Oral testosterone-triglyceride conjugate in rabbits: single-dose pharmacokinetics and comparison with oral testosterone undecanoate.

Development of a safe and effective oral form of testosterone has been inhibited by the rapid hepatic metabolism of nonalkylated androgens. Since triglycerides are absorbed via lymphatics and bypass the liver, we hypothesized that a testosterone-triglyceride conjugate (TTC) might allow for safe and effective oral testosterone therapy. Therefore, we studied the single-dose pharmacokinetics of oral administration of TTC in rabbits. Female New Zealand rabbits were administered 2, 4, or 8 mg/kg of TTC in sesame oil by gastric lavage. Testosterone undecanoate (TU) by gastric lavage was used as a positive control. Blood was sampled from a catheter in the auricular artery at 0, 15, 30, 60, 90, 120, 180, 240, 360, 480, and 600 minutes after drug administration. Samples were assayed for testosterone by a fluoroimmunoassay. Mean serum testosterone, area under the curve (AUC), and terminal half-life were calculated. Oral TTC administration resulted in rapid and marked increases in serum testosterone. Oral TTC resulted in higher maximum serum testosterone concentrations than oral TU at 8 mg/kg (TTC: 28.6 +/- 7.9 nmol/L vs TU: 11.9 +/- 2.1 nmol/L; P <.001) and 4 mg/kg (TTC: 11.5 +/- 4.2 nmol/L vs TU: 3.6 +/- 1.0 nmol/L; P <.001). In addition, the AUC was 1.8 to 2.6 times greater for TTC than TU at both doses (P <.05). The terminal half-life for both TU and TTC was between 3 and 5 hours and was not significantly different. We conclude that oral TTC is rapidly absorbed from the rabbit intestine and results in elevated concentrations of serum testosterone. The absorption of TTC appears to be superior to that of TU; however, the in vivo persistence of the 2 compounds is similar. TTC may offer an alternative to the use of TU for oral testosterone therapy. Further testing of this compound is warranted.

The halo-Milwaukee brace. Case series of a revived technique.

STUDY DESIGN: A case series in which the halo-Milwaukee brace was used for postoperative immobilization in children with complex congenital and developmental spinal deformities. OBJECTIVES: To describe the use of halo-Milwaukee orthosis in a pediatric population for stabilization of the cervical and upper thoracic spine. SUMMARY AND BACKGROUND DATA: Postoperative immobilization of the neck and upper thorax can be achieved with cervical orthoses, cervicothoracic lumbar orthosis, halo cast, Minerva jacket, or halo vest. In the young child or in individuals with severe deformities, prefabricated braces often do not provide adequate stability or predictable fit. The halo-Milwaukee brace has proven to be an effective and versatile technique in the management of complex pediatric spinal deformities. METHODS: Halo-Milwaukee brace immobilization was used in 12 patients after surgical stabilization of the upper thoracic or cervical spine. Technique and indications are discussed in this report. Surgical outcomes and complications were reviewed retrospectively in all cases. RESULTS: Application of the halo-Milwaukee brace was a clinically effective and safe means of controlling the upper thoracic and cervical spine. The orthosis was well tolerated and allowed access to the posterior incision. The brace is easily converted to a standard Milwaukee brace with neck ring. The pelvic segment of the brace is molded before surgery, and in most instances did not require postoperative modification. CONCLUSION: The halo-Milwaukee brace is a simple and convenient method of intraoperative and postoperative immobilization. The technique is applicable in patients who cannot be treated with more conventional off-the-shelf orthoses. The brace was well tolerated and allowed for early patient mobilization.

Cerebral emboli and serum S100beta during cardiac operations.

