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Appropriate number of plasma exchanges in Guillain-Barr syndrome.

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ORIGINAL ARTICLES
Appropriate Number of Plasma Exchanges in
Guillain-Barri: Syndrome
The French Cooperative Group on Plasma Exchange in Guillain-Barrt Syndrome*
Plasma exchange (PE) is the standard treatment in Guillain-Barrt syndrome (GBS) patients who have lost the ability to
walk. The effect of exchanges before this stage and the optimal number of exchanges for the other patients are still
unknown. We randomized 556 GBS patients according to severity and number of exchanges as follows: Zero versus 2
PEs for patients who could walk-with or without aid-but not run, or who could stand up unaided (mild group); 2
versus 4 PEs for patients who could not stand up unaided (moderate group); and 4 versus 6 PEs for mechanically
ventilated patients (severe group). In the mild group, 2 PEs were more effective than none for time to onset of motor
recovery (median, 4 vs 8 days, respectively). In the moderate group, 4 PEs were more beneficial than 2 for time to walk
with assistance (median, 20 vs 24 days) and for 1-year full muscle-strength recovery rate (64% vs 46%). Six PEs were no
more beneficial than 4 in the severe cases. Patients with mild GBS on admission should receive 2 PEs. Patients with
moderate and severe forms should benefit from 2 further exchanges.
The French Cooperative Group on Plasma Exchange in Guillain-Bard Syndrome. Appropriate number of plasma
exchanges in Guillain-Bard syndrome. Ann Neurol 1997;41:298-306
Since the disappearance of poliomyelitis, Guillain-Barrt
syndrome (GBS) is the most common cause of acute
flaccid paralysis. For the last three decades, GBS mortality has been halved with the improvement of intensive care procedures [l]. However, 5 to 10% of patients still die and motor sequelae persist in 15 to 25%
[ 1-31. Therefore, a specific treatment is needed.
Oral [4] and intravenous steroids [5] have proved
ineffective. The rationale for plasma exchange (PE) was
the existence of a circulating factor that reproduces in
vitro the electrophysiological and histological patterns
of demyelination [6-10]. Two large randomized clinical trials in severe GBS, comparing exchange with no
treatment, have previously shown a short-term [ 11, 121
or 1-year benefit [13] of PE. More recently, a Dutch
trial [ 141 has produced strong evidence that intravenous immune globulin (IVIg) is as effective as PE in
severe GBS. However, the indications for PE and IVIg,
respectively, are still controversial [ 15-17]. Preliminary
results of the Plasma ExchangeISandoglobulin
Guillain-Barrt Syndrome Trial Group [ 181 suggested,
in 383 patients unable to walk without aid at randomization, no difference in outcomes after 5 PEs, or IVIg
for 8 days at 0.5 gmlkglday, or the combination of
both treatments. At the present time, combined therapy associating IVIg with intravenous methylpred-
nisolone or PE is under prospective assessment in one
international randomized clinical trial.
Most patients enrolled in previous trials of PEs
could not walk at randomization and the number of
exchanges ranged from 3 to 5 over 2 weeks [12] to 4
over 1 week [13]. The potential benefit of PE for patients who can still walk remains to be determined; it is
also possible that patients with severe forms requiring
mechanical ventilation might benefit from a greater
number of sessions, given the delayed disappearance of
the demyelinating factor [9]. The aim of this multicenter study was to compare two treatment schedules
in each of three severity groups. Patients who could
or without aid-but who could not run,
walk-with
or who could stand up unaided (mild group) were randomly assigned to surveillance alone or 2 PEs; those
who could not stand up unaided (moderate group)
randomly received 2 or 4 exchanges; and mechanically
ventilated patients (severe group) had 4 or 6 exchanges.
*The members of the French Cooperative Croup on Plasma Exchange in Guillaiti-Bard Syndrome are listed in the Appendix.
Study chairman: Jean-Claude Raphael, MD, HBpital Raymond
Poincart-, Garches; Statistical center: Sylvie Chevret, MD, PhD,
Claude Chastang, MD, PhD, HBpital Saint-Louis, Paris; Study secretary: Marie-Claude Jars-Guincestre, MD, Hhpital Raymond Poincare, Garches.
Received Feb 23, 1996, and in revised form Jun 17, Sep 3, and Oct
24, 1996. Accepted for publication Oct 28, 1996.
298
Patients and Methods
Eligibility
All patients more than 16 years old with GBS [19] were
eligible for the trial if motor signs had first occurred less than
1 month previously. Excluded patients were pregnant
women, patients with atypical forms [I 11, spontaneous im-
Address correspondence to Prof Raphael, Service de R6aniination
MCdicale, HBpital Raymond Poincark, 92380 Garches, France.
