The effects of tramadol and morphine on immune responses and pain after surgery in cancer patients.

UNLABELLED: There has been growing interest in determining the possible immune consequences of opioid administration for the management of postoperative pain. We studied the effects of morphine and tramadol on pain and immune function during the postoperative period in 30 patients undergoing abdominal surgery for uterine carcinoma. Phytohemoagglutinin-induced T lymphocyte proliferation and natural killer cell activity were evaluated immediately before and after surgery, and 2 h after the acute administration of either 10 mg of morphine IM or 100 mg tramadol IM for pain. In all patients, phytohemagglutinin-induced lymphoproliferation was significantly depressed by surgical stress. However, in the morphine-treated group, proliferative values remained lower than basal levels for 2 h after treatment, whereas in tramadol-administered patients proliferative values returned to basal levels. Natural killer cell activity was not significantly affected by surgery nor by morphine administration, whereas tramadol significantly enhanced the activity of natural killer cells. Both drugs produced a comparable reduction in postoperative pain. We conclude that, as previously observed in the experimental animal, tramadol and morphine, when administered in analgesic doses, induce different immune effects. IMPLICATIONS: Recent studies suggest that opioids can have an adverse impact on the immune system. Because surgical stress also induces immune dysfunction, the search for analgesic drugs devoid of immunosuppressive effects is of import. This study compared the effects on immune responses of morphine and of the atypical opioid analgesic, tramadol, given for postoperative pain to gynecological cancer patients. Tramadol and morphine showed comparable analgesic activity; however, tramadol, in contrast to morphine, induced an improvement of postoperative immunosuppression and, therefore, may be preferred to morphine for the treatment of postoperative pain.

Safety of absorbable suture for sternal closure after pulmonary or mediastinal resection.

The reliability of polyglyconate monofilament (Maxon) suture for sternal closure was tested on 216 consecutive sternotomies, performed on 208 patients in our department from January 1986 to December 1990. The reason of sternotomy was primary lung cancer in 34 cases (16%), lung metastases in 127 (59%), and disorders of the thymus in 55 (25%). Mean age was 38 years (range 3 to 78 years); multiple lung resections were performed in 102 patients (average 7 lesions, range 2 to 30); maximum extent of the operation was pneumonectomy in 2 cases, lobectomy in 53, segmentectomy in 27, and wedge resection in 74. Prior chemotherapy had been administered in 75 cases (35%). A second sternotomy was performed in 8 cases. No cases of sternal dehiscence, sternal infection, or empyema were observed, after a median follow-up of 27 months. Overall perioperative mortality was 0.9% (2/216). Our series demonstrates the safety of polyglyconate monofilament (Maxon) suture for sternal closure. Absorbable sutures appear to be a safe alternative to steel wire closure in patients undergoing extended pulmonary or mediastinal resection.

[Use of buprenorphine after right hepatectomy]. / Impiego della buprenorfina dopo intervento di epatectomia destra.

Ten patients who underwent surgery (5 right hepatectomy and 5 colectomy) for cancer participated in a clinical controlled study. They were treated with buprenorphine (i.v. slow infusion) to relieve postsurgical pain. We found an increased urinary excretion of this drug in patients who underwent hepatectomy as compared with patients who underwent colectomy. However no differences in the occurrence of side-effects and/or in the therapeutic effect were observed between the two groups. We conclude that buprenorphine can be effectively and safely used also in patients with a resection of liver parenchyma.

Complicaciones de la linfadenectomía retroperitoneal / Complications of the retroperitoneal lymphadenectomy

La resección de los ganglios retroperitoneales, próximos a los grandes vasos, es difícil y peligrosa. Complicaciones importantes han sido relatadas, vinculadas a la disección ganglionar retroperitoneal. En este trabajo se examina la experiencia de 682 casos consecutivos ocurridos en el Instituto de Tumores de Milán, entre 1967 y 1988 (AU)

Complicaciones de la linfadenectomía retroperitoneal / Complications of the retroperitoneal lymphadenectomy

La resección de los ganglios retroperitoneales, próximos a los grandes vasos, es difícil y peligrosa. Complicaciones importantes han sido relatadas, vinculadas a la disección ganglionar retroperitoneal. En este trabajo se examina la experiencia de 682 casos consecutivos ocurridos en el Instituto de Tumores de Milán, entre 1967 y 1988

Anti-melanoma monoclonal antibody 225-28S: evaluation of toxicity in man.

