Steffen Berger

Effects of diaspirin-cross-linked hemoglobin (dclhbtm) on local tissue oxygen tension in striated skin muscle: An efficacy study in the hamster

Using the dorsal skin fold chamber model in the hamster, we analyzed local tissue partial oxygen pressure (PO2) in the striated skin muscle under nonischemic and postischemic conditions with a Clark-type multiwire oxygen surface electrode. Hypervolemic infusion (500 mg x kg(-1) I.V.) or isovolemic exchange transfusion (3.3 gm x kg(-1) I.V.; hematocrit 30%) with diaspirin-cross-linked hemoglobin (DCLHb) resulted in a slight decrease of the mean value of the local tissue PO2 (mm Hg) 1 hour after administration. Concomitantly, the frequency distribution curves of local tissue PO2 values were found to be more narrow (fewer values > 25 mm Hg and < 10 mm Hg). Resuscitation from severe hemorrhagic shock (bleeding of 33 ml x kg(-1) at 0.4 ml x min(-1)) with autologous blood (AuB), Dx-60, or DCLHb led to an increase of mean tissue PO2 values by 4.2-fold (p < 0.05 versus Dx-60), 1.9-fold, and 3.7-fold (p < 0.05 versus Dx-60), respectively, 2 hours after resuscitation. The reduction of tissue hypoxia (0-5 mm Hg) was significant only in the AuB- and DCLHb-treated animals. This study indicates that DCLHb effectively reverses tissue hypoxia after resuscitation from severe hemorrhagic shock by inducing a more homogeneous distribution of the local tissue PO2 levels.

7.2% NaCl/10% dextran 60 versus 20% mannitol for treatment of intracranial hypertension.

Severe head injury is frequently associated with extracranial injuries causing hemorrhagic hypotension. Volume replacement with isotonic fluids not only is therapeutically of limited efficacy but may aggravate posttraumatic brain edema. On the other side, hypertonic/hyperoncotic saline/dextran solution (HHS) shown to restore cardiovascular function in hemorrhagic shock instantaneously, was found to decrease intracranial pressure in experimental head injury. Currently the therapeutic efficacy of HHS and mannitol on ICP was compared at 24 hrs after a focal cerebral lesion and inflation of an epidural balloon in rabbits. Both solutions given at an equimolar dose rapidly lowered the ICP. After the first injection, ICP reduction was longer maintained with mannitol (189 +/- 27 min) as compared to HHS (98 +/- 14 min), while no difference in duration of lowering ICP was found after the second injection. Due to its blood pressure effects, HHS afforded a higher cerebral perfusion pressure than mannitol. In animals with HHS, the water content of the traumatized hemisphere was increased while the contralateral hemisphere was dehydrated. With mannitol, no differences in water content were found between the injured and uninjured hemisphere. The efficiency of HHS in hemorrhagic shock and intracranial hypertension render the fluid mixture particularly promising in patients with polytrauma in combination with head injury.

The effect of hypertonic fluid resuscitation on brain edema in rabbits subjected to brain injury and hemorrhagic shock.

Small-volume resuscitation with 7.2% NaCl/10% dextran 60 (HHS) restores cardiovascular stability faster than all other therapeutic modalities currently known. This study was undertaken to elucidate the effects of HHS on the brain, specifically on the formation of posttraumatic brain edema. HHS was administered to anesthetized albino rabbits with or without a focal cryogenic brain lesion and hemorrhagic shock. Specific gravity of small tissue samples was determined 4 h after injury and values were topographically assembled to form a color-coded map of both hemispheres, allowing for a high resolution mapping of brain edema. Cerebral blood flow on the side of the lesion, as assessed by the H2 clearance method, increased transiently after injury but remained unchanged from baseline during shock and after infusion of HHS, indicating intact cerebrovascular autoregulation. The cryogenic lesion without subsequent HHS infusion resulted in significant brain edema formation in grey and white matter of the exposed hemisphere. In injured animals resuscitation with HHS led to a global reduction of brain water content in both hemispheres. We conclude that small-volume resuscitation with HHS does not worsen posttraumatic brain edema. To the contrary, our results show that it decreases cerebral water content even in regions close to the injury. This makes it worthwhile to investigate the benefits of HHS for the treatment of intracranial hypertension.

