Cynthia Melinda Boyd, M.D., M.P.H.

• Professor of Medicine

https://www.hopkinsmedicine.org/profiles/results/directory/profile/0007719/cynthia-boyd

They are excreted primarily by renal glomerular filtration effective glyset 50 mg, with little tubular reabsorption purchase glyset master card. The renal clearance of aminoglycosides is approximately equal to the creatinine clearance 50 mg glyset mastercard, because creatinine is also filtered at the glomerulus but is not secreted or reabsorbed significantly by the tubules buy glyset on line. Because the clearance of aminoglycosides is proportional to the glomerular filtration rate discount 50 mg glyset overnight delivery, the dosage of aminoglycosides must be reduced in patients with renal impairment generic glyset 50mg online. B, Macrolides, chloramphenicol, and dalfopristin block peptidyl transferase, the enzyme that catalyzes the formation of a peptide bond between the nascent peptide and the amino acid attached to the A site. C, Macrolides and clindamycin block the translocation step in which the nascent peptide is transferred from the A site to the P site after the formation of a new peptide bond. Chapter 39 y Inhibitors of Bacterial Protein Synthesis the plasma concentrations of aminoglycosides are routinely measured to ensure adequate dosage and to minimize toxicity. The peak concentration is found about 30 minutes after completing an intravenous infusion of an aminoglycoside, whereas the trough concentration is found immediately before administration of the next dose. Optimal peak and trough concentrations have been established and can be used to guide dosage adjustments for individuals receiving the standard regimen of three daily doses given at 8-hour intervals. For example, therapeutic concentrations of gentamicin and tobramycin are usually between 4 and 8 mg/L. A peak concentration above 12 mg/L or a trough concentration above 2 mg/L is considered toxic and indicates the need to reduce the dosage of gentamicin or tobramycin. Therapeutic concentrations of amikacin are between 16 and 32 mg/L, and the toxic peak and trough concentrations are above 35 mg/L and above 10 mg/L, respectively. Spectrum and Indications the aminoglycosides are active against a wide range of aerobic gram-negative bacilli. Streptomycin is the least active against most gram-negative bacilli and is primarily used to treat tuberculosis and infections caused by Yersinia pestis (plague) and Francisella tularensis (tularemia). Tobramycin is the most active aminoglycoside against many strains of Pseudomonas aeruginosa, whereas gentamicin is more active against Escherichia coli, Klebsiella species, and other species of Enterobacteriaceae. Gentamicin is also used in combination with a penicillin to treat serious enterococcal, staphylococcal, or viridans group streptococcal infections such as endocarditis. Amikacin is more resistant to bacterial enzymes that inactivate aminoglycosides, and it is active against some strains resistant to gentamicin and tobramycin. Bacterial Resistance Resistance to aminoglycosides is primarily caused by inactivation of the drugs by bacterial enzymes that combine the drugs with acetate, phosphate, or adenylate. Resistance to aminoglycosides can also be caused by decreased binding of the drugs to the 30S ribosomal subunit or to decreased uptake of the drugs by porins in bacterial membranes (Table 39-3). Adverse Effects the most serious adverse effects of aminoglycosides are nephrotoxicity and ototoxicity. The risk of toxicity is related to the dosage and duration of treatment and varies with the specific drug. Irreversible toxicity can occur, even after use of the drug is discontinued, but serious toxicity is less likely if the offending drug is discontinued at the earliest sign of dysfunction. When the drugs accumulate in proximal tubule cells, they can cause acute tubular necrosis. These effects impair renal function and lead to a rise in plasma concentrations of the aminoglycosides. The elevated drug concentrations can further impair renal function and contribute to ototoxicity. Increasing the interval between doses to 24 hours or longer in persons with impaired renal function decreases the likelihood of toxicity. Ototoxicity is associated with the accumulation of aminoglycosides in the labyrinth and hair cells of the cochlea and has been attributed to activation of caspase-dependent apoptosis (programmed cell death) in hair cells. Manifestations of vestibular toxicity include dizziness, impaired vision, nystagmus, vertigo, nausea, vomiting, and problems with postural balance and walking. Cochlear toxicity is characterized by tinnitus and hearing impairment and can lead to irreversible deafness. Often, a delay occurs between drug administration and the onset of symptoms, so many hospitalized patients are ambulatory before signs of toxicity appear. The aminoglycosides vary in their tendency to cause cochlear or vestibular toxicity. Amikacin produces more cochlear toxicity (deafness), whereas gentamicin and streptomycin cause more vestibular toxicity. Neomycin is the most nephrotoxic aminoglycoside, and its use is limited to topical treatment of superficial infections. Neomycin is available in ointments and creams in combination with bacitracin and polymyxin. These triple-antibiotic preparations have been shown to prevent infections after minor skin trauma. Bacitracin provides gram-positive coverage, polymyxin provides gram-negative coverage, and neomycin is active against both gram-positive and gram-negative organisms. Neomycin can elicit hypersensitivity reactions, especially with long-term administration, and products containing only bacitracin and polymyxin are also available. Tetracyclines Chemistry and Pharmacokinetics the tetracycline antibiotics are four-ring anthracycline compounds produced by Streptomyces species. Doxycycline, minocycline, and tetracycline are semisynthetic derivatives of older tetracyclines, whereas tigecycline is a semisynthetic glycylcycline compound. The properties and clinical uses of these drugs are outlined in Tables 39-1 and 39-2. In this condition, antibiotics suppress the growth of Propionibacterium acnes, an organism found on the skin that can infect sebaceous glands. This organism converts sebum triglycerides to fatty acids, which then cause skin irritation and contribute to sebaceous gland inflammation and the formation of comedones. Minocycline is often used for the treatment of acne because of its excellent penetration of the skin. Doxycycline and minocycline have also been used to treat skin and soft tissue infections caused by methicillin-resistant Staphylococcus aureus (Table 39-4). Tetracyclines are also used in the treatment of brucellosis, ehrlichiosis, and granuloma inguinale. Whereas oral rehydration therapy is the most important treatment modality for persons with severe diarrhea caused by Vibrio cholerae, a tetracycline can be used to shorten the course of cholera and reduce the risk of disease transmission to other persons. A tetracycline is included in some regimens to treat peptic ulcers caused by Helicobacter pylori. Bacterial Resistance Although tetracyclines inhibit the growth of a wide range of bacteria, they are no longer used to treat infections caused by many common pathogens because strains of these organisms have become