Neutrophil extracellular traps promote cancer-associated inflammation and myocardial stress.

Cancer is associated with systemic pathologies that contribute to mortality, such as thrombosis and distant organ failure. The aim of this study was to investigate the potential role of neutrophil extracellular traps (NETs) in myocardial inflammation and tissue damage in treatment-naïve individuals with cancer. Mice with mammary carcinoma (MMTV-PyMT) had increased plasma levels of NETs measured as H3Cit-DNA complexes, paralleled with elevated coagulation, compared to healthy littermates. MMTV-PyMT mice displayed upregulation of pro-inflammatory markers in the heart, myocardial hypertrophy and elevated cardiac disease biomarkers in the blood, but not echocardiographic heart failure. Moreover, increased endothelial proliferation was observed in hearts from tumor-bearing mice. Removal of NETs by DNase I treatment suppressed the myocardial inflammation, expression of cardiac disease biomarkers and endothelial proliferation. Compared to a healthy control group, treatment-naïve cancer patients with different malignant disorders had increased NET formation, which correlated to plasma levels of the inflammatory marker CRP and the cardiac disease biomarkers NT-proBNP and sTNFR1, in agreement with the mouse data. Altogether, our data indicate that NETs contribute to inflammation and myocardial stress during malignancy. These findings suggest NETs as potential therapeutic targets to prevent cardiac inflammation and dysfunction in cancer patients.

The pro-inflammatory role of platelets in cancer.

Thrombosis is a frequent issue in cancer patients. Tumor-induced platelet activation and coagulation does not only constitute a significant risk for thrombosis, but also contribute to tumor progression by promoting critical processes such as angiogenesis and metastasis. In addition to their role in hemostasis, platelets are increasingly recognized as regulators of inflammation. By modulating the immune system, platelets regulate several aspects of cancer-associated pathology. Platelets influence the inflammatory response in cancer by affecting the activation status of the endothelium and by recruiting leukocytes to primary and metastatic tumor sites, as well as to distant organs unaffected by tumor growth. Furthermore, platelets participate in the formation of neutrophil extracellular traps, which can promote metastasis, thrombosis, and contribute to organ failure. In this review, we discuss the role of platelets as coordinators of the immune system during malignant disease and the potential of targeting platelets to prevent cancer-associated pathology.

Tumor-Induced Local and Systemic Impact on Blood Vessel Function.

Endothelial dysfunction plays a role in several processes that contribute to cancer-associated mortality. The vessel wall serves as a barrier for metastatic tumor cells, and the integrity and activation status of the endothelium serves as an important defense mechanism against metastasis. In addition, leukocytes, such as cytotoxic T-cells, have to travel across the vessel wall to enter the tumor tissue where they contribute to killing of cancer cells. Tumor cells can alter the characteristics of the endothelium by recruitment of leukocytes such as neutrophils and macrophages, which further stimulate inflammation and promote tumorigenesis. Recent findings also suggest that leukocyte-mediated effects on vascular function are not limited to the primary tumor or tissues that represent metastatic sites. Peripheral organs, such as kidney and heart, also display impaired vascular function in tumor-bearing individuals, potentially contributing to organ failure. Here, we discuss how vascular function is altered in malignant tissue and distant organs in individuals with cancer and how leukocytes function as potent mediators of these tumor-induced effects.

Immediate and 5-year cumulative outcome after paediatric intensive care in Sweden.

