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. 2022 Oct 25;4(1):vdac171. doi: 10.1093/noajnl/vdac171

A scoping review of pediatric microdialysis: A missed opportunity for microdialysis in the pediatric neuro-oncology setting

Mahalia R Dalmage 1, Anthony Nwankwo 2,✉, Hannah Sur 3,✉, Edjah Nduom 4,5, Sadhana Jackson 6,✉
PMCID: PMC9683385  PMID: 36438644

Abstract

Background

Brain microdialysis is a minimally invasive technique for monitoring analytes, metabolites, drugs, neurotransmitters, and/or cytokines. Studies to date have centered on adults with traumatic brain injury, with a limited number of pediatric studies performed. This scoping review details past use of brain microdialysis in children and identifies potential use for future neuro-oncology trials.

Methods

In December 2020, Cochrane Library: CENTRAL, Embase, PubMed, Scopus, and Web of Science: Core Collection were searched. Two reviewers screened all articles by title and abstract review and then full study texts, using microdialysis in patients less than 18 yo.

Results

Of the 1171 articles screened, 49 were included. The 49 studies included 472 pediatric patients (age range 0–17 years old), in the brain (21), abdominal (16), and musculoskeletal (12) regions. Intracerebral microdialysis was performed in 64 collective patients, with a median age of 11 years old, and predominance in metabolic evaluations.

Conclusion

Historically, pediatric microdialysis was safely performed within the brain in varied neurologic conditions, except neuro-oncology. Adult brain tumor studies using intratumoral/peritumoral microdialysis sampling can inform future pediatric studies to advance diagnosis and treatment options for such aggressive tumors.

Keywords: brain tumor, cancer, intracerebral monitoring, microdialysis, pediatric, pharmacokinetics

Microdialysis is a minimally invasive technique that has been used for over 60 years in adults; making it a potential candidate for increased utilization in the pediatric population. The technique was first reported in the 1960s by J.H. Gaddum, an English pharmacologist, as a method of measuring varied neurotransmitters in preclinical free-moving models.1 Initially, microdialysis involved push–pull perfusion, requiring extensive monitoring for sampling, collection, and storage. By the 1970s and 1980s, Delgado et al. created the “dialytrode,” as an automated pump for cerebral microdialysis.1 Eradicating the push–pull method, Urban Ungerstedt, helped to revolutionize the field of neuromonitoring for real-time dialysate sampling, especially in the traumatic brain injury setting (Figure 1).1–6

Figure 1.

Figure 1.

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Modern intratumoral microdialysis technique depiction. The diagram demonstrates the intracerebral microdialysis tool sampling tumoral tissue pre or post-surgical intervention. The continuous infusion pump holds dialysate fluid to allow for automated infusion akin to passive diffusion (A). The semipermeable microdialysis catheter is placed within tumor tissue (B), while the microvial continuously collects brain interstitial fluid for further solute processing and measurements (C).

The modern intracerebral microdialysis technique relies on concentration gradients to drive analyte movement across a semipermeable catheter membrane which acts as a blood capillary by mimicking passive diffusion.7,8 While the semi-permeable end of the catheter is placed in interstitial space, the automated pump connected to a syringe containing artificial cerebrospinal fluid (NaCl, KCl, KH2PO, and NaHCO), Ringer’s lactate solution, or 0.9% saline solution with or without albumin, enables continuous passive diffusion for optimal solute collection.3–6In vitro experiments using microdialysis catheters help measure analyte recovery rates (RR) within the normal or diseased tissue.1–3,5 This data is then combined to calculate the relative concentration of the desired analyte in the extracellular fluid compared with plasma concentrations (Figure 2).9 These analyte concentrations can be used to better understand various microenvironments in the brain, thus making microdialysis a useful technique for continuous real-time monitoring of various analytes.

Figure 2.

Figure 2.

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Microdialysis recovery equation detailing extraction efficiency through a semipermeable membrane.

