Dosage of intrathecal baclofen maintenance therapy in the spastic syndromes.
Fares Y, Khazim RM, del Barrio ER, Burzaco JA.
Neurosurgical Service, Ntra Sra Clinic of the Conception (Jimenez Diaz Foundation), Madrid, Spain. Faresdr@hotmail.com
Twenty-three patients affected with severe spasticity as a result of several clinical pathologies were treated with intrathecal Baclofen and administered at a lumbar level by means of an implantable infusion system. The system allows programming of any drug dosage in a continuous infusion fashion in the subarachnoid space. The appropriate patients were selected using specific criteria and the patients were regularly reviewed regarding the level of the spasticity and functional capacity. The required daily doses were determined using a specific detailed system. The doses needed varied according to the pathologic or clinical diagnosis. The doses administered by the global method at the beginning of the treatment were 91.96 microg/day and 137.81 microg/day in the final phase. These doses were higher in patients with medullary traumatic lesion, diffuse cerebral lesion and spastic idiopathic paraparesis. Relatively mild side effects were produced by the therapeutic doses used.

Unique considerations for the spinal cord injured patient undergoing cardiac surgery utilizing cardiopulmonary bypass.

A 37-year-old male with mitral valve regurgitation presented for mitral valve replacement. He has been a C5 quadriplegic for 13 years. The patient had been discharged 2 months before to this admission after a complicated hospital course for Staphylococcus aureus infection of the left hip. His course was complicated by adult respiratory distress syndrome (ARDS) requiring prolonged intubation, acute renal failure (ARF) requiring dialysis, 10-day coma, and bacterial endocarditis now requiring mitral valve replacement. After initial stabilization with antibiotics and gradual improvement of the multiorgan system failure, the patient presented for valve replacement and worsening congestive heart failure (CHF). Para- and quadriplegic patients rarely undergo cardiac surgery requiring cardiopulmonary bypass (CPB). The explanation for this low incidence of heart surgery in this patient population ranges from physiologic changes from the spinal cord injury to their relatively short life span. Therefore, there is no vast knowledge of how these patients with spinal cord injury will physiologically respond to CPB. Chronic paraplegia presents unique anesthetic and perfusion challenges. General anesthesia for a patient with prolonged spinal cord damage can be difficult because of dysreflexia, muscle wasting, and potassium changes with depolarizing muscle relaxants. For the perfusionist, chronic paraplegia also accentuates hemodynamic responses to nonpulsatile flow with low peripheral vascular resistance common and difficult to treat. Dramatic increases in circulating catecholamine levels are a secondary result of the initiation of CPB that can cause a hypo- and hypertensive state. Depending on the level of spinal cord injury, one might expect acute hypo- or hypertension with the various phases of open-heart surgery and CPB. A viscous circle may occur because the hypertensive state is exaggerated because of inhibitory signals not passed below the spinal cord lesion and, therefore, the vasoconstrictive reflex continues unabated. The attack usually occurs abruptly and can lead to cerebrovascular hemorrhage and death if not controlled. Fortunately, we found this patient did not develop mass autonomic dysreflexia and was not difficult to wean from CPB. The problems associated with spinal cord injury present potential complications to this patient population. Numerous triggering mechanisms may lead to a variety of clinical complications. Consideration of a response/ treatment management plan for potential problems must be exercised by the surgical team.

