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Three Part Question

In [patients with traumatic brain injury], does [suxamethonium] [significantly increase intracranial pressure]?

Clinical Scenario

You are the middle grade doctor attending a patient with an isolated head injury in the Emergency Department. The GCS on arrival is now E2V2M4 (8/15). There is a history of vomiting en route to the hospital. The anaesthetist present agrees that the patient should be intubated following rapid sequence induction for CT scan; while you are pre-oxygenating another middle grade appears and helpfully reminds you that "suxamethonium will only increase this patient's intracranial pressure." You wonder whether the evidence is compelling enough to avoid suxamethonium altogether in patients with head injury.

Search Strategy

Ovid MEDLINE® 1948 to September 09 2011
EMBASE® 1980 to present
Cochrane Database

exp Succinylcholine/ OR suxamethonium.mp OR depolarising muscle relaxant*.mp OR anectine.mp
AND exp Intracranial Pressure/ OR intracranial pressure.mp OR ICP.mp LIMIT TO Humans, English Language

The references of review articles were also searched for articles relevant to the three-part question.

Search Outcome

The MEDLINE search produced 33 papers, of which 6 was relevant to the three-part question.

The EMBASE search produced 6 papers of which none was relevant to the three part-question.

The Cochrane database contained one review which was not directly relevant to the three-part question.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
McLeskey, Cullen et al. 1976 USA	12 patients undergoing craniotomy; 8 intubated with thiopentone and pancuronium, 4 intubated with thiopentone, d-tubocurarine and suxamethonium.	Expert opinion without explicit critical appraisal; level V	ICP, MAP and CPP.	“Significant”rise in blood pressure in pancuronium group during intubation. “Significant” elevation of ICP in 2/4 patients in suxamethonium group despite well maintained CPP.	Anecdotal; small sample, limited detail within published paper regarding methods, randomisation, patient demographics etc. Used d-tubocurarine in addition to suxamethonium so unable to exclude confounding effect. No statistics or data given.
White, Schlobohm et al. 1982 USA	15 comatose patients with diffuse brain injury on ICU. Selected by increase in ICP on suctioning. Randomised to pre-suctioning regimen one of 2mL saline, 1µg/kg fentanyl, 3mg/kg thiopentone, 1.5mg/kg lidocaine or 1mg/kg suxamethonium intravenously, or 1.5mg/kg lidocaine via endotracheal tube. Each patient had all treatments repeated 2-8 times in differing sequence and cough score recorded. ANOVA and Duncan’s multiple range test at 5% level.	Single blinded crossover study, level IIa	ICP and MAP before, during and 3-5mins after endotracheal suctioning for each pre-treatment. Subjective cough score after suctioning.	Suxamethonium: no acute ICP rise with administration, no ICP rise with suction (P<0.01). Significant cough score reduction (P<0.01)	Small sample size. No details given regarding randomisation.
Minton, Grosslight et al. 1986 USA	19 patients undergoing elective craniotomy for brain tumours, aged 35-75 years. Non-randomised into three groups; group 1a premedicated with glycopyrrolate and morphine, group 1b and group 2 not premedicated. Anaesthesia induced with thiopental (6mg/kg) and suxamethonium (1mg/kg) given once MAP and ICP were stable for 1 min. At return of first muscle twitch, second dose of thiopental (4mg/kg) was administered to all subjects. Group 1a and 1b then received vecuronium (0.14mg/kg) and a second suxamethonium dose (1m/kg). Fisher’s exact test was used to determine significant increases in ICP.	Poor quality cohort study; level IV	Changes in parameters (cardiovascular, ICP) within individuals pre-and post-intervention. Peripheral radial arterial catheter and subarachnoid ICP bolt to gather data.	Group 1: mean ICP rise from 15±1mmHg to 20±2mmHg after first suxamethonium dose (P<0.05).	Non-random group allocation; patients in group 2 were predicted to have ICP response to suxamethonium based on CT findings. Non-matched groups. Difficult to extract results from narrative of result section. Pre- and post- suxamethonium data table for Group 1 patients only. Internal validity poor due to three sub-groups without control; heterogeneity between group 1 and group 2. External validity in question for head injured patients; this cohort had slowly increasing ICP due to progressing neoplasms.
