Genetic variant in the osteoprotegerin gene is associated with aromatase inhibitor-related musculoskeletal toxicity in breast cancer patients.

BACKGROUND: Aromatase inhibitor (AI) therapy is associated with musculoskeletal (MS) toxicity, which adversely affects quality of life and therapy adherence. Our objective was to evaluate whether genetic variants may predict endocrine therapy-related MS pain and hot flashes in a prospective observational cohort study. PATIENTS & METHODS: 254 early breast cancer patients starting AI (n = 159) or tamoxifen therapy (n = 95) were included in this genetic biomarker study. MS and vasomotor symptoms were assessed at baseline and after 3, 6 and 12 months of therapy. AI-induced MS pain was defined as an increase in arthralgia or myalgia relative to baseline. Single nucleotide polymorphisms (SNP) in candidate genes involved in oestrogen signalling or previously associated with AI-related MS pain or oestrogen levels were selected. RESULTS: Overall, 13 SNPs in CYP19, CYP17, osteoprotegerin (OPG) and oestrogen receptor 1 exhibited an allele frequency >0.05 and were included in the analysis. Patients carrying the G allele of rs2073618 in OPG experienced significantly more AI-induced MS toxicity compared to the wildtype allele, after correction for multiple testing (P = 0.046). Furthermore, this SNP was associated with severity of pain (P = 0.018). No association was found with regard to the other SNPs, both in AI and tamoxifen-treated patients. Neither could an association with vasomotor symptoms be demonstrated. CONCLUSION: The SNP rs2073618 in OPG is associated with an increased risk of MS symptoms and pain with AI therapy, which has not been reported previously. Validation of this finding in larger cohorts and further functional studies are required.

Genetic variability in the multidrug resistance associated protein-1 (ABCC1/MRP1) predicts hematological toxicity in breast cancer patients receiving (neo-)adjuvant chemotherapy with 5-fluorouracil, epirubicin and cyclophosphamide (FEC).

BACKGROUND: To assess the impact of single-nucleotide polymorphisms (SNPs) on predefined severe adverse events in breast cancer (BC) patients receiving (neo-)adjuvant 5-fluorouracil (FU), epirubicin and cyclophosphamide (FEC) chemotherapy. PATIENTS AND METHODS: Twenty-six SNPs in 16 genes of interest, including the drug transporter gene ABCC1/MRP1, were selected based on a literature survey. An additional 33 SNPs were selected in these genes, as well as in 12 other genes known to be involved in the metabolism of the studied chemotherapeutics. One thousand and twelve female patients treated between 2000 and 2010 with 3-6 cycles of (neo-)adjuvant FEC were genotyped for these SNPs using Sequenom MassARRAY. Severe adverse events were evaluated through an electronic chart review for febrile neutropenia (FN, primary end point), FN first cycle, prolonged grade 4 or deep (<100/µl) neutropenia, anemia grade 3-4, thrombocytopenia grade 3-4 and non-hematological grade 3-4 events (secondary end points). RESULTS: Carriers of the rs4148350 variant T-allele in ABCC1/MRP1 were associated with FN relative to homozygous carriers of the G-allele [P = 0.0006; false discovery rate (FDR) = 0.026]. Strong correlations with secondary end points such as prolonged grade 4 neutropenia (P = 0.002, FDR = 0.046) were also observed. Additionally, two other SNPs in ABCC1/MRP1 (rs45511401 and rs246221) correlated with FN (P = 0.007 and P = 0.01, respectively; FDR = 0.16 and 0.19), as well as two SNPs in UGT2B7 and FGFR4 (P = 0.024 and P = 0.04; FDR = 0.28 and 0.38). CONCLUSION: Genetic variability in ABCC1/MRP1 was associated with severe hematological toxicity of FEC.

Levosimendan: a promising treatment for myocardial stunning?