resistant. Resistance to tetracyclines is caused by the transmission of plasmids containing resistance factors by bacterial conjugation. The resistance factors include genes that express modified bacterial porins that do not permit uptake of the tetracyclines. Resistance can also result from increased drug efflux, altered target binding, and enzymatic inactivation. The practice of including tetracyclines in animal feeds to promote weight gain has contributed to the development and transmission of tetracycline resistance around the the oral bioavailability of the tetracyclines varies from 70% for tetracycline to over 90% for doxycycline and minocycline. All tetracyclines bind divalent and trivalent cations, including calcium, aluminum, and iron. For this reason, their oral bioavailability is reduced if they are taken with foods or drugs containing these ions. Dairy products reduce the oral bioavailability of tetracycline but have little effect on the bioavailability of doxycycline and minocycline. None of the tetracyclines, however, should be taken with antacids or iron supplements. The tetracycline drugs undergo minimal biotransformation and are excreted primarily in the urine and feces. Unlike other tetracyclines, doxycycline is not dependent on renal elimination, and doses do not need to be adjusted in persons with renal insufficiency. Spectrum and Indications the tetracyclines are broad-spectrum, bacteriostatic drugs that inhibit the growth of many gram-positive and gramnegative organisms, rickettsiae, spirochetes, mycoplasmas, chlamydiae, and protozoa. Tetracyclines are the drugs of choice for Rocky Mountain spotted fever and other infections caused by Rickettsia species. They are also used for the treatment of two spirochetal infections, Lyme disease and relapsing fever, which are caused by Borrelia burgdorferi and Borrelia recurrentis, respectively. Tetracyclines are alternatives to macrolides to treat infections caused by Mycoplasma pneumoniae. For most genital infections caused by Chlamydia trachomatis, a 7-day course of oral doxycycline is effective. For pelvic inflammatory disease caused by chlamydiae, intravenous doxycycline may be necessary. This practice continues to promote microbial resistance to other antimicrobial agents. Adverse Effects Tetracyclines can cause many adverse effects, including several that are potentially life-threatening. These effects, however, can be avoided in most cases by avoiding their use in susceptible patients. Their use by pregnant women or children under 8 years of age can cause discoloration of the teeth and hypoplasia of the enamel. In affected children, yellow-brown or gray mottling of a significant portion of the enamel of the front teeth occurs and is cosmetically unattractive. Tetracyclines can cause potentially severe nephrotoxicity and hepatotoxicity in the form of fatty degeneration. Both of these reactions are rare, but the fact that pregnant women are at increased risk of hepatotoxicity is another reason for not administering tetracyclines to this population. Use of tetracyclines potentiates the nephrotoxicity of aminoglycosides and other nephrotoxic drugs and should be avoided in patients undergoing treatment with these other drugs. Tetracyclines are slowly degraded in pharmaceutical preparations to products that are more nephrotoxic than the parent drug. For this reason, tetracycline preparations must be used or discarded by their expiration date. Tetracyclines sometimes cause photosensitivity in individuals who are exposed to the sun during therapy. This adverse effect results from the absorption of ultraviolet radiation by the tetracycline after its accumulation in the skin. The activated drug then emits energy at a lower frequency that damages skin tissue, leads to erythema, and either exacerbates sunburn or causes a reaction similar to sunburn. Doxycycline is more frequently associated with photosensitivity than are tetracycline and minocycline. Tigecycline is a glycylcycline antibiotic that is a semisynthetic derivative of minocycline. This unique compound has increased affinity for the 30S ribosomal subunit and decreased susceptibility to resistance mechanisms that affect other tetracyclines. Tigecycline is indicated for treatment of complicated skin and soft tissue infections caused by methicillin-sensitive S. It is also approved for treating community-acquired pneumonia and complicated intra-abdominal infections caused by various gram-positive and gram-negative organisms. Azithromycin and clarithromycin are semisynthetic derivatives of erythromycin that have improved pharmacokinetic properties and antibacterial activity. Macrolides are usually administered orally, but erythromycin and azithromycin are available in intravenous formulations for the treatment of serious infections such as Legionnaire disease. Azithromycin and clarithromycin are reliably absorbed from the gut, have a greater degree of bioavailability, and achieve higher tissue concentrations (see Table 39-1). Erythromycin also has a shorter half-life than other macrolides and is administered two to four times a day. The macrolides undergo variable degrees of hepatic metabolism and are excreted in the bile and urine. Spectrum and Indications the macrolides are active against many gram-positive and gram-negative bacteria that cause upper respiratory tract infections and pneumonia, including group A streptococci, pneumococci, chlamydiae, M. Azithromycin is also active against pathogens responsible for sinusitis, otitis media, and bronchitis. Macrolides have little activity against gram-negative bacteria such as Klebsiella pneumoniae that typically cause pneumonia in neonates, elderly persons, and chronic alcoholics. As shown in Table 39-2, some macrolides are active against chlamydiae and are effective in treating pneumonia and genitourinary tract infections caused by Chlamydia pneumoniae and C. Indeed, azithromycin is an effective single-dose treatment for uncomplicated chlamydial urethritis. Either azithromycin or clarithromycin can be used to treat Mycobacterium aviumintracellulare infections, such as those occurring in patients with acquired immunodeficiency syndrome. As discussed in Chapter 28, clarithromycin is used in combination with other antibiotics and a gastric acid inhibitor to treat this condition. Bacterial Resistance Resistance to macrolide antibiotics has gradually increased over several decades. Acquired resistance to macrolides can result from decreased binding to the 50S ribosomal subunit, enzymatic inactivation, and increased bacterial efflux. Most strains of staphylococci are now resistant, and pneumococci are increasingly resistant to macrolides. Many pneumococcal strains express the macrolide efflux (mef [A]) transporter, and about 30% of pneumococcal isolates from all over the world are resistant to macrolides. Staphylococcal resistance is often associated with the erm gene, which is inducible by erythromycin and which confers resistance to macrolides, clindamycin, and quinupristin. Their most common adverse effects are stomatitis, heartburn, nausea, anorexia, abdominal discomfort, and diarrhea. The properties and major clinical uses of these drugs are compared in Tables 39-1 and 39-2. Chemistry and Pharmacokinetics Each macrolide antibiotic consists of a large 14-atom ring with two attached sugars.

