Journal of Neuroscience Nursing:
Neuromonitoring in Intensive Care: Focus on Microdialysis and Its Nursing Implications
Presciutti, Mary; Schmidt, J. Michael; Alexander, Sheila
J. Michael Schmidt, PhD, is an assistant professor of Clinical Neuropsychology in Neurology and the informatics director, Neurological Intensive Care Unit, Critical Care Neuromonitoring, Columbia University College of Physicians and Surgeons, New York, NY.
Sheila A. Alexander, PhD, is affiliated with the University of Pittsburgh School of Nursing, Pittsburgh, PA.
Questions or comments about this article may be directed to Mary Presciutti, BSN RN, at email@example.com. She is a staff nurse at New York Presbyterian Hospital, New York, NY.
Neuromonitoring in Intensive Care: Focus on Microdialysis and Its Nursing Implications: Erratum
In the title of Table 1 on page 134, the perfusate flow rate was incorrectly given as 0.3 ml/min when this article was published in the June 2009 issue of Journal of Neuroscience Nursing. The correct perfusate flow rate is 0.3 μl/min.
This erratum appears in the August 2009 issue of Journal of Neuroscience Nursing.
Neuromonitoring with the microdialysis technique is now being utilized at the bedside. Cerebral metabolism monitoring enables identification of clinical events hours or even days before clinical examination changes, providing clinical staff an opportunity for earlier intervention. Cerebral microdialysis also allows clinicians to evaluate the impact of therapeutics on cerebral metabolism and certain metabolic patterns, which can trigger specific alerts and/or clinical protocols. Cerebral metabolism monitoring through microdialysis can guide clinicians to institute therapeutic measures that prevent the occurrence of secondary injury. This article focuses on the state-of-the-art application of cerebral microdialysis, the rationale for its use, and the nursing implications of this technique.
Patients experiencing neurological injury and diseases often have poor outcomes. Much of the care currently provided to these patients in the intensive care unit (ICU) is supportive in nature. Currently, serial neurological examinations are the primary method of identifying changes in the patient's neurological condition. Unfortunately, by the time a patient exhibits a neurological deficit, brain tissue may have already sustained irreparable damage. Newer methods of identifying secondary complications that jeopardize at-risk brain tissue are vital to improving outcomes from brain injury and diseases.
Basic neuromonitoring is commonplace in neurointensive care units in which traditional methods include monitoring intracranial pressure (ICP) via a parenchymal bolt or external ventricular drain and cerebral perfusion pressure (CPP). In the last 10 years, brain tissue oxygen (PbtO2) monitoring and continuous electroencephalogram have become much more common in the neurocritical care setting. In 2002, CMA/Mcrodialysis received Food and Drug Administration (FDA) approval for the application of cerebral microdialysis, which made clinical cerebral metabolism monitoring available in the United States for the first time. CMA/Microdialysis has supported cerebral metabolism monitoring in Europe since 1995 and is currently the only company with FDA approval for cerebral microdialysis.
Microdialysis allows online monitoring of the extracellular environment and, in particular, bedside monitoring of the substrates of cerebral energy metabolism. These additional physiological data, along with other monitoring parameters, provide clinicians with information regarding impending episodes of neurological events, which is critical in patients whose underlying neurological status is unclear or who are experiencing varying degrees of coma. The aim of microdialysis monitoring is to identify signals of cellular disturbance before clinical symptoms are manifest. This identification may provide an opportunity for earlier intervention and prevention of secondary injury. This article is meant to provide an overview of the cerebral application of the microdialysis technique and its nursing implications.
Principle of Microdialysis
After more than three decades of developing, refining, and perfecting microdialysis, the technique is being adopted as a bedside tool for patients in various clinical settings (Klaus, Heringlake, & Bahlmann, 2004; Pojar & Mand'ak, 2006). As a technique, it is applicable to any clinical situation in which it is relevant to monitor organ metabolism. In addition to cerebral metabolism monitoring, recent literature outlines its application in myocardial (Mantovani et al., 2006; Poling et al., 2006), liver (Meybohm et al., 2006), pancreas (Esmatjes et al., 2003), intestinal (Krejci et al., 2006), intraperitoneal (Jansson, Strand, & Jansson, 2006), splanchnic (Knuesel et al., 2006), rectal (Solligard et al., 2007), and intraoral monitoring (Jyranki, Suominen, Vuola, & Back, 2006).