We report a case of a 55-year-old male undergoing major orofacial cancer surgery. A stent to the left anterior descending artery had been implanted for ischaemic heart disease 3 years previously. Twenty-four hours after uneventful anaesthesia and surgery, the patient developed myocardial infarction and cardiogenic shock. Immediate percutaneous transluminal coronary angioplasty, intra aortic balloon counterpulsation, and catecholamine therapy failed to stabilise haemodynamics. In light of successful reperfusion therapy and an only moderate elevation of troponin I, myocardial stunning rather than myonecrosis was considered to be the major contributor to life-threatening left ventricular failure. Therefore, the calcium-sensitising drug levosimendan, which exerts positive inotropic activity without increasing myocardial oxygen demand, was administered as a rescue medication. Within 24 h, levosimendan resulted in decreased filling pressures, reduced left ventricular end-diastolic volume, and augmented systemic pressures. Seven days following surgery, the patient was discharged from the intensive care unit in good clinical condition.

Success rate of unilateral spinal anesthesia is dependent on injection flow.

BACKGROUND AND OBJECTIVES: The dependence of unilateral spinal anesthesia on injection flow is controversial. We hypothesized that it is possible to achieve strictly unilateral sympathetic block (as assessed by temperature measurements of the limbs) and unilateral sensory and motor block, respectively, during spinal anesthesia by a slow and steady injection of a hyperbaric local anesthetic solution. METHODS: Forty-four patients (American Society of Anesthesiologists [ASA] physical status I-III) undergoing surgery of one lower extremity were randomly assigned to one of two groups. Dependent on the patients' height, 1.4 to 1.7 mL hyperbaric bupivacaine 0.5% was injected manually with the patient in the lateral decubitus position, which was maintained for 30 minutes after injection. Injection flow was approximately 0.5 mL/min in group I ("air-buffered" injections performed by 4 mL air between the local anesthetic and the syringe's plunger, n = 25) and approximately 7.5 mL/min in group II ("conventional" injections, n = 19). Sympathetic block was defined as a temperature increase of more than 0.5 degrees C at the foot. Any reduction in the ability to move the hip, knee, or ankle as well as loss of temperature discrimination and/or pinprick even in one dermatome on the nondependent side was considered as a bilateral block. RESULTS: Before surgery, significant differences (P < .05) were observed for unilateral motor paralysis (92% in group I v 68.4% in group II), unilateral sensory block (48.0% v 10.5%), and unilateral sympathetic block (72% v 42.1%). Strictly unilateral spinal anesthesia was found to be significantly more frequent in group I (40% v 5.3%). Significant hemodynamic differences between the groups were not detected. CONCLUSIONS: For hyperbaric spinal anesthesia, the injection flow is an important factor in achieving unilateral sympathetic block. A slow injection proves useful to restrict spinal anesthesia to the side of surgery.

Early onset of regional intestinal ischemia can be detected with carbon dioxide tension measurement inside the peritoneal cavity.

UNLABELLED: Methods for detecting regional gastrointestinal ischemia are rare. An early detection of ischemia in the stomach or ileum can be achieved by the continuous intramucosal PCO(2) (PiCO(2)) measurement in the region. However, physiological consideration suggests that the placement of a fiberoptic CO(2) sensor in the peritoneal cavity should yield comparable results. We tested the hypothesis that a continuous PCO(2) measurement in the peritoneal cavity allows the early detection of regional intestinal ischemia. A laparotomy was performed in six pigs (54.7 +/- 3.7 kg) with a tourniquet being placed around respective vessels to allow complete ischemia of a 2. 75-m part of the ileum. A fiberoptic CO(2) sensor (PiCO(2)-ileum) was placed intraluminally in the ileum outside this segment. A second fiberoptic CO(2) sensor to measure intraperitoneal PCO(2) (i. p.-PCO(2)) was placed inside the peritoneal cavity in close vicinity to the ischemic gut segment. Gastric PiCO(2) was determined by using air tonometry. After baseline measurements, ileal ischemia was induced for 180 min followed by a 30-min reperfusion period. Statistics were performed with a Friedman test followed by Wilcoxon Analysis with P: < 0.01 considered significant. With the onset of local ileal ischemia, a sudden increase in i.p.-PCO(2) from 48.9 (45. 0-51.5) mm Hg (mean and 25-75 percentiles) to 94.3 (87.9-95.5; P: < 0.01) mm Hg was observed. Gastric PiCO(2) (49.0 [47.5-51.0]/53.5 [49. 0-54.0] mm Hg), and ileal PiCO(2) (56.4 [44.6-57.0]/54.3 [46.1-57.8] mm Hg) did not change. With reperfusion, the i.p.-PCO(2) decreased but stayed above baseline values. IMPLICATIONS: Unless systemic changes are induced, regional intestinal perfusion deficits cannot be detected with a PCO(2) measurement in the gastric lumen. In pigs, an occlusion of blood flow to an isolated gut segment resulted in a significant increase in intraperitoneal CO(2) tension. Thus, the measurement of intraperitoneal PCO(2) could allow the early detection of regional intestinal ischemia.

