Drug utilization review of sedative/hypnotic agents in Texas Medicaid patients. Texas Medicaid Vendor Drug Program Drug Utilization Review Board.

OBJECTIVE: To assess use of sedative/hypnotic agents in Texas Medicaid patients and evaluate practitioner receptiveness to intervention letters concerning sedative/hypnotic prescribing generated by the Texas Medicaid Drug Utilization Review (DUR) Board. DESIGN: Retrospective DUR. SETTING: Texas Medicaid retrospective DUR program. PATIENTS OR OTHER PARTICIPANTS: 244 Texas Medicaid patients and 291 Texas physicians. INTERVENTION: Patient profiles for Texas Medicaid patients were reviewed retrospectively to quantify sedative/hypnotic prescribing practices. Intervention letters were prepared and sent to physicians directly involved in the care of patients receiving excessive sedative/hypnotic therapy. Physician responses were categorized based on information presented in the intervention letter and circumstances surrounding the identified patient. Prescribing practices were assessed approximately 1 year after the intervention to determine the impact of intervention letters on prescribing. MAIN OUTCOME MEASURE: Physician response to intervention letter. RESULTS: Responses were received from 208 of 291 physicians (71.5%). Approximately 40% of physicians agreed in principle with the suggestions offered by the Texas Medicaid DUR Board to minimize chronic sedative/hypnotic use. Almost one-half of these physicians had discontinued sedative/hypnotic therapy for the identified patients 1 year after the intervention. Approximately 9% justified continued sedative/hypnotic use based on patient diagnosis or refractory response to treatment, and 55 physicians (26.4%) were unwilling to alter therapy because of patient-specific factors. CONCLUSION: Through the use of retrospective DUR, Texas Medicaid patients receiving excessive amounts of sedative/hypnotic agents were identified and improvements in sedative/hypnotic therapy were initiated. DUR can be useful not only in identifying problem areas, but also in encouraging physicians to modify prescribing practices through educational means.

Epidemiological association in US veterans between Gulf War illness and exposures to anticholinesterases.

To investigate complaints of Gulf War veterans, epidemiologic, case-control and animal modeling studies were performed. Looking for OPIDP variants, our epidemiologic project studied 249 Naval Reserve construction battalion (CB24) men. Extensive surveys were drawn for symptoms and exposures. An existing test (PAI) was used for neuropsychologic. Using FACTOR, LOGISTIC and FREQ in 6.07 SAS, symptom clusters were sought with high eigenvalues from orthogonally rotated two-stage factor analysis. After factor loadings and Kaiser measure for sampling adequacy (0.82), three major and three minor symptom clusters were identified. Internally consistent by Cronbach's coefficient, these were labeled syndromes: (1) impaired cognition; (2) confusion-ataxia; (3) arthro-myo-neuropathy; (4) phobia-apraxia; (5) fever-adenopathy; and (6) weakness-incontinence. Syndrome variants identified 63 patients (63/249, 25%) with 91 syndromes. With pyridostigmine bromide as the drug in these drug-chemical exposures, syndrome chemicals were: (1) pesticide-containing flea and tick collars (P < 0.001); (2) alarms from chemical weapons attacks (P < 0.001), being in a sector later found to have nerve agent exposure (P < 0.04); and (3) insect repellent (DEET) (P < 0.001). From CB24, 23 cases, 10 deployed and 10 non-deployed controls were studied. Auditory evoked potentials showed dysfunction (P < 0.02), nystagmic velocity on rotation testing, asymmetry on saccadic velocity (P < 0.04), somatosensory evoked potentials both sides (right P < 0.03, left P < 0.005) and synstagmic velocity after caloric stimulation bilaterally (P-range, 0.02-0.04). Brain dysfunction was shown on the Halstead Impairment Index (P < 0.01), General Neuropsychological Deficit Scale (P < 0.03) and Trail Making part B (P < 0.03). Butylcholinesterase phenotypes did not trend for inherent abnormalities. Parallel hen studies at Duke University established similar drug-chemical delayed neurotoxicity. These investigations lend credibility that sublethal exposures to drug-chemical combinations caused delayed-onset neurotoxic variants.

Is there a Gulf War Syndrome? Searching for syndromes by factor analysis of symptoms.