Bedside cerebral microdialysis allows frequent sampling of specific molecular substances within the interstitial fluid including but not limited to markers of energy metabolism (glucose, lactate, and pyruvate), excitotoxicity (glutamate), and phospholipid degradation (glycerol). Monitoring of molecular substrates, together with frequent clinical assessment, and other physiological and hemodynamic parameters provides information regarding cellular processes that can alert clinical staff to pathophysiological processes that may lead to secondary brain injury (Hillered, Vespa, & Hovda, 2005; Ungerstedt & Rostami, 2004).
The microdialysis catheter can be inserted emergently at the bedside in the ICU through a bolt via a burr hole or in surgery during an open craniotomy. It is typically inserted into the pericontusional brain tissue in patients with traumatic brain injury or in the region of the parent vessel at risk for vasospasm in patients with subarachnoid hemorrhage (Ungerstedt & Rostami, 2004). Perfusion fluid is pumped through the catheter, which has a 10-mm semipermeable membrane at the distal end which functions similar to a blood capillary, allowing molecules to diffuse into perfusion fluid, enabling collection. At a perfusion fluid flow rate of 0.3 μl/min, the concentration of metabolites recovered represents approximately 70% of the true concentration in the interstitial fluid. The standard catheter allows a molecular weight cutoff of 20 kDa or smaller to be collected into a microvial, which includes glucose, lactate, and pyruvate (see Fig 1). A catheter with a molecular cutoff of 100 kDa is available, allowing larger molecules to be collected, such as cytokines or inflammatory markers, and which is used as a part of an institutional review board research protocol. Metabolite concentration levels from hourly samples are calculated at the bedside using a colorimetric-based analyzer. Immediate bedside analysis alerts clinicians of perturbed cellular energy metabolism (Ungerstedt & Rostami, 2004).
Review of Cerebral Metabolism
For brain tissue to survive and retain function, it must first receive fuel from the bloodstream in the form of oxygen and glucose and then convert that fuel into the major cellular energy source, adenosine triphosphate (ATP). Neurons use energy to maintain ionic homeostasis, normal cellular metabolic functions, and synaptic communication. Adequate cerebral blood flow provides oxygen, glucose, and other nutrients for the brain. Glucose is extracted from the blood and delivered to neurons by astrocytes. At the cellular level, energy production occurs first through glycolysis, the process of converting glucose to pyruvate and/or lactate, generating 2 ATP molecules for every mole of glucose. Oxygen availability enables pyruvate to enter the mitochondria where it generates 18 times as much energy (net 36 ATP) as glycolysis alone does through aerobic metabolism. This fact exemplifies the critical importance of proper oxygenation of brain tissue (Zauner, Daugherty, Bullock, & Warner, 2002).
By measuring interstitial glucose, pyruvate, and lactate concentration levels, microdialysis provides clinical insight related to altered or disrupted cerebral energy production (Ungerstedt & Rostami, 2004). Normal fluctuations in energy production lead to variations in lactate and pyruvate concentrations in the interstitial fluid. This makes it more difficult to determine when energy metabolism is faltering; therefore, it is common to also evaluate the ratio of lactate concentration to pyruvate concentration, which has the effect of normalizing these fluctuations and eliminating differences due to variation in metabolite recovery (Hillered et al., 2005). This calculation is commonly referred to as the lactate:pyruvate ratio (LPR), which is the most thoroughly evaluated metabolic ratio in the literature.
When the brain tissue does not have enough energy to perform cellular maintenance, it is unable to maintain normal homeostasis, and the membrane walls begin to breakdown. One of the byproducts of cell membrane degradation is the release of glycerol into the extracellular space (Ungerstedt & Rostami, 2004). Glutamate is the major excitatory neurotransmitter of the central nervous system. It is also an important component of cellular metabolism. Both glycerol and glutamate interstitial fluid concentrations can be monitored using microdialysis and have been used as clinical metabolic markers in Europe for many years (Ungerstedt & Rostami, 2004). At the time of this writing, both glycerol and glutamate measurements are under review by the FDA for clinical use in the United States. Under conditions of metabolic derangement, both elevations of glycerol and glutamate levels confirm that energy disruption is resulting in cellular damage. Some institutions use glycerol and glutamate under the auspices of research protocol approved by the institutional review board.
