Promising Developments in Critical Care
Pearls
There are many new and old technologies currently being used in the neuro–intensive care units (NICUs) to assess brain function prior to seeing a change in the neurologic exam. Currently, these modalities have been useful in the trauma population, but need urther investigation in other patient populations in the NICU prior to making conclusions regarding their efficacy.
Many modalities for neuroprotection are being investigated, the best known and most efficacious being hypothermia.
New medications are consistently being investigated that are useful in the NICU population. The newer antiepileptics are showing great promise. The use of conivaptan in this patient population and the clinical scenarios for its safety and efficacy are still being debated.
The near future of neurocritical care is not likely to include the large shifts that have been seen in the past two decades. The paradigm-shifting events including the development of dedicated neurologic intensive care units (NICUs) (initially in neurosurgery but more recently combined with neurology), the advent of dedicated intensive care physicians with specialization in neurocritical care, and advances in imaging and intracranial monitoring techniques have moved neurocritical care into the mainstream. In the near future, we will see refinements of existing technologies and, it is hoped, the development of fully formed treatments from the prospective treatments that have been under study for years. It is clear that the refinements in our understanding of cerebral physiology in the injured brain, control of neuroinflammation, and neuroprotection will lead the list of advances in the next decade.
Another important trend that will manifest in the years to come is not unique to neurocritical care. As we struggle to find our place in the broader field of general critical care, advances in process improvement techniques that are being implemented in many ICUs will come to the NICU as well.
In this chapter we discuss technologic advances that are and will be used more frequently, but we focus on intracranial monitoring and continuous electroencephalogram (EEG) monitoring. In addition, we discuss promising neuroprotective strategies and control of inflammation. We highlight a few medications that are likely to have a big impact on the future care of these patients. Finally, we discuss process improvement strategies that will be coming to common practice in the near future.
♦ Intracranial Monitoring and Our Understanding of Brain Physiology
Ischemic stroke, hemorrhagic stroke, and subarachnoid hemorrhage can lead to devastating neurologic deficits. In the acute setting, the goal of treatment is to protect and restore salvageable brain tissue. This goal can be accomplished by restoring blood flow to the ischemic areas and decreasing the metabolic and inflammatory mediators that potentiate further ischemic damage.
The concept of the autoregulation of the brain vasculature is critical to understanding the challenges of cerebral blood flow (CBF) in the injured brain. In normal patients, the brain and the cerebral arteries are able to maintain CBF within the cerebral perfusion pressure range of 50 to 150 mm Hg. However, in the setting of acute neurologic injury, the injured tissue loses its autoregulatory capability. The end result is a system where CBF is entirely dependent on the perfusion pressure.1
In these acute neurologic emergencies, blood pressure is closely monitored and adequate cerebral perfusion pressure (CPP) is tightly controlled, augmented with the use of vasopressors if needed. Unfortunately, studies have shown that altered autoregulation may include only regional areas of the brain, and global measures of systemic blood pressure may miss areas at risk.2 To combat this problem, direct or indirect CBF monitoring in the brain may be useful to guide management. Three specific modalities are currently in use either clinically or investigationally to measure blood flow or substrate delivery in the brain: thermodilution CBF, brain tissue oxygenation, and cerebral microdialysis.
Thermodilution Cerebral Blood Flow
Using the principles of heat dissipation, the technology includes a heating element proximal to a thermometer. The amount of energy required to maintain a temperature above the local body temperature is proportional to the washout volume, or blood flow. The technology has been tested in several neurologic conditions and is in use clinically in several centers in the United States and Europe. The major limitation of the CBF monitor is that it measures flow in a very focal area of the brain. As discussed above, there are differences in the competence of autoregulation in brain injury. There is a risk of placement errors that can either under- or overestimate the actual blood flow.3
Brain Tissue Oxygenation
In the setting of a primary neurologic insult (traumatic brain injury [TBI], subarachnoid hemorrhage), increased intracranial pressure or decreased CBF can result in secondary neurologic injury. Brain tissue oxygenation probes measure the partial pressure of oxygen of the interstitial space surrounding the Clark’s electrode in the probe. The information obtained by this method infers oxygen delivery and so is thought to be proportional to blood flow.
