Sebnem Atici

Liver and kidney toxicity in chronic use of opioids: An experimental long term treatment model

In this study, histopathological and biochemical changes due to chronic usage of morphine or tramadol in liver and kidney were assessed in rats. Thirty male Wistar rats (180–220 g) were included and divided into three groups. Normal saline (1 ml) was given intraperitoneally as placebo in the control group (n = 10). Morphine group (n = 10) received morphine intraperitoneally at a dose of 4, 8, 10 mg/kg/day in the first, second and the third ten days of the study, respectively. Tramadol group (n = 10), received the drug intraperitoneally at doses of 20, 40 and 80 mg/kg/day in the first, second and the third ten days of the study, respectively. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), creatinin, blood urea nitrogen (BUN) and malondialdehyde (MDA) levels were measured in the serum. Liver and kidney specimens were evaluated by light microscopy. Serum ALT, AST, LDH, BUN and creatinin levels were significantly higher in morphine group compared to the control group. Serum LDH, BUN and creatinin levels were significantly increased in the morphine group compared to the tramadol group. The mean MDA level was significantly higher in morphine group compared to the tramadol and control groups (P<0.05). Light microscopy revealed severe centrolobular congestion and focal necrosis in the liver of morphine and tramadol groups, but perivenular necrosis was present only in the morphine group. The main histopathologic finding was vacuolization in tubular cells in morphine and tramadol groups. Our findings pointed out the risk of increased lipid peroxidation, hepatic and renal damage due to long term use of opioids, especially morphine. Although opioids are reported to be effective in pain management, their toxic effects should be kept in mind during chronic usage

OPIOID NEUROTOXICITY: COMPARISON OF MORPHINE AND TRAMADOL IN AN EXPERIMENTAL RAT MODEL

Histopathologic changes in rat brain due to chronic use of morphine and/or tramadol in progressively increased doses were investigated in this study. Thirty male Wistar rats (180-220 g) were included and divided into three groups. Normal saline (1 ml/kg) was given intraperitoneally as placebo in the control group (n = 10). Morphine group (n = 10) received morphine intraperitoneally at a dose of 4 mg/kg/day for the first 10 days, 8 mg/kg/day between 11-20 days, and 12 mg/kg/day between 21-30 days. The tramadol group (n = 10) received the drug intraperitoneally at doses of 20, 40, and 80 mg/kg/day in the first, second, and the third 10 days of the study, respectively. All rats were decapitated on the 30th day and the brain was removed intact for histology. The presence and the number of red neurons, which are a histologic marker of apoptosis, were investigated in the parietal, frontal, temporal, occipital, entorhinal, pyriform, and hippocampal CA1, CA2, CA3 regions. Red neurons were found in morphine and tramadol groups but not in the control group. The total number of red neurons was not different in morphine and tramadol groups, but the numbers of red neurons were significantly higher in the temporal and occipital regions in tramadol group as compared with the morphine group (p < .05). In conclusion, chronic use of morphine and/or tramadol in increasing doses is found to cause red neuron degeneration in the rat brain, which probably contributes to cerebral dysfunction. These findings should be taken into consideration when chrome use of opioids is indicated.

Ischemic preconditioning reduces intestinal epithelial apoptosis in rats.

Recent experimental studies have described protective effect of ischemic preconditioning (IPC) on ischemia–reperfusion (I/R) injury of the intestine. We hypothesize that to reach a new point of view on the effect of IPC in intestinal barrier function, the relationship between I/R-induced mucosal injury and apoptosis must first be clarified. The present study was undertaken to investigate the role of IPC on intestinal apoptosis and probable contributions of bcl-2 expression to this process. We also investigated the effect of intestinal IPC on ileal malondyaldihyde levels. Forty-four male Wistar rats were randomized into four groups each consisting of 11 rats: sham-operated control, I/R group (30 min of superior mesenteric artery occlusion), IPC-I/R group (10 min of temporary artery occlusion prior before an ischemic insult of 30 min), and IPC alone group (10 min of preconditioning). Twenty-four hours later, ileum samples were obtained. Ileal malondyaldihyde levels were increased in the I/R group (31.9 ± 18.8 vs. 106.8 ± 39.8) but not in the IPC alone and IPC-I/R groups (38.1 ± 13.6 and 44.7 ± 12.7;P < 0.01). The number of apoptotic cells was significantly lower in IPC-I/R group than that of I/R group, and these findings were further supported by DNA laddering and M30 findings. Diminished bcl-2 expression observed in the ileal specimens of I/R group was prevented by IPC. Our results indicate that IPC may provide a protective effect on ileal epithelium and that this effect is probably the result of a significant increase in the expression of bcl-2 after the insult. The reversal of apoptosis by IPC might help preserving the vitality of intestinal structures that have a critical function, cessation of which often leads to multiorgan dysfunction syndrome.

