British Journal of Anaesthesia 1992; 69: 513-516
CASE REPORTS
PLASMA LIGNOCAINE CONCENTRATIONS ASSOCIATED WITH
EXTRADURAL ANALGESIA IN PATIENTS WITH AND
WITHOUT MULTIPLE ORGAN FAILURE
C. PUTENSEN, W. LINGNAU, G. PUTENSEN-HIMMER AND M. HEROLD
SUMMARY
We have measured plasma concentrations of/igno-
caine after thoracic extradural analgesia with con-
tinuous infusion of lignocaine in eight intensive
care patients with chest wall trauma or after major
upper abdominal surgery. Four patients developed
multiple organ failure (MOF). Plasma concen-
trations of lignocaine in arterial blood were
measured 4, 8, 24 and 48 h after a continuous
infusion of lignocaine was commenced in the
extradural space. Plasma concentrations of ligno-
caine were greater in all patients with MOF
(range 2.7-5.1 ng ml~1) than in patients without
MOF (range 0.8-1.2 fig mh1). Because plasma
concentrations in patients with MOF were within
the low toxic range, extradural infusion of ligno-
caine should only be considered in intensive care
patients without MOF or when plasma concen-
trations of lignocaine are monitored. (Br. J.
Anaesth. 1992; 69: 513-516)
KEY WORDS
Anaesthetic techniques: extradural. Anaesthetics, local: ligno-
caine infusion, plasma concentrations. Intensive care: analgesia,
multiple organ failure.
Extradural administration of either local anaesthetics
or opioids has been shown to be effective for pain
management in patients with thoracic injury [1,2]
and in high risk patients requiring intensive care
after upper abdominal surgery [3]. However, these
patients may be at risk of developing multiple organ
failure (MOF).
Extradural administration of local anaesthetics
may be associated with systemic toxic effects [4].
Differences in the plasma concentrations of local
anaesthetics may be caused by organ dysfunction
[5]; there are no data on the plasma concentrations of
local anaesthetics during extradural analgesia in
patients developing MOF. We have measured,
therefore, plasma concentrations of lignocaine
during continuous extradural infusion of lignocaine
in patients with and without MOF.
PATIENTS AND METHODS
We have studied patients admitted to our intensive
care unit with chest wall trauma or after major upper
abdominal surgery. All had required ventilatory
support for adequate gas exchange and thoracic
extradural analgesia was considered appropriate for
pain management. Organ failure was defined as
severity grade 2 in the multiple organ failure score
originally described by Goris and colleagues [6].
Downloaded from http://bja.oxfordjournals.org/ at University of Exeter on July 18, 2015
Multiple organ failure was present when at least two-
organ failure was present. Sepsis was diagnosed
according to the definition of Montgomery and
colleagues [7]. Patients were excluded from the study
if they had neurological injury, spinal injury, sepsis
or coagulopathy.
The study was explained in detail to each patient,
and informed consent was obtained for all pro-
cedures.
All patients were placed in a lateral decubitus
position and a- 16-gauge Tuohy needle was intro-
duced in the extradural space at the T5-6 or T6-7
level. A therapeutic dose of 2% lignocaine 10 ml
without adrenaline was injected extradurally and an
18-gauge extradural catheter was advanced approxi-
mately 4-5 cm into the extradural space. A con-
tinuous infusion of 2 % lignocaine 0.5-0.6 ml kg"1
h"1 (1-1.2 mg kg"1 h"1) without adrenaline [8, 9] was
begun 3-5 min after the test dose had been given. In
four patients, an additional extradural infusion of
fentanyl 1 ugkg"1 h"1 [10] was required to achieve
adequate analgesia (table I).
Arterial blood samples were collected 4, 8, 24 and
48 h after the continuous infusion of lignocaine was
started and their plasma concentrations of lignocaine
analysed immediately in duplicate by fluorescence-
polarization immunoassay as described previously
[11, 12], using commercially available immunoassay
kits (Abbot, TDx, Chicago, IL).