Low brain tissue oxygen readings in patients with TBI are associated with worse outcome. In the trauma literature, low and prolonged brain tissue oxygenation (defined as less than 10 mm Hg for greater than 150 minutes) correlates with poor outcome in TBI patients.4 There is still debate about whether treatment improves outcome. A review by Maloney-Wilensky and colleagues4 reported an insertion hematoma rate of <1%, and no reported risk of infection.
There are few trials studying brain tissue oxygenation and subarachnoid hemorrhage, with no clear evidence that treatment strategies based on tissue oxygenation improve outcome.
Cerebral Microdialysis
Microdialysis exploits the movement of small molecules across a semipermeable membrane down a concentration gradient. The process entails inserting a microdialysate catheter ipsilateral to the area of damage. The catheter collects dialyzed extracellular neurochemicals that are indicators of cellular processes; lactate/pyruvate levels, glutamate, and glycerol are most common tested. Specific changes in the levels of these mediators presumably detect ischemia adjacent to the catheter.5 This method has the advantage of measuring the output of the cell, not the delivery of substrate to determine the adequacy of substrate delivery. This minimizes the interpatient variability of substrate needs. In trauma, microdialysis has been used to detect worsening cerebral edema, allowing for interventions to take place for further interventions for reduction of elevated intercranial pressures.
In acute ischemic stroke, Schneweis et al examined potential predictors of malignant edema in large middle cerebral artery (MCA) infarcts with intracranial pressure (ICP) monitoring and microdialysis catheters.6 The study included 10 patients and found patients who developed massive edema on computed tomography (CT) scan and elevated ICPs correlating with increased dialysate levels of lactate/pyruvate, glutamate, and glycerol. However, there was no clear pattern to elevations in dialysate levels with timing of ICP elevation. Berger et al examined the dialysate levels in 24 patients with large MCA strokes.7 The patients were allocated to conservative management, hypothermia, or hemicraniectomy. The dialysate levels of lactate/pyruvate, glycerol, and glutamate in the conservative group were seven times higher than in the hypothermic and hemicraniectomy groups, suggesting a benefit in both hypothermia and hemicraniectomy.
Multimodal Monitoring Approaches to Patient Management
Cerebral blood flow monitoring, intraparenchymal oxygen tension monitoring, and microdialysis have all been shown to be promising therapies for the treatment of brain-injured patients. All have also been found to have limitations. In clinical practice, tissue oxygen and CBF readings are sometimes difficult to interpret in isolation. Microdialysis also has drawbacks having to do with the sampling time and rate. In the near future, it is likely that these devices will be used in combination. By having different but related data about the brain, it may be possible to develop more complete and nuanced conclusions about the brain physiology. The idea of a “bundle” of multiple brain devices has been tried in several centers in the U.S. and in Europe (Fig. 6.1). There is still too little evidence to suggest its use. In addition, complication risks need to be clearly evaluated along with potential benefits.
Continuous Electroencephalogram Monitoring
In addition to the intraparenchymal monitoring expansion occurring in the NICU is a resurgence in interest in the electroencephalogram (EEG), particularly continuous EEG. The standard of care for neurologic patients with worsening neurologic functioning has traditionally been CT of the head and EEG to investigate the cause of the worsening. However, continuous EEG (cEEG) may now be a better modality to assess the brain function in confused or comatose patients prior to acute clinical worsening. As stated by Vespa,8 cEEG monitoring for the brain is like telemetry for the heart; it allows one to see changes prior to the clinical consequences. There are multiple modes of cEEG interpretation that are currently being studied.
Continuous EEG has been studied in several settings. It is illustrative to discuss the role of cEEG in ischemic stroke and intracerebral hemorrhage as it has been well studied. The frequency of clinically manifested seizures in stroke ranged from 5 to 17%, with the majority occurring from large arterial distribution and cardioembolic strokes.8 With the use of cEEG, the actual frequency of seizures (electrographic seizures) increases to approximately 25% in some studies. Carrera et al9 found an association of increased seizure frequency with worsening National Institutes of Health Stroke Scale (NIHSS) scores.
