Samuel R. Nussbaum

Multifactorial Index of Cardiac Risk in Noncardiac Surgical Procedures

To determine which preoperative factors might affect the development of cardiac complications after major noncardiac operations, we prospectively studied 1001 patients over 40 years of age. By multivariate discriminant analysis, we identified nine independent significant correlates of life-threatening and fatal cardiac complications: preoperative third heart sound or jugular venous distention; myocardial infarction in the preceding six months; more than five premature ventricular contractions per minute documented at any time before operation; rhythm other than sinus or presence of premature atrial contractions on preoperative electrocardiogram; age over 70 years; intraperitoneal, intrathoracic or aortic operation; emergency operation; important valvular aortic stenosis; and poor general medical condition. Patients could be separated into four classes of significantly different risk. Ten of the 19 postoperative cardiac fatalities occurred in the 18 patients at highest risk. If validated by prospective application, the multifactorial index may allow preoperative estimation of cardiac risk independent of direct surgical risk.

Osteoporosis in women with anorexia nervosa.

Because estrogen deficiency predisposes to osteoporosis, we assessed the skeletal mass of women with anorexia nervosa, using direct photon absorptiometry to measure radial bone density in 18 anorectic women and 28 normal controls. The patients with anorexia had significantly reduced mean bone density as compared with the controls (0.64 +/- 0.06 vs. 0.72 +/- 0.04 g per square centimeter, P less than 0.001). Vertebral compression fractures developed in two patients, and bone biopsy in one of them demonstrated osteoporosis. Bone density in the patients was not related to the estradiol level (r = 0.02). Levels of parathyroid hormone, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D were normal despite low calcium intakes. The patients with anorexia who reported a high physical activity level had a greater bone density than the patients who were less active (P less than 0.001); this difference could not be accounted for by differences in age, relative weight, duration of illness, or serum estradiol levels. The bone density of physically active patients did not differ from that of active or sedentary controls. We conclude that women with anorexia nervosa have a reduced bone mass due to osteoporosis, but that a high level of physical activity may protect their skeletons.

Cardiac risk factors and complications in non-cardiac surgery.

In an attempt to assess cardiac risk in non-cardiac surgery, 1001 patients over 40 years of age who underwent major operative procedures were examined preoperatively, observed through surgery, studied with at least one postoperative electrocardiogram, and followed until hospital discharge or death. Documented postoperative myocardial infarction occurred in only 18 patients; though most of these patients had some pre-existing heart disease, there were few preoperative factors which were statistically correlated with postoperative infarction. Postoperative pulmonary edema was strongly correlated with preoperative heart failure, but 21 of the 36 patients who developed pulmonary edema did not have any prior history of heart failure. Nearly all of these 21 patients were elderly, had abnormal preoperative electrocardiograms, and had intraabdominal or intrathoracic surgery. In the absence of an acute infarction, bifascicular conduction defects, with or without PR interval prolongation, never progressed to complete heart block. Spinal anesthesia protected against postoperative heart failure but not against other cardiac complication. By multivariate regression analysis, postoperative cardiac death was significantly correlated with (a) myocardial infarction in the previous 6 months; (b) third heart sound or jugular venous distention immediately preoperatively; (c) more than five premature ventricular contractions per minute documented at any time preoperatively; (d) rhythm other than sinus, or premature atrial contractions on preoperative electrocardiogram; (e) age over 70 years; (f) significant valvular aortic stenosis; (g) emergency operation; (h) a 33% or greater fall in systolic blood pressure for more than 10 minutes intraoperatively. Notably unimportant factors included smoking, glucose intolerance, hyperlipidemia, hypertension, peripheral atherosclerotic vascular disease, angina, and distant myocardial infarction.

