Prospective randomised double-blind comparative study of rocuronium and pancuronium in adult patients scheduled for elective ‘fast-track’ cardiac surgery involving hypothermic

FORUM

Cerebrovascular reactivity to carbon dioxide

in sepsis syndrome*

R. A. Bowie,1 P. J. O’Connor2 and R. P. Mahajan3

1 Specialist Registrar, 3 Reader and Honorary Consultant, University Department of Anaesthesia and Intensive Care,

Nottingham City Hospital, Nottingham, NG5 2PB, UK

2 Consultant Anaesthetist, Gilbert Bain Hospital, South Road, Lerwick, UK

Summary

Cerebral dysfunction in sepsis is common in critically ill adults. However, little is known of the

effects of sepsis on cerebral haemodynamics. We studied 12 sedated and ventilated patients in

whom sepsis had been established for > 24 h. Transcranial Doppler measurements of the middle

cerebral artery flow velocity were made at normocapnia, then hypocapnia ()1 kPa) and

hypercapnia (+1 kPa). From these data, cerebrovascular reactivity to carbon dioxide was calcul-

ated. Variables indicating disease severity, systemic cardiovascular status and outcome were also

recorded. We found significant changes in cerebrovascular reactivity to carbon dioxide. Only three

of 12 patients had a cerebrovascular reactivity to carbon dioxide in the normal range; seven patients

had a reduced cerebrovascular reactivity to carbon dioxide, whereas in two patients it was raised.

In this small sample, we could not find any trend of association between altered cerebrovascular

reactivity to carbon dioxide and severity of illness, cardiovascular status or outcome. This study

suggests that established sepsis profoundly affects the vascular tone and reactivity, not only of the

systemic circulation, but also of the cerebral vasculature.

Keywords Cerebral circulation; carbon dioxide, vasomotor reactivity, sepsis syndrome, Doppler

ultrasound.

........................................................................................................

Correspondence to: R. A. Bowie

*Presented in part at the World Congress of Intensive and Critical Care

Medicine, Sydney, October 2001.

Accepted: 20 October 2002

On an adult intensive care unit, sepsis and its sequelae are

the leading causes of mortality, accounting for up to 50%

of deaths [1, 2]. Sepsis affects vascular tone leading to

decreased systemic vascular resistance and reduced perfu-

sion pressures across vascular beds, which may cause

subsequent organ dysfunction. Cerebral dysfunction

manifesting itself as confusion, agitation or coma is

common in sepsis and is associated with significantly

higher mortality [3]. Altered cerebrovascular reactivity

may be responsible for the dysfunction associated with

sepsis. Previous work with animal models of sepsis has

found a decreased cerebrovascular reactivity to carbon

dioxide [4, 5]. When sepsis was induced in healthy

human volunteers, cerebral blood flow (CBF) was

preserved despite changes in systemic haemodynamics

[6]. In a study of cerebral autoregulation and carbon

dioxide reactivity in early sepsis (< 24 h), no significant

change was found [7]. However, a recent study of septic

neurosurgical patients has shown significant impairment

of cerebrovascular reactivity to carbon dioxide [8]. Data

on non-neurosurgical patients who have had sepsis for

> 24 h are lacking. Our aim was to study the effects of

sepsis, established for > 24 h, on cerebrovascular reactiv-

ity to carbon dioxide in an adult intensive care unit using

transcranial Doppler ultrasonography.

Methods

After obtaining appropriate hospital ethics committee

approval, we studied the cerebral reactivity to carbon

dioxide in 12 septic patients. Sepsis was defined as patients

meeting two or more of the following standardised

Anaesthesia, 2003, 58, pages 261–279.....................................................................................................................................................................................................................

� 2003 Blackwell Publishing Ltd 261

criteria [9] in addition to strong suspicion of pathology

associated with sepsis.

1 Temperature < 36 �C or > 38 �C2 Tachycardia > 90 beat.min)1

3 Respiratory rate > 20 breath.min)1

4 White cell count < 4000 or > 12 000 cell.mm)3

Patients were not studied if they had comorbidity that

may affect cerebrovascular reactivity to carbon dioxide

such as neurological disease, peripheral vascular disease,

recent head injury, chronic vasoactive medication or

pregnancy. All patients were ventilated and sedated using

combinations of propofol, morphine and midazolam.

Monitoring included invasive arterial blood pressure,

ECG, oxygen saturation and in-line end-tidal carbon

dioxide partial pressure (ETCO2). Nine patients had

pulmonary artery catheters from which cardiovascular

parameters were regularly calculated. Daily venous and

arterial blood samples were taken for haematological and

biochemical analysis. All patients received inotropes accord-

ing to our intensive care unit protocol; they received

intravenous infusions of dopamine (< 5 lg.kg)1.min)1),

epinephrine or norepinephrine either alone or in com-

bination, depending upon the cardiovascular status. Other

supportive measures, common to most intensive care

units, were instituted such as nutrition, prophylaxis

against stomach acidity and deep vein thrombosis, and

daily physiotherapy.

For the study, middle cerebral artery blood flow

velocity was measured using a transcranial Doppler

ultrasound probe. After identifying the middle cerebral

artery by standard criteria [10] the angle of insonation

was kept constant using a head brace to fix the probe.

After a period of baseline measurements tidal volume and

respiratory rate were altered to obtain an ETCO2 +1 kPa

and )1 kPa from baseline. Once the new level had been

maintained for 3 min, and provided the mean arterial

blood pressure had not altered by > 15% from the value at

normocapnia, new middle cerebral artery blood flow

velocity measurements were made. The cerebrovascular

reactivity to carbon dioxide was calculated as the

difference between the middle cerebral artery blood flow

velocity at hypocapnia and hypercapnia expressed as a

percentage of the baseline middle cerebral artery blood

flow velocity per kPa change in ETCO2. In addition to

data collected via the various monitoring modalities

above, Acute Physiology and Chronic Health Evaluation

scores (APACHE II) on the day of cerebrovascular

reactivity to carbon dioxide measurement and outcome

(died or survived) were recorded for all the patients. Step-

wise regression analysis was performed to analyse the

association of cerebrovascular reactivity to carbon dioxide

with APACHE II scores, white cell count (WCC),

temperature, cardiac index, systemic vascular resistance

index, number of inotropes, arterial blood gas pH, blood

albumin concentration, length of stay on intensive care

and fractional inspired oxygen (FIO2). Previous work in

healthy volunteers by other investigators [11] and within

our establishment (unpublished data) indicate that for a

normal population the mean cerebrovascular reactivity to

carbon dioxide is 25%.kPa)1, with a coefficient of

variation of 30%. This would give a normal range for

cerebrovascular reactivity to carbon dioxide of 17–

33%.kPa)1. Based on this a v2 contingency table was

constructed to analyse the impact of an abnormally

heightened or diminished cerebrovascular reactivity to

carbon dioxide on outcome.

Results

The 12 patients (10 male and two female) had a mean age

of 68 (range 39–83) years. The values of cerebrovascular

reactivity to carbon dioxide ranged widely (Table 1). Of

Table 1 Effect of end-tidal carbon dioxide (ETCO2) on middle cerebral artery flow velocity (MCAFV). Mean arterial pressure, MAP;cerebrovascular reactivity to carbon dioxide, CRCO2.

Normocapnic values MCAFV (cm.s-1) during:

Patient no MAP (mmHg) ETCO2 (kPa) Hypocapnia Normocapnia Hypercapnia CRCO2 (% kPa-1)

1 75 6.0 86.1 99.3 104.0 12.92 73 5.5 22.8 25.0 25.3 6.53 116 4.3 25.5 30.1 33.8 23.14 79 5.3 16.4 22.1 23.7 16.55 78 3.4 46.8 56.7 73.1 23.26 109 5.9 57.0 62.6 75.0 14.47 88 5.4 39.6 47.6 67.9 35.18 65 5.0 82.3 69.2 76.6 )4.39 92 5.4 68.9 73.5 80.4 7.1

10 72 5.4 72.2 80.1 94.0 15.111 65 4.2 40.0 37.0 51.0 19.712 72 4.2 44.4 52.1 83.4 49.9

Forum Anaesthesia, 2003, 58, pages 261–279......................................................................................................................................................................................................................

