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Doi:10.1016/j.healun.2003.10.020
Lung Transplantation: A Decade of Experience
Susan D. Moffatt, MD, PhD,a Philippe Demers, MD,a Robert C. Robbins, MD,a Ramona Doyle, MD,bAnn Wienacker, MD,b Noreen Henig, MD,b James Theodore, MD,b Bruce A. Reitz, MD,a andRichard I. Whyte, MDa
Background:
Over the past 3 decades, the field of lung transplantation has been refined. However, many barriersexist that limit long-term success. The purpose of this study was to review a single institution’slong-term experience with single and double lung transplantation and to assess the effect ofdifferent immunosuppressive therapies on outcomes. Methods:
Lung transplant recipients, both single and double, were reviewed, retrospectively. Patientswere divided into five groups: group I, all lung transplants (n ϭ 127); group II, single lungtransplants (n ϭ 73); group III, double lung transplants (n ϭ 54); group IV, OKT3 inductiontherapy recipients (n ϭ 27); and group V, RATG induction therapy recipients (n ϭ 100). Ratesof survival, rejection, bronchiolitis obliterans syndrome (BOS) and infection were analyzed at 1,3, and 5 years. Results:
There were no significant differences in survival, acute rejection rate, freedom from BOS, norinfection between single and double lung transplant recipients. Induction therapy with RATG(group V) was associated with significantly improved survival and freedom from acute rejection,BOS, and infection when compared to OKT3 induction therapy (group IV). Conclusions:
An earlier impression that RATG is superior to OKT3 induction therapy has borne true in terms ofoverall survival and incidence of BOS, acute rejection and infection rates. Lung transplantation,using RATG induction therapy, remains an important modality for end-stage pulmonary disease. J Heart Lung Transplant 2005;24:145–51. Copyright 2005 by the International Society for Heartand Lung Transplantation.
Since Cooper and Patterson described successful single
morbidity and mortality in the first 5 years after trans-
and double lung transplantation in 1986 and 1988,
respectively, more than 8,000 lung transplants have
Chronic rejection has been reported in up to 50% of
been performed in the United During the past
three decades, the field of transplantation has improved
target of the immune response in chronic rejection is
in the areas of organ preservation, immunosuppressive
the bronchial epithelium and the disease is manifested
therapy, and control of infectious and neoplastic com-
histologically as obliterative bronchiolitis (OB). Since
OB is difficult to diagnose, a committee sponsored by
now accepted as appropriate treatment for end-stage
the International Society for Heart and Lung Transplan-
tation (ISHLT) proposed a clinical description of OB,
One-year survival for lung transplant recipients has
termed bronchiolitis obliterans syndrome This
risen from 47% in 1988 to 75% in 2001. By comparison,
is defined by pulmonary function changes rather than
long-term survival is 47% at 5 years and only 20% at 10
histology. BOS encompassed both a decline in pulmo-
Acute graft failure and reperfusion injury are the
nary function and/or histologic evidence of chronic
most common causes of early mortality whereas infec-
tion and chronic rejection are the major causes of
Currently, there is no consensus as to the best
immunosuppressive regimen and in particular the useof induction Induction therapy is the use
From the aDepartment of Cardiothoracic Surgery, and bDivision of
of an immunosuppressive agent other than that used for
Pulmonary and Critical Care Medicine, Stanford University, Stanford,
maintenance immunosuppression to attempt tolerance
induction in the perioperative period. OKT3 and RATG
Submitted June 26, 2003; revised September 10, 2003; accepted
are induction agents used in lung as well as heart and
Reprint requests: Richard I. Whyte, MD, Department of Cardiothoracic
Surgery, CVRB 205, 300 Pasteur Drive, Stanford, CA 94305-5407. Tele-
clonal antibody that binds to the CD3/T cell receptor
phone: 650-723-6649. Fax: 650-725-3846. E-mail: riwhyte@stanford.edu
complex and inhibits the generation of cytotoxic T
Copyright 2005 by the International Society for Heart and Lung
cells. RATG is a polyclonal anti-thymocyte antibody that
Transplantation. 1053-2498/05/$–see front matter. doi:10.1016/j.healun.2003.10.020
reduces the number of effector T lymphocytes. Advo-
The Journal of Heart and Lung Transplantation
Table 1. Ischemic Times for Lung Allografts
the availability of the locally produced RATG. As of
December 1993, RATG was routinely used with a dose
of 1.5 mg/kg given intravenously on post-transplant
days 1, 2, 3, 5, and 7 after pre-medication with diphen-
hydramine and acetaminophen. OKT3 (5 mg/kg) was
given intravenously on post-transplant days 1 to 5 with
Methylprednisolone 500 mg IV was given to all patients
immediately before reperfusion. Cyclosporin was startedpostoperatively when hemodynamics and renal function
cates of induction therapy believe that it reduces the
were stable; azathioprine was initiated in the operating room.