Continuous intramucosal PCO2 measurement allows the early detection of intestinal malperfusion.

OBJECTIVES: The intestinal metabolic and histologic changes that occur in the gastrointestinal tract with ischemia and that form the basis of intramucosal pH and PCO2 alterations have not been well established. Recent evidence suggests that apart from technical problems with gastric tonometry, some methodologic misconceptions in the interpretation of intramucosal pH and PCO2 exist. The present study was designed to demonstrate the effects of impaired mesenteric perfusion with specific consideration to the induced intramucosal PCO2 changes using a new technique, the continuous fiberoptic CO2 sensor, and a new concept of interpretation. DESIGN: Randomized, controlled intervention trial. SETTING: University animal laboratory. SUBJECTS: Twelve anesthetized female pigs, weighing 67+/-6 kg. INTERVENTIONS: The pigs were assigned to control and stenosis groups. In the stenosis group, blood flow in the superior mesenteric artery was reduced by 70% from baseline for 180 mins, followed by 120 mins of reperfusion. Serum lactate concentration, pH, PCO2, PO2, and bicarbonate concentration (cHCO3-) were determined in arterial, superior mesenteric venous, portal venous, hepatic venous, and pulmonary arterial blood. In the lumen of the ileum, intramucosal PCO2 was continuously determined by a fiberoptic CO2 sensor. At the end of the experiment, the gut was examined for histologic changes. MEASUREMENTS AND MAIN RESULTS: During mesenterial hypoperfusion, a sudden and significant increase in intramucosal PCO2 was observed. This increase was paralleled by increases in superior mesenteric venous PCO2 and portal venous PCO2 (p < .05) and a concomitant decrease in intramucosal pH, superior mesenteric venous pH, and portal venous pH. Arterial and mixed venous PCO2 and pH did not change. cHCO3- did not change in local or systemic blood samples. CONCLUSIONS: Compromised mesenteric blood flow causes significant metabolic and histologic changes. These local changes could not be detected by arterial or mixed venous lactate concentrations, pH, and PCO2 determinations. Under closed-system conditions, mesenteric CO2 accumulation causes an impairment of the CO2-HCO3- buffer, resulting in an unchanged cHCO3-. With impaired mesenteric perfusion, only intramucosal PCO2 alterations occur and an intramucosal pH calculation based on systemic cHCO3-changes is not necessarily correct. Therefore, the only parameter of importance is the intraluminal measurement of intramucosal PCO2 that can reflect isolated mesenteric changes. Thus, we recommended abolishing the terms "intramucosal pH measurement" and "gastric tonometry" and propose using the definition "intramucosal PCO2 measurement."

Anaesthetic considerations for acute spinal cord injury.

The recently published research data on the possible pathophysiology of acute spinal cord injury provide the basis of a number of exciting possibilities for its treatment. The present article reviews these lines of investigation. It focusses on methylprednisolone, which is the only effective proven therapy to limit secondary spinal cord injury known to date. In addition, the initial evaluation of patients with possible spinal cord trauma and airway management in patients with cervical spine injury are also discussed. Finally, the anaesthetic regimen in patients with these injuries is reviewed, showing that no anaesthetic agent or technique is superior to other anaesthetic methods.

[Intramucosal pCO2 measurement as gastrointestinal monitoring]. / Die intramukosale pCO2-Messung als gastrointestinales Monitoring.

