Use of lumbar laminoplasty vs. laminotomy for transection of the filum terminale does not affect early complication rates or postoperative course.

INTRODUCTION: Various techniques are used for spinal cord untethering. The purpose of this study was to compare patient characteristics, postoperative course, and early complications after laminotomy vs. laminoplasty for transection of the filum terminale for tethered cord release. METHODS: Retrospective analysis of clinical and magnetic resonance imaging data was undertaken for all patients (<18 years) who underwent tethered cord release by transection of the filum terminale at Oregon Health & Science University, Doernbecher Children's Hospital, from 2000 to 2011. RESULTS: Data from two hundred and forty-eight patients were analyzed. Mean age was 5.2 years (range 0.3 to 16.8 years). Access to the thecal space during surgery was achieved using laminotomy or laminoplasty in 82 (33.1 %) and 166 (66.9 %) patients, respectively. Laminoplasty patients were significantly younger than laminotomy patients (3.2 vs. 9.3 years, p<0.0001); other clinical and radiographic characteristics were similar between the groups. Nine patients (3.6 %) experienced early complications, including cerebrospinal fluid leak (n=2), suprafascial infection requiring surgical management and intravenous (IV) antibiotics (n=3) or IV antibiotics alone (n=1), a small area of peri-incisional cutaneous necrosis (n=1), perioperative seizures (n=1), and mild, transient malignant hyperthermia (n=1). There was no difference in the number of early complications between the two groups. Univariate and multivariate analyses revealed no significant risk factor for postoperative complication associated with technique. As judged by caregivers, independent of surgical technique, 97 % of patients improved after surgery. CONCLUSION: There was no difference in complication risk when performing transection of the filum terminale for tethered cord release using laminotomy or laminoplasty.

Replacement with GABAergic steroid precursors restores the acute ethanol withdrawal profile in adrenalectomy/gonadectomy mice.

The neurosteroid allopregnanolone (ALLO) is a progesterone metabolite that is one of a family of neuroactive steroids (NAS) that are potent positive allosteric modulators of gamma-aminobutyric acid(A) (GABA(A)) receptors. These GABAergic NAS are produced peripherally (in the adrenals and gonads) and centrally in the brain. Peripherally produced NAS modulate some effects of ethanol intoxication (e.g., anxiolytic, antidepressant, and anticonvulsant effects) in rodents. We have found that NAS also may be involved in the rebound neural hyperexcitability following a high ethanol dose. Removal of the adrenals and gonads (ADX/GDX) increased withdrawal severity following 4 g/kg ethanol, as measured by handling-induced convulsions (HICs) in male and female DBA/2J mice. NAS are produced through the metabolism of progesterone (PROG), deoxycorticosterone (DOC), or testosterone, which can be blocked with the administration of finasteride (FIN), a 5alpha-reductase enzyme inhibitor. The current investigation was undertaken to clarify the step(s) in the biosynthetic NAS pathway that were sufficient to restore the acute ethanol withdrawal profile in ADX/GDX mice to that seen in intact animals. Male and female DBA/2J mice underwent ADX/GDX or SHAM surgery. After recovery, separate groups of animals were administered PROG, DOC, PROG+FIN, DOC+FIN, FIN, ALLO, ganaxalone (a synthetic ALLO derivative), corticosterone, or vehicle. Animals were then administered a 4 g/kg ethanol dose and allowed to undergo withdrawal. HICs were measured for 12 h and again at 24 h. The results indicate that replacement with PROG and DOC restored the withdrawal profile in ADX/GDX animals to SHAM levels, and that this effect was blocked with co-administration of FIN. Administration of FIN alone increased the withdrawal profile in both SHAM and ADX/GDX males. These findings indicate that the increase in acute withdrawal severity after ADX/GDX may be due to the loss of GABAergic NAS, providing insight into the contribution of endogenous GABAergic NAS to ethanol withdrawal severity.

