We are searching data for your request:
Upon completion, a link will appear to access the found materials.
1-How does massaging of carotid artery at chassaignac tubercle( anterior tubercle of transverse process of C6 vertebra ) can relieve the symptoms of Supraventricular Tachycardia?
My attempt: I think by massaging carotid artery we are somehow stimulating the satellate ganglion present at level of c7. Or, I think, by massaging the carotid artery we are increasing BP, thereby affecting the baroreceptors and somehow this relieves the symptoms of supraventricular tachycardia.
2-Why can't the same massage be done at level of other cervical vertebrae?
The reason massaging the carotid artery can relieve symptoms of supraventricular tachycardia is because by massaging the artery, as you point our yourself, you artificially increase BP within the carotid artery, this activates a reflex (via the glossopharyngeal nerve) that lowers bloodpressure by reducing the heart rate via the vagus nerve, by increasing the refractory period of the AV-node, so the heart rate drops.
It should be noted though, that it can be a bit dangerous to play with these reflexes in some patients, especially because massaging the carotid arteries can lead to an embolism in older individuals with atherosclerosis, or in some patients, it can lead to asystole or ventricular fibrillation (i.e. cardiac arrest).
It's not really about which vertebra is at the level you are massaging, rather it's about being near the carotid sinus, which is where the baroreceptors are located, and that might vary between individuals and how you position the head etc.
First Cervical Vertebra
The first cervical vertebra , or atlas, articulates with the occiput rostrally and the axis caudally. It consists of two articulating lateral masses that are connected anteriorly and posteriorly by neural arches ( Fig. 2-3 ). The lateral masses are also connected coronally by the transverse atlantal ligament. The superior articulation with the occiput is biconcave and provides flexion and extension. The inferior articulating surface of the atlas articulates with the rostral joint surfaces of the axis in a noncongruent manner. This allows for a wider rotational range of motion but a greater potential for instability. The atlas has been described as acting as an intercalated segment, in that its movements are a reaction to the motion of the occiput versus the axis and lower cervical spine ( Fig. 2-4 ), for example, its rotating and translating with lateral bending of the occipitocervical spine.
The sympathetic nervous system has an important role in generating pain. Various pathomechanisms are involved that respond well to the application of local anesthetics (LA), for example to the stellate ganglion block (SGB).
We wanted to know more about the effects of SGB on cardiovascular parameters.
We included 15 healthy volunteers another 15 healthy volunteers as a control group (sham injection of LA). In order to produce a more precise SGB, we employed only a small volume of LA (3 mL), a LA with a lower permeability (procaine 1%), and a modified injection technique. Systolic and diastolic blood pressure (SBP, DBP), heart rate (HR), and echocardiographic parameters were recorded before and after SGB. We also investigated whether there are side differences (left and right SBG).
At baseline all parameters were within the normal range. After performing right and left SGB DBP significantly increased (on the right side from 68.73 ± 8.61 to 73.53 ± 11.10, p = 0.015 on the left side from 70.66 ± 13.01 to 77.93 ± 10.40, p = 0.003). In the control group no increase in DBP was observed. No side-specific differences were found, except a significant reduction in the maximum velocity of myocardial contraction during the systole with left-sided SGB.
Even with our methods we could not prevent the simultaneous occurrence of a partial parasympatholytic effect. For this reason, the SGB has only minor hemodynamic effects, which is desirable as it enhances the safety of the SGB.
The transverse ligament is the major stabilizer of the atlantoaxial complex (Fig. 17–3). It attaches laterally to tubercles located on the posterior aspect of the anterior arch of C1, where it blends with the lateral mass. Secondary stabilizers include the thick alar ligament, which arises from the sides of the dens to the medial aspects of the condyles of the occipital bone, and the apical ligament, which arises from the apex of the dens to the anterior edge of the foramen magnum. In some individuals, an anterior atlantodental ligament exists connecting the base of the dens to the anterior arch of the atlas. 17 The tectorial membrane, the superior continuation of the posterior longitudinal ligament, covers the dens and all the occipitoaxial ligaments and extends from the posterior body of C2 to the basilar portion of the occipital bone and the anterior aspect of the foramen magnum.
The posterior longitudinal ligament, lying within the vertebral canal on the posterior aspect of the vertebral body and intervertebral disc, is wider in the upper cervical spine than the lower cervical spine. 18 Superiorly, it is continuous with the tectorial membrane, and as it descends it widens over the intervertebral discs and narrows behind each vertebral body. The posterior longitudinal ligament supplies additional strength and stability to the posteromedial fibers of the anulus. There is an area of relative weakness in the posterolateral corners of the disc, however, at the junction of the posterior longitudinal ligament and uncinate process as a result, it is the site of most cervical disc herniations. 19 According to Hayashi and colleagues, 20 the posterior longitudinal ligament is double-layered, and the deep layer sends fibers to the anulus fibrosus and continues laterally to the region of the intervertebral foramina. The superficial or more dorsal layer of the posterior longitudinal ligament is adjacent to the dura mater and continues as a connective tissue membrane, which envelops the dura mater, nerve roots, and vertebral artery, suggesting that this membrane may serve as a protective barrier.
Part 4: Targeting M. tuberculosis Carbon Metabolism In Vivo
00:00:04.09 In the last lecture, I told you about some of our
00:00:06.07 studies to try to understand the persister phenomenon in Mycobacterium tuberculosis.
00:00:11.01 That is an attempt to understand why the drugs that we currently use
00:00:13.24 to treat this disease are not more effective than they are.
00:00:16.19 In this last lecture, I want to tell you about some of the work we're doing in my lab
00:00:20.16 to try to identify new and hopefully better targets
00:00:23.23 for development of new drugs against tuberculosis
00:00:26.05 that we hope will allow us to kill the bacteria more rapidly and overcome
00:00:30.18 this persistence problem.
00:00:31.20 Now, our segue into this area has been to study the basic metabolism
00:00:36.22 of M. tuberculosis when it's living in the lung,
00:00:39.08 as opposed to living in a test tube, ex vivo.
00:00:41.06 And our segue into this area came from some really beautiful biochemical studies
00:00:45.13 that were published more than half a century ago now
00:00:48.23 and had since been forgotten, but were rediscovered by us a few years ago.
00:00:53.03 And here's an important lesson for the students who might be watching this lecture.
00:00:56.02 Pay attention to the pre-Pubmed literature because there are real gems there,
00:01:00.26 particularly in fields like tuberculosis and malaria that have
00:01:03.14 undergone periods of dormancy among the research community.
00:01:07.02 So, in these studies, which were essentially biochemical studies,
00:01:11.13 the authors focused on characterizing the physiology of bacteria
00:01:16.21 that were grown in the in vivo environment.
00:01:19.04 And they did this by using as their starting material
00:01:21.28 the lungs of infected mice -- that is mice that harbored M. tuberculosis --
00:01:26.14 which was then homogenized and fractionated
00:01:29.26 using the rather crude methods that they had available at the time
00:01:33.04 (density-gradient centrifugation, in this case)
00:01:35.28 to yield a population of more-or-less pure, in vivo-grown mycobacteria
00:01:40.08 which they then subjected to a battery of biochemical and physical tests.
00:01:44.21 And these studies, which were published over the period of about a decade,
00:01:49.24 culminated in the conclusion that when the bacteria are grown
00:01:53.06 in their natural environment (that is, the mammalian lung),
00:01:55.27 they're very, very different physiologically than they are
00:01:59.24 when the same bacteria are grown under the artificial conditions
00:02:02.21 that we use to study them ex vivo.
00:02:04.29 So, these studies emphasize the importance of studying
00:02:08.07 the bacteria in their natural environment
00:02:11.14 if you want to gain a full understanding of their actual physiology during infection.
00:02:15.12 Now, among the observations that they made,
00:02:18.07 a set of observations that particularly piqued my curiosity
00:02:21.13 is summarized down here.
00:02:23.11 First, they found that the ability to metabolize carbohydrates
00:02:27.18 was essentially shut off in these bacteria.
00:02:30.01 That's an interesting observation because, even to this day,
00:02:33.17 we still continue to cultivate bacteria for in vitro studies
00:02:36.26 on carbohydrate-containing media.
00:02:39.22 But, apparently, this is not what the bacteria are using
00:02:42.05 when they're actually growing in the mammalian lung.
00:02:44.12 Conversely, they found that the ability of these bacteria to metabolize
00:02:48.01 fatty acid substrates was apparently switched on
00:02:51.05 when they were grown in the mammalian lung.
00:02:53.18 Concomitant with that physiologic switch, if you like,
00:02:57.11 or metabolic switch, they found that expression of the enzymes of two pathways --
00:03:01.13 the fatty acid beta-oxidation cycle, and the glyoxylate cycle --
00:03:05.08 were strongly switched on when these bacteria were grown in vivo,
00:03:08.24 as opposed to in vitro.
00:03:10.22 Now, most of the work in my lab that I wanted to tell you about today
00:03:13.25 has been focused on the glyoxylate cycle, although we study
00:03:16.16 both of these pathways in my lab.
00:03:18.27 We elected to target the glyoxylate cycle for analysis first
00:03:22.22 for the simple reason that this pathway was lost in evolution.
00:03:26.22 So, although it's widely found in bacteria and in fungi,
00:03:30.02 it is not found in any vertebrate, including humans.
00:03:33.03 And, although the work we do in our lab is largely basic research,
00:03:37.06 we always try to point it in a direction that might
00:03:39.17 have potential applications in the future.
00:03:41.14 If you're thinking ahead to the possibility of drug development,
00:03:45.05 obviously it's most attractive to target molecules
00:03:48.15 like the enzymes in the glyoxylate cycle,
00:03:51.07 which are present in the bacteria that you want to kill
00:03:54.01 but absent in the host cells that you want to spare.
00:03:57.03 The risk of toxicity is much, much lower thereby.
00:03:59.28 So, to remind you, the fatty acid beta-oxidation cycle is this
00:04:05.01 iterated cycle, shown here, in which long-chain fatty acids
00:04:08.18 are sequentially broken down through a series of steps
00:04:11.24 into these two-carbon acetyl-CoA units.
00:04:15.14 So, two-carbon units at a time, in a sense, are bitten off the fatty acid chain.
00:04:20.00 These acetyl-CoA units can enter metabolism --
00:04:23.10 either the citric acid cycle or the glyoxylate cycle.
00:04:27.24 Now, I'll remind you that the citric acid cycle, in fact, plays two essential roles
00:04:31.24 in metabolism of carbon substrates.
00:04:36.03 The role in generating reducing potential in the form of NADH and FADH,
00:04:40.19 which is responsible for respiration and the generation of ATP,
00:04:45.00 the energy currency of the cell.
00:04:46.28 But also, an important role in biosynthetic pathways
00:04:50.24 because many of these carbon intermediates, such as alpha-keto-glutarate here,
00:04:54.00 are constantly being siphoned off to the biosynthesis of
00:04:58.23 small molecules like amino acids, hemes, nucleotides, and so on.
00:05:05.05 So, there's a constant drain of carbon to these biosynthetic pathways.
00:05:09.03 And this creates a problem for the cell
00:05:11.16 because with each turn of a citric acid cycle, two carbons
00:05:14.28 enter from acetyl-CoA up here, and two carbons leave as CO2 here and here.
00:05:21.15 So, the balance sheet is 0: two carbons in, two carbons out.
00:05:24.12 There's no net gain or loss of carbon.
00:05:26.07 But, as I said, there's this constant drain of carbon to biosynthetic pathways.
00:05:29.16 So, the cell faces an anaplerotic problem, as it's called --
00:05:33.05 a filling up problem.
00:05:34.14 It has to find some way to replenish these carbon intermediates
00:05:38.14 that are drained to biosynthetic pathways,
00:05:40.11 else the Krebs cycle will run down, energy metabolism will fail,
00:05:43.24 and eventually the cell will die.
00:05:45.12 Now, a variety of different pathways are used for carbon anaplerosis.
00:05:49.19 Which pathway is used depends largely on which type of substrate
00:05:53.20 the bacteria, in fact, are metabolizing.
00:05:55.27 Most bacteria, when they're growing on fatty acid substrates
00:05:59.27 utilize a simple subroutine within the citric acid cycle
00:06:04.22 called the glyoxylate cycle -- so this is the pathway
00:06:07.07 that's required for anaplerosis on fatty acid substrates.
00:06:10.17 As I said, it's a very simple pathway, comprising just two
00:06:14.00 dedicated enzymes: isocitrate lyase (or ICL, as I'll call it)
00:06:17.23 and malate synthase (or MLS, as I'll call it).
00:06:20.21 ICL takes the isocitrate from the citric acid cycle,
00:06:25.21 and it splits it to form succinate and glyoxylate,
00:06:29.08 from which the glyoxylate cycle gets its name.
00:06:31.24 Malate synthase then takes that glyoxylate and condenses it
00:06:35.15 with a second molecule of acetyl-CoA
00:06:37.21 to make malate, down there.
00:06:39.12 The important point here is that the carbon-losing steps in the citric acid cycle
00:06:43.22 are bypassed by the glyoxylate cycle,
00:06:46.16 and with each turn of the subroutine, four carbons
00:06:49.15 coming from acetyl-CoA here and acetyl-CoA here
00:06:53.15 are fixed in the cycle in the form of malate.
00:06:57.00 So, it's a way of replenishing carbon intermediates
00:07:00.19 that are lost to biosynthetic pathways.
00:07:02.29 We wanted to know, what's the role of this pathway in tuberculosis metabolism
00:07:08.22 in physiology during an infection.
00:07:10.14 We took a genetic approach to this problem
00:07:12.26 using tools that had only just been developed for genetics in M. tuberculosis,
00:07:17.14 and we asked what would happen if we eliminated
00:07:20.15 the genes encoding isocitrate lyase in M. tuberculosis.