incidence of early acute rejection and the development
Maintenance immunosuppression consisted of cyclosporin
of BOS; critics argue that the increased risk of infec-
(Sandimmune or Neoral) 5 to 10 mg/kg po daily to maintain
tion and post transplant lymphoproliferative disorders
whole blood levels of approximately 300 ng/ml, azathioprine
(Imuran) 2 mg/kg po daily, and prednisone 0.6 mg/kg po
This study reviewed a single institution’s long-term
experience with single and double lung transplantation. Furthermore, to better understand the role of induction
Long-term Follow-up and Management
therapy and improve patient outcomes, a comparison
Surveillance bronchoscopy with transbronchial biopsy
of RATG vs OKT3 therapy was undertaken.
was performed at 2, 4, 8, and 12 weeks and then at 6months and 1 year post-transplant. Long-term follow-up
MATERIAL AND METHODS
included bronchoscopy every 6 months to 1 year or
Patients who underwent single or double lung transplan-
when clinically indicated. Pulmonary function tests, a
tation at Stanford University between 1989 and 1999 were
chest X-ray and arterial blood gases were done at each
reviewed retrospectively. Patients who had previously
follow up visit or when clinically warranted. Acute
received heart-lung transplants or lung transplants (n ϭ 4)
rejection was defined as any episode of grade II rejec-
were excluded from the analysis. Patients who did not
tion diagnosed on transbronchial biopsy. Rejection was
receive adult (Ͼ16 years old) donor allografts were ex-
treated with methylprednisolone 1 g intravenously daily
cluded (n ϭ 4). The remaining 127 patients were analyzed
for 3 days and an increase in the prednisone dose.
according to type of transplant (double vs single) and type
Persistent rejection was treated with an additional
of induction therapy (OKT3 vs RATG) with respect to
course of steroids followed by RATG, OKT3 or total
survival, freedom from rejection, freedom from BOS and
Patients were divided into group I (all lung trans-
Infection Prophylaxis
plants [n ϭ 127]), group II (single lung transplants [n ϭ
Infection was defined as any infectious event that
73]), group III (double lung transplants [n ϭ 54]),
required treatment, either as an inpatient or outpatient.
group IV (OKT3 induction therapy [n ϭ 27]), and
Infections could have been viral, bacterial, fungal or
group V (RATG induction therapy [n ϭ 100]).
