Dan C. Martin

Pulsed radiofrequency application in treatment of chronic zygapophyseal joint pain

BACKGROUND CONTEXT Chronic zygapophyseal joint arthropathy is a cause of back and neck pain. One proposed method of treating facet joint pathology is ablation of medial branches and dorsal rami with pulsed radiofrequency (RF) waves. PURPOSE Assessment of efficacy of pulsed RF application for treatment of chronic zygapophyseal joint pain. STUDY DESIGN/SETTING Retrospective study of 114 patients at a pain management clinic. PATIENT SAMPLE A total of 114 patients with clinical signs of facet joint involvement and a favorable response to a diagnostic medial branch block using local anesthetic, including 82 females and 32 males with a mean age of 52.8+/-12.6 years. Mean duration of pain was 7.52+/-5.26 years. Twenty-seven had previous back surgery, 83 patients had low back pain and 31 had cervical pain. Pain was on the left side in 47 patients, on the right side in 45 patients, bilateral in 22. OUTCOME MEASURES Result was regarded as successful if pain reduction was more than 50% on visual analog scale and the duration of effect was more than 1.5 months. METHODS After obtaining positive stimulation, pulsed RF was applied to medial branches of dorsal rami for 120 seconds with temperature at the tip of the electrode 42 C. RESULTS Of 114 patients, who had positive response to diagnostic block, 46 patients did not respond favorably to pulsed RF application (pain reduction less than 50%). In 68 patients, the procedure was successful and lasted on average 3.93+/-1.86 months. Eighteen patients had the procedure repeated with the same duration of pain relief that was achieved initially. Previous surgery, duration of pain, sex, levels (cervical vs. lumbar) and stimulation levels did not influence outcomes. CONCLUSION The results of our study showed that the application of pulsed RF to medial branches of the dorsal rami in patients with chronic facet joint arthropathy provided temporary pain relief in 68 of 118 patients.

Inhibition of neuronal 5-HT uptake by ketamine, but not halothane, involves disruption of substrate recognition by the transporter

The effects of halothane and ketamine on (1) serotonin (5-hydroxytryptamine; 5-HT) uptake and (2) paroxetine binding to the 5-HT transporter in neuronal membranes were determined in rat brain. Both anesthetics inhibited the uptake of [3H]5-HT by synaptosomes, but only ketamine affected binding of [3H]paroxetine to the 5-HT transporter. Saturation analysis indicated that ketamine inhibition of [3H]paroxetine binding was competitive (Ki = 18.8 microM). These results indicate that halothane and ketamine inhibit 5-HT transport by different mechanisms.

Pulsed Radiofrequency Application in the Treatment of Chronic Pain

Abstract:  The efficacy of pulsed radiofrequency (PRF) in the treatment of painful lumbosacral spondylosis has been reported. This case series reviews 22 consecutive patients presenting to clinic who had been previously treated with PRF with good results. Patients being prescribed opioids were excluded. During the PRF application, tissue temperature was limited to 43°C. A minimum of 200 mA of current was delivered in each case. The minimum current (at 50 Hz) necessary to stimulate the involved nerve was recorded. The duration of time from PRF treatment until the patient requested a subsequent application was documented. The effective duration of PRF in patients treated for lumbosacral spondylosis ranged from 5 to 18 months (mean ± SD: 9 ± 3.7 months; n = 16). PRF applications to dorsal root ganglia were effective from 2 to 12 months (7 ± 3.8 months; n = 8). Similar results were observed when PRF was applied to cervical medial branch nerves, one suprascapular nerve, and one stellate ganglion. The mean (50 Hz) sensory stimulation thresholds obtained before treatment ranged from 0.08 V to 0.14 V. In this select population of patients not receiving controlled substances, who had a favorable response to a previous PRF application, the duration of pain relief supports the use of PRF as an effective pain treatment.

Anesthetic effects on 5-hydroxytryptamine uptake by rat brain synaptosomes

As a neurotransmitter involved in modulating central nervous system nociception and awareness, 5-hydroxytryptamine (5-HT) may play an important role in the clinical sequelae of certain anesthetic compounds. Anesthetic agents are known to affect peripheral, non-neuronal 5-HT uptake but little is known about their effects on 5-HT metabolism in the central nervous system. The effects of several anesthetic compounds on 5-HT uptake were examined in synaptosomes isolated from rat brain cortex. Inhibition of this uptake process was observed by exposure to clinically relevant concentrations of the volatile anesthetics halothane, isoflurane, and enflurane. The non-volatile agent, ketamine also inhibited uptake while the narcotic fentanyl had an effect only at the highest concentrations tested. Non-volatile agents which had neither a consistent nor significant effect on synaptosomal 5-HT uptake included pentobarbital, sufentanil, and etomidate. These alterations of 5-HT metabolism could represent a mechanism that contributes to anesthetic action.

