Multimodal approach to therapy-related neuropathic pain in breast cancer.

PURPOSE: This study evaluated the effects of the multimodal therapy (gabapentin-non steroidal anti inflammatory drug [NSAID]-morphine) on intensity and relief of treatmentrelated neuropathic pain in patients with breast cancer. METHODS: This study involved 75 breast cancer outpatients who had previously undergone anti-neoplastic therapy (surgery, chemotherapy, radiotherapy). The patients were randomly divided into 3 groups, which were formed depending on the planned analgesic therapy (gabapentin, gabapentin- NSAID, gabapentin-NSAID-morphine). Each group was a control group to itself. The pain intensity difference and scores of daily activities were collated and assessed by the modified Brief Pain Inventory (BPI) questionnaire (VAS/Likert Scale). Monitoring the additional medication and side effects optimized the therapy efficiency evaluation. RESULTS: During this 6-week study, the decrease of pain intensity was significant in all 3 groups (p <0.0001). Although there was intergroup difference, it was statistically not significant (p >0.05). The variant analysis of pain relief showed differences both among and within the groups in the first 3 weeks of the study (F(1)=7.79, p=0.000; F(2)=7.01, p=0.001; F(3) =5.49, p=0.001). The multimodal group needed the least of additional medication and the variant analysis showed a statistically significant difference (p=0.001) from the 4th week of the trial period. The correlation between the increase trend of side effects and the frequency of additional medication was significant (p <0.05). CONCLUSION: The multimodal therapy ensures adequate cancer-related neuropathic pain control with minimal side effects.

Influence of bile acid derivates on tramadol analgesic effect in mice.

Influence of two newly synthesized bile acids derivates, namely sodium salt of monoketocholic acid MKH-Na and methyl ester of monoketocholic acid MKH-Me on tramadol (12.5 mg/kg oral and intramuscular) analgesic effect was examined in this research. Analgesic effect was measured by antinociceptive hot plate method. Interaction was estimated by detection of changes in analgesic effect of tramadol combined with bile acids (subcutaneous administration of 4 mg/kg 20 min before tramadol) compared to analgesic effect of the same dose of tramadol given alone. Hydrosoluble sodium salt of monoketocholic acid did not show interaction with tramadol, regardless of the route of administration of tramadol. However, methyl ester of monoketocholic acid increased the analgesic effect of tramadol when it was given intramuscularly. After oral administration of tramadol, methyl ester of monoketocholic acid decreased the analgesic effect of tramadol. According to the time point when interaction reached statistically significant difference, it can be presumed that after intramuscular administration of tramadol, methyl ester of monoketocholic acid increases tramadol absorption and transport to brain and in that way increases its analgesic effect. The analgesic effect of tramadol after oral administration was decreased, which could be explained by the induction of tramadol metabolism in the liver, but should be examined in more details.

Clinical efficacy of goserelin (Zoladex) in the treatment of uterine myomas in infertile patients.

This study investigated the efficacy of Zoladex depot 3.6 mg (goserelin acetate) during a 4-month treatment of infertile patients with uterine myomas of different size and location. The investigation comprised 30 patients aged 22-42 years, distributed into 2 groups regarding uterine and myoma volume. The first group included patients with uterine myomas less than 70 ml and uterus less than 300 ml. The second group included patients in whom these volumes exceeded the above mentioned values. Zoladex depot was administered every 28 days for 4 months with ultrasonographic follow-up of volume decrease, whereas patients with submucous myomas underwent control hysteroscopy. The obtained results point to efficacy of Zoladex in decreasing the volumes of both myomas and uterus by more than 50%, which correlates with literature data. Of particular interest is complete disappearance of myomas in about 60% of patients of the first group. Serum concentrations of follicle stimulating hormone (FSH), luteinizing hormone (LH) and estradiol (E2) were followed-up prior to and during Zoladex therapy where multivariate variance analysis showed statistically significant differences. The side effects were recorded and are similar to those of other GnRH analogues.

[Prevention of multiple organ dysfunction syndrome in severely injured patients--current approach]. / Prevencija sindroma multiple organske disfunkcije tesko traumatizovanih pacijenata--savremeni pristup.