Crack cocaine becomes aerosolized when it is heated order glyset overnight, and inhaling the substance into the lungs causes it to be rapidly absorbed into the circulation generic 50mg glyset otc. Inhalation of crack cocaine produces serum levels that are comparable to those obtained by intravenous administration of the drug quality 50 mg glyset. For this reason order line glyset, crack cocaine produces a euphoric effect that is more intense than that obtained by snorting cocaine purchase 50 mg glyset mastercard. The higher serum levels achieved with crack cocaine use also increase the potential for overdose toxicity purchase glyset 50 mg, particularly during repeated administration. Unlike other drugs of abuse, cocaine can alter tactile sensation, causing its users to feel as if insects were crawling under their skin (cocaine bugs) and causing them to scratch and produce self-inflicted skin lesions. Cocaine often stimulates respiration at lower doses, and high doses can produce irregular breathing and apnea known as Cheyne-Stokes respiration. With frank overdoses, the potential for neurotoxicity and cardiac toxicity increases. Cocaine overdose victims often experience delirium and can become aggressive and violent. In some cases, cocaine overdose causes tonic-clonic seizures (including status epilepticus), malignant encephalopathy, or myocardial infarction. When fatalities occur, they typically result from ventricular fibrillation or cardiac arrest. For this reason, the management of cocaine overdose must include cardiovascular and pulmonary support, as well as the administration of a benzodiazepine. Cocaine withdrawal produces fatigue, depression, nightmares or other sleep disturbances, and increased appetite. Bromocriptine, a dopamine receptor agonist (see Chapter 24), has been used to reduce craving for the drug, but the effectiveness of this treatment for withdrawal has not been firmly established. Chapter 25 y Drugs of Abuse ingesting caffeine tablets, but abuse of caffeine tablets is limited by the fact that large doses of them produce such unpleasant symptoms. The manifestations of caffeine withdrawal are relatively mild; they include headache, impaired concentration, irritability, depression, anxiety, flulike symptoms, and blurred vision. The withdrawal symptoms can be lessened by reducing caffeine consumption gradually over a period of several weeks. The recently discovered endogenous ligand for cannabinoid receptors is called anandamide (from ananda, the Sanskrit word for bliss). Thereafter it declines slowly, owing to metabolism and excretion in the urine and feces. The stimulant phase is described as a dreamlike euphoric state characterized by an altered sense of time, increased visual acuity, difficulty in concentrating, and impaired short-term memory. The depressive phase is characterized by drowsiness, lethargy, and increased appetite. The psychoactive effects of marijuana depend somewhat on the environment and the extent of prior use of the drug. For example, first-time users are more likely to experience anxiety than are habitual users. Marijuana has been implicated as the cause of an amotivational syndrome that is characterized by a lack of desire to work or excel in any part of life. It has also been described as a gateway drug whose initial use leads to the subsequent use of other drugs. Marijuana, however, causes minor decreases in the levels of testosterone in men, low birth weight in neonates, increased fetal malformations, and decreased ovulation in females. There is also some evidence linking marijuana use in adolescents to schizophrenia, although these data are controversial. Experimental studies have demonstrated that cannabinoids are effective in the treatment of asthma, glaucoma, and nausea and vomiting. This is because their use causes bronchodilation, decreased intraocular pressure, and inhibition of nausea. More recently, nabilone (Cesamet), another cannabinoid agonist, was also approved for the same indications. Proponents of medical marijuana maintain that the products of the natural product are superior to isolated compounds, and a number of states now allow the operation of medical marijuana clinics in spite of being in violation of federal law. The common signs and symptoms of marijuana intoxication and withdrawal are listed in Tables 25-1 and 25-3. Prescription drugs, fever, and disorders such as schizophrenia are all capable of causing hallucinations, which are false perceptions that result from abnormal sensory processing. These street drugs are taken orally and usually begin to produce hallucinations within an hour. Visual hallucinations often follow a temporal pattern in which amorphous bursts of light are followed by geometric forms and then by faces or scenes. Some users also report the occurrence of synesthesia, a condition in which one sensory modality assumes the characteristics of another. In a synesthetic hallucination, for example, sounds may be seen or colors may be heard. If mood changes occur, they are generally an exaggeration of the predrug mood and are highly context dependent. They are usually pleasant, but they can be terrifying and cause sufficient anxiety to resemble a panic attack. Mood changes are accompanied by somatic signs of sympathetic activation, including increased heart rate, increased blood pressure, and dilated pupils. They are classified as controlled substances, making it illegal to possess an anabolic steroid without a prescription. Unlike other drugs of abuse, there is not an immediate rush or euphoria experienced by the steroid abuser. Abuse of steroids is driven by desires to change physical appearance and increase athletic ability. Anabolic steroids can lead to heart attack, stroke, hepatic toxicity, renal failure, and serious psychiatric problems. In females, steroid abuse results in growth of facial hair, menstrual cycle dysfunction, enlargement of the clitoris, and reduced breast size. There is also evidence that steroid abuse contributes to violent crime owing to increased aggression associated with users of anabolic steroids. Most unfortunate, media reports of a number of celebrity athletes exposed as having used steroids send a dangerous message to youth who often revere these athletes as role models. Overdoses are rarely serious, but the occasional panic attack ("bad trip") may require intervention that consists of removing the patient to a quiet room and having someone remain with the patient for reassurance. The drug is incompletely and erratically absorbed from the gut, so it is usually smoked. As shown in Table 25-1, these effects include euphoria, hallucinations, and psychotomimetic activity, sometimes accompanied by hostility and violent behavior. It is estimated that 48 million people ages 12 and older have used prescription drugs for nonmedical reasons. Most alarming is the fact that recent government data showed that nearly 20% of young teenagers reported using opioids (Vicodin or OxyContin) without a prescription, making these medications among the most commonly abused drugs by adolescents, second only to marijuana. Drug dealers routinely sell prescription drugs in additional to their illicit wares. Accessibility is likely a contributing factor, with a growing number of medications available in the home medicine cabinet and through some online pharmacies that dispense medications without prescriptions and without identity verification, allowing minors to order the medications easily over