Hyperosmolar hyperglycemic nonketotic syndrome. Report of 22 cases and brief review

In a series of 22 patients with the hyperosmolar hyperglycemic nonketotic syndrome managed during a five-year period in a community hospital setting, 21 patients were known to be diabetic and only six patients were in coma. The overall mortality was 36.3 percent, and seven of the eight deaths were explained by associated nonmetabolic causes. In this study, hyperosmolarity was not related to coma or to final outcome of treatment. Patients were managed with relatively small amounts of fluid, and the type of fluid used did not influence the final outcome.     

Adrenomedullary response to maximal stress in humans

The most important neuroendocrine response to stress is an increase in plasma epinephrine concentration. To investigate the clinical significance of this response, plasma catecholamine levels were measured (single-isotope derivative assay) in chronic stress (severe illness; n = 22) and acute maximal stress (cardiac arrest; n = 23). The results were then compared with the values from 60 normal resting subjects: epinephrine (mean +/- SEM) 0.034 +/- 0.002 ng/ml; norepinephrine 0.228 +/- 0.01 ng/ml. Chronic stress (intensive care unit patients) was associated with a fourfold elevation of epinephrine concentration (0.14 +/- 0.06 ng/ml; range 0.01 to 1.37; p less than 0.01 versus normal control subjects). Acute maximal stress (resuscitation following cardiac arrest) resulted in a greater than 300-fold increase in the plasma epinephrine level (10.3 +/- 2.9 ng/ml; range 0.36 to 35.9; n = 15; p less than 0.01). Peak plasma epinephrine levels in successfully resuscitated patients (n = 6) ranged from 0.36 to 273 ng/ml (three patients had received epinephrine therapy). The plasma norepinephrine level was increased twofold in intensive care unit patients (0.52 +/- 0.06 ng/ml; p less than 0.01) and 32-fold after cardiac arrest (7.37 +/- 1.8 ng/ml; p less than 0.01). During resuscitation, the correlation between the simultaneous epinephrine and norepinephrine levels was highly significant: r = 0.76; p less than 0.01. It is concluded that (1) chronic, severe stress produces only moderate elevations of plasma epinephrine levels (up to 1.37 ng/ml), whereas acute stress produces marked increases of plasma epinephrine that may reach the extraordinarily high level of 35.9 ng/ml, (2) the potential toxicity from the adrenomedullary response to acute stress is further exacerbated by the parallel release of norepinephrine, and (3) under close medical monitoring, it is possible to survive with plasma epinephrine concentrations as high as 273 ng/ml.     

Left ventricular function during spontaneous angina pectoris: effect of sublingual nitroglycerin

Global and regional left ventricular function was assessed at rest, during spontaneous angina pectoris and after nitroglycerin therapy in 14 patients with ischemic heart disease. Cardiac output, left ventricular pressure and left ventricular volume were measured when patients experienced spontaneous angina pectoris during cardiac catheterization. In every patient control measurements had already been made; further measurements were made after nitroglycerin had relieved pain. Subsequent coronary angiography showed significant two or three vessel disease in all 14 patients. The S-T segment was depressed in every patient during pain (average 0.26 + 0.04 mV; mean + standard error of the mean [SEM]). During spontaneous angina, there was a significant increase in left ventricular end-diastolic pressure (17 ± 2 to 35 ± 2 mm Hg, p < 0.001), left ventricular end-diastolic volume (77 ± 6 to 88 ± 8 ml/m², p < 0.005) and left ventricular end-systolic volume (35 ± 4 to 52 ± 7 ml/m², p < 0.001). Concomitantly stroke index decreased from 42 ± 2 to 36 ± 3 ml/beat per m² (p < 0.01) and ejection fraction from 56 ± 4 to 44 ± 4 percent (p < 0.001).Assessment of regional left ventricular performance during spontaneous angina revealed either development of new areas or extension of already existing areas of abnormal wall motion in all patients. Nitroglycerin restored global and regional left ventricular function to a normal state. In six individual patients there was an excellent correlation between the S-T depression (V₅) and left ventricular end-diastolic pressure during spontaneous angina (correlation coefficient [r] = 0.88 to 0.96) and after nitroglycerin therapy (r = 0.76 to 0.84). For the group, there was a good correlation between change in S-T depression and changes in left ventricular end-diastolic pressure (r = 0.87) and left ventricular end-diastolic volume (r = 0.78). Thus, these data indicate marked systolic and diastolic dysfunction of the left ventricle during spontaneous angina pectoris, characterized by decreases in stroke index and ejection fraction and increases in left ventricular end-systolic and end-diastolic volumes and left ventricular filling pressure.     