The rationale for this scoping review was to evaluate the use of microdialysis in pediatric populations and the conditions in which it was used. Moreover, our desire to improve drug delivery for CNS brain tumors in pediatric patients has caused us to look for other avenues to evaluate drug neuropharmacokinetics and neuropharmacodynamics of pediatric high-grade-gliomas. We identified gaps in the existing literature regarding the pediatric settings in which microdialysis is used, particularly for intracerebral sampling uses within pediatric brain tumor patients.

Methods

The Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) was used for reporting this scoping review.10 Inclusion criteria incorporated any study that utilized microdialysis in pediatric populations (<18 years old). Exclusion criteria were applied in the following order: no available English abstract, unable to obtain the full text, wrong publication type: personal communications, letters, opinion piece, wrong study design: review (literature/narrative, systematic review, or meta-analysis), wrong population (ie, 18 or older) or that the study did not report results separately for adults and children, duplication: interim results updated in a more recent publication (Supplementary File 1).

The citation and abstract databases Cochrane Library: CENTRAL (Wiley & Sons), Embase (Elsevier), PubMed (US National Library of Medicine), Scopus (Elsevier), and Web of Science: Core Collection (Clarivate Analytics) were searched by a biomedical librarian in December 2020. A combination of keywords and controlled vocabulary terms (ie, MeSH, EMTREE) were used to describe microdialysis and pediatric populations. The searches were not limited by language or publication year but did exclude letters, editorials, retractions, errata, reviews, conference proceedings/abstracts, and corrigenda (Supplementary File 2). EndNote X9 (Clarivate Analytics) was used to manage and identify duplicates from the database searches.

Two reviewers (MD, SJ) independently screened each article using the a priori inclusion and exclusion criteria by first reviewing the titles and abstracts and then the full texts. Covidence (Veritas Health Innovations) was used for the screening. Screening conflicts were resolved by discussion between the 2 reviewers.

For data charting, reviewers (MD, SJ) extracted the data items specified in Supplementary File 3 into Microsoft Excel. Data analyses were completed using Microsoft Excel.

Results

Literature Search and Study Selection

A total of 2622 records were retrieved from the database searches, of which 1451 were duplicates and 1171 were unique records that were screened (Supplementary Fig. 1). Of 1171 screened at the title and abstract level, 280 passed to full-text screening and a total of 49 articles were included. Of the 231 excluded articles, the majority comprised adults or did not separately report pediatric results (n = 190), full text not available (n = 15), microdialysis was not performed (n = 11), wrong study design (n = 7), not in humans (n = 5), duplication ( = 2), and not available in English (n = 1).

The remaining 49 articles detailed pediatric enrollment, with the following microdialysis locations identified: brain (21), abdominal (16), and musculoskeletal regions (12).11–59Supplementary Table S1 details the key characteristics of these studies. Of the 49 studies involving 472 pediatric patients, none reported major complications due to microdialysis use.

Upon further analysis of pediatric microdialysis use, it became clear that the scoping review identified intracerebral microdialysis as the most common setting and identified a gap in use within the pediatric neuro-oncology setting. Thus, we have chosen to focus our results and discussion around this gap by detailing the use of pediatric intracerebral microdialysis based on the 21 studies, with a total of 64 patients less than 18 years of age (Supplementary Table S1).

Intracerebral Microdialysis

The sub-specialities of these neurologic studies included traumatic brain injury (TBI), seizure disorder, secondary brain ischemia, hyperglycemia, and viral meningoencephalitis. All studies concluded intracerebral microdialysis sampling was feasible, without major complications and useful for diagnostic, and/or applicable treatment purposes.

