British Journal of Anaesthesia 94 (1): 46–8 (2005)

doi:10.1093/bja/aeh288 Advance Access publication October 1, 2004

Case Report

Remifentanil in the management of severe tetanus

Department of Anaesthesia and Intensive Care, Pinderfields General Hospital, Aberford Road, Wakefield,
West Yorkshire WF1 4DG, UK
*Corresponding author. E-mail: christina@feelingsleepy.com
A 61-yr-old woman presented with severe tetanus. Her intensive care management was
complicated by severe generalized tetanic spasms despite the use of propofol, midazolam,
alfentanil, magnesium sulphate, and atracurium. We describe the management of this problem
with a variable dose remifentanil infusion.
Br J Anaesth 2005; 94: 46–8
Keywords: analgesics opioid, remifentanil; complications, infection, tetanus
Accepted for publication: September 3, 2004

Despite widespread immunization programmes since 1961, (ICU). Following insertion of a radial arterial catheter,
there are still an average of 10 cases of tetanus reported per she was electively intubated using a rapid sequence induc-
year in the UK.1 Tetanus causes muscle rigidity and weak- tion technique. The patient was then sedated with propofol
ness, muscle spasms, and autonomic instability. When (0–5 mg kg 1 h 1) and alfentanil (0–2.5 mg h 1) infusions,
severe, the muscle spasms can lead to respiratory comprom- given boluses of midazolam (0.1–0.2 mg kg 1) to control the
ise. The mainstay of the management of tetanus is supportive spasms, and paralysed with boluses of the non-depolarizing
care with sedation, airway protection, and controlled venti- neuromuscular blocking agent atracurium (0.5 mg kg 1),
lation routinely required. Many different drugs have been while further invasive monitoring was established. During
used to suppress and control tetanic spasms. We present a this period, she suffered a period of fast atrial fibrillation at a
case of generalized tetanus complicated by severe tetanic rate of 170–200 beat min 1, and a mean arterial pressure of
spasms managed with a variable dose remifentanil infusion. 30 mm Hg. This spontaneously reverted to sinus rhythm
after 90 s, and once stable the patient was transferred to
the ICU. Here she was given a bolus of tetanus immune
Case report globulin (150 u kg 1 i.m.), and a magnesium sulphate infu-
A 61-yr-old woman sustained a 5-cm wound to the right sion was commenced (0–10 mmol h 1, titrated to maintain
temple following a fall in the garden. The wound was plasma magnesium at 2–4 mmol litre 1). She was also
cleaned and sutured in the accident and emergency depart- prescribed i.v. metronidazole (500 mg tds) for 7 days.
ment. A tetanus booster was not given as the patient had The wound on the right temple was surgically debrided
received one 6 yr earlier. Before that injection, she had not following transfer to the ICU.
had a booster vaccination for 20 yr. The patient remained haemodynamically stable during
Nine days later she presented with a right upper motor her ICU admission with no signs of autonomic instability.
neurone facial nerve palsy and, with a presumed diagnosis of However, she continued to have severe generalized spasms
Bell’s palsy, was prescribed a course of steroids. Following occurring spontaneously and triggered by the most minor
treatment, she developed a local infection around the ori- stimuli. She was ventilated using a pressure control mode
ginal wound with severe trismus. She was admitted with tidal volumes of 5–7 ml kg 1. Between spasms, arti-
for rehydration, i.v. antibiotics (co-fluampicil 250 mg/ ficial ventilation was achieved satisfactorily. However, dur-
250 mg qds) and investigated further. Thirteen days ing a spasm, tidal volumes dropped to less than 1 ml kg 1,
following the initial injury, whilst still an in-patient, she and manual bagging was impossible because of chest wall
collapsed and suffered a 15-s period of apnoea. She re- rigidity. With frequent and often prolonged spasms, this
started breathing after use of basic airway manoeuvres caused major problems in administering basic intensive
and suction. A diagnosis of cephalic tetanus progressing care, and made physiotherapy almost impossible. Gas
to generalized tetanus was made. exchange worsened and oxygen requirements increased.
The patient was taken to an anaesthetic room for Initially the spasms were managed with propofol,
stabilization before transfer to the intensive care unit alfentanil, midazolam (0–10 mg h 1), and magnesium

# The Board of Management and Trustees of the British Journal of Anaesthesia 2004
 Remifentanil in the management of severe tetanus