OBJECTIVE: To search for syndromes in Persian Gulf War veterans. PARTICIPANTS: Two hundred forty-nine (41%) of the 606 Gulf War veterans of the Twenty-fourth Reserve Naval Mobile Construction Battalion living in 5 southeastern states participated; 145 (58%) had retired from service, and the rest were still serving in the battalion. DESIGN: Participants completed a standardized survey booklet measuring the anatomical distributions or characteristics of each symptom, a booklet measuring wartime exposures, and a standard psychological personality assessment inventory. Two-stage factor analysis was used to disentangle ambiguous symptoms and identify syndromes. MAIN OUTCOME MEASURES: Factor analysis-derived syndromes. RESULTS: Of 249 participants, 175 (70%) reported having had serious health problems that most attributed to the war, and 74 (30%) reported no serious health problems. Principal factor analysis yielded 6 syndrome factors, explaining 71% of the variance. Dichotomized syndrome indicators identified the syndromes in 63 veterans (25%). Syndromes 1 ("impaired cognition," characterized by problems with attention, memory, and reasoning, as well as insomnia, depression, daytime sleepiness, and headaches), 2 ("confusion-ataxia," characterized by problems with thinking, disorientation, balance disturbances, vertigo, and impotence), and 3 ("arthro-myo-neuropathy," characterized by joint and muscle pains, muscle fatigue, difficulty lifting, and extremity paresthesias) represented strongly clustered symptoms; whereas, syndromes 4 ("phobia-apraxia"), 5 ("fever-adenopathy"), and 6 ("weakness-incontinence") involved weaker clustering and mostly overlapped syndromes 2 and 3. Veterans with syndrome 2 were 12.5 times (95% confidence interval, 3.5-44.8) more likely to be unemployed than those with no health problems. A psychological profile, found in 48.4% of those with the syndromes, differed from posttraumatic stress disorder, depression, somatoform disorder, and malingering. CONCLUSION: These findings support the hypothesis that clusters of symptoms of many Gulf War veterans represent discrete factor analysis-derived syndromes that appear to reflect a spectrum of neurologic injury involving the central, peripheral, and autonomic nervous systems.

Evaluation of neurologic function in Gulf War veterans. A blinded case-control study.

OBJECTIVE: To determine whether Gulf War-related illnesses are associated with central or peripheral nervous system dysfunction. DESIGN: Nested case-control study. PARTICIPANTS: Twenty-three veterans with factor analysis-derived syndromes (the cases), 10 well veterans deployed to the Gulf War (the deployed controls), and 10 well veterans not deployed to the Gulf War (the nondeployed controls). METHOD: With investigators blinded to group identities, participants underwent objective neurophysiological, audiovestibular, neuroradiological, neuropsychological, and blood tests. MAIN OUTCOME MEASURES: Evidence of neurologic dysfunction. RESULTS: Compared with the 20 controls, the 23 cases had significantly more neuropsychological evidence of brain dysfunction on the Halstead Impairment Index (P=.01), greater interside asymmetry of the wave I to wave III interpeak latency of brain stem auditory evoked potentials (P=.02), greater interocular asymmetry of nystagmic velocity on rotational testing, increased asymmetry of saccadic velocity (P=.04), more prolonged interpeak latency of the lumbar-to-cerebral peaks on posterior tibial somatosensory evoked potentials (on right side, P=.03, and on the left side, P=.005), and diminished nystagmic velocity after caloric stimulation bilaterally (P values range from .02 to .04). Cases (n=5) with syndrome 1 ("impaired cognition") were the most impaired on brain stem auditory evoked potentials (P=.005); those (n=13) with syndrome 2 ("confusion-ataxia") were the most impaired on the Halstead Impairment Index (P=.006), rotational testing (P=.01), asymmetry of saccadic velocity (P=.03), and somatosensory evoked potentials (P< or =.01); and those (n=5) with syndrome 3 ("arthro-myo-neuropathy") were the most impaired on caloric stimulation (P< or =.01). CONCLUSIONS: The 3 factor-derived syndromes identified among Gulf War veterans appear to represent variants of a generalized injury to the nervous system.

Self-reported exposure to neurotoxic chemical combinations in the Gulf War. A cross-sectional epidemiologic study.

