Patricia Ewalenko

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.

Isoflurane and desflurane impair right ventricular-pulmonary arterial coupling in dogs

Background:Halogenated anesthetics depress left ventricular function, but their effects on the right ventricle have been less well studied. Therefore, the authors studied the effects of isoflurane and desflurane on pulmonary arterial (PA) and right ventricular (RV) properties at baseline and in hypoxia. Methods:Right ventricular and PA pressures were measured by micromanometer catheters, and PA flow was measured by an ultrasonic flow probe. PA mechanics were assessed by flow–pressure relations and by impedance spectra derived from flow and pressure waves. RV contractility was assessed by end-systolic elastance (Ees), RV afterload was assessed by effective PA elastance (Ea), and RV–PA coupling efficiency was assessed by the Ees:Ea ratio. Anesthetized dogs were randomly assigned to increasing concentrations (0.5, 1, and 1.5 times the minimum alveolar concentration) of isoflurane (n = 7) or desflurane (n = 7) in hyperoxia (fraction of inspired oxygen, 0.4) and hypoxia (fraction of inspired oxygen, 0.1). Results:Isoflurane and desflurane had similar effects. During hyperoxia, both anesthetics increased PA resistance and characteristic impedance, increased Ea (isoflurane, from 0.82 to 1.44 mmHg/ml; desflurane, from 0.86 to 1.47 mmHg/ml), decreased Ees (isoflurane, from 1.09 to 0.66 mmHg/ml; desflurane, from 1.10 to 0.72 mmHg/ml), and decreased Ees:Ea (isoflurane, from 1.48 to 0.52; desflurane, from 1.52 to 0.54) in a dose-dependent manner (all P < 0.05). Hypoxia increased PA resistance, did not affect characteristic impedance, increased afterload, and increased contractility. During hypoxia, isoflurane and desflurane had similar ventricular effects as during hyperoxia. Conclusions:Isoflurane and desflurane markedly impair RV–PA coupling efficiency in dogs, during hyperoxia and hypoxia, both by increasing RV afterload and by decreasing RV contractility.

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

Abstract 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 α (rHuTNF-α) (4 mg). Bioactive TNF-α and interleukin 6 (IL-6) serum levels were measured serially, In the limb, TNF-α rapidly reached a plateau at 2 μ/ml, while IL-6 appeared later and progressively increased until the end of ILP. In the systemic circulation TNF-α 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-α infusion in ILP results in extremely high levels of bioactive TNF-α 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.

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.

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 hyperosmolar hyperglycemic, hypernatremic, and hypochloremic solution which may be a less effective volume expander than other albumin-containing solutions, due to its lower albumin content.

Is lumbar epidural analgesia an alternative in patients who have incomplete colonoscopy with standard premedication

Total colonoscopy is unsuccessful in about 10% of attempts. In three fourths of the cases, failure is due to the patients inability to tolerate the procedure and difficulty in negotiating the sigmoid colon. Lumbar epidural analgesia has been used in a series of 29 patients referred for total colonoscopy which had been unsuccessful using intravenous analgesia. The cecum was reached in 27 of 29 examinations. Mean time required to perform total colonoscopy was 10 min and took less than 5 min in one third of the cases. Complete visceral analgesia was responsible for one case of perforation.