Traumatic Brain Injury and Vascular Disorders

Three studies utilized neuroimaging and microdialysis in the TBI setting. Hutchinson et al., over the course of two studies, demonstrated the ease of microdialysis use in conjunction with PET or FDG-PET imaging to evaluate the injured brain microenvironment.48,49 Both studies included 17 patients (ages 17–66 years for PET and FDG-PET) and characterized the relationship between cerebral glycolysis to PET parameters and metabolic levels of pyruvate and lactate. They concluded that combining microdialysis with PET and FDG-PET scans was feasible due to the significant linear relationship between PET-derived parameters and lactate and pyruvate dialysate concentrations. Similarly, Magoni et al. used microdialysis and diffusion tensor imaging (DTI) to assess traumatic axonal injury in 15 patients (ages 16–46 years). They found that measurements of glucose, pyruvate, lactate, and glutamate along with DTI collectively reflected the pathophysiological processes in axonal injury patients.46

Interestingly, only one study focused on microdialysis along with measuring drug concentrations in the pediatric TBI setting. Ketharanathan et al. used microdialysis to assess morphine levels in eight TBI patients (ages 0–13 years), requiring the agent for pain relief. They found that differing brain morphine levels were dependent on brain injury severity; even if the plasma morphine levels were relatively similar.13 They recommended further larger studies to demonstrate the feasibility of utilizing microdialysis in children for pharmacokinetic and pharmacodynamics for varied agents.13

All of the intracerebral microdialysis metabolic studies centered on extracellular concentrations of metabolites (glycerol, glutamate, glutamine, glucose, pyruvate, lactate, aspartate, urea), amino acids, and cytokines (interleukin and tumor necrosis factor) in TBI patients.14,41,42,44,45,50,53,57 These studies concluded measuring these solutes was feasible, and again demonstrated the ease of prolonged microdialysis use in the microenvironment of injured cerebral regions.

Three microdialysis studies focused on vascular disorders. Ahlsson et al.15 examined an 11-year-old boy with extreme hyperglycemia who was at risk for cerebral edema. Their study concluded, through the use of microdialysis, that the normalization of cerebral glucose was delayed in comparison to normalization in the plasma. Thus, when calculating proper diabetic treatment, these findings should be factored into avoid risks for cerebral edema associated with diabetic ketoacidosis.15 Boret et al. investigated the use of microdialysis and brain tissue oxygenation (PtiO2) while monitoring a 14-year-old TBI patient. They found that intracranial hypertension could be predicted by focal signs of ischemia by measuring PtiO2, in an effort to avoid irreversible brain damage.56 Lastly, Dizdarevic et al. found cerebral microdialysis real-time monitoring of brain metabolites (glycerol, lactate, and pyruvate) showed better results than cerebral perfusion pressure-targeted therapy for the treatment of secondary brain ischemia in comatose patients. These results provided additional evaluation tools specifically for patients with aneurysmal subarachnoid hemorrhage and severe TBI (n = 60, ages 16–73 years).55 All three of these studies concluded that microdialysis was feasible in adolescent and adult TBI patients.

Seizure Disorder

Three seizure focused studies included adolescents, examining microdialysis use to monitor drug uptake, potassium/chloride concentrations, and amino acid concentrations within seizure foci.43,51,52 Rambeck et al.43 showed that for patients (ages 15–54 years) with seizure disorder, microdialysis was helpful in delineating variabilities in epileptogenic tissue uptake of carbamazepine, 10-hydroxy-carcazepine, levetiracetam, and topiramate; however, they noted variability in the catheter performance which could have contributed to these results. Gorji et al. used microdialysis to explore the role of ion concentrations in neuronal function and epileptogenesis in eleven patients (ages 16–52 years). Their team found that following epicortical electric stimulation, extracellular potassium levels were increased in all patients but the rate at which the concentrations returned to pre-stimulation levels was either a fast decline, slow decline, or fast and slow declines in adjacent sites. These findings suggested that there may be abnormalities in ion homeostasis, characteristic of an epileptic brain; which may be useful for profiling morbidity.52 Lastly, Hamberger et al. used microdialysis to study amino acid concentrations in the microenvironment of focal epileptic lesions in 23 patients (ages 3–49 years). Their sampling of epileptic lesioned areas and non-epileptic lesioned areas (neoplasms, non-tumoral, and “special cases”) demonstrated epileptic lesions have higher extracellular concentrations of glycine, phosphoethanolamine, and alanine, which could assist with future tissue profiling studies; however, follow up studies are warranted.51