Practice parameter update: the care of the patient with amyotrophic lateral sclerosis: multidisciplinary care, symptom management, and cognitive/behavioral impairment (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology.

OBJECTIVE: To systematically review evidence bearing on the management of patients with amyotrophic lateral sclerosis (ALS). METHODS: The authors analyzed studies from 1998 to 2007 to update the 1999 practice parameter. Topics covered in this section include breaking the news, multidisciplinary clinics, symptom management, cognitive and behavioral impairment, communication, and palliative care for patients with ALS. RESULTS: The authors identified 2 Class I studies, 8 Class II studies, and 30 Class III studies in ALS, but many important areas have been little studied. More high-quality, controlled studies of symptomatic therapies and palliative care are needed to guide management and assess outcomes in patients with ALS. RECOMMENDATIONS: Multidisciplinary clinic referral should be considered for managing patients with ALS to optimize health care delivery and prolong survival (Level B) and may be considered to enhance quality of life (Level C). For the treatment of refractory sialorrhea, botulinum toxin B should be considered (Level B) and low-dose radiation therapy to the salivary glands may be considered (Level C). For treatment of pseudobulbar affect, dextromethorphan and quinidine should be considered if approved by the US Food and Drug Administration (Level B). For patients who develop fatigue while taking riluzole, withholding the drug may be considered (Level C). Because many patients with ALS demonstrate cognitive impairment, which in some cases meets criteria for dementia, screening for cognitive and behavioral impairment should be considered in patients with ALS (Level B). Other management strategies all lack strong evidence.

Deposition of 7-aminoflunitrazepam and flunitrazepam in hair after a single dose of Rohypnol.

In recent years, there has been a notable increase in the number of reports on drug-facilitated sexual assault. Benzodiazepines are the most common so-called "date-rape" drugs, with flunitrazepam (Rohypnol) being one of the most frequently mentioned. The aim of this study was to determine whether flunitrazepam and its major metabolite 7-aminoflunitrazepam could be detected in hair collected from ten healthy volunteers after receiving a single 2 mg dose of Rohypnol using solid phase extraction and NCI-GC-MS. Such data would be of great importance to law enforcement agencies trying to determine the best time interval for hair collection from a victim of drug-facilitated sexual assault in order to reveal drug use. Ten healthy volunteers (eight women and two men, 21 to 49 years old) participated in the study. The following hair samples were collected from each volunteer: one before flunitrazepam administration, and 1, 3, 5, 14, 21, and 28 days after. In five volunteers, 7-aminoflunitrazepam was detected 24 h after flunitrazepam administration and remained in hair throughout the entire 28-day study period (0.6-8.0 pg/mg). In two cases, 7-aminoflunitrazepam appeared in hair 21 days after drug intake (0.5-2.7 pg/mg), and in two subjects 14 days later (0.5-5.4 pg/mg). In one volunteer, 7-aminoflunitrazepam was detected on day 14 and 21 but concentrations were below the quantitation limit. Flunitrazepam was detected in some samples but all concentrations were below the quantitation limit (0.5-2.3 pg/mg).

Motor neuronal death in sporadic amyotrophic lateral sclerosis (ALS) is not apoptotic. A comparative study of ALS and chronic aluminium chloride neurotoxicity in New Zealand white rabbits.

Whether diseased motor neurones in sporadic amyotrophic lateral sclerosis (ALS) die via apoptosis is unknown. Because this relates primarily to difficulties in utilizing post-mortem tissue from end-stage disease, motor neurone degeneration in ALS spinal cord was compared with that of a model of a chronic motor neurone degeneration. Degenerating motor neurones in ALS, identified by ubiquitin immunoreactivity, did not demonstrate the morphological characteristics of apoptosis and were not c-Jun immunoreactive or TUNEL positive. A temporal analysis of spinal motor neurone death in the chronic AlCl3 neurotoxicity model of motor neurone degeneration was also undertaken. AlCl3 was administered intracisternally every 4 weeks and, at intervals of 51, 107, 156 and 267 days, evidence of apoptosis was sought by morphology, TUNEL hybridization or DNA laddering. Double-labelling immunostudies were also performed with antibodies to either c-Jun, ubiquitin or high molecular weight neurofilament (NFH) with TUNEL hybridization. Although significant neurone loss was evident, apoptosis was not found. These studies demonstrate a lack of apoptosis in ALS spinal motor neurones and suggest that this observation does not relate to the utilization of post-mortem tissue in which apoptotic neurones may have been lost.

