Pekka Mellergård

Intracerebral microdialysis and bedside biochemical analysis in patients with fatal traumatic brain lesions

Background: Microdialysis with bedside biochemical analysis was used to monitor cerebral biochemical alterations that precede and accompany increase in intracranial pressure (ICP), resulting in a complete cessation of cerebral blood flow.

Intracerebral temperature in neurosurgical patients.

Recent laboratory results have indicated that the ischemic brain is very sensitive to minor variations in temperature. This has created new interest in hypothermia and brain temperature. There is, however, very little information available regarding human intracerebral temperature and its relation to body core temperature during normal and pathological circumstances. We therefore made continuous measurements of the temperature of the lateral ventricle in 15 neurosurgical patients utilizing a newly developed technique with copper-constantan thermocouples introduced through a plastic catheter also used for monitoring intracranial pressure. The intraventricular temperature was higher than the rectal temperature during approximately 90% of all measurements. The largest temperature gradient measured was 2.3 degrees C. Usually the difference between the temperature of the rectum and the brain was much smaller, the mean value being 0.33 degrees C. For the patients in the most severe condition, the rectal temperature was sufficiently close to the brain temperature to afford a reliable basis for adequate clinical judgment.

Changes in Human Intracerebral Temperature in Response to Different Methods of Brain Cooling

The rectal, epidural, and intraventricular temperatures were continuously monitored in 10 seriously injured and unconscious patients admitted for neurosurgical intensive care. Different attempts were made to lower their brain temperatures. Isolated head cooling, whether with frozen liquid (Hypotherm Gel Kap; Flexoversal, Hilden, Germany) or a cooling helmet, had very limited effect. Nasopharyngeal cooling had no effect. During barbiturate coma, a considerable increase in brain temperature was observed. The administration of paracetamol was the single most effective method by which to lower brain temperature, at times by 2 degrees C and usually with a concomitant decrease in the temperature gradient between the rectum and the brain. However, in order to achieve a lasting reduction of brain temperature to 35 degrees C, we had to use a combination of head cooling and intensive whole-body cooling.

Preservation of brain temperature during ischemia in rats.

Our objectives were to study the loss of heat from ischemic brain and to devise a method of maintaining brain temperature. Reversible forebrain ischemia was induced by carotid clamping and exsanguination in 30 anesthetized and artificially ventilated rats. Rectal, skull, and brain temperatures were measured, confirming previous findings that brain temperature falls by 4-5 degrees C during 15 minutes of ischemia unless measures are taken to maintain head temperature by external heating. Temperature gradients developed within the ischemic brain, superficial tissues being cooler than deep ones. These temperature gradients were reversed when skull temperature was maintained at core body (rectal) temperature by external heating. With rectal and skull temperatures maintained at 38 degrees, 37 degrees, 35 degrees, or 33 degrees C, brain temperatures nonetheless decreased by approximately 1 degree C during ischemia. This decrease in brain temperature could be prevented by placing the rat in a Plexiglas box with circulating air at temperatures close to that of the body core and a relative humidity of approximately 100%. We also found that, unless special precautions are taken, a temperature gradient develops between the brain and body core during recirculation.

Epidural temperature and possible intracerebral temperature gradients in man

Although it has been known for a long time that pronounced hypothermia has a protective effect on the brain during ischemia, and that severe hyperthermia damages neuronal tissue, knowledge of human brain temperature is very limited. The recent findings by two independent research groups, that even small differences in brain temperature significantly influence the degree of neuronal damage following cerebral ischemia, became the incentive for measuring brain temperature in neurosurgical patients. The temperature of the lateral ventricle, epidural space, membrana tympani and rectum were measured with copper-constantan thermocouples. During the implantation of an intraventricular catheter for measuring intracranial pressure, a temperature gradient of 0.4-1.0 degrees C between the lateral ventricle and the epidural space was noted. Continuous measurements for 1-5 days showed that the rectal temperature usually adequately reflects the temperature of the epidural space, although the temperature of the membrana tympani followed changes in epidural temperature more closely. However, at times, and in one patient during most of the time, the temperature of the epidural space was up to 1 degree C above rectal temperature. The relevance of these findings for the care of neurosurgical patients is discussed in relationship to what is known about brain temperature from animal experiments.

Operations and re-operations for chronic subdural haematomas during a 25-year period in a well defined population

SummaryIn this retrospective study the hospital records of all patients being operated on for chronic subdural haematomas (CSD) at the Neurosurgical clinic in Lund in the years 1969, 1979, 1989, and 1993 were examined. 218 patients were operated on, 25 of whom had bilateral haematomas. During the 25-year period the incidence of surgically treated CSD rose from 2 to 5.3 per 100 000 inhabitants per year. The mean age (70.5 years) and the relationship males: females (2 ∶ 1) did not significantly change. The clinical condition of the patients on admission steadily improved during the period. The relative proportion of patients with known chronic alcoholism decreased over the years, but the proportion of patients suffering from other complicating diseases increased, as did the proportion of patients treated with anticoagulants.There was no mortality directly related to surgery, but if defined as deaths within one month after surgery, the overall mortality rate was 3.2%. 84.2% of the patients improved following the first operation, in a majority of cases back to the premorbid state. The relative frequency of re-operations for CSD was 12.3% and did not significantly change during the period. No pre- or peri-operative variable could be identified which could predict who of the patients was at higher risk of re-operation. Surprisingly, the data suggest that the less experienced neurosurgeons had better operative results compared with their older collegues.

Influence of acid-base changes on the intracellular calcium concentration of neurons in primary culture.

