Edward D. Miller

Influence of surgically induced varicocele on testicular blood flow, temperature, and histology in adult rats and dogs.

Varicocele had been repeatedly implicated as a cause of infertility in selected men, although neither a causal relationship nor a mechanism has been documented. The purpose of this investigation was to create a varicocele model in animals and to study the subsequent alterations in testicular physiology. Secondary dilatation of the left internal spermatic vein was achieved either by partial ligation of the left renal vein in rats and dogs or by surgical destruction of the valve of the left testicular vein in a second group of dogs. 1 mo after partial ligation in the rats and 3 mo after partial ligation or valve destruction in the dogs, testicular blood flow was measured using Strontium 85 (SR-85)-labeled microspheres (15 +/- 1.1 micrometer). Intratesticular temperature was measured with a Bailey needle probe thermometer and biopsies were obtained for histologic sections. Mean testicular blood flow in milliliters per minute per 100 g was significantly greater in the partially ligated rats; right testis control 26 +/- 2, left testis control 24 +/- 2 compared to right testis experimental 35 +/- 3, left testis experimental 35 +/- 4 (p less than 0.02). Dogs undergoing either partial vein ligation or valve destruction showed similar increases in mean testicular blood flow; right testis control 8 +/- 1, left testis control 8 +/- 1 vs. right testis experimental 16 +/- 3, left testis experimental 18 +/- 4 (p less than 0.01). The mean difference between intratesticular and intraperitoneal temperature in control rats was significantly higher (4.02 +/- 0.25 degrees C right testis, 3.77 +/- 0.14 degrees C left testis), than rats who underwent partial vein ligation (right testis 2.14 +/- 0.09 degrees C, left testis 2.34 +/- 0.12 degrees C) (p less than 0.001). Control dogs also had a significantly higher mean difference between intratesticular and rectal temperatures; (right testis control 3.61 +/- 0.42 degrees C, left testis control 3.60 +/- 0.40 degrees C) than the partially ligated or valve destruction dogs (right testis 2.31 +/- 0.17 degrees C, left testis 2.67 +/- 0.32 degrees C) (p less than 0.05). In addition, histologic evaluation revealed abnormalities in spermatogenesis in some of the animals. Thus, venous dilatation secondary to partial vein ligation or testicular vein valve obliteration is followed by large bilateral increases in testicular blood flow in these two species. A consequence of this increased flow is an elevation in bilateral testicular temperature, which it is postulated, leads to impaired spermatogenesis in some of the animals. In selected men varicocele may impair spermatogenesis by a similar physiologic mechanism.

The Renin—Angiotensin—Aldosterone System during Cardiac Surgery with Morphine—Nitrous Oxide Anesthesia

Ten consecutive adult patients undergoing elective cardiac surgery with extracorporeal circulation were anesthetized using morphine (1-3 mg/kg) and nitrous oxide. Pre-bypass plasma renin activity showed a 3.5-fold elevation (P smaller than 0.001) over baseline values. This correlated with maximal blood pressure elevation. Plasma renin activity remained elevated during bypass. High baseline aldosterone levels increased 3.4-fold (P smaller than 0.001) after 15 minutes on bypass and 4.0-fold by the end of bypass. Plasma potassium decreased from 3.9 mEq/1 before bypass to 3.2 mEq/1 (P smaller 0.0001) during bypass, and the fractional urinary excretion of potassium was 32 per cent before bypass with a mean of 34.4 per cent during bypass. Urinary output remained high during bypass despite a progressive decrease in glomerular filtration rate. Catecholamine levels showed no significant change. The data suggest that the renin-angiotensin-aldosterone system may play a role in blood pressure regulation during cardiopulmonary bypass and may result in the excessive urinary excretion of potassium and decrease in plasma potassium levels.