Hungry bone syndrome : clinical and biochemical predictors of its occurrence after parathyroid surgery

The hospital course of 218 consecutive patients with primary hyperparathyroidism admitted over a three-year period for parathyroidectomy at the Massachusetts General Hospital was reviewed to determine the incidence and identify the risk factors for the development of the hungry bone syndrome. Twenty-five patients with the hungry bone syndrome were identified (12.6 percent). Compared to patients with uncomplicated metabolic responses to parathyroid surgery, these patients were older by a mean of 10 years; they had higher preoperative serum levels of calcium, alkaline phosphatase, N-terminal parathyroid hormone, and blood urea nitrogen; and their resected parathyroid adenomata were larger. The mean duration of hospitalization averaged three days longer in the group with hungry bone disease. Stepwise multivariate analysis of preoperative variables enabled the development of a discriminant function for prediction of postoperative hypocalcemia and hypophosphatemia. Identified predictive variables were volume of resected parathyroid adenoma, blood urea nitrogen, alkaline phosphatase, and age. When validated on an independent patient population, these readily obtainable preoperative clinical and laboratory parameters will allow identification of a subgroup of patients who are at greater risk for the development of the hungry bone syndrome following parathyroid surgery.

Single-dose intravenous therapy with pamidronate for the treatment of hypercalcemia of malignancy: Comparison of 30-, 60-, and 90-mg dosages

PURPOSE To determine the efficacy, dose-response relationship, and safety of 30, 60, and 90 mg of a single intravenous dose of an aminobisphosphonate, pamidronate (APD), for the treatment of moderate to severe hypercalcemia of malignancy. PATIENTS AND METHODS Patients with histologically proven cancer and a corrected serum calcium level of at least 12.0 mg/dL after 48 hours of normal saline hydration were enrolled in a double-blind, multicenter, randomized clinical trial. Pamidronate in 30-, 60-, or 90-mg doses was administered as a single 24-hour infusion. Serum calcium corrected for albumin, urine hydroxyproline, and calcium excretion, and serum parathyroid hormone (PTH) (1-84) were determined before and after pamidronate therapy. RESULTS Thirty-two men and 18 women entered the study. A dose-response relationship for normalization of corrected serum calcium was seen after pamidronate administration. Corrected serum calcium normalized in 40% of patients who received 30 mg, in 61% of patients who received 60 mg, and in 100% of patients who received 90 mg of pamidronate. The decline in the serum calcium level was associated with decreased osteoclastic skeletal resorption evidenced by a decrease in urine calcium and hydroxyproline excretion. Among those with a normalized corrected serum calcium level, the mean (median) duration of normalization of the corrected serum calcium value was 9.2 (4), 13.3 (5), and 10.8 (6) days in the 30-, 60-, and 90-mg treatment groups, respectively. The response of hypercalcemia to pamidronate was not significantly influenced by the presence of skeletal metastases. PTH 1-84, suppressed in patients on entry into this study, increased to a greater extent in those patients with osteolytic skeletal metastases compared with those with humoral hypercalcemia of malignancy. Clinical improvement, including improved mental status and decreased anorexia, accompanied the decline in the corrected serum calcium level in all three treatment groups. Side effects included low-grade fever, asymptomatic hypocalcemia, hypomagnesemia, and hypophosphatemia. CONCLUSIONS A single-dose infusion of 60 to 90 mg of pamidronate was highly effective and well tolerated and normalized corrected serum calcium in nearly all patients (61% to 100%) with hypercalcemia of malignancy.

Hypomagnesemia is common following cardiac surgery

Hypomagnesemia is a common disorder in noncardiac surgical patients in the postoperative period, but the effect of cardiac surgery on serum magnesium concentrations remains unclear. The authors hypothesized that cardiac surgery is associated with hypomagnesemia, and prospectively studied 101 subjects (60 +/- 13.1 years of age) undergoing coronary artery revascularization (n = 70), valve replacement (n = 24), or both simultaneously (n = 7). Blood samples and clinical biochemical data were collected before induction of anesthesia, prior to cardiopulmonary bypass (CPB), immediately after CPB, and on postoperative day 1. Blood samples were analyzed for ultrafilterable magnesium, total magnesium, ionized calcium, parathyroid hormone, and free fatty acid concentrations. Outcome variables were also determined. Eighteen of 99 (18.2%) subjects had hypomagnesemia preinduction and this number increased to 71 of 100 (71.0%) following cessation of CPB (P less than 0.05). Patients with postoperative hypomagnesemia had a higher frequency of atrial dysrhythmias (22 of 71 [31.0%] v 3 of 29 [10.3%], P less than 0.05) and required prolonged mechanical ventilatory support (22 of 63 [34.9%] v 4 of 33 [12.1%], P less than 0.05). Hypomagnesemia is common following cardiac surgical procedures with CPB and is associated with clinically important postoperative morbidity.

