Daniel E. Rusyniak

Hyperbaric Oxygen Therapy in Acute Ischemic Stroke: Results of the Hyperbaric Oxygen in Acute Ischemic Stroke Trial Pilot Study

Background and Purpose— Hyperbaric oxygen therapy (HBO) has promise as a treatment for acute stroke. This study was conducted to evaluate the efficacy, safety, and feasibility of using HBO in acute ischemic stroke. Methods— We conducted a randomized, prospective, double-blind, sham-controlled pilot study of 33 patients presenting with acute ischemic stroke who did not receive thrombolytics over a 24-month period. Patients were randomized to treatment for 60 minutes in a monoplace hyperbaric chamber pressurized with 100% O2 to 2.5-atm absolute (ATA) in the HBO group or 1.14 ATA in the sham group. Primary outcomes measured included percentage of patients with improvement at 24 hours (National Institutes of Health Stroke Scale [NIHSS]) and 90 days (NIHSS, Barthel Index, modified Rankin Scale, Glasgow Outcome Scale). Secondary measurements included complications of treatment and mortality at 90 days. Results— Baseline demographics were similar in both groups. There were no differences between the groups at 24 hours (P =0.44). At 3 months, however, a larger percentage of the sham patients had a good outcome defined by their stroke scores compared with the HBO group (NIHSS, 80% versus 31.3%;P =0.04; Barthel Index, 81.8% versus 50%;P =0.12; modified Rankin Scale, 81.8% versus 31.3%;P =0.02; Glasgow Outcome Scale, 90.9% versus 37.5%;P =0.01) with loss of statistical significance in a intent-to-treat analysis. Conclusions— Although our HBO protocol appears feasible and safe, it does not appear to be beneficial and may be harmful in patients with acute ischemic stroke.

Carvedilol reverses hyperthermia and attenuates rhabdomyolysis induced by 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) in an animal model*

Objective:Hyperthermia is a potentially fatal manifestation of severe 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) intoxication. No proven effective drug treatment exists to reverse this potentially life-threatening hyperthermia, likely because mechanisms of peripheral thermogenesis are poorly understood. Using a rat model of MDMA hyperthermia, we evaluated the acute drug-induced changes in plasma catecholamines and used these results as a basis for the selection of drugs that could potentially reverse this hyperthermia. Design:Prospective, controlled, randomized animal study. Setting:A research institute laboratory. Subjects:Male, adult Sprague-Dawley rats. Interventions:Based on MDMA-induced changes in plasma catecholamine levels, rats were subjected to the nonselective (&bgr;1 + &bgr;2) adrenergic receptor antagonists propranolol or nadolol or the &agr;1- + &bgr;1,2,3-adrenergic receptor antagonist carvedilol before or after a thermogenic challenge of MDMA. Measurement and Main Results:Plasma catecholamines levels 30 mins after MDMA (40 mg/kg, subcutaneously) were determined by high-pressure liquid chromatography and electrochemical detection. Core temperature was measured by a rectal probe attached to a thermocouple. Four hours after MDMA treatment, blood was drawn and serum creatine kinase levels were measured as a marker of rhabdomyolysis using a Vitros analyzer. MDMA induced a 35-fold increase in norepinephrine levels, a 20-fold increase in epinephrine, and a 2.4-fold increase in dopamine levels. Propranolol (10 mg/kg, intraperitoneally) or nadolol (10 mg/kg, intraperitoneally) administered 30 mins before MDMA had no effect on the thermogenic response. In contrast, carvedilol (5 mg/kg, intraperitoneally) administered 15 mins before or after MDMA prevented this hyperthermic response. Moreover, when administered 1 hr after MDMA, carvedilol completely reversed established hyperthermia and significantly attenuated subsequent MDMA-induced creatine kinase release. Conclusion:These data show that &agr;1 and &bgr;3-adrenergic receptors may contribute to the mediation of MDMA-induced hyperthermia and that drugs targeting these receptors, such as carvedilol, warrant further investigation as novel therapies for the treatment of psychostimulant-induced hyperthermia and its sequelae.

