The Future of Neurocritical Care Research: Proceedings and Recommendations from the Fifth Neurocritical Care Research Network Conference.

The Fifth Neurocritical Care Research Network (NCRN) Conference held in Boca Raton, Florida, in September of 2018 was devoted to challenging the current status quo and examining the role of the Neurocritical Care Society (NCS) in driving the science and research of neurocritical care. The aim of this in-person meeting was to set the agenda for the NCS's Neurocritical Care Research Central, which is the overall research arm of the society. Prior to the meeting, all 103 participants received educational content (book and seminar) on the 'Blue Ocean Strategy®,' a concept from the business world which aims to identify undiscovered and uncontested market space, and to brainstorm innovative ideas and methods with which to address current challenges in neurocritical care research. Three five-member working groups met at least four times by teleconference prior to the in-person meeting to prepare answers to a set of questions using the Blue Ocean Strategy concept as a platform. At the Fifth NCRN Conference, these groups presented to a five-member jury and all attendees for open discussion. The jury then developed a set of recommendations for NCS to consider in order to move neurocritical care research forward. We have summarized the topics discussed at the conference and put forward recommendations for the future direction of the NCRN and neurocritical care research in general.

Use of sedative and analgesic agents in neurotrauma patients: effects on cerebral physiology.

Sedation and analgesia is used primarily in the intensive care unit (ICU) to limit the stress response to critical illness, provide anxiolysis, improve ventilatory support, and facilitate adequate ICU care. However, in the neurotrauma ICU there are many other reasons for the use of these agents. The primary aim is to prevent secondary cerebral damage by maintaining adequate cerebral perfusion pressures. This is accomplished in several different ways. Controlling intracranial pressure (ICP) and maintaining an adequate mean arterial pressure (MAP) is at the cornerstone of this management. Lowering the metabolic demands of the brain is also an important consideration as a treatment strategy. Analgesic and sedative agents are utilized to prevent undesirable increases in ICP and to lower cerebral metabolic demands. Concerns surrounding the use of these agents include time to awakening after discontinuation, effect on the cerebrovasculature, and the effect on patient outcome. There are many different pharmacological agents available, each with their distinct advantages and disadvantages. The purpose of this review is to evaluate the pharmacokinetic and pharmacological effects of each of these agents when used in neurotrauma patients.

Gabapentin: a unique anti-epileptic agent.

Gabapentin is an anti-epileptic drug (AED) that was approved in 1993 for the adjunct treatment of complex partial seizures (CPS) with and without generalization. Although the mechanism of action of gabapentin has not been fully elucidated, it has been shown to be effective not only as an adjunct AED in patients with CPS, but also in children with epilepsy, many pain syndromes (most notably neuropathic pain), and several other neurological diseases. The efficacy of the drug as an AED In both adults and children has been mostly seen when used as an adjunct with other AEDs. When used as monotherapy, it has been most effective for CPS in adults at higher doses. Gabapentin as monotherapy in children has not been shown to be as beneficial as in adults. Also, the dosing of the drug in children has been complicated by negative behavioral adverse effects. Overall, gabapentin has a low incidence of adverse effects, a pharmacokinetic profile that limits its drug interactions, and limited effects on cognition when compared to traditional AEDs. The dosing of the drug is dependent on the disease state targeted, the number of specific therapeutic drugs used, and the renal function of the patient.

Cost-minimization analysis of phenytoin and fosphenytoin in the emergency department.

STUDY OBJECTIVE: To determine the value of fosphenytoin compared with phenytoin for treating patients admitted to an emergency department following a seizure. DESIGN: Cost-minimization analysis performed from a hospital perspective. SETTING: Hospital emergency department. PATIENTS: Two hundred fifty-six patients participating in a comparative clinical trial. INTERVENTION: Estimation of adverse event rates and resource use. MEASUREMENTS AND MAIN RESULTS: In our base case, phenytoin was the preferred option, with an expected total treatment cost of $5.39 compared with $110.14 for fosphenytoin. One-way sensitivity analyses showed that the frequency and cost of treating purple glove syndrome (PGS) possibly could affect the decision. Monte Carlo simulation showed phenytoin to be the preferred option 97.3% of the time. CONCLUSION: When variable costs of care are used to calculate the value of phenytoin compared with fosphenytoin in the emergency department, phenytoin is preferred. The decision to administer phenytoin was very robust and changed only when both the frequency and cost of PGS was high.

