Serum cleaved Tau protein and neurobehavioral battery of tests as markers of brain injury in experimental bacterial meningitis.

Brain injury due to bacterial meningitis affects multiple areas of the brain with a heterogeneous distribution generating a challenge to assess severity. Tau proteins are microtubular binding proteins localized in the axonal compartment of neurons. Brain injury releases cleaved Tau proteins (C-tau) into the extracellular space where they are transported to the cerebral spinal fluid. We hypothesized that C-tau crosses the blood-brain barrier during inflammation and that it can be detected in serum. The correlation between serum C-tau levels and the extent of the meningitic insult was examined. Furthermore, we studied whether the use of a subset of neurobehavioral tasks can assess the extent of brain injury after meningitis. The tests were chosen primarily for their ability to detect deficits in the acoustic system, low brain, reflexive responding, as well as for impaired motor coordination and the higher brain functions of learning and memory. A rat model of group B streptococcal meningitis with variable severity was utilized. At five days after bacterial inoculation followed by antibiotic therapy neurobehavioral tests were performed and serum C-tau and histologic samples of the brain were obtained. Our study shows that during meningitis C-tau appears in serum and reflects the extent of neurologic damage. Neurobehavioral performance was altered after bacterial meningitis and could be correlated with histologic and biochemical markers of neurologic sequelae. We conclude that serum C-tau and a composite of neurobehavioral tests could become useful markers for assessing the severity of neurological damage in experimental bacterial meningitis.

Hypothermia attenuates beta1 integrin expression on extravasated neutrophils in an animal model of meningitis.

Brain injury in meningitis occurs in part as a consequence of leukocyte migration and activation. Leukocyte integrins are pivotal in the inflammatory response by mediating adhesion to vascular endothelium and extracellular matrix proteins. We have demonstrated that moderate hypothermia early in the course of meningitis decreases leukocyte sequestration within the brain parenchyma. This study examines whether hypothermia alters neutrophil integrin expression in a rabbit model of bacterial meningitis. Prior to the induction of meningitis, peripheral blood samples were obtained and the neutrophils isolated. Sixteen hours after inducing group B streptococcal meningitis, animals were treated with antibiotics, i.v. fluids, and mechanically ventilated. Animals were randomized to hypothermia (32-33 degrees C) or normothermia conditions. After 10 hours of hypothermia or normothermia, neutrophils were isolated from the blood and cerebral spinal fluid (CSF), stained for beta1 and beta2 integrins, and analyzed using flow cytometry. Cerebral spinal fluid neutrophil beta1 integrin expression was significantly decreased in hypothermic animals. Beta-1 integrins can assume a higher affinity or "activated" state following inflammatory stimulation. Expression of "activated" beta1 integrins was also significantly decreased in hypothermic animals. Beta2 CSF neutrophil integrin expression was decreased in hypothermic animals, but failed to reach significance. These data suggest hypothermia may attenuate extravasated leukocyte expression of both total and "activated" beta1 integrins.

La Crosse encephalitis in children.

BACKGROUND: La Crosse encephalitis is a mosquito-borne disease that can be mistaken for herpes simplex encephalitis. It has been reported in 28 states but may be underrecognized. METHODS: We investigated the manifestations and clinical course of La Crosse encephalitis in 127 patients hospitalized from 1987 through 1996. The diagnosis was established by serologic testing for IgM and IgG antibodies to La Crosse virus. Data were collected by chart review. RESULTS: Most of the patients were school-aged children (mean [+/-SD] age, 7.8+/-3.5 years; range, 0.5 to 15.0). Symptoms included headache, fever, and vomiting (each in 70 percent or more of the patients), seizures (in 46 percent), and disorientation (in 42 percent). Thirteen percent had aseptic meningitis. Hyponatremia developed in 21 percent, and there were signs of increased intracranial pressure in 13 percent. Six patients, including three with cerebral herniation, underwent intracranial-pressure monitoring. The 13 patients (11 percent) whose condition deteriorated in the hospital had decreases in serum sodium levels (P=0.007), and increases in body temperature (P=0.003) at the time of deterioration. At admission, these patients more often had a history of vomiting (P=0.047) and a score of 12 or lower on the Glasgow Coma Scale (P=0.02) than the others; a trend toward a greater prevalence of seizures at admission was also evident in this group (P=0.07). All the patients survived, but 15 of them (12 percent) had neurologic deficits at discharge. Follow-up assessments, performed in 28 children, suggested an increase in cognitive and behavioral deficits 10 to 18 months after the episode of encephalitis. CONCLUSIONS: La Crosse virus infection should be considered in children who present with aseptic meningitis or encephalitis. Hyponatremia and increasing body temperature may be related to clinical deterioration.