262 � 2003 Blackwell Publishing Ltd

the 12 patients, only three had normal cerebral reactivity

to carbon dioxide (i.e. between 17 and 33%), whereas

seven had decreased reactivity. Interestingly, two patients

had increased cerebrovascular reactivity to carbon

dioxide. We found that none of the factors studied

(APACHE II scores, WCC, arterial blood gas pH, blood

albumin concentration, length of stay on intensive care,

temperature, cardiac index, systemic vascular resistance

index, number of inotropes and FIO2) had any significant

association with cerebrovascular reactivity to carbon

dioxide (p ¼ 0.48) (Table 2).

Cerebrovascular reactivity did not significantly affect

outcome (p ¼ 0.68) (Table 3).

Discussion

In a small group of patients with sepsis for > 24 h, we

have shown that 75% had abnormal cerebrovascular

reactivity to carbon dioxide. Similar animal studies with

sepsis induced via caecal ligation ⁄ perforation or strepto-

coccal infusions [4, 5] showed consistent changes in the

systemic circulation with decreased cardiac output,

lowering of the systemic blood pressure and an altered

response to vasoactive drugs. These changes were also

associated with a decreased cerebral blood flow and

reduced cerebral reactivity that could not be explained

by the decreased cardiac output and systemic blood

pressure.

When a sepsis model has been induced in healthy

human volunteers, using an intravenous bolus of Escheri-

chia coli endotoxin [6], cerebral blood flow measured 5 h

later was found to be preserved, as was cerebral function,

despite a drop in systemic vascular tone. However, a study

in septic patients with similar mortality to our study group

[12], indexed carotid blood flow, showed that cerebral

blood flow was proportional to cardiac output. It was not

clear if this reflected loss of cerebral autoregulation or

changes in cerebral metabolic requirements in sepsis.

A transcranial Doppler study in patients on a general

intensive care unit examined cerebrovascular reactivity to

carbon dioxide in early (< 24 h) sepsis, and showed no

difference in cerebrovascular reactivity to carbon dioxide

from values obtained in comparable awake, non-septic

historical controls [7]. The results from our study are

markedly different from this work and may be explained

by the fact that we measured cerebrovascular reactivity to

carbon dioxide once sepsis was established (> 24 h) and

that our patient group had significantly higher mortality

(67 vs. 0%). Therefore, the difference in cerebrovascular

reactivity to carbon dioxide may be due to the timing of

the measurements in relation to onset of sepsis or disease

severity. In another study, septic patients admitted to a

neurological critical care unit showed significantly altered

cerebrovascular reactivity to carbon dioxide when com-

pared with the same patients following recovery from

their septic illness [8]. In this study of eight patients, the

main confounding factor was the underlying neurological

illness that may have impaired vascular reactivity even in

absence of sepsis. However, the values of cerebrovascular

reactivity to carbon dioxide were significantly reduced,

being about a third of those recorded in the follow-up

Table 3 A Chi-squared contingency table to analyse the impactof cerebrovascular reactivity (CRCO2) on outcome.

CRCO2 Outcome Died Survived

Diminished 5 2Normal 1 1Increased 2 1

Table 2 Cerebrovascular reactivity to carbon dioxide (CRCO2), data relating to disease severity and outcome for each patient.Systemic vascular resistance index, SVRI; Cardiac index, CI; Intensive care unit, ICU; White cell count, WCC; Arterial blood gas,ABG; Fractional inspired oxygen, FiO2. *Data not available.

Patientno.

CRCO2

(% kPa-1)APACHEII

SVRI(dyne.s-1.cm-5.m-2)

CI(l.min-1.m-2) Outcome

Albumin(g.l-1)

ICU(days)

Temp(�C)

WCC(109.l-1)

No.inotropes

ABGpH FIO2

1 12.9 21 856 4.9 Died 15 3 38.1 31.25 2 7.252 0.502 6.5 16 * * Survived 26 34 38.7 11.92 1 7.560 1.003 23.1 8 * * Died 15 1 34.0 3.20 2 7.260 0.464 16.5 14 1918 3.3 Died 22 1 38.7 27.99 3 7.387 0.995 23.2 19 1439 2.5 Survived 16 9 35.5 12.95 1 7.240 1.006 14.4 17 1472 3.8 Survived * 7 38.7 45.00 2 7.247 0.467 35.1 19 * * Died 14 43 38.6 15.95 1 7.466 0.408 )4.3 33 1001 4.8 Died 16 20 37.3 16.37 3 7.210 0.759 7.1 11 1386 4.2 Died 14 6 39.8 25.10 2 7.385 0.46

10 15.1 24 752 6.1 Died 12 21 38.5 13.87 1 7.454 0.5011 19.7 21 1358 3.4 Died 12 12 38.5 10.10 2 7.490 0.3512 49.9 15 1133 5.5 Survived 21 21 36.6 11.42 2 7.374 0.44

Anaesthesia, 2003, 58, pages 261–279 Forum......................................................................................................................................................................................................................


period after recovery from sepsis. Recent in vitro work

would seem to support our findings [13]. When healthy

omental arteries are placed in plasma from septic patients,

in most cases, their responses to vasopressin are signifi-

cantly diminished when compared with a control group.

Interestingly, some vessels had normal response with a

small proportion having exaggerated response, a range of

results mirroring the findings of our study. In vivo studies

of patients have also shown that the effect of vasopressors

on cerebral blood flow is altered when sepsis is present

[14].

Transcranial Doppler monitoring of septic patients

showed that some transcranial Doppler abnormalities

were strongly associated with disease severity and out-

come [15]. A decreased pulsatility index and latent

downstroke steal phenomena, which are both consistent

with abnormally low cerebral vascular resistance, have

been described [15]. However, when transcranial Dop-

pler monitoring was used in neonates with perinatal risk

factors for developing permanent cerebral dysfunction

[16], cerebrovascular reactivity to carbon dioxide was

found to have no predictive power.

The methodology we used assumes that the changes

in middle cerebral artery blood flow velocity faithfully

reflect changes in cerebral blood flow (i.e. the insonated

vessel does not significantly alter in calibre). This has

been well established in an intact cerebral circulation

[17–19] and a recent study in septic patients demon-

strated that transcranial Doppler measured changes in

middle cerebral artery blood flow velocity were accu-

rate in assessing changes in cerebral blood flow

produced by halothane and altering carbon dioxide

tensions [20].

It is possible that drugs may have affected cerebrovas-

cular reactivity to carbon dioxide in our patients;

however, the inotropes [21] and all sedative ⁄ analgesic

drugs used do not directly alter cerebral haemodynamics.

Recent work has indicated that variations in systemic

blood pressure during cerebrovascular reactivity to carbon

dioxide testing may influence the results [22]. In our

study, mean arterial pressure did not change > 15% during

the study period, and although even this difference may

have had a small effect, it would have done little to

confound the significantly abnormal results seen in the

majority of our patients.

Changes in cerebrovascular reactivity to carbon dioxide

are often associated with changes in autoregulation due to

the overlapping of their mechanisms. Therefore, it may

be safe to surmise that in septic patients with significantly

impaired cerebrovascular reactivity to carbon dioxide, the

ability of the cerebral circulation to adapt to changes in

perfusion pressure would be reduced, leaving the brain

susceptible to changes in systemic blood pressure.

The wide variation in the effect of sepsis seen within

our study and between studies appears to indicate the

variability in individual responses to a septic stimulus.

The size and even direction of shift may change not only

between individuals, but also within each individual over

time. Our study failed to show any correlation between

cerebrovascular reactivity to carbon dioxide and out-

come or disease severity (as assessed by the recorded

parameters) and this may be due in part to the

heterogeneity of each individual’s response. In order to

elicit the degree and direction of changes in cerebro-

vascular reactivity to carbon dioxide brought about by

sepsis, a much larger study would be required. Also, the

correlation of impaired cerebral vascular reactivity with

neurological impairment in septic patients remains

unknown.

In conclusion, this study shows that in septic patients,

the cerebral vascular response to carbon dioxide may be

significantly affected; its impact on patient outcome

remains to be established.

