Improving the efficacy and stability of coronary reperfusion following thrombolysis: Exploring the thrombin hypothesis

A major assumption in the treatment of patients with acute myocardial infarction (MI) implies that the speed of coronary arterial reperfusion correlates directly with the overall extent of myocardial salvage, and that the extent of myocardial salvage, in turn, determines the absolute reduction in patient mortality. While a growing experience has made it clear that myocardial salvage-independent (time-independent) mechanisms of benefit also exist, few would argue with the hypothesis that the greatest benefit derived from coronary thrombolysis occurs with early (time-dependent) treatment. Thus, improvements in the efficacy of reperfusion and the stability of reperfusion are likely to have considerable impact on patient outcome.     

UCHP: a case study of access for the medically uninsured

Utah Community Health Plan (UCHP) is one of fifteen Robert Wood Johnson Foundation Programs for the uninsured. The experience of UCHP is similar to the other nine demonstration programs for the uninsured who have actually enrolled individuals: offering premium subsidies to uninsured small employers is an ineffective way to expand coverage among the working uninsured.     

Economic impact and clinical benefits of pharmacist involvement on surgical wards

A one-year pilot project was performed to assess the economic and clinical benefit of pharmacist involvement on the surgical wards of a 600-bed tertiary care, teaching hospital. A total of 405 recommendations were collected with a physician acceptance rate of 90%. From these recommendations, 1416 patient follow-ups were performed to document outcome. The total documented cost avoidance of the pharmacists' activities was $33,265.58. The total annual drug expenditure for the department of surgery declined by $59,662 representing a 9% decrease over the previous year with the greatest decline involving antimicrobials which decreased by $52,587 compared with the previous year. Most of the cost-avoidance in this area was attributable to antimicrobial selection and dosing adjustment in renal impairment. Pharmacist-directed pharmacokinetic monitoring of aminoglycosides resulted in a clinical success rate of 93.8% for treatment regimens and a 6.2% incidence of nephrotoxicity. Housestaff education aimed at improving prescribing practices were identified and provided for select agents including midazolam, ketorolac, vancomycin and aminoglycosides. As well, select recommendations were documented which illustrated the benefit to patient care of pharmacist involvement. Pharmacist involvement on the surgery services produced both financial and clinical benefits.     

Aromatase inhibitor development for treatment of breast cancer

Summary Inhibition of estrogen production provides effective therapy for patients with hormone-dependent breast cancer. The source of estrogens in premenopausal women is predominantly the ovary, but after the menopause, estradiol is synthesized in peripheral tissues through the aromatization of androgens to estrogens. Uptake from plasma is the primary mechanism for maintenance of estradiol concentrations in breast cancer tissue in premenopausal women, whereas several steps may be operant in postmenopausal women. These include enzymatic synthesis of estradiol via sulfatase, aromatase, and 17-hydroxysteroid dehydrogenase in the tumor itself. Aromatization of androgens secreted by the adrenal to estrogens in peripheral tissues and transport to the tumor via circulation in the plasma provides another means of maintaining breast tumor estradiol levels in postmenopausal women. These various sources contribute to the high tissue estrogen levels measured in breast tumor tissue.To effectively suppress tissue concentrations of estrogens and circulating estradiol in postmenopausal patients, various aromatase inhibitors have been developed recently. These include steroidal inhibitors such as 4-hydroxy-androstenedione as well as non-steroidal compounds with imidazole and triazole structures. The most potent of these, CGS 20267, is reported to suppress levels of active estrogens (i.e., estrone, estrone sulfatase, and estradiol) by more than 95%. This compound can suppress both serum and 24-hrurine estrogens to a greater extent than produced by the second generation inhibitor, CGS 16949A. CGS 20267 is highly specific since it does not affect cortisol and aldosterone serum levels during ACTH stimulation tests nor sodium and potassium balance in 24-hr urine samples. These data suggest that CGS 20267 can be expected to bring improved response rates in the treatment of metastatic hormone-dependent breast cancer without substantial side effects.Presented by R.J. Santen at the 16th Annual San Antonio Breast Cancer Symposium, San Antonio TX, November 4, 1993; Mini-symposium on New Agents in Breast Cancer (supported by an educational grant from Rhône-Poulenc Rorer).     

Mivacurium-induced neuromuscular blockade during sevoflurane and halothane anaesthesia in children