CASE REPORTS
Patients with MOF
Patient No. 1. A 52-yr-old male with acute alcohol-
related necrotizing pancreatitis underwent lapar-
GHRISTIAN PUTENSEN*, M:D., WERNER LINGNAU, M.D.~, GXBRIELE
PUTENSEN-HIMMER, M.D. (Clinic of Anesthesia and Intensive Care
Medicine); MANFRED HEROLD, PH.D., M.D. (Clinic of Internal
Medicine); University of Innsbruck, Austria. Accepted for
Publication: June 10, 1992.
* Address for correspondence: Klinik fur Anasthesie und
Allgemeine Intensivmedizin, Anichstrasse 35, A-6020 Innsbruck,
Austria.
514 BRITISH JOURNAL OF ANAESTHESIA
TABLE I. Continuous extradural infusion of lignocaine in patients with and without multiple organ failure {MOF). Organ
failure was defined as severity grade 2 in the MOF score described by Goris and colleagues [6] and MOF was deemed present
when at least two organs failed

Patient Age Height Weight Extradural infusion

No. Sex (yr) (cm) (kg) per hour
MOF
1 M 52 185 98 2% Lignocaine 5 ml + fentanyl 1 ml
2 M 24 178 92 2% Lignocaine 5 ml + fentanyl 1 ml
3 F 35 165 70 2% Lignocaine 4 ml
4 M 24 182 87 2% Lignocaine 5 ml
Non-MOF
1 M 21 175 72 2% Lignocaine 4 ml + fentanyl 1 ml
2 F 27 164 62 2% Lignocaine 5 ml
3 F 35 168 60 2% Lignocaine 3 ml + fentanyl 1 ml
4 M 30 178 82 2% Lignocaine 5 ml

otomy for early resection of pancreatic necrosis the second day, resulting in a reduction in the dose
and drainage with peritoneal lavage. Postoperative of midazolam from 15 to 7.5 mg h"1 i.v., without the
ventilatory support with Fi Ot 0.6 and positive end- need for additional i.v. analgesics. The patient was
expiratory pressure (PEEP) 12 cm H8O was necess- weaned from the ventilator to a CPAP of 6 cm H2O

Downloaded from http://bja.oxfordjournals.org/ at University of Exeter on July 18, 2015

ary to achieve adequate gas exchange. Dopamine
3 ug kg"1 min"1, and dobutamine 5 ug kg"1 min"1
were required for cardiovascular support. A con-
tinuous extradural infusion of lignocaine (table I)
was started on the first day after operation, per-
mitting a reduction in i.v. midazolam from 20 to
10 mg h"1 and discontinuation of fentanyl 0.3 mg h"1
i.v. Renal failure developed subsequently requiring
haemofiltration on the third day after operation.
Patient No. 2. A 24-yr-old male with acute
necrotazing pancreatitis underwent laparotomy for
early resection of pancreatic necrosis and drainage
with peritoneal lavage. Adequate gas exchange was
achieved by ventilatory support (FiOf 0.5, PEEP
10 cm H2O). Adrenaline 0.5 ug kg"1 min"1 was re-
quired. A continuous extradural infusion of ligno-
caine (table I) was started on the first day after
operation, but sedation with midazolam 20 mg h"1
i.v. was necessary to allow artificial ventilation.
Patient No. 3. A 35-yr-old female with acute
necrotizing pancreatitis underwent laparotomy for
drainage with peritoneal lavage. Ventilatory support
with FiOt 0.5 and PEEP 10 cm HSO was required to
achieve adequate gas exchange. A continuous extra-
dural infusion of lignocaine (table I) was commenced
on the second day, resulting in a reduction of the
dose of midazolam from 15 to 7.5 mg h"1 i.v., with no
need for additional i.v. analgesics. The patient was
weaned from artificial ventilation to a continuous
positive airway pressure (CPAP) of 8 cm H2O within
4 days. To maintain diuresis, dopamine was infused
at 3 ug kg"1 min"1. Before operation there was evi-
dence of impaired liver function (aspartate amino-
transferase (ASAT) 44 u litre"1, gamma glutamyl
transferase 89 u litre"1) which worsened steadily,
resulting in hepatic failure (ASAT 124 u litre"1,
bilirubin 7.4 mg dl"1) on the third day after op-
eration.