OBJECTIVE: To identify risk factors of factor analysis-derived Gulf War-related syndromes. DESIGN: A cross-sectional survey. PARTICIPANTS: A total of 249 Gulf War veterans from the Twenty-fourth Reserve Naval Mobile Construction Battalion. DATA COLLECTION: Participants completed standardized booklets measuring self-reported wartime exposures and present symptoms. MAIN OUTCOME MEASURES: Associations of factor analysis-derived syndromes with risk factors for chemical interactions that inhibit butyrylcholinesterase and neuropathy target esterase. RESULTS: Risk of syndrome 1 ("impaired cognition") was greater in veterans who reported wearing flea collars during the war (5 of 20, 25%) than in those who never wore them (7 of 229, 3%; relative risk [RR], 8.7; 95% confidence interval [CI], 3.0-24.7; P<.001). Risk of syndrome 2 ("confusion-ataxia") increased with a scale of advanced adverse effects from pyridostigmine bromide (chi2 for trend, P<.001), was greater among veterans who believed they had been involved in chemical weapons exposure (18 of 108, 17%) than in those who did not (3 of 141, 2%; RR, 7.8; 95% CI, 2.3-25.9; P<.001), and was increased in veterans who had been in a sector of far northeastern Saudi Arabia on the fourth day of the air war (6 of 21, 29%) than in those who had not been (15 of 228, 7%; RR, 4.3; 95% CI, 1.9-10.0; P=.004). Effects of perceived chemical weapons exposure and advanced adverse effects from pyridostigmine were synergistic (Rothman S, 5.3; 95% CI, 1.04-26.7). Risk of syndrome 3 ("arthro-myo-neuropathy") increased with an index of frequency and amount of government-issued insect repellent containing 75% DEET (N,N-diethyl-m-toluamide) in ethanol applied during the war (chi2 for trend, P<.001) and with advanced adverse effects from pyridostigmine (chi2 for trend, P<.001). CONCLUSION: Some Gulf War veterans may have delayed, chronic neurotoxic syndromes from wartime exposure to combinations of chemicals that inhibit butyrylcholinesterase and neuropathy target esterase.

Neuropsychological correlates of Gulf War syndrome.

As part of a comprehensive multispecialty project, the present study reports on the neurocognitive and psychological function of veterans who report Persian Gulf War-related symptoms. The neuropsychological and psychological performances of 26 ill Gulf War veterans were compared to 20 well veterans from the same military unit. Neurocognitive functions assessed included intelligence, abstraction and problem-solving, attention and concentration, memory and learning, language and visual-spatial function, and sensorimotor abilities. Psychological function was measured by self-report questionnaires. Results indicated global and consistently poorer intellectual and neurocognitive function among the ill veterans compared to the control veterans. A generalized pattern of neuropsychological deficit was evident for the ill veterans. Psychological profiles of the ill veterans were similar to those in general medical patients. Based on these findings and results from the multispecialty investigation, we conclude that some of the ill veterans have experienced neurotoxic injury resulting in chronic neuropsychological impairment that is related to their service in the Persian Gulf War.

Increased neurotoxicity following concurrent exposure to pyridostigmine bromide, DEET, and chlorpyrifos.

The operating environment of the service personnel during the Persian Gulf War involved psychological, biological, and chemical elements including exposure to pesticides such as the insect repellent DEET (N,N-diethyl-m-toluamide) and the insecticide chlorpyrifos (O,O-diethyl O-3,5,6-trichloropyridinyl phosphorothioate) and to pyridostigmine bromide (PB,3-dimethylaminocarbonyloxy-N-methylpyridinium bromide) that was administered as a prophylactic agent against possible nerve gas attack. The present study was designed to determine the toxicity produced by individual or coexposure of hens 5 days/week for 2 months to 5 mg PB/kg/day in water, by gavage; 500 mg DEET/kg/day, neat, sc; and 10 mg chlorpyrifos kg/day in corn oil, sc. Coexposure to various binary treatments produced greater neurotoxicity than that caused by individual exposures and was characterized by severe neurologic deficit and neuropathological alterations. Also, neurotoxicity was further enhanced following concurrent administration of the three chemicals. Severe inhibition of plasma butyrylcholinesterase (BuChE) activity was produced in hens treated with PB (activity 17% of control) compared to those treated with chlorpyrifos (activity 51% of control) or DEET (activity 83% of control). BuChE inhibition was further increased in binary and tertiary treatment groups compared to individual treatment groups. In contrast, a significant inhibition of brain acetylcholinesterase (AChE) was produced in hens administered chlorpyrifos alone (activity 67% of control), while those given chlorpyrifos in combination with other compounds exhibited a significant inhibition of brain AChE activity ranging from 43 to 76%. Brain neurotoxicity target esterase (NTE) was not inhibited in any of the individual treatment groups or PB/DEET, but was significantly inhibited and had activity expressed as a percentage of control in groups administered combined chlorpyrifos with PB of 73% or DEET of 74% and in the tertiary treatment group of 71%. We hypothesize that test compounds may compete for xenobiotic metabolizing enzymes in the liver and blood and may also compromise the integrity of the blood-brain barrier, leading to an increase in their "effective concentrations" in the nervous system to levels equivalent to the toxic doses of individual compounds. This is consistent with the present observation of increases in (1) the inhibition of brain AChE and NTE, (2) the extent of neurologic dysfunction, and (3) the severity and frequency of neuropathologic lesions in the combined treatment groups compared to those administered individual compounds.