Infection related to intracranial pressure monitors in adults: analysis of risk factors and antibiotic prophylaxis.

OBJECTIVE: Infection is a complication related to intracranial pressure monitoring devices. The timing, duration, and role of prophylactic antimicrobial agents against intracranial pressure monitor (ICPM) related infection have not previously been well defined. Risk factors and selection, duration, and timing of antibiotic prophylaxis in patients with ICPMs were evaluated. METHODS: Records of all consecutive patients who underwent ICPM insertion between 1993 and 1996 were reviewed. Patients included were older than 12 years with an ICPM placed for at least 24 hours. Exclusion criteria consisted of ICPM placed before admission or documented CSF infection before or at the time of insertion. Standard criteria were applied to all patients for diagnosis of CSF infection. RESULTS: A total of 215 patients were included, 16 (7.4%) of whom developed CSF infection. Antibiotic prophylaxis for ICPM placement was administered to 63% of infected and 59% of non-infected patients. Vancomycin (60%) and cefazolin (34%) were used most often. Sixty per cent (6/16) of patients who developed infection and 45% (53/199) of those without CSF infection received their first antibiotic dose within the 2 hours before ICPM insertion. Risk factors for CSF infection included duration of monitoring greater than 5 days (RR 4.0 (1.3-11.9)); presence of ventriculostomy (RR 3.4 (1.0-10.7)); CSF leak (RR 6.3 (1.5-27.4)); concurrent systemic infection (RR 3.4 (1.2-9.5)); or serial ICPM (RR 4.9 (1. 7-13.8)). CONCLUSIONS: Administration of antibiotics to patients before or at the time of ICPM placement did not decrease the incidence of CSF infection. Patients found to be at greater risk for infection at our institution included duration of ICPM greater than 5 days, use of ventricular catheter, CSF leak, concurrent systemic infection, or serial ICPM.

Anticonvulsant prophylaxis and timing of seizures after aneurysmal subarachnoid hemorrhage.

OBJECTIVE: There is no evidence that seizure prophylaxis is indicated after aneurysmal subarachnoid hemorrhage (SAH). This study examines prophylactic antiepileptic drug (AED) prescription and the occurrence of seizures within a single university-affiliated institution. METHODS: The authors reviewed 95 SAH patient charts using standardized forms. Variables included prophylaxis duration, seizure incidence and timing, CT findings, AED adverse events, and 1-year patient follow-up. RESULTS: Prehospital seizures occurred in 17.9% (17/95) of patients; another 7.4% (7/95) had a questionable prehospital seizure. In-hospital seizures occurred in 4.1% (4/95) of patients, a mean of 14.5 +/- 13.7 days from ictus; three of these four patients were receiving an AED at the time of seizure. Inpatient AED were prescribed to 99% of the cohort for a median of 12 (range 1 to 68) days. Approximately 8% of the cohort had posthospital discharge seizures; this included the patients who had prehospital or in-hospital seizures, 50% of whom were receiving AED therapy at the time of the seizure. Adverse effects occurred in 4. 1%; none were serious. The thickness of cisternal clot was associated with having a seizure; no other clinical predictors were identified. Having a seizure at any time did not adversely affect outcome. CONCLUSIONS: In this SAH population, the majority of seizures happened before medical presentation. In-hospital seizures were rare and occurred more than 7 days postictus for patients receiving AED prophylaxis. The vast majority of putative clinical predictors did not help predict the occurrence of seizures; only the thickness of the cisternal clot was of value in predicting seizures. Patient selection for and the efficacy and timing of AED prophylaxis after SAH deserve prospective evaluation.

Safety and feasibility of continuous infusion of remifentanil in the neurosurgical intensive care unit.