BACKGROUND: The glial protein S100beta has been used to estimate cerebral damage in a number of clinical settings. The purpose of this investigation was to determine the correlation between cerebral microemboli and S100beta levels during cardiac operations. METHODS: Transcranial Doppler ultrasonography was used to measure emboli in the right middle cerebral artery. Emboli counts (n = 111) were divided into five time periods: (1) incision to aortic cannulation; (2) aortic cannulation to cross-clamp onset; (3) cross-clamp onset to cross-clamp release; (4) cross-clamp release to decannulation; and (5) decannulation to chest closure. The level of S100beta (n = 156) was measured at baseline, at the end of cardiopulmonary bypass, then 150 and 270 minutes after cross-clamp release. RESULTS: The level of S100beta correlated with age, cardiopulmonary bypass time, cross-clamp time, and number of emboli at time period 2. Although cardiopulmonary bypass time was univariately associated with S100beta level, it became nonsignificant in a multivariable model that included age and cross-clamp time. CONCLUSIONS: The correlation of S100beta level with emboli measured during cannulation (time period 2) supports the hypothesis that cannulation is a high-risk time period for cerebral injury.

Transcranial Doppler blood flow velocity versus 133Xe clearance cerebral blood flow during mild hypothermic cardiopulmonary bypass.

OBJECTIVE: Transcranial doppler (TCD) is used during cardiopulmonary bypass (CPB) to assess cerebral emboli and to estimate cerebral perfusion. We sought to compare TCD middle cerebral artery blood flow velocity (Vmca) to 133Xe clearance cerebral blood flow (CBF) measurements during mild hypothermic CPB thus determining its utility in cerebral perfusion assessment. METHODS: Thirty-four patients undergoing mild hypothermic CPB (35 degrees C) were studied and had comparisons of Vmca and 133Xe CBF at three time intervals, 10, 30 and 60 min after the institution of CPB. Linear regression analysis was performed on data from each of the 3 intervals as well as for pooled data from all 3 periods. RESULTS: The correlation coefficients for the 3 time periods were, r = 0.32 (p = 0.12), r = 0.32 (p = 0.11), r = 0.48 (p = (0.02), respectively. The pooled data correlation had a coefficient of 0.34 (p = 0.003). CONCLUSION: These findings suggest that TCD Vmca is a relatively poor correlate of CBF during mild hypothermic CPB.

Omental transfer for salvage of the moribund lower extremity.

Use of omental flaps is well documented in soft tissue reconstruction of the head and neck, chest wall, and abdomen. Three cases of omental transfer for soft tissue reconstruction of the lower extremities are presented. In two patients, free vascularized omental flaps were used to cover deep soft tissue defects over the lower leg and in one patient, a pedicle flap was used to cover a deep groin defect extending into the hip joint. In all patients, use of an omental graft allowed revascularization and subsequent wound healing with good cosmetic results.

Effect of perfusion pressure on cerebral blood flow during normothermic cardiopulmonary bypass.

BACKGROUND: We have recently shown that during hypothermic cardiopulmonary bypass (CPB), cerebral autoregulation has a positive slope such that for every 10 mm Hg change in pressure, a 0.86 mL.100 g-1.min-1 change in cerebral blood flow (CBF) is predicted. The purpose of this study was to define the influence of mean arterial blood pressure (MAP) on CBF during normothermic CPB. METHODS AND RESULTS: CBF was measured by use of 133Xe washout and alpha-stat blood gas management during nonpulsatile CPB. CBF measurements were made at a pump flow of 2.4 L.min-1.m-2 at stable normothermia and approximately 15 minutes later after the MAP was increased or decreased > or = 20%. A third data set was recorded after the pressure was returned to the initial value. Forty-five patients were entered into the study. Temperature was held constant. We found a significant effect (P = .016) of change in MAP on change in CBF during normothermic CPB. For a 10 mm Hg increase in MAP, an increase in CBF of 1.78 mL.100 g-1.min-1 is predicted. Along with change in CBF, significant increases in both cerebral metabolic rate and cerebral oxygen delivery were observed. CONCLUSIONS: This information, along with our previous data shows that autoregulation during CPB has a positive slope that is greater with normothermia than hypothermia. Although it is unlikely that these small changes in flow are an important primary effect in the development of hypoperfusion, increased metabolic rate with increased CBF may indicate pressure-dependent collateral flow potentially in regions embolized during CPB.

The effects of sevoflurane and isoflurane on recovery from outpatient surgery.