A morphological analysis of the motor neuron degeneration and microglial reaction in acute and chronic in vivo aluminum chloride neurotoxicity.

The monthly intracisternal inoculation of aluminum chloride (AlCl3) to young adult New Zealand white rabbits induces motor neuron degeneration marked by intraneuronal neurofilamentous aggregates similar to that observed in amyotrophic lateral sclerosis (ALS). However, in contrast to ALS, this process occurs in the experimental paradigm in the absence of a glial response. In addition, whereas ALS is a fatal disorder, the cessation of aluminum exposure leads to both clinical and neuropathological recovery. Because microglia can influence neuronal regeneration, we have examined the effect of both acute and chronic aluminum exposure on microglial activation in vivo. We have studied microglial morphology in young adult New Zealand white rabbits receiving either single (1000 microg) or repeated sublethal (100 microg monthly) intracisternal inoculums of AlCl3. In addition, rabbits receiving 1000 microg AlCl3 inoculums were studied following an unilateral sciatic axotomy 48 h prior to the AlCl3 exposure. Our studies demonstrate that microglial activation in vivo is inhibited by AlCl3 exposure, and that a correlation exists between the extent of microglia suppression and the potential for recovery. This suggests that microglial activation is an important determinant of neuronal injury.

Surgical treatment of interventional coronary angiographic accidents.

Newer methodologies have increased the incidence of coronary interventions. At the authors' institution, 5,614 coronary interventional procedures (28% of all catheterizations) were performed over a 3-year period, from 1995 to 1997. Eighty-one patients (1.4%) suffered angiographic accidents, including coronary artery dissection, free rupture, tamponade, foreign body embolism, and wire entrapment, and were retrospectively reviewed. All patients were taken for emergency surgery in less than 4 hours. The mean age was 61.2 years, 44 (54%) were men, and 37 (46%) were in cardiogenic shock at the time of surgery. Fifty-seven patients (70%) had intraaortic balloon counterpulsation. The number of previous cardiac interventions ranged from one to four with a mean of 1.9. One to five bypass grafts (mean, 2.2) were performed, and three patients required temporary ventricular assist devices. There were six deaths for a 30-day mortality rate of 7.4%. Thirty-two patients (39.5%) suffered significant morbidity, including cerebrovascular accidents, and renal and respiratory failure. Perioperative myocardial infarctions were diagnosed in 39 (48%) patients. Average length of stay was 12.1 days. One-year survival was satisfactory at 90% (73/81), with 56 survivors (77%) regaining normal everyday activity. Early surgical intervention, rapid revascularization, and temporary mechanical support are keys to low mortality in this high-risk group. Identification of high-risk interventions and significant comorbid conditions, with concomitant surgical consultation, need to be pursued to reduce the high morbidity rate.

Diagnostic difficulties in myasthenia gravis.

Four patients with myasthenia gravis presented with severe, largely isolated, bulbar and respiratory muscles weakness. Tensilon tests were positive and antiacetylcholine receptor (anti-AChR) antibody titers were negative in all patients. Only 1 patient had a greater than 10% decremental response during the period of respiratory failure. Although routine nerve conduction studies were normal, all had very low-amplitude diaphragmatic compound muscle action potentials. Three patients had abundant fibrillation potentials and positive sharp waves largely restricted to respiratory muscles. Clinical and electrophysiological findings improved with corticosteroids, and surprisingly, decremental responses became positive in all patients. The assessment of patients with largely isolated bulbar and respiratory muscle weakness due to myasthenia gravis may be difficult and misleading, as anti-AChR antibody titers may be negative, decremental responses may be absent, and electrophysiological assessment atypical. Due consideration of clinical symptomatology, a Tensilon test, and a trial of immunosuppression may be necessary to establish the diagnosis.

