Perioperative complications of NMB

Jørgen Viby-Mogensen

Neuromuscular blocking agents (NMBA) may produce a long row of unfavourable or harmful effects perioperatively. Many of these complications have been known for many years and not much new information has appeared in the literature recently (about for instance complications caused by the use of succinylcholine, complications in patients with neuromuscular disorders, burns, or acid-base or electrolyte disturbances). In the following lecture, Dr. M.C. Laxenaire will be talking on anaphylaxis and NMBA. Therefore, in my lecture I am going to concentrate on the non-depolarising NMBA with emphasis on:

1. The cardiovascular complications

2. The direct histamine releasing properties

3. Complications caused by impaired metabolism and/or excretion

4. Neostigmine and postoperative nausea and vomiting (PONV)

5. Complications caused by residual neuromuscular blockade

1. Cardiovascular complications

With the exception of vecuronium and cisatracurium, all non-depolarising NMBA have some effects on the cardiovascular system. The pharmacological effects are caused by varying degrees of ganglionic blockade, sympathetic stimulation, vagal stimulation, vagolytic effect or histamine release. Fig. 1 shows the principle cardiovascular changes of the non-depolarising NMBA in current use.

Fig. 1. Cardiovascular changes of non-depolarising neuromuscular blocking agents

		Heart rate	Blood pressure
Steroidal NMBA	· Pancuronium · Vecuronium · Rocuronium · Rapacuronium	+++ - + +	() - - () (¯)
Benzylisoquinolines	· Atracurium · Cisatracurium · Mivacurium	- () - - ()	(¯) - (¯)

2. Direct histamine releasing properties

Most neuromuscular blocking agents may cause local histamine release resulting in local rash or a more widespread flush not causing any reduction in arterial pressure. More seldom a more pronounced histamine release is seen followed by clinical significant tachycardia and/or hypertension. Fig. 2 shows the direct histamine releasing properties of the different non-depolarising NMBA. Note that the ability to produce severe anaphylactic reactions (type I reactions) does not correlate with the direct histamine releasing effect.

2. Direct histamine releasing properties of non-depolarising neuromuscular blocking agents

		Property for (local) histamine release
Steroidal NMBA	· Pancuronium · Vecuronium · Rocuronium · Rapacuronium	- - - ?
Benzylisoquinolines	· Atracurium · Cisatracurium · Mivacurium	++ - ++

3. Impaired metabolism and/or excretion

Hepatic disease

For many years it has been known that patients with severe liver disease are often resistant to an initial normal dose of a NMBA. Also, these patients often show great variation in the response to equipotent doses of the same drug. If a NMBA that is excreted or metabolised in the liver is being used (the steroidal NMBA) then both a prolonged action after repeated doses of the drug and difficulty in obtaining satisfactory antagonism of residual block should be expected.

Renal disease

In patients with renal diseases prolonged block may be seen after drugs largely excreted by the kidney - especially after incremental doses. Also, difficulty in obtaining satisfactory antagonism of residual block is to be expected. Patients with renal disease may have decreased plasma cholinesterase activity, and therefore mivacurium may produce a prolonged block in these patients.

Genetic defects in plasma cholinesterases

As mivacurium is hydrolysed by plasma cholinesterase, genetic defects in this enzyme may cause severely prolonged paralysis after injection of the drug (fig. 3).

Fig. 3. Correlation between genotypes and response to mivacurium 0.2 mg/kg.

Genotype	1. response (min)	TOF ratio > 0.7 (min)
Homozygous - normal	10-15	25-45
Heterozygous + Bambuterol	15-35 60	30-60 120
Homozygous for two abnormal genes	120-480	180-640

4. Neostigmine for reversal and PONV

The significance of neostigmine for PONV is controversial. Three studies published in the years 1988 to 1995 (1-3) indicated that neostigmine used for reversal did cause postoperative nausea and vomiting. However, four more recent studies (4-7) did not find such an effect. A recent systematic review by Tramér and Fucks-Buder (8) indicated, however, that neostigmine 2.5 mg may increase the risk of PONV.