Infection

Only 2 studies have used intracerebral microdialysis with viral infections. Kofler et al. examined the use of microdialysis for studying viral meningoencephalitis in 2 patients (ages 17 and 38 years). They demonstrated the metabolic profile was inconsistent with a pattern of ischemic distress and instead suggestive of mitochondrial dysfunction.47 These findings concluded cerebral microdialysis is tolerated in poor-grade (inflammation of the brain parenchyma and neurologic dysfunction) patients with meningoencephalitis and could be used to understand secondary brain injury associated with mechanisms of viral encephalitis. Loxton et al. conducted a pilot study in 7 patients (ages 0.6–12.6 years) with tuberculous meningitis (TBM); finding that microdialysis could be used to monitor inflammatory cytokines within brain extracellular fluid, linking findings to potential predictions of disease severity and treatment response.58

Discussion

Collectively, the 21 intracerebral microdialysis studies identified by our scoping review have demonstrated microdialysis as a useful tool to improve understanding of drug neuropharmacokinetics and neuropharmacodynamics for pediatric brain tumors. Supplementary Table S1 specifically details the wealth of information gained from these studies in the pediatric population, as well as outlines the minimal adverse events noted with placement and sampling for prolonged periods. In addition, these studies highlighted the usefulness of the technique in learning more about intracerebral microenvironments related to the immune system, metabolism, cytokine fluctuations, and drug concentrations, thus further illuminating the value of brain microdialysis. Most interesting was not the settings that pediatric intracerebral was used in, but rather the setting that failed to utilize microdialysis—the neuro-oncology field.

Brain tumors are the most common type of solid tumors in children and one of the leading causes of death in children with cancer.60 Pediatric malignant brain tumor patients often present acutely ill, requiring quick and efficient clinical management. Despite providing expedious and quality clinical care, survival rates for children with malignant brain tumors remain bleak, prompting the need for additional understanding of these tumors/tumor microenvironments.61,62 Despite neurosurgical advancements, pediatric neuro-oncology studies have failed to employ the use of continuous intratumoral fluid sampling via microdialysis, in either an acute or chronic setting. In adults with primary and metastatic brain tumors, there have been a few microdialysis studies, most recently in 2019, that have demonstrated the technique was safe and useful for monitoring neuropharmacokinetics of systematically administered chemotherapy, cytokine levels, and amino acid levels.63–67 Sampling extracellular fluid amongst intratumoral and/or peritumoral tissue in children with malignant brain tumors could help clinical teams improve 1) diagnostic applications, 2) treatment response evaluations, and 3) prognostication of disease course. As such, we have identified a use for intracerebral microdialysis within the pediatric neuro-oncologic setting.63,64,66,67

Diagnostics

To date, many discoveries surrounding tumor microenvironments, BBB permeability, and drug distribution patterns have been performed with brain microdialysis sampling post-surgical resection, so as to better understand neurochemical profiling. Specifically, Bianchi et al.67 described the different amino acid and choline levels of 21 high-grade glioma patients when they sampled extracellular fluid in tumor versus adjacent normal brain. Higher tumor grades and degree of tumor infiltration positively correlated with specific elevated metabolites (choline, glutamate, leucine, taurine, and tyrosine). While another group identified a pattern of elevated extracellular protease levels correlated with tumor cell invasion of adjacent tissue in patients diagnosed with astrocytoma.68 Collectively, these studies further demonstrate microdialysis’s effectiveness to assess differences in the brain tumor microenvironment in ways that were previously only possible through very invasive techniques.

