Intravenous tramadol compared to propacetamol for postoperative analgesia following thyroidectomy.

We compared the efficacy and side effects of propacetamol (P), an injectable prodrug of acetaminophen, 2 g and tramadol (T), a weak synthetic opioid, 1.5 mg.kg-1, given intravenously following thyroidectomy. 80 patients were randomly assigned to blindly receive one dose of P or T on request in the PACU. Residual pain was treated with i.v. PCA morphine. Pain and patient satisfaction were assessed with Visual Analog Scales. Demographic and peroperative data were comparable in both groups. Although the morphine consumption was comparable (p = 0.71), the decrease in VAS pain scores was significantly higher following tramadol (p = 0.03). More patients complained of nausea and vomiting (p = 0.01) during the first two hours following injection of tramadol, but there was no difference throughout the whole study. Oversedation was not observed in any group. We conclude that a single dose of tramadol provides a better quality of analgesia than propacetamol during the first six hours after thyroidectomy, but fails to ensure optimal analgesia, since VAS pain scores failed to fall below 3 despite the use of supplemental morphine.

Predictive accuracy of target-controlled propofol and sufentanil coinfusion in long-lasting surgery.

BACKGROUND: The predictive accuracy of target concentration infusions of propofol has been documented only for less than 4 h, and no prospective study of sufentanil target controlled infusion is available. The authors investigated the predictive accuracy of pharmacokinetic models for propofol and sufentanil coadministered during long-lasting surgery. METHODS: Ten patients, American Society of Anesthesiologists physical status I and II, were studied during extended cervicofacial surgery. Target controlled infusion of propofol and sufentanil was administered during surgery using decisional algorithms, taking into consideration pain assessment, hemodynamic changes, and peroperative blood losses. Intrasubject data analysis included calculation of performance error, median performance error, median absolute performance error, divergence, and wobble. RESULTS: The range of plasma target concentrations was 2-5 microgram/ml for propofol and 0.2-1 ng/ml for sufentanil. Median performance error was -12.1% for propofol and -10% for sufentanil. The wobble values were 11.6% and 22.3% for propofol and sufentanil, respectively. The pharmacokinetic sets used slightly overpredicted the concentrations, with negative values of divergence of 2.92% and 0.22% units/h for propofol and sufentanil, for a mean infusion period of 762 min. CONCLUSIONS: This prospective study demonstrates the predictive accuracy of the pharmacokinetic model for sufentanil infusion and confirms that for propofol during long-lasting surgery using standardized rules for the management of target controlled infusion and blood loss replacement.

Comparison of the effects of isoflurane with those of propofol on pulmonary vascular impedance in experimental embolic pulmonary hypertension.

Inhaled but not i.v. anaesthetics are reported to decrease pulmonary vascular resistance. The aim of this study was to compare the effects of isoflurane with those of propofol on the interaction between right ventricular (RV) function and the pulmonary vascular system in embolic pulmonary hypertension. Nine dogs received in random sequence propofol 18 mg kg-1 h-1 and 1.4% end-tidal isoflurane. Pulmonary haemodynamic state was evaluated by pulmonary arterial pressure/flow (PAP/Q) plots and pulmonary vascular impedance (PVZ) spectra. Right ventricular function was assessed by total hydraulic power (Wtot), ratio of oscillatory power (Wosc) to Wtot, and dP/dtmax. Measurements were obtained, with both anaesthetics, before and after pulmonary embolic hypertension induced by autologous blood clots. Embolism increased PAP, 0 Hz and low frequency input impedance, displaced first minimum of PAP/Q moduli and zero crossing of phase to higher frequencies, decreased characteristic impedance, decreased Wosc/Wtot without affecting Wtot, and increased dP/dtmax. Compared with propofol, isoflurane at baseline did not affect PAP/Q plots, PVZ or hydraulic power data, but decreased dP/dtmax. After embolism, isoflurane shifted PAP/Q plots to lower PAP without affecting PVZ, did not affect hydraulic power data and decreased dP/dtmax. We conclude that in canine embolic pulmonary hypertension, isoflurane compared with propofol impeded RV vascular coupling caused by decreased RV contractility, while after-load remained unchanged despite some decrease in pulmonary vascular tone.

