Postoperative hyperthermia of unknown origin treated with dantrolene sodium.
Inada H, Jinno S, Kohase H, Fukayama H, Umino M.
Section of Anesthesiology and Clinical Physiology, Department of Oral Restitution, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan. inada.anph@tmd.ac.jp
An 11-year-old girl was scheduled for alveolar cleft bone grafting with an iliac bone under general anesthesia. Anesthesia was performed with 70% nitrous oxide, 30% oxygen, and propofol. On the first and second postoperative day, persistent hyperthermia was observed. Because the administration of diclofenac sodium had not been effective for the hyperthermia, dantrolene sodium was given. Her body temperature gradually dropped and returned to normal level on the fifth postoperative day. The hyperthermia in the present case might have been caused by a rapidly elevated muscle metabolism in response to pain and stress after the propofol anesthesia. The oral administration of dantrolene sodium successfully lowered the patient's high body temperature.


Short use of muscle relaxants / relaxant following single stage laryngotracheoplasty in children.
Roeleveld PP, Hoeve LJ, Joosten KF, de Hoog M.
Erasmus MC-Sophia Children's Hospital, Department of Pediatric Intensive Care, Dr. Molewaterplein 60, 3015 GJ Rotterdam, Netherlands. pproeleveld@hetnet.nl
OBJECTIVE: The postoperative management of children undergoing single stage laryngotracheoplasty (SSLTP) includes intubation and muscle paralysis to secure the airway and protect the wound. We reduced the period of postoperative muscle paralysis in an attempt to decrease the incidence of pulmonary complications. The objective of this study was to evaluate the influence of the duration of muscle paralysis on pulmonary complications and outcome. METHODS: Medical records of all children admitted, between 1994 and 2002, to the pediatric intensive care unit following SSLTP were analysed. Children were grouped according to the number of days muscle paralysis was used. RESULTS: Thirty-six children (15 male, 21 female, mean age 32 months (9-162 months)) underwent SSLTP for laryngeal stenosis. Prior to surgery 29 needed a tracheotomy (mean duration 11.1 months). Shorter muscle paralysis leads to shorter intubation and mechanical ventilation and therefore PICU and hospital length of stay were 12.4 and 9.9days shorter in the group with short use of muscle paralysis (p<0.001 and p=0.002, respectively). There was no significant difference in postoperative complications, but a trend towards fewer atelectases in children with short muscle paralysis could be recognised. Postoperatively we observed no auto-extubations in either group and success rate of SSLTP was comparable in both groups (94 and 95%). CONCLUSION: Children undergoing SSLTP can safely benefit from a postoperative strategy using a short duration of muscle relaxants. They have fewer days on mechanical ventilation with a concomitant decrease in duration of hospital stay.


Weight and height gain after intrathecal baclofen pump implantation in children with spastic tetraparesis'.

Bertolasi L.

Analysis of the pharmacodynamic parameters in a model for neuromuscular block.
Nigrovic V, Anton A, Bengez R.
Department of Anesthesiology, Medical College of Ohio, Toledo, OH 43614-2598, USA. vnigrovic@mco.edu
BACKGROUND: The study examines the roles of the pharmacodynamic parameters and of the assumptions underlying the pharmacokinetic-pharmacodynamic model proposed by Sheiner and coworkers to interpret the time course of neuromuscular block (NMB) produced by nondepolarizing muscle relaxants. MATERIAL/METHODS: The model of Sheiner et al. was modified by considering (a) a multiexponential equation for the time course of the relaxant's concentrations in plasma, (b) the transport of a hypothetical muscle relaxant / relaxants from plasma to the site of action via diffusion, and (c) NMB as a function of the relaxant's concentration at the site of action, of gamma and IC50. The feasibility of obtaining reliable estimates of the PD parameters was evaluated for either a complete or an incomplete NMB. RESULTS: The results confirmed that reliable estimates of the PD parameters, i.e., of the transport rate constant, gamma, and IC50, may be obtained simultaneously if NMB is incomplete. Estimates of the same parameters obtained from a complete NMB are interdependent and, hence, unreliable. The assumptions in the original model of (i) a negligibly small amount of the relaxant in the effect compartment, (ii) steady state plasma concentration at half-maximal NMB, Cp(ss)(50), and (iii) transport of the muscle relaxant / relaxants from the effect compartment to "Outside", are neither needed nor are justified. CONCLUSIONS: The model proposed by Sheiner et al. interprets well the time course of an incomplete NMB even without the three assumptions. The simulations suggest methods to verify independently the estimates for the transport rate constant and gamma.

Guided intrathecal baclofen administration by using soleus stretch reflex in moderate-severe spastic multiple sclerosis patients with implanted pump.

