A Uniform Description of Perioperative Brain MRI Findings in Infants with Severe Congenital Heart Disease: Results of a European Collaboration.

BACKGROUND AND PURPOSE: A uniform description of brain MR imaging findings in infants with severe congenital heart disease to assess risk factors, predict outcome, and compare centers is lacking. Our objective was to uniformly describe the spectrum of perioperative brain MR imaging findings in infants with congenital heart disease. MATERIALS AND METHODS: Prospective observational studies were performed at 3 European centers between 2009 and 2019. Brain MR imaging was performed preoperatively and/or postoperatively in infants with transposition of the great arteries, single-ventricle physiology, or left ventricular outflow tract obstruction undergoing cardiac surgery within the first 6 weeks of life. Brain injury was assessed on T1, T2, DWI, SWI, and MRV. A subsample of images was assessed jointly to reach a consensus. RESULTS: A total of 348 MR imaging scans (180 preoperatively, 168 postoperatively, 146 pre- and postoperatively) were obtained in 202 infants. Preoperative, new postoperative, and cumulative postoperative white matter injury was identified in 25%, 30%, and 36%; arterial ischemic stroke, in 6%, 10%, and 14%; hypoxic-ischemic watershed injury in 2%, 1%, and 1%; intraparenchymal cerebral hemorrhage, in 0%, 4%, and 5%; cerebellar hemorrhage, in 6%, 2%, and 6%; intraventricular hemorrhage, in 14%, 6%, and 13%; subdural hemorrhage, in 29%, 17%, and 29%; and cerebral sinovenous thrombosis, in 0%, 10%, and 10%, respectively. CONCLUSIONS: A broad spectrum of perioperative brain MR imaging findings was found in infants with severe congenital heart disease. We propose an MR imaging protocol including T1-, T2-, diffusion-, and susceptibility-weighted imaging, and MRV to identify ischemic, hemorrhagic, and thrombotic lesions observed in this patient group.

Epidemiology and Etiology of Severe Childhood Encephalitis in The Netherlands.

BACKGROUND: Limited data are available on childhood encephalitis. Our study aimed to increase insight on clinical presentation, etiology, and clinical outcome of children with severe encephalitis in the Netherlands. METHODS: We identified patients through the Dutch Pediatric Intensive Care Evaluation database and included children diagnosed with encephalitis <18 years of age admitted to 1 of the 8 pediatric intensive care units (PICU) in the Netherlands between January 2003 and December 2013. We analyzed demographic characteristics, clinical symptoms, neurologic imaging, etiology, treatment and mortality. RESULTS: We included 121 children with a median age of 4.6 years (IQR 1.3-9.8). The most frequently described clinical features were headache (82.1%), decreased consciousness (79.8%) and seizures (69.8%). In 44.6% of the children, no causative agent was identified. Viral- and immune-mediated encephalitis were diagnosed in 33.1% and 10.7% of the patients. A herpes simplex virus infection (13.2%) was mainly seen in children <5 years of age, median age, 1.73 years (IQR 0.77-5.01), while immune-mediated encephalitis mostly affected older children, median age of 10.4 years (IQR, 3.72-14.18). An age of ≥ 5 years at initial presentation was associated with a lower mortality (OR 0.2 [CI 0.08-0.78]). The detection of a bacterial (OR 9.4 [CI 2.18-40.46]) or viral (OR 3.7 [CI 1.16-11.73]) pathogen was associated with a higher mortality. CONCLUSIONS: In almost half of the Dutch children presenting with severe encephalitis, a causative pathogen could not be identified, underlining the need for enhancement of microbiologic diagnostics. The detection of a bacterial or viral pathogen was associated with a higher mortality.

Brain and CSF Volumes in Fetuses and Neonates with Antenatal Diagnosis of Critical Congenital Heart Disease: A Longitudinal MRI Study.