sulphate infusions along with boluses of atracurium when causes the muscle rigidity and the characteristic generalized
required. However, even with maximum doses of this ther- contractions of a tetanic spasm, along with autonomic
apy, the spasms remained problematical. On day 2, the instability.
alfentanil and midazolam infusions were discontinued Since the widespread immunization programme intro-
along with the atracurium boluses, and a remifentanil infu- duced in 1961, tetanus has become a rare disease in the
sion was started at a rate of 0.05–0.1 mg kg 1 min 1 as an UK. Vaccination guidelines are widely available.2 Omission
adjunct to sedation and for analgesia. The infusion rate was of the tetanus booster in this case follows current guidelines
increased 1 min before any therapy, and titrated to effect for the management of tetanus-prone wounds, but with no
(0.3–0.6 mg kg 1 min 1). This controlled spasms suffi- booster having been given for 20 yr, the patient’s immunity
ciently to allow therapy to continue without the need for should have been considered further. In this case, the dia-
neuromuscular block or the use of benzodiazepines, and gnosis was delayed. This was because the patient initially
allowed the propofol to be reduced to 0.5–2.0 mg kg 1 presented with a facial nerve palsy. This was treated and,
h 1. The patient remained haemodynamically stable with when she then developed trismus, more common causes of
this infusion regimen. When the remifentanil infusion was in this were investigated first. Cephalic tetanus, when a cranial
progress and the spasms were controlled, the magnesium nerve is affected leading to a localized motor weakness (in
sulphate infusion was also stopped. The spasms did not this case, the facial nerve) is a rare form of tetanus and is
worsen after stopping the magnesium. On day 2, an elective associated with a poor prognosis, especially if it progresses
percutaneous tracheostomy was performed with propofol to generalized tetanus.
sedation, remifentanil, and local anaesthetic infiltration of A review article3 comprehensively discussed the pre-
the skin (lidocaine 2% with 1:200 000 epinephrine). sentation and management of tetanus, which has traditionally
The propofol and remifentanil infusions were stopped on been with sedation, anticonvulsants, neuromuscular block-
a regular basis to ensure optimal sedation levels and to ing agents, and intermittent positive pressure ventilation.
monitor progress of the disease. The spasms gradually However, this approach is associated with a degree of
reduced both in frequency and severity, allowing the pro- morbidity and mortality,4 5 and different methods to control
pofol and remifentanil infusion rates to be reduced. After the spasms have been sought including magnesium sulphate
2 weeks of intensive care, the tetanic spasms had ceased and infusions,6 dantrolene infusions,7 and intrathecal adminis-
the propofol and remifentanil infusions were successfully tration of baclofen.8 9 The mainstay of control of rigidity and
discontinued. However, with cessation of sedation, spasms is sedation with a benzodiazepine,3 and in this case
the patient showed no conscious response to stimuli and midazolam was used. Anticonvulsants are also used for addi-
decerebrate posturing. There was also spontaneous facial tional sedation, particularly phenobarbitone.3 There were
twitching. She could not be weaned from ventilatory sup- supply problems with phenobarbitone in this case and whilst
port. An EEG performed on day 8, whilst the patient was waiting for the drug to arrive, and in the face of worsening
sedated, had shown alternating slow wave activity and per- spasms, the remifentanil was started. When an EEG on day
iods of suppression, attributable to her sedated state. No 8 did not show any epileptiform activity, anticonvulsants
epileptiform activity was seen. However, with the history were not added as spasms were being controlled.
of a respiratory arrest and a period of haemodynamic com- Remifentanil, a phenylpiperidine derivative, is a selective
promise shortly before transfer to the ICU, we were con- mu-opioid receptor agonist, which has recently been
cerned that the patient may have sustained a hypoxic brain licensed for use in critical care. It has an established
injury. On day 17, cerebral function monitoring was com- role in neurosurgical intensive care,10 and is becoming
menced, which showed epileptiform activity. After a loading established within cardiac and general intensive care.11
dose of phenytoin (1 g as an i.v. infusion over 20 min) both Remifentanil has a rapid onset of action and is metabolized
the seizure activity seen on the cerebral function monitor and by non-specific ester hydrolysis in the blood and tissues. It
the facial twitching stopped. At this time, the patient also has a short clinical duration of action (3–5 min) independent
developed severe bronchopneumonia, and in view of this and of the duration of infusion.12 As such, its half time is context-
the cerebral function findings, treatment was not increased. insensitive, allowing precise titration of infusion rates.
The patient died on day 18. Subsequent post-mortem In this case, a maintenance infusion dose of remifentanil
examination showed evidence of hypoxic brain injury. was sufficient to provide analgesia and tolerance of artificial
ventilation. Increasing the infusion rate 1 min before therapy
proved successful in controlling spasms and with titration of
Discussion the dose, procedures such as physiotherapy could be per-
Tetanus is caused by the toxin tetanospasmin, which is formed. There was also a rapid fall in oxygen requirements
released by the germinated spore of the tetanus bacillus. (from Fio2 0.6 to 0.3). On day 2 of the remifentanil infusion,
This toxin primarily affects inhibitory neurones, preventing we successfully performed a percutaneous tracheostomy
the release of the neurotransmitters glycine and gamma- using propofol sedation and an increase in the infusion
aminobutyric acid, and leading to failure of inhibition of rate of remifentanil (0.5 mg kg 1 min 1) with local anaes-
motor reflex responses to sensory stimulation. This thetic infiltration of the skin. Gupta and colleagues13 report

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 Beecroft et al.