Acknowledgements

An Association of Anaesthetists of Great Britain and

Ireland project grant funded the purchase of the trans-

cranial Doppler ultrasound machine used in this study.

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FORUM

Prospective randomised double-blind comparative study

of rocuronium and pancuronium in adult patients

scheduled for elective �fast-track� cardiac surgery

involving hypothermic cardiopulmonary bypass

R. Thomas,1 D. Smith2 and P. Strike3

1 Specialist Registrar in Anaesthetics and 2 Senior Lecturer and Consultant Anaesthetist, Shackleton Department of

Anaesthetics, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK

3 Medical Statistician, Research and Development Support Unit, Salisbury District Hospital, Salisbury, UK

Summary

The majority of cardiac anaesthetists in the UK use pancuronium for fast-track cardiac surgery.

We compared the duration of action of pancuronium and rocuronium in patients undergoing

fast-track hypothermic cardiopulmonary bypass and cardiac surgery. We determined whether

patients would have had residual neuromuscular blockade at extubation. Twenty patients were

randomly allocated to receive either pancuronium 0.1 mg.kg)1 or rocuronium 1 mg.kg)1.

Neuromuscular function was assessed by acceleromyography; spontaneous recovery was evaluated

by the train-of-four ratio measured at the adductor pollicis longus muscle. Median times to recover

train-of-four ratio of 0.9 were 3 h 38 min for rocuronium and 7 h 52 min for pancuronium.



The median difference in recovery times was 4 h 15 min (95% CI 2 h 30 min to 6 h 20 min;

p ¼ 0.0003 by Mann–Whitney test). None of the patients in the rocuronium group and seven

of 10 patients in the pancuronium group had their extubations delayed because of residual

neuromuscular blockade. Unless fast-track patients have neuromuscular function assessed before

extubation, pancuronium should not be used.

Keywords Neuromuscular block: pancuronium, rocuronium. Surgery: cardiovascular.

........................................................................................................

Correspondence to: R. Thomas

This work was presented to the European Association of Cardiothoracic

Anaesthesiologists, Dublin, 14 June 2002, and to the Association of

Cardiothoracic Anaesthetists, Cambridge, 21 June 2002. Published in

abstract form in the Critical Care Forum 2002; 6 (Suppl 2): 7.

Accepted: 12 November 2002

Selected cardiac surgical patients can be managed safely

and cost-effectively using the �fast-track� approach invol-

ving early extubation [1, 2]. In some centres (including our

institution), high-dependency units (HDUs) manage the

postoperative care of such patients. Recent work questions

the use of pancuronium in this setting [3, 4] despite its

continuing popularity among cardiac anaesthetists [5].

Although the sympathomimetic actions are theoretically

attractive [6], its duration of action can be unpredictable,

prolonged and difficult to reverse in patients following

hypothermic cardiopulmonary bypass. This may make it

potentially unsuitable for patients in whom early extuba-

tion is planned. We measured the duration of action of

pancuronium and whether patients would have had

residual neuromuscular blockade at the time of planned

extubation and compared this with rocuronium, which

has been suggested as an alternative agent [3].

Methods

After obtaining approval from the local research ethics

committee and written informed consent, we studied

adult patients scheduled for elective fast-track cardiac

surgery. Those patients with known or suspected adverse

drug reactions or hypersensitivity to the study drugs were

not studied, nor were patients with neuromuscular, liver

or renal diseases, those who had a body mass index

> 35 kg.m)2 or if rapid-sequence induction or awake

fibre-optic intubation was required.

Patients were allocated, using a computer-generated

randomisation list, to receive either pancuronium

0.1 mg.kg)1 or rocuronium 1 mg.kg)1. Personnel not

involved in the study prepared identical 20 ml syringes

containing either 200 mg rocuronium or 20 mg pan-

curonium. To achieve the target volume of 20 ml, 20 mg

of pancuronium was diluted with 10 ml of normal saline.

The dilutions were designed so that 0.1 ml of the study

drug was to be administered per kg of patient weight.

A standardised anaesthetic technique was used. All staff

involved in the care of the patient were unaware which

neuromuscular blocking agent the patient had received.

Patients received pre-anaesthetic medication of lorazepam

2 mg orally, morphine 10 mg by intramuscular injection

and oxygen 4 l.min)1 until arrival in the anaesthetic

room. Prior to induction, 14 G venous and 20 G arterial

cannulae were sited and the patient connected to a five-

lead ECG and pulse oximeter. The patient was attached

to the accelerometer (TOF Guard, NV Organon, The

Netherlands) whilst awake. This involved shaving the

sites chosen for stimulating electrode placement (ulnar

nerve at the wrist), cleaning the area with an alcohol-

based antiseptic, allowing evaporation and using

Ag ⁄AgCl gel electrodes. A temperature probe was

secured to the thenar eminence and the accelerometer

to the distal phalanx of the thumb. A padded plastic splint

was attached to the forearm and hand for stability,

allowing full and unrestricted thumb movement but no

movement of the hand or fingers. The splint was also

attached to the operating table and protected with rigid

plastic supports.

Three minutes pre-oxygenation was administered.

Anaesthesia was induced with propofol 1 mg.kg)1 and

fentanyl 10 lg.kg)1. The accelerometer was calibrated

and a stable baseline was recorded, followed by slow

intravenous injection of the study drug. Anaesthesia was

maintained with a target-controlled propofol infusion

(Diprifusor, Astra Zeneca UK Ltd, UK) aiming for plasma

concentrations of 2.5–5.0 lg.ml)1. Vasoactive drugs were

used to maintain haemodynamic parameters within 20%

of baseline values if the propofol infusion rate limits had

been reached. Ventilation with an air ⁄ oxygen mixture

was adjusted to maintain end-tidal carbon dioxide



concentration at 4.5–5.3 kPa throughout surgery. The

protocol did not allow the use of nitrous oxide or volatile

anaesthetics. Whilst in the anaesthetic room, central

venous access was established; a urinary catheter, naso-

pharyngeal and axillary temperature probes were also

inserted. The patient was then transferred to the operating

theatre. Cefuroxime 1.5 g was given as antibacterial

prophylaxis with a further identical dose administered

after cardiopulmonary bypass. Heparin 300 i.u. kg)1 was

administered before aortic cannulation for those patients

not receiving aprotonin and at 400 i.u. kg)1 for those that

were. The decision to use either or both aprotonin and

tranexamic acid was made by the surgeon.

A standard perfusion protocol was used. The bypass

circuit was primed with 1300 ml Hartmann’s solution,

500 ml modified gelatin solution (Gelofusine, B Braun

Melsungen, Germany) and 5000 i.u. heparin. A pulsatile

perfusion technique was used with a target nasopharyn-

geal temperature of 32 �C. Cold blood cardioplegia was

used for myocardial protection. For coronary artery

bypass procedures, rewarming was commenced as the

last distal coronary anastomosis was being fashioned.

Phenylephrine was used to maintain mean arterial

pressure at 50–70 mmHg; no other drugs were given

during bypass.

The train-of-four (TOF) ratio was measured automat-

ically at 15-s intervals. TOF data and thenar eminence

temperatures were recorded onto a data card and

subsequently downloaded into a spreadsheet (Microsoft

EXCEL) on a personal computer. The protocol allowed

for further doses of study drug (quarter of initial

volume; equating to 0.025 mg.kg)1 pancuronium or

0.25 mg.kg)1 rocuronium) at the discretion of the cardiac

anaesthetist. Neuromuscular blockade was not reversed.

Once surgery was complete, the patient was transferred

to the HDU and the target-controlled infusion of propofol

was reduced to 1.5–2.5 lg.ml)1 and continued until

extubation. The investigator accompanied the patient to

the HDU and sat within view of the TOF Guard and

measuring equipment. This ensured constant hand and

arm position in addition to monitoring thenar eminence

temperature. The aim in all patients was to achieve

minimum nasopharyngeal and thenar eminence temper-

atures of 35 and 32 �C, respectively, while on the HDU.

