Intracerebral hemorrhage in pregnancy: frequency, risk factors, and outcome.

OBJECTIVE: To describe the frequency, risk factors, and outcome of intracerebral hemorrhage (ICH) in pregnancy and the postpartum period using a large database of US inpatient hospitalizations. METHODS: The authors obtained data from an administrative dataset, the Nationwide Inpatient Sample, which includes approximately 20% of all discharges from non-Federal hospitals, for the years 1993 through 2002. Women aged 15 to 44 years with a diagnosis of ICH were selected from the database for analysis, and within this group patients coded as pregnant or postpartum were identified. Using US Census data, estimates were made of the rates of ICH in pregnant/postpartum and non-pregnant women. Rates of various comorbidities in patients with pregnancy-related ICH were compared to the rates found in the general population of delivering patients using multivariate logistic regression to identify independent risk factors for pregnancy-related ICH. RESULTS: The authors identified 423 patients with pregnancy-related ICH, which corresponded to 6.1 pregnancy-related ICH per 100,000 deliveries and 7.1 pregnancy-related ICH per 100,000 at-risk person-years (compared to 5.0 per 100,000 person-years for non-pregnant women in the age range considered). The increased risk of ICH associated with pregnancy was largely attributable to ICH occurring in the postpartum period. The in-hospital mortality rate for pregnancy-related ICH was 20.3%. ICH accounted for 7.1% of all pregnancy-related mortality recorded in this database. Significant independent risk factors for pregnancy-related ICH included advanced maternal age (OR 2.11, 95% CI 1.69 to 2.64), African American race (OR 1.83, 95% CI 1.39 to 2.41), preexisting hypertension (OR 2.61, 95% CI 1.34 to 5.07), gestational hypertension (OR 2.41, 95% CI 1.62 to 3.59), preeclampsia/eclampsia (OR 10.39, 95% CI 8.32 to 12.98), preexisting hypertension with superimposed preeclampsia/eclampsia (OR 9.23, 95% CI 5.26 to 16.19), coagulopathy (OR 20.66, 95% CI 13.67 to 31.23), and tobacco abuse (OR 1.95, 95% CI 1.11 to 3.42). CONCLUSION: Intracerebral hemorrhage (ICH) accounts for a substantial portion of pregnancy-related mortality. The risk of ICH associated with pregnancy is greatest in the postpartum period. Advanced maternal age, African American race, hypertensive diseases, coagulopathy, and tobacco abuse were all independent risk factors for pregnancy-related ICH.

Treatment of unruptured cerebral aneurysms in California.

BACKGROUND AND PURPOSE: The impact of endovascular therapy on treatment outcomes of unruptured cerebral aneurysms has not been studied in a defined geographic area. METHODS: All primary diagnoses of unruptured aneurysms were retrieved from a statewide database of hospital discharges in California from January 1990 through December 1998. Admissions for initial treatment and all follow-up care were combined to reflect the entire course of therapy. An adverse outcome was defined as an in-hospital death or discharge to nursing home or rehabilitation hospital at any point during the treatment course. Multivariable analyses were performed with generalized estimating equations with adjustment for age, sex, ethnicity, source of admission, year of treatment, hospital volume, and clustering of observations at institutions. RESULTS: A total of 2069 patients were treated for unruptured aneurysms. Adverse outcomes were more frequent in the 1699 patients treated with surgery (25%) than in those treated with endovascular therapy (10%; P:<0.001). The difference persisted after multivariable adjustment (surgery versus endovascular therapy: odds ratio for adverse outcomes, 3.1; 95% CI, 2.5 to 4.0; P:<0.001). Adverse outcomes declined from 1991 to 1998 in patients treated with endovascular therapy (P:<0.005) but not for surgery. In-hospital deaths occurred in 3.5% of surgical cases and 0.5% of endovascular cases (P:=0.003), and the difference remained significant after adjustment (odds ratio, 6.3; 95% CI, 3.5 to 11.4; P:<0.001). Total length of stay and hospital charges were greater in surgical cases (both P:<0.001). Results were similar in a confirmatory analysis focusing on treatment differences between institutions. Institutional treatment volume was also associated with outcome but did not account for the differences between surgery and endovascular therapy. CONCLUSIONS: In California, endovascular therapy of unruptured aneurysms is associated with less risk of adverse outcomes and in-hospital death, lower hospital charges, and shorter hospital stays compared with surgery. Differences between therapies became more distinct through the years. Uncontrolled differences in prognosis of patients receiving endovascular therapy and surgery cannot be ruled out in this study of discharge abstracts.

The epidemiology of brain arteriovenous malformations.

