The differential effects of norepinephrine and dopamine on cerebrospinal fluid pressure and spinal cord perfusion pressure after acute human spinal cord injury.

STUDY DESIGN: Prospective vasopressor cross-over interventional studyObjectives:To examine how two vasopressors used in acute traumatic spinal cord injury (SCI) affect intrathecal cerebrospinal fluid pressure and the corresponding spinal cord perfusion pressure (SCPP). SETTING: Vancouver, British Columbia, Canada. METHODS: Acute SCI patients over the age of 17 with cervical or thoracic ASIA Impairment Scale (AIS). A, B or C injuries were enrolled in this study. Two vasopressors, norepinephrine and dopamine, were evaluated in a 'crossover procedure' to directly compare their effect on the intrathecal pressure (ITP). The vasopressor cross-over procedures were performed in the intensive care unit where ITP, mean arterial pressure (MAP) and heart rate were being continuously measured. The SCPP was calculated as the difference between MAP and ITP. RESULTS: A total of 11 patients were enrolled and included in our analysis. There were 6 patients with AIS A, 3 with AIS B and 2 with AIS C injuries at baseline. We performed 24 cross-over interventions in these 11 patients. There was no difference in MAP with the use of norepinephrine versus dopamine (84±1 mm Hg for both; P=0.33). Conversely, ITP was significantly lower with the use of norepinephrine than with dopamine (17±1 mm Hg vs 20±1 mm Hg, respectively, P<0.001). This decrease in ITP with norepinephrine resulted in an increased SCPP during the norepinephrine infusion when compared with dopamine (67±1 mm Hg vs 65±1 mm Hg respectively, P=0.0049). CONCLUSION: Norepinephrine was able to maintain MAP with a lower ITP and a correspondingly higher SCPP as compared with dopamine in this study. These results suggest that norepinephrine may be preferable to dopamine if vasopressor support is required post SCI to maintain elevated MAPs in accordance with published guidelines.

Can Cerebrospinal Fluid Pressure Detect Catheter Complications in Patients Who Experience Loss of Effectiveness With Intrathecal Baclofen Therapy?

OBJECTIVE: The catheter status of patients who presented with loss of intrathecal baclofen (ITB) therapy effectiveness was investigated using measurements of cerebrospinal fluid (CSF) pressure transmitted through the catheter fluid path to the pump. The aim of the study was to estimate the appropriate threshold separating catheter complications from "normal" catheter function, and to compare catheter status based on CSF pressure with the clinical diagnosis. METHODS: This was a prospective, masked nonsignificant risk, research study. Patients (N = 47) received ITB for the treatment of severe spasticity and presented with symptoms of catheter malfunction. CSF pressure data were recorded using an external sensor connected to a needle inserted into the catheter access port. An algorithm calculated the energy of the variations in CSF pressure caused by respiration and heartbeat within the intrathecal space. These data were evaluated against a threshold that separated normal from abnormal catheter function. Catheter status based on the algorithm was compared with the clinical diagnosis. RESULTS: Complete data were available for 37 patients. Mean CSF pressure energy was significantly higher (p = 0.025; student t-test) for patients diagnosed with normal catheter function vs. catheters with complications. The CSF pressure algorithm matched the clinical diagnosis in 16 of 18 patients with catheter complications (sensitivity = 89%), and 13 of 19 patients with normal catheter function (specificity = 68%). CONCLUSION: In-clinic CSF pressure data acquisition is technically feasible. Overall, catheter status based on the algorithm demonstrated concordance with the clinical diagnosis in 29 of 37 patients (78.4%).

Interventions for idiopathic intracranial hypertension.

