Incidence and prevalence of multiple sclerosis in the UK 1990-2010: a descriptive study in the General Practice Research Database.

OBJECTIVES: To estimate the incidence and prevalence of multiple sclerosis (MS) by age and describe secular trends and geographic variations within the UK over the 20-year period between 1990 and 2010 and hence to provide updated information on the impact of MS throughout the UK. DESIGN: A descriptive study. SETTING: The study was carried out in the General Practice Research Database (GPRD), a primary care database representative of the UK population. MAIN OUTCOME MEASURES: Incidence and prevalence of MS per 100 000 population. Secular and geographical trends in incidence and prevalence of MS. RESULTS: The prevalence of MS recorded in GPRD increased by about 2.4% per year (95% CI 2.3% to 2.6%) reaching 285.8 per 100 000 in women (95% CI 278.7 to 293.1) and 113.1 per 100 000 in men (95% CI 108.6 to 117.7) by 2010. There was a consistent downward trend in incidence of MS reaching 11.52 per 100 000/year (95% CI 10.96 to 12.11) in women and 4.84 per 100 000/year (95% CI 4.54 to 5.16) in men by 2010. Peak incidence occurred between ages 40 and 50 years and maximum prevalence between ages 55 and 60 years. Women accounted for 72% of prevalent and 71% of incident cases. Scotland had the highest incidence and prevalence rates in the UK. CONCLUSIONS: We estimate that 126 669 people were living with MS in the UK in 2010 (203.4 per 100 000 population) and that 6003 new cases were diagnosed that year (9.64 per 100 000/year). There is an increasing population living longer with MS, which has important implications for resource allocation for MS in the UK.

Blood pressure and chronic kidney disease progression in a multi-racial cohort: the Multi-Ethnic Study of Atherosclerosis.

The relationship between blood pressure (BP) and kidney function among individuals with chronic kidney disease (CKD) remains controversial. This study evaluated the association between BP and estimated glomerular filtration rate (eGFR) decline among adults with nondiabetic stage 3 CKD. The Multi-Ethnic Study of Atherosclerosis participants with an eGFR 30-59 ml min(-1) per 1.73 m2 at baseline without diabetes were included. Participants were followed over a 5-year period. Kidney function change was determined by annualizing the change in eGFR using cystatin C, creatinine and a combined equation. Risk factors for progression of CKD (defined as a decrease in annualized eGFR>2.5 ml min(-1) per 1.73 m2) were identified using univariate analyses and sequential logistic regression models. There were 220 participants with stage 3 CKD at baseline using cystatin C, 483 participants using creatinine and 381 participants using the combined equation. The median (interquartile range) age of the sample was 74 (68-79) years. The incidence of progression of CKD was 16.8% using cystatin C and 8.9% using creatinine (P=0.002). Systolic BP>140 mm Hg or diastolic BP>90 mm Hg was significantly associated with progression using a cystatin C-based (odds ratio (OR), 2.49; 95% confidence interval (CI), 1.12-5.52) or the combined equation (OR, 2.07; 95% CI, 1.16-3.69), but not when using creatinine after adjustment for covariates. In conclusion, with the inclusion of cystatin C in the eGFR assessment hypertension was an important predictor of CKD progression in a multi-ethnic cohort with stage 3 CKD.

Camostat attenuates airway epithelial sodium channel function in vivo through the inhibition of a channel-activating protease.

