Hyperbaric treatment for children with autism: a multicenter, randomized, double-blind, controlled trial.

BACKGROUND: Several uncontrolled studies of hyperbaric treatment in children with autism have reported clinical improvements; however, this treatment has not been evaluated to date with a controlled study. We performed a multicenter, randomized, double-blind, controlled trial to assess the efficacy of hyperbaric treatment in children with autism. METHODS: 62 children with autism recruited from 6 centers, ages 2-7 years (mean 4.92 +/- 1.21), were randomly assigned to 40 hourly treatments of either hyperbaric treatment at 1.3 atmosphere (atm) and 24% oxygen ("treatment group", n = 33) or slightly pressurized room air at 1.03 atm and 21% oxygen ("control group", n = 29). Outcome measures included Clinical Global Impression (CGI) scale, Aberrant Behavior Checklist (ABC), and Autism Treatment Evaluation Checklist (ATEC). RESULTS: After 40 sessions, mean physician CGI scores significantly improved in the treatment group compared to controls in overall functioning (p = 0.0008), receptive language (p < 0.0001), social interaction (p = 0.0473), and eye contact (p = 0.0102); 9/30 children (30%) in the treatment group were rated as "very much improved" or "much improved" compared to 2/26 (8%) of controls (p = 0.0471); 24/30 (80%) in the treatment group improved compared to 10/26 (38%) of controls (p = 0.0024). Mean parental CGI scores significantly improved in the treatment group compared to controls in overall functioning (p = 0.0336), receptive language (p = 0.0168), and eye contact (p = 0.0322). On the ABC, significant improvements were observed in the treatment group in total score, irritability, stereotypy, hyperactivity, and speech (p < 0.03 for each), but not in the control group. In the treatment group compared to the control group, mean changes on the ABC total score and subscales were similar except a greater number of children improved in irritability (p = 0.0311). On the ATEC, sensory/cognitive awareness significantly improved (p = 0.0367) in the treatment group compared to the control group. Post-hoc analysis indicated that children over age 5 and children with lower initial autism severity had the most robust improvements. Hyperbaric treatment was safe and well-tolerated. CONCLUSION: Children with autism who received hyperbaric treatment at 1.3 atm and 24% oxygen for 40 hourly sessions had significant improvements in overall functioning, receptive language, social interaction, eye contact, and sensory/cognitive awareness compared to children who received slightly pressurized room air. TRIAL REGISTRATION: clinicaltrials.gov NCT00335790.

High connectivity on a global scale in the pelagic wahoo, Acanthocybium solandri (tuna family Scombridae).

The population genetic structure and phylogeography of wahoo, Acanthocybium solandri, were investigated on a global scale with intron six of lactate dehydrogenase-A (ldhA6, 8 locations, N = 213) and mtDNA cytochrome b (Cytb, 10 locations, N = 322). Results show extensive sharing of haplotypes across the wahoo's entire global range, and analyses were unable to detect significant structure (nuclear F(ST) = 0.0125, P = 0.106; mtDNA Phi(ST) < 0.0001, P = 0.634). Power analyses indicated 95% confidence in detecting nuclear F(ST) > or = 0.0389 and mtDNA Phi(ST) > or = 0.0148. These findings appear unique, as most other tunas, billfishes, and oceanic sharks exhibit significant population structure on the scale of East-West Atlantic, Atlantic vs. Indian-Pacific, or East-West Pacific. Overall nuclear heterozygosity (H = 0.714) and mtDNA haplotype diversity (h = 0.918) are both high in wahoo, while overall mtDNA nucleotide diversity (pi = 0.006) and nuclear nucleotide diversity (pi = 0.004) are uniformly low, indicating a recent increase in population size. Coalescence analyses yield an estimate of effective female population size (NeF) at approximately 816,000, and a population bottleneck approximately 690,000 years ago. However, conclusions about population history from our Cytb data set are not concordant with a control region survey, a finding that will require further investigation. This is the first example of a vertebrate with a single globally distributed population, a finding we attribute to extensive dispersal at all life stages. The indications of a worldwide stock for wahoo reinforce the mandate for international cooperation on fisheries issues.

The effects of hyperbaric oxygen therapy on oxidative stress, inflammation, and symptoms in children with autism: an open-label pilot study.