Standard practice on this unit is to actively warm patients

with a forced air device, and if thenar eminence

temperature fell below 32 �C, warm air was specifically

directed at the hand. Study end-point was defined as a

TOF ratio of ‡ 0.9 sustained for 5 min. Once this point

had been reached, neuromuscular monitoring was dis-

continued in preparation for stopping sedation and

extubation. No neuromuscular stimulation was underta-

ken in unsedated patients. Standard nursing protocols

were followed with respect to warming, control of

haemodynamics, ventilatory care, analgesia and prepara-

tions for extubation. The decision to prepare the

patient for extubation was made independently by nursing

staff blinded to the study group. Proposed extubation time

was defined as 1 h following the administration of

suppositories (diclofenac 100 mg and domperidone

30 mg). The investigator took no active part in the

patient’s management unless the TOF ratio remained

below 0.9 at the proposed extubation time, when sedation

was continued and extubation was postponed until the

study end-point of TOF ratio > 0.9 had been reached.

Multiple arterial blood gas samples were taken during

surgery and whilst the patients were on HDU. Three

venous blood samples were taken: a first sample obtained

on the day prior to surgery, a second sample obtained an

hour after admission to HDU and a final sample taken at

08.00 on the first postoperative day. Results for magnes-

ium (Mg2+), calcium (Ca2+), albumin and creatinine

Ca2+ values were corrected for plasma protein variations

by adding or subtracting 0.02 mmol.l)1 Ca2+ for each

g.l)1 albumin below or above 40 g.l)1.

Nasopharyngeal, axillary and thenar eminence temper-

atures were recorded every 5 min whilst on cardiopul-

monary bypass and every 30 min otherwise.

Power calculation was based upon the findings of one

study specifically examining the time taken to recover

TOF ratios of 0.9 after hypothermic cardiopulmonary

bypass with rocuronium [3]. From this, a sample size of

20 patients (10 in each treatment group) was required for

a standardised effect size of two, with 90% power at a

two-sided significance level of 5%. This translated into an

ability to detect a difference in duration of action of at

least 60 min with the median (SD) duration of action of

rocuronium estimated as 60 (30) min. Sample size was

determined using the software package NQUERY ADVISOR

v 3.0 (Statistical Solutions Ltd, Cork, Ireland).

Thirty randomisations were allocated in the first

instance, to allow for a proportion of �drop-outs�. The

progress of the study was monitored by an independent

third party who kept a record of numbers per treatment

group (after exclusions) and terminated the study when a

minimum of 10 patients in each group was obtained.

The statistical significance of observed differences in

the treatment outcomes was assessed using Mann–Whit-

ney confidence interval and test.

Results

Patient characteristics, surgical procedures

and timings were similar in both groups

There were no demographic differences between the

groups (Table 1). Table 2 describes the temperature



measurements. Both groups were cooled to the same

extent during cardiopulmonary bypass. We achieved our

(minimum) target nasopharyngeal and thenar eminence

temperatures (i.e. 35 and 32 �C) in all patients at the TOF

0.9 point. HDU nasopharyngeal and thenar eminence

temperature measurements in the pancuronium group

were higher than in the rocuronium group, reflecting the

longer time taken for the pancuronium group to recover a

TOF ratio of 0.9 (and hence that they received more

�warming� before the study end-point was reached). The

rocuronium group had cooler thenar eminence temper-

atures than the pancuronium group at the TOF end-point

of 0.9. Temperature results obtained intra-operatively

were otherwise similar between groups. There were no

differences between groups in the arterial and venous

blood measures.

Figure 1 illustrates the recovery of neuromuscular

function (TOF ratio of 0.9). Median times to recover a

TOF ratio of 0.9 were 3 h 38 min and 7 h 52 min for the

rocuronium and pancuronium groups, respectively. The

observed difference in TOF 0.9 medians was 4 h 15 min

(95% CI 2 h 30 min to 6 h 20 min, p ¼ 0.0003 by

Mann–Whitney test).

Seven of the 10 patients who received pancuronium had

their extubation delayed because of residual neuromuscular

blockade. The average time extubation was delayed was

62.5 min (range: 15–200 min). This contrasts with no

delayed extubations in the rocuronium group. Five of the

patients who were administered rocuronium had reached

the study end-point by the time they arrived on HDU. The

average time spent on HDU with a TOF of less than 0.9

was 28 min (range: 0 to 2 h 35 min) for rocuronium

Table 2 Temperature measures. Values are mean [range].

Site Timing Rocuronium (n = 10) Pancuronium (n = 10)

Pre-cardiopulmonary bypass 35.7 [34.7–36.9] 35.5 [34.5–36.3]Nasopharyngeal; �C

Lowest on cardiopulmonary bypass 31.5 [30.0–32.2] 31.5 [28.8–32.8]Average on cardiopulmonary bypass 34.0 [33.1–34.9] 33.9 [32.4–34.9]At skin closure 36.1 [35.1–36.7] 36.0 [35.4–36.4]Lowest on HDU 35.7 [34.8–36.6] 35.7 [35.3–36.3]Average on HDU 35.7 [34.9–36.6] 36.5 [35.9–37.1]At TOF 0.9 36.0 [35.0–36.7] 37.1 [36.1–37.9]Pre- cardiopulmonary bypass 32.7 [31.6–33.5] 32.7 [31.2–34.7]Pre- cardiopulmonary bypass 32.7 [31.6–33.5] 32.7 [31.2–34.7]

Thumb; �CLowest on cardiopulmonary bypass 31.8 [30.8–33.0] 31.6 [30.2–32.5]Average on cardiopulmonary bypass 32.9 [31.8–34.1] 33.0 [30.8–34.1]At skin closure 34.4 [32.0–36.2] 34.2 [31.6–35.5]Lowest on HDU 32.3 [30.7–34.8] 32.0 [31.2–33.5]Average on HDU 32.8 [31.6–34.8] 34.5 [33.3–35.8]At TOF 0.9 33.9 [32.0–36.2] 35.3 [33.2–36.6]

Rocuronium (n = 10) Pancuronium (n = 10)

Sex; M ⁄ F 8 ⁄ 2 8 ⁄ 2Age; years 62.6 [49–74] 64.8 [54–78]Body mass index; kg.m)2 28.4 [21.8–33.8] 27.0 [21.6–33.2]Smokers 1 1Pre-operative creatinine; l.mol.l)1 89.8 [74–113] 94.8 [73–122]Procedure 8 Coronary artery bypass

grafting procedures8 Coronary artery bypassgrafting procedures

1 Mitral valve repair 1 Mitral valve repair1 Atrial septal defect closure 1 Atrial septal defect closure

Cross-clamp time; min 37.6 [18–57] 40.1 [25–66]Cardiopulmonary bypasstime; min

71.8 [43–105] 71.2 [54–99]

Cardioplegia dose; l 1.32 [1–1.8] 1.25 [1–1.6]Induction to HDU arrivaltime; h min

3.37 [2 55 to 4 26] 3.56 [3 23 to 4 47]

Antifibrinolytics Aprotonin 6 Aprotonin 4Tranexamic acid 1 Tranexamic acid 3

Table 1 Patient characteristics anddetails of surgery. Values are numbers ormean [range].



patients and 3 h 47 min (range: 1 h 42 min to 6 h 50 min)

for pancuronium patients. Although two patients in the

pancuronium group demonstrated some recovery of

neuromuscular function (coughing) prior to their TOF

ratios recovering to 0.9, no patient in either group required

a further dose of non-depolarising muscle relaxant.

Four patients were not included in the data analysis. In

onepatient, the accelerometer transducerbecamedefective.

In another, the study drug syringe was diluted incorrectly.

During one case, normothermic cardiopulmonary bypass

was used at the request of the surgeon. The final patient had

pre-extubation plasma magnesium of 2.05 mmol.l)1. This

was still elevated at 1.23 mmol.l)1 on testing the following

day. Other electrolytes were within the normal range with

the exception of a high plasma potassium whilst on

cardiopulmonary bypass (6.6 mmol.l)1).

We were not able to identify any adverse events directly

related to administration of the study drugs. No patient

recalled any awareness of stimulation by the accelerometer.