The Regulatory Function of the Renin–Angiotensin System during General Anesthesia

Variation of plasma renin activity has been shown to occur during anesthesia, but its significance remains obscure. The recent development of a specific angiotensin II antagonist, saralasin, allows the delineation of the role of the renin-angiotensin system in blood pressure control during anesthesia. Twenty-seven rats were divided into four groups: awake, halothane (1 MAC), ketamine (125 mg/kg), and fluroxene (1 MAC). Arterial pressure was recorded continuously and plasma renin activity was determined by radioimmunoassay at the end of a two-hour awake control period, after one hour of anesthesia, and after half an hour of saralasin infusion. A similar protocol for enflurane with 1.75 vol per cent was also followed in seven anesthetized rats, but renin analysis was not performed. Anesthesia resulted in decreases in mean arterial pressure from 123.0 ± 1.3 torr to 95.2 ± 2.2 torr for ketamine, 91.6 ± 3.9 torr for halothane, 96.9 ± 7.9 torr for fluroxene, and 84.5 ± 3.8 torr for enflurane. Renin activity did not change significantly from control (4.33 ± 0.51 ng/ml/hr). When saralasin was infused only the rats anesthetized with halothane or enflurane had significant decreases in mean blood pressure, to 75.0 ± 4.8 and 66.1 ± 3.4 torr, respectively. It is concluded that the anesthetic agents studied do not cause a detectable increase in plasma renin activity. However, through the use of a competitive inhibitor of angiotensin II, a significant role for the maintenance of blood pressure by the renin-angiotensin system during halothane and enflurane anesthesia has been demonstrated.

The Renin–Angiotensin System during Controlled Hypotension with Sodium Nitroprusside

The role of the rennin–angiotensin system in blood pressure homeostasis during sodium nitroprusside (SNP) infusion in the rat was evaluated. Rats received infusions of SNP, 40 µg/kg/min, for one hour, and blood samples for renin determinations were drawn from the arterial cannula before and after infusion. Renin activity was measured by radioimmunoassay. At the termination of the SNP infusion, plasma renin activity had increased from 3.23 ± 1.53 to 13.25 ± 0.76 ng/ml/hr (P < 0.05). Control animals that received only vehicle showed no change in renin activity. When rats that had received SNP at 40 µg/kg/min for one hour were treated with a competitive inhibitor of angiotensin II (saralasin), there was a 7-torr decrease in blood pressure (P < 0.01). Control animals showed no hypotensive response to saralasin. The hypotensive response to the administration of SNP at 40 µg/kg/min in acutely nephrectomized rats exceeded that obtained in normal rats by 30 torr (P < 0.01). Enflurane anesthesia did not modify the renin response to SNP-induced hypotension. In conscious rats, larger doses of SNP (80 or 160 µg/kg/min) resulted in elevations of renin activity to 22.50 ± 0.90 and 19.84 ± 1.94 ng/ml/hr, respectively. When saralasin was infused into rats receiving 160 µg/kg/min, blood pressure decreased precipitously and the rats died. SNP-induced hypotension stimulates renin release and the subsequent production of angiotensin II helps maintain blood pressure.

Captopril Reduces the Dose Requirement for Sodium Nitroprusside Induced Hypotension

The authors studied 12 patients who required deliberate hypotension for spinal fusion operations in order to investigate the efficacy of captopril for reducing dose requirement for sodium nitroprusside (SNP). Six patients, selected at random, were pretreated with captopril, 3 mg/kg po, and the remaining six patients served as controls. All patients received a similar anesthetic technique, consisting of thiopental 3 mg/kg, pancuronium 0.1 mg/kg, morphine 0.5 mg/kg, plus nitrous oxide 70% in oxygen. SNP was used to maintain mean arterial pressure (MAP) at 50–55 mmHg during deliberate hypotension lasting 140 · 13 minutes (mean · SE). Patients who received captopril required less SNP than untreated patients both early during hypotension (1.4 · 0.5 μg · kg−1 · min−1 vs. 4.8 · 0.8 μg·kg−1 · min−1, P < 0.05), as well as late during hypotension (2.2 · 0.2 μg · kg−1 · min−1 vs. 5.6 · 0.6 μg · kg−1 · min−1, P < 0.05). Whole blood cyanide was significantly lower in the patients pretreated with captopril than the untreated controls both early in the hypotensive period (2.7 · 0.6 μmol/1 vs. 13 · 4 μmol/1, P < 0.05) and also late in the hypotensive period (3.7 · 0.8 μmol/1 vs. 30 · 10 μmol/1, P < 0.05). MAP was reduced by captopril pre-treatment both following induction of anesthesia (64 · 4 mmHg captopril vs. 80 · 4 mmHg control, P < 0.05) and during surgery before deliberate hypotension (86 · 5 mmHg captopril vs. 100 · 4 control, P < 0.05). Cardiac output did not differ significantly between the groups, either awake or after anesthetic induction. The authors conclude that captopril pretreatment significantly reduces the dose of SNP required to produce deliberate hypotension and, therefore, reduces the potential for cyanide toxicity. No adverse hemodynamic consequences of combining captopril with thiopental, N2O, or morphine anesthesia were observed.

