Antithrombin III for critically ill patients

  • Review
  • Intervention

Authors

  • Arash Afshari,

    Corresponding author
    1. Rigshospitalet, The Cochrane Anaesthesia Review Group & Copenhagen Trial Unit and Department of Paediatric and Obstetric Anaesthesia, Copenhagen, Denmark
    • Arash Afshari, The Cochrane Anaesthesia Review Group & Copenhagen Trial Unit and Department of Paediatric and Obstetric Anaesthesia, Rigshospitalet, Blegdamsvej 9, Afsnit 3342, rum 52, Copenhagen, 2100, Denmark. arriba.a@gmail.com. afshari@rocketmail.com.

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  • Jørn Wetterslev,

    1. Rigshospitalet, Copenhagen University Hospital, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Copenhagen, Denmark
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  • Jesper Brok,

    1. Rigshospitalet, Paediatric Department 4072, Copenhagen, Denmark
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  • Ann Merete Møller

    1. Herlev University Hospital, The Cochrane Anaesthesia Review Group, Rigshospitalet & Department of Anaesthesiology, Herlev, Denmark
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Abstract

Background

Critical illness is associated with uncontrolled inflammation and vascular damage which can result in multiple organ failure and death. Antithrombin III (AT III) is an anticoagulant with anti-inflammatory properties but the efficacy and any harmful effects of AT III supplementation in critically ill patients are unknown.

Objectives

To assess the benefits and harms of AT III in critically ill patients.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library); MEDLINE; EMBASE; Science Citation Index Expanded; International Web of Science; CINAHL; LILACS; and the Chinese Biomedical Literature Database (up to November 2006). We contacted authors and manufacturers in the field.

Selection criteria

We included all randomized clinical trials, irrespective of blinding or language, that compared AT III with no intervention or placebo in critically ill patients.

Data collection and analysis

Our primary outcome measure was mortality. We each independently abstracted data and resolved any disagreements by discussion. We presented pooled estimates of the intervention effects on dichotomous outcomes as relative risks (RR) with 95% confidence intervals (CI). We performed subgroup analyses to assess risk of bias, the effect of AT III in different populations (sepsis, trauma, obstetric, and paediatric patients), and the effect of AT III in patients with or without the use of concomitant heparin. We assessed the adequacy of the available number of participants and performed a trial sequential analysis to establish the implications for further research.

Main results

We included 20 randomized trials with a total of 3458 participants; 13 of these trials had high risk of bias. When we combined all trials, AT III did not statistically significantly reduce overall mortality compared with the control group (RR 0.96, 95% CI 0.89 to 1.03; no heterogeneity between trials). A total of 32 subgroup and sensitivity analyses were carried out. Analyses based on risk of bias, different populations, and the role of adjuvant heparin gave insignificant differences. AT III reduced the multiorgan failure score among survivors in an analysis involving very few patients. AT III increased bleeding events (RR 1.52, 95% CI 1.30 to 1.78).

Authors' conclusions

AT III cannot be recommended for critically ill patients based on the available evidence. A randomized controlled trial of AT III, without adjuvant heparin, with prespecified inclusion criteria and good bias protection is needed.

Résumé scientifique

Antithrombine III pour les patients gravement malades

Contexte

Une maladie grave est associée à une inflammation incontrôlée et à des lésions vasculaires susceptibles d'entraîner une défaillance multiviscérale et la mort. L'antithrombine III (AT III) est un anticoagulant ayant des propriétés anti-inflammatoires, mais l'efficacité et les effets délétères de la supplémentation en antithrombine III chez des patients gravement malades sont inconnus.

Objectifs

Évaluer les effets bénéfiques et les effets délétères de l'antithrombine III (AT III) chez des patients gravement malades.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans le registre Cochrane des essais contrôlés (CENTRAL) (The Cochrane Library); MEDLINE, EMBASE, Science Citation Index Expanded; International Web of Science; CINAHL; LILACS ; et dans la base de données de la littérature chinoise biomédicale (Chinese Biomedical Literature Database) (jusqu'à novembre 2006). Nous avons contacté les auteurs et les fabricants dans ce domaine.

Critères de sélection

Nous avons inclus tous les essais cliniques randomisés comparant l'administration d'antithrombine III (AT III) à l'absence d'intervention ou à un placebo chez des patients gravement malades, indépendamment des conditions d'aveugle ou de la langue de ces essais.

