By U. Tippler. Art Center College of Design.
Repeated clinical assessment through the Glasgow Coma Scale (GCS) is the cornerstone of neurological evaluation cheap duphalac 100 ml. Ventilated head-injured patients with intracranial pathology on CT require ICP monitoring purchase 100 ml duphalac mastercard. Invasive or non-invasive neurospecific monitoring requires careful interpretation when assisting goal-directed therapies cheap duphalac 100 ml on line. Multimodal monitoring using a combination of techniques can overcome some of the limitations of individual methods purchase duphalac 100 ml overnight delivery. Cerebral Edema Nabil Kitchener Cerebral edema is a challenging problem in the neurocritical care setting. Different etiologies may cause increased intracranial pressure. Secondary brain injury may ensue as a result of cerebral edema, and may result in different herniation syndromes. Brain monitoring for increased intracranial pressure may by employed in certain patient populations. Serial neuroimaging may be useful in monitoring exacerbations of brain edema. Osmotherapy has been recommended for management of cerebral edema. Mannitol and hypertonic saline are the two agents widely used for this purpose. Knowledge of possible side effects of osmotherapeutic agents is necessary. Common concerns of such therapies include renal insufficiency, pulmonary edema, and exacerbation of congestive heart failure, hypernatremia, hemolysis, and hypotension. Specific measures as controlled ventilation, sedation and analgesia, pharmacologic coma, hypothermia and surgical decompression may be required in patient subpopulations. Important questions still need to be answered regarding the timing of the decompressive surgery and patient selection criteria. Surgical decompression may be applicable in certain patients. Recent studies indicate that surgical decompression may 80 | Critical Care in Neurology significantly reduce mortality in young patients with malignant cerebral infarcts. General medical management is focused toward limiting secondary brain damage. General measures include head and neck position, optimization of cerebral perfusion and oxygenation, management of fever, nutritional support and glycemic control. Abnormalities of intracranial pressure may result in pathology requiring urgent evaluation and intervention to prevent life- threatening consequences. This pathology may represent intracranial hyper- or hypotension, or it may manifest as an abnormality of cerebrospinal fluid (CSF) dynamics, such as hydrocephalus. Elevated intracerebral pressure is the final common pathway for almost all pathology leading to brain death, and interventions to treat ICP may preserve life and improve neurologic function after head trauma, stroke, or other neurologic emergencies. Common causes of raised intracranial pressure are shown in Table 7. Lead encephalopathy Hepatic coma Renal failure Diabetic ketoacidosis Burns Near drowning Hyponatremia Status epilepticus Types of Cerebral Edema Cerebral swelling or edema can complicate many intracranial pathologic processes including neoplasms, hemorrhage, trauma, autoimmune diseases, hyperemia, or ischemia. There are essentially three types of cerebral edema: 1. Cytotoxic edema is associated with cell death and failure of ion homeostasis. Cytotoxic edema results from energy failure of a cell as a result of hypoxic or ischemic stress, 82 | Critical Care in Neurology which leads to cell death. Intracellular swelling occurs and results in the CT and MR appearance of both gray and white matter edema, usually in the distribution of a vascular or borderzone territory after hypoxia or stroke. Vasogenic edema is associated with breakdown of the blood-brain barrier. Vasogenic edema represents breakdown of the blood-brain barrier, appears mostly in the white matter, and is more likely to be associated with neoplasms or cerebral abscesses. In reality, cerebral edema in many situations, usually exhibit a combination of vasogenic and cytotoxic edema. Interstitial (hydrostatic or hydrocephalic) edema is associated with hydrocephalus, in which there is increased tension of CSF across the ependyma. Interstitial edema, or transependymal flow, is radiographically seen with hypodense areas surrounding the ventricular system and is associated with increased CSF volume or pressure. In cytotoxic edema, osmotic therapy with mannitol and hypertonic saline may not reduce edema in the Cerebral Edema | 83 lesion itself, but may reduce the volume of normal brain allowing for some increased margin of safety by decreasing intracranial pressure (Raslan 2007). Steroids are of no value in cytotoxic edema due to stroke, and may be harmful in the settings of brain trauma. Surgical decompression of cytotoxic edema with decompressive craniectomy may be therapeutic, and life-saving (Hofmeijer 2009). Vasogenic edema responds to steroids and surgical resection of the lesion, and may also benefit from osmotic therapy with mannitol or hypertonic saline (Oddo 2009). Hydrostatic edema is treated surgically with CSF removal or shunting, and it is treated medically with agents to decrease production of CSF, such as acetazolamide and furosemide. General Neurological Treatment Strategies Magdy Khalaf, Nabil Kitchener The concept of neurocritical care has been developed to coordinate the management of critically ill neurological patients within a single specialist unit and to include clinical situations such as swallowing disturbances, respiratory problems management in neurocritical care, infection control in the unit, pain relief and sedation in some patients, as well as diagnosing brain death. Acute rehabilitation is important in securing improved long-term neurological outcomes after many brain insults, trauma, ischemia or hemorrhage. Intervention from neurophysiotherapists, as part of the neurocritical care multiprofessional team, must occur as early as possible. Respiratory muscle impairment is the most common reason for admission to the ICU in patients with neuromuscular disorders. Objective measures of respiratory muscle function are necessary because significant respiratory muscle impairment may exist despite a paucity of symptoms. Analgesia in the neurocritical care unit is indicated in many situations such as postoperative pain, traumatic injury, and subacute or chronic pains. Although it is mandatory and beneficial in many situations, precautions must be taken before General Neurological Treatment Strategies | 85 applying many agents; e. Some agents may cause decreased level of consciousness or obtundation leading to impairment of neurological exam. This chapter will cover management of these issues in the neurocritical care setting. Swallowing Disturbances Weakness, spasticity or both of the pharynx and tongue cause dysphagia and tendency for aspiration. A feeding tube through a percutaneous endoscopic gastrostomy (PEG), cervical esophagostomy or jejunostomy is a reliable method of patient feeding when prolonged deficit is expected.
Programmed cell death has several key characteris- School of Medicine buy duphalac 100 ml low price, Pittsburgh discount duphalac 100 ml without a prescription, Pennsylvania duphalac 100 ml for sale. Hickey: Department of Pediatrics purchase 100 ml duphalac, University of Pittsburgh tics: (a) The death process is active, and the expression of School of Medicine, Pittsburgh, Pennsylvania. CHARACTERISTICS OF NECROSIS AND PROGRAMMED CELL DEATH Necrosis Programmed Cell Death Process Passive Active Energy failure Primary Secondary Protein translation Blocked Exacerbates cell death Morphology Coagulative necrosis Apoptosis DNA fragmentation None or random, resulting in Occurs at histosome boundaries, either no migration or a resulting in multiples of 400 smear on DNA gels base fragments producing laddering on DNA gels Inflammation Prominent Little or none are normal until the final stages of cellular death; therefore, with little time or energy available for the synthesis of new energy failure is a late, secondary event in programmed cell gene products. The result is DNA fragments in multiples of may produce neuronal death with many of the characteris- 400 base pair size that produce characteristic 'laddering' tics of programmed cell death. Under programmed cell death results in neuronal death with little these circumstances, cleavage of genomic DNA into frag- or no accompanying inflammation. Thus, 'collateral dam- ments of various sizes on DNA gels, characteristic of pro- age' to neighboring cells is avoided. However, the most con- In contrast to programmed cell death, necrotic cell death vincing evidence that the production of new gene products is characterized by energy failure, which results in inhibition may be important in the pathogenesis of neuronal death of protein synthesis. Therefore, new gene products may not after transient ischemia is that protein synthesis inhibitors be expressed. Histologic characteristics of necrotic cell death block delayed death of neurons (8–10). Thus, depending are cytoplasmic and nuclear swelling, loss of integrity of cell on the duration and severity of ischemia, stroke may pro- organelles, rupture of the cell membrane, and dissolution duce cell death with features of necrosis or apoptosis. In vivo, necrotic cell death is often accompanied by intense inflammation with recruitment of inflammatory cells. This inflammatory response can injure MECHANISMS OF NECROTIC CELL DEATH adjacent normal cells. The characteristics of programmed cell death and necrosis are summarized in Table 92. The primary pathologic mechanism in stroke is the deple- tion of energy stores; however, considerable