BACKGROUND: Little has been reported about intensive care of children in Sweden. The aims of this study are to (I) assess the number of admissions, types of diagnoses and length-of-stay (LOS) for all Swedish children admitted to intensive care during the years 1998-2001, and compare paediatric intensive care units (PICUs) with other intensive care units (adult ICUs) (II) assess immediate (ICU) and cumulative 5-year mortality and (III) determine the actual consumption of paediatric intensive care for the defined age group in Sweden. METHODS: Children between 6 months and 16 years of age admitted to intensive care in Sweden were included in a national multicentre, ambidirectional cohort study. In PICUs, data were also collected for infants aged 1-6 months. Survival data were retrieved from the National Files of Registration, 5 years after admission. RESULTS: Eight-thousand sixty-three admissions for a total of 6661 patients were identified, corresponding to an admission rate of 1.59/1000 children per year. Median LOS was 1 day. ICU mortality was 2.1% and cumulative 5-year mortality rate was 5.6%. Forty-four per cent of all admissions were to a PICU. CONCLUSIONS: This study has shown that Sweden has a low immediate ICU mortality, similar in adult ICU and PICU. Patients discharged alive from an ICU had a 20-fold increased mortality risk, compared with a control cohort for the 5-year period. Less than half of the paediatric patients admitted for intensive care in Sweden were cared for in a PICU. Studies are needed to evaluate whether a centralization of paediatric intensive care in Sweden would be beneficial to the paediatric population.

Effects of dexamethasone on clinical course, C-reactive protein, S100B protein and von Willebrand factor antigen after paediatric cardiac surgery.

BACKGROUND: Anti-inflammatory treatment with glucocorticoids during cardiopulmonary bypass can reduce inflammatory mediator release, but the effects of glucocorticoid on outcome are controversial. METHODS: We studied the effects of dexamethasone on clinical course, C-reactive protein, von Willebrand factor antigen (vWf:Ag) and S100B in a randomized masked study of children after open cardiac surgery. Twenty children weighing >10 kg received dexamethasone (1 mg kg(-1)) and 20 controls received saline after induction of anaesthesia. We measured vWf:Ag as a marker of endothelial activation, S100B as a marker of cerebral protein release and C-reactive protein as a marker of inflammatory activity. Oxygenation, body temperature, fluid balance, leucocyte and platelet counts, days in the intensive care unit (ICU) and days on mechanical ventilation were noted. RESULTS: Dexamethasone decreased C-reactive protein concentration on the first postoperative day (P<0.05), but did not affect the release of vWf:Ag or S100B. There was no significant difference in oxygenation, body temperature, fluid balance, leucocyte and platelet counts, days in the ICU or days on mechanical ventilation between the placebo and dexamethasone-treated groups. CONCLUSION: Administration of dexamethasone before cardiopulmonary bypass for paediatric cardiac surgery decreased the inflammatory response, but did not affect the immediate features after surgery or changes in vWf:Ag or S100B.

How common is severe pulmonary hypertension after pediatric cardiac surgery?

BACKGROUND: Pulmonary hypertension may result in significant morbidity and mortality after pediatric cardiac surgery. The objective of this study was to determine the incidence and outcome of severe pulmonary hypertension, defined as a ratio of pulmonary to systemic arterial pressure equal to or greater than 1.0, after cardiac surgery in children. METHODS: Data from all children younger than 18 years who had undergone cardiothoracic surgery from January 1, 1994, to December 31, 1998, were examined. To find children with severe pulmonary hypertension, we reviewed intensive care unit charts from patients who had been monitored with a pulmonary artery catheter after the operation (n = 151), had received mechanical ventilation for more than 4 days after the operation (n = 124), or had died in the operating room or the intensive care unit (n = 22). Intraoperative and postoperative measurements of mean pulmonary arterial pressure and postoperative echocardiographic studies during the first 3 postoperative days were used to select the children. RESULTS: During the study period, 1349 children (including 164 neonates and 511 infants, median age 12 months) underwent cardiac operations with an overall perioperative mortality of 22 patients (1.6%). Twenty-seven children (2%, median age 4.2 months) had severe pulmonary hypertension. Of these, 2 (7.4%) died within 30 days of the operation, and 3 others (11%) died within a year (median follow-up 53 months). Nitric oxide inhalation was used in 5 of the 27 cases, and it probably saved the life of 1 patient, may have helped in 1 case, and had no discernible effect in 3 cases. Severe pulmonary hypertension was most common after correction of complete atrioventricular septal defects (14%, n = 12/85). Thirteen of 131 children with Down syndrome (9.9%) had severe pulmonary hypertension. CONCLUSION: Severe postoperative pulmonary hypertension occurred after 2% of the cardiac procedures and in most cases was managed successfully with conventional treatment and had a favorable postoperative outcome. The low incidence relative to previous reports may reflect the benefits of early correction and improved intraoperative and postoperative care.