Lipoatrophic diabetes: Endocrine dysfunction and the response to control of hypertriglyceridemia

Endocrine function was studied in a 24 year old female with lipoatrophic diabetes (LD). Baseline endocrine studies (serum triglycerides: 2600 mg/dl) demonstrated hyperprolactinemia (serum prolactin 51 ng/ml), increased ACTH levels, absence of suppression of ACTH to a high dose of dexamethasone which suppressed serum cortisol normally and, hyperresponsiveness of TSH to stimulation with TRH. Thyroid hormone levels (total and free fraction) were essentially normal. Major metabolites of thyroid hormone (T₃, rT₃, 3, 3′? T₂, and 3′, 5′?T₂ were also normal and exhibited a normal response to the administration of L-thyroxine and propylthiouracil. Exchange of 84% of the patient's plasma resulted in a decrease in serum triglycerides (700 mg/dl) which was followed by a rebound to the original level in seven days. After the sixth plasmapheresis serum triglycerides stabilized at less than 1000 mg/dl. Plasmapheresis was associated with the appearance of amenorrhea and galactorrhea; also hypertension and proliferative retinopathy developed during this therapy. Repeat endocrine function studies (serum triglycerides: 700 mg/dl) showed a further rise in serum prolactin (>160 ng/ml), persistence of abnormal ACTH secretion and normalization of TSH responsiveness. Lipoatrophic diabetes is associated with abnormal central endocrine function but appropriate peripheral target gland secretion. A course of plasmapheresis improves the hypertriglyceridemia but not the endocrine dysfunction. In this patient with LD the most important side effect of plasmapheresis was the development of cardiovascular complications.     

Endotoxin, prekallikrein, complement and systemic vascular resistance. Sequential measurements in man.

Eighteen patients were studied prior to and again within 6 hours after transurethral resection or cystoscopy. In addition to hemodynamic measurements, detection of endotoxin by limulus assay and bacteriologic sampling; prekallikrein, C3, C3 proactivator and lysosomal enzyme levels were measured. In five patients limulus assays were positive, and in one, gram-positive bacteremia developed but limulus assay remained negative. All six had significant decreases in prekallikrein, C3 or C3 proactivator. Systemic vascular resistance fell in all six. Four additional patients who had a decrease in systemic vascular resistance were not endotoxemic or bacteremic; one of these had a decrease in prekallikrein only. In the remaining eight patients with neither bacteremia nor endotoxemia, systemic vascular resistance did not change or increase after instrumentation. One had a decrease in C3 proactivator, another in prekallikrein. There was no significant difference in age, disease, antibiotic therapy or bactermia in the two groups of patients. Four of the five resectional procedures were performed in the group that showed decreases in systemic vascular resistance. The data suggest that acute endotoxemia or gram-positive bacteremia in man is associated with depletion of prekallikrein, decreased peripheral resistance and, in some instances, activation of the complement system.     

An evaluation of diabetic and pseudodiabetic glomerulosclerosis.