00:07:24.05 Now, this turned out to be a somewhat more complicated undertaking
00:07:27.14 than we had originally envisaged
00:07:28.24 because, interestingly, it turns out that mycobacteria have
00:07:32.10 not just one, but actually two isocitrate lyase enzymes
00:07:36.04 in their genomes -- a rather unique arrangement.
00:07:39.03 We have called them (rather unimaginatively)
00:07:40.23 ICL1 and ICL2.
00:07:42.15 As shown here, encircled, they are not linked on the bacterial chromosome,
00:07:47.03 and these two enzymes are very different in size.
00:07:49.27 ICL1 is quite a bit smaller than ICL2.
00:07:52.12 In terms of evolution, ICL1 looks, for all the world,
00:07:56.04 like a typical eubacterial isocitrate lyase.
00:07:59.06 ICL2 is a real outlier. It looks more like a plant or fungal isocitrate lyase,
00:08:05.22 and we have no idea how it got there.
00:08:07.10 There's an interesting evolutionary problem there that has yet to be understood.
00:08:11.11 So, the question we wanted to address is what happens if we delete these genes
00:08:16.04 from the chromosome of M. tuberculosis.
00:08:18.04 What impact would those mutations have on the ability of these bacteria
00:08:22.03 to metabolize, to grow, and to persist in the lungs of a mammalian host?
00:08:26.16 So, we deleted ICL1. We deleted ICL2.
00:08:30.07 And then, we made a strain in which both of those genes were deleted together.
00:08:33.19 We then took that mutant ICL1 strain for starters
00:08:38.18 and put it into the lungs of mice
00:08:41.01 and monitored the growth and persistence of the bacteria in the lungs of those mice.
00:08:44.29 So, in this graph, I'm plotting on the y-axis the logarithm (base 10)
00:08:49.20 of the colony forming units or viable units in the lungs of mice
00:08:53.01 versus weeks post-infection.
00:08:55.17 What we found is that the ICL1-deficient mutant
00:08:59.06 actually grew quite well during the acute phase of infection --
00:09:02.12 the first couple of weeks of infection --
00:09:04.03 but it was somewhat defective for persistence
00:09:06.29 during the chronic phase of infection after bacterial numbers
00:09:10.04 had more-or-less stabilized
00:09:11.07 under pressure from the host immune response.
00:09:13.28 There's the curve for wild-type bacteria.
00:09:16.17 There's the curve for the ICL1-deficient strain.
00:09:19.05 So it's quite a significant attenuation, specifically during the chronic phase of infection.
00:09:22.28 In contrast, we found that when we knocked out ICL2 alone
00:09:27.13 and deleted that gene,
00:09:28.19 the mutant bacteria showed no defect whatsoever
00:09:32.23 for either acute phase growth or chronic phase persistence
00:09:35.13 in the lungs of mice.
00:09:36.28 As it turns out, that doesn't mean that ICL2 is irrelevant.
00:09:40.10 In fact, it's an extremely important gene for physiology of M. tuberculosis in vivo.
00:09:44.02 But, the function of this gene, as we found, is heavily buffered by the presence of ICL1.
00:09:48.28 And we know that's true because when we deleted both genes simultaneously
00:09:53.08 from the chromosome of the bacteria, something really remarkable happened.
00:09:56.13 We found that the double mutant, lacking both ICL1 and ICL2,
00:10:01.14 as shown by the red symbols here,
00:10:03.11 was completely unable to establish infection,
00:10:05.22 and, in fact, was totally cleared from the lungs within 2 weeks of infection.
00:10:10.04 Just to put this in context of chemotherapy,
00:10:12.23 using the best cocktail of drugs that we currently have for treatment of tuberculosis,
00:10:16.23 if we were to infect mice and immediately put them on chemotherapy,
00:10:20.13 it would require about 8 weeks of continuous chemotherapy
00:10:25.17 (even TB is not that difficult to cure)
00:10:27.06 to, in fact, eliminate the organisms from the lungs of these mice.
00:10:31.26 So, this is a spectacularly rapid clearance of bacteria from the lungs of these animals.
00:10:36.07 Clearly, these enzymes are very important for growth and survival in vivo.
00:10:40.07 Now, we also found that these enzymes are very important for growth and survival
00:10:47.10 in a simplified model of tuberculosis,
00:10:49.27 in which we take macrophages from the mouse, we culture them
00:10:52.23 ex vivo, and we then infect those macrophages with the bacteria.
00:10:57.06 As you will recall from the first lecture in this series,
00:11:00.05 the tubercle bacillus is an intracellular pathogen.
00:11:03.25 It actually makes its living by invading into macrophages and replicating within
00:11:08.04 a vacuolar compartment inside those macrophages.
00:11:11.10 So, we can replicate this process ex vivo.
00:11:13.27 It's a much simpler model and a more manipulable model
00:11:16.24 than the mouse for our experiments.
00:11:18.23 What we find in what are called non-activated, resting macrophages
00:11:23.09 that have not been immunologically activated
00:11:26.10 is that wild-type bacteria in blue grow quite well
00:11:28.27 inside these macrophages. The ICL-deficient strain
00:11:32.01 fails to grow and slowly loses viability.
00:11:34.16 If we now activate those macrophages using the cytokine interferon-gamma,
00:11:40.29 which is thought to be the key immune effector for activation
00:11:44.17 of macrophages during infection,
00:11:46.02 what we find in the case of wild-type bacteria
00:11:48.20 is that this leads to bacteriostasis.
00:11:51.23 It's literally a curtailment of growth inside the macrophages.
00:11:54.26 In contrast, the ICL-deficient bacteria are very rapidly killed in activated macrophages.
00:12:01.09 So, the phenotype that we see in a whole-animal model
00:12:03.29 can, to some extent, be replicated in this simpler, tissue culture model of infection,
00:12:08.19 which makes it much more easy to study the processes involved.
00:12:12.12 Now, we can get even simpler than this,
00:12:15.12 which we need to do for drug development purposes.
00:12:17.23 And we can study the behavior of the bacteria in an in vitro system.
00:12:24.13 The aim of these studies is to try to develop inhibitors
00:12:30.02 against ICL1 and ICL2 that would simultaneously block the function
00:12:34.07 of both enzymes.
00:12:36.11 Now, this essentially becomes a structural problem.
00:12:39.01 I told you before that the two enzymes are very different from each other
00:12:41.29 evolutionarily. The question really is, what about their molecular shape?
00:12:45.24 We now know from studies in many labs
00:12:48.06 that very different primary amino acid sequences can lead to essentially
00:12:51.26 the same molecular shape, and that's what we want
00:12:54.25 to target with drug development.
00:12:56.24 So, going to a purely in vitro system here,
00:12:59.01 we have obtained, through collaboration with the crystallography experts
00:13:03.26 in Jim Sacchettini's lab at Texas A&M
00:13:06.21 the 3-dimensional structure of the isocitrate lyase 1
00:13:10.17 molecule at atomic resolution. Here, I'm showing just the alpha-carbon backbone
00:13:14.23 tracing of this enzyme, shown in blue.
00:13:17.12 ICL2 has been a difficult molecule to crystallize.
00:13:21.03 We do not yet have a definitive structure for ICL2.
00:13:24.18 But, the theoretical structure for ICL2, which we have modeled
00:13:28.11 in silico is shown here in red.
00:13:33.08 So, my point is that, although there are large areas of divergence
00:13:36.01 between the two enzymes -- for example, here in red, there's a domain
00:13:39.05 present in ICL2 that's altogether lacking in ICL1.
00:13:42.27 If we just focus on the active site of the enzyme, shown here,
00:13:46.09 it's very similar. In fact, it overlaps in space almost perfectly between ICL1
00:13:51.08 and ICL2. And this gave us our first confidence that we might, in fact, be able to
00:13:55.22 develop dual-specific inhibitors that would simultaneously
00:13:59.29 block the action of both ICL1 and ICL2,
00:14:02.18 which would be necessary to achieve the maximal
00:14:05.10 therapeutic effect. So, towards that goal,
00:14:09.24 Jim's lab and my lab and the laboratory of our collaborator David Russell at Cornell
00:14:13.19 University entered into a partnership with GlaxoSmithKline,
00:14:17.20 where they have carried out a drug discovery program
00:14:20.08 targeting the isocitrate lyase enzymes of Mycobacterium tuberculosis.
00:14:24.24 Now, as I said, we have mouse and tissue culture models that we can use
00:14:29.02 to study the function of these enzymes.
00:14:32.00 But even the tissue culture model is still a rather cumbersome model.
00:14:34.16 What we'd really like to have
00:14:36.03 is a whole-cell assay that we can use to look at the activity of
00:14:39.28 ICL inhibitors against bacteria grown under appropriate conditions.
00:14:43.13 We've succeeded in developing such a system,
00:14:46.24 and that's shown here.
00:14:47.24 So, in axenic culture, we can grow bacteria,
00:14:50.24 either on carbohydrate substrates, shown in the far panel,
00:14:54.10 or on fatty acid substrates, as shown here,
00:14:56.24 with and without the addition of ICL inhibitors, like this protoinhibitor,
00:15:00.23 3-nitropropionate -- not a drug-like molecule, but a very useful tool compound.
00:15:05.17 When we grow the bacteria on carbohydrate substrates
00:15:08.13 we find that whether we add the inhibitor or not, we get robust growth.
00:15:12.22 The inhibitor has a slight inhibition of growth on the bacteria, but it's quite minimal.
00:15:17.24 In contrast, when we grow the bacteria on fatty acid substrates,
00:15:21.21 as shown in this panel, we see that although the bacteria
00:15:25.16 in the absence of inhibitor grow on fatty acids just fine,
00:15:27.24 their ability to do so is completely blocked by the addition of this inhibitor.
00:15:32.06 In fact, more recently, we found that these bacteria
00:15:34.15 are not only failing to grow, as indicated by this spectrophotometric assay,
00:15:39.05 but they are in fact being killed. And we still don't understand why it is
00:15:43.09 that inhibition of isocitrate lyase leads, in fact, to rapid cell death
00:15:48.16 in the presence of fatty acid substrates,
00:15:51.00 but we think that this probably explains why this bacteria in vivo
00:15:55.00 undergoes such rapid cell death and clearance.
00:15:57.06 Now, we can, in fact, use at the next level of complexity, our macrophage
00:16:03.18 model of infection to look at the activity of compounds against bacteria
00:16:07.26 when they're living inside their host cell.
00:16:10.15 And this is obviously a very important model for us,
00:16:12.19 because a stumbling block for many drugs that we might develop against TB
00:16:15.28 is their ability to reach the bacteria when they are living inside a vacuole
00:16:21.01 inside a macrophage.
00:16:22.17 So, just to remind you, if we compare the behavior of ICL-deficient
00:16:26.14 and wild-type bacteria in non-activated macrophages,
00:16:30.04 we find that wild-type bacteria grow luxuriantly,
00:16:33.05 whereas ICL-deficient bacteria fail to grow.
00:16:36.17 We can phenocopy this behavior of the bacteria
00:16:40.01 by simply growing wild-type bacteria
00:16:42.18 inside the macrophages, but either in the presence or the absence
00:16:46.13 of the ICL inhibitor 3-nitropropionate.
00:16:48.29 Again, in the absence of inhibitor, the bacteria grow just fine,
00:16:52.08 as indicated by the blue symbols.
00:16:54.18 When we add 3-nitropropionate, this completely blocks the ability
00:16:57.03 of these bacteria to grow inside macrophages.
00:16:59.10 So, we now have enzyme assays that we can use to look at inhibitors,
00:17:04.11 using pure recombinant enzymes,
00:17:06.15 as were used for the crystallographic studies.
00:17:09.16 We have whole-cell assay in axenic culture
00:17:13.14 as I showed previously, and we now have a macrophage culture system as well
00:17:17.13 that we can use to study inhibitors and their activity against the tubercle bacillus.
00:17:22.02 Now, it turns out that ICL1, although biologically it's an extremely attractive target
00:17:28.28 for the reasons I've described already,
00:17:30.27 is a very difficult target for structural reasons.
00:17:34.13 So, this is a 3-dimensional depiction of the X-ray crystallographic structure
00:17:38.29 of ICL that was obtained by Jim Sacchettini and Vivek Sharma
00:17:42.24 in his lab at Texas A&M.
00:17:45.01 This depicts a cut-away showing the active site of the enzyme.
00:17:49.02 It's a very shallow groove in the surface of the molecule.
00:17:52.03 And when the drug actually binds to the enzyme,
00:17:55.21 this protein flap here folds down over the molecule,
00:17:59.19 essentially locking it in place.
00:18:01.19 This means that the active site, particularly when it contains a ligand,
00:18:05.10 is extremely space constrained, and this is a problem for drug development
00:18:08.12 we found because it means that there's very little room to tinker with the molecule
00:18:12.06 to try to add and move groups to achieve a higher potency drug
00:18:17.02 by promoting different interactions with the enzyme itself.
00:18:20.23 So, it turns out that we can isolate inhibitors of ICL,
00:18:25.00 but as soon as you start to tinker with their structure, they tend to lose activity,
00:18:28.13 rather than becoming more potent.
00:18:30.00 There's also the fact that there are two of these molecules in the cell,
00:18:34.06 and although I think it might be feasible to develop a dual-specific inhibitor
00:18:38.08 like 3-nitropropionate, again, it adds to the complexity of the problem.
00:18:42.15 So, it's not at all clear now that the efforts on the part of Glaxo Smith Kline
00:18:47.10 to develop ICL inhibitors, in fact, in the end are going to bear fruit.