Recueil et analyse des données

Notre critère de jugement principal était la mortalité. Nous avons chacun, de manière indépendante, extrait les données et nous avons résolu les différends par des discussions. Nous avons présenté des estimations regroupées des effets de l'intervention sur les résultats dichotomiques sous forme de risques relatifs (RR) avec des intervalles de confiance (IC) à 95 %. Nous avons effectué des analyses de sous-groupes pour évaluer le risque de biais, l'effet de l'antithrombine III (AT III) dans différentes populations (patients avec septicémie, patients en traumatologie, obstétrique et pédiatrie), et l'effet de l'antithrombine III (AT III) chez des patients avec ou sans traitement concomitant par héparine. Nous avons évalué l'adéquation du nombre de participants disponibles et effectué une analyse séquentielle des essais afin d'établir les implications pour les recherches futures.

Résultats principaux

Nous avons inclus 20 essais randomisés avec un total de 3 458 participants ; 13 de ces essais présentaient un risque élevé de biais. Lorsque nous avons combiné tous les essais, l'AT III n'a pas statistiquement réduit significativement la mortalité globale par rapport au groupe témoin (RR = 0,96, IC à 95 % : 0,89 à 1,03; aucune hétérogénéité entre les essais). Au total 32 analyses de sous-groupe et de sensibilité ont été effectuées. Les analyses fondées sur le risque de biais, différentes populations, et le rôle de l'héparine en adjuvant ont mis en évidence des différences insignifiantes. L'AT III a réduit le score de défaillance multiviscérale chez les survivants dans une analyse portant sur très peu de patients. L'AT III a entraîné une augmentation des événements hémorragiques (RR = 1,52, IC à 95 % : 1,30 à 1,78).

Conclusions des auteurs

Au vu des preuves disponibles, l'AT III ne peut être recommandée pour les patients gravement malades. Il est nécessaire de réaliser un essai contrôlé randomisé de l'AT III, sans héparine en adjuvant, avec des critères d'inclusion prédéfinis et une bonne protection contre le risque de biais.

Plain language summary

Antithrombin III for critically ill patients

Insufficient evidence is available from randomized controlled trials to support the use of antithrombin III to improve the survival of critically ill patients. Antithrombin III (AT III) is an anticoagulant with anti-inflammatory properties. In the present systematic review we set out to assess the benefits and harms of its use in critically ill patients. We identified 20 randomized trials comparing AT III versus placebo or no intervention. We could not identify a clear beneficial effect of AT III on our predefined outcomes, overall or among various types of patients or subgroups. The number of bleeding events was increased with AT III and we conclude that there is a need for a large scale clinical trial with low risk of bias to assess the benefits and harms of this intervention in patients who are not also given heparin.

Résumé simplifié

Antithrombine III pour les patients gravement malades

Il n'existe pas suffisamment de preuves émanant des essais contrôlés randomisés pour encourager l'utilisation de l'antithrombine III aux fins d'améliorer la survie des patients gravement malades. L'antithrombine III (AT III) est un anticoagulant doté de propriétés anti-inflammatoires. Dans cette revue systématique, nous avons entrepris d'évaluer les effets bénéfiques et les effets délétères de son utilisation chez des patients gravement malades. Nous avons identifié 20 essais randomisés comparant l'AT III versus un placebo ou l'absence d'intervention. Nous n'avons pas pu clairement identifier un effet bénéfique de l'AT III sur les critères que nous avions prédéfinis, globalement ou pour divers types de patients ou de sous-groupes. Le nombre d'événements hémorragiques a augmenté avec l'AT III et nous concluons qu'il est nécessaire de réaliser un essai clinique à grande échelle, présentant un faible risque de biais, pour évaluer les effets bénéfiques et les effets délétères de cette intervention chez les patients auxquels il n'est pas administré non plus de l'héparine.