The influence of changes in intra- and extracellular pH (pHi and pHe, respectively) on the cytosolic, free calcium concentration ([Ca2+]i) of neocortical neurons was studied by microspectrofluorometric techniques and the fluorophore fura-2. When, at constant pHe, pHi was lowered with the NH4Cl prepulse technique, or by a transient increase in CO2 tension, [Ca2+]i invariably increased, the magnitude of the rise being proportional to ΔpHi. Since similar results were obtained in Ca2+-free solutions, the results suggest that the rise in [Ca2+]i was due to calcium release from intracellular stores. The initial alkaline transient during NH4Cl exposure was associated with a rise in [Ca2+]i. However, this rise seemed to reflect influx of Ca2+ from the external solution. Thus, in Ca2+-free solution NH4Cl exposure led to a decrease in [Ca2+]i. This result and others suggest that, at constant pHe, intracellular alkalosis reduces [Ca2+]i, probably by enhancing sequestration of calcium. When cells were exposed to a CO2 transient at reduced pHe, Ca2+ rose initially but then fell, often below basal values. Similar results were obtained when extracellular HCO3-concentration was reduced at constant CO2 tension. Unexpectedly, such results were obtained only in Ca2+-containing solutions. In Ca2+-free solutions, acidosis always raised [Ca2+]i. It is suggested that a lowering of pHe stimulates extrusion of Ca2+ by ATP-driven Ca2+/2H+ antiport.

Regulation of intracellular pH in single rat cortical neurons in vitro : a microspectrofluorometric study

Intracellular pH (pHi) and the mechanisms of pHi regulation in cultured rat cortical neurons were studied with microspectrofluorometry and the pH-sensitive fluorophore 2′,7′-bis(carboxyethyl)-5,6-carboxyfluorescein. Steady-state pHi was 7.00 ± 0.17 (mean ± SD) and 7.09 ± 0.14 in nominally HCO3− -free and HCO3−-containing solutions, respectively, and was dependent on extracellular Na+ and Cl−. Following an acid transient, induced by an NH1 prepulse or an increase in CO2 tension, pHi decreased and then rapidly returned to baseline, with an average net acid extrusion rate of 2.6 and 2.8 mmol/L/min, in nominally HCO3− -free and HCO3− -containing solutions, respectively. The recovery was completely blocked by removal of extracellular Na+ and was partially inhibited by amiloride or 5-N-methyl-N-isobutylamiloride. In most cells pHi recovery was completely blocked in the presence of harmaline. The recovery of pHi was not influenced by addition of 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid (DIDS) or removal of Cl−. The rapid regulation of pHi seen following a transient alkalinization was not inhibited by amiloride or by removal of extracellular Na+, but was partially inhibited by DIDS and by removal of extracellular Cl−. The results are compatible with the presence of at least two different pHi-regulating mechanisms: an acid-extruding Na+/H+ antiporter, possibly consisting of different subtypes, and a passive Cl−/HCO3− exchanger, mediating loss of HCO3− from the cell.

Changes in extracellular concentrations of some cytokines, chemokines, and neurotrophic factors after insertion of intracerebral microdialysis catheters in neurosurgical patients.

OBJECTIVEThe extracellular levels of eight different inflammatory agents were analyzed during the initial 36 hours after insertion of microdialysis catheters in patients. METHODSCerebral extracellular fluid from 38 patients who were treated in a neurosurgical intensive care unit for severe brain injury was collected every 6 hours for 36 hours. The concentration of interleukin (IL)-1β, IL-6, IL-8, macrophage inflammatory protein-1β, regulated on activation, normal T-cell expressed and secreted (RANTES), fibroblast growth factor-2, and vascular endothelial growth factor was determined by a multiplex assay, and IL-10 was determined by enzyme-linked immunosorbent assay. RESULTSThis is the first report regarding the presence of IL-10, IL-8, macrophage inflammatory protein-1β, regulated on activation, T-cell expressed and secreted, vascular endothelial growth factor, and fibroblast growth factor-2 in the tissue level proper of the living human brain. The study also provides new information regarding the response of IL-1β and IL-6 after insertion of a microdialysis catheter. The study confirms that the intriguing patterns of interplay between different components of the inflammatory response studied in laboratory settings are present in the human brain. This was most clearly observed in the variations in response between the three different chemokines investigated, as well as in the rapid and transient response of fibroblast growth factor-2. CONCLUSIONThe data presented illustrate the opportunity to monitor biochemical events of possible importance in the human brain and indicate the potential of such monitoring in neurosurgical intensive care. The study also underlines that any analysis of events in the brain involving mechanical invasiveness needs to take into account biochemical changes that are directly related to the manipulation of brain tissue.

Chapter 3 Acidosis-related brain damage

Publisher Summary This chapter updates information on the coupling among hyperglycemia, intra and extracellular acidosis and brain damage because of ischemia or hypoxia, and discusses cellular and molecular mechanisms that may be involved. When ischemia is complicated by excessive acidosis, the ischemic damage encompasses post-ischemic seizures, edema, and pannecrosis. The cellular and molecular mechanisms responsible for these alterations have not been adequately defined. However, it seems likely that the acidosis causes damage to inhibitory GABAergic cells by raising Ca i 2+ to levels, which will overload the buffering systems and cause cell death, thereby explaining the proclivity to post-ischemic seizure discharge. The rapidly evolving damage following long periods of ischemia is probably caused by several adverse effects of a raised H + activity: inhibition of Na + /H + exchange and lactate – oxidation, inhibition of mitochondria1 respiration, and acceleration of coupled Na + /H + and Cl – /HCO 3 – exchange. However, an important factor may be a lingering rise in Ca i 2+ in cells whose pH i is reduced over a longer period, predisposing to Ca 2+ -related damage. The molecular mechanisms underlying delayed acidosis-related damage probably comprise Fe 2+ and NO · -related production of free radicals that have the microvessels as their main target.