Inhibition of airway epithelial sodium channel (ENaC) function enhances mucociliary clearance (MCC). ENaC is positively regulated by channel-activating proteases (CAPs), and CAP inhibitors are therefore predicted to be beneficial in diseases associated with impaired MCC. The aims of the present study were to 1) identify low-molecular-weight inhibitors of airway CAPs and 2) to establish whether such CAP inhibitors would translate into a negative regulation of ENaC function in vivo, with a consequent enhancement of MCC. To this end, camostat, a trypsin-like protease inhibitor, provided a potent (IC(50) approximately 50 nM) and prolonged attenuation of ENaC function in human airway epithelial cell models that was reversible upon the addition of excess trypsin. In primary human bronchial epithelial cells, a potency order of placental bikunin > camostat > 4-guanidinobenzoic acid 4-carboxymethyl-phenyl ester > aprotinin >> soybean trypsin inhibitor = alpha1-antitrypsin, was largely consistent with that observed for inhibition of prostasin, a molecular candidate for the airway CAP. In vivo, topical airway administration of camostat induced a potent and prolonged attenuation of ENaC activity in the guinea pig trachea (ED(50) = 3 microg/kg). When administered by aerosol inhalation in conscious sheep, camostat enhanced MCC out to at least 5 h after inhaled dosing. In summary, camostat attenuates ENaC function and enhances MCC, providing an opportunity for this approach toward the negative regulation of ENaC function to be tested therapeutically.

Diagnosis and treatment of lower urinary tract symptoms suggestive of overactive bladder and bladder outlet obstruction among men in general practice in the UK.

OBJECTIVE: To assess the epidemiology and treatment of storage symptoms suggestive of overactive bladder (OAB) and voiding symptoms suggestive of bladder outlet obstruction (BOO) because of benign prostatic hyperplasia in UK general practice. PATIENTS AND METHODS: This was a retrospective analysis of data collected between 2000 and 2006 and entered in The Health Improvement Network general practice database, containing medical records for > 1 million men (aged >or= 18 years) in the UK. Using Read codes, we analysed the prevalence of storage and voiding lower urinary tract symptoms (LUTS) as well as prescribing trends for 5alpha-reductase inhibitors (5ARIs) and alpha-blockers for LUTS secondary to BOO and antimuscarinics for OAB. RESULTS: In 2006, the prevalence of diagnosed LUTS/OAB was only 0.3% and the recorded prevalence of LUTS/BOO was only 2.2%. Treatment rates also remained low throughout the study period. In the 12 months before 1 January 2006, only 25% of men diagnosed with OAB and 6-7% of men with storage LUTS received antimuscarinics, whereas 36% of men with a record of LUTS/BOO received alpha-blockers and/or 5ARIs. Alpha-blockers were prescribed to approximately 10% of men diagnosed with OAB or storage LUTS who did not have any recorded BOO diagnosis or symptoms. CONCLUSION: Diagnosis of both storage and voiding LUTS occurs at much lower rates than indicated by prevalence estimates. Despite the availability of effective prescription therapies, many men with storage and/or voiding LUTS may not be receiving appropriate treatment in UK general practice.

Chronically increased intra-abdominal pressure produces systemic hypertension in dogs.

OBJECTIVE: Determine if increased intra-abdominal pressure (IAP) alone can cause systemic hypertension in a chronic canine model. DESIGN: Evaluate effects of increase in IAP with progressive inflation and deflation of an intra-abdominal balloon on systemic blood pressure in experimental and control animals. SUBJECTS: Male dogs weighing 15-25 kg underwent placement of an intra-abdominal balloon which was progressively inflated on a weekly basis in the experimental animals (5) over 4 weeks to 25 mmHg above baseline and kept there for an additional 2 weeks before gradual deflation over 2 weeks. Control animals (5) had the balloon placed but not inflated. Pain was controlled with osmotic analgesic pumps. MEASUREMENTS: The animals were anesthetized, blood pressure (BP) measured and blood drawn for plasma renin activity (PRA), aldosterone, atrial naturetic peptide (ANP), catecholamines, and serum sodium (Na). A right heart catheter was inserted for measuring cardiac output (CO) and pulmonary artery occlusion pressure (PAOP) at baseline, week 5 (maximal IAP) and week 7 (after balloon deflation). The animals were weighed and urinary bladder pressures recorded weekly before and after abdominal balloon inflation. RESULTS: Systolic (122+/-3 to 155+/-5 mmHg, P<0.05) and diastolic (82+/-4 mmHg to 107+/-7 mmHg, P<0.05) BP rose at 5 weeks at 25 mmHg IAP>baseline and returned to control with balloon deflation. Both systolic and diastolic BP rose (P<0.05) above control animals BP at 15 mmHg IAP at 2 weeks and remained elevated until abdominal decompression, at week 7. There were no significant changes in net animal weight, PRA, aldosterone, ANF, catecholamines, Na, CO or PAOP. CONCLUSION: Increased IAP from progressively inflating an intra-abdominal balloon in dogs was associated with significant increases in systolic and diastolic BP that resolved with balloon deflation. Increased IAP may be a cause for systemic hypertension in central obesity and pre-eclampsia.