5. Residual neuromuscular blockade

The incidence of clinically significant residual block is high following the use of long-acting NMBA (30-45%) but lower (5-10%) following proper use of intermediate acting NMBA. However, in a recent French study (9) clinically significant residual block (TOF < 0.7) was found in 42% of 568 patients after routine use of vecuronium without reversal or the use of a nerve stimulator. Thirty-three percent of the 435 patients extubated before arrival in the recovery room had clinically significant residual block.

The clinical significance of residual neuromuscular block has been questioned. However, recently it was shown in an RCT that postoperative residual block following the use of pancuronium caused hypoxia and pulmonary complications (10). To avoid postoperative residual block the long-acting NMBA should not be used and/or the extent of neuromuscular recovery should always be quantitated using acceleromyography, electromyography or mechanomyography. At a minimum, the TOF ratio should be measured during recovery whenever a non-depolarising neuromuscular block is not antagonised (11). Further, the response to nerve stimulation should always be considered in relation to reliable clinical signs and symptoms of residual block (fig. 4).

Fig. 4. Clinical tests of postoperative neuromuscular recovery

Unreliable	· Sustained eye opening · Protrusion of the tongue · Arm lift to opposite shoulder · Normal or near normal vital capacity · Maximum inspiratory pressure £ 25 cm H2O
Reliable	· Sustained head lift for 5 sec · Sustained leg lift for 5 sec · Sustained hang grip for 5 sec · Sustained tongue depressor test · Maximum inspiratory pressure ³ 50 cm H2O

References

1. King MJ, Milazkiewicz R, Carli F, Deacock AR. Influence of neostigmine on postoperative vomiting. Br J Anaesth 1988;61:403-6

2. Ding Y, Fredman B, White PF. Use of mivacurium during laparoscopic surgery: Effect of reversal drugs on postoperative recovery. Anesth Analg 1994;78:450-4

3. Watcha MF, Safavi FZ, McCulloch DA, Tan TSH, White PF. Effect of antagonism of mivacurium-induced neuromuscular block on postoperative emesis in children. Anesth Analg 1995;80:713-7

4. Boeke AJ, de Lange JJ, van Druenen B, Langemeijer JJM. Effect of antagonizing residual neuromuscular block by neostigmine and atropine on postoperative vomiting. Br J Anaesth 1994;72:654-6

5. Hovorka J, Korttila K, Nelskylä K, Soikkeli A, Sarvela J, Paatero H, Halonen P, Yli-Hankala A. Reversal of neuromuscular blockade with neostigmine has no effect on the incidence or severity of postoperative nausea and vomiting. Anesth Analg 1997;85:1359-61

6. Nelskylä K, Yli-Hankala A, Soikkeli A, Korttila K. Neostigmine with glycopyrrolate does not increase the incidence or severity of postoperative nausea and vomiting in outpatients undergoing gynaecological laparoscopy. Br J Anaesth 1998;81:757-60

7. Joshi GP, Garg SA, Hailey A, Yu SY. The effects of antagonizing residual neuromuscular blockade by neostigmine and glycopyrrolate on nausea and vomiting after ambulatory surgery. Anesth Analg 1999;89:628-31

8. Tramér MR, Fuchs-Buder T. Omitting antagonism of neuromuscular block: effect on postoperative nausea and vomiting and risk of residual paralysis. A systemic review. Br J Anaesth 1999;82:379-86

9. Baillard C, Gehan G, Reboul-Marty J, Larmignat P, Samama CM, Cupa M. Residual curarization in the recovery room after vecuronium. Br J Anaesth 2000 (in press)

10. Berg H, Viby-Mogensen J, Roed J, Mortensen CR, Engbæk J, Skovgaard LT, Krintel JJ. Residual neuromuscular block is a risk factor for postoperative pulmonary complications. Acta Anaesthesiol Scand 1997; 41: 1095-1103

11. Viby-Mogensen J. Postoperative residual curarization and evidence-based anaesthesia. Br J Anaesth 2000 (in press)