The role of the sympathetic nervous system and uncoupling proteins in the thermogenesis induced by 3,4-methylenedioxymethamphetamine.

Body temperature regulation involves a homeostatic balance between heat production and dissipation. Sympathetic agents such as 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) can disrupt this balance and as a result produce an often life-threatening hyperthermia. The hyperthermia induced by MDMA appears to result from the activation of the sympathetic nervous system (SNS) and the hypothalamic-pituitary-thyroid/adrenal axis. Norepinephrine release mediated by MDMA creates a double-edged sword of heat generation through activation of uncoupling protein (UCP3) along with α1- and β3-adrenoreceptors and loss of heat dissipation through SNS-mediated vasoconstriction. This review examines cellular mechanisms involved in MDMA-induced thermogenesis from UCP activation to vasoconstriction and how these mechanisms are related to other thermogenic conditions and potential treatment modalities.

Neurologic Manifestations of Chronic Methamphetamine Abuse

Methamphetamine abuse has reached epidemic proportions in the United States. The repetitive use of methamphetamine causes massive and sustained elevations in central monoamines. These elevations, particularly in dopamine, can cause changes in the function of the central nervous system that can manifest as a variety of neurologic disorders. This article focuses on these disorders, such as neurocognitive disorders and mental illness, including drug-induced psychosis; motor disorders, including the possible risk of Parkinsons disease, the development of choreoathetoid movements, and punding; and changes in the physical appearance of the methamphetamine users, including dental caries.

Attenuation of 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy)-induced rhabdomyolysis with α1- plus β3-adrenoreceptor antagonists

Studies were designed to examine the effects of α1 (α1AR)‐ plus β3‐adrenoreceptor (β3AR) antagonists on 3,4‐methylenedioxymethamphetamine (MDMA, Ecstasy)‐induced hyperthermia and measures of rhabdomyolysis (creatine kinase (CK)) and renal function (blood urea nitrogen (BUN) and serum creatinine (sCr)) in male Sprague–Dawley rats. MDMA (40 mg kg−1, s.c.) induced a rapid and robust increase in rectal temperature, which was significantly attenuated by pretreatment with the α1AR antagonist prazosin (100 μg kg−1, i.p.) plus the β3AR antagonist SR59230A (5 mg kg−1, i.p.). CK levels significantly increased (peaking at 4 h) after MDMA treatment and were blocked by the combination of prazosin plus SR59230A. At 4 h after MDMA treatment, BUN and sCr levels were also significantly increased and could be prevented by this combination of α1AR‐ plus β3AR‐antagonists. The results from this study suggest that α1AR and β3AR play a critical role in the etiology of MDMA‐mediated hyperthermia and subsequent rhabdomyolysis.

3,4-Methylenedioxymethamphetamine- and 8-Hydroxy-2-di-n-propylamino-tetralin-Induced Hypothermia: Role and Location of 5-Hydroxytryptamine 1A Receptors

The popular drug of abuse 3,4-methylenedioxymethamphetamine (MDMA) has complex interactions with thermoregulatory systems, resulting in either hyperthermia or hypothermia. MDMA induces hypothermia when given to animals housed at a low ambient temperature. In this study we report that MDMA (7.5 mg/kg i.p.) given at normal ambient temperatures of 24 to 25°C caused, in conscious freely moving rats, hypothermia (mean decrease from baseline of 1.1 ± 0.06°C at 40 min). Pretreating animals with a 0.5 mg/kg i.p. dose of the 5-hydroxytryptamine 1A (5-HT1A) antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide (WAY 100635) not only prevented MDMA-induced hypothermia, but resulted in the development of hyperthermia (mean temperature increase from baseline of 0.74 ± 0.2°C at 120 min). After treatment with WAY 100635, MDMA also elicited an enhanced tachycardia (mean increases in heart rate from baseline of 110 ± 16 beats/min at 90 min). To identify the location of 5-HT1A receptors responsible for hypothermia induced by MDMA, we first investigated the role of 5-HT1A receptors in the rostral raphe pallidus (rRP) in decreases in temperature evoked by the known 5-HT1A agonist 8-hydroxy-2-di-n-propylamino-tetralin (DPAT). Microinjections of 0.5 nmol of WAY 100635 into the rRP significantly attenuated DPAT (0.2 mg/kg i.p.)-elicited hypothermia. In parallel experiments, we found that microinjections of WAY 100635 into the rRP, while significantly augmenting MDMA-mediated tachycardia, did not alter body temperature. These results demonstrate that although hypothermia mediated by both MDMA and DPAT shares a common dependence on the activation of 5-HT1A receptors, the location of these receptors is different for each drug.