Patient No. 4. A 24-yr-old male with multiple rib
fractures, pulmonary contusion, ruptured liver and
pelvic fracture underwent laparotomy for haem-
orrhage. Ventilatory support (FiOl 0.4, PEEP 10 cm
H2O) was required. Diuresis was maintained with
dopamine 3 ug kg"1 min1. A continuous extradural
infusion of lignocaine (table I) was commenced on
by the third day. Liver enzyme activity and bilirubin
increased steadily, resulting in hepatic failure
(ASAT 86 u litre"1, bilirubin 5.9 mg dl"1) on the
third day after operation.
Patients without MOF
Patient No. 1. A 21-yr-old male with bilateral
multiple rib fractures and pulmonary contusion
received ventilatory support (Fi o , 0.6, PEEP 12 cm
H2O) to achieve adequate gas exchange. On the
second day, a continuous extradural infusion of
lignocaine (table I) was started. Subsequently,
administration of midazolam was reduced from 20
to 5 mg h"1 i.v. and i.v. infusion of fentanyl was
discontinued. The patient was weaned from the
ventilator to a CPAP of 8 cm H2O within 4 days.
Patient No. 2. A 27-yr-old female with multiple rib
fractures received continuous extradural infusion of
lignocaine (table I) immediately after admission.
Mask-CPAP of 5 cm H2O was applied to prevent
development of atelectasis.
Patient No. 3. A 35-yr-old female with multiple rib
fractures received a continuous extradural infusion
of lignocaine (table I) immediately after admission.
Mask-CPAP of 5 cm HSO was applied to prevent
development of atelectasis.
Patient No. '4. A 30-yr-old male with multiple rib
fractures and pulmonary contusion received ventil-
atory support (FiOi 0.5, PEEP 10 cm H2O) to
provide adequate gas exchange. A continuous extra-
dural infusion of lignocaine (table I) was started
immediately after admission.
RESULTS
There were no adverse local or systemic effects of
lignocaine in either the MOF or the non-MOF
patients.
We terminated the study because four patients
developing MOF had plasma lignocaine concen-
trations which exceeded the stated lower toxic
concentration of 3 ug ml"1 [13]. The plasma ligno-
caine concentrations for patients with and without
MOF are shown in table II.
LIGNOCAINE EXTRADURALS AND MULTIPLE ORGAN FAILURE 515
TABLE II. Plasma concentrations of lignocaine in patients with and without multiple organ failure (MOF). Organ failure was defined as
severity grade 2 in the MOF score described by Goris and colleagues [6] and MOF was deemed present when at least two organs failed.
t Maximal values during the study period
Plasma lignocaine concn
Arterial pH (ug ml-1)
Pflticnt ASATf Rilirubin"h
No. Organ failure (u litre"1) (mg dl-1) Minimal Maximal H,-blocker 8h 12 h 24 h 48 h

MOF
1 Lung, circulatory, 39 3.1 7.33 7.38 Yes 2.7 3.2 • 2.9 3.1
gastrointestinal, renal
2 Lung, circulatory, 45 3.6 7.32 7.37 Yes 3.6 4.4 4.6 4.7
gastrointestinal
3 Lung, hepatic, 124 7.4 7.34 7.41 Yes 4.3 4.8 4.6 5.1
gastrointestinal
4 Lung, hepatic 89 5.9 7.33 7.40 No 3.1 2.9 3.3 3.0
Non-MOF
1 Lung 29 1.4 7.34 7.40 No 0.7 0.6 0.8 0.6
2 — 22 0.9 7.35 7.43 No 0.9 1.0 1.1 0.9
3 — 27 1.1 7.38 7.44 No 0.7 0.8 0.8 0.7
4 Lung 31 1.3 7.36 7.41 No 0.7 0.9 0.9 1.0

Downloaded from http://bja.oxfordjournals.org/ at University of Exeter on July 18, 2015

DISCUSSION
We have found that administration of a continuous
extradural infusion of 2 % lignocaine was associated
with toxic plasma concentrations of lignocaine
(^ 3 ug ml"1) [13] in patients with MOF. In contrast,
plasma lignocaine concentrations remained smaller
than toxic values in patients without MOF.