BACKGROUND: Idiopathic intracranial hypertension (IIH) has an estimated incidence of one to three people per 100,000 people per year, and occurs most commonly in obese, young women. IIH is associated with severe morbidity, notably due to a significant threat to sight and severe headache. Several different management options have been proposed. Conservative measures centre on weight loss. Pharmacological therapy includes use of diuretics. Refractory and sight-threatening cases demand surgical intervention, most often in the form of cerebrospinal fluid (CSF) diversion or optic nerve sheath fenestration. Other treatments include venous sinus stenting and bariatric surgery. OBJECTIVES: To assess the effects of any intervention for IIH in any patient group. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2015 Issue 6), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to July 2015), EMBASE (January 1980 to July 2015), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 22 July 2015. SELECTION CRITERIA: We included only randomised controlled trials (RCTs) in which any intervention was compared to placebo, or to another form of treatment, for people with a clinical diagnosis of IIH. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the search results for trials to be included in the review. We resolved any discrepancies by third party decision. MAIN RESULTS: We identified two completed RCTs (enrolling a total of 211 participants and conducted in the UK and US) and two ongoing trials that met the inclusion criteria. Both completed trials compared acetazolamide to placebo, in conjunction with a weight loss intervention in both groups. Attrition bias was a problem in both trials with high loss to follow-up, in one study this loss to follow-up occurred particularly in the acetazolamide arm. One trial was unmasked and we judged it to be at risk of performance and detection bias.In these studies, change in visual acuity was similar in the treatment and control groups as measured by logMAR acuity. In one study people in the acetalomazide group had a similar change in logMAR acuity compared to the placebo group between baseline and 12 months in the right eye (MD 0.04 logMAR, 95% CI -0.08 to 0.16) and left eye (MD 0.03 logMAR, 95% CI -0.09 to 0.15). In the other study people in the acetalomazide group had a similar change in vision over six months compared with people in the placebo group (mean difference in change in letters read was 0.01 (95% CI -1.45 to 1.46). One study reported no cases of visual loss in 21 people treated with acetalomazide compared to 2/20 cases in the placebo group (odds ratio 0.17, 95% CI 0.01, 3.82).The prespecified outcome for this review was reduction in CSF pressure to normal levels which was not reported by the two trials. One trial reported that, in a subsample of 85 participants who agreed to lumbar puncture at 6 months, people in the acetalomazide group on average had a greater reduction in CSF pressure (MD -59.9 mmH(2)O, 95% CI -96.4, -23.4).In one study, people in the acetalozamide group on average experienced a greater reduction in papilloedema as assessed by fundus photographs MD -0.70 (95% CI -1.00 to -0.40) and by clinical grading MD -0.91 (95% CI -1.27 to -0.54) between baseline and six months in the study eye.Headache was recorded as present/absent in one study at 12 months (OR 0.42, 95% CI 0.12,1.41, 41 participants). Both studies reported headache on visual analogue scales (different ones) but results were inconclusive (MD for change in headache score measured on 10-point visual analogue scale at 12 months was 1.0 (-1.80, 3.70, 41 participants) and MD for change in headache score on a 6 point scale measured at 6 months was -0.45 (-3.5,2.6, number of participants unclear).In one study, a similar proportion of people in the acetalomazide group were in remission (however, the trial authors did not state their definition of this term) at 12 months compared to the placebo group. However, the 95% CIs were wide and there is considerable uncertainty as to the effect (OR 1.13 (95% CI 0.32 to 3.90, 41 participants).In one study of 185 participants, people in the acetalomazide group had an increased risk of decreased CO2, diarrhoea, dysgeusia, fatigue, nausea, paresthesia, tinnitus and vomiting compared to people in the placebo group. In general, the estimates of effect were uncertain with wide 95% CIs. Adverse effects were not reported in the other study.One study reported that quality of life was better in acetazolamide-treated patients based on the visual quality of life (VFQ-25) (MD 6.35, 95% CI 2.22 to 10.47) and the physical (MD 3.02, 95% CI 0.34 to 5.70) and mental (MD 3.45, 95% CI 0.35 to 6.55) components of the 36-Item Short Form Health Survey tool at six months. Costs were not reported in either study.We judged the evidence to be low certainty (GRADE) downgrading for imprecision and risk of bias. AUTHORS' CONCLUSIONS: Although the two included RCTs showed modest benefits for acetazolamide for some outcomes, there is insufficient evidence to recommend or reject the efficacy of this intervention, or any other treatments currently available, for treating people with IIH. Further high-quality RCTs are required in order to adequately assess the effect of acetazolamide therapy in people with IIH.

The idiopathic intracranial hypertension treatment trial: design considerations and methods.

BACKGROUND: The objectives of this study were to present the rationale for the main aspects of the study design and describe the trial methodology for the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT). METHODS: Eligible candidates with mild visual field loss (automated perimetric mean deviation [PMD] -2 to -7 dB) were randomized to receive either acetazolamide or matching placebo tablets. Randomized participants were offered participation in a supervised dietary program. The primary outcome variable, PMD, was measured at 6 months. Additionally, cerebrospinal fluid from subjects and serum from study participants and matched controls were collected for genetic analysis and vitamin A studies. An ancillary optical coherence substudy was added to investigate the changes of papilledema in the optic nerve head and retina that correlate with Frisén grading, visual field deficits, and low-contrast visual acuity. RESULTS: The randomized trial entered 165 participants from March 17, 2010, through November 27, 2012, from the United States and Canada. The primary outcome (month 6) visits were successfully completed by June 15, 2013. Blood specimens were obtained from 165 controls without IIH to investigate vitamin A metabolism and genetic markers of potential risk factors for IIH. CONCLUSIONS: The IIHTT is the first randomized, double-masked placebo-controlled trial to study the effectiveness of medical treatment for patients with IIH.