BACKGROUND AND PURPOSE: Fetuses and neonates with critical congenital heart disease are at risk of delayed brain development and neurodevelopmental impairments. Our aim was to investigate the association between fetal and neonatal brain volumes and neonatal brain injury in a longitudinally scanned cohort with an antenatal diagnosis of critical congenital heart disease and to relate fetal and neonatal brain volumes to postmenstrual age and type of congenital heart disease. MATERIALS AND METHODS: This was a prospective, longitudinal study including 61 neonates with critical congenital heart disease undergoing surgery with cardiopulmonary bypass <30 days after birth and MR imaging of the brain; antenatally (33 weeks postmenstrual age), neonatal preoperatively (first week), and postoperatively (7 days postoperatively). Twenty-six had 3 MR imaging scans; 61 had at least 1 fetal and/or neonatal MR imaging scan. Volumes (cubic centimeters) were calculated for total brain volume, unmyelinated white matter, cortical gray matter, cerebellum, extracerebral CSF, and ventricular CSF. MR images were reviewed for ischemic brain injury. RESULTS: Total fetal brain volume, cortical gray matter, and unmyelinated white matter positively correlated with preoperative neonatal total brain volume, cortical gray matter, and unmyelinated white matter (r = 0.5-0.58); fetal ventricular CSF and extracerebral CSF correlated with neonatal ventricular CSF and extracerebral CSF (r = 0.64 and 0.82). Fetal cortical gray matter, unmyelinated white matter, and the cerebellum were negatively correlated with neonatal ischemic injury (r = -0.46 to -0.41); fetal extracerebral CSF and ventricular CSF were positively correlated with neonatal ischemic injury (r = 0.40 and 0.23). Unmyelinated white matter:total brain volume ratio decreased with increasing postmenstrual age, with a parallel increase of cortical gray matter:total brain volume and cerebellum:total brain volume. Fetal ventricular CSF:intracranial volume and extracerebral CSF:intracranial volume ratios decreased with increasing postmenstrual age; however, neonatal ventricular CSF:intracranial volume and extracerebral CSF:intracranial volume ratios increased with postmenstrual age. CONCLUSIONS: This study reveals that fetal brain volumes relate to neonatal brain volumes in critical congenital heart disease, with a negative correlation between fetal brain volumes and neonatal ischemic injury. Fetal brain imaging has the potential to provide early neurologic biomarkers.

[Childhood drowning in the Netherlands]. / Verdrinking bij kinderen in Nederland.

OBJECTIVE: To investigate susceptible groups and risk factors for childhood drowning in the Netherlands with the aim of improving prevention campaigns. DESIGN: Prospective and partly retrospective. METHOD: Information about drowning accidents in 2010 and 2011 was collected using two methods. Firstly, drowning - with or without a fatal outcome - was added to the list of conditions to be reported to the Netherlands Paediatric Surveillance Unit (NSCK). Paediatricians received a comprehensive questionnaire when they had reported on drowning. Additional information on drowning was collected from online media (news websites and online journals). RESULTS: A total of 82 reports of drowning were analysed (63 from the paediatricians' survey and 19 additional reports from online media). Twenty-three children died as a result of drowning in the Netherlands in 2010 and 2011. Fifty-four percent of all cases of drowning were in children younger than 4 years. Boys were victims in 71% of the cases. Half (51%) of the accidents happened because the parents or caregivers lost sight of the children. In 27% of cases the accident took place in or around the home. Twenty-one children (26%) were victims of drowning in a public swimming pool and 5 of these children died. CONCLUSION: Better and continuous supervision of young children could help prevent more cases of drowning. Open water in proximity to the home should be fenced off. Continuous good supervision is also essential in public swimming pools.

Liposome-encapsulated dexamethasone attenuates ventilator-induced lung inflammation.