This randomized, open-label study compared the investigational inhalational anesthetic sevoflurane with isoflurane in 47 healthy women undergoing elective ambulatory surgery. The women were randomized to receive either sevoflurane or isoflurane in 60% nitrous oxide-oxygen. Induction with thiopental 3-6 mg/kg was followed by vecuronium 0.1 mg/kg and fentanyl 0-200 micrograms. Duration of anesthesia, time to emergence, orientation, length of stay in the surgical unit, and hospital discharge were recorded. The emergence, length of stay, and discharge times after discontinuation of sevoflurane were 9.7 +/- 0.7, 120.6 +/- 8.0, and 244 +/- 15 minutes, respectively, and for isoflurane were 11.9 +/- 1.4, 106.8 +/- 7.1, and 282 +/- 24 minutes, respectively (NS). The isoflurane group had a higher frequency of postoperative cough. At the end of surgery, the sevoflurane group received a deeper level of anesthesia (minimum alveolar concentration 1.5 vs 1.3), however, these patients were oriented earlier (13.6 +/- 1.1 min vs 17.0 +/- 1.5 min isoflurane; p = 0.02) after discontinuation of anesthesia, although this difference is of little clinical significance.

Comparison of intranasal midazolam and sufentanil premedication in pediatric outpatients.

BACKGROUND: Intranasally administered midazolam was compared with sufentanil as a premedicant for 60 patients, aged 1/2 to 6 years, undergoing outpatient surgery of 2 hours or less. METHODS: Thirty minutes before anesthetic induction (halothane in 50% nitrous oxide/oxygen), patients were randomly assigned to receive either intranasal midazolam (0.2 mg/kg) or sufentanil (2 microg/kg). A "blinded" observer evaluated preoperative emotional state, response to premedication, induction, and emergence from anesthesia and side effects. RESULTS: Children who had not previously cried were more likely to cry when midazolam was administered compared with sufentanil (71% versus 20%, p = 0.0031). Of 31 midazolam patients, 20 experienced nasal irritation. Approximately 15 to 20 minutes after drug administration, most patients in both groups could be comfortably separated from their parents. The sufentanil group appeared to be more sedated and more cooperative during induction of anesthesia. Vital signs and oxygen saturation did not change significantly with either medication before or after surgery, although two sufentanil patients had a moderate reduction in ventilatory compliance after anesthetic induction. Sufentanil was associated with more nausea and vomiting than midazolam (34% versus 6%, p < 0.02). CONCLUSION: Both intranasal midazolam and sufentanil provide rapid, safe, and effective sedation in small children before anesthesia for ambulatory surgery. Sufentanil provided somewhat better conditions for induction and emergence. Midazolam causes more nasal irritation during instillation, and sufentanil causes more postoperative nausea and vomiting. Both drugs enabled patients to be separated from their parents with a minimum of distress. Patients in the midazolam group were discharged approximately 40 minutes earlier (p <0.005).

Regional cerebral oxygenation during cardiopulmonary bypass.

A significant number of patients suffer transient neuropsychological dysfunction after coronary artery bypass graft (CABG) surgery. Recent studies have implicated reduced levels of O2 supply/demand ratio during the rewarming phase of cardiopulmonary bypass (CPB). Using a near infrared spectroscopy (NIRS) system that permits continuous noninvasive monitoring of regional cerebral O2 saturation (rSO2), we investigated rSO2 during CPB. Following Institution Review Board approval and informed consent, 10 patients undergoing elective CABG were studied. Nonpulsatile CPB with a membrane oxygenator, haemodilution and alpha-state pH management was used. The NIRS system consisting of two low-power laser diode sources (780 nm and 810 nm) with a photodetector placed on the frontal cortex was used to measure continuously haemoglobin, oxyhaemoglobin and cerebral blood volume. Continuous rSO2 measurements were obtained before, during moderate hypothermia, and during the rewarming phase of CPB. A rSO2 < 50% was defined as abnormal. Onset of rSO2 < 50% was at 32 degrees C, and the highest incidence occurred during the late stages of rewarming (35-37 degrees C). On rewarming from hypothermic CPB, 70% of our patients sustained a rSO2 < 50% for an average total duration of 9.3 minutes, primarily at the end of the rewarming period. This suggests a transient global imbalance in cerebral O2 supply and demand in a large percentage of patients during the rewarming phase of CPB. However, it has not been determined how long a rSO2 < 50% can be permitted before neuropsychological dysfunction is induced. Additional studies correlating psychometric testing with rSO2 measurements should prove useful in detecting episodes of impaired cerebral oxygenation, and help define rewarming protocols.