OBJECTIVE: Remifentanil is a selective mu-opioid agonist with a context-sensitive half-time of 3 to 5 minutes, independent of dose or administration duration. Other desirable effects include decreased cerebral metabolism and intracranial pressure (ICP) with minimal cerebral perfusion pressure changes. We present six cases illustrating indications for the use of remifentanil in the neurosurgical intensive care unit. METHODS: Patients received bolus doses of remifentanil of 0.05 to 1.0 microg/kg, followed by continuous infusions of 0.03 to 0.26 microg/kg/min, titrated to effect. When infusions were discontinued for neurological examinations, another bolus dose preceded infusion reinstitution. Indications for the use of remifentanil included mean arterial pressure and cerebral perfusion pressure decreases with the use of other agents (e.g., codeine or propofol) for ICP control, elevated ICP that was refractory to propofol/mannitol treatment, agitation that was unresponsive to standard therapies, and coughing that caused ICP increases after subarachnoid hemorrhage. RESULTS: Three patients experienced spontaneous intracranial bleeding (two cases of subarachnoid hemorrhage and one case of intraventricular hemorrhage), and three patients exhibited severe traumatic subdural hemorrhage. All patients recovered from the effects of remifentanil within 3 minutes after discontinuation of infusion, which allowed frequent rapid neurological assessments. Procedures for pulmonary toilet (i.e., endotracheal suctioning, postural drainage, and bronchoscopy) were performed without deleterious ICP increases or mean arterial pressure or cerebral perfusion pressure decreases during remifentanil infusions. CONCLUSION: The ultrashort duration of action of remifentanil allowed easy performance of frequent neurological examinations in the neurosurgical intensive care unit. No patient experienced deleterious hemodynamic or neurological effects as a result of remifentanil use.

Urokinase activity after freezing: implications for thrombolysis in intraventricular hemorrhage.

The retention of urokinase activity after frozen storage was studied. Urokinase powder was reconstituted aseptically in sterile water for injection or preservative-free 0.9% sodium chloride injection to a final concentration of 5000 IU/mL. Samples were stored in 5-mL plastic syringes at -20 or -70 degrees C for up to six months. Samples containing urokinase 25,000 IU/mL were similarly prepared by using sodium chloride injection as the diluent and were stored frozen at the same temperatures for up to 93 days. Urokinase activity was measured with a chromogenic assay at each test interval. Samples were also cultured after thawing to evaluate their potential to support microbial growth. The activity of urokinase at either concentration did not change appreciably during the study period. The method of thawing-at room temperature or in a refrigerator-had no effect on urokinase activity. No microbial growth was observed. Urokinase 5000 IU/mL did not show any changes in activity when reconstituted with sterile water for injection or 0.9% sodium chloride injection and frozen for up to six months. Urokinase 25,000 IU/mL in sodium chloride injection was also stable after 93 days of frozen storage.

Indomethacin: a review of its cerebral blood flow effects and potential use for controlling intracranial pressure in traumatic brain injury patients.

Traumatic brain injury (TBI) causes about 75,000 deaths and leaves approximately 200,000 people disabled in USA each year. Brain swelling and increased intracranial pressure (ICP) contribute to this morbidity and mortality. Aggressive management protocols, including ICP control, have been shown to reduce the overall mortality from 50% to 36% following severe head injury. Despite these encouraging results, new and improved pharmacologic strategies to control ICP are required. Indomethacin (IND) is a non-steroidal anti-inflammatory agent with unique effects on cerebral blood flow physiology which may be of benefit in reducing elevated ICP in TBI patients. Data from animal models and randomized, controlled studies with pre-term infants have shown that i.v. IND produces rapid, significant reductions in cerebral blood flow (CBF). Controlled studies of i.v. IND in normal volunteers show a reduction in CBF from 26%-40%. Case series involving severe TBI patients suggest that IND i.v. boluses of 30-50 mg reduce ICP by 37%-52%, reduce CBF by 22%-26%, with a modest 14% increase in cerebral perfusion pressure (CPP). Despite these encouraging results, i.v. IND should only be considered an experimental treatment for control of refractory ICP in TBI patients. Larger, well-designed randomized trials in TBI patients will provide more efficacy and safety data and delineate the effects of IND alone or in combination with other proven, effective, or experimental therapies. Once these concerns have been addressed, larger outcome studies will ultimately be needed to determine the role of IND for ICP control in TBI patients.