BACKGROUND: Recently, hyperbaric oxygen therapy (HBOT) has increased in popularity as a treatment for autism. Numerous studies document oxidative stress and inflammation in individuals with autism; both of these conditions have demonstrated improvement with HBOT, along with enhancement of neurological function and cognitive performance. In this study, children with autism were treated with HBOT at atmospheric pressures and oxygen concentrations in current use for this condition. Changes in markers of oxidative stress and inflammation were measured. The children were evaluated to determine clinical effects and safety. METHODS: Eighteen children with autism, ages 3-16 years, underwent 40 hyperbaric sessions of 45 minutes duration each at either 1.5 atmospheres (atm) and 100% oxygen, or at 1.3 atm and 24% oxygen. Measurements of C-reactive protein (CRP) and markers of oxidative stress, including plasma oxidized glutathione (GSSG), were assessed by fasting blood draws collected before and after the 40 treatments. Changes in clinical symptoms, as rated by parents, were also assessed. The children were closely monitored for potential adverse effects. RESULTS: At the endpoint of 40 hyperbaric sessions, neither group demonstrated statistically significant changes in mean plasma GSSG levels, indicating intracellular oxidative stress appears unaffected by either regimen. A trend towards improvement in mean CRP was present in both groups; the largest improvements were observed in children with initially higher elevations in CRP. When all 18 children were pooled, a significant improvement in CRP was found (p = 0.021). Pre- and post-parental observations indicated statistically significant improvements in both groups, including motivation, speech, and cognitive awareness (p < 0.05). No major adverse events were observed. CONCLUSION: In this prospective pilot study of children with autism, HBOT at a maximum pressure of 1.5 atm with up to 100% oxygen was safe and well tolerated. HBOT did not appreciably worsen oxidative stress and significantly decreased inflammation as measured by CRP levels. Parental observations support anecdotal accounts of improvement in several domains of autism. However, since this was an open-label study, definitive statements regarding the efficacy of HBOT for the treatment of individuals with autism must await results from double-blind, controlled trials. TRIAL REGISTRATION: clinicaltrials.gov NCT00324909.

Hyperbaric oxygen therapy may improve symptoms in autistic children.

Autism is a neurodevelopmental disorder that currently affects as many as 1 out of 166 children in the United States. Recent research has discovered that some autistic individuals have decreased cerebral perfusion, evidence of neuroinflammation, and increased markers of oxidative stress. Multiple independent single photon emission computed tomography (SPECT) and positron emission tomography (PET) research studies have revealed hypoperfusion to several areas of the autistic brain, most notably the temporal regions and areas specifically related to language comprehension and auditory processing. Several studies show that diminished blood flow to these areas correlates with many of the clinical features associated with autism including repetitive, self-stimulatory and stereotypical behaviors, and impairments in communication, sensory perception, and social interaction. Hyperbaric oxygen therapy (HBOT) has been used with clinical success in several cerebral hypoperfusion syndromes including cerebral palsy, fetal alcohol syndrome, closed head injury, and stroke. HBOT can compensate for decreased blood flow by increasing the oxygen content of plasma and body tissues and can even normalize oxygen levels in ischemic tissue. In addition, animal studies have shown that HBOT has potent anti-inflammatory effects and reduces oxidative stress. Furthermore, recent evidence demonstrates that HBOT mobilizes stem cells from human bone marrow, which may aid recovery in neurodegenerative diseases. Based upon these findings, it is hypothesized that HBOT will improve symptoms in autistic individuals. A retrospective case series is presented that supports this hypothesis.

Postnatal growth retardation exacerbates acidosis-induced retinopathy in the neonatal rat.

PURPOSE: We have previously described a metabolic acidosis-induced retinopathy in the neonatal rat, similar to retinopathy of prematurity (ROP). We also have reported exacerbation of oxygen-induced retinopathy by postnatal growth retardation, produced by raising newborn rats in 'expanded' litters. In the present study, we investigated the effect of postnatal growth retardation on the incidence and severity of acidosis-induced retinopathy. METHODS: 100 newborn Sprague-Dawley rats were randomly assigned to two expanded litters of 25 pups each and five standard control litters of 10 pups each. All rats were gavaged with 10 mM/kg NH(4)Cl twice daily from days two to seven. Following five days of recovery, retinal vasculature was assessed using ADPase staining, light microscopy, and computer-assisted image analysis. The presence of neovascularization (NV), severity of NV (clock hours), and vascularized retinal areas, were evaluated in a masked manner. RESULTS: NV occurred in 52% of rats in expanded litters versus 18% of rats in standard control litters (p = 0.005). Postnatal growth retardation of pups in expanded litters was confirmed by comparing total body weight of pups raised in expanded and standard control litters (10.8g vs 13.4g on day 8, p < 0.001; 20.8g vs 25.2g on day 13, p = 0.002). CONCLUSIONS: Postnatal growth retardation increases the incidence of acidosis-induced retinopathy in the neonatal rat. Our study provides further evidence that postnatal growth retardation is a risk factor for preretinal neovascularization in immature retinae and is consistent with the clinical observation that the smallest and sickest premature infants are more likely to suffer from ROP.