As of December 1993, all CMV-mismatched donor–
Lung Procurement and Implantation
recipient pairs received intravenous Ganciclovir, 5 mg/kg
Donor lung preservation consisted of 500 g of Prosta-
IV twice a day for 14 days and 6 mg/kg IV daily for 20 days
glandin E that was given directly into the pulmonary
for a total of 34 days, Cytovene (oral Ganciclovir), 1,000
artery followed by an infusion of 4 liters of ice cold
mg per os three times a day for 6 weeks and Cytogam (IgG
Eurocollins solution. The lung block was placed in iced
immunoglobulin), 150 mg/kg 72 hours post-transplant,
saline for transport. All allograft ischemic times were
100 mg/kg weeks 2, 4, 6, 8 post-transplant, and 50 mg/kg
weeks 12 and 16. Before the introduction of Cytovene and
Allograft implantation was performed without cardio-
Cytogam in 1993, all CMV-mismatched recipients received
pulmonary bypass for the majority of the single lung
transplants whereas double lung transplants were per-
Pneumocystis carinii pneumonia prophylaxis con-
formed with cardiopulmonary bypass support in the
sisted of trimethoprim/sulfamethoxazole DS twice
daily, Monday, Wednesday and Friday. Aspergillus pro-phylaxis consisted of aerosolized Amphotericin B 20 mg
Immunosuppression Regimem
twice daily while hospitalized and itraconazole 200 mg
Between January 1989 and November 1993, patients
per os every morning and 100 mg per os every night for
received RATG or OKT3 induction therapy based on
The Journal of Heart and Lung Transplantation
Table 2. Indications for Lung Transplantation
COPD, chronic obstructive pulmonary disease. Definition of BOS
immunosuppressive regimens among the two groups (p
Bronchiolitis obliterans syndrome is defined by the
ISHLT as a greater than 20% decline in FEV and/or
Survival Rates Higher for Recipients of RATG Induction
Individual charts were reviewed and a diagnosis of BOSwas based on either decline in lung function that was
The overall survival rate of all lung transplant recipients
demonstrated on two separate visits at least 2 weeks
(Group I) was 83%, 67%, and 47% at 1, 3, and 5 years,
apart and/or histologic evidence of obliterative bronchi-
respectively. The survival rates for the single lung
transplant recipients (Group II) were 81%, 69%, and45%, respectively, whereas those for double lung recip-
Data Collection and Statistics
ients (Group III) were 88%, 66%, and 55%, respectively,
Patient data were systematically collected pre- and
at 1, 3, and 5 years with no significant difference
post-transplant by the Stanford transplant nurse coordi-
nators. Actuarial life-table data were calculated by the
Recipients treated with OKT3 induction therapy
Cutler-Ederer method. Time-related event-free rates
(group IV) had survival rates of 71%, 50%, and 29% at 1,
were reported from actuarial estimates as the mean Ϯ
3, and 5 years, respectively, while those who received
standard error. Comparison between actuarial curves
RATG (group V) had survival rates of 86%, 71%, and
was made by the Gehan method. Comparison between
53%, respectively. These results were statistically differ-
group demographics was made using the Student’s
t-test. Significance for all comparisons was defined as p
There were a total of 69 deaths among the 127
recipients. The major causes of death among all lungtransplant recipients were BOS (n ϭ 35, 51%), infection
(n ϭ 21, 30%), and malignancy (n ϭ 3, 5%) as outlined
Transplant Patient Demographics
in Type of transplant (single vs double) nor
The mean age at time of transplantation was 34 Ϯ 10
type of induction therapy (RATG vs OKT3) influenced
years and 74 (58%) were women. The most common
the cause of death (p Ͻ 0.005).
indications for lung transplantation were emphysema/COPD (26%), cystic fibrosis (24%), and idiopathic pul-
Acute Rejection Rates Higher Among Lung Transplant
monary fibrosis (14%) as detailed in Among the
Recipients That Received OKT3 Induction Therapy
single lung transplant recipients, 56 received RATG and
The overall freedom from acute rejection for all lung
17 received OKT3. Among the double lung transplant
transplant recipients (group I) was 57%, 53%, and 53%
recipients, 44 received RATG and 10 received OKT3.
at 1, 3, and 5 years, respectively. The corresponding
This represented a statistically equivalent distribution of
rates for single and double lung transplant recipients
Table 3. Lung Transplant Survival Data
The Journal of Heart and Lung Transplantation
Figure 1. Survival rates among OKT3 (group IV) and RATG (group V) Figure 2. Freedom from acute rejection, at 1 year, in lung transplant
treated lung transplant recipients. There was significantly improved
recipients treated with OKT3 induction therapy (group IV) or RATG
survival among those transplant recipients who received RATG induc-
induction therapy (group V). Freedom from rejection was significantly
tion therapy compared with those who received OKT3 induction
less when lung transplant recipients were treated with OKT3 induction
therapy (p Ͻ 0.005). OKT3 ϭ OKT3 induction therapy group (group IV);
therapy. (p Ͻ 0.005) OKT3 ϭ OKT3 induction therapy group (group IV);
RATG ϭ RATG induction therapy group (group V).
