Continuous Systemic Infusion Research Articles

A novel delivery system for continuous desferrioxamine infusion in transfusional iron overload.

Fifteen iron-overloaded thalassaemia major (TM) patients and two homozygous sickle cell patients (SCD) were treated continuously for 7d each week with the novel 48 h continuous subcutaneous (s.c.) desferrioxamine (DFX) delivery device (code C1083, Baxter) and 10 TM patients received the 24 h continuous intravenous (i.v.) DFX delivery device (code C1071). The 27 patients had previously received conventional s.c. DFX for 8-10h on 5 or more days each week. The serum non-transferrin bound iron (NTBI) levels fell significantly in both groups within 12h of commencing the continuous infusion. In the s.c. group the mean level fell from 4.2 to 2.0 mumol/l (P = 0.001), whereas in the i.v. group the mean level fell from 3.6 to 0.1 mumol/l (P = 0.006) the initial levels being measured 12h after stopping conventional s.c. DFX. After 4 weeks there was a significant fall in serum ferritin in both groups (P = 0.009). The new DFX delivery device is effective at removing toxicfree iron from plasma and reducing body iron. Moreover, it is preferred by patients with much improved compliance compared to the conventional s.c. DFX pump.

A new system for continuous intravenous infusion of pigs

The swivel system described has been used by ILOB-TNO for prolonged periods of continuous infusion. It allows for less restricted movement of animals. The swivel prevents the infusion tube from twisting. The swivel system is simple, safe to operate and cost-effective. Animals have greater movement, can stretch and turn around. The physical discomfort and psychological stress of restricted movement are greatly reduced. The potentially complicating/confusing effects on the measurements taken during an experiment are reduced.

Evaluation of a continuous systemic infusion of iloprost, a stable PGI-2 analog, on the survival of experimental skin flaps.

Numerous investigators have attempted to enhance the survival of ischemic experimental skin flaps using various pharmacologic manipulations. Recently, the authors' laboratory demonstrated the beneficial effect of iloprost, a stable PGI2 analogue, as a post-ischemic perfusion washout, in improving the survival of ischemic skin flaps. The rat unilateral abdominal skin flap, based on the superficial epigastric vessels, was utilized in this study involving 30 animals. The animals were divided into three different treatment groups, with ischemic periods of 16 and 18 hr. Perfusion washouts were performed at the completion of the various ischemic periods. Alzet osmotic pumps were used to deliver a continuous systemic infusion of iloprost for 7 days postoperatively. The groups consisted of the following: Group 1 (single ILO)--perfusion washout with iloprost only; Group 2 (continuous LD ILO)--low-dose systemic iloprost infusion (0.066 mcg/kg/min) and perfusion washout with iloprost; and Group 3 (continuous HD ILO)--high-dose systemic iloprost infusion (0.1 mcg/kg/min) and perfusion washout with iloprost. The percentage of flap survival was assessed on postoperative day 7. Skin flaps of the animals receiving the continuous systemic infusion of iloprost were noted to have varying percentages of survival, while skin flaps undergoing perfusion washout only were found to have either complete survival using a continuous systemic infusion of iloprost, compared to iloprost perfusion washout alone. In addition, the hypotensive side effects of systemic iloprost infusion limit its use in the rat skin-flap model.

The effect of continuous morphine analgesia on chronic thermal hyperalgesia due to sciatic constriction injury in rats

We employed hindfoot withdrawal latencies to radiant heat to assess the analgesic effect of prolonged morphine infusion on thermal hyperalgesia induced by chronic constriction injury (CCI) of the rat sciatic nerve. All CCI rats developed thermal hyperalgesia while sham-operated animals did not. Continuous systemic infusion of morphine dose-dependently reversed the thermal hyperalgesia in the CCI rats. In contrast, thermal hyperalgesia persisted in saline-treated CCI rats. Tolerance to morphine's analgesic effect did not develop over a period of seven days of morphine infusion, which is considered long-term for animal models. These data suggest that morphine acts rapidly and effectively to reduce behavioral signs of hyperalgesia in rats with sciatic CCI, without the concomitant development of tolerance. Scheduled administration of morphine might be an appropriate treatment regimen for relief of neuropathic pain, and the infrequent use of opioids in equivalent human clinical pain syndromes due to fear of opioid unresponsiveness and tolerance might need to be re-evaluated.