Antiemetic effect of subhypnotic doses of propofol after thyroidectomy.

Postoperative nausea and vomiting (PONV) are unpleasant, often underestimated side effects of anaesthesia and surgery, not devoid of medical complications. Prevention with antiemetics is only partially effective. Propofol has been shown recently to possess antiemetic properties in several situations. In this prospective, randomized, controlled trial, we have compared the antiemetic efficacy of subhypnotic doses of propofol, with Intralipid as placebo, after thyroidectomy. We studied 64 patients of both sexes, aged 22-71 yr, ASA I or II, undergoing thyroidectomy. After premedication with a benzodiazepine, balanced anaesthesia was produced with isoflurane and nitrous oxide in oxygen, and supplementary analgesia with fentanyl i.v. as required. Postoperative analgesia was provided with non-opioids, and piritramide 0.25 mg kg-1 i.m. on demand. Patients were allocated randomly and blindly to receive a 20-h infusion of either propofol or 10% Intralipid 0.1 ml kg-1 h-1. Intralipid, the excipient of propofol, was chosen as placebo as it is devoid of antiemetic effects. Sedation scores, respiratory and cardiovascular variables, and incidence of PONV were assessed every 4 h for 24 h. Pulse oximetry and ECG were monitored continuously. Both groups were comparable in characteristics, surgical and anaesthesia procedures, amount of opioids given during and after operation, and total amount of the study drug infused after operation. Occurrence of PONV was similar before the start (propofol 41%, Intralipid 50%) and after completion (propofol 0.64%, Intralipid 1.6%) of infusion and decreased with time in both groups during the infusion. However, symptoms were reduced to nil with propofol but persisted and were more severe with Intralipid during infusion (P < or = 0.01). The overall incidence of PONV during infusion was 10% (three of 32 patients) in the propofol group and 65% (21 of 32 patients) in the Intralipid group. Cardiovascular and respiratory variables, and SpO2 were unaltered, and sedation decreased similarly with time in both groups. We conclude that propofol, given at subhypnotic doses, effectively reduced the incidence of PONV without untoward sedative or cardiovascular effects.

Pulmonary vascular impedance vs. resistance in hypoxic and hyperoxic dogs: effects of propofol and isoflurane.

The pulmonary vascular effects of inhaled anesthetics have been reported variably. We compared the effects of intravenous anesthesia (propofol) and inhalational anesthesia (isoflurane) on multipoint mean [pulmonary arterial pressure (Ppa)-pulmonary arterial occluded pressure (PpaO)]/cardiac output (Q) plots and on pulmonary vascular impedance (PVZ) spectra in eight dogs alternatively ventilated in hyperoxia [inspired O2 fraction (FIO2) 0.4] and in hypoxia (FIO2 0.1). Q was altered by a manipulation of venous return. During propofol, hypoxia increased (Ppa-PpaO) by an average of 2-3 mmHg over the entire range of Q studied, from 1 to 2.5 l.min-1 x m-2. This hypoxic pulmonary vasoconstriction (HPV) was associated with insignificant changes in PVZ. Decreasing Q in hypoxia and hyperoxia did not affect PVZ. Compared with propofol, isoflurane decreased (Ppa-PpaO) by an average of 2-5 mmHg at all levels of Q studied in both hypoxia and hyperoxia but did not affect HPV. During isoflurane anesthesia, 0 Hz PVZ was lower (P < 0.01) in hypoxia, but otherwise the PVZ spectrum was not different from that recorded during propofol anesthesia. We conclude that, in dogs, 1 degree general anesthesia with isoflurane alone decreases pulmonary vascular tone without inhibition of HPV and that 2 degrees pressure/Q plots in the time domain are more sensitive than those in the frequency domain to subtle hemodynamic changes induced by hypoxia or isoflurane at the periphery of the pulmonary vasculature.