BACKGROUND AND PURPOSE: Systemic glucocorticoid therapy may effectively attenuate lung inflammation but also induce severe side-effects. Delivery of glucocorticoids by liposomes could therefore be beneficial. We investigated if liposome-encapsulated dexamethasone inhibited ventilator-induced lung inflammation. Furthermore, we evaluated whether targeting of cellular Fcγ-receptors (FcγRs) by conjugating immunoglobulin G (IgG) to liposomes, would improve the efficacy of dexamethasone-liposomes in attenuating granulocyte infiltration, one of the hallmarks of lung inflammation. EXPERIMENTAL APPROACH: Mice were anaesthetized, tracheotomized and mechanically ventilated for 5 h with either 'low' tidal volumes ∼7.5 mL·kg(-1) (LV(T) ) or 'high' tidal volumes ∼15 mL·kg(-1) (HV(T) ). At initiation of ventilation, we intravenously administered dexamethasone encapsulated in liposomes (Dex-liposomes), dexamethasone encapsulated in IgG-modified liposomes (IgG-Dex-liposomes) or free dexamethasone. Non-ventilated mice served as controls. KEY RESULTS: Dex-liposomes attenuated granulocyte infiltration and IL-6 mRNA expression after LV(T) -ventilation, but not after HV(T) -ventilation. Dex-liposomes also down-regulated mRNA expression of IL-1ß and KC, but not of CCL2 (MCP-1) in lungs of LV(T) and HV(T) -ventilated mice. Importantly, IgG-Dex-liposomes inhibited granulocyte influx caused by either LV(T) or HV(T) -ventilation. IgG-Dex-liposomes diminished IL-1ß and KC mRNA expression in both ventilation groups, and IL-6 and CCL2 mRNA expression in the LV(T) -ventilated group. Free dexamethasone prevented granulocyte influx and inflammatory mediator expression induced by LV(T) or HV(T) -ventilation. CONCLUSIONS AND IMPLICATIONS: FcγR-targeted IgG-Dex-liposomes are pharmacologically more effective than Dex-liposomes particularly in inhibiting pulmonary granulocyte infiltration. IgG-Dex-liposomes inhibited most parameters of ventilator-induced lung inflammation as effectively as free dexamethasone, with the advantage that liposome-encapsulated dexamethasone will be released locally in the lung thereby preventing systemic side-effects.

Transmission of respiratory syncytial virus at the paediatric intensive-care unit: a prospective study using real-time PCR.

Transmission of respiratory syncytial virus (RSV) from children with lower respiratory tract infection (LRTI) at a paediatric intensive-care unit (PICU) was examined using a highly sensitive real-time PCR. Twenty-four children with RSV LRTI were admitted during the study period (total days of potential transmission: 239). Forty-eight RSV-negative patients were followed up for RSV acquisition every 5 days (total days of exposure: 683). No single RSV transmission was documented with this highly sensitive diagnostic method. Therefore, routine infection control measures of LRTI patients seem to be adequate to prevent RSV transmission at the PICU.

Mechanical ventilation of healthy rats suppresses peripheral immune function.

This study was designed to investigate the possible effect of injurious mechanical ventilation on peripheral immune function of healthy rats. Three ventilation strategies were compared: 1) low peak inspiratory pressure (PIP)/positive end-expiratory pressure (PEEP); 2) high PIP/PEEP; and 3) high PIP/zero PEEP (ZEEP). As a reference group, healthy, nonventilated, sham-operated, anaesthetised rats were used. After 4 h, rats were sacrificed and macrophage inflammatory protein (MIP)-2 levels in lung and plasma were determined. Peripheral immune function was determined by measurement of splenic natural killer (NK) activity, mitogen-induced splenocyte proliferation and in vitro cytokine production. All immune measurements in the low PIP/PEEP group did not differ from the immune measurements in the reference group. High PIP strategies, irrespective of applied PEEP, enhanced MIP-2 levels in lung and plasma. NK cell activity, mitogen-induced splenocyte proliferation and MIP-2 and interleukin (IL)-10 production significantly decreased after high PIP/PEEP ventilation. In the high PIP/ZEEP-ventilated group, the decrease in splenocyte proliferation, MIP-2 and IL-10 production and NK cell activity was more pronounced and interferon-gamma production was also significantly lower than in the low PIP/PEEP group. These data show that high positive inspiratory pressure ventilation induces an inflammatory response in the lung, whereas at the same time the peripheral immune response is downregulated. Ventilator-induced peripheral immune suppression may contribute to poor outcome in acute respiratory distress syndrome patients.