In addition to the detection of seizures in stroke, the pyramidal neurons of layers 3, 5, and 6 produce excitatory and inhibitory potentials that are detected by scalp electrodes and are sensitive to hypoxia. Therefore, EEG has the potential to be a sensitive, real-time detector of acute ischemia, which has been shown intraoperatively.10 Some studies have specifically shown EEG abnormalities with changes in CBF. When CBF reaches 25 to 30 mL/100 g/min, the EEG signal changes in morphology, amplitude, and frequency, whereas when CBF decreases to less than 15 mL/100 g/min, the EEG signal becomes isoelectric.11 Importing this real-time operating room technology to the ICU bedside has technical and logistic challenges but will likely become a standard of ICU care in the near future. More reliable means of postprocessing the EEG signal is necessary to make the analysis less time-consuming.
In primary intracerebral hemorrhage, seizure frequency is higher than in ischemic strokes, with frequencies in the high 20%. Vespa et al8 studied seizure frequency in ischemic and hemorrhagic stroke, and noted that (1) hemorrhages with the highest seizure frequency occurred in the setting of arteriovenous malformations, and (2) seizures occurred more frequently with lobar hemorrhages but still occurred with subcortical hemorrhages. Monitoring seizures has a few intended and unintended attributes. Preventing seizures may decrease the metabolic demand incurred in partially injured neurons, allowing them to heal more effectively. From a psychological standpoint, the most common reason for death in intracerebral hemorrhage is the withdrawal of life-sustaining care. Removing the encephalopathy associated with frequent seizures makes it easier for physicians to make a clear assessment of the patient’s progress before decisions of limitation of care are started.8
♦ Neuroprotection
The concept of neuroprotection has been studied in depth in stroke, TBI, and hemorrhages with little success. With the possible exception of nimodipine in subarachnoid hemorrhage, neuroprotectant medications are not routinely used in clinical practice. Despite this, the preclinical data for several compound classes is very promising. It is likely that some medication with neuroprotective effects will be used in the near future. Below is a brief analysis of some of the most promising classes.
Medications
Among the most promising new compounds are the spin trap compounds that derive from the parent compound α-phenylN-tert-butyl nitrone. They act as free radical scavengers and thereby inhibit mediators of oxidative stress. Disodium-([tert-butylimino] methyl) benzene-1,3-disulfonate N-oxide (NXY-059) was studied in two large human stroke trials, Stroke Acute Ischemic NXY-059 (SAINT) I and II. As a compound in this class, NXY-059 is unique due to its lack of polarity. This quality also confers a greater affinity for free radicals but limits its availability to the brain because poorly polar compounds do not pass through the blood–brain barrier well. This has the advantage of limiting cerebral side effects while controlling oxidative stress in the body outside the brain. The phase III stroke trial did not show improved outcome defined as disability at 90 days.12 , 13 Interestingly, post hoc analysis showed a significant decreased frequency of hemorrhagic transformation (symptomatic and asymptomatic) in the patients receiving NXY-059, which may ultimately be the greatest utility of this drug.14
There are other spin traps that are being investigated in animal models with hopes of human trials. Stilbazunenlyl nitrone (STAZN) is an alternative spin trap molecule with increased hydrophobic properties. The rationale for this compound compared with NXY-059 is that higher concentrations are achieved in the brain, allowing for increased neuroprotective action in the brain parenchyma than in the arteries with a greater risk of neuronal side effects.12 , 13
N-methyl-D-aspartate (NMDA) antagonists have been studied for several years as neuroprotective medications. The NMDA receptor is a calcium channel found on neurons that is sensitive to glutamate (and indirectly glycine) and mediates slow calcium currents into the neuron that is important in several neuronal processes, most notably memory consolidation. The NMDA receptor has been implicated in excitotoxic secondary brain injury after acute injury. In the 1990s, several compounds were tried in clinical trials of stroke that failed to improve the outcome. Despite this, the mechanism of NMDA blockade makes sense as a therapeutic target. Currently, there are no NMDA antagonists being tried in multicenter trials in neurocritical care in the U.S.
Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