Bradyzide, a potent non-peptide B(2) bradykinin receptor antagonist with long-lasting oral activity in animal models of inflammatory hyperalgesia.

Bradyzide is from a novel class of rodent-selective non-peptide B(2) bradykinin antagonists (1-(2-Nitrophenyl)thiosemicarbazides). Bradyzide has high affinity for the rodent B(2) receptor, displacing [(3)H]-bradykinin binding in NG108-15 cells and in Cos-7 cells expressing the rat receptor with K(I) values of 0.51+/-0.18 nM (n=3) and 0.89+/-0.27 nM (n=3), respectively. Bradyzide is a competitive antagonist, inhibiting B(2) receptor-induced (45)Ca efflux from NG108-15 cells with a pK(B) of 8.0+/-0.16 (n=5) and a Schild slope of 1.05. In the rat spinal cord and tail preparation, bradyzide inhibits bradykinin-induced ventral root depolarizations (IC(50) value; 1.6+/-0.05 nM (n=3)). Bradyzide is much less potent at the human than at the rodent B(2) receptor, displacing [(3)H]-bradykinin binding in human fibroblasts and in Cos-7 cells expressing the human B(2) receptor with K(I) values of 393+/-90 nM (n=3) and 772+/-144 nM (n=3), respectively. Bradyzide inhibits bradykinin-induced [(3)H]-inositol trisphosphate (IP(3)) formation with IC(50) values of 11.6+/-1.4 nM (n=3) at the rat and 2.4+/-0.3 microM (n=3) at the human receptor. Bradyzide does not interact with a range of other receptors, including human and rat B(1) bradykinin receptors. Bradyzide is orally available and blocks bradykinin-induced hypotension and plasma extravasation. Bradyzide shows long-lasting oral activity in rodent models of inflammatory hyperalgesia, reversing Freund's complete adjuvant (FCA)-induced mechanical hyperalgesia in the rat knee joint (ED(50), 0.84 micromol kg(-1); duration of action >4 h). It is equipotent with morphine and diclofenac, and 1000 times more potent than paracetamol, its maximal effect exceeding that of the non-steroidal anti-inflammatory drugs (NSAIDs). Bradyzide does not exhibit tolerance when administered over 6 days. In summary, bradyzide is a potent, orally active, antagonist of the B(2) bradykinin receptor, with selectivity for the rodent over the human receptor. British Journal of Pharmacology (2000) 129, 77 - 86

The site-specific integration of genetic elements may modulate thermostable protease production, a virulence factor in Dichelobacter nodosus, the causative agent of ovine footrot.