We tested the hypothesis that changes in soleus stretch reflex was correlated to changes in intrathecal baclofen dose in 12 multiple sclerosis patients with moderate-severe spasticity treated with intrathecal baclofen pump. Twice patients were evaluated clinically and biomechanically. The short-latency soleus stretch reflex was elicited by rotating the ankle joint 4 degrees with a velocity from 3.1 to 180 degrees/s. There was a strong correlation between changes in intrathecal baclofen dose and amplitude of the short-latency stretch reflex (r=-0.88, P<0.001), which means that with an increase in baclofen dose there is a decrease in the amplitude. In contrast, no correlation exists between changes in intrathecal baclofen dose and clinical assessment of spasticity by using the Ashworth scale. The amplitude of the stretch reflex was very small (5 microV) compared with previous findings (>50 microV), which indicates an effective antispastic effect of intrathecal baclofen. We suggest that clinical evaluation of spasticity using Ashworth scale is insensitive to detect minor changes in moderate-severe spasticity and consequently might not be very useful in evaluating spasticity in relation to ambulatory filling of baclofen pumps. The soleus stretch reflex might be useful in situations when there is doubt about the effect of intrathecally administered baclofen.

Intrauterine baclofen exposure: a multidisciplinary approach.

Maternal use of the antispasmodic baclofen during pregnancy is an uncommon clinical scenario and leads to uncertainty regarding neonatal risks. We present a team-based, peripartum management plan designed for safe monitoring and minimizing the risk of neonatal withdrawal after unusual drug exposure. Incorporating the expertise of neonatology, nursing, pharmacy, neurology, and the lactation service, as well as parental input, this consensus approach was implemented in a case of maternal oral baclofen use with a successful outcome for the infant and family.

Premedication for tracheal intubation: a prospective survey in 75 neonatal and pediatric intensive care units.

OBJECTIVE: In children, like in adults, tracheal intubation is a painful procedure that may induce hypertension, tachycardia, and other undesirable hemodynamic disorders. Although premature neonates are very sensitive to pain and vulnerable to its long-term effects, the need for sedation before tracheal intubation is still discussed in neonatal units. Our objective was to investigate the practice of premedication before tracheal intubation in neonatal and pediatric units and determine the influence of premedication on intubating conditions. DESIGN: We performed a 10-day prospective survey in 75 neonatal and pediatric intensive care units among the 98 licensed in France. A questionnaire was completed for each intubation performed in each surveyed unit. SUBJECTS: A total of 204 patients were studied: 140 neonates, 52 infants, and 12 children. MAIN RESULTS: Data on 204 tracheal intubations were collected from 223 that were performed during the study period (participation rate, 91.4%). Premedication was used before intubation for 37.1%, 67.3%, and 91.7% of neonates, infants, and children, respectively (p <.0001). In the subgroup of neonates, premedication was particularly rare for the youngest and the smallest infants. Midazolam was the principle hypnotic used in neonates, whereas propofol was mainly used in children. Opioids or muscle relaxants / relaxant were used in 16.2% and 4.4% of the patients, respectively. A low success rate and a high incidence of hypoxemia and bradycardia were correlated with the inexperience of the operator. Premedication did not significantly influence either the success rate or the undesirable events associated with tracheal intubation. CONCLUSION: Use of premedication before tracheal intubation is limited in neonates and increases according to the age of the patient. Midazolam does not seem to be an accurate choice to improve intubating conditions in neonates and infants. Because tracheal intubation is a technique that requires a skill only developed by regular practice, operators who have limited experience with intubating children should be supported by senior operators.

Impaired 6-hydroxychlorzoxazone elimination in patients with kidney disease: Implication for cytochrome P450 2E1 pharmacogenetic studies.

OBJECTIVE: The purposes of this study were (1) to describe the disposition of chlorzoxazone and 6-hydroxychlorzoxazone in patients with kidney disease, (2) to develop a population pharmacokinetic model including covariates that may influence the pharmacokinetic variability of both compounds, and (3) to examine the effect of covariates on the chlorzoxazone metabolic ratio. METHODS: Twenty-one subjects received a single oral dose of chlorzoxazone, 250 mg, and plasma and urine samples were collected for up to 120 hours. The impact of creatinine clearance (CL(cr)), age, and weight on chlorzoxazone and 6-hydroxychlorzoxazone clearance terms was assessed with NONMEM software (v.5, level 1.1; Globomax LLC, Hanover, Md) by use of a stepwise backward-elimination technique and the likelihood ratio test. RESULTS: A linear model with first-order absorption for chlorzoxazone and first-order formation for 6-hydroxychlorzoxazone simultaneously described the disposition of both compounds. Weight was a significant predictor of 6-hydroxychlorzoxazone formation clearance and other, unaccounted for clearance of chlorzoxazone, whereas CL(cr) was a significant predictor of 6-hydroxychlorzoxazone renal clearance. No relationship between CL(cr) and formation clearance was observed. The 6-hydroxychlorzoxazone area under the plasma concentration-time curve was inversely related to CL(cr), even within the range of normal renal function, resulting in chlorzoxazone metabolic ratio values that were substantially higher in subjects with kidney disease. Both the experimental data and model-based Monte Carlo simulations revealed greatly increased chlorzoxazone metabolic ratio values when CL(cr) was low and weight was high. CONCLUSIONS: Although cytochrome P450 (CYP) 2E1 activity, as estimated by 6-hydroxychlorzoxazone formation clearance, was not affected by kidney disease, the chlorzoxazone metabolic ratio was substantially elevated in these subjects. The results of this study show that the commonly used plasma-based chlorzoxazone metabolic ratio is dependent on renal function and, therefore, does not provide a reliable index of CYP2E1-mediated metabolism. Clinical Trial