Dexamethasone for treatment of patients mechanically ventilated for lower respiratory tract infection caused by respiratory syncytial virus.

BACKGROUND: A study was undertaken to evaluate the efficacy of dexamethasone in patients mechanically ventilated for lower respiratory infection caused by respiratory syncytial virus (RSV-LRTI). METHODS: In a multicentre randomised controlled trial patients were randomised to receive either intravenous dexamethasone (0.15 mg/kg 6 hourly for 48 hours) or placebo. End points were the duration of mechanical ventilation, length of stay (LOS) in the pediatric intensive care unit (PICU) and in hospital, and the duration of supplemental oxygen administration. RESULTS: Thirty seven patients received dexamethasone and 45 received placebo. There was no significant difference in any of the end points between the two groups. In a post hoc analysis patients were stratified into those with mild gas exchange anomalies (PaO(2)/FiO(2) >200 mm Hg and/or mean airway pressure 10 cm H(2)O, pneumonia group). In the 39 patients with bronchiolitis the duration of mechanical ventilation was 4.3 days shorter in the dexamethasone group than in the placebo group (4.9 v 9.2 days, 95% CI -7.8 to -0.8, p=0.02) and the duration of supplemental oxygen was 3.6 days shorter (7.7 v 11.3 days, 95% CI -8.0 to -0.1, p=0.048). No differences in end points were found in the pneumonia group. CONCLUSIONS: Dexamethasone had no beneficial effect in patients mechanically ventilated for RSV-LRTI but was found to have a beneficial effect in patients with bronchiolitis.

Anomalies associated with oesophageal atresia in Asians and Europeans.

Oesophageal atresia (OA) is often associated with anomalies of other systems. The genetic contribution to the formation of the VACTERL association is not clear. The objective of this study was to evaluate the incidence of associated anomalies in two different racial populations. The associated anomalies in neonates with OA managed in an Asian and a European paediatric surgical centre from 1982 to 1998 were reviewed. Non-Asian and non-European patients were excluded from the respective centres. The incidence of anomalies was compared using Fisher's exact test, taking #E5/E5# below 0.05 as statistically significant. Forty-eight consecutive Asian (25 boys and 23 girls) and 34 consecutive European patients (20 boys and 14 girls) were included in the analysis. The percentage of patients with at least one associated anomaly was 50% and 74% in the Asian and European populations, respectively, which was significantly different (#E5/E5#=0. 04). There was no statistically significant difference in the incidence of associated cardiovascular (29% vs 39%), anorectal (11% vs 18%), and musculoskeletal (16% vs 22%) anomalies, duodenal atresia (4% vs 3%), or Down's syndrome (3% vs 6%) between the two populations. However, the European patients had a significantly higher incidence of urogenital (UG) anomalies (26% vs 4%, #E5/E5#=0.006), the most common being agenesis (n=4) and dysplasia (n=3) of one or both kidneys. Hereditary factors may influence the incidence of associated anomalies in children with OA, particularly of the UG system. However, environmental factors cannot be excluded.

Acampomelic campomelic syndrome.

Campomelic syndrome (or campomelic dysostosis, CD; MIM *114290) is an autosomal dominant skeletal malformation syndrome characterized by shortness and bowing of long bones, especially of the lower limbs. Additional radiological and clinical findings are 11 pairs of ribs and a bell-shaped thorax, hypoplastic scapulae, narrow iliac wings, non-mineralized thoracic pedicles, clubbed feet, Robin sequence, typical facial anomalies and tracheomalacia. The disorder is frequently lethal due to respiratory distress. Sex reversal occurs in most patients with an XY karyotype. CD is caused by heterozygous mutations in the SOX9 gene, an SRY-related gene at 17q24.3-q25.1 with pleiotropic effects on the skeletal and genital systems. In addition, cases with chromosomal rearrangements involving 17q have been described that are most likely caused by disturbing one or more cis-regulatory elements from an extended control region. Campomelia (bowed limbs) is seen in most but not all patients, defining a so-called acampomelic campomelic dysostosis (ACD). Half of the CD cases with 17q rearrangements have no or mild campomelia. Furthermore, campomelia is absent or only mildly present in a small subgroup of cases with a normal karyotype. We present a chromosomally normal boy with ACD and his clinical follow-up up to the age of 2 years, in whom a heterozygous SOX9 missense mutation (H165Y) was identified. A SOX9 missense mutation was published in two other patients with ACD. Although up to now a general genotype-phenotype correlation could not be established for CD, a correlation emerges for the ACD variant that needs further confirmation.