OBJECTIVE: Common estimates of the prevalence rate for pial arteriovenous malformations (AVMs) of the brain vary widely, and their accuracy is questionable. Our objective was to critically review the original sources from which these rates were derived and to establish best estimates for both the incidence and prevalence of the disease. METHODS: We reviewed all of the relevant original literature: autopsy series, the Cooperative Study of Intracranial Aneurysms and Subarachnoid Hemorrhage and related analyses, and other population-based studies. We also modeled the confidence intervals of estimates for a process of low prevalence such as AVMs. RESULTS: Many of the prevalence estimates (500-600/100,000 population) were based on autopsy data, a source that is inherently biased. Other estimates (140/100,000 population) originated from an inappropriate analysis of data from the Cooperative Study. The most reliable information comes from a population-based study of Olmsted County, MN, but prevalence data specific to AVMs was not found in that study. CONCLUSION: The estimates for AVM prevalence that are published in the medical literature are unfounded. Because of the rarity of the disease and the existence of asymptomatic patients, establishing a true prevalence rate is not feasible. Owing to variation in the detection rate of asymptomatic AVMs, the most reliable estimate for the occurrence of the disease is the detection rate for symptomatic lesions: 0.94 per 100,000 person-years (95% confidence interval, 0.57-1.30/100,000 person-years). This figure is derived from a single population-based study, but it is supported by a reanalysis of other data sources. The prevalence of detected, active (at risk) AVM disease is unknown, but it can be inferred from incidence data to be lower than 10.3 per 100,000 population.

Determinants of resource utilization in the treatment of brain arteriovenous malformations.

BACKGROUND AND PURPOSE: Preoperative embolization of arteriovenous malformations (AVMs) is thought to improve outcome following surgical resection of these lesions. The purpose of this study was to examine the cost associated with preoperative embolization and different surgical risk categories in the surgical treatment of brain AVMs. METHODS: In a review of 126 patients treated surgically for resection of AVMs, we noted the total days spent in the hospital and calculated the associated costs (from hospital and estimated professional fees). Surgical risk category was determined using the Spetzler-Martin grading system. We examined the effect of risk category, preoperative embolization, and outcome (Rankin score) on cost and inpatient days. RESULTS: Preoperative embolization and greater surgical risk were independently associated with higher total costs. Average adjusted cost for embolization and surgery was $78,400 +/- $4,900 versus $49,300 +/- $5,800 for surgery alone. Patients ranged in preoperative risk category from Spetzler-Martin grades II through V, with an average increase of $20,100 in total cost per Spetzler-Martin grade (95% CI, $13,500 to $28,100). Higher surgical risk category was also associated with more days spent in hospital, with an average increase of 6 days per increment in Spetzler-Martin grade (95% CI, 4 to 8). After surgical resection of an AVM, new neurologic deficits were associated with large differences in cost: $68,500 +/- $6,100 and 15 +/- 2 days in hospital for patients who were neurologically worse after surgery, versus $44,700 +/- $3,900 and 10 +/- 1 days for patients who were unchanged. CONCLUSION: Preoperative embolization in the treatment of AVMs is associated with higher cost but not more days in the hospital. Patients with higher Spetzler-Martin grade AVMs utilize more hospital resources, in part because they have poorer neurologic outcome, and postoperative deficits are associated with higher costs and more days in the hospital.

The effect of a drug and supply cost feedback system on the use of intraoperative resources by anesthesiologists.

UNLABELLED: We performed a randomized, prospective study to evaluate the use of a written feedback system in reducing the intraoperative costs of drugs and supplies used by anesthesiologists. Over 6 mo, 27 anesthesiology residents were randomized to feedback and control groups for their rotations in neurosurgical anesthesia. We recorded the cost of drugs and supplies for three procedures: carotid endarterectomy, lumbar decompression, and cervical decompression. For each study case, members of the feedback group received a written cost analysis showing their performance relative to the departmental average. Members of the feedback group had significantly lower costs for carotid endarterectomies ($79.98 +/- $15.20 vs $97.59 +/- $21.53) and for lumbar decompressions ($56.72 +/- $16.49 vs $76.05 +/- $20.11). The source of savings included lower use rates for propofol and etomidate and for patient warming devices. Analysis of data from recovery areas revealed a trend toward lower patient temperature in lumbar procedures performed by the feedback group. Three months after the feedback period, we collected a follow-up data set in the absence of feedback. This revealed a significant rebound in overall cost by the feedback group for both carotid endarterectomies and lumbar surgery. IMPLICATIONS: This is the first randomized, prospective evaluation of a cost management system in anesthesia. Using resident anesthesiologists, we showed that the written feedback of individualized performance data can be used to lower the overall cost of intraoperative drugs and supplies used for an anesthetic in the absence of mandated clinical guidelines.