Use of patient-controlled analgesia with alfentanil for extracorporeal shock wave lithotripsy.

STUDY OBJECTIVE: To compare the efficacy of patient-controlled analgesia (PCA) to physician-controlled analgesia in patients undergoing extracorporeal shock wave lithotripsy (ESWL). DESIGN: Prospective, randomized trial. SETTING: New Jersey Kidney Stone Treatment Center at Robert Wood Johnson University Hospital, New Brunswick, NJ. PATIENTS: 62 ASA I, II, and III patients undergoing ESWL. INTERVENTIONS: The control group (n = 29) received physician-controlled analgesia with continuous infusions (0.75 mcg/kg/min) and intermittent boluses (5 mcg/kg) of alfentanil. PCA patients (n = 33) initially received alfentanil 0.5 mcg/kg followed by a continuous background infusion (0.2 to 0.5 mcg/kg/min) and self-administered alfentanil (3 to 5 mcg/kg) with a 5-minute lockout period. Bolus doses and infusion rates were determined by patient comfort and cardiorespiratory response to alfentanil. MEASUREMENTS AND MAIN RESULTS: Prior to the procedure, the patients completed two questionnaires (State-Trait Anxiety Inventory and Multidimensional Health Locus of Control Scales). During ESWL, blood pressure, heart rate, respiratory rate, oxygen saturation, end-tidal CO2, and pain and sedation levels were measured at 0, 800, 1,600, 2,400, and 3,000 shock waves. The total doses of alfentanil administered were calculated. PCA patients received 31% less alfentanil than control group patients (p < 0.0001). Patients with more preoperative anxiety required larger doses of alfentanil (p < 0.05). The pain level was slightly higher in the patients receiving PCA (p > 0.05) but most patients reported either no or only mild pain. Side effects from the therapy, such as nausea and vomiting, were either not present or were mild in both groups, with one patient (3% to 4%) in each group reporting mild nausea. Both patients and urologists were very satisfied with the pain management in both groups. CONCLUSIONS: PCA is a useful alternative to physician-controlled analgesia during ESWL since it provides equivalent pain control while using less alfentanil.

Effects of intravenous famotidine on gastric acid secretion in patients undergoing cardiac surgery.

OBJECTIVE: To determine the effects of cardiopulmonary bypass and famotidine on gastric acid secretion in adults undergoing cardiac surgery. DESIGN: Prospective, randomized, double-blind, placebo-controlled study. SETTING: University teaching hospital. PARTICIPANTS: Eighteen patients undergoing elective cardiac surgery with cardiopulmonary bypass. MAIN OUTCOME MEASURES: Famotidine 20 mg or NaCl 0.9% placebo was administered intravenously following induction of anesthesia and placement of a nasogastric pH probe. A second dose was given 12 hours after surgery in the intensive care unit. Gastric pH was measured continuously and gastric volume was measured every 4 hours for up to 24 hours after cardiopulmonary bypass. RESULTS: Following famotidine administration, pH increased by 43% within 45 minutes and remained above 5.5 throughout the study period (p < 0.05 vs placebo and baseline). The gastric pH did not increase, but remained above 4.0 in most patients in the placebo group for up to 12 hours after cardiopulmonary bypass. Gastric volumes were on average 24% lower in the famotidine group (p > 0.05). CONCLUSIONS: Gastric acid secretion is decreased during and for 12 hours after cardiopulmonary bypass. Perioperative administration of famotidine suppresses gastric secretion in cardiac surgery patients.