Vomiting post tonsillectomy at the University Hospital of the West Indies.
Scarlett M, Tennant I, Ehikhametalor K, Nelson M.
Department of Surgery, Radiology, Anaesthesia and Intensive Care, The University of the West Indies, Kingston 7, Jamaica, West Indies. mdscarl@yahoo.com
A three-year observational study of patients undergoing tonsillectomy at the University Hospital of the West Indies was conducted to determine the incidence of postoperative vomiting. Data were collected to assess possible risk factors for vomiting as well as possible alleviating agents. Two hundred and fifty-two patients were included in the study and a thirteen per cent incidence of postoperative vomiting was found. This is significantly less than that quoted in other studies (40-73%). Results also showed that steroids significantly reduced the incidence of postoperative vomiting in the study population. muscle relaxants / relaxant reversal agents and antibiotics particularly co-trimoxazole and ceftriaxone significantly increased its incidence. Usual antiemetic agents including dimenhydrinate (gravol) and promethazine (phenergan), as well as drugs known to possess antiemetic properties such as midazolam and propofol, lacked any significant protective effect against emesis. Opioid analgesia, inhalational induction and blood loss of greater than 10% of estimated blood volume appeared to increase emesis but failed to achieve statistical significance.

Quinine intoxications reported to the Scottish Poisons Information Bureau 1997-2002: a continuing problem.

Quinine is widely prescribed in the UK for night cramps. Its potential toxicity in overdose is well known. We have reviewed the Scottish experience of enquiries regarding quinine overdose to the poisons information service responsible for Scotland over a 6-year period. Between 1997 and 2002 there were 96 reports of suspected quinine toxicity from Scotland (population 5.2 million), 19 of which were in children. The largest quantities of drug ingested were in patients between the ages of 11 and 30. In comparison with older studies the pattern of quinine poisoning does not appear to have changed in the UK over 20 years, despite recognition that it is a toxic agent in overdose, and particularly in children.

Fluvoxamine drastically increases concentrations and effects of Tizanidine ( Zanaflex ): a potentially hazardous interaction.

OBJECTIVE: Our objective was to study the effect of fluvoxamine on the pharmacokinetics and pharmacodynamics of Tizanidine ( Zanaflex ), a centrally acting skeletal muscle relaxant. METHODS: In a double-blind, randomized, 2-phase crossover study, 10 healthy volunteers took 100 mg fluvoxamine or placebo orally once daily for 4 days. On day 4, each ingested a single 4-mg dose of Tizanidine ( Zanaflex ). Plasma concentrations of Tizanidine ( Zanaflex ) and fluvoxamine and pharmacodynamic variables were measured. A caffeine test was performed on day 3 to examine the role of cytochrome P450 (CYP) 1A2 in Tizanidine ( Zanaflex ) pharmacokinetics. RESULTS: On average, fluvoxamine increased the total area under the concentration-time curve [AUC(0- infinity )] of Tizanidine ( Zanaflex ) 33-fold (range, 14-fold to 103-fold; P =.000002) and the peak plasma concentration 12-fold (range, 5-fold to 32-fold; P =.000001). The mean elimination half-life of Tizanidine ( Zanaflex ) was prolonged from 1.5 to 4.3 hours (P =.00004) by fluvoxamine. The AUC(0- infinity ) of Tizanidine ( Zanaflex ) and its increase by fluvoxamine correlated with the caffeine/paraxanthine ratio and its increase, respectively (P <.03). All pharmacodynamic variables revealed a significant difference between the fluvoxamine and placebo phases, eg, in the maximal effects on systolic blood pressure (-35 mm Hg, P =.000009), diastolic blood pressure (-20 mm Hg, P =.00002), heart rate (-4 beats/min, P =.007), Digit Symbol Substitution Test (P =.0003), subjective drug effect (P =.0000001), and drowsiness (P =.0002). In particular, the decrease in systolic blood pressure, to the level of 80 mm Hg or even less, was an alarming finding. CONCLUSIONS: Fluvoxamine seriously affects the pharmacokinetics of Tizanidine ( Zanaflex ) and increases the intensity and duration of its effects. Inhibition of Tizanidine ( Zanaflex )-metabolizing enzyme(s), mainly CYP1A2, by fluvoxamine seems to explain the observed interaction. Because of the potentially hazardous consequences, the concomitant use of Tizanidine ( Zanaflex ) with fluvoxamine, or other potent inhibitors of CYP1A2, should be avoided.