Volatile anesthetics inhibit NMDA-stimulated45Ca uptake by rat brain microvesicles

We have previously shown that volatile anesthetics inhibit glutamate-stimulated [3H]MK-801 binding to the ionophore of NMDA receptor complexes in rat brain. In the present study, we examined the influence of enflurane and halothane on NMDA-stimulated45Ca uptake by a microvesicle fraction isolated from rat brain. NMDA stimulated45Ca uptake (30 sec) by rat brain microvesicles by up to 70% with an EC50 of 1.4±0.5 μM. The NMDA-stimulated45Ca uptake was inhibited by MK-801 and D-AP-5 with IC50s of ≈10 μM. Enflurane and halothane inhibited45Ca uptake stimulated by 100 μM NMDA by as much as 60–80% with IC50s of 0.2–0.3 mM, concentrations achieved during routine clinical use. Basal45Ca uptake measured in the absence of agonist was not affected by the anesthetics. Glycine did not affect the level of NMDA-stimulated45Ca uptake, but markedly reduced the inhibition of uptake caused by enflurane and halothane. Preincubation of microvesicles with NMDA resulted in a desensitization of NMDA-stimulated45Ca uptake, with a t1/2 of ≈20 sec. Enflurane and halothane diminished both the extent and rate of development of this desensitization, as did glycine. These findings support the idea that volatile anesthetic interference with neurotransmission at NMDA receptor complexes contributes to the development of the anesthetic state.

Volatile anesthetics and NMDA receptors. Enflurane inhibition of glutamate-stimulated [3H]MK-801 binding and reversal by glycine

The influence of enflurane, a volatile general anesthetic, on [3H]MK-801 binding to a site in the ion channel of the N-methyl-D-aspartate (NMDA) receptor was determined in membranes from rat cerebral cortex. Enflurane disrupted glutamate stimulation of [3H]MK-801 (1 nM) binding with an IC50 of 0.4 mM. This inhibition was associated with a decrease in receptor affinity with no change in the number of [3H]MK-801 binding sites. Basal [3H]MK-801 binding measured in the absence of glutamate was not affected by enflurane. In contrast, [3H]CGS-19775 binding to the glutamate recognition site on the NMDA receptor was only weakly inhibited by enflurane (e.g., less than 20% inhibition of 5 nM [3H]CGS binding by 1.2 mM enflurane). Glycine, a positive allosteric NMDA receptor modulator, markedly attenuated the inhibition of glutamate-stimulated [3H]MK-801 binding by enflurane, with an EC50 of approximately 0.8 microM. Thus, enflurane selectively inhibits glutamate activation of the NMDA receptors, and an allosteric modulator attenuates this action. These effects could reflect anesthetic action at the glycine binding site or at another, undefined site which influences activation of the ion channel. These findings raise the possibility that inhibition of transmission at NMDA receptors contributes to the development of the anesthetic state.

Measurement of the low-frequency component of blood pressure variability can assist the interpretation of heart rate variability data.