RATG ϭ RATG induction therapy group (group V).
were 54%, 49%, and 49% compared with 58%, 56%, and56% at 1, 3, and 5 years, respectively; these did not
respectively. The infection rate among the single lung
recipients (group II) was 79%, 91%, and 91%, and for
The freedom from rejection among the transplant
double lung transplants recipients (group III) 64% at 1,
recipients that received RATG was significantly higher
3, and 5 years, respectively. These infection rates were
than compared to recipients of OKT3 induction therapy
(64%, 62%, and 62% vs 26%, 13%, and 13%, at 1, 3, and
The cytomegalovirus (CMV) infection rate among all
5 years, respectively; p Ͻ 0.005;
lung transplant recipients (group I) was 54%, 65%, and70% at 1, 3, and 5 years. The CMV infection rate among
Incidence of BOS Significantly Higher Among Transplant
the single lung recipients (group II) was 72%, 84%, and
Recipients Receiving OKT3 Induction Therapy
88%; CMV infection rate for the double lung transplant
A total of 54 patients of BOS were diagnosed: 22
recipients (group III) was 57%, 64%, and 64%, at 1, 3,
(41%) by histology and 32 (59%) by clinical deterio-
and 5 years, respectively. These CMV infection rates
were not found to be significantly different.
BOS (group I) was 84%, 64%, and 40% at 1, 3, and 5
The rate of infectious events requiring treatment,
years, respectively. For single lung transplant recipi-
was significantly higher among the OKT3 treated
ents (group II), freedom from BOS was 86%, 63%, and
recipients (group IV 89%, 100%, and 100% at 1, 3, and
34%, and for double lung transplant recipients (group
5 years, respectively) compared with the RATG
III), it was 81%, 66%, and 49%, at 1, 3, and 5 years,
treated recipients (66%, 80%, and 80% at 1, 3, and 5
respectively. These rates of BOS were not signifi-
years, respectively; p Ͻ 0.005; group V). The rate of
CMV infection was also significantly higher among
Lung transplant patients who received OKT3 (group
the OKT3 treated recipients (group IV, 74%, 87%, and
IV) had significantly less freedom from BOS (77%, 47%,
87%) compared with RATG treated recipients (group
and 20% at 1, 3, and 5 years, respectively) compared with
V, 61%, 71%, and 73%) at 1, 3, and 5 years respec-
those who received RATG (group V; 89%, 72%, and 49% at
1, 3, and 5 years, respectively; p Ͻ 0.005;
DISCUSSION Infection Rates Higher Among Lung Transplant Recipients
This 10-year review of lung transplant experience re-
Receiving OKT3 Induction Therapy
veals overall survival rates similar to the United Net-
The infection rate among lung transplant recipients
work of Organ Sharing (UNOS) and ISHLT databases
(group I) was 72%, 84%, and 84% at 1, 3, and 5 years,
that report 1, 3, and 5 year survival rates of 75%, 58%,
Table 4. Cause of Death in Lung Transplant Recipients
The Journal of Heart and Lung Transplantation
further compared the use of OKT3 vs RATGinduction therapy in lung transplant recipients andfound no difference in survival. These varying dataprompted us to compare our recipient outcomes usingthe different induction regimens and present the resultsof this comparison.