INTRODUCTION: Multiple organ dysfunction syndrome (MODS) is frequent after trauma. Predisposing factors for MODS after trauma are: hypovolemic shock, massive volume replacement, time of resuscitation before hospitalization, systemic inflammatory response syndrome, infection, sepsis. Prevention of tissue hypoxia is a priority in prevention of MODS. MONITORING THE ADEQUACY OF TISSUE OXYGENATION: Assessment of tissue oxygenation and potential hypoxia is indirect, based on measuring aspects of whole body oxygen transport and uptake, some regional parameters and indirect biochemical markers. Assessing oxygen transport involves: clinical evaluation of the patient, delivery of oxygen to the alveoli, oxygenation of arterial blood, delivery of oxygen to the tissues (DO2), oxygen uptake (VO2), oxygenation of the mixed venous blood, lactate and assessment of regional PCO2 or pH. THERAPEUTIC PRINCIPLES: Haemodynamic optimization for improvement of perfusion and tissue oxygenation is of primary importance. Nutritional support antibiotic prophylaxis, pain relief, sedation and other therapeutic modalities allow patient to survive a trauma and decrease risk of systemic complications. CONCLUSION: Tissue hypoxia and oxygen debt in injured patients are major factors which determine development of MODS. Prevention of MODS starts with respiratory and circulatory resuscitation and monitoring of tissue oxygenation prehospitally and hospitally. The first line therapy, "goal directed therapy" is not obligatory. Nutritional support, antibiotic therapy, analgesia, sedation and other therapeutic modalities contribute the ability of injured patients to survive and decrease the incidence of MODS.

[Preemptive analgesia in cholecystectomy using pethidine]. / Preemptivna analgezija petidinom u holecistektomiranih pacijenata.

INTRODUCTION: Preemptive analgesia given before noxious stimulation prevents or reduces subsequent pain. Pain associated with central sensitization is called pathological pain. Preemptive analgesia could be defined as analgesia that prevents the development of pathological pain. The clinical significance of central sensitization lies in prediction that preemptive analgesia may prevent the establishment of central sensitization and reduce pain experienced following peripheral injury. Various pharmacological agents and methods have a potential in prevention of acute postoperative pain by blocking the somatosensory system and abolishing hypersensitivity. But the role of preemptive analgesia in postoperative pain is still controversial. The goal of the present study was to examine whether pethidine administration before skin incision is more effective in reducing postoperative pain than the same dose of pethidine given intraoperatively. MATERIAL AND METHODS: Thirty patients (ASA 1 to 2), aged from 40 to 65 years, admitted for elective laparotomic cholecystectomy entered the study. Group 1 (n = 15) received 1 mg/kg of pethidine i.v. 5 minutes before induction of anaesthesia (before skin incision) and 0.9% NaCl of equal volume intraoperatively (after peritoneal opening). Group 2 (n = 15) received pethidine and 0.9% NaCl in a reverse manner. Premedication was omitted. No other analgesics were administered at induction and intraoperatively. Anaesthesia was induced with midazolam, thiopentone and succinylcholine for tracheal intubation. Pancuronium was administered for muscle relaxation and halothane with O2/N2O for maintenance of anaesthesia. The duration of surgery (time from skin incision to skin closure) and time from skin closure to the first analgesic request were measured and recorded. In the ward, patients were given metamizol (2500 mg) i.m. at request during the first 12 h. If the regimen was not sufficient, piritramide (2 mg) i.m. was given at request. The intensity of pain was estimated before the first analgesic request and 4, 8, 12 and 24 h thereafter. Pain scores were recorded using VAS (0 = no pain; 10 = worst pain). Data are presented as mean values with their standard deviations and as the ranges of each parameter. The differences in data between two groups were evaluated with Student's t-test. P > 0.05 was considered statistically significant. RESULTS: Demographic data, duration of surgery and time from skin closure to the first analgesic request are presented in Table 1. No significant difference was found between the two groups. The postoperative analgesic requirements in two groups were similar and piritramide requirement was omitted. VAS scores at each time (Table 2) did not differ between the two groups. DISCUSSION: The findings of many clinical investigations remain controversial. Some clinical studies comparing the same analgesic intervention before and after the painful stimulus have shown a benefit of preemptive analgesia. The results of our study did not show a significant difference in pain scores neither in analgesic requirements of patients who received systemic pethidine before the painful stimulus compared with the patients treated with the opioid intraoperatively. However, epidural opioid administration may be more effective (17,18). It is important to say that inhalational anaesthetics, including N2O and some i.v. anaesthetic agents may have preemptive effects themselves, significantly reducing spinal sensitization (19,20). In clinical studies when the preemptive effect of analgesics is under investigation, inhalational and i.v. anaesthetics which are administered to induce and maintain anaesthesia are given before surgery. Therefore development of central sensitization may be attenuated or prevented by the anaesthetics overlapping the preemptive effect of analgesics. CONCLUSION: The results of this study did not demonstrate a preemptive effect of pethidine. (ABSTRACT TRUNCATED)

[Sedation and analgesia in intensive therapy]. / Sedacija i analgezija u intenzivnoj terapiji.

