Essay: Definitive control of the airway

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Definitive control of the airway, a skill anaesthesiologists now consider paramount, developed only after many harrowing and apneic episodes spurred the development of safer airway management techniques1[barash pg no 7]. Anaesthesiologists who practised before muscle relaxants recall the anxiety they felt when a premature attempt to intubate the trachea under cyclopropane caused persisting laryngospasm[ barash chapter 1 page 17]
Curare and the drugs that followed transformed anaesthesia profoundly. Because intubation of the trachea could now be taught in a deliberate manner, a neophyte could fail on the first attempt without compromising on the safety of the patient.2 [barash chapter 1 page 17]
Successful clinical use of curare led to the introduction of other muscle relaxants. Succinylcholine was prepared by Nobel laureate Daniel Bovet in 1949 and was in wide international use before historians noted that the drug had been synthesized and tested long beforehand. [barsh chapter 1 page 18]
In the 1970s and 1980s, research shifted towards identification of specific receptor biochemistry and development of receptor specific drugs. From these isoquinolones, four related products emerged : vecuronium, pipecuronium, rocuronium and pancuronium.3 [barash chapter 1 page 18]
With the introduction of endotracheal anaesthesia during World War I and balanced anaesthesia in 1926, a search began for a drug which could cause jaw relaxation to facilitate endotracheal intubation. Most of the intubations were done with inhalational technique which was associated with problems like laryngospasm and bronchospasm. Further there was a need to take the patient sufficiently deep before intubation which lead to haemodynamic disturbances.4 (1 in old)

The first skeletal muscle relaxant d-tubocurarine which was non-depolarizing in nature was introduced in 1942 to fulfil the need for jaw relaxation. Though this drug provided excellent muscle relaxation, it had additional ganglion blocking properties causing tachycardia, hypotension even in clinical doses. Further it had a delayed onset at jaw, making it unsuitable for use during rapid sequence intubation in emergency cases. Hence a search began for a relaxant which had a rapid onset and short duration of action.5 (2 in old)

Succinylcholine chloride, introduced in 1951, was a synthetic depolarizing muscle relaxant. It fulfilled both of the above requirements, and soon became the drug of choice for endotracheal intubation especially in rapid sequence intubation in emergency cases. But all did not go well for succinylcholine chloride when its adverse effects started surfacing especially hyperkalemia, rise in intragastric, intraocular, intracranial pressures and cardiovascular effects. Thus the quest began for a safer substitute for succinylcholine chloride.

The aim of research on neuromuscular drugs was to have nondepolarising muscle relaxant, which is like succinylcholine chloride without its side effects.
Though many NDMR drugs like atracurium besylate, vecuronium bromide and mivacurium chloride were introduced, none of them could challenge succinylcholine chloride in terms of its onset.
The new NDMR drug rocuronium bromide introduced in 1994 became the first competitor for succinylcholine chloride. Rocuronium bromide when given in two to three times the ED95 dose is said to produce excellent to good intubating conditions in 60 seconds. Further rocuronium bromide is said to be devoid of the adverse effects that are seen with succinylcholine chloride.

Hence, the present study was undertaken to evaluate the intubating conditions with Rocuronium Bromide 0.9 mg/kg and 1.2 mg/kg body weight and to compare the intubating conditions with that of succinylcholine chloride 1.5 mg/kg body weight, for use during rapid sequence intubation of anaesthesia in adult patients.

OBJECTIVES OF THE STUDY

a. To compare the intubating conditions of rocuronium bromide 0.9 mg/kg, 1.2 mg/kg body weight with that of succinylcholine chloride 1.5 mg/kg body weight at

60 seconds.

b. To study the clinical duration of action of rocuronium bromide 0.9 mg/kg, 1.2 mg/kg body weight and succinylcholine chloride 1.5 mg/kg body weight.

c. To study the cardiovascular responses associated with the administration of rocuronium bromide and succinylcholine chloride.
d. To study the side effects associated with the use of rocuronium bromide and succinylcholine chloride like histamine release.

PHARMACOLOGY OF ROCURONIUM BROMIDE

Rocuronium bromide is a non-depolarizing muscle relaxant. Its salt preparation is a monoquaternary aminosteroid non-depolarizing skeletal muscle relaxant.

Chemistry6 (3 in old)

Figure 1: Rocuronium bromide (ORG9426)

C32H53BrN2O4 = 609.7

1-(17β-Acetoxy-3α-hydroxy-2β-morpholino-5α-androstan-16β-yl)-1-altylpyrrolidinium bromide

Figure 2: Vecuronium bromide

Rocuronium bromide (Figure 1) was introduced in 1994 in order to provide a very rapid relaxation for endotracheal intubation. It was synthesized from its parent molecule Vecuronium Bromide (Figure 2) by various substitutions by chemists at Organon Lab, Holland under the leadership of Dr. J. Sleigh and late Dr. D. Savage

Rocuronium bromide (Figure 1) differs from Vecuronium Bromide (Figure 2) in three positions.