Notes de traduction

Traduit par: French Cochrane Centre 5th March, 2013
Traduction financée par: Instituts de Recherche en Sant� du Canada, Minist�re de la Sant� et des Services Sociaux du Qu�bec, Fonds de recherche du Qu�bec Sant� et Institut National d'Excellence en Sant� et en Services Sociaux

Background

Despite advances in the medical field, growing numbers of patients are becoming critically ill. Each year, 750,000 people in the United States of America are admitted to intensive care units (Angus 2001). Sepsis resulting from a generalized inflammatory and procoagulant response to an infection is associated with a death rate of 30% to 50% (Bernard 2001). This rate increases in the presence of circulatory shock despite aggressive antimicrobial therapy, adequate fluid resuscitation, and optimum care (Periti 2000); and may reach as high as 70% in patients with multiple organ dysfunction (Polderman 2004). Circulatory shock is defined as the failure of the circulatory system to maintain adequate perfusion. It may arise from: cardiogenic shock (heart failure); septic shock (severe infection); bleeding (haemorrhagic shock); brain and spinal cord injury (neurogenic shock); and allergic reactions (anaphylactic shock) (Müllner 2004). Severe sepsis is the second most frequent cause of death in intensive care patients, surpassed only by cardiovascular events (Polderman 2004).

Critical illness results in uncontrolled inflammation and vascular damage even when the cause of the illness is not infection; other causes are, for example: trauma; malignancy; complications of pregnancy; poisoning; allergic reactions; or liver failure (Periti 2000). With the above-mentioned disorders, a systemic activation of coagulation may occur which, at its worst, results in a fulminant disseminated intravascular coagulation (DIC). DIC is characterized by simultaneous widespread microvascular thrombosis and profuse bleeding from various sites (Levi 2004).

The inflammation associated with critical illness is characterized by an increase in the number and activity of numerous molecules, such as platelet activating factor, von Willebrand factor, and tumour necrosis factor. There is a simultaneous increase in the activity of pro-inflammatory and pro-coagulant processes, such as: thrombin formation; fibrin deposition at the vascular wall; and the formation of aggregates containing platelets and leukocytes. Leukocyte rolling, adhesion, and transmigration are also important parts of the inflammatory reaction. These processes lead to capillary leakage, severe disturbance of the microcirculation, tissue damage, and eventually multiorgan failure and death (Becker 2000).

Any proposed treatment of critical illness should aim to eliminate the underlying disorder or condition and to restore microvascular function, hence reducing organ dysfunction (Levi 2004).

Antithrombin III (AT III) is primarily a potent anticoagulant with independent anti-inflammatory properties. AT III irreversibly inhibits serine proteases (for example activated factor X and thrombin) in a one-to-one ratio, with the generation of protease-AT III complexes. Heparin prevents AT III from interacting with the endothelial cell surface by: binding to sites on the AT III molecule; competing for the AT III binding site; and reducing AT III ability to interact with its cellular receptor. AT III's anticoagulant effect is thus greatly accelerated (by a factor of 1000) by heparin; heparin reduces AT III's anti-inflammatory properties, weakens vascular protection, and increases bleeding events (Opal 2002; Rublee 2003). The theoretical beneficial effect of heparin among patients with DIC, a standard therapy in many intensive care units, has yet to be validated in a multicentre trial setting. There is also insufficient data to conclude that heparin is safe in DIC (Levi 2004; Wiedermann 2004).

The blood concentration of AT III falls by 20% to 40% in septic patients and these levels correlate with disease severity and clinical outcome (Opal 2002; Wiedermann 2002). This reduction in concentration is due to the combined effect of: decreased production of AT III in the liver; inactivation by the enzyme elastase, which is increased during inflammation; and loss of AT III from the circulation into tissues through inflamed and leaking capillary blood vessels. These processes reduce the half-life of AT III from a mean of 55 hours to 20 hours (Fourrier 2000). The main mechanism of AT III depletion in severe sepsis is linked to consumption of the molecule.

It is this depletion of AT III that has prompted research into the potential benefits of replenishing AT III levels. Investigators have often tried to increase the antithrombin concentration to supranormal values because the activity of proinflammatory and procoagulant molecules are increased in critically ill patients. Thus artificially high levels of AT III may be required to overcome the inhibitory effect of thrombin and other such serine proteases. This is because the normal serum concentration of AT III does not necessarily reflect the amount bound to endothelial receptors and appears insufficient (Fourrier 2000).

Finally, by blocking the actions of thrombin AT III may have antiangiogenic and antitumour properties (Larsson 2001).