Nurses should be aware that the precise metabolic relationship of glucose, pyruvate, and lactate within the context of aerobic and anaerobic conditions is under scrutiny. More specifically, it has been proposed and supported by in vitro experimentation that glucose is always converted to lactate (Schurr, 2006; Schurr & Payne, 2007), contrary to the classical view that the conversion of glucose to lactate only occurs during anaerobic metabolism (Champe, Harvey, & Ferrier, 2005; Hillered et al., 2005; Ungerstedt & Rostami, 2004). This is not a trivial distinction to make because it has broad implications about what lactate elevations might mean clinically and what response(s) may be warranted. It has been understood for some time that lactate is the preferred cerebral fuel source after ischemia (Schurr, Dong, Reid, West, & Rigor, 1988; Schurr, Payne, Miller, & Rigor, 1997a, 1997b; Schurr, Payne, Miller, & Tseng, 2001). Astrocytes produce and shuttle lactate to neurons to support their high-energy demands, and therefore strict interpretation of lactate concentration changes is complicated (Magistretti, 2006; Magistretti & Pellerin, 1999, 2000; Magistretti, Sorg, Yu, Martin, & Pellerin, 1993). It has also been shown that the brain will extract systemic lactate circulating in blood (Glenn et al., 2003).
An elevated LPR is very sensitive to episodes of hypoxia and ischemia, and because this relationship is so well studied, it is easy to associate the two together exclusively. However, although elevations in the LPR are sensitive to hypoxia-ischemia, it is not very specific because other states such as seizures and/or edema may also impact the LPR (Hillered et al., 2005). In a clinical study of traumatic brain injury patients coordinating microdialysis and PET measurements, Vespa et al. (2005) found that an elevated LPR was associated with ischemia in only 1 of 20 patients. Metabolism data should be carefully interpreted with the entire team while considering all available information about the patient.
Metabolic Rationale for Clinical Cerebral Microdialysis
The rationales for monitoring cerebral metabolism are as follows: (a) Cerebral metabolism changes may occur hours or even days before clinical examination changes, particularly for comatose patients, providing clinical staff an opportunity for earlier intervention; (b) its sensitivity allows monitoring the impact of therapeutics on cerebral metabolism; and (c) certain metabolic patterns, such as the hypoxic-ischemic pattern, can trigger specific alerts and/or clinical protocols. Normal concentrations for cerebral metabolites vary across studies (Hillered et al., 2005; Reinstrup et al., 2000; Schulz, Wang, Tange, & Bjerre, 2000). Clinical data patterns that incorporate nonmicrodialysis data including CPP, medications (e.g., sedatives), laboratories (e.g., systemic glucose), and neuroimaging results are generally more important to pay attention to than pure metabolite concentration levels. However, knowing normal concentration levels will help clinicians identify clinically meaningful data patterns. Normal metabolite concentrations reported in the literature are provided in Table 1.
Critical energy failure is associated with an elevated LPR above 50, with above-normal lactate concentrations and below-normal pyruvate concentrations. Prolonged energy failure results in cellular dysfunction and damage, which is reflected by increases in glycerol and glutamate concentration levels (Ungerstedt & Rostami, 2004). Energy failure is commonly associated with episodes of hypoxia-ischemia triggered by hypotension, cerebral vasospasm, anemia, poor oxygen saturation, or intracranial hypertension.
Alternatively, overactivity triggered by seizure activity or hyperthermia could also produce energy failure resulting in a similar metabolic pattern (Hillered et al., 2005). Energy failure should therefore be viewed as a mismatch between the supply of glucose and the supply of oxygen to the metabolic demands of the tissue. As a result, when faced with changes in microdialysate substrates suggesting energy failure, one can either increase the supply, for example, by adjusting body position, reducing insulin, increasing FiO2, and administering vasopressors or a mannitol bolus or decrease demand, for example, by increasing sedation or instituting therapeutic cooling protocol to ameliorate the metabolic crisis. Because there are many potential triggers for energy failure, additional diagnostics may be needed to determine the cause before some interventions can be made confidently. For example, when suspected cerebral vasospasm may be the source of the observed metabolic crisis, a less invasive computed tomography (CT) perfusion study may be performed to confirm ischemia before performing cerebral angiography.
The pattern for cerebral hyperglycolysis is less well characterized. In principle, cerebral hyperglycolysis is a metabolic overdrive response designed to generate enough energy to restore homeostasis and cell integrity during recovery from the initial brain injury (Cesarini et al., 2002; Nilsson, Hillered, Olsson, Sheardown, & Hansen, 1993; Nilsson, Hillered, Ponten, & Ungerstedt, 1990). The metabolic pattern associated with hyperglycolysis is both an elevation of lactate concentrations with parallel increasing levels of pyruvate, an LPR less than 40, and measurable amounts of brain glucose (Cesarini et al., 2002). Cesarini et al. (2002) demonstrated that subarachnoid hemorrhage (SAH) patients exhibiting this metabolic pattern early in their course had a more favorable outcome than that of other patients. In contrast, patients that did poorly often had elevated lactate concentrations without increased pyruvate concentrations in conjunction with higher brain glucose levels, suggesting depressed metabolism and reduced consumption of glucose. Reduced cerebral blood flow and cerebral metabolism after brain injury are not uncommon (Heilbrun, Olesen, & Lassen, 1972; James, 1968; Voldby, Enevoldsen, & Jensen, 1985).
