Jimmi Hatton

A review of neuroprotection pharmacology and therapies in patients with acute traumatic brain injury.

Traumatic brain injury (TBI) affects 1.6 million Americans annually. The injury severity impacts the overall outcome and likelihood for survival. Current treatment of acute TBI includes surgical intervention and supportive care therapies. Treatment of elevated intracranial pressure and optimizing cerebral perfusion are cornerstones of current therapy. These approaches do not directly address the secondary neurological sequelae that lead to continued brain injury after TBI. Depending on injury severity, a complex cascade of processes are activated and generate continued endogenous changes affecting cellular systems and overall outcome from the initial insult to the brain. Homeostatic cellular processes governing calcium influx, mitochondrial function, membrane stability, redox balance, blood flow and cytoskeletal structure often become dysfunctional after TBI. Interruption of this cascade has been the target of numerous pharmacotherapeutic agents investigated over the last two decades. Many agents such as selfotel, pegorgotein (PEG-SOD), magnesium, deltibant and dexanabinol were ineffective in clinical trials. While progesterone and ciclosporin have shown promise in phase II studies, success in larger phase III, randomized, multicentre, clinical trials is pending. Consequently, no neuroprotective treatment options currently exist that improve neurological outcome after TBI. Investigations to date have extended understanding of the injury mechanisms and sites for intervention. Examination of novel strategies addressing both pathological and pharmacological factors affecting outcome, employing novel trial design methods and utilizing biomarkers validated to be reflective of the prognosis for TBI will facilitate progress in overcoming the obstacles identified from previous clinical trials.

Vancomycin Administration into the Cerebrospinal Fluid: A Review

OBJECTIVE: To discuss administering vancomycin directly into the cerebrospinal fluid (CSF) to treat serious central nervous system (CNS) infections. DATA SOURCES: References were obtained through an online search of MEDLINE, limited to material published in English. In addition, information was extracted from clinical trials, review articles, abstracts, and textbooks. STUDY SELECTION: Systematic evaluation of this topic in humans has not been done in a prospective manner. Related research articles describing the pathophysiology of CNS infections, intrathecal drug administration, and case reports of CSF vancomycin administration were reviewed. DATA EXTRACTION: Case reports regarding CSF vancomycin dosing were evaluated and included: Drug dosing, infecting organism, infectious disease state, infectious outcome, CSF dynamics/flow abnormalities, methods of drug administration, drug monitoring, and toxicities. DATA SYNTHESIS: The results of this review are based on qualitative evaluations of anecdotal case reports and a basic understanding of intrathecal and intraventricular drug dosing principles. CSF administration of vancomycin is an effective means of bypassing the blood-brain barrier to achieve greater drug concentrations within the CSF. Current limitations to the CSF administration of vancomycin include a lack of data describing its safety, efficacy, and pharmacokinetics. CONCLUSIONS: CNS infections may require the CSF administration of vancomycin for successful eradication. Recommendations for dosing in the literature vary. Because of the potential toxicities associated with elevated CSF concentrations of vancomycin, dosing should be conservative.

Dosing and safety of cyclosporine in patients with severe brain injury

OBJECT Cyclosporine neuroprotection has been reported in brain injury models but safety and dosing guidelines have not been determined in humans with severe traumatic brain injury (TBI). The purpose of this investigation was to establish the safety of cyclosporine using 4 clinically relevant dosing schemes. METHODS The authors performed a prospective, blinded, placebo-controlled, randomized, dose-escalation trial of cyclosporine administration initiated within 8 hours of TBI (Glasgow Coma Scale score range 4-8; motor score range 2-5). Four dosing cohorts (8 patients treated with cyclosporine and 2 receiving placebo treatment per cohort) received cyclosporine (1.25-5 mg/kg/day) or placebo in 2 divided doses (Cohorts I-III) or continuous infusion (Cohort IV) over 72 hours. Adverse events and outcome were monitored for 6 months. RESULTS Forty patients were enrolled over 3 years (cyclosporine cohorts, 24 male and 8 female patients; placebo group, 8 male patients). Systemic trough concentrations were below 250 ng/ml during intermittent doses. Higher blood concentrations were observed in Cohorts III and IV. There was no significant difference in immunological effects, adverse events, infection, renal dysfunction, or seizures. Mortality rate was not affected by cyclosporine administration, independent of dose, compared with placebo (6 of 32 patients receiving cyclosporine and 2 of 8 receiving placebo died, p>0.05). At 6 months, a dose-related improvement in favorable outcome was observed in cyclosporine-treated patients (p<0.05). CONCLUSIONS In patients with acute TBI who received cyclosporine at doses up to 5 mg/kg/day, administered intravenously, with treatment initiated within 8 hours of injury, the rate of mortality or other adverse events was not significantly different from that of the placebo group.

