Neostigmine Antagonism Research Articles

The Incidence of Residual Neuromuscular Block in Pediatrics: A Prospective, Pragmatic, Multi-institutional Cohort Study.

Introduction Residual neuromuscular block, defined as a quantitatively measured train-of-four ratio (TOFr) <0.9, is common postoperatively.Using a pragmatic trial design, we hypothesized that qualitative and/or clinical assessment of neuromuscular block would inadequately detect residual block following antagonism with neostigmine or sugammadex. Method After IRB approval and written informed consent, 74 children (aged 2-17 years), undergoing elective surgery and receiving rocuronium, were prospectively enrolled in the study at Children's Hospital Colorado and Children's Healthcare of Atlanta. Routine clinical practice at both institutions consisted of clinical signs and/or qualitative assessment with peripheral nerve stimulators. Children at the Colorado hospitalroutinely received sugammadex antagonism; whereas children at the Atlanta hospital received neostigmine. Residual neuromuscular block was assessed postoperatively using quantitative electromyography. If TOFr was <0.9, patients received sugammadex until TOFr ≥0.9. Result Qualitative and clinical assessment failed to detect residual block in 29.7% of patients in the neostigmine reversal cohort (adjusted odds ratio (aOR) 29.8, 95% confidence interval (CI): 2.7 to 5,559.5, p-value = 0.002). No residual block was detected in the sugammadex reversal cohort. A correlation between increasing patient weight and incidence of postoperative residual block was observed in the neostigmine cohort (aOR 1.05, 95% CI: 1.02 to 1.10, p-value = 0.002). Conclusion Qualitative and/or clinical assessment of neuromuscular block inadequately detects residual block following neostigmine antagonism.

Predictive study of pharmacological reversal for residual neuromuscular blockade and postoperative pulmonary complications: a prospective, observational, cohort study

In recent years, some studies have generated controversy since they conclude that intraoperatively pharmacological reversal of neuromuscular blockade does not contribute to the reduction of postoperative residual neuromuscular blockade or pulmonary complications. Therefore, the main objective of this study was to assess the incidence of residual neuromuscular blockade and postoperative pulmonary complications according to spontaneous or pharmacological neuromuscular reversal. The secondary aim was to present a prognostic model to predict the probability of having postoperative residual neuromuscular blockade depending on a patient's comorbidities and intraoperative neuromuscular blocking agents management. A single-center, prospective, observational cohort study including patients undergoing surgical procedures with general anesthesia was designed. A total of 714 patients were analyzed. Patients were divided into four groups: cisatracurium with spontaneous reversal, cisatracurium with neostigmine antagonism, rocuronium with spontaneous reversal, and rocuronium with sugammadex antagonism. According to our binomial generalized linear model, none of the studied comorbidities was a predisposing factor for an increase in the residual neuromuscular blockade. However, in our study, pharmacological reversal of rocuronium with sugammadex and, particularly, neuromuscular monitoring during surgery were the factors that most effectively reduced the risk of residual neuromuscular blockade as well as early and late postoperative pulmonary complications.

Neostigmine antagonism of morphine's effects on intestinal transit.

Journal Article Neostigmine antagonism of morphine's effects on intestinal transit Get access John J Stewart John J Stewart Department of Pharmacology and Therapeutics, Louisiana State University Medical Center, Shreveport, Louisiana 71130, U.S.A. Search for other works by this author on: Oxford Academic Google Scholar Journal of Pharmacy and Pharmacology, Volume 34, Issue 6, June 1982, Pages 405–407, https://doi.org/10.1111/j.2042-7158.1982.tb04743.x Published: 12 April 2011 Article history Received: 08 October 1981 Published: 12 April 2011

The Neuromuscular Pharmacodynamics for Rocuronium at the Adductor Pollicis and the Flexor Hallucis Brevis Muscle