Diabetic glomerulosclerosis must be either a primary manifestation or a secondary consequence of the metabolic abnormalities of diabetes. Several earlier reports have attempted to support the former hypothesis by describing cases of pathognomonic renal lesions in nondiabetic subjects; however, the clinical and pathologic data in these reports are inconclusive. We have reviewed our experience at the University of Virginia Hospital with 447 percutaneous renal biopsies performed over a period of four years from July 1973 through July 1977. Of these cases, only two appeared to represent diabetic glomerulosclerosis occurring in nondiabetic subjects. Upon further investigation, one case provided to be light chain disease demonstrated by immunofluorescence staining. The other case, on repeat renal biopsy, proved to be membranoproliferative glomerulonephritis. We conclude that a diagnosis of diabetic glomerulosclerosis must be viewed with suspicion in nondiabetic subjects. Suspected cases should be labeled pseudodiabetic glomerulosclerosis and investigated further.     

The nephrotic syndrome associated with neoplasia: An unusual paraneoplastic syndrome: Report of a case and review of the literature

The nephrotic syndrome complicating malignancy in the absence of renal vein thrombosis, amyloid or neoplastic infiltration of the kidney is an unusual occurrence. A case of diffuse, well differentiated, lymphocytic lymphoma and lipoid nephrosis documented by light microscopy, electron microscopy and immunofluorescent studies is reported. A review of the literature revealed 76 case reports in which the nephrotic syndrome was associated with neoplasia. The most frequently associated neoplasms are Hodgkin's disease, various carcinomas, nonHodgkin's lymphoma and leukemia in descending order. The most frequent renal lesion in patients with the nephrotic syndrome associated with various carcinomas is membranous glomerulonephritis (81 per cent) as opposed to patients with lymphomas or leukemias who have predominantly lipoid nephrosis (60 per cent). The evidence is reviewed suggesting that the lesions in membranous nephropathy are immunologically mediated by tumor or viral antigen-antibody complexes and in lipoid nephrosis perhaps by a defect in T-lymphocyte function.     

Immunologically-mediated renal disease in Waldenström's macroglobulinemia

A patient with Waldenström's macroglobulinemia associated with nephrotic syndrome is described. Serum cryoglobulin and rheumatoid factor were absent. Intramembranous electron-dense deposits were demonstrated in kidney biopsy material by electron microscopy. Deposits of immunoglobulin G (IgG), M (IgM) and the third component of complement (C3) were identified hi kidney biopsy tissue by immunofluorescent staining methods. The serum immunoglobulins were characterized by Chromatographic and immunochemical methods and showed a monoclonal IgM-κ, IgG-κ and γ-chain piece of undefined structure. Free κ- and γ-chains were found in the urine. The IgM was not complexed to the IgG or vice versa, but the IgG was in an aggregated form. Although it is not known which immunoglobulin initiated the tissue injury, IgG, IgM and complement deposits probably contributed to the renal dysfunction.The nephrotic syndrome diminished after treatment with chlorambucil and corticosteroids.     

The prehospital course of patients with chest pain. Analysis of the prodromal, symptomatic, decision-making, transportation and emergency room periods

In order to determine whether prehospitalization characteristics of patients with chest pain are useful in predicting their subsequent course, we analyzed the precoronary care course in 211 consecutive patients admitted because of suspected myocardial infarction. On the basis of serial electrocardiograms and enzymes, 61 patients had a definite myocardial infarction on admission, 30 patients evolved criteria for an infarction during hospitallzation, 102 patients had cardiac pain without infarction, and 18 patients were judged to have noncardiac pain. The mean patient delay from onset of chest pain to arrival at the hospital was 456 ± 703 minutes (median 210 minutes). The decision to seek medical help consumed a mean 307 ± 575 minutes of this delay, whereas transportation to the hospital required only a mean of 17 ± 49 minutes. Known heart disease, known stable angina and progressive unstable angina tended to prolong the patient's decision to seek medical help. Of 140 patients who contacted a physician, 67 (48 per cent) were sent to the emergency room; whereas 71 had an additional mean 180 ± 436 minutes (median 38 minutes) of physician-advised delay consisting of office visits (59 patients), house call (five patients) and other attempted therapy (seven patients). The presence of prodromas or chest pain consistent with unstable angina was not significantly different in any patient group. We conclude that prodromas, although common, are not helpful in differentiating those with infarction from those without infarction among the patients hospitalized because of chest pain. Furthermore, the mean patient delay of over 6 hours and median delay of 3 $\text{1}\text{2}\text{hours}$ indicates that this delay is the most immediate problem to be solved in order to decrease out of hospital mortality.     