The improvement of tissue perfusion by alterations in global parameters has led to the concept of supranormal oxygen delivery. However, this approach did not cause a significant reduction in the mortality of critical illness. As a consequence, recent research activity concentrates on regional monitoring and on the therapy of especially vulnerable, injury-prone organ systems. Gastric tonometry, a monitoring device of the gastrointestinal region that has produced promising results, can be considered as an area of special attention. The intramucosal pCO2 (piCO2) and the calculated intramucosal pH (pHi) of gastric tonometry can indicate an impairment of the gastrointestinal perfusion and thus point to an immanent injury of the barrier function of the gut mucosa. In clinical practice, however, apart from several technical problems with conventional, discontinuous gastric tonometry, some misconceptions exist in respect of the interpretation of derived pHi data. The technical problems can be overcome by a new fibreoptic piCO2 measurement, an automatic and continuous technique. The analysis of the obtained data must take the physiology of the CO2- and HCO3(-)-metabolism into account. Coupling of the locally derived piCO2 with systemic arterial HCO3- concentration that results in the pHi as the sensitive parameter of the gastrointestinal malperfusion as suggested by Fiddian Green, is not correct. Taking respiratory pCO2 changes into consideration, only the PiCO2 can detect gastrointestinal malperfusion. Therefore, the rather confusing terms "gastric tonometry" and "pHi measurement" should be avoided and the new monitoring technique be defined as "intramucosal pCO2 measurement". Continuous piCO2-measurement is a monitoring technique with high sensitivity in detecting gastrointestinal hypoperfusion based on an intramucosal CO2 accumulation. The clinical significance of the primary parameter piCO2 as well as the suitability of this technique as a monitoring tool for the daily routine must be re-assessed.

Cardiopulmonary effects of enoximone or dobutamine and nitroglycerin on mitral valve regurgitation and pulmonary venous hypertension.

OBJECTIVE: To compare the cardiovascular and pulmonary effects of the phosphodiesterase III inhibitor enoximone (EN) or a combination of dobutamine (DOB) and nitroglycerin (NTG) before and after mitral valve repair or replacement. DESIGN: Prospective, randomized, controlled clinical study. SETTING: University hospital. PARTICIPANTS: Twenty patients with mitral regurgitation and pulmonary venous hypertension scheduled for elective mitral valve surgery. INTERVENTIONS: Patients fulfilling the inclusion criteria of the study were randomly allocated into a group treated with EN (group 1, n = 10) or DOB and NTG (group 2, n = 10). A cardiopulmonary status was obtained after induction of anesthesia and mechanical ventilation during stable hemodynamic conditions (control). Then the patients received either EN (bolus dose 1.0 mg/kg followed by a continuous infusion of 10 micrograms/kg/min) or DOB (8.0 micrograms/kg/min) and NTG (1.0 microgram/kg/min) according to the randomization. After a period of 20 minutes, all parameters were measured again. The study drugs were stopped, and cardiac surgery was performed. Infusions of EN (without additional loading dose) or DOB and NTG were started again in the above-described doses 10 minutes before separation from cardiopulmonary bypass (CPB). Respiratory and hemodynamic measurements were made 20 minutes after weaning from CPB and 60 minutes after admission of the patient to the intensive care unit. MEASUREMENTS AND MAIN RESULTS: Both groups were comparable regarding preoperative and control data. Before mitral valve surgery, cardiac output (CO) and heart rate (HR) increased by 46% (p < 0.05) and 31% (p < 0.01) during infusion of EN with minor changes of mean systemic arterial pressure (PSA) and gas exchange. Mean pulmonary arterial pressure (PPA) decreased from 32 +/- 11 mmHg to 23 +/- 11 mmHg (p < 0.05). Similar alterations were observed in group 2 (delta CO + 26%, p < 0.05, delta HR + 39%, p < 0.01); however, PPA and calculated pulmonary vascular resistance remained unchanged. After separation from CPB, EN and DOB-NTG achieved comparable effects on CO, HR, and PSA, but PPA was significantly lower in group 1. In addition, venous admixture and alveolo-arterial oxygen tension gradient were lower in EN-treated patients. CONCLUSION: Enoximone or DOB and NTG have comparable effects on CO, PSA, and HR in mitral regurgitation and pulmonary hypertension, but EN is more effective in reducing PPA without deterioration of gas exchange.

Effects of enflurane and isoflurane on splanchnic oxygenation in humans.