Background: Neuromuscular block is commonly monitored using the adductor pollicis (AP) because of its easy access. However, the hand may not always be accessible for neuromuscular monitoring during surgery. In that situation, monitoring of the flexor hallucis brevis (FHB) secondary to stimulation of the tibial nerve at the ankle joint may be used as an alternative. Methods: During propofol and remifentanil anesthesia, acceleromyography of the thumb and big toe were recorded. Single twitch responses were measured simultaneously after cumulative administration of rocuronium from 80 to 200μg/kg at intervals of 40μg/kg. Furthermore, the amount of rocuronium required for 50% and 95% twitch height depression were calculated. Rocuronium was infused continuously to maintain 5% to 15% twitch responses. We also obtained the onset, duration of action, and antagonism effect of neostigmine from both muscles via neostigmine (20μg/kg) administration. Results: ED50 and ED95 were significantly lower in the AP than in the FHB. The highest twitch response at peak and neostigmine antagonism were significantly higher in the FHB than in the AP. However, there was no significant difference in the onset time or duration of neostigmine between AP and FHB. Conclusions: Due to its resistance to rocuronium, the onset of FHB is not a good indicator of optimal conditions for tracheal intubation. Also, because of its higher antagonism effect, there is potential risk of overlooking a residual block. Sufficient recovery of the block should be readjusted to estimate recovery in the FHB with the use of other reliable clinical tests.

Antagonism of profound cisatracurium and rocuronium block: the role of objective assessment of neuromuscular function

Study Objective The purpose of this study is to determine the incidence of significant (train-of-four [TOF] ratio <0.70), but clinically undetectable (TOF ratio >0.40), residual neuromuscular block after neostigmine antagonism of profound cisatracurium (CIS) or rocuronium (ROC) block. Design Prospective, randomized, open-label study. Setting University hospital. Patients Forty ASA physical status I and II undergoing elective surgical procedures. Interventions Anesthesia was induced with propofol 1.5 to 2.5 mg/kg IV plus fentanyl 2 to 4 μg/kg and maintained with N 2O/desflurane plus narcotic supplementation. The electromyographic response of the adductor pollicis was recorded. Train-of-four stimulation was given every 20 seconds. Twitch height (T1) and TOF fade ratio were continuously recorded. In group 1 (n = 20), neuromuscular block was induced with CIS 0.10 mg/kg, and T1 was maintained at 5% of control by a constant infusion of CIS until the end of surgery. One minute after the termination of the infusion, neostigmine 0.05 mg/kg was administered. T1 and TOF values were monitored continuously for the next 20 minutes. Group 2 (n = 20) is identical to group 1 except that the initial drug was ROC 0.60 mg/kg, and paralysis was maintained with an infusion of ROC. Measurements and Main Results There were no significant differences in the recovery patterns of CIS vs ROC. The duration (bolus to end of infusion) in both groups averaged 2.7 hours, and the mean cumulative dose of relaxant approximated 4 × the ED 95. T1 at the time of reversal was 6% (4%-10%) of control. Mean TOF ratios at 10, 15, and 20 minutes were 0.55, 0.71, and 0.0.81, respectively. Return to a TOF ratio >0.40 was always achieved in 15 minutes or less. However, at 20 minutes postreversal, 5 of 40 subjects had TOF ratios <0.70 and only 11 individuals had recovered to a TOF ratio of 0.90 or greater. Conclusions Most clinicians cannot detect tactile fade once the TOF ratio exceeds 0.40. When reversing profound block, an objective monitor of neuromuscular function is required if the extent of residual block is to be assessed with any confidence.

Criteria of adequate clinical recovery from neuromuscular block.

This study was undertaken to compare the sensitivities of the train-of-four response (2 Hz for 2 s), the single twitch (0.15 Hz), and the tetanic response (50 Hz for 5 s) as indices of residual nondepolarizing block. Spontaneous or induced recovery of evoked thumb adduction in response to ulnar nerve stimulation was studied. One hundred and seven adult surgical patients were divided according to the relaxant used, into six groups. We found that when the single twitch recovered to control height, the train-of-four ratio was well below 1.0. This ratio was significantly lower during spontaneous recovery than following neostigmine antagonism of the block (P < 0.01). The tetanic response was fully sustained when the train-of-four ratio was above 0.7. When the ratio was less than 0.7, variable degrees of fade of tetanus were evident. Analysis of variance indicated similar train-of-four ratios among the six groups at complete recovery of the single twitch irrespective of the relaxant technique used (P < 0.1). It is concluded that a train-of-four ratio of 0.7 or higher reliably indicates the recovery of the single twitch to control height and a sustained response to tetanic stimulation at 50 Hz for 5 s. The clinical significance of this study is as follows: the train-of-four response provides the same indication of clinical recovery from nondepolarizing block as obtained from tetanic stimulation at a physiological frequency; and reliance on the recovery of the single twitch to control height as a criterion of spontaneous return to normal clinical neuromuscular function may be misleading.