The plasma concentration of a local anaesthetic
during continuous extradural infusion is determined
mainly by absorption into the systemic circulation,
its distribution and its rate of clearance by the liver
[14]; all of these factors may be altered in the
presence of MOF. Body weight and renal disease [5]
are reported to have minor effects on the elimination
of lignocaine, whereas hypovolaemia [15], cardio-
vascular disease [16] and hepatic cirrhosis [5] are
associated with a decrease in plasma clearance.
Clearance of lignocaine is mainly flow dependent
[14]. Liver blood flow is determined principally by
cardiac output, which in our patients was kept in a
higher range (cardiac index > 3.5 litre min"1) to
increase oxygen delivery by adequate volume re-
placement and if necessary by positive inotropic
therapy. Thus the presence of either cardiovascular
failure or hepatic failure alone may not explain the
increased plasma lignocaine concentrations in our
MOF patients. Drugs (e.g. H2-blockers, sedatives)
have been shown to decrease both hepatic blood flow
and enzyme activity [17] and these factors may also
have reduced lignocaine clearance in our MOF
patients (table II).
Plasma concentrations of lignocaine in our patients
without MOF were slightly smaller than those
observed in parturients receiving extradural anal-
gesia with a similar continuous infusion of ligno-
caine [9]. In contrast, plasma concentrations in our
MOF patients were greater than those in patients
receiving pain relief with i.v. lignocaine infusions
[18]. Despite these concentrations, we did not
observe any signs of systemic toxicity in our patients
with MOF. The relationship between blood concen-
trations of local anaesthetic to symptoms of toxicity
is less clear [19]. Increased protein binding of local
anaesthetics in the presence of increased plasma
concentrations of local anaesthetics has been shown
to exist without signs of serious toxicity in post-
operative patients [20]. Changes in the plasma
protein profile of our patients were not measured and
so a similar mechanism cannot be excluded. The
central nervous system toxicity of lignocaine is
sensitive to acid—base balance; all our patients had
changes varying between mild acidosis and mild
alkalosis (table II). Three of the four MOF patients
required additonal i.v. sedation with midazolam that
might have masked neurological signs of toxicity.
Although extradural analgesia relieved pain and
facilitated weaning from the ventilator, our obser-
vations suggest that a continuous extradural infusion
of lignocaine should only be considered in intensive
care patients without MOF or in the presence of
regular monitoring of plasma concentrations of
lignocaine.
REFERENCES
1. Worthley LIG. Thoracic epidural in the management of chest
trauma. A study of 161 cases. Intensive Care Medicine 1985;
11: 312-315.
2. Cicala RS, Voeller GR, Fox T, Fabian TC, Kudsk K,
Mangiante EC. Epidural analgesia in thoracic trauma: effects
of lumbar morphine and thoracic bupivacaine on pulmonary
function. Critical Care Medicine 1990; 18: 229-231.
3. Yeager MP, Glass DD, NeffRK, Brinck-Johnsen T. Epidural
anesthesia and analgesia in high-risk surgical patients.
Anesthesiology 1987; 66: 729-736.
4. Thorburn J, Moir DD. Bupivacaine toxicity in association
with extradural analgesia for Caesarean section. British
Journal of Anaesthesia 1984; 56: 551-553.