[Rupture of thoracic aneurysm in a 10-year old boy]. / Ruptuur van een thoracaal aneurysma bij een 10-jarige jongen.

A 10-year-old boy with a medical history of fatigue became nauseous, short of breath and cyanotic within 24 hours after a frightening incident. He was successfully resuscitated after a cardiac arrest. A CT scan revealed a ruptured aneurysm of the ascending aorta. During emergency surgery the ascending aorta and aortic arch were replaced with a 22 mm synthetic graft. No postoperative complications occurred. There was no associated trauma, syphilis, collagen diseases (Marfan's syndrome, Ehlers-Danlos syndrome), congenital heart disease or autoimmune disease. The cause of the aneurysm and rupture remain unclear.

Conventional gas ventilation, liquid-assisted high-frequency oscillatory ventilation, and tidal liquid ventilation in surfactant-treated preterm lambs.

This study was designed to compare the efficacy and potential protective or injurious effects of tidal liquid ventilation (TLV), liquid-assisted high-frequency oscillatory ventilation (LA-HFOV), and high PEEP conventional mechanical ventilation (CMV) in neonatal respiratory distress syndrome. Preterm lambs (124-126 days gestation), prophylactically treated with natural surfactant, were allocated to one of the treatment modalities or to an untreated fetal control group (F), euthanised after tracheal ligation. LA-HFOV animals received an intratracheal loading dose of 5 mL x kg(-1) followed by a continuous intrapulmonary instillation of 12 mL x kg(-1);h(-1) FC-75 perfluorocarbon liquid. The ventilation strategies aimed at keeping clinically appropriate arterial blood gases for a study period of 5 hours. A histological lung injury score was calculated and semiquantitative morphometry was performed on lung tissue fixed by vascular perfusion. The alveolar-arterial pressure difference for O2 was significantly lower throughout the study in TLV compared to CMV lambs; at 1, 2, and 5 hours, oxygenation was better in TLV when compared to LA-HFOV. Total lung injury scores in TLV lambs were significantly lower than in either CMV or LA-HFOV animals, but higher when compared to F. CMV and LA-HFOV induced an excess of collapsed and overdistended alveoli, whereas in TLV alveolar expansion was normally distributed around predominantly normal alveoli. CMV and LA-HFOV, but not TLV, were associated with an excess of dilated airways. Thus, in the ovine neonatal RDS model, TLV compared favourably to either gas ventilation strategy by its more uniform ventilation, reduced lung injury, and improved gas exchange.

[Child with tubercular meningoencephalitis, etiologically related to a microepidemic of tuberculosis in Southern Limburg by DNA 'fingerprinting']. / Een kind met meningo-encephalitis tuberculosa, door DNA-'fingerprinting' in verband gebracht met een micro-epidemie van tuberculose in Zuid-Limburg.

