Cardiovascular toxicity of local anesthetics: an alternative hypothesis

The current study examined the possibility that high local anesthetic concentrations within the central nervous system could contribute to the toxic cardiovascular effects observed clinically after an accidental intravenous injection. Equal numbers of molecules of lidocaine (1.6 microliter of a 2% solution) and bupivacaine (1.0 microliter of a 4% solution) were injected at three vasomotor and cardioactive areas in the rat medulla by means of a 28-gauge hypodermic needle and a microsyringe. These areas were the C1 region, the intermediolateral column (IML), and the nucleus tractus solitarius (NTS). Both lidocaine and bupivacaine at C1 significantly decreased mean arterial pressure and, at IML, resulted in significant bradycardia and hypotension. At NTS, both lidocaine and bupivacaine caused significant bradycardia and hypotension, which were accompanied by ventricular arrhythmias in 55% of the animals. In all animals in whom ventricular arrhythmias were associated with lidocaine, the arrhythmias spontaneously reverted to normal sinus rhythm. In 50% of animals developing ventricular arrhythmias after bupivacaine, the arrhythmias resulted in death. Using an equal number of molecules of lidocaine and bupivacaine, all three regions studied demonstrated that bupivacaine was 2-4 times more potent than lidocaine in producing cardiovascular effects. These data demonstrate that direct application of local anesthetics within the medullary region of the central nervous system can result in hypotension, bradycardia, and ventricular arrhythmias similar to what may be seen in humans after accidental intravenous injections of local anesthetics. Moreover, the sites and mechanisms of action appear to be identical for bupivacaine and lidocaine. Thus bupivacaine does not appear to be an aberrant local anesthetic, as some have suggested, but rather produces more profound effects related to its potency and physicochemical properties.     

Update on tenofovir toxicity in the kidney

Tenofovir (TFV) is a widely used and effective treatment for HIV infection. Numerous studies have shown that TFV exposure is associated with small but significant declines in estimated glomerular filtration rate (eGFR). However, TFV toxicity is targeted mainly at the proximal tubule (PT), and in severe cases can cause the renal Fanconi syndrome or acute kidney injury. Severe toxicity occurs in a minority of patients, but milder PT dysfunction is more common; the long-term significance of this on kidney and bone health is uncertain. Recent work suggests that changes in eGFR on TFV therapy might be explained by inhibition of PT creatinine secretion rather than actual alterations in glomerular function. Risk factors for nephrotoxicity include pre-existing kidney disease, increased age, and low body mass. Mitochondria in the PT are the targets of TFV toxicity, but the exact mechanisms remain unclear. Substantial improvement of renal function occurs in many patients with TFV toxicity upon stopping therapy, but function does not always return to baseline. In recent years, TFV usage has been extended to new clinical spheres, including pediatrics, resource-poor settings and treatment of Hepatitis B infection; theoretical reasons exist as to why some of these patients might be at higher or lower risk of TFV toxicity. Finally, strategies have been proposed to prevent TFV toxicity or enhance recovery.     

Co-morbidity and interstitial herniation in the adult: an hypothesis

Whereas interstitial hernias of infancy are a result of congenital abnormalities, those in adults have been blamed on anatomical banding. Many of the latter are associated with systemic, genetic, or acquired connective tissue disease, however. This results in attenuated aponeuroses, ruptured tendons, and atrophied fascia from collagen malformation and destruction. Muscle contractility is compromised by loss of connective tissue septae, reducing capillary density. The result is wasting and disaggregation, which explains interstitial defects filled with herniated extraperitoneal fat, which account for 1% of primary inguinal herniae. These were originally described in the transversus and internal oblique musculature by Hessert (Surg Gyn Obstet 16:566–568, 1913). Similar slits are seen with Spigelian herniae, all of which are interstitial. This hypothesis, if proven, would imply treatment of the pervasive co-morbidity with the protrusions.     

Relation between epidural and ventricular pressures in canine brain: an experimental study.

Complications of epidural pressure (EDP) monitoring are much less severe than those of ventricular fluid pressure (VFP) monitoring. Hence, an insight into the relationship between the epidural and the ventricular pressures is of clinical importance. The pressure volume response as obtained during infusion tests performed on dogs can be categorized into two phases: (i) the latent phase and (ii) the monotonic rise phase. During the latent phase the VFP first rises to a maximum and then falls to a minimum, but these changes in VFP are not reflected in EDP. The latent phase is followed by the monotonic rise phase during which both VFP and EDP rise simultaneously and monotonically. Although the changes in VFP and EDP are similar the epidural pressure remains consistently less than the ventricular fluid pressure. Hence, changes in VFP can be estimated by monitoring EDP during the monotonic rise phase but not during the latent phase.     