Although critically ill patients are a heterogeneous population they are characterized by having systemic inflammation, no matter what the cause of their illness is. This inflammation causes further damage to tissues and organs and can result in multiple organ failure and death. The process of inflammation can be modified by AT III, whether or not clotting is abnormal, and it is possible that AT III can reduce the high death rate or permanent damage experienced by critically ill patients. The benefit of AT III supplementation in critically ill patients is still controversial and its efficacy is debated. The aim of this review is to assess the evidence that AT III therapy is beneficial for critically ill patients.

Objectives

We assessed the benefits and harms of AT III administration in critically ill patients.

Methods

Criteria for considering studies for this review

Types of studies

We included published and ongoing randomized controlled trials irrespective of blinding status or language. We excluded studies published as abstracts and studies that did not provide mortality data.

Types of participants

We included critically ill patients as variously defined by trial authors. However, we excluded trials of adjuvant AT III administration for the reduction of cardiovascular events in the invasive treatment of acute myocardial infarction.

The terminology for sepsis as originally proposed by the American College of Chest Physicians and the Society of Critical Care Medicine is in many ways outdated (Opal 2003). A loose definition of sepsis can easily result in enrolment of a heterogeneous population and hence in exaggerated findings, in either direction, that are difficult to reproduce. However, we accepted the various definitions of sepsis, septic shock, DIC, and other critical illnesses as proposed by the authors; we did not exclude any study based on their definitions. We chose to accept the term 'standard treatment of sepsis and DIC' as reported by many authors despite the lack of a generally accepted treatment regimen.

Types of interventions

We included AT III versus no intervention or placebo. We included any dose of AT III, any duration of administration, and co-interventions but excluded trials that compared different doses of AT III.

Types of outcome measures

Primary outcomes

The primary outcome measure was overall mortality. We used the longest follow-up data from each trial regardless of the period of follow up.

Secondary outcomes
  1. Number of days in hospital

  2. Mean length of stay in an intensive care unit (ICU)

  3. Quality of life assessment, as defined by authors in included studies

  4. Severity of sepsis (according to different organ dysfunction scores; sepsis versus septic shock if adequately defined by authors)

  5. Incidence of respiratory failure (mechanically assisted ventilation)

  6. Duration of mechanical ventilation

  7. Bleeding events

  8. Incidence of surgical intervention

  9. Complications specific to the trial intervention, e.g. bleeding, limb venous thrombosis, line sepsis, local haematoma

  10. Complications during the in-patient stay not specific to the trial intervention, e.g. pneumonia, congestive cardiac failure, respiratory failure, myocardial infarction, renal failure, cerebrovascular accident

We defined bleeding events (7.) as intracranial bleeding or bleeding requiring transfusion of at least three units of blood. We counted repeated transfusions in the same participant as a singular event.

Search methods for identification of studies

Electronic searches

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2006, Issue 4); MEDLINE (1950 to November 2006); EMBASE (OVID platform) (1980 to November 2006); International Web of Science (1945 to November 2006); Latin American Caribbean Health Sciences Literature (LILACS) (up to November 2006); the Chinese Biomedical Literature Database (up to November 2006); and Cumulative Index to Nursing & Allied Health Literature (CINAHL) (up to November 2006). We performed a systematic and sensitive search strategy to identify relevant randomized clinical trials with no language or date restrictions.

For specific information regarding our search strategies and results please see Appendix 1.

We searched for ongoing clinical trials and unpublished studies on the following Internet sites (up to March 2005):

  1. Current Controlled Trials;

  2. ClinicalTrials.gov;

  3. Centre Watch Clinical Trials Listing Service.

Searching other resources

We handsearched the reference list of reviews, randomized and non-randomized studies, and editorials for additional studies. We contacted the main authors of studies and experts in this field to ask for any missed, unreported, or ongoing studies.

Data collection and analysis

Data extraction

We used the above strategy to search for relevant trials. We then screened the titles and abstracts in order to identify studies for eligibility. We independently extracted and collected the data on a standardized paper form. We were not blinded to the author, source institution, or the publication source of trials. We resolved disagreements by discussion and approached all first authors of the included trials for additional information on risks of bias. For more detailed information please see the section 'Contributions'.

Evaluation of risk of bias in trials

We evaluated the validity and design characteristics of each trial. Trials were evaluated for major potential sources of bias (random sequence generation, allocation concealment, blinding, intention-to-treat analysis, and completeness of follow up) (Higgins 2005). We assessed each study quality factor separately and defined the trials as having low risk of bias only if they adequately fulfilled all of the criteria.

