Simulation of acute spinal cord injury: effects on respiration.

The respiratory effects of acute spinal injury and paralysis are difficult to study. Urgent medical needs of human spinal cord injury victims usually preclude study, while induction of spinal cord lesions in awake animals is not feasible ethically. We utilized controlled, segmental infusion of epidural anesthetic in awake, highly trained, implanted canines to reversibly simulate the effects of thoracic and cervical (paraplegic and quadriplegic) spinal cord injury. We studied six animals, an average of 29 days after implantation with electromyogram and sonomicrometry transducers in transversus abdominis, external intercostal, parasternal intercostal and costal diaphragm muscles. Anesthetic was infused through an epidural catheter inserted percutaneously, under fluoroscopic guidance. Asymmetrical motor blockade was prevented using repositioning during epidural infusions. By sequential infusion we were able to induce three distinct, functional levels of spinal paralysis showing cumulative paralysis of abdominal, external intercostal, and parasternal intercostal muscles. Paralysis of the abdomen and chest wall, sparing only the diaphragm, showed unexpected bradypnea and failure to maintain minute ventilation.

Detection and prevention of NSAID-induced enteropathy.

Non-steroidal anti-inflammatory drugs (NSAIDs) may cause damage distal to the duodenum. We reviewed the prevalence, clinical spectrum, assessment, pathogenesis, and treatment of adverse effects of NSAIDs on the small intestine. NSAIDs can cause small intestinal perforation, ulcers, and strictures requiring surgery. NSAIDs produce inflammation of the small intestine in 40 to 70% in long-term users, and the associated complications of blood loss and protein loss are difficult management problems. The pathogenesis of NSAID enteropathy is a multi-stage process involving specific biochemical and subcellular organelle damage followed by inflammatory tissue reaction. Various suggested treatments of NSAID-induced enteropathy (e.g., sulphasalazine, misoprostol, and metronidazole) have yet to undergo rigorous clinical trials. Cyclo-oxygenase-2 inhibitors appear to be safer to the small intestine than traditional NSAIDs. Pre-clinical and clinical data suggests meloxicam, celecoxib, nimesulide and rofecoxib may have less small intestine toxicity than traditional non-selective NSAIDs.

Choosing the right nonsteroidal anti-inflammatory drug for the right patient: a pharmacokinetic approach.

Effective use of the growing number of nonsteroidal anti-inflammatory drugs (NSAIDs), a group that has recently been augmented by the introduction of the selective cyclo-oxygenase-2 inhibitors, requires adequate knowledge of their pharmacokinetics. After oral administration, the absorption of NSAIDs is generally rapid and complete. NSAIDs are highly bound to plasma proteins, specifically to albumin (>90%). The volume of distribution of NSAIDs is low, ranging from 0.1 to 0.3 L/kg, suggesting minimal tissue binding. NSAID binding in plasma can be saturated when the concentration of the NSAID exceeds that of albumin. Most NSAIDs are metabolised by the liver, with subsequent excretion into urine or bile. Enterohepatic recirculation occurs when a significant amount of an NSAID or its conjugated metabolites are excreted into the bile and then reabsorbed in the distal intestine. NSAID elimination is not dependent on hepatic blood flow. Hepatic NSAID elimination is dependent on the free fraction of NSAID within the plasma and the intrinsic enzyme activities of the liver. Renal elimination is not an important elimination pathway for NSAIDs, except for azapropazone. The plasma half-life of NSAIDs ranges from 0.25 to >70 hours, indicating wide differences in clearance rates. Hepatic or renal disease can alter NSAID protein binding and metabolism. Some NSAIDs with elimination predominantly via acylglucuronidation can have significantly altered disposition. Pharmacokinetics are also influenced by chronobiology, and many NSAIDs exhibit stereoselectivity. There appear to be relationships between NSAID concentration and effects. At therapeutically equivalent doses, NSAIDs appear to be equally efficacious. The major differences between NSAIDs are their therapeutic half-lives and safety profiles. NSAIDs undergo drug interactions through protein binding displacement and competition for active renal tubular secretion with other organic acids. When choosing the right NSAID for the right patient, individual patient-specific and NSAID-specific pharmacokinetic principles should be considered.

