Neurological critical care

Of utmost importance in the practice of neurological critical care is the treatment of cerebral edema, when possible, and the control of life-threatening seizures. In this regard, severe traumatic head injury and refractory status epilepticus are useful clinical therapeutic paradigms. Evidence-based treatment established for these conditions has, by necessity, a wider application to other much less frequent causes of coma and acute neurological illness managed in the intensive therapy unit. Therefore, this review of pediatric neurocritical care literature in 1999 highlights central clinical reports of the medical management of severe traumatic brain injury, the benzodiazepines used in the treatment of status epilepticus, and the emerging or recently appreciated encephalopathies occurring in children.     

Vaccination in patients with HIV infection

Although vaccine-preventable diseases are common in HIV, concerns about vaccine safety and lack of efficacy in this patient population often lead to missed opportunities for vaccination. In this article, we review the literature regarding vaccine risks and benefits and offer recommendations regarding their use and timing in patients with HIV infection.     

Cerebral edema in children with diabetic ketoacidosis: vasogenic rather than cellular?

Cerebral edema (CE) is accumulation of water in the intracellular or extracellular spaces of the brain. Vasogenic edema occurs when there is breakdown of the tight endothelial junctions of the blood–brain barrier (BBB), leading to extravasation of intravascular protein and fluid into the interstitial space of the brain. In cellular edema the BBB remains intact and there is swelling of astrocytes with corresponding reduction in extracellular space. In this review we bring together clinical evidence from neuropathology and cerebral magnetic resonance (MR) studies in pediatric patients presenting in diabetic ketoacidosis (DKA), and use applied physiology to understand whether CE complicating DKA is vasogenic, rather than cellular in origin. Because the first‐line of defense against CE is the interface between the intravascular compartment and the extracellular space in the brain much of the focus in this review is the BBB. The principal pathologic finding in fatal cases is perivascular with BBB disruption and albumin extravasation, suggesting increased vascular permeability. DKA induces an inflammatory response and the mechanism of BBB transcellular permeability may be an immunologic cascade that disrupts tight junctions. The principal MR finding in subclinical cases of CE is vasogenic rather than cellular edema. We propose that the following physiology be considered when treating cases: bolus dose of intravenous mannitol may result in fall in serum sodium concentration, and therefore clinical worsening. Failure to respond to mannitol should prompt the use of 3% hypertonic saline (HS). Bolus dose of intravenous 3% HS is expected to effect vasogenic edema provided that the reflection coefficient is close to 1. Failure to respond to 3% HS should prompt the use of mannitol.     

Mechanism of antithrombin III inhibition of factor VIIa/tissue factor activity on cell surfaces. Comparison with tissue factor pathway inhibitor/factor Xa-induced inhibition of factor VIIa/tissue factor activity

Recent studies have shown that antithrombin III (AT III)/heparin is capable of inhibiting the catalytic activity of factor VIIa bound either to relipidated tissue factor (TF) in suspension or to TF expressed on cell surfaces. We report studies of the mechanism of which by AT III inhibits factor VIIa bound to cell surface TF and compare this inhibitory mechanism with that of tissue factor pathway inhibitor (TFPI)-induced inhibition of factor VIIa/TF. AT III alone and AT III/heparin to a greater extent reduced factor VIIa bound to cell surface TF. Our data show that the decrease in the amount of factor VIIa associated with cell surface TF in the presence of AT III was the result of (1) accelerated dissociation of factor VIIa from cell surface TF after the binding of AT III to factor VIIa/TF complexes and (2) the inability of the resultant free factor VIIa-AT III complexes to bind effectively to a new cell surface TF site. Binding of TFPI/factor Xa to cell surface factor VIIa/TF complexes markedly decreased the dissociation of factor VIIa from the resultant quaternary complex of factor VIIa/TF/TFPI/factor Xa. Addition of high concentrations of factor VIIa could reverse the AT III-induced inhibition of cell surface factor VIIa/TF activity but not TFPI/factor Xa-induced inhibition of factor VIIa/TF activity.     

Acute hypoxemic respiratory failure in children: case mix and the utility of respiratory severity indices

Objective: Acute hypoxemic respiratory failure (AHRF) is a common reason for emergency pediatric intensive care. An objective assessment of disease severity from acute physiological parameters would be of value in clinical practice and in the design of clinical trials. We hypothesised that there was a difference in the best early respiratory indices in those who died compared with those who survived. Design: A prospective observational study of 118 consecutive AHRF admissions with data analysis incorporating all blood gases. Setting: A pediatric intensive care unit in a national children's hospital. Interventions: None. Results: Mortality was 26/118, 22 % (95 % confidence interval 18–26 %). There were no significant differences in the best alveolar-arterial oxygen tension gradient (A-aDO₂, torr), oxygenation index (OI), ventilation index (VI), or PaO₂/FIO₂ during the first 2 days of intensive care between the survivors and non-survivors. Only the mean airway pressure (MAP, cm H₂O) used for supportive care was significantly different on days 0 and 1 (p K 0.05) with higher pressure being used in non-survivors. Multiple logistic regression analysis did not identify any gas exchange or ventilator parameter independently associated with mortality. Rather, all deaths were associated with coincident pathology or multi-organ system failure, or perceived treatment futility due to pre-existing diagnoses instead of unsupportable respiratory failure. When using previously published predictors of outcome (VI > 40 and OI > 40; A-aDO₂ > 450 for 24 h; A-aDO₂ > 470 or MAP > 23; or A-aDO₂ > 420) the risk of mortality was overestimated significantly in the current population. Conclusion: The original hypothesis was refuted. It appears that the outcome of AHRF in present day pediatric critical care is principally related to the severity of associated pathology and now no longer solely to the severity of respiratory failure. Further studies in larger series are needed to confirm these findings. Received: 16 December 1997 Accepted: 31 March 1998     