To investigate possible undesirable effects due to the intravenous administration of a reagent of a xenogenic nature (monoclonal antibody 225-28S) in man, a toxicologic study was carried out on 85 patients with metastatic cutaneous melanoma. Two reagents were tested in this study: purified monoclonal antibody (MoAb) 225-28S and its F(ab')2 fragment. Purified MoAb was labelled with 131I and F(ab')2 fragment with 131I, or 123I, or 111In or 99Tc. The quantity of MoAb or F(ab')2 injected ranged from 14 to 750 micrograms, and the specific activity from 37.0 to 2116.4 MBq/mg. The total radioactivity injected varied from 25.9 to 891.7 MBq/mg. In addition to a careful clinical examination, the following tests were done to monitor possible adverse effects: blood glucose, azotemia, RBC, WBC, platelet count, serum creatinine, creatinine clearance, plasma electrolyte levels, serum proteins, albumin/globulin ratio, serum bilirubin, SGOT, SGPT, gamma GT, and CPK. These tests were done before the injection and on days 7 and 14. No patient experienced adverse general effects like fever, nausea, vomiting or allergic reactions. None of the aforementioned hematometric and biochemical tests showed significant variations compared with the initial values. It is concluded that a single injection of these reagents at the dosages tested is completely atoxic.

Total parenteral nutrition prevents further nutritional deterioration in patients with cancer cachexia.

The effects of total parenteral nutrition (TPN) on some nutritional variables were prospectively investigated in 12 severely cachectic patients with advanced cancer. The following variables were determined before and at 5-day intervals during the 20-day administration of TPN: anthropometric indices (body weight, arm circumference, triceps skinfold, arm muscle circumference, arm muscle area, arm fat area, total body muscle mass); biochemical indices (total protein, albumin, cholinesterase, total iron binding capacity, thyroxin-binding prealbumin, retinol binding protein, urinary 3-methylhistidine and creatinine excretion, nitrogen balance); and peripheral lymphocyte count. TPN was delivered at 49.5 nonprotein kcal/kg-1/day-1 (80% as dextrose and 20% as fat) and amino acids 1.9 g/kg-1/day-1. A significant increase was obtained in body weight, triceps skinfold, arm fat area, and retinol binding protein. All remaining anthropometric and biochemical parameters did not show any significant positive or negative change, although nitrogen balance remained positive. No significant liver toxicity was apparent after the TPN period. It was concluded that although TPN is unable to completely reverse some nutrition-related variables in cachectic patients with cancer, most patients were kept within a normal range and some improved. Therefore, further deterioration of the nutritional state, which is characteristic of this phase of disease, was at least prevented.

Interventional radiology with venous port (chemotherapy and infusional support).

A completely portable permanent central venous access, consisting of a steel capsule sealed with a silicone membrane and connected to a silicone catheter (Port-a-Cath), was implanted in the subcutaneous tissue of 36 patients, most of whom no longer had accessible peripheral veins and needed to continue chemotherapy or undergo total parenteral nutrition. The access vessel was mostly the subclavian vein and the capsule was sutured to the pectoral fascia. Total subcutaneous implantation seems to afford optimum safety from infection and freedom for personal hygiene, produced no noteworthy complications and proved relatively simple to maintain.

Evaluation of toxic effects following administration of monoclonal antibody MBr1 in patients with breast cancer.

Twelve patients with disseminated breast cancer were injected with monoclonal antibody MBr1 at the National Cancer Institute of Milan, Italy, from January 1983 to March 1985. The first seven patients had advanced disease and the remaining five operable breast cancer. In the first seven patients the initial dosage of MBr1 was 0.5 mg and was doubled in the next patient up to 16 mg. The last five women received 10 mg of MBr1. No general side effects such as bronchospasm, hypotension, immediate or delayed allergic reactions were observed. Four patients who were injected with 10 mg or more experienced fever, shudder and vague abdominal and articular pain. The following tests were monitored: R.B.C., W.B.C., percentage of lymphocytes, blood glucose, urea nitrogen and creatinine, serum levels of Na+, K+, Cl-, total proteins levels, albumins and globulins, bilirubin, GOT, GPT, alkaline phosphatase, LDH, amylase, gamma GT and CPK. No major modifications were observed: a limited increase of the transaminases, LDH and gamma GT was evident at the last check. An early temporary alteration of CPK was observed in the four patients who had symptoms. Serum levels of MBr1 are detectable immediately after injection starting from 4 mg, and all sera were negative 48 hours later. It is concluded that the scanty toxicity allows to continue clinical investigations to verify the linkage between MBr1 and Ca-MBr1 "in vivo" after a single injection of no more than 16 mg of the MoAb. The increase of this dosage as well as multiple injections do not seem safe at present.

