Stover, John F. MD; Kempski, Oliver S. MD, PhD
Objectives: Animal studies have shown that the elevation of plasma glutamate levels increase cerebral edema formation whenever the blood-brain barrier is disturbed. Therefore, changes in plasma glutamate levels as influenced by the administration of a glutamate-containing amino acid solution were investigated in neurosurgical patients.
Design: Prospective, descriptive study.
Setting: Eight-bed neurosurgical intensive care unit in a university hospital.
Patients: Twenty-three neurosurgical patients requiring parenteral nutrition.
Interventions: Parenteral nutrition was begun 24 hrs after craniotomy. Patients receiving a glutamate-containing amino acid solution (3.75 g/L glutamate) were compared with patients infused with a glutamate-free solution.
Measurements and Main Results: Arterial plasma and urine amino acids were analyzed using high-performance liquid chromatography. Administration of a glutamate-containing solution doubled plasma glutamate levels in neurosurgical patients (from 53.3 ± 9.8 µM [preinfusion] to 98.5 ± 18.7 µM [after 4 hrs of infusion]; p < 0.001), whereas no elevation was seen when infusing a glutamate-free solution (from 52.3 ± 7.3 [1 hr of infusion] to 53.6 ± 6.4 µM [4 hrs of infusion]). Upon terminating the glutamate-containing infusion, arterial plasma glutamate levels decreased immediately (from 120 ± 13.2 µM to 81.2 ± 19.5 µM). Glutamate as infused in excess appears to exceed a renal threshold and is eliminated renally.
Conclusions: As shown in animal models, administration of a glutamate-containing amino acid solution significantly increased plasma glutamate levels. Because such an increase in plasma glutamate levels could aggravate cerebral edema formation, glutamate-containing amino acid solutions cannot be recommended for patients with a disturbed blood-brain barrier.
As a part of the postsurgical routine, patients who have undergone craniotomy receive parenteral nutrition to reduce stress-related catabolic metabolism. For this purpose, glutamate-containing as well as glutamate-free amino acid solutions are combined with carbohydrates for parenteral nutrition. Currently, no standard type of parenteral nutrition for neurosurgical patients exists. Glutamate and aspartate, however, are known for their excitotoxic potential for causing cellular swelling (1), neuronal death (2), and subsequent loss in function (3) if these amino acids enter the extracellular space of the brain. Animal studies indeed indicate that any elevation of plasma glutamate levels may pose a risk for patients already suffering from a damaged blood-brain barrier (BBB): Intravenous infusion of glutamate increases extracellular glutamate accumulation after traumatic brain injury (4) and aggravates cerebral edema formation in rats after cryogenic BBB lesion (5) or reversible osmotic opening of the BBB (6).
Therefore, we investigated the changes in plasma glutamate, aspartate, and their nontoxic complementary forms (glutamine and asparagine) during a 24-hr infusion period, comparing the influence of a glutamate-containing (3.75 g/L glutamate) and a glutamate-free amino acid solution as used in routine clinical practice.
Patient Selection. Regardless of diagnosis, 13 neurosurgical patients received a glutamate-containing amino acid solution and ten were infused with a glutamate-free solution. Only patients who were free from chemical or clinical signs of metabolic, renal, or hepatic disorders were entered into this study after elective craniotomy when parenteral nutrition was required and no enteral feeding had been started previously. The physician responsible for the patient decided on the amino acid solution to be used, and the decision was not influenced by the investigator. According to the existing therapeutic protocol (which was also not altered by these investigations), patients received glucose (5%) and physiologic saline solution during the first 24 hrs after surgery, before intravenous alimentation was started. The study protocol was approved by the University Hospital Medical Ethics Board, which waived the need for informed consent.
Controls. Control plasma amino acid levels were measured in blood samples taken from 20 healthy female and male volunteers after an overnight fast.