Pharmacological treatment of traumatic brain injury. A review of agents in development

Successful treatment strategies for patients with traumatic brain injury (TBI) remain elusive despite standardised clinical treatment guidelines, improved understanding of mechanisms of cellular response to trauma, and a decade of clinical trials aimed at identifying therapeutic agents targeted at mediators of secondary injury.The information explosion relative to mechanisms of secondary injury has identified several potential targets for intervention. Depending on the type of injury to the brain and the intensity and the success of resuscitation, necrosis, apoptosis, inflammatory and excitotoxic cellular damage can be seen. These same processes may continue postinjury, depending on the adequacy of clinical care. Each of these mechanisms of cellular damage can initiate a cascade of events mediated by endogenous signals that lead to secondary neurological injury.Several factors contributed to the failure of earlier clinical trials. Now that these have been recognised, a positive impact on future drug development in TBI has been realised. Both the US and Europe have organised brain injury consortiums where experts in the treatment of TBI provide insight into study design, implementation, conduct and oversight in conjunction with the pharmaceutical industry. Consequently, future clinical trials of new investigational treatments have greater potential for identifying therapies of merit in specific populations of patients with TBI.Pharmacological strategies under investigation are targeting sites involved in the secondary cascade that contribute to overall poor outcome following the primary injury. These treatments include ion channel antagonists including calcium channel antagonists, growth factors, antioxidants, stem cells, apoptosis inhibitors, and inhibitors of other signal modulators.In conclusion, the complexity of TBI pathology and the mechanisms contributing to secondary injury present unique therapeutic challenges. Appropriate research targets for intervention continue to be investigated, however, the likelihood of improving outcomes with a single approach is extremely small. There is a need for collaborative efforts to investigate the optimal time for drug administration and the logical sequence or combination of treatments that will ultimately lead to improved neurological outcomes in this population.

Cyclosporine A for neuroprotection: establishing dosing guidelines for safe and effective use

Numerous neuroprotective compounds have been investigated to ameliorate secondary changes and the progression of injury after the primary insult in traumatic brain injury (TBI). This cascade of events is complex and difficult to abate once initiated following the primary injury. The clinical consequences of this secondary injury are unpredictable and often permanently incapacitating. Cyclosporine A (CsA) interrupts the endogenous mediators of secondary insult through inhibition of the mitochondrial permeability transition pore and prevention of subsequent mitochondrial dysfunction. This drug may have a role in neuroprotection but has several pharmacologic effects that must be considered when using it in the TBI population. This review discusses the physiologic responses following TBI that may affect CsA efficacy and safety when used for neuroprotective indications. So far, CsA seems to be safe in the TBI population. The role of CsA after acute TBI will be better defined after the completion of upcoming planned clinical trials.

Management of Bacterial Urinary Tract Infections in Adults

OBJECTIVE: To provide a comprehensive review of the diagnosis and therapeutic management considerations in patients with urinary tract infections (UTIs). DATA SOURCES: A MEDLINE search was used to identify pertinent English language literature, including reviews. Infectious disease textbooks were used for background information. STUDY SELECTION: Clinical trials evaluating drug therapy in a variety of patient populations with UTIs were reviewed. DATA EXTRACTION: Background information was obtained from comprehensive reviews. Drug dosing strategies and efficacy comparisons were extracted from the investigations in this area. DATA SYNTHESIS: Information was processed to provide general guidelines and resources for practitioners to use in managing UTIs. CONCLUSIONS: There are a number of useful antibiotics for the management of UTIs. The distinctions between infection severity and underlying risk factors within a given population influence the appropriateness of drug selection and duration of treatment.

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.

Prevalence and characteristics of adverse drug reactions in neurosurgical intensive care patients.

OBJECTIVE: To evaluate the prevalence and characteristics of adverse drug reactions (ADRs) in neurosurgical intensive care patients. METHODS: Retrospective analysis of ADR data obtained from a spontaneous reporting system in a tertiary care university hospital. Reports of suspected ADRs in adult patients admitted emergently or electively to the neurosurgical service were included. RESULTS: Over the 3 year period, 3496 neurosurgical intensive care unit (ICU) patient admissions accounted for 5% of all hospital admissions. A total of 10% of all neurosurgical patients developed a suspected ADR, with three patients experiencing multiple reactions. Other adult ICU patients developed ADRs at a comparable rate (9%, P > 0.05). Overall, neurosurgery patients accounted for 12% of all spontaneously reported ADRs. Preventable reactions were observed in 43 (13%) cases, and treatment was required for 76%. The majority (96%) of ADRs resolved or improved at the time of the ADR report. Nausea, pruritus, thrombocytopenia, and vomiting were most frequently noted. Therapies most often associated with reported events were analgesics, antipyretics, antibiotics, anticonvulsants, and histamine H2 antagonists. The relationship between central nervous system disease and adverse event occurrence is not clear. CONCLUSION: Despite the narrow scope of drug regimens in neurosurgical ICU patients, ADRs can complicate therapy in this critically ill population. Neurosurgical ICU patients seem to experience ADRs no more frequently than their adult ICU counterparts.

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.