Massive osteolysis. An unusual cause of bone destruction

A patient who presented with multiple lytic lesions of bone was found to have massive osteolysis. The clinical course of this patient is described and the literature on massive osteolysis reviewed. This disease of uncertain etiology is pathologically marked by resorption of bone, and replacement by angiomas and fibrosis. X-ray findings are usually more severe than expected from the patients' clinical presentation. Laboratory studies, including attempts at biopsy, are generally unrevealing. Drug therapy is of no value, and success of surgical attempts at bone union are unpredictable. Massive osteolysis should be considered in the differential diagnosis of osteolytic lesions, particularly since this disorder can result in serious morbidity.     

The pharmacology of sulfonylureas

In this report we review the pharmacology of the hypoglycemic sulfonylurea drugs. The early work with sulfonylureas is briefly described. The pharmacokinetics of first-generation sulfonylureas, such as tolbutamide, chlorpropamide, acetohexamide and tolazamide, are described. The first-generation sulfonylureas are compared with second-generation sulfonylureas such as glyburide, glipizide and glibornuride. These latter drugs have a more nonpolar or lipophilic side chain, which results in a marked increase in their hypoglycemic potency. Because of the low serum concentration required for effective therapy, it is necessary to measure the serum concentration of second-generation sulfonylureas by gas-liquid chromatography or radioimmunoassay. The second-generation sulfonylureas do not produce facial flushing after ethanol ingestion (Antabuse effect) and are not uricosuric. Glyburide (but not glipizide or glibornuride) has been evaluated for its effect on water excretion. Glyburide not only does not increase water retention but in fact also increases free water clearance. The second-generation sulfonylureas bind to human serum albumin by nonionic forces in contrast with tolbutamide and chlorpropamide which bind by ionic forces. Thus, anionic drugs such as phenylbutazone, warfarin and salicylate do not displace glyburide from albumin as they displace tolbutamide and chlorpropamide. Therefore, it may be safer to administer the second-generation sulfonylureas than the more polar sulfonylureas when concurrent administration of other pharmacologic agents is likely. The sulfonylurea drugs lower plasma glucose concentrations in diabetic patients by stimulating insulin secretion and by potentiating the biologic effect of the insulin on such tissues as skeletal muscle, fat and liver. The mechanism of the latter so-called extra-pancreatic effect may be activated by increasing the deficient numbers of insulin receptors on muscle, fat or liver cells.     

Gastrointestinal hemorrhage—An unusual manifestation of neurofibromatosis

Hemorrhage from intestinal neurofibromas or leiomyomas is an infrequent but often life-threatening complication of neurofibromatosis. Despite typical cutaneous findings, the bleeding tumor usually cannot be demonstrated because of its inaccessible location in the jejunum or ileum. In the present case, superior mesenteric arteriography successfully demonstrated hemorrhage from a jejunal leiomyoma. Review of the literature demonstrates the difficulty of establishing the correct diagnosis by other means. Arteriography should be the contrast procedure of first choice in the patient with neurofibromatosis and gastrointestinal bleeding.     

Thyroid antigen associated immune complex glomerulonephritis in Graves' disease

A 60 year old hyperthyroid black woman with long-standing Graves' disease treated with methimazole presented with anasarca and congestive heart failure. She was found to have the nephrotic syndrome with a urinary protein excretion of 32 g/day. Light and electron microscopy revealed a stage II membranous glomerulopathy. Direct and indirect immunofluorescence demonstrated immunoglobulin G (IgG), immunoglobulin M (IgM), third component of complement and thyroglobulin in a granular diffuse pattern consistent with an immune complex glomerulonephritis. Total thyroidectomy led to a decrease in proteinuria with little change in glomerular filtration rate during an 11 month follow-up period. We believe this to be the first report of immune complex glomerulonephritis associated with thyroid antigen in Graves' disease.     