00:18:50.20 That is, fruit in this scenario means a drug
00:18:55.14 that we can actually use to treat tuberculosis.
00:18:57.23 So, more recently, we have focused our sights on
00:19:02.12 looking at the second unique step in the glyoxylate cycle.
00:19:06.28 That is the enzyme malate synthase,
00:19:09.04 the 3-dimensional structure of which has also been solved
00:19:12.00 by Claire Smith in Jim Sacchettini's lab, using x-ray crystallography.
00:19:16.21 Now, malate synthase is a much more attractive target from a
00:19:20.13 structural point of view for two reasons.
00:19:21.27 First, there's very clearly only one of these enzymes
00:19:25.13 in Mycobacterium tuberculosis
00:19:26.26 And second, the active site is configured very differently in this enzyme.
00:19:30.28 So, this little acidic patch here shows the opening into
00:19:35.12 the active site of malate synthase.
00:19:37.19 And if we now look at a cutaway view of that active site,
00:19:40.07 what we see is that, in fact, the active site, right here, where catalysis takes place
00:19:44.00 is reached by this long, hydrophilic tunnel.
00:19:47.19 This gives us a lot of elbow room, so to speak,
00:19:50.14 for tinkering with molecules to try to create new contacts to the enzyme
00:19:55.18 that would increase the interaction, and therefore the potency of a drug,
00:20:03.08 based on an inhibitor of malate synthase.
00:20:05.11 This is a very attractive feature of the enzyme,
00:20:10.03 and our current efforts in my lab, Jim Sacchettini's lab, and at GlaxoSmithKline
00:20:13.25 are to target malate synthase for the same kind of drug discovery program
00:20:17.26 that we've been pursuing for isocitrate lyase.
00:20:20.18 Our hope is, of course, that if we can stop up this hole
00:20:22.27 in malate synthase, we may also be able to stop TB in its tracks.
00:20:26.21 So, to sum up what I've told you,
00:20:30.08 there are old problems that have been around throughout the history of TB
00:20:36.12 that continue to be problems today, but I think
00:20:38.14 we now see on the horizon the hope and the prospect of developing new tools
00:20:43.16 to attack these old problems.
00:20:45.21 Before I close, I just want to identify three areas
00:20:48.18 where I think there's a particularly urgent need for development of new tools,
00:20:51.27 and I think in all cases, academic scientists, like myself,
00:20:55.16 have an important role to play in driving discovery efforts.
00:20:58.19 First, as I hope I've made clear,
00:21:01.14 there's a tremendous need for a new vaccine against tuberculosis.
00:21:05.13 This is probably the greatest unmet need of all.
00:21:07.28 Ideally, we would like a prophylactic vaccine that is consistently effective
00:21:12.09 to replace the current BCG vaccine.
00:21:15.15 So this would be ideally a vaccine that would be given in childhood --
00:21:18.28 hopefully at birth -- that would prevent development of tuberculosis
00:21:22.19 later in life, when these individuals reach adulthood.
00:21:26.02 Obviously, that's a huge scientific and medical challenge.
00:21:29.01 But, a prophylactic vaccine like this is, presumably, not going to do anything
00:21:34.04 to address another problem that already exists, and that's
00:21:37.02 the problem of these 2 billion people who are currently latently infected.
00:21:41.04 There's no reason to think that using an effective prophylactic vaccine
00:21:45.15 on these people would be effective in preventing reactivation.
00:21:48.23 As I said, we can look forward to hundreds of millions of new cases of TB
00:21:52.07 due to reactivation of infections that are already established
00:21:57.07 at this time.
00:21:58.23 So, I think there's also a tremendous need for a post-exposure vaccine,
00:22:01.28 if you like, that could be administered to individuals that are lately infected already
00:22:05.22 that will effectively prevent them from reactivating,
00:22:09.11 either by putting the bacteria into a permanently suppressed state,
00:22:12.12 or hopefully inciting the immune system to a state that's capable
00:22:16.10 of completely eradicating these bacteria.
00:22:18.22 There's a tremendous need for new diagnostics, which is an area
00:22:22.22 that I didn't really talk about.
00:22:24.11 But, it's an extremely important area, where we're starting to see
00:22:27.17 some activity. I would say, in terms of diagnostics,
00:22:30.28 there are 2 things that we need. First, we need an ability to identify active cases of TB
00:22:37.16 with high specificity, and also with high sensitivity.
00:22:41.13 We need to be able to identify the people who are sick and need treatment.
00:22:44.19 But we also need to be able to distinguish between individuals
00:22:48.08 who have active tuberculosis and those who have latent tuberculosis,
00:22:52.13 who might be handled in a somewhat different way, clinically.
00:22:55.13 So, that's an important distinction that any new diagnostic needs to be able
00:22:59.01 to make.
00:23:00.16 Also, we need a diagnostic that is capable of distinguishing between
00:23:03.13 tuberculosis infection and BCG vaccination.
00:23:06.17 Undoubtedly, BCG will continue to be used for a long time to come.
00:23:10.03 And it is a very widely used vaccine in developing countries.
00:23:13.26 One of the major problems with BCG vaccination,
00:23:17.09 besides the fact that it is not always effective,
00:23:19.25 is that it compromises what is currently the only diagnostic that we
00:23:23.25 have for tuberculosis, namely the tuberculin skin test
00:23:27.14 that was originally devised by Robert Koch in the 19th century.
00:23:31.28 So, it's a very antiquated tool.
00:23:33.10 A diagnostic that, with great sensitivity and specificity,
00:23:37.22 could distinguish active TB from latent TB from BCG vaccination
00:23:42.06 would be an extremely powerful new tool in the TB armamentarium.
00:23:46.12 Lastly, as I've emphasized, there's a tremendous need for development
00:23:52.03 of new drugs. We need new drugs for the treatment of the multi-drug-resistant cases
00:23:56.01 that already exist in the world.
00:23:57.21 There are many essentially untreatable cases that have emerged in recent years.
00:24:02.13 So, there's always going to be a need for a pipeline
00:24:06.01 for new drugs to emerge, simply for treatment of drug-resistant TB.
00:24:09.12 But, more important, I would say, we need a new drug
00:24:12.26 that does something none of our current drugs accomplish,
00:24:16.00 and that is an ultra-short chemotherapeutic regimen for tuberculosis.
00:24:19.13 And this is to deal with the human problem of adherence
00:24:23.08 or compliance. If we could develop
00:24:24.18 a new drug that would radically shorten the time for treatment
00:24:27.27 of TB from 6-9 months to 6-9 days,
00:24:31.27 this would have an enormous impact on the rates of adherence and compliance
00:24:37.02 with chemotherapy and the cure rates that we achieve with chemotherapy.
00:24:41.06 This is a very daunting scientific challenge, but I'm actually quite
00:24:44.07 hopeful that we will, in the not too distant future
00:24:47.13 see new drugs coming into the clinic and onto the market
00:24:51.25 that achieve at least faster, if not ultra-short, therapeutic regimens.
00:24:57.28 Lastly, we need a drug. and it might be the same, or it might be a different drug
00:25:02.13 that we can use prophylactically. Again, this gets to the problem of this latent
00:25:06.02 population of individuals for whom we currently have no effective
00:25:10.08 and practicable tools for intervention.
00:25:12.15 If we could achieve an ultra-safe and ultra-short course chemotherapeutic regimen
00:25:18.12 to give to people who are already latently infected to prevent them
00:25:22.06 from reactivating, we could finally do something
00:25:26.01 to confront and deal with this huge reservoir of 2 billion
00:25:30.21 latently infected individuals worldwide, who in fact
00:25:32.24 are responsible for the majority of active cases that we are going to see in the future.
00:25:38.00 Thanks very much. I hope I've managed to
00:25:41.27 outline for you some of the problems that we confront in TB.
00:25:45.26 Clearly, they're not just scientific problems. They're problems of delivery of medicines
00:25:51.01 and the public health goods. I hope I've also made it clear to you that
00:25:56.07 there is an important role for academic labs to play in development
00:26:00.09 of these new interventions against tuberculosis.
00:26:02.09 And I've tried to give you a couple of examples of how my lab has tried to
00:26:05.24 contribute to this process. Thanks very much.
- Part 1: Tuberculosis a Persistent Threat
VI. Transverse section of the same body through the neck at the level of the cricoid cartilage and sixth cervical vertebra
Braune W. An atlas of topographical anatomy after plane sections of frozen bodies. (1877) Trans. by Edward Bellamy. Philadelphia: Lindsay and Blakiston.
THIS plate is taken from a section of the same body as the last, and has been prepared in the usual manner.
The section passed through the larynx, and should properly have kept to the plane of the lower vocal cords, but it passed above them in a horizontal direction, and fell on the lower half of the sixth cervical vertebra.
The body has a peculiarly well-arched thorax, and owing to the great muscular development, the shoulders are high up, and although there are the normal number of vertebra the neck appears short, corresponding in the most marked degree with the male type of neck formation. Here again the section does not show a circular contour, but rather a prismatic one. It is easily seen that this is owing, to a great extent, to the powerful muscular development of the sterno-cleido-mastoids and the trapezii.
As the section has not passed through the head of the humerus, but through the acromio-clavicular articulation, it did not traverse the shoulders at their greatest breadth, but at the junction of the regions of the neck and shoulder. Therefore the lateral portions of the plate represent only the upper portion of the roundness of the shoulder, the supplementary parts of which will be shown in following plates.
The slight irregularity noticed in the edges is owing to loss of substance after the use of the saw.
In the female, or slightly developed male subject, the lamina, which in this case was about 0.4 in. thick, would have taken a totally different form, as the position of the shoulder would be lower in the so-called cylindrical portion of the neck, and consequently exhibit no lateral expansion in the region of the junction of the shoulder and neck, the upper surface of such a section, however, would offer another shape, and approximate more to the circular. Pirogoff's plate (fasc. i, tab. x, fig. 5) should be examined in order to prove that it is the feebly-developed muscular neck which takes the circular form. Pirogoff, moreover, says that his section was taken from an emaciated body however, I maintained from recent sections on a man of fifty years of age (such as is represented in Tab. ix of the first volume), that a section at the level of the sixth cervical vertebra is tolerably round. The present case must then be regarded as typical of the neck of a young powerful male, and deviations towards the circular form on the living body are to be referred to want of muscular development.
Sections on unhardened bodies naturally give no fixed forms corresponding with their original relations. The parts yield so much on bodies which have been frozen and subsequently thawed that the neck gradually acquires a circular shape. This may very likely be the reason that the plates of Beraud and Nuhn, which represent very similar regions of the neck, differ so essentially from mine as regards external form. (Beraud's plate is in his 'Atlas d'Anatomie Chirurgicale,' Paris, 1862, pi. xxxvii. Nuhn's is represented by Henle, 4 Muskellehre,' p. 131, and by Henke, ' Abl. der Topographischen Anatomie,' taf. Ixix.)
As to individual portions of the present plate to be studied, the first of all is the larynx, which is divided close below the vocal cords anteriorly is the arc, formed by the section of the thyroid cartilage, and close behind it the section of the cricoid. Of the arytenoid cartilages only the muscular processes are met with, and nothing is seen of the vocal processes, as they lie higher. The space between the thyroid and cricoid cartilages is filled up with the thyro-artenoideus and crico-arytenoideus lateralis. On the other side are some fasciculi of the thyro-epiglottideus. Behind this and on the anterior surface of the crico-arytenoidei postici lie the inferior laryngeal nerve and artery.
From the form of the transversely divided trachea it will be observed that the section does not pass far below the rima glottidis, and that the surface of the cricoid cartilage is divided obliquely forwards and downwards. The space expands still wider further downwards, and changes its laterally compressed form for that of a cylinder, as far as to the point where the cricoid cartilage encloses it completely. Finally, in the trachea it becomes in section a segment of a circle.
As the present plate offers no points of great interest as regards the relations of the larynx, I have made on a preparation hardened in alcohol, a section exactly in the plane of the vocal cords and introduced it in the accompanying woodcut. It will be seen that FIG. 11.
the processus vocales are continuous immediately with the elastic fibres of the vocal cords. At the line of section, which is not sharply defined, some reticulated cartilage exists. In front the vocal cords pass into a roll of connective tissue to which the thyroarytenoid muscles are attached. The mucous membrane on the vocal cords is destitute of ciliated epithelium, 'and is stretching tightly over and is firmly attached to them. Beneath the mucous membrane the glands in this plane lie in the angle between the anterior extremities of the vocal cords and between the arytenoid cartilages posteriorly. On either side of the vocal cords are seen the two cut surfaces of the thyro-arytenoidei, of which the median is shown as internal and the lateral as external. Still more externally are the cut fibres of a muscle which passes partly to the thyroid cartilage and partly to the epiglottis, the thyro-aryteno-epiglottideus (Henle). Behind the section of the arytenoid cartilage the arytenoideus is seen in section passing across from one cartilage to the other. Referring again to the large plate, we see behind the cricoid cartilage and behind the section of the crico-arytenoideus posticus, the transverse chink of the pharynx. The section shows it empty, therefore its anterior and posterior walls are in contact behind it is the middle portion of the inferior constrictor of the pharynx. As the pharynx lies immediately upon the vertebrse, and the longus colli and recti capitis postici majores, the space required by the morsel of food in passing downwards is provided for by the dragging forward of the anterior wall of the pharynx and the advancement of the larynx. The larynx is, moreover, lifted in swallowing. The result of this twofold change in position is a movement of the larynx towards the chin, which can be easily observed during the act of deglutition. The lax cellular tissue which lies between the pharynx and the vertebrae appears in the section as a narrow border, and by its extraordinary looseness it permits of the movements of the pharynx upon the vertebrae. But it is of such a nature that haemorrhage into it would cause great distension. This condition is, moreover, favorable to the infiltration of pus.