Copyright 0 1997 by the American Neurological Association
provement over the first 2 days, severe intercurrent disease
(cancer, blood dyscrasia, insulin-dependent diabetes mellitus,
or severe kidney or liver disorders), any motor sequelae of a
previous neurological disorder, contraindications to PE (major hemostatic disorders, infection in progress, or unstable
cardiovascular status), and those who could not be exchanged
due to technical constraints on the randomization day. Only
misdiagnosed patients could be excluded after randomization. The protocol was approved by the ethics committee of
the Socittt de Rkanimation de Langue Francaise; written informed consent was not required, in keeping with French
legislation at the time.
Randomization and Treatment Schedule
Twenty-seven centers in France and Switzerland participated.
Eligibility criteria were first checked for 2 days, then patients
were randomized (day 2) through a centralized telephone assignment procedure stratified by center and severity group, as
assessed on the randomization day. Definitions of severity
groups were the following: Mild group: patients who could
walk more than 5 m without human or technical assistance
but who could not run (grade 2 of Hughes’ Classification)
[5]; patients who could walk more than 5 m with assistance,
that is, with the help of one adult, walking frame, or stick
(Hughes’ grade 3); and patients who could stand unaided.
Moderate group: patients unable to stand unaided. Severe
group: mechanically ventilated patients (Hughes’ grade 5). In
each group, patients were randomized between two treatment arms, as follows: (1) mild group: observation only
(control arm) or 2 PEs; (2) moderate group: 2 or 4 PEs; and
(3) severe group: 4 or 6 PEs.
PEs began on the randomization day and were repeated
every second day. Each session consisted of 1.5 plasma volumes; they were pursued even if amelioration, stabilization,
or relapse occurred (see below). However, patients with mild
or moderate forms who showed clinical deterioration were
reclassified in the three-group severity scale and received 2 or
4 further exchanges. For instance, patients initially placed in
the mild group and randomized into the control arm would
receive 2 exchanges if they reached the moderate stage and 2
additional exchanges if they required mechanical ventilation.
Sessions would be discontinued in case of serious adverse
events. Several methods were used to limit morbidity [I 1,
201; ie, each session was preceded by volume expansion with
500 ml of gelatin solution and intravenous injection of 1 mg
of atropine [2O], and the replacement fluid consisted of equal
amounts of gelatin solution and 4% albumin solution. The
equipment, vascular access, and calcium injection were decided by each center. Each exchange was described on a standardized form recording parameters measured before and after each session and including all adverse events [20].
Neither immunosuppressive therapy nor infusion of immune
globulin was allowed.
FOLLOW-up
Patients were examined at randomization, every 2 days for
12 days, every 3 days until day 30, on day 45 and day 60,
and then every month until hospital discharge. Each examination included a complete neurological assessment, with an
evaluation of cranial nerve functions, trunk or respiratory
muscle involvement, sensory loss, reflexes, and a functional
score. The purpose of this functional score was to provide a
more sensitive evaluation of muscle strength than traditional
scales (see below) [ I l l . Functional score was based on 28
equally weighted functional tests of either the upper limbs
(move fingers, hold a pen between thumb and forefinger,
flex forearm over arm in the pronation and supination position, lift elbow above bed plane, and maintain arms outstretched) or the lower limbs (move toes, ankle dorsiflexion
and plantar flexion, knee flexion above bed plane, raise and
maintain lower limb above bed plane, stand up, walk with
and without assistance, and stand up from a squatting position) [ I l l . In an attempt to reduce the interobserver and
intercenter variability, score responses were binary (yes or
no). The raw score was the number of completed tasks out
of 28, which was subsequently converted to the functional
score by dividing by 28 and multiplying by 100. For example, a subject who completed seven tasks would receive a raw
score of 7,which would then be divided by 28 and multiplied by 100 to give a functional score of 25. The delta
score, ie, the algebraic difference between the score at each
evaluation day and the baseline score value measured at randomization, was then computed. A negative delta score indicated deterioration, whereas positive delta scores indicated
improvement. Other treatments and complications such as
pneumonia, bacteremia, and autonomic dysfunction (severe
bradycardia, ie, a fall of more than 20 beatslmin; rise or drop
in systolic blood pressure exceeding 40 m m Hg) were recorded. Relapse was defined as a deterioration of at least two
functional items on two consecutive examinations. A final
neurological examination was scheduled at 12 months.
Endpoints
A primary endpoint was the time required to recover the
ability to walk with assistance (Hughes’ grade 3). This could
not be assessed when patients were able to walk with assistance at randomization (mild group). The time to onset of
motor recovery was thus used as a main endpoint for the
mild group, and was defined as the time required to recover
at least two functional items or one item with an improvement in cranial nerve function or trunk or respiratory muscle
involvement. This was a secondary endpoint in the moderate
and severe groups.
The following secondary endpoints were used: (1) the
delta score at day 8 as defined above; (2) the proportion of
patients with mild and moderate forms who deteriorated, ie,
whose severity group worsened; or (3) those who required
ventilator assistance; (4)the time on the ventilator; (5) the
time required to walk unassisted (Hughes’ grade 2); (6) the
time to hospital discharge; and (7) the frequency of relapse.