the Internet. Unintentional fatal drug overdoses nearly doubled from 1999 to 2004 and are now the leading cause of accidental death in the United States, surpassing deaths from automobile accidents in 2012. For the first time since records were kept, more than half of drug overdose admissions to hospital emergency rooms were a result of overdose of prescription drugs, rapidly eclipsing the number of admissions for illicit drug overdose. Educational efforts by governmental agencies, by the media, and by physicians are making an impact, and the pharmaceutical companies are developing formulations that will make overdose on prescription drugs less likely. An example of this is the new formulation of the potent opioid oxycodone in a crushproof tablet (see Chapter 23). Although attention in the drug abuse field is focused on the nonmedical use of prescription drugs, alcohol, tobacco, or illegal drugs, there are increasing numbers of children and adolescents abusing the most easily obtained mind-altering substances: household solvents, sprays, and cleaners. According to nationwide studies, over 15% of eighth graders reported using inhalants to "get high. Regular inhalant abuse results in toxicity to the brain, heart, kidneys, and liver. Products such as nail polish remover, lighter fluid, spray paints, deodorant and hair sprays, pressurized air cleaners, and any type of liquid fuel are soaked in rags or emptied in plastic bags, and their concentrated vapors inhaled, a practice called huffing or sniffing. The latest reports indicate that the organic solvents in these products, such as toluene, activate the dopamine system much like any other abused drug, leading to repeated administration and drug dependence. The severity of these problems varies markedly among different classes of drugs and patterns of drug use. They are available in tablets, in the initial treatment of drug intoxication or overdose consists of supporting cardiovascular and pulmonary functions. Chapter 25 y Drugs of Abuse Lorazepam can be used to control agitation, and an antipsychotic drug. Haloperidol should not be used in cases of cocaine overdose, however, because it lowers the seizure threshold and can exacerbate or precipitate seizures. The next stage of treatment is the management of withdrawal reactions that occur as the drug is eliminated from the body. The pharmacologic treatment of withdrawal consists primarily of substitution therapy and symptomatic relief. Methadone is usually used to suppress withdrawal reactions in opioid users because it is long acting and orally effective. Methadone is also given on a long-term basis in outpatient treatment of heroin dependence (see later). Clonidine, an 2-adrenoceptor agonist, is effective in reducing the sympathetic nervous system symptoms of alcohol, opioid, or nicotine withdrawal, and it may facilitate continued abstinence in persons who are dependent on these drugs. After treatment of drug intoxication and withdrawal, attention can be directed to the more difficult problem of treating drug dependence. In this endeavor, behavioral therapy and personal motivation are as important as subsequent pharmacologic treatments. Patients are rarely cured, and most clinicians view treatment as a lifelong process in which patients are continually recovering. Twelve-step groups, such as Alcoholics Anonymous and Narcotics Anonymous, have been successful in reducing recidivism, partly because they recognize that the individual is always in a state of remission from drug or alcohol dependence and that an ever-present possibility exists of slipping into drug use again. Among the pharmacologic agents used for the treatment of alcohol dependence is disulfiram, a drug that inhibits acetaldehyde dehydrogenase. When disulfiram is taken and ethanol subsequently ingested, the accumulation of acetaldehyde causes nausea, profuse vomiting, sweating, flushing, palpitations, and dyspnea. Because of its ability to cause these extremely unpleasant symptoms, disulfiram is sometimes prescribed to encourage alcoholic patients to abstain from ethanol use. Other drugs that can cause disulfiram-like effects when administered concurrently with ethanol include metronidazole (a drug used in the treatment of protozoal infections) and some of the third-generation cephalosporin antibiotics. Recently, a new dependence medication for alcohol called acamprosate calcium was approved. The mechanism of action of acamprosate in maintenance of alcohol abstinence is not completely understood. Chronic alcohol exposure is hypothesized to alter the normal balance between neuronal 269 Treatment of Drug Dependence excitation and inhibition. Methadone maintenance therapy for the treatment of heroin dependence began in the 1960s and has been successful in terms of decreasing crime associated with illicit drug use and transmission of infectious disease from shared needles. However, owing to the decrease in public funding and long patient waiting lists, the need for daily clinic visits and supervised administration, and the stigma attached to the methadone clinic, this method for providing opioid substitution therapy for heroin and opioid dependency is insufficient to meet the needs of all patients. It lasts about 3 days and therefore requires fewer visits to the clinic than methadone. Buprenorphine was recently approved for physician outpatient treatment of opioid dependence to overcome the limitations of visits to a treatment clinic. It is formulated in a sublingual tablet or oral form in combination with naloxone (Suboxone) to prevent intravenous abuse. Naltrexone is available in oral (ReVia, Depade) and extended-release injectable suspension (once a month; Vivitrol) formulations and is used to treat alcohol and opioid dependence. For opioid-dependent patients, naltrexone directly blocks opioid receptors and prevents the euphoria associated with opioid abuse. It is effective for the treatment of alcohol dependence, because endogenous opioid systems play a key role in the pathway that leads to reinforcement of alcohol and other drugs. Clonidine, a centrally acting 2-agonist, is used to facilitate withdrawal from opioids and nicotine. Nicotine chewing gum, lozenges, and skin patches have been developed to mitigate nicotine withdrawal reactions in persons who are trying to quit smoking. Another drug used to treat nicotine dependence is the antidepressant bupropion (Zyban), now available in a long-acting formulation for this purpose. The ability of bupropion to block the reuptake of dopamine may contribute to its effectiveness in treating drug dependence. The combined use of bupropion and nicotine patches is currently being investigated. Recently, varenicline (Chantix) was approved for smoking cessation and shows a relatively high degree of success. The efficacy of varenicline is believed to be the result of partial agonist activity, with simultaneous prevention of the full agonist nicotine binding to 42receptors. Food and Drug Administration strengthened the warnings that in patients taking varenicline, serious neuropsychiatric symptoms have occurred, including agitation, depressed mood, suicidal ideation, and attempted and successful suicide. Spurred on by both the commercial and medical success of bupropion and varenicline for smoking cessation, government and industry leaders are awakening to the treatment needs of drug-dependent individuals. Many anticraving agents and pharmacologic approaches are currently in development.