Evaluating the frequency rate of hypomagnesemia in critically ill pediatric patients by using multiple regression analysis and a computer-based neural network.

OBJECTIVES: To determine the frequency rate of hypomagnesemia in patients admitted to the pediatric intensive care unit (ICU), and to identify subsets of patients (grouped by disease) who are at greatest risk of hypomagnesemia. We also compared a neural network model with multiple regression analysis to identify independent variables that would correlate with hypomagnesemia and to predict serum magnesium values in critically ill pediatric patients overall. DESIGN: Prospective, multicenter study. SETTING: Tertiary level medical/surgical pediatric ICUs. PATIENTS: Data were obtained at admission to the pediatric ICU for 463 patients from newborn to 18 yrs old who were admitted with a variety of surgical and nonsurgical conditions. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Total serum magnesium values were obtained within the first 24 hrs after admission in 463 pediatric patients admitted to four pediatric ICUs. Hypomagnesemia (defined as total serum magnesium <0.75 mmol/L) was found in 51 (11%) of the 463 patients, with the highest frequency rate (72%) and lowest mean serum magnesium level (0.66 +/- 0.17 mmol/L) in patients admitted after surgery with extensive osseous involvement (spinal fusion and craniofacial reconstruction). To determine whether hypomagnesemia could be predicted on the basis of other laboratory and clinical criteria, multiple regression analysis was performed and showed age, weight, and albumin levels weakly associated (r2 = .14, p < .001) with magnesium levels within the different diagnostic groups. These data were used to produce a mathematical model able to predict magnesium levels within 5% of the actual values in 23% of patients. A neural network was also created to compare its predictive capabilities to those of the multiple regression model. Once trained on a random subset (85%) of the patient population, the neural network was able to predict magnesium levels to within 5% of actual values for 88% of the remaining 15% of patients, comparing favorably with the predictions derived from the multiple regression model. CONCLUSIONS: Hypomagnesemia is not uncommon (11%) in critically ill pediatric patients, but is very common (72%) in patients admitted after surgery for spinal fusion or craniofacial reconstruction. Patients who undergo surgery for correction of scoliosis and craniofacial anomalies should have serum magnesium levels monitored closely after surgery. In other patients, a neural network or multiple regression model could help predict which patients would be at risk of developing hypomagnesemia, thereby focusing testing on patients likely to benefit from such testing.

Hypothermia as an adjunctive treatment for severe bacterial meningitis.

Brain injury due to bacterial meningitis results in a high mortality rate and significant neurologic sequelae in survivors. The objective of this study was to determine if the application of moderate hypothermia shortly after the administration of antibiotics would attenuate the inflammatory response and increase in intracranial pressure that occurs in meningitis. For this study we used a rabbit model of severe Group B streptococcal meningitis. The first component of this study evaluated the effects of hypothermia on blood-brain barrier function and markers of inflammation in meningitic animals. The second part of the study evaluated the effects of hypothermia on intracranial pressure, cerebral perfusion pressure and brain edema. This study demonstrates that the use of hypothermia preserves CSF/serum glucose ratio, decreases CSF protein and nitric oxide and attenuates myeloperoxidase activity in brain tissue. In the second part of this study we show a decrease in intracranial pressure, an improvement in cerebral perfusion pressure and a decrease in cerebral edema in hypothermic meningitic animals. We conclude that in the treatment of severe bacterial meningitis, the application of moderate hypothermia initiated shortly after antibiotic therapy improves short-term physiologic measures associated with brain injury.

Mercaptoethylguanidine attenuates inflammation in bacterial meningitis in rabbits.

Reactive oxygen and nitrogen species participate in the inflammatory process during meningitis. Among them, superoxide, nitric oxide (NO), and their reaction product peroxynitrite exert cytotoxic effects. Mercaptoethylguanidine (MEG) exerts beneficial effects in in vivo inflammatory conditions by scavenging peroxynitrite and inhibiting the inducible NO synthase. This study was designed to investigate whether MEG may attenuate inflammation and brain injury in experimental meningitis. Meningitis increased nitrite/nitrate, and protein content in the cerebrospinal fluid (CSF). In the brain tissue high levels of malondialdehyde and formation of nitrotyrosine indicated lipid peroxidation and nitrosative stress, respectively. Myeloperoxidase activity was increased indicating accumulation of neutrophils into the brain parenchyma. Treatment with MEG decreased nitrite/nitrate levels whereas it did not affect the bacterial clearance from the CSF. Furthermore, treatment with MEG markedly reduced brain tissue levels of myeloperoxidase and malondialdehyde. These data demonstrate that MEG could have a therapeutic role in meningitis.

