A non BPI menincococcal trial:SEPSIS ASSOCIATED PURPURA
FULMINANS
(meningococcemia, meningococcal sepsis, thrombolytic therapy)
University of Graz
Karl-Franzens-Universität Graz
Department of Pediatrics
Director: Ao.Univ.-Prof. Dr. Wilhelm Müller
A-8036 Graz, Auenbruggerplatz 30, Austria
Tel: ++43 316 385 - FAX: ++43 316 385-3264
Univ. Doz. Dr. Werner Zenz
Dept. of Pediatrics, Karl Franzens University of Graz
Auenbruggerplatz 30 A 8036 Graz, Austria
Tel.:++43(0)316 3852605 Fax:++43(0)316 3853264
Sepsis associated purpura fulminans - use of thrombolytic therapy with recombinant tissue plasminogen activator in
patients with septic shock - an international prospective controlled multicenter study
Dear colleague!
We want to invite you to participate in our study „Sepsis associated purpura fulminans - use of thrombolytic therapy
with recombinant tissue plasminogen activator in patients with septic shock - an international prospective controlled
multicenter study". In 1995 we have described the use of recombinant tissue plasminogen activator (rt-PA) in the
successful therapy of two infants with sepsis associated purpura fulminans (SAPF) and shock (Zenz et al. Pediatrics
1995;96:144-8). Because of these promising observations which have been also confirmed by other authors (Knöfler
et al. Haemostaseologie 1996;16:232-5, Aiuto L et al. Crit Care Med 1997;25:1079-82) we plan to investigate the
efficacy of this treatment in an international prospective controlled randomized multicenter study. The underlying idea
is that disseminated intravascular microthrombosis due to disseminated intravascular coagulation (DIC) plays a major
role in the pathogenesis of organ failure in SAPF. Impairment of fibrinolysis that is caused by elevation of
plasminogen activator inhibitor 1 (PAI-1), the physiologic inhibitor of naturally occurring tissue plasminogen
activator, is part of these clotting abnormalities and has prognostic significance. The extend of elevation of PAI-1
levels obtained on hospital admission may accurately predict the development of severe septic shock, multiorgan
failure, and death in patients with meningococcemia. Thus progressive DIC coupled with an inability to break down
fibrin deposits and thromboses in the microvasculature leads to increasing ischemia, necrosis, and eventual organ
failure. Recombinant tissue plasminogen activator (rt-PA) could dissolve the disseminated intravascular
microthromboses associated with a selective restoration of impaired fibrinolysis with the result of restored organ
perfusion and decreased rates of mortality and autoamputations. However, thrombolytic therapy is associated with a
risk of devastating bleeding complications. To know more about this risk we have performed an intensive literature
search about children with thrombolytic therapy (Zenz et al. Semin Thromb Haemost in press). Part of this literature
review was a search about children with SAPF who have been treated with thrombolytic substances (submitted as an
abstract for presentation at the Internal meeting of ESPIC in Bratislava 1997). These data suggest that the risk to
develop devastating bleeding complications under thrombolytic therapy in sepsis associated purpura fulminans is not
high and is a rationale for us to go on with our intention to perform this study. We plan this study as an open
randomized controlled study (central randomization by phone) because this is the only way to get real information
about the efficacy of this treatment in septic patients with a complex medication. The inclusion criteria for the patients
should be SAPF with a Glasgow meningoccocal septicaemia prognostic score of 8 or >8 which predicts a mortality of
about 30 % or more. Rt-PA should only be applied to patients who show no response to „conventional" therapy (see
provisional therapy protocol). However, as we know from thrombolytic patients with myocardial infarction or stroke,
the therapeutic efficacy of thrombolysis is the greater the earlier therapy is started and the risk to develop an
intracranial hemorrhage increases with each hour of disease progression. Therefore we suggest an utmost early start
of rt-PA (maximal after 12 hours after starting exanthema) simultaneous with the use of (nor)epinephrine. We plan to
offer an insurance for all patients included in our study, however we have not yet found a sponsor for this project.