• having a 2β-morpholino group

• a 3α-hydroxy group

• 16-pyrrolidino function attached to a 16-N-allyl group

The faster onset of action is conferred by lowered potency induced by D and A

ring modifications.6 (3 in old)

Preparations7 (5 in old)

Rocuronium Bromide is available in 5 ml and 10 ml vials (Figure 3). Each ml contains: 10 mg of rocuronium bromide, 2 mg sodium acetate, adjusted to isotonicity with sodium chloride and to a pH of 4 with acetic acid and sodium hydroxide. It is incompatible with alkaline solutions like barbiturates and should not be mixed with them in the same syringe.

Vials should be stored under refrigeration at 2°C to 8°C. They should not be frozen.

Upon removal from refrigeration to room temperature, the drug should be used within 60 days.

Opened vials should be used within 30 days.

When properly stored between 2°C to 8°C, it has a shelf life of 3years.
Mechanism of action7,8 (6,7 in old)
Rocuronium bromide like any other non-depolarizing skeletal muscle relaxant,

binds to α subunit of acetylcholine receptor in post junctional membrane and produces competitive blockade of the receptor, leading to skeletal muscle relaxation. Its faster onset of action can be explained by its chemical structure which is slightly different from its parent molecule vecuronium bromide in three positions. It is seven to eight times less potent than vecuronium bromide, but has the same molecular weight; thus, a greater number of drug molecules are able to reach junctional receptors within a few circulation
times, enabling faster development of neuromuscular blockade. Weaker binding to receptors (lower potency) accounts for intermediate duration of action.
Plasma concentrations of rocuronium decrease rapidly after bolus injection because of hepatic uptake. Thus, the duration of action of the drug is determined chiefly by redistribution, rather than by its rather long terminal elimination half-life (1 to 2 hours). Metabolism to 17-deacetylrocuronium is a very minor elimination pathway. Most of the drug is excreted unchanged in urine, bile or feces.
With an ED95 of 0.3mg/kg rocuronium has one-sixth the potency of vecuronium, a more rapid onset but a similar duration of action and similar pharmacological profile. With equipotent doses, rocuronium onset at the adductor pollicis muscle is much faster than that of cisatracurium, atracurium and vecuronium. After doses of 0.6mg/kg (2 X ED95) maximal block occurs in 1.5 to 2 minutes. In a multicentre trial of 349 patients, intubating conditions at 60 seconds after 0.6mg/kg rocuronium were good to excellent in 77% of cases. To obtain results similar to those after 1mg/kg succinylcholine, the dose of rocuronium had to be increased to 1mg/kg, which provided 92% good or excellent conditions. However, the duration of action is longer than for succinylcholine, ranging between 30 and 40 minutes for a 0.6mg/kg dose to approximately 60 minutesafter 1mg/kg in adukts. Thus, rouronium is an intermediate duration drug.9 (barash page 539)

Pharmacological actions

1. Skeletal muscle: Rocuronium bromide being a non-depolarizing skeletal muscle relaxant produces competitive blockade at Ach receptor in post junctional membrane leading to skeletal muscle relaxation.10 (old 8) As for other nondepolarising agents, the onset of action of rocuronium is more rapid at the diaphragm and adductor laryngeal muscles than at the adductor pollicis, probably a result of greater blood flow to the centrally located muscles. Laryngeal adductor muscles are resistant to the effect of rocuronium, and the plasma concentration required for equivalent blockade is greater at the larynx than at the adductor pollicis muscle.11( barash 538) Thus the central group of muscles are paralysed prior to peripheral group. Further unlike depolarizing blockers, it does not produce fasciculations or tonic contracture of extra ocular muscles.
Some of the terminologies employed during usage of NDMR drug in the course of neuromuscular blockade are

lag time = time between administration of rocuronium bromide and the first measurable neuromuscular effect (twitch depression  5% of control value).10

Onset time = time between administration of rocuronium bromide and maximum twitch depression.10

Clinical duration (CD) = Time between administration of rocuronium bromide and recovery to 25% twitch height.10

Recovery index (RI) = Time from 25% to 75% twitch height recovery.10

Duration 75 (D75) = Time between administration of rocuronium bromide and recovery to 75% twitch height.10

Duration 90 (D90) = Time between administration of rocuronium bromide and recovery to 90% twitch height.12 (old 9)