Myocardial function during halothane and enflurane anesthesia in patients with coronary artery disease

Halothane and enflurane are known myocardial depressants in healthy individuals. Whether these two agents produce the same degree of myocardial depression in patients with coronary artery disease has not been studied. Informed consent was obtained from 16 adults with ischemic heart disease undergoing coronary artery bypass grafting. Patients with significant ventricular dysfunction were excluded from the study. Control measurements were made while the patient breathed 100% oxygen. The patients were divided into two groups, anesthetized with either halothane or enflurane, and repeat measurements made at 1/2 and 3/4 MAC for each agent. The last series of measurements (3/4 MAC) was made approximately 1 hour after the induction of anesthesia but before intubation, surgical skin preparation or surgical incision. Our data indicate that at 1/2 and 3/4 MAC for halothane, mean arterial blood pressure (MAP) decreased from 92 ± 2 torr to 73 ± 3 torr and 67 ± 2 torr, respectively (p < 0.05). Pulmonary capillary wedge pressure (PCWP) increased from 6.2 ± 0.7 torr to 9.1 ± 1.6 torr and 9.4 ± 1.7 torr at 1/2 and 3/4 MAC halothane (p < 0.05). Cardiac index decreased from the control values of 2.67 ± 0.08 L/min/m2 to 2.19 ± 0.06 L/min/m2 for 1/2 MAC and to 2.24 ± 0.08 L/min/m2 at 3/4 MAC halothane (p < 0.05). Assisted ventilation was maintained throughout and arterial Pco2 was unchanged from control. Enflurane likewise resulted in a decrease in MAP from 99 ± 6 torr to 75 ± 4 torr at 1/2 MAC and 68 ± 5 torr at 3/4 MAC (p < 0.05). PCWP did not increase. In contrast, however, cardiac index was unchanged from control value of 2.65 ± 0.16 L/min/m2 at both 1/2 and 3/4 MAC. Arterial Pco2 was unchanged from the awake control value. Our data indicate that while both halothane and enflurane decrease mean arterial blood pressure, the mechanisms responsible differ. The primary afterload-reducing effect of enflurane may be beneficial to some patients with ischemic heart disease whereas other patients may benefit from the greater myocardial depression seen with halothane.

Indices of myocardial oxygenation during coronary-artery revascularization in man with morphine versus halothane anesthesia.

A prospective study in 12 adult male patients undergoing coronary-artery revascularization was conducted to compare the effects of a morphine versus a halothane anesthetic technique on several indices of myocardial oxygen supply and demand. Indices reflecting myocardial contractility, preload, afterload, and heart rate were measured. Undesirable increases in systemic and pulmonary capillary wedge pressure were minimized using sodium nitroprusside as needed. In the period after sternotomy but before revascularization, patients anesthetized with morphine (mean 2.1 mg/kg) had significant (P < .05) increases in rate-pressure product, tension-time index, blood pressure, and heart rate, as well as relative myocardial ischemia, evidenced by significant ST-segment depression in the V3 lead of the EKG and a decreased diastolic pressure-time index/tension-time index compared with patients anesthetized with halothane (mean .75 per cent inspired). Few difficulties associated with myocardial depression were seen in patients anesthetized with halothane. Halothane, at least in a well-monitored environment, is safe for use in patients without severe ventricular dysfunction undergoing coronary-artery revascularization.

Effects of Propranolol on the Cardiovascular and Renin-Angiotensin Systems during Hypotension Produced by Sodium Nitroprusside in Humans