Until now colleagues from Austria, Germany, Switzerland, and Lithuania are interested to participate in our study .
We plan to further invite colleagues in children's hospitals in Croatia, Czech Republic, Hungary, Italy, Lithuania,
Poland, Slovakia, and Slovenia. Please tell us if you or one of your colleagues from your hospital is interested in
participating in our study. If you know other colleagues in other hospital in your country who might be interested in
participating in our study please pass on this information.
Therapy protocol
THROMBOLYTIC THERAPY IN SEPSIS ASSOCIATED PURPURA FULMINANS
INTRACEREBRAL HEMORRHAGE DURING FIBRINOLYTIC THERAPY IN CHILDREN
Treatment of fulminant meningococcemia with recombinant tissue plasminogen activator (letter)
The treatment of disseminated intravascular coagulation due to septical infection with recombinant tissue
plasminogen activator in childhood
Thrombolytic therapy with rt-PA
Recombinant tissue plasminogen activator restores perfusion in meningococcal purpura fulminans
Recombinant tissue plasminogen activator restores perfusion in meningococcal purpura fulminans (letter to
the editor)
Recombinant tissue plasminogen activator treatment in two infants with fulminant meningococcemia. Zenz
W, Muntean W, Gallistl S, Zobel G, Grubbauer HM: Pediatrics. 1995 Jul; 96(1 Pt 1): 144-8
Sepsis-associated purpura fulminans - therapy protocol (21.5.1997)
Zenz W, Zobel G Department of Pediatrics, University of Graz, Austria
A. CLASSIFICATION
GMSPScore (Sinclair et al. Lancet 1987;ii:38) and PRISM Score (Pollack et al. Crit Care Med 1988;16:1110-6)
B. INVESTIGATONS
necessary before starting thrombolysis: scoring, BGA (blood gas analysis) cap., routinelab, PT, aPTT, TT, fibr,
AT III, lactate desirable before starting thrombolysis: PAI-1 antigen, t-PA antigen (investigation in study center
possible) patient's photograph before starting thrombolyis
C. TREATMENT PROTOCOL
I. Step by step - proceeding
if BP decreased and GMSPS - Score 8 or above 8
1.) fluid resuscitation (colloid, crystalloid solutions) 10-30 ml/kgbw iv.
2.) prednisolon 5 mg/kgbw iv.
3.) ceftriaxon 100 mg/kg in 1 ED iv.
4.) antithrombin III-concentrate 50 U/kgbw as bolus iv. and continuing infusion to maintain AT III levels at 100%
5.) heparin 100 U/kgbw as bolus iv. and continuing 15-25 U/kgbw/h according to thrombin time (2-3 fold
prolongation)
if BP decreased and GMSPS - Score not better than 8
6.) measurement of central venous pressure (CVP)or cardiac sonography
7a.) if CVP below 7 cm H2O or low ventricle filling in echocardiography: repeated fluid supplement (if possible
fresh frozen plasma)
7b.) if CVP over 10 cm H2O, or. echocardiographic good ventricular filling: dopamine 5-10 µcg/kgbw/min
if BP decreased and GMSPS - Score not better than 8
8.) norepinephrine (epinephrine) starting with 0.5µg/kgbw/min and
9.) recombinant tissue plasminogen activator (rt-PA) 0.5 mg/kgbw/h for 1 hour - continued by 0.25 mg/kgbw/h till
disappearance of clinical signs of shock reappearance of peripheral pulses, , normalization of peripheral perfusion,
reappearance of urine production (bladder catheter) thrombolysis should be started as soon as possible; only patients
within 12 hours after starting of purpura are appropriate for rt-PA
10.) mechanical ventilation, further fluid supplement etc. according to clinical situation
II. Rescue - proceeding
within 30 minutes step 1 - 9 without step 6 and 7a
THROMBOLYTIC THERAPY IN SEPSIS ASSOCIATED PURPURA FULMINANS
Zenz W, Bodo Zs, Zobel G. Department of Pediatrics, University of Graz, Austria - ESPIC Congres Bratislava 1997
Objective of the study: In 1995 we have described the use of tissue plasminogen activator (t-PA) in the therapy of
sepsis associated purpura fulminans (SAPF) (Zenz et al. Pediatrics 1995;96:144-8). The underlying idea is that