La séedation et i’anesthésie pour i’endoscopie digestive

RésuméEn Belgique, la majorité des sédations pour endoscopies digestives est effectuée par l’endoscopiste. L’anesthésiste n’est généralement requis que pour des examens spéciaux, longs ou douloureux.L’utilisation correcte des benzodiazépines (BZD) et des opiacés nécessite la connaissance de leur pharmacologic Le diazepam (D) et le midazolam (M) procurent le même degré de sédation et de cooperation de la part du patient. Lorsqu’une seule dose équivalente est injectée, la recouvrance se fait dans un temps similaire, dépendant du temps de distribution (T 1/2 α D: 15-25 min; M: 14-18 min). Le M est 1,7 à 2 fois plus puissant que D, agit plus vite et est plus vite éliminé (T 1/2 β D: 25-50 H; M: 2-4 H). A doses répétées, le D agit plus longtemps, la recouvrance et les tests psychomoteurs sont davantage et plus longtemps perturbes. Son metabolite actif, le desméthyldiazepam a une longue 1/2 vie d’élimination (T 1/2 β 36-200 h). La dépression respiratoire est semblable pour les 2 drogues, trés marquee et de longue durée chez les patients souffrant d’affection respiratoire obstructive chronique. Le M déprime davantage le systéme cardiovasculaire. L’amnesie de type antérograde est plus marquée avec M.La péthidine est l’opiacé le plus communément utilisé par les endoscopistes. Elle déprime la respiration et le systéme cardiovasculaire de facon marquee. Son métabolite la norpéthidine, est un psychostimulant et un convulsivant.L’âge, le sexe, les antécédents, l’etat général (insuffisance hépatique, rénale, hypoprotéinémie, hypovolémic...) peuvent influencer la pharmacocinétique et la pharmacodynamic des BZD et des opiacés. La bonne connaissance du dossier du patient est done indispensable. Dans ce but, une solution concernant les patients ambulants est suggérée.Les antagonistes flumazénil et naloxone sont efficaces, mais donnent un sentiment de fausse sécurité, vu leur courte durée d’action.Certains opiacés puissants et de courte durée d’action (fentanyl, alfentanil), les anesthésiques généraux intraveineux (barbituri-ques, étomidate, propofol) ou par inhalation sont du domaine exclusif des anesthésiologistes. Parmi ces drogues, le propofol, par sa maniabilité et la qualité du réveil, est une drogue de choix, mais non dépourvue d’effets secondaires (apnée, dépression cardiovascu-laire). Les régies de sécurité appliquées au bloc opératoire doivent être respectées en salle d’endoscopie: surveillance du patient par une personne compétente, appareillage adéquat, source d’oxygéne, monitoring, matériel et drogues de réanimation cardiorespiratoire.Après ’intervention, le patient doit pouvoir bénéficier d’une surveillance dans une salle de réveil ou de repos avant que son retour en salle ou á domicile ne soit autorisé. Il ne peut ni conduire, ni manipuler de machines pendant 24 h. La responsabilité médico-légale de ’endoscopiste et de l’anesthesiste est rappelee.SummaryIn Belgium the great majority of sedations for GI endoscopies are performed by the endoscopist himself. The anesthesiologist is generally required for special, long or painful procedures.The proper use of benzodiazepines (BZD) and opiates depends on the knowledge of their pharmacology. Diazepam (D) and Midazolam (M) provide the same degree of sedation and cooperation from the patient.When one bolus of an equipotent dose is injected, recovery time is similar for both drugs, depending on the time of distribution (T 1/2 α D: 15-25 min; M: 14-18 min). M is 1.7 to 2 times more potent than D, its onset of action is shorter and it is rapidly eliminated ( T 1/2 β D: 25-50 H; M: 2-4 H). When larger or repeated doses of D are injected, recovery time is longer and psychomotor tests are more affected and delayed. Its active metabolite desmethyldiazepam has a long elimination half-line (T 1/2 36-200 h).Respiratory depression exists for both drugs, more pronounced and of greater duration in the COPD patient. Cardiovascular system is more depressed with M. Anterograde amnesia is more marked with M.Pethidine is the most commonly used opioid by endoscopists. Both respiration and cardiovascular system are markedly depressed. Its metabolite norpethidine is a psychostimulant and convulsivant drug.Age, sex, the medical history, the general status (hepatic and renal failure, hypoproteinemia, hypovolemia...) can influence the pharmacokinetics and the pharmacodynamics of BZD and opiates. The good knowledge of the patients record