The gram-negative anaerobe Dichelobacter nodosus is the causative agent of footrot in sheep. The authors have previously characterized two genetic elements, the intA (vap) and intB elements, which integrate into the genome of D. nodosus. In the virulent strain A198 there are two copies of the intA element. One copy is integrated into the 3' end of the tRNA-serGCU gene, close to the aspartokinase (askA) gene, and the second copy is integrated into the 3' end of the tRNA-serGGA gene, next to the polynucleotide phosphorylase (pnpA) gene. In this study, a new genetic element was identified in the benign strain C305, the intC element, integrated into the 3' end of the tRNA-serGCU gene, next to askA. The intC element was found in most D. nodosus strains, both benign and virulent, which were examined, and was integrated into tRNA-serGCU in most strains. Between the askA and tRNA-serGCU genes, a gene (designated glpA), was identified whose predicted protein product has very high amino acid identity with RsmA from the plant pathogen Erwinia carotovora. RsmA acts as a global repressor of pathogenicity in E. carotovora, by repressing the production of extracellular enzymes. In virulent strains of D. nodosus the intA element was found to be integrated next to pnpA, and either the intA or intC element was integrated next to glpA. By contrast, all but one of the benign strains had intB at one or both of these two positions, and the one exception had neither intA, intB nor intC at one position. The loss of the intC element from the virulent strain 1311 resulted in loss of thermostable protease activity, a virulence factor in D. nodosus. A model for virulence is proposed whereby integration of the intA and intC genetic elements modulates virulence by altering the expression of glpA, pnpA, tRNA-serGCU and tRNA-serGGA.

El cuidado de la familia del neonato gravemente enfermo / Family care of acute newborn patient

El niño entregado a nuestro cuidado en terapia intensiva y en las distintas etapas de su enfermedad, pertenece a una familia cuyo bienestar también nos concierne, y a cuyas necesidades tenemos que estar atentos, ya que de ellos depende el futuro de nuestro niño. Todos nosotros como equipo de salud, y siendo fieles con nosotros mismos ya que al seguir esta vocación optamos por el paciente, no podemos abandonar este otro aspecto de la relación con él, que no por ser menos urgente es menos importante. sólo necesitamos ponernos en el lugar del que sufre en este caso, la familia del niño grave e intentar acogerlo y alivianar su temor. Al hacerlo, no estamos siendo más que lo que estamos llamados a ser: médicos, en la real dimensión que esto implica

Physiologic effects of externally applied continuous negative abdominal pressure for intra-abdominal hypertension.

BACKGROUND: To determine the ability of an externally applied continuous negative abdominal pressure device (CNAP) to reverse the effects of elevated intra-abdominal pressure on the central nervous and cardiovascular systems. METHODS: Anesthetized, ventilated swine had catheters placed for measurement of intra-abdominal (IAP), intracranial (ICP), central venous, pulmonary artery, pulmonary artery occlusion, mean arterial, peak inspiratory, inferior vena cava, and femoral vein pressures. After the animals stabilized, baseline measurements were obtained. IAP was increased by incrementally instilling an isosmotic polyethylene glycol solution into the peritoneal cavity until it was 25 mm Hg above baseline. IAP was maintained at 25 mm Hg above baseline for 2 hours. CNAP was then applied for 2 hours. All parameters were remeasured 30 minutes after each increase in IAP, at 2 hours after attaining maximum IAP, and lastly at 2 hours after abdominal decompression. Cardiac index was maintained near baseline by volume expansion. RESULTS: Elevation of IAP to 25 mm Hg above baseline for 2 hours caused increases (p<0.05) in central venous pressure (10.3+/-0.9 to 15.2+/-1.7), inferior vena cava pressure (13.0+/-1.0 to 29.5+/-1.5), femoral vein pressure (13.5+/-0.5 to 33.3+/-1.3), ICP (10.6+/-1.5 to 21.0+/-1.5), and peak inspiratory pressure (18.3+/-0.3 to 34.2+/-1.0). The mean arterial pressure (106.3+/-3.5 to 125.8+/-3.4), pulmonary artery pressure (24.3+/-2.3 to 31.3+/-1.7), and pulmonary artery occlusion pressure rose (12.3+/-0.9 to 17.5+/-3.5), but not significantly. Cardiac index (3.3+/-0.5 to 3.4+/-0.4) remained essentially unchanged. CNAP significantly (p<0.05) decreased IAP (30.7+/-1.3 to 18.2+/-1.3), central venous pressure (15.2+/-1.7 to 12.4+/-2.1), inferior vena cava (29.5+/-1.5 to 19.2+/-1.3), and ICP (21.0+/-1.5 to 16.2+/-1.3). Pulmonary artery occlusion pressure (17.5+/-3.5 to 15.0+/-3.1) and peak inspiratory pressure (34.2+/-1.0 to 29.7+/-1.1) decreased, but not significantly. CONCLUSION: Acutely elevated IAP causes a significant increase in ICP and impaired cardiovascular and pulmonary function. Abdominal decompression remains the standard of care for abdominal compartment syndrome. However, in patients in whom an increased IAP does not require surgical decompression, the results of this study suggest that externally applied CNAP may be of value.