The neuromuscular blocking effects of mivacurium during sevoflurane or halothane anaesthesia was studied in 38 paediatric patients aged 1–12 yr. All received premedication with midazolam, 0.5 mg · kg⁻¹ po and an inhalational induction with up to 3 MAC of either agent in 70% N₂O and O₂. The ulnar nerve was stimulated at the wrist by a train-of-four stimulus every ten seconds and the force of adduction of the thumb recorded with a Myotrace force transducer. Anaesthesia was maintained with a one MAC end-tidal equivalent of either volatile agent for five minutes before patients received mivacurium (0.2 mg · kg⁻¹) iv. The onset of maximal blockade occurred in 2.4 ± 1.26 (mean ± SD) min with halothane and 1.8 ± 0.54 min with sevoflurane (NS). Four patients failed to achieve 100% block (3 halothane, 1 sevoflurane). The times from injection to 5, 75, and 95% recovery during sevoflurane (9.8 ± 2.6, 19.5 ± 4.4, and 24.2 ± 4.8 min) were greater than during halothane anaesthesia (7.2 ± 2.2, 15.0 ± 4.0, 19.2 ± 4.9 min, respectively (P < 0.005). All patients demonstrated complete spontaneous recovery of neuromuscular function (T₁ > 95%, T₄/T₁ > 75%) during the surgery which lasted 24–63 min. All patients showed clinical signs of full recovery of neuromuscular blockade (i.e., headlift, gag, or cough). Pharmacological reversal was not required. It is concluded that following a single intubating dose of mivacurium, the time to maximum relaxation was not different during halothane and sevoflurane anaesthesia; recovery times to 5, 75 and 95% twitch height were longer during sevoflurane anaesthesia and neuromuscular reversal was not necessary. L’activité neurobloquante du mivacurium pendant l’anesthésie au sévoflurane ou à l’halothane fait l’objet de cette étude réalisée chez 38 enfants de 1 à 12 ans. Tous ont été prémédiqués au midazolam 0,5 mg · kg⁻¹ et l’anesthésie est induite avec un agent volatil jusqu’à MAC 3 de l’un des agents dans du N₂O à 70%. Le nerf cubital était stimulé au poignet au train de quatre aux dix seconds et la force de l’adduction du pouce mesurée avec un transducteur de force Myotrace. L’anesthésie était entretenue avec l’équivalent MAC I d’un des deux agents volatils pendant cinq minutes avant l’administration de mivacurium (0,2 mg · kg⁻¹). Le début du bloc maximum est survenu dans 2,4 ± 1,26 (moyenne ± SD) min avec l’halothane et 1,8 ± 0,54 min avec le sévoflurane (NS). Quatre patients n’ont pas été bloqués à 100% (trois avec l’halothane, un avec le sévoflurane). L’intervalle séparant l’injection à 5; 75, et 95% de la récupération pendant l’anesthésie au sévoflurane (9,8 ± 2,6, 19,5 ± 4,4 et 24,2 ± 4,8 min) a été plus long que pendant l’anesthésie à l’halothane (7,2 ± 2,2, 15,0 ± 4,0, 19,2 ± 4,9 min, respectivement (P < 0,005). An moniteur, chez tous les patients, la fonction neuromusculaire a récupéré spontanément (T₁ > 95%, T₄/T₁ > 75%) au cours de la chirurgie qui a duré de 24–63 min. Tous les patients montraient aussi les signes cliniques d’une récupération complète (par ex., levée de la tête, réflexe pharyngé ou toux). Aucun antagoniste pharmacologique n’a été requis. Il est conclu que le délai jusqu’à la relaxation maximum après une seule dose d’intubation de mivacurium ne diffère pas entre l’anesthésie à l’halothane et l’anesthésie au sévoflurane; les délais de retour à 5, 75 et 95% de la hauteur du twitch sont plus longs pendant l’anesthésie au sévoflurane et il n’est pas nécessaire d’antagoniser le bloc neuromusculaire.

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Supported in part by a grant from Abbott Laboratories, Chicago, Illinois.     

Recombinant human growth hormone in infants and young children with chronic renal insufficiency

Children with chronic renal insufficiency (CRI) secondary to congenital structural abnormalities frequently have significant growth retardation by 2 years of age. In a multicenter placebo-controlled study of the use of recombinant human growth hormone (rhGH), 30 of 125 (24%) participants were<2.5 years of age at enrollment. Since the treatment arms of the study were balanced for age at randomization, data for these patients were examined for efficacy and safety. During the first 2 years of the study, approximately two-thirds of the patients (n=19) received rhGH 0.05 mg/kg per day subcutaneously and one-third (n=11) received placebo injections. At entry into the study, the mean (± SD) calculated creatinine clearance was 29.2±14.3 (range 12.0–63.7) ml/min per 1.73 m² in the rhGH-treated group and 23.3±15.1 (range 8.0–59.4) ml/min per 1.73 m² in the placebo-treated group. The 1st year growth rate was 14.1±2.6 cm/year for the rhGH-treated group and 9.3±1.5 cm/year in the placebo-treated group (P<0.00005). During the 2nd year of the study, the growth rate was 8.6±1.2 cm/year in the rhGH-treated group compared with 6.9±1.0 in the placebo groupP=0.025). The height standard deviation score was +2.0±0.7 for the rhGH-treated group compared with –0.2±1.1 in the placebo-treated group (P<0.00005) during the 2 years of the study. Minor adverse events occurred with similar frequency in both groups. These data suggest that rhGH is efficacious and safe in children with CRI under age 2.5 years. rhGH therapy may correct significant loss of growth at this age when used in conjunction with optimal medical management.     