Integrin expression on neutrophils in a rabbit model of Group B Streptococcal meningitis.

Products released by polymorphonuclear cells (PMNs) during an acute inflammatory response can result in diffuse tissue injury. Integrins are cell surface adhesion proteins that play a pivotal role in inflammation by allowing PMNs to adhere to the endothelium and migrate through the extracellular matrix. We examined the expression of beta1 and beta2 integrins on neutrophils from blood and cerebrospinal fluid (CSF) in an animal model of Group B Streptococcal meningitis. We further evaluated whether integrin expression correlates with pathophysiologic markers of central nervous system inflammation. Our data demonstrate that beta3 and beta2 integrin expression on circulating neutrophils does not significantly increase as a consequence of meningitis. In extravesated CSF neutrophils, a significant increase in expression of both beta1 and beta2 integrins is noted. Furthermore, a majority of the beta1 integrins on extravesated neutrophils have undergone affinity modulation. Using regression analysis, we demonstrated that increasing beta1 integrin expression correlates with decreasing CSF glucose concentration and serum/CSF glucose ratio. Regression analysis approached significance when CSF protein was compared to PMN beta1 integrin expression. Polymorphonuclear leukocytes beta1 integrin expression also showed a direct correlation to myeloperoxidase activity in brain tissue. Beta2 expression on CSF PMNs did not correlate with these markers of inflammation/sequestration. These data demonstrate integrin expression on extravesated neutrophils markedly increases during meningitis and support a role for beta1 integrins on neutrophils in the pathophysiologic consequences of meningitis.

Hypothermia decreases excitatory neurotransmitter release in bacterial meningitis in rabbits.

The excitatory neurotransmitters glutamate (GLU) and aspartate (ASP) are involved in the pathogenesis of neuronal injury in meningitis. Based on past findings that the induction of moderate hypothermia (32-34 degrees C) attenuates the release of GLU in ischemic brain injury, this study was designed to detect if the application of moderate hypothermia decreases the release of excitatory amino acids (EAA) from brain tissue of animals with bacterial meningitis. Also examined was whether meningitis induces the expression of 72-kDa heat shock protein (HSP 70) in the cerebellum and how hypothermia affects it, for induction of HSP 70 has been used as a sensitive marker of neuronal stress in other forms of brain injury. Meningitis was induced by injecting Group B Streptococcus (GBS) into the cisterna magnae of rabbits. Antibiotic treatment began 16 h later. At this time the animals were anesthetized, instrumented, and randomized to normothermic (Nor) or hypothermic (Hy) conditions. Temperatures were strictly regimented for the following 10 h while maintaining stable cardiorespiratory parameters. Cerebrospinal fluid (CSF) samples were then withdrawn to measure concentrations of bacteria, protein, and amino acids. Meningitis causes CSF contents of GLU and ASP to increase significantly. Hypothermia treated animals demonstrated a 40-50% reduction in CSF GLU and ASP. Meningitis induced the expression of HSP 70 in the cerebellum while hypothermic animals experienced a significant decrease HSP 70 induction. These data demonstrate that hypothermia produces an attenuation of the release of excitatory neurotransmitters in meningitis and suggest that this treatment may attenuate neuronal stress.

Topical nitroglycerin and pain in purpura fulminans.

Topical nitroglycerin has been previously described as an adjunctive therapy to increase perfusion to areas of purpura affected in purpura fulminans. We report a case of purpura fulminans in which topical nitroglycerin was found to provide analgesia after its application to purpuric lesions. The broader role for the use of topical nitroglycerin in pain management deserves further study and evaluation.

Decrease in costs for management of lower airway disease in the pediatric intensive care unit.

BACKGROUND: We investigated whether a recently restructured pediatric intensive care unit (PICU) had a decrease in the cost of patient care over the years. METHODS: We retrospectively studied 89 previously healthy patients admitted to the PICU of a community-based, university-affiliated teaching hospital over a 4-year period (1991 to 1994) for treatment of lower airway disease. Data collected were patient age, severity of illness, length of stay in both PICU and hospital, prorated hospital bill, year of admission, and patient-specific PICU-originated costs (POC). RESULTS: There was a decrease of POC over the 4-year period, though two factors were associated with a cost increase in this group of patients: an increase in the severity of illness and intubation. The decrease over the years remained present even when excluding intubated patients and adjusting for severity of illness. A decline of 58% below the initial cost for diagnostic tests was the most prominent of all the individual areas studied. Decreases in POC correlated with decreases in the prorated hospital bill. CONCLUSIONS: The costs of management for these previously healthy patients treated for lower airway disease decreased over the study period. We speculate that the time related decrease in costs is a reflection of the learning curve of the pediatric critical care team. The decrease in POC did not shift costs to other areas of the hospital.