Stirt, Grosslight et al. 1987 USA	12 patients aged 25-79years, undergoing craniotomy for excision of malignant supratentorial gliomas. Randomised to receive 0.03mg/kg of metocurine or 0.015mL/kg saline IV prior to induction with thiopentone 4mg/kg and 70% nitrous/O2 maintenance. Four minutes after thiopentone all subjects received suxamethonium 1mg/kg. Student’s t-test for intragroup comparison, MANOVA for intergroup comparison. Fisher’s exact for fasciculations.	Double-blinded randomised controlled trial, level Ib	Changes to MAP and ICP at each minute after suxamethonium administration.	Mean increase in ICP from 11±2mmHg to 23±4mmHg in saline (control) group; statistically significant (P<0.05) compared with pre-suxamethonium ICP in same group and post-suxamethonium ICP in metocurine group.	Small sample size. No detail given regarding randomisation procedure. External validity in question for head injured patients; this cohort had slowly increasing ICP due to progressing neoplasms.
Barrington, Finer et al. 1989 Canada	20 preterm neonates on NICU undergoing nasotracheal intubation. Randomised to atropine alone (20µg/kg) or atropine plus suxamethonium (2mg/kg) by computer-generated code.	Individual case-control study in very limited population; level IIIb	Monitored HR, MAP, transcutaneous oxygen tension, and ICP via fibreoptic sensor attached to shaven anterior fontanelle.	No significant change in ICP in suxamethonium group throughout trial. Both atropine groups showed significant rise in ICP during intubation. No significant change in CPP.	Small sample size. Unable to blind due to obvious effects of suxamethonium. Unequal groups with suxamethonium group having a greater gestational age than atropine groups. Suxamethonium intubations were significantly shorter to perform and therefore associated with shorter periods of hypoxia. External validity affected by neonatal population; extrapolation of findings to head injured adult population may be inappropriate.
Brown, Parr et al. 1996 UK	11 adult patients within 48h of closed head trauma, already intubated and ventilated on ICU. 7 males, 4 females, aged 17-70 (mean 36 years). Patients received either 1mg/kg (in 50mg/mL) suxamethonium or 0.02mL/kg saline, with ICP and MAP measured at 1,2,4,6,8 and 10mins. 5 mins later contents of the other syringe were administered and observations repeated. Observers blinded to syringe order but degree of fasciculation was recorded. ANOVA for ICP and CPP measurements for 10mins after suxamethonium or saline. Student’s t-test for changes from baseline to maximal change in ICP and CPP.	Single blinded crossover study; level IIa.	ICP measured by subdural catheter, BP/MAP by intraarterial catheter.	No significant change in ICP following administration of suxamethonium or saline.	Small study. No details of randomisation protocol. Heterogenous population; four patients had undergone haematoma evacuation; no mention of coexisting craniectomy or ventricular drainage. Patients were being hyperventilated prior to study commencement with potential for blunting of ICP effect when suxamethonium administered.
Kovarik WD et al 1994 US	Ten patients with intracranial pathology ( 6 with ruptured aneurysms, 4 with cerebral oedema following trauma).	Each patient received .05 ml/kg bolus of saline, followed five minutes later by a 1mg/kg bolus of succinylcholine. Mean arterial pressure, intra-cranial pressure, heart rate and EEG were monitored continuously.	Change to cerebral perfusion pressure	Central perfusion pressure remained unchanged following saline and succinylcholine administration.	Small study. Patients studied some days after original injury. Patients were already intubated at the time of the study.

Comment(s)

No large randomised-controlled trial that answers the exact clinical question could be identified. The vast majority of studies regarding the effect of suxamethonium on intracranial pressure, including those referenced in review articles, are animal studies. So what conclusions can be drawn from the papers identified? First, there is some evidence that suxamethonium may, in subgroups of patients, increase intracranial pressure. This was seen to a degree in the papers by Stirt (Stirt, Grosslight et al, 1987), Minton (Minton, Grosslight et al 1986) and McLeskey (McLeskey, Cullen et al, 1976), although the McLeskey paper contains so little clinical information that it is of no practical use. This effect was not demonstrated, however, in the study by Kovarik (Kovarik et al, 1994). In both the Minton and Stirt papers, the effect was ameliorated by preceding use of a non-depolarising muscle relaxant (vecuronium or metocurine). While this effect may be valid and of clinical importance, the use of these agents necessitated active ventilation in both study groups prior to suxamethonium administration - a measure which the principle of rapid sequence induction injured adult population may be inappropriate.