Addition of a gonadotropin releasing hormone (GnRH) antagonist and exogenous gonadotropins to unstimulated in vitro fertilization (IVF) cycles: Physiologic observations and preliminary experience

Purpose To describe our preliminary experience with the addition of a GnRH antagonist (Nal-Glu) and exogenous gonadotropins (follicle stimulating hormone; FSH) to unstimulated IVF cycles.Method Seven spontaneously ovulatory women underwent eight unstimulated IVF cycles at our institution. They were treated with a single dose of Nal-Glu, 50 g/ kg, or with a combination of Nal-Glu, 50 g/kg, and exogenous FSH, 150–300 IU, during the late follicular phase of spontaneous cycles. They then received 10,000 IU of human chorionic gonadotropin (hCG) to time accurately follicle aspiration in unstimulated IVF cycles.Results Two women underwent three cycles with Nal-Glu alone on the day of hCG administration. One pregnancy resulted. Five women underwent five cycles with 3 to 6 days of daily Nal-Glu and FSH. Four of these cycles resulted in aspiration after the FSH dose was increased to 300 IU. Nal-Glu and FSH allowed continued development of the dominant follicle without the occurrence of luteinizing hormone (LH) surge.Conclusions (1) Nal-Glu alone given 18 hr prior to hCG did not interfere with continued follicle viability or with the attainment of pregnancy. (2) Simultaneous Nal-Glu and FSH allowed for continued growth and development of the dominant follicle without the occurrence of an LH surge. (3) This preliminary experience confirms the feasibility of this novel approach, which may ultimately enhance the efficacy of unstimulated IVF cycles by eliminating premature ovulation and maximizing control of gonadotropin delivery to the developing follicle.Presented at the 39th Meeting of The Society for Gynecologic Investigation, San Antonio, Texas, March 18–21, 1992.     

Identification of the central vestibular projections in man: a positron emission tomography activation study

The cerebral representation of space depends on the integration of many different sensory inputs. The vestibular system provides one such input and its dysfunction can cause profound spatial disorientation. Using positron emission tomography (PET), we measured regional cerebral perfusion with various vestibular stimulations to map central vestibular projections and to investigate the cerebral basis of spatial disorientation. We showed that the temporoparietal cortex, the insula, the putamen, and the anterior cingulate cortex are the cerebral projections of the vestibular system in man and that the spatial disorientation caused by unilateral vestibular stimulation is associated with their asymmetric activation.     

Managed behavioral health care and supply-side economics. 1998 Carl Taube Lecture

BACKGROUND: Within the past decade, the mental health care system in the United States has undergone a significant transformation in terms of delivery, financing and work force configuration. Contracting between managed care organizations (MCOs) and providers has become increasingly prevalent, paralleling the trend in health care in general. These managed care carve-outs in behavioral health depend on networks of providers who agree to capitated rates or discounted fees for service for those patients covered by the carve-out contracts. Moreover, the carve-outs use a broader array of mental health providers than is typically found in traditional indemnity plans, encourage time-limited versus long-term treatments and favor providers who are engaged in outpatient care. This phenomenal growth in managed behavioral health care over the past decade includes the rapid growth and quick consolidation of mental health MCOs. The period 1992-1998 shows steady and substantial annual increases in the number of enrollees in mental health MCOs, the figure more than doubling from 78.1 million people in 1992 to a projected 156.6 million in 1998, or 70% of insured lives. Moreover, these vast numbers of enrollees are becoming increasingly consolidated into a smaller number of firms. In 1997, 12 companies controlled nearly 85% of the managed behavioral health care market, with 60% of the market held by the three largest firms. STUDY AIMS: This article reviews empirical data and draws policy implications from the literature on managed behavioral health care in the United States. Starting with spending and spending trend estimates that show the average annual growth rate of mental health expenditures to be lower than that of health care expenditures in general over the past decade, the author examines utilization and price factors that may account for managed-care-induced cost reductions in behavioral health care, with special attention to hospital use patterns, fee discounting and the supply and earnings patterns of various types of mental health provider. In addition, data on staffing ratios and provider mixes of health maintenance organizations and mental health MCOs are reviewed as they reveal at least part of the dynamics of reconfiguration of the mental health work force in this era of managed care. CONCLUSIONS: As measured by changes in utilization and price, widespread application of "classic" managed care techniques such as preadmission review (gatekeeping), concurrent review, case management, standardized clinical guidelines and protocols, volume purchase of services and fee discounting appears to have led to significant cost reductions for providers of both impatient and outpatient mental health services. However, amidst a complex flux of market variables such as risk shifting, changing financial incentives and intensity of competition, not all of the reduction or slowdown in spending can be clearly and purely attributed to managed care. The data on the ongoing reconfiguration of the mental health work force are clearer in their implications: with an oversupply of all types of mental health providers, managed care has significant potential to increase the incidence of provider substitutions and spur the growth of integrated group practices. IMPLICATIONS FOR FURTHER RESEARCH: The current body of empirical and policy literature in mental health economics suggests several salient areas of follow-up. Is the proportionately greater impact of managed care on the annual growth rate of mental health care spending a temporary phenomenon or does it signal an enduring difference in the rates of increase between behavioral health care and health care in general? Beyond industry downsizing, what are the substitutions among mental health providers that are going on, and will go on, to produce cost-effective practices? What are the new financial or risk-sharing arrangements between providers and MCOs that will produce appropriate and high-quality mental health services?