Preretinal neovascularization associated with acetazolamide-induced systemic acidosis in the neonatal rat.

PURPOSE: NH4Cl gavage in the neonatal rat produces a metabolic acidosis-induced retinopathy which serves as a model for retinopathy of prematurity (ROP). Acetazolamide induces a metabolic acidosis via an alternative biochemical mechanism (bicarbonate loss versus hydrogen ion load). In the present study, the following hypothesis was tested: acetazolamide-induced acidosis is associated with preretinal neovascularization in the neonatal rat. METHODS: All studies used newborn Sprague-Dawley rats raised in expanded litters of 25. Arterial blood pH was measured to determine the level of acidosis induced by intraperitoneal (IP) acetazolamide (50 or 200 mg/kg) or saline. In a separate retinopathy study, newborn rats (n = 75) were randomized to either IP acetazolamide, 50 mg/kg (low-dose), or IP saline twice daily from days 2 to 7. After 5 days of recovery, retinal vasculature was assessed using ADPase staining and light microscopy. The presence and severity (clock hours) of neovascularization were assessed by three masked observers. In an additional retinopathy study, newborn rats (n = 100) were randomized to either IP acetazolamide, 200 mg/kg (high-dose), or IP saline twice daily from days 2 to 7. After 5 days of recovery, the retinas were similarly analyzed. RESULTS: Neovascularization occurred in 59% of rats receiving high-dose acetazolamide (200 mg/kg). High-dose acetazolamide produced a severe acidosis (pH 7.13 +/- 0.06) during drug delivery. Low-dose acetazolamide (50 mg/kg) produced a pH (7.22 +/- 0.07) that was intermediate between high-dose (200 mg/kg) acetazolamide (P < 0.001) and saline controls (7.42 +/- 0.06, P < 0.001); however, neither low-dose acetazolamide nor saline induced preretinal neovascularization. CONCLUSIONS: Acidosis induced by high-dose acetazolamide, independent of hyperoxemia or hypoxemia, is associated with preretinal neovascularization in the neonatal rat. Induction of neovascularization appears to depend on a critical threshold of acidosis severity. This study further supports a proposed independent role for acidosis in the pathogenesis of ROP.

The effect of chronic dexamethasone-induced hyperglycemia and its acute treatment with insulin on brain glucose and glycogen concentrations in rats.

BACKGROUND: In the rat model of forebrain ischemia, long-term dexamethasone treatment is reported to cause hyperglycemia and worsen postischemic functional and histologic injury. This effect was assumed to result from glucose enhancement of intraischemic lactic acidosis within the brain. Short-term insulin therapy restored normoglycemia but did not return histologic injury completely to baseline values. Using a nonischemic rat model, the current study attempted to identify a metabolic basis for such outcome data. METHODS: Fifty-eight halothane-anesthetized (1.3% inspired) Sprague-Dawley rats were assigned randomly to be administered either no treatment (N = 18) or 2 mg/kg intraperitoneal dexamethasone (N = 40). The latter were administered dexamethasone 3 h before the study only (N = 8) or for 3 h before the study plus daily for 1 day (N = 8), 2 days (N = 8), or 4 days (N = 16). Of the rats treated with dexamethasone for 4 days, one half (N = 8) were administered an insulin-containing saline infusion subsequently to restore normoglycemia short-term. All other rats (N = 50) were administered an infusion of saline without insulin. Plasma glucose was quantified, and brains were excised after in situ freezing. Brain glucose and glycogen concentrations were measured using enzymatic fluorometric analyses. RESULTS: After 4 days of dexamethasone treatment, plasma glucose was 159% greater than in rats administered placebo (i.e., 22.01 +/- 4.66 vs. 8.51 +/- 1.65 micromol/ml; mean +/- SD; P < 0.0001). Brain glucose concentrations increased parallel to plasma glucose. An insulin infusion for 27 +/- 5 min restored normoglycemia but resulted in a brain-to-plasma glucose ratio that was 32% greater than baseline values (P < 0.01). Neither dexamethasone nor the combination of dexamethasone plus insulin affected brain glycogen concentrations. CONCLUSIONS: In a nonischemic rat model, dexamethasone alone had no independent effect on the brain-to-plasma glucose ratio. However, short-term insulin therapy caused a dysequilibrium between plasma and brain glucose, resulting in an underestimation of brain glucose concentrations when normoglycemia was restored. The dysequilibrium likely was caused by the rapid rate of glucose reduction. The magnitude of the effect may account for the failure of insulin to reverse dexamethasone enhancement of neurologic injury completely in a previous report that used the rat model of forebrain ischemia.

