Effect of preoperative supplementation with alpha-tocopherol and ascorbic acid on myocardial injury in patients undergoing cardiac operations.

Augmentation of antioxidant defenses may help protect tissues against ischemia-reperfusion injury associated with operations involving cardiopulmonary bypass. In this study we examined the effect of pretreating patients with alpha-tocopherol (vitamin E) and ascorbic acid (vitamin C) or placebo on injury to the myocardium. Seventy-six subjects undergoing elective coronary artery bypass grafting participated in a prospective, double-blind, placebo-controlled randomized trial, receiving either placebo or both 750 IU dl-alpha-tocopherol per day for 7 to 10 days and 1 gm ascorbic acid 12 hours before the operation. Plasma alpha-tocopherol concentrations, raised fourfold by supplementation, fell by 70% after the operation in the supplemented group and to negligible levels in the placebo group. There were no significant differences between the groups with respect to release of creatine kinase MB isoenzyme over 72 hours, nor in the reduction of the myocardial perfusion defect determined by thallium 201 uptake. Electrocardiography provided no evidence of a benefit from antioxidant supplementation. Thus the supplementation regimen prevented the depletion of the primary lipid soluble antioxidant in plasma, but provided no measurable reduction in myocardial injury after the operation.

Demonstration of late cardiotoxicity following bone marrow transplantation by assessment of exercise diastolic filling characteristics.

We evaluated the role of rest and exercise left ventricular diastolic filling parameters as a marker of cardiotoxicity in 25 consecutive patients 1 year following BMT. Ten age- and sex-matched subjects served as controls. Patients were evaluated in toto and in three sub-groups according to chemotherapy. Left ventricular ejection fraction (EF), peak filling rate (PFR) and time to peak filling (TTPF) were assessed at rest and at peak exercise. EF and PFR were similar at rest and at peak exercise in patients and controls. TTPF was significantly prolonged at rest in patients compared to controls (200 +/- 65 vs 131 +/- 26 ms, P = 0.003) and at peak exercise was markedly longer in patients (142 +/- 40 vs 54 +/- 19 ms, P < 0.001). Sub-group analysis demonstrated abnormal resting TTPF in those patients who had received either combination anthracycline and CY or anthracycline and melphalan, while those patients who received CY alone had normal resting TTPF. However, exercise TTPF was abnormally prolonged in all patient groups. While all controls demonstrated a normal decrease in TTPF during exercise, four of the 25 patients had a paradoxical increase in TTPF during exercise. Exercise diastolic function may provide evidence of cardiotoxicity in long-term survivors of BMT.

Failure of reflex venoconstriction during exercise in patients with vasovagal syncope.

BACKGROUND: In this study, we tested two hypotheses. First, we tested the hypothesis that reflex constriction of the venous capacitance beds in patients with vasovagal syncope is impaired during both subhypotensive lower-body negative pressure. Second, we proposed that splenic venoconstriction may be impaired during exercise in patients with vasovagal syncope. METHODS AND RESULTS: We evaluated 25 patients with vasovagal syncope (age, 45.0 +/- 15.9 years; 12 men, 13 women) and 24 control subjects (age, 41.3 +/- 13.7 years; 16 men, 8 women). A nuclear technique was used to assess changes in forearm venous tone during lower-body negative pressure and in splenic venous volume during cycle exercise. Changes in forearm vascular resistance (FVR) during cycle exercise were assessed with a strain-gauge plethysmography technique. The percentage reduction in unstressed forearm vascular volume during lower-body negative pressure was similar in patients and control subjects (9.0 +/- 8.0% versus 9.7 +/- 5.9%, P=NS). During exercise, splenic venous volume decreased less in patients than in control subjects (15.8 +/- 21.7% versus 42.6 +/- 12.6%, P < .0001). FVR decreased by 2 +/- 32% in patients but increased 108 +/- 90% in control subjects (P < .0001). There was no relation between percentage change in splenic volume and percentage change in FVR during exercise in either patients or control subjects (r= -.06, P=NS and r= -.18, P=NS, respectively). CONCLUSIONS: Patients with vasovagal syncope exhibit a failure of the normal increase in tone in the splenic capacitance bed and in forearm resistance vessels during dynamic exercise. Forearm venous tone increases normally during lower-body negative pressure.

Increased skeletal uptake of Tc-99m methylene diphosphonate in milk-alkali syndrome.

A case of milk-alkali syndrome is described in a 34-year-old man taking an over-the-counter antacid preparation for gastroesophageal reflux. A Tc-99m MDP bone scan performed in the initial investigation of the hypercalcemia was markedly abnormal with a "metabolic" pattern of tracer uptake similar to that seen in hyperparathyroidism and humoral hypercalcemia. Following withdrawal of the antacid and calcium, the bone scan appearance returned to normal, as did the biochemical markers of his disease.