Dose-response relationships for neostigmine antagonism of rocuronium-induced neuromuscular block in children and adults

Dose-response relationships for the antagonism of intermediate-acting neuromuscular blocking agents have not been evaluated previously in children. We have examined the dose-response relationships for neostigmine antagonism of 90% rocuronium-induced neuromuscular block in children and adults, during nitrous oxide-1 MAC of isoflurane anaesthesia. We studied 40 children, aged 2-10 yr, and 50 adults, aged 18-60 yr; all received a single bolus dose of rocuronium 0.6 mg kg-1 and accelerometry was used to monitor neuromuscular transmission. When the first twitch of the train-of-four (TOF) response (T1) recovered to 10% of its control (T0), one of five doses of neostigmine 0, 5, 10, 20 or 50 micrograms kg-1 was given by random allocation to each of the study groups (n = 8 children and n = 10 adults). Recovery of T1 and TOF ratio (T4/T1%) was recorded for 10 min after initial administration of neostigmine. Onset time of rocuronium-induced block was faster in children than in adults (mean 64.6 (95% confidence intervals 57.7-71.5) s vs 83.7 (70.7-96.6) s; P < 0.05). The time to 10% recovery of T1/T0 was shorter in children than in adults (25.4 (22.9-27.9) min vs 38.8 (36.1-41.4) min; P < 0.001). Spontaneous and antagonist-assisted recovery were more rapid in children than in adults. Adequate recovery (T4/T1 of 80%) occurred in children at 4, 5 and 8 min after neostigmine 50, 20 and 10 micrograms kg-1, respectively. Adequate recovery was not produced in adults by any dose of neostigmine within 10 min. The effective doses of neostigmine required to achieve a TOF ratio of 80% (ED80) after 10 min in children and adults were, respectively, 7.10 (5.2-9.8) micrograms kg-1 and 56.56 (45.5-71.9) micrograms kg-1 (P < 0.001). There was no advantage in administering doses of neostigmine greater than 20 micrograms kg-1 to antagonize 90% rocuronium-induced neuromuscular block in children. In contrast, it appeared prudent to use neostigmine 50 micrograms kg-1 or more for adequate antagonism of a similar degree of block in adults.

The Time of Neostigmine Antagonism for the Rapid Recovery of Profound Muscle Relaxation in Rabbits

The Time of Neostigmine Antagonism for the Rapid Recovery of Profound Muscle Relaxation in Rabbits

Inadequate Antagonism of Vecuronium-Induced Neuromuscular Block by Neostigmine During Sevoflurane or Isoflurane Anesthesia

To examine the effects of discontinuing sevoflurane or isoflurane anesthesia (1 minimum alveolar anesthetic concentration [MAC] of end-tidal concentrations, together with 66% N2O/O2) on the reversal of vecuronium-induced neuromuscular blockade (an initial dose = 100 micrograms/kg), the electromyographic response of the abductor digiti minimi was monitored at 20-s intervals after train-of-four (TOF) stimulation of the ulnar nerve in 192 ASA grades I and II patients. When the amplitudes of the first response (T1) had recovered to 10% of the control, neostigmine (0;spontaneous recovery, 10, 20, 30, 40, or 55 micrograms/kg, eight patients each) was given and the ratio of the fourth TOF to the first response (TOFR) was monitored at 1-min intervals for 15 min in the presence of the volatile anesthetics, or after discontinuation of anesthetic administration. Spontaneous TOFR recovery was also assessed in another eight patients who were anesthetized with 66% N2O/O2-fentanyl-diazepam. Adequate antagonisms (TOFR > 75%) were achieved after discontinuation of both administrations, but not during anesthetic administration at the neostigmine doses tested. The dose-response curves for neostigmine (10, 20, 30, and 40 micrograms/kg) were constructed using the TOFR values at 5-11 min, from which the ED50 values (a neostigmine dose required for a TOFR value of 50%) were derived. Sevoflurane impaired neostigmine antagonism more than isoflurane, as demonstrated by the significantly higher ED50 values at 7-11 min (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Recovery characteristics after early administration of anticholinesterases during intense mivacurium-induced neuromuscular block