UNLABELLED: MICROEPIDEMIC: In a child fatal tuberculous meningoencephalitis was diagnosed and the Regional Public Health Service Geleen, Limburg, the Netherlands, was notified. Source identification and contact tracing (ring investigation) did not reveal a source of the infection. In a person living in the same village pulmonary tuberculosis had been diagnosed, but there was no evident contact between both patients. When the mycobacteria from all patients with tuberculosis were typed by DNA fingerprinting, both patients belonged to the same cluster, thus identifying the infection source of the meningoencephalitis patient. In the management of the outbreak 950 persons were examined in a contact tracing survey. Of them 35 had recently been infected and four of these had recently acquired pulmonary tuberculosis. DISCUSSION: Highly infectious patients with tuberculosis are able to infect persons who cannot be found by conventional contact tracing survey as the transmission of tuberculosis is more subject to casual encounters than was hitherto believed. DNA fingerprinting is a very useful method in contact investigation of tuberculosis. In the Netherlands, therefore, the early diagnosis and treatment of symptomatic patients with infectious tuberculosis is more important to stop the transmission of Mycobacterium tuberculosis than the identification and screening of risk groups in the population.

Reduction in adverse effects of mechanical ventilation in rabbits with acute respiratory failure by treatment with extracorporeal CO2 removal and a large fluid volume of diluted surfactant.

The long-term outcome of infants with severe respiratory distress syndrome can be improved by optimizing surfactant therapy and minimizing the risk for pulmonary barovolutrauma and oxygen toxicity. The authors hypothesized that this may be achieved with low frequency ventilation and extracorporeal CO2 removal (LFV-ECCO2R), in combination with intratracheal instillation of a large fluid volume with diluted surfactant. Lung lavaged rabbits were initially ventilated with continuous positive pressure ventilation. The rabbits were randomized to treatment with LFV-ECCO2R and surfactant (experimental group), or surfactant only (control group). In the experimental group, the rabbits were treated with a large volume (16 ml/kg) of diluted surfactant (6.25 mg/ml) at a dose of 100 mg/kg body weight. After surfactant therapy, the FiO2 100% was gradually decreased. During 4 hours, the extracorporeal bloodflow was adjusted to maintain the PaCO2 between 4.0-6.0 kPa. Thereafter, the rabbits were allowed to breathe spontaneously with 2.5 cm H2O continuous positive airway pressure ventilation (CPAP) and 40% oxygen. In the control group, the rabbits received the same surfactant therapy. During the study period, the rabbits remained ventilated with an inspiratory oxygen concentration (FiO2) of 100% for 4 hours. The ventilator flow was adjusted to maintain the PaCO2 between 4.0 and 6.0 kPa. Thereafter, positive-end expiratory pressure was decreased to 2.5 cm H2O and FiO2 was gradually decreased to 40%. In the experimental group, FiO2 was decreased to 40% in a stepwise fashion whereby the PaO2 could be maintained easily within the normal range. Extracorporeal flow rates during perfusion ranged from 20-35 ml/kg/min and were sufficient to keep the PaCO2 and pH within normal limits. After 4 hours, the rabbits could breathe spontaneously with CPAP and 40% oxygen, while normal blood gas values were maintained. All rabbits survived the experiment. In the control group, all rabbits experienced severe hypoxemia, despite FiO2 of 100% oxygen and, during the course of weaning, all rabbits died because of hypoxia. In conclusion, the present study demonstrated that barovolutrauma due to mechanical ventilation, and oxygen toxicity due to high FiO2, can be minimized in an animal model of acute respiratory failure by the combination of LFV-ECCO2R and surfactant therapy.

Endotoxin release and tumor necrosis factor formation during cardiopulmonary bypass.

Endotoxin, when released into the systemic circulation during cardiopulmonary bypass (CPB), might induce activation of plasmatic systems and blood cells during CPB, in addition to a material-dependent blood activation during CPB. However, the role of endotoxin in the development of this so-called whole-body inflammatory reaction in CPB is still unclear. We investigated the release of endotoxin into the systemic circulation in relation with the activation of the complement system and in particular the formation of tumor necrosis factor in 10 patients undergoing CPB. Immediately after the start of CPB the endotoxin concentrations increased significantly (p less than 0.01), accompanied by increases in C3a concentration (p less than 0.05). After release of the aortic cross-clamp, there was a second increase in endotoxin followed by a continuous increase in tumor necrosis factor, reaching a peak concentration 1 hour after the end of CPB (p less than 0.01). These observations demonstrate a release of endotoxin into the systemic circulation associated with tumor necrosis factor formation, which contributes to the whole-body inflammatory reaction associated with CPB.