Utilization of diagnostic resources for meningoencephalitis in the pediatric ICU.

To determine whether a Pediatric Critical Care team has an evolution of medical practice that decreases the utilization of diagnostic tests and consults, we examined the records of 69 patients admitted for meningitis or meningoencephalitis at Women and Children's Hospital in Charleston, W.Va., a university-affiliated, teaching hospital. The study was conducted from August 1990 to August 1994. We found that utilization of diagnostic resources (UDR) decreased over the four years, and there was a direct relationship between an increase in severity of illness and an increase in UDR. When adjusted per severity of illness, UDR decreased by $423 per year. The presence of a consult was a factor leading to an increase in resources, which were associated with an increased utilization of diagnostic tests and length of stay. The consultation rate was independent of the severity of illness and experienced a decrease over the years.

Compared contralateral application of topical nitroglycerin on purpura fulminans.

In cases of purpura fulminans (PF), various treatments have been used to prevent the cutaneous involvement and extensive skin necrosis that can be both disfuguring and debilitating. In this article, we present a case where improvement in the progression of purpuric areas was accomplished by topical administration of nitroglycerin (TNG), as evidenced by comparison with symmetrical contralateral areas not so treated.

Outcome and cost of child abuse.

OBJECTIVE: To compare the cases of child abuse (CA) with other admissions in a pediatric intensive care unit (PICU) for differences in patient-specific health care costs, severity of illness (SI) and mortality, and describe their outcome. METHOD: A retrospective cohort study of all patients admitted to the PICU between January 1991 and August 1994. Discharge diagnosis, age, SI, mortality rate, length of stay, hospitalization charges ($Hosp), and mortality were retrieved. RESULTS: There were 937 admissions; 13 were secondary to CA. Cases of CA represented 1.4% of admissions and 17% of deaths. CA patients had the highest SI (61%), $Hosp ($30,684), daily charges ($5,294) and mortality rates (53%) than any other group. In our patients, SI is a factor that affects charges. Even when compared to a cohort group with SI, child abuse patients had higher daily hospitalization charges (p < .05). The medical bills for the acute care of a CA patient averaged $35,641 per case. Even with these expenditures, 70% died and 60% of the survivors had severe residual morbidity. CONCLUSION: These results confirm that interventional medical care in response to severe CA is very costly and the ultimate outcome is significantly worse than other diseases. Therefore, we believe it is imperative to allocate resources to prevention.

Simple method of multipurpose airway access through percutaneous tracheostomy in rabbits (Oryctolagus cuniculus).

Before percutaneous tracheostomy, rabbits were anesthetized and placed in the supine position with the head extended. A needle cricothyroidotomy was then performed. With the help of a guidewire and vessel dilator, a sheath introducer with sideport extension was secured into the airway. This system provided airway access for introduction or sampling of materials while the animal was breathing around the sheath introducer or through the sideport. This simple procedure was used successfully in more than 25 rabbits that recuperated and lived for several days without ongoing medical support.

Intratracheal administration of fentanyl: pharmacokinetics and local tissue effects.

OBJECTIVE: To study the pharmacokinetics and local tissue effects resulting from the intratracheal administration of preservative-free fentanyl. DESIGN: Prospective, randomized, blinded and controlled animal study. SETTING: University research laboratory. SUBJECTS: Eighteen adult male New Zealand rabbits. INTERVENTIONS: Preservative-free fentanyl citrate or normal saline was administered by the intratracheal (i.t.) and intravenous (i.v.) routes to randomized groups of rabbits. The animals were killed at 24, 48 and 72 h following administration. MEASUREMENTS AND MAIN RESULTS: Plasma concentrations of fentanyl were measured before administration and at 2, 5, 10, 30, 60 and 120 min following administration by a specific radioimmunoassay. A detailed histological examination of the lung and tracheal tissue was performed to identify local side effects. There were no significant differences in the plasma fentanyl concentrations resulting from the i.v. or i.t. route of administration. In both groups, the concentrations of fentanyl were within the therapeutic range (i.t. 2.37 ng/ml, i.v. 2.53 ng/ml) by 2 min after injection and reached a maximum concentration within 5 min. The bioavailability of i.t. fentanyl was 71%. Microscopic examination of the respiratory system did not show significant differences between the two random groups overall. However, in the sub-group of animals killed at 24 h, more animals in the i.t. group showed signs of inflammation in the lung parenchyma. CONCLUSIONS: There is rapid absorption of fentanyl following i.t. administration. Pharmacokinetic parameters for fentanyl were not significantly altered by the route of administration. Although there were no signs that i.t. administration of preservative-free fentanyl produces lung injury, a transient and mild inflammatory response was detected at 24 h after administration.