Behind the pharynx lies the section of the sixth cervical vertebra, which has been divided in its lower half. As the section fell to the right side, and exactly at the springing of its arch, a clear view is furnished of the lumen of the spinal canal, which has the form of an equilateral triangle, and is so spacious that in the most extensive movements of the cervical vertebrae the spinal cord has free room, and is thoroughly protected from strain.
The relation of the vertebra to the surrounding soft parts is worthy of notice, inasmuch as it appears to be pushed remarkably forwards. If half the diameter, for instance, be taken from before backwards, the body of the vertebra would lie completely in the anterior half of the section. By comparing the measurements with those of the section shown in Plate I, and also in the other figures, it is seen that this position of the vertebra is correct. This appearance is owing to the cervical curvature of the spinal column. The distance of the medulla from the surface of the neck on the living body is usually represented as far too slight. Very similar relations will be found in Pirogoff (fasc. i, tab. iii, fig. 2 tab. ii, fig. 1 fasc. i, tab. x, fig. 66).
As the body of the vertebra is cut through near its lower border, its connection with the transverse process is clear. The vertebral artery full of injection, with its satellite vein, is seen in the bony canal on either side. On the left side, the section has fallen rather deeper, so that the canal in the transverse processes is closed in posteriorly merely by ligamentous tissue it involves also the superior articular process of the seventh cervical vertebra and its joint cavity. Since the body of the sixth cervical vertebra with its transverse process is divided, a proper opportunity is afforded of examining the so-called tubercle of Chassaignac and its relation to the common carotid artery. Among surgeons this process is known as Chassaignac's tubercle, and is considered, according to the statements of authors, to be a most valuable landmark in seeking the vessel, in cases where ligature is rendered difficult on account of swelling of the tissues or the presence of a tumour.
It is clearly seen that the anterior of the tubercles of the bifurcated transverse process, which proceeds from the side of the body of the vertebra, and encloses the sixth cervical nerve, is a direct guide to the common carotid artery, which lies immediately upon it. Further, with regard to this tubercle, it has a morphological importance as a rudimentary rib, and is correctly called the eminentia costaria, jutting out more markedly from the sixth vertebra than from any of the others. It can be readily felt in the living body if gentle pressure be made on the side of the body of the vertebra upwards towards the level of the larynx.
Although advantage may be taken of the presence of this tubercle in looking for the vessel, for the sake of demonstration, and of making beginners acquainted with its locality, still it is not necessary for surgeons of experience to avail themselves of such a means of assistance, even in complicated cases. If the vessel has to be ligatured exactly at this spot, it is better to make the usual dissection over the course of the artery, dividing layer by layer. In this way there is less danger of wounding important parts, whilst the course to the vessel is sure.
The position of the vessels is denned by muscles and fasciae, but these can be easily pushed away from their relations with the bony points. When, however, the vessels lie in bony canals, and are enclosed as fixedly and unalterably as the vertebral, for instance, then undoubtedly the determination of their position is facilitated. But, on the other hand, the means of reaching them may be rendered proportionately difficult. As, however, the carotid can be easily drawn away from its relation to Chassaignac's tubercle, this prominence as a means of assistance is not directly suitable in all cases, as is already proved by examination of the normal thyroid body (see figure), the upper lobe of which lies between the artery and the thyroid cartilage. Swellings of this gland must draw the artery away from the bony prominence, but they do not permit of its being released from the strong fibrous sheath, which is formed by the investment of the sterno-cleido-mastoid and scalene muscles, and of the gland itself.
From a section which I made at a similar level in the neck on a well-frozen body affected with goitre, the carotid was half an inch external to the tubercle in question, but the relations of the muscle and fasciae were unaltered. On a closer examination of the plate the relation of the fasciae to the artery will be seen. It is true that such representations are insufficient and in order to make clear the relations of all the fasciae one is compelled to represent them as white lines. I have therefore been able to mark out satisfactorily the coalescence of the several laminae. Moreover, actual fasciae cannot be properly distinguished from layers of cellular tissue. For the more accurate relations of this part I refer to the works of Dittl, Pirogoff, and Henle. I may add that the contours of the muscles which chiefly determine the arrangement of fasciae are sufficiently accurately represented in the preparation, and in this respect furnish trustworthy points of reference.
Externally, and somewhat behind the artery, is the internal jugular vein, and between these vessels is the vagus, which in ligature of the artery must be carefully protected from injury. It is moist safely avoided, if after division of the fibrous sheath a fine director be passed through the cellular tissue immediately over the artery, and then the edges of the fascia pulled aside with two pairs of forceps, before passing the ligature needle. By this means the ligature can be as readily applied, either from without inwards or from within outwards. Behind, and nearer the artery, is the sympathetic nerve, which may be avoided if merely the old rule be followed with respect to the vagus, of introducing the needle from without inwards. Behind the vagus, and on the anterior scalene muscle, lies the phrenic nerve.
Behind the jugular vein, between the sterno-cleido-mastoid and the middle scalene muscles, are the supra-clavicular twigs from the fourth cervical nerve.
Between the anterior and middle scalene muscles are the sections of the fifth and sixth cervical nerves, which are figured collectively on the plate as brachial plexus, so as not to disturb the detail of the clearness of the drawings. The seventh cervical nerve comes off from the spinal cord in the vertebral canal, and takes a direction outwards and backwards behind the vertebral artery.
The above-mentioned figures of Nuhn (' Chirurg. Anat. Tafeln.,' tat', iv, fig. 2) and Beraud (' Atlas d'Anat. Chirurg.,' Plate XXXVII, fig. 2) should be compared, as the question to be proved is whether in these plates of sections of the neck the natural relations are represented, since they show not round but polygonal contours. There is one word to be added here on the relations of this section with respect to the vertebra, in order that no misconception may arise : Nuhn's section of the larynx is taken almost at the same level as mine, whilst in Beraud's nothing of the trachea below the cricoid cartilage is seen. Both authors make the corresponding vertebra the fourth cervical, whereas in mine the sixth is shown. One might easily conjecture, therefore, that I have represented a wrong vertebra an error which may be easily committed if one has been already making many sections of the neck. I, however, expressly state that I went to work most accurately in the definition of the vertebra, and believe that I have made no mistake in the accompanying plate.
By comparing the vertical sections on PI. I and II, as Pirogoff gives it, the fourth cervical vertebra is on the level of the epiglottis, and the seventh has the flat surface of the cricoid cartilage in front of it, which also in this particular agrees with my plate. It cannot be disputed that other variations in this respect happen to the extent of the level of a vertebra. These variations are in all probability occasioned by the different degree of curvature of the cervical spine. Nevertheless, I do not think that this change in position can be extended to two vertebrae, and I maintain that Beraud's statement that the fourth cervical vertebra lies deeper than the cricoid cartilage is not correct. There is a vertical section in Beraud's atlas (PI. XXVIII, fig. 2) which bears out my statement. Perhaps, therefore, the parts were pushed out of their places in making a section of a soft preparation.
Pirogoffs transverse sections of the regions of the neck (fasc. i, tab. x) coincide with my account. The cricoid cartilage here lies in front of the sixth cervical vertebra.
Braune W. An atlas of topographical anatomy after plane sections of frozen bodies. (1877) Trans. by Edward Bellamy. Philadelphia: Lindsay and Blakiston.
Transition from Deep Regional Blocks toward Deep Nerve Hydrodissection in the Upper Body and Torso: Method Description and Results from a Retrospective Chart Review of the Analgesic Effect of 5% Dextrose Water as the Primary Hydrodissection Injectate to Enhance Safety
Deep nerve hydrodissection uses fluid injection under pressure to purposely separate nerves from areas of suspected fascial compression, which are increasingly viewed as potential perpetuating factors in recalcitrant neuropathic pain/complex regional pain. The usage of 5% dextrose water (D5W) as a primary injectate for hydrodissection, with or without low dose anesthetic, could limit anesthetic-related toxicity. An analgesic effect of 5% dextrose water (D5W) upon perineural injection in patients with chronic neuropathic pain has recently been described. Here we describe ultrasound-guided methods for hydrodissection of deep nerve structures in the upper torso, including the stellate ganglion, brachial plexus, cervical nerve roots, and paravertebral spaces. We retrospectively reviewed the outcomes of 100 hydrodissection treatments in 26 consecutive cases with a neuropathic pain duration of
months and the mean Numeric Pain Rating Scale (NPRS) 0–10 pain level of
. The mean percentage of analgesia during each treatment session involving D5W injection without anesthetic was 88.1% ± 9.8%. The pretreatment Numeric Pain Rating Scale score of improved to
at 2 months after the last treatment. Patients received treatments over
months from the first treatment to the 2-month posttreatment follow-up. Pain improvement exceeded 50% in all cases and 75% in half. Our results confirm the analgesic effect of D5W injection and suggest that hydrodissection using D5W provides cumulative pain reduction.
Deep regional blocks have been used for years to provide perioperative anesthesia for surgery and postoperative pain control . In the management of patients with chronic pain, such as those with complex regional pain syndrome (CRPS) and postherpetic neuralgia, deep regional blocks, for example, stellate ganglion blocks (SGBs), serve as an alternative to other medical treatments. The mechanism of action of deep regional blocks or repeated peripheral focal nerve blocks for neuropathic pain remains unclear . A benefit from repeated depolarization by a local anesthetic was originally proposed however, the effects of this method with regard to the normalization of nerve physiology have not been confirmed . More recently, the concept has emerged that fascial compression of nerves can occur in multiple locations and that part of the benefit of deep regional blocks may be through partial amelioration of fascial compression . Nerve hydrodissection is a technique involving the use of fluid injection under pressure to purposely and more completely separate nerves from their surrounding tissue . Ultrasound is used to guide the needles and fluid (hydro) is used to separate and release (dissect) the nerves from the surrounding soft tissue/fascia.
Potential safety concerns with any perineural injection method using an anesthetic include temporary muscular weakness and loss of protective sensation . The rate of inadvertent intraneural injection under ultrasound guidance approximates 16%-17% [6, 7], although long-term sequelae appear to be quite rare [6, 7]. Furthermore, inadvertent intravascular injection may occur because of the frequent close proximity of nerves and vessels. Injection of a high volume of anesthetic for hydrodissection is associated with an increased risk of both dose-related systemic anesthetic toxicity and inadvertent intravascular injection. The use of 5% dextrose water (D5W) as the primary injectate for perineural injection during hydrodissection in the presence of chronic pain, particularly neuropathic pain, is receiving increasing attention [8–12]. D5W is also considered for use as a coadministration injectate along with noxious agents such as chemotherapeutics [13, 14] and microbiospheres  to decrease pain, as well as a means to separate nerves from fascia while decreasing the risk of anesthetic toxicity . An independent-of-anesthetic analgesic potential of D5W has been demonstrated in a recent randomized controlled trial of epidural D5W injection versus saline injection for patients with back pain accompanied by either buttock or leg pain , with potential long-term efficacy suggested by long-term follow-up data in those patients .
Although low-level studies have demonstrated the effectiveness of nerve hydrodissection, no high-level studies have been reported . Performance of high-level studies will be facilitated by procedural methods that are reproducibly performed, consistent in clinical effect and safe. The objectives of this study were to illustrate reproducible methods of hydrodissection for deep nerve structures in the upper torso, including the stellate ganglion, brachial plexus, cervical nerve roots, and paravertebral spaces and gather preliminary data related to the analgesic effect and efficacy of D5W without lidocaine as the primary injectate during hydrodissection for patients with chronic neuropathic pain.
3. Materials and Methods
A formal letter of exemption allowing retrospective chart review was obtained from the International Cellular Medicine Society Institutional Review Board (ICMS-IRB). We reviewed consecutive outpatient charts for patients who underwent hydrodissection of the stellate ganglion, brachial plexus, cervical nerve roots, or paravertebral spaces for the management of pain with neuropathic characteristics. Videos and still photographs of these patients were all deidentified for use. Charts were consecutively reviewed to identify participants who received hydrodissection exclusively with D5W, with the use of lidocaine only for the placement of skin blebs. Chart selection continued until data from 100 treatments was available for analysis. Methods of hydrodissection utilized for these consecutively recruited patients were illustrated with the use of both anatomical diagrams and ultrasound images.
Neuropathic pain, for the purpose of this write-up, was defined in standard fashion as pain arising as a direct consequence of a lesion or disease affecting the somatosensory system either at the peripheral or at central level [19, 20]. Neuropathic pain is commonly characterized by allodynia, hyperalgesia, and/or changes in temperature sensation (e.g., burning or cold pain) the extent of the pain does not typically correspond to the extent of the nervous structure damage.
Ultrasound findings were not useful for the diagnosis of neuropathic pain unless the cervical nerve roots and brachial plexus were scanned. In case of unilateral lesions, a comparison of the cross-sectional area and echotextures of cervical nerve roots or the brachial plexus on the painful side with those on the contralateral side without pain generally showed that the painful side was larger in cross-sectional area .
The decision to hydrodissect was based on the following factors.
(1) A clinical diagnosis indicating that a neurogenic pain source is likely and knowledge of the corresponding involved deep nerve structures in patients with neuropathic pain, for example, dermatomes of the nerves involved in patients with postherpetic neuralgia
(2) Awareness of the effects of compression on the function of peripheral nerves
(3) Knowledge of all potential sites of compression of peripheral nerves, for example, the radial nerve at entry to and exit from the radial tunnel
(4) Experience regarding the appearance of peripheral nerves when they are encased in fascia, obtained by observing the “plumping up” of nerves upon freeing them from the surrounding fascial encasement
(5) Confidence to proceed with a higher volume of perineural injection in the absence of a risk of lidocaine toxicity, considering the lidocaine component is absent or negligible
Hydrodissection involved consistent fluid injection at all times during needle advancement, ostensibly to push away any small nerve fibers and avoid pain during advancement. This eliminated the need for anesthetic injection. Because fluid always leads needle advancement during hydrodissection and pushes away nerve structures, vessels, and other soft tissues, this technique, if performed properly, prevents soft tissue damage by the needle. Without inclusion of a local anesthetic, typical signs of motor blockade, such as Horner’s syndrome, were not expected during stellate ganglion infiltration. Accordingly, the primary endpoint was pain reduction. Typically, 20–30 ml of fluid was utilized for each area of hydrodissection.