Volatile induction/maintenance of anaesthesia with sevoflurane increases jugular venous oxygen saturation and lumbar cerebrospinal fluid pressure in patients undergoing craniotomy.

BACKGROUND AND OBJECTIVE: Sevoflurane is a widely used volatile agent in neuroanaesthesia, and its nonirritant properties on the respiratory tract make sevoflurane suitable for volatile induction/maintenance of anaesthesia (VIMA). In the current trial, we investigate the effects of sevoflurane VIMA on lumbar cerebral fluid pressure (LCSFP) and jugular venous oxygen partial pressure in patients undergoing craniotomy for supratentorial intracranial surgery under bispectral index monitoring, determine jugular bulb venous oxygen saturation (SjvO2) and calculate cerebral perfusion pressure (CPP), arteriojugular venous oxygen content difference and cerebral oxygen extraction rate (COER) at different time points during the operation. Moreover, we compare these with total intravenous anaesthesia (TIVA) in patients receiving remifentanil and propofol continuous infusion. METHODS: Twenty-six adult patients undergoing elective craniotomy were randomly allocated to either remifentanil-propofol (group TIVA) or sevoflurane (group VIMA). Mean arterial blood pressure, heart rate, LCSFP, CPP, SjvO2, arteriojugular venous oxygen content difference and COER were compared in the two groups at different time points under bispectral monitoring. Heart rate, mean arterial blood pressure, saturation of peripheral oxygen, BIS value and LCSFP were recorded at the time points including intubation (Tintub), 5 min (T5'int) and 15 min (T15'int) after intubation, the beginning of surgery (Tsurg), 5 min (T5m), 0.5 h (T0.5h), 1 h (T1h), 1.5 h (T1.5h), 2 h (T2h) and 2.5 h (T2.5h) after incision, the end of surgery (Tend), extubation (Textub) and 30 min (T30'end) after surgery. Arterial blood gas and jugular venous bulb blood gas analysis were performed at the time points of T0, T5'int, T5m, T1h, T2h, Tend, 15 min after operation (T15'end) and T30'end. RESULTS: LCSFP was increased above baseline levels in group VIMA and decreased in group TIVA from Tintub to T5m, and decreased to similar levels from T0.5h to T30'end in both groups. Mean arterial blood pressure was decreased to similar levels from T0.5h to Tend and returned to baseline levels at T30'end in both groups, and was significantly higher in group VIMA than in group TIVA at T5'int, T15'int, Tsurg and T5m. CPP was decreased to similar levels between the groups from T0.5h to Tend and returned to baseline levels at T30'end in both groups, and was significantly higher at Tintub, T5'int and T15'int in group VIMA than in group TIVA. Jugular venous oxygen partial pressure and SjvO2 were increased above baseline level from T5'int to T30'end in group VIMA, and decreased from T5'int to Tend, and returned to baseline level at T30'end in group TIVA. Arteriojugular venous oxygen content difference and COER were decreased from T5'int to T30'end in group VIMA, and increased above the baseline level from T5'int to Tend, and returned to the baseline level at T30'end in group TIVA. CONCLUSION: Sevoflurane VIMA increases SjvO2, lumbar CSF pressure and CPP, and decreases COER, which suggested that VIMA could be a better choice for patients with the risk of cerebral hypoperfusion or insufficient oxygen delivery. Propofol-based TIVA is associated with decreased SjvO2, LCSFP and CPP, and increased COER, and it might be suitable for patients with increased intracranial pressure.

Intraventricular injection of antibodies to beta1-integrins generates pressure gradients in the brain favoring hydrocephalus development in rats.