Physicians' recommendations for patients who undergo noncardiac surgery.

OBJECTIVE: To investigate how consulting physicians attempt to modify perioperative cardiac risk for patients who undergo noncardiac surgery by comparing the preoperative cardiac recommendations of consulting physicians in 2 university centres. DESIGN: Retrospective cross-sectional analysis. SETTING: Five hospitals affiliated with 2 Canadian universities. PATIENTS: Three hundred and eight preoperative consultations were evaluated in 297 patients who were 40 years of age or older and scheduled for noncardiac surgery. OUTCOME MEASURES: Cardiac drug recommendations at the preoperative consultation [corrected]; overall recommendations and practice variation between the 2 centres. RESULTS: The greatest changes in drug management suggested by consultants were the initiation of nitrates in 13% of the patients and a decrease in acetylsalicylic acid administration from 27% to 17%. Centre A physicians recommended adding an angiotensin-converting enzyme inhibitor 11% of the time, whereas centre B physicians recommended such an inhibitor in only 1% of the patients (p = 0.001). In patients taking acetylsalicylic acid at the preoperative consultation, Centres A and B physicians recommended withholding the drug 47% and 22% of the time, respectively (p = 0.03). These differences persisted between the 2 centres after controlling for physician estimates of risk. CONCLUSIONS: Consultants frequently recommended perioperative changes in the use of cardiac medications, and there were differences in practice patterns between the 2 centres. These differences may be affecting patient outcomes and highlight the need for randomized clinical trials to determine the impact of perioperative drug administration on bleeding, myocardial infarction and death.

Screening for hypothyroidism in sleep apnea.

Primary sleep apnea-hypopnea syndrome (obstructive sleep apnea [OSA]) and hypothyroidism have many signs and symptoms in common. The overlap in clinical presentation, and the sleep-disordered breathing that can accompany hypothyroidism, create a significant risk of misdiagnosis of sleep apnea among patients referred to sleep clinic who have undiagnosed hypothyroidism. We determined the point prevalence of hypothyroidism in our sleep clinic patients with newly diagnosed sleep-disordered breathing. Of 290 sequential patients referred to sleep clinic, 200 (69%) patients judged at high risk for OSA underwent polysomnography (PSG) and biochemical screening for hypothyroidism. Of these, 124 (62%) were judged to have sleep apnea. This included three patients (1.5% of patients undergoing PSG or 2. 4% of those judged to have OSA) who were also discovered to have previously undiagnosed hypothyroidism. These three patients with "secondary" sleep apnea were treated with thyroxine therapy alone, and followed with sequential sleep studies and serum thyroid hormone assays; symptoms, sleep-disordered breathing, nocturnal hypoxia, and thyroid deficiency resolved simultaneously. We conclude that biochemical screening for hypothyroidism is required to prevent inadvertent misdiagnosis of hypothyroid sleep-disordered breathing as primary sleep apnea, and that it is a cost-effective component of the investigation of sleep apnea.

Clinical pharmacokinetics and pharmacodynamics of bromfenac.

Bromfenac is a nonsteroidal anti-inflammatory drug whose peak plasma concentration is reached 0.5 hours after oral administration. Bromfenac binds extensively to plasma albumin. The area under the plasma concentration-time curve is linearly proportional to the dose for oral doses up to 150 mg. The relationship between the total plasma and analgesic effect has been established. Only small amounts of bromfenac are eliminated unchanged, with the remaining drug being biotransformed into glucuronide metabolites which are excreted in urine and bile. Rapid elimination occurs in healthy individuals (half-life 0.5 to 4.0 h). Renal disease, hepatic disease and aging alter the disposition kinetics of bromfenac, and dosage adjustment may be advisable. Bromfenac modestly decreases free phenytoin concentrations. Bromfenac can cause idiosyncratic hepatic toxicity and has been withdrawn by its manufacturer pending further investigation of these case reports.