Adequacy of a particular hydrodissection procedure was based on patient symptoms, because visualization of fluid surrounding the nerve is only directly observable during hydrodissection of the brachial plexus and cervical nerve roots. In our experience, the analgesic effect of dextrose occurs within 5 min after deep regional hydrodissection for a variety of chronic neuropathic pain conditions. Accordingly, 5 min after completion of the initial procedure, the pain was rated on a 0–10 Numeric Pain Rating Scale (NPRS) using the question “how much pain do you have?” A score of 0 represented “no pain” and a score of 10 represented the “most severe pain imaginable.” If the pain was rated as 3/10 or less, the reported score was considered to represent the postprocedural pain level. If residual pain was rated as 4/10 or more, another regional procedure that was reasonably expected to affect the region of pain was performed, and pain was rated again at 5 min after the procedure. This process was repeated for up to three pertinent procedures, and the final pain level was that following the last hydrodissection procedure. The same sequence was performed during follow-up visits.
The primary measure for a potential intraprocedural analgesic effect of D5W hydrodissection was the mean difference between pretreatment and immediate (5 min) posttreatment NPRS scores.
Routine follow-up procedure in the primary investigator’s office was to contact patients at 2 months after treatment to inquire about any further need for treatment and verbally obtain a final NPRS score to monitor the treatment efficacy. Data were analyzed using PASW 18 (Predictive Analytics 180 Software 18.0.0, IBM Corporation, 1 New Orchard Road, Armonk, New York 10504-1722). Descriptive statistics (means ± standard deviations) were reported at baseline and at each time point for NPRS scores.
The cumulative improvement in pain levels over time was determined by calculating the mean difference between pretreatment NPRS scores and those obtained at 2 months after the last treatment visit. The proportion of patients who achieved more than 50% and more than 75% pain reduction was calculated.
3.1. Description of Hydrodissection Procedures by Area
3.1.1. Stellate Ganglion Hydrodissection
Applications. The stellate ganglion is part of the sympathetic network formed by the inferior cervical and first thoracic ganglia. It lies anterolateral to the C7 vertebral body (Figure 1), receives input from the paravertebral sympathetic chain, and provides sympathetic efferents to the upper extremities, head, neck, and heart. During pain management for CRPSs, particularly type I reflex sympathetic dystrophy (RSD) [22, 23], postherpetic neuralgia [24, 25], and chronic pain of the head and neck [26, 27] or thorax, a local anesthetic solution is injected as a local block for the stellate ganglion. Posttraumatic stress disorder [28, 29] may also be seen in these patients [30, 31]. Accordingly, its presence or absence was recorded, although the symptomatology was not assessed in the present study. Other applications of SGBs, such as vascular insufficiency and hyperhidrosis, were not within the scope of this study.
Nonhydrodissection Methods. A consecutive patient study described the efficacy and safety of using ultrasound to guide needles for SGB without the use of a high-volume technique . Ultrasound guidance helps in the visualization of soft tissues to prevent complications and the subfascial deposition of the drug under direct vision [32, 33].
Primary Ultrasound Landmarks for Hydrodissection. The anterior tubercle of the C6 vertebral body, known as the Chassaignac tubercle or carotid tubercle, is an important landmark located superior to the stellate ganglion. C7 does not have an anterior tubercle, while the anterior tubercle of C5 is less prominent. Therefore, the anterior tubercle of C6 can be easily found. Identification of the longus colli is also key (Figure 2), as a cadaveric study using dye and clinical validation has shown adequate spread of the anesthetic solution to the stellate ganglion using a technique in which the needle tip is deep to the prevertebral fascia to avoid spread along the carotid sheath and superficial to the fascia investing the longus colli to avoid injection into the muscle substance .
Patient Position. The patient is supine, with a rolled towel underneath the neck for slight extension and another thin pillow or rolled towel beneath the ipsilateral shoulder for slight rotation of the head to the side contralateral to the point of needle entry (Figure 3).
Probe Position. Probe placement is transverse to the neck. A lateral to medial in-plane approach is used, with the needle orientation slightly posterior to anterior (Figure 3).
Sonoanatomy. Figure 4 shows a dual sonographic image (left, B-mode right, power Doppler) depicting the sonoanatomy and a sonographic view of the needle just past the anterior tubercle of the C6 vertebra (superior to the C6 nerve root and inferior to the C5 nerve root).
Needle Advancement/Injection. Visualize the hypoechoic nerve roots situated between the anterior and posterior tubercles of the transverse processes of the cervical vertebrae. Locate the longus colli and the anterior tubercle of C6 and the C6 nerve root. It is essential to follow the basic principle of hydrodissection that is, the fluid opens the channel or space in front of the needle tip, and the needle just follows. Advance the needle (Figure 5(a)) and stop advancing when the tip reaches the prevertebral fascia superficial to the longus colli (Figure 5(b)). After reaching the prevertebral fascia, turn the bevel of the needle down so that the injectate will push down the soft tissues in front of and beneath the needle. The idea is to use the force of the injectate to open a potential space between the prevertebral fascia and the longus colli. The tracking of the fluid beneath the prevertebral fascial can be further observed by turning the probe 90 degrees to show a sagittal image. Upon continued hydrodissection the fluid will be seen tracking caudally to reach the stellate ganglion (Figure 5(c)). Video 1 (in Supplementary Material available online at https://doi.org/10.1155/2017/7920438) shows the procedure for stellate ganglion hydrodissection.
Treatment Frequency. The effects may last from one to a few weeks depending on the severity of the symptoms. Typically, after 3–6 repeated treatments at 4–6-week intervals, the patient’s pain will be relieved to a satisfactory level.
3.1.2. Brachial Plexus Hydrodissection
Applications. Brachial plexus block is used for regional anesthesia during upper extremity surgery (arm, elbow, forearm, wrist, and hand) . In chronic pain management, ultrasound-guided hydrodissection of the brachial plexus has been used to treat severe neck sprains (brachial plexus injury without rupture it is only used to treat neuropraxia with or without axonotmesis) with radiating pain to the ipsilateral upper limb , CRPS  involving the ipsilateral upper limb, and thoracic outlet syndrome or other double/triple crush syndromes involving the ipsilateral upper limb .
General Approaches and Selection of the Right Approach. There are four different approaches/sites to perform brachial plexus hydrodissection: interscalene, supraclavicular , infraclavicular, and axillary . Each approach has its own unique advantages and indications. Interscalene blocks are the most effective for anesthesia of the shoulder and proximal upper limb, while supraclavicular blocks are best suited for anesthesia from the mid-humerus to the fingers. Infraclavicular blocks are useful for procedures requiring continuous anesthesia, and axillary blocks provide effective anesthesia distal to the elbow. During brachial plexus hydrodissection for chronic pain management, the interscalene or supraclavicular approaches are typically used because these are two very common entrapment points for the brachial plexus . The choice of approach depends on how proximal the cause of the neuropathic pain is. If the entrapment/neurological injuries are at the cervical root levels, interscalene brachial plexus hydrodissection is recommended. If the cause of the neuropathic pain is at the trunk or division level of the brachial plexus or if there is an excessive upward movement of the shaft of the first rib due to excessive pulling of the anterior and middle scalene, supraclavicular brachial plexus hydrodissection may provide better relief.
3.2. Interscalene Approach
Muscular Landmarks. The anterior, middle, and posterior scalenes are identified (Figure 6). The interscalene brachial plexus is generally formed by the C5, C6, C7, and C8 nerve roots. The needle is inserted in a direction posterior to anterior and lateral to medial, and it passes through the middle scalene to reach the interscalene brachial plexus.
Patient and Probe Positions. The patient is supine, with a rolled towel underneath the neck for slight extension and the head is straight up or slightly rotated to the side contralateral to the point of needle entry (Figure 7). The probe is transverse to the neck.
Sonoanatomy. Visualize the scalenes and the hypoechoic oval nerve roots of C5–C8, which are situated between the anterior and middle scalenes. The pertinent sonoanatomy is shown in Figure 8.
Needle Advancement/Injection (Figures 9(a)–9(c)). An in-plane approach is used, with the needle advancing in a direction from posterior to anterior and lateral to medial (Figures 6 and 7). At the interscalene level, the cervical nerve roots start to form the superior trunk (C5/6), middle trunk (C7), and inferior trunk (C8/T1). The fascial sheath for these trunks is formed from the fascia of the surrounding scalenes. To perform interscalene brachial plexus hydrodissection, one needle entry point is typically used, and the needle should hydrodissect its way into the fascial sheath of each trunk. Once inside the fascial sheath, the injectate will surround the trunk effectively, although occasionally, hydrodissection above and below becomes necessary to separate the fascia from the trunk. Figure 9(d) shows visualization of the injectate during hydrodissection, and video 2 shows the procedure for interscalene brachial plexus hydrodissection.
3.3. Supraclavicular Approach
The anterior and middle scalenes may be traced to their insertions on the first rib, and the entire brachial plexus will gather on top of the first rib as the supraclavicular brachial plexus, lateral to the subclavian artery (Figures 10 and 11).
Patient and Probe Positions. The patient is supine, with a rolled towel underneath the neck for slight extension and another thin pillow or layers of towel beneath the ipsilateral shoulder for slight rotation of the entire trunk and neck to the side contralateral to the point of needle entry (Figure 11). The probe is transverse to the trunk and nearly parallel to the clavicle. An in-plane approach is used, with the needle advancing in a direction from posterior to anterior and lateral to medial.
Sonoanatomy. Visualize the brachial plexus gathered on top of the first rib, with the subclavian artery on the medial side (Figure 12).
Needle Advancement and Hydrodissection. Visualize the brachial plexus gathered on top of the first rib, with the subclavian artery on the medial side. Figures 13(a)–13(c) show sequential needle placement for hydrodissection below, above, and between portions of the supraclavicular brachial plexus. If the patient achieves good pain relief with hydrodissection below and above the brachial plexus, a third-needle placement does not appear to be necessary. Figure 13(d) shows the anechoic injectate during hydrodissection, and video 3 shows the procedure for supraclavicular brachial plexus hydrodissection.
3.3.1. Cervical Nerve Root Hydrodissection
Indications. Selective cervical nerve root blocks play an important role in the conservative treatment of patients with cervical radicular pain . In chronic pain management, hydrodissection of selective cervical nerve roots has been used to treat patients with postherpetic neuropathic pain involving the dermatome of specific cervical nerve roots, patients with postradiation neuritis, and patients with nerve compression from fibrosis of the neck muscles.
Bony Landmarks. Bony landmarks include the hyperechoic anterior and posterior tubercles of the cervical vertebra, noting that C7 has no anterior tubercle and C8 has no anterior or posterior tubercle. Figure 14 shows the cross-sectional anatomy at the C6 level for C6 root hydrodissection.
Patient and Probe Positions. The patient is supine, with the neck straight or slightly tilted to the contralateral side. The probe is transverse to the neck (Figures 15 and 16). An in-plane approach is used, with the needle advancing in a direction from posterior to anterior and lateral to medial.
Sonoanatomy. Figure 17 is a snapshot showing the needle passing between the middle and posterior scalenes or, in some cases, only through the middle scalene. The needle tip is almost touching the posterior tubercle of the C6 transverse process.
Needle Advancement and Hydrodissection. Visualize the hypoechoic nerve roots situated between the anterior and posterior tubercles of the transverse processes of the cervical vertebrae. As illustrated in the representative image of C6 nerve root hydrodissection (Figure 18), the needle tip stops at the posterior tubercle to hydrodissect the soft tissue around the C6 nerve roots to the point where the injectate surrounds the entire nerve root. Typically, 20–30 ml of D5W is used to achieve satisfactory pain relief with fluid surrounding the nerve root. Exercise caution during C7 cervical nerve root hydrodissection, because C7 does not have an anterior tubercle. Ensure that power Doppler view is switched on to avoid mistaking the vertebral artery for the C7 nerve root. Figure 18(d) shows the anechoic injectate after hydrodissection of the C6 nerve root, and video 4 shows the procedure for C6 nerve root hydrodissection.
3.3.2. Paravertebral Hydrodissection
General Indications. Paravertebral block involves injection of a local anesthetic in a space immediately lateral to the point of emergence of the spinal nerves from the intervertebral foramina. This technique is increasingly being used for both intra- and postoperative analgesia and as a sole anesthetic technique for various procedures. Its popularity is mainly attributed to the ease of performance and lower complication rate when compared with techniques using catheters.
Hydrodissection Applications. In our experience, paravertebral hydrodissection has been observed to result in analgesia in patients who present with acute herpes zoster, prevent the development of postherpetic neuralgia, and benefit patients with established postherpetic neuralgia. This analgesic effect is consistently noted within 5 min of procedure completion and is often noted within seconds. It peaks within 30 min, maintains its peak for 2–4 h, and declines over 48 h, with a common residual effect of 10%–20% at 4 weeks.