Case of the month: June 1997--a 42 year old man with left facial weakness.

A 42 yr old male presented with left facial weakness. MRI showed lesions affecting the distal seventh nerve and third division of the trigeminal nerve. The seventh nerve was biopsied and showed a malignant epithelioid schwannoma. The patient underwent extensive resection followed by irradiation. This is one of very few examples of intracranial malignant peripheral nerve sheath tumors and the first reported example of an intracranial malignant epithelioid schwannoma. The literature is reviewed and completeness of resection appears to be the most pertinent prognostic factor.

Enhanced ex vivo cosedimentation of high molecular weight neurofilament protein (NFH) with microtubules following in vivo aluminum chloride exposure: inhibition of dephosphorylation-dependent dissociation.

We have investigated the effect of acute in vivo aluminum exposure on the subsequent ex vivo cross-linking of the high molecular weight neurofilament protein (NFH) with polymerized microtubules. Young adult female New Zealand white rabbits were inoculated intracisternally with 1000 micrograms of AlCl3 in 0.9% NaCl or with 0.9% NaCl alone, and killed 48 hours later. Following isolation of a cytoskeletal-enriched protein fraction from the cervical spinal cord, NFH was purified by either electroelution or column chromatography. Tubulin was isolated from New Zealand white rabbit brains by repeated temperature-dependent polymerization and depolymerization, purified over phosphocellulose, and cosedimented with either phosphorylated or dephosphorylated NFH. Following incubation for 30 minutes at 32 degrees C with tubulin in the presence of 20 microM Taxol, 1.0 mM MgCl2 and 1.0 mM GTP, the insoluble pellet containing NFH/microtubules was isolated. Both the pellet and supernatent were fractionated by SDS.PAGE and the amount of NFH present quantified by transmission densitometry following silver-staining. Results were identical regardless of the technique utilized for the purification of NFH. Control NFH preferentially cosedimented with microtubules when in the fully phosphorylated isoform, but remained in the soluble fraction following dephosphorylation. Phosphorylated NFH derived from AlCl3-inoculated rabbits demonstrated similar binding characteristics to control NFH, but following exhaustive dephosphorylation, exhibited a 4.5 fold induction of NFH/microtubule binding (p = 0.0314). Incubating dephosphorylated control NFH with microtubules in the presence of increasing concentrations of AlCl3 failed to induce similar cosedimentation. These experiments suggest that phosphorylation promotes NFH cross-linking to microtubules. In addition, the phosphorylation/dephosphorylation dependent regulation of NFH cross-linking to microtubules is disrupted following in vivo AlCl3 exposure by a mechanism that s independent of NFH/Al3+ binding.

Comparative study of chronic aluminum-induced neurofilamentous aggregates with intracytoplasmic inclusions of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is characterized neuropathologically by chromatolysis, Bunina bodies, hyaline inclusions, skein-like inclusions and axonal spheroids. Aluminum, a known neurotoxin, is the cause of dialysis encephalopathy and is considered to be a causative agent in high incidence foci of ALS in the western Pacific. We have developed an experimental model of motor neuron degeneration in New Zealand white rabbits using chronic low-dose intracisternal administration of aluminum and compared the clinical and neuropathological changes to those of human ALS. Aluminum-inoculated rabbits developed progressive hyperreflexia, hypertonia, limb splaying, gait impairment, muscle wasting, hindlimb paralysis and impaired tonic immobility responses without overt encephalopathic features over a 14-month period. Examination of spinal cords from these animals demonstrated the frequent occurrence and progressive development of anterior horn cell lesions that included small, round, argentophilic perikaryal inclusions similar to hyaline inclusions seen in human ALS. Other inclusions were more condensed and eosinophilic, while still others had neurofibrillary tangle-like morphologies. Axonal spheroids and neuritic thickenings were also prominent and were identical to those seen in human ALS. We believe that the similar and progressive development of neuropathological changes observed in the chronic aluminum-intoxication model, compared to human ALS, warrants further study to aid in understanding the cellular and molecular mechanisms of human motor neuron disease.