STUDY OBJECTIVES: To determine the effects of enflurane and isoflurane on hepatic venous oxygen saturation (ShvO2) and splanchnic oxygen (O2) extraction. To measure hemodynamic parameters and ShvO2, mixed venous, and arterial lactate concentrations during enflurane and isoflurane anesthesia. DESIGN: Randomized, prospective study. SETTING: University hospital. PATIENTS: 20 ASA physical status I, II, and III adults, who underwent major abdominal surgery requiring mechanical ventilation a few hours postoperatively. INTERVENTIONS: After placement of catheters in the pulmonary artery, radial artery, peripheral and right hepatic vein, one hour postoperatively either enflurane or isoflurane was applied at different minimum alveolar concentration (MAC) of 0.5, 1.0, and 1.5 in a randomized order. MEASUREMENTS AND MAIN RESULTS: Before and 10 minutes after administration of each desired end-expiratory anesthetic concentration, the following parameters were determined: hemodynamic parameters, arterial (SaO2), mixed venous (SvO2), and hepatic venous oxygen saturations, systemic and splanchnic O2 extraction, arterial, mixed venous, and hepatic venous lactate concentrations. Cardiac output (CO) and mean arterial pressure (MAP) decreased in a dose dependent manner. SaO2, SvO2, and systemic O2 extraction remained unchanged with enflurane and isoflurane anesthesia. In the enflurane group, but not in the isoflurane group, ShvO2 decreased with increasing inhalational concentrations. This decrease in ShvO2 reflected an increase in splanchnic O2 extraction with enflurane; in contrast to isoflurane. CONCLUSIONS: Enflurane causes a decrease in ShvO2, which indicates an impairment of splanchnic perfusion corresponding to the reduction in CO and MAP in a dose-dependent manner. Isoflurane maintains splanchnic perfusion in contrast to enflurane.

Effects of positive end-expiratory pressure ventilation on splanchnic oxygenation in humans.

OBJECTIVES: To examine the influence of positive end-expiratory pressure (PEEP) ventilation on splanchnic oxygenation and lactate production in humans without pulmonary disorders. DESIGN: Prospective study. SETTING: Single-institutional surgical intensive care unit in a university hospital. PARTICIPANTS: Twenty patients who underwent major abdominal surgery. INTERVENTIONS: Radial artery, pulmonary artery, and right hepatic vein catheters. Blood samples were collected to determine lactate concentrations and oxygen saturations. MEASUREMENTS AND MAIN RESULTS: Six hours postoperatively PEEP levels (5, 10, and 15 cmH2O) were applied in a randomized order, and the following parameters were determined before and at the end of each PEEP level: cardiac output (CO); mean arterial pressure (MAP); arterial (SaO2), mixed venous (SvO2) and hepatic venous oxygen saturation (ShvO2); systemic (C[a-v]O2) and splanchnic (C[a-hv]O2) arterial venous oxygen content difference; and arterial, mixed venous, and hepatic venous lactate concentration. CO and MAP were reduced at PEEP 10 and 15 cmH2O, accompanied by a decrease in SvO2 but unchanged SaO2. A decrease in ShvO2 was seen at PEEP 15 cmH2O. C(a-v)O2 and C(a-hv)O2 were increased at PEEP 15 cmH2O. However, at PEEP 15 cmH2O, the percent increment in C(a-hv)O2 was greater than the increment in C(a-v)O2. Lactate concentrations remained unchanged. CONCLUSIONS: Ventilation with PEEP causes reductions in CO and MAP, resulting in a comparable impairment of systemic and splanchnic oxygen. The absence of changes in lactate concentrations indicates that a critical reduction in systemic and splanchnic oxygenation is unlikely during ventilation with low or high PEEP levels.

A new method for continuous intramucosal PCO2 measurement in the gastrointestinal tract.