The time course of recovery after early administration of anticholinesterases during intense mivacurium-induced block was evaluated by recording the mechanomyographic response of the adductor pollicis to post-tetanic count (PTC) and train-of-four (TOF) ulnar nerve stimulation. Seventy-two adult patients receiving thiopentone, fentanyl, nitrous oxide, isoflurane anaesthesia and mivacurium 0.15 mg kg-1 were allocated randomly to one of six equal groups according to the type of anticholinesterase and intensity of block at which antagonism was attempted. Groups 1, 3 and 5 received neostigmine 0.07 mg kg-1, while groups 2, 4 and 6 received edrophonium 1 mg kg-1. At the time of administration of antagonist there was no response to PTC in groups 1 and 2, a PTC of 1 or more was detectable in groups 3 and 4 and the first twitch of the TOF (T1) had recovered to 10% in the conventional antagonism groups (5 and 6). The longest clinical duration (CD) values (time from administration of mivacurium to T1 25%) were encountered in groups 1, 5 and 6 and were 17.4 (7.9), 19.7 (3.4) and 21.4 (4.8) min, respectively. CD was reduced significantly in groups 2, 3 and 4 and values were 13.9 (3.5), 13.7 (3.5) and 13.8 (3.3) min, respectively. Recovery indices (RI) (time interval between T1 25% and 75%) were 13.8 (7.3), 6.3 (1.4), 4.6 (1.8), 6.0 (2.1), 3.7 (2.2) and 4.8 (3.1) min in groups 1-6, respectively and was prolonged with neostigmine antagonism at PTC 0 (group 1).(ABSTRACT TRUNCATED AT 250 WORDS)

Dose-Response Relationships for Edrophonium and Neostigmine Antagonism of Pipecuronium-Induced Neuromuscular Block

We have studied the dose-response relationships for neostigmine and edrophonium during antagonism of neuromuscular block induced by pipecuronium bromide. Fifty-six ASA physical status I or II adults were given pipecuronium 70 micrograms/kg during fentanylthiopental-nitrous oxide-halothane anesthesia. Train-of-four (TOF) stimulation was applied to the ulnar nerve every 10 s, and the force of contraction of the adductor pollicis muscle was recorded. When spontaneous recovery of first twitch height reached 20% of its initial control value, edrophonium (0.125, 0.25, 0.75, or 1 mg/kg) or neostigmine (0.015, 0.03, 0.045, or 0.06 mg/kg) was administered by random allocation. Neuromuscular function in another seven subjects was allowed to recover spontaneously. This study demonstrated that the dose-response curves for these two drugs for reversal of first twitch and TOF ratio were not parallel. The doses of neostigmine required to achieve 50% (ED50) and 80% (ED80) recovery of the first twitch after 10 min were 8.5 (7.3-9.7) and 17.4 (16.2-18.7) microgram/kg [mean (95% confidence intervals)], respectively. Corresponding ED50 and ED80 values for endrophonium were 84.1 (72.9-96.9) and 233 (215.7-253.3) microgram/kg, respectively. These values corresponded to neostigmine:edrophonium potency ratios of 9.89 (7.4-12.3) and 13.4 (11.8-14.9) for first twitch ED50 and ED80 height, respectively. The calculated doses producing 50% (ED50) recovery of the TOF ratio at 10 min were 18.8 (17.5-20.2) and 271.3 (246.5-298.6) microgram/kg for neostigmine and edrophonium, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Dose-Response Relationships for Edrophonium and Neostigmine Antagonism of Rocuronium Bromide (ORG 9426)-induced Neuromuscular Blockade