Investigated Amino Acid Solutions. The choice of the amino acid solutions that were used in the clinical routine as part of parenteral nutrition for these neurosurgical patients was not influenced by the investigator. Consequently, the glutamate-containing solution (+Glu) with 3.75 g/L (PERIAMIN X®; Pfrimmer, Erlangen, Germany) was compared with the glutamate-free solution (-Glu) (AMINOMIX 5®; Fresenius, Bad Homburg v.d.H., Germany). These two were the only solutions available at our hospital. Both solutions are free from aspartate, glutamine, and asparagine (Table 1). Administration of the glutamate-containing and glutamate-free solutions was begun in all patients at 5 pm and was maintained for 24 hrs.
Collection of Plasma Samples. Plasma samples were drawn using heparin-coated syringes 1 hr before and 1 hr after beginning of infusion, followed by sampling in 4-hr intervals during the next 24 hrs. All parenterally applied solutions were administered via central venous catheters, and plasma samples were taken from arterial lines. These arterial samples were the remainders of routine samples for blood gas analysis, which would have been discarded otherwise. Urine samples were drawn with conventional syringes and were collected during 24 hrs.
Analysis of Amino Acids. Enzymatic transformation of glutamate results in increased plasma glutamine, aspartate, and asparagine levels. Because the administered amino acid solutions do not contain glutamine, aspartate, and asparagine, any changes in plasma levels of these amino acids should, therefore, unmask endogenous metabolism of infused glutamate. Immediately after collection, blood and urine samples were deproteinized with perchloric acid (6%), centrifuged, mixed with potassium carbonate, centrifuged once more, and stored at -70°C (-158°F) until analysis by high-performance liquid chromatography (7). After thawing, the samples were centrifuged anew to prevent injection of precipitated potassium carbonate. High-performance liquid chromatography was performed using a solvent delivery system chromatograph (model 2700; Biorad, Munich, Germany) linked to a fluorescence detector (Biotronik, Maintal, Germany), set at 330 nm (excitation) and 450 nm (emission wave length). The column was a Spherisorb C-18 (3 µm particle size), 125 × 4 mm (Grom, Herrenberg-Kayh, Germany). Mobile phases were as follows: a) stock buffer mixed with 1% tetrahydrofuran and 5% acetonitrile (pH 7); and b) stock buffer-acetonitrile (50/50; pH 7). Stock buffer consisted of 1.724 g/L sodium dihydrogenphosphate-1.77 g/L disodium hydrogenphosphate (40/60). After injection, a stepped gradient at a flow rate of 0.6 mL/min was applied, consisting of 0-5 mins of 100% A, 5-52 mins of 0-95% B, and 52-60 mins of 95-0% B. Before injection, blood samples were mixed with an equal amount of orthophthalaldehyde and incubated for 2 mins (orthophthalaldehyde precolumn derivatization). A standard mixture of the amino acids of interest was analyzed as an external standard before measurement of blood samples. Sample peak areas were compared with the areas of corresponding standard amino acids of known concentration, which allowed subsequent calculation of the measured sample concentration. Amino acids were measured in duplicate, and all results are given as mean ± SEM.
Statistical Analysis. Results within the two different groups and between the two groups were compared for statistical significance by the Student's t-test and one-way analysis of variance, respectively, after testing for normal distribution. Results were rated significant whenever p < 0.05.
Patient Data. Postoperatively, five female and five male patients (51 ± 3 yrs) received the glutamate-containing amino acid solution, whereas four female and nine male patients (53 ± 3 yrs) were parenterally fed with a glutamate-free solution. The underlying neurologic diseases in both groups were heterogeneous and comprised patients with tumors (5 vs. 4), subarachnoid and subdural hemorrhages (3 vs. 5), cerebellar infarctions (1 vs. 2), and head injuries (1 vs. 2). During and after this 24-hr study period, no neurologic deterioration could be attributed to the infusion of the amino acid solutions, and the length of hospitalization was not prolonged in patients receiving the glutamate-containing amino acid solution (21 ± 10 days vs. 25 ± 12 days).