術前化学療法としての５‐ＦＵの単独持続投与が奏功した亜有茎性直腸癌の１例

5-FU持続投与による術前化学療法中に完全に脱落した直腸癌の1例を経験した.大腸癌は抗癌剤に対して抵抗性が高いが,化学療法のみで脱落したことは術前化学療法を考える上で示唆に富むと考えられるので報告する.症例は70歳,女性.Ra部の約4cm大の亜有茎性のIsp'型の直腸癌に対して術前化学療法として5-FUを3週間(250mgで1週間,375mgで2週間)24時間持続全身投与したところ,手術時に潰瘍病変部のみを残して完全に脱落しており,病理学的にも悪性細胞を認あなくなっていた.この著効例を通して直腸癌に対する5-FUによる術前化学療法を持続投与で行う意義について文献的考察を加えて検討した.

Continuous systemic interleukin-1α infusion suppresses food intake without increasing lateral hypothalamic dopamine activity

In addition to its immunomodulatory action, interleukin-1 (IL-1α) induces anorexia centrally. Whether IL-1-induced anorexia is mediated by dopaminergic activity in the lateral hypothalamic area (LHA) was investigated by using microdialysis in freely moving rats. After recovery from jugular vein catheterization and LHA cannulation, rats had a microdialysis probe inserted into the LHA. Microdialysis samples were continuously collected fn control rats not infused, and in IL-1-treated rats during and after a 24 h continuous systemic infusion of 6 μg IL-1α. IL-1α significantly suppressed food intake from 13.6 ± 0.1 g to 4.3 ± 0.8 g ( p < 0.001), but there was no significant difference in dopamine concentration in the LHA dialysates before, during and after IL-1α infusion relative to controls. Although IL-1α has been shown to act centrally, our results suggest that the anorexic effect of IL-1α is not mediated through dopaminergic activity in the LHA.

A Versatile, Computer-Controlled, Closed-Loop System for Continuous Infusion of Muscle Relaxants

A computer-controlled, closed-loop system for continuous infusion of muscle relaxants that allows the operator to choose either atracurium besylate or vecuronium bromide to provide any desired target level of neuromuscular blockade is described. This new system offers certain advantages over computer-controlled systems described previously for continuous infusion of muscle relaxants--that is, the option to choose either of two muscle relaxants to be infused and the inclusion of monitors to provide feedback about the dosage needed to produce a target level of neuromuscular blockade. The clinical performance of this system was tested in 36 patients who were 18 to 65 years old, were classified in American Society of Anesthesiologists physical status 1 or 2, and were undergoing elective orthopedic, abdominal, or thoracic procedures. In all patients, the control algorithm rapidly induced the target level of neuromuscular blockade and maintained that level of blockade at steady state with minimal oscillation. We conclude that the automatic feedback control system described can induce and precisely maintain any predetermined target level of neuromuscular blockade.

Comparison of the Effects of Intravenously Bolus‐administered Endothelin‐1 and Infused Angiotensin II on the Subcutaneous Tumor Blood Flow in Anesthetized Rats

To evaluate the effects of endothelin‐1 (ET‐1) on tumor blood flow, the authors measured the mean arterial blood pressure (MABP) of enflurane‐anesthetized male Donryu rats and the tissue blood flow of subcutaneously implanted tumor (Yoshida rat ascites hepatoma LY‐80) by using a hydrogen clearance method. The tumor blood flow was evaluated in terms of the ratio to the maximum blood flow, which was defined as the largest flow in the same position during successive measurements. After bolus intravenous administration of ET‐1 (1.0 nmol/kg), MABP reached approximately 140 mmHg (at 5 30 min), diminishing gradually to the baseline level over 2 h. The tumor blood flow increased from 36.7 ± 20.6 to 59.5 ± 30.2% (n = 32, P <0.001, at 2 min), returning to the baseline level at 10 min. On the other hand, at 2 min after the beginning of continuous intravenous infusion of [Asp1, Ile5]‐angiotensin II (AII; the dose was determined by a blood pressure control system for keeping MABP at approximately 150 mmHg, consequently 0.26 μg/kg/min on the average), the tumor blood flow increased from 42.3 ±21.6 to 76.4±22.6% (n = 32, P < 0.001), which was significantly larger than the flow after ET‐1. The results indicate that hypertension induced by systemic ET‐1 injection is less effective than hypertension induced by continuous systemic AII infusion in increasing tumor blood flow; AII is probably a suitable agent as a safe and effective enhancer of tumor blood flow. Moreover, ET‐1 appears to constrict arterial vessels in the microcirculation time‐dependently, while AII constricts probably only normal peripheral arterioles.