Aerosol deposition in cystic fibrosis using an aerosol conservation device and a conventional jet nebulizer.

The deposition of technetium radiolabelled aerosol within the lungs of 12 stable cystic fibrosis patients (mean age 12.7 years) was compared using the Acorn nebulizer and mouthpiece alone, and the Acorn nebulizer attached to the Mizer Aerosol Conservation Device (MACD). The total activity delivered to the patient using the MACD was 11.1% (+/- 7.8% s.d.) of the initial dose, compared to 5.8% (+/- 4.2% s.d.) with the nebulizer and mouthpiece alone (P < 0.05). With the MACD, 84% of the intrapulmonary dose was delivered to the peripheral regions, compared to 76.5% with the nebulizer and mouthpiece (P < 0.05). No significant correlation was found between aerosol deposition and pulmonary function. The Mizer Aerosol Conservation Device significantly increases both total intrapulmonary aerosol deposition and peripheral aerosol distribution.

The validity of the geometric mean method for estimating internal activities in nuclear medicine.

The activity of an internal radioactive source may be calculated by comparing the geometric mean of the regional counts in a pair of conjugate gamma camera images with the geometric mean of the counts from a small surface reference source of known activity. Allowance must be made for the effects of differential forward scatter in the detector count rates from the internal and reference sources. The magnitude of these can be predicted, and a suitable correction factor for a given collimator and energy acquisition window calculated by applying a simple count rate build-up model to the observed count rate-depth data for a point and plate source in a water tank. Using a high resolution collimator with 99mTc sources in three sets of phantom trials, the model shows that a scatter build-up correction factor of 1.20-1.22 is suitable for an internal 99mTc source in a typical adult chest or abdomen.

Blunted parathyroid response to correction of hypercalcemia in subjects with squamous cell carcinoma.

In malignancy-associated hypercalcemia (MAH) elevated plasma calcium levels are believed to inhibit parathyroid secretion independently of the underlying tumor. This predicts that correction of hypercalcemia should disinhibit circulating parathyroid hormone (PTH) levels, irrespective of the underlying disease. We have tested this hypothesis in subjects with multiple myeloma (MM) and squamous cell carcinoma (SCC) treated with pamidronate. In the MM group, PTH levels returned to normal as hypercalcemia was corrected. In contrast, PTH levels remained low in the SCC group despite a similar fall in plasma calcium. Calcitriol levels were significantly higher and magnesium levels slightly lower in the SCC group than those in the MM group. We conclude that the parathyroid response to the correction of hypercalcemia is blunted in subjects with SCC but not MM. In addition to hypercalcemia, other factors, perhaps related to tumor secretion of PTH-related protein, may therefore contribute to suppressing PTH secretion in MAH due to SCC.

Clinical significance of the large adrenal mass.

Current clinical teaching indicates that large (greater than 5 cm in diameter) adrenal masses are often malignant. In a retrospective analysis of patients studied between 1977 and 1988 with computed tomography (CT), adrenal scintigraphy, and when available, magnetic resonance imaging (MRI) 45 were found to have adrenal masses greater than 5 cm (range 5-19 cm) in diameter. Thirty were benign (16 phaeochromocytomas, six adrenocortical adenomas, four adrenal cysts, two myelolipomas, an adrenal hematoma and a ganglioneuroma). Of 15 malignant masses, there were seven adrenocortical carcinomas, five adrenal metastases and three adrenal lymphomas. With the exception of the adrenal myelolipomas, cysts, and the ganglioneuroma neither CT nor MRI demonstrated sufficient diagnostic specificity to distinguish benign from malignant lesions. Functional scintigraphy with 131I-6-beta-iodomethyl-19-norcholesterol for suspected adrenocortical lesions and 131I-metaiodobenzylguanidine for suspected phaeochromocytomas frequently provided useful information.

Single-dose intravenous pamidronate is effective alternative therapy for Paget's disease refractory to calcitonin.

We have conducted an open, prospective study to investigate the efficacy of a single 60 mg infusion of pamidronate as alternative therapy in 15 subjects with severe Paget's bone disease refractory to calcitonin. Disease activity was assessed with a visual-analogue score of symptom severity, plasma alkaline phosphatase and quantitative estimation of 99mTc-methylene biphosphonate uptake on bone scan. All indices of disease activity fell after pamidronate, reaching a nadir at 3 months. Although disease activity increased thereafter, only 3 subjects required retreatment within 12 months. Plasma calcium fell after 3 days and remained below baseline levels for 6 months associated with evidence of secondary hyperparathyroidism. Pamidronate was well tolerated; femoral neck fractures occurred in 2 subjects with severe local Paget's disease but were unlikely to be due to the drug. We conclude that pamidronate is an effective and promising alternative for treatment of patients with severe Paget's disease no longer adequately controlled by calcitonin. Calcium supplementation may be prudent to prevent secondary hyperparathyroidism associated with the use of this agent.