An analogue of cAMP mimics developmental change in neonatal rat ventricular myocyte sodium current kinetics.

During development, the voltage dependence of single rat ventricular sodium channels shifts to more negative potentials. This shift is mimicked by coculture of neonatal myocytes with sympathetic neurons or by a 96-h exposure to 8-(4-chlorophenylthio) adenosine 3',5'-cyclic monophosphate (CPT-cAMP). The prolonged exposure to CPT-cAMP suggests that this is not a short-term modulatory effect on the sodium channel, but rather may reflect a trophic action. Here we examine the effect of CPT-cAMP using whole cell recording to investigate further the time period required for the effect. Sodium current was measured in a 50 mM NaCl bath solution at 20 +/- 1 degree C using the whole cell patch-clamp technique after exposure of myocytes to CPT-cAMP (0.25 mM) for 0,0.5,20, or 24 h. The relationship between the time constant of decay (tauh) of the sodium current and test voltage (V1) showed a shift to more hyperpolarizing voltages after exposure to CPT-cAMP for 24 h. In addition, the midpoint of the steady-state inactivation curve (V 1/2) was shifted from -75.8 +/- 1.1 mV (0-h exposure) to -83.3 +/- 1.6 mV (24-h exposure) (P < 0.05). Exposure for 0.5 h to CPT-cAMP did not alter the tauh or V 1/2 of the sodium current. However, exposure to CPT-cAMP for 20 h, followed by a 4-h washout period, produced an effect similar to that of the 24-h exposure. Thus the lack of effect of acute (0.5 h) exposure to CPT-cAMP and the persistence of the effect after washout of CPT-cAMP for 4 h suggest that adenosine 3',5'-cyclic monophosphate may play a trophic role in sodium channel development.

Implantable cardioverter-defibrillator. Evaluation of clinical neurologic outcome and electroencephalographic changes during implantation.

During placement of implantable cardioverter-defibrillators, ventricular arrhythmias are induced to test the function of the devices. Although cerebral hypoperfusion and ischemic electroencephalographic changes occur in patients while implantable cardioverter-defibrillators are being tested, no investigation has assessed neurologic outcome in these patients. Nine patients having either implantation or change of an implantable cardioverter-defibrillator underwent neurologic examination and neuropsychometric tests before and after the operation. After induction of general anesthesia and insertion of implantable cardioverter-defibrillator leads (when needed), ventricular fibrillation, ventricular flutter, or ventricular tachycardia, was induced by means of programmed electrical stimulation. Implantable cardioverter-defibrillator testing continued until satisfactory lead placement was confirmed. The intraoperative electroencephalographic recording was analyzed for evidence of ischemic change. In all, an electroencephalogram was recorded during 50 periods of circulatory arrest. Mean duration of the arrest periods was 13.6 seconds. By means of conventional visual inspection of the raw electroencephalogram, high-amplitude rhythmic delta or theta, voltage attenuation, or loss of fast frequency activity was observed in 30 of the arrests. By means of an automated technique of electroencephalographic interpretation based on power spectral analysis, electroencephalographic changes were correctly identified in 26 of the arrests. The incidence of these electroencephalographic changes was dependent on the arrest duration. The mean interval from arrest onset to electroencephalographic change was 7.5 seconds (standard deviation +/- 1.8 seconds). In patients with electroencephalographic changes during multiple arrests, no downward trend in this interval was detected in later arrests and no evidence of persistent ischemic change was observed in electroencephalograms recorded after the conclusion of implantable cardioverter-defibrillator testing. Postoperative neurologic and neuropsychometric testing was completed in eight patients, none of whom exhibited a new neurologic deficit, exacerbation of a preexisting neurologic condition, or significant deterioration in neuropsychometric performance. We conclude that the brief arrest of cerebral circulation induced during insertion of an implantable cardioverter-defibrillator is not associated with permanent neurologic injury.

Relative sodium current block by bupivacaine and lidocaine in neonatal rat myocytes.