Estimating the Weight of Children in Kenya: Do the Broselow Tape and Age-Based Formulas Measure Up?

STUDY OBJECTIVE Validated methods for weight estimation of children are readily available in developed countries; however, their utility in developing countries with higher rates of malnutrition and infectious disease is unknown. The goal of this study is to determine the validity of a height-based estimate, the Broselow tape, compared with age-based estimations among pediatric patients in Western Kenya. METHODS A prospective cross-sectional study of all sick children presenting to the emergency department of a government referral hospital in Eldoret, Kenya, was performed. Measured weight was compared with predicted weights according to the Broselow tape and commonly used advanced pediatric life support (APLS) and Nelsons age-based formulas. A Bland-Altman analysis was used to determine agreement between each method and actual weight. The method for weight prediction was determined a priori to be equivalent to the actual weight if the 95% confidence interval for the mean percentage difference between the predicted and actual weight was less than 10%. RESULTS Nine hundred sixty-seven children were included in analysis. The overall mean percentage difference for the actual weight and Broselow predicted weight was -2.2%, whereas APLS and Nelsons predictions were -5.2% and -10.4%, respectively. The overall agreement between Broselow color zone and actual weight was 65.5%, with overestimate typically occurring by only 1 color zone. CONCLUSION The Broselow tape and APLS formula predict the weights of children in western Kenya. According to its better performance, ease of use, and provision of drug dosing and equipment size, the Broselow tape is superior to age-based formulas for estimation of weight in Kenyan children.

When administered to rats in a cold environment, 3,4-methylenedioxymethamphetamine reduces brown adipose tissue thermogenesis and increases tail blood flow: Effects of pretreatment with 5-HT1A and dopamine D2 antagonists

When given in a warm environment MDMA (3,4-methylenedioxymethamphetamine, ecstasy) causes hyperthermia by increasing interscapular brown adipose tissue (iBAT) heat production and decreasing heat loss via cutaneous vasoconstriction. When given in a cold environment, however, MDMA causes hypothermia by an unknown mechanism. This paper addresses these mechanisms and in addition examines whether antagonists at 5-HT(1A) and D(2) receptors reduce the hypothermic action of MDMA. Male Sprague-Dawley rats instrumented with a Doppler probe for measuring tail blood flow, and probes for measuring core and iBAT temperatures, were placed in a temperature-controlled chamber. The chamber temperature was reduced to 10 degrees C and vehicle (0.5 ml Ringer), the 5-HT(1A) antagonist WAY 100635 (0.5 mg/kg), the D(2) antagonist spiperone (20 mug/kg), or the combination of Way 100635 and spiperone were injected s.c. Thirty minutes later the antagonists were injected again along with MDMA (10 mg/kg) or vehicle. MDMA reduced core body temperature by preventing cold-elicited iBAT thermogenesis and by transiently reversing cold-elicited cutaneous vasoconstriction. Pretreatment with WAY 100635 prevented MDMA induced increases in tail blood flow, and briefly attenuated MDMAs effects on iBAT and core temperature. While spiperone alone failed to affect any of the parameters, the combination of spiperone and WAY 100635 decreased MDMA-mediated hypothermia by attenuating both the effects on tail blood flow and iBAT thermogenesis. MDMAs prevention of cold-induced iBAT thermogenesis appears to have a central origin as it rapidly reverses cold-induced increases in iBAT sympathetic nerve discharge in anesthetized rats. Our results demonstrate that MDMA in a cold environment reduces core body temperature by inhibiting iBAT thermogenesis and tail artery vasoconstriction and suggest that mechanisms by which this occurs include the activation of 5-HT1A and dopamine D2 receptors.