Treatment of intracranial hypertension using nonsurgical abdominal decompression.

BACKGROUND: Elevated intra-abdominal pressure (IAP) increases intracranial pressure (ICP) and reduces cerebral perfusion pressure (CPP). We evaluated a nonsurgical means of reducing IAP to reverse this process. METHODS: Swine with a baseline ICP of 25 mm Hg produced by an intracranial balloon catheter were studied. In group 1 (n = 5), IAP was increased by 25 mm Hg. Continuous negative abdominal pressure (CNAP) was then applied. Group 2 (n = 4) had neither IAP elevation nor CNAP. Group 3 (n = 4) had CNAP without IAP elevation. RESULTS: Elevation of IAP by 25 mm Hg above baseline led to deleterious changes in ICP (25.8+/-0.8 to 39.0+/-2.8; p < 0.05) and CPP (85.2+/-2.0 to 64.8+/-2.6; p < 0.05). CNAP led to a reduction in IAP (30.2+/-1.2 to 20.4+/-1.3; p < 0.05) and improvements in cerebral perfusion (ICP, 33+/-2.7; CPP, 74.4+/-1.2; both p < 0.05). Group 2 had stable ICP (25.8+/-0.25 to 28.7+/-1.7; p > 0.05) and CPP (80.8+/-1.4 to 80.5+/-1.8; p > 0.05). In group 3, CNAP decreased cardiac index (2.9+/-0.2 to 1.1+/-0.4; p < 0.05), mean arterial pressure (105.2+/-4.0 to 38.2+/-12.0; p < 0.05), and CPP (74.2+/-4.7 to 14.5+/-12.2; p < 0.05). CONCLUSION: Elevations in IAP led to increased ICP and decreased CPP. CNAP ameliorated these intracranial disturbances. With normal IAP, CNAP impaired cerebral perfusion.

Multisystem organ failure secondary to increased intraabdominal pressure.

Acutely increased intraabdominal pressure can lead to multisystem organ dysfunction. Organ dysfunction consists of acute pulmonary failure secondary to compressive atelectasis and associated with high peak inspiratory pressures and impaired gas exchange, acute renal failure with marked oliguria without hypernaturia, intestinal and hepatic ischemia possibly leading to bacterial translocation or necrosis with peritonitis, increased intracranial pressures which may cause brain dysfunction or aggravate head injury edema, venous thrombosis and thromboembolism, and abdominal wall ischemia or necrosis. The diagnosis is made clinically in a patient with high peak inspiratory pressures, oliguria and an apparently tight abdomen, although urinary bladder pressure > or = 20 cm H2O pressure is suggestive. However, chronically increased intraabdominal pressure as is seen in the morbidly obese, pregnancy and cirrhosis may be misleading. As to treatment, once the diagnosis is made, the patient's abdomen should be opened and the tension relieved. The intestinal contents need to be protected and evaporative water loss minimized by either closing the skin and not the fascia or, if this is not possible, using an impermeable protective dressing. If the abdomen is difficult to close at the primary operation, it is best to prevent the development of an acute abdominal compartment syndrome by closing only the skin or leaving it open and using an impermeable dressing. In conclusion, the acute abdominal compartment syndrome has become increasingly recognized as a cause for multisystem organ failure. Recognition of the problem or prevention is mandatory for optimal patient survival.