Discussion

Achieving the early extubation required for fast-track

cardiac anaesthesia has been made possible, in part, by the

adoption of balanced anaesthesia techniques and aban-

doning high-dose narcotic regimens. Other modifications

of the anaesthetic technique, and in particular the choice of

non-depolarising neuromuscular relaxant, is reported not

to contribute to earlier extubation times [7], although this

has been challenged recently [8]. Our study purposely did

not investigate whether using a muscle relaxant with an

intermediate duration of action, such as rocuronium,

could specifically shorten the time to extubation when

compared with pancuronium. Our main impetus was to

examine the recovery profiles of the two drugs, as we were

interested in the relative risk of residual neuromuscular

blockade when early extubation is performed.

When high-dose narcotic techniques were popular for

cardiac anaesthesia, pancuronium was a popular choice of

non-depolarising muscle relaxant. Quite apart from antag-

onising opiate-induced vagotonia, the long duration of

action of pancuronium could actually be considered advan-

tageous for patients who were routinely ventilated for

12–24 h post operatively. However, more recently, other

work has highlighted concerns regarding residual neuro-

muscular blockade associated with pancuronium [8–12].

Finding the most appropriate non-depolarising muscle

relaxant for fast-track cardiac surgery involving hypo-

thermic cardiopulmonary bypass remains an interesting

challenge. This technique involves a complex series of

pathophysiological alterations associated with electrolyte,

acid–base and temperature disturbances that have pro-

found effects upon the pharmacokinetics and pharmaco-

dynamics of non-depolarising muscle relaxants [13].

Hence, it is not possible to assume that the actions of

non-depolarising muscle relaxants measured under other

conditions will still apply.

Other work has looked for an alternative neuromuscular

blocking agent. Cisatracurium has been examined under

normothermic cardiopulmonary bypass [4]. Rocuronium

has been examined previously in cardiac surgery. This

work established that rocuronium is an attractive alternat-

ive agent because of its haemodynamic effects [14, 15],

duration of action when administered by both bolus and

infusion [3] and incidence of residual neuromuscular

blockade [12]. Identifying an agent that could be admin-

istered as a single dose at induction has the attraction of

simplicity and avoids resource, technical and pharmaco-

kinetic issues associated with infusion.

Eriksson identified residual neuromuscular blockade as

a major risk factor contributing to critical events in the

immediate postoperative period [16]. Other work has

demonstrated that residual neuromuscular blockade is a

common aetiological factor in anaesthesia-related mortal-

ity [17] and morbidity [18], including admission to an

intensive care unit [19] and postoperative pulmonary

complications [20].

Our decision to use a TOF ratio of 0.9 as our end-point is

based upon work which suggests that this should replace

the previous �standard� of 0.7 [21]. Using a TOF of

0.9 recognises that postoperative complications associated

with residual neuromuscular blockade are more complex

than purely upper airway obstruction [22], or respiratory

muscle weakness [23]. Work carried out by Eriksson [24]

and Sundman et al. [25] has proposed that other aetiologies

such as pharyngeal and upper oesophageal dysfunction or

reduced hypoxic chemosensitivity [26] are also relevant.

Assessment of residual neuromuscular blockade

has been the subject of a number of previous studies

[21, 27–29]; a review article [23] cautioned against using

Pancuronium Rocuronium

2

3

4

5

6

7

8

9

10

11

Tim

e ta

ken

to r

ecov

er T

OF

of 0

.9 (

hrs)

Figure 1 Time taken to recover train-of-four ratio of 0.9 inhours. Values are medians, interquartile ranges and range.



a peripheral nerve stimulator as the only neuromuscular

monitoring. However, as we were unable to use validated

bedside clinical tests [21] in our study conditions, we

chose to use TOF measurement by accelerometry as a

practical and previously studied alternative [4, 30–32].

Both groups of patients were similar in terms of

demographic details and other confounding variables; the

only obvious difference between the groups was their

differing exposure to antifibrinolytic drugs. We are

unaware of any specific effect of aprotonin or tranexamic

acid upon the neuromuscular junction, or other relevant

drug interactions. We have demonstrated that the median

time to recover a TOF of 0.9 is at least twice as long

when pancuronium (0.1 mg.kg)1) is used compared with

rocuronium (1 mg.kg)1). In terms of relative potency

(using effective dose 95% data), the dose of rocuronium

used was larger than that of pancuronium. We decided to

use 1 mg.kg)1 of rocuronium to simplify dilution and to

reduce the likelihood of needing supplemental doses

before cardiopulmonary bypass. Therefore, we may have

underestimated the difference between the two drugs

when potency is considered.

Under the conditions studied and at the doses chosen,

the variability in the duration of action of pancuronium

was nearly double that of rocuronium. As a result, no

patients in the rocuronium group and seven patients in

the pancuronium group would have been extubated with

residual neuromuscular blockade. Only a few cardiac

anaesthetists in the UK assess neuromuscular function as

part of a fast-track extubation protocol [5]. Consequen-

tially, we suggest that pancuronium should not be used as

the non-depolarising muscle relaxant in such a setting.

Pancuronium could be used safely for fast-track surgery, if

better neuromuscular monitoring is used.

We recommend monitoring of the neuromuscular

junction prior to extubation. This would reduce the

risk of residual neuromuscular blockade at extubation,

regardless of which non-depolarising muscle relaxant was

used. We found accelerometry an acceptable peri-opera-

tive technique.

Acknowledgments

This work was supported by Organon, who provided a

grant and TOF Guard accelerometer. The authors wish to

thank Miss Wendy Sotheran for her management of the

randomisation database.

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paralysis and respiratory status: a comparative study of pan-

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11 Van Oldenbeek C, Knowles P, Harper NJ. Residual

neuromuscular block caused by pancuronium after cardiac

surgery. British Journal of Anaesthesia 1999; 83: 338–9.

12 McEwin L, Merrick PM, Bevan DR. Residual neuro-

muscular blockade after cardiac surgery: pancuronium vs.

rocuronium. Canadian Journal of Anaesthesia 1997; 44:

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13 Heier T, Caldwell JE, Eriksson LI, Sessler DI, Miller RD.

The effect of hypothermia on adductor pollicis twitch ten-

sion during continuous infusion of vecuronium in isoflura-

ne-anesthetized humans. Anesthesia and Analgesia 1994; 78:

312–17.

14 Hudson ME, Rothfield KP, Tullock WC, Firestone LL.

Haemodynamic effects of rocuronium bromide in adult

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45: 139–43.

15 McCoy EP, Maddineni VR, Elliot P, Mirakhur RK, Carson

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FORUM

The impact of Acinetobacter baumannii in the intensive

care unit

C. Theaker,1 B. Azadian2 and N. Soni3

1 Research Nurse, Intensive Care Unit, 2 Consultant Microbiologist, Department of Medical Microbiology, 3 Consultant

Anaesthetist, Magill Department of Anaesthesia, Chelsea and Westminster Hospital, 369 Fulham Road, London

SW10 9NH, UK

Summary

Acinetobacter baumannii is a significant problem in critically ill patients. It is widespread, can colonise

patients quickly and causes virulent infections. However, its overall impact on morbidity and

mortality in the critically ill remains unmeasured. This study was designed to investigate

A. baumannii colonisation and infection rates in a critically ill population over an 18-month

period. Twenty-seven patients from a population of 347 were identified as having A. baumannii.

Sixteen were colonised, whereas 11 were infected. Eleven of the 27 patients with A. baumannii

died (41%). Of these, eight were colonised and three were infected. In the same period, 320



patients did not have A. baumannii and their mortality rate was 20% (n ¼ 64). The mortality rate

of patients with A. baumannii was significantly higher than that of patients without infection.

Keywords Resistant organisms: Acinetobacter baumannii. Intensive care: adult, mortality.

........................................................................................................

Correspondence to: C. Theaker

Accepted: 24 November 2002

Acinetobacter is an emerging organism with worrying

patterns of resistance. Concerns about its multiresistance

were raised in 1991 with the first documented hospital-

wide outbreak [1, 2]. Since then there have been many

reported outbreaks of resistance [3–7], but a longitudinal

analysis of the severity of Acinetobacter infection in the

critically ill is not available.