Wound dressing in major head and neck cancer surgery: a prospective randomized study of gauze dressing vs sterile vaseline ointment.

A total of 207 patients were randomized in a prospective comparative study of standard gauze dressing vs sterile vaseline ointment. 179 patients were evaluable. All patients received antimicrobial prophylaxis. The two groups (86 standard and 93 vaseline) were comparable as far as age (mean, 57 yr; range, 21-84), genders (155 males/24 females), weight (mean, 66 kg; range, 40-69), type of surgery, previous or concomitant anticancer treatment. Severity of surgery was identical, as was the severity of cancer, in the two groups. Wound infection within 20 days of surgery occurred in 31.2% (29/93) of the vaseline group and 24.4% (21/86) in the standard group (NSS). Bacteremia occurred in three patients from the vaseline group and in four patients from the standard group. Bronchopneumonia occurred in 10 patients from the vaseline group and 14 patients in the standard group. The spectrum of microorganisms recovered was similar in the two groups. The need for antimicrobial treatment (empiric or for documented infections) within 20 days after surgery was 34.4% (32/93) in the vaseline group and 36.0% (31/86) in the standard group. The median delay to infection (range in days) in the vaseline group was 9 (5-15) for wound and 6 (1-12) for bronchopneumonia. For the standard group the corresponding delays were 8 (4-15) and 7 (2-19). Vaseline dressing was not associated with an increased risk of infection as compared to the standard gauze dressing.

High serum levels of TNF-alpha after its administration for isolation perfusion of the limb.

In a phase II study, 18 patients with locally spreading melanoma or sarcoma of lower limb were treated by isolation perfusion (ILP) with hyperthermia and local infusion of high dose of recombinant human tumor necrosis factor alpha (rHuTNF-alpha) (4 mg). Bioactive TNF-alpha and interleukin 6 (IL-6) serum levels were measured serially. In the limb, TNF-alpha rapidly reached a plateau at 2 mu/ml, while IL-6 appeared later and progressively increased until the end of ILP. In the systemic circulation TNF-alpha rose up to a median concentration of 31 ng/ml after 1 hour, then decreased and became negligible after 6 hours. IL-6 peaked only after 5 hours after start of ILP (median: 36.7 ng/ml). In patients with substantial leakage towards systemic circulation, both cytokines peaked higher and earlier as compared with patients with minimal leakage. No correlation was found between cytokine levels and severity of side effects which in all cases were reversible. We conclude that high dose TNF-alpha infusion in ILP results in extremely high levels of bioactive TNF-alpha in the systemic circulation without irreversible side effect, and provokes a delayed blood release of large amounts of IL-6; there was a correlation between leakage from the limb during procedure and the magnitude of systemic cytokines levels.

Antimicrobial prophylaxis for major head and neck surgery in cancer patients: sulbactam-ampicillin versus clindamycin-amikacin.