Intubation time = Time from start of intubation until definitive placement of oral tube.10

2. Haemodynamic effects13 (barash 538), 14 (old 11)

No hemodynamic changes (blood pressure, heart rate, or ECG) were seen in humans, and there were no increases in plasma histamine concentrations after doses of upto 4 X ED95. Only slight hemodynamic changes observed in coronary artery bypass grafting. ( barash pg 538) Eamon P. McCoy et al. (1993) have demonstrated that rocuronium bromide 0.6 mg kg-1 produces changes in heart rate (+7%), mean arterial pressure (-5%), systemic vascular resistance (-12%) that were insignificant. Thus rocuronium bromide in doses 0.6 mg kg-1 is associated with changes of only small magnitude in haemodynamic variables.

Mark E. Hudson et al. measured the haemodynamic effects of rocuronium bromide in adults undergoing cardiac surgery with cardiopulmonary bypass. They found the haemodynamic profile for a dose of 0.6 mg kg-1 bolus of rocuronium bromide to be acceptable for patients with coronary artery disease. There was no change in myocardial oxygen demand and supply. Although CVP and PAP decreased significantly, rocuronium bromide had no effect on pulmonary capillary wedge pressure, systemic vascular resistance, mean arterial pressure and cardiac index.11(old)

Thus rocuronium bromide is a haemodynamically stable drug.

3. Histamine release15 (old 12)

Levy and Jerrold H. et al. (1993) have demonstrated no increases in plasma histamine levels at 1, 3 and 5 min after the rapid IV bolus doses of 0.6, 0.9, 1.2 mg kg-1 body weight of rocuronium bromide as determined by a new radioimmuno assay with a sensitivity for histamine quantification of 0.05 ng ml-1.

Clinical signs of histamine release (e.g. flushing, rash, bronchospasm) associated with the administration of rocuronium bromide were reported in 9 of 1137 (0.8%) patients.
Thus rocuronium bromide has minimal to nil histamine releasing property.

4. Intraocular effects16 (old 13)

No significant effects on the intraocular pressure were seen following administration of rocuronium bromide.

Dosage and duration of action17(old 14)

The ED95 dose of rocuronium bromide is 0.3 mg kg-1 body weight. Rocuronium bromide has been employed in multiples of ED95 dose to achieve intubating conditions.

It has been employed in a dose of 0.6 mg kg-1 body weight (2 x ED95 dose) by K.C. McCourt et al., Toni Magorian et al., Friedrich K. Duhringer et al., Fuchs Buder et al. and all the authors have attempted intubation at 60 seconds. The clinical duration of neuromuscular paralysis noted by these authors ranged from 30-37 minutes.

It has been employed in a dose of 0.9 mg kg-1 body weight (3 x ED95) by Toni Magorian et al., Fuchs Budor et al. and P. Schultz et al. and intubation was attempted at 60 seconds. The clinical duration of neuromuscular paralysis noted by these

authors ranged from 34  11 minutes to 58  7.8 minutes.

Further some authors like Tom Heier et al. and Kirkegaard Nelsen et al. have employed rocuronium bromide in dose of 0.4 mg kg-1 and 1.2 mg kg-1 body weight and attempted intubation at 60 seconds. They have noted the respective clinical duration to range from 20 to 22 minutes for a dose of 0.4 mg kg-1 body weight and 70-80 minutes for the dose of 1.2 mg kg-1 body weight.

Table 1

Dosage (mg/kg)
Duration (min)

ED95 0.3-0.4
Intubation (at t = 60-90 seconds) 0.6-1.0 35-75

Relaxation (N2O/O2) 0.3-0.4 30-40

Relaxation (vapour) 0.2-0.3 30-40

Maintenance 0.1-0.15 15-25

Infusion 8-12 g kg-1 min-1

Continuous infusion

Rocuronium bromide can be used by infusion to maintain surgical relaxation, titrated after intubation with a bolus dose. Infusion dose is 8-12 g kg-1 min-1. Upon reaching the desired level of neuromuscular block, the infusion must be individualized for each patient. The rate of administration has to be adjusted according to the patient’s twitch response as monitored with the use of a peripheral nerve stimulator. Infusion rates have to be reduced by 30% to 50% when used with inhalational agents like enflurane and isoflurane.

Spontaneous recovery and reversal of neuromuscular blockade following discontinuation of Rocuronium Bromide may be expected to proceed at rates comparable to that following comparable total doses administered by repetitive bolus injections.
It is compatible in solution with 0.9% NaCl, sterile water for injection, 5% dextrose in water, ringer lactate solution. Infusion has to be used within 24 hours of formation.