Hemodynamic effects of intravenous famotidine in patients undergoing cardiac surgery.

STUDY OBJECTIVE: To determine the hemodynamic effects of famotidine in patients undergoing cardiac surgery. DESIGN: A prospective, randomized, double-blinded, placebo-controlled study. SETTING: A large university teaching hospital. PATIENTS: Twenty-one patients undergoing elective cardiac surgery with cardiopulmonary bypass. INTERVENTIONS: The patients received a rapid intravenous bolus injection of famotidine 20 mg or saline placebo after anesthesia induction. A second dose was given 12 hours after surgery in the intensive care unit. MEASUREMENTS AND MAIN RESULTS: Serial hemodynamic measurements (heart rate, arterial blood pressure, cardiac index, pulmonary arterial pressure, central venous pressure, systemic vascular resistance) were obtained after each famotidine or placebo dose and analyzed by ANOVA: The values were not altered (p > 0.05) after intraoperative or postoperative famotidine or placebo administration. CONCLUSIONS: Rapid intravenous bolus administration of famotidine does not alter patient hemodynamics after anesthesia induction or in the intensive care unit after cardiac surgery.

Iontophoretically enhanced transdermal delivery of an ACE inhibitor in induced hypertensive rabbits: preliminary report.

Both conventional direct current (DC) and pulsed-mode DC constant-current iontophoresis were used to investigate enhanced transdermal delivery of the angiotensin-converting enzyme (ACE) inhibitor captopril to rabbits with acutely induced hypertension. Passive transdermal captopril administration and pulsed DC constant-current iontophoresis of the vehicle were studied as control experimentation. Mean arterial pressure (MAP) was not significantly (p > 0.05) altered following passive transdermal delivery of captopril (n = 4) or after iontophoretic delivery of the vehicle alone (n = 4). Pressure reduction was evident within 10 minutes of iontophoretic enhancement of transdermal captopril delivery. DC mode constant-current (n = 4) iontophoretic transdermal captopril administration caused MAP to fall by 21% from a mean hypertensive level of 66 +/- 5 mmHg to a mean post-treatment level of 52 +/- 6 mmHg (p < 0.05) within 60 minutes. Pulsed DC mode constant-current (n = 4) iontophoresis of captopril caused mean MAP to fall on average by 27% from 62 +/- 6 to 45 +/- 5 mmHg (p < 0.05), also within 60 minutes. This paper provides the first report on the enhanced efficiency during iontophoretic delivery of an ACE inhibitor. We have concluded that both modes of constant-current iontophoresis of captopril offer a safe and effective means of pressure reduction in rabbits with induced hypertension and that there is no significant difference in efficacy between the two forms of enhanced delivery. These results have potential applications for enhanced transdermal delivery of ACE inhibitors in humans.

Use of a continuous alfentanil infusion for extracorporeal shock wave lithotripsy in the treatment of renal calculi.

Extracorporeal shock wave lithotripsy (ESWL) is the most widely used treatment for renal calculi. Newer second generation lithotripters are being produced, which are considered to be less painful than their prototypes. Thus, the trend in anesthesia for ESWL is away from general endotracheal and regional anesthesia and toward less involved and more easily monitored techniques such as intravenous analgesia (IVA). This report relates our experience with a continuous alfentanil infusion for ESWL treatment of renal calculi with a nonimmersion second generation Dornier HM-4 lithotripter model. Thirty-five patients treated pre-operatively with droperidol and midazolam, followed by a continuous infusion of alfentanil, reported excellent pain relief via a numerical pain score and manifested little, if any, hypertension or tachycardia. Stone fragmentation, fluoroscopy, and recovery time did not differ between patients receiving IVA or general anesthesia. Potential disadvantages of IVA include elevation of transcutaneous CO 2, bradycardia in 14 patients requiring the use of atropine, slightly longer ESWL time, increased number of shocks needed for fragmentation, and a small failure rate, with 11% of patients requiring general anesthesia. With proper patient selection and respiratory monitoring, IVA is highly recommended for ESWL in the treatment of renal calculi.