The authors examined the effects of controlled hypotension induced with sodium nitroprusside (SNP) with and without propranolol on the cardiovascular, pulmonary, and reninangiotensin systems in 10 consecutive anesthetized patients with kyphoscoliosis undergoing posterior spinal fusion. SNP infusion (4.1 μg·kg−1·min−1) alone decreased mean systemic arterial pressure (&OV0408;Ā&OV0440;) by 25 torr ± 3 SE (P < 0.001), systemic vascular resistance index (SVRI) by 1113 dyne·sec·cm−5·m2 ± 125 SE (P < 0.001), mean pulmonary artery pressure (&OV0440;Ā&OV0440;) by 6 torr ± 2 SE (P < 0.02), pulmonary capillary wedge pressure (PCWP) by 4 torr ± 1 SE (P < 0.01), pulmonary vascular resistance (PVR) by 50 dyne·sec·cm−5 ± 18 (P < 0.05), and PaO2 by 16 torr ± 7 SE (P < 0.05), whereas cardiac index increased by 1.08 l·min−1·m2 ± 0.24 SE (P < 0.01) and heart rate increased 16 beats/min ± 5 SE (P < 0.02). After 40 min of hypotension, 0.03 mg/kg propranolol was injected intravenously while the SNP infusion rate was held constant. Ten min later there was a significant decrease in the heart rate (10 beats/min ± 4 SE, P < 0.02) and cardiac index (0.65 l·min−1·m−2 ± 0.21, P < 0.02). Plasma renin activity (PRA) increased from 2.37 ng·ml−1·h−1 ± 0.7 SE before anesthesia to 6.50 ng·ml−1 ± h−1 ± 1.45 SE (P < 0.05) after 40 min of nitroprusside infusion. Forty min after propranolol there was a significant reduction in PRA to 4.07 ng·ml−1·h−1 ± 0.73 SE (P < 0.05). Thus propranolol, when given during SNP hypotension, exhibits an early cardiovascular response manifested as a decrease in cardiac output and heart rate and a delayed action on the kidney resulting in an inhibition of renin release.

Blood Pressure Support during General Anesthesia in a Renin-dependent State in the Rat

Previous work had shown that halothanc and enflurane at 1 MAC and ketamine, 125 mg/kg, did not increase plasma rcnin activity (PRA) in the normal sodium-replete rat. To investigate the renin-angiotensin system with increased PRA, 25 rats were fed a low-sodium diet for five to seven days and divided into four groups: awake; halothane, 1.26 vol per cent; enflurane, 1.75 vol per cent; ketaminc, 125 mg/kg, intramuscularly. The protocol consisted of a two-hour awake period, then an hour of stable anesthesia, followed by 30 min infusion of saralasin, an angiotensin II competitive inhibitor. An additional 18 rats had PRA measured by radioimmunoassay before and after an hour of stable anesthesia. Stable anesthesia decreased mean arterial pressure from 122 ± 2 to 69 ± 4 torr for the halothane group, 70 ± 3 torr for the enflurane group, and 103 ± 7 torr for the ketamine group. When saralasin was infused for 30 min, blood pressure decreased to 100 ± 3 torr for the awake groiip, 40 ± 1 torr for the halothane group, 44 ± 2 torr for the enflurane group, and 73 ± 3 torr for the ketamine group. PRA increased from 4.3 ± 0.5 ng/ml/hr for sodium-replete rats to 12.9 ± 1.7 ng/ml/hr for sodium- depleted rats. After an hour of stable anesthesia, PRA increased in all the anesthetized groups. The authors conclude that the anesthetic agents studied increase renin release in the sodium-depleted rat. The initial renin level may be important in. determining whether changes in rcnin release occur with anesthetic agents.

Future Directions for Academic Practice Plans: Thoughts on Organization and Management from Johns Hopkins University and the University of Pennsylvania

Academic practice plans have been challenged in recent years by increasing pressures for productivity and financial performance. Most practice plans began as relatively loose affiliations among the clinical departments associated with their respective medical schools, and such approaches were adequate in an earlier era. However, this model is not well suited to deal with the current and future challenges that face the practice plans, hospitals, and medical schools that comprise our academic medical centers. The current clinical, financial, and regulatory environment requires highly effective business management, a shared commitment to common goals, and meticulous attention to regulatory compliance. In turn, the organizational structures, daily management, and overall governance of academic practice plans must be revised to address these new expectations. The business, clinical, and academic performance of the individual practices must be aligned to meet the diverse, and sometimes conflicting, needs of the academic health center. Both Johns Hopkins Medicine and the University of Pennsylvania (Penn Medicine) have been addressing these issues independently, but their approaches share many common principles. Among others, these principles include (a) organizational alignment, (b) strong practice plan business management, (c) shared resources and strategies, (d) accountability for performance in each practice based on credible data generated by the practice plan, (e) uniform audit and compliance standards, and (f) application of market strategy principles to assure the right mix of primary and specialist physicians, and appropriate incentive-based compensation for physicians. The application of these approaches at two academic health centers, and the rationale for these approaches, are discussed in detail.