One year after randomization, the last endpoint was the proportion of patients attaining full muscle strength, that is, the
proportion of complete and incomplete recoveries as defined
through the use of the following four-group classification
[ 131: Complete recovery was defined by normal neurological
examination, notably with full motor recovery; incomplete
recovery was defined as full motor recovery of the four limbs
and cranial nerves associated with persistent abnormal neurological findings such as loss of tendon reflexes or impaired
sensation; severe motor sequela was defined by the loss of at
French Cooperative Group: Plasma Exchange in Guillain-Bark Syndrome
299
The required sample size was estimated for each main endpoint. On the basis of our previous results [ 111, the median
time to onset of motor recovery was estimated at 8 days in
the mild group; the median time to walk with assistance after
2 PEs was estimated at 50 days in the moderate group and
55 days in the severe group. Treatment benefit was defined
in the mild group 3s a 50% reduction in the median time to
onset of motor recovery; in the other groups, it was defined
as recovery of walking ability within a median of 40 days.
With a type I error of 0.10 and a type I1 error of 0.10 in a
two-sided test, the estimated sample sizes in the mild, moderate, and severe groups were 91, 121, and 53 patients, respectively. Given the expected recruitment frequencies for severity groups, an esrirnated 480 patients had to be recruited.
Results
From January 1386 to March 1933, 684 patients with
GBS were eligible for inclusion; 121 of these patients
were not randomized because of atypical forms or serious intercurrent disorders (n = 5 8 ) , contraindications
to PE (n = 30), spontaneous improvement (n = 21),
human immunodeficiency virus infection (n = 8), refusal (n = G), motor sequelae (n = 3), and/or technical problems (n = 1). Seven misdiaposed patients
(four chronic forms, spinal compression, diabetic neuropathy, and acute intermittent porphyria) were excluded.
Of the 556 randomized patients, 91 were in the
mild group, 304 in the moderate, and I61 in the severe groups. Age increased from the mild to severe
groups as severity did, more expectedly. Some imbalances, for instance, in mean score value, were observed
between the two treatment arms in each group (Table
1). We further examined treatment effects separately in
each severity group (Table 2).
Statistical Analysis
Mild Group
least one of the following six functions: ability to walk, with
or without aid, climb stairs, dress, cut meat, or write; and
remainders. This remaining group contained patients with
moderate paralysis that did not inhibit any of the six functions listed above (for example, isolated facial paralysis).
Estimation of Sample Size
Of the 91 patients with mild forms at randomization,
51 could walk unaided, 30 could walk with assistance,
and 10 could only stand up alone. Forty-five patients
were assigned to receive 2 exchanges and 46 to receive
none. Randomizations in the 2 PEs arm were less de-
The analysis was done on an intention-to-treat basis, with
July 1, 1994, as the reference date for failure time data analyses. Wilcoxon’s rank sum test and Fisher’s exact test were
used for uncensored data [211. The Kaplan-Meier estimate
and the log rank test were used for censored data, and the
Cox model was used to adjust the treatment difference for
unbalanced and prognostic covariates, then tested by the
likelihood ratio test [22]. We computed the 95% confidence
intervals of relative hazard using “chance of” rather than
“risk of” owing to the desirable outcome. Patients who died
were censored at the time of death in all calculations of failure times. Treatments were compared by using two-sided
tests. p values of 0.05 or les5 denoted statistical significance.
We used the SAS (SAS Institute Inc, Cary, NC) and BMDP
(BMDP Statistical Software, Los Angeles, CA) software
packages.