is thus mandatory. In this respect a solution for out- patients scheduled for endoscopy is suggested.The antagonists flumazenil and naloxone are effective but can give a false sense of security because of their short half-life. Some potent and short-acting opioids (fentanyl, alfentanil), general intravenous anesthetics (barbiturates, etomidate, propofol) or inhalational anesthetics are strictly reserved to anesthesiologists. Among these drugs, propofol seems to be a drug of choice: it can be used as repeated bolus or as a continuous infusion which can be easily modulated according to the desired depth of anesthesia. It is not devoid of adverse effects (apnea and cardiovascular depression). As the forensic responsability of the endoscopist and the anesthesiologist is involved, the safety rules recommended in the operating theater must be of application in the endoscopy room, which must be equipped with oxygen, suction, a good monitoring (EKG, pulseoxymeter, capnometer) a blood pressure monitor, all the material and drugs for CPR ressuscitation, an anesthesia machine if necessary, and first of all a trained person must take care of the patient during the procedure.After the procedure, the patient must be watched closely in a recovery or rest room before he is allowed to return to the ward or to leave the hospital. He is not authorized to drive or to operate machinery for 24 h.ResumenEn Belgica, la mayoria de les sedaciones en endoscopia digestiva son realizadas por los endospistas. El anesthesiologo es requerido en procedimientos especiales, largos o dolorosos.Para usar correctamente las Benzodiacepinas (BZD) y opiáceos es necesario el conocimiento de su farmacologiá. Diacepam (D) y Midazolam (M) tienes mismo-grado de sedatión y de cooperatión por parte del paciente. Quando se inyecta una sola dosis equivalente, la recuperatión es en tiempo similar, de-pendiendo del tiempo de distributión (t 1/2 α D: 15-25 min; M: 14-18 min). El MMZ es 1,7 a 2 veces mas potente que el D, actua mas rápido y es eliminado también más rapidamente (t 1/2 β D: 25-50 H; M: 2–4 H). Cuando se dan dosis repetidas, el D act mas tiempo, los test psicomotores tardan más en normalizarse. El desmethydiace-pam (metabolito activo de D) tiene una 1/2 vida eliminacion muy larga (T 1/2 β 36-200 H). La depresión respiratoria es identica para las dos drogas; mucho más marcada en aquellos pacientes afectos de BNCO. EI M deprime más el sisteme cardiovascular asi como tiene mayor poder de amnesia anterograda.La pethidina es el mórfico mas utilizado por los endoscopistas. Tiene una accion depresiva cardiovascular y respiratoria importante. La norpethidina (su metabolito) es psicoestimulante y convulsivante.La edad, sexo, antecedentes, estado general (Insuf. hepatica, renal, hipoproteinemia, hipovolemia...) pueden influenciar la farmacocinetica y farmacodinamica de las BZD y opiáceos. El buen conocimiento del dossier del paciente es indispensable. Con este objetivo hay que tomar soluciones con los pacientes ambulatorios.Los antagonistas flumazenil y naloxona son eficaces; pero dan la impresión de falsa seguridad en relatión con su corta acción.Algunos mórficos potentes y de corta acción (Fentanyl, alfentanil), los anesthesicos grales. Intravenosos (barbituricos, etomidato, propofol) ó inhalatorios son de uso exclusivo de los anesthesistes. Entre todas estas drogas, el propofol, por su manejabilidad, calidad del despertar, es de electión. Sin embargo no esta desprovista de efectos secundarios (apnéa, depression cardiovascular). Las reglas de seguridad aplicadas en quirofano tienen que serlo tambien en la sala de endoscopia: vigilancia por personal competente, monitorage adecuado, fúente O2, material y drogas para reanimación cardiorespiratoria.Al finalizar la interventión el patiente debe ser controlado en una sala de despertar antes de su vuelta a la habitatión o domicilio. Se le desautoriza a conducir o manipular máquinas durante 24 h. A tener en cuenta la responsabilidad médico-legal del anesthesiólogo y del endoscopista.

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.

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.

Evaluation of Serum Protein S-100 as a New Melanoma Marker

Protein S-100 is a calcium-binding protein composed of various associations of subunits α and β. The latter is present at high concentrations in the central nervous system which may explain its expression in other embryologically-related cells such as melanocytes.