Pictorial Anatomy. The target of this technique has been postulated to be the wedge-shaped paravertebral space whose boundaries were defined by Klein et al.  using a small (2.3 mm) fiber optic scope. These boundaries include the parietal pleura ventrolaterally heads of the ribs, transverse process, and superior costotransverse ligament dorsally and vertebra, intervertebral discs, and intervertebral foramina medially. There is a lateral extension in continuity with the intercostal space (Figure 19). A single injection into this space accesses not only the ventral and dorsal rami but also the sympathetic chain and gray rami communicantes. The advantage of using ultrasound guidance for injection into the paravertebral space has been described by Batra et al. .
Patient and Probe Positions. The patient is prone, with a rolled towel or pillow underneath the chest to increase the degree of thoracic kyphosis (Figure 20). The probe position is transverse to the trunk, parallel to the ribs above, and below the transverse process.
Pertinent Sonoanatomy. Figure 21(a) shows the surrounding structures when the transducer is placed immediately caudal to the costotransverse joint. Because the probe has a width and all the three-dimensional information scanned beneath the probe will be processed by the computer to be presented as a two-dimensional image on the monitor, the tip of the transverse process, which is not in the same plane of the needle and injection, will often appear as if it is in the same plane, providing additional information to confirm the costotransverse ligament position through visualization of its superomedial origin on the transverse process.
Needle Advancement and Hydrodissection. Hydrodissect while advancing the needle through the external and internal intercostals (Figure 21(a)). A 22-gauge needle is preferable to a 25-gauge needle, because a 22-gauge needle may provide a feeling of penetration. Stop advancing when penetration is felt or when the needle tip is observed to just pass through the costotransverse ligament (Figure 21(b)). With the needle tip beneath the lateral tip of the transverse process, further hydrodissection should be accompanied by visualization of the parietal pleura pushing away to confirm paravertebral space injection (Figure 21(c)). The fluid should then be able to access the nerve root and dorsal root ganglion, which are the targets for chronic pain control, considering the pleura forms the floor of the paravertebral space. Video 5 shows the procedure for paravertebral space hydrodissection.
Treatment of two to three levels of the paravertebral nerve roots is generally necessary for complete pain relief. To determine the thoracic spinal level by ultrasound, a paramedian sagittal view with the transducer in cross section to the transverse processes of the thoracic vertebrae and ribs is utilized to count down from the first rib or up from the twelfth rib. Video 6 explains how to use ultrasound to count the levels of the thoracic spinal nerves.
Empirically, one to two treatments are required for acute pain relief, with the second administered after rash subsidence to prevent the development of postherpetic neuralgia. In patients with established postherpetic neuralgia, pain scores will drop to 0–3/10 or to a tolerable level immediately after each injection and gradually increase thereafter, albeit with some cumulative effect. Four to six injections typically result in pain scores of 1-2/10.
4.1. Retrospective Data Collection
Figure 22 depicts the flow chart for data selection in this retrospective study. In total, 30 consecutive patients who received D5W as the primary injectate during hydrodissection for neuropathic pain in the upper body were included. Of these, five patients requested the use of lidocaine in the injectate at some point during their treatment course because of injection discomfort. The remaining 25 patients (26 cases after considering two treatment sides in the patient with bilateral treatment) received lidocaine only for the placement of subcutaneous anesthetic blebs to numb the needle entry point. Data for 100 consecutive hydrodissection sessions performed in these 26 cases was collected by telephonic follow-up at 2 months after the last treatment session. Data capture was 100% up to the 2-month follow-up time point. All procedures were performed in Hong Kong at the office of the primary author between March 31, 2015, and December 29, 2016.
Baseline demographics for the 26 cases are shown in Table 1. The sex distribution was even and the patients were middle-aged. The pain duration was 6 months or more except three with acute zoster pain (3 days, 3 days, and 1 week, resp.) and two with acute thoracic outlet symptoms (1 month each). Baseline pain was moderately severe to severe in this group. Only 1 patient rated their pain as less than 8.0.
4.3. Selection of Treatment Method according to the Primary Diagnosis and Area of Pain
Table 2 lists the number of cases with each primary diagnosis. Multiple diagnoses were frequent diagnoses other than the primary diagnosis are mentioned in parentheses in the column titled “neuropathic pain areas.” The hydrodissection method was selected on the basis of the area of neuropathic pain and the other diagnoses.
= number of cases with the same combination of diagnoses. Not all cases with the same diagnoses underwent hydrodissection in the same region. The number of cases receiving a given hydrodissection type is listed in each column under the main column titled “Regional hydrodissection.”
PV = paravertebral hydrodissection, typically performed for neuropathic pain in the thoracic region.
SG = stellate ganglion hydrodissection, typically performed for CRPS and other chronic neuropathic pain conditions involving the head and neck region.
SCBP = supraclavicular brachial plexus hydrodissection, typically performed for CRPS, other chronic neuropathic pain conditions involving the ipsilateral upper limb, and double crush syndrome involving the ipsilateral upper limb.
ISCP = interscalene brachial plexus hydrodissection, typically performed for CRPS and other chronic neuropathic pain conditions involving the ipsilateral upper limb, particularly areas closer to the nerve roots.
CR = cervical root hydrodissection, typically performed for nerve root compression of any kind and neuropathic pain involving specific nerve roots.
Although panic attacks were not a primary diagnosis, they were recorded because of their frequent exacerbation by chronic pain and treatment by stellate ganglion hydrodissection.
4.4. Intrasession Effects of D5W
The consistency of postprocedural analgesia was strong. The minimum degree of pain reduction for the 100 procedures was 69%, with 35 procedures resulting in 100% pain reduction. The mean degree of pain reduction at 5 min after the last injection was administered across all 100 treatment sessions for the 26 cases was %.
4.5. Cumulative Effects of D5W
From baseline to the 2-month posttreatment follow-up, a total of treatments were performed over months. Figure 23 is a graph showing changes in pain levels over time for all 26 cases. Each line represents the changes in the mean NPRS over time for cases that received the same number of treatments. For example, the middle line shows the findings for two cases that received four treatments. When all 26 cases were combined for analysis, the mean NPRS improved from before treatment to after treatment, with an improvement of
points. The degree of pain improvement exceeded 50% in all cases and 75% in 50% (13/26).
4.6. Effects of D5W Hydrodissection on Patients with Acute Pain
Of the 26 cases, 21 had pain for more than 6 months and five had pain for less than 2 months. Cases of acute pain received only one treatment, and the degree of pain reduction 5 minutes after the last injection was 97.0% ± 6.9% in cases of acute pain and 87.7% ± 9.8% in cases of chronic pain (
). The mean improvement in NPRS at the 2-month posttreatment follow-up was
points for cases of acute pain ( to ) and points for cases of chronic pain ( ).
In the present study, we proposed and illustrated potentially reproducible methods of hydrodissection of the stellate ganglion, brachial plexus, cervical nerve roots, and paravertebral spaces. Salient methods common to all approaches included the following.
(1) One method is use of a skin bleb to eliminate pain at the point of needle entry.
(2) Another method is use of a 22- to 25-gauge needle, with minimization of the probe to needle angle and an emphasis on a needle in-plane approach to maximize needle visibility.
(3) Another one is constant hydrodissection, with marked reduction of any discomfort through dissection of soft tissue in front of the needle to lead the needle, rather than splitting of the soft tissue by the needle itself, as well as further improvement of needle tip visualization.
(4) Another method is an emphasis on D5W use without lidocaine to eliminate any possibility of intravascular anesthetic injection during the hydrodissection procedure.
If an anesthetic is preferred by a patient because of discomfort, a mixture of D5W and a low dose anesthetic, for example, 0.1%–0.2% lidocaine, can be injected along the needle track before the target area is reached, followed by a switch to D5W alone so that a higher volume can be instilled for the bulk of the hydrodissection procedure for the target nerve structures. However, although small doses of lidocaine may help in increasing patient comfort, the physician is advised to limit lidocaine application during stellate ganglion hydrodissection because of potential changes in vagal modulation and baroreceptor sensitivity  and during deep cervical plexus hydrodissection because of potential effects on the recurrent laryngeal nerve, particularly if the patient has an unrecognized baseline dysfunction of the contralateral recurrent laryngeal nerve or if bilateral hydrodissection is required .
(5) One of them is slow needle advancement, which allows the injectate to dissect the tissue layer by layer until the nerve/plexus is reached, with emphasis on precise visualization of the needle tip when the needle is approaching nerves and blood vessels.
(6) Another one is fluid delivery above and below the nerve for more complete hydrodissection.
This should preferably start just below the nerve, because if there is any air in the injectate, the acoustic shadow of the air will not block the view.
This retrospective data collection provides preliminary data which supports a consistent analgesic effect of D5W across a variety of neuropathic pain conditions and a cumulative benefit of repeated D5W hydrodissection. An important observation was that the onset speed of analgesia was fast enough that pain relief could be used to determine whether the procedure was sufficiently complete. The effect of D5W injection in patients with chronic neuropathic pain in the present study was similar, in both the speed of onset and magnitude of analgesic effect, to that in a recent randomized controlled trial of D5W versus saline injection in the epidural space of patients with chronic low back pain with various etiologies . In that study, saline exhibited no analgesic effects. Moreover, the cumulative effect of repeated D5W hydrodissection was consistent with that in a prospective trial of epidural D5W injection . However, the follow-up period in the present study was only 2 months after treatment completion. A prospective study with a long-term follow-up period and preferably including a control group is necessary to confirm our findings. The study should be of sufficient size to effectively compare treatment outcomes between patients with acute pain and those with chronic pain.
The mechanism of action of dextrose-induced analgesia is not clear, although research supports several hypotheses. First, dextrose may act at the level of pain receptors. Chronic neuropathic pain is associated with persistent upregulation of the transient receptor potential vanilloid receptor-1 (TRPV1) ion channel , which is upregulated by capsaicin. Mannitol (an analog of dextrose) application to the lip reduced the burning pain associated with capsaicin application in a lip pain model , and in our experience, dextrose has a similar effect. A class effect of sugars to indirectly reduce the effects of TRPV1 receptor activation is proposed, because neither dextrose nor mannitol has a known binding point to the TRPV1 receptor .
Second, extracellular dextrose elevation may hyperpolarize normoglycemic C fibers, lowering their firing rate. Dextrose elevation to 0.5% (from the normal blood level of 0.1) in the intestinal lumen rapidly results in hyperpolarization of enterocytic cell membranes to facilitate transport across the cell membrane by sodium glucose cotransporter (SGLT1) . In peripheral nerves, the primary glucose transport is via glucose transporter one, not SGLT1 . However, SGLT1 is still present on neuronal cell membranes . The effect of a 50-fold increase in extracellular dextrose (D5W) on SGLT activity in normoglycemic C fibers has not been directly studied. However, recent reports on the coadministration of D5W to decrease the pain from infusion of chemotherapeutic agents [13, 14] or microspheres  point to a potential analgesic effect in normoglycemic subjects, although the mechanism remains to be confirmed.
Third, dextrose may reverse a proposed energy-deficient state of neuropathic nerves. A decrease in blood dextrose of only 25% (1.5 mM) from the normal fasting range in rats is reported to initiate histopathological changes in the peripheral nervous system  long before blood levels that will initiate brain damage in the rat  or brain dysfunction in humans  are reached. We propose that pain is an alarm signal produced by nociceptive C fibers which begins promptly upon development of intraneural hypoglycemia, prior to onset of histopathologic changes in the C fiber. Maclver and Tanelian  studied action potential changes in response to hypoglycemia in C fibers of the New Zealand White rabbit cornea in vitro and noted an increase in the C fiber discharge frequency of 653% ± 28% relative to that in a normoglycemic control within 15 min of hypoglycemia onset, followed by rapid return to normal firing levels after the administration of dextrose.
The theoretical basis for the clinical benefits of hydrodissection is compelling. Bennett and Wie developed an animal model of neuropathic pain caused by chronic constriction injury, which is widely utilized and involves the application of a ligature that is barely snug around the sciatic nerve . Specific recommendations for the induction of neuropathic pain are as follows: use a high-power objective lens to observe the flow of red blood cells in the epineural vasculature and tie the ligature just tight enough for the flow to slow down without stopping or tighten the ligature so that it will slide along the nerve, but not smoothly. The result is the development of a neural swelling, typically within 24 h, on both sides of the ligature, accompanied by classic findings of neuropathic pain such as hyperalgesia, allodynia, and, frequently, dysesthesia . A similar swelling of nerves, accompanied by a graded compromise in the vascular nerve supply, is notable on high-resolution ultrasound examinations and is strongly associated with nerve compression, such as that occurring in carpal tunnel syndrome . Ultrasound examination of peripheral nerves in the presence of neuropathic pain commonly demonstrates an increase in individual nerve fascicle size, an increase in neural volume, or, typically, both . An example is shown in Figure 24, which depicts the smaller left and larger right common fibular (peroneal) nerve at the level of the knee in the same patient (symptomatic on the right side). Studies with large or formal data collection procedures showing changes in fascicular swelling in response to D5W injection have not yet been reported.
Future studies, particularly prospective studies are necessary to evaluate the frequency of intraneural edema in various neuropathic pain syndromes, long-term efficacy of hydrodissection in comparison to that of standard-volume anesthetic blocks, and use of injectates other than D5W, such as platelet-rich plasma, which may have a favorable effect on dysfunctional nerves by itself . In addition, because the amount of compression necessary to create a chronic constriction effect appears to be minimal , it is important to consider all possible points of constriction on these predominantly small-fiber sympathetic nerves between their peripheral origin and central process entry into the neural foramina, without restriction to the classic entrapment locations.
The potential importance of the analgesic effect of dextrose in the absence of anesthetic should not be overlooked in clinical applications and research. Compared with a nerve block with anesthetic, injection of dextrose for diagnostic purposes may provide a more precise method for identifying which branch or portion of a peripheral nerve is the nociceptive source within the nerve tree because it does not depolarize the nerve .