Bupivacaine is more cardiotoxic than lidocaine and can produce fatal arrhythmias during accidental overdose or intravascular injection. Studies using Vmax in adult guinea pig myocytes suggest that this toxicity is due to the greater inhibition of sodium current by bupivacaine. Human neonates and cardiac tissue from neonatal animals show resistance to the cardiac effects of many local anesthetic and antiarrhythmic drugs, and a slower onset of use-dependent block. We used whole-cell patch clamp (20 degrees C, [Na]o = 50 mmol/L) to examine directly the kinetics of sodium current block by bupivacaine and lidocaine in ventricular myocytes from 1- to 2-day-old rats. We found that 1 microgram/mL bupivacaine and 5 micrograms/mL lidocaine produced equivalent amounts of use-dependent block for protocols corresponding to 30-200 depolarizations per minute (cell resting potential of -85 mV). Block due to bupivacaine surpassed that from lidocaine (37.6% +/- 3.4% vs 26.4% +/- 2.7%) (P < 0.01) only after the resting membrane potential was hyperpolarized to -110 mV and the length of depolarization and repolarization were increased to nonphysiologic durations (1 s and 0.5 s, respectively). Double-pulse protocols were used to measure the underlying rate of onset and recovery from block. At these concentrations, blockade development was more than seven times slower for bupivacaine (4.11 +/- 0.32 s vs 0.57 +/- 0.06 s) (P < 0.01, and recovery from block was five times slower (10.81 +/- 0.54 s vs 2.14 +/- 0.50 s) (P < 0.01). In these neonatal myocytes, bupivacaine does not produce more use-dependent block than lidocaine, and the effect of bupivacaine is limited by its slow binding to the sodium channel.

Functional role of the NH2-terminal cytoplasmic domain of a mammalian A-type K channel.

It has been shown for a Shaker channel (H-4) that its NH2-terminal cytoplasmic domain may form a "ball and chain" structure, with the "chain" tethering the "ball" to the channel while the "ball" capable of binding to the channel in its open state and causing inactivation. Equivalent structures have not been identified in mammalian Shaker homologues. We studied the functional role of the NH2-terminal region of a fast-inactivating mammalian K channel, RHK1 (Kv1.4), by deleting different domains in this region and examining the resultant changes in channel properties at whole cell and single channel levels. Deleting the NH2-terminal hydrophobic domain (domain A) or the subsequent positive charges (domain I) from RHK1 greatly slowed the decay of whole cell currents, suggesting the existence of a ball-like structure in RHK1 similar to that in the Shaker channel. The function of the ball appeared to be abolished by deleting domain A, while modified but maintained by deleting domain I. In the latter case, the data suggest that the positive charges needed for the function of the ball can be replaced by amino acids from a following region (domain III) that has a high positive charge density. Deleting multiple domains from the NH2 terminus of RHK1 corresponding to the chain in Shaker H-4 did not induce expected changes in channel properties that might result from a shortening of a chain. A comparison of single channel kinetics of selected mutant channels with those of the wild-type channel indicated that these deletion mutations slowed whole cell currents by prolonging burst durations and by increasing the probability of reopening during depolarization. There were no changes in single channel current amplitude or latency to first opening. In conclusion, our observations indicate that the inactivation mechanism of RHK1 is similar to that of Shaker H-4 in that a positively charged cytoplasmic domain is important for such a process. The NH2-terminal domain is not involved in channel activation or ion permeation process.

Pancuronium increases the duration of electroencephalogram burst suppression in dogs anesthetized with isoflurane.

Earlier studies have demonstrated both a decrease as well as no effect on halothane MAC after administration of nondepolarizing neuromuscular relaxants. To clarify further the relationship between neuromuscular blocking agents and anesthetic potency, the authors studied the effect of pancuronium on steady-state electroencephalogram (EEG) burst suppression produced by isoflurane in dogs. Anesthesia was induced using isoflurane and oxygen via mask without the administration of other drugs. The trachea was intubated, and isoflurane was administered at a concentration sufficient to produce EEG burst suppression. Thereafter, end-tidal isoflurane concentration, temperature, and end-tidal PCO2 were meticulously maintained at constant values. Dogs in group 1 (n = 6) received pancuronium 0.1 mg.kg-1. The percent of the EEG that was isoelectric increased from 21 +/- 9% (mean +/- SD) to 35 +/- 11% (P less than 0.01). After the return of single-twitch response to train-of-four stimulation, neostigmine 0.05 mg.kg-1 and glycopyrrolate 0.01 mg.kg-1 were administered. This resulted in a reduction in EEG isoelectricity to 19 +/- 8% (P less than 0.01), similar to the value before pancuronium administration. In group 2 dogs (n = 6), the percent isoelectricity of the EEG prior to pancuronium was 25 +/- 10%. After administration of pancuronium 0.02, 0.04, and 0.2 mg.kg-1 sequentially, the percent isoelectricity of the EEG was 29 +/- 11, 37 +/- 15, and 43 +/- 9%, respectively. This represents a dose-related increase in isoelectricity for the 0.04- and 0.2-mg.kg-1 doses (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

The susceptibility of thermistor-based esophageal temperature probes to errors caused by electrically conductive fluids ("artificial saliva").