Effects of Isoflurane, Fentanyl, or Thiopental Anesthesia on Regional Cerebral Blood Flow and Brain Surface Po2 in the Presence of a Focal Lesion in Rabbits

These studies were conducted to determine the effect of anesthetic drugs on tissue perfusion and O2 supply in the brain with focal cerebral edema. Using an open cranium preparation, we studied the effects of isoflurane (I; 1 minimum alveolar anesthetic concentration), of fentanyl (F; 0.5-1 microgram.kg-1 x min-1), or of thiopental (T; 32.5 mg.kg-1 x h-1) on regional cerebral blood flow (rCBF) and regional brain tissue PO2 in albino rabbits (n = 6 per group) with a focal brain lesion (cold injury). The doses of anesthetics were sufficient to suppress nociception. rCBF (H2 clearance) and tissue PO2 (multiwire surface electrode) were studied adjacent to and distant from the lesion. Cerebral hyperemia developed immediately after trauma in all groups, although the flow increase did not attain statistical significance. rCBF was subsequently reduced by about 25% in the vicinity of the lesion. Distant from the trauma, a continuing hyperemia (+30%) was later observed in animals with isoflurane, whereas rCBF was decreased then by 10%-20% in animals with fentanyl, or was unchanged with thiopental. Brain tissue PO2 was increased with isoflurane in areas distant from the lesion, but decreased with fentanyl. However, with thiopental, the PO2 level had already been lowered before trauma with a subsequent tendency toward normalization. The heterogeneity of the tissue PO2 in fentanyl anesthesia, as well as the increased frequency of hypoxic PO2 values with thiopental, might have resulted from microcirculatory disturbances. Thus, although isoflurane seemed to facilitate hyperemia with an increased O2 supply to the brain, fentanyl tended to induce the opposite response. Although these properties suggest the potential to manipulate perfusion and O2 supply in cerebral ischemia or hyperemia after head injury, the effects of such measures on intracranial pressure, neurologic status, and outcome have yet to be proven.

Influence of isoflurane, fentanyl, thiopental, and alpha-chloralose on formation of brain edema resulting from a focal cryogenic lesion.

The objective of this study was to analyze the effects of various anesthetics on the formation of brain edema resulting from a focal cryogenic lesion.Thirty rabbits (six per group) were anesthetized with isoflurane (1 minimum alveolar anesthetic concentration [MAC] 2.1 vol%), fentanyl (bolus 5 micro gram/kg; infusion rate 1.0-0.5 micro gram centered dot kg-1 centered dot min-1), thiopental (32.5 mg centered dot kg-1 centered dot h-1), or alpha-chloralose (50 mg/kg). Control animals (sham operation, no lesion) received alpha-chloralose (50 mg/kg). Regional cerebral blood flow (rCBF) in perifocal brain tissue was measured by H2-clearance. Animals anesthetized with isoflurane required support of arterial pressure by angiotensin II (0.15 micro gram centered dot kg-1 centered dot min-1). Six hours after trauma the animals were killed. Formation of brain edema was studied by specific gravity of cortical gray matter, white matter, hippocampus, caudate nucleus, putamen, and thalamus. Brain tissue samples were collected at multiple sites close to and distant from the lesion. Mean arterial pressure, arterial PCO2 and PO2, hematocrit, body temperature, and blood glucose were not different between groups during the posttraumatic course (except for an increased arterial pressure with alpha-chloralose compared to thiopental 4-6 h after trauma). The specific gravity of cortical gray matter was significantly reduced up to a distance of 6 mm from the center of the lesion in animals anesthetized with isoflurane, thiopental, or alpha-chloralose and up to 9 mm in animals given fentanyl. In white matter, vasogenic edema extended up to 12 mm from the lesion focus in animals anesthetized with fentanyl, thiopental, or alpha-chloralose. In isoflurane-anesthetized animals, white matter samples in all regions were similar to control. The specific gravity in hippocampus, caudate nucleus, putamen, or thalamus was not altered as compared to the controls. rCBF studied before cryogenic injury had a range of 37-44 mL centered dot 100 g-1 centered dot min-1, except in animals given fentanyl (i.e., 59.9 mL centered dot 100 g-1 centered dot min-1). During the first 3 h after trauma, animals given fentanyl had significantly higher rCBF values than animals with thiopental or the controls. At 4-6 h after trauma, rCBF was decreased in animals with fentanyl or thiopental as compared to the baseline level, although differences were not observed between groups. Regression analyses of data from all experimental groups do not reveal a relationship between the formation of posttraumatic brain edema and mean arterial pressure or rCBF. We conclude that isoflurane anesthesia attenuates cerebral edema from a standard cerebral lesion as compared to fentanyl, thiopental, or alpha-chloralose. (Anesth Analg 1995;80:1108-15)

Therapeutical Efficacy of a Novel Chloride Transport Blocker and an IP3-Analogue in Vasogenic Brain Edema