Continuous systemic 5-fluorouracil infusion in refractory prostatic cancer

Twenty patients with metastatic prostatic cancer were treated on an ambulatory basis with continuous 5-fluorouracil (5-FU) infusion 250-300 mg/M2 per day through a chronic indwelling central venous catheter. All patients had symptomatic, progressive disease despite previous standard therapies. Partial remission was seen in 2 of 20 patients (10%), stable disease in 9 of 20 (45%), and progressive disease in 9 of 20 (45%); mean duration of benefit in responding and stable disease patients was six months. Improvement in pain and ECOG performance status were seen in most of the patients in the responding and stable disease categories. Forty percent of the patients experienced no significant drug toxicity; treatment interruption was necessary for stomatitis in 6 patients (30%), hand/foot syndrome in 3 patients (15%), and diarrhea in 1 patient (5%). No significant myelosuppression or other significant organ toxicities were encountered. Continuous systemic venous infusion of 5-FU may provide significant palliative effect for some patients with symptomatic, refractory carcinoma of the prostate.

Electron microscopic observations on the accumulation of large granular lymphocytes (pit cells) and kupffer cells in the liver of rats treated with continuous infusion of interleukin-2

Treatment schedules were investigated for in vivo induction of lymphokine-activated killer cells in the rat liver. Treatment of rats with continuous systemic or regional infusion of recombinant human interleukin-2 with a dose of 4 to 8 x 10(4) U/day during 7 days, resulted in an increase in number of large granular lymphocytes or pit cells in the liver up to 43 times normal. Kupffer cells, nongranular lymphocytes, monocytes and neutrophils also increased in number, but with a maximal fivefold increase this was much less pronounced than for large granular lymphocytes. Kupffer cells showed morphological signs of activation and were frequently seen in mitosis. Frequent mitoses were also observed for large granular lymphocytes, but not for other leukocytes. This indicates that the effect of interleukin-2 treatment on hepatic (sinusoidal) cells was primarily directed to large granular lymphocytes and Kupffer cells. The large granular lymphocyte accumulation occurred mainly intrasinusoidally, but they were also frequently observed in the space of Disse where they are not found in control rats. This may be explained partly by the observed damage or gaps in the endothelial lining. The intrasinusoidal large granular lymphocytes adhered to the endothelium and to Kupffer cells. Higher responses, for all cell types, were found when interleukin-2 was administered regionally, that is, through the hepatic artery rather than through the systemic route (jugular vein), although the differences were not statistically significant. Doses below 4 x 10(4) U/day did not result in significant increases of large granular lymphocytes in the liver.

Intrarenal de novo production of angiotensin I in subjects with renal artery stenosis.

To estimate the renal extraction and de novo production of angiotensin I and to assess the contribution of blood-borne renin to renal angiotensin I production, the aortic and renal venous plasma levels of renin and intact [125I]angiotensin I and endogenous angiotensin I during continuous systemic intravenous infusion of monoiodinated [125I]angiotensin I were measured in subjects with unilateral renal artery stenosis (n = 8) who were treated with captopril (50 mg b.i.d.). Results demonstrated that 80% of angiotensin I delivered by the renal artery was extracted both by the affected and the unaffected kidney and that on both sides a major part of angiotensin I in the renal vein was derived from intrarenal de novo production. Production of plasma angiotensin I was in excess over extraction (p less than 0.01) on the affected side, whereas extraction was in excess over production (p less than 0.01) on the contralateral side. The plasma level of de novo intrarenally produced angiotensin I in the renal vein was seven times higher on the affected side than the contralateral side. This difference was by far too big to be explained by a difference in the transit time of blood between the two kidneys, by an augmented production of angiotensin I in the circulating blood passing through the affected kidney due to the higher level of venous plasma renin activity in that kidney, or by the combination of both.(ABSTRACT TRUNCATED AT 250 WORDS)

Ontogeny of the renal response to natriuretic peptide in sheep

The ontogeny of the renal response to continuous systemic infusion of atrial natriuretic peptide (ANP) was studied in chronically instrumented fetal, newborn, and adult nonpregnant sheep. Plasma immunoreactive ANP (ANPir) concentrations during low (0.025 microgram.kg-1.min-1) and high rate (0.1 microgram.kg-1.min-1) ANP infusion were similar between each group of animals. Decrease in renal blood flow velocity (RBFV) and rise in renal vascular resistance (RVR) were observed in fetal and newborn lambs during ANP infusion. The percent changes in RBFV and RVR were of significantly (P less than 0.05) greater magnitude during high ANP infusion rate in fetuses (-28.5 +/- 8.5 and 93 +/- 6.4%) than in adult sheep (-6.6 +/- 3.2 and -4.4 +/- 4.9%). ANP produced no changes in urine flow (V) in fetuses but increased V significantly in newborn lambs and adult sheep. Glomerular filtration rate increased significantly during ANP infusion in adult sheep but not in fetal and newborn lambs. Percentage changes in urinary excretion rate of Na (UNaV) during high ANP infusion rate were significantly higher in adult sheep (3,520 +/- 2,414%) than in newborn (157 +/- 106%) and fetal lambs (198 +/- 84%). These results suggest that the cardiovascular, renal hemodynamic, and possibly renal function responses to continuous ANP infusion increase during maturation, the overall response being larger in adult animals.