Plasma Glutamate (Fig. 1). Arterial plasma glutamate levels were significantly increased in patients receiving the glutamate-containing solution (controls, 56 ± 5.5 µM; +Glu, 53.3 ± 9.8 µM [-1 hr]; 88.4 ± 13.9 µM [1 hr]; 98.5 ± 18.7 µM [4 hrs]; p < 0.001) followed by a transient decrease by 12 hrs after beginning of the infusion with a further significant increase (61.3 ± 8.6 µM [12 hrs]; 87.3 ± 10.8 µM [24 hrs]; p < 0.001). These levels were significantly elevated compared with the values in the glutamate-free group (-Glu, 52.3 ± 7.3 [1 hr]; 53.6 ± 6.4 µM [4 hrs]; 59.0 ± 6.4 µM [24 hrs]; p < 0.02), which remained nearly unchanged (Table 2).
Three of these patients had first received the glutamate-containing amino acid solution before being fed intravenously with the glutamate-free solution. Immediately after plasma glutamate levels were changed, the solutions decreased from 120 ± 13.2 µM to 81.2 ± 19.5 µM. Thereafter, plasma glutamate values remained nearly uninfluenced and tended to decrease to control values.
Plasma Aspartate. There was a significant increase in plasma aspartate levels in those patients receiving the glutamate-containing solution compared with healthy controls and patients fed with the glutamate-free solution (controls, 10.7 ± 1.4 µM; -Glu, 10.2 ± 1.6 µM [1 hr]; +Glu, 17.5 ± 2.3 µM [1 hr]; p < 0.003). As seen with glutamate, the plasma aspartate levels showed a transient decrease to normal values by 12 hrs after beginning the infusion but were doubled again after 24 hrs (+Glu, 8.8 ± 1.5 µM [12 hrs]; 17 ± 2.3 µM [24 hrs]; p < 0.003) (Table 2).
Plasma Glutamine. Whereas plasma glutamine levels remained unchanged with the infusion of the glutamate-free solution, there was a significant elevation during administration of the glutamate-containing solution (727 ± 80.6 µM [-1 hr]; 998.3 ± 124.6 µM [16 hrs]; p < 0.03). The mean values of plasma glutamine levels in the group receiving the glutamate-containing solution were markedly but not significantly higher compared with the glutamate-free group. Compared with values of healthy controls, the preinfusion levels in both groups were significantly decreased (controls, 943 ± 63.4 µM; +Glu, 727 ± 80.6 µM; -Glu, 651.3 ± 82 µM; p < 0.025) (Table 2).
Plasma Asparagine. During infusion of the glutamate-containing solution, plasma asparagine values increased continuously (+Glu, 58 ± 5.6 µM [-1 hr]; 70.3 ± 9.5 µM [4 hrs]; 82.5 ± 12.4 µM [16 hrs]; p < 0.05). They were also significantly increased compared with values of the glutamate-free group, which remained unchanged during the investigated 24 hrs (+Glu, 82.5 ± 12.4 µM [16 hrs]; -Glu, 50.2 ± 4.3 µM [16 hrs]; p < 0.02). As seen with glutamine preinfusion, plasma asparagine levels were significantly decreased in both groups as compared with healthy controls (controls, 72.7 ± 5.7 µM; +Glu, 58 ± 5.6 µM [-1 hr]; -Glu, 55.3 ± 5 µM [-1 hr]) (Table 2).
Urine Amino Acids. Despite a trend to higher glutamate levels in urine collected during 24 hrs in those patients receiving the glutamate-containing solution (+Glu, 74.3 ± 6.5 µM; -Glu, 53.3 ± 9.8 µM), there was no statistically significant difference compared with patients receiving the glutamate-free solution. There was no difference as to urine glutamine (551.4 ± 84 µM vs. 467.1 ± 34.2 µM), aspartate (55.1 ± 10 vs. 45.3 ± 9.5 µM), or asparagine (126 ± 36.5 vs. 95.4 ± 12.4 µM) levels between the two groups (Table 2). Urine volume passed during the study period was the same in both groups (+Glu, 2.5 ± 0.6 l; -Glu, 2.8 ± 0.9 l).