Sometimes (what seems to be) a heart attack is (really) a pain in the neck.

A 31-year-old patient complained of severe crushing chest pain that radiated to his left arm and jaw. After admission to the hospital, tests revealed a normal electrocardiogram, normal treadmill, normal coronary arteriogram, and normal cardiac enzymes. However, the patient continued to have pain, which was relieved by sublingual and intravenous nitroglycerine. He was discharged from the hospital with a diagnosis of "musculoskeletal" chest pain, taking nonsteroidal anti-inflammatory drugs, muscle relaxants, and narcotics. Two weeks later, the patient returned with worsening symptoms. Cardiac work-up was again negative. Thoracic and cervical spine radiographs were ordered for possible discogenic pain. After abnormalities were found on cervical radiographs, magnetic resonance imaging (MRI) was ordered, and the patient was referred to an orthopedic surgeon. Further work-up revealed a herniated disk at C6-C7, with radicular pain. Surgery on the suspect disk totally relieved the patient's pain.

Current and future treatment of chest pain of presumed esophageal origin.

Patients with chest pain of presumed esophageal origin should be reassured and should undergo an esophageal manometry study. In patients with spastic esophageal disorders, a trial with calcium channel blockers or low-dose antidepressants used as visceral analgesics is the best approach. Inpatients with non GERD-related, nonspastic esophageal motility disorder, low-dose antidepressants seem reasonable. Anxiolytics are useful in patients with panic disorders, and psychological interventions (eg, cognitive-behavioral therapy) are also valuable, mainly in patients in whom reassurance is not sufficient to avoid the misinterpretation of their symptoms. In the future, visceral sensitivity modifying agents such as serotoninergic agonists or antagonists may become the cornerstone of therapy in patients with chest pain of presumed esophageal origin.Combinations of different approaches, such as proton pump inhibitors and psychotropic or antinociceptive agents, should also be evaluated in clinical trials.

A clinical and pharmacologic review of skeletal muscle relaxants / relaxant for musculoskeletal conditions.
Beebe FA, Barkin RL, Barkin S.
New World Health, Division of Nelson Communications Co. Inc., 202 Carnegie Center, Suite 101, Princeton, NJ 08540, USA. fbeebe@nelsoncomm.com
Muscle strains and other musculoskeletal disorders (MSDs) are a leading cause of work absenteeism. Muscle pain, spasm, swelling, and inflammation are symptomatic of strains. The precise relationship between musculoskeletal pain and spasm is not well understood. The dictum that pain induces spasm, which causes more pain, is not substantiated by critical analysis. The painful muscle may not show EMG activity, and when there is, the timing and intensity often do not correlate with the pain. Clinical and physiologic studies show that pain tends to inhibit rather than facilitate reflex contractile activity. The decision to treat and choice of therapy are largely dictated by the duration, severity of symptoms, and degree of dysfunction. Trigger point injections are sometimes used with excellent results in the treatment of muscle spasm in myofacial pain and low-back pain. NSAIDs are used with much greater frequency than oral skeletal muscle relaxants / relaxant (SMRs) or opioids in the treatment of acute MSDs. Unfortunately, remarkably little sound science guides the choice of drug for the treatment of acute, uncomplicated MSDs, and the evaluation of efficacy of one agent over another is complicated by numerous factors. Only a limited number of high-quality, randomized, controlled trials (RCTs) provide evidence of the effectiveness of NSAIDs or SMRs in the treatment of acute, uncomplicated MSDs. The quality of design, execution, and reporting of trials for the treatment of MSDs needs to be improved. The combination of an SMR and an NSAID or COX-2 inhibitor or the combination of SMR and tramadol/acetaminophen is superior to single agents alone.


