Aaron M. Cook

Guideline for Reversal of Antithrombotics in Intracranial Hemorrhage : A Statement for Healthcare Professionals from the Neurocritical Care Society and Society of Critical Care Medicine.

BackgroundThe use of antithrombotic agents, including anticoagulants, antiplatelet agents, and thrombolytics has increased over the last decade and is expected to continue to rise. Although antithrombotic-associated intracranial hemorrhage can be devastating, rapid reversal of coagulopathy may help limit hematoma expansion and improve outcomes.MethodsThe Neurocritical Care Society, in conjunction with the Society of Critical Care Medicine, organized an international, multi-institutional committee with expertise in neurocritical care, neurology, neurosurgery, stroke, hematology, hemato-pathology, emergency medicine, pharmacy, nursing, and guideline development to evaluate the literature and develop an evidence-based practice guideline. Formalized literature searches were conducted, and studies meeting the criteria established by the committee were evaluated.ResultsUtilizing the GRADE methodology, the committee developed recommendations for reversal of vitamin K antagonists, direct factor Xa antagonists, direct thrombin inhibitors, unfractionated heparin, low-molecular weight heparin, heparinoids, pentasaccharides, thrombolytics, and antiplatelet agents in the setting of intracranial hemorrhage.ConclusionsThis guideline provides timely, evidence-based reversal strategies to assist practitioners in the care of patients with antithrombotic-associated intracranial hemorrhage.

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.

Nutrition Considerations in Traumatic Brain Injury

The provision of adequate nutrition support for patients with traumatic brain injury (TBI) has been a clinical challenge for decades. The primary and secondary injuries create unique metabolic derangements along with accompanying issues such as optimal timing and route of nutrition, appropriate fluid and electrolytes, drug administration, rehabilitation, and dysphagia. Enteral nutrition is clearly established as the preferential route of nutrition support for this population vs parenteral nutrition. There appears to be a consensus on early initiation of enteral nutrition, but less definitive are recommendations on advancement timing and formula components. Nutrition therapies should include exact fluid resuscitation goals specific for TBI and strict electrolyte monitoring to avoid extreme fluid, electrolyte, or glucose shifts that could be detrimental to the patient. While the critical care patient often tolerates small bowel feeding, the long-term rehabilitation patient should transition to and tolerate gastric feeding. Drug-nutrient and adverse drug reactions such as diarrhea should be routinely evaluated in patients receiving enteral nutrition. Monitoring for dysphagia is critical to avoid the costly negative aspects associated with aspiration and to capitalize on quality of life and appropriate oral nutrition. Emphasizing the priority of early nutrition support within a multi-disciplinary team may be the critical key for successful provision and tolerance of nutrition support in the TBI population.

Acute Intrathecal Baclofen Withdrawal: A Brief Review of Treatment Options

BackgroundAcute baclofen toxicity and withdrawal can present with a constellation of symptoms making differentiation between these two entities and other potential diagnoses challenging. Baclofen withdrawal is associated with numerous complications which may require neurocritical care expertise such as respiratory failure, refractory seizures, delirium, and blood pressure lability.MethodsCase report and literature review.ResultsThis case report discusses a case of intrathecal baclofen (ITB) withdrawal, focusing on the differential diagnosis for acute baclofen withdrawal and reviews the various options that exist to treat the symptoms of acute baclofen withdrawal such as benzodiazepines, propofol, skeletal muscle relaxants, and tizanidine.ConclusionsCritical care practitioners should be prepared to treat this potentially devastating and often refractory complication of ITB therapy.

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.

Pharmacokinetics of Intravenous Levofloxacin Administered at 750 Milligrams in Obese Adults

ABSTRACT The physiochemical properties of levofloxacin suggest that it is an agent which may exhibit altered pharmacokinetics in obese individuals. The purpose of this study was to describe the pharmacokinetics of a single 750-mg intravenous dose of levofloxacin in both hospitalized and ambulatory obese individuals. The hypothesis was that a standard dose of levofloxacin in obese individuals would achieve serum concentrations likely to be therapeutic. A single levofloxacin dose of 750 mg was infused over 90 min, and seven serial serum samples were subsequently obtained to evaluate the pharmacokinetics after the first dose. The peak concentrations of levofloxacin were comparable to those seen with normal-weight individuals. However, the area under the concentration-time curve and clearance were quite variable. Accelerated clearance was evident in the ambulatory obese individuals. Further investigation of the effects of obesity on the pharmacokinetics of levofloxacin is necessary to ensure optimal dosing.