evidence indi- cates that excitatory amino acids (EAAs) exacerbate ischemic NATURE OF NEURONAL DEATH IN injury. EAAs such as glutamate are released by approxi- CEREBRAL ISCHEMIA mately 40% of all synapses in the central nervous system (11). Under physiologic conditions, EAAs participate in In ischemia, a mismatch between energy supply and de- many neurologic functions, including memory, movement, mand may result in energy failure. Without adequate en- sensation, cognition, and synaptic plasticity (12,13). How- ergy, protein synthesis cannot occur, and the genes that ever, EAAs can also have a pathologic effect. EAA-mediated execute programmed cell death may not be expressed. The toxicity was first demonstrated by Olney and co-workers predominant histologic feature of stroke is infarction. In- (14) by peripheral administration of an EAA agonist that farction is synonymous with necrosis (i. These neurons contain high concentrations of and inflammation are present). Choi (15) demonstrated that micro- cerebral artery occlusion model in the rat, loss of glucose molar extracellular glutamate and other EAAs produce rapid 2 utilization is rapid and complete within a few hours (5), increases in intraneuronal cytosolic Ca concentrations. Chapter 92: Molecular Pathophysiology of Stroke 1319 This increase in intracellular calcium concentration is rap- tively resistant to excitotoxic injury (24,25). These data pro- idly lethal to primary neuronal cultures. The importance vide compelling evidence that EAA-induced increases in in- of calcium entry and excitotoxicity is supported by data tracellular Ca2 are toxic to neurons in culture. A rapid and large The increase in intraneuronal Ca2 in response to extra- increase in the concentration of extracellular amino acids cellular EAAs in vitro is mediated by the opening of a recep- can be monitored by microdialysis after cerebral ischemia tor-gated ion channel, the N-methyl-D-aspartate (NMDA) (26). Although NMDA antagonists are not effective in channel (17). The NMDA channel, named after its highest- global ischemia models in which temperature is carefully affinity ligand, primarily gates calcium entry into the neu- controlled (27), a large number of studies have found that ron. Treatment with antagonists that compete with gluta- they decrease infarction volume in both permanent and mate and other EAAs for the receptor (competitive NMDA temporary middle cerebral artery occlusion models in ro- antagonists) or antagonists that bind to the ion channel dents (28). Blocking the translation of a gene that encodes itself (noncompetitive antagonists) can block calcium entry a subunit of the NMDA receptor with intraventricular in- into neurons and prevent cell death induced by glutamate jection of antisense oligonucleotides also decreases infarc- (18,19). Glycine is a co-agonist that is required in addition tion volume after middle cerebral artery occlusion in the to glutamate to open the NMDA Ca2 channel (20). These data and many other studies support the tagonists that bind to the glycine site on the NMDA recep- hypothesis that excitotoxicity contributes to ischemic injury tor also block excitotoxicity in vitro (21). These include nitric oxide synthase, cyclooxy- media following glutamate exposure (18). Conversely, inhi- genase, phospholipase A2, and calpain 1. Calpain 1 is a bition of the sodium–calcium exchanger that normally facil- calcium-activated protease that has been specifically linked itates extrusion of calcium results in an increase in neuronal to glutamate receptors in the rat hippocampus (30). Similarly, dantrolene, which attenuates de- 1 participates in the conversion of xanthine dehydrogenase compartmentalization of intracellular stores of calcium, can to xanthine oxidase, which metabolizes xanthine to its reac- reduce glutamate neurotoxicity in cortical neurons (23). Similarly, phospholi- nally, neurons containing high concentrations of calcium- pase A2 is activated by calcium and facilitates the release of binding proteins, such as calbindin or parvalbumin, are rela- arachidonic acid from injured cell membranes (32). Schematic diagram illustrating the mechanisms by which ischemia and excito- toxicity injure neurons. The cyclooxygenase en- ingly, these non-NMDA subunits may become calcium- zyme may produce a superoxide ion as a by-product of permeable after ischemia. The metabotropic receptors may arachidonic acid metabolism (33). In addition, intracellular also increase intracellular calcium by mobilizing calcium calcium can activate calcium-dependent isoforms of nitric from stores in the endoplasmic reticulum. Studies with an- oxide synthase to produce nitric oxide (34). The nitric oxide tagonists of the metabotropic receptor show that, depending then combines with the superoxide produced as the by- on their subunit