Treatment Response and Prognostication

Advancements in adult brain tumor microdialysis studies have aided in understanding dynamic shifts within the tumor microenvironment linked with neuroimaging and varied therapy options over time.63,64,66,69 Early studies in glioblastoma patients receiving 5 days of radiotherapy found differing metabolic profiles when comparing extracellular fluid from microdialysis cathether placement intracranially versus the subcutaneous abdomen.70 These findings not only suggested specific metabolite differences in the tumor and peritumoral tissue but also detailed intrapatient variability despite the standardization of radiation dosing. To evaluate dynamic pharmacokinetic changes in the CNS, several research teams examined tumoral and peritumoral chemotherapy concentrations (temozolomide, methotrexate) in primary and secondary brain tumor patients; identifying differences in BBB permeability based on contrast-enhancing tissue.63,64,71 To further understand temporal changes in interleukins and chemokines, Portnow et al.72 later described shifts within peritumoral tissue following brain tumor resection in primary adult brain tumor patients. They found that IL-8, MCP-1, IP-10, and IL-6 levels were markedly elevated in peritumoral tissue initially post craniotomy, but then steadily declined 96 h post-surgery; helping to demonstrate the transient yet dynamic nature of tumor microenvironmental inflammatory proteins. Another study utilized microdialysis to assess metabolic and cytokine changes in the glioma tissue baseline, during and post 5 days of radiotherapy; finding that high baseline IL-6 and IL-8 values correlated with increased survival rates.73 An ongoing microdialysis study, intelligently aims to evaluate cytokine profiles pre-and post-checkpoint inhibitor immunotherapy in recurrent glioblastoma patients; with intent to help identify response patterns by interferon gamma levels.65 These studies further demonstrate the potential role microdialysis could play to illuminate treatment response patterns for the selection and optimization of clinical decision-making.

Pediatric vs. Adult Tumors

Evidently, there are inherent differences in the outcomes and behavior of tumors in children vs. adults. Specifically, evaluating immune markers of adult vs. pediatric diffuse midline gliomas, researchers found profound differences in H3K27M frequency and CD8 expression, indicating that there should be significantly different treatment options for differing genetic and immune profiles, respectively.74 Another study examining the prognosis of adult vs. pediatric midline glioma patients harboring the H3K27M mutation, found that H3K27M mutation was associated with poorer prognosis for pediatric patients, but not a significant predictor for survival in adult patients.75 Comparing children and adults with oligodendroglioma, there exist significant differences in location, size, grade of tumors and key prognostic factors affecting survival.76 Therefore, having more methods to specifically assess pediatric brain tumor/tumor microenvironment (eg, drug concentrations, metabolite profiles, and/or cytokine profiles) differences in adult vs. pediatrics is crucial to improving diagnostic and treatment options.

Limitations and Ethical Implications

Though microdialysis has the potential to produce great results, there are many limitations to the technique. Despite the technique itself being minimally invasive, it requires invasive surgery for initial placement which includes multiple risks. However, for both the adult and pediatric patients who have undergone placement, most often in the traumatic brain injury setting, placement and continuous sampling have been shown to be both safe, tolerable, and with minimal side effects relative to the patients’ conditions. Yet, there are limitations to the types of drugs that can be used with microdialysis catheters, particularly in the case of lipophilic drugs, which are known for their non-specific binding capabilities to catheter tubing. In this case, extensive in-vitro studies prior to performing in-vivo studies are warranted to select additional agents that can be added to the perfusate solution (eg, bovine serum albumin). While only Belli et al. reported one patient experienced an intracerebral hematoma requiring evacuation in a patient presenting with traumatic brain injury prior to catheter insertion, no issues were noted in any of the additional 20 published studies which included children.57 However, these studies did not report long-term follow-up data post-catheter removal, so we cannot draw conclusions about the sustained impact of the microdialysis technique in the setting of neurologic dysfunction. Additionally, there are ethical implications to consider with innovative neurosurgical interventions in pediatric populations. Informed consent is impaired in children, especially in young children with brain cancer that exhibits neurologic/cognitive dysfunction, making them a vulnerable population that lacks autonomy. Thus, consent from parents/guardians is imperative to ensure a proper understanding of the surgical risks and potential benefits this additional surgical experience would afford their child and/or the neurosurgical/neuro-oncologic field. Yet, because of these vulnerabilities, few studies in the adult population are extended to children, which limits discoveries and advancements. In spite of the limitations and ethical implications, we are confident that the risks the outweigh benefits of adding this surgical expertise into the care of pediatric patients with malignant brain tumors. Microdialysis has the potential to help illuminate differences in pediatric neuro-oncology PK and PD values compared to adults, to enhance informed treatment plans and outcomes for children with aggressive brain tumors.

