Biomedical subjects
Publications and source records attributed to A Bothe.
Technetium-99m macroaggregated albumin is used to assess the proper location and condition of a totally implanted venous and arterial access system prior to infusion therapy. The risk of drug extravasation is thus avoided. Delivery of the chemotherapeutic agents to the intended location is assured.
Twenty-six patients received vinblastine by ambulatory pump infusion via the subclavian vein for a median duration of 30 days of continuous therapy at an average dose rate of 0.5 mg/m2/day. Drug toxicity was minimal compared to the standard bolus schedule but bone marrow suppression was dose-limiting. There was no gastrointestinal or neurologic toxicity. The maximum duration of continuous therapy was 89 days (at 0.5 mg/m2/day) with the duration of therapy specifically related to the daily dose rate. Nondrug-related toxicity included subclavian vein thrombosis in two patients. Two of 11 patients with malignant melanoma had transient objective responses and 1/3 patients with soft tissue sarcoma had a partial response. Expanded phase II studies are ongoing at the dose of 0.5 mg/m2/day for a minimum duration of 30 days.
The use of continuous, low-dose heparin in total parenteral nutrition (TPN) formulas to limit central venous thrombosis was retrospectively evaluated. Seven of 129 patients (5.4%) developed central vein thrombosis when TPN solutions provided less than 6,000 units (usually 1,000 units/liter) heparin per day. In the subsequent period when heparin was increased to 6,000 units per day, 10 of 858 (less than 1.2%) patients developed a TPN-related thrombosis (P less than 0.0005). The incidence of antithrombin III (AT III) deficiency in a subset of high-risk patients scheduled to receive TPN was 51% (23 of 55). Twelve of the 23 had clinical evidence of thrombosis, whereas only 3 of 22 patients with normal AT III levels did (P less than 0.01) A major contributing factor to the development of thrombosis in TPN appears to be depression in antithrombin III levels, which is commonly found in patients who require this therapy. Low-dose heparin appears to reduce the incidence of thrombosis with TPN when provided continuously in sufficient amounts.
One hundred twenty-four patients with metastatic malignancy were treated with four different single agent infusion programs by constant intravenous infusion for 30 or more days. Drug was administered via a tunneled subclavian line by a battery-driven peristaltic pump (Cormed model ML6) on an ambulatory basis. This schedule allowed for increased cumulative drug dose for 5-Fu, decreased tolerated dose for vinblastine, and comparable doses for adriamycin and mitomycin-C relative to that delivered with the standard intermittent bolus schedule. Therapeutic effects were observed for three of four drugs studied: 5-Fu 13/31 colorectal cancer; adriamycin 7/29; and vinblastine 4/12, including 2/4 melanoma. Adverse effects were significantly reduced, particularly with regard to gastrointestinal toxicity, but also in adriamycin-associated cardiac effects and hair loss. Phase III comparative trials of intermittent bolus therapy with protracted infusion therapy are in progress for 5-Fu in advanced colorectal cancer and for adriamycin in specific tumors. Ambulatory pump infusion (API) chemotherapy is technically feasible and has improved patient tolerance to chemotherapy while demonstrating similar, if not comparable, antitumor effects.
Eighteen patients received a continuous intravenous infusion of adriamycin for 14-60 days in a phase I study in which the dose rates were escalated from 2 mg/sq m/day to 5 mg/sq m/day to establish the optimal dose to be delivered over a 30-day period. The drug was delivered via a tunneled subclavian catheter by a portable infusion pump (Cormed model ML-6) primed to provide a volume of diluted drug of 10 cc/day. Leukopenia and stomatitis were observed at 4 mg/sq m/day doses or greater in 50% of courses. At doses less than 4 mg/sq m/day, only 3/17 courses (18%) were associated with stomatitis. Partial alopecia developed in all patients, but less than 50% of scalp hair was affected. The cumulative dose of continuous infusion adriamycin at 30 days is comparable to the dose delivered by standard bolus intermittent schedules (60-90 mg/sq m g 21 days), but the adverse drug effects are eliminated or substantially reduced. Cardiac toxicity was assessed in selected patients treated to 450 mg/sq m or greater by cardiac biopsy and/or gated pool studies. No histopathologic lesions were noted in 3 patients receiving 450 mg/sq m or greater. The recommended daily dose rate of adriamycin in this protracted infusion regimen is 3 mg/sq m/day. The phase II study of this schedule and dose rate in 38 additional patients (a total of 52 evaluable patients) demonstrated objective responses in 1/9 soft tissue sarcoma, 1/3 mesothelioma, 1/3 hepatoma, and 2/13 breast cancer. Phase III studies of the protracted continuous infusion schedule for adriamycin are indicated in that clinical activity is demonstrated at a substantial reduction in toxicity. Pharmacologic studies expanding the existing data base are also necessary.