specificity, some, but not all, drugs of this product of cyclooxygenase, xanthine oxidase, or other class are neuroprotective in models of focal ischemia (40, sources to form the highly reactive species peroxynitrite, 41). Therefore, EAA-me- In addition to the direct downstream effects of enzymes diated elevation of intracellular calcium concentrations acti- that are activated by elevation of intracellular calcium, a vates both cyclooxygenase and nitric oxide synthase, which number of complex interactions and positive feedback loops then synergistically contribute to ischemic brain injury augment the contribution of EAAs to ischemic brain injury. For example, free arachidonic acid can potentiate NMDA- Extracellular EAAs may activate other receptors besides evoked currents in neurons (42) and inhibit reuptake of the NMDA channel. EAA receptors can be categorized as glutamate by astrocytes (43). In addition, platelet-activating ionotropic or metabotropic receptors. Ionotropic receptors factor, a phospholipase A2 metabolite, can stimulate the are coupled directly to membrane ion channels, whereas release of glutamate (44). Acidotic conditions favor the re- metabotropic receptors are coupled to G proteins and mod- lease of free iron, which can then participate in the metabo- ulate intracellular second messengers such as inositol tri- lism of peroxide into the hydroxyl radical (Fenton reaction) phosphate, calcium, and cyclic nucleotides. In addition, glutamate can interfere with the function genes have been identified that encode subunits of these of the cystine transporter. The subunits combine in a variety of confirma- porter results in decreased intracellular concentrations of tions to yield receptors with specific pharmacologic and glutathione and diminished intracellular endogenous anti- electrophysiologic characteristics (37).
C purchase duphalac 100 ml with visa, Resistance of 10 proxim al tubule cells isolated from iN O S knockout m ice to hypox- ia-induced injury buy discount duphalac 100 ml online. The vasodilators counteract the effects of the renal failure (ARF) 100 ml duphalac. A generic duphalac 100 ml visa, Adm inistration of iothalam ate, a radiocon- vasoconstrictors so that intrarenal vasoconstriction in response to trast dye, to rats increases m edullary blood flow. Inhibitors of radiocontrast is usually m odest and is associated with little or no either prostaglandin production (such as the N SAID, loss of renal function. H owever, in situations when there is pre- indom ethacin) or inhibitors of N O synthesis (such as L-N AM E) existing chronic renal insufficiency (CRF) the vasodilator response abolish the com pensatory increase in m edullary blood flow that to radiocontrast is im paired, whereas production of endothelin and occurs in response to radiocontrast adm inistration. Thus, the stim - other vasoconstrictors is not affected or even increased. As a result, ulation of prostaglandin and N O production after radiocontrast radiocontrast adm inistration causes profound intrarenal vasocon- adm inistration is im portant in m aintaining m edullary perfusion striction and can cause ARF in patients with CRF. This hypothesis and oxygenation after adm inistration of contrast agents. B, would explain the predisposition of patients with chronic renal Radiocontrast stim ulates the production of vasodilators (such as dysfunction, and especially diabetic nephropathy, to contrast- prostaglandin [PGI2] and endothelium -dependent nitric oxide induced ARF. B, Patho- physiologic m echanism s ignited by the elevation of cytosolic calci- um concentration. B, Administration of calcium channel inhibitor permission; B, adapted from Burke et al. M echanisms of acti- vation and feedback con- trol of the inducible heat shock gene. In the nor- mal unstressed cell, heat shock factor (HSF) is rendered inactive by association with the con- stitutively expressed HSP70. After hypoxia or ATP depletion, partially denatured proteins (DP) become preferentially associated with HSC73, releasing HSF and allow- ing trimerization and binding to the heat shock element (HSE) to initiate the transcription of the heat shock gene. After translation, excess inducible HSP (HSP72) interacts with the trimer- ized HSF to convert it back to its monomeric state and release it from the HSE, thus turning off the response. Hydrogen H O peroxide 2 2 Outer Hydrogen H2O2 Hydroperoxyl peroxide membrane radical Inner HO membrane 2 O – HO 2 2 Hepatocyte Superoxide (and other cells) Plasma EC–SOD anion (From glycolysis/ Proteinase? Superoxide and hydro- gen peroxide are produced during norm al cellular m etabolism. RO S are constantly being produced by the norm al cell during a num ber of physiologic reactions. M itochondrial respiration is an im portant source of superoxide production under norm al conditions and can be