Neurologic deficits restored after elective posterior fossa decompression.

Arnold Chiari malformation is a condition in which the contents of the posterior fossa are herniated below the level of the foramen magnum, and it occurs in three basic forms. Patients with this condition frequently have obstructive hydrocephalus which requires a ventriculo-peritoneal shunt. This article describes the case of a infant female patient with Arnold Chiari Type I, who suffered an episode of acute hydrocephalus and neurologic deterioration after ventriculo-peritoneal shunt malformation. A shunt revision did not reverse her neurologic deficits, so a posterior fossa decompression was performed which did improve her condition.

Effects of fentanyl administration on respiratory system compliance in infants.

OBJECTIVE: To determine if the analgesic doses of fentanyl used in a pediatric intensive care unit (ICU) setting adversely affect dynamic total respiratory system compliance in awake, intubated infants. DESIGN: Prospective case-control study. SETTING: Pediatric and pediatric cardiac ICUs of a tertiary university hospital. PATIENTS: Thirteen awake and mechanically ventilated children < 6 months of age. INTERVENTIONS: Measurements of dynamic total respiratory system compliance were obtained during steady-state conditions for 6 mins and continued for 10 mins after the rapid, intravenous administration of 4 micrograms/kg of fentanyl. No patient had received a narcotic, benzodiazepine, or muscle relaxant within the previous 4 hrs. MEASUREMENTS AND MAIN RESULTS: After fentanyl administration, dynamic total respiratory system compliance was unchanged in three patients, improved in nine patients, and deteriorated in one patient. The mean value for the entire group increased from 0.76 mL/cm H2O/kg before infusion to 0.82 mL/cm H2O/kg after infusion (p < .02), representing a 9.6% increase. None of the patients showed oxygen desaturation as assessed by continuous pulse oximeter, or episodes of chest wall rigidity. CONCLUSIONS: This work corroborates our clinical impression that rapid infusions of fentanyl at the dose tested in small infants do not adversely affect dynamic total respiratory system compliance. To the contrary, the sedating and analgesic effects may improve synchronous breathing and decrease voluntary muscle tone, resulting in improved dynamic total respiratory system compliance.

Monitoring in pediatric intensive care.

Monitoring plays an essential role in the management of critically ill children, although continuous observation along with frequent clinical examination remains the best readily available monitor. Unfortunately, human beings do not have the capability of a prolonged, uninterrupted attention span and nurses often have multiple tasks assigned that limit their ability for continuous observation. Furthermore, some information cannot be obtained accurately by clinical examination alone, e.g. oxygen saturation, ICP, etc. Therefore, it is important to understand the principles and practical points to be able to use these monitors, and first rule out malfunction, disconnection, or improper electrode placement when abnormal reading appear on these monitors before initiating clinical intervention on a patient.

Laser Doppler measurements of skin blood flow before, during, and after lumbar sympathetic blockade in children and young adults with reflex sympathetic dystrophy syndrome.

Changes in the skin capillary blood flow (SBF) and temperature before, during, and 1 hour after unilateral lumbar paravertebral sympathetic blockade (LSB) were studied simultaneously with laser Doppler flowmetry and thermometry in patients with reflex sympathetic dystrophy syndrome. The baseline flow measurements in the toes on the affected limb were significantly lower than in the contralateral limb (p less than 0.01). During LSB, a 10-fold increase in SBF was detected within 4 minutes after injection of a local anesthetic agent when the sympathetic blockade was effective; an increase of more than 1 degrees C in the skin temperature occurred within 11 minutes. Measurements 1 hour after blockade showed an 18-fold (mean) increase in SBF in the toes (p less than 0.0001) and a 2-fold (mean) increase in SBF in the thighs (p less than 0.001). There was a significant decrease in the skin blood flow in the contralateral toes after the sympathetic blockade (p less than 0.01). We conclude that laser Doppler flow measurements can be used to detect immediate onset of sympathetic blockade in patients under general anesthetic or conscious sedation.