Neurotoxicity resulting from coexposure to pyridostigmine bromide, deet, and permethrin: implications of Gulf War chemical exposures.

Of the three-quarters of a million service personnel involved in the Persian Gulf War, approximately 30,000 have complained of neurological symptoms of unknown etiology. One contributing factor to the emergence of such symptoms may be the simultaneous exposure to multiple agents used to protect the health of service personnel, in particular, the anti-nerve agent pyridostigmine bromide (PB; 3-dimethylaminocarbonyloxy-N-methylpyridinium bromide), the insect repellent DEET (N,N-diethyl-m-toluamide), and the insecticide permethrin (3-(2,2-dichloro-ethenyl)-2,2-dimethylcyclopropanecarboxylic acid (3-phenoxyphenyl)methyl ester). This study investigated neurotoxicity produced in hens by individual or simultaneous exposure to these agents (5 d/wk for 2 months to 5 mg/kg/d PB in water, po; 500 mg/kg/d DEET, neat, sc; and 500 mg/kg/d permethrin in corn oil, sc). At these dosages, exposure to single compounds resulted in minimal toxicity. Combinations of two agents produced greater neurotoxicity than that caused by individual agents. Neurotoxicity was further enhanced following concurrent administration of all three agents. We hypothesize that competition for liver and plasma esterases by these compounds leads to their decreased breakdown and increased transport of the parent compound to nervous tissues. Thus, carbamylation of peripheral esterases by PB reduces the hydrolysis of DEET and permethrin and increases their availability to the nervous system. In effect, PB "pumps" more DEET and permethrin into the central nervous system. Consistent with this hypothesis, hens exposed to the combination of the three agents exhibited neuropathological lesions with several characteristics similar to those previously reported in studies of near-lethal doses of DEET and permethrin. If this hypothesis is correct, then blood and liver esterases play an important "buffering" role in protecting against neurotoxicity in the population at large. It also suggests that individuals with low plasma esterase activity may be predisposed to neurologic deficits produced by exposure to certain chemical mixtures.

Fatal iatrogenic iodine toxicity in a nine-week old infant.

BACKGROUND: Povidone-iodine has been used since the 1950s for various labelled uses as a topical antiseptic. The toxicity of an excessive dose in internal use is described in this case report. CASE REPORT: A 9-week old infant was treated for colic by a pediatric gastroenterologist with loperamide and the elimination of nonhuman milk. Without improvement he was hospitalized and given an enema of 50 mL of povidone-iodine diluted in 250 mL of a bowel irrigant. The enema was promptly expelled and 50 mL of the described solution was given hourly for three doses by nasogastric tube. The infant was found lifeless three hours after the last dose and resuscitation was unsuccessful. Autopsy showed a corroded and necrotic intestinal tract, serous fluid in body cavities, a blood total iodine of 14,600 micrograms/dL, protein-bound iodine of 3,400 micrograms/dL and inorganic iodine of 11,700 micrograms/dL.

Severe ethanol intoxication in an adolescent.

A 15-year-old boy presented to the emergency department with status epilepticus and a blood ethanol concentration of 757 mg/dL. Mechanical ventilation and substantial amounts of benzodiazepines were required. His hospital course was complicated by aspiration pneumonia, but he had no episodes of hypoglycemia. He received 2.8 hours of hemodialysis, which increased the rate of ethanol elimination, but there is no evidence that hemodialysis improved his clinical outcome. To our knowledge, this is the highest blood ethanol level reported in a child or adolescent who survived.

Multiple chemical sensitivities--a syndrome of pseudotoxicity manifest as exposure perceived symptoms.

The history of and nomenclature of the multiple chemical sensitivities are reviewed. The author's definition of multiple chemical sensitivity is a symptom complex 1) triggered by odor or a perceived exposure; 2) occurring at exposure levels below those of allergic sensitivity or irritation; 3) analogous to the symptoms of panic disorder as defined by DSM-IV-R; 4) lacking objective clinic pathologic criteria; and 5) responsive to panic disorder management.