A casein kinase I motif present in the cytoplasmic domain of members of the tumour necrosis factor ligand family is implicated in 'reverse signalling'.

We have identified a putative signalling feature of the cytoplasmic domains of the tumour necrosis factor (TNF) family members based on available amino acid sequence data. A casein kinase I (CKI) consensus sequence is conserved in the cytoplasmic domain of six of 15 members of the type II integral membrane TNF ligand family. We examined the phosphorylation state of transmembrane tumour necrosis factor-alpha (mTNF) with [32P]orthophosphate labelling and in vitro kinase assays, in lipopolysaccharide-stimulated RAW264.7 cells. A dimeric form of the type I soluble TNF receptor (sTNFR) was found to dephosphorylate mTNF. This effect could be prevented by treatment with phosphatase inhibitors. Recombinant CKI was able to phosphorylate mTNF that had been dephosphorylated by sTNFR ligation in vivo, and this was less effective if phosphatase inhibitors had been used to prevent mTNF dephosphorylation. A mutated form of mTNF, lacking the CKI recognition site, cannot be phosphorylated by the enzyme. Binding of sTNFR to mTNF induced an increase in intracellular calcium levels in RAW264.7 cells, implying the presence of an associated signalling pathway. We predict that this CKI motif is phosphorylated in other TNF ligand members, and that it represents a new insight into the mechanism of 'reverse signalling' in this cytokine family.

Are reactive oxygen species involved in the pathogenesis of murine cerebral malaria?

To investigate the involvement of oxidative tissue damage in the pathogenesis of murine cerebral malaria (CM), brain levels of protein carbonyls, 3,4-dihydroxyphenylalanine (DOPA), o-tyrosine, and dityrosine were measured during Plasmodium berghei ANKA (PbA) and P. berghei K173 (PbK) infections. During PbA infection in a CM model, brain levels of the substances were similar to those in uninfected mice. The role of phagocyte-derived reactive oxygen species in the pathogenesis of CM was examined in gp91phox gene knockout mice. The course of CM in these mice was the same as in their wild type counterparts. To examine whether superoxide production in the central nervous system could have occurred via increased xanthine oxidase activity, brain concentrations of urate were measured in CM mice and in mice infected with PbK (which does not cause CM). Brain urate concentration increased significantly in both groups of mice, suggesting that purine breakdown is not specific to CM. These results indicate that reactive oxygen species probably do not contribute to the pathogenesis of murine CM.

Abdominal compartment syndrome.

The ACS is a clinical entity that develops from progressive, acute increases in IAP and affects multiple organ systems in a graded fashion because of differential susceptibilities. The gut is the organ most sensitive to IAH, and it develops evidence of end-organ damage before the development of the classic renal, pulmonary, and cardiovascular signs. Intracranial derangements with ACS are now well described. Treatment involves expedient decompression of the abdomen, without which the syndrome of end-organ damage and reduced oxygen delivery may lead to the development of multiple organ failure and, ultimately, death. Multiple trauma, massive hemorrhage, or protracted operation with massive volume resuscitation are the situations in which the ACS is most frequently encountered. Knowledge of the ACS, however, is also essential for the management of critically ill pediatric patients (especially those with AWD) and in understanding the limitations of laparoscopy. The role of IAH in the pathogenesis of NEC, central obesity co-morbidities, and pre-eclampsia/eclampsia remains to be fully studied.

OPC-6535, a superoxide anion production inhibitor, attenuates acute lung injury.

