Long-Term Outcomes of Breast Cancer Patients Receiving Levobupivacaine Wound Infiltration or Diclofenac for Postoperative Pain Relief.

Breast cancer is the most common malignant disease in women. Preclinical studies have confirmed that the local anesthetic levobupivacaine has a cytotoxic effect on breast cancer cells. We examined whether postoperative wound infiltration with levobupivacaine influences survival in 120 patients who were operated on for breast cancer and underwent quadrantectomy or mastectomy with axillary lymph node dissection. Groups with continuous levobupivacaine wound infiltration, bolus wound infiltration, and diclofenac analgesia were compared. Long-term outcomes examined were quality of life, shoulder disability, and hand grip strength (HGS) after one year and survival after 5 and 10 years. Groups that had infiltration analgesia had better shoulder function compared to diclofenac after one year. The levobupivacaine PCA group had the best-preserved HGS after 1 year (P = 0.022). The most significant predictor of the 5-year outcome was HGS (P = 0.03). Survival at 10 years was 85%, 92%, and 77% in the diclofenac, levobupivacaine bolus, and levobupivacaine PCA groups (ns. P = 0.36). The extent of the disease at the time of surgery is the most important predictor of long-term survival (P = 0.03). A larger prospective clinical study could better confirm the effect of levobupivacaine wound infiltration on outcomes after breast cancer surgery observed in this pilot study-trial number NCT05829707.

Gastrointestinal Motility Disorders Correlate with Intracranial Bleeding, Opioid Use, and Brainstem Edema in Neurosurgical Patients.

BACKGROUND: Gastrointestinal (GI) motility disorders may be directly associated with the intensity of acute brain injury, edema of the brainstem, and opioid use in neurosurgical patients. METHODS: In this retrospective study, patient demographic characteristics, computed tomography (CT) scans, the occurrence of gastroparesis, constipation, and opioid use were registered during the intensive care unit (ICU) stay and correlated with days of mechanical ventilation, length of ICU stay, and survival. Gastroparesis was defined as residual gastric volume > 250 mL per day, and constipation was defined as the absence of stool for 3 days or more during the ICU stay. RESULTS: Of 207 neurosurgical patients screened, 69 adult patients who spent more than 4 days in the ICU were included in the study. Gastroparesis was observed in 48 (69.6%) patients, constipation was observed in 67 (97.1%) patients, and stress ulcers were observed in 4 (5.8%) patients. Patients with brainstem edema (n = 57, 82.6%) had the first stool evacuation later compared with patients with no edema (8 [interquartile range (IQR) 5.25-9.75] vs. 3.5 [IQR 2.25-4] days; P < 0.001). In the logistic regression analysis, factors that were associated with GI dysmotility were central nervous system (CNS) bleeding (odds ratio [OR] 5.1, 95% confidence interval [CI] 1.26-20.8, P = 0.02), opioid use > 19.3 morphine equivalents (ME) per day (OR 5.37, 95% CI 1.1-27.1, P = 0.04), and brainstem edema (OR 4.9, 95% CI 1.1-21.6, P = 0.04). A receiver operating characteristic curve analysis confirmed that the cutoff value of > 6.78 ME per day was a good predictor determining GI dysmotility, with 89.5% sensitivity and 72.7% specificity (95% CI 0.67-0.88, area under the curve 0.784, Youden index 0.62, P = 0.001). Poor survival correlated with lower Glasgow Coma Score values (ρ = - 520, P < 0.001), CNS bleeding (ρ = 0.393, P < 0.001), associated cardiac diseases (ρ = 0.279, P < 0.001), and cardiorespiratory arrest on admission (ρ = 0.315, P < 0.001), but not with GI dysmotility (ρ = 0.175, P = 0.402). CONCLUSIONS: Significant correlation was registered between brainstem edema, gastrointestinal dysmotility, and opioids. CNS bleeding was the most important single factor influencing GI dysmotility. Further studies with opioid and nonopioid sedation may distinguish the influence of acute brain lesions versus drugs on GI dysmotility.

Predictive role of selected biomarkers in differentiating gram-positive from gram-negative sepsis in surgical patients: a retrospective study.