Physician estimates of perioperative cardiac risk in patients undergoing noncardiac surgery.

BACKGROUND: We know little about how physicians assess perioperative cardiac risk in patients undergoing noncardiac surgery. OBJECTIVES: To evaluate preoperative medical consultations and determine the extent to which consultants used validated cardiac risk indices and specialized noninvasive cardiac tests, and to assess agreement between physician ratings of cardiac risk (low, moderate, or high) and risk estimates derived using validated cardiac risk indices or, in the case of vascular surgery, a risk index. METHODS: This observational study was conducted at 5 Canadian teaching hospitals affiliated with 2 universities. We retrospectively evaluated 308 preoperative consultations performed in 297 patients and examined the frequency with which consultants recorded the use of validated cardiac risk indices. We used K statistics to quantify the extent to which physician ratings of cardiac risk agreed with risk estimates derived using validated cardiac risk indices. RESULTS: Physicians recorded use of a risk index in 31% of the consultations, but the index used was almost always the suboptimal classification of the American Society of Anesthesiologists. The agreement between physician estimates of cardiac risk and the validated cardiac risk indices was only fair, with a weighted K of 0.38 (95% confidence interval, 0.28-0.49). Overestimation and underestimation of cardiac risk occurred in 16% and 13% of the consultations, respectively. Consultants did not order dipyridamole thallium imaging or dobutamine stress echocardiography for any moderate-risk patients undergoing vascular surgery. CONCLUSIONS: Physicians underuse validated cardiac risk indices, and the agreement between the cardiac risk estimates and risk as determined by validated cardiac indices is suboptimal. Physicians are also underusing dipyridamole thallium imaging and dobutamine stress echocardiography for moderate-risk patients undergoing vascular surgery.

Clinical pharmacokinetics of meloxicam. A cyclo-oxygenase-2 preferential nonsteroidal anti-inflammatory drug.

Meloxicam [4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine -3-carboxamide-1, 1-dioxide] is a nonsteroidal anti-inflammatory drug (NSAID) of the oxicam class which shows preferential inhibition of cyclo-oxygenase-2. Meloxicam has a plasma half-life of approximately 20 hours, making it convenient for once-daily administration. Meloxicam is eliminated after biotransformation to 4 pharmacologically inactive metabolites, which are excreted in urine and faeces. Meloxicam and its metabolites bind extensively to plasma albumin. Substantial concentrations of meloxicam are attained in synovial fluid, the proposed site of action in chronic inflammatory arthropathies. Neither moderate renal nor hepatic insufficiency significantly alter the pharmacokinetics of meloxicam. Dosage adjustment is not required in the elderly. Drug-drug interaction studies are available for some commonly co-prescribed medications. Concentration-dependent therapeutic and toxicological effects have yet to be extensively elucidated for this NSAID.

Clinical pharmacokinetics of lornoxicam. A short half-life oxicam.

Lornoxican (chlorotenoxicam) is a nonsteroidal anti-inflammatory drug (NSAID) of the oxicam class. Unlike other oxicams, lornoxicam has a relatively short plasma half-life (3 to 5 hours). Lornoxicam is eliminated following biotransformation to 5'-hydroxy-lornoxicam, which does not undergo enterohepatic recirculation. Glucoroconjugated metabolites are excreted in urine and faeces with a half-life of about 11 hours. Lornoxicam and its metabolites bind extensively to plasma albumin. Substantial concentrations of lornoxicam are attained in synovial fluid, the proposed site of action in chronic inflammatory arthropathies. The effects of lornoxicam concentration on its therapeutic and toxicological properties have not yet been extensively reported. Lornoxicam, like other NSAIDs, appears to interact with warfarin, sulphonylureas, digoxin and furosemide.