5. Thomson PD, Melmon KL, Richardson JA, Cohn K,
Steinbrunn W, Cudihee R, Rowland M. Lidocaine pharma-
cokinetics in advanced heart failure, liver disease and renal
failure in humans. Annals of Internal Medicine 1973; 78:
499-508.
6. Goris RJA, teBoekhorst TPA, Nuytinck JKS, Gimbrcre
JSF. Multiple-organ failure. Generalized autodestructive
inflammation? Archives of Surgery 1985; 120: 1109-1115.
7. Montgomery AB, Stager MA, Carrico CJ, Hudson LD.
Causes of mortality in patients with respiratory distress
syndrome. American Review of Respiratory Disease 1985; 132:
"485=489." - - - - - - - - - -
8. Spoerel WE, Thomas A, Gerula GR. Continuous epidural
analgesia: experience with mechanical injection devices.
Canadian Journal of Anaesthesia 1970; 17: 37-51.
9. Abboud TK, Afrasiabi A, Sarkis F, Daftarian F, Nagappala
S, Noueihed R, Kuhnert BR, Miller F. Continuous infusion
epidural analgesia in parturients receiving bupivacaine,
516
chloroprocaine, or lidocaine—maternal, fetal, and neonatal
effects. Anesthesia and Analgesia 1984; 63: 421^28.
10. Fischer RL, Lubenow TR, Liceaga A, McCarthy RJ,
Iankovich AD. Comparison of continuous epidural infusion
of fentanyl-bupivacaine and morphine-bupivacaine in man-
agement of postoperative pain. Anesthesia and Analgesia
1988; 67: 559-563.
11. Eudeikis JR, Groth MC, Smith CM. A fluorescence polar-
ization immunoassay for the quantitation of lidocaine. Clinical
Chemistry 1982; 28: 1667.
12. Glosten B, Sessler DI, Ostman LG, Faure EAM, Karl L,
Thisted RA. Intravenous lidocaine does not cause shivering-
like tremor or alter thermoregulation. Regional Anesthesia
1991; 16: 218-222.
13. Aps C, Bell JA, Jenkins BS, Pool-Wilson PA, Reynolds F.
Logical approach to lignocaine therapy. British Medical
Journal 1976; 1: 13-15.
14. Tucker GT. Pharmacokinetics of local anaesthetics. British
Journal of Anaesthesia 1986; 58: 717-731.
15. Benowitz N, Forsyth RP, Melmon KL, Rowland M.
BRITISH JOURNAL OF ANAESTHESIA
Lidocaine disposition kinetics in monkey and man. II: Effects
of hemorrhage and sympathomimetic drug administration.
Clinical Pharmacology and Therapeutics 1974; 16: 99-109.
16. Davison R, Parker M, Atkinson AJ. Excessive serum
lidocaine levels during maintenance infusions: mechanisms
and preventions. American Heart Journal 1982; 104: 203-208.
17. Feely J, Wilkinson GR, McAllister CB, Wood AJJ. Increased
toxicity and reduced clearance of lidocaine by cimetidine.
Annals of Internal Mediane 1982; 96: 592-594.
18. Birch K, Jorgensen J, Chraemmer-Jergensen B, Kehlet H.
Effect of i.v. lignocaine on pain and the endocrine metabolic
responses after surgery. British Journal of Anaesthesia 1987;
59:721-724.
19. Wildsmith JAW. "Neurological" complications of extradural
bupivacaine. British Journal of Anaesthesia 1992; 68: 327-
328.
20. Renck H, Edstrdm H, Kinnberger B, Brandt G. Thoracic
epidural analgesia—II: Prologation in the early postoperative
period by continuous injection of 1 % bupivacaine. Ada
Anaesthesiologica Scandinavica 1976; 20: 47—56.
Downloaded from http://bja.oxfordjournals.org/ at University of Exeter on July 18, 2015