THE ROLE OF POLY(ADP-RIBOSE) SYNTHETASE INHIBITION IN PREVENTING ENDOTOXEMIA-INDUCED INTESTINAL EPITHELIAL APOPTOSIS

In this lipopolysaccharide (LPS)-induced endotoxemia model, the effects of 3-aminobenzamide (3-AB), a poly(ADP-ribose) synthetase (PARS) inhibitor, on ileal apoptosis were evaluated by light microscopy and M30 cell death staining. Moreover, the relationship between Bcl-2, iNOS expression, and serum nitrate (NO(3)(-)) levels were investigated. Thirty-two male Wistar rats, weighing 180-220g were randomly divided into four groups. The group I (control; n=8) received saline and group II (sepsis; n=8) received 10 mg kg(-1) LPS intraperitoneally. 3-AB was given to the group IV (S+3-AB; n=8) 20 min before giving LPS and to the group III (C+3-AB; n=8) 20 min before giving saline. Six hours later, blood and ileum samples were taken. Endotoxemic group exhibited significant apoptosis in intestinal epithelial cells and the immunohistochemical examination with M30 was demonstrated that the 3-AB reduced the LPS-induced intestinal apoptosis. Serum NO(3)(-) level was increased in endotoxemic group, whereas the elevation of NO(3)(-) level was prevented in LPS+3-AB group (P<0.05). The increased iNOS expression observed in the LPS group was also prevented by 3-AB. Compared with the endotoxemic group, ileal epithelial columnar cells from LPS+3-AB group had a dense Bcl-2 staining which was almost identical with control. In conclusion, 3-AB decreases LPS-induced apoptosis in ileum by preventing LPS-induced depletion of Bcl-2 and blocking iNOS gene. Modification of Bcl-2 expression by PARS inhibitors should further be investigated as a new therapeutic alternatives in septic states.

Hormonal and hemodynamic changes during percutaneous nephrolithotomy.

The aim of this study was to investigate the hormonal and hemodynamic changes during percutaneous nephrolithotomy (PCNL) procedure. Twenty-one patients between 15–65 years of age were included in the study. Invasive blood pressure and heart rate were monitored during PCNL. Serum sodium, potassium, BUN and creatinine levels were measured before and after the operation. Sodium and potassium levels were also measured during the operation. Arterial blood gases, renin, aldosterone and adrenocorticotrophic hormone (ACTH) levels were measured before and during irrigation. The mean systolic and diastolic blood pressure levels were significantly higher (p < 0.05) during PCNL compared to post-procedure levels while heart rate remained constant. Serum sodium,potassium bicarbonate and base-excess levels were decreased during the operation compared to the base-line levels (p < 0.001). BUN and creatinine levels remained unchanged during the study (p > 0.05). In conclusion, a tendency to hyponatremia and metabolic acidosis developed in addition to significant increases in renin, aldosterone and ACTH levels during PCNL procedures. These changes may be due to the invasive nature of the intervention to the kidney and the continuous irrigation of this vital organ. This should be taken into consideration during PCNL. More detailed studies with larger groups are needed for more precise comments on this topic.