Clinical isolation and characterization of aminoglycoside-resistant small colony variants of Enterobacter aerogenes.

Small colony variants of Enterobacter aerogenes, as well as the parental large colony type, grew in blood drawn for cultures on three separate days from a patient who had received suboptimal gentamicin therapy. Minimum inhibitory concentrations of four aminoglycoside antibiotics were eight to more than 16 times higher for small colony variants than for the normal large colony type. Small colony variants had defective catalase activity, which may have interfered with oxidative metabolism and aminoglycoside uptake. Small colony variants reverted readily to the parental type in vitro in the absence of aminoglycosides. Clinically isolated small colony variants appeared similar to those selected in the presence of gentamicin in vitro, with respect to colony morphology, aminoglycoside resistance and catalase deficiency. The isolation of small colony variants during gentamicin therapy in vivo suggests that such variants may be a cause of treatment failure in patients receiving aminoglycosides.     

Spectrum of hyperparathyroidism

A new classification of hyperparathyroidism is proposed, based on data obtained by immunoassay of parathyroid hormone (PTH). The customary modifiers “primary,” “secondary” and “tertiary” are avoided because they no longer have precise meaning. The frequency of transition from one form of hyperparathyroidism to another is described as maladaptation to a variety of possible stimulators of PTH secretion. The need for clinical research focused on the antecedents of hypercalcemia is stressed.     

Pericardial disease in rheumatoid arthritis.

Six patients with rheumatoid constrictive pericarditis, five seen in a two and one half year period, are described. All patients were male, all had rheumatoid factor, and all had active arthritis. Diagnosis was suspected from careful physical examination and confirmed in five patients by cardiac catheterization. Pericardiectomy was successful in all five patients on whom it was performed. Rheumatoid constrictive pericarditis should be suspected in any patient with rheumatoid arthritis and unexplained signs of right heart failure.     

Ventriculojugular shunt nephritis with Corynebacterium bovis. Successful therapy with antibiotics.

A patient with hydrocephalus and a ventriculojugular shunt presented with acute nephritis, nephrotic syndrome (proteinuria 10 g/24 hours), decreased complement levels, circulating immune complexes and diminished creatinine clearance (41 ml/min). Seven blood cultures grew Corynebacterium bovis. A renal biopsy specimen revealed mesangiocapillary glomerulonephritis by light microscopy, and thickened glomerular basement membranes with areas of increased granular density by electron microscopy. Immunofluorescent examination of the biopsy specimen demonstrated 2+ granular glomerular basement membrane deposits of immunoglobulin M (IgM), with trace third component of complement (C-3), fourth component of complement (C-4) and immunoglobulin G (IgG). Rabbits immunized with C. bovis produced a line of partial identity in agar with patient serum against a sonicate of C. bovis. Indirect fluorescein staining of the biopsy specimen with the rabbit antiserum demonstrated 1+ granular glomerular basement membrane deposits. Potassium thiocyanate microelution of sections prior to examination markedly diminished staining with antihuman antiserum, but did not affect staining with rabbit antiserum. Following initial therapy with intravenous penicillin for six weeks the bacteremia cleared, serum complement levels returned to normal, proteinuria decreased and creatinine clearance increased. A relapse occured four weeks later with decreased complement levels, increased proteinuria and decreased creatinine clearance. Blood cultures were again positive for C. bovis. Following therapy with erythromycin and rifampin, the bacteremia cleared and there was a sustained improvement of all parameters. To our knowledge, this is the first time an association has been noted between C. bovis ventriculojugular shunt infection and glomerulonephritis. These findings support the potential role of C. bovis as an etiologic agent in human renal disease and further define the immune complex nature of shunt nephritis.     

Angio-immunoblastic lymphadenopathy. Diagnosis and clinical course.

