Neurocrit Care DOI 10.1007/s12028-014-0035-3


International Multidisciplinary Consensus Conference on Multimodality Monitoring: Cerebral Metabolism Peter Hutchinson • Kristine O’Phelan • The Participants in the International Multidisciplinary Consensus Conference on Multimodality Monitoring

Ó Springer Science+Business Media New York 2014

Abstract Microdialysis is a powerful technique, which enables the chemistry of the extracellular space to be measured directly. Applying this technique to patients in neurointensive care has increased our understanding of the pathophysiology of traumatic brain injury and spontaneous hemorrhage. In parallel, it is important to determine the place of microdialysis in assisting in the management of patients on an individual intention to treat basis. This is made possible by the availability of analyzers which can measure the concentration of glucose, pyruvate, lactate, and glutamate at the bedside. Samples can then be stored for later analysis of other substrate and metabolites e.g., other amino acids and cytokines. The objective of this paper is to review the fundamental literature pertinent to the clinical application of microdialysis in neurointensive care and to give recommendations on how the technique can be applied to assist in patient management and contribute to outcome. A literature search detected 1,933 publications of which 55 were used for data abstraction and

And the Participants in the International Multidisciplinary Consensus Conference on Multimodality Monitoring Group members are listed in the Appendix.

Electronic supplementary material The online version of this article (doi:10.1007/s12028-014-0035-3) contains supplementary material, which is available to authorized users. P. Hutchinson (&) Department of Clinical Neurosciences, University of Cambridge, Box 167 Addenbrooke’s Hospital, Cambridge CB2 2QQ, UK e-mail: [email protected] K. O’Phelan Department ofNeurology, Universityof Miami, MillerSchool of Medicine, 1120 14th StreetMiami, Miami FL 33136, USA

analysis. The role of microdialysis was evaluated in three conditions (traumatic brain injury, subarachnoid hemorrhage, and intracerebral hemorrhage) and recommendations focused on three fundamental areas (relationship to outcome, application of microdialysis to guide therapy, and the ability of microdialysis to predict secondary deterioration). Keywords Microdialysis  Glucose  Lactate  Glutamate  Lactate pyruvate ratio  Traumatic brain injury  Subarachnoid hemorrhage  Intracerebral hemorrhage

Introduction While patients who require neurocritical care suffer from a number of different conditions, there are common underlying pathophysiological principles that contribute to acute tissue injury that requires monitoring and treatment to optimize clinical outcome. One of the goals of neurocritical care is to intercept the vicious cycle of cellular injury, energy crisis, and brain swelling. Multimodality monitoring of intracranial pressure (ICP), cerebral oxygenation, and cerebral blood flow (CBF) [1] enables these pathophysiological processes to be tracked at the bedside in the intensive care unit (ICU). The introduction of microdialysis (pioneered by Ungerstedt) [2] to neurocritical care in the 1990s [3, 4] further advanced the concept of multimodality monitoring by enabling the energy status of the brain to be measured directly. The purpose of this review is to interrogate the literature and explore the evidence for the clinical utility of microdialysis to assist in the individual management of patients on an intention to treat basis.


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Summary of the Literature

This systematic review was performed according to the preferred reporting items for systematic reviews and metaanalyses (PRISMA) statement [5].

This discussion will focus on how continuous monitoring of brain chemistry with cerebral microdialysis techniques is used in patients with acute brain injury (ABI) in the ICU setting. Please refer also to published recommendations for the clinical implementation of microdialysis to patients with TBI and subarachnoid hemorrhage (SAH) that have been provided in a previous consensus statement published 10 years ago [7]. Our search retrieved 1933 eligible citations; 54 original publications were used for this review. There were no prospective randomized trials that directly tested the benefit of microdialysis monitoring. The majority of the data was generated by retrospective analysis of prospectively collected data. There was one prospective randomized controlled trial using brain chemistry as an outcome measure [8]. There was one prospective nonrandomized with subject crossover trial [9]. There were 10 studies that used brain chemistry as an outcome end point when comparing therapeutic strategies.