A large body of evidence has demonstrated that inhibition of the neutrophil's oxidant burst attenuates sepsis-induced acute lung injury. The present study sought to evaluate the ability of OPC-6535, a superoxide anion production inhibitor, to attenuate sepsis-induced acute lung injury. Four groups of swine were anesthetized, ventilated, and studied for 5 hr. Following surgical preparation, control (n = 10) and OPC-control (n = 2) animals received a 1-hr infusion of sterile saline. Sepsis was induced with a 1-hr intravenous infusion of live Pseudomonas aeruginosa. Untreated septic animals (n = 10) received no treatment. Animals treated with OPC-6535 (n = 6) received a 1 mg/kg bolus of OPC-6535 15 min prior to initiation of the bacterial infusion. Changes in systemic and pulmonary hemodynamics, arterial oxygen tension, bronchoalveolar lavage protein and neutrophil content, neutrophil integrin expression, neutrophil oxidant burst, and lung myeloperoxidase content were used as outcome measures. Treatment with OPC-6535 significantly reduced acute lung injury, as indicated by improved bronchoalveolar lavage protein and neutrophil content, resulting in a significant improvement in arterial oxygenation. Treatment with OPC-6535 failed to prevent the development of pulmonary hypertension and systemic hypotension. Neutrophils from animals with both treated and untreated sepsis exhibited significant up-regulation of CD18 and production of increased levels of oxidants, indicating significant activation when compared to neutrophils from control animals. Although animals treated with OPC-6535 produced 25% less superoxide anion than untreated septic animals, this decrease was not statistically significant. Treatment of animals with OPC-6535 prior to the onset of sepsis produced significant protection against acute lung injury but failed to attenuate hemodynamic derangements associated with sepsis.

How many neonates in New Zealand would qualify for extracorporeal membrane oxygenation?

AIM: To estimate how many neonates in New Zealand would qualify for extracorporeal membrane oxygenation (ECMO), using both standard published criteria and locally derived criteria. METHODS: Retrospective chart review of all babies with a birth weight over 2000 g admitted to neonatal intensive care in Auckland from June 1990 to June 1993. Ventilation and blood gas indices were calculated for all babies who were ventilated in 100% O2 for more than 4 hours and who met the basic criteria for ECMO (less than 1 week old with no neurological or chromosomal problems). These indices were compared with published ECMO criteria. Using a threshold of an 80% mortality, Auckland criteria for ECMO were derived. RESULTS: Of the published criteria for ECMO, only an oxygenation index of greater than 40 for 4 hours predicted a mortality of more than 80% in our population. From our own findings a PaO2 < 6.5 kPa for 4 hours predicted a mortality of 79%. CONCLUSION: Approximately 19 neonates might qualify for ECMO in New Zealand each year.

Elevated intra-abdominal pressure increases plasma renin activity and aldosterone levels.

OBJECTIVE: To study the effects of elevated intra-abdominal pressure upon renal function and the renin-angiotensin-aldosterone system. MATERIALS AND METHODS: Two groups of anesthetized, ventilated swine were studied. Intra-abdominal pressure was increased in experimental animals (n = 6) by incrementally instilling an isosmotic ethylene glycol solution into the peritoneal cavity until intra-abdominal pressure was 25 mm Hg above baseline. The intravascular volume was then expanded until cardiac index returned to baseline. Lastly, the solution was drained to decompress the abdomen. Control animals underwent surgical preparation but did not have their intra-abdominal pressure raised. Changes in systemic and pulmonary hemodynamic parameters, renal venous pressure, and urine output were recorded. Venous samples for plasma renin activity, aldosterone, and atrial natriuretic factor were drawn after each change in either intra-abdominal pressure or intravascular volume in experimental animals, and at the same time points in control animals. MEASUREMENTS AND MAIN RESULTS: Elevated intra-abdominal pressure significantly (p < 0.05, analysis of variance) increased renal venous pressure, pleural pressure, wedge pressure, and pulmonary artery pressure compared to both baseline and control animals; whereas cardiac index and urine output decreased significantly. Both plasma renin and aldosterone levels increased significantly compared with baseline and controls. Intravascular volume expansion significantly increased urine output and decreased significantly both plasma renin activity and aldosterone levels. Abdominal decompression further significantly decreased both plasma renin activity and aldosterone levels. There were no significant changes in atrial natriuretic factor at any time point. CONCLUSIONS: Elevated intra-abdominal pressure decreases urine output and significantly up-regulates the hormonal output of the renin-angiotensin-aldosterone system. Intravascular volume expansion in combination with abdominal decompression reverses the effects of acutely elevated intra-abdominal pressure upon renal function and the renin-angiotensin-aldosterone system.