Phaeochromocytoma and functioning paraganglioma in childhood and adolescence: role of iodine 131 metaiodobenzylguanidine.

Phaeochromocytomas and functioning paragangliomas are rare tumours in childhood and adolescence. We review our experience of 43 cases (24 men, 19 women) who were first diagnosed at the age of less than or equal to 18 years. All patients were evaluated at some point in their illness with iodine 131 metaiodobenzylguanidine (131I-mIBG) scintigraphy. Eight patients (19%) had bilateral adrenal tumours, 12 (28%) had solitary extra-adrenal tumours, and 8 (19%) had multiple tumours. In 10 patients (23%), the tumours were associated with a familial neurocristopathic syndrome. Thirteen of 24 (54%) unifocal tumours which were initially considered to be benign ultimately proved to be multi-focal and/or malignant. The final prevalence of malignancy was 60%--26 patients, of whom only 15 (57%) had obviously malignant tumours at the time of diagnosis. Primary tumour size greater than or equal to 5 cm was more commonly associated with a malignant course in adrenal but not extra-adrenal tumours. No other clinical, biochemical or morphological characteristic was significantly associated with malignancy. Although the high prevalence of malignancy in this series at least partly reflects referral bias, the need for lifelong follow-up of these patients is underscored. 131I-mIBG scintigraphy was positive in 36 patients (84%), with a somewhat lower false-negative rate (12%) than X-ray computed tomography (20%). Eight patients with malignant tumours received therapeutic doses of 131I-mIBG, with partial tumour responses in 3. Thus, 131I-mIBG is an efficacious, non-invasive, localising agent and may be considered as a palliative therapeutic agent when alternatives have failed.

Use of aminohydroxypropylidene bisphosphonate (AHPrBP, "APD") for the treatment of hypercalcemia in patients with renal impairment.

Aminohydroxypropylidene bisphosphonate (AHPrBP, "APD") is a relatively new bisphosphonate which has been shown to be effective for control of hypercalcemia due to a variety of causes. Renal impairment has been reported following the use of other bisphosphonates and pre-existing renal impairment has been regarded as a contraindication to the use of AHPrBP. We report the successful use of intravenous AHPrBP to control hypercalcemia in three patients with renal impairment, one of whom was dialysis-dependent. No significant side effects were noted; in particular, there was no further deterioration in renal function. Intravenous AHPrBP may be a safe and effective agent for the control of hypercalcemia in patients with renal impairment.

Multiple endocrine neoplasia type 2b: long-term follow-up of a case.

Multiple endocrine neoplasia type 2b is a rare inherited syndrome which comprises the association of medullary thyroid carcinoma, phaeochromocytoma, widespread neuromatous proliferation and a characteristic body habitus. In this report we present the late clinical course and autopsy findings of the first patient with this syndrome described in Australia. At presentation she was found to have a right adrenal phaeochromocytoma and medullary thyroid carcinoma which were resected in separate operations. No clinical or biochemical evidence of residual medullary thyroid carcinoma was identified in life. However, in spite of serial vanillylmandelic acid estimations, which showed normal or only mildly elevated levels, and normal results of urinary catecholamine studies, a left adrenal phaeochromocytoma was identified in a metaiodobenzylguanidine (MIBG) study performed 14 years after presentation. Her late clinical course was dominated by progressive dysphagia, intestinal dysmotility and megacolon associated with unrelenting malnutrition. After her death due to an intracerebral haemorrhage, an autopsy confirmed the presence of a left adrenal phaeochromocytoma and revealed diffuse intestinal ganglioneuromatosis to be the cause of her intestinal dysmotility. No residual medullary thyroid carcinoma was found. This case emphasises the propensity for multiple endocrine tumours in these patients and highlights the potentially significant role of intestinal ganglioneuromatosis in the natural history of this condition.

Insensitivity of Tc-99m pertechnetate for detecting metastases of differentiated thyroid carcinoma.

To evaluate the use of Tc-99m pertechnetate whole body scanning for the detection of metastases of differentiated thyroid carcinoma, the authors performed sequential Tc-99m pertechnetate and I-131 scans in five patients with known or suspected metastatic thyroid cancer. All five patients had abnormal I-131 uptake, but only two patients had abnormal Tc-99m pertechnetate uptake. A total of 33 abnormal foci were located with I-131; Tc-99m pertechnetate detected only 3 of these foci, and did not demonstrate any foci that were not apparent with I-131. Despite the theoretical advantages of Tc-99m pertechnetate, it cannot be recommended as a substitute for I-131 for locating thyroid cancer metastases.