In some tissues, the injection of antibodies to the beta(1)-integrins leads to a reduction in interstitial fluid pressure, indicating an active role for the extracellular matrix in tissue pressure regulation. If perturbations of the matrix occur in the periventricular area of the brain, a comparable lowering of interstitial pressures may induce transparenchymal pressure gradients favoring ventricular expansion. To examine this concept, we measured periventricular (parenchymal) and ventricular pressures with a servo-null micropipette system (2-microm tip) in adult Wistar rats before and after anti-integrin antibodies or IgG/IgM isotype controls were injected into a lateral ventricle. In a second group, the animals were kept for 2 wk after similar injections and after euthanization, the brains were removed and assessed for hydrocephalus. In experiments in which antibodies to beta(1)-integrins (n = 10) but not isotype control IgG/IgM (n = 7) were injected, we observed a decline in periventricular pressures relative to the preinjection values. Under similar circumstances, ventricular pressures were elevated (n = 10) and were significantly greater than those in the periventricular interstitium. We estimated ventricular to periventricular pressure gradients of up to 4.3 cmH(2)O. In the chronic preparations, we observed enlarged ventricles in many of the animals that received injections of anti-integrin antibodies (21 of 29 animals; 72%) but not in any animal receiving the isotype controls. We conclude that modulation/disruption of beta(1)-integrin-matrix interactions in the brain generates pressure gradients favoring ventricular expansion, suggesting a novel mechanism for hydrocephalus development.

A randomized trial of maximum cephalad sensory blockade with single-shot spinal compared with combined spinal-epidural techniques for cesarean delivery.

BACKGROUND: Previous studies have shown more extensive cephalad sensory blockade in women receiving combined spinal-epidural (CSE) anesthesia compared with single-shot spinal (SSS) anesthesia for elective cesarean delivery. It has been postulated that introduction of the epidural needle during CSE disturbs the negative pressure in the epidural space, resulting in relatively greater cerebrospinal fluid (CSF) pressure and increased spread of intrathecal local anesthetic. We tested the hypothesis that CSE results in more extensive cephalad sensory blockade than SSS anesthesia and that loss-of-resistance during initiation of CSE anesthesia increases CSF pressure compared with SSS. METHODS: Thirty parturients scheduled for elective cesarean delivery were enrolled in this randomized, double-blind study. Patients received either SSS or CSE anesthesia with equal doses of intrathecal anesthetic (hyperbaric bupivacaine 12 mg, fentanyl 10 microg and morphine 200 microg). Before the intrathecal injection, the CSF pressure was measured with a fiberoptic pressure sensor. Maximum cephalad sensory blockade to pinprick, cold and touch was measured. The total dose of phenylephrine required to maintain baseline arterial blood pressure was also recorded. RESULTS: There were no significant differences in the median (interquartile range) pinprick sensory block height [T4 (T4-2) vs T3 (T4-1)] or CSF pressures [6 (4-12) vs 9 (8-12) mm Hg] between the SSS and CSE groups. There were no significant correlations between CSF pressure and block height or total dose of phenylephrine. CONCLUSION: The SSS and CSE techniques inserted in the lateral decubitus position resulted in similar extent of sensory blockade and CSF pressure. These findings suggest that altering the intrathecal dose is not necessary and that any difference in intrathecal pressure associated with initial placement of an epidural needle in the epidural space during CSE anesthesia is clinically inconsequential.

Measurement of the puncture profile and extradural pressure of cattle during extradural anaesthesia.

OBJECTIVE: To measure the pressure profile during caudal extradural puncture and subsequent extradural anaesthesia in cattle and to investigate the presence of extradural pressure waves. STUDY DESIGN: Prospective experimental study. ANIMALS: Eleven cattle aged 4.1 +/- 2.5 years (range 0.8 to 8.8 years), with a body weight of 613 +/- 162 kg (range 302-840 kg). METHODS: Caudal extradural puncture was performed. To measure the extradural pressure profile, the needle was connected to an electronic pressure transducer placed at the height of the base of the tail. The pressure profile was recorded for 3 minutes following extradural puncture. Lack of resistance to injection of saline was assessed. One minute and 10 minutes after extradural anaesthesia with procaine extradural pressure was recorded. Correct extradural needle placement was assessed by clinical response. RESULTS: Three minutes after extradural puncture the median pressure was -16 (range -25 to 25) mmHg. Pressure in the extradural space 1 minute after the lack of resistance, 3 seconds after injection, and 10 minutes after injection was -15 (-24 to 33) mmHg, 8 (-17 to 84) mmHg, and -7 (-25 to 27) mmHg respectively. Pressure waves were visible after puncture, after lack of resistance, 3 seconds and 10 minutes after injection, in 4, 6, 8 and 7 cattle respectively. Pressure after testing lack of resistance, after the injection of local anaesthetic, as well as at the end of the measurement, period was significantly higher than baseline. All cattle showed clinical signs indicative of successful extradural needle placement. CONCLUSION AND CLINICAL RELEVANCE: Extradural pressure was sub-atmospheric in 82% of the animals. Pressure waves were not consistently present before or after extradural injection, which limits their usefulness to confirm correct extradural needle placement. Extradural pressures increase significantly after injection of local anaesthetic solution. However, the clinical significance of the increase in extradural pressures was not clear.

