The rat L 5 dorsal root ganglion (DRG) was chronically compressed by inserting a hollow perforate... more The rat L 5 dorsal root ganglion (DRG) was chronically compressed by inserting a hollow perforated rod into the intervertebral foramen. The DRG was constantly perfused through the hollow rod with either lidocaine or normal saline delivered by a subcutaneous osmotic pump. Behavioral evidence for neuropathic pain after DRG compression involved measuring the incidence of hindlimb withdrawals to both punctate indentations of the hind paw with mechanical probes exerting different bending forces (hyperalgesia) and to light stroking of the hind paw with a cotton wisp (tactile allodynia). Behavioral results showed that for saline-treated control rats: the withdrawal thresholds for the ipsilateral and contralateral paws to mechanical stimuli decreased significantly after surgery and the incidence of foot withdrawal to light stroking significantly increased on both ipsilateral and contralateral hind paws. Local perfusion of the compressed DRG with 2% lidocaine for 7 days at a low flow-rate (1 l/h), or for 1 day at a high flow-rate (8 l/h) partially reduced the decrease in the withdrawal thresholds on the ipsilateral foot but did not affect the contralateral foot. The incidence of foot withdrawal in response to light stroking with a cotton wisp decreased significantly on the ipsilateral foot and was completely abolished on the contralateral foot in the lidocaine treatment groups. This study demonstrated that compression of the L 5 DRG induced a central pain syndrome that included bilateral mechanical hyperalgesia and tactile allodynia. Results also suggest that a lidocaine block, or a reduction in abnormal activity from the compressed ganglia to the spinal cord, could partially reduce mechanical hyperalgesia and tactile allodynia.
Local perfusion of the dorsal root ganglion (DRG) with tumor necrosis factor ␣ (TNF-␣) in rats in... more Local perfusion of the dorsal root ganglion (DRG) with tumor necrosis factor ␣ (TNF-␣) in rats induces cutaneous hypersensitivity to mechanical stimuli. Thus we investigated the cellular mechanisms of TNF-␣-induced mechanical hyperalgesia. The L 4 and L 5 DRGs with the sciatic nerves attached were excised from rats for in vitro dorsal root microfilament recording. After baseline recording for 15 min, TNF-␣ (0.001, 0.01, 0.1, or 1 ng/ml) was applied to the DRG for 15 min, followed by washout for at least 30 min. Alternatively, H-89 or Rp-cAMPS, two specific cAMP-dependent protein kinase (PKA) inhibitors, was added to the perfusion solution for 15 min prior to TNF-␣ application. TNF-␣ (1 ng/ml) induced neuronal discharges in 67% (14/21) of C fibers and 27% (4/15) of A fibers when applied topically to the DRG. Acute TNF-␣ application not only evoked discharges in silent fibers, but also enhanced ongoing activity of spontaneously active fibers and increased neuronal sensitivity to electrical stimulation of the peripheral nerves. H-89 (10 M) and Rp-cAMPS (100 M) each completely blocked the TNF-␣-evoked response in most C and A fibers tested but did not affect fiber conductivity. Our results demonstrates that exogenous inflammatory cytokines such as TNF-␣ can elicit a PKAdependent response in sensory neurons and thus strongly suggest that endogenous TNF-␣ may contribute to the development of certain pathological pain states.