In summary, there are four fundamental cerebral metabolic patterns: (a) depressed or hypometabolism, (b) normal metabolism, (c) hyperglycolysis, and (d) and energy failure. Differentiating among these patterns often requires consideration of other neuromonitoring data including ICP, brain oxygen tension, cerebral blood flow, and continuous electroencephalograph monitoring. The following references review the rationale and utility of multimodality monitoring (De Georgia & Deogaonkar, 2005; Kett-White et al., 2002; Vespa, 2005; Wartenberg, Schmidt, & Mayer, 2007). For reviews of cerebral metabolism monitoring specifically, see the following references (Hillered et al., 2005; Peerdeman, van Tulder, & Vandertop, 2003; Sarrafzadeh, Kiening, & Unterberg, 2003; Tisdall & Smith, 2006; Ungerstedt & Rostami, 2004).
Bedside insertion of the microdialysis catheter is similar to that of an ICP catheter or external ventricular drain. It is best to follow standard institutional policies about procedural consent and infection control. As with any invasive procedure, any coagulation abnormalities are corrected prior. It is imperative to reassure the patient's family of the importance of neuromonitoring. It is also essential to answer any questions that may arise, referring them to appropriate physicians and/or surgeons before catheter placement. Reassure them that appropriate sedatives and analgesia will be used for comfort. Explain that routine head CT is performed afterward to confirm the catheter location.
The nurse should establish a baseline neurological assessment before catheter insertion, after which the patient may be sedated, or, if currently receiving sedation, the sedation may be increased. The nurse's role in microdialysis catheter insertion is to assist the neurosurgeon in preparing and maintaining a sterile field, provide tools and equipment at the appropriate time, and monitor the patient's hemodynamic parameters. Once the catheter has been inserted, an occlusive dressing should be applied at the catheter site. Next, attach the microdialysis catheter to the microdialysis syringe that has been filled with perfusion fluid to the pump. The nurse should note that the pump is working when a green light is visible. Once the device is functioning, the nurse should secure pump on an arm board. For documentation purposes, note the date, time, catheter location, initial values, and the patient's response. After catheter insertion, the patient should undergo a head CT to assure proper placement and that no bleeding is occurring in the catheter track. The gold tip of the catheter allows for visualization of its location on CT scan.
Machine Setup and Calibration
Setup of the microdialysis analyzer is a multistep process (refer to Table 2 for a list of materials needed). A reagent is a substance that, when mixed with a specific metabolite, such as glucose, is consumed in a chemical reaction. The product of the chemical reaction can be spectrophotometrically measured, allowing the concentration of the metabolite to be determined. Separate reagents are needed for the analyses of specific metabolites, and therefore, a separate reagent is needed for glucose, lactate, pyruvate, glycerol, and glutamate. Reagents degrade in 5 days and are therefore stored in a refrigerator as a solid (reagent) and liquid (buffer) that need to be mixed together before use. Step 1 is to mix the reagents for the metabolites you wish to measure and load them into the machine. To verify that the reagents are providing accurate concentration readings, the machine must be tested using samples that have a known metabolite concentration. Each box of reagents also includes a bottle labeled Calibrator A that is used for this purpose and also must be loaded into the machine (see Fig 2). Loading the reagents and calibrator into the machine begins its self-calibration process that lasts approximately 1 hour. A green light appears for each metabolite that passes calibration, and a red light will appear if a metabolite does not pass. Do not analyze patient data if a metabolite does not pass calibration because the readings will not be accurate. Recalibrate the machine, and should it fail a second time, call your support representative for further guidance.
To be in compliance with Clinical Laboratory Improvement Amendments regulations, quality control sampling must be conducted and documented daily when using the analyzer for patient care. A control is a sample that contains a known metabolite concentration. Quality control samples are provided by CMA for this purpose at low, medium, and high concentration levels. Each box of controls has a "unique" sheet that reports the concentration range for each metabolite. Speak with your CMA representative to ensure that the controls you purchase are all from the same production so that the control range values do not change from box to box. Control sample bottles are refrigerated and once opened last for 2 weeks. To conduct quality control sampling, pipette ∼50 μl of fluid from the low, medium, and high control bottles into three separate microvials. Select the icon with the check mark to analyze one microvial at a time. Record the glucose, lactate, and pyruvate values reported by the analyzer and compare them with the ranges specified on the controls samples sheet that came in the box. See Table 3 for troubleshooting.