A functional role for ERK in gene induction, but not in neurite outgrowth in differentiating neuroblastoma cells.

The human neuroblastoma cell line SH-SY5Y can differentiate into a functional sympathetic neuronal phenotype when treated with low concentrations of the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) in the presence of serum or defined growth factors. When TrkA is introduced into the cells, NGF also induces differentiation. In both cases, protein kinase C (PKC) is pivotal for induction and maintenance of the differentiated phenotype. We have recently shown that PKC activity is needed to enable the MAPK ERK to accumulate in the nucleus of SH-SY5Y cells and hence activate transcription. To find out whether this could be one reason for the PKC dependency in the differentiation process we have investigated the role of ERK during neuronal differentiation of these cells. The results show that ERK was needed for full upregulation of the neuronal marker genes NPY and GAP-43. However, ERK activity was not necessary for TPA-induced neurite formation. Neither was activation of ERK sufficient to promote neurite outgrowth. The results clearly show that there was no correlation between nuclear ERK activity, measured as SRE transactivation, and neurite formation in TPA-differentiated SH-SY5Y neuroblastoma cells.

Activation and protein kinase C-dependent nuclear accumulation of ERK in differentiating human neuroblastoma cells.

The human neuroblastoma cell line SH-SY5Y is a well characterized model for sympathetic neuronal differentiation in vitro. Several differentiation protocols exist, one of which, the addition of the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) in the presence of serum, has been thoroughly studied. Wild-type SH-SY5Y cells are unresponsive to nerve growth factor (NGF), but cells transfected with the high-affinity NGF receptor TrkA (SH-SY5Y/TrkA) differentiate in response to NGF. In the present study, we have addressed the existence of a differentiation-specific mode of activation and subcellular distribution of the extracellular signal-regulated kinases ERK1 and ERK2 in SH-SY5Y/wt and SH-SY5Y/TrkA. Both TPA and NGF induced a sustained activation and nuclear accumulation of ERK that was accompanied by transactivation of a serum response element (SRE)-driven reporter and of the c-fos gene. However, activation and nuclear accumulation of ERK were not sufficient to induce neuronal differentiation in SH-SY5Y, as demonstrated by the response to TPA in serum-free cultures. Nuclear accumulation but not activation of ERK was demonstrated to require active protein kinase C (PKC). The effect of specific PKC inhibitors on subcellular distribution of ERK and ERK-dependent transcription suggests a functional role for PKC in the regulation of nuclear ERK activity in SH-SY5Y neuroblastoma cells.

Serum S-100 protein levels after pediatric cardiac operations: a possible new marker for postperfusion cerebral injury.

BACKGROUND: The release of neuron-specific astroglial S-100 protein to the cerebrospinal fluid is a marker of cerebral damage. The aim of this study was to determine the pattern of release of S-100 protein to serum after pediatric cardiac operations and extracorporeal circulation. METHODS: Sequential blood samples from 97 children (up to 16 years) were taken after induction of anesthesia, immediately after the discontinuation of extracorporeal circulation, and 5 and 15 hours after extracorporeal circulation. The children were divided into five groups including three age groups, children with Mb Down syndrome, and children undergoing circulatory arrest. RESULTS: The serum concentrations of S-100 protein before the cardiac operation were found to be highest in neonates. Children with Down syndrome, regardless of age, had basal levels comparable to those in neonates. There was an increase in S-100 protein concentration immediately after extracorporeal circulation and a multivariate regression analysis showed this difference in S-100 protein concentration to be significant with respect to age (p = 0.002), perfusion time (p < 0.001), and circulatory arrest (p < 0.001), but the difference was not significant with respect to weight, Down syndrome, and core temperature (p > 0.8). In children younger than 1 month old and after circulatory arrest, levels of S-100 protein remained high at 5 hours after extracorporeal circulation. CONCLUSION: These findings emphasize the necessity of using age-matched reference values and taking perfusion time into consideration when S-100 protein levels are evaluated with respect to cerebral postperfusion injuries in pediatric patients undergoing cardiac operations.