hile generally considered low-risk procedures, gastrointestinal (GI) endoscopy, and specifically ... more hile generally considered low-risk procedures, gastrointestinal (GI) endoscopy, and specifically endoscopic retrograde cholangiopancreatography (ERCP), can be associated with life-threatening complications such as vascular air embolism (VAE). As with many other procedures associated with uncommon, yet devastating complications, limited data exist to clarify the incidence, mechanisms, or mitigation strategies for the occurrence of VAE. To the initial question, Afreen et al 1 have provided intriguing evidence that VAE occurs in nearly 2.5% of ERCP patients. Moreover, half of these VAE events are associated with measurable hemodynamic perturbations, potentially including hypotension, decreased cardiac output, and even cardiovascular collapse. Given that the number of reports of this complication associated with ERCP in both the anesthesiology and GI literature is limited, 3-7 one might erroneously conclude that VAE is a rare event. The current study by Afreen et al 1 indicates otherwise, and their observational analysis leaves other vital questions unanswered:
T he article by McLean et al.2 builds on a burgeoning body of literature that for more than 50 yr... more T he article by McLean et al.2 builds on a burgeoning body of literature that for more than 50 yr has described potential complications associated with the use of neuromuscular-blocking agents (NMBAs). There seem to be two themes: The first irrefutable finding is affirmation that the use of NMBAs is associated with postoperative residual weakness that may lead to significant morbidity and, rarely, mortality. Although the second theme is also supported by good science, it is more controversial as it appears to “fly in the face” of the typical anesthesiologist who feels that administration of neostigmine to induce pharmacologic reversal is routinely and reliably sufficient to ensure adequate postoperative neuromuscular function (and thus avoid respiratory complications). however, both the anesthesia and the critical care medicine literature is replete with studies documenting that with or without neostigmine, a significant proportion of our patients exhibits significant residual neuromuscular block (defined as train-of-four [TOF] ratio <0.90) when tested objectively in the postanesthesia care unit (PACU).3 In a sense, NMBAs are similar to opioids—they are both “life-saving” and “complicationproducing” drugs. When used appropriately, NMBAs allow the performance of surgical procedures that would be much more difficult and sometimes impossible without the induced paralysis. Similarly, opioids allow the performance of surgical procedures that would otherwise induce a more significant physiologic trespass with increased risks and complications. But both NMBAs and opioids have significant, sometimes deadly, side effects unless monitored appropriately. Monitoring the depth of analgesia and respiratory depression produced by opioids can be difficult, inexact, and unreliable. Unlike opioids, however, the depth of neuromuscular block, and the adequacy of reversal, can and should be measured— easily, predictably, and routinely. We have the technology, and we have the proof—so far, we have just not had the resolve. It is inexplicable that monitoring of the depth of NMBA block and adequacy of pharmacologic reversal are still not used routinely, and several previous editorials have pointed out the lack of understanding of clinicians of, and perhaps interest in, neuromuscular monitoring.4,5 Why should this be? We believe that a host of factors6 provide some explanation and should include medical heuristics. These heuristics are mental shortcuts used to assist our everyday decisionmaking during patient care, but in essence these are educated Reversal of Neuromuscular Blockade
Local anesthetics, such as bupivacaine, have been reported to block calcium currents in primary s... more Local anesthetics, such as bupivacaine, have been reported to block calcium currents in primary sensory neurons and to interfere with the release of neurotransmitters in central nervous system neurons. However, it is unknown whether local anesthetics affect the calcium current activity of central nervous system neurons. Methods: Using a traditional whole cell voltage clamp technique, effects of bupivacaine and ropivacaine on high-voltageactivated calcium currents (HVA-Ic a ) were investigated in enzymatically dissociated dorsal horn neurons of neonatal rats. Calcium currents were evoked by testing pulses from a holding potential of ؊90 to 0 mV. Results: Bupivacaine significantly reduced HVA-Ic a in a dosedependent manner. The peak HVA-Ic a decreased by 24.5 ؎ 2.5, 32.0 ؎ 6.8, 59.4 ؎ 6.2, 88.3 ؎ 1.5, and 91.6 ؎ 1.1% in response to 10, 30, 50, 100 and 200 M bupivacaine, respectively. Unlike bupivacaine, ropivacaine markedly increased HVA-Ic a at lower concentrations (< 50 M) but decreased HVA-Ic a at higher con- centrations (> 50 M). The percent increases in peak HVA-Ic a induced by 10 and 30 M ropivacaine were 95 ؎ 19.1 and 41.6 ؎ 8.3%, respectively. The percent decreases in response to 50, 100, and 200 M ropivacaine were 21.1 ؎ 2.1, 63.2 ؎ 6.0 and 79.1 ؎ 7.6%, respectively. Results indicate that the inhibitory potency of ropivacaine on HVA-Ic a was significantly lower than that of bupivacaine at the same concentrations. Conclusions: The current study showed that bupivacaine inhibited HVA-Ic a recorded from dorsal horn neurons and that ropivacaine increased HVA-Ic a at lower concentrations but decreased HVA-Ic a at higher concentrations. The inhibitory potency of ropivacaine was lower than that of bupivacaine. Inhibition of calcium currents of central nervous system neurons may be related to the systemic neurotoxic effects of local anesthetics (e.g., convulsions, seizures).
Sugammadex, a modified gamma-cyclodextrin, has changed clinical practice of neuromuscular reversa... more Sugammadex, a modified gamma-cyclodextrin, has changed clinical practice of neuromuscular reversal dramatically. With the introduction of this selective relaxant binding agent, rapid and reliable neuromuscular reversal from any depth of block became possible. Sugammadex can reverse neuromuscular blockade without the muscarinic side effects typically associated with the administration of acetylcholinesterase inhibitors. However, what remained unchanged is the incidence of residual neuromuscular blockade. It is known that sugammadex cannot always prevent its occurrence, if appropriate dosing is not chosen based on the level of neuromuscular paralysis prior to administration determined by objective neuromuscular monitoring. Alternatively, excessive doses of sugammadex administered in an attempt to ensure full and sustained reversal may affect the effectiveness of rocuronium in case of immediate reoperation or reintubation. In such emergent scenarios that require onset of rapid and reliable neuromuscular blockade, the summary of product characteristics (package insert) recommends using benzylisoquinolinium neuromuscular blocking agents or a depolarizing agent. However, if rapid intubation is required, succinylcholine has a significant number of side effects, and benzylisoquinolinium agents may not have the rapid onset required. Therefore, prior administration of sugammadex introduces a new set of potential problems that require new solutions. This novel reversal agent thus presents new challenges and anesthesiologists must familiarize themselves with specific issues with its use (e.g., bleeding risk, hypermagnesemia, hypothermia). This review will address sugammadex administration in such special clinical situations.
