Nitric oxide synthase inhibition in sepsis? Lessons learned from large-animal studies

Nitric Oxide (NO) plays a controversial role in the pathophysiology of sepsis and septic shock. Its vasodilatory effects are well known, but it also has pro- and antiinflammatory properties, assumes crucial importance in antimicrobial host defense, may act as an oxidant as well as an antioxidant, and is said to be a vital poison for the immune and inflammatory network. Large amounts of NO and peroxynitrite are responsible for hypotension, vasoplegia, cellular suffocation, apoptosis, lactic acidosis, and ultimately multiorgan failure. Therefore, NO synthase (NOS) inhibitors were developed to reverse the deleterious effects of NO. Studies using these compounds have not met with uniform success however, and a trial using the nonselective NOS inhibitor N-G-methyl-L-arginine hydrochloride was terminated prematurely because of increased mortality in the treatment arm despite improved shock resolution. Thus, the issue of NOS inhibition in sepsis remains a matter of debate. Several publications have emphasized the differences concerning clinical applicability of data obtained from unresuscitated, hypodynamic rodent models using a pretreatment approach versus resuscitated, hyperdynamic models in high-order species using posttreatment approaches. Therefore, the present review focuses on clinically relevant large-animal studies of endotoxin or living bacteria-induced, hyperdynamic models of sepsis that integrate standard day-today care resuscitative measures.

Hypoxic/ischemic models in newborn piglet: Comparison of constant FiO(2) versus variable FiO(2) delivery

A comparison of a constant (continuous delivery of 4% FiO(2)) and a variable (initial 5% FiO(2) with adjustments to induce low amplitude EEG (LAEEG) and hypotension) hypoxic/ischemic insult was performed to determine which insult was more effective in producing a consistent degree of survivable neuropathological damage in a newborn piglet model of perinatal asphyxia. We also examined which physiological responses contributed to this outcome. Thirty-nine 1-day-old piglets were subjected to either a constant hypoxic/ischemic insult of 30- to 37-min duration or a variable hypoxic/ischemic insult of 30-min low peak amplitude EEG (LAEEG < 5 mu V) including 10 min of low mean arterial blood pressure (MABP < 70% of baseline). Control animals (n = 6) received 21% FiO(2) for the duration of the experiment. At 72 h, the piglets were euthanased, their brains removed and fixed in 4% paraformaldehyde and assessed for hypoxic/ischemic injury by histological analysis. Based on neuropathology scores, piglets were grouped as undamaged or damaged; piglets that did not survive to 72 h were grouped separately as dead. The variable insult resulted in a greater number of piglets with neuropathological damage (undamaged = 12.5%, damaged = 68.75%, dead = 18.75%) while the constant insult resulted in a large proportion of undamaged piglets (undamaged = 50%, damaged = 22.2%, dead = 27.8%). A hypoxic insult varied to maintain peak amplitude EEG < 5 mu V results in a greater number of survivors with a consistent degree of neuropathological damage than a constant hypoxic insult. Physiological variables MABP, LAEEG, pH and arterial base excess were found to be significantly associated with neuropathological outcome. (c) 2006 Elsevier B.V. All rights reserved.

Perinatal outcomes with laser surgery for twin-twin transfusion syndrome

The aim of this tertiary hospital-based cohort study was to determine and compare perinatal outcome and neonatal morbidities of pregnancies with twin-twin transfusion syndrome (TTTS) before and after the introduction of a treatment program with laser ablation of placental communicating vessels. Twenty-seven pregnancies with Stage II-IV TTTS treated with amnioreduction were identified (amnioreduction group). The data were compared with that obtained from the first 31 pregnancies with Stage II-IV TTTS managed with laser ablation of placental communicating vessels (laser group). Comparisons were made for perinatal survival and neonatal morbidities including abnormalities on brain imaging. The median gestation at therapy was similar between the two groups (20 vs. 21 weeks, p = .24), while the median gestation at delivery was significantly greater in the laser treated group (34 vs. 28 weeks, p = .002). The perinatal survival rate was higher in the laser group (77.4% vs. 59.3%, p = .03). Neonatal morbidities including acute respiratory distress, chronic lung disease, requirement for ventilatory assistance, patent ductus arteriosus, hypotension, and oliguric renal failure had a lower incidence in the laser group. On brain imaging, ischemic brain injury was seen in 12% of the amnioreduction group and none of the laser group of infants (p = .01). In conclusion, these findings indicate that perinatal outcomes are improved with less neonatal morbidity for monochorionic pregnancies with severe TTTS treated by laser ablation of communicating placental vessels when compared to treatment by amnioreduction.

Physiological and haematological findings and clinical observations in a model of acute systemic anaphylaxis in Dirofilaria immitis-sensitised cats

Objective This study aims to understand the pathophysiology of anaphylaxis in Dirofflaria immitis-sensitised cats by analysing objective physiological and haematological measurements after challenge. Design Nineteen healthy D immitis-naive cats were sensitised using weekly injections of aluminium hydroxide-adjuvanted D immitis antigen, administered subcutaneously over 6 weeks. After sensitisation, cats (n = 16) were anaesthetised and challenged with intravenous D immitis antigen. A control group (n = 3) was sham-challenged using intravenous sterile 0.9% saline. Systolic blood pressure (measured non-invasively/indirectly), respiratory rate, degree of dyspnoea, blood 0, saturation, expired CO2, and heart rate and were measured immediately before and at 10 to 15 min intervals after challenge until terminal apnoea occurred or euthanasia at 140 mins post-challenge. Blood was collected for complete blood count immediately before and at 10, 20 and 35 mins after challenge. Clinical observations were recorded as they occurred. Results Antigen-challenged cats were divided into two groups: acute (apnoea occurred within 25 mins of challenge) and subacute (breathing at 25 mins after challenge). In both groups, the degree of dyspnoea increased and blood O-2 saturation and blood pressure decreased. Respiratory rate increased in the subacute group. Expired CO2 decreased in both Ag-challenged and control groups. Haematocrit increased in the subacute group. Neutrophil count decreased in the acute group and platelet count decreased in the subacute group. Eosinophil count decreased in the subacute and control groups. Sustained dyspnoea and gastrointestinal signs were the most common clinical manifestations of anaphylaxis in the antigen-challenged cats. Conclusions Intravenous challenge with D immitis antigen in sensitised cats results in dyspnoea, hypoxaemia and systemic hypotension accompanied by haemoconcentration.