Tiagabine: a novel antiepileptic drug.

OBJECTIVE: To provide a comprehensive review of tiagabine, including its pharmacology, toxicology, pharmacokinetics, drug interactions, efficacy, adverse effects, and dosing recommendations. DATA SOURCES: A computerized search of the MEDLINE database from 1966 to December 1997 was used to identify publications related to tiagabine and nipecotic acid derivatives. Included in this review was information gathered from scientific meetings. Manufacturer's information was used when there was no primary literature. DATA SYNTHESIS: Tiagabine amplifies gamma-aminobutyric acid (GABA) neurotransmission, the predominant inhibitory neurotransmitter in the brain. Its mechanism of action is selective and has shown promise as an antiepileptic drug (AED) in patients with seizures refractory to other pharmaceutical products. Tiagabine exhibits dose-independent absorption, 90-95% bioavailability, high protein binding (96%), metabolism via hepatic cytochrome P450 enzymes (CYP3A subfamily), and displays first-order elimination pharmacokinetics. The mean plasma half-life is 5-8 hours. Concomitant medications that induce hepatic metabolism enhance tiagabine elimination; metabolism is reduced in patients with hepatic dysfunction. Adverse events of tiagabine typically involve the central nervous system, have been mild to moderate in intensity, and also have been transient in nature. CONCLUSIONS: Tiagabine has demonstrated a good safety profile and, while it has not been demonstrated to be superior to other second-line AEDs for partial seizures, its safety and select mechanism of action warrant its further evaluation in the clinical setting. Tiagabine should be a good alternative add-on agent for patients with unsatisfactory seizure control or intolerable adverse effects of traditional therapies; thus, this agent should be made available to these patients.

Urokinase in the treatment of intraventricular hemorrhage.

Large, randomized, double-blind trials on the use of urokinase for IVH are not available, and the studies published in the literature are not without flaws. However, it appears that in the current case-control reports, administration of urokinase through ventricular catheters is safe and is a promising alternative to current medical or surgical management. Investigation of other fibrinolytic agents such as recombinant alteplase is available, but is even more limited. Further trials will help to determine the best dosage and duration of urokinase therapy, as well as the overall efficacy of this new treatment option.

Neuromuscular blocking agents in the neurosurgical intensive care unit.

The long-term administration of neuromuscular blocking (NMB) agents in the ICU has increased in frequency the last several years. NMB agents in the ICU patient facilitate intubation and ventilatory support, decrease oxygen demand and consumption, facilitate bedside procedures and diagnostics, and potentially decrease intracranial pressure. However, NMB agents have extensive adverse effect profiles and require close monitoring. Two major classes of NMB agents exist: depolarizing and nondepolarizing. Depolarizing NMB agents work by mimicking the effect of acetylcholine at the nicotinic cholinergic receptor. Continuous depolarization inhibits repolarization, resulting in paralysis. Nondepolarizing NMB agents induce muscle paralysis by their competitive antagonism at the nicotinic cholinergic receptor. The neurosurgeon must be aware that NMB agents are paralytics only and should only be used in patients who are sedated and receiving adequate analgesia. Appropriate drug selection demands a thorough knowledge and understanding of each patient's neurologic, metabolic, and cardiovascular status and the hemodynamic, autonomic, pharmacokinetic, pharmacodynamic, and cost profiles of the NMB agents.

New and investigational treatment options for ischemic stroke.