The current study evaluated the duration and magnitude of post-tetanic effects in 56 patients rec... more The current study evaluated the duration and magnitude of post-tetanic effects in 56 patients recovering from a bolus dose of nondepolarizing relaxant to assess the impact of tetanus on monitoring in a common clinical setting. After induction of general anesthesia (thiopental, fentanyl, oxygen, nitrous oxide, and isoflurane), a baseline response to train-of-four (TOF) stimulation was recorded using an adductor pollicis force transducer, and the ratio of the fourth response (T4) to the first (T1) was calculated. Patients then received a bolus dose of either atracurium 0.50 mg.kg-1 (n = 28) or vecuronium 0.10 mg.kg-1 (n = 28). TOF was recorded at 12-s intervals between 25% and 75% recovery of T1 (time25-75%, first data set); then, block was reestablished with the same agent (atracurium 0.10 or vecuronium 0.02 mg.kg-1), and monitoring of time25-75% was repeated (second data set). Subjects were randomized such that none, one, or both sets had TOF monitoring interrupted by a 5-s, 50-Hz tetanic stimulus at 50% recovery (TET). For each drug, 7 patients were assigned to each of the four possible sequences: no tetanus (NOTET) set followed by NOTET set; NOTET-TET; TET-NOTET; and TET-TET. After either drug, the TET data sets demonstrated significant acceleration of recovery of T1 from 50% to 75% (time50-75%) of its baseline height (P less than 0.05 by paired t test). After atracurium, time50-75% was shortened by the tetanic stimulation from a control of 6.3 +/- 1.1 to 5.0 +/- 1.3 min (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
HE literature is replete with information about perioperative use of neuromuscular blocking agent... more HE literature is replete with information about perioperative use of neuromuscular blocking agents (NMBAs), and recent review articles 1,2 have summarized current knowledge. We know that residual neuromuscular weakness is common, despite advances in the pharmacology of NMBAs; we know that most clinicians believe clinically significant weakness is a rare event; that the use of acceleromyography allows measurement of the intraoperative train-of-four (TOF) ratio; that acceleromyography reduces the incidence of postoperative residual weakness in the postanesthesia care unit (PACU); that TOF less than 0.9 is associated with multiple respiratory events and complications, and with delays in PACU discharge; and that awake volunteers described significant discomfort from residual block, defined as TOF less than 0.90. What we did not know (but perhaps suspected) was whether intraoperative acceleromyography (objective) monitoring would result in less subjective weakness and associated symptoms of residual paresis. In this issue of the journal, Murphy et al. report that objective acceleromyography monitoring reduces unpleasant symptoms of muscle weakness in the PACU and improves quality of patient recovery. This study 5 is unique and important because precise measurement of TOF ratios in the PACU was followed by a standardized examination designed to evaluate patients for signs and symptoms of muscle weakness. Thus, objective criteria (a battery of 11 individual tests) of muscle strength were followed by subjective assessments of symptoms of residual block. These assessments included questions about the "ease" or "comfort" associated with performing the tests. In addition, patients rated five other symptoms of residual weakness: blurry or double vision, facial weakness or numbness, and generalized weakness. This study also confirms another piece of information we already knew: that assessments based on clinical tests of muscle strength (e.g., head lift for 5 s, grip strength) are not reliable predictors of neuromuscular function. The reader may also note that the authors used the accelerograph monitor without previous calibration or normalization. However, the authors did apply preload to the thumb by attaching a hand adapter. Application of a preload is
In dystrophic mice, a model of merosin-deficient congenital muscular dystrophy, laminin-2 mutatio... more In dystrophic mice, a model of merosin-deficient congenital muscular dystrophy, laminin-2 mutations produce peripheral nerve dysmyelination and render Schwann cells unable to sort bundles of axons. The laminin receptor and the mechanism through which dysmyelination and impaired sorting occur are unknown. We describe mice in which Schwann cell-specific disruption of beta1 integrin, a component of laminin receptors, causes a severe neuropathy with impaired radial sorting of axons. Beta1-null Schwann cells populate nerves, proliferate, and survive normally, but do not extend or maintain normal processes around axons. Interestingly, some Schwann cells surpass this problem to form normal myelin, possibly due to the presence of other laminin receptors such as dystroglycan and ␣ 6  4 integrin. These data suggest that PI integrin links laminin in the basal lamina to the cytoskeleton in order for Schwann cells to ensheath axons, and alteration of this linkage contributes to the peripheral neuropathy of congenital muscular dystrophy.