Glutamate-An Excitotoxin That May Enhance Brain Edema Formation. Cerebral manipulation during neurosurgery may go along with structural and functional damage to neurons, astrocytes, and the BBB (7). Animal experiments (5) have shown that rats suffering from a disturbed BBB are highly susceptible to the excitotoxic and edema-enhancing potential of infusion-related increases in plasma glutamate, an effect that can be prevented by specific glutamate-receptor antagonists (6). Because craniotomized patients suffer from vasogenic edema formation after surgery because of a disturbed BBB (8), elevation of plasma glutamate levels must be considered an additional risk factor for these patients to develop further cerebral edema with its hazardous complications. In addition to its well-known neurotoxic effects, glutamate has also been shown to induce swelling of glial cells resulting from an increased energy-dependent uptake of glutamate from the extracellular space (9). Because glutamate uptake is coupled to electrogenic co-transport of Na+ and Cl- ions (10), water will accumulate intracellularly, resulting in cytotoxic edema formation. This, in turn, aggravates cerebral edema formation and increases preexisting edema (5, 6).
As found in rats after glutamate infusion (5), doubling of plasma glutamate levels is also seen in the current study in neurosurgical patients receiving the glutamate-containing amino acid solution. Comparable increases have also been shown in other patient populations (11). Therefore, a risk for those patients with a damaged BBB cannot be excluded. In the present study, the patient populations were not uniform as to the extent of barrier breakdown. To estimate the risk of individual patients, the extracellular glutamate levels would have to be assessed by microdialysis. This is indeed planned for future studies. In a recent article, Bullock et al. (12) demonstrated vast increases of extracellular glutamate in patients with severe head injuries. The authors provide evidence that the glutamate originated from damaged cells rather than from synaptic release. A possible inflow via the open BBB has not been taken into account so far. However, it is quite evident that any additional glutamate filtered from plasma will pose an additional risk for the already compromised homeostatic mechanisms of the brain. In fact, Koizumi et al. (4) injected rats with radioactively labeled glutamate and showed an accumulation of radioactivity in the vicinity of a cerebral lesion, i.e., in the vasogenic edema territory. Hence, care has to be taken to avoid increases in plasma glutamate in patients with a compromised BBB.
Glutamate Metabolism. While infusing free amino acids intravenously with the aim of ameliorating the postoperative metabolic situation, the physiologic pathway via the gastrointestinal tract is bypassed and substituted by an unphysiologic route. Normally, glutamate and aspartate are metabolized and transformed enzymatically to glutamine, asparagine, or [alpha]-ketoforms by intestinal epithelial cells, released abluminally, and transported via the portal circulation to the liver for further metabolism (13). With normal nutritional amounts of carbohydrates and protein, free glutamate will be metabolized mainly by the intestinal epithelium (14), reducing the rise in plasma glutamate compared with the oral uptake of free glutamate without protein or sugar (15). Up to 4 g of solubilized glutamate in sugar- and protein-free liquid causes a significant five-fold increase in venous plasma glutamate after oral intake (16). A complex of neurologic symptoms in healthy but sensitive individuals occurring after meals prepared with large quantities of glutamate is known as the "Chinese restaurant syndrome" (17). Mechanisms trying to explain this syndrome are still debated.
For parenteral nutrition, amino acids are directly infused into the general circulation via central venous catheters. Consequently, the brain is one of the first organs to be perfused with increased arterial plasma glutamate levels before this amino acid can be cleared by the intestinal tract from the abluminal side (18). Therefore, a possible "detoxification" can only occur after the first contact of this potentially toxic amino acid with cerebral parenchyma. With continuing infusion, the brain remains exposed to high concentrations of arterial plasma glutamate. It certainly would have been of clinical interest to compare plasma glutamate levels after oral and intravenous feeding of neurosurgical patients. This, however, was not possible with the current study protocol, during which no influence of the investigators on treatment paradigms was permitted.