Successful thrombolysis of an occluded modified Blalock shunt three days after operation.

A 10-day-old boy with pulmonary atresia received a right-sided aortopulmonary polytetrafluoroethylene shunt. Three days after the operation he became cyanotic and was reintubated. Shunt occlusion was confirmed with angiography. Recombinant tissue plasminogen activator was given locally into the proximal end of the shunt. The thrombus was completely resolved after 2 days. When administration of recombinant tissue plasminogen activator was stopped, heparin infusion was started for 5 days. Shunt patency was demonstrated by angiography at 3 months postoperatively.

Hemodynamic effects of tracheal and intravenous adrenaline in infants with congenital heart anomalies.

BACKGROUND: If intravenous access cannot be accomplished during cardiopulmonary resuscitation in children, tracheal administration of 100 micrograms/kg of adrenaline (ten times greater than the intravenous dose) is recommended. METHODS: In a randomized crossover study we recoreded the hemodynamic effect of a low dose of intravenous adrenaline and a ten times greater tracheal dose. While anesthetized for open heart surgery, fourteen infants received one dose of adrenaline intravenously (0.3 microgram/kg) and the other tracheally (3 micrograms/kg). RESULTS: During the first 5 minutes after administration mean arterial pressure (MAP) and heart rate (HR) increased after both intravenous and tracheal administration (P < 0.001). The maximum increase in MAP was 28% (17-68%, median and range) after intravenous injection and 20% (6-69%, P < 0.05 when compared to intravenous injection) after tracheal instillation. In four infants, MAP increased less than 10% after tracheal instillation. The maximum increases in MAP and HR occurred 1 min (1-2 min) after intravenous injection and 3 min (2-4 min) after tracheal instillation (P < 0.001). CONCLUSION: Tracheal administration 3 micrograms/kg adrenaline increased mean arterial blood pressure in infants with congenital cardiac anomalies, but the increase occurred later and was less consistent than after 0.3 microgram/kg of adrenaline given intravenously.

Congenital heart malformations and ventilatory efficiency in children. Effects of lung perfusion during halothane anaesthesia and spontaneous breathing.

The efficiency of spontaneous ventilation during halothane anaesthesia was investigated in 18 infants and children with congenital heart disease presenting either with hyperperfusion and left-to-right shunt (group LR: n = 10, body weight 3.7-16 kg) or with hypoperfusion and right-to-left shunt (group RL: n = 8, body weight 3.4-12 kg). Minute ventilation (VE) and tidal volume (VT) were greater in group RL than in group LR (P less than 0.05) while ventilatory rates were similar. Dynamic compliance and total pulmonary resistance were of the same magnitude in the two groups. Alveolar ventilation (VA) calculated from arterial carbon dioxide tensions (PaCO2) was the same in both groups while corresponding deadspace ventilation (VD) was higher in group RL (P less than 0.01). VE/VCO2 and VD/VT ratios were higher in children with a diminished pulmonary blood flow than in children with an increased pulmonary blood flow (P less than 0.05 and P less than 0.01, respectively) indicating a less efficient gas exchange in children with a right-to-left shunt. This was compensated for by an increased inspiratory drive as reflected by higher VT/TI ratio (P less than 0.01) and a more pronounced airway occlusion pressure (P less than 0.05).

Spontaneous versus controlled ventilation in anaesthetized children with congenital cardiac malformations.