5-Fluorouracil (5-Fu) was administered by a constant venous infusion schedule at a dose of 300 mg/m2/d for 30-180 days. The dose schedule was associated with minimal toxicity in 32 patients with gastrointestinal cancer treated by employing a portable infusion pump for ambulatory drug delivery. Cumulative dose of 5-Fu was extended to three to four times that achieved by intermittent bolus therapy or short-term 5-day infusion therapy. Objective tumor regression was observed in six of 22 patients with measurable disease; 10 patients had stable disease, five of whom had a decrease in CEA levels. The responses according to tumor type were as follows: 1/1 gastric cancer; 1/2 hepatoma; and 4/18 colon cancer. The superiority of this new treatment schedule for 5-Fu will need to be established by prospective randomized clinical trials.
Morbid obesity has been associated with increased risks for thrombotic diseases. Patients with morbid obesity are shown to have decreased activity and decreased concentration of antithrombin (AT) III. This deficit can be corrected by giving the patients low doses of the oral anticoagulant warfarin. The same beneficial effect was not observed in normal lean control volunteers in whom the levels of AT III were normal at all times. Thus, it may be possible to offer prophylactic protection against the effects of having depressed levels of AT III in patients at increased risk for thrombotic diseases without using full anticoagulant doses of warfarin, including morbidly obese patients.
Fifty chemotherapy trials with 5-fluorouracil; mitomycin C; vinblastine; Adriamycin; and cis-platinol were initiated employing constant (24-hour) intravenous infusion for protracted periods (14-94 days). The use of the tunneled subclavian line for greater than 2200 patient days was associated with minimal complications and no instances of thrombosis or infection were observed. The use of an ambulatory infusion pump was associated with a pump efficiency of greater than 85% in 38 of 39 evaluable trials. Only four of 50 trials were associated with excess drug infusion and in no instance was a drug complication encountered. Constant infusion cancer chemotherapy is feasible, reliable, and safe. Objective tumor regression is observed but the superiority of this drug schedule over the standard intermittent bolus schedule is yet to be determined. Nonetheless, drug toxicity patterns are altered substantially and, in particular, gastrointestinal side effects of chemotherapeutic drugs may be eliminated without compromising cumulative dose.
The present study was designed to determine whether alterations in host metabolism associated with progressive tumor growth were a result of the anorexia frequently observed with cancer or could be attributed to other direct tumor effects. Rates of tyrosine flux, oxidation, and incorporation into protein, as well as fractional protein-synthetic rates in nonsecretory liver, muscle, and tumor, were determined in overnight-fasted rats, 5 to 6 (Stage I), 10 to 11 (Stage II), and 15 to 16 (Stage III) days following s.c. implantation of RNC-254 fibrosarcoma. Tumor-bearing rats were allowed to consume a purified diet containing 20% protein ad libitum, and results were compared to non-tumor-bearing rats pair fed quantities of food equivalent to tumor-bearing animals or allowed to consume the diet ad libitum. Results demonstrate that during later stages of tumor growth (Stage III) calorie intake and nontumor body weight gain were reduced in tumor-bearing rats (p less than 0.05). Fifteen and 16 days following implantation, there were significant changes in amino acid kinetics that were not observed after earlier periods of tumor growth and that could not be explained by any reduction in dietary intake. Rates of tyrosine appearance in the plasma and subsequent incorporation into whole-body protein were increased 33 and 34%, respectively (p less than 0.05), when compared to non-tumor-bearing rats fed equivalent quantities of food. Whole-body tyrosine oxidation rates were unchanged. Skeletal protein synthesis, as reflected by gastrocnemius or rectus abdominus muscle, was reduced from 10.5 and 10.1%/day to 7.4 and 6.0%/day, respectively (p less than 0.05), in tumor-bearing compared to pair-fed animals. The findings suggest that significant alterations in protein metabolism occur in advanced stages of experimental neoplastic disease which cannot be explained by reductions in dietary intake and are aimed at providing adequate quantities of endogenous amino acids for net tumor growth.
Thirty patients received mitomycin C by constant infusion for 5 consecutive days (16 patients ) or for extended period by an ambulatory infusion pump (Cor-Med model) for 9 to 30 days (14 patients). The short-term 5-day infusions were delivered at dose rates of 2, 3, 4, 5 and 6 mg/m2/d with a cumulative dose of 15-50 mg. The protracted infusions were delivered at dose rates of 0.75-3 mg/m2/d with a cumulative dose of 21.6-65.2 mg. Marrow suppression was dose-limiting and occurred in 5/6 evaluable patients receiving more than 30 mg in the short-term infusion schedule and 8/10 evaluable patients receiving more than 20 mg in the protracted infusion schedule. The characteristics of the marrow suppression are that: a) thrombocytopenia precedes or is observed without concomitant leukopenia and b) the nadir day is delayed (WBC day 42, platelet day 36). Mitomycin C delivered by constant infusion leads to dose-limiting marrow toxicity at 20 to 30 mg cumulative dose depending upon the dose rate and duration of treatment. For short-term 5-day therapy, 3 mg/m2/d and for protracted therapy (up to 30 d) 0.75 mg/m2/d are the recommended dose rates for the constant infusion schedule.