Intraflagellar transport and cilia-dependent renal disease: the ciliary hypothesis of polycystic kidney disease

Epithelial cells that line mammalian kidney nephrons have solitary nonmotile primary cilium projecting from their surface into the lumens of the ducts and tubules. Mutations that block the assembly of these cilia cause cystic kidney disease. The products of human autosomal dominant and recessive polycystic kidney disease genes and products of the nephronophthisis disease genes are at least partially localized to primary cilia. This suggests that the cilium serves as an organizing center for the early steps of the signal transduction pathway that is responsible for monitoring the integrity of the kidney nephron and controlling cell proliferation and differentiation.     

Relation between limb toxicity and treatment outcomes after isolated limb perfusion for recurrent melanoma

BACKGROUND: The optimal toxic reaction of the normal tissues in perfused limbs after isolated limb perfusion (ILP) is unknown. Theoretically, more severe limb toxicity could reflect a concomitant increased toxic effect to the tumor and improved outcomes. We determined whether there is a relation between limb toxicity and treatment outcomes after ILP for recurrent limb melanoma. STUDY DESIGN: Among 252 patients with recurrent melanoma of the limbs, treatment outcomes in 192 patients (76%) with no or mild acute limb toxicity were compared with those in 60 (24%) with more severe reactions. Multivariate analysis was used to identify prognostic factors for complete response, limb recurrence-free interval, and survival. RESULTS: Among 112 patients with measurable disease, 65 patients (58%) had a complete response and 27 (42%) experienced a relapse in the perfused limb. For complete response, uninvolved regional lymph nodes (p = 0.0025) and ILP using tumor necrosis factor-alpha (p = 0.0076) appeared to be favorable prognostic factors in multivariate analysis. There was no evidence of a relation between limb toxicity and complete response either in univariate (p = 0.16) or multivariate analysis (p = 0.46). For limb recurrent-free interval, only the number of lesions was a significant prognostic factor (p = 0.047); limb toxicity was not (p = 0.095). In 140 patients with recurrent melanoma excised before or at the moment of ILP, independent prognostic factors for survival were gender, the number of positive nodes, and stage of disease. There was no relation between limb toxicity and survival in either univariate (p = 0.53) or multivariate analysis (p = 0.94). Forty-eight (34%) of the 140 patients had a relapse in the perfused limb. No prognostic factors for limb recurrent-free interval could be identified; limb toxicity was not related to relapse time in univariate or multivariate analyses (p = 0.16 and p = 0.14, respectively). CONCLUSIONS: More severe acute limb toxicity is not associated with improved outcomes. One should aim at grade II toxicity (slight erythema or edema, compatible with complete recovery) at the most to increase the therapeutic ratio of ILP.     

Melamine toxicity: one more culprit in calcium kidney lithiasis

An outbreak of uric acid and melamine kidney stones and obstructive acute renal failure in children appeared recently in China due to the ingestion of melamine-tainted formula. Liu and colleagues show that calcium urolithiasis is also strongly associated with urine melamine in adults in Taiwan. Although its effect measure is still uncertain, such an association is likely to be causal. These findings prompt further research into the source of exposure, impact in other settings, and changes over time.     

Microvascular compression: an alternative view and hypothesis

The concept of microvascular compression (MVC) is discussed critically. The root entry or exit zone is defined: it is much shorter than generally realized. The anatomy of the intracranial vessels is considered, as well as known facts concerning trigeminal neuralgia, hemifacial spasm, and glossopharyngeal neuralgia relating to MVC. The results of microvascular decompression (MVD) are analyzed; one-third of patients do not obtain an optimum result. The evidence used to support the hypothesis of MVC, including neurophysiology, is discussed and it is believed to be insufficient and unconvincing. The basis of MVC could be trauma of the nerve during operative dissection and "decompression." The concept of MVC might be more convincing if MVD can be shown to cure a condition such as spasmodic torticollis, which cannot be remedied by damage to or section of the same cranial nerve or nerves.     