layed after motor onset and patients presented, on average, higher functional score than in the control arm
(see Table 1). The median estimated time to onset of
motor recovery (Fig 1A) was 4 days in the 2 PEs arm
compared with 8 days in the control arm ( p = 0.0002,
by the log rank test). The treatment comparison was
adjusted for two imbalanced (time since motor onset
and functional score) and two prognostic (ability to
walk aided or unaided) covariates. Accounting for these
imbalances did not markedly modify the results. The
Table 1. Main Baseline Characteristics (Mean i Standard Deviation) of
According to Treatment Allocation at Randomization
the
Three Severity Group
Number of Scheduled Sessions
Mild Group
Moderate Group
Severe Group
0
2
2
4
4
6
(n = 46)
(n = 45)
(n = 149)
(n = 155)
(n = 81)
(n = 80)
Age (yr)
Male gender
Time since motor onset (days)
Score
4 0 2 15
29 (63Y0)
10 % 6
89 +- 12
4 0 1 15
28 (62%)
7 i 4
93 % 6
4 6 % 117
83 (56%)
58 % 25
4 7 % 18
87 (56%)
826
62 2 22
5 0 % 19
43 (53%)
7 2 5
33 % 24
48 2 19
47 (59%)
7 f 5
30 ? 24
Ability to walk
Walking unassisted
Walking assisted
Stand up unaided
26 (56%)
15 (33%)
5 (11%)
25 (56%)
15 (33%)
5 (11%)
2 (1%)
0
0
5 (3%)
0
0
300
Annals of Neurology
Vol 41
No 3
March 1997
8 2 4
0
0
0
0
0
0
Table 2. Clinical Course According to Severity Group and Treatment Arm
Number of Scheduled Sessions
Mild Group
0
(n = 46)
Short-term endpoints
Time (median, days) to
Onset of motor recovery
Walk assisted
Walk unassisted
8
14
28
Mean delta score on day 8
Clinical deterioration
Ventilated patients
Length of ventilation (median,
days)
Time to hospital discharge
(median, days)
-6 t 19
One-year endpoint'
Full muscle-strength recovery
Complete recovery
Incomplete recovery
Severe motor sequelae
Remainders
(n = 42)
25 (60%)
20
18 (39%)
6 (13%)
2
(n = 45)
4
12
15
3 2 7
2 (4%)
1 (2%)
Moderate Group
p
2
(n = 149)
4
(n = 1 5 5 )
0.0002
0.80
0.40
6
24
64
20
52
0.005
0.0001
0.11
I>
b
18
13
0.02
(n = 42)
33 (77%)
28
0.10
5
2 (50/0)
15 (35%)
5
0
9 (23%)
0.24
5
Severe Group
p
4
(n = 81)
6
(n = 80)
p
0.10
0.04
0.13
8
56
113
8
60
103
0.1 1
0.89
0.64
6 2 26
0.48
6 2 22
6 2 22
8 2 2
42 (28%)
37
41 (26%)
15
1.00
0.005
43
80 (100Yn)
34
0.96
26
21
0.04
50
44
0.57
(n = 79)
45 (57%)
29
16
15 (19%)
19 (24%)
(n = 7 3 )
39 (53%)
31
8
14 (19%)
20 (28%)
(n
67
45
22
24
49
= 140)
(48%)
(17%)
(35%)
(n = 144)
93 (64%)
67
26
12 (9%)
39 (27%)
0.006
0.05
81 (100%)
0.88
0.63
1.00
"Deteriorations in the moderate group coincided with ventilated patients, but it was not defined in the severe group.
hMedian times were not computed, given the small sample sizes.
'Excluding patients lost to follow-up or dead at 1 year (see Table 3).
adjusted chance of motor recovery in the 2 PEs arm
was twice that of the control arm (95% confidence interval, 1.4-3.7; p = 0.001). The favorable effect of
exchanges was confirmed on the secondary endpoints
(see Table 2). Fewer patients in the 2 PEs arm deteriorated ( p = 0.0001) or required mechanical ventilation, although nonsignificantly ( p = 0.1 1). In the control arm, the mean delta score first fell, then rose,
reflecting the natural course of the disease, while in the
2 PEs arm it increased immediately (Fig 2A) with a
significant difference on day 8 relative to the control
arm ( p = 0.005, by the Wilcoxon test). As expected,
the estimation of time to walk, with or without assistance, was not informative in this group as most of
these patients could walk at randomization. Indeed, the
loss of walking with assistance only concerned I 0 patients and that of wallung unassisted, 40 patients.
Seven patients were lost to follow-up or dead at 1 year.
In the 84 remaining patients, a mild but not statistically significant ( p = 0.10, by Fisher's test) increase of
the proportion of patients attaining full muscle
strength was observed in the 2 PEs arm.
Modeyate Group
Seven patients of the moderate group were misplaced
(see Table 1) because they could still walk without assistance (Hughes' grade 2) at randomization; they were
kept in the moderate group for the analysis. One hundred forty-nine patients were assigned to receive 2 ex-
changes and 155 to receive 4 exchanges. The time required to walk with assistance (Fig 1B) was shorter in
the 4 PEs than in the 2 PEs arm ( p = 0.04, by the log
rank test). This relative benefit was slightly reduced after adjusting for the prognostic functional score assessed at randomization (relative chance of motor recovery, 1.2; 95% confidence interval, 0.95-1.6; p =
0.1 1). A similar trend toward the benefit of 4 versus 2
exchanges was observed in terms of time required to
walk unassisted ( p = 0.13), the time on the ventilator
( p = 0.005), and the mean delta score (Fig 2B), although the latter did not differ significantly between
the treatment arms on day 8 ( p = 0.48). The time to
onset of motor recovery was also slightly shortened in
the 4 PEs relative to the 2 PEs arm ( p = 0.10), as was
the hospital stay ( p = 0.04). Finally, from the 284
one-year assessments, the frequency of full musclestrength recovery was increased in the 4 PEs arm telative to the 2 PEs arm ( p = 0.006).