Pretreatment with inhaled nitric oxide inhibits neutrophil migration and oxidative activity resulting in attenuated sepsis-induced acute lung injury.

OBJECTIVE: To determine if, and by what mechanisms, inhaled nitric oxide attenuates acute lung injury in a porcine model of adult respiratory distress syndrome induced by Gram-negative sepsis. DESIGN: Nonrandomized, controlled study. SETTING: Laboratory at a university medical center. SUBJECTS: Thirty pathogen-free Yorkshire swine (15 to 20 kg). INTERVENTIONS: Four groups of swine were anesthetized, mechanically ventilated, and studied for 5 hrs. Both control-nitric oxide and septic-nitric oxide animals received inhaled nitric oxide at 20 parts per million throughout the study. Control (n = 10) and control-nitric oxide (n = 5) animals received a 1-hr infusion of sterile saline. Sepsis was induced in septic (n = 10) and septic-nitric oxide (n = 5) animals with a 1-hr intravenous infusion of live Pseudomonas aeruginosa. MEASUREMENTS AND MAIN RESULTS: Untreated septic animals developed a progressive decrease in Pao2 that was prevented in septic-nitric oxide animals (73 +/- 4 vs. 214 +/- 23 torr [9.7 +/- 0.5 vs. 28.5 +/- 3.1 kPa], respectively, at 5 hrs, p < .05). Untreated septic animals showed a significant increase in bronchoalveolar lavage protein and neutrophil count at 5 hrs, compared with the baseline value, indicating acute lung injury. Septic-nitric oxide animals showed no significant increase in these parameters. Peripheral blood neutrophils from untreated septic animals and septic-nitric oxide animals exhibited significant (p < .05) up-regulation of CD18 receptor expression and oxidant activity (10.5 +/- 0.9 and 5.0 +/- 0.9 nmol of superoxide anion/10(6) neutrophils/10 mins, respectively) compared with both control and control-nitric oxide animals (3.0 +/- 0.6 and 2.6 +/- 0.2 nmol of superoxide anion/10(6) neutrophils/10 mins, respectively). Also, priming for the oxidant burst at 5 hrs was decreased by 50% in septic-nitric oxide animals compared with untreated septic animals. Both untreated septic and septic-nitric oxide animals showed a significant increase in pulmonary arterial pressure at 30 mins (47.5 +/- 2.4 and 51.0 +/- 3.0 mm Hg, respectively), followed by a progressive decrease (32.8 +/- 2.6 and 31.3 +/- 5.4 mm Hg, respectively, at 5 hrs). Both of these changes were significant (p < .05) compared with baseline values and compared with the control groups. There was no significant difference in pulmonary arterial pressure or systemic arterial pressure at any time between untreated septic and septic-nitric oxide animals. CONCLUSIONS: These results demonstrate that inhaled nitric oxide attenuates alveolar-capillary membrane injury in this porcine model of Gram-negative sepsis but does not adversely affect systemic hemodynamics. The data suggest that inhaled nitric oxide preserves alveolar-capillary membrane integrity by the following means: a) inhibiting transendothelial migration of activated, tightly adherent neutrophils; and b) possibly by attenuating the neutrophil oxidant burst.