Brain death increases COX-1 and COX-2 expression in the renal medulla in a pig model.

BACKGROUND: Brain death is linked to a systemic inflammatory response that includes prostaglandins and cytokines among its mediators. The levels of cyclooxygenase-1 and cyclooxygenase-2 (COX-1 and COX-2) affect graft survival, but it remains unknown whether these enzymes are modified during brain death. The aims of this study were to investigate the organ expression of COX and to analyse the cytokine response in the plasma, cerebrospinal fluid (CSF), and organs in a porcine model of intracerebral haemorrhage and brain death. METHODS: Twenty pigs were randomly assigned to either a brain death group or a control group. Brain death was induced by an intracerebral injection of blood, and the animals were observed over the next 8 h. Tissue samples were tested for COX-1, COX-2 messenger RNA (mRNA) expression (heart, lung, and kidney), haeme oxygenase-1 (HO-1) (kidney), interleukin-1ß (IL-1ß), IL-6, IL-8, IL-10, and tumour necrosis factor-α. These cytokines were also measured at eight time points in the plasma and CSF. RESULTS: At the organ level, the levels of COX-1 and COX-2 mRNA expression were increased only in the renal medulla (P = 0.03 and P = 0.02, respectively). The cytokine levels in the tissue, plasma, and CSF revealed no differences between the groups. HO-1 expression decreased (P = 0.0088). CONCLUSION: Brain death increases the expression of COX-1 and COX-2 mRNA in the renal medulla. The release of cytokines into the plasma and CSF did not vary between the groups.

Brain death induced by cerebral haemorrhage - a new porcine model evaluated by CT angiography.

BACKGROUND: Brain death and complications to brain death affects the function of organs in the potential donor. Previous animal models of brain death have not been able to fully elucidate the mechanisms behind this organ dysfunction, and none of the available animal models mimic the most common insult prior to brain death: intracerebral haemorrhage. The objective of this study was to develop a large animal model of brain death based on a controlled intracerebral haemorrhage and verified by computerised tomographic angiography (CTA). METHODS: Twenty pigs (range: 26.6-31.2 kg) were randomised to brain death or control. Brain death was induced by infusion of blood through a stereotaxically placed needle in the internal capsule. Brain death was confirmed by the measured intracranial pressure (ICP), lack of corneal and pupillary light reflexes, and atropine test. CTA was performed 120-180 min after brain death. The pigs were observed for 8 h after brain death. RESULTS: Brain death was declared when the ICP exceeded mean arterial pressure after a median of 36 min (range: 28-51 min). Significant increases in heart rate, and mean arterial pressure (MAP) were followed by a steep decrease. With fluid therapy, the animals demonstrated haemodynamic stability. Reflexes disappeared, and atropine did not induce an increase in heart rate in the brain dead animals. CTA confirmed loss of cerebral circulation. CONCLUSION: This study offers a standardised, clinically relevant porcine model of brain death induced by a haemorrhagic attack. Brain death was verified by the disappearance of corneal and pupil reflex, atropine test, and CTA.

Systemic inflammation in the brain-dead organ donor.

Brain death itself impairs organ function in the potential donor, thereby limiting the number of suitable organs for transplantation. In addition, graft survival of kidneys obtained from brain-dead (BD) donors is inferior to that of kidneys obtained from living donors. Experimental studies confirm an inferior graft survival for the heart, liver and lungs from BD compared with living donors. The mechanism underlying the deteriorating effect of brain death on the organs has not yet been fully established. We know that brain death triggers massive circulatory, hormonal and metabolic changes. Moreover, the past 10 years have produced evidence that brain death is associated with a systemic inflammatory response. However, it remains uncertain whether the inflammation is induced by brain death itself or by events before and after becoming BD. The purpose of this study is to discuss the risk factors associated with brain death in general and the inflammatory response in the organs in particular. Special attention will be paid to the heart, lung, liver and kidney and evidence will be presented from clinical and experimental studies.

Psychological stress during pregnancy and stillbirth: prospective study.

OBJECTIVE: To study the association between psychological stress during pregnancy and stillbirth. DESIGN: Prospective follow-up study. SETTING: Aarhus University Hospital, Skejby, Denmark,1989-98. POPULATION: A total of 19 282 singleton pregnancies in women with valid information about psychological stress during pregnancy. METHODS: Information about psychological stress during pregnancy was obtained from questionnaires and measured by the 12-item General Health Questionnaires (GHQ). A score was generated by the sum of all the answers, each contributing a value between 0 (low psychological stress) and 3 (high psychological stress). Women with an intermediate level of psychological stress (scores of 7-11) were considered the reference group. Scores of 0-6 were defined as a low level of psychological stress and scores of 12-36 as the highest level. The association between psychological stress and stillbirth was presented as relative risks with 95% CIs. Adjustment for potential confounding factors was carried out by logistic regression analyses. MAIN OUTCOME MEASURES: Stillbirth (delivery of a dead fetus at >28 weeks of gestation). RESULTS: There were 66 stillbirths (3.4 per thousand) in the population studied. Compared with women with an intermediate level of psychological stress during pregnancy, women with a high level of stress had 80% increased risk of stillbirth (relative risk = 1.8; 95% CI 1.1-3.2). Adjustment for maternal age, parity, maternal pre-pregnancy body mass index, smoking habits, alcohol and caffeine intake during pregnancy, education and cohabitation failed to change the result. The results remained essentially unchanged after exclusion of preterm deliveries. Exclusion of women with complications during pregnancy such as diabetes, hypertension, vaginal bleeding, immunisation and imminent preterm delivery failed to change the results. Likewise, restriction to women's first pregnancy in the cohort did not change the results. CONCLUSION: Psychological stress during pregnancy was associated with an increased risk of stillbirth.