Central venous catheter sepsis: prognosis and treatment.

The purpose of this study was to evaluate the prognosis of patients with central venous catheter (CVC) sepsis, with particular reference to two therapeutic procedures, 1) CVC exchange over a guide wire and 2) removal of the catheter An evaluation was made of the clinical records of 22 cancer patients receiving total parenteral nutrition because of severe malnutrition and of 27 CVC-related septic episodes defined as growth of the same microorganism on the CVC and in peripheral blood. Bacteriological findings included Candidae n = 17, S albus n = 4, E Cloacae n = 4, Enterococcus n = 1 and P aeruginosa n = 1. In 22 cases the CVC was exchanged and in five cases it was removed on the clinical suspicion of CVC-related sepsis. Nineteen of the 22 patients had their blood culture rendered negative with CVC exchange and in three of the other five patients it was resolved bacteriologically after removal of the CVC. There was no clear effect of the CVC sepsis on the final outcome of the patients' illness. In fact, seven patients eventually died because of reasons apparently unrelated to the CVC sepsis-which had bacteriologically and clinically resolved-and seven patients recovered and were discharged in good condition despite the initial failure of CVC manipulation. The conclusion reached was that death should not occur as a result of CVC sepsis, provided this is properly identified and adequately treated. Since CVC change allows earlier recognition of the complication and effective treatment, it may be considered the therapy of choice in the management of suspected CVC sepsis.

Imaging with 131I-labeled monoclonal antibodies to a high-molecular-weight melanoma-associated antigen in patients with melanoma: efficacy of whole immunoglobulin and its F(ab')2 fragments.

In vitro experiments selected optimal conditions to radiolabel with 131I the whole immunoglobulin and F(ab')2 fragments of the monoclonal antibody (MoAb) 225.28S to a high-molecular-weight melanoma-associated antigen (HMW-MAA). Injection of the radiolabeled whole immunoglobulin and F(ab')2 fragments of the MoAb 225.28S into eight patients with melanoma resulted in the accumulation of radioactivity in 10 of 18 metastases. This localization is specific because of the close relationship between detection of HMW-MAA in lesions by immunohistochemical techniques and outcome of immunoscintigraphy and because of the different distribution in tumors and adjacent tissues of radiolabeled F(ab')2 fragments of MoAb 225.28S compared with 99mTc-pertechnetate and with radiolabeled F(ab')2 fragments of MoAb 4C4 to hepatitis B surface antigen. F(ab')2 fragments are superior to whole immunoglobulins to perform immunoscintigraphy, since they markedly reduce the background in bone marrow, liver, and spleen. The sensitivity of the procedure allows the detection of lesions with a diameter of at least 1.5 cm and is influenced by the level of the HMW-MAA in lesions and by their anatomical site.

"Nutritional" markers as prognostic indicators of postoperative sepsis in cancer patients.

A study was undertaken to identify the nutritional parameters associated with a high risk of postoperative sepsis. The nutritional status of 162 cancer patients subjected to clean or clean-contaminated elective surgery was preoperatively evaluated according to the following parameters: percentage weight loss, arm circumference, triceps skinfold, arm muscle circumference, creatinine-height index, total serum protein, serum albumin, total iron-binding capacity, cholinesterase, peripheral lymphocytes, complement C3-C4 components, and skin tests. Patients were followed postoperatively according to a precise protocol to classify them as infected or noninfected. Postoperative sepsis was present in 40 patients who had significantly different mean values for four nutritional parameters from those of 114 patients with no complications, ie, total serum protein, 6.60 vs 6.99 g/dl, p = 0.008; serum albumin, 3.39 vs 3.66 g/dl, p = 0.001; total iron-binding capacity 301.32 vs 337.17 mmg/dl, p = 0.006; and cholinesterase, 2389.77 vs 2770.10 mU/ml, p = 0.005. Moreover, the relative risk and the attributable risk for these variables were evaluated and the significance was tested by the chi 2 test. By using multiple logistic analysis it appeared that only total serum protein and total iron-binding capacity gave an independent contribution to the risk of postoperative sepsis, while serum albumin disappeared and cholinesterase became non significant when the contribution of the first two variables was accounted for. It was also possible to identify, in a small number of patients, combinations of two variables that were associated with a very high risk of postoperative sepsis.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood culture as a guide for the diagnosis of central venous catheter sepsis.