Intra-aortic balloon pump counterpulsation in the management of concomitant cerebral vasospasm and cardiac failure after subarachnoid hemorrhage: technical case report generic glyset 50mg online. Intraaortic balloon counterpulsation augments cerebral blood flow in the patient with cerebral vasospasm: a xenon-enhanced computed tomography study buy discount glyset 50mg online. Intraaortic balloon counterpulsation augments cerebral blood flow in a canine model of subarachnoid hemorrhage-induced cerebral vasospasm 50mg glyset amex. Perfusion augmentation in stroke using controlled aortic obstruction: pilot study results buy glyset 50 mg with mastercard. Partial aortic obstruction improves cerebral perfusion and clinical symptoms in patients with symptomatic vasospasm buy cheap glyset. Use of the peak troponin value to differentiate myocardial infarction from reversible neurogenic left ventricular dysfunction associated with aneurysmal subarachnoid hemorrhage order glyset 50 mg on-line. Incidence and significance of early aneurysmal rebleeding before neurosurgical or neurological management. Impact of a protocol for acute antifibrinolytic therapy on aneurysm rebleeding after subarachnoid hemorrhage. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Sinking skin flaps, paradoxical herniation, and external brain tamponade: a review of decompressive craniectomy management. Sinking skin flap syndrome and paradoxical herniation secondary to lumbar drainage. The time of onset of symptoms was established as approximately 20 minutes before arrival. Nonmodifiable risk factors include advanced age, male gender, and African American race and Japanese ethnicity. Other risk factors include cocaine use, low cholesterol levels, oral anticoagulants, and excessive alcohol abuse. Analyses of brain tissue have indicated the presence of microscopic and macroscopic bleeding in the area surrounding the fatal hemorrhage, perhaps representing ruptured arterioles or venules. Similarly, the association between early hematoma growth and irregular clot morphology, which may reflect multifocal bleeding, has been reported. In these studies, the incidence of hematoma growth was greater in patients with irregularly shaped hematomas compared with those with round hematomas, and it was postulated that the irregular shape indicated bleeding from multiple arterioles. Failure to recognize imminent airway loss may result in complications, such as aspiration, hypoxemia, and hypercapnia. Both agents are short acting and should not obscure the neurologic examination for a prolonged period of time. Succinylcholine is the most commonly administered muscle relaxant owing to its rapidity of onset (30-60 seconds) and short duration (5-15 minutes). Level A, based on multiple high-quality randomized controlled trials; level B, based on single randomized trial or nonrandomized studies; level C, based on case reports and series, and expert opinion. Measuring and improving quality of care: a report from the American Heart Association/American College of Cardiology First Scientific Forum on Assessment of Healthcare Quality in Cardiovascular Disease and Stroke. Clinical review: critical care management of spontaneous intracerebral hemorrhage. Isotonic fluid resuscitation and vasopressors may be indicated in patients who are in shock. An expanding hematoma may result from persistent bleeding and/or rebleeding from a single arteriolar rupture. Some studies have reported evidence of hematoma growth from bleeding into an ischemic penumbra zone surrounding the hematoma, but other reports have not confirmed the existence of ischemia at the hypo-perfused area in the periphery of the hematoma. Some studies have demonstrated that a controlled, pharmacologically based reduction in blood pressure has no adverse effects on cerebral blood flow in humans or animals. In mechanically ventilated patients, in addition, the need for head elevation should be guided by changing pulmonary and volume needs. Good long-term outcomes can occur when the combination of osmotherapy and hyperventilation is successfully used to reverse transtentorial herniation. These two techniques require expertise, advanced tools, and continuous monitoring of cerebral electrical activity and may be associated with significant complications. A state of euvolemia should be maintained by monitoring fluid balance and body weight and by maintaining a normal central venous pressure (range, 5 to 8 mm Hg). Potential complications of hypertonic saline use are encephalopathy, subdural hematomas, coagulopathy, fluid overload, hypokalemia, cardiac arrhythmias, and hyperchloremic metabolic acidosis. Nutrition As is the case with all critically ill neurologic patients, enteral feeding should be started within 48 hours to avoid protein catabolism and malnutrition. Emergency Hemicraniectomy Hemicraniectomy with duraplasty has been proposed as a lifesaving intervention for several neurologic catastrophes such as malignant middle cerebral artery infarction and poor-grade subarachnoid hemorrhage. Improvement in neurologic outcome at 14 days and at 3 months was better in the treatment group, although no differences were seen in long-term mortality. More aggressive blood pressure reduction may be preferable and is currently under study. Cocaine use and hypertension are major risk factors for intracerebral hemorrhage in young African Americans. Clinical features and functional outcome of intracerebral hemorrhage in patients aged 85 and older. Serum cholesterol levels and six-year mortality from stroke in 350,977 men screened for the multiple risk factor intervention trial. Heavy drinking, but not moderate or intermediate drinking, increases the risk of intracerebral hemorrhage. Cerebrovascular complications of the use of the "crack" form of alkaloidal cocaine. Risk factors for intracerebral hemorrhage in the general population: a systematic review. The risk of intracerebral hemorrhage during oral anticoagulant therapy: a population study. Relative edema volume is a predictor of outcome in patients with hyperacute spontaneous intracerebral hemorrhage. Use of the original, modified, or new intracerebral hemorrhage score to predict mortality and morbidity after intracerebral hemorrhage. Multivariate analysis of predictors of hematoma enlargement in spontaneous intracerebral hemorrhage. Three-dimensional computerized tomography angiography in patients with hyperacute intracerebral hemorrhage. Simultaneous bleeding from multiple lenticulostriate arteries in hypertensive intracerebral haemorrhage. Efficacy of standard dose and 30 ml/kg fresh frozen plasma in correcting laboratory parameters of haemostasis in critically ill patients. Effects of rocuronium and vecuronium on intracranial