The present study was undertaken to determine whether the discomfort associated with the sequenti... more The present study was undertaken to determine whether the discomfort associated with the sequential bursts of stimuli comprising the two recommended forms of double burst stimulation (DBS) is comparable to that associated with the repetitive stimuli of train-of-four (TOF). Twenty-one un-medicated volunteers rated on a visual analog scale the discomfort associated with randomly applied DBS and TOF stimulations at 20, 30 and 50 mA. All participants were blinded to the mode of stimulation, as well as to the current intensity. At each amperage tested, TOF produced significantly less discomfort than either form of DBS (P < 0.01). Stimulation at 50 mA produced median visual analog scale scores of 7.5, 7.0, and 5.0 for DBS3.2′ DBS3.3′ and TOF, respectively. At 30 mA the corresponding median visual analog scale scores were 4.5, 5.5, and 3.0, whereas at 20 mA the scores were 4.0, 4.5, and 2.0, respectively. Thus, DBS is more uncomfortable than TOF at each current tested; however, in light of reports of its higher sensitivity, DBS may be the preferred means of assessing neuromuscular function in the awake as well as the anesthetized patient when a force transducer and recorder are not readily available.
Sugammadex, a modified γ-cyclodextrin, is the first selective relaxant binding agent. Sugammadex ... more Sugammadex, a modified γ-cyclodextrin, is the first selective relaxant binding agent. Sugammadex forms very tight complexes in a 1:1 ratio with steroidal neuromuscular blocking agents (rocuronium &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; vecuronium &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; pancuronium). This guest-host complex, which exists in equilibrium, is stable because of its very high association rate and very low dissociation rate. Sugammadex has no effect on acetylcholinesterases or on any receptor system in the body, eliminating the need for anticholinergic drugs, which have undesirable adverse effects. Phase I-III trials found that sugammadex can antagonize any level of neuromuscular blockade, including the profound blockade induced by rocuronium, adding flexibility to the use of nondepolarizing relaxants. Sugammadex rapidly clears from most organs. Sugammadex in doses ranging from 2 to 16 mg/kg is recommended, depending of the level of rocuronium- or vecuronium-induced blockade. Common (incidence of 1-10%) adverse effects are similar for sugammadex and placebo, and include anesthetic complications (movement, coughing, grimacing or suckling on the tracheal tube) and cough. The US FDA has had concerns regarding the safety of sugammadex (hypersensitivity and allergic reactions), but upcoming international studies and the drug&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s widespread use in the EU will provide additional information.
The authors evaluated train-of-four (TOF) fade, as quantified by accelography, in response to neu... more The authors evaluated train-of-four (TOF) fade, as quantified by accelography, in response to neurostimulation at currents ranging from 10 to 60 mA. This was done to determine the range of currents over which measurements of fade remain consistent. In 31 patients (ASA Physical Status 1,2, and 3), anesthesia was induced with fentanyl, midazolam, and thiopental and was maintained with isoflurane and 66% nitrous oxide in oxygen. Surface stimulating electrodes were placed over the ulnar nerve, and an acceleration transducer was placed on the thumb. Succinylcholine was administered to facilitate tracheal intubation; after neuromuscular recovery, a bolus of vecuronium (0.01-0.05 mg.kg-1) and an infusion (0.25-1.5 micrograms.kg-1.min-1) were administered. After documentation of a stable TOF ratio, accelographic TOF responses were quantified in response to 200-microseconds stimulation at 10, 15, 20, 30, 40, 50, and 60 mA, in random order. A total of 95 data sets were collected at different depths of blockade. The TOF