Intramuscular route4

Intramuscular injection of rocuronium bromide 1 mg kg-1 into deltoid muscle permitted tracheal intubation to be carried out in lightly anaesthetized infants after

2.5 minutes. In children a dose of 1.8 mg kg-1 enabled tracheal intubation after 3 minutes. However, the mean time to initial recovery after these doses was 57 minutes in infants and 70 minutes in children.

Metabolism and excretion4

Following intravenous administration, plasma concentration of rocuronium bromide follows a three compartment open model. There is an initial distribution phase with a half-life of 1 to 2 minutes followed by a slower distribution phase with a half-life of 14 to 18 minutes. It is reported to be about 30% bound to plasma proteins. The elimination half-life is about 1.4 to 1.6 hours. Upto 40% of a dose may be excreted in bile. The main metabolite of rocuronium bromide, 17-desacetylrocuronium, is reported to have a weak neuromuscular blocking effect.

Factors affecting the pharmacokinetics of rocuronium bromide
1. Hepatic impairment15,16

In patients with hepatic disease, the distribution volume of rocuronium bromide is increased and its clearance may be decreased. Both the onset time and duration of action are prolonged so that a higher initial dose may be needed to achieve rapid sequence induction.

2. Renal impairment17

The clearance of rocuronium bromide is reduced in patients with renal failure when compared with healthy patients, but the accompanying increase in duration of clinical relaxation did not reach statistical significance. However, it is recommended that rocuronium bromide should be used with caution in the presence of renal failure as there were large interpatient variations.

Rocuronium bromide in special groups

1. Elderly18

The onset times were the same for both elderly and younger control group, but the duration of action of rocuronium bromide was significantly prolonged in elderly patients. Elderly patients, when compared with the younger, also exhibited a significant decrease in plasma clearance. The volume of distribution was decreased. The decreased total body water and decreased liver mass were the probable explanations.
In elderly patients, the ED95 is similar to that found in younger adults, but the duration of action is prolonged slightly. The drug has an increased terminal half life in renal failure patients, probably because of its partial renal elimination, but this translates to only a slight prolongation of the block. In hepatic disease, the slower uptake and elimination of rocuronium by the liver tends to prolong the duration of action of the drug, but this is compensated to some extent by the larger volume of distribution. (barash 539)

2. Intensive care19

The pharmacokinetics of the drug is changed. The volume of distribution at steady state may be increased, the plasma clearance decreased and terminal half-life prolonged. Recovery time on discontinuation is prolonged.

3. Pregnancy20

Abouleish et al. have demonstrated that the ratio of mean concentration of rocuronium bromide in umbilical venous plasma to maternal venous plasma after a dosage of 0.6 mg kg-1 was 0.16. That is about 10% of drug was in foetus. In all patients, the 5 min Apgar scores were normal, indicating no side effects of rocuronium bromide on foetus. Further they showed that rocuronium bromide 0.6 mg kg-1 provided excellent to good intubating conditions in 90% of caesarean section patients at 80 seconds.

4. Children21,22

Rocuronium bromide provides excellent to good intubating conditions at 1 minute with 2 to 3 times the ED95 dose, with a trend to better conditions with higher dose. There is no change in pharmacokinetics of drug as compared to that in adults.
Children (2 to 12 years old) require more rocuronium and the duration of action is less. Thus the recommended doses are 0.9mg/kg to 1.2mg/kg in this age group. Rocuronium is more potent in infants than in older children. Doses of 0.6mg/kg have a longer duration in neonates than in infants, so a reduced dosage is recommended. (barash 539)
Indications

1. To facilitate endotracheal intubation.

2. To maintain skeletal muscle relaxation for surgical procedures.

Contraindications

1. Hypersensitivity to rocuronium bromide

2. Any anticipated difficult airway

Adverse effects

Rocuronium bromide is reported to have minimal to nil adverse effects. It is a cardiostable drug and has least or no histamine releasing properties. High doses have mild vagolytic activity.

1. Pain on administration:23 Severe transient burning pain is associated with injection of rocuronium bromide. It is recommended that rocuronium bromide should be administered only when a deep stage of unconsciousness has been achieved.

2. Hypersensitivity:24 Although rocuronium bromide is considered to have minimal histamine releasing effects, histaminoid reactions have been reported on induction of anaesthesia in three patients.

3. Hepatic and renal impairment patients: Caution has to be exercised while administering rocuronium bromide in patients with hepatic and renal impairment. The pharmacokinetics in these patients has already been discussed.

PHARMACOLOGY OF SUCCINYLCHOLINE CHLORIDE

Other names: Suxamethonium, Diacetylcholine

Succinylcholine chloride is a short acting depolarizing skeletal muscle relaxant.