A total of 99 patients with head and neck cancer who were to undergo surgery were randomized in a prospective comparative study of sulbactam-ampicillin (1:2 ratio; four doses of 3 g of ampicillin and 1.5 g of sulbactam intravenously [i.v.] every 6 h) versus clindamycin (four doses of 600 mg i.v. every 6 h)-amikacin (two doses of 500 mg i.v. every 12 h) as prophylaxis starting at the induction of anesthesia. The two groups of evaluable patients (43 in the clindamycin-amikacin treatment group and 42 in the sulbactam-ampicillin treatment group) were comparable as far as age (mean, 57 years; range, 21 to 84 years), sex ratio (71 males, 28 females), weight (mean, 66 kg; range, 40 to 69 kg), indication for surgery (first surgery, 48 patients; recurrence, 37 patients), previous anticancer treatment (surgery, radiation therapy, chemotherapy), type of surgery, and stage of cancer. The overall infection rate (wound, bacteremia, and bronchopneumonia) within 20 days after surgery was 20 patients in each group. Wound infections occurred in 14 (33%) sulbactam-ampicillin-treated patients and 9 (21%) clindamycin-amikacin-treated patients (P = 0.19; not significant). The rates of bacteremia were 2 and 4%, respectively. The rates of bronchopneumonia were 14.3 and 23.2%, respectively (P was not significant). Most infections were polymicrobial, but strict anaerobes were recovered only from patients who received sulbactam-ampicillin. Antimicrobial treatment was required within 20 days after surgery for 42% of the sulbactam-ampicillin-treated patients and 44% of the clindamycin-amikacin-treated patients. By comparison with previous studies, we observed a decreased efficacy of antimicrobial prophylaxis in patients with head and neck cancer undergoing surgery because of the increased proportion of patients who were at very high risk for infection (extensive excision and plastic reconstruction in patients with recurrent stage III and IV cancers) and because of the longer duration of surgery.

In transit metastases of malignant melanoma treated by high dose rTNF alpha in combination with interferon-gamma and melphalan in isolation perfusion.

To increase the therapeutic efficacy of recombinant tumor necrosis factor alpha (rTNF alpha) and reduce the systemic side effects, a protocol was designed using isolation perfusion of the limbs with hyperthermia for in transit metastases of melanoma. A triple combination of high dose rTNF alpha + recombinant interferon-gamma (rIFN-gamma) + melphalan was chosen because of a synergistic anti-tumor effect of rTNF alpha with rIFN-gamma and of rTNF alpha with alkylating agents reported in the literature. Twenty-nine patients of mean age 60 years (range 22-82 years) entered the study after informed consent and received a total of 31 isolation perfusions with the triple combination. There were 24 women and 5 men with multiple progressive in transit melanoma metastases of the lower limb (stage IIIa or IIIab). rTNF alpha at the unique dose of 4 mg was injected as a bolus in the arterial line, under mild hyperthermic conditions (40 to 40.5 degrees C) for 90 minutes. rIFN-gamma was given subcutaneously on days -2 and -1 and in the perfusate, with rTNF alpha, at the dose of 0.2 mg. Melphalan was administered in the perfusate at dose giving a concentration of 40 micrograms/ml. In all the 31 isolation perfusions performed in the triple combination protocol, in order to prevent a septic shock-like syndrome which had been encountered in 2 patients treated outside this protocol for sarcoma and carcinoma, the patients received dopamine continuous infusion at 3 micrograms/kg/min from the start of isolation perfusion and for 48 hours, and only showed mild hypotension and very transient chills and temperature.(ABSTRACT TRUNCATED AT 250 WORDS)

High-dose recombinant tumor necrosis factor alpha in combination with interferon gamma and melphalan in isolation perfusion of the limbs for melanoma and sarcoma.