thrombolytic therapy can dissolve the disseminated intravascular microthromboses that are observed in this disorder
and can restore organ perfusion with the result of decreased rates of mortality and autoamputations. However,
thrombolytic therapy is associated with a risk of devastating bleeding complications. To get further information about
this problem we have performed an extended literature research with analysis of all available patients and studies of
the last thirty years. Results: 64 patients with SAPF and thrombolytic therapy (50 with streptokinase, 1 with
urokinase, and 13 with t-PA) are described in the literature or reported to us by personal communication. Only one of
these patients developed a devastating bleeding complication (a lethal intracerebral hemorrhage reported by personal
communication). Mortality rates ranged from 0 to 83% (in summary: 19 deaths and 39 survivors). Conclusion:
These data suggest that the risk to develop devastating bleeding complications in patients with SAPF and thrombolytic
therapy is low and supports our efforts to prepare a prospective multicenter study with the use of t-PA in patients who
do not respond to „conventional" therapy. Due to the absence of control groups, treatment of patients more than
twenty years ago, and frequently very late onset of thrombolytic therapy no comment can be given about the efficacy
of the use of thrombolytic therapy in SAPF.
INTRACEREBRAL HEMORRHAGE DURING FIBRINOLYTIC THERAPY IN CHILDREN - A REVIEW OF
THE LITERATURE OF THE LAST THIRTY YEARS
Zenz W, Arlt F, Sodia S, Berghold A: Semin Thromb Hemost. 1997;23:321pp
Abstract: In a retrospective study all available publications concerning children with thromboembolic disease and
fibrinolytic therapy between January 1, 1964, and June 30, 1995, were reviewed with regard to the occurence of
intracerebral hemorrhages (ICH). ICH was found in 14/929 patiens analysed. According to the age when
thrombolytic therapy was performed, ICH was described in 2/468 children after the neonatal period, in 1/83 term
infants; and in 11/86 preterm infants; 10/40 preterm infants who were treated in the first week of life developed ICH.
ICH during thrombolytic therapy in children is reported with the use of streptokinase, urokinase (UK), UK-aktivated
plasmin, UK and plasminogen, and recombinant tissue plasminogen activator (rt-PA). The risk of developing an ICH
from thrombolytic therapy seems to be low in children after the neonatal period and in term infants. Because of the
high incidence of „spontaneous" ICH in preterm infants, it cannot be established whether the more frequently
described ICH in these patients is a complication of thrombolytic therapy. In the absence of randomized trials this
analysis may be helpful for decision making in children with thromboembolic disorders. However, the data have to
be regarded with caution because of the summation of cases with different thromboembolic disorders, treatment with
different substances in different dosages, and the retrospective study design that could lead to an underrepresentation
of this complication.
Treatment of fulminant meningococcemia with recombinant tissue plasminogen activator (letter):
Zenz-W; Muntean-W; Zobel-G; Grubbauer-HM; Gallistl-S SO: Thromb-Haemost. 1995 Aug; 74(2): 802-3
Fijnvandraat and colleagues reported that acquired protein C deficiency in meningococcal septic shock (MSS) is
related to the pathogenesis of purpura fulminans and constitutes a major factor contributing to morbidity and
mortality. They concluded that in accordance to the succesful use of protein C concentrate in newborns with purpura
fulminans and congenital protein C deficiency, their data indicate that therapeutic intervention in MSS should focus on
specific inhibition of coagulation activation or at supplementation of protein C concentrate.....