The clinical and pathologic findings in 24 patients with "angio-immunoblastic lymphadenopathy with dysproteinemia" (AILD) are presented. The patients' ages ranged from 44 to 80 years, with a median age of 68 years. The disease has an acute onset. In many respects, the clinical presentation is suggestive of malignant lymphoma. Generalized lymphadenopathy was always present. Hepatomegaly was found in 20 patients, splenomegaly in 17, constitutional symptoms in 20 and skin rashes in nine. Twenty patients had anemia, with positive Coombs' test in eight of 14 tested. Polyclonal hypergammaglobulinemia was found in 17 of 22 patients. Two patterns of evolution were recognizable: (1) long survival (24 to 67 months) without treatment or after the administration of intensive combination chemotherapy; and (2) rapid progression (one to 19 months) regardless of the treatment given. Sixteen patients died; postmortem examination in 10 cases showed the cause of death to be attributable to severe infection in eight patients, to renal disease in one and to cardiovascular disease in one. No evidence of malignant lymphoma was seen in any of these autopsies. Histologically, the disease is systemic, with specific lesions in the lymph nodes. The spleen, liver, bone marrow, skin and lung are also involved, but the changes are less characteristic than in the lymph nodes. In the patients in whom sequential biopsies were performed, a trend toward restoration of the nodal architecture was observed. AILD is a clinical-pathologic entity in a spectrum of yet to be defined immune reactions. The clinical, laboratory and pathologic manifestations of AILD are consistent with an autoimmune disorder, in which a deficiency of the T-cell regulatory functions probably predisposes to an abnormal proliferative and autoaggressive reaction of the B-cell system. Surgical staging procedures do not appear to be indicated. Intensive cytotoxic treatment may be hazardous in some patients, precipitating their death, but long survival after such therapy has been observed in others. Supportive therapy and small doses of steroids appear to be a safer therapeutic approach.     

Clinical,electrophysiologic and hemodynamic profile of patients resuscitated from prehospital cardiac arrest

Of 352 prehospital cardiac arrest patients studied during a three year period, the initial mechanism recorded by rescue personnel was ventricular fibrillation in 220 (62 per cent), ventricular tachycardia in 24 (7 per cent) and bradyarrhythmias or asystole in 108 (31 per cent). Early survival was best in the group with ventricular tachycardia (16 of 24 patients resuscitated and survived hospitalization—67 per cent); the prognosis was worst in the group with bradyarrhythmias asystole (nine of 108 admitted to the hospital alive—none survived hospitalization); and 51 of 220 patients with ventricular fibrillation (23 per cent) were resuscitated and survived subsequent hospitalization, a significantly better outcome than previously reported for ventricular fibrillation.Central nervous system damage accounted directly or indirectly for 28 of 48 in-hospital deaths (59 per cent), and hemodynamic abnormalities for 31 per cent. Only five in-hospital deaths (10 per cent) were primary arrhythmic. The majority of survivors had evidence of left ventricular hemodynamic abnormalities (mean left ventricular end-diastolic pressure = 17.80 ± 8.99 mm Hg; mean cardiac index = 2.62 ± 0.72 liters/min/m²; mean ejection fraction = 38.58 ± 17.55 per cent), but approximately one third of the surviving patients had normal left ventricular function. Early in-hospital electrophysiologic data demonstrated persistent, drug-resistant complex ventricular arrhythmias during the first 72 hours; but intracardiac electrophysiologic studies elicited specific patterns only in patients with ventricular tachycardia, whose arrhythmias were reproducible in five of six patients studied. The risk of recurrent ventricular fibrillation in the first 72 hours was predicted better by coexistent conducting system abnormalities, than by the persistent ventricular arrhythmia alone.We conclude that the electrical mechanism of prehospital cardiac arrest provides early prognostic information, that early survival rates are improving and that one third of the discharged survivors have normal indices of left ventricular function. The presence of conducting system abnormalities identifies a subgroup at high risk for in-hospital recurrent ventricular fibrillation.