Can the mechanisms of aluminum neurotoxicity be integrated into a unified scheme?

Regardless of the host, the route of administration, or the speciation, aluminum is a potent neurotoxicant. In the young adult or developmentally mature host, the neuronal response to Al exposure can be dichotomized on morphological grounds. In one, intraneuronal neurofilamentous aggregates are formed, whereas in the other, significant neurochemical and neurophysiological perturbations are induced without neurofilamentous aggregate formation. Evidence is presented that the induction of neurofilamentous aggregates is a consequence of alterations in the posttranslational processing of neurofilament (NF), particularly with regard to phosphorylation state. Although Al has been reported to impact on gene expression, this does not appear to be critical to the induction of cytoskeletal pathology. In hosts responding to Al exposure without the induction of cytoskeletal pathology, impairments in glucose utilization, agonist-stimulated inositol phosphate accumulation, free radical-mediated cytotoxicity, lipid peroxidation, reduced cholinergic function, and altered protein phosphorylation have been described. The extent to which these neurochemical modifications correlate with the induction of a characteristic neurobehavioral state is unknown. In addition to these paradigms, Al is toxic in the immediate postnatal interval. Whether unique mechanisms of toxicity are involved during development remains to be determined. In this article, the mechanisms of Al neurotoxicity are reviewed and recommendations are put forth with regard to future research. Primary among these is the determination of the molecular site of Al toxicity, and whether this is based on Al substitution for divalent metals in a number of biological processes. Encompassed within this is the need to further understand the genesis of host- and developmental-specific responses.

Internal thoracic artery for coronary artery grafting in octogenarians.

BACKGROUND: Use of the left internal thoracic artery as a bypass graft has been shown to result in better long-term patency and improved survival. In elderly patients, the internal thoracic artery has been used less often for coronary artery bypass grafts because of the belief that greater morbidity and mortality are associated with this procedure. This study was undertaken to test this premise in the octogenarian population. METHODS: Over an 8-year period, 474 consecutive patients 80 years of age and greater had coronary artery bypass grafting. The left internal thoracic artery was used in 188 patients (39.7%) (group 1) and saphenous vein grafts only (group 2), in 286 (60.3%). The mean age was 82.6 years (range, 80 to 95 years). There were 312 men (65.8%) and 162 women (34.2%). RESULTS: Use of the internal thoracic artery as a graft has risen steadily each year, as has the number of patients who are octogenarians. The hospital mortality rate was 7.8%. Patients in group 1 had a mortality rate of 9.0% and patients in group 2, a mortality rate of 7.0%. The mortality rate among survivors at 1 year was 6.7%. Long-term survival was significantly greater in group 1. CONCLUSIONS: On the basis of this study, we conclude that the internal thoracic artery is the bypass graft of choice, especially in regard to long-term mortality, and should not be denied to this high-risk group.

Proximal sciatic axotomy does not inhibit the induction of neurofilamentous inclusions following intracisternal aluminum chloride exposure.