To the Editor:—Dowd et al. have provided important information about the pharmacokinetics of tranexamic acid (TA) in cardiac surgery with cardiopulmonary bypass. Particularly, they demonstrated the necessity of a continuous infusion of TA to obtain stable therapeutic concentrations. Then, they proposed two different dosage schemes in lowand high-risk patients for bleeding, to obtain TA plasma concentrations of 334 M and 800 M, respectively. Considering the patients with low-risk for bleeding, they recommended a loading dose of 12.5 mg/kg (or greater) over 30 min, a continuous infusion of 6.5 mg · kg 1 · hr , and 1 mg/kg (or greater) added to the priming, whereas in patients with high-risk for bleeding they proposed doses about 2.5 higher. My group published various studies proposing an original pharmacologic protocol for TA that seem very similar to that proposed by Down et al. For patients with low-risk for bleeding; that is, a loading dose of 1 g over 20 min before sternotomy (and not 1 g, 20 min before sternotomy, as erroneously reported in the work of my group cited by Dowd et al.), followed by a continuous infusion of 400 mg/h, and 500 mg added to pump priming. We also applied the same protocol in high-risk patients for bleeding, obtaining a significant reduction of blood loss and allogeneic transfusions. One criticism of the study of Dowd et al. is that the need to increase the doses of TA in this type of patient requires further clinical demonstrations, particularly considering (as the same authors report) that TA plasma concentrations of about 200 M completely inhibit fibrinolysis. Concerning the administration of TA after surgery, I agree with Dowd et al. regarding benefits in the postoperative period depending on intraoperative dosing techniques, but I do not understand why the authors claim that the efficacy of prolonged TA administration in the postoperative period is an open question. In reality, the authors, applying their pharmacokinetic model to our TA protocol, confirmed the conclusions of our study. Our intraoperative TA dosage scheme guarantees therapeutic concentrations for about 12 h, rendering unnecessary postoperative infusion of the drug. It also seems that the potential thrombotic risk intrinsic to antifibrinolytic drugs is underestimated by Down et al. I particularly disagree with their statement, “TA appears to be a very safe medication. . .. Thus our attempt to avoid excessive TA concentrations may not be necessary.” An extensive literature search showed cases of thrombosis following the use of hemostatic drugs such as -aminocaproic acid, aprotinin, and TA, but it would be sufficient to cite a recent case report describing two fatal cases of thrombosis after the use of -aminocaproic acid (very similar to TA with a potency 10 times lower) in cardiac surgical patients operated on with deep hypothermic circulatory arrest, wherein postmortem laboratory analysis revealed the presence of Factor V Leiden. Because it is impossible to identify patients with a preoperative prothrombotic state, it is appropriate to use the minimal effective doses of hemostatic drugs to avoid amplifying these thrombotic complications. Furthermore, the same authors’ group reported in a previous study three cases of stroke in cardiac surgical patients with known peripheral vascular disease, treated intraoperatively with high doses of TA. One would speculate that high concentrations of TA facilitated the formation of a thrombus in the presence of blood flow reductions in a diseased vessel. In conclusion, only large, prospective, blinded studies will establish the real safety and efficacy of the various doses of tranexamic acid in cardiac surgery. Currently, caution is required when using a hemostatic drug.

The influence of isoflurane on the synaptic activity of 5-hydroxytryptamine

The effects of isoflurane on uptake of 5-hydroxytryptamine(serotonin; 5-HT) by rat brain synaptosomes and binding of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and ketanserin to 5-HT1A and 5-HT2 receptors were examined. Isoflurane caused a concentration-dependent decrease in synaptosomal 5-HT uptake that was kinetically defined as non-competitive; exposure to isoflurane decreased Vmax but had no effect on the apparent Km. Removal of the drug from the reaction mixture resulted in the return of 5-HT accumulation rates to control levels. Isoflurane inhibited 8-OH-DPAT binding to hippocampal membranes by up to 27±6% at 4.5 mM, but did not significantly affect ketanserin binding to 5-HT2 receptors. These findings suggest that presynaptic actions are more important than postsynaptic actions in the modulation of serotonergic neutrotransmission by isoflurane.

Spermidine attenuation of volatile anesthetic inhibition of glutamate-stimulated [3H](5D, 10S)-(+)-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine ([3H]MK-801) binding to N-methyl-D-aspartate (NMDA) receptors in rat brain

The influence of spermidine, a polyamine agonist, on volatile anesthetic inhibition of N-methyl-D-aspartate (NMDA) receptor activation, as indicated by glutamate stimulation of [3H]MK-801 ([3H](5D,10S)-(+)-methyl-10,11-dihydro-5H- dibenzo[a,d]cyclohepten-5,10-imine) binding, was studied in rat brain. Spermidine reserved the inhibition caused by four volatile anesthetics (enflurane, halothane, methoxyflurane and chloroform) at the same concentrations (EC50 approximately 3 microM) at which it potentiated glutamate opening of the NMDA ion channel. The anesthetics had no effect on the direct stimulation of channel opening by spermidine, which occurred at concentrations of spermidine greater than 30 microM in the absence of receptor agonist. In these actions, spermidine closely resembled the allosteric co-agonist glycine. The present results suggest that anesthetic action on NMDA receptors involves a set of sites on the channel complex that is distinct from the recognition sites for glutamate, glycine, and channel blockers, and are consistent with the idea that blockade of NMDA receptors contributes to the development of the anesthetic state.

Effects of sodium pentothal and sufentanil on serotonin induced constriction of canine coronary artery rings without endothelium

Abstract 1. 1. The individual and combined effects of sufentanil and sodium pentothal on canine coronary artery vasomotor responses to 5-HT were studied in an isolated vascular ring preparation. 2. 2. Clinical concentrations of sufentanil have little effect on basal coronary tension or constriction induced by either 5-HT or sodium pentothal individually, until very high doses > 0.26 μM are reached. 3. 3. Sodium pentothal causes coronary constriction at clinical concentrations and this effect is additive and possibly potentiated when combined with 5-HT. 4. 4. Sufentanil inhibits coronary constriction induced by the combination of sodium pentothal and 5-HT.