PURPOSE: To determine the toxicity and the therapeutic efficacy of the combination of the recombinant tumor necrosis factor alpha (rTNF alpha), recombinant interferon gamma (rIFN-gamma), and melphalan, we designed a protocol using isolation limb perfusion (ILP) with hyperthermia for in-transit metastases of melanoma and recurrent sarcoma. The triple combination was chosen because of the reported synergistic antitumor effect of rTNF alpha with IFN-gamma and of rTNF alpha with alkylating agents. PATIENTS AND METHODS: Twenty-three patients received a total of 25 ILPs with the triple combination. There were 19 females and four males with either multiple progressive in-transit melanoma metastases of the extremities (stage IIIa or IIIab; 19 patients) or recurrent soft tissue sarcoma (five). The rTNF alpha was injected as a bolus in the arterial line, and total dose ranged between 2 and 4 mg, under hyperthermic conditions (40 degrees C to 40.5 degrees C) for 90 minutes. The rIFN-gamma was given subcutaneously (SC) on days -2 and -1 and in the perfusate, with rTNF alpha at the dose of 0.2 mg. Melphalan (Alkeran; Burroughs Wellcome Co, London, England) was administered in the perfusate at 40 micrograms/mL. RESULTS: Toxicity observed during three ILPs in a pilot study with rTNF alpha included only two severe toxicities: one severe hypotension with tachycardia and transient oliguria and one moderate hypotension for 4 hours followed by severe kidney failure with complete recovery on day 29. In all 18 ILPs performed in the triple combination protocol, the patients received continuous infusion dopamine at 3 micrograms/kg/min from the start of ILP and for 72 hours and showed only mild hypotension and transient chills and temperature. Regional toxicity attributable to rTNF alpha was minimal. There have been 11 cases with hematologic toxicity consisting of neutropenia (one grade 4 and one grade 3) and neutropenia with thrombocytopenia (one grade 4 and three grade 2). Twelve patients had been previously treated with melphalan in ILP (11) or with cisplatin (one). The 23 patients are assessable: there have been 21 complete responses (CRs; range, 4 to 29 months; 89%), two partial responses (PRs; range, 2 to 3 months), and no failures. Overall disease-free survival and survival have been 70% and 76%, respectively, at 12 months. In all cases, softening of the nodules was obvious within 3 days after ILP and time to definite response ranged between day 5 and 30. CONCLUSION: This preliminary analysis of a phase II study suggests that high-dose rTNF alpha can be administered with acceptable toxicity by ILP with dopamine and hyperhydration. Tumor responses can be evidenced in melanoma and sarcoma. Furthermore, combination of rTNF alpha, rIFN-gamma, and melphalan seems to achieve high efficacy with minimal toxicity, even after failure of prior therapy with melphalan alone.

Propofol infusion with or without fentanyl supplementation for microlaryngoscopy.

20 patients (ASA I to III) scheduled for microlaryngoscopy were randomly allocated to receive by infusion either 12-15 mg/kg/h propofol alone (group A) or 6-9 mg/kg/h with fentanyl supplementation (group B). All patients were premedicated with oral diazepam one hour before the procedure; they received an induction dose of 2 mg/kg propofol, preceded in group B by a bolus dose of fentanyl 1 microgram/kg. Significant hypotension was observed at induction in both groups to a similar degree (A:--26%; B:--30.2% compared to baseline). Placement of the laryngoscope induced sustained hypertension throughout the procedure in both groups (A: +28%; B: +20%) subsiding only at the removal of the instrument. Heart rate was never significantly altered. Arterial blood concentrations of propofol at induction reached high peak values (A: 16.82 +/- 8.52 micrograms/ml--B: 19.52 +/- 8.87 micrograms/ml--mean +/- SD) then remained stable throughout the procedure (A: 5.44 +/- 1.40 micrograms/ml--B: 2.91 +/- 1.06 micrograms/ml). At awakening, they were lower in group B (0.62 +/- 0.2 micrograms/ml) than in group A (1.17 +/- 0.55 micrograms/ml--p less than 0.05). Recovery was a little faster in group A (at the limit of significance). Though patients may present some excitation at awakening, recovery was usually very pleasant and characterized by swift return to consciousness, alertness and of all reflexes. We conclude that a propofol infusion is particularly suitable for microlaryngeal surgery. The addition of a narcotic agent allows reduction of the propofol dose range and does not alter recovery significantly. The proper dose of narcotic agent necessary to abolish cardiovascular reactivity to laryngoscopy must still be ascertained.

Results of 206 isolated limb perfusions for malignant melanoma.