We have previously demonstrated an acute, dose-dependent suppression of low molecular weight neurofilaments (NFL) and intermediate molecular weight neurofilaments (NFM) steady state mRNA levels while sparing those of high molecular weight (NFH) mRNA 48 hours (h) following the intracisternal inoculation of AlCl3 in young adult New Zealand white rabbits. To determine whether this alteration in NF steady state mRNA stoichiometry is a necessary prerequisite to the induction of neurofilamentous inclusions, we examined the response of spinal motor neurons to aluminum exposure in vivo following axotomy. Forty-eight h following a complete transection of the proximal sciatic nerve, rabbits were inoculated intracisternally with either 1000 microg AlCl3 in 100 microl 0.9% NaCl or 0.9% NaCl alone. Rabbits were killed at either 48 or 120 h post-inoculation, and the extent of neurofilamentous inclusion formation quantified in both the cervical and the lumbosacral cord. Following the axotomy, rabbits developed an ipsilateral hind-limb paralysis. In spinal motor neurons ipsilateral to the axotomy, chromatolytic changes were observed and both NFH and NFM mRNA levels were significantly reduced (p<0.001). At 48 h post-AlCl3 inoculation, 29% of motor neurons contralateral to the axotomy demonstrated inclusions, whereas 43% of ipsilateral motor neurons demonstrated inclusions (Fisher's test, two tailed, p = 0.0196). At 120 h post-axotomy 75% and 83%, respectively, of neurons were involved (p = 0.0212). Neurofilamentous inclusions did not form in NaCl-inoculated rabbits. These observations indicate that an altered stoichiometry of NF mRNA steady levels, with a relative overexpression of NFH mRNA, is not critical to the induction of neurofilamentous inclusions following AlCl3 exposure.

Spinal motor neuron neuroaxonal spheroids in chronic aluminum neurotoxicity contain phosphatase-resistant high molecular weight neurofilament (NFH).

It has previously been shown that a single intracisternal inoculum of AlCl3 in young adult New Zealand white rabbits will induce a dose-dependent phosphatase resistance of high molecular weight neurofilament protein (NFH) that is proportionate to the extent of neurofilamentous inclusion formation (Strong and Jakowec, 1994). To determine if the potential for dissolution of aluminum-induced neurofilamentous inclusions was dependent on the degree of NFH phosphatase resistance, we have examined NFH phosphatase sensitivity in a reversible chronic model of aluminum neurotoxicity. Rabbits receiving repeated intracisternal inoculums of 100 microgram AlCl3 at 28 day intervals until day 267 develop spinal motor neuron perikaryal and neuroaxonal neurofilamentous aggregates in a stereotypic, dose-dependent fashion. In the rabbits receiving inoculums until day 156 with survival until day 267 without further aluminum exposure, neuroaxonal spheroids remained prominent while perikaryal inclusions largely resolved. Immunoreactivity to a monoclonal antibody recognizing phosphorylated NFH (SMI 31) was abolished in perikaryal aggregates at each time interval by dephosphorylation with bovine alkaline phosphatase. However, neuroaxonal spheroids maintained their immunoreactivity. Using time-course dephosphorylation studies of spinal cord homogenates, we observed a significant reduction in the rate of dephosphorylation of NFH following 267 days of AlCl3 exposure (P < 0.05). These observations suggest that neuroaxonal spheroids contain phosphatase-resistant NFH isoforms and that the potential for resolution of intraneuronal neurofilamentous inclusions correlates with the susceptibility of NF within these inclusions to enzymatic dephosphorylation.

Cardiac surgery in nonagenarians.

OBJECTIVES AND BACKGROUND: The purpose of this study was to document our initial experience with patients 90 years of age and older and to determine whether cardiac surgery is justified in this age group. Cardiac surgery in octogenarians has proven to be a successful and worthwhile procedure. A small group of nonagenarians with severe coronary artery disease (CAD) and aortic valve disease refractory to medical therapy have been considered for surgery. METHODS: Fourteen patients aged 90 or more underwent cardiac surgery for symptomatic CAD or aortic valvular disease refractory to medical therapy. Eight patients underwent isolated coronary artery bypass grafting (CABG) and six patients underwent aortic valve replacement (AVR). All patients were in NYHA Class IV preoperatively. RESULTS: Hospital mortality occurred in one patient (7%). Hospital morbidity occurred in 10 patients (71%) and included 7 cardiac, 5 neurological, 1 gastrointestinal, 1 infectious, and 1 pulmonary event. All survivors left the hospital symptomatically improved. The mean length of stay was 26 days. Four CABG patients went on to die at a mean of 2 years and 2 months, and 3 remain alive at a mean of 2 years and 4 months. Three AVR patients expired at a mean of 3 years and 4 months, and 3 remain alive at 4 years and 1 month. CONCLUSIONS: Cardiac surgery in carefully selected nonagenarians is justified and can be performed with acceptable results.