The human organism seems to be able to reduce potentially toxic amino acids, such as glutamate and aspartate. This is achieved by important organs, such as skeletal muscle (19), liver (20), intestine (21), and kidney (22), which are able to clear these amino acids from blood, metabolize, store, or use them for energetic supply, protein, purine, or pyrimidine synthesis (22, 23).
The rise in plasma glutamine, aspartate, and asparagine levels in the investigated patient group receiving the glutamate-containing amino acid solution can best be explained by hepatic enzymatic transformation (24). The significantly lower preinfusion plasma glutamine and asparagine levels compared with healthy controls could be attributable to an increased postsurgical utilization.
The observed decrease in plasma glutamate and aspartate levels 12 hrs after beginning the infusion could be attributed to the persisting circadian rhythm for amino acids (25). Under normal circumstances, all amino acids have maximum values between 12 pm and 8 pm and minimum values between 4 am and 8 am. In the present study, minimum plasma glutamate and aspartate levels were measured at 5 am, 12 hrs after starting the infusion period, which appears to correspond to a preserved circadian rhythm for amino acids as found in healthy adults (26).
Is Glutamate Needed in Neurosurgical Patients? When estimating a daily glutamate synthesis of 150 g for an adult weighing 70 kg (24) and assuming that an adequate amount liberated from stored skeletal glutamine (27) with post-surgically unchanged plasma glutamate levels (28), the question arises whether there is any need to infuse glutamate in nonseptic, metabolically fairly stable neurosurgical patients. In various clinical settings a reduction in plasma glutamate does not make this amino acid a semiessential amino acid with the need of substitution. Because glutamate itself and glutamine (29), the precursor of glutamate, are present in sufficient amounts that can be liberated from muscular storage (30, 31) and because enzymatic transformation remains intact during stressful events, humans are able to maintain adequate amounts of plasma glutamate (32), as seen in those patients receiving the glutamate-free amino acid solution.
Infusing glutamate with the aim of preventing depletion of stored muscular glutamine and breakdown of structural proteins is bound to fail because glutamate is transported against its gradient and can only be co-transported with glucose via energy-dependent uptake processes. Because hormonal changes as found in the postsurgical phase lead to a postreceptor resistance for insulin, glucose and amino acids will not be transported into muscle cells in sufficient amounts (33). Consequently, the decreased uptake of glutamate by muscle cells will contribute to high plasma glutamate levels when infusing glutamate intravenously.
The slightly (statistically not significant) elevated glutamate levels in urine collected during this 24-hr infusion period are probably caused by a surpassed renal threshold with the infusion of amino acids intravenously, as seen in healthy individuals who excrete amino acids renally after oral intake of meals. Individuals who have fasted, however, eliminate significantly less amino acids renally (34). Urine and plasma glutamine concentrations did not differ significantly between the two groups. Therefore, changes in urine glutamate in the group receiving the glutamate-containing solution cannot be a result of enzymatic transformation from glutamine. Because the amount of urine passed during the 24-hr infusion period is comparable in both groups, diluted or concentrated effects seem unlikely to have affected urine glutamate concentrations.
In conclusion, the doubling in plasma glutamate levels as found in nonseptic, metabolically stable neurosurgical patients receiving 3.75 g/L glutamate intravenously will lead to elevated plasma glutamate levels. This, in turn, could result in increased extracellular glutamate levels whenever the BBB is disturbed, as seen in brain-injured rats (4). As a consequence, the activation of glial uptake mechanisms and neuronal glutamate receptors may go along with glial and neuronal swelling, i.e., cytotoxic edema formation. Therefore, the administration of glutamate-containing amino acid solutions cannot be recommended for patients suffering from a damaged BBB.
The authors thank Mr. Malzahn, Mrs. Karpi, and Mrs. Kempski for their technical assistance and the nursing staff of the neurosurgical intensive care unit for the collection of blood and urine samples.
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Key Words: amino acids; asparagine; aspartate; brain edema; excitotoxicity; glutamate; glutamine; parenteral nutrition