Manufacturing defect in an endotracheal tube connector: risk of foreign body aspiration

To the editor: Routine inspection and testing of endotracheal tubes (ETTs) prior to use may fail to identify certain manufacturing defects [1]. We would like to discuss the potential morbid complication of foreign body aspiration associated with a manufacturing defect in the tip of an ETT connector. A 28-year-old woman was scheduled for laparoscopic ovarian cystectomy. Induction of anesthesia was performed with 2 mg·kg propofol, 0.1 mg fentanil, and 0.1 mg·kg vecuronium bromide i.v. Tracheal intubation was achieved with a size 7.5-mm ETT (Well Lead Medical Instruments, Jinhu Industrial Estate Hualong, Panyu Guangzhou, P. R. China). Chest auscultation revealed clear, bilaterally equal breath sounds. The lungs were ventilated at 6 l·min and 17-mmHg peak airway pressure. While we were fi xing the ETT with tape, a moving particle was noticed in the lumen of the ETT. The ETT was immediately disconnected from the ventilator, and a tiny particle was noted in the distal part of the tube connector (Fig. 1). The connector was changed immediately and ventilation was maintained with no problem during the operation. Inspection of the connector revealed that the presence of the particle was caused by a manufacturing defect. Neither atelectasis nor a foreign body was seen on chest radiograph taken at the end of the operation. The postoperative course was uneventful. Problems associated with an ETT defect, if not corrected immediately, would lead to failure in ventilating the lungs, hypoxemia, and serious complications [2,3]. It is recommended that the use of transparent tubes and a pre-use check might allow visualization of the lumen and hence prevent problems [3]. However, some problems may still occur even with high-quality, pre-packed single-use transparent plastic ETTs [3]. In our patient, the foreign body moved with ventilation, and then it could be seen only in the lumen of the tube. If it had not been noticed, a possible problem would have been the inward migration of the particle, possibly leading to serious complications. There has been no previous report of this type of structural defect in an ETT. We suggest that an internal visual check of the lumen should be performed routinely, because the opaque nature of the connector makes visual Fig. 1. A Tiny particle in the distal part of an endotracheal tube connector. B The foreign body moved with ventilation, and then it could be seen in the lumen of the tube

The Effect of Preventive Use of Alanyl-Glutamine on Diaphragm Muscle Function in Cecal Ligation and Puncture-Induced Sepsis Model

BACKGROUND Low muscle glutamine levels during sepsis are associated with reduced protein synthesis and elevated protein breakdown, in particular myofibrillar protein breakdown. Thus, in a cecal ligation and puncture (CLP)-induced sepsis model in the rat, we hypothesized that glutamine pretreatment would protect the diaphragm muscle function. METHODS Eighty-four male Wistar rats weighing between 180 g and 200 g received standard amino acid solution 1.2 g kg(-1) per day intraperitoneally (IP) or standard amino acid solution 1.2 g kg(-1) per day plus alanyl-glutamine (GLN) 0.25 g kg(-1) per day (IP) during the first 6 days of the experiment. On the seventh day, CLP or sham procedures were applied. The sham and CLP groups were equally divided into 3 subgroups according to the termination of the experiment, which took place at either the 24th hour, 48th hour, or 72nd hour. After the compound muscle action potentials (CMAP) were recorded from the diaphragms of the rats at these selected times, they were decapitated under ketamine/xylazine anesthesia, and diaphragms were harvested for biochemical and histopathological examination. RESULTS The mean area and amplitude of CMAP were significantly larger in sham+GLN groups when compared with CLP and CLP+GLN groups at all times (p < .05). Diaphragm Ca+2 -ATPase levels were found to be significantly decreased in CLP group at all times compared to sham groups (p < .05). Diaphragm reduced glutathione levels were significantly higher in sham+GLN groups when compared with CLP and CLP+GLN groups at all times (p < .05). In histopathologic assessment, moderate neutrophil infiltration, which was observed in CLP48, was significantly reduced with alanyl-glutamine supplementation in CLP+GLN48 group (p < .05). CONCLUSIONS This study showed that glutamine pretreatment did not improve diaphragm muscle function, but prevented the biochemical and histopathological changes in diaphragmatic muscle in CLP-induced sepsis. However, further studies are needed to clarify whether a higher dose of glutamine supplementation might protect the diaphragmatic muscle functions.