The efficacy of torasemide, a novel chloride-channel blocker, and of PP56, an IP3 analogue, was currently examined in experimental brain edema. Following trephination in anesthesia rats were subjected to a focal cold injury of the left cerebral hemisphere. Animals of 4 experimental groups receiving either torasemide (i.v. at 30 min before and 6 h after lesion) or PP56 (continuous infusion beginning at 30 min before until 24 h after lesion) at two dose levels were compared with controls administered with i.v. saline. 24 h after trauma the brain was removed from the skull, and the hemispheres were separated in the median plane for gravimetric assessment of hemispheric swelling. Hct, blood gases and body temperature remained constant in all groups. Blood pressure was found to increase in a dose-dependent manner in animals with torasemide. No significant reduction of brain swelling was found in animals with low-dose torasemide (8.51 +/- 0.63%) or low- (7.91 +/- 0.60) and high-dose PP56 (6.85 +/- 1.05%) as compared to the untreated controls. Brain swelling, however, was significantly attenuated by high-dose torasemide to 7.04 +/- 0.36%, as compared to 8.89 +/- 0.29% of the untreated group (p < 0.005). It is currently studied whether torasemide reduces brain swelling when given after the insult.

Relationship of Cerebral Blood Flow Disturbances with Brain Oedema Formation

Brain oedema is an important factor which compromises maintenance of the cerebral blood flow. Conversely, primary blood flow disturbances are leading to brain oedema. The mechanisms underlying blood flow impairment by brain oedema are associated with an increased regional tissue pressure in proportion to the degree of water accumulation in the parenchyma. The release of vasoactive mediator compounds might be considered in addition. Primary disturbances of the cerebral blood flow, such as focal or global cerebral ischaemia are leading to an increased cerebral water content. A decrease of the cerebral blood flow to ca. 40% of normal or below has been found to result in the development of brain oedema. This flow threshold is in the neighbourhood of the ischaemic flow level causing irreversible tissue damage. Whereas in focal ischaemia oedema formation is a function of the severity of the flow decrease, it is a pathophysiological hallmark of early postischaemic recirculation in global cerebral ischaemia. Nevertheless, during complete interruption of cerebral blood flow translocation of interstitial fluid into the intracellular compartment occurs as manifestation of ischaemic cell swelling. Cell swelling under these conditions may, however, not necessarily indicate cell damage, but more likely a compensatory response attributable to the uptake of excitotoxic transmitters such as glutamate, and of K(+)-ions which are excessively released at the onset of ischaemia into the extracellular space. Purpose of the swelling process, thus, is clearance of extracellular fluid from this material to re-establish homeostasis.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of Hypertonic-Hyperoncotic Solutions (HHS) on Increased Intracranial Pressure after a Focal Brain Lesion and Inflation of an Epidural Balloon

Many trauma victims with hemorrhagic shock sustain head injury in addition to their peripheral injuries. As in other patients with shock, rapid resuscitation is lifesaving under these conditions. Small volumes of hypertonic-hyperoncotic solutions have been successfully used in severe hemorrhage for prompt restoration of the cardio-vascular function [3, 4]. The effects of this method, of small volume resuscitation, on the general circulation, are well understood, while little is known about its effects in the central nervous system. Among others, it is very important to obtain information on the effects or side effects, respectively, of treatment with the hypertonic-hyperoncotic solution on the intracranial pressure in the presence of a damaged blood-brain barrier and intracranial mass.

Effects of Anesthetic Agents on Brain Edema and Cerebral Blood Flow from a Focal Cold Lesion in Rabbit Brain

Brain edema is a major cause of morbidity and mortality in patients with severe head injury. Anesthetic agents, which often have to be administered in these patients for diagnostic or operative procedures, usually decrease cerebral metabolism [7]. On the other hand, inhalation anesthetics may increase cerebral blood flow (CBF) by vasodilation of brain vessels [1]. Therefore, anesthesia may either protect the injured brain by reduction of metabolism, or contribute to the spread of brain edema by cerebral hyperemia. To date, little information is available about the effect of anesthetic agents in traumatized brain. We therefore carried out experimental investigations to analyze the influence of isoflurane, fentanyl, thiopental, and α-chloralose on regional cerebral blood flow (rCBF) and formation of brain edema from a focal injury to the brain.

Small Volume Resuscitation in Hemorrhagic Shock by Hypertonic/Hyperoncontic Saline-Dextran: Effects on the Central Nervous System

Secondary ischemia of the brain is common in fatal head injury (Graham et al. 1989). Bouma et al. (1991) observed in patients a close correlation between the impairment of cerebral blood flow during the first hours after trauma and final outcome. Based on the United States traumatic coma databank study, Marmarou et al. (1991) reported that periods of elevated intracranial pressure (ICP) (>20mmHg) or of a decreased blood pressure (<80mmHg) were highly predictive for poor outcome from severe head injury. Since 10%-20% of head-injured patients are simultaneously affected by severe peripheral injuries causing hemorrhagic hypotension (Miller et al. 1978), primary care must reestablish and maintain an appropriate cerebral as well as systemic circulation.