The purpose of this study was to evaluate the predictability of peripheral (PBC) and central blood cultures (CBC) in the diagnosis of central venous catheter (CVC) sepsis (growth of the same microorganism in the peripheral blood and on the catheter tip). The contamination and sepsis rate of 256 CVCs and the relationship with PBC and CBC was evaluated in a series of cancer patients included in a prospective protocol on CVC infections at the Istituto Nazionale Tumori of Milan. Overall CVC contamination was 10.5% and sepsis rate was 3.1%. The positive predictive value for CVC sepsis was 46.7% for positive PBC + CBC, 38.1% for positive PBC and 16.6% for positive CBC. The small gain in the predictive positive value obtained with the use of PBC and CBC and the slight increase in the specificity does not justify, in our opinion, the use of both these parameters for the diagnosis of CVC sepsis.

Subclavian venous thrombosis due to indwelling catheters: a prospective study on 52 patients.

Clinical occurrence of subclavian venous thrombosis due to indwelling catheters is rare, but there is some evidence that subclinical thrombosis frequently occurs. It is purpose of this study to report the results of a prospective investigation in patients with subclavian vein catheters. Fifty-two patients admitted to the Istituto Nazionale Tumori of Milan and candidate to infraclavicular percutaneous catheterization of the subclavian vein were evaluated. There were 26 polyvinyl chloride and 26 rubber silicone catheters, which were correctly positioned in the superior vena cava-atrium. Average duration of the intravenous stay was 12.8 days. Asymptomatic thrombosis was venographically demonstrated in 46.1% of the polyvinyl chloride catheters and in 11.5% of the silicone ones (p = 0.005). The average age of catheters with or without thrombosis was 10.8 and 13.8 days, respectively. Addition of heparin to the infusate (1 U/ml) did not reduce the thrombosis rate in polyvinyl chloride or in silicone catheters, but risk of thrombosis was significantly higher (p = 0.03) in polyvinyl chloride catheters without heparin in comparison to the silicone ones. Osmolarity of the infusional fluid, manipulation during the cannulation, colonization of the catheter tip, and duration of the intravenous stay of the catheter apparently did not influence the rate of thrombosis. Since the natural history of the thrombotic subclavian veins is not known, some caution must be paid to repeat the percutaneous cannulation of the same vein and the change the catheter over a guidewire.

Hypocupremia in patients receiving total parenteral nutrition.

Although hypocupremia is a well-known consequence of long-term total parenteral nutrition (TPN), its incidence as well as the duration of TPN necessary to induce it are still unsettled. The purpose of this study is to review the changes in serum copper level in 25 patients receiving TPN for a period longer than 2 wk (mean duration 6 wk) at the Istituto Nazionale Tumori of Milan and to evaluate the possible relationship of cupremia with the basic disease. Main indications for TPN included enterocutaneous fistulas (11 patients), cancer cachexia (10 patients), radiation enteropathy (two patients), and severe postoperative stricture following esophagogastric resection (two patients). Mean value of serum copper at the beginning of the study was 143 micrograms/100 ml (normal value 65-165 micrograms/100 ml), and the regression analysis showed a mean fall of 5.64 micrograms/100 ml/wk. Hypocupremia occurred in four patients (three with intestinal fistulas and one with radiation obstructive enteritis) at 5th, 6th, 9th, and 6th wk of TPN, respectively. No patient with cancer cachexia developed hypocupremia. No patient with hypocupremia had clinical evidence of a copper deficiency syndrome. We conclude that 1) hypocupremia does not occur within the first month of TPN; 2) its incidence is about 16% in patients intravenously fed for period longer than 2 wk; 3) it is more frequent in patients with enterocutaneous fistulas, whereas it never occurs in patients with cancer cachexia, and 4) it is not necessarily associated to a clinicometabolic syndrome of copper deficiency. Finally, the "nutritional" meaning of serum copper should be questioned in cancer patients since it could represent a "tumor marker."

Prevention and treatment of central venous catheter sepsis by exchange via a guidewire. A prospective controlled trial.