pressure, mean arterial pressure and heart rate in neurosurgical patients. Guidelines for the management of spontaneous intracerebral hemorrhage: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Reversible ischemia around intracerebral hemorrhage: a single-photon emission computerized tomography study. Acute pharmacological hypotension after intracerebral hemorrhage does not change cerebral blood flow. Pharmacologic reduction of mean arterial pressure does not adversely affect regional cerebral blood flow and intracranial pressure in experimental intracerebral hemorrhage. Effect of systolic blood pressure reduction on hematoma expansion, perihematomal edema, and 3-month outcome among patients with intracerebral hemorrhage: results from the antihypertensive treatment of acute cerebral hemorrhage study. Neurologic deterioration in noncomatose patients with supratentorial intracerebral hemorrhage. Mechanical ventilation for ischemic stroke and intracerebral hemorrhage: indications, timing, and outcome. Prediction of death in patients with primary intracerebral hemorrhage: a prospective study of a defined population. Volume of ventricular blood is an important determinant of outcome in supratentorial intracerebral hemorrhage. Outcome in 200 consecutive cases of severe head injury treated in San Diego County: a prospective analysis. Hypertensive caudate hemorrhage prognostic predictor, outcome, and role of external ventricular drainage. Effects of cisatracurium on cerebral and cardiovascular hemodynamics in patients with severe brain injury. Intensive insulin therapy exerts antiinflammatory effects in critically ill patients and counteracts the adverse effect of low mannose-binding lectin levels. Hyperthermia is not an independent predictor of greater mortality in patients with primary intracerebral hemorrhage. Hyperthermia delayed by 24 hours aggravates neuronal damage in rat hippocampus following global ischemia. The effect of mild hyperthermia and hypothermia on brain damage following 5, 10, and 15 minutes of forebrain ischemia. Clinical trial of an aircirculating cooling blanket for fever control in critically ill neurologic patients. Use of hypertonic saline solutions in treatment of cerebral edema and intracranial hypertension. Treatment of transtentorial herniation unresponsive to hyperventilation using hypertonic saline in dogs: effect on cerebral blood flow and metabolism. Admission blood glucose and short term survival in primary intracerebral haemorrhage: a population based study. Effects of admission hyperglycemia on mortality and costs in acute ischemic stroke. Early surgical treatment for supratentorial intracerebral hemorrhage: a randomized feasibility study. Intraventricular hemorrhage and hydrocephalus after spontaneous intracerebral 51 105. Endoscopic surgery versus medical treatment for spontaneous intracerebral hematoma: a randomized study. How safely and for how long can warfarin therapy be withheld in prosthetic heart valve patients hospitalized with a major hemorrhage She then exhibited stereotypical picking behavior of her clothes followed by head deviation to the right and generalized tonic-clonic arm and leg movements lasting approximately 3 minutes. Her pupils are bilaterally reactive to light, and she has an intact oculocephalic reflex and intact corneal reflexes. She localizes to painful stimulation with the left arm but does not move the right side. Furthermore, observations have shown that most isolated clinical and electrographic seizures last less than 5 minutes, and prolonged seizures beyond this time typically are not self-resolving. Classic clinical features can range from obvious positive signs of rhythmic jerking and posturing, to more subtle positive symptoms of twitching, nystagmus, automatisms, and eye deviation. Negative symptoms of seizures include staring, coma, lethargy, confusion, and aphasia. Initiation of treatment should begin immediately, and the situation should be managed as a neurologic emergency. Hypoglycemia should be recognized early because hypoglycemic seizures will respond only to glucose administration and permanent damage will result if not corrected rapidly (Table 3-1). Target Serum Level: total 15-25 g/mL, free level 2-3 g/mL (monitor free level when on valproate, benzodiazepines, other highly protein-bound medications, low albumin or critically ill), adjustments if free level not available: total level/(Alb 0. If patient continues having seizures after 20 mg/kg, an additional 5-10 mg/kg may be given. Maintenance: 5-7 mg/kg/d in 2-3 divided doses Onset of Action: 20-25 min (can be given faster than phenytoin but needs to be converted to phenytoin prior to onset of action, which takes approximately 15 min) Main Side Effect: see phenytoin, additionally transient pruritus from solvent. In combination with phenobarbital, valproate can cause severe impaired mental status. Main Side Effect: Hepatotoxicity, thrombocytopenia, pancreatitis, hyperammonenic encephalopathy (consider L-carnitine 33 mg/kg q8h), fibrinogen levels. Target Serum Levels: Total: 80-140 g/mL, free: 4-11 g/mL (only consider if toxicity suspected) 5. However, as stated earlier, previous trials have established the safety of therapeutic doses of benzodiazepines. In what circumstance should another antiepileptic medication be given, and which medication should be chosen Despite this, phenytoin/ fosphenytoin (Table 3-2) is recommended by most neurologists. A recent meta-analysis has suggested that agents such as levetiracetam and valproate are more efficacious than the historically preferred phenytoin. An additional retrospective comparative review of phenytoin, valproate, and levetiracetam has also revealed the efficacy of valproate over phenytoin; however, it has also revealed that levetiracetam may be the least efficacious of these three. Our patient receives total of 4 mg lorazepam, is loaded with 20 mg/kg of fosphenytoin, and is intubated for airway protection. Medical stability: Hypotension and arrhythmias may be seen during loading with phenytoin or fosphenytoin. Hemodynamic monitoring may require the placement of an arterial line or central line if not done already. Diagnostic work up: the underlying differential is wide (Tables 3-3 and 3-4), and the diagnostic workup should be individualized depending on the clinical scenario (Table 3-5). Empiric treatment with bacterial and viral coverage should be started until the lumbar puncture and additional imaging results are available. These two processes appear to be interrelated, causing a hyperexcitable cascade, but their exact pathophysiologic mechanism has yet to be determined. Frequently used agents include continuous drips of midazolam, propofol, or pentobarbital (Table 3-6).