INTRODUCTION: Patients after major surgery are at high risk of developing sepsis, which is accompanied by elevated serum levels of C-reactive protein (CRP) and procalcitonin (PCT). This study aimed to examine the differences in serum biomarker levels concerning the causative agent of sepsis in surgical patients. MATERIAL AND METHODS: A retrospective study was carried out in the surgical intensive care unit (ICU) and included 81 septic patients admitted from January 2019 to May 2022, who had positive blood cultures (BC). Serum levels of PCT, CRP, white blood cells (WBC) and platelet counts were recorded on the day of the positive BC and over the following 3 days. RESULTS: Patients with gram(-) sepsis had significantly higher PCT levels, and lower platelet count compared to patients with gram(+) sepsis. High PCT and low platelets levels in all measurements were a significant predictor of gram(-) isolate with the highest predictive value on the third day after BC sampling, with AUROC 0.821 (95% CI: 0.692-0.950), P = 0.001, and AUROC 0.676 (95% CI: 0.541-0.811), P = 0.02, respectively. In multivariate logistic regression, platelets the day after BC sampling and PCT on the third day made a significant contribution in distinguishing gam(+) from gram(-) BC. Age and high serum CRP levels were significant predictors of poor outcomes. CONCLUSIONS: PCT and platelets may be useful biomarkers for predicting the causative agent of sepsis in surgical patients.

ANALGESIC EFFECT OF TRAMADOL IS NOT ALTERED BY POSTOPERATIVE SYSTEMIC INFLAMMATION AFTER MAJOR ABDOMINAL SURGERY.

Tramadol is a commonly used analgesic in intensive care units (ICUs) for acute postoperative pain. Conversion of tramadol into active metabolites may be impaired in inflammatory states. Catechol-O-methyltransferase may influence pain. The aim of the study was to examine differences in the analgesic effect of tramadol between ICU patients with and without signs of systemic inflammation. Forty-three patients were admitted to ICU after a major abdominal surgery. The patients received a dose of 100 mg of tramadol intravenously every 6 hours during the first 24 hours after surgical procedure. Pain scores were measured by the Numeric Rating Scale before and 30 minutes after tramadol administration in awake patients. Systemic inflammation was considered when at least two of the following postoperative parameters were present in the first 24 hours of ICU admission: fever or hypothermia, tachycardia, pCO2 <4.3 kPa, white blood cells >12000/mm3 or <4000/mm3, or preoperative value of C-reactive protein (CRP) >50 mg/L or/and procalcitonin (PCT) >0.5 mg/L. Catechol-O-methyltransferase was analyzed postoperatively. Fifteen (34.8%) patients met the criteria for systemic inflammation. Tramadol was proven to be an effective analgesic for the treatment of postoperative pain regardless of the presence of systemic inflammation (p<0.05). Lower perception of pain before tramadol application was observed in patients with systemic inflammation, but the difference was not significant. A negative correlation was observed between the preoperative values of CRP and PCT and the analgesic effect of tramadol assessed at the second measurement point (r=-0.358, p=0.03, and r=-0.364, p=0.02, respectively). Catechol-O-methyltransferase variants were not in correlation with pain and opioid consumption. Based on our findings, tramadol is effective in lowering pain scores after major abdominal surgery irrespective of the presence of systemic inflammation.

Different Pharmacokinetics of Tramadol, O-Demethyltramadol and N-Demethyltramadol in Postoperative Surgical Patients From Those Observed in Medical Patients.

Background: Most studies examining tramadol metabolism have been carried out in non-surgical patients and with oral tramadol. The aim of this study was 1) to measure concentrations of tramadol, O-demethyltramadol (ODT), and N-demethyltramadol (NDT) in the surgical patients admitted to the intensive care unit (ICU) within the first 24 postoperative hours after intravenous application of tramadol, and 2) to examine the effect of systemic inflammation on tramadol metabolism and postoperative pain. Methods: A prospective observational study was carried out in the surgical ICU in the tertiary hospital. In the group of 47 subsequent patients undergoing major abdominal surgery, pre-operative blood samples were taken for CYP2D6 polymorphism analysis. Systemic inflammation was assessed based on laboratory and clinical indicators. All patients received 100 mg of tramadol intravenously every 6 h during the first postoperative day. Postoperative pain was assessed before and 30 min after tramadol injections. Tramadol, ODT, and NDT concentrations were determined by high-performance liquid chromatography. Results: CYP2D6 analysis revealed 2 poor (PM), 22 intermediate (IM), 22 extensive (EM), and 1 ultrafast metabolizer. After a dose of 100 mg of tramadol, t1/2 of 4.8 (3.2-7.6) h was observed. There were no differences in tramadol concentration among metabolic phenotypes. The area under the concentration-time curve at the first dose interval (AUC1-6) of tramadol was 1,200 (917.9-1944.4) µg ×h ×L-1. NDT concentrations in UM were below the limit of quantification until the second dose of tramadol was administrated, while PM had higher NDT concentrations compared to EM and IM. ODT concentrations were higher in EM, compared to IM and PM. ODT AUC1-6 was 229.6 (137.7-326.2) µg ×h ×L-1 and 95.5 (49.1-204.3) µg ×h ×L-1 in EM and IM, respectively (p = 0.004). Preoperative cholinesterase activity (ChE) of ≤4244 U L-1 was a cut-off value for a prediction of systemic inflammation in an early postoperative period. NDT AUC1-6 were significantly higher in patients with low ChE compared with normal ChE patients (p = 0.006). Pain measurements have confirmed that sufficient pain control was achieved in all patients after the second tramadol dose, except in the PM. Conclusions: CYP2D6 polymorphism is a major factor in O-demethylation, while systemic inflammation accompanied by low ChE has an important role in the N-demethylation of tramadol in postoperative patients. Concentrations of tramadol, ODT, and NDT are lower in surgical patients than previously reported in non-surgical patients. Clinical Trial Registration: ClinicalTrials.gov, NCT04004481.

