in seminal plasma and no cystatin SN was found in seminal plasma. These data indicate that S-type cystatins are secreted into the oral cavity without significant degradation in salivary glands or ducts and that they are expressed tissue specifically.

Effect of different methods of internal thoracic artery harvest on pulmonary function.

BACKGROUND: In several clinical studies, internal thoracic artery (ITA) grafting for myocardial revascularization has been identified as increasing the risk of postoperative pulmonary complications. This study was designed to determine whether the technique used to harvest the ITA has an effect on postoperative pulmonary function. METHODS: Seventy-nine consecutive patients undergoing coronary artery bypass grafting using the left ITA were compared with patients undergoing coronary artery bypass grafting using saphenous vein grafts only. Two methods of ITA harvesting were used: (1) incision of the endothoracic fascia dissected off the ITA as a skeletonized vessel (group 1, n = 33) and (2) mobilization of the ITA as a wide musculofascial pedicle (group 2, n = 46). Thirty-two patients underwent coronary artery bypass grafting using saphenous vein grafts only (group 3). Pulmonary function tests were performed between postoperative days 20 and 30. RESULTS: The postoperative values of forced vital capacity were reduced in patients in all groups (p < 0.0001). The ratios of postoperative to preoperative forced vital capacity were 84% in group 1, 77% in group 2, and 84% in group 3. The reduction in group 2 was significant compared with group 1 (p < 0.05) and group 3 (p < 0.05). CONCLUSIONS: Postoperative pulmonary dysfunction was significantly greater in patients who underwent wide musculofascial pedicle dissection of the ITA compared with skeletonization of the artery. Thus, of the two techniques, the latter may be the method of choice with regard to lowering the incidence of postoperative pulmonary dysfunction.

Mycotic aneurysm of the left coronary artery.

We report a 24-year-old man with mitral valve endocarditis complicated by acute myocardial infarction due to coronary embolism. Percutaneous transluminal coronary angioplasty and subsequent mitral valve replacement were performed. Postoperative coronary angiography revealed formation of a mycotic aneurysm of the left anterior descending coronary artery at the site of balloon inflation. The patient then underwent successful resection of the aneurysm with coronary artery bypass grafting.

Cysteine proteinase inhibitor levels in semen.

New proteinase inhibitors have recently been found in seminal plasma which specifically inhibit cysteine proteinases such as ficin, papain, cathepsin H and cathepsin B. The inhibitors consist of two components, In-A and In-B, both of which are effective in native semen. In the present work, a method of assay is devised to determine activities of both components separately. Under conditions in which In-B is denatured completely while In-A is not, inhibitory activity of In-A alone is determined. The mean In-A inhibitory level is 1.52 +/- 0.28 inhibitor unit/mL and the level is independent of the number of spermatozoa. In-B level is calculated by subtracting In-A level from the total ficin inhibition level of the semen. The mean In-B level is 1.47 +/- 0.52 inhibitor unit/ml. In-B level has a tendency to increase with increasing number of spermatozoa. The correlation coefficient is 0.307 and statistical significance p less than 0.005.

Serum alpha-cysteine proteinase inhibitor levels in pregnancy.

Variation in alpha-cysteine proteinase inhibitor levels in human sera were investigated with special attention to the effect of pregnancy and diseases. The inhibitor level in 111 pregnant women, examined by our previous method, increased as the pregnancy advanced. The correlation coefficient between the level and the duration, r, was 0.578 with the level of significance p less than 0.001. The mean value for 50 pregnant women in the third trimester of gestation was 0.49 +/- 0.04 unit/mL, which was 47% higher than the control value, 0.33 +/- 0.04 unit/mL (p less than 0.001). However, the levels in patients with myoma of uterus, endometritis, cervical cancer, ovarian cyst and ovarian cancer were not significantly different from the control value. From these results, it was concluded that pregnancy enhanced appreciably the alpha-cysteine proteinase inhibitor level in serum.

Increase in production of ascorbate radical in tissues of rat treated with paraquat.

The production of ascorbate radical (A*-) was investigated in tissues of rats intoxicated with paraquat (PQ) to know the protective role of antioxidant ascorbate (AH-) in tissues. The electron spin resonance (ESR) method is applied to observe A*-. To eliminate increased biosynthesis of ascorbic acid (AH2) by PQ intoxication, ODS rats were chosen and fed with or without 250 ppm PQ in the diet. The radical A*- was detected only in the lung and spleen homogenates of both intoxicated and control rats at the beginning of ESR measurement. The radical levels of intoxicated rat lung and spleen were increased rapidly to twice the initial level after 3 h and decreased to 0.2-0.6 times the initial level after 24 h, whereas those of control rats were increased slowly to 1.1 times the initial level after 4 h and decreased slowly to 0.7 times the initial level after 24 h at 4 degrees C. In other organs such as liver, kidney, heart and testis, A*- was not detected initially but detected afterwards. Higher A*- level was observed in the intoxicated rat liver than the control but no appreciable differences of A*- levels were observed between the intoxicated kidney, heart and testis and the respective controls. In the intoxicated rat lung the concentration of AH2 is only half but that of A*- is twice as high as that of the control. Larger amounts of A*- produced in the intoxicated rats decayed more quickly than those in the control rats. The simple addition of PQ to the control organ enhanced neither A*- production nor A*- quenching. These facts suggest that the tissues damaged by PQ require larger amounts of AH- to detoxicate harmful oxidants, resulting in concomitant production of A*-.