Several brands of esophageal stethoscopes with thermistor-based thermometers were tested to determine the susceptibility of the probe connector to contamination by oral secretions. A solution of half normal saline and 1% carboxy-methyl-cellulose was used to model the conductivity and viscosity of saliva. When 1 ml of test solution was allowed to track down the probe wires to the connector, several brands of thermistors gave erroneously elevated readings. The mean changes in temperature according to brand of thermistor were as follows: Electromedics, 0.1 +/- 0.1 degree C; Mallinckrodt, 1.7 +/- 0.8 degrees C; Respiratory Products, 0.1 +/- 0.2 degrees C; Sheridan, 3.6 +/- 1.9 degrees C; Vital Signs, 4.8 +/- 1.3 degrees C (peak) and 1.4 +/- 1.6 degrees C (final); and Yellow Springs, 0.9 +/- 0.4 degrees C. The manufacturers of the probes susceptible to this type of error should implement the appropriate design modifications. In the meantime, clinicians should be aware of this problem and may choose to prevent these errors by wrapping the connection with waterproof tape.

Single sodium channels from canine ventricular myocytes: voltage dependence and relative rates of activation and inactivation.

1. Single sodium channel currents were recorded from canine ventricular myocytes in cell-attached patches. The relative rates of single-channel activation vs. inactivation as well as the voltage dependence of the rate of open-channel inactivation were studied. 2. Ensemble-averaged sodium currents showed relatively normal activation and inactivation kinetics, although the mid-point of the steady-state inactivation (h infinity) curve was shifted by 20-30 mV in the hyperpolarizing direction. This shift was due to the bath solution, which contained isotonic KCl to depolarize the cell to 0 mV. 3. Steady-state activation showed less of a voltage shift. The threshold for eliciting channel opening was around -70 mV and the mid-point of activation occurred near -50 mV. 4. The decline of the ensemble-averaged sodium current during a maintained depolarization was fitted by a single exponential function characterizing the apparent time constant of inactivation (tau h). The apparent rate of inactivation was voltage dependent, with tau h decreasing e-fold for a 15.4 mV depolarization. 5. The relative contributions of the rates of single-channel activation and inactivation in determining the time course of current decay (tau h) were examined using the approach of Aldrich, Corey & Stevens (1983). Mean channel open time (tau o) showed significant voltage dependence, increasing from 0.5 ms at -70 mV to around 0.8 ms at -40 mV. At -70 mV tau h was much greater than tau o, while at -40 mV the two time constants were similar. 6. The degree to which the kinetics of single-channel activation contribute to tau h was studied using the first latency distribution. The first latency function was fitted by two exponentials. The slow component was voltage dependent, decreasing from 19 ms at -70 mV to 0.5 ms at -40 mV. The fast component (0.1-0.5 ms) was not well resolved. 7. Comparing the first latency distribution with the time course of the ensemble-averaged sodium current at -40 mV showed that activation is nearly complete by the time of peak inward sodium current. However, at -70 mV, activation overlaps significantly with the apparent time course of inactivation of the ensemble-averaged current. 8. Using the methods of Aldrich et al. (1983) we also measured the apparent rate of open-channel closing (a) and open-channel inactivation (b). Both rates were voltage dependent, with a showing an e-fold decrease for an 11 mV depolarization and b showing an e-fold increase for a 30 mV depolarization.(ABSTRACT TRUNCATED AT 400 WORDS)

Essential role of GTP in the expression of adenylate cyclase activity after cholera toxin treatment.

Expression of activation of rat liver adenylate cyclase by the A1 peptide of cholera toxin and NAD is dependent on GTP. The nucleotide is effective either when added to the assay medium or during toxin (and NAD) treatment. Toxin treatment increases the Vmax for activation by GTP and the effect of GTP persists in toxin-treated membranes, a property seen in control membranes only with non-hydrolyzable analogs of GTP such as Gpp(NH)p. These observations could be explained by a recent report that cholera toxin acts to inhibit a GTPase associated with denylate cyclase. However, we have observed that one of the major effects of the toxin is to decrease the affinity of guanine nucleotides for the processes involved in the activation of adenylate cyclase and in the regulation of the binding of glucagon to its receptor. Moreover, the absence of lag time in the activation of adenylate cyclase by GTP, in contrast to by Gpp(NH)p, and the markedly reduced fluoride action after toxin treatment suggest that GTPase inhibition may not be the only action of cholera toxin on the adenylate cyclase system. We believe that the multiple effects of toxin action is a reflection of the recently revealed complexity of the regulation of adenylate cyclase by guanine nucleotides.