The osmolar gap should be calculated in patients receiving lorazepam doses > 1 mg/kg/d order glyset overnight delivery. Characteristic findings include progressive lactic acidosis (an important warning sign) discount 50mg glyset mastercard, triglyceride elevations order discount glyset line, and arrhythmias; death is usually due to intractable cardiac failure cheap glyset 50mg line. Patients quickly return to the level of sedation they were at prior to its administration cheap glyset uk. To achieve a longer effect order generic glyset from india, repeated doses or continuous infusion is usually necessary. However, it is more prudent to restrict the use of flumazenil to confirming a diagnosis of lorazepam overdose and then supporting the patient to allow ultimate elimination of the benzodiazepine. Among the common undesired side effects are nausea, vomiting, pruritus, urinary retention, delayed gastric emptying, suppression of bowel motility, constipation, and ileus. In contrast to naloxone, these medications do not cross the blood-brain barrier and, therefore, do not antagonize the central (analgesic) effects of opioids. They act on peripheral receptors only, blocking side effects such as constipation and ileus, while preserving analgesia. Remifentanil versus morphine analgesia and sedation for mechanically ventilated critically ill patients: a randomized double blind study. A protocol of no sedation for critically ill patients receiving mechanical ventilation: a randomised trial. Early intensive care sedation predicts long-term mortality in ventilated critically ill patients. Generalised clonic tonic seizures triggered by anaesthesia with propofol and sevoflurane [in Spanish]. The evolution of pain management in the critically ill trauma patient: emerging concepts from the global war on terrorism. Remifentanilinduced postoperative hyperalgesia and its prevention with small-dose ketamine. Propofol-ketamine technique: dissociative anesthesia for office surgery (a 5-year review of 1264 cases). Central nervous system effects of subdissociative doses of (S)-ketamine are related to plasma and brain concentrations measured with positron emission tomography in healthy volunteers. Mapping of punctuate hyperalgesia around a surgical incision demonstrates that ketamine is a powerful suppressor of central sensitization to pain following surgery. The Richmond Agitation-Sedation Scale: validity and reliability in adult intensive care unit patients. Understanding posttraumatic stress disorder-related symptoms after critical care: the early illness amnesia hypothesis. Evaluating pain, sedation, and delirium in the neurologically critically ill-feasibility and reliability of standardized tools: a multi-institutional study. Pain assessment in the critically ill ventilated adult: validation of the Critical-Care Pain Observation Tool and physiologic indicators. Pharmacokinetics and haemodynamics of ketamine in intensive care patients with brain or spinal cord injury. The effects of ketamine-isomers on neuronal injury and regeneration in rat hippocampal neurons. The effects of small-dose ketamine on morphine consumption in surgical intensive care unit patients after major abdominal surgery. S(+)ketamine as an analgesic adjunct reduces opioid consumption after cardiac surgery. Mechanisms of hyperalgesia and morphine tolerance: a current view of their possible interactions. Clinical monitoring scales in acute brain injury: assessment of coma, pain, agitation, and delirium. Suppression of shivering during hypothermia using a novel drug combination in healthy volunteers. Clonidine decreases vasoconstriction and shivering thresholds, without affecting the sweating threshold. Clonidine comparably decreases the thermoregulatory thresholds for vasoconstriction and shivering in humans. Dexmedetomidine and meperidine additively reduce the shivering threshold in humans. Biphasic concentration change during continuous midazolam administration in braininjured patients undergoing therapeutic moderate hypothermia. Mild hypothermia alters propofol pharmacokinetics and increases the duration of action of atracurium. Pharmacology of sedative-analgesic agents: dexmedetomidine, remifentanil, ketamine, volatile anesthetics, and the role of peripheral mu antagonists. The alpha2-adrenoceptor agonist dexmedetomidine converges on an endogenous sleep-promoting pathway to exert its sedative effects. Dexmedetomidine-induced sedation in volunteers decreases regional and global cerebral blood flow. Dexmedetomidine, an alpha 2-adrenergic agonist, decreases cerebral blood flow in the isoflurane-anesthetized dog. Effect of dexmedetomidine, a selective and potent alpha 2-agonist, on cerebral blood flow and oxygen consumption during halothane anesthesia in dogs. Effect of dexmedetomidine on cerebral blood flow velocity, cerebral metabolic rate, and carbon dioxide response in normal humans. Dexmedetomidine for the treatment of paroxysmal autonomic instability with dystonia. Effects of propofol on cerebral hemodynamics and metabolism in patients with brain trauma. Intracranial pressure in patients with craniocerebral trauma after administration of propofol and thiopental [in German]. Predictors of severe hypotension in neurocritical care patients sedated with propofol. A comparison of severe hemodynamic disturbances between dexmedetomidine and propofol for sedation in neurocritical care patients. Refractory generalized convulsions in a patient undergoing brain tumor resection during propofol anesthesia [in Japanese]. Comparative effects of propofol vs dexmedetomidine on cerebrovascular carbon dioxide reactivity in patients with septic shock. Prolonged dexmedetomidine infusion as an adjunct in treating sedation-induced withdrawal. Dexmedetomidine in the treatment of withdrawal syndromes in cardiothoracic surgery patients. Dexmedetomidine facilitates the withdrawal of ventilatory support in palliative care. Using dexmedetomidine to manage patients with cocaine and opioid withdrawal, who are undergoing cerebral angioplasty for cerebral vasospasm. Dexmedetomidine as an adjuvant in the treatment of alcohol withdrawal delirium: a case report. Dexmedetomidine infusion as adjunctive therapy to benzodiazepines for acute alcohol withdrawal. Subcutaneous dexmedetomidine infusions to treat or prevent drug withdrawal in infants and children. Use of dexmedetomidine to facilitate extubation in surgical intensive-care-unit patients