Of the 19 Acinetobacter species that exist, Acinetobacter

baumannii is the one isolated most commonly from

clinical specimens. It has established itself as important in

humans, especially in regards to nosocomial infection. In

recent years, A. baumannii has been increasingly linked

with outbreaks related to contamination of medical

equipment [8], the skin of healthcare personnel [9] and

even dry fabrics, such as bed linen and curtains surround-

ing patients’ bed spaces [10].

Because of its ubiquitous nature, A. baumannii acqui-

sition in an intensive care setting is often difficult to

interpret owing to its ability to both colonise [11] and

contribute to infections such as ventilator-associated pneu-

monia and bacteraemia [12]. Its ability to cause serious

infections is compounded by the frequent development of

multiple antimicrobial resistances that can make therapy

particularly difficult. Although high mortalities in the

critical care setting have been attributed to Acinetobacter

bacteraemia and pneumonia [13], overall impact on mor-

bidity and mortality is not known. Therefore, an 18-month

study was conducted to measure rates of A. baumannii

colonisation and infection in non-neutropenic critically ill

adult patients.

The specific aims of the study were to: (i) determine

the number of patients with A. baumannii and categorise

these patients into colonisation or infection, (ii) examine

the demographic data of these patients and compare sites

of Acinetobacter isolation, (iii) assess the overall mortality

and morbidity associated with colonisation and infection,

and (iv) report on the sensitivities of isolates.

Methods

This study is part of an on going audit into the presence

and distribution of resistant organisms in the critically ill

population. The intensive care unit (ICU) admits � 330

adult patients each year. Elective high-risk surgical

patients comprise � 30% of all admissions. An 18-month

prospective observational study was conducted. All

patients admitted over the study period were deemed

eligible, although patients who stayed less than 48 h were

not studied unless they were identified, upon routine

screening, as having A. baumannii colonisation within this

time. Infections were identified using the Centre for

Disease Control and Prevention criteria [14] but further

refined to clarify whether the infection was definite,

possible or probable, as follows:

1 Definite, clinical evidence of infection at a defined site.

A. baumannii the only or most likely infective agent

2 Probable, clinical evidence of infection. No other cause

or other bacteria present

3 Possible, clinical evidence of infection. Other sites and

other bacteria present (no single site identified and no

pathogens isolated).

Those patients identified as having A. baumannii but

who did not meet the above criteria were classed as

colonised. Patients were assessed on days 1 and 3, and a

senior intensivist and a consultant microbiologist catego-

rised the patients into the groups.

Mortality rates were determined by analysing the crude

mortality rates of patients with and without A. baumannii.

A Chi-squared test was used to compare mortality rates.

The Mann–Whitney U-test was used to analyse demo-

graphic data. Statistical analysis was performed using

ABACUS STATVIEW v5.0. (SAS, Cary, NC, USA).

Results

Over an 18-month period, 27 patients from a total

population of 347 were identified upon routine

screening as having A. baumannii (Table 1). Of the 11

patients assumed to be infected on preliminary diagno-

sis, 7 were definitely infected with A. baumannii, 2

probably infected and 2 possibly. However, after 48 h

of treatment with appropriate antibiotics, nine patients

were judged to be definitely infected, one probably and

one possibly. The sites and sensitivities of the organisms



from both the colonised and infected groups are shown

in Table 2.

Eleven of the 27 A. baumannii patients died giving a

crude mortality rate of 41% (Table 3). In the same period,

320 patients were identified as negative to A. baumannii

and stayed in the ICU longer than 48 h. Of these, 64 died

giving a crude mortality rate of 20% (p ¼ 0.012, relative

risk 1.9).

Using APACHE II as a marker of severity of illness,

there was no statistical significance between those with

A. baumannii and those without (p ¼ 0.101).

Discussion

Acinetobacter baumannii is becoming increasingly common

in our ICU. In 1999, eight patients were identified as

being positive for A. baumannii. By the end of 2001, this

figure had risen to 19. Samples sent for microbiological

analysis confirmed clinical impression that the chest was

the most frequently infected site. In this set of patients the

respiratory tract, especially in intubated patients, was a

common site for both colonisation and infection. The

presence of A. baumannii in samples of both blood and

sputum was commonly associated with clinical infection.

Positive samples from other sites proved more difficult

to evaluate. Biotyping was not performed as this is

more useful for infection control and this was not the

main focus of the study. Moreover, most nosocomial

A. baumannii outbreaks are associated with only a few

clones [1, 15, 16].

This study demonstrates that the overall mortality rate

of both the colonised and infected A. baumannii patients

was 41%. In the same period, those patients without

A. baumannii had a significantly lower mortality rate of

20%. The APACHE II scores of those with and those

without A. baumannii did not differ.

In this study, three patients died as a result of

A. baumannii nosocomial pneumonia infection. Some

authors suggest that other resistant organisms such as

methicillin-resistant Staphylococcus aureus (MRSA) are

associated with a higher mortality, whereas others are

reluctant to define a specific link between cause and effect

[17–23]. In a previous study in this unit, based on a similar

population, death directly attributable to MRSA infection

was unusual [17].

Resistance to gentamicin and ciprofloxacin was com-

mon. This means that at present in our unit there are only

a handful of antimicrobial agents such as tobramycin,

Table 3 Mortality rates of infected and colonised patients withAcinetobacter baumannii.

Infected Colonised

No. of patient deaths 3 8Length of stay; days (median [range]) 28 [11–160] 20 [26–63]APACHE II score; (median [range]) 26 [16–37] 13 [8–27]

Table 1 Demographic data for allpatients identified with Acinetobacterbaumannii.

Colonised Infected Overall

No. of patients 16 11 27Age; years (median [range]) 63 [31–85] 70 [25–80] 66 [25–85]Length of stay; days (median [range]) 14.25 [2.6–267] 20 [6.6–160] 17 [2.6–267]APACHE II score; (median [range]) 16 [8–41] 26.3 [15–37] 16 [8–41]

Table 2 Antibiotic sensitivities and sitesof samples taken from patients positiveto Acinetobacter baumannii.

Sites

GentamicinTobramycinCiprofloxacinImipenem

TobramycinCiprofloxacinImipenemMeropenem

TobramycinImipenemMeropenem

GentamicinTobramycinImipenemMeropenem

Sputum 3 1 6 7Broncho-alveolar lavage 0 2 3 0Wound 1 0 4 0Blood culture 0 0 5 0Central venous catheter tip 0 2 2 0Ascites 1 0 0 0



imipenim and meropenim that are effective therapies

against A. baumannii. These agents are not first-line

treatments for suspected gram-negative sepsis and so

may result in a treatment delay.

A type II error in this study cannot be excluded because

of the small number of patients identified with A. bau-

mannii. However, the crude mortality rates are a cause for

concern.

A. baumannii has been seen increasingly on our unit

over the past years and has a significant impact on

mortality. It has impressive resistance patterns and is

difficult to treat. The data obtained in this study should

alert clinicians to the emergence of a potentially difficult

and dangerous organism.

References

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368–73.



FORUM

The incidence of flushing on induction of anaesthesia

in patients who blush easily

J. Olday,*1 E. Currie2 and G. B. Drummond3

1 Specialist Registrar, 2 Research Nurse and 3 Senior Lecturer, Department of Anaesthesia, Critical Care, and Pain

Medicine, Royal Infirmary of Edinburgh, Edinburgh, UK

Summary

Flushing (reddening and blotching of the skin) is seen frequently at induction of anaesthesia,

is associated with anaesthetic agents such as thiopental and muscle relaxants, and is attributed to

histamine release. The changes are generally confined to the neck and upper chest (the

blush area). In conscious subjects, the mechanisms responsible for blushing in the same skin

distribution are well defined and neurally mediated. We investigated the relationship between

a history of blushing easily and flushing after intravenous induction of anaesthesia. We

interviewed 898 patients about to undergo general anaesthesia and asked them if they blushed

easily. Anaesthesia was induced with thiopental followed by suxamethonium and ⁄ or alcuro-

nium. We noted skin colour and the presence of a flush every 5 min for 20 min. Women

reported blushing more than men (47% of women, compared with 33% of men, p < 0.001),

and blushing was more common in young people (p < 0.001). In those women with a history

of blushing, 32% flushed on induction of anaesthesia, compared with 6% of those who did

not blush. In men, a flush was seen in 22% of those who blushed, and in 0.2% of those who

did not. These differences in the frequency of flushing were significant (p < 0.001). In con-

clusion, flushing after induction of anaesthesia appears to be related to individual predisposition

and may be neurally mediated.