Rocuronium bromide (ORG 9426) is a new nondepolarizing muscle relaxant with a rapid onset but an intermediate duration of action. The dose-response relationships for neostigmine and edrophonium were studied during antagonism of neuromuscular block induced by rocuronium bromide. Sixty-four ASA physical status 1 or 2 adults were given 0.6 mg/kg rocuronium bromide during thiopental-fentanyl-nitrous oxide-isoflurane anesthesia. Train-of-four (TOF) stimulation was applied to the ulnar nerve every 10 s, and the force of contraction of the adductor pollicis muscle was recorded. When spontaneous recovery of first twitch height reached 10% of its initial control value, edrophonium (0.1, 0.2, 0.4, or 1 mg/kg) or neostigmine (0.005, 0.01, 0.02, or 0.05 mg/kg) was administered by random allocation. Neuromuscular function in another eight subjects was allowed to recover spontaneously. Assisted recovery was defined as actual recovery minus mean spontaneous recovery in patients who were not given antagonists. The dose-response curves for neostigmine- and edrophonium-assisted antagonism of rocuronium bromide neuromuscular blockade for the single twitch and TOF ratio were not parallel. The doses of neostigmine required to achieve 50% and 80% recovery (ED50 and ED80, respectively) of the first twitch after 10 min were 0.017 (0.001) and 0.033 (0.001) mg/kg (mean (standard error of estimate for the mean)), respectively. Corresponding ED50 and ED80 values for edrophonium were 0.161 (0.001) and 0.690 (0.001) mg/kg, respectively. These values corresponded to neostigmine:edrophonium potency ratios of 9.5 (0.56) and 21 (0.67) for first twitch ED50 and ED80 height, respectively. The calculated doses producing ED50 of the TOF ratio at 10 min were 0.017 (0.001) and 0.469 (0.001) mg/kg for neostigmine and edrophonium, respectively. These values corresponded to a potency ratio of 27.5 (1.66). Under the conditions described in this study, if reversal was attempted at 10% first twitch recovery, edrophonium was less capable than neostigmine of reversing fade (potency ratio of 19.2 and 27.5 at 5 and 10 min, respectively) than first twitch (potency ratio of 6.7 and 9.5 at 5 and 10 min, respectively) during antagonism of rocuronium bromide-induced blockade. Edrophonium was found to be less effective than neostigmine at reversing rocuronium bromide-induced TOF fade.

Memory modulation with peripherally acting cholinergic drugs.

Physostigmine (PHYSO), in doses as low as 0.003 mg/kg IP, antagonized scopolamine (SCOP, 3 mg/kg) induced amnesia of step-through passive avoidance in mice. The peripherally acting acetylcholinesterase (AChE) inhibitor neostigmine (NEO) was also found to reliably, though less strongly, antagonize the SCOP induced amnesia at a dose of 0.03 mg/kg. The NEO antagonism of the SCOP amnesia could be reversed with SCOP (0.3, 1, and 3 mg/kg) and mecamylamine (MECA, 1, 3, and 10 mg/kg), muscarinic and nicotinic antagonists, respectively, which are active both peripherally and centrally, as well as with M-SCOP (0.3 and 1 mg/kg) and hexamethonium (HEX, 1 and 3 mg/kg), muscarinic and nicotinic antagonists, respectively, which are active only in the periphery. In contrast to the ability of these four compounds to attenuate the SCOP amnesia, only the centrally acting compounds SCOP (3 mg/kg) and MECA (10 mg/kg) induced an amnesia when administered alone. These findings suggest that the induction of amnesia of passive avoidance involves central cholinergic systems, whereas the NEO, and possibly PHYSO, reversal of the SCOP induced amnesia is mediated peripherally by both muscarinic and nicotinic receptors. It is hypothesized that the release of adrenal catecholamines, the influence of which on memory processes is well known, and secondarily glucose, may be responsible for the NEO antagonism of the SCOP amnesia.

Neostigmine antagonism of vecuronium paralysis during fentanyl, halothane, isoflurane, and enflurane anesthesia.

Neostigmine antagonism of vecuronium paralysis during fentanyl, halothane, isoflurane, and enflurane anesthesia.

Neostigmine and Edrophonium Antagonism of Varying Intensity

Neostigmine and Edrophonium Antagonism of Varying Intensity

Neostigmine Antagonism of Succinylcholine Phase II Block

To assess the efficacy of neostigmine antagonism of succinylcholine phase II block, succinylcholine infusions were given to 17 patients for durations varying from 44 to 192 minutes. A control group (17 patients) received a pancuronium infusion for similar times. Ninety per cent neuromuscular block was maintained in these two groups by adjustment of the infusion rates and, in a third group, with intermittent doses of pancuronium. Neuromuscular transmission was monitored with train-of-four stimulation every 12 seconds and anaesthesia was maintained with N2O-O2-enflurane. Ten minutes after the infusion was stopped, atropine and neostigmine were given to all patients who received pancuronium and to 11 patients in the succinylcholine group whose train-of-four ratio (T4/T1) was less than 0.7. During the subsequent 15 minutes, recovery was more rapid in the succinylcholine group than in either the pancuronium-infusion or pancuronium-bolus groups. It is concluded that succinylcholine-induced phase II block can be safely and rapidly antagonized with neostigmine.