Severe Group
Six exchanges (n = 8 1 ) were no more beneficial than 4
exchanges (n = 80), whatever the endpoint used (see
Table 2). The relative chance of recovering the ability
to walk with assistance (95% confidence interval, 0.61.4; p = 0.89; Fig 1C) or unaided (95% confidence
interval, 0.8-1.6; p = 0.64) was similar in both arms,
as was the mean delta score at day 8 ( p = 0.88; Fig
2C). The time to onset of motor recovery was slightly
French Cooperative Group: Plasma Exchange in Guillain-Bard Syndrome
301
A
shortened in the 4 PEs arm, with a relative chance of
motor recovery estimated at 1.25 (95% confidence interval, 0.9-1.7; p = 0.11). The time on the ventilator
was close in the two arms ( p = 0.96), as was the
length of hospital stay ( p = 0.57). Finally, a t 1 year,
besides the 9 patients lost to follow-up or dead, no
difference was observed between the two arms in terms
o f full muscle-strength recovery rate ( p = 0.63).
%with onset 01 motor recovery
10090 80
70
60
50
...Y
~
~
-
Plasma Excbanges: Compliance a n d Adverse Events
The protocol scheduled the first PE on the randomization day. In the mild group, 38 (84%) of the 45 patients assigned to the 2 PEs arm had the first session
on the randomization day, 5 on the following day, and
2 thereafter. In the moderate group, PE started on the
randomization day in 277 patients (91%), including
133 (89%) patients in the 2 PEs arm and 144 (93%)
in the 4 PEs arm. In the severe group, PE began on the
randomization day in 74 patients (91%) of the 4 PEs
arm and 72 (90%) of the 6 PEs arm. Whatever the
severity group, the main cause for delayed PE was technical constraints.
A total of 1,925 PEs were done, on either a cell separator (40%) or a filtration membrane (60%). The exchanges were distributed as follows: 165 in the mild
group, 1,015 in the moderate group, and 745 in the
severe group. The median volume exchanged was
3,500 ml/session (range, 3,000-7,500 ml).
At least one adverse event occurred during 455
(24%) sessions in 248 patients (29%, 48%, and 48%
in the mild, moderate, and severe groups, respectively).
The most frequent events were a fall (8%) or rise (5%)
in systolic blood pressure of at least 40 mm Hg, a fall
in heart rate o f at least 20 beatdmin (3%), chills (4%),
a rise in temperature exceeding 1°C (3%), and skin
rashes (0.8%).
In 37 patients (?Yo), PEs were discontinued (mild
group, n = 2; moderate group, n = 16; severe group,
n = 19). One death occurred before the first session in
the 4 PEs arm of the severe group, due to aortic dissection during catheterization of the subclavian vein.
Otherwise, treatment discontinuation was mostly due
to the occurrence of intercurrent complications (n =
24), primary vascular access difficulties (n = 14),
andlor severe intolerance (n = 9).
40.
2
30-
-mild
6-
20:
group, control arm
---.mild group, 2 PE-arm
1
;
10-
'r
B
% with walking ability aided
1001
J
.<.<.<.*
.._.
.......................
50
40group, 2 PE-arm
-moderate
30-
moderate group, 4 PE-arm
-:-=
' 5
lo-;
0
1
.
.
.
.
,
2
0
,
.
6
4
.
.
,
8
10
.
~
12
months after randomization
C
%with walking abillty aided
lo
90o
1
~.
..--.
-.
.>>.
f7i'
?f
50 40
-
30
-
20
.
=.
...?
70 60
.._.
,.-..--.
~
80 -
:/
-severe
group, 4 PE-arm
.:--.severe group, 6 PE-arm
10 -
0j.E.
0
.
2
.
4
,
4
6
8
10
12
months after randomization
302 Annals of Neurology
Vol 41
No 3
March 1997
Fig 1. Estimation of tbe primary endpoints in the mild, moderate, and severe groups. (A) Mild group: Percentages of patients with onset of motor recovery after randomization in the
control arm (-) and in the 2 PEs arm (- - -). (B) Moderate
group: Percentages of patients becoming able to walk with
assistance after randomization in the 2 PEs arm (-1 and in
the 4 PEs arm (- - -). (C) Severe group: Percentages o f patients becoming able to walk with assistance after randomization in the 4 PEs arm (-) and in the 6 PEs arm (- - -).
A
Complications
mean A score i SEM
I
f
mild group, control arm
-8-
mild group, 2 PE-arm
Complications are listed in Table 3 according to the
severity group and treatment arm. In the mild group,
there was no difference between the two treatment
arms in the frequency of complications, except for relapses, all three of which occurred in the 2 PEs arm
(on days 13, 16, and 17), although the difference was
not significant ( p = 0.12, by Fisher’s test). In the
moderate group, systolic blood pressure instability
( p = 0.04), hematomas ( p = 0.02), and deaths ( p =
0.05) were more frequent in the 4 PEs arm than in the
2 PEs arm, while the relapse rate was similar in both
( p = 1.00). No difference in the frequency of complications in the two severe arms was observed, apart
from a lower frequency of systolic blood pressure instability in the 4 PEs arm (26% vs 46%, p = 0.001).