Role of 131I-metaiodobenzylguanidine in the localization of suspected phaeochromocytomas.

Iodine-131-metaiodobenzylguanidine is a recently-developed radiopharmaceutical agent for adrenal medullary scintigraphy. Twenty-one scans with 131I-metaiodobenzylguanidine were performed in 20 adults with suspected phaeochromocytomas over a four-year period. All patients previously had undergone computed tomographic scans of the abdomen and pelvis. The computed-tomographic scans were abnormal in 14 patients (16 tumours), eight (nine tumours) of whose 131I-metaiodobenzylguanidine scans gave positive results. Both types of scan gave negative results in the remaining six patients. Among 12 patients who underwent surgery or postmortem examination, the 131I-metaiodobenzylguanidine scan correctly showed eight phaeochromocytomas; six tumours that were found on computed-tomographic scans but not on 131I-metaiodobenzylguanidine scans proved not to be phaeochromocytoma. The 131I-metaiodobenzylguanidine scan probably gave a true-positive result in an additional case (surgical confirmation was not available). None of the remaining seven patients in whom the 131I-metaiodobenzylguanidine scan gave negative results has been shown to harbour a phaeochromocytoma on extended follow-up (2.5 to four years). Iodine-131-metaiodobenzylguanidine is a highly sensitive and specific agent for the localization of phaeochromocytomas. In patients with suspected phaeochromocytomas and abnormal computed-tomographic findings, 131I-metaiodobenzylguanidine permits a non-invasive, functional evaluation of the morphological abnormalities to be made. The importance of making a biochemical diagnosis of a phaeochromocytoma before attempting localization studies is emphasized.

Labetalol reduces iodine-131 MIBG uptake by pheochromocytoma and normal tissues.

Iodine-131 metaiodobenzylguanidine [131I]MIBG has proven to be an effective radiopharmaceutical for the scintigraphic localization of pheochromocytomas. Uptake of MIBG is inhibited by blockade of the neuronal uptake pathway for catecholamines ("uptake-1") and by depletion of catecholamine storage vesicle contents, but is not significantly affected by conventional alpha- and beta-adrenoreceptor blocking drugs. Labetalol is an antihypertensive agent with combined alpha- and beta-blocking properties that has been used to manage patients with suspected pheochromocytomas. We report eight patients in whom concurrent or recent therapy with labetalol significantly reduced the uptake of [131I]MIBG into salivary glands, liver, spleen, and general body background. Tumor uptake of MIBG was also reduced in two of the three patients who were proven to have pheochromocytomas. In one case, the effect of labetalol persisted for 36 hr after the drug had been discontinued. The inhibitory effect of labetalol on MIBG uptake in sympathomedullary tissues is likely to be a result of the drug's little-known, additional properties of uptake-1 blockade and depletion of storage vesicle contents, rather than its alpha- or beta-blocking effects. Additionally, labetalol would also appear to hasten clearance of MIBG from other tissues. Labetalol therapy should be discontinued for several days (possibly up to 1 wk) before undertaking [131I]MIBG scintigraphy. A comprehensive list of drugs that should be avoided in patients undergoing MIBG scintigraphy is appended.

SPECT evaluation of arterial perfusion in regional chemotherapy.

Simultaneous emission and transmission tomography was performed after the injection of [99mTc]MAA in 30 patients undergoing intra-arterial chemotherapy to nonhepatic sites to determine the accuracy of catheter placement. The transmission and emission data were reconstructed in transverse, and optionally, coronal and sagittal planes. The correlation of the emission scan with the reconstructed transmission data allowed accurate anatomical localization of the infusate distribution. In seven patients, catheter placement resulted in perfusion to nontumor sites, and hence required repositioning. MAA accumulation was seen in the lungs of all patients, regardless of tumor site, indicating arterio-venous shunting of the MAA. The degree of uptake in the lungs was quantified from planar anterior/posterior thorax images in terms of injected dose in ten patients, with values of 5-50% of injected dose present in the lungs. The technique provides a noninvasive means of accurately determining regional perfusion of chemotherapeutic agents delivered intra-arterially.

Intestinal pseudo-obstruction in pheochromocytoma.

Intestinal pseudo-obstruction is a rare complication of pheochromocytoma. We describe a 39 year old man with a large right adrenal pheochromocytoma and extremely high catecholamine levels, who developed pseudo-obstruction which responded promptly to intravenous phentolamine infusions. This case supports the concept that this complication is attributable to high circulating levels of catecholamines, acting by direct and indirect inhibition of gastrointestinal motility.