[Benign intracranial hypertension: the role of medical treatment]. / Hypertension intracrânienne bénigne: place du traitement médical.

The goal of medical treatment in benign intracranial hypertension (BIH) is to treat intracranial hypertension symptoms as well as to preserve vision. Reducing the production rate of cerebrospinal fluid can be achieved using acetazolamide and/or furosemide (carbonic anhydrase inhibitors), although acetazolamide is the most effective drug. The use of steroids is debatable in BIH. This review focuses on the pathophysiology of these medications, followed by the report of a series of 16 pediatric patients suffering from BIH (1996-2006). BIH was idiopathic for eight children. Depletive lumbar punctures were effective, but this result was often transient. All children were treated with acetazolamide. Doses of acetazolamide (10-20mg/kg per day) must be given every 8h to respect its kinetics. This treatment has to be continued for at least several months and decreasing the dosage must be progressive. Hypokalemia is always prevented with oral potassium. There was only one true treatment failure requiring surgery. The authors therefore advise acetazolamide as a first-line treatment (combined with etiologic treatment, if available, in cases of nonidiopathic situations) in BIH.

New Insight into the Mechanism of Mannitol Effects on Cerebrospinal Fluid Pressure Decrease and Craniospinal Fluid Redistribution.

Intracranial hypertension, which often follows a severe brain injury, is usually treated with intravenous (i.v.) application of hyperosmolar solutions. The mechanism of intracranial cerebrospinal fluid (CSF) pressure decrease after such a treatment is still unclear. The aim of this article was to try to explain the mechanism of CSF pressure reduction after i.v. hyperosmolar mannitol bolus in regard to the changes in CSF volume. Two types of experiments were done on anesthetized cats before and after hyperosmolar mannitol application: ventriculo-cisternal perfusion at different perfusion rates, simultaneously measuring the perfusate outflow volume, and CSF pressure recording in the lateral ventricle before and during artificial CSF infusion. Mannitol application in the first group of cats significantly reduced collected prefusate volume during ventriculo-cisternal perfusion, and in the second group it prevented CSF pressure increase caused by artificial CSF infusion. Our results strongly suggest that the mechanism of hyperosmolar mannitol action after its i.v. application is based on osmotic fluid retrieval from interstitial and cerebrospinal compartments into the microvessels. This shift, without significant volume change inside the cranium, causes a predominant decrease of CSF volume in the spinal part of the system, which in turn leads to lowering of the CSF pressure. Spinal CSF volume decrease is enabled by the extensibility of the spinal dura, this way providing the possibility for CSF volume redistribution inside the CSF system, together with CSF pressure decrease. This mechanism of mannitol action is in accordance with the new hypothesis of CSF physiology.

A New Subtype of Chronic Daily Headache Presenting in Older Women.

OBJECTIVE: To describe a new subtype of chronic daily headache in women of a specific age group. METHODS: Case series. RESULTS: Eight patients were included in the presented case series. The average age of onset of this distinct headache condition is 57 years. All patients were either perimenopausal or in menopause when the headaches started. The syndrome is marked by bilateral head pain that starts daily from onset and is typically at its most severe intensity the first thing in the morning before arising or when in the supine position. Immediate worsening in Trendelenburg appears to be an almost diagnostic test for the syndrome and occurred in all patients. The majority of the patients had a history of episodic migraine, but the migraines were either very well controlled or had ceased by the time the new headache arose. The bulk of the patients (6/8) were either overweight or obese, although two patients were of normal body mass index (BMI). Neuroimaging showed no abnormalities. All patients responded to cerebrospinal fluid (CSF) pressure-/volume-lowering medications (acetazolamide or spironolactone), but only one patient was able to completely taper off treatment without headache recurrence. CONCLUSION: This newly defined subtype of chronic daily headache appears to be caused by a state of elevated CSF pressure. It is hypothesized that a combination of an elevated BMI and the presence of cerebral venous insufficiency leads to this form of daily headache.