Bispectral Index Monitoring and Observer Rating Scale Correlate with Dreaming during Propofol Anesthesia for Gastrointestinal Endoscopies.

Background and objectives: Dreaming is a commonly reported side effect of propofol anesthesia. Materials and Methods: We investigated the inci-dence and character of dreams in patients undergoing intravenous propofol anesthesia and cor-related it with an observer rating scale of facial expression on the seven-point scale from pain to smile. A total of 124 patients undergoing gastrointestinal endoscopy were recruited in the pro-spective observational study. Bispectral index (BIS), blood pressure (BP), and pulse were moni-tored. Upon emergence from anesthesia, the patient's facial expression was rated numerically. Thereafter, patients were asked whether they had dreams and to rate their dreams as pleasant or unpleasant. The mean age of participants was 53; body mass index, 26.17; duration of procedure, 20 min; and average propofol dose, 265 mg. Results: Dreaming was reported by 43% of patients. Dreams were pleasant in all but one patient. There was a significant correlation of the observer's rating of facial expression with dreaming (r = 0.260; p = 0.004). Dreamers had higher scores of observer rating of facial expression (1 (0-2) vs. 0.5 (0-1), p = 0.006). Conclusions: BIS values were lower in the dreamers vs. non-dreamers 2 min after the endoscopy started (48 (43-62) vs. 59 (45-71), p = 0.038). Both BIS and observer ratings correlate with dreaming in patients undergoing gastrointestinal endos-copy. Trial registration number: NCT04235894.

Workload changes during the COVID-19 pandemic and effects on the flow of cancer patients in the Maxillofacial Surgery Department.

Aim A SARS Coronavirus 2 (COVID-19) pandemic drastically changed the way the health system works. In Croatia, lockdown measures to curb virus spread lasted from March to May 2020, and all non-essential medical procedures and patients' visits have been cancelled. The study aimed to compare patients' flow and interventions in the surgical department before, during and after the lockdown period. Methods This cross-sectional study analysed the workload at the Maxillofacial and Oral Surgery Department (Department), Osijek University Hospital, during the COVID-19 pandemic (March-May 2020) and four subsequent months. The same period of 2019 was compared as a control. The data were subtracted from hospitals' electronic database. Results During COVID-19 lockdown from March to May 2020 the number of hospitalizations (306 vs. 138), surgical procedures (306 vs. 157), and scheduled outpatient visits (2009 vs. 804), dropped significantly as compared to 2019. The number of skin tumour removals was halved (from 155 in 2019 to 58 in 2019) (p<0.001), and the number of emergency patients was unchanged in the 3-month period. A significant decrease in outpatient visits and hospital admissions continued after the lockdown (p<0.001). Conclusion A decrease in the number of outpatient visits, hospitalizations, and tumour removals may result in larger proportions of patients with advanced cancers in the future. The second wave of COVID-19 pandemic is ongoing, and special effort must be paid to reduce the number of cancer patients receiving suboptimal treatment.

Epidural analgesia for acute ischemic pain after intra-arterial zolpidem injection in opioid-addicted patient-A case report.

A patient taking opioid maintenance therapy unintentionally injected dissolved zolpidem pills into the femoral artery and suffered acute limb ischemia. High amounts of opioids with supplemental therapies were inefficient for intractable ischemic pain, suggesting the presence of opioid-induced hyperalgesia (OIH). Epidural analgesia efficiently relieved pain and symptoms of OIH.

DOES THE ANESTHESIA TECHNIQUE AFFECT ARTERIAL PRESSURE AND REGIONAL CEREBRAL OXYGEN SATURATION DURING SHOULDER ARTHROSCOPY IN THE BEACH CHAIR POSITION?