the routine use of this technique in general intensive 3 Cook TM, Protheroe RT, Handel JM. Tetanus: a review of the
care, and note excellent haemodynamic stability during literature. Br J Anaesth 2001; 87: 477–87
procedures. 4 Edmondson RS, Flowers MW. Intensive care in tetanus; manage-
ment, complications, and mortality in 100 cases. Br Med J 1979; 1:
Tetanic spasms are extremely painful and may be
1401–4
so severe as to cause fractures and tendon avulsions. 5 Appadu BL, Greiff JMC, Thompson JP. Postal survey on the long-
Remifentanil is known to be a highly effective analgesic term use of neuromuscular block in the intensive care. Intensive
with recent work suggesting it inhibits muscular pain to a Care Med 1996; 22: 862–66
greater degree than cutaneous pain in human volunteers.14 It 6 Attygalle D, Rodrigo N. Magnesium as first line therapy in the
also has fewer of the side-effects seen with the agents com- management of tetanus: a prospective study of 40 patients.
monly used for sedation in the ICU.15 With its rapid meta- Anaesthesia 2002; 57: 778–817
7 Checketts MR, White RJ. Avoidance of intermittent positive pres-
bolism it is non-cumulative even in patients with hepatic or
sure ventilation in tetanus with dantrolene therapy. Anaesthesia
renal failure,16 17 a problem seen with other such agents and 1993; 48: 969–71
their metabolites. 8 Dressnandt J, Konstanzer A, Weinzierl FX, Pfab R, Klingelhöfer J.
Potential problems do exist with the use of remifentanil. It is Intrathecal baclofen in tetanus: four cases and a review of
expensive but appears to have a sparing effect on other drugs. reported cases. Intensive Care Med 1997; 23: 896–902
With tetanus being primarily a disease of the developing 9 Saissy JM, Demaziere J, Vitris M, et al. Treatment of severe tetanus
world, access to this new drug in the areas where the disease by intrathecal injections of baclofen without artificial ventilation.
Intensive Care Med 1992; 18: 241–4
is more commonly seen may be limited by its cost. One of the
10 Tipps LB, Coplin WM, Murry KR, Rhoney DH. Safety and feas-
side-effects of remifentanil is muscle rigidity,12 but this did ibility of continuous infusion of remifentanil in the neurosurgical
not cause any problems with chest wall compliance or venti- intensive care unit. Neurosurgery 2000; 46: 596–602
lation in this case. Remifentanil by infusion is also associated 11 Cohen J, Royston D. Remifentanil. Curr Opin Crit Care 2001;
with hypotension and bradycardia, both of which are undesir- 7: 227–31
able in a patient already prone to cardiovascular instability by 12 Egan TD. Remifentanil pharmacokinetics and pharmacodynamics.
the nature of the disease. In this case, autonomic instability A preliminary appraisal. Clin Pharmacokinet 1995; 29: 80–94
13 Gupta A, Ravalia A. Remifentanil for percutaneous
was not problematical either before or during the infusion.
tracheostomies in ITU. Anaesthesia 2000; 55: 491–92
However, remifentanil should be used with caution to avoid 14 Curatolo M, Petersen-Felix S, Gerber A, Arendt-Nielsen L.
this side-effect. Tolerance is also a side-effect of the opiates. Remifentanil inhibits muscular more than cutaneous pain in
Evidence for the development of tolerance following a remi- humans. Br J Anaesth 2000; 85: 529–32
fentanil infusion is conflicting, and studies have only exam- 15 Murdoch S, Cohen A. Intensive care sedation: a review of current
ined tolerance following short (less than 3 h) periods of use. British practice. Intensive Care Med 2000; 26: 922–28
One study18 found a profound and rapid decline in the analge- 16 Dershwitz M, Hoke JF, Rosow CE, et al. Pharmacokinetics and
pharmacodynamics of remifentanil in volunteer subjects with
sic effect of remifentanil and a corresponding increase in
severe liver disease. Anesthesiology 1996; 84: 812–20
opioid requirements, but subsequent studies19 20 found no 17 Hoke JF, Shlugman D, Dershwitz M et al. Pharmacokinetics and
clinical evidence of acute opioid tolerance. pharmacodynamics of remifentanil in persons with renal failure
compared with healthy volunteers. Anesthesiology 1997; 87:
533–41
18 Vinik HR, Kissin I. Rapid development of tolerance during
References remifentanil infusion in humans. Anesth Analg 1998; 86: 1307–11
1 Data from Public Health Laboratory Service Communicable 19 Cortı́nez LI, Brandes V, Mu~ noz HR, Guerrero ME, Mur M. No
Disease Surveillance Centre, 61 Colindale Avenue, London clinical evidence of acute opioid tolerance after remifentanil-
NW9 5EQ based anaesthesia. Br J Anaesth 2001; 87: 866–9
2 British National Formulary Number 47. British Medical Association 20 Gustorff B, Nahlik G, Hoerauf K, Kress HG. No early tolerance
and Royal Pharmaceutical Society of Great Britain: Pharmaceutical during remifentanil infusion in volunteers. Eur J Anaesthesiol 2001;
Press, March 2004; 592–93 18 (Suppl 21): 138–138 (abstract A494)

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