Acute rejection typically occurs in the first 3 to 6
months after transplantation with most recipientssuffering at least one episode.The rejection ratesamong our single and double transplant patients were
Figure 3. Freedom from BOS in lung transplant recipients treated
similar and in keeping with those of other centers
with OKT3 induction therapy (group IV) vs those treated with RATG
Rejection rates were, however, significantly less in
induction therapy (group V), at 5 years. There was a significant
the RATG treated group compared to the OKT3
difference in the incidence of BOS between these OKT3 and RATG
treated group. This difference between treatment
treatment groups (p Ͻ 0.005). BOS ϭ bronchiolitis obliterans
groups had been pre-viously perceived and prompted
syndrome; OKT3 ϭ OKT3 induction therapy group (group IV); RATG
changing to RATG induction therapy in 1993. Wain et
ϭ RATG induction therapy group (group V).
aldemonstrated that OKT3 induction preventedearly rejection and reduced the overall incidence of
acute rejection episodes. Likewise, Palmer et al
plantation as well as our demographics appear to be in
using RATG, demonstrated that the number of pa-
tients experiencing biopsy proven rejection was sig-
Induction therapy is an attempt at inducing a “toler-
nificantly reduced compared to the patients without
induction therapy. These findings differ with Brock et
not use induction therapy, however, report survival
who, in a 4-year prospective controlled clinical
outcomes as high as 80% at 2 Differing opinions
trial comparing OKT3, ATG, and dacluzimab, re-
and outcomes using induction therapy exist in the
vealed no significant differences in episodes of acute
literature. Wain et investigated the role of OKT3 in
a prospective trial whereby OKT3 induction therapy
Our comparison demonstrated that the incidence
was given for 10 days followed by cyclosporin-based
of pulmonary infection was significantly greater
maintenance therapy. The overall survival of lung trans-
among the OKT3 treated patients compared with the
plant recipients was similar to those patients not receiv-
RATG treated recipients. Brock et asimilarly found
ing OKT3 but acute rejection was Wiebe et
that OKT3 resulted in significantly more infections.
investigated ATG induction therapy in both lung and
Our rates of infection may relate to the fact that
heart-lung transplant recipients and found no survival
OKT3 treated patients were part of our early experi-
benefit compared with no induction therapy. Palmer et
ence when CMV prophylaxis was not optimized. Since 1994 a rigorous regimen of CMV prophylaxishas been successfully implemented including oraland IV Ganciclovir and immune gamma globulinAlternatively, the high incidence of infections amongOKT3 recipients may reflect additional immunosup-pression required for treatment of acute rejectionepisodes in this group.
In this 10-year review the incidence of BOS was
found to be equal among the single and double lungtransplant recipients but overall higher than that re-ported by the ISHLT registry (60% vs 50% at 5 years,
Figure 4. Freedom from CMV infection, at 1 year, among the lung
respectively) which may reflect a long study period and
transplant recipients that received OKT3 induction therapy (group IV)
an aggressive examination of transplant data on our
and RATG induction therapy (group V). There was a significant
part. Our data reveals that the OKT3-treated recipients
difference among the immunosuppressive regimen groups in that the
had a higher incidence of BOS compared to those
OKT3 treated (group IV) recipients had a significantly higher incidence
having received RATG. In addition, OKT3-treated recip-
of CMV infection events when compared with the recipients treated
ients suffered more acute rejection and CMV infection
with RATG (p Ͻ 0.005). CMV ϭ cytomegalovirus; OKT3 ϭ OKT3induction therapy group (group IV); RATG ϭ RATG induction therapy
episodes as compared to those treated with RATG.
Although not causal, the association of multiple acute
The Journal of Heart and Lung Transplantation
rejection and CMV infection episodes resulting in BOS,
the UNOS/ISHLT International Registry for thoracic organ
as reported by others, are supported by our results
transplantation. Clin Transpl 2000;31– 44.
Induction therapy and outcome data are difficult to
4. DeMeo DL, Ginns LC. Clinical status of lung transplanta-
interpret due to variation in drug administration in
tion. Transplantation 2001;72:1713–24.