Search Criteria We searched the PubMed database for English language articles from January 1990 up to August 2013 encompassing the following terms with microdialysis as the key word: traumatic brain injury (TBI), head trauma, neurotrauma, head injury, brain injury, subarachnoid hemorrhage, intracerebral hemorrhage, ischemic stroke, ischemia, secondary ischemia, brain hypoxia, brain tissue hypoxia, hypoxia, cerebral ischemia, brain ischemia, delayed cerebral ischemia, vasospasm, cerebral perfusion pressure (CPP), cerebral perfusion, and outcome. Study Selection and Data Collection We excluded animal experiments, unpublished data or congress presentations/abstracts, review articles, studies that included 25

The length of time in metabolic crisis was significantly associated with outcome. The OR for poor outcome for 12 h of metabolic crisis was 2.16 (CI 1.05–4.45 p = .036)

Nagel et al. [14]


192 Multivariate analysis to identify factors associated with Elevated glutamate and L/P ratio were associated with 12-month GOS in patients with low ICP after SAH worse 12-month GOS and were more common in the versus high ICP high ICP group. The majority of patients with elevated ICP displayed abnormal microdialysis pattern before the rise in ICP

Oddo et al. [15]


31 Episodes of elevated brain lactate were divided into two Episodes of hypoxic elevations in brain lactate were groups. Those with a low brain tissue oxygen associated with mortality while episodes of (hypoxic) and normal tissue oxygen hyperglycolytic lactate were strong predictors of good (hyperglycolytic). Outcome using dichotomized mRS outcome

Nikaina et al. [16]


27 Linear regression model to evaluate the relationship between CPP + L/P ratio and 6-month outcome measured by GOS

elevated during the monitoring period (Pattern 2). Overall, the mortality rate was 30.3 % in patients with glutamate levels >20 lmol and 18 % in patients with glutamate levels 25, the odds of having a poor outcome more than doubled. They concluded that metabolic crisis occurs frequently after TBI despite adequate resuscitation and controlled ICP, and is a strong independent predictor of poor outcome at 6 months. While most studies have focused on the relationship between brain chemistry and clinical outcome, the focal nature of microdialysis also allows examination of the relationship between brain chemistry and tissue outcome. Marcoux et al. [13] demonstrated that metabolic crisis defined by an elevation in the microdialysis lactate/pyruvate ratio is associated with chronic frontal lobe atrophy seen on MRI in patients with TBI [13]. In 15 patients they demonstrated that the percentage of time of elevated lactate/pyruvate ratio correlated with the extent of frontal lobe atrophy but not global brain atrophy.

The combination of CPP > 75 and L/P < 36 was associated with a favorable 6-month GOS p = .054

ratios after SAH. For example, Nagel et al. [14], in a multivariant analysis on 182 patients showed a relationship between glutamate, lactate/pyruvate ratio, and outcome at 12 months. The relationship, however, may depend on why the lactate is abnormal, and the patterns of combinations of microdialysis analytes may be more important than the absolute value of any individual parameter. For example, Oddo et al. [15] demonstrated that SAH patients and patterns of elevated interstitial lactate concentrations consistent with tissue hyperglycolysis rather than hypoxia seem to have a better long term outcome.

Effect of Clinical Therapy on Brain Chemistry There are a number of studies that demonstrate that cerebral chemistry can be improved by therapy i.e., a more favorable metabolic pattern. Whether improved physiology means better clinical outcome, however, is still to be fully elucidated. This evidence is summarized below in Table 2. Administration of Glucose/Insulin

Subarachnoid Hemorrhage Several studies have demonstrated that poorer outcome associated with higher lactate and higher lactate/pyruvate

Microdialysis studies have shown that low brain glucose concentrations are associated with poor outcome in SAH and TBI. Although it is yet to be shown that keeping brain


Neurocrit Care Table 2 Can clinical therapy change brain metabolism? Population




Vespa et al. TBI [9]

47 Nonrandomized consecutive design comparing brain Patients in the intensive therapy group had lower chemistry in patients managed with ‘‘loose’’ versus brain glucose concentrations associated with an ‘‘intensive’’ insulin therapy increase in glutamate and L/P ratio

Oddo et al. [15]

20 Multivariate logistic regression used to examine relationship between multiple physiologic and microdialysis variables and in-hospital mortality

Systemic glucose concentration and insulin dose were independent predictors of metabolic crisis and mortality

Helbok SAH et al. [19]