INTRODUCTION: In the operating room, anaesthetist must provide unconsciousness, analgesia and muscular relaxation. In intensive therapy (IT), the rules are different and not every patient requires sedation, but almost every patient needs analgesia. The patient who is alert, calm and comfortable despite the presence of tubes and cannulas in the nose, mouth, radial artery, central vein, urethra, surgical wounds, pleural space etc. does not need any sedation. However, sedation and analgesia are clinically inseparable. If mechanical ventilation is not well controlled, muscular relaxants must be prescribed. There are a lot of trials in formulating an ideal sedative/analgesic regimen for each individual patient. THE RISKS OF SEDATION AND ANALGESICS: It is not rare that IT patients are oversedated or undersedated. Undersedation is followed by anxiety, pain, hypertension, tachycardia. The most important effect of oversedation is respiratory depression, hypotension, bradycardia, CNS depression, renal dysfunction, immunological depression. SEDATIVES AND HYPNOTICS: Benzodiazepines are among the most widely used drugs in IT. They have sedative, hypnotic, anxyolytic, amnestic, anticonvulsant and myorelaxant effects. Prolonged continuous infusion of benzodiazepines ought to be escaped because of prolonged sedation, accumulation and presence of pharmacologically active metabolites. They have proved to be safe, although they can depress ventilation. Since benzodiazepines are not analgesics, the combined use of an opioid and benzodiazepines is necessary. Many different benzodiazepines are available, but the agents most commonly used in critically ill are: midazolam, diazepam and lorazepam. Midazolam is the most extensively used. PSYCHOTROPIC DRUGS: The most frequently used drugs in the group of the butyrophenones are droperidol and haloperidol. Although these drugs are chemically unrelated to the phenothiazines they have similar actions. ANALGESICS: Opioids have the main place in management of analgesia in IT, especially in patients on mechanical ventilation. In management of postoperative analgesia, epidural route has advantage because less drug is necessary and cardiovascular and respiratory effects are minimal. Morphine is a standard opioid to which all others are compared. Intravenous bolus dose is 1-5 mg (0.1-0.15 mg/kg) or continuous infusion 2-15 mg/h. Hypotensive effect is caused by direct vasodilation and relief of histamine. Morphine has long elimination half-time and there is a danger of acummulation after prolonged administration. Morphine metabolites are pharmacologically active and renally eliminated. Prolonged i.v. infusion needs careful titration because of tolerance. Pethidine is less potent than morphine, usually given as a bolus dose (10 mg) or a continuous i.v. infusion (10-20 mg/h). Other opioid agents used in IT are: fentanil, alfentanil, sufentanil. Non-steroidal anti-inflammatory drugs (NSAID-s) are: aspirin, ibuprofen, ketoprofen, diclofenac, ketorolac. NSAID-s may have an opioid sparing effect and be of particular benefit for the relief of pain from bones and joints. They interfere with the metabolism at the site of the sensory nerve terminals. Several chemicals are released locally in response to tissue injury. Arachidonic acid is produced from damaged cell membranes. One series reactions is mediated by the enzyme cyclo-oxygenase (COX) and results in the formation of prostaglandins, prostacyclins and thromboxane. The cyclo-oxygenase pathway is inhibited by NSAID-s. These analgesics, besides peripherally, also work centrally by mechanisms which are not in connection with COX inhibition. INTRAVENOUS AND INHALED ANAESTHETIC AGENTS: There are two barbiturates in use: thiopentone and pentobarbital. Although the main effect is hypnosis, the most important is anticonvulsant effect. Thiopentone is an agent for cerebral protection. Barbiturates have not achieved popularity in IT because of prolonged elimination and slow recov

[Regional technics for postoperative analgesia]. / Regionalne tehnike za postoperativnu analgeziju.

Postoperative analgesia has been neglected for a long time, whereas postoperative pain has been considered inevitable cost of operations. Postoperative pain causes not only subjective difficulties, but as a stress factor affects functions of the autonomous and endocrine system, which may cause a number of disorders after the surgery. Advances in anesthesiology have contributed to increased role of anesthesiologists in application of regional techniques for postoperative pain. This paper describes regional techniques for postoperative analgesia: epidural, spinal analgesia, intercostal, paravertebral, interpleural, plexus blockade, peripheral nerve blockade and infiltrative local analgesia. Advantages and disadvantages of these techniques in regard to traditional method of parenteral analgesia in the postoperative period have been pointed out. Application of regional analgesia is recommended before the surgery, because it prolongs the time when analgesia is needed for the first time and decreases both pain and postoperative analgesia.

