Effects of mechanical ventilation on gene expression profiles in renal allografts from brain dead rats.

Pathophysiological changes of brain death (BD) are impairing distal organ function and harming potential renal allografts. Whether ventilation strategies influence the quality of renal allografts from BD donors has not been thoroughly studied. 28 adult male Wistar rats were randomly assigned to four groups: 1) no brain death (NBD) with low tidal volume/low positive endexpiratory pressure (PEEP) titrated to minimal static elastance of the respiratory system (LVT/OLPEEP); 2) NBD with high tidal volume/low PEEP (HVT/LPEEP); 3) brain death (BD) with LVT/OLPEEP; and 4) BD with HVT/LPEEP. We hypothesized that HVT/LPEEP in BD leads to increased interleukin 6 (IL-6) gene expression and impairs potential renal allografts after six hours of mechanical ventilation. We assessed inflammatory cytokines in serum, genome wide gene expression profiles and quantitative PCR (qPCR) in kidney tissue. The influence of BD on renal gene-expression profiles was greater than the influence of the ventilation strategy. In BD, LVT ventilation did not influence the inflammatory parameters or kidney function in our experimental model.

Drugs and brain death.

IN THE EARLY HOURS of the morning, a fit young man leaves a party, where drugs are reported to have been consumed, to walk home. A short time later he is found unconscious by the roadside, with severe head injuries. En route to hospital by ambulance, he suffers a cardiac arrest and is successfully resuscitated. On arrival at the Emergency Department he has obvious head injuries and is deeply unconscious, but shows spontaneous ventilatory movements. Available history is that he is a 20-year-old student with well-controlled epilepsy for which he takes phenytoin. It is not known how he sustained his injuries. Pupils are equal, small and react sluggishly to light. There is generalised flaccidity and an extensor-plantar response to painful stimuli. Skull x-rays show no fractures and computed tomography shows early cerebral oedema and scattered cerebral contusions with evidence of subarachnoid haemorrhage. He is transferred to the intensive care unit and measures to inhibit cerebral oedema, including mannitol, are commenced. An N-methyl-D-aspartate (NMDA) inhibitor is administered for neuroprotection and ventilatory support is commenced. Over the next 24 hours haemodynamic support is needed with fluid loading and vasopressors. A urine drug screen by Toxilab (Toxilab Incorporated, Irvine, Calif.) shortly after arrival shows the presence of phenytoin and morphine. The report states that the presence of benzodiazepines is suspected. Plasma phenytoin concentration at the time of arrival was 78 mumol/L (optimal range, 40-80 mumol/L). Forty hours after admission his condition has deteriorated. His pupils are at midposition, no longer reactive to light and his lower limbs exhibit only spinal reflexes. His relatives begin to prepare themselves for the fact he may not survive and raise the issue that he would have been keen to donate organs under such circumstances. What is the opinion regarding withdrawal of life support at this time?

Drugs and brain death.

Brain death protocols facilitate early recognition of death in patients on life support systems. When the clinical situation has deteriorated to a level where brain death is to be considered, it is essential that the effects of drugs be excluded. Most centrally acting drugs depress respiration and would be expected to affect apnoea testing of brain stem function. However, the pharmacodynamic and pharmacokinetic properties of drugs are altered when patients are critically ill, so projections made from data derived from less ill patients or normal volunteers are inappropriate. The entry of drugs into the brain is also altered in some disease states, but there are few data relating to the effects of central depressant drugs in the situation of a disrupted blood-brain barrier or brain damage. Drug screens can assist in determining whether drugs are present, but correct interpretation of the results depends on close liaison between the clinical and laboratory staff. It is in the patient's interests to avoid termination of life support if any centrally active drug is present, unless there are other categorical factors consistent with irreversible brain death, such as demonstrated lack of cerebral blood flow.

Cardiovascular consequences of severe hypophosphataemia in brain-dead patients.

Hypophosphataemia is known to induce reversible myocardial dysfunction, but the incidence of hypophosphataemia and its effect on myocardial function during brain death are unknown. In 90 consecutive brain-dead patients, we measured plasma concentrations of phosphate and left ventricular ejection fraction area (LVEFa), using transoesophageal echocardiography. In 15 severely hypophosphataemic (< 0.40 mmol litre-1), consecutive, brain-dead patients, haemodynamic status, LVEFa, and oxygen delivery and consumption were assessed before and after phosphorus loading (0.30 mmol kg-1). In 10 other brain-dead patients, urine elimination of phosphates was measured. Only 30 (33%) brain-dead patients had normal plasma phosphate concentrations, 22 (24%) had mild hypophosphataemia (0.40-0.80 mmol litre-1) and 38 (42%) had severe hypophosphataemia (< 0.40 mmol litre-1). There were no significant differences in LVEFa between these three groups (mean 53 (SD 16), 55 (12) and 51 (17)%, respectively) and no significant correlation between LVEFa and plasma phosphate concentration (r = 0.04). In 15 severely hypophosphataemic patients, phosphorus loading increased plasma phosphate concentration from 0.30 (0.10) to 1.06 (0.41) mmol litre-1, but did not modify haemodynamic status, LVEFa or oxygen delivery and consumption. In 10 other patients, urine phosphorus elimination was 16.8 (23.3) mmol/24 h while plasma phosphate concentration was at its highest level (0.80 (0.37) mmol litre-1), and only one of these patient had a slightly elevated phosphaturia. In conclusion, hypophosphataemia frequently occurs after brain death but has no significant cardiovascular consequences, suggesting that it is related to intracellular transfer and not phosphorus depletion.(ABSTRACT TRUNCATED AT 250 WORDS)