who failed previous weaning attempts following prolonged mechanical ventilation: a pilot study. The effect on serum lipid concentrations of a prolonged infusion of propofol-hypertriglyceridaemia associated with propofol administration. The pathophysiology of propofol infusion syndrome: a simple name for a complex syndrome. Propofol and sufentanil titration with the bispectral index to provide anesthesia for coronary artery surgery. Bispectral index monitoring allows faster emergence and improved recovery from propofol, alfentanil, and nitrous oxide anesthesia. Bispectral Index monitoring correlates with sedation scales in brain-injured patients. The correlation between the Richmond agitation-sedation scale and bispectral index during dexmedetomidine sedation. Daily interruption of sedative infusions and complications of critical illness in mechanically ventilated patients. The long-term psychological effects of daily sedative interruption on critically ill patients. Daily sedative interruption in mechanically ventilated patients at risk for coronary artery disease. Daily interruption of sedative infusions in an adult medical-surgical intensive care unit: randomized controlled trial. Effects of the neurological wake-up test on intracranial pressure and cerebral perfusion pressure in braininjured patients. On examination, she requires mild sternal rub to remain awake and is able to follow simple, one-step commands. There are no cranial nerve abnormalities, but a mild left pronator drift is noted. While in the operating room, a left subclavian central line and radial arterial line is placed along with a right external ventricular drain. Postinjury elevations in temperature have been shown to increase inflammatory processes, including elevations in proinflammatory cytokines, the increased accumulation of polymorphonuclear leukocytes in injured tissue. Several studies also suggest that one of the key impacts of fever is an increase in neuronal excitotoxicity. Elevations in temperature have been reported to increase neurotransmitter release, accelerate free-radical production, increase intracellular glutamate concentrations, and potentiate the sensitivity of neurons to excitotoxic injury. The hypothalamus is a key center for thermoregulation, and damage to this structure can result in hyperthermia. A meta-analysis of all brain injury types found that fever was consistently associated with mortality and worse outcomes across multiple outcome measures of morbidity. Neurocritical Care Monitoring What are the initial management steps for fever in this patient The new onset of fever should trigger a careful diagnostic evaluation to find a source of infection. For example, patients presenting in coma who require emergent endotracheal intubation are likely at a higher risk for developing pneumonia from aspiration. Review of chest radiographs should focus on any evidence of new infiltrates or effusions. If the patient is endotracheally intubated or has a tracheotomy, obtain a sample of sputum for Gram stain either by blind suctioning or bronchoalveolar lavage. Central venous catheters that have been in place for > 96 hours should be removed, and the tip should be submitted for semiquantitative microbiology. Pharmacologic Interventions Endogenous pyrogens released by leukocytes in response to infection, drugs, blood products, or other stimuli cause fever by stimulating cerebral prostaglandin E synthesis and as a result raise the hypothalamic temperature set point. Therefore, they are more likely to be ineffective in brain-injured patients with impaired thermoregulatory mechanisms. Corticosteroids also have antipyretic properties but are not used clinically to treat fever because of their side effects. The majority of studies have been conducted in the pediatric population, where weight-adjusted doses have been shown to be effective in reducing fever. In the adult neurocritical care population, acetaminophen has been most widely studied in an attempt to maintain normothermia in patients with acute stroke. However, only one randomized, controlled study has been conducted in adult patients with brain injury, which demonstrated that ibuprofen (2400 mg/d) was not shown to be better than acetaminophen or placebo in maintaining normothermia after ischemic stroke. Nonpharmacologic Interventions External cooling External cooling reduces body temperature by promoting heat loss without affecting the hypothalamic set point. Four modes of heat transfer constitute the basis of interventions to promote heat loss: (1) evaporation (eg, water sprays or sponge baths); (2) conduction (eg, ice packs, water-circulating cooling blankets, immersion); (3) convection (eg, fans, air-circulating cooling blankets); and (4) radiation (ie, exposure of the skin). However, external cooling can result in reflex shivering and vasoconstriction as the body attempts to generate heat and counteract the cooling process. Few controlled studies have evaluated the efficacy of external cooling interventions for lowering body temperature in humans. One study compared the use of acetaminophen alone with tepid water sponging or with a water-circulating cooling blanket in febrile neurologic patients and found no difference between the three treatments. Each system works by utilizing tightly wrapped pads that circulate cold water to promote conductive heat loss. In a randomized controlled trial, 53 neurologically injured patients who had a fever (temperature 38. Despite having a slightly higher baseline mean temperature, patients treated with the advanced system experienced a 75% reduction in fever burden and became normothermic faster than the control group, despite a significantly higher rate of shivering. They all work to control fever by directly lowering the blood temperature with cooled saline, which circulates through balloons or channels around an intravascular catheter. Although there is no direct contact with the blood, the cold saline solution extracts heat from the blood, thus lowering body temperature. Therefore, the administration of large-volume cold saline could be considered during the induction phase of fever control. Preclinical and preliminary clinical data suggest that intraarterial cold infusions may induce highly selective and rapid decrease in brain temperatures without significantly affecting body core temperatures, thus potentially diminishing systemic side effects of therapeutic temperature management.