Chemistry25

Figure 3: C14H30Cl2N2O4

2,2’-[(1,4 dioxo-1,4 butanedyl) bis (oxy)] bis[N,N,N-trimethylethanaminium]dichloride

* Molecular weight = 361.30

* Solubility in alcohol = 1 in 350

* Solubility in water = 1 in 1

Preparations25

Succinylcholine chloride is an entirely synthetic product. It is available as succinylcholine chloride. It is available in solutions to be injected intravenously and as powder forms which have to be reconstituted before injection.

Solutions

Succinylcholine Chloride is available in vials and ampoules as clear solution containing a dose of 50 mg/ml. It is available in 10 ml vials and 2 ml ampoules. These

solutions have to be stored between 2C to 8C and protected from light. Dilutions of

infusions if prepared should be used within 24 hours. Preservatives added to solutions include benzyl alcohol, sodium chloride and methyl paraben.
Succinylcholine chloride solution has a pH of 3.5. It should not be mixed in a syringe with other drugs because precipitation occurs. It is incompatible with alkaline solutions such as barbiturate injections.
Shelf life for solutions is 18 months.

Powder – Succinylcholine chloride is a white, odourless, slightly bitter powder which is very soluble in water. It is supplied as a powder in vials containing 500 mg or 1 g succinylcholine chloride and is intended to be used to prepare solutions containing
1 mg ml-1 and 2 mg ml-1 succinylcholine chloride for intravenous infusions. Compatible infusion fluids include 5% dextrose or 0.9% sodium chloride.

Mechanism of action14

Succinylcholine chloride attaches to each of α subunit of acetylcholine receptor in postjunctional membrane and mimics the action of acetylcholine causing depolarization of membrane. It remains bound to receptor for a longer time causing sustained depolarization making membrane refractory to subsequent dose of acetylcholine and causing neuromuscular blockade. This is phase I blockade caused by succinylcholine chloride.
Succinylcholine chloride when administered in large doses (> 2 mg kg-1) or when administered by continuous infusions may cause phase II blockade. This is a desensitization neuromuscular blockade and resembles blockade produced by non-depolarizing neuromuscular blockers.

Pharmacological actions

1. Skeletal muscle: It causes phase I block initially, which may progress to phase II block if higher dose is given or given by continuous infusion. Skeletal muscle relaxation provided by succinylcholine chloride is dense and provides excellent conditions for endotracheal intubation.

2. Cardiovascular effects:14 The drug stimulates all cholinergic autonomic receptors.

Nicotinic receptors on both sympathetic and parasympathetic ganglia.

Muscarinic receptors in SA node of heart.

Thus succinylcholine chloride has a parasympathomimetic action on heart causing

• sinus bradycardia

• nodal (junctional) rhythms

• ventricular arrhythmias causing premature ventricular contractions to ventricular fibrillation.

Bradycardia is especially common in children who have not received atropine premedication. Bradycardia is also common in adults who receive a second dose of succinylcholine chloride especially 5 minutes after the first dose.

3. Serum electrolytes: Sustained opening of acetylcholine receptors by succinylcholine chloride results in leakage of potassium from interior of cells sufficient to produce an average of 0.5 mEq L-1 increase in serum potassium concentration.

4. Intraocular effects: Intraocular pressure increases by 5 to 15 mm Hg after injection of Succinylcholine, and this increase is still present after detachment of intaocular muscle, suggesting an intraocular etiology. Precurarisation with a nondepolarising blocker has little or no effect on this increase. This information has led to the widespread recommendation to avoid Succinylcholine in open eye surgeries. There is little evidence that the use of succinylcholine has led to blindness or extrusion of eye contents (barash 533). Succinylcholine chloride causes an increase in intraocular pressure manifested within 1 min after injection, peaks at 2 to 4 min and subsides by 6 minutes. There are situations in ocular surgeries where succinylcholine chloride is to be avoided.

(a) if the patient is about to undergo repair of recent ocular surgical incision.

(b) if the patient is to undergo repair of ocular laceration.

5. Intragastric Pressure: Succinylcholine Chloride raises the intragastric pressure and this effect is blocked by precurarisation. However, succinylcholine causes even greater increases in lower esophageal sphincter pressure. Thus, succinylcholine does not appear to increase the risk of aspiration of gastric contents unless the lower esophageal sphincter is incompetent. (barash 532)
6. Intracranial Pressure: Succinylcholine may increase intracranial pressure and this response is probably diminished by precurarisation.(barash 532)
Dosage and duration25

• ED95 of succinylcholine chloride is 0.392 mg kg-1.