Superoxide dismutase and catalase failed to improve neurologic outcome after complete cerebral ischemia in the dog.

Superoxide dismutase (SOD) and catalase, natural scavengers of free oxygen radicals, or saline were administered as a continuous systemic infusion to 12 dogs, in a blind randomized fashion, starting 10 min prior to a 10-min episode of complete cerebral ischemia, and continued thereafter for 60 min. Reversible complete cerebral ischemia was achieved by simultaneously occluding the ascending aorta and venae cavae. There were no significant differences in physiological variables (arterial blood gases, hemoglobin, mean arterial blood pressure, heart rate, and temperature) between the two groups, either pre-ischemia or post-ischemia. There was no significant difference in neurologic outcome when evaluated at 48 h post-ischemia. It has previously been reported that the same dose of SOD and catalase as used in the current study could reduce infarct size by 50% when given systemically before reperfusion following coronary ischemia in dogs. The lack of a measurable effect on neurologic outcome in our cerebral ischemic model might be because of the failure of the free oxygen radical scavengers to reach the ischemic cells in sufficient amounts, or because free oxygen radicals do not contribute to brain injury following complete cerebral ischemia.

Effect of continuous systemic infusion of d-amphetamine on the sensitivity of nigral dopamine cells to apomorphine inhibition of firing rates

Using a single-unit recording technique, sensitivity of nigral dopamine neurons to the inhibitory effect of apomorphine was examined on various days after a 7-day pretreatment with osmotic minipumps containing d-amphetamine. Continuous systemic infusion of d-amphetamine produced a short-lasting subsensitivity of nigral neurons to apomorphine (0–2 days after d-amphetamine), followed by a supersensitivity on days 7, 8 and 9, post-amphetamine. The supersensitivity seems to persist at least for one week, suggesting one possible mechanism mediating long-term behavioral and biochemical changes following chronic high-dose amphetamine administration.

Compact portable system for continuous central venous infusion in rats.

A new method of cannula protection is described. This allows the use of a shorter connection between the infusion pump and the mobile rat, and the whole apparatus is easily transportable.

Effect of epinephrine infusion on maternal and uterine oxygen uptake in the pregnant ewe

Ten chronically instrumented pregnant ewes were studied to assess the effect of an epinephrine-induced decrease in uterine blood flow on the oxygen uptake of the uteroplacental-fetal tissue mass. Additional measurements of maternal cardiac output, oxygen uptake, arterial pressure, and hematocrit were obtained. Continuous systemic infusion of epinephrine at a rate of 0.3 to 0.4 μg per kilogram per minute produced a mean decrease in uterine blood flow of 42 per cent (288 ± 15 to 157 ± 8 ml. per kilogram per minute). However, the oxygen uptake of the uteroplacental-fetal tissue mass remained at control levels due to an associated 79 per cent increase in the arteriovenous oxygen content difference across the uterine circulation. The calorigenic and cardiovascular systemic effects of epinephrine (a 22 per cent increase in maternal oxygen uptake and a 43 per cent increase in maternal cardiac output) were not related to the changes in either uterine flow or oxygen uptake. The implications of these observations are discussed.

Treatment of experimental liver tumors by continuous intra-arterial chemotherapy

A system for continuous infusion into the hepatic artery in rats is described. Rats were intrahepatically inoculated with Walker 256 carcinoma cells and then treated by the administration of 5-fluorouracil through the canula. Rats so treated developed significantly smaller tumours than did control animals. This system allows free movement of the animals, does not affect the liver blood supply and permits prolonged administration of drugs. This method of investigation can also be applied to other research programs.

Inactivation of 5-fluorouracil by the liver during continuous regional and systemic infusion in pigs.

During continuous systemic or portal infusion of 5-fluorouracil (5-FU) to anaesthetized pigs, the cytostatic activity was reduced in blood traversing the liver. The liver eliminated between 15 and 50% of the amount 5-FU given per time unit. During jugular infusion the concentration of cytostatic compounds in portal blood was equal to or less than in systemic blood. The cytostatic activity was much higher in portal blood and lower in systemic blood during portal infusion. The findings speak in favour of portal infusions of 5-FU to patients with disseminated cancer in the liver.