Pharmacologic options for reducing the shivering response to therapeutic hypothermia.

Recent literature has demonstrated significant improvements in neurologic outcomes in patients who have received induced hypothermia in the setting of out‐of‐hospital cardiac arrest. Through multiple metabolic mechanisms, the induction of hypothermia slows the progression and devastation of transient cerebral hypoxia. Despite these benefits, the desired reduction in core temperature is often a challenging venture as the body attempts to maintain homeostasis through the induction of thermoregulatory processes aimed at elevating body temperature. Shivering is an involuntary muscular activity that enhances heat production in an attempt to restore homeostasis. For successful induction and maintenance of induced hypothermia, shivering, as well as other thermoregulatory responses, must be overcome. Several pharmacologic options are available, either used alone or in combination, that safely and effectively prevent or treat shivering after the induction of hypothermia. We conducted a PubMed search (1966–March 2009) to identify all human investigations published in English that discussed pharmacologic mechanisms for the control of shivering. Among these options, clonidine, dexmedetomidine, and meperidine have demonstrated the greatest and most clinically relevant impact on depression of the shivering threshold. More research in this area is needed, however, and the role of the clinical pharmacist in the development and implementation of this therapy needs to be defined.

Pharmacokinetic Alterations in Obesity

Although some medications have established dosing adjustments for obesity (Table 2), it remains unknown for the majority of medications if dosing adjustment is warranted. It is important to remember dosage adjustments may not be as simple as doubling an antibiotic dose because a patient is morbidly obese. Individualizing drug dosing is imperative in the obese, postoperative patient to ensure they simultaneously have therapeutic serum concentrations without drug toxicity. Much of what has been learned from studies in obese patients is that the pharmacokinetic alterations of medications are variable. Broad application of dosing guidelines even among medications within the same therapeutic class is likely not appropriate. An increased emphasis in researching the effects of obesity on the fate of medications is of paramount importance as the obese population grows. Practitioners should use caution and be vigilant in monitoring pharmacotherapy in obese individuals.

Linezolid for the Treatment of a Heteroresistant Staphylococcus aureus Shunt Infection

The emergence of multidrug-resistant bacteria as the cause of ventriculoperitoneal shunt infections is a disconcerting phenomenon that often requires the use of alternative antimicrobials due to resistance against commonly used agents. The following is a case report describing the successful treatment of a ventriculoperitoneal shunt infection caused by a heteroresistant strain of Staphylococcus aureus with linezolid. Linezolid may have utility in treating pediatric CNS infections due to its tolerability, excellent blood-brain barrier penetration, and activity against multiple resistant Gram-positive organisms such as S. aureus, vancomycin-resistant Enterococcus faecium and Streptococcus pneumoniae.

Potential roles for statins in critically ill patients.

The 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors (statins) are the most commonly prescribed agents for hypercholesterolemia and have revolutionized the management of hyperlipidemia and the area of cardiovascular risk reduction. However, recent data suggest that their effects go well beyond the lipid lowering seen with long‐term use and may include acute antiinflammatory activity, anticoagulation, immunomodulation, as well as promotion of changes in smooth‐muscle tone. Because of these data, promising research has begun into the use of these agents in various critical care areas such as the early phases of sepsis, bacteremia, and ischemic stroke. Recent data also show a decrease in cerebral vasospasm after subarachnoid hemorrhage, an area deficient in therapeutic options. More research is necessary to ascertain the true role of statins in the treatment of these various disorders. Nevertheless, the concept of a statins role as being only a routine preventive therapy with benefits limited to patients undergoing extended treatment is rapidly becoming inaccurate.