Between 1976 and 1988, 182 patients--135 females (74.3%) and 47 males (25.7%)--were submitted to 206 isolation perfusions, using melphalan and mild hyperthermia for 34 upper and 172 lower limbs. Stage I melanoma represented 37.4% including 75.4% greater than 1.5 mm Breslow thickness or with regression, ulceration or incisional biopsy. Stage II melanoma included 62.6% of the cases. Peri-operative mortality occurred in 2/182 patients. Amputation was performed within 1 month for toxic reasons in three patients and delayed in six for progressive disease. Regional toxicity consisted in oedema (76%), pain (61%), nerve palsy (24%), thrombosis (7%), septicemia (3%), thrombocyto-granulopenia (1.5%), minor miscellaneous (52%). Mean peripheral leakage was 1.0, 7.8 and 12.4% at respectively 5, 10 and 60 minutes. Projected 5-year disease-free survival was 79% for Stage I and 27% for Stage II. Survival at 5 years was 92% in Stage I and 53.5% in Stage II. Twenty-five patients were perfused twice for recurrence or incomplete response. Although the median disease-free interval was only about 8 months, the 5-year survival was 67%. This may indicate that isolation perfusion renders melanoma metastases less aggressive despite the fact they may recur at a high rate.

[Peroperative radiotherapy]. / La radiothérapie per-opératoire.

Tolerance of normal tissues limits the radiation dose which can be safely delivered to tumors especially for gastro-intestinal cancers. Intraoperative radiotherapy is a specialized technique for treating infradiaphragmatic and deeply located tumors allowing to deliver a high dose to the tumor while avoiding surrounding normal tissues which can be moved aside. The authors describe the technique and review indications and possibilities.

Production of interleukin 1 by activated blood monocytes and alveolar macrophages from melanoma patients.

The production of Interleukin 1 (Il1) by circulating blood monocytes and alveolar macrophages was studied in melanoma patients. There were 144 patients in the monocytes study and 5 patients in the alveolar macrophages study. The Il1 activity was tested by a bioassay and reported in units based on the integration of the area under the curve. This was shown to be preferable to the standard method, i.e. probit analysis. Results showed that there was no depression of Il1 activity in melanoma patients as compared to control (98 + 32 units, versus 100 units). There was no difference when the values were compared according to sex, age and stage of the disease. However, a significant difference was found between phototype I and phototype IV. Alveolar macrophages, in all experiments (n = 5), had a significantly lower Il1 activity than the autologous monocytes. It is concluded that we can question the relevance of Il1 production by peripheral blood monocytes to the state of the immunity of melanoma patients.

Composition of fresh frozen plasma.

We analyzed 35 samples of fresh frozen plasma (FFP), finding mean concentrations of 535 mg/dl glucose, 172 mEq/L sodium, 73 mEq/L chloride, 3.5 mEq/L potassium, 15 mEq/L bicarbonate, and 5.5 g/dl protein with 60% albumin. Thus, FFP is a hyperosmolal, hyperglycemic, hypernatremic, and hypochloremic solution which may be a less effective volume expander than other albumin-containing solutions, due to its lower albumin content.

Production of the effector molecule thymidine by human lung alveolar macrophages.

Cultured human alveolar macrophages (HAM phi) were found to produce soluble factors which inhibit tritiated thymidine [( 3H]-TdR) incorporation into tumour cells in vitro. We present evidence that thymidine (TdR) can be detected in HAM phi culture supernatants by thin-layer chromatography. Moreover, TdR secretion by HAM phi is an active process. Using [6-14C]-orotic acid as an early precursor to TdR and [3H]-TMP as the phosphorylation product, we were able to show that cultured HAM phi transformed them into labelled TdR. The very efficient thin-layer chromatography of the labelled metabolites was backed up by high-pressure liquid chromatography of nucleotides. HAM phi produce TdR by de novo synthesis and dephosphorylation. This phenomenon is due to the lack of thymidine kinase in normal mature macrophages. Since TdR, in high concentrations, can inhibit DNA synthesis through the 'TdR blockade' phenomenon, it is suggested that TdR secretion by HAM phi is a mechanism of non-specific modulation of tumour cell growth but highly restricted to the immediate macrophage microenvironment in vivo. The effectiveness of the thymidine gradient may thus be quite narrow, but is worthy of interest.