The treatment of disseminated intravascular coagulation due to septical infection with recombinant tissue plasminogen
activator in childhood.
Avenarius S, Gosch G, Karstedt J, Korb C, Mittler U, Lamme W: Pädiatr Grenzgeb 1995;33:427-36.
We report on a 2-month-old infant, who was suffering from a severe septicaemia with disseminated intravascular
coagulationand purpura fulminans after pylorotomia. Besides treatment of the underlying disease therapy of
consumption coagulopathy was initially performed with heparin and streptokinase. An acute renal insufficiency
required the administration of recombinant tissue plasminogen activator (rt-PA, ActilyseR , Fa. Tomae) in
combination with high-dosaged heparin. On the hand of this case we discuss the present possibilities in the
management of DIC and give a contribution to the application of rt-PA in treating this lifethreating complication. With
a literature review on the use in rt-PA in children we will try to help finding the right dosage for this drug.
Key Words: septicaemia, tissue-type-plasminogen activator, disseminated intravascular coagulation
Thrombolytic therapy with rt-PA.
Knöfler R, Weißbach G, Rupprecht E, et al.: Hämostaseologie 1996;16:232-5
Summary: For the improvement of the thrombolytic therapy in the children more clinical data are needed. Therefore
we report on our experiences with rt-PA presenting the clinical course of 12 patients /7 days to 16 years) with venous
thromboses (n=10) and purpura fulminans by meningococcosis (n=2). The venous thromboses were localized in
iliac-femoral veins (n=5), brachiocephalic-jugular-subclavian veins (n=4) and the cava superior vein (n=1). Central
venous catheters were of pathogenic importance in 4 cases. The patients were treated with rt-PA (Actilyse®) for 10.5
hours to 13 days. The dosage range was between 0.2 to 0.5 mg/kg for the initial dose and 1.0 to 2.0 mg/kg/d for the
continous infusion. Eleven patients received heparin simultaneously. Complete clot dissolution was found in 7 cases,
partial clot dissolution in 1 patient. Lysis was not successful in 4 patients with a history of the first clinical signs of
thrombosis lasting 3 weeks or more. Small bleeding episodes on former venipuncture sites were observed in 5
patients. Systemic effects such as the decrease of fibrinogen and an increase of aPTT were rare. In conclusion, the
thrombolysis with rt-PA presents an effective and safe therapy in children with the rt-PA dosage used.
Recombinant tissue plasminogen activator restores perfusion in meningococcal purpura fulminans.
McDonald KH: Crit Care Med 1997;25:909 (letter to the editor)
Key Words: tissue plasminogen activator; disseminated intravascular coagulation; meningococcal purpura fulminans;
thrombosis
Recombinant tissue plasminogen activator restores perfusion in meningococcal purpura fulminans.
Aiuto LT, Barone SR, Cohen PS, Boxer RA: Crit Care Med 1997;25:1079-82
Objective: To investigate whether an infusion of recombinant tissue plasminogen activator would dissolve
microvascular thromboses and improve organ perfusion in a patient with fulminant meningococceia. Patient: A
4-month-old male with fulminant meningococcemia, refractory schock, and multiple organ failure. Interventions: In
addition to standard aggressive ICU care, the patient received a recombinant tissue plasminogen activator infusion at a
total dose of 1.25 mg/kg over 4 hrs. Conclusions: In this patient, recombinant tissue plasminogen activator infusion
resulted in improved organ perfusion and cardiac performance. Selective use of recombinant tissue plasminogen
activator in the treatment of fulminant meningococcemia merrits further investigation.
Key Words: meningococcal infections; shock,septic; disseminated intravascular coagulation; fibrinolytic agents;
thrombolytic therapy; alteplase; purpura; plasminogen activator inhibitor-1; perfusion; thrombosis
If you have comments or suggestions, email me at
werner.zenz@kfunigraz.ac.at
letzte Änderung: 21.8.1997
betreut von Zsombor Bodó MD |