Peripapillary Retinal Pigment Epithelium Layer Shape Changes From Acetazolamide Treatment in the Idiopathic Intracranial Hypertension Treatment Trial.

Purpose: Recent studies indicate that the amount of deformation of the peripapillary retinal pigment epithelium and Bruch's membrane (pRPE/BM) toward or away from the vitreous may reflect acute changes in cerebrospinal fluid pressure. The study purpose is to determine if changes in optic-nerve-head (ONH) shape reflect a treatment effect (acetazolamide/placebo + weight management) using the optical coherence tomography (OCT) substudy of the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT) at baseline, 3, and 6 months. Methods: The pRPE/BM shape deformation was quantified and compared with ONH volume, peripapillary retinal nerve fiber layer (pRNFL), and total retinal (pTR) thicknesses in the acetazolamide group (39 subjects) and placebo group (31 subjects) at baseline, 3, and 6 months. Results: Mean changes of the pRPE/BM shape measure were significant and in the positive direction (away from the vitreous) for the acetazolamide group (P < 0.01), but not for the placebo group. The three OCT measures reflecting the reduction of optic disc swelling were significant in both treatment groups but greater in the acetazolamide group (P < 0.01). Conclusions: Change in the pRPE/BM shape away from the vitreous reflects the effect of acetazolamide + weight management in reducing the pressure differential between the intraocular and retrobulbar arachnoid space. Weight management alone was also associated with a decrease in optic nerve volume/edema but without a significant change in the pRPE/BM shape, implying an alternative mechanism for improvement in papilledema and axoplasmic flow, independent of a reduction in the pressure differential. (ClinicalTrials.gov number, NCT01003639.).

Ketamine increases opening cerebrospinal pressure in children undergoing lumbar puncture.

Intravenous ketamine, often administered concomitantly with midazolam, is one of the most commonly used drugs for procedural sedation in children. Although it is considered safe for use in children, ketamine can increase intracranial pressure. Hence, this study was carried out to determine whether adding ketamine to midazolam prior to performing lumbar puncture would be associated with a higher cerebrospinal fluid opening pressure in children with suspected aseptic meningitis. Thirty-nine children aged 6 months to 14 years were included: 26 in group A (intravenous midazolam plus ketamine) and 13 in group B (intravenous midazolam only). Mean cerebrospinal fluid opening pressure in group A was 24.4 cm H2O (median 23 cm H2O) compared with 20 cm H2O (median 19.8 cm H2O) in group B (P = .011). Intravenous ketamine prior to performing lumbar puncture is associated with a significantly higher lumbar cerebrospinal fluid opening pressure in children with aseptic meningitis. However, no outcome differences have been found between the two groups.

Hydrodynamics of the spinal epidural space in pigs determined by constant-flow methods.

BACKGROUND AND OBJECTIVES: Impressive quantities of fluid can be infused into the epidural space of the spine without causing dramatic or sustained increases in pressure. The epidural space is considered "leaky," but questions remain about how fluid leaves the epidural space. We used constant-flow infusions of saline to gain insight into the hydrodynamics involved. METHODS: We infused saline at a constant rate into the lumbar epidural space of 6 anesthetized pigs while measuring pressure at the adjacent interspace. Three or 4 infusions were performed at different flow rates in each animal. RESULTS: Epidural space pressure in the absence of flow was consistently 2 to 3 mm Hg above right atrial pressure. During each infusion, pressure increased slowly to a steady plateau value between 15 and 70 mm Hg. When flow was stopped, pressure declined exponentially to the starting pressure. The presence of a plateau indicates that fluid leaving the epidural space ends up in a structure with high capacitance. Plateau pressures were linearly related to flow rate in each animal, indicating constant resistance to outflow. The flow-pressure relation showed neither a critical opening pressure nor moderating pressures with increased flow. CONCLUSIONS: Fluid leaves the porcine spinal epidural space through channels that are open at baseline rather than being recruited as epidural pressure increases. This behavior is inconsistent with the view that the epidural space behaves like a Starling resistor.

Spinal contribution to CSF pressure lowering effect of mannitol in cats.