Causes of the 21 deaths observed within the first year
in the three severity groups are given in Table 3 . Only
one death, as described above, could be directly related
to the exchanges.
1
-12
’
2
4
6
8
10
12
days after randomization
14
mean A score f SEM
1
J
c
Discussion
Until recently, the standard treatment for GBS was PE,
but the optimal procedure and the number of sessions
are still unknown. We standardized the exchange technique to minimize the risk of adverse events in these
patients exposed to autonomic impairment [2].The exchanged volume was reduced from 2 to 1.5 plasma volumes (40 ml/kg), in accordance with previous reports
in other autoimmune diseases [23]. Sessions were
scheduled every second day, although more frequent
sessions have been recommended [24]. Severity was
classified into three groups, based on previous reports
demonstrating that poor outcome is likely after rapid
onset [2, 3 , 25, 261. Incidentally, we confirmed the
prognostic value of this classification. The median time
to walk with assistance was 13 days in the mild group
but rose to 58 days in the severe group; likewise, the
percentage of patients with full muscle strength at 1
year was 69% in the mild group and rose to 55% in
the severe group.
Two PEs were more beneficial than none in patients
with mild forms at randomization, as shown by shortterm endpoints. The 2 PEs arm seemed to be favored
at randomization, as illustrated by the shorter mean
time since motor onset and the higher mean score in
that group than in the control group (see Table 1).
Nevertheless, the benefit of this 2 PEs arm, in terms of
days after randomization
mean A score k SEM
2o
1
I
2
4
6
8
10
12
days after randomization
14
4
Fig 2. Changes over time of mean deha score (A score) ?
standard error of the mean (SEM) after randomiation, in
the mild (A), moderate (B), and severe groups (C), according
to the treatment arm. The A score is the algebraic dzfference
between the score at each evaluation duy and at randomization day (day 2). Negative and positive values correspond to
deterioration and improvement of muscle function, respectively.
French Cooperative Group: Plasma Exchange in Guillain-Barre Syndrome 303
Table 3. Complications During Plasma Exchanges
Number of Scheduled Sessions
Moderate Group
Mild Group
0
(11
Pneumonia
Systolic blood pressure
instability
Bradycardia
Septicemia
Pulmonary embolism
Gastrointestinal bleeding
Complications of endotracheal
intubation
Hemaromas at vein
puncture site
Relapses
Death at 12 months”
=
46)
2
(n
2
=
45)
p
(n = 149)
4
(n
Severe Group
4
=
155) p
(n = 81)
6
(n
=
80)
p
6 (13%)
8 (17%)
2 (4%)
4 (9%)
0.27 41 (28%)
0.54 27 (18%)
33 (22%)
44 (29%)
0.28 49 (6OYo)
0.04 21 (26%)
59 (74%)
37 (46%)
0.12
6 (13%)
2 (4%)
5 (11%)
0
0
0.41 22 (27%)
0.59 9 (11%)
0.28 1 (1%)
0.44 2 (2%)
0.76 6 (7%)
20 (25%)
15 (19%)
2 (2%)
1(2%)
2 (4%)
1.00 19 (13%)
0.49 6 (4%)
5 (3%)
1.00 4 (3%)
0.50 5 (3%)
25 (17%)
0
1.00
0.34
1.00
0.44
1.00
1(2%)
1 (2%)
1.00
9 (6%)
23 (15%)
0.02
7 (9%)
0
3 (7%)
0
0.12
1.00
5 (3%)
5 (30/0)
11 (7%)
1.00
0.05
5 (6%)
1 (2YO)
3 (2%)
8 (5%)
2 (1%)
2 (1%)
7 (5%)
2 (2%)
5 (6%)
5 (6%)
0.001
11 (14%) 0.33
1(1%)
4 (5%)
0.21
0.44
”Mild group, control arm: pneumonia with esophageal-tracheal fistula; moderate group, 2 PEs arm: pneumothorax, septic shock,
or myocardial infarction; moderate group, 4 PEs arm: cirrhosis (n = 3), infection (n = 2), myocardial infarction (n = 2), aortic
rupture, pulmonary embolism, pneumothorax, or cardiac arrest in a bedridden patient; severe group, 4 PEs arm: pulmonary
embolism or infection; severe group, 6 PEs arm: infection (n = 2), adult respiratory distress syndrome, or coma.
time to onset of motor recovery, persisted after adjustment on four imbalanced and prognostic covariates.
Another benefit of 2 over no exchanges concerned the
percentage of patients with further clinical deterioration. These findings were confirmed by the mean delta
score course (see Fig 2A). The traditional endpoint,
that is, time to walk assisted or unassisted, was not useful in this group, because, by definition, most mild patients did not lose these functions after randomization.