We conducted a MEDLINE search of new treatment strategies and experimental agents for treating acute ischemic stroke published from 1989-1996. Clinical trials involving thrombolytics, glutamine release inhibition, N-methyl-D-aspartate receptor antagonism, opioid antagonism, calcium channel blockade, free radical scavenging, membrane stabilization, intercellular adhesion molecule-1 antagonism, ganglioside administration, and growth factor administration were included. Basic research articles were selected based on progress of the therapeutic class toward clinical trials. Approval of tissue plasminogen activator indicates progress in new treatments for acute ischemic stroke. Experimental therapies with potential may become available soon. Recognizing signs and symptoms of stroke is crucial to ensure prompt administration of these agents. The time to diagnosis determines the therapeutic approach for acute ischemic stroke.

A review of stress ulcer prophylaxis in the neurosurgical intensive care unit.

STRESS ULCERS OCCUR frequently in intensive care unit patients who have intracranial disease. After major physiological stress, endoscopic evidence of mucosal lesions of the gastrointestinal tract appears within 24 hours of injury; 17% of these erosions progress to clinically significant bleeding. Gastrointestinal hemorrhage has been associated with mortality rates of up to 50%. The pathogenesis of stress ulcers may not be completely understood, but gastric acid and pepsin appear to play significant roles. Antacids, H2 antagonists, and sucralfate are effective prophylactic agents in the medical/surgical intensive care unit. Appropriate therapy for neurosurgical patients remains unclear, however. This review summarizes the current literature regarding the pathogenesis and therapy of stress ulcers in neurosurgical patients.

A step-wise protocol for stress ulcer prophylaxis in the neurosurgical intensive care unit.

BACKGROUND: Neurosurgical patients are at risk for stress induced gastric erosion. Clinical criteria for monitoring stress ulcer prophylaxis (SUP) efficacy and predicting clinical bleeding are limited. SUP in the neurosurgical intensive care unit (NSICU) was evaluated utilizing a multidisciplinary quality assurance program with defined criteria for therapy. METHODS: All patients admitted to the NSICU were managed using this protocol. Therapy was initiated with a single drug (cimetidine 300 mg IV every 6 hours, or continuous infusion up to 2400 mg/day) in 136 evaluable cases. Combination therapy was implemented if continued gastric pH < 4 and guaiac positive aspirates occurred (N = 45). RESULTS: Significant correlations were observed between low gastric pH values and both GCS < 8 (P < or = 0.01) and length of ventilatory support (P < or = 0.005). Single agent therapy was more effective in patients with GCS > or = 8 (P < or = 0.001). Endoscopy was performed in 25 patients. No patient with GCS < 8 had pathologic lesions. The presence of asymptomatic gastrointestinal lesions was higher in patients requiring longer ventilatory support (P < or = 0.001) and intensive care unit stay (P < or = 0.0001). Patients requiring pentobarbital and vasopressors had statistically higher rates of clinical bleeding (P < 0.05). Patients with GCS < 8 had increased rates of pneumonia (P < or = 0.005) with a higher pneumonia rate when treated with combination therapy (P < or = 0.05). Overall, the incidence of clinical bleeding was 3.7%. CONCLUSIONS: This protocol was effective for prospective monitoring of SUP efficacy and limited multiple drug therapy to patients at risk for clinical bleeding.

New pharmacologic strategies for acute neuronal injury.

The number of new drugs for treating neurotrauma is rapidly expanding. Emerging theories regarding the mechanisms of secondary neuronal injury provide the scientific basis for evaluating these new agents. Some of the most promising mechanisms for intervention are ionotropic channel antagonism, inhibition of lipid peroxidation, and neurotrophic factor augmentation. Many of these new agents are undergoing clinical trials to establish their roles in therapy.

New pharmacologic approaches to acute spinal cord injury.

The incidence of spinal cord injury (SCI) in the United States is approximately 10,000 new cases per year. Strategies to prevent injury or salvage a few dermatomal levels may have significant effects on outcome. Several pharmacologic agents have been evaluated for their efficacy in patients with acute SCI. Methylprednisolone, when administered early, was the first drug to show significant improvement in outcome and is a standard of comparison for future agents. Several new drugs show promising results in animal models of SCI, with more extensive human trials currently under way. Results of more well-controlled clinical trials are necessary to determine which agents have significant neurologic benefits.