• It is used intravenously in dosage of 1-1.5 mg kg-1 body weight to facilitate endotracheal intubation within 60 seconds. When given in this dosage, relaxation

develops within 45-60 seconds, maximum muscle paralysis may persist for

2 minutes, after which recovery takes place within 4-6 minutes.

Metabolism: The brief duration of action of succinylcholine chloride (3-8 min) is principally due to its hydrolysis by plasma cholinesterase (pseudocholinesterase).

Succinylcholine Plasma Succinylmonocholine

chloride Cholinesterase (1/20 to 1/80 as potent)
Succinylmonocholine Plasma Succinic acid + Choline

Cholinesterase

Plasma cholinesterase is synthesized by liver. In diseases of liver and abnormal genes coding for plasma cholinesterase, the duration of action of succinylcholine chloride is abnormally prolonged. 1 to 2 percent of drug is excreted unchanged in urine.

Indications25

1. To facilitate endotracheal intubation.

2. To treat laryngospasm either intraoperatively or postoperatively.

3. To reduce the intensity of muscular contractions associated with pharmacologically or electrically induced convulsions.
4. As an adjunct to general anaesthesia for short surgical procedures, e.g. fracture

reduction.

Contraindications25

1. Hypersensitivity to succinylcholine chloride.

2. Patients with genetically determined disorder of plasma pseudocholinesterase.

3. Family history of malignant hyperthermia.

4. Patients with open eye injuries.

5. Neurological injuries, burns, massive trauma.

6. Muscular dystrophies, myasthenia gravis.

Adverse effects

1. Cardiac dysrhythmias: has already been discussed.

2. Hyperkalemia: Studies have shown that in patients with certain diseases or conditions, an exaggerated release of potassium in response to succinylcholine chloride may occur. They are
(a) Burns: The rise in serum potassium is due to proliferation of extrajunctional receptors. Risk period appear to start from 24 to 48 hours after burns and duration has not been clearly defined.
(b) Trauma: Patients with massive trauma are susceptible to hyperkalemia for atleast 60 days following trauma.
(c) Nerve damage and Neuromuscular disease: Hyperkalemia following succinylcholine chloride in these patients is due to proliferation of extrajunctional receptors.

(d) Intra-abdominal infection: If the infection persists for more than one week, the incidence of hyperkalemia is increased.
3. Myalgia: The incidence of muscle pain following administration of succinylcholine chloride varies from 0.2 to 89 per cent.

4. Increased intragastric, intracranial, intraocular pressures.

5. Masseter spasm: Incomplete jaw relaxation, masseter spasm is especially seen in children. It is also seen in patients with myotonia congenita or myotonic dystrophia.

REVIEW OF LITERATURE

Endotracheal anaesthesia was introduced to the clinical practice in early part of 20th century. Though endotracheal anaesthesia was practiced with metal tubes and chloroform anaesthesia, true concept of endotracheal intubation was actually introduced by Sir Ivan Magill during the World War I.

As it is rightly said that ‘necessity is the mother of invention’, Sir Ivan Magill along with Stanley Rowbotham developed this technique out of necessity. They had to administer anaesthesia for reconstructive operations on the face and jaw in wounded soldiers during World War I. Obviously they could not use masks for administering anaesthesia for these surgeries. After a series of trials, they could intubate the trachea using gum elastic tubes, one afferent and other efferent tube. Later the two tube technique was replaced by a single rubber tube. The first portable Boyle’s apparatus was also introduced around the same time in 1917 by Sir Edmund Gaskin Boyle.
Further to add up to the positive developments, the concept of “balanced anaesthesia” was introduced by John S. Lundy in 1926 which incorporated premedication, regional analgesia and general anaesthesia. Rees and Gray of Liverpool then divided anaesthesia into three basic components involving narcosis, analgesia and relaxation. Gray renamed the triad as narcosis, reflex suppression and relaxation. The components of narcosis, reflex suppression were met with the availability of ether, chloroform and thiopentone which was introduced into clinical practice in 1934.1 The analgesic component was met with the availability of morphine. What really lacked in the requirement of balanced anaesthesia was relaxation. Now this component of relaxation

could be achieved by deepening the level of anaesthesia and obtaining surgical relaxation by central mechanisms. But this came with its own penalty and that was the severe haemodynamic disturbances and organ damage that followed with ether and chloroform when used in high doses to obtain surgical relaxation.
Moreover, with the lack of a relaxant most intubations were done using inhalational technique which was associated with laryngospasm and bronchospasm when intubation was attempted with inadequate depth. Further due to the increased concentration of inhalational agents that were used to deepen the plane of anaesthesia, more hemodynamic disturbances were met with.
A breakthrough was obtained in 1942 when Harrold Griffith introduced d-tubocurarine to the world. With this relaxant, jaw relaxation could easily be obtained to facilitate orotracheal intubation. This invention soon instigated R.R. Macintosh to invent the famous Macintosh laryngoscope in 1943.