Optimal Trial Design

Due to the invasiveness of such a procedure and a paucity of clinical data within the pediatric tumor setting, we recommend all future studies be completed through thoughtful clinical trials, starting within a single institution with a stable neurosurgical oncology team; so as to minimize variables. These initial microdialysis studies would aim to evaluate the safety of catheter placement and removal, as well as the tolerability and safety of continuous intracerebral sampling in a pediatric oncology setting. Insertion of catheter probes in intratumoral and/or peritumoral extracellular spaces would aid in ensuring placement was achieveable at the time of surgical resection and/or biopsy. Close attention to adverse events past catheter placement is of utmost importance, such as microdialysis pump and tubing malfunction, and ensuring ease of post-operative patients’ comfort in the intensive care setting, during the dialysate recovery period. As such, we suggest initiating studies in the adolescent and young adult population before assessing safety and feasibility in the younger ages (<12 years old). First using microdialysis in cortical-based tumors is advised since this location has been shown to have minimal to no side effects upon placement, sampling, and removal in adults with brain tumors and children with traumatic brain injury. Additionally, we also suggest potentially starting with high-grade/malignant gliomas receiving cell cycle and/or MEK inhibitors; as these agents are characteristically small in size, which favors high CNS permeability, despite historically having heterogeneous treatment responsivity in highly proliferative gliomas.

These initial pediatric studies would assist in clarifying the feasibility of catheter placement post biopsy or resection and then further aid in optimizing sampling techniques for younger children with both small and large space occupying lesions. With continued studies, younger patients with midline tumors could be explored with intratumoral microdialysis placement, since these are typically diffuse, and often portend an aggressive tumor microenvironment. Akin to the successful studies completed in adult primary brain tumor microdialysis studies, we recommend initial pediatric trials evaluate 1) intratumoral drug concentrations matched with neuro-imaging profiling, 2) cytokine levels post biopsy or resection, and/or 3) metabolite shifts linked with tumor pathology and/or treatment responsivity. Once these studies could be shown to be safe and feasible in a single institution with a stable neurosurgical team, additional trials at multiple academic centers and within pediatric brain tumor groups/consortiums could be explored.

Since the first application of microdialysis 60 years ago, this tool has continuously improved its current tolerated and efficacious form for use in varied regions of the body.1,7,77 This intelligent diagnostic and monitoring tool has a variety of applications that have been discussed in detail, yet has never been documented for use in pediatric brain tumors. Thus, we implore the neurosurgical and neurooncologic community to make a concerted effort to incorporate microdialysis sampling within future pediatric neuro-oncology trials. Being intentional with such a multi-use tool would allow us better understanding of malignant brain tumor pathophysiology, tumor microenvironment dynamic changes, and treatment resistance mechanisms, which may have the potential to ultimately influence diagnostics, treatment responsivities, and overall disease prognostication.

Supplementary Material

vdac171_suppl_Supplementary_Figures
Click here for additional data file. (32.4KB, docx)
vdac171_suppl_Supplementary_Materials
Click here for additional data file. (16.7KB, docx)
vdac171_suppl_Supplementary_Table_S1
Click here for additional data file. (34.5KB, docx)

Acknowledgments

Thank you to Alicia A. Livinski and Bradley Otterson, biomedical librarians at the NIH Library, for help with the scoping review methodology, designing and conducting the literature searches, and manuscript editing assistance.

Contributor Information

Mahalia R Dalmage, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.

Anthony Nwankwo, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.

Hannah Sur, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.

Edjah Nduom, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA; Department of Neurosurgery, Emory University School of Medicine, Atlanta, Georgia 30322, USA.

Sadhana Jackson, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.

Funding

This work has been performed with the support of the NINDS Intramural Research Program.

Conflict of interest statement

The authors have declared that they have no conflicts of interest in relation to the completion of this work

Authorship statement

All authors contributed to the research and composition of manuscript preparation.

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