Impaired Neostigmine Antagonism of Pancuronium during Enflurane Anaesthesia in Man

Impaired Neostigmine Antagonism of Pancuronium during Enflurane Anaesthesia in Man

A new non-depolarizing myorelaxant with high activity and specificity

The curare-like activity and mode of action of tercuronium (p,p"-bistriethylammonium-p-terphenyl dibenzen-sulphonate) have been investigated in experiments with cats, rabbits, mice and pigeons as well as with rat phrenic diaphragm preparations. The curare-like activity of tercuronium was higher than that of tubocurarine and was close to that of pancuronium bromide. The curare-like activity of tercuronium was higher than that of tubocurarine and was close to that of pancuronium bromide. The neuromuscular blocking doses (ED95) of tercuronium, (+)-tubocurarine and pancuronium in cats, for example, were 0.08 microM/kg, 0.4 microM/kg and 0.04 microM/kg respectively. The time of development and duration of action were similar to those of (+)-tubocurarine and pancuronium. Tercuronium is a nondepolarizing myorelaxant. In experiments with cats the antagonism of neostigmine (0.1 mg/kg) to tercuronium was more pronounced than in the case of (+)-tubocurarine, pancuronium or gallamine. Tercuronium affected neither the arterial pressure nor the heart rate when given in neuromuscular blocking doses. Tercuronium did not block transmission through autonomic ganglia and had no atropine-like action. Only a 10-fold increase in the dose of tercuronium produced the ganglion blocking effect in cats. Under artificial respiration, cats and rabbits tolerated tercuronium in a dose 200 times exceeding its myoparalytic dose. It is concluded that tercuronium is distinguishable from (+)-tubocurarine by its high neuromuscular blocking activity as well as by its specificity and more pronounced neostigmine antagonism.

ACID-BASE BALANCE AND NEOSTIGMINE ANTAGONISM OF PANCURONIUM NEUROMUSCULAR BLOCKADE

In 40 cases anesthetized with chloralose and urethane, pancuronium was infused i.v. at a constant rate to produce and maintain 90% depression twitch tension of the anterior tibialis muscle following supramaximal stimulation of the peroneal nerve. Neither respiratory alkalosis nor metabolic acidosis influenced the infusion rate required to produce 90% depression of twitch tension or antagonism of this depression yb neotigmine. Respiratory acidosis (pH 7.15; PaCO2 10 kPa) did not alter the required infusion rate but did prevent complete antagonism by neostigmine. Metabolic alkalosis (pH 7.65; PaCO2 4.8 kPa) reduced both the required infusion rate and prevented complete restoration of twitch tension by neostigmine. The duration of neostigmine antagonism was shortened by metabolic alkalosis. We conclude that respiratory acidosis and metabolic alkalosis prevent antagonism of pancuronium by neostigmine.

The Effect of Acid–Base Balance on Neostigmine Antagonism of d-Tubocurarine-induced Neuromuscular Blockade

d-Tubocurarine (dTc) was infused intravenously into 35 cats anesthetized with chloralose and urethane at a constant continuous rate to produce and maintain 90 per cent depression of twitch height of the anterior tibial muscle following supramaximal stimulation of the peroneal nerve. The mean infusion rates that produced 90 per cent depression were not significantly altered by respiratory acid-base changes. Metabolic alkalosis decreased (32.5 per cent) and metabolic acidosis increased (27.7 per cent) the required infusion rate of dTc. When pH and Paco2 were maintained at 7.37 and 38 torr, respectively, the addition of a bolus of neostigmine, 10.5 mug/kg, intravenously, to the continuing infusion of dTc produced 50 per cent antagonism of the dTc-depressed twitch. Respiratory alkalosis and metabolic acidosis did not alter the dose of neostigmine needed to produce 50 per cent antagonism. However, during respiratory acidosis (pH 7.13, Paco2 66 torr) and metabolic alkalosis (pH 7.59, Paco2 36 torr) 20.0 and 18.0 mug/kg neostigmine, respectively, were needed to produce 50 per cent antagonism. Still larger doses of neostigmine (75 mug/kg) could not completely antagonize the block unless pH and Paco2 were returned to 7.30-7.50 and 35-45 torr, respectively. It is concluded that respiratory acidosis and metabolic alkalosis limit and oppose antagonism of dTc by neostigmine.