The effects of intermittent positive pressure ventilation on gas exchange were studied in 12 children with congenital cardiac malformation. Six children (b.w. 3.7-16 kg) had a left-to-right shunt (Group LR) resulting in overperfused lungs, while six others (b.w. 3.4-12 kg) had a right-to-left shunt (Group RL) with oligaemic lungs. Measurements, prior to surgery, were done during spontaneous breathing (SB) and controlled mechanical ventilation (CMV) with a short (25%) and a long (55%) duration of inspiration. In children with oligaemic lungs P(a-E')CO2 differences and VD/VT ratios were greater and PaO2 was lower than in those with overperfused lungs, indicating a less efficient ventilation. In Group RL, ventilation and gas exchange during SB were similar at the two settings of CMV. In Group LR, however, VD/VT was reduced during CMV, with the lowest VD/VT ratio at the longer inspiration time. It is concluded that in children with an oligaemic lung perfusion, either of the two ventilator settings could be used. When controlled ventilation is to be used in children with overperfused lungs, the longer duration of inspiration seems to be preferable.

Respiratory drive and timing before and during CO2 inhalation in infants anaesthetized with halothane.

To evaluate respiratory drive and timing in 11 spontaneously breathing infants anaesthetized with halothane, ventilation was followed before and during CO2 provocation, and occlusion tests were performed. All infants were younger than 6 months of age and their weights ranged from 3.8 to 7.5 kg. All measurements were performed prior to surgery. Tidal volumes (VT) were followed by pneumotachography and end-tidal CO2 concentration [E'CO2) by an in-line capnograph. Occlusion pressure curves were biphasic with an initial fast phase (pressure: P degree fast, duration: T degree fast) followed by a slower phase to the maximal occluded infra-airway pressure (P degree max, T degree max). During CO2 breathing, mean values of P degree fast increased by 75% (P less than 0.001) and of P degree max by 73% (P less than 0.001) compared with at CO2-free breathing. The slope of the fast phase (delta P/delta t) was significantly increased during CO2 breathing while the slow phase was unchanged by the presence of CO2. The P degree fast/P degree max ratio was of the same size before and during CO2 inhalation. Inhalation of CO2 did not influence inspiratory (T1) and expiratory (TE) times during unoccluded breathing. A variable respiratory pattern was revealed during occlusion whilst CO2-free breathing: T degree max was longer than (T1) in nine cases and shorter in two. A more uniform response in ventilatory timing was found at CO2 loaded ventilation and T degree max as well as the total duration of the ventilatory cycle (T degree tot) were significantly longer than (T1) (P less than 0.01) and (Ttot) (P less than 0.05) respectively. The V1/T1 ratio was increased by 66% during CO2 provocation during unoccluded breathing. The net effect of increased inspiratory drive during CO2 breathing resulted in a VT which on average was increased by 67% (P less than 0.001) so that the mean value of E'CO2 only rose by 0.98% (P less than 0.01) from 5.18% before to 6.16% during CO2 breathing. It was concluded that ventilatory compensation to CO2 was adequate, indicating preserved respiratory centre activity. Respiratory timing, however, was unaffected by CO2 indicating a discrepancy between the effects of halothane on respiratory motor centre activity and the bulbopontine pacemaker in these young infants.

Pulmonary ventilation, CO2 response and inspiratory drive in spontaneously breathing young infants during halothane anaesthesia.