Binding of factor VIIa to tissue factor permits rapid antithrombin III/heparin inhibition of factor VIIa

Because free factor VIIa is inactivated only very slowly by a plasma concentration of antithrombin III (AT III) even in the presence of heparin, it has been assumed that AT III plays no significant role in regulating the initiation of tissue factor-dependent blood coagulation. However, in the present study, we present evidence that factor VIIa bound to tissue factor, unlike free factor VIIa, is readily inactivated by AT III in the presence of heparin. In a reaction mixture containing calcium ions and approximately equimolar concentrations of relipidated tissue factor (8.9 nmol/L) and factor VIIa (10 nmol/L), AT III (100 micrograms/mL) plus heparin (1 U/mL) inhibited 50% of the factor VIIa coagulant activity of the reaction mixture within 5 minutes. AT III/heparin was also shown to inhibit the catalytic activity towards factor X of factor VIIa/tissue factor complexes formed on monolayers of an ovarian carcinoma cell line (OC-2008) that constitutively expresses surface membrane tissue factor. AT III, even in the absence of exogenously added heparin, substantially inhibited the functional activity of factor VIIa/cell surface tissue factor complexes on intact monolayers. AT III alone and AT III/heparin, to a greater extent, also inhibited factor VIIa on "nonfunctional" factor VIIa/tissue factor complexes on intact monolayers, with resultant inhibition of their expression of factor VIIa/tissue factor catalytic activity toward factor X after cell lysis. The potential physiologic significance of these findings is discussed.     

Evidence for persistence of upper airway narrowing during sleep, 12 years after adenotonsillectomy.

AIMS: To establish whether subjects with previous evidence of sleep apnoea prior to adenotonsillectomy continue to have evidence of narrower upper airways during sleep, 12 years later. METHODS: Twenty subjects (median age 16 years) underwent repeat sleep studies at home, 12 years after such studies had shown significant sleep apnoea in many of them prior to an adenotonsillectomy. Twenty control subjects, also studied 12 years ago, underwent repeat home sleep studies as well. The sleep studies provided information on snoring, hypoxia, and inspiratory effort (from measures of pulse transit time). A questionnaire was also administered, the subjects were weighed, and their heights measured. RESULTS: There was more reported snoring in the previous adenotonsillectomy group (50% versus 20%) and also during the sleep study (80 versus 31 snores per hour). The measure of inspiratory effort overnight was higher in the previous adenotonsillectomy group (15.6 versus 12.3 ms). Allowance for potentially confounding variables (obesity and nasal congestion) partially reduced the statistical significance of the difference in snoring, but not that of the measure of inspiratory effort. CONCLUSION: Results suggest that a narrower upper airway during sleep, to the point of snoring, persists 12 years after adenotonsillectomy, and may partly account for the occurrence earlier of preoperative sleep apnoea while adenotonsillar hypertrophy was present. It is not known if this narrowing is one of the risk factors for later development of adult sleep apnoea.     

The partial positive allosteric GABAA receptor modulator EVT 201 is efficacious and safe in the treatment of adult primary insomnia patients

Objective: To evaluate polysomnographic (PSG) and self-reported measures of the efficacy and safety of EVT 201 in patients with primary insomnia.Patients and methods: Following clinical and PSG screening, 75 patients (mean age: 45.1 ± 11.2y; 50f, 25m) meeting DSM-IV criteria for primary insomnia entered this crossover study and were randomly assigned to double-blind treatment sequences of 1.5 mg or 2.5 mg EVT 201, or placebo using a balanced Latin square design. For each study condition study medication was administered on two consecutive nights and PSG and self-reported data were collected. Safety assessments included physical examination, clinical laboratory measures, electrocardiogram, documentation of adverse events, and the digit symbol substitution test (DSST) and self-reported sleepiness/alertness ratings to detect residual sedation. Data were collected at five US sleep laboratories. Efficacy analyses were performed for the 67 patients completing the study. Safety analyses included all 75 randomized patients.Results: On PSG measures compared to placebo, EVT 201 1.5 mg and 2.5 mg increased total sleep time (TST; 33.1, 45.0 min; both p < 0.0001), reduced wake after sleep onset (WASO; −16.7, −25.7 min; both p < 0.0001), reduced latency to persistent sleep (LPS; −17.0, −20.7 min; both p < 0.0001), and reduced the number of awakenings (−1.2, −2.6; both p < 0.0001). Significant reduction of wake time was seen with 1.5 mg during each of the first three quarters of the night (p < 0.0001–0.002), and with 2.5 mg in all four quarters (p < 0.0001–0.0005). Both doses also improved all key self-reported measures of sleep including total sleep time (rTST; 51.9, 51.1 min; both p < 0.0001), wake after sleep onset (rWASO; −29.3, −29.6 min; both p < 0.0001), sleep latency (rSL; −24.0 min, p < 0.004; −25.1 min, p < 0.0002), and number of awakenings (rNAW; −1.1, −1.2; both p < 0.0001). Sleep quality was also improved by both doses. Self-rated sleepiness in the morning did not differ from placebo for either dose; however, there was a small negative effect on the DSST for both doses. Both doses had similar effects on sleep architecture including an increase in Stage 2 sleep and REM latency and a small, but significant decrease in REM (REM −5.7, −8.3 min; p = 0.0175, p = 0.0006). No effect on other sleep architecture parameters, including SWS, was seen. EVT 201 was well tolerated. No serious or unexpected adverse events were reported.Conclusion: This first study of EVT 201 in adult patients with primary insomnia demonstrated improved measures of sleep onset and sleep maintenance, including during the third and fourth quarters of the night. Adverse events were infrequent and all were mild to moderate in severity.