It is worth noting that subjects in the Barrington paper (Barrington, Finer et al, 1989) were also manually ventilated, though in this case after suxamethonium administration. If the purpose of selecting suxamethonium as a muscle relaxant in head-injured patients is as part of a rapid sequence induction to minimise the risk of aspiration of gastric contents, then any period of manual ventilation is counter-productive and regimes which necessitate manual ventilation are inappropriate in this patient scenario. Second, only two of the six studies considered a patient population similar to that of the three- part question; White (White, Schlobohm et al, 1982) and Brown (Brown, Parr et al, 1996), with the other papers involving elective resection of intracranial tumours and airway procedures in neonates. While both of these studies involved only small patient numbers, neither demonstrated the dramatic and statistically significant ICP rises after suxamethonium administration seen in other papers. It is worth considering the findings of the White paper in a broader sense; the study found significant evidence that subjective cough score was reduced following suxamethonium, where in other treatment arms the coughing in itself had led to ICP rise. This suggests that there may be a distinct advantage to interim paralysis in head injured patients, although we cannot extrapolate this to be unique to suxamethonium as a neuromuscular blocking agent. Finally, it is important at this point to consider the main alternative agent to suxamethonium. A Cochrane review (Perry, Lee et al, 2008) compared intubating conditions achieved with suxamethonium versus rocuronium for emergency rapid sequence induction and found that, overall, suxamethonium was superior, and even when compared with 1.2 mg/kg rocuronium the authors considered suxamethonium's shorter duration of action to be advantageous. While this review did not consider any particular patient group nor the relative side effect profiles of the two agents, it nevertheless provides an additional point for consideration when challenged regarding the selection of suxamethonium.

Clinical Bottom Line

There is insufficient evidence that administration of suxamethonium causes an increase in intracranial pressure when administered to patients with traumatic brain injury. Further adequately powered studies are required to assess such a relationship. Until such evidence exists, the superior intubation conditions created by suxamethonium in comparison with rocuronium mean that suxamethonium should remain the first choice agent for neuromuscular blockade as part of a rapid sequence induction in head injured patients unless absolute contraindications to suxamethonium use exist.

Level of Evidence

Level 3 - Small numbers of small studies or great heterogeneity or very different population.

References

1. McLeskey, C. H., G. F. Cullen, et al. "Control of Cerebral Perfusion Pressure During Induction of Anesthesia in High-Risk Neurosurgical Patients." Survey of Anesthesiology 1976;20(1): 30
2. White, P. F., R. M. Schlobohm, et al. "A Randomized Study of Drugs for Preventing Increases in Intracranial Pressure during Endotracheal Suctioning." Anesthesiology 1982; 57(3): 242-244
3. Minton, M. D., K. Grosslight, et al. "Increases in Intracranial Pressure from Succinylcholine: Prevention by Prior Nondepolarizing Blockade." Anesthesiology 1986; 65(2): 165-169.
4. Stirt, J. A., K. R. Grosslight, et al. ""Defasciculation" with Metocurine Prevents Succinylcholine-induced Increases in Intracranial Pressure." Anesthesiology 1987; 67(1): 50-53.
5. Barrington, K. J., N. N. Finer, et al. "Succinylcholine and atropine for premedication of the newborn infant before nasotracheal intubation: A randomized, controlled trial." Critical Care Medicine 1989; 17(12): 1293-1296
6. Brown, M. M., M. J. A. Parr, et al. "The effect of suxamethonium on intracranial pressure and cerebral perfusion pressure in patients with severe head injuries following blunt trauma." European Journal of Anaesthesiology 1996; 13(5): 474-477.
7. Kovarik WD, Mayberg TS et al Succinylcholine Does Not Change Intracranial Pressure, Cerebral Blood Flow Velocity, or the Electroencephalogram in Patients with Neurologic Injury Anesth Analg 1994; 78: p469-73