Cerebral microdialysis testing is considered a test of moderate complexity according to standards established by Clinical Laboratory Improvement Amendments (2005, see http://www.cdc.gov/clia/regs/toc.aspx). In addition to the self-calibration that the machine conducts, quality control samples must be performed and officially documented daily. Contact your local Core Labs to ensure that you are following the latest regulatory requirements for clinical testing.
Catheter and Pump Care
Maintenance of microdialysis includes careful inspection of the insertion site. Monitor for any leakage. Dressing guidelines should be followed according to institutional policy. Monitor for sign and symptoms of infection. The microdialysis pump should be monitored for a green blinking light, which ensures that the pump is functioning appropriately. Energy substrates should be monitored at least hourly. When obtaining microvials from the patient, inspect to ensure that there is fluid present before analysis. The microdialysis catheter and pump are fragile; care is taken to avoid catheter strain and kinks, especially when moving a patient in bed or during transport. Refer to Figures 3 and 4 for troubleshooting help when no fluid is collecting in the microvial.
Patient and Family Education
Educate family members regarding the fragility of the device to prevent accidental dislodging of the catheter or damage to the pump, the necessity of ongoing monitoring, the results of monitoring (such as normal versus elevated levels), and the significance of the results. The results of this neuromonitoring tool are used to guide patient care and should be explained to family members in a fashion similar to the manner in which one would present CT scan results, alterations in neurological examination, or other monitoring devices.
Interpretation of Cerebral Metabolism Data
The goals of patient care are to optimize physiological conditions in which the brain can heal and to identify pathophysiological processes that can cause secondary insults. Interpreting cerebral metabolism data can be intimidating and must be performed within the context of the clinical examination and catheter location because at-risk tissue may experience metabolic crises whereas healthy tissue does not. The method of level-trend-comparison is most commonly utilized when interpreting results from microdialysis data (Ungerstedt & Rostami, 2004) and is akin to using serial clinical assessments such as the Glasgow Coma Scale to monitor patient status.
When using the neurological examination to direct clinical care, it is important to note whether the patient's examination remains steady or if it is slowly getting better or worse. A sharp or sudden change in neurological status can indicate the emergence of an acute secondary complication that warrants immediate attention. A worsening clinical examination provides valuable but incomplete information about patient status, and further investigation is often required to find the source of a patient's neurological deterioration. Interpreting significant changes or patterns in the microdialysis data is a similar process. Start by obtaining the level of metabolic status by evaluating the patient's hourly data, monitor the trends or pattern (such as is the data steady or changing), and compare new data to the patient's baseline. A change in the LPR >30 (L. Hillered, personal communication, September 19, 2007) should trigger a discussion with the intensivist-ICU team. Cerebral metabolism results, such as the neurological examination, provide insightful but incomplete information about patient status, and frequently, one will need to investigate further before intervention strategies can be considered.
It is critical to remember that many pathophysiological processes can disturb cerebral metabolism including circulatory shock, hypoxemia, hyperthermia, hypoglycemia, cerebral edema, intracranial hypertension, reduced perfusion pressure, vasospasm, and seizure activity (Hillered et al., 2005). Therefore, significant changes in metabolism should be compared with changes in current medications, other physiological parameters (e.g., temperature, CO2, and systemic glucose), hemodynamic variables (e.g., mean arterial pressure, ICP, CPP, brain oxygen tension, and/or regional cerebral blood flow), and clinical assessments to determine the underlying trigger of the observed metabolic changes (Ungerstedt & Rostami, 2004). It may prove that metabolic changes are expected and normal given this broader context or other diagnostic tests may be needed such as a electroencephalograph monitoring (such as seizure detection), head CT, or cerebral angiography to determine the cause of the observed metabolic crisis (Vespa et al., 2005).
The role of the neuroscience nurse at the bedside continues to be challenging because he or she faces patients with very complex, critical illnesses. Used collaboratively by the intensive care healthcare team, cerebral microdialysis provides an exciting tool that can be used in conjunction with other hemodynamic devices to provide an integrated approach to neuromonitoring and managing neurological injury patients. Microdialysis may also serve as an invaluable tool in helping clinicians more fully understand the mechanisms of secondary injury. Incorporating the microdialysis technique into current care may lead to earlier interventions that limit or prevent secondary insults.
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