28 Multivariate logistic regression to examine relationship between serum glucose and microdialysis patterns

Reductions in serum glucose by 25 % were associated with episodes of elevated L/P ratio and decreased glucose

Vespa et al. TBI [9]

13 Prospective within-subject crossover trial of ‘‘tight’’ versus ‘‘loose’’ glycemic control and measured glucose metabolism using FDG PET

‘‘Tight’’ glycemic control was associated with elevated L/P ratio and decreased brain glucose as well as an increase in brain global glucose uptake

Tolias et al. TBI [22]

52 Prospective study of 24 h of normobaric hyperoxia. Microdialysis compared with baseline and also with age, GCS-, and ICP-matched controls

Normobaric hyperoxia treatment was associated with an increase in brain glucose and a decrease in L/P ratio as well as a reduction in ICP

Nortje et al. TBI [23]

11 Brain tissue oxygen, cerebral microdialysis and 15O-PET scans were performed at normoxia and hyperoxia

Normobaric oxygen was associated with an increase in brain tissue oxygen; however. the association with microdialysis changes and oxygen metabolism on PET was variable

Rockswold et al. [8]


Both normobaric and hyperbaric hyperoxia improved 69 Patients randomized to normobaric O2 treatment, microdialysis parameters. Hyperbaric O2 had a hyperbaric O2 treatment or control. Brain oxygen, microdialysis, and ICP were monitored more robust and long lasting effect

Marion TBI et al. [25]

20 30 min of hyperventilation performed at two time Brief hyperventilation was associated with increased points (24 h and 3 days) after injury, microdialysis glutamate and elevated lactate and L/P ratio. This and local cerebral blood flow in vulnerable tissue relationship was more marked at the early time was studied point

Hutchinson TBI et al. [26]

13 Hyperventilation with simultaneous PET scan to measure Oxygen extraction fraction (OEF)

SAH, TBI, ICH, Ischemic stroke

Sakowitz TBI et al. [27]

Hyperventilation was associated with a reduction in microdialysis glucose and an elevated OEF

6 ICP, brain oxygen, and microdialysis parameters were Microdialysis concentrations rose up to 40 % over the recorded before and after therapeutic doses of first hour after mannitol in a nonspecific pattern mannitol

Helbok SAH et al. [28] ICH

12 ICP, brain oxygen, and microdialysis parameters were Mannitol therapy was associated with a decrease in measured before and after therapeutic mannitol ICP as well as an 18 % decrease in L/P ratio doses without a change in brain glucose

Ho et al. [29]

16 ICP, brain oxygen, autoregulation and microdialysis There was a decrease in microdialysis lactate, L/P parameters were measured before and after ratio, and glycerol in patient treated with decompressive craniectomy for refractory decompressive craniectomy in those who had a intracranial hypertension. Outcome was measured favorable outcome with 6-month GOS


Nagel et al. SAH [14]

7 Data from a database was retrospectively studied to In patients treated with decompressive craniectomy determine the effect of decompressive craniectomy glucose and glycerol were lower after he procedure. on cerebral metabolism. 12-month GOS assessed However, L/P ratio and glutamate did not change for outcome

Soukup TBI et al. [30]

58 ICP, brain oxygen, and microdialysis parameters were Therapeutic hypothermia was associated with lower measured before and after mild therapeutic microdialysis glucose and lactate consistent with hypothermia was used to treat refractory ICP decreased metabolic demand

Berger et al. CVA [31]

12 ICP and microdialysis parameters measured before Glutamate, lactate and pyruvate were all affected by and during therapeutic hypothermia used as rescue therapeutic hypothermia. However, the degree of therapy for large MCA infarcts change varied depending on the probe position

glucose within a target range improves outcome, given that hypo- and hyper-glycaemia are both associated with adverse effects, monitoring cerebral glucose with microdialysis and adjusting the plasma glucose concentration pro-actively makes sense, at least in theory.