Dantrolene stabilizes domain interactions within the ryanodine receptor.
Kobayashi S, Bannister ML, Gangopadhyay JP, Hamada T, Parness J, Ikemoto N.
Boston Biomedical Research Institute, Watertown, Massachusetts 02472, USA.
Interdomain interactions between N-terminal and central domains serving as a "domain switch" are believed to be essential to the functional regulation of the skeletal muscle ryanodine receptor-1 Ca(2+) channel. Mutational destabilization of the domain switch in malignant hyperthermia (MH), a genetic sensitivity to volatile anesthetics, causes functional instability of the channel. Dantrolene, a drug used to treat MH, binds to a region within this proposed domain switch. To explore its mechanism of action, the effect of dantrolene on MH-like channel activation by the synthetic domain peptide DP4 or anti-DP4 antibody was examined. A fluorescence probe, methylcoumarin acetate, was covalently attached to the domain switch using DP4 as a delivery vehicle. The magnitude of domain unzipping was determined from the accessibility of methylcoumarin acetate to a macromolecular fluorescence quencher. The Stern-Volmer quenching constant (K(Q)) increased with the addition of DP4 or anti-DP4 antibody. This increase was reversed by dantrolene at both 37 and 22 degrees C and was unaffected by calmodulin. [(3)H]Ryanodine binding to the sarcoplasmic reticulum and activation of sarcoplasmic reticulum Ca(2+) release, both measures of channel activation, were enhanced by DP4. These activities were inhibited by dantrolene at 37 degrees C, yet required the presence of calmodulin at 22 degrees C. These results suggest that the mechanism of action of dantrolene involves stabilization of domain-domain interactions within the domain switch, preventing domain unzipping-induced channel dysfunction. We suggest that temperature and calmodulin primarily affect the coupling between the domain switch and the downstream mechanism of regulation of Ca(2+) channel opening rather than the domain switch itself.

Predictors of outcome in prolonged posttraumatic disorders of consciousness and assessment of medication effects: A multicenter study.
Whyte J, Katz D, Long D, DiPasquale MC, Polansky M, Kalmar K, Giacino J, Childs N, Mercer W, Novak P, Maurer P, Eifert B.
Moss Rehabilitation Research Institute/Albert Einstein Healthcare Network, Philadelphia, PA, USA. jwhyte@einstein.edu
OBJECTIVES: To develop predictive models of recovery from the vegetative state (VS) and minimally conscious state (MCS) after traumatic brain injury (TBI) and to gather preliminary evidence on the impact of various psychotropic medications on the recovery process to support future randomized controlled trials. Design Longitudinal observational cohort design, in which demographic information, injury and acute care history, neuroimaging data, and an initial Disability Rating Scale (DRS) score were collected at the time of study enrollment. Weekly follow-up data, consisting of DRS score, current psychoactive medications, and medical complications, were gathered until discharge from inpatient rehabilitation. SETTING: Seven acute inpatient rehabilitation facilities in the United States and Europe with specialized programs for treating patients in the VS and MCS. PARTICIPANTS: People with TBI (N=124) who were in the VS or MCS 4 to 16 weeks after injury. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: DRS score at 16 weeks after injury and time until commands were first followed (among those participants demonstrating no command following at study enrollment). Results DRS score at enrollment, time between injury and enrollment, and rate of DRS change during the first 2 weeks of poststudy observation were all highly predictive of both outcomes. No variables related to injury characteristics or lesions on neuroimaging were significant predictors. Of the psychoactive medications, amantadine hydrochloride was associated with greater recovery and dantrolene sodium was associated with less recovery, in terms of the DRS score at 16 weeks but not the time until commands were followed. More detailed analysis of the timing of functional improvement, with respect to the initiation of amantadine provided suggestive, but not definitive, evidence of the drug's causal role. CONCLUSIONS: These findings show the feasibility of improving outcome prediction from the VS and MCS using readily available clinical variables and provide suggestive evidence for the effects of amantadine and dantrolene, but these results require confirmation through randomized controlled trials.