Morphine added to local anaesthetic improves epidural analgesia in minimally invasive Nuss operation for pectus excavatum

Editor—The Nuss operation is a minimally invasive technique for repair of pectus excavatum. However, postoperative pain is the major problem, and meticulous pain management in postoperative period is important to maintain a stable supine position without turning to either side. Thoracic epidural local anaesthetic and morphine are commonly used for postoperative pain management, but patients were randomized without considering the pectus index. In this report, we aimed to discuss the management of three patients with high pectus index, and thoracic epidural local analgesia was insufficient for pain control in two of them who obtained relief by the addition of morphine to local anaesthetic. General anaesthesia was induced with propofol 2 mg kg, fentanyl 0.1 mg, and vecuronium 0.1 mg kg in all patients, before tracheal intubation with a left doublelumen endobronchial tube. The epidural catheter was inserted by a median approach at T8 – 9 space after induction of anaesthesia. After the bar was placed into its position, levo-bupivacaine 0.25% (Chirocaine, Abbott) as a 10 ml bolus followed by 3 ml h (2.5 mg ml solution) infusion was started via epidural catheter. At the end of the operation, if no pneumothorax was seen on a chest X-ray, patients were extubated and sent to the ward. Sufficient pain control could be achieved in the first case with epidural local anaesthetic administration. However, the second and third cases experienced pain after operation, despite suitable epidural technique (Table 1). The pain was successfully managed with additional morphine 2 mg to the thoracic epidural local anaesthetic. Forcing the sternum anteriorly causes significant pain in the chest and back in the skeletally mature patient. The increased pressure on the bar by less flexible chest increases the magnitude of pain which involves dermatomes T1 – 10. Although, thoracic epidural analgesia with local anaesthetic is considered the gold standard for this operation, the high incidence of hypotension related to the complete sympathectomy caused by the large doses of local anaesthetic is the main problem. However, the incidence of side-effects in epidural morphine has limited its routine use. Morphine can be considered as an adjuvant in patients in whom epidural local anaesthetic is insufficient, and could be considered for routine use in patients with a high pectus index.

Comparison of the effects of sevoflurane and total intravenous anaesthesia in percutaneous nephrolithotomy.

Background and objective: Although percutaneous nephrolithotomy has many advantages over open surgery, some endocrine and haemodynamic responses have been reported. However, the effects of anaesthetic agents on these responses have not previously been reported. This study compared the effects of sevoflurane and total intravenous anaesthesia using propofol and alfentanil on the haemodynamic and hormonal changes during percutaneous nephrolithotomy. Methods: Forty-two ASA I-II patients aged between 15 and 65 yr were studied. Sevoflurane in Group S (21 patients) or TIVA in Group TIVA (21) was used for the maintenance of anaesthesia. Haemodynamic variables and serum concentrations of sodium and potassium were measured before, during and after the procedure. Arterial blood-gas status, plasma renin, aldosterone and adrenocorticotrophic hormone concentrations were measured before and during the procedure. Results: Mean heart rate was lower during percutaneous nephrolithotomy in Group TIVA compared with Group S (P < 0.01). The mean systolic and diastolic arterial pressures were not different in both groups at any stage of measurement (P < 0.05). Plasma renin, aldosterone and adrenocorticotrophic hormone concentrations were increased during percutaneous nephrolithotomy in both groups, but the increase was greater in Group S (P < 0.05). Conclusions: In the sevoflurane group, the concentrations of renin, aldosterone and adrenocorticotrophic hormone were significantly higher after 15 min of irrigation compared with the total intravenous anaesthesia group. Although the clinical significance of this difference was not clear, these changes should be considered in certain patient groups.

The effects of caudal magnesium administration on anaesthesia depth and analgesia requirement: A-613

Background and Goal of Study: Recently most studies reported that magnesium was a N-methyl-D-aspartate (NMDA)-receptor antagonist and its analgesic and perioperative anesthesic effects were discussed with central desentisation pathway. We aimed to study effects of caudal ropivacaine plus magnesium o