A new approach for preventing and treating sepsis due to central venous catheter (CVC) has been devised at the Istituto Nazionale Tumori of Milan. A prospective protocol has been developed that includes the weekly exchange of the CVC via a guidewire as well as its exchange when a CVC-related sepsis is suspected. Growth of microorganisms on the tip of the CVC is defined as contamination if peripheral blood culture is negative and as sepsis if it is positive for the same microorganism. Colonization simply means growth of microorganism independently of the results of peripheral blood culture. Two hundred seven CVCs (64 polyvinyl chloride and 143 rubber silicone) were evaluated in 62 patients, for a total of 170 exchanges. The incidence of colonization and sepsis was 33.8% and 4.8%, respectively, a rate which is not significantly different from the values found in 81 historical controls (30.8% and 11.1%). However, it is noteworthy that the sepsis rate was reduced strongly during the first month of observation (0% vs. 11.9%; p = 0.01), whereas in the second month, it was similar in both groups (15% vs. 7.1%). Moreover, it should be noted that three-fourths of the colonized CVCs became negative after the first exchange, and virtually all were negative at the fourth exchange. All of the episodes of sepsis resolved spontaneously with the CVC exchange. The study, therefore, concludes that this procedure: 1) is without risk for CVC cross contamination, 2) is effective in the treatment of contaminated CVCs and of septic patients without any interruption of total parenteral nutrition, and 3) can reduce the incidence of CVC sepsis during the first month of total parenteral nutrition. One must be cautious about the possible onset of pulmonary embolism in patients with subclavian venous thrombosis, since a transient pulmonary embolism occurred in one of the patients. With the use of silastic CVCs, which are less thrombogenic than polyvinyl ones, the rate of pulmonary embolism due to blind exchange (without previous venography) is estimated to be 0.1% to 0.2%.

Management of lymphatic fistulas by total parenteral nutrition.

Lymphatic fistula is a rare surgical complication, which mainly occurs after cervical or retroperitoneal lymph node dissection and which frequently requires a surgical repair. A small series of nine postoperative lymphatic fistulas treated conservatively with total parenteral nutrition (TPN) is reported. All the patients were malnourished at the beginning of the TPN, and all exhibited an objective improvement of their nutritional status after completion of the treatment. Due to the interruption of the enteral alimentation or to the nutritional repletion, spontaneous closure of the fistula was achieved in eight of nine patients treated with TPN longer than 1 week. The authors conclude that whenever the immediate surgical repair is not recommended, or it is not successful, a 2- to 3-week course of TPN may be used with the chance of spontaneous healing. In any case, patients conservatively treated by TPN can undergo a delayed operation with minimal risk because of the improved nutritional status.

Impact of cancer, type, site, stage and treatment on the nutritional status of patients.

This study analyzed the nutritional status of cancer patients in relation to type and site of origin of the tumor, stage of disease, and previous chemical or radiation therapy. The analysis was performed on 321 patients (280 with cancer and 41 controls). The nutritional parameters included per cent of weight loss, anthropometric indices (arm circumference, triceps skinfold, arm muscle circumference), creatinine-height index, serum protein, albumin, total iron binding capacity and cholinesterase, C3 and C4 components of complement, total peripheral lymphocytes, and skin tests. The statistical comparison between patients with different tumors and controls, between patients with different stages of the same tumor, and between patients treated with or without previous chemical or radiation therapy led to the following conclusions: 1) malnutrition is mainly related to the type and site of origin of the tumor and, in the early stages of disease, is more pronounced in patients with cancer of the esophagus and stomach; 2) except in patients with breast and cervix cancer, malnutrition gets more severe as the disease becomes advanced; 3) chemical or radiation therapy has a variable impact on the nutritional status, but in selected patients it causes a drop in body weight, arm circumference, arm muscle circumference, and peripheral lymphocytes; 4) body weight, cutaneous delayed hypersensitivity and serum albumin are the most commonly altered parameters.

Pathogenesis and predictability of central venous catheter sepsis.

The purposes of this study were to analyze the causes and routes of infection of indwelling central venous catheters and to improve the diagnosis of catheter sepsis before the removal of the cannula. One hundred forty catheter tips were prospectively studies; also, cultures of 52 proximal segments of catheters, 44 swabs of the subcutaneous segment, 195 skin entry sites, 181 infusional fluids, 208 blood samples, and 106 infected distant sites were examined. The catheter sepsis rate was 7.6%, but this sepsis was primary in only 3.4%, because in 4.2% prior isolation of organisms from the wound, urine, throat, or sputum was possible, indicating that the catheter was not primarily responsible for the infection. Primary infection always disappears with removal of the cannula (with or without antibiotics), whereas the course of the secondary infection is related to the gravity of the infected foci and the involved microorganisms. Contamination of the infusional fluid, the skin entry site, and some distant foci carry a real risk of seeding the catheter (from 5.8% to 19.5%). The cultures of the skin entry sites, infusional fluids, distant foci, and the subcutaneous segment of the catheter did not prove useful in predicting the infection. Only the blood cultures were a reliable diagnostic tool: a positive blood culture meant colonization of the catheter tip in 44% of cases and sepsis in 36%. Although the potential colonization varied greatly for different microorganisms, the growth of microorganisms in the blood was a strong indication for removing the cannula.