Random sequence generation

Adequate: the method used generated random sequences, e.g. random number generation, toss of coin.

Unclear: no information on random sequence generation available.

Inadequate: alternate medical record numbers or other non-random sequence generation.

Allocation concealment

Adequate: allocation method prevented investigators or participants from knowing the next allocation, e.g. central allocation; sealed opaque envelopes; serially-numbered, sequentially-numbered but otherwise identical vehicles, including their contents; or other descriptions of convincing concealment of allocation.

Unclear: no information on allocation method available or the description did not allow a clear distinction.

Inadequate: allocation method allowed the investigators or participants to know the next allocation, e.g. alternate medical record numbers; reference to case record numbers or date of birth; an open allocation sequence, unsealed envelopes.

Blinding

Adequate: double blinded and the method of blinding involved identical placebo. Studies were categorised as double blinded if the participant and at least one other of the personnel (relative, investigator, one of the many intensive care doctors, one of the many intensive care nurses, one of the many other people looking after the participant who could affect their outcome) were unaware of whether AT III or placebo was being given.

Unclear: blinding not described.

Inadequate: not double blinded; categorized as an open-label study; or without use of placebo.

Intention-to-treat (ITT) analysis

Adequate: we could extract data according to ITT principles.

Unclear: we could not extract data according to ITT principles.

Inadequate: use of per protocol analyses, i.e. participants who were randomized were not included in the analysis because they did not receive trial intervention; withdrew from the trial; or were not included because of protocol violation.

We defined a trial as at low risk of bias if all the above components were adequately conducted. The remaining trials were defined as at high risk of bias.

Data analysis

We used Review Manager software (RevMan 5.0). We calculated the relative risks (RR) with 95% confidence intervals (CI) for dichotomous variables and mean difference (MD) with CI for continuous outcomes. We used the chi-squared test to provide an indication of heterogeneity between studies, with P < 0.1 considered significant. The degree of heterogeneity observed in the results was quantified using the I-squared (I²) statistic, which can be interpreted as the proportion of the total variation observed between the studies that is attributable to differences between studies rather than sampling error (chance) (Higgins 2002). I² > 75% is considered as very heterogeneous. We used both a random-effects model and a fixed-effect model. If I² = 0 we only reported the results from the fixed-effect model; and in the case of I² > 0 we reported only the results from the random-effects model.

Subgroup analysis

We planned the following subgroup analyses:

  1. the effect of AT III in participants given heparin (all types and doses) versus participants not given heparin;

  2. comparing estimates of the pooled intervention effect in trials with low risk of bias to estimates from trials with high risk of bias (i.e. trials having at least one inadequate risk of bias component);

  3. duration of drug administration (up to one week, more than one week);

  4. completeness of follow up (the actual number of randomized participants with outcome data at the defined end of follow up for the trial, where we compared the groups of trials based on the degree of follow-up completeness);

  5. comparing the pooled intervention effect in trials with a follow up that was longer than the median follow up with trials having a follow up equal to or shorter than the median follow up of trial participants. This was in order to detect a possible dependency of the estimate of intervention effect with length of follow up. There was no biological rationale for choosing the median follow up as a fixed time point but rather this was a pragmatic approach in order to perform a subgroup analysis;

  6. the effect of AT III in the trauma population;

  7. the effect of AT III in obstetrics (eclampsia, pre-eclampsia, or DIC);

  8. the effect of AT III in paediatrics (we defined an age below 18 years for our inclusion criteria);

  9. the effect of AT III in sepsis.

If analyses of various subgroups were significant, we performed a test of interaction (Altman 2003). We considered P values < 0.05 as indicating significant interaction between the AT III effect and subgroup category.

We looked for bias by using the method proposed by Egger (Egger 1997) (see Additional Figure 1). We included entire trials for subgroup analysis of trauma, obstetric, and paediatric participants.

Figure 1.

Funnel plot, overall mortality regardless of follow up (quality)

Results

Description of studies

Search results

Through electronic searches and from reading the references of potentially relevant articles, we identified 8775 publications on AT III. We excluded 8716 publications as they were either duplicates or were clearly irrelevant. A total of 61 relevant publications were retrieved for further assessment. From these, we included 20 trials that were described in 21 publications (see Additional Figure 2) and which randomized a total of 3458 participants. The sample size varied from 25 to 2314 participants. We excluded 40 publications for the reasons detailed in the Characteristics of excluded studies. We found one ongoing trial (D'angelo 2005) but no data were provided for this trial.