- This study aimed to investigate the impact of posture and anesthesia techniques on blood pressure changes, heart rate and regional cerebral oxygen saturation during shoulder arthroscopy in the beach chair position (BCP). Sixty patients were included in this prospective cohort study: 30 patients mechanically ventilated and subjected to general anesthesia (GA) and 30 patients subjected to interscalene block (ISB) without mechanical ventilation. Noninvasive blood pressure, heart rate (HR), peripheral blood oxygen saturation and regional oxygen saturation of the brain were measured in twelve predefined points during perioperative period. The GA group patients had significantly lower mean arterial pressure and heart rate values compared to patients in ISB group during BCP (p<0.001). There was a significant difference in regional cerebral saturation between the groups measured only in points of induction and emergence from anesthesia in favor of GA group when receiving 100% oxygen (p<0.001). Changes in the mean arterial pressure and regional cerebral oxygen saturation for both brain hemispheres correlated only at the 10th minute after setting up BCP in GA patients (right, p=0.004 and left, p=0.003). This correlation did not exist in the ISB group patients at any of the points measured. Cerebral desaturation events recorded in both groups were not statistically significantly different. Results of this study demonstrated that GA preserved regional cerebral oxygenation in a safe range during BCP despite changes in the arterial blood pressure and heart rate in comparison to ISB.

Integrity of gut mucosa during anaesthesia in major abdominal surgery.

The aim of the study was to examine a perfusion and integrity of small bowel in 60 subsequent patients during the major open abdominal surgery which lasted from 2 to 7 hours. Two samples of the intestinal mucosa were removed: at the beginning, and at the end of the surgical procedure in general anaesthesia. A mucosal injury was classified into 4 grades. pH, PCO2 and lactate level were measured in the blood samples from the arterial and mesenteric vein in one hour time intervals. The changes of intestinal mucosa were found in 31 patients (51.7%): in 19 patients (31.7%) grade 1 changes were recorded, in 10 patients (16.7%) grade 2, and in 2 patients (3.3%) grade 3. Grade 4 lesions were not recorded. There was a statistically significant correlation between grades of the mucosal damage and the surgery duration (p = 0.001). Analysis during the one hour intervals showed that there was no exact time point when the significant aggravation of the pathohistological changes in intestinal mucosa occurred. However, when patients were allocated into two subgroups with surgical procedures lasting less than 4 hours and more than 4 hours, there was a statistically significant difference in the grades of mucosal damage between subgroups (p < 0.05). More biopsies without pathohistological changes were observed in the patients whose procedure duration was < 4 hours. A significantly higher lactate concentrations in arterial and mesenteric venous blood were observed in the patients with pathohistological changes at 6 hours time point as compared to 2 hour time point in the patients without pathohistological changes (p < 0.05). During the open abdominal surgery in general anaesthesia, the length of the procedure influences the grade of the intestinal mucosa injury. Deterioration of the pathohistological findings in the intestinal mucosa correlates with high lactate blood level, suggesting that the cause of these changes may result from tissue hypoxia.

Conservative surgical management of necrotic tissues following meningococcal sepsis: case report of a child treated with hyperbaric oxygen.

This article presents the case of a 5-month-old infant, who survived a fulminant meningococcal sepsis with purpura fulminans, septic shock and severe DIC with gastrointestinal bleeding. Amputation and reconstructive surgery were considered to treat the multiple skin and limb necroses at high risk of superinfection, but the surgical intervention was delayed due to the extremely doubtful outcome. On Day 10 after the onset of the disease, a hemodynamic improvement was achieved. The baby overcame early critical period, but was still in poor general condition. The hyperbaric oxygenation (HBO2) as adjuvant therapy was started in the monoplace chamber using the following protocol: from first through fifth day 45 minutes twice a day on 1.5 atmosphere absolute (ATA); after a two-day break, once a day on 1.8 ATA for 60 minutes. During 52 HBO2 treatments multiple areas of necrotic skin and subcutaneous tissue, together with fingertips and toes, detached spontaneously. All wounds healed without reinfections. An increased oxygen concentration during HBO2 therapy promoted spontaneous wound healing. Bacterial superinfection was not observed in numerous low-perfused lesions. Since repeated anesthesia and surgical interventions were not needed, a final invalidity was minimized. To the best of our knowledge, this is the first report on the successful conservative surgical treatment of this mutilating disease without aggressive reconstructive surgery in an infant with the help of HBO2.

An overview of coagulation disorders in cancer patients.