Increased adolescent opioid use and complications reported to a poison control center following the 2000 JCAHO pain initiative

Context. Adolescents are at risk to abuse opioid analgesics for many reasons, including inaccurate perception of risk and increased drug availability. In 2000, the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) released pain management standards that emphasized pain control as a patient rights issue. This focus on analgesia may have increased both the prescribing and use of opioid analgesics, thereby increasing availability. Objective. Using data from a US poison center, this study aims to compare the number of adolescent opioid cases and their outcome severity before and after the 2000 JCAHO pain initiative. Methods. Retrospective case series of opioid exposures involving persons 12–18 years of age reported to a US poison center from 1994 to 2007. The main outcome measure was the number of adolescent opioid cases reported for 1994–2000 compared to 2001–2007. Secondary outcomes included outcome severity, number of cases involving specific opioids, and correlation between the number of cases and the amount of opioids distributed to the state. Results. There were 1634 adolescent opioid-related cases with 187 cases developing medical complications. Compared with 1994–2000, the rate ratio of cases involving adolescents and opioid analgesics for the years 2001–2007 was 1.69 (95% CI: 1.53, 1.86), and these cases were 2.84 (95% CI: 2.06, 3.91) times more likely to have had medical complications. Medical complications involving methadone (p =0.001) increased after the JCAHO initiative, while complications related to codeine (p =0.001) and propoxyphene (p =0.030) decreased. There were 15 deaths in 2001–2007 and none in 1994–2000 (p =0.012). Lastly, there was a correlation between the rate of adolescent opioid cases and the amount of opioids distributed to the state (r2 =0.90; p < 0.001). Conclusion. In the 7 years following the JCAHO pain standards, there was an increase in the number and severity of adolescent opioid-related poison center cases. The increase correlates with statewide availability of opioids. These data may prove useful in drug education and prevention programs targeting adolescents.

The Orexin-1 receptor antagonist SB-334867 decreases sympathetic responses to a moderate dose of methamphetamine and stress

We recently discovered that inhibiting neurons in the dorsomedial hypothalamus (DMH) attenuated hyperthermia, tachycardia, hypertension, and hyperactivity evoked by the substituted amphetamine 3, 4-methylenedioxymethamphetamine (MDMA). Neurons that synthesize orexin are also found in the region of the DMH. As orexin and its receptors are involved in the regulation of heart rate and temperature, they would seem to be logical candidates as mediators of the effects evoked by amphetamines. The goal of this study was to determine if blockade of orexin-1 receptors in conscious rats would suppress cardiovascular and thermogenic responses evoked by a range of methamphetamine (METH) doses. Male Sprague-Dawley rats (n=6 per group) were implanted with telemetric transmitters measuring body temperature, heart rate, and mean arterial pressure. Animals were randomized to receive pretreatment with either the orexin-1 receptor antagonist SB-334867 (10mg/kg) or an equal volume of vehicle. Thirty minutes later animals were given intraperitoneal (i.p.) injections of either saline, a low (1mg/kg), moderate (5mg/kg) or high (10mg/kg) dose of METH. Pretreatment with SB-334867 significantly attenuated increases in body temperature and mean arterial pressure evoked by the moderate but not the low or high dose of METH. Furthermore, animals treated with SB-334867, compared to vehicle, had lower temperature and heart rate increases after the stress of an i.p. injection. In conclusion, temperature and cardiovascular responses to a moderate dose of METH and to stress appear to involve orexin-1 receptors. The failure to affect a low and a high dose of METH suggests a complex pharmacology dependent on dose. A better understanding of this may lead to the knowledge of how monoamines influence the orexin system and vice versa.