Serotonin toxicity caused by an interaction between fentanyl and paroxetine

PURPOSE: To report a case of serotonin toxicity, presenting in the postoperative period, caused by an interaction between paroxetine (a selective serotonin reuptake inhibitor, SSRI) and fentanyl (a phenylpiperidine opioid). Serotonin toxicity precipitated by fentanyl is unusual and has not previously been described in combination with SSRIs in the perioperative setting. CLINICAL FEATURES: A 60-yr-old woman, established on paroxetine for depression, underwent excision of a chest wall myxofibrosarcoma and chest wall reconstruction. Fentanyl was administered for intraoperative and postoperative analgesia (1 mg intraoperatively, and 2.5 mg by infusion in the first 36 hr, postoperatively). She developed a vague affectation, intermittent agitation, bilateral hyper-reflexia, inducible clonus, and a period of hypertension, suggestive of serotonin toxicity. There was complete resolution after cessation of fentanyl and paroxetine.Conclusion: The co-administration of SSRIs and fentanyl may precipitate serotonin toxicity. There must be consideration of this unusual interaction when administering fentanyl to patients established on SSRIs. Physicians should be vigilant of the features of serotonin toxicity developing in such patients.     

Uremic toxicity and sclerostin in chronic kidney disease patients

Background and aimsSclerostin is a circulating inhibitor of the Wnt/β-catenin pathway and may have a role in chronic kidney disease (CKD)-mineral and bone disorder. Blood sclerostin levels are known to be elevated in patients undergoing maintenance dialysis. The aims of the present study were to evaluate sclerostin levels in patients at different CKD stages and study potential associations between sclerostin levels and (i) biochemical parameters that are disturbed in CKD, (ii) markers of vascular disease and (iii) mortality.MethodsOne hundred and forty patients at CKD stages 2-5D were included in the present study. Routine clinical biochemistry tests and assays for sclerostin, protein-bound uremic toxins (indoxylsulphate [IS] and p-cresyl sulphate [PCS]) and the toxin β2 microglobulin (β2M) were performed. Aortic and coronary calcification and arterial stiffness were assessed by multislice spiral computed tomography and pulse wave velocity measurements. The enrolled patients were prospectively monitored for mortality.ResultsSclerostin levels were found to be elevated in CKD patients (especially those on hemodialysis). Furthermore, sclerostin levels were positively correlated with inflammation markers, phosphate, fibroblast growth factor 23, IS, PCS, β2M and arterial stiffness. A multivariate linear regression analysis indicated that sclerostin levels were independently associated with IS, PCS and β2M levels. Elevated serum sclerostin appeared to be associated with mortality (independently of age and inflammation). However, this association disappeared after adjustment for a propensity score including age, phosphate, interleukin-6, CKD stage and PCS.ConclusionOur results indicate that sclerostin levels are elevated in CKD patients and are associated with inflammation, vascular lesions, uremia and (potentially) mortality.     

Vitamin D deficiency and toxicity in chronic kidney disease: in search of the therapeutic window

Both vitamin D deficiency and vitamin D toxicity are associated with cardiovascular complications in chronic kidney disease (CKD). Clinical and experiment data indicate that the association of vitamin D levels with cardiovascular disease is best illustrated as a biphasic, or U–shaped, curve. Children and adolescents with CKD need vitamin D due to the demands of a growing skeleton, to prevent renal rickets. However, this therapy carries the risk of severe side effects and chronic toxicity. Observational studies show that vitamin D deficiency and toxicity are frequently present in patients with CKD. In view of the importance of cardiovascular complications for the long-term survival of young patients, these findings demand a judicious use of vitamin D preparations. In clinical practice, the therapeutic window is rather small, presenting a therapeutic challenge to avoid both vitamin D deficiency and toxicity.     

Histopathological analysis of chemical carcinogenesis process by streptozotocin in the mouse kidney]

Renal adenocarcinoma was induced in CBA/H/T6J mice by a single intraperitoneal injection of 250 mg/kg of streptozotocin (STZ). Light and electron microscopic examination revealed that the carcinoma was a granular cell type-adenocarcinoma with abundant microvilli, basal lamina and intermediate junction indicating an epithelial cell origin. In histopathological analysis of the process of this carcinogenesis, all of the kidneys examined had a dilatation of proximal tubules in the second month and thereafter. In the fifth month, one of eight kidneys developed an adenoma. The adenoma was found in all the kidneys after the ninth month. An adenocarcinoma developed in one of the 14 kidneys in the twelfth month and in all others in the fifteenth month. In vivo labeling of bromodeoxyuridine on the cells in various stages demonstrated an increase of the labeling index which paralleled with progression of the carcinogenesis process. This finding in in vivo analysis of cell proliferation also supports the idea that serial changes of the kidney which are histopathologically proven correspond to the carcinogenesis process. The original carcinoma (STZ-RCC) has serially been passed in vivo at the present. Intrasplenic injection of STZ-RCC yielded multiple macroscopic foci of metastasis in the liver. This indicates that STZ-RCC has a malignant potential. Thus, STZ-induced mouse renal adenocarcinoma can be applied to the model system to investigate carcinogenesis and biological behaviors of renal cell carcinoma.