OBJECTIVES: After application of hyperosmolar mannitol the cerebrospinal (CSF) pressure is usually lowered within 30 min but this effect cannot be explained either by changes in intracranial blood volume and flow or by changes in brain volume. We assume that this effect of mannitol my be consequence of CSF volume decrease primarily in the spinal CSF due to high compliance of the spinal dura. METHODS: To explore such a possibility we planned to separate spinal and cerebral CSF. In chloralose anaesthetized cats dorsal laminectomy of C2 vertebrae was performed and a plastic semi ring was positioned extradurally separating cranial and spinal CSF. CSF pressures were recorded via cannulas positioned in lateral ventricle and lumbar subarachnoid space at L3 vertebrae, respectively. RESULTS: After intravenous bolus of 20% mannitol (0.5 or 1.0 g/kg/ 3 min) in control animals without cervical stenosis, the fall of both ventricular and lumbar CSF pressures was equal over time. At 15 min after mannitol application in cats with cervical stenosis an slight increase of ventricular and a fall of lumbar CSF pressures were observed, while at 30 min a gradient of these pressures of 5.5 and 7 cm H2O at lower and higher dose of mannitol, respectively, were registered. However, after removal of cervical stenosis these gradients disappeared. CONCLUSION: The observed changes of CSF pressures in spinal and intracranial space indicate that spinal subarachnoid space contributes a great deal to overall fall of CSF pressure and volume in the early period after mannitol application probably due to high compliance of the spinal dura.

CSF pressure, papilledema grade, and response to acetazolamide in the Idiopathic Intracranial Hypertension Treatment Trial.

Previous reports suggest an association between the degree of optic nerve head edema and CSF pressure (CSFp) in idiopathic intracranial hypertension (IIH). We hypothesized that CSFp would be associated with Frisén papilledema grade (FPG) and other clinical features, and that FPG would modify the CSFp response to acetazolamide in participants in the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT). In the IIHTT, eligible patients underwent lumbar puncture (LP) prior to enrollment and were randomly assigned to one of two treatment groups: acetazolamide plus supervised diet or placebo plus supervised diet. Trial eligibility required baseline CSFp ≥250 mm H2O or ≥200 mm H2O with compelling clinical or imaging IIH findings. Associations between CSFp and FPG and other clinical features were examined at baseline. The effect of acetazolamide on 6-month change in CSFp was examined in those with low FPG (grades I-III) and those with high FPG (grades IV-V) at baseline. All 165 enrolled subjects had a baseline LP and 85 had an LP at 6 months. There was an association between CSFp and FPG at baseline: CSFp was more elevated in subjects with high FPG (378 ± 90 mm H2O, n = 50) than in subjects with low FPG (331 ± 77, n = 115, p = 0.002). At 6 months, acetazolamide had a similar effect on CSFp in subjects with high FPG (-79.9 mm H2O) and in subjects with low FPG (-50.9 mm H2O, p = 0.50). We found a modest association between CSFp and FPG. Acetazolamide had a beneficial effect on CSFp regardless of baseline FPG.

The methodology and pharmacokinetics study of intraventricular administration of vancomycin in patients with intracranial infections after craniotomy.

OBJECTIVE: The purpose of the study was to investigate the pharmacokinetics of combined intravenous (i.v.) and intracerebroventricular (i.c.v.) vancomycin for patients with intracranial infections after craniotomy and to provide the basis for establishing the intracranial local administration criterion. METHODS: Fourteen postoperative intracranial infection cases with surgical cavity/ventricular drainages were given vancomycin (1.0 g, i.v. drip for 2 hours, quaque 12 h, and a simultaneous i.c.v. injection of 10 mg). Their blood and cerebral spinal fluid (CSF) specimens were collected at each time point before and after administrations. The concentrations and biochemical properties were measured. RESULTS: The 1-hour serum vancomycin concentration reached a peak of 46.38 ± 33.39 mg/L; the trough concentration of 48 hours was 8.10 ± 7.11 mg/L; the CSF vancomycin concentration reached a peak of 382.17 ± 421.00 mg/L at 0.25 hours, and the 48-hour trough concentration was 30.82 ± 29.53 mg/L. The inhibitory quotient was calculated at 15.4 by the minimum inhibitory concentration 2 mg/L of target bacteria and had reached the range of 10 to 20 recommended by Infectious Diseases Society of America guidelines. The pH value and osmotic pressure of CSF were found to have no significant changes before and after administration. There was no increasement of seizures and ototoxicity in our study. Before the drug administration and 1 week later, the changes of creatine had no statistically significant, with P > .05. CONCLUSIONS: The combined i.v. and i.c.v. administration may improve CSF vancomycin concentrations without side effects at the same dosage. Our finding suggests that it can be an option for the treatment of severe intracranial infections after craniotomy; however, its safety and effectiveness need to be confirmed by further large-scale studies.