[Infertility and endometriosis]. / Infertilitet i endometrioza.

The goal of this study was to set the relation between infertility and endometriosis. It included 500 infertile female patients who underwent laparoscopy in order to find out the cause of infertility. The prevalence of endometriosis in these patients was 26%, that is significantly higher than in the control group which consisted of 200 randomly chosen fertile women in whom prevalence of endometriosis was 5%. Patients with endometriosis mainly belong to the group of 25-29 years of age with a median duration of infertility of 2-4 years. Endometriosis occurs three times more often in the group of patients with primary sterility than in patients with secondary sterility. Majority of patients (71.5%) are with minimal or mild endometriosis.

[Nutritional status in women and estrogen production in surgical menopause]. / Uhranjenost zena i produkcija estrogena u hirurskoj postmenopauzi.

The objective of this study was to examine how nutritional status, in women with bilateral ovariectomy and after preservation of ovaries, influences estrogen production. After bilateral ovariectomy statistically significant low values of urinary estrogens were recorded (21.76 nmol) in regard to ovarian preservation (87.80 nmol). Urinary estrogen values correlated with obesity in women with bilateral ovariectomy: in undernourished they were 10.50 nmol, in normally nourished 21.05 nmol, and in obese women 25.05 nmol. These differences are statistically significant. This can be explained by a higher conversion of androstendione to estrone, in the massive tissue, which is the main source of estrogen in postmenopause. This correlation does not exist in women with preserved ovaries, because in that case they are the basic source of estrogen.

[Immunologic characteristics of peritoneal fluid in endometriosis]. / Imunoloske karakteristike peritonealne tecnosti kod endometrioze.

Increased volume of peritoneal fluid is found more frequently in patients with endometriosis (51%) than in infertile patients without endometriosis (13%). Immunologic analysis of the peritoneal fluid shows that in patients with endometriosis the level of immunoglobulin G (IgG) increases. We analyzed 34 samples of peritoneal fluid from patients with and 13 from patients without endometriosis. The mean value of IgG in the group of patients with endometriosis was 7.73g/L and 3.94g/L in the control group. This difference is statistically significant, but there is no statistically significant difference in regard to immunoglobulin A (IgA), while it has been significant for immunoglobulin M (IgM) only in the third stage of the disease. In certain stages of illness there are no statistically significant differences in values of all three immunoglobulin types. A golden standard of immunoglobulin G in peritoneal fluid is 5g/L and in regard to this level we calculated the following: sensitivity, specificity, prognostic value and accuracy of the test. Sensitivity and positive prognostic value reached 85.3%. On the basis of these findings it can be concluded that if no endometriosis can be seen during laparascopy while the volume of peritoneal fluid is increased, immunologic analysis should be performed. If IgG values are 5g/L or higher, the patient should be treated as a patient with possible "precursor endometriosis".

[Serum lipids in surgical and natural postmenopause]. / Serumski lipidi u hirurskoj i prirodnoj postmenopauzi.

Values of serum lipids in women of different estrogenic status were analyzed in this paper. A deficit of estrogen was established in groups of surgically induced and natural postmenopausal women, but a relatively preserved production of estrogenic hormones in the group of women with preserved ovaries and group of premenopausal women. Serum triglycerides, the total serum cholesterol and LDL fraction of cholesterol were highest in surgically induced premenopausal women, somewhat lower in natural postmenopausal women, while they were statistically significantly lower in premenopausal women and women with preserved ovaries. Values of HDL cholesterol did not statistically significantly differ in certain groups of women. Index of atherosclerosis (IA) was highest in surgically induced postmenopausal women (3.18), somewhat lower in natural postmenopausal women (2.99) and premenopausal women (2.64), while it was statistically significantly lower in women with preserved ovaries (2.57).

[Antagonists in anesthesiology practice]. / Antagonisti u anestezioloskoj praksi.

The present paper delineates some of the current opinions as well as our own experiences with pharmacologic antagonists in anaesthetic practice. Non specific (Aminophylline, Physostigmine) as well as specific-opiate and benzodiazepine antagonists are therapeutic agents which cans shorten time of awakening or reverse respiratory depression induced by different anaesthetic drugs.

[Postspinal headache--incidence and prognosis]. / Postspinalna glavobolja--incidenca i prognoza.