Therefore, one could not compute the time to recover
walking after randomization in these patients who are
still walking. There was also a trend toward the benefit
of 2 over no exchanges in the mild group at 1 year, as
shown by the higher percentage of full muscle-strength
recoveries (77% vs GO%), although this was not statistically significant. In the mild group, exchanges were
finally well tolerated and did not increase the frequency
of complications of GBS, with the exception of relapses, an unexpected finding.
In mechanically ventilated patients (severe group), 6
exchanges were no more beneficial than 4, either in the
short term or at 1 year. In regard to adverse events
during the exchanges, the only difference between the
two arms concerned systolic blood pressure instability,
which was more frequently reported in the 6 PEs arm
(46% vs 26%). Severe complications were otherwise
similarly observed in both arms of that group, with six
relapses and six deaths. Given that treatment started
about 1 week after motor onset (see Table 1) and that
4 exchanges took 1 week to complete, the lack of benefit of 2 additional exchanges is in agreement with the
poor reported efficacy of delayed exchanges [ 121.
304
Annals of Neurology Vol 41
No 3
March 1997
In patients with moderate forms, those assigned to 4
PEs better improved than those assigned to receive 2
PEs. For instance, the time on the ventilator was
shorter after 4 than after 2 exchanges, as previously
shown [12, 131. Notably, this decreased time on ventilator in the 4 PEs arm could explain the lower incidence of pneumonia in that arm relative to the 2 PEs
arm (22% vs 28%, respectively). Otherwise, the frequency of blood pressure instability increased with the
number of PEs from 18% with 2 PEs to 29% with 4
PEs, possibly related to the volemic disturbances induced by the exchanges in these patients at high risk of
dysautonomia. In this moderate group, the higher
1-year mortality rate in the 4 PEs arm (7% vs 2%)
should be interpreted cautiously, given these deaths occurred after cotnpletion of PE and involved various
causes.
In all patients, whatever the severity group, the overall incidence of adverse events was lower than that observed in our previous protocol (24% of sessions compared with 65%) [21]. In addition, fewer sessions had
to be discontinued (7% vs 14%), possibly due to our
increased experience and the use of albumin solution as
replacement fluid. The overall relapse rate was low
(3%) but within the range of reported values (2-13%)
11, 5, 12, 141. This challenges strongly the opinion
that PEs can cause relapses [27, 281.
Several methodological points must be discussed.
First, our trial was based on a three-group severity classification instead of the commonly used scale proposed
by Hughes [5]. Nevertheless, the two classifications are
close, as described below: The severe group coincides
with Hughes’ grade 5; the moderate group is close to
Hughes’ grade 4; all other patients constitute the mild
group, including patients from Hughes’ grade 2 (onehalf) or grade 3 (one-third) and patients intermediate
between Hughes’ grades 3 and 4. Second, the trial was
not blinded, as observers could easily know the administered treatment. Further, we considered sham exchanges to be unethical in this acute disease. Third,
owing to the high number of involved centers, discrepancies between centers and observers regarding the
measure of the severity groups and endpoints may have
been introduced. In order to limit such inter- and
within-observer variability, the protocol scheduled
checkup procedures, notably with centralized review of
all information gathered in case reports. This allowed
us to identify 7 (2%) misplaced patients in the moderate group at randomization. However, contrary to
the Dutch Trial Group [14], the endpoints were not
independently measured by a physician unaware of the
randomization process, owing to the large number of
patients and centers involved. Nevertheless, concordant
results were observed in our series, suggesting such
endpoints were clinically relevant; ie, the time to recover walking with or without assistance increased according to the severity of the GBS at randomization,
and was associated with the 1-year outcome. The decreased time to onset of motor recovery in the 2 PEs
mild group and the 4 PEs moderate group was associated with a decreased length of hospital stay in these
groups. Finally, many results are in agreement with
previous results, increasing our level of confidence in
the results. The median time to onset of motor recovery was 8 days in the severe group, as previously reported [l I]. The median time to recover walking ability with assistance ranged from 56 to 60 days in the
severe group, compared with 50 days in our previous
study [ 111. The median time on the ventilator was between 34 and 43 days in the severe group, while this
was 27 days in the North-American study [12], and
ranged between 18 and 27 days in the recent international study assessing corticosteroids [ 5 ] .
Optimal treatment of GBS has been investigated for
almost 15 years. The first effective treatment was PE.
Results of controlled clinical studies showed that PE
alone reduced the time to walk, with or without assistance, as well as the time on the ventilator. In addition,
PE was reported to reduce the frequency of neurovegetative disorders and to increase at 1 year the proportion of patients recovering muscle strength, but without decreased frequency of severe sequelae [ I I , 131.