Although d-tubocurarine could produce jaw relaxation to facilitate orotracheal and nasotracheal intubation, it brought with it its own drawbacks. It produced muscarinic block and ganglionic block leading to tachycardia and hypotension. The onset of action was also delayed; taking up to 3 minutes to produce good intubating condition. This created a problem in emergent situations and in patients with a full stomach cases where rapid procurement of airway was the priority to avoid regurgitation and aspiration into the lungs.
Succinylcholine chloride, the first synthetic depolarizing muscle relaxant introduced in 1951 by Thesleff and Foldes, brought about a revolution in practice of anaesthesia. This drug could produce a dense and profound muscle relaxation with an onset time of 60 seconds. Thus, airway could be rapidly secured within a maximum of a minute.
Furthermore, this drug had one more advantage in its short duration of action of about 4-8 minutes; in that if there was a failed intubation, patient could be brought back to spontaneous respiration by mask ventilation in the apneic period without any hypoxic central nervous system damage. This was a real boon to the anaesthesiologists.
But even this revolutionary drug came with its own set of disadvantages. They include hyperkalemia of about 0.5 mEq L-1 for every dose. This was prominent in patients with neuromuscular disorders. It had adverse cardiac effects like bradycardia, nodal and junctional rhythm and asystole following the second dose which was highly dangerous and unpredictable. Further it was associated with rise in intraocular, intracranial and intragastric pressures; malignant hyperthermia in susceptible patients and development of phase II block after a large dose or continuous infusion. Moreover, the duration of succinylcholine chloride was prolonged in patients with pseudocholinesterase deficiency. Once these life threatening disadvantages came to the fore, a search for a newer, better muscle relaxant began.

Essentially the drug was expected to have a fast and rapid onset of action as that of succinylcholine chloride to facilitate rapid procurement of airway and at the same time be devoid of the side effects of succinylcholine chloride.
Pancuronium bromide was introduced into anaesthesia in 1967 by Baird and Reid. Although it found widespread acceptance as a safe, reliable agent, it had a few drawbacks. The onset of action with two times the ED95 dose (0.12 mg kg-1) was 2 to 3 minutes and duration of action being 45 to 60 minutes. Further it had a moderate vagolytic effect and caused sympathetic nervous system stimulation. This lead to increase

in heart rate, blood pressure and cardiac output. Due to these effects on cardiovascular system and onset of action, the search for better relaxants continued.14

Vecuronium bromide (Org NC 45) was synthesized by Savage and colleagues in 1979. Chemically the drug was a monoquaternary analogue of pancuronium. This drug proved to be more cardiostable than pancuronium with very weak vagolytic effect. But it had an onset of action of about 1.5 to 3 minutes with two to three times the ED95 (0.5 mg kg/dose).14

Atracurium besylate, described by Hughes and Payne in 1981, was also an intermediate duration non-depolarizing blocking drug. It was claimed to have an edge over previous drugs in that it was broken down in plasma by non-enzymatic spontaneous degradation (Hoffman elimination) thus limiting its duration to 30 minutes. But even this drug had an onset time of about 2-3 minutes. Moreover, it also had histamine releasing property.14

Mivacurium chloride, a short acting non-depolarizing muscle relaxant introduced into clinical practice in 1993 provided good intubating conditions at 2 to 3 minutes with two or three times the ED95 dose (0.07-0.08 mg kg-1). This drug was metabolized in plasma by pseudocholinesterase thus limiting its duration of action to 15-20 minutes. This drug also had histamine releasing property.14

Rocuronium bromide (ORG 9426) was introduced in 1994 in order to provide a very rapid relaxation for endotracheal intubation. It was synthesized from its parent molecule vecuronium bromide by various substitutions by Dr. T. Sleigh and Dr. Savage at Organon Lab.
Rocuronium bromide after its introduction was the first drug to challenge the onset time of succinylcholine chloride. Moreover, Rocuronium Bromide is devoid of all the
adverse effects of Succinylcholine Chloride. Rocuronium Bromide had an onset time of 60 seconds as studied by various authors with two or three times the ED95 dose (0.3 mg kg-1). The duration of action of rocuronium bromide with two times the ED95 is about 25-35 minutes and with three times the ED95 is about 45-55 minutes on an average. Thus, rocuronium bromide came largely to replace succinylcholine chloride for rapid procurement of airway.

Various authors have established the efficacy of rocuronium bromide for rapid procurement of airway. Most of them have attempted intubation at 60 seconds and studied rocuronium bromide either alone or compared the intubating conditions of rocuronium bromide with succinylcholine chloride at 60 seconds. Some have used neuromuscular monitor to note down the time of onset. Further some of them have even compared the intubating conditions among various doses of rocuronium bromide.