Coronary artery bypass grafting in patients with chronic renal failure: A reappraisal.

BACKGROUND AND AIMS: Chronic renal failure (CRF) is known to increase the morbidity and mortality in patients undergoing cardiac operations. Successful outcome of coronary artery bypass grafting (CABG) in some patients with CRF has been reported, but remains controversial. METHODS: Forty-four patients with CRF who underwent CABG were examined. Two groups were analyzed. Group I consisted of 13 patients with end-stage renal disease on hemodialysis. Group II consisted of 31 patients with a creatinine > or = 1.6 gm/dL for a minimum of 6 months, but were not on dialysis. There were 36 male and 8 female patients, with a mean age of 71 years. RESULTS: The hospital mortality was 10 patients (23%) with 4 (31%) hospital deaths in Group I, and 6 (19%) in Group II. There was major morbidity in 35 (80%) patients. In Group II there were 8 (26%) patients who required permanent postoperative dialysis. A control group of 547 patients 70 years of age who underwent CABG had 30 hospital mortalities (5%) and 75 morbidities (13%). The average length of stay was 27 days. Fifteen patients died at a mean of 34 months after being discharged from the hospital. Nineteen of the original 44 patients remain alive at a mean of 32 months. The total mortality at 6 years and 4 months was 57%. CONCLUSIONS: Older and sicker patients with CRF who undergo CABG are at an exceptionally high risk for mortality and morbidity. For CRF patients not on dialysis with a creatinine 2.5 gm/dL, there is a strong likelihood of permanent postoperative dialysis. Long-term follow-up shows survival to be well below their non-CRF counterparts.

The dose-response relationship of tranexamic acid.

BACKGROUND: Prophylactic administration of the antifibrinolytic drug tranexamic acid decreases bleeding and transfusions after cardiac operations. However, the best dose of tranexamic acid for this purpose remains unknown. This study explored the dose-response relationship of tranexamic acid for hemostatic efficacy after cardiac operation. METHODS: In prospective, randomized, double-blinded fashion, 148 patients undergoing cardiac operation with extracorporeal circulation were divided into six groups: a placebo group and five groups receiving tranexamic acid in loading doses before incision (range 2.5 to 40 mg.kg-1) and one-tenth the loading dose hourly for 12 h. The mass of blood collected by chest tubes over 12 h represented blood loss. Allogeneic transfusions within 12 h and within 5 d of surgery were tallied. RESULTS: The six groups presented similar demographics. Patients receiving placebo had increased postoperative D-dimer concentration compared to groups receiving tranexamic acid. Patients receiving at least 10 mg.kg-1 tranexamic acid followed by 1 mg.kg-1.h-1 bled significantly less (365, 344, and 369 g.12 h-1, respectively, for those three groups) compared with patients who received placebo (552 g, P < 0.05). Tranexamic dose did not affect transfusions. Only initial hematocrit affected whether a patient received an allogeneic transfusion within 5 days of operation (odds ratio 2.08 for each 3% absolute decrease in hematocrit). CONCLUSIONS: Prophylactic tranexamic acid, 10 mg.kg-1 followed by 1 mg.kg-1.h-1, decreases bleeding after extracorporeal circulation. Larger doses do not provide additional hemostatic benefit.