Keywords Allergy. Anaesthetic techniques: induction. Signs and symptoms: flushing. Skin: colour.

........................................................................................................

Correspondence to: Dr J. Olday

*Present address: Department of Anaesthetics, Frenchay Hospital,

Frenchay Park Road, Bristol BS16 1LE, UK.

Accepted: 2 December 2002

Some people flush on induction of anaesthesia. This flush-

ing is generally confined to the neck and upper chest region

and lasts for around 20 min. This distribution is similar to

that of blushing [1]. Blushing is common in young women.

The tendency appears to be inherited and its stimuli and

distribution are relatively constant [1]. We studied whether

flushing of the face and upper chest at induction of

anaesthesia was more common in those who blush.

Methods

All patients gave informed consent and our local research

ethics committee approved the study.

The data were originally collected prospectively as a

study of the false-positive rate of radioimmunosorbent

assay tests for anaesthetic agent allergy, as preliminary

studies suggested poor specificity. This study was not

completed. A research nurse visited 898 patients about to

undergo general surgical, gynaecology, orthopaedic or

ENT procedures. She used a semi-structured question-

naire, which included asking if the patient blushed easily

and if there were any allergies. After induction of anaes-

thesia with thiopental (up to 5 mg.kg)1 i.v.) and neuro-

muscular blockade with either suxamethonium (up to

2 mg.kg)1) or suxamethonium followed by alcuronium

(0.2–0.3 mg.kg)1), skin colour and the presence of a flush

over the face and upper neck were noted by the

anaesthetist every 5 min for a total of 20 min.

Categorical comparisons of blush tendency and flush-

ing on induction of anaesthesia were made using the



Chi-squared test. Further statistical significance was tested

with a Chi-squared trend test. Histograms comparing age,

sex, blush tendency and flushing on induction were

constructed. Categorical comparisons were made with

Fisher’s exact test and the Chi-squared test for trends,

using SPSS for Windows version 9 (SPSS Inc., Chicago,

IL, USA).

Results

We obtained data from 898 patients. Sex and age

distribution are shown in Fig. 1a. The risk of blushing

was greater in female patients (1.47, 95% CI 1.19–1.67,

p < 0.001) and in the young (p < 0.001, Fig. 1b).

On induction of anaesthesia, flushing was noted in

120 patients: 86 females and 34 males. Flushing was

related to a history of blushing (p < 0.001, Fig. 1c). The

relative risk of flushing in females who blush was 5.3

(95% CI 3.2–8.9) and in males this was 11.7 (95% CI

4.6–29.5).

Discussion

Flushing of the face and neck (the �blush� region [1]) is

often seen after induction of anaesthesia. It usually fades

quickly and is usually attributed to histamine release

by anaesthetic induction agents or muscle relaxants.

Although histamine release is well documented after

anaesthetic induction agents and muscle relaxants, not

all serious adverse reactions during anaesthesia are

caused by histamine release [2]. Most of the more

frequent skin changes seen after induction of anaesthe-

sia may not be mediated by histamine release, and the

sign may be nonspecific. Descriptions of morphine-

induced histamine release emphasise widespread cuta-

neous manifestations but no data suggest that particular

skin sites are more likely to release histamine than

others [3].

Our study was not masked, as the patients had their

pre-operative interview responses recorded on the form

that was used to record their skin changes during

anaesthesia. However, the observers had no a priori

expectations. A second observer corroborated all the

records of skin changes at the time of induction, and the

skin signs recorded were objective. We do not believe

that associations of this strength could have resulted from

observer bias. The agents we studied are not now used

frequently in current practice, but were common when

many of the previous reports of histamine release were

made [2, 4–6]. Interpretation of such studies depends, to

some extent, on accounting for confounding factors. In

addition, if the changes we report are not mediated by

specific drugs, but by the changes of conscious state, then

they may be relevant to current observations. Confound-

ing factors such as age, sex and the propensity to blush

could affect the conclusions drawn from epidemiological

(a)

(b)

(c)

Figure 1 (a) Age and gender distribution of the sample. Malepatients are shaded. (b) Percentage of patients in each age rangethat stated they blushed easily. The association with age andgender is significant (p < 0.001). (c) Percentage of patients (95%CI) that flushed on induction of anaesthesia, in relation togender and blushing history. The association with blush historyand gender is significant (p < 0.001).



studies, particularly those that implicate exposure to other

factors such as cosmetics [5, 6]. However, perhaps

separation of neural and pharmacological mediation of

skin reactions is not possible: mediator release can be

conditioned [7], suggesting that neural- and mediator-

generated mechanisms may interact.

Flushing and blushing are more obvious on the face

and neck than other sites. Skin here has a larger

number of vessels with greater capacitance nearer the

surface of the skin, but the proportional increase in

erythrocyte flux is the same as in other skin regions

[8]. Three mechanisms of blushing have been identi-

fied [9, 10], namely, relaxation of sympathetic vaso-

constrictor tone, cholinergic stimulation mediated by

bradykinin, and beta adrenoceptor stimulation. Facial

flushing is attributed to parasympathetic vasodilator

reflexes, release of sympathetic vasoconstrictor tone by

an a-adrenergic mechanism, and release of vasoactive

intestinal peptide (VIP) from reflexly activated trige-

minal pathways [11].

We have found that patients who blush easily are much

more likely to flush on induction of anaesthesia, and

propose that the mechanisms for flushing and blushing

may be related. Blushing appears to be neurally mediated

and histamine has no clear role. The flush often seen

following induction of anaesthesia may be mediated by

these same neural mechanisms. Further study is needed to

establish if histamine is relevant in this response, and

whether these frequent minor reactions indicate more

severe events. Otherwise, clinical signs such as these may

divert or mislead clinical management if they are not

interpreted correctly.

References

1 Leary MR, Cutlip WD II, Brit TW, Templeton JL. Social

blushing. Psychology Bulletin 1992; 3: 446–60.

2 McKinnon RP, Wildsmith JAW. Histaminoid reactions in

anaesthesia. British Journal of Anaesthesia 1995; 74: 217–28.

3 Tharp MD, Kagey-Sobotka A, Fox CC, Marone G, Lich-

tenstein LM, Sullivan TJ. Functional heterogeneity of

human mast cells from different anatomical sites: in vitro

responses to morphine sulphate. Journal of Allergy and Clinical

Immunology 1987; 79: 646–53.

4 Lorenz W, Doenicke A, Schoning B, Neugebauer E. The

role of histamine in adverse reactions to intravenous agents.

In: Thornton G, ed. Adverse Reactions of Anaesthetic Drugs.

New York: Elsevier, 1981: 169–238.

5 Galletly DC, Treuren BC. Anaphylactoid reactions during

anaesthesia. Anaesthesia 1985; 40: 329–33.

6 Laexenaire MC. Drugs and other agents involved in

anaphylactic shock occurring during anaesthesia. A French

multicentre epidemiological inquiry. Annales Francaises

d’Anesthesie et de Reanimation 1993; 12: 91–6.

7 Russell M, Dark KA, Cummins RW, Ellman G, Callway E,

Peek HVS. Learned histamine response. Science 1984; 255:

733–4.

8 Wilkin JK. Why is flushing limited to a mostly facial cuta-

neous distribution? Journal of American Academic Dermatology

1988; 19: 309–13.

9 Van der Meer C. Pharmacotherapy of idiopathic excessive

blushing and hyperhidrosis. Acta Neurochirugica 1985; 74:

151–2.

10 Rowell LB. Reflex control of the cutaneous vasculature.

Journal of Investigative Dermatology 1985; 69: 154–66.

11 Drummond PD, Lance JW. Facial flushing and sweating

mediated by the sympathetic nervous system. Brain 1987;

110: 793–803.