Hypocalcemia in critically ill children

To determine the prevalence and clinical consequences of hypocalcemia in pediatric intensive care unit patients, we prospectively studied calcium homeostasis in 145 of these patients. The total serum calcium concentration was measured in all patients. The serum ionized calcium concentration was measured in blood samples collected from those 71 (49%) patients who had low total serum calcium values (less than 8.5 mg/dl (2.12 mmol/L). Of the 71 patients, 26 (36.6%) had ionized hypocalcemia. Therefore the prevalence of ionized hypocalcemia was at least 17.9% (26/145). Death occurred in 8 (31%) of 26 patients with ionized hypocalcemia versus 3 (2.5%) of 119 patients with normocalcemia (p less than 0.0001). However, the severity of illness score was higher (p less than 0.05) in the children with ionized hypocalcemia than in normocalcemic children (mean Therapeutic Intervention Scoring System score 33 +/- 17 vs 22 +/- 11, respectively). More of the children with ionized hypocalcemia had sepsis (p = 0.0299) and they required the administration of vasopressor agents more often (p = 0.0002) than their normocalcemic counterparts. Of the 26 patients with ionized hypocalcemia, 17 (65.4%) had biochemical evidence of either absolute or relative hypoparathyroidism, determined by means of an immunoradiometric assay that measures only biologically active parathyroid hormone. We conclude the following: (1) ionized hypocalcemia is common in severely ill children. (2) Patients with ionized hypocalcemia have a higher mortality rate than those with normocalcemia; however, because the former are more severely ill, no causality is apparent or suggested. (3) Functional hypoparathyroidism may occur in critically ill children.

Design of analogues of parathyroid hormone: A conformational approach

An approach to the design of peptide-hormone analogues in which amino acid substitutions are based on predicted effects on secondary structure was investigated. The structural requirements for parathyroid-hormone (PTH) action are distinct from the determinants necessary for receptor binding alone without subsequent activation of adenylate cyclase. Two analogues of PTH containing substitutions in the principal binding domain of PTH, the region 25–34, were synthesized by the solid-phase method and evaluated for bioactivity. The sequence 25–34 was predicted to have nearly equal conformational potential for both α-helix and β-sheet using Chou and Fasman parameters. A previously studied analogue, [Tyr34]bPTH(1–34) amide, containing substitutions in this region, was more active than was bPTH-(1–34). The substitution of tyrosine for phenylalanine at position 34 in this analogue is predicted to promote β-sheet conformation. The analogues [Ile28, Tyr30, Tyr34]bPTH-(1–34) amide and [Arg32, Tyr34]bPTH-(1–34) amide each contain substitutions predicted to further enhance or stabilize β-sheet formation. The solution conformation of these analogues, determined by circular dichroism studies in an aqueous buffer and an organic solvent, indicated promotion of β-sheet secondary structural content in both analogues in a hydrophobic environment chosen to simulate that of the interaction of the peptide and the membrane receptor. In contrast, the native sequence lacks β-structure. Biological activity of these analogues in the rat renal adenylate cyclase assay in vitro and binding affinity in a radioreceptor assay were threefold those of unsubstituted PTH-(1–34). Peptide analogue design based on conformational prediction, rather than substitution of primary structure alone, offers an attractive alternative approach to the development of hormone analogues and antagonists.

Development of monoclonal antibodies against parathyroid hormone: genetic control of the immune response to human PTH

Publisher Summary In normal physiology, parathyroid hormone (PTH) serves an important homeostatic role in the regulation of extracellular calcium levels through its effects on kidney, bone, and gut. Extracellular calcium levels are maintained within the narrow limits required for optimal functioning of nerve, muscle, enzymes, and hormones. Analysis of the relation of structure to hormonal function for parathyroid hormone has provided important insights into the physiological roles served by certain regions of the hormone molecule and the initial events and mechanisms by which hormonal messages are translated into physiological actions. The principal secreted form of the hormone contains 84 amino acids. PTHs critical role in the physiology of calcium homeostasis results from its multiple actions on kidney and bone. Expression of hormone action is linked to a number of biochemical events at the surface and within target tissue cells. PTH interacts with hormone-specific receptors on the plasma membrane of target-tissue cells.