ratios maintained intercurrent consistency (P = not significant by nonparametric repeated measures analysis of variance), except at currents near the fourth-twitch (T4) threshold current. This inconsistency was eliminated by testing at greater than or equal to 10 mA above threshold. TOF ratios obtained at 10 mA above T4 threshold correlated highly with those at 60 mA (Spearman r value = 0.94). The authors conclude that the TOF ratio is consistent over a wide range of stimulating currents and that testing with submaximal currents can be performed reliably at greater than or equal to 10 mA above the T4 threshold.(ABSTRACT TRUNCATED AT 250 WORDS)
The rat L 5 dorsal root ganglion (DRG) was chronically compressed by inserting a hollow perforate... more The rat L 5 dorsal root ganglion (DRG) was chronically compressed by inserting a hollow perforated rod into the intervertebral foramen. The DRG was constantly perfused through the hollow rod with either lidocaine or normal saline delivered by a subcutaneous osmotic pump. Behavioral evidence for neuropathic pain after DRG compression involved measuring the incidence of hindlimb withdrawals to both punctate indentations of the hind paw with mechanical probes exerting different bending forces (hyperalgesia) and to light stroking of the hind paw with a cotton wisp (tactile allodynia). Behavioral results showed that for saline-treated control rats: the withdrawal thresholds for the ipsilateral and contralateral paws to mechanical stimuli decreased significantly after surgery and the incidence of foot withdrawal to light stroking significantly increased on both ipsilateral and contralateral hind paws. Local perfusion of the compressed DRG with 2% lidocaine for 7 days at a low flow-rate (1 l/h), or for 1 day at a high flow-rate (8 l/h) partially reduced the decrease in the withdrawal thresholds on the ipsilateral foot but did not affect the contralateral foot. The incidence of foot withdrawal in response to light stroking with a cotton wisp decreased significantly on the ipsilateral foot and was completely abolished on the contralateral foot in the lidocaine treatment groups. This study demonstrated that compression of the L 5 DRG induced a central pain syndrome that included bilateral mechanical hyperalgesia and tactile allodynia. Results also suggest that a lidocaine block, or a reduction in abnormal activity from the compressed ganglia to the spinal cord, could partially reduce mechanical hyperalgesia and tactile allodynia.
Local perfusion of the dorsal root ganglion (DRG) with tumor necrosis factor ␣ (TNF-␣) in rats in... more Local perfusion of the dorsal root ganglion (DRG) with tumor necrosis factor ␣ (TNF-␣) in rats induces cutaneous hypersensitivity to mechanical stimuli. Thus we investigated the cellular mechanisms of TNF-␣-induced mechanical hyperalgesia. The L 4 and L 5 DRGs with the sciatic nerves attached were excised from rats for in vitro dorsal root microfilament recording. After baseline recording for 15 min, TNF-␣ (0.001, 0.01, 0.1, or 1 ng/ml) was applied to the DRG for 15 min, followed by washout for at least 30 min. Alternatively, H-89 or Rp-cAMPS, two specific cAMP-dependent protein kinase (PKA) inhibitors, was added to the perfusion solution for 15 min prior to TNF-␣ application. TNF-␣ (1 ng/ml) induced neuronal discharges in 67% (14/21) of C fibers and 27% (4/15) of A fibers when applied topically to the DRG. Acute TNF-␣ application not only evoked discharges in silent fibers, but also enhanced ongoing activity of spontaneously active fibers and increased neuronal sensitivity to electrical stimulation of the peripheral nerves. H-89 (10 M) and Rp-cAMPS (100 M) each completely blocked the TNF-␣-evoked response in most C and A fibers tested but did not affect fiber conductivity. Our results demonstrates that exogenous inflammatory cytokines such as TNF-␣ can elicit a PKAdependent response in sensory neurons and thus strongly suggest that endogenous TNF-␣ may contribute to the development of certain pathological pain states.