In conclusion, we described and illustrated potentially reproducible methods of hydrodissection of the stellate ganglion, brachial plexus, cervical nerve roots, and paravertebral spaces, provided data supporting a consistent analgesic effect of D5W used as the primary injectate, and suggested a potentially sustainable clinical benefit in patients with chronic upper back/thoracic pain of neuropathic origin. The mechanism of analgesia may be related to an indirect (allosteric) effect on the TRPV1 cation channel, hyperpolarization of normoglycemic C fibers, correction of local neural hypoglycemia, or undiscovered, probably multiple, mechanisms. The well-developed chronic constriction injury model, which results in neuropathic pain and neural swelling, is the primary rationale behind hydrodissection to release the nerve from suspected local neural compression, particularly those nerves with fascicular swelling or an increase in the overall volume. The frequency of neural edema and the long-term efficacy for nerve hydrodissection in patients with neuropathic pain, as opposed to those for low-volume anesthetic nerve blocks, are important foci for future research on neuropathic pain conditions.
Conflicts of Interest
The authors declare that there are no conflicts of interest regarding the publication of this article.
Permission was obtained from Essential Anatomy Apps to use their anatomy illustrations as figures in this paper. This manuscript has been professionally edited by Editage.
Video 1 shows the actual procedure for stellate ganglion hydrodissection using D5W.
Video 2 shows the actual procedure for interscalene brachial plexus hydrodissection using D5W.
Video 3 shows the actual procedure for supraclavicular brachial plexus hydrodissection using D5W.
Video 4 shows the actual procedure for C6 nerve root hydrodissection using D5W.
Video 5 shows the actual procedure for paravertebral space hydrodissection using D5W.
Video 6 explains how to use ultrasound to count the levels of the thoracic spinal nerves.
- A. Wadhwa, S. K. Kandadai, S. Tongpresert, D. Obal, and R. E. Gebhard, “Ultrasound guidance for deep peripheral nerve blocks: a brief review,” Anesthesiology Research and Practice, vol. 2011, Article ID 262070, 6 pages, 2011. View at: Publisher Site | Google Scholar
- F. Dach, Á. L. Éckeli, K. D. S. Ferreira, and J. G. Speciali, “Nerve block for the treatment of headaches and cranial neuralgias—a practical approach,” Headache, vol. 55, no. 1, pp. 59–71, 2015. View at: Publisher Site | Google Scholar
- S. Clendenen, R. Greengrass, J. Whalen, and M. I. O’Connor, “Infrapatellar saphenous neuralgia after TKA can be improved with ultrasound-guided local treatments,” Clinical Orthopaedics and Related Research, vol. 473, no. 1, pp. 119–125, 2015. View at: Publisher Site | Google Scholar
- S. P. Cass, “Ultrasound-guided nerve hydrodissection: what is it? a review of the literature,” Current Sports Medicine Reports, vol. 15, no. 1, pp. 20–22, 2016. View at: Publisher Site | Google Scholar
- J. M. Neal, M. J. Barrington, R. Brull et al., “The second ASRA practice advisory on neurologic complications associated with regional anesthesia and pain medicine: executive summary 2015,” Regional Anesthesia and Pain Medicine, vol. 40, no. 5, pp. 401–430, 2015. View at: Publisher Site | Google Scholar
- K. Hara, S. Sakura, N. Yokokawa, and S. Tadenuma, “Incidence and effects of unintentional intraneural injection during ultrasound-guided subgluteal sciatic nerve block,” Regional Anesthesia and Pain Medicine, vol. 37, no. 3, pp. 289–293, 2012. View at: Publisher Site | Google Scholar
- S. S. Liu, J. T. Yadeau, P. M. Shaw, S. Wilfred, T. Shetty, and M. Gordon, “Incidence of unintentional intraneural injection and postoperative neurological complications with ultrasound-guided interscalene and supraclavicular nerve blocks,” Anaesthesia, vol. 66, no. 3, pp. 168–174, 2011. View at: Publisher Site | Google Scholar
- J. Lyftogt, “Pain conundrums: which hypothesis? Central nervous system sensitization versus peripheral nervous system autonomy,” Australasian Musculoskeletal Medicine, vol. 13, pp. 72–74, 2008. View at: Google Scholar
- J. Lyftogt, “Subcutaneous prolotherapy for Achilles tendinopathy,” Australasian Musculoskeletal Medicine, vol. 12, pp. 107–109, 2007. View at: Google Scholar
- J. Lyftogt, “Subcutaneous prolotherapy treatment of refractory knee, shoulder and lateral elbow pain,” Australasian Musculoskeletal Medicine, vol. 12, no. 2, pp. 110–112, 2007. View at: Google Scholar
- J. Lyftogt, “Prolotherapy for recalcitrant lumbago,” Australasian Musculoskeletal Medicine, vol. 13, pp. 18–20, 2008. View at: Google Scholar
- M. J. Yelland, K. R. Sweeting, J. A. Lyftogt, S. K. Ng, P. A. Scuffham, and K. A. Evans, “Prolotherapy injections and eccentric loading exercises for painful Achilles tendinosis: a randomised trial,” British Journal of Sports Medicine, vol. 45, no. 5, pp. 421–428, 2011. View at: Publisher Site | Google Scholar
- A. Hosokawa, T. Nakashima, Y. Ogawa, K. Kozawa, and T. Kiba, “Coadministration of 5% glucose solution relieves vascular pain in the patients administered gemcitabine immediately,” Journal of Oncology Pharmacy Practice, vol. 19, no. 2, pp. 190–192, 2013. View at: Publisher Site | Google Scholar
- T. Nakashima, Y. Ogawa, A. Kimura et al., “Coadministration of 5% glucose solution has a decrease in bendamustine-related vascular pain grade,” Journal of Oncology Pharmacy Practice, vol. 18, no. 4, pp. 445–447, 2012. View at: Publisher Site | Google Scholar
- K. J. Paprottka, S. Lehner, W. P. Fendler et al., “Reduced periprocedural analgesia after replacement of water for injection with glucose 5% solution as the infusion medium for 90Y-Resin microspheres,” Journal of Nuclear Medicine, vol. 57, no. 11, pp. 1679–1684, 2016. View at: Publisher Site | Google Scholar
- E. Dufour, N. Donat, S. Jaziri et al., “Ultrasound-guided perineural circumferential median nerve block with and without prior dextrose 5% hydrodissection: a prospective randomized double-blinded noninferiority trial,” Anesthesia and Analgesia, vol. 115, no. 3, pp. 728–733, 2012. View at: Publisher Site | Google Scholar
- L. Maniquis-Smigel, K. D. Reeves, H. J. Rosen et al., “Short term analgesic effects of 5% dextrose epidural injections for chronic low back pain: a randomized controlled trial,” Anesthesiology and Pain Medicine, vol. 7, no. 1, Article ID e42550, 2017. View at: Publisher Site | Google Scholar
- L. Maniquis Smigel, K. D. Reeves, J. Lyftogt, A. L. Cheng, and D. Rabago, “Caudal epidural injections with 5% dextrose for chronic low back pain with accompanying buttock or leg pain: results of a consecutive participant open-label trial with long-term follow-up,” Archives of Physical Medicine and Rehabilitation, vol. 2016, no. 8, 2016. View at: Google Scholar
- T. S. Jensen, R. Baron, M. Haanpää et al., “A new definition of neuropathic pain,” Pain, vol. 152, no. 10, pp. 2204-2205, 2011. View at: Publisher Site | Google Scholar
- R.-D. Treede, T. S. Jensen, J. N. Campbell et al., “Neuropathic pain: redefinition and a grading system for clinical and research purposes,” Neurology, vol. 70, no. 18, pp. 1630–1635, 2008. View at: Publisher Site | Google Scholar
- H. Ebadi, H. Siddiqui, S. Ebadi, M. Ngo, A. Breiner, and V. Bril, “Peripheral nerve ultrasound in small fiber polyneuropathy,” Ultrasound in Medicine and Biology, vol. 41, no. 11, pp. 2820–2826, 2015. View at: Publisher Site | Google Scholar
- W. E. Ackerman III and J.-M. Zhang, “Efficacy of stellate ganglion blockade for the management of type 1 complex regional pain syndrome,” Southern Medical Journal, vol. 99, no. 10, pp. 1084–1088, 2006. View at: Publisher Site | Google Scholar
- I. Yucel, Y. Demiraran, K. Ozturan, and E. Degirmenci, “Complex regional pain syndrome type I: efficacy of stellate ganglion blockade,” Journal of Orthopaedics and Traumatology, vol. 10, no. 4, pp. 179–183, 2009. View at: Publisher Site | Google Scholar
- A. Sinofsky, T. Sharma, and T. Wright, “Stellate ganglion block for debilitating photophobia secondary to trigeminal, postherpetic neuralgia,” Pain Practice, vol. 16, no. 7, pp. E99–E102, 2016. View at: Publisher Site | Google Scholar
- M. Y. Makharita, Y. M. Amr, and Y. El-Bayoumy, “Effect of early stellate ganglion blockade for facial pain from acute Herpes Zoster and Incidence of postherpetic neuralgia,” Pain Physician, vol. 15, no. 6, pp. 467–474, 2012. View at: Google Scholar
- M. Melis, K. Zawawi, E. Al-Badawi, S. L. Lobo, and N. Mehta, “Complex regional pain syndrome in the head and neck: A review of the literature,” Journal of Orofacial Pain, vol. 16, no. 2, pp. 93–104, 2002. View at: Google Scholar
- R. L. Arden, S. J. Bahu, M. A. Zuazu, and R. Berguer, “Reflex sympathetic dystrophy of the face: current treatment recommendations,” Laryngoscope, vol. 108, no. 3, pp. 437–442, 1998. View at: Publisher Site | Google Scholar
- S. W. Mulvaney, J. H. Lynch, and R. S. Kotwal, “Clinical guidelines for stellate ganglion block to treat anxiety associated with posttraumatic stress disorder,” Journal of Special Operations Medicine, vol. 15, no. 2, pp. 79–85, 2015. View at: Google Scholar
- J. H. Lynch, S. W. Mulvaney, E. H. Kim, J. B. de Leeuw, M. J. Schroeder, and S. F. Kane, “Effect of stellate ganglion block on specific symptom clusters for treatment of post-traumatic stress disorder,” Military Medicine, vol. 181, no. 9, pp. 1135–1141, 2016. View at: Publisher Site | Google Scholar
- M. R. Summers and R. L. Nevin, “Stellate ganglion block in the treatment of post-traumatic stress disorder: a review of historical and recent literature,” Pain Practice, vol. 17, no. 4, pp. 546–553, 2017. View at: Publisher Site | Google Scholar
- S. W. Mulvaney, J. H. Lynch, M. J. Hickey et al., “Stellate ganglion block used to treat symptoms associated with combat-related post-traumatic stress disorder: a case series of 166 patients,” Military Medicine, vol. 179, no. 10, pp. 1133–1140, 2014. View at: Publisher Site | Google Scholar
- A. Ghai, T. Kaushik, Z. S. Kundu, S. Wadhera, and R. Wadhera, “Evaluation of new approach to ultrasound guided stellate ganglion block,” Saudi Journal of Anaesthesia, vol. 10, no. 2, pp. 161–167, 2016. View at: Publisher Site | Google Scholar
- A. Ghai, T. Kaushik, R. Wadhera, and S. Wadhera, “Stellate ganglion blockade-techniques and modalities,” Acta Anaesthesiologica Belgica, vol. 67, no. 1, pp. 1–5, 2016. View at: Google Scholar
- M. Gofeld, A. Bhatia, S. Abbas, S. Ganapathy, and M. Johnson, “Development and validation of a new technique for ultrasound-guided stellate ganglion block,” Regional Anesthesia and Pain Medicine, vol. 34, no. 5, pp. 475–479, 2009. View at: Publisher Site | Google Scholar
- Q. H. Tran, A. Clemente, J. Doan, and R. J. Finlayson, “Brachial plexus blocks: a review of approaches and techniques,” Canadian Journal of Anesthesia, vol. 54, no. 8, pp. 662–674, 2007. View at: Publisher Site | Google Scholar
- Brachial Plexus Injury (BPI) at http://www.hopkinsmedicine.org/neurology_neurosurgery/centers_clinics/peripheral_nerve_surgery/conditions/brachial_plexus_injury_bpi.html.