A diversity of coagulation disorders in cancer patients arise from tumor-specific growth characteristics, neoangiogenesis with impaired endothelial lining, defective myelopoiesis, hypoproteinemia or metastatic lesions growth with organ dysfunction. Recent investigations have found a clinically relevant correlation of coagulation disorders and tumor growth. These prompted new therapeutic strategies focused on growth factors with the aim to control tumor metastasis, particularly if used for the treatment of micrometastatic disease. However, such treatment may lead to the life threatening coagulation imbalance. A coagulation homeostasis may become further impaired after nonsurgical cancer therapy, especially after preoperative irradiation, which produces lesions precipitating both bleeding and thrombosis. Anticancer chemotherapy may affect liver function and decrease the synthesis of both procoagulation and anticoagulation factors. The most of chemotherapeutic protocols affect platelet synthesis, which arises as a principal dose-limiting side effect. It was observed both during combined systemic chemotherapy and local antitumor therapy. Although the side effects produced by chemotherapy are reversible, endothelial lesions may persist for many years after the anticancer treatment. Instead of cancer patients, there's a growing cohort of patients with nonmalignant diseases who use cytostatics in the perioperative period, and are candidates for surgical procedures not related to their malignant disease, i.e. hernia repair. In this patient population a special attention must be paid to the preoperative evaluation of coagulation status and thromboprophylaxis. This overview reminds the most common coagulation disorders in cancer patients in the perioperative period. It emphasizes the need for proper patient monitoring which may facilitate the diagnostics and treatment of cancer-related coagulation disorders in the perioperative setting.

Knowledge and practices of obtaining informed consent for medical procedures among specialist physicians: questionnaire study in 6 Croatian hospitals.

AIM. To assess physicians' knowledge and practices for obtaining patients' informed consent to medical procedures. METHODS. An anonymous and voluntary survey of knowledge and practices for obtaining informed consent was conducted among 470 physicians (63% response rate) working in 6 hospitals: 93 specialists in anesthesiology, 166 in internal medicine, and 211 in surgery. RESULTS. Only 54% physicians were acquainted with the fact that the procedure for obtaining consent was regulated by the law. Internists and surgeons were better informed than anesthesiologists (P=0.024). More than a half of respondents (66%) were familiar with the fact that a law on patient rights was passed in Croatia; there were no differences among different specialties (P=0.638). Only 38% of the physicians were fully informed about the procedure of obtaining consent. Internists and surgeons provided detailed information to the patient in 33% of the cases and anesthesiologists in 16% of the cases (P<0.050). Internists reported spending more time on informing the patient than anesthesiologists and surgeons (P<0.001). There were no differences in knowledge and practices for obtaining informed consent between physicians working in university and those working in community hospitals (P> or =0.05 for all questions). CONCLUSION. Physicians in Croatia have no formal education on informed consent and implement the informed consent process in a rather formal manner, regardless of the type of hospital or medical specialty. Systemic approach at education and training at the national level is needed to improve the informed consent process.

Effects of inhalation anesthetics halothane, sevoflurane, and isoflurane on human cell lines.

Cytotoxic and antiproliferative effects of halothane, isoflurane, and sevoflurane in anesthetic doses on human colon carcinoma (Caco-2), larynx carcinoma (HEp-2), pancreatic carcinoma cells (MIA PaCa-2), poorly differentiated cells from lymph node metastasis of colon carcinoma (SW-620), and normal fibroblasts were investigated. Cells were exposed to anesthetic gas mixture consisting of O(2): N2O (35:60 vol.%), halothane (1.5 vol.%) or isoflurane (2.0 vol.%) or sevoflurane (3.0 vol.%), and CO(2) (5 vol.%), for 2, 4, and 6 h. Cytotoxicity of anesthetics was analyzed by validated tetrazolium dye assay MTT test. All anesthetics expressed cytotoxic effects on treated tumor cells in time and cell line dependent manner. Growth suppression in cells exposed to halothane was enhanced in HEp-2 (to 67.7%), Caco-2 (to 76.3%), and SW620 cells (to 80.9%), and was minimal in normal fibroblasts (to 89.4%). Antiproliferative activity of halothane was measured via radioactive precursors incorporation assay. In Caco-2 cells treated by halothane, decrease in DNA synthesis (52.4%, p=0.001), RNA synthesis (39.2%, p<0.001), and protein synthesis (19.2%, p=0.004) was observed. In HEp-2 cells, DNA and RNA syntheses were decreased to 72.5% and 79.9%, whereas protein synthesis was 14.0% of control (p<0.001). In SW620 cells, protein synthesis after 4 h was 24.4% (p=0.007). A DNA fragmentation was observed in Caco-2 and MIA PaCa-2 cells. Exposition of phosphatidylserine on outer lipid bilayer plasma membrane of tumor cell treated by halothane proved apoptosis as mode of cell death.