Unfortunately, PE is not widely available due to technical constraints, also responsible for delayed administration of PE. Indeed, in 7 to 16% of cases, PE did not
begin on the randomization day, as scheduled by the
protocol. Moreover, some GBS patients have contraindications to PE, either prior to randomization (4% in
our series) or resulting in treatment discontinuation
(7%). More recently, IVIg has been proposed as a
promising treatment for GBS, possibly as effective as
PE but easier to administer [14]. Such a view should
be confirmed, notably on 1-year endpoints and, at this
time, IVIg should not be used solely on the basis of its
simplicity. Preliminary results of the International London Group [18] seem to confirm the equivalence of
IVIg and PE, with no superiority of the IVIg-PE combination. The optimal choice between PE and IVIg
and the optimal dosage of IVIg remain to be determined. Therefore, we have initiated two multicenter
randomized clinical trials to compare PE and I&.
The first trial aims at a comparative assessment of PE
and IVIg in three severity groups as defined above. The
second double-blind controlled clinical trial compares
two dosages of IVIg in GBS patients with contraindications to exchange. Another study, still under way,
which compares Ivlg and IVIg with methylprednisolone, suggests that PE could be abandoned as the
standard treatment of GBS by some neurologists.
In summary, we recommend that mild forms of
GBS should receive 2 PEs; a further 2 exchanges
should be done in case of deterioration or advanced
forms of the syndrome (loss of walking ability, or mechanical ventilation). W e also recommend that PE be
started as early as possible and be given thereafter on
alternative days until 2 or 4 exchanges are completed.
This study was supported by a grant from INSERM (CRE no.
878023).
We thank Cynthia Capellazzi, Sriphanie Gourdain, and Chrisrel Lebas for technical assistance, and the SociCtC de Rkanimation de
Langue Franpise for helping in the management of this group.
Appendix
The following investigators participated in the French
Cooperative Group on Plasma Exchange in GuillainBarrt Syndrome: HBpital Raymond Poincari., Garches:
D. Annane, B. Clair, D. Elkharrat, J. B. Vetcken, and
P. Gajdos; HBpital de la Pitik Salpttrikre: F. Bolgert,
M. 0. Josse, and P. Tassan; HBpital Pontchaillou,
Rennes: J. Bouget, F. Cartier, Y. Le Tulzo, and R.
Thomas; HBpital Charles Nicolle, Rouen: J. Leroy and
F. Moritz; HBpital Bretonneau, Tours: P. Dequin and
D. Perrotin; HBpital Pellegrin Tripode, Bordeaux, Service de Reanimation Midicale A: J. C. Favarel-Garrigue and Y. Castaing, and Service de Rkanimation
Mtdicale B: J. P. Cardinaud and G. Hilbert; Centre
Hospitalier Universitaire, BesanGon: F. Barale and A.
Boillot; Centre Hospitalier, Belfort: J. P. Faller arid 0.
Ruyer; HBpital Universitaire Vaudois, Lausanne: C.
Perret, A. Steck, and M. D. Schaller; HBpital A
Calmette, Lille: C. Chopin and F. Fourier; Centre
Hospitalier, Angers: J. Achard and G. Bouachour; H6-
French Cooperative Group: Plasma Exchange in Guillain-Bard Syndrome 305
pita1 Saint-Antoine, Paris: B. Guidet and G. Offenstadt; HBpital La Beauchke, Saint-Brieuc, Service de
Rtanimation Mtdicale: G. Guivarch and F. Zim
Bacca, and Service de Neurologie: J. Dien; HBpital
Edouard Herriot, Lyon: D. Perrot and J. Motin; Centre Hospitalier Universitaire Rangueil, Toulouse: G.
Geraud; Centre Hospitalier Universitaire, HBpital Sud,
Amiens: B. De Cagny; Centre Hospitalier, Cornpikgne:
Y. Domart; Centre Hospitalier, Annonay: P. L. Blanc;
HBpital Jean Bernard, Poitiers: R. Robert; Centre Hospitalier Gtnkral, Niort: J. M. Descamps; HGpital
Andri. Mignot, Le Chesnay: S. Grosbuis; Centre
Medico-Chirurgical Gui de Chauliac, Montpellier: 0.
Jonquet; Centre Hospitalier Gaston Doumergue,
NPmes: C. Arich; Centre Hospitalier, Saint-Nazaire: R.
Devallikre; HBtel Dieu, Nantes: F. Nicolas and P.
Rodineau; HBpital des Chanaux, Macon: G. Janin;
Centre Hospitalier Universitaire, HBpital Nord, SaintEtienne: R. Jospe; HBpital Paul Morel, Vesoul: F.
Tiberghien; HBpital Avicenne, Bobigny: T. D. Hoang;
Hapita1 Saint-Joseph, Paris: J. Carlet; Centre
Hospitalier Universitaire, Vandoeuvre les Nancy: A.
GCrard; Centre Hospitalier Gknkral, Dunkerque: S.
Moulront.
Statistical center: S. Chevret and C. Chastang, Dkpartement de Biostatistique et Informatique Mtdicale,
HBpital Saint-Louis, Paris.
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