A Phase I study of protracted continuous infusion 5-fluorouracil was undertaken at a starting dose of 200 mg/m2/day. The drug was delivered via a tunneled subclavian venous access site by a portable infusion pump (Cor-Med) permitting ambulatory monitoring. Seventeen patients were administered 19 courses at incremental dose rates from 200 mg/m2/day to 600 mg/m2/day; treatment was terminated at the onset of stomatitis. At dose rates of 300 mg/m2/day or less, the treatment did not require interruption for up to 60 days or up to 36 g cumulative dose. For dose rates of 350 to 600 mg/m2/day, the treatment always required interruption: mean duration 20 day for 350 mg/m2/day; 9 day for 400 mg/m2/day; and 14 day for 600 mg/m2/day. Mean cumulative dose at the higher dose rates was 10.9 g (350 mg/m2/day); 7.9 g (400 mg/m2/day); and 15.3 g (600 mg/m2/day). Mean cumulative dose at 200 mg/m2/day was 11.5 g and at 300 mg/m2/day, was 22.6 g. Protracted venous infusion allows for a substantial cumulative dose of 5-FU and at dose rate delivery of 300 mg/m2/day may be administered for up to 60 days without adverse effects due to the drug or to the presence of an indwelling venous access line.
Of 366 cases of portal hypertension in adult patients referred for evaluation and management in the past 15 years, the cause was not related to cirrhosis or hemochromatosis in 41. No specific cause was demonstrated for portal hypertension in four cases, which were excluded from further evaluation. Of the remaining 37 patients, 26 had a presinusoidal block characterized primarily by bleeding from esophagogastric varices, and 9 had a postsinusoidal block characterized by the rapid development of intractable ascites. In two cases an arteriovenous fistula was the cause of portal hypertension. Treatment was operative or nonoperative depending on the nature and prognosis of the basic disease. The various approaches to therapy include shunting procedures for the control of ascites or esophagogastric varices, the use of a type of portal-azygous disconnection and a direct approach to a valve or a fistula. In the absence of a rapidly fatal primary disease, portal hypertension is not a threatening problem and may be controlled with minimal mortality by appropriate surgical management.
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Changes in protein metabolism 8 hr after anesthesia and femur fracture were studied in healthy rats fasted or receiving either intravenous glucose or crystalline amino acids. Whole body rates of amino acid turnover (flux) and release from protein (breakdown) as well as fractional synthetic rates of mixed muscle, liver, and plasma protein were measured using the constant infusion of L-(I-14C)-leucine. Injury resulted in a 24% increase in the synthesis of liver (p less than 0.05) and plasma proteins (p less than 0.01), respectively. Amino acid infusions in the injured animals further increased the synthesis of liver protein (from 36.6% to 44.3%/day, p less than 0.05) and increased muscle protein synthesis (from 7.0% to 9.3%/day, p less than 0.05) without altering rates of protein breakdown. Glucose infusions, in contrast, reduced whole body protein breakdown 36% (p less than 0.05) when compared to fasting, and depleted the plasma essential amino acid pool (p less than 0.05). The usual increases in liver protein synthesis observed in fasted rats following injury were not seen when the animals were receiving intravenous glucose. The nitrogen-sparing mechanism of these two infusions are different. Protein-free glucose infusions impair the normal response to injury aimed at increasing visceral protein synthesis and maintaining plasma essential amino acid concentrations.
Alternatives to total parenteral nutrition (TPN) can play an invaluable role in the support of the critically ill patient. However, the efficacy of this depends on: (1) early nutritional assessment; (2) sequential nutritional assessment as dictated by the clinical condition of the patient; (3) careful estimation of requirements based on calculated energy expenditure and use of the "stress-index"; (4) early use of enteral feedings in combination with peripheral and central intravenous routes, especially with the use of "feeding modules" to provide patient's specific concentrated diet; (5) use of intravenous fat as an isotonic supplement to dextrose in the presence of carbohydrate intolerance; (6) avoid overfeeding as rigorously as underfeeding; (7) continued clinical trials to determine optimal nutritional/metabolic support of the critically ill.
A patient with recurrent upper gastrointestinal bleeding after having a "C"-shaped mesocaval shunt created is reported. During endoscopic examination, the graft was seen to have eroded into the duodenal lumen. This rare complication of mesocaval shunts may become more common with the increaseing use of "C"-shaped grafts.