SG Chavan et al in their double blinded randomised control trial compared effects of rocuronium at two different doses; that is, 0.6 mg/kg (2 × ED95) and 0.9 mg/kg (3 × ED95), were compared with succinylcholine (2 mg/kg) when used for endotracheal intubation in adult patients for elective surgeries under general anesthesia.

After a computer generated randomisation, three different groups of 30 each were labeled as Group A (rocuronium 0.6 mg/kg), Group B (rocuronium 0.9 mg/kg), and Group C (succinylcholine 2 mg/kg).

As per ANOVA, it was concluded that the onset time was considerably shorter with Group B than Group A. The onset time of Group B was found to be significantly longer than that of Group C.
Time taken to intubate was shortest with Group C. The time taken to intubate with the Group B was found to be comparable to that of Group A.
Intubation score of Group B was the best (17.75), which was comparable with Group C. However, the intubation score obtained with Group A was found to be inferior.
Duration of action is shortest with Group C. The duration of action is prolonged when the dose of rocuronium is increased from 0.6 (Group A) to 0.9 mg/kg (Group B).
As per unpaired t-test, difference in time to intubate is not significant in Group A and Group B. Difference in intubation score in Group B and Group C is not significant
Onset time of rocuronium was less by 36% in Groups B than A with increase in dose from 0.6 to 0.9 mg/kg. The intubation score of rocuronium at a dose of 0.9 mg/kg was the best as compared to succinylcholine at 2 mg/kg.
The time taken to intubate with rocuronium at 0.6 mg/kg and 0.9 mg/kg was found to be comparable. Rocuronium at 0.9 mg/kg has a longer duration of action than at a dose of 0.6 mg/kg. The onset time is 39% more prolonged with rocuronium at 0.9 mg/kg as compared to succinylcholine at 2 mg/kg. The time taken to intubate is the shortest with succinylcholine. The time taken to intubate with rocuronium at a dose of 0.6 mg/kg was 41% prolonged and with rocuronium at a dose of 0.9 mg/kg was 20% prolonged as compared with that of succinylcholine. The intubation conditions were found to be inferior with rocuronium at 0.6 mg/kg. The duration of neuromuscular blockade is shortest with succinylcholine. The duration of action with rocuronium at 0.6 mg/kg is 3.75 times that of succinylcholine and with rocuronium at a dose of 0.9 mg/kg is 7.5 times that of succinylcholine.

Sorensen MK et al did a randomized and patient and observer-blinded trial, the aim of which was to assess how rapidly spontaneous ventilation could be re-established after RSII. In addition to this they assessed the intubation conditions and the duration of action of NMBA using acceleromyography.
They selected elective surgical patients undergoing RSI using either alfentanil and propofol with either Rocuronium (1mg/kg) or Succinylcholine (1mg/kg). Sugammadex (16mg/kg) wwas used as the reversal agent for Rocuronium after tracheal intubation. The primary end point of this study was time to return of spontaneous ventilation
They used neuromuscular monitoring with acceleromyography using the TOF-Watch SX (MSD,Glostrup, Denmark) connected to a computer.

In the rocuronium group, the time taken to intubate was slightly shorter as compared to that of the Succinylcholine group. The intubating conditions were found to be excellent in 76% of the patients in the Succinylcholine group whereas in the Rocuronium-Sugammadex group, 93% of patients achieved excellent conditions.
24% of the Succinylcholine group of patients had good conditions as compared to only 2% of patients in the Rocuronium-Sugammadex group.
None of the patients in either group had poor intubating conditions.
They concluded that RSII with rocuronium followed by Sugammadex allowed earlier re-establishment of spontaneous ventilation than with Succinylcholine. Also, they said that Rocuronium provides marginally better intubating conditions than Succinylcholine.
Marsch SC et al2 conducted a prospective randomized controlled single-blind trial in 401 critically ill patients requiring emergent RSI who were randomized to receive 1 mg/kg Succinylcholine or 0.6 mg/kg Rocuronium for neuromuscular blockade.

The outcomes measured were
1) the duration of the intubation sequence, defined as the time interval between the injection of the induction agent and the first appearance of end-tidal carbon dioxide on the screen of the monitor;
2) the incidence of failed first intubation attempts;
3) numerical and qualitative intubation conditions as rated by the intubating study physician using a scoring system proposed for good clinical research practice in studies of neuromuscular blocking drugs.
4) haemodynamic conse- quences of intubation between the start of the induction sequence and five minutes after the completion of the intubation.

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