Several retrospective studies also show an association between aggressive insulin therapy and microdialysis patterns of metabolic crisis [17–19]. However, the relationship between serum and brain glucose is not consistent. Rostami et al. [20] showed that the serum, subcutaneous, and brain

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glucose concentrations correlated in ‘‘normal’’ brain but that this correlation was inconsistent in injured brain. More recently, Vespa et al. [9] conducted a prospective randomized within-subject crossover trial comparing ‘‘tight’’ with ‘‘loose’’ glycaemic control. Significantly, lower glucose, pyruvate, and a greater percentage of time where the LP ratio was greater than 28 were associated with the aggressive insulin regimen. Hyperoxia The application of hyperoxia to improve outcome after ABI is controversial. Several authors have used multimodal monitoring techniques to help determine the role of normobaric or hyperbaric hyperoxia. Their findings include improved brain chemistry and brain tissue oxygen [21], improved brain chemistry and ICP [22], and improved brain tissue oxygen with variable changes on brain chemistry [23]. Rockswold et al. have performed two prospective, randomized clinical trials of hyperoxia in severe TBI. The first [8] compared the effect of hyperbaric to normobaric hyperoxia on cerebral metabolism, ICP, and oxygen toxicity. Both hyperbaric and normobaric oxygen reduced the lactate/pyruvate ratio. CBF, CMRO2, microdialysate lactate, and the lactate/pyruvate ratio had significantly greater improvement, when a brain tissue oxygen C200 mmHg was achieved during treatment. Hyperbaric hyperoxia had a more robust post-treatment effect than normobaric hyperoxia on oxidative cerebral metabolism related to its ability to produce a brain tissue oxygen C200 mmHg. In the second trial Rockswold et al. [24] compared the effect of combined hyperbaric/normobaric oxygen treatment to standard care. The authors observed significantly improved markers of oxidative metabolism in relatively uninjured brain and pericontusional tissue, less intracranial hypertension, and demonstrated improvement in markers of cerebral toxicity. There was significant reduction in mortality and improved favourable GOS outcome. Hyperventilation Hyperventilation (HV) can reduce ICP, but its use is associated with potentially deleterious consequences and so, when used other monitors are necessary. The potential risk of excessive HV has been confirmed by microdialysis studies. Marion et al. [25] in a study of 20 min of HV showed that prophylactic HV was associated with increases in glutamate, lactate, and lactate/pyruvate ratio. Hutchinson et al. [26] demonstrated that HV-reduced extracellular glucose in association with increasing the oxygen extraction fraction as defined by PET. Osmotic Agents Clinical use of mannitol has been shown to improve the pattern of brain chemistry over the course of 1 h in patients

following TBI [27] as well as reduce lactate/pyruvate ratio when given after hemorrhagic stroke [28].

Decompressive Craniectomy The role of decompressive craniectomy in TBI and SAH is still being elucidated. Monitoring has the potential to yield surrogate endpoints and guide when to intervene. Microdialysis studies have shown a decrease in the extracellular level of lactate and glycerol, and the lactate/pyruvate ratio in 16 TBI patients undergoing decompressive craniectomy [29]. However, a study in 7 SAH patients although showing a reduction in the concentration of glycerol revealed no change in the lactate/pyruvate ratio and glutamate levels continued to increase [14].

Therapeutic Temperature Management The role of hypothermia in TBI and SAH remains controversial, and again microdialysis has provided data to help inform care. Several authors have shown improvement in brain chemistry with cooling that at times reverts upon re-warming [30, 31]. When the chemical profile of pyrexic SAH patients is investigated hyperthermia per se did not seem to induce any further significant neurochemical changes as long as substrate and oxygen delivery remained adequate [32].

Are Changes in Brain Chemistry Predictable and Can They be Used to Predict Secondary Deterioration? Microdialysis has the potential to monitor the effect of pathophysiology above and beyond that of other monitoring. First, microdialysis can reveal derangements in cerebral metabolism, when ICP is normal. Second, microdialysis can determine whether raised ICP is deleterious, i.e., associated with biochemical changes [33]. Third, microdialysis findings may precede the clinical features of delayed cerebral ischemia (DCI) and an ICP increase. It is clinically relevant to understand if the derangements in energy metabolism described above are predictably seen in specific clinical scenarios. Schmidt et al. [34] demonstrate a relationship between oxidative metabolic crisis and CPP

International multidisciplinary consensus conference on multimodality monitoring: cerebral metabolism.

Microdialysis is a powerful technique, which enables the chemistry of the extracellular space to be measured directly. Applying this technique to pati...
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