Gastric tonometry has been introduced for the early detection of impaired splanchnic perfusion by determination of the intramucosal PCO2. However, due to methodological problems, i.e., instability of CO2 in water, to assess the exact intramucosal PCO2 with the nasogastric tonometer is unreliable. The present in vitro and in vivo study examines a new fiberoptic PCO2 sensor for the continuous determination of the intramucosal PCO2 and compares these data with that of conventional tonometry. In an in vitro experiment the fiberoptic PCO2 sensor was used to determine the PCO2 of water and humidified air with predefined CO2 values. In both media, predefined CO2 values (35, 42, 49 mm Hg) could be assessed exactly after 9 min of equilibration with a maximum deviation less than 3.5%. In contrast, the values obtained by conventional tonometry showed larger differences. In in vivo experiments on six pigs PCO2 differences were induced by ventilatory changes to validate the fiberoptic PCO2 sensor. Under anesthesia a laparotomy was performed, the ileum punctured, and the fiberoptic PCO2 sensor introduced into the ileal lumen. Arterial PCO2 (PaCO2), mesenteric venous PCO2 (PmvCO2), and intramucosal PCO2, (PiCO2) were determined during normoventilation, hypoventilation, and hyperventilation. During hypoventilation the PiCO2 increased from 53.8 +/- 2.0 mm Hg (PaCO2 = 39.8 +/- 1.4 mm Hg, PmvCO2 = 48.7 +/- 2.7 mm Hg) to 66.5 +/- 4.9 mm Hg (PaCO2 = 52.7 +/- 3.1 mm Hg, PmvCO2 = 62.4 +/- 5.7 mm Hg). With hyperventilation the PiCO2 decreased to 46.8 +/- 2.5 mm Hg (PaCO2 = 29.8 +/- 1.8 mm Hg, PmvCO2 = 41.8 +/- 2.7 mm Hg). The coefficient of correlation (r2) between PiCO2 and PaCO2 was 0.82, and between PiCO2 and PmvCO2 0.94. The fiberoptic PCO2 sensor can determine PiCO2 in a precise and reliable manner, and can continuously record fast intraluminar changes of CO2 in the ileum that were caused by ventilatory changes. The fiberoptic PCO2 sensor is the only method that reliably monitors PiCO2 in the gastrointestinal tract. By the direct measurement of PCO2 the methodological problems associated with the conventional nasogastric tonometry are abolished.

Gastric tonometry: precision and reliability are improved by a phosphate buffered solution.

OBJECTIVE: To compare a phosphate buffered solution with normal saline as tonometric fluid in intramucosal PCO2 measurement in humans. DESIGN: Prospective, unblinded comparison. SETTING: Postsurgical critical care unit of a university hospital. PATIENTS: Six septic patients. INTERVENTIONS: Two tonometric probes were positioned in the gastric lumen in each patient. One tube was used for conventional tonometry (saline-filled balloon), while phosphate buffered solution was instilled into the second tube. MEASUREMENTS AND MAIN RESULTS: PCO2 was determined with three blood gas analyzers (ABL 2 [Radiometer, Copenhagen, Denmark], Corning 288 [Ciba Corning Diagnostics GmbH, Neuss, Germany], and StatProfile 9 Plus [Nova Biomedical, Waltham, MA]). Eight parallel PCO2 measurements per patient were evaluated, yielding a total of 48 measurements with each tonometric solution. Intrainstrumental comparison of the PCO2 determinations demonstrated an increase of 12.3 +/- 9.9% for ABL 2, 3.10 +/- 12.9% for Ciba Corning 288, and 101.2 +/- 31.5% for StatProfile 9 Plus with the phosphate buffered solution. The PCO2 values were decreased by the following amounts when the three instruments were compared, using the saline method: 14.2 +/- 8.2% (Ciba Corning 288 vs. ABL 2); 40.7 +/- 9.9% (StatProfile 9 Plus vs. ABL 2); and 30.9 +/- 9.35% (StatProfile 9 Plus vs. Ciba Corning 288). The difference in PCO2 determination, resulting from the different instrument designs, were significant between the three blood gas analyzers (p<.001). In addition, the variance of the intramucosal PCO2 values was significant between blood gas analyzers (p<.001) with normal saline as tonometric solution, but not with phosphate buffered solution. The coefficients of determination between PCO2 values in saline and phosphate buffered solution were r2=.85 for ABL 2, r2=.81 for Ciba Corning 288, and r2=.74 for StatProfile 9 Plus. When all 48 PCO2 values were analyzed, the interinstrumental coefficients of determination within a method for saline (and for phosphate buffered solution in parenthesis) were:r2=.83 (.92) between ABL 2 and Ciba Corning 288, r2=.72 (.92) between ABL 2 and StatProfile 9 Plus, and r2=.81 (.98) between Ciba Corning 288 and StatProfile 9 Plus. CONCLUSIONS: A considerable instrumental bias in PCO2 analysis is observed when saline is used as tonometric fluid in gastric tonometry, thus preventing a reliable determination of intramucosal pH. The present in vivo data show that the accuracy and reliability of intramucosal pH measurement can be improved by the use of phosphate buffered solution as tonometric fluid.