Indomethacin reduces CSF pressure in intracranial hypertension.

The CSF-pressure-lowering effects of indomethacin in seven patients with idiopathic intracranial hypertension and one patient with symptomatic intracranial hypertension due to a non-space-occupying meningioma are reported. CSF opening pressure between 350 and 500 mm H2O (mean 400 mm H2O) was promptly reduced by 80 to 200 mm H2O (mean reduction, 139 mm H2O) for at least 10 minutes in all patients after IV administration of 50 mg indomethacin. Four patients had mild and transient side effects (dizziness). Indomethacin might be an alternative drug for treatment of intracranial hypertension.

Urapidil. A reappraisal of its use in the management of hypertension.

UNLABELLED: Urapidil is a peripheral postsynaptic alpha 1-adrenoceptor antagonist with central agonistic action at serotonin 5-HT1A receptors. It reduces blood pressure by decreasing peripheral vascular resistance. Oral urapidil decreases blood pressure in patients with mild to moderate essential hypertension and associated risk factors such as hyperlipidaemia or type 2 (non-insulin-dependent) diabetes mellitus with no effect on heart rate. The antihypertensive efficacy of urapidil is similar to that of most comparators in patients with mild to moderate essential or secondary hypertension and no concomitant risk factors. However, the antihypertensive efficacy of urapidil was lower than that of hydrochlorothiazide in a well designed trial. Lipid levels and glucose metabolism are not adversely affected and may improve with urapidil in patients with lipid or glucose abnormalities. Urapidil can be safely combined with other antihypertensive agents such as hydrochlorothiazide and nifedipine and improves blood pressure control in previous nonresponders to monotherapy. Intravenous urapidil reduces blood pressure in patients with pre-eclampsia or hypertension in pregnancy and in patients with hypertensive crises or peri- or postoperative hypertension. The decrease in blood pressure is similar to that observed after nifedipine, enalaprilat, sodium nitroprusside and dihydralazine, greater than that of ketanserin according to 1 larger study, and greater than that of sublingual nitroglycerin in 1 trial in patients with nonsurgical hypertensive crises and pulmonary oedema. However, more patients responded to treatment with urapidil than with enalaprilat or nifedipine. Heart rate is less likely to be altered by urapidil than with some comparator drugs. Urapidil appears to be well tolerated, with most adverse events being mild and transient. The incidence of adverse events with urapidil is similar to that with prazosin, metoprolol, atenolol, sodium nitroprusside and hydrochlorothiazide and less than that with nifedipine and clonidine. Urapidil may not be as well tolerated as captopril and, in 1 study, more urapidil than nitrendipine recipients discontinued treatment because of adverse events. CONCLUSIONS: urapidil reduces blood pressure without altering heart rate. The oral formulation is an effective choice in patients with hypertension and concomitant dyslipidaemia or type 2 diabetes mellitus, in whom the drug does not adversely affect and may improve lipid profiles and glucose metabolism. The intravenous formulation is effective in controlling various hypertensive crises and hypertension associated with pregnancy or surgery and is similar to or better than other first-line agents used in these conditions. Thus, urapidil may be a useful alternative to currently available antihypertensive agents.

Spinal cord protection with intravenous nimodipine. A functional and morphologic evaluation.

The purpose of this study is to determine the effects of ischemia in the spinal cord when a calcium channel blocker, nimodipine, is administered intravenously before, during, and after crossclamping of the thoracic aorta. In this series of experiments, 18 pigs underwent thoracotomies and had 17.5 to 18.0 cm of the thoracic aorta clamped for 30 minutes. By random selection, nine animals received intravenous nimodipine (2 micrograms/kg per minute) and nine control animals received only a carrier solution. Of the nine animals that received nimodipine, eight walked after the operation. In contrast, in the control group only two of nine animals walked. The ninth nimodipine-treated animals walked but had a severe delayed deterioration response. All animals, except one control animal, had a negative central spinal perfusion pressure. Morphologic examination of serial sections of spinal cords from control animals showed diffuse neuronal necrosis. In comparison, cords from the nimodipine group had swollen neurons accompanied by an inflammatory infiltrate and only occasional necrotic neurons. With this data, we conclude that certain calcium channel blockers, when administered in sufficient doses, can lend a protective effect to the spinal cord during ischemic events even when cord perfusion pressure has dropped to dangerously low levels.