Exaggerated hemodynamic responses to nasal injection and awakening from anesthesia in a Cushingoid patient having transsphenoidal hypophysectomy.

A 51-year-old female patient, with an adrenocorticotrophic hormone-secreting pituitary tumor, was scheduled for transphenoidal hypophysectomy. She had a history of recent onset diabetes mellitus and a 2-year history of arterial hypertension. Despite ongoing medical therapy, preoperative blood pressure was 150-160/90-120 mm Hg. During general anesthesia, in response to perinasal infiltration with 10 ml of a solution containing lidocaine 200 mg and epinephrine 100 microg, blood pressure increased from 144/80 mm Hg to 317/175 over 3 minutes, as assessed by direct blood pressure monitoring. At the completion of the anesthetic, as the patient awakened and coughed and moved, blood pressure again increased dramatically, this time from 154/87 mm Hg to 285/170 over 3 minutes. Five months postoperatively, the patient's serum cortisol concentrations had normalized and her cuff blood pressure was 126/82, despite a reduction in her antihypertensive medications. The dramatic intraoperative blood pressure changes in this patient were attributed to the effects of hypercortisolemia on the normal physiologic responses to epinephrine and patient movement.

Anesthetic management for two-stage computer-assisted, stereotactic thalamotomy in a child with Hallervorden-Spatz Disease.

We report the numerous management challenges surrounding the care of a child in whom bilateral thalamotomies were used to treat end-stage Hallervorden-Spatz Disease (HSD). The management of this patient was greatly facilitated by the use of modern anesthetic agents and a multidisciplinary team to care for the patient. The outcome was an improved life expectancy and quality of life.

The prevention and treatment of cerebral ischemia.

Although the major focus of recent cerebral protection research has been aimed at developing receptor-specific drugs, this effort has currently resulted in few improvements in patient outcome. Until advances in pharmacology translate to improvements in humans, the clinician and his patients will be well served by using more traditional techniques to prevent and treat cerebral ischemic events. This approach will involve interventions to a) identify patients who are experiencing or are at risk for developing cerebral ischemia, and b) alter systemic physiology in an attempt to lessen the duration and severity of any ischemic insults. Initial therapy should include interventions to improve cerebral perfusion and the oxygen carrying capacity of the blood. Once this is accomplished, measures should be taken to control blood glucose concentrations and treat fever. In otherwise stable surgical patients, mild reductions in patient temperature also may be of benefit, provided the temperature reductions do not introduce problems in systemic physiology and the patient is rewarmed prior to awakening from general anesthesia. General anesthetic choice may be of importance in controlling intracranial pressure and seizure activity; however, if direct cerebral protection is desired, the anesthetic of choice should be a barbiturate. Finally, in the patient at risk for cerebral vasospasm, nimodipine treatment should be considered. Collectively, these interventions should increase the patient's chance for optimal neurologic recovery following ischemia.

Acute pulmonary edema associated with placement of waist-high, custom-fit compression stockings.

Compression stockings are a safe, noninvasive treatment for patients with symptomatic orthostatic hypotension due to autonomic nervous system dysfunction. In this report, we describe a 75-year-old man who had development of pulmonary edema approximately 45 minutes after placement of compression stockings on the first postoperative day following a carotid endarterectomy. No sudden changes were noted on an electrocardiogram or echocardiogram or in the cardiac isoenzymes associated with the pulmonary edema. The patient had a history of coronary artery disease, diabetes mellitus-induced autonomic nervous system dysfunction, and recent surgery near the carotid baroreceptor. All these factors may have limited his ability to compensate for a rapid increase in central blood volume. The temporal relationship of the patient's respiratory distress to the placement of the compression stockings, in the absence of laboratory findings of primary cardiac dysfunction, make stocking-related fluid shift the likely precipitating event in the formation of acute pulmonary edema. This case suggests that compression stockings should be used with caution in patients with limited cardiac reserve.