FORUM

Effect of the Confidential Enquiries into Maternal Deaths

on the use of Syntocinon� at Caesarean section in the UK*

T. J. Bolton,1 K. Randall1 and S. M. Yentis2

1 Specialist Registrar and 2 Consultant, Magill Department of Anaesthesia, Intensive Care & Pain Management, Chelsea

and Westminster Hospital, London SW10 9NH, UK

Summary

The recommended dose of Syntocinon� used for uterine contraction at Caesarean section is

5 units intravenously, given slowly. We conducted a survey of the use of Syntocinon at Caesarean

section among 240 lead obstetric anaesthetists in the UK in 2001 and found that 155 (87%) of

the 179 (75%) respondents gave 10 units, 77 of them (50%) by rapid bolus. The risks of Syntoc-

inon, especially given by rapid injection, were highlighted in the report of the Confidential

Enquiries into Maternal Deaths in the UK (1997–99), which was published at the end of 2001,



and so the survey was repeated in 2002. Of the 256 forms sent, 198 completed replies were

returned (77%); these indicated a dramatic change of practice: only 30 (15%) now gave 10 units and

only 7 of these (23%) by a rapid injection. One hundred and sixty-seven respondents to the

second survey (84%) stated they had changed their practice and 159 of these (95%) gave the

Confidential Enquiries report as the main reason for change. These results highlight the importance

of the Confidential Enquiries as a means of improving practice.

Keywords Oxytocics; Syntocinon. Medical audit. Maternal mortality. Caesarean section.

........................................................................................................

Correspondence to: S. M. Yentis

*Presented in part at the Obstetric Anaesthetists’ Association’s Annual

Meeting, Nottingham, May 2002.

Accepted: 7 December 2002

Syntocinon� is commonly used to cause uterine

contraction at Caesarean section although its adverse

cardiovascular properties are well known [1]. The

recommended dose is 5 units given by slow intravenous

injection [2], although it has been our experience that

obstetric anaesthetists often give more than this during

surgery.

Audit is an important tool for assessing standards of

care and is an integral part of clinical governance [3].

The Confidential Enquiries into Maternal Deaths

(CEMD) audit is seen as one of the most successful

clinical audits in the UK and is a major influence on

obstetric practice [4], although there is little objective

evidence that individual reports actually lead to major

changes in practice [5]. The latest CEMD report (1997–

99) was published in 2001 [4], soon after we had

conducted a national survey into the use of Syntocinon

in the UK. We therefore repeated this survey in the

following year in order to assess whether practice had

changed and how significant the report had been in

influencing any change.

Methods

A survey form was sent to 240 lead consultants for

obstetric anaesthesia in all UK maternity units in mid-

2001, according to a list held by the Obstetric Anaes-

thetists’ Association (OAA). Subjects were asked about

the routine use of Syntocinon for emergency and elective

Caesarean section in their unit, and whether they had

noticed any problems involving the drug. The audit was

completed by November 2001, shortly before publication

of the CEMD report (1997–99) [4]. Preliminary results

were presented at the OAA’s Annual Meeting in May

2002. Shortly afterwards (July 2002) an editorial about the

1997–99 report was published, in which the dangers of

Syntocinon were again highlighted [6].

In August 2002 we repeated the survey, sending forms

to the 256 lead obstetric anaesthetists then on the OAA’s

list. The questions were similar to those of the previous

survey; in addition, we asked whether respondents’

practice had changed in the past year and if so, the main

reason for it from a list (1997–99 CEMD report [4];

discussions with colleagues; presentation at meeting(s);

July’s editorial [6]).

The OAA’s Audit Subcommittee approved both

surveys.

Results

There were 179 respondents to the first survey (75%) and

198 to the second (77%). Dosages of Syntocinon given are

shown in Fig. 1. In the first survey, 68 respondents (38%)

mentioned that they had noticed tachycardia following

Syntocinon injection; 63 (36%) had noticed hypotension

and 47 (27%) had noticed other side-effects (nausea,

vomiting, flushing and dizziness). One hundred and sixty-

Figure 1 Proportion of lead obstetric anaesthetists using differentdoses of Syntocinon� given as slow or bolus (stat) injection atCaesarean section in 2001 (clear) and 2002 (solid).



seven respondents to the second survey (84%) stated that

they had changed their practice during the previous year;

almost all of these giving the CEMD report as the main

reason for change (Table 1).

Discussion

The British National Formulary (BNF) gives the recom-

mended dose of Syntocinon during Caesarean section as

5 units �…by slow intravenous injection immediately

after delivery�; it also specifically warns against the

cardiovascular effects of rapid injection [2]. These

cardiovascular effects have been known about for over

25 years [1], yet, despite this, our first survey found that

the majority of lead obstetric anaesthetists were using

10 units and half were giving the drug by rapid injection.

We can only presume that the reason for this was habit,

lack of awareness of the recommended dose, and possibly

pressure from equally unaware obstetric colleagues. It is

also possible that, as this dose has presumably been given

for a great many years without apparent problems, the

adverse effects have been overstated – for example, there

were only two deaths in the CEMD report to which

Syntocinon was felt to contribute [4]. However, approxi-

mately one third of our respondents reported problems,

mostly cardiovascular, following the use of Syntocinon.

Anecdotally, reports of severe tachycardia, hypotension

and even myocardial ischaemia exist [7], especially in

patients with compromised circulation, such as those with

cardiac disease [8].

It is important to consider also the possibly deleterious

result of changing to a lower dose of Syntocinon, i.e. an

increased incidence of haemorrhage at or after Caesarean

section, or inadequate treatment of postpartum haemor-

rhage should it occur. It should be noted that the BNF

recommends a dose of 5–10 units by slow intravenous

injection for treatment of postpartum haemorrhage,

followed by an infusion if required [2]. We have

anecdotal experience of one patient in our unit who was

given an inadequate dose of Syntocinon following

delivery, despite significant haemorrhage, for fear of

causing hypotension.

It was the recommendation of the latest CEMD

report that 5 units of Syntocinon should be given slowly

during Caesarean section and that the dose should be

revised in cases of cardiovascular disease or hypotension

[4]. We believe that this advice is correct, although one

should be mindful of the risk of undertreatment.

Irrespective of the correctness or otherwise of this

recommendation, however, its effects are striking, with

over 80% of our respondents indicating that they had

changed their practice between 2001 and 2002, and

almost all of these giving the CEMD report as their

reason for change. Our results strongly support the

continuation of the activities of the CEMD within its

new home as part of the National Institute of Clinical

Excellence [9].

Acknowledgements

We are doubly grateful to all the obstetric anaesthetists

who contributed to our two surveys.

References

1 Weis FR, Markello R, Mo B, Bochiechio P. Cardiovascular

effects of oxytocin. Obstetrics and Gynecology 1975; 46:

211–14.

2 British National Formulary, 44th edn. London: British

Medical Association ⁄ British Pharmaceutical Society of Great

Britain, 2002.

3 Commission for Health Improvement. http://www.chi.

nhs.uk/ (accessed 23 ⁄ 10 ⁄ 02).

4 Why Mothers Die. Report on Confidential Enquiries into Maternal

Deaths, 1997–9. Royal London: College of Obstetricians and

Gynaecologists, 2001.

5 Hibbard B, Milner D. Reports on Confidential Enquiries into

Maternal Deaths: an audit of previous recommendations.

Health Trends 1994; 26: 26–8.

6 May A. The Confidential Enquiries into Maternal Deaths

1997–99. What can we learn? International Journal of Obstetric

Anesthesia 2002; 11: 153–5.

7 Spence A. Oxytocin during Caesarean section. Anaesthesia

2002; 57: 722–3.

8 Yentis SM, Dob DP. Caesarean section in the presence of

aortic stenosis. Anaesthesia 1998; 53: 606–7.

9 National Institute of Clinical Excellence. http://www.

nice.org.uk/article.asp?a=30231 (accessed 08 ⁄ 11 ⁄ 02).

Table 1 Stated reasons for 167 lead obstetric anaesthetistschanging their practice regarding Syntocinon� for Caesareansection. Values are number (%). Respondents were able tochoose more than one reason.

Report on Confidential Enquiries intoMaternal Deaths 1997–99 [4]

159 (95)

Discussions with colleagues 113 (68)Presentations at meeting(s) 34 (20)Editorial about the ConfidentialEnquiries [6]

29 (17)

Others 5 (3)



Documents

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