Rapid quantitative analysis of paraquat by electron spin resonance spectroscopy.

A very simple and sensitive method for quantitative measurement of paraquat in plasma, urine and some drinks is described. The paraquat radical formed by its reduction can be detected by electron spin resonance spectroscopy (ESR) at room temperature without clean-up or concentration process of samples. The sensitivity limit is 0.1 microgram paraquat/ml and the required amount of sample is 100 microliter. The time needed for the measurement is within 10 min.

Extraction of diquat with 1-butanol from biological materials.

Diquat can be extracted with 1-butanol from high pH solution in the presence of several moderate reductants. The red colored reduced compound of diquat in water turns to a purple compound in 1-butanol. The absorption of the purple compound is 0.105 at 383 nm and 0.119 at 520 nm in 1 microgram diquat/ml 1-butanol. The latter value is a little higher than that of the red compound at 495 nm in water. The purple compound is much more stable than the red compound in water. More than 80% of 10 ppm diquat added can be extracted from serum, blood, tissues, urine and some drinks. The extraction with 1-butanol is useful for concentration of diquat contained in large volume. The lower limit of detection is 0.1 microgram/ml 1-butanol. Paraquat is insoluble in 1-butanol under the same condition. Therefore, this method is applicable for the determination of diquat when paraquat is also contained in the solution.

Quantitative analysis of chlorpromazine by electron spin resonance (ESR) spectroscopy.

A simple and sensitive method is described for quantitative analysis of chlorpromazine in blood, serum, urine and tissue homogenate. The chlorpromazine cation radical produced by adding perchloric acid and 2,3-dichloro-5,6-dicyano-p-benzoquinone to the sample can be detected by the ESR method at room temperature. The sensitivity limit is 10 ng, that is, 20 microliters of the solution containing 0.5 microgram chlorpromazine/ml. The time needed for the measurement is within 10 min. The chlorpromazine radical thus produced is very stable; for example, 95% of the radical was observed after 24 h. The advantage of this method is discussed by comparing with the ordinary spectrophotometry which requires the purification of the sample.

Correlation between plasma alpha-cysteine proteinase inhibitor level and pyruvate kinase activity in vitamin E-deficient rats.

Weaning rats were divided into two groups, one group being fed a vitamin E-deficient diet, and the other an alpha-tocopherol-containing (50 mg/kg) control diet. Rats were killed at 1, 2, 3 and 4 months of feeding. The following results were obtained. 1. Both plasma and liver alpha-tocopherol levels decreased greatly by feeding vitamin E-deficient diet for 1 month, and thereafter decreased gradually by continued feeding. 2. Somehow different results were obtained concerning liver peroxidation value by the method of analysis. In the case of chemiluminescence, the value increased by vitamin E deficiency during the first 2 months, but thereafter, the value was almost unchanged. On the contrary, in the case of TBA-RS, the value increased gradually throughout the entire 4 months of feeding period. 3. Both plasma alpha-CPI level and pyruvate kinase activity increased by vitamin E deficiency, showing similar pattern of change with feeding period. Especially, marked increase of these values was observed in vitamin E-deficient rats fed for longer than 2 months, and differences from control groups were highly significant (in both cases, at 2 months, p < 0.005, and at 3 and 4 months, p < 0.001). And, in vitamin E-deficient group, including all the rats fed on test diet for 1 to 4 months, correlation between both values was very high, and was highly significant (r = 0.9060, p < 0.001).

Effects of vitamin E on toxicity by minute amounts of paraquat fed continuously to rats.