- S. Fallatah, “Successful management of complex regional pain syndrome type 1 using single injection interscalene brachial plexus block,” Saudi Journal of Anaesthesia, vol. 8, no. 4, pp. 559–561, 2014. View at: Publisher Site | Google Scholar
- V. Golovchinsky, Double-Crush Syndrome, Springer, Boston, Mass, USA, 2000. View at: Publisher Site
- K. Vermeylen, S. Engelen, L. Sermeus, F. Soetens, and M. Van De Velde, “Supraclavicular brachial plexus blocks: review and current practice,” Acta Anaesthesiologica Belgica, vol. 63, no. 1, pp. 15–21, 2012. View at: Google Scholar
- A. Mian, I. Chaudhry, R. Huang, E. Rizk, R. S. Tubbs, and M. Loukas, “Brachial plexus anesthesia: a review of the relevant anatomy, complications, and anatomical variations,” Clinical Anatomy, vol. 27, no. 2, pp. 210–221, 2014. View at: Publisher Site | Google Scholar
- N. Pratt, “Anatomy of nerve entrapment sites in the upper quarter,” Journal of Hand Therapy, vol. 18, no. 2, pp. 216–229, 2005. View at: Publisher Site | Google Scholar
- J. Van Zundert, M. Huntoon, J. Patijn, A. Lataster, N. Mekhail, and M. Van Kleef, “Cervical radicular pain,” Pain Practice, vol. 10, no. 1, pp. 1–17, 2010. View at: Publisher Site | Google Scholar
- S. M. Klein, K. C. Nielsen, N. Ahmed, C. C. Buckenmaier III, and S. M. Steele, “In situ images of the thoracic paravertebral space,” Regional Anesthesia and Pain Medicine, vol. 29, no. 6, pp. 596–599, 2004. View at: Publisher Site | Google Scholar
- R. K. Batra, K. Krishnan, and A. Agarwal, “Paravertebral block,” Journal of Anaesthesiology Clinical Pharmacology, vol. 27, no. 1, pp. 5–11, 2011. View at: Google Scholar
- J.-G. Song, G.-S. Hwang, H. L. Eun et al., “Effects of bilateral stellate ganglion block on autonomic cardiovascular regulation,” Circulation Journal, vol. 73, no. 10, pp. 1909–1913, 2009. View at: Publisher Site | Google Scholar
- A. Weiss, C. Isselhorst, J. Gahlen et al., “Acute respiratory failure after deep cervical plexus block for carotid endarterectomy as a result of bilateral recurrent laryngeal nerve paralysis,” Acta Anaesthesiologica Scandinavica, vol. 49, no. 5, pp. 715–719, 2005. View at: Publisher Site | Google Scholar
- N. Malek, A. Pajak, N. Kolosowska, M. Kucharczyk, and K. Starowicz, “The importance of TRPV1-sensitisation factors for the development of neuropathic pain,” Molecular and Cellular Neuroscience, vol. 65, pp. 1–10, 2015. View at: Publisher Site | Google Scholar
- H. Bertrand, M. Kyriazis, K. D. Reeves, J. Lyftogt, and D. Rabago, “Topical mannitol reduces capsaicin-induced pain: results of a pilot-level, double-blind, randomized controlled trial,” PM and R, vol. 7, no. 11, pp. 1111–1117, 2015. View at: Publisher Site | Google Scholar
- M. Cui, V. Gosu, S. Basith, S. Hong, and S. Choi, “Polymodal transient receptor potential vanilloid type 1 nocisensor: structure, modulators, and therapeutic applications,” Advances in Protein Chemistry and Structural Biology, vol. 104, pp. 81–125, 2016. View at: Publisher Site | Google Scholar
- L. Chen, B. Tuo, and H. Dong, “Regulation of intestinal glucose absorption by ion channels and transporters,” Nutrients, vol. 8, no. 1, 2016. View at: Publisher Site | Google Scholar
- S. G. Patching, “Glucose transporters at the blood-brain barrier: function, regulation and gateways for drug delivery,” Molecular Neurobiology, vol. 54, no. 2, pp. 1046–1077, 2017. View at: Publisher Site | Google Scholar
- V. F. H. Jensen, A.-M. Mølck, I. B. Bøgh, and J. Lykkesfeldt, “Effect of insulin-induced hypoglycaemia on the peripheral nervous system: focus on adaptive mechanisms, pathogenesis and histopathological changes,” Journal of Neuroendocrinology, vol. 26, no. 8, pp. 482–496, 2014. View at: Publisher Site | Google Scholar
- V. F. H. Jensen, I. B. Bøgh, and J. Lykkesfeldt, “Effect of insulin-induced hypoglycaemia on the central nervous system: evidence from experimental studies,” Journal of Neuroendocrinology, vol. 26, no. 3, pp. 123–150, 2014. View at: Publisher Site | Google Scholar
- S. Pramming, B. Thorsteinsson, B. Stigsby, and C. Binder, “Glycaemic threshold for changes in electroencephalograms during hypoglycaemia in patients with insulin dependent diabetes,” British Medical Journal, vol. 296, no. 6623, pp. 665–667, 1988. View at: Publisher Site | Google Scholar
- M. B. Maclver and D. L. Tanelian, “Activation of C fibers by metabolic perturbations associated with tourniquet ischemia,” Anesthesiology, vol. 76, no. 4, pp. 617–623, 1992. View at: Publisher Site | Google Scholar
- G. J. Bennett, J. M. Chung, M. Honore, and Z. Seltzer, “Models of neuropathic pain in the rat,” Current Protocols in Neuroscience, 2003. View at: Google Scholar
- C. Dejaco, M. Stradner, D. Zauner et al., “Ultrasound for diagnosis of carpal tunnel syndrome: comparison of different methods to determine median nerve volume and value of power Doppler sonography,” Annals of the Rheumatic Diseases, vol. 72, no. 12, pp. 1934–1939, 2013. View at: Publisher Site | Google Scholar
- S. Anjayani, Y. W. Wirohadidjojo, A. M. Adam, D. Suwandi, A. Seweng, and M. D. Amiruddin, “Sensory improvement of leprosy peripheral neuropathy in patients treated with perineural injection of platelet-rich plasma,” International Journal of Dermatology, vol. 53, no. 1, pp. 109–113, 2014. View at: Publisher Site | Google Scholar
Copyright © 2017 Stanley K. H. Lam et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Ilioinguinal and Iliohypogastric Nerve Blockades
The patient lies supine. The landmarks are the umbilicus, ipsilateral anterosuperior iliac spine, and pubic tubercle ( Fig. 49-4 ). A line is drawn between the anterior superior iliac spine and the umbilicus, and another line is drawn between the anterior superior iliac spine and the pubic tubercle both lines are divided into three equal segments. On each line, the site of puncture is located at the junction of the lateral and medial thirds. At both puncture sites, the short bevel needle is inserted at a 50- to 70-degree angle to the skin in an anteroposterior and caudal direction. It is advanced until a loss of resistance is felt, which occurs as the aponeurosis of the external oblique muscle is pierced. After negative aspiration, 5 mL of local anesthetic is injected. The needle is then advanced deeper to pierce the internal oblique muscle aponeurosis, and a similar amount of local anesthetic is administered.
The classic approach can be inaccurate and it is not surprising that ilioinguinal-iliohypogastric nerve blocks yield failure rates of 20% to 30%. 92 Furthermore, severe complications, such as intestinal per-foration, 93 have been reported. The safety and effectiveness of the blocks can be greatly improved by direct visualization with ultrasonography. 94-96 The ultrasound examination should be performed with a high-frequency linear probe. The ilioinguinal nerve is best visualized immediately medial to the anterior superior iliac spine. It is located at a mean distance of 6 mm from this bony landmark. The iliohypogastric nerve is close (less than 1 cm) to the ilioinguinal nerve and both nerves are located close to the peritoneum. 96 The needle is inserted transverse to the ultrasound probe and placed between the obliquus internus abdominis and transversus abdominis muscles. The volume of local anesthetic required to anesthetize both nerves is 0.075 mL/kg in a child 95 or 0.2 mL/kg in an adult, 96 a dose much smaller than that recommended with the blind technique. The ultrasound-guided technique yields a 96% success rate 94,96 and avoids potential complications such as accidental intestinal puncture.
Philosophy of biology used not to pay a great deal of attention to microbes (aka microorganisms) and microbiology. This neglect occurred not because of active bias but simply because of habits gained from contingent influences on the development of the field. For example, the scientists most connected with the expansion of philosophy of biology in the 1960s and 1970s happened to be zoologists and evolutionists (e.g., Ernst Mayr and Richard Lewontin). Their interests and expertise naturally and productively shaped the way in which philosophy of biology made headway throughout the 1980s and 1990s (see the entry on philosophy of biology). 
But once the field was strong and thriving, a &ldquozoocentric perspective&rdquo on philosophy of biology became hard to justify (O&rsquoMalley and Dupré 2007). In biology, ever-increasing molecular insight into life on Earth disclosed massive roles for microbes, both ecologically and evolutionarily. Philosophically, treating animals and particularly humans as paradigm organisms was recognized as indefensible, except for particular metazoan (i.e., animal) features of philosophical interest thought to have no microbial analogues (e.g., predation, ageing, kin recognition, cognition). 
The tide turned in the mid-2000s, when increasing numbers of philosophers began using microbes as examples, or microbiological science as a source of case studies. Evolutionary, classificatory and phylogenetic issues took up the bulk of this new attention (Franklin-Hall 2007 Ereshefsky 2010 Velasco 2010), which expanded to include questions about individuality (Dupré and O&rsquoMalley 2007 Ereshefsky & Pedroso 2013) and the origins and nature of life in its earliest microbial forms (Cleland 2007 Parke 2013). New topics that refer to microbes these days include even the evolution of mind and subjectivity (Godfrey-Smith 2016 Allen 2017). It is now fairly mainstream to mention microbes or use microbiological case material in philosophical discussions of any sort of biological phenomenon.
A clarification necessary at the outset is that none of this work depends on or justifies drawing a hard line between microbes and non-microbes. Life is not most effectively divided into two obvious groups of microbes and macrobes, nor unicellular and multicellular organisms (see Table 1). These are terms of pure convenience, with many exceptions (O&rsquoMalley 2014). Older &ldquokingdom&rdquo perspectives identified at least two kinds of microorganisms (bacteria and protists), plus three kinds of multicellular organisms (plants, fungi, and animals) (Whittaker 1969). Subsequent classifications expanded the category to which bacteria belong, and sometimes continued to conflate them with a superficially similar group of organisms now called Archaea (e.g., Margulis 1996). From cell-biological and evolutionary perspectives, however, lumping Bacteria and Archaea together as one kind of life is seriously misleading (Woese 1994 Pace 2006 Embley & Williams 2015 Table 1).
|Term||Usage/definition||Issues and context|
|Microorganism, microbe (informal)||Unicellular organism sometimes any organism viewed microscopically||Many microbes form multicellular colonies or structured consortia some single cells are visible (e.g., slime moulds) no classificatory or evolutionary basis|
|Macroorganism, macrobe (very informal)||Multicellular organism sometimes any organism visible without a microscope||Most multicellular organisms are occupied by unicellular ones some multicellular organisms are microscopic (e.g., tardigrades) no classificatory or evolutionary basis|
|Bacteria (informally bacteria (not in title case), singular bacterium), for a short while called eubacteria (still popular in some accounts) colloquially known as &lsquogerms&rsquo||Domain-level category of life that includes dozens of phyla of bacteria||Takes off as a term for the smallest unicellular organisms in the mid-nineteenth century included Archaea until their identification in the 1970s|
|Archaea (informally archaea (not in title case), singular archaeon), previously archaebacteria (still used in some accounts)||Domain-level category of life that includes several major branches, of which eukaryotes are now widely believed to be one||Considered by some systematists not to be sufficiently important to be a domain of equal status to eukaryotes questions now about whether eukaryotes are part of Archaea or a new domain derived from it.|
|Prokaryote (informal)||Older term of convenience often used to mean non-eukaryote cells without classic nucleus and other compartments||No evolutionary basis obscures major evolutionary divergence of Bacteria and Archaea potentially emphasizes the mere absence of eukaryote features|
|Eukaryote (informally eukaryote(s)), sometimes Eukaryota/Eucaryota or Eukarya/Eucarya||Cells with nucleus and other compartments, including mitochondria (not obligatory to definition) includes kingdom-level groups of animals, plants and algae, fungi, and protists||Not clear this distinctive cell type is best considered a domain may be an important diversification within Archaea traditional kingdom categories do not capture the mostly microbial nature of eukaryotes.|
|Protist (informal), previously Protista, Proctoctista etc (includes protozoa)||Unicellular eukaryotes of mixed lineages can include fungi and multicellular algae. Classic examples are pathogens (e.g., Giardia) and photosynthesizers (e.g., algae)||Most eukaryotes are protists of one sort or another.|
|Virus||Non-cellular replicators using either eukaryotic or archaeal cells to reproduce not microorganismal, but often included in casual discussions of microbes||Despite not being cellular or self-replicating without a host, and thus not &lsquoliving&rsquo by most accounts, it is difficult to understand microbial life without paying attention to viruses.|
|Bacteriophage, phage||Non-cellular replicators using bacterial cells to reproduce not microorganismal, but often included in casual discussions of microbes||Despite not being cellular or self-replicating without a host, and thus not &lsquoliving&rsquo by most accounts, it is difficult to understand bacterial life without paying attention to phages.|
|&lsquoLower organism&rsquo: antiquated terminology for small and less apparently complex lifeforms||Persists in non-microbiological discussions of microbes||Not validated by any biological or evolutionary approach tends to imply great-chain-of-being progressivism.|
|&lsquoHigher organism&rsquo: similarly antiquated terminology for large and more obviously complex organisms||Persists in zoology, botany, and some broader communication of biology (see Rigato & Minelli 2013)||Not validated by any biological or evolutionary approach tends to imply great-chain-of-being progressivism.|
Table 1: serves as a glossary for subsequent sections. It shows some of the historical terminology and classifications of microbes, plus issues with various terms and categories.
Recognizing the looseness of the terms used to designate microbes does not mean, however, that either the study or impact of microorganisms is incoherent or disconnected. Unicellular life forms&mdashorganisms with the ability to live and reproduce as a single cell most (but not necessarily all) of the time  &mdashare often argued to have large biological spheres of action and thus implications for all living things.
Studying for my Christian Ed exam, someone please debunk these statements.
Science is just beginning to understand that parts of the body that were once thought to be unnecessary are vitally important.At one point in time, there were about 180 parts of the body that evolutionist classified as vestigial, or serving no useful purpose today . Now scientist realize that there are no useful vestigial organs, only organs only organs that we do not fully understand.
Twenty years ago tonsillectomies were commonly done but today they are not performed as readily. Science has discovered that the liver alone has over 500 important functions in the human body.
Our nose is thought to be what causes us to shift position throughout tonight as we sleep. Without it we would wake up sore from sleeping in the same position all night
Taken from the book Bible Doctrines for Today. I know this is really r/askscience question but I found it to be to asinine to post there.