Does brain death induce a pro-inflammatory response at the organ level in a porcine model?

BACKGROUND: Organs from brain-dead donors have a poorer prognosis after transplantation than organs from living donors. A possible explanation for this is that brain death might initiate a systemic inflammatory response, elicited by a metabolic stress response or brain ischemia. The aim of this study was to investigate the effect of brain death on the cytokine content in the heart, liver, and kidney. In addition, the metabolic and hemodynamic response caused by brain death was carefully registered. METHODS: Fourteen pigs (35-40 kg) were randomized into two groups (1) eight brain-dead pigs and (2) six pigs only sham operated. Brain death was induced by inflation of an epidurally placed balloon. Blood samples for insulin, glucose, catecholamine, free fatty acids (FAA), and glucagon were obtained during the experimental period of 360 min. At the conclusion of the experiment, biopsies were taken from the heart, liver, and kidney and were analyzed for cytokine mRNA and proteins [tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-6, and IL-10). RESULTS: We found a dramatic response to brain death on plasma levels of epinephrine (P=0.004), norepinephrine (P=0.02), FAA (P=0.0001), and glucagon (P=0.0003) compared with the sham group. There was no difference in cytokine content in any organ between the groups. CONCLUSION: In this porcine model, brain death induced a severe metabolic response in peripheral blood. At the organ level, however, there was no difference in the cytokine response between the groups.

Insulin alters cytokine content in two pivotal organs after brain death: a porcine model.

BACKGROUND: To optimize the quantity and quality of organs available for transplantation, it is crucial to gain further insight into the treatment of brain dead organ donors. In the current study we hypothesized that insulin treatment after brain death alters cytokine content in the heart, liver, and kidney. METHODS: Sixteen brain dead pigs (35-40 kg) were treated with either (1) no insulin [brain dead without insulin treatment treatment (BD)], or (2) insulin infusion intravenously (i.v.) at a constant rate of 0.6 mU/kg/min during 360 min [brain dead with insulin treatment (BD+I)]. Blood glucose was clamped at 4.5 mmol/l by infusion of 20% glucose. Blood samples for insulin, glucose, catecholamines, free fatty acids, and glucagon were obtained during the experimental period. Six hours after brain death biopsies were taken from the heart, liver, and kidney. These were analyzed for cytokine mRNA and proteins [tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, and IL-10]. RESULTS: The BD+I compared with the BD animals had lower IL-6 concentrations in the right ventricle of the heart (P=0.001), in the renal cortex (P=0.04) and in the renal medulla (P=0.05), and lower IL-6 mRNA in the renal medulla (P=0.0002). Furthermore, the BD+I animals had lower concentrations in the renal medulla of IL-10 (P=0.01), and tended to have lower TNF-alpha in the renal cortex (P=0.06) than the BD animals. In the right ventricle of the heart TNF-alpha mRNA and IL-10 mRNA were higher in the BD+I than in the BD group (P=0.002 and 0.004). CONCLUSION: Insulin has anti-inflammatory effects on cytokine concentration in the heart and kidney after brain death.

Maximal hysteresis: a new method to set positive end-expiratory pressure in acute lung injury?

BACKGROUND: No methods are superior when setting positive end-expiratory pressure (PEEP) in acute lung injury (ALI). In ALI, the vertical distance (hysteresis) between the inspiratory and expiratory limbs of a static pressure-volume (PV) loop mainly indicates lung recruitment. We hypothesized that PEEP set at the pressure where hysteresis is 90% of its maximum (90%MH) would give similar oxygenation, but less cardiovascular depression than PEEP set at the pressure at lower inflection point (LIP) on the inspiratory limb or at the point of maximal curvature (PMC) on the expiratory limb in ALI. METHODS: In 12 mechanically ventilated pigs, ALI was induced in a randomized fashion by lung lavage, lung lavage plus injurious ventilation, or by oleic acid. From a static PV loop obtained by an interrupted low-flow method, the pressures at LIP [25 (25, 25) cmH(2)O, mean and 25, 75 percentiles], at PMC [24 (20, 24) cmH(2)O], and at 90% MH [19 (18, 19) cmH(2)O] were determined and used for the PEEP-settings. We measured lung inflation (by computed tomography), end-expiratory lung volume (EELV), airway pressures, compliance of the respiratory system (Crs), blood gases, cardiac output and arterial blood pressure. RESULTS: There were no differences between the PEEP settings in EELV or oxygenation, but the 90%MH setting gave lower end-inspiratory pause pressure (P<0.025), higher Crs (P<0.025), less hyper-aeration (P<0.025) and better maintained hemodynamics. CONCLUSION: In this porcine lung injury model, PEEP set at 90% MH gave better lung mechanics and hemodynamics, than PEEP set at PMC or LIP.