Inhibition by dexamethasone of the reperfusion phenomena in cardiopulmonary bypass.

A placebo-controlled double-blind study of patients undergoing cardiopulmonary bypass was conducted, comparing the effects of dexamethasone and a placebo on the activation of the plasmatic systems and blood cells and on the postoperative course after cardiopulmonary bypass. In the placebo group two patterns of blood activation could be distinguished. From the start of bypass, blood-material interaction caused an increase in complement C3a and elastase concentration. After release of the aortic cross-clamp, a statistically significant increase was observed in tumor necrosis factor, leukotriene B4, and tissue plasminogen activator activity (p less than 0.01, p less than 0.05, p less than 0.05, respectively). Dexamethasone treatment was not able to inhibit complement activation and elastase release during cardiopulmonary bypass. However, dexamethasone treatment effectively inhibited the increase in tumor necrosis factor, leukotriene B4, and tissue plasminogen activator activity after release of the crossclamp (p less than 0.01 compared with the placebo group). In the postoperative period the patients in the placebo group had hyperthermia and hypotension and required considerable intravenous fluid administration and cardiotonic treatment. The dexamethasone-treated patients, however, showed normothermia (p less than 0.01), had significantly higher blood pressures (p less than 0.01) without supportive treatment, and consequently were in the intensive care unit for a shorter period of time. We conclude that dexamethasone prevents the hemodynamic instability after cardiopulmonary bypass and thus improves the postoperative course by inhibition of the leukocyte and tissue plasminogen activator activity generated after release of the aortic crossclamp.

Activation of plasma systems and blood cells by endotoxin in rabbits.

Endotoxin plays an important role in the pathogenesis of septicaemia by activation of cellular and plasmatic systems. This study was performed to investigate the effects of infusion of endotoxin in rabbits by measuring the activation of cellular and plasma systems. Endotoxin was infused at a rate of 1 mg/kg body wt for 10 min, which caused death of all rabbits within 72 h. Endotoxin induced early leukopenia and thrombopenia, increased plasma levels of beta-glucuronidase and leukotriene B4 (LTB4), and decreased complement total hemolytic activity (CH50) and tissue plasminogen activator (t-PA) activity. These observations correlate with the cellular and plasma changes that have been documented in severely ill endotoxemic patients. Therefore, we conclude that this endotoxin model in rabbits is a valuable tool for investigation of pathophysiology and treatment of endotoxic shock.

Methylprednisolone prophylaxis protects against endotoxin-induced death in rabbits.

Endotoxemia in patients can lead to sepsis and shock by activation of cellular and plasmatic systems. Corticosteroids are described to have a beneficial effect on these phenomena. In this study of controlled endotoxic shock, we investigated the protective effects of prophylactic corticosteroid treatment against activation of cellular and plasmatic systems. In this respect, a low-dose methylprednisolone (1 mg/kg body wt) treatment was compared with that of a high-dose methylprednisolone (40 mg/kg body wt) treatment. Endotoxin infusion induced death of all rabbits, which was associated with leukopenia, thrombopenia, increased levels of beta-glucuronidase, and leukotriene B4 (LTB4) and decreased levels of complement total hemolytic activity (CH50) and tissue plasminogen activator (t-PA) activity. Both methylprednisolone regimens prevented death of the rabbits after endotoxin infusion, which correlated with a significant decrease of the granulocyte release product beta-glucuronidase (P less than 0.01). The early leukopenia and thrombopenia were not prevented; however, both cell numbers returned more rapidly to baseline values than in the placebo group (P less than 0.01, P less than 0.05). The LTB4 and CH50 concentration and t-PA activity did not differ significantly between the treated and placebo groups. These results indicate that although methylprednisolone has no inhibitory effect on the activation of the complement, arachidonic acid, and fibrinolytic systems, it protected the animals from the deleterious effects of endotoxin shock by inhibition of leukocyte activation. In this regard a low dosage of methylprednisolone is equally effective as the most often recommended high dose.