hile generally considered low-risk procedures, gastrointestinal (GI) endoscopy, and specifically ... more hile generally considered low-risk procedures, gastrointestinal (GI) endoscopy, and specifically endoscopic retrograde cholangiopancreatography (ERCP), can be associated with life-threatening complications such as vascular air embolism (VAE). As with many other procedures associated with uncommon, yet devastating complications, limited data exist to clarify the incidence, mechanisms, or mitigation strategies for the occurrence of VAE. To the initial question, Afreen et al 1 have provided intriguing evidence that VAE occurs in nearly 2.5% of ERCP patients. Moreover, half of these VAE events are associated with measurable hemodynamic perturbations, potentially including hypotension, decreased cardiac output, and even cardiovascular collapse. Given that the number of reports of this complication associated with ERCP in both the anesthesiology and GI literature is limited, 3-7 one might erroneously conclude that VAE is a rare event. The current study by Afreen et al 1 indicates otherwise, and their observational analysis leaves other vital questions unanswered:
T he article by McLean et al.2 builds on a burgeoning body of literature that for more than 50 yr... more T he article by McLean et al.2 builds on a burgeoning body of literature that for more than 50 yr has described potential complications associated with the use of neuromuscular-blocking agents (NMBAs). There seem to be two themes: The first irrefutable finding is affirmation that the use of NMBAs is associated with postoperative residual weakness that may lead to significant morbidity and, rarely, mortality. Although the second theme is also supported by good science, it is more controversial as it appears to “fly in the face” of the typical anesthesiologist who feels that administration of neostigmine to induce pharmacologic reversal is routinely and reliably sufficient to ensure adequate postoperative neuromuscular function (and thus avoid respiratory complications). however, both the anesthesia and the critical care medicine literature is replete with studies documenting that with or without neostigmine, a significant proportion of our patients exhibits significant residual neuromuscular block (defined as train-of-four [TOF] ratio <0.90) when tested objectively in the postanesthesia care unit (PACU).3 In a sense, NMBAs are similar to opioids—they are both “life-saving” and “complicationproducing” drugs. When used appropriately, NMBAs allow the performance of surgical procedures that would be much more difficult and sometimes impossible without the induced paralysis. Similarly, opioids allow the performance of surgical procedures that would otherwise induce a more significant physiologic trespass with increased risks and complications. But both NMBAs and opioids have significant, sometimes deadly, side effects unless monitored appropriately. Monitoring the depth of analgesia and respiratory depression produced by opioids can be difficult, inexact, and unreliable. Unlike opioids, however, the depth of neuromuscular block, and the adequacy of reversal, can and should be measured— easily, predictably, and routinely. We have the technology, and we have the proof—so far, we have just not had the resolve. It is inexplicable that monitoring of the depth of NMBA block and adequacy of pharmacologic reversal are still not used routinely, and several previous editorials have pointed out the lack of understanding of clinicians of, and perhaps interest in, neuromuscular monitoring.4,5 Why should this be? We believe that a host of factors6 provide some explanation and should include medical heuristics. These heuristics are mental shortcuts used to assist our everyday decisionmaking during patient care, but in essence these are educated Reversal of Neuromuscular Blockade
Local anesthetics, such as bupivacaine, have been reported to block calcium currents in primary s... more Local anesthetics, such as bupivacaine, have been reported to block calcium currents in primary sensory neurons and to interfere with the release of neurotransmitters in central nervous system neurons. However, it is unknown whether local anesthetics affect the calcium current activity of central nervous system neurons. Methods: Using a traditional whole cell voltage clamp technique, effects of bupivacaine and ropivacaine on high-voltageactivated calcium currents (HVA-Ic a ) were investigated in enzymatically dissociated dorsal horn neurons of neonatal rats. Calcium currents were evoked by testing pulses from a holding potential of ؊90 to 0 mV. Results: Bupivacaine significantly reduced HVA-Ic a in a dosedependent manner. The peak HVA-Ic a decreased by 24.5 ؎ 2.5, 32.0 ؎ 6.8, 59.4 ؎ 6.2, 88.3 ؎ 1.5, and 91.6 ؎ 1.1% in response to 10, 30, 50, 100 and 200 M bupivacaine, respectively. Unlike bupivacaine, ropivacaine markedly increased HVA-Ic a at lower concentrations (< 50 M) but decreased HVA-Ic a at higher con- centrations (> 50 M). The percent increases in peak HVA-Ic a induced by 10 and 30 M ropivacaine were 95 ؎ 19.1 and 41.6 ؎ 8.3%, respectively. The percent decreases in response to 50, 100, and 200 M ropivacaine were 21.1 ؎ 2.1, 63.2 ؎ 6.0 and 79.1 ؎ 7.6%, respectively. Results indicate that the inhibitory potency of ropivacaine on HVA-Ic a was significantly lower than that of bupivacaine at the same concentrations. Conclusions: The current study showed that bupivacaine inhibited HVA-Ic a recorded from dorsal horn neurons and that ropivacaine increased HVA-Ic a at lower concentrations but decreased HVA-Ic a at higher concentrations. The inhibitory potency of ropivacaine was lower than that of bupivacaine. Inhibition of calcium currents of central nervous system neurons may be related to the systemic neurotoxic effects of local anesthetics (e.g., convulsions, seizures).
Sugammadex, a modified gamma-cyclodextrin, has changed clinical practice of neuromuscular reversa... more Sugammadex, a modified gamma-cyclodextrin, has changed clinical practice of neuromuscular reversal dramatically. With the introduction of this selective relaxant binding agent, rapid and reliable neuromuscular reversal from any depth of block became possible. Sugammadex can reverse neuromuscular blockade without the muscarinic side effects typically associated with the administration of acetylcholinesterase inhibitors. However, what remained unchanged is the incidence of residual neuromuscular blockade. It is known that sugammadex cannot always prevent its occurrence, if appropriate dosing is not chosen based on the level of neuromuscular paralysis prior to administration determined by objective neuromuscular monitoring. Alternatively, excessive doses of sugammadex administered in an attempt to ensure full and sustained reversal may affect the effectiveness of rocuronium in case of immediate reoperation or reintubation. In such emergent scenarios that require onset of rapid and reliable neuromuscular blockade, the summary of product characteristics (package insert) recommends using benzylisoquinolinium neuromuscular blocking agents or a depolarizing agent. However, if rapid intubation is required, succinylcholine has a significant number of side effects, and benzylisoquinolinium agents may not have the rapid onset required. Therefore, prior administration of sugammadex introduces a new set of potential problems that require new solutions. This novel reversal agent thus presents new challenges and anesthesiologists must familiarize themselves with specific issues with its use (e.g., bleeding risk, hypermagnesemia, hypothermia). This review will address sugammadex administration in such special clinical situations.