Spinal anaesthesia was performed in 776 adult patients with 22 G and 25 G spinal needle. The incidence of postdural puncture headache was 3.5%. Its association to age, sex, needle size, duration of postoperative recumbency was analyzed. Our results show that the age was a significant predictor of postlumbar puncture headache. Postspinal headache was more often found in younger patients (p < 0.001).

[Postspinal headache as an anesthesiology problem]. / Postspinalna glavobolja kao anestezioloski problem.

Spinal anaesthesia, is nowadays one of the safest anaesthetic techniques with low complication rates. Postspinal headache is a complication of spinal anaesthesia. This paper presents several factors associated with the development of postspinal headache and discusses the reduction, prediction and treatment of postspinal headache.

[Anesthesia in peritoneovenous shunt placement]. / Anestezija za ugradnju peritoneojugularnog santa.

Since 1984 the peritoneovenous shunt has been installed in 33 patients because of resistant ascites. The aim of this study was to find the optimal type of anesthesia in our conditions on our own clinical-patient material. All patients were classified by the ASA, Goldman, Child and Child-Puigh score. The patient, surgeon and anesthesiologist were polled about the quality of anesthesia, and all observed complications were followed, like after different premedications as well as in the course and after different types of neuroleptic anesthesia. General neuroleptic anesthesia was applied in 23 patients (69.7%), one was operated on in ketamine anesthesia (3.0%) and 9 (27.3%) in local anesthesia with 2% Xylocaine. After premedication with Thalamonal in all patients there came to a fall in arterial pressure for more than 20% of initial values and the feeling of uneasiness and fear was present. All patients with local anesthesia absolutely needed additional application of sedation or analgesia, especially during the formation of the subcutaneous tunnel, and neither patient nor surgeon were satisfied with the achieved comfort. During the course of neuroleptic anesthesia with Thalamonal hypotension developed, in 17/20 patients an in 2/20 the presence of prolonged apnea demanded additional artificial ventilation. In the patient operated on in ketamine anesthesia, an acute psychotic reaction developed, followed by visual and acustic hallucinations without signs of metabolic encephalopathy. On the basis of our own experience, we conclude that general neuroleptic anesthesia with the use of Flormidal as an anesthetic and Fentanil as an analgetic, is the method of choice, and that local anesthesia can be recommended only on one operative site (except the subcutaneous tunnel).

The insulin response to oral glucose, concentrations of total cholesterol, triglycerides and uric acid in women with idiopathic hirsutism.

The glucose and insulin responses to an oral glucose tolerance test, concentrations of total cholesterol, triglycerides and uric acid were evaluated in women with idiopathic hirsutism (IH). Clinical data and laparoscopy of the ovaries were used in diagnosis. According to body weight the patients were divided into two groups: obese (OB-IH) and non-obese (NO-IH). In the IH and NO-IH groups the glucose response was significantly greater than in the control group (p less than 0.05). The insulin response to oral glucose was significantly higher in the IH and OB-IH groups compared with the control group (p less than 0.01). The concentrations of total cholesterol and triglycerides were significantly increased in the IH and OB-IH groups compared to those of normal women (p less than 0.01). All groups had significantly higher levels of uric acid compared with the control group (p less than 0.01). The results of our study suggest that alterations of carbohydrate, lipid and uric acid metabolism are present in patients with IH and further studies are needed to establish their mechanisms.

[The effect of synthetic gonadotropin releasing hormone on the plasma levels of FH and LSH in women with hirsutism and polycystic ovaries]. / Uticaj sintetskog rilizing hormona za gonadotropine na nivo LH i FSH u plazmi u zena sa hirzutizmom i policisticnim ovarijumima.

GN-RH test was performed in 33 women with hirsutism and irregular menstrual cycles. Fourteen patients had polycystic ovary syndrome (PCO) and 19 had idiopathic hirsutism (IH). In the control group, there were 5 healthy women with regular menstrual cycles. Absolute cumulative increase of LH as significantly higher in the examinees with hirsutism than in the control group. A significantly higher net increase of LH was found only in the PCO group. However, absolute and net increase of FSH in examinees with hirsutism did not significantly differ from that in the control group. Patients with PCO had a significantly higher increase of FSH than the IH group. Only the PCO group had a significant correlation between basal LH and LH increase during the test. It was found that patients with hirsutism and irregular menstrual cycles had an increased reactivity of the hypophysis to a direct stimulation with synthetic GN-RH. The degree of disfunction of the gonad axis in women with PCO is significantly higher than in patients with IH.