5. Hertz MI, Taylor DO, Trulock EP, Boucek MM, Mohacsi
terms of dose, formulation, duration of therapy and era
PJ, Edwards LB, Keck BM. The registry of the Interna-
of administered. Induction immunosuppression has tra-
tional Society for Heart and Lung Transplantation: nine-
ditionally been used at our institution but clearly OKT3
teenth official report–2002. J Heart Lung Transplant 2002;
was administered early on in our experience when
organ preservation, operative technique, and postoper-
6. Taylor DO. Immunosuppressive therapies after heart
ative care varied from current standards. The decision
transplantation: best, better and beyond. Curr Opin Car-
to administer OKT3 or RATG was based on personal
pre-ference and drug availability, ultimately resulting in
7. Reichenspurner H, Girgis RE, Robbins RC, et al. Obliter-
a small number of OKT3-treated patients. Early in our
ative bronchiolitis after lung and heart-lung transplanta-
experience, RATG was not commercially available and
tion. Ann Thorac Surg 1995;60:1845–53.
8. Estenne M, Maurer JR, Boehler A, et al. Bronchiolitis
was in fact “home brewed” for recipients in a local
obliterans syndrome 2001: an update of the diagnostic
laboratory. Barlow et alpreviously investigated out-
criteria. J Heart Lung Transplant 2002;21:297–310.
comes among lung and heart-lung recipients who re-
9. Brock MV, Borja MC, Ferber L, et al. Induction therapy in
ceived OKT3 or RATG early in our experience and
lung transplantation: a prospective controlled clinical trial
found there to be a survival and outcome advantage for
comparing OKT3, antithymocyte globulin, and dacli-
RATG transplant recipients. Our study, incorporating a
zumab. J Heart Lung Transplant 2001;20:1282–90.
decade of experience, further supports and emphasizes
10. Barr ML. Current status of heart and lung transplantation.
The limitations of this review, therefore, include it
11. Wain JC, Wright CD, Ryan DP, et al. Induction immuno-
being retrospective whereby patients could not be
suppression for lung transplantation with OKT3. AnnThorac Surg 1999;67:187–93.
randomized to RATG, OKT3 or no induction therapy.
12. Wiebe K, Harringer W, Wahlers T. ATG induction therapy
CMV prophylaxis has changed over time. The effect
and the incidence of bronchiolitis obliterans after lung
cardiopulmonary bypass on outcomes was not studied
transplantation: does it make a difference? Trans Proc
because practically all single lung transplants were
performed without cardiopulmonary bypass whereas
13. Kriett JM, Smith CM, Hayden AM, et al. Lung transplanta-
the majority of double lung recipients had cardiopul-
tion without the use of antilymphocyte antibody prepa-
monary support. Donor and recipient age criteria were
rations. J Heart Lung Transplant 1993;12:915–22.
not changed during our study period and the effect of
14. Palmer SM, Miralles AP, Lawrence CM, et al. Rabbit anti
HLA on outcomes has had no proven effect and there-
thymocyte globulin decreases acute rejection after lungtransplantation. Chest 1999;116:127–33.
15. Barlow CW, Moon MR, Green GR, et al. Rabbit antithy-
In summary, our data suggest that RATG is associated
mocyte globulin versus OKT3 induction therapy after
with improved survival and a decrease in CMV infec-
heart-lung and lung transplantation: effect on survival,
tion, acute rejection and BOS rates when compared to
rejection, infection and obliterative bronchiolitis. Transpl
OKT3 therapy among lung transplant recipients. As a
result of these findings, RATG will continue to be used
16. Soghikian MV, Valentine VG, Berry GJ, et al. Impact of
in induction therapy protocols until better agents are
ganciclovir prophylaxis on heart-lung and lung transplant
proven to be more efficacious. Novel induction agents,
recipients. J Heart Lung Transplant 1996;15:881.
including Dacluzimab, which are currently being intro-
17. Girgi RE, Tu I, Berry GJ, et al. Risk factors for the
duced into clinical lung transplantation, may ultimately
development of obliterative bronchiolitis after lungtransplantation. J Heart Lung Transplant 1996;15:
further improve survival and outcomes for lung trans-
18. Sharples LD, McNeil K, Stewart S, Wallwork J. Risk
factors for bronchiolitis obliterans: a systematic review
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