The current study evaluated the duration and magnitude of post-tetanic effects in 56 patients rec... more The current study evaluated the duration and magnitude of post-tetanic effects in 56 patients recovering from a bolus dose of nondepolarizing relaxant to assess the impact of tetanus on monitoring in a common clinical setting. After induction of general anesthesia (thiopental, fentanyl, oxygen, nitrous oxide, and isoflurane), a baseline response to train-of-four (TOF) stimulation was recorded using an adductor pollicis force transducer, and the ratio of the fourth response (T4) to the first (T1) was calculated. Patients then received a bolus dose of either atracurium 0.50 mg.kg-1 (n = 28) or vecuronium 0.10 mg.kg-1 (n = 28). TOF was recorded at 12-s intervals between 25% and 75% recovery of T1 (time25-75%, first data set); then, block was reestablished with the same agent (atracurium 0.10 or vecuronium 0.02 mg.kg-1), and monitoring of time25-75% was repeated (second data set). Subjects were randomized such that none, one, or both sets had TOF monitoring interrupted by a 5-s, 50-Hz tetanic stimulus at 50% recovery (TET). For each drug, 7 patients were assigned to each of the four possible sequences: no tetanus (NOTET) set followed by NOTET set; NOTET-TET; TET-NOTET; and TET-TET. After either drug, the TET data sets demonstrated significant acceleration of recovery of T1 from 50% to 75% (time50-75%) of its baseline height (P less than 0.05 by paired t test). After atracurium, time50-75% was shortened by the tetanic stimulation from a control of 6.3 +/- 1.1 to 5.0 +/- 1.3 min (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
HE literature is replete with information about perioperative use of neuromuscular blocking agent... more HE literature is replete with information about perioperative use of neuromuscular blocking agents (NMBAs), and recent review articles 1,2 have summarized current knowledge. We know that residual neuromuscular weakness is common, despite advances in the pharmacology of NMBAs; we know that most clinicians believe clinically significant weakness is a rare event; that the use of acceleromyography allows measurement of the intraoperative train-of-four (TOF) ratio; that acceleromyography reduces the incidence of postoperative residual weakness in the postanesthesia care unit (PACU); that TOF less than 0.9 is associated with multiple respiratory events and complications, and with delays in PACU discharge; and that awake volunteers described significant discomfort from residual block, defined as TOF less than 0.90. What we did not know (but perhaps suspected) was whether intraoperative acceleromyography (objective) monitoring would result in less subjective weakness and associated symptoms of residual paresis. In this issue of the journal, Murphy et al. report that objective acceleromyography monitoring reduces unpleasant symptoms of muscle weakness in the PACU and improves quality of patient recovery. This study 5 is unique and important because precise measurement of TOF ratios in the PACU was followed by a standardized examination designed to evaluate patients for signs and symptoms of muscle weakness. Thus, objective criteria (a battery of 11 individual tests) of muscle strength were followed by subjective assessments of symptoms of residual block. These assessments included questions about the "ease" or "comfort" associated with performing the tests. In addition, patients rated five other symptoms of residual weakness: blurry or double vision, facial weakness or numbness, and generalized weakness. This study also confirms another piece of information we already knew: that assessments based on clinical tests of muscle strength (e.g., head lift for 5 s, grip strength) are not reliable predictors of neuromuscular function. The reader may also note that the authors used the accelerograph monitor without previous calibration or normalization. However, the authors did apply preload to the thumb by attaching a hand adapter. Application of a preload is
In dystrophic mice, a model of merosin-deficient congenital muscular dystrophy, laminin-2 mutatio... more In dystrophic mice, a model of merosin-deficient congenital muscular dystrophy, laminin-2 mutations produce peripheral nerve dysmyelination and render Schwann cells unable to sort bundles of axons. The laminin receptor and the mechanism through which dysmyelination and impaired sorting occur are unknown. We describe mice in which Schwann cell-specific disruption of beta1 integrin, a component of laminin receptors, causes a severe neuropathy with impaired radial sorting of axons. Beta1-null Schwann cells populate nerves, proliferate, and survive normally, but do not extend or maintain normal processes around axons. Interestingly, some Schwann cells surpass this problem to form normal myelin, possibly due to the presence of other laminin receptors such as dystroglycan and ␣ 6  4 integrin. These data suggest that PI integrin links laminin in the basal lamina to the cytoskeleton in order for Schwann cells to ensheath axons, and alteration of this linkage contributes to the peripheral neuropathy of congenital muscular dystrophy.