Pulmonary ventilation, CO2 response and inspiratory drive were studied during halothane anaesthesia prior to surgery in 13 spontaneously breathing infants less than 6 months of age. Pneumotachography and capnography were used. Airway and oesophageal pressures were measured and occlusion tests were performed at functional residual capacity. Measurements were made before and during 8 min of 4% CO2 stimulation. Inspiratory drive increased significantly (P less than 0.001) at CO2 stimulation. This resulted in increased minute ventilation (P less than 0.001) and tidal volume (P less than 0.001) while respiratory rate was unchanged. As VBohrD/VT ratios were the same, the net effect was increased alveolar ventilation (P less than 0.001). CO2 elimination was unpredictable in these young infants and decreased during CO2 stimulation (P less than 0.05), while mean end-tidal CO2 concentration only increased from 5.2 to 6.3% (P less than 0.001). The ventilatory response to 4% CO2 could therefore be deemed to be adequate during the short period (8 min) of CO2 breathing. However, this was achieved at the cost of increased work as witnessed by the increased ratio between minute ventilation and CO2 elimination (P less than 0.01). Stabilisation of end-tidal CO2 concentrations during CO2 inhalation took only 10 s while the maximal increase in ventilation volumes was not achieved until after 150 s. It is concluded that young spontaneously breathing infants anaesthetized with halothane (MAC 1.3) have an increased respiratory drive with greater tidal volumes during CO2 stimulations. Respiratory timing, dynamic compliance and total pulmonary resistance were, however, uninfluenced by 4% CO2 stimulation. Increased monitoring of CO2 output in anaesthetized infants is suggested.

Ventilation, dynamic compliance and ventilatory response to CO2. Effects of age and body weight in infants and children.

Age dependent variations in minute ventilation (VE), tidal volume (Vr), respiratory rate and dynamic compliance (Cdyn) as well as ventilatory response to inhalation of carbon dioxide (CO2) were investigated in 20 spontaneously breathing intubated infants and children during halothane anaesthesia. Ages ranged from 6 days to 5 years. Seven patients were younger than 6 months of age. Ventilation volumes were measured by pneumotachography and end tidal carbon dioxide concentration by an in-line capnograph. Fluid-filled oesophageal catheters were used for pressure recordings. Measurements were made before surgery (with and without 2.22 and 3.71% of CO2 in inspired gas) and during surgery. Regression analysis of the relationship between VE and body weight revealed no direct proportionality. On a weight basis, VE was significantly higher in younger than in older patients. Tidal volume was directly proportional to body weight. The mean (SEM) value of tidal volume was 4.3 (0.2) ml/kg. Dynamic compliance showed a direct proportionality with weight. The mean (SEM) value of Cdyn was 10 (1.1) ml/kPa/kg. There was no ventilatory response in any patient to inhalation of 2.22% CO2. In the older group of children (greater than 6 months of age) VE increased by 34% during inhalation of 3.71% CO2 (p less than 0.025). In the younger patients (less than 6 months of age) no ventilatory response to inhalation of 3.71% of CO2 was found, indicating a more pronounced depression of ventilation in these infants.

[Buprenorphine (Temgesic) as a peroperative analgesic. A multicenter study]. / Buprenorphin (Temgesic) als peroperatives Analgetikum. Eine multizentrische Studie.

Using buprenorphine as sole intravenous analgesic in balanced anaesthesia, we tried to find the most suitable dose of buprenorphine, and compared it to fentanyl, regarding analgetic, circulatory and side effects. Initial doses of 5, 10 and 15 micrograms/kg buprenorphine and 10 micrograms/kg fentanyl were compared. Peroperative analgesia was adequate with both drugs and neither gave circulatory effects of clinical significance. After buprenorphine three of 60 patients and after fentanyl five of 11 patients were given naloxone. Nausea was more common after buprenorphine. Postoperative analgesia after the last dose of buprenorphine averaged 13 h, highly significantly longer than the 2 h after fentanyl. The overall course was considered good in 93% of buprenorphine and 100% of fentanyl cases. Buprenorphine doses are discussed.

Malignant hyperthermia in a myopathic child. Prolonged postoperative course requiring dantrolene.

An 18-month-old boy with congenital muscular dystrophy began to develop clear signs of the malignant hyperthermia syndrome after 85 min of halothane/nitrous oxide anaesthesia. Dantrolene, 2 mg/kg i.v., was immediately effective, but temperature, heart rate and carbon dioxide production were all increased for 2 days postoperatively in spite of repeated dantrolene administration.