The effects of vitamin E on toxicity by minute amounts of paraquat fed continuously for some period to rats were investigated. Two experiments were carried out as experiments 1 and 2. In both experiments, weaning rats were divided at first into two groups; one group was given a vitamin E-deficient diet, and the other a vitamin E-supplemented control diet (50 mg alpha-tocopherol/kg of diet). They were fed on these diets for 40 days. After that, in both experiments, the rats that had been fed the vitamin E-deficient diet were further divided into two groups, which were either given a paraquat-added diet (+PQ-E) or continuously fed the same vitamin E-deficient diet (-E). The amount of paraquat added was 250 mg of methyl viologen per kg of diet. After the addition of paraquat, these two groups were pair-fed. In experiment 1, paraquat was given to all the rats fed the vitamin E-supplemented control diet (+PQ+E). In experiment 2, rats fed the control diet were divided into paraquat-added (+PQ+E) and non-paraquat-added (+E) groups, similar to those of vitamin E-deficient rats. These two groups were also pair-fed thereafter. In both experiments, about 35 days after paraquat addition, they were sacrificed. Plasma and liver alpha-tocopherol contents were measured by HPLC, and liver peroxidation value was measured by chemiluminescence and the TBA method. And, as parameters of vitamin E deficiency, plasma pyruvate kinase and GOT activities and alpha-cysteine proteinase inhibitor (alpha-CPI) level were measured. When the analyzed values were compared between paraquat-added and the corresponding not-added control groups (+PQ-E vs. -E, +PQ+E vs. +E), the following results were obtained. In experiment 1, the values of plasma and liver alpha-tocopherol levels were significantly lower in the +PQ-E group than those of the -E group; however, liver peroxidation values and values of the three parameters of vitamin E deficiency were not different significantly. In experiment 2, the value of liver alpha-tocopherol level was significantly lower in the +PQ+E group than that of the +E group.(ABSTRACT TRUNCATED AT 400 WORDS)

[Surgical treatment of infective endocarditis associated with cerebral mycotic aneurysm].

We experienced two cases of infective endocarditis associated with cerebral mycotic aneurysm. Case 1: 58 year-old man underwent emergency aortic and mitral valve replacement due to active infective endocarditis and congestive heart failure diagnosed by transesophageal echocardiography. After the operation, he did not wake up and his bilateral pupils were dilated. Computed tomography demonstrated massive intracranial hemorrhage and severe brain edema. He died from multiple organ failure 22th postoperative day. Rupture of cerebral mycotic aneurysm was strongly suspected. Case 2: 56 year-old man was admitted with severe headache and high grade fever. Computed tomography demonstrated intracranial hemorrhage. Cerebral mycotic aneurysm was detected at left distal middle cerebral artery by cerebral angiography. Infective endocarditis and mitral regurgitation were also diagnosed by echocardiography. He underwent cerebral mycotic aneurysmectomy after intensive antibiotics therapy, followed by successful mitral valve replacement. We review the literatures and discuss the problems of surgical management of infective endocarditis with cerebral mycotic aneurysm.

[Right ventricular function in patients with poor left ventricular function: studies in patients undergoing coronary artery bypass surgery].

In many patients, right ventricular (RV) dysfunction is due to RV infarction. In some patients, however, RV dysfunction may be secondary to the left ventricular (LV) dysfunction. In order to clarify the influence of poor LV function on RV function, RV ejection fraction (EF) was evaluated serially by thermodilution techniques (REF-1, Edwards Laboratories) in patients with LVEF less than 40% who underwent aorto-coronary bypass surgery with uneventful postoperative course. The patients were divided into four groups depending on the site of LV infarction; anterior (n = 13), inferior (n = 8), anterior + inferior (n = 16), and no infarction (n = 4). Control (n = 11) consisted of the patients with LVEF more than 60% and with no significant stenosis of the right coronary artery. Cardiac index, intracardiac pressures and amount of catecholamine used during postoperative course showed no significant differences among the groups including control. However, the groups except for the group of anterior infarction showed significantly low pre- and postoperative RVEF compared with control. Only the group of anterior infarction had almost normal RVEF. These results mean that RV dysfunction associated with inferior infarction remain long afterwards and that low LVEF due to anterior infarction caused little effect on RV function.

[Treatment of subacute cardiac rupture after myocardial infarction].

Five successfully treated cases of subacute cardiac rupture after myocardial infarction are described. There were 4 men and 1 woman, ranging in age from 51 to 71 years. Two patients had systemic hypertension. Rupture occurred during the first myocardial infarction in all patients. The interval from the onset of myocardial infarction to cardiac rupture ranged from 1 to 6 days (mean 4 days). In one patient, the rupture was repaired under cardiopulmonary bypass using an autologous pericardial patch over the infarcted myocardium. Two patients underwent sutureless repair with fibrin glue; one of them developed a left ventricular pseudoaneurysm 2 years after the operation, requiring resection. These three patients were operated on through a median sternotomy. The remaining two patients were treated for cardiac tamponade by pericardial drainage through a subxiphoid incision; one died 38 days after the operation due to congestive heart failure. The four surviving patients are currently well 22, 39, 41 and 60 months after surgery. In summary, a conservative approach may be effective for treatment of subacute cardiac rupture.