Increased cAMP as a positive inotropic factor for mammalian skeletal muscle in vitro.

To test the hypothesis that an increased cAMP concentration improves skeletal muscle force development, we stimulated mouse soleus and extensor digitorum longus (EDL) in the presence of isoproterenol (1 x 10(-5) mol.L-1), a beta-adrenergic agonist, or N6,2'-O-dibutyryladenosine 3':5'-cyclic monophosphate (dcAMP) (1 x 10(-3) mol.L-1), a membrane-permeable cAMP analogue. Drugs used in the challenges were dissolved in Krebs-Henseleit bicarbonate buffer (Krebs) at 27 degrees C and gassed with 95% O2 - 5% CO2. Stimulation at 50 impulses.s-1 for 0.5 s produced an isometric tetanic contraction. Over 25 min of contractions at 0.6 contractions.min-1, developed force increased significantly with the addition of isoproterenol (soleus, 2.5% +/- 1.1%; EDL, 13.8% +/- 2.0%) or dcAMP (soleus, 2.3% +/- 0.5%; EDL, 10.9% +/- 1.9%) as compared with vehicle controls (cont) with Krebs added (soleus, 0.0% +/- 0.2%; EDL, -2.5% +/- 0.7%). To investigate the role of Ca2+ availability, we amplified or attenuated sarcolemmal L-type Ca2+ channels with Bay K 8644 (Bay K) (5.6 x 10(-6) mol.L-1) or diltiazem hydrochloride (dilt) (10(-4) mol.L-1), respectively. Ca2+ release from the sarcoplasmic reticulum was increased with caffeine (2 x 10(-3) mol.L-1) or decreased with dantrolene sodium (dant) (4.2 x 10(-7) mol.L-1). With Ca2+availability modified, dcAMP addition in soleus significantly increased force development above control (cont, 2.3% +/- 0.4%; Bay K, 4.0% +/- 1.0%; dilt, 52.3% +/- 3.6%; caffeine, 2.3% +/- 0.7%; dant, 6.0% +/- 2.0%; dilt + dant, 55.0% +/- 23.0%). In EDL, the addition of dcAMP also increased force development above control (cont, 13.7% +/- 1.9%; Bay K, 17.0% +/- 4.0%; dilt, 170.0% +/- 40.0%; caffeine, 23.0% +/- 4.0%; dant, 72.0% +/- 10.0%; dilt + dant, 54.0% +/- 14.0%). Thus, a positive inotropic effect of cAMP existed in both fast- and slow-twitch mammalian skeletal muscle with both normal and altered Ca2+ flux into the sarcoplasm.

Carisoprodol ( Soma ) intoxications and serotonergic features.
Bramness JG, Morland J, Sorlid HK, Rudberg N, Jacobsen D.
Division of Forensic Toxicology and Drug Abuse, Norwegian Institute of Public Health, Oslo, Norway. jorgen.bramness@labmed.uio.no
The symptoms and signs of Carisoprodol ( Soma ) intoxications do not resemble those caused by its metabolite meprobamate. Meprobamate most probably produces its effects through the GABAergic neurotransmitter system. The signs and symptoms of Carisoprodol ( Soma ) intoxications, however, are not easily explained by interaction with this neurotransmitter system. In the present study, four cases of Carisoprodol ( Soma ) intoxications are presented with emphasis on the presence of serotonergic signs and symptoms. All four cases fulfilled three different sets of criteria for the diagnosis of serotonin syndrome. These findings could indicate that an increased serotonin level in the central nervous system could explain some of the symptoms and signs of Carisoprodol ( Soma ) intoxications. This may have implications for the clinical evaluation and treatment of such intoxications. Since few laboratories routinely screen for Carisoprodol ( Soma ) it is important to keep this drug in mind when encountering intoxications displaying serotonergic symptoms.