increased during ischem ia-reflow or gentam ycin- induced renal injury. A num ber of enzym es generate superoxide and hydrogen peroxide during their catalytic cycling. These include cycloxygenases and lipoxygenes that catalyze prostanoid and leukotriene synthesis. Som e cells (such as leukocytes, endothelial cells, and vascular sm ooth m uscle cells) have N ADH / or N ADPH oxidase enzym es in the plasm a m em brane that are capable of generating superoxide. Xanthine oxidase, which converts hypoxathine to xanthine, has been im plicated as an im portant source of RO S after ischem ia-reperfu- sion injury. Cytochrom e p450, which is bound to the m em brane of the endoplasm ic reticulum , can be increased by the presence of high concentrations of m etabolites that are oxidized by this cytochrom e or by injurious events that uncouple the activity of the p450. Finally, the oxidation of sm all m olecules including free hem e, thiols, hydroquinines, catecholam ines, flavins, and tetrahydropterins, also contribute to intracellular superoxide production. The increased RO S production results from two ISCHEM IC ACUTE RENAL FAILURE m ajor sources: the conversion of hypoxanthine to xanthine by xan- thine dehydrogenase and the oxidation of N ADH by N ADH oxi- dase(s). During the period of ischem ia, oxygen deprivation results Enhanced generation of reactive oxygen metabolites and xanthine oxidase and in the m assive dephosphorylation of adenine nucleotides to hypox- increased conversion of xanthine dehydrogenase to oxidase occur in in vitro and in anthine. N orm ally, hypoxanthine is m etabolized by xanthine dehy- vivo models of injury. H owever, during vented by scavengers of reactive oxygen metabolites, xanthine oxidase inhibitors, or ischem ia, xanthine dehydrogenase is converted to xanthine oxi- iron chelators. W hen oxygen becom es available during reperfusion, the Glutathione redox ratio, a parameter of “oxidant stress” decreases during ischemia and m etabolism of hypoxanthine by xanthine oxidase generates super- markedly increases on reperfusion. Conversion of N AD+ to its reduced form , N ADH , and the Scavengers of reative oxygen metabolites, antioxidants, xanthine oxidase inhibitors, accum ulation of N ADH occurs during ischem ia. During the reper- and iron chelators protect against injury. Superoxide is converted to O– 3+ 2 +Fe hydrogen peroxide by superoxide dism utase. Superoxide and hydrogen peroxide per se are not highly reactive and cytotoxic. H owever, hydrogen peroxide can be converted to Iron stores the highly reactive and injurious hydroxyl radical by an iron-catalyzed reaction that (Ferritin) requires the presence of free reduced iron. The availability of free “catalytic iron” is a Release of Hydrogen critical determ inant of hydroxyl radical production. In addition to providing a source of free iron Peroxide hydroxyl radical, superoxide potentiates hydroxyl radical production in two ways: by (H2O2) releasing free iron from iron stores such as ferritin and by reducing ferric iron and recy- Fe2+ cling the available free iron back to the ferrous form. The hem e m oiety of hem oglobin, m yoglobin, or cytochrom e present in norm al cells can be oxidized to m ethem e (Fe3+). Fe3+ The further oxidation of m ethem e results in the production of an oxyferryl m oiety (Fe4+=O ), which is a long-lived, strong oxidant which likely plays a role in the cellular OH Hydroxyl Radical injury associated with hem oglobinuria and m yoglobinuria. This superoxide and hydrogen peroxide can be converted to hydroxyl radical via the H aber-W eiss reaction. Also, the enzym e m yeloper- oxidase, which is specific to leukocytes, converts hydrogen peroxide to another highly reactive and injurious oxidant, hypochlorous acid. Large Gibbs energy 2 the reduced oxygen interm ediates–generat- ONOO– Propagation L• + O LOO• 9 –1 –1 2 ing and reduced nitrogen interm ediates– :O •– 6. Faster than SOD 2 generating pathways, A, and m echanism s O2 + H2O2 of lipid peroxidation, B. A, Form ation of nitrotyrosine as an HNE indicator of O N O O - production. Interactions between reactive oxygen species such as the hydroxyl radical results in injury to Ab the ribose-phosphate backbone of DN A. This results in single- HNE OH OH O OO and double-strand breaks. RO S can also cause m odification and deletion of individual bases within the DN A m olecule. Interaction between reactive oxygen and nitrogen species results in injury to X X the ribose-phosphate backbone of DN A, nuclear DN A fragm enta- Protein tion (single- and double-strand breaks) and activation of poly- (X: Cys, His, Lys) Formation of stable D hemiacetal adducts (ADP)-ribose synthase. B, Im m unohistochem ical staining of kid- neys with antibodies to nitrotyrosine. D, Reactions describing lipid peroxidation and for- process is called lipid peroxidation.