The present study was undertaken to determine whether the discomfort associated with the sequenti... more The present study was undertaken to determine whether the discomfort associated with the sequential bursts of stimuli comprising the two recommended forms of double burst stimulation (DBS) is comparable to that associated with the repetitive stimuli of train-of-four (TOF). Twenty-one un-medicated volunteers rated on a visual analog scale the discomfort associated with randomly applied DBS and TOF stimulations at 20, 30 and 50 mA. All participants were blinded to the mode of stimulation, as well as to the current intensity. At each amperage tested, TOF produced significantly less discomfort than either form of DBS (P < 0.01). Stimulation at 50 mA produced median visual analog scale scores of 7.5, 7.0, and 5.0 for DBS3.2′ DBS3.3′ and TOF, respectively. At 30 mA the corresponding median visual analog scale scores were 4.5, 5.5, and 3.0, whereas at 20 mA the scores were 4.0, 4.5, and 2.0, respectively. Thus, DBS is more uncomfortable than TOF at each current tested; however, in light of reports of its higher sensitivity, DBS may be the preferred means of assessing neuromuscular function in the awake as well as the anesthetized patient when a force transducer and recorder are not readily available.
Sugammadex, a modified γ-cyclodextrin, is the first selective relaxant binding agent. Sugammadex ... more Sugammadex, a modified γ-cyclodextrin, is the first selective relaxant binding agent. Sugammadex forms very tight complexes in a 1:1 ratio with steroidal neuromuscular blocking agents (rocuronium &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; vecuronium &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; pancuronium). This guest-host complex, which exists in equilibrium, is stable because of its very high association rate and very low dissociation rate. Sugammadex has no effect on acetylcholinesterases or on any receptor system in the body, eliminating the need for anticholinergic drugs, which have undesirable adverse effects. Phase I-III trials found that sugammadex can antagonize any level of neuromuscular blockade, including the profound blockade induced by rocuronium, adding flexibility to the use of nondepolarizing relaxants. Sugammadex rapidly clears from most organs. Sugammadex in doses ranging from 2 to 16 mg/kg is recommended, depending of the level of rocuronium- or vecuronium-induced blockade. Common (incidence of 1-10%) adverse effects are similar for sugammadex and placebo, and include anesthetic complications (movement, coughing, grimacing or suckling on the tracheal tube) and cough. The US FDA has had concerns regarding the safety of sugammadex (hypersensitivity and allergic reactions), but upcoming international studies and the drug&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s widespread use in the EU will provide additional information.
The authors evaluated train-of-four (TOF) fade, as quantified by accelography, in response to neu... more The authors evaluated train-of-four (TOF) fade, as quantified by accelography, in response to neurostimulation at currents ranging from 10 to 60 mA. This was done to determine the range of currents over which measurements of fade remain consistent. In 31 patients (ASA Physical Status 1,2, and 3), anesthesia was induced with fentanyl, midazolam, and thiopental and was maintained with isoflurane and 66% nitrous oxide in oxygen. Surface stimulating electrodes were placed over the ulnar nerve, and an acceleration transducer was placed on the thumb. Succinylcholine was administered to facilitate tracheal intubation; after neuromuscular recovery, a bolus of vecuronium (0.01-0.05 mg.kg-1) and an infusion (0.25-1.5 micrograms.kg-1.min-1) were administered. After documentation of a stable TOF ratio, accelographic TOF responses were quantified in response to 200-microseconds stimulation at 10, 15, 20, 30, 40, 50, and 60 mA, in random order. A total of 95 data sets were collected at different depths of blockade. The TOF ratios maintained intercurrent consistency (P = not significant by nonparametric repeated measures analysis of variance), except at currents near the fourth-twitch (T4) threshold current. This inconsistency was eliminated by testing at greater than or equal to 10 mA above threshold. TOF ratios obtained at 10 mA above T4 threshold correlated highly with those at 60 mA (Spearman r value = 0.94). The authors conclude that the TOF ratio is consistent over a wide range of stimulating currents and that testing with submaximal currents can be performed reliably at greater than or equal to 10 mA above the T4 threshold.(ABSTRACT TRUNCATED AT 250 WORDS)
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