Figure 2.

How searching results found

Types of participants

We classified two trials as obstetric studies (Kobayashi 2003; Maki 2000); three trials as paediatric trials (Fulia 2003; Mitchell 2003; Schmidt 1998); and a further two trials as trauma studies (Grenander 2001; Waydhas 1998). The remaining trials consisted of mixed populations of critically ill participants, mainly with sepsis.

Types of interventions

The duration of intervention varied from less than 24 hours to four weeks. Three trials had a median duration of AT III intervention that was longer than one week (Inthorn 1997; Mitchell 2003; Smith-Erichsen 1996). Follow up ranged from seven days to 90 days.
The comparison group received placebo in 10 trials (Baudo 1998; Diaz-Cremades 1994; Eisele 1998; Fourrier 1993; Fulia 2003; Haire 1998; Maki 2000; Schmidt 1998; Warren 2001; Waydhas 1998). The agent used as placebo was albumin, in different concentrations. One trial did not provide information on the placebo agent used (Eisele 1998).

Risk of bias in included studies

Generation of the allocation sequence

Generation of allocation sequence was adequately reported in nine trials (45%) (Albert 1992; Baudo 1998; Fulia 2003; Haire 1998; Kobayashi 2003; Maki 2000; Mitchell 2003; Schmidt 1998; Warren 2001).

Allocation concealment

Allocation concealment was adequately reported in 12 trials (60%) (Albert 1992; Baudo 1998; Fourrier 1993; Fulia 2003; Grenander 2001; Haire 1998; Kobayashi 2003; Maki 2000; Mitchell 2003; Schmidt 1998; Warren 2001; Waydhas 1998) (see Analysis 1.3).

Blinding

Ten trials provided sufficient data to be categorized as double blinded (50%) (Baudo 1998; Eisele 1998; Fourrier 1993; Fulia 2003; Haire 1998; Kobayashi 2003; Maki 2000; Schmidt 1998; Warren 2001; Waydhas 1998). The remaining trials were either open label or did not provide sufficient data on how the double blinding was achieved (see Analysis 1.4).

Follow up

Two trials did not provide data on follow up (Baudo 1992; Diaz-Cremades 1994). Twelve trials (60%) had complete follow up (Eisele 1998; Fourrier 1993; Fulia 2003; Grenander 2001; Haire 1998; Inthorn 1997; Kobayashi 2003; Langely 1993; Schmidt 1998; Schorr 2000; Smith-Erichsen 1996; Waydhas 1998) (see Analysis 1.5).

Eight trials did not have complete follow up (Albert 1992; Baudo 1992; Baudo 1998; Diaz-Cremades 1994; Harper 1991; Maki 2000; Mitchell 2003; Warren 2001).

Intention-to-treat analysis (ITT)

Thirteen trials (65%) performed analysis according to the ITT method or provided sufficient data to perform ITT analyses (Baudo 1992; Eisele 1998; Fourrier 1993; Fulia 2003; Haire 1998; Harper 1991; Inthorn 1997; Langely 1993; Maki 2000; Schmidt 1998; Schorr 2000; Smith-Erichsen 1996; Waydhas 1998) (see Analysis 1.6).

Sample size calculation

Eight trials (40%) reported sample size calculations (Baudo 1998; Fourrier 1993; Haire 1998; Inthorn 1997; Kobayashi 2003; Mitchell 2003; Schmidt 1998; Warren 2001).

Effects of interventions

Mortality

Combining all trials showed no statistically significant effect of AT III on mortality: 667/1708 deaths (39.1%) in the experimental group compared with 699/1750 deaths (39.9%) in the control group (RR (fixed) 0.96, 95% CI 0.89 to 1.03). Heterogeneity was absent (see Analysis 1.1). Combining the data provided in Table 1 (which excluded articles published as abstracts) with the overall mortality analysis based on risk of bias did not alter the overall picture: 645/1895 deaths (34.0%) in the AT III group compared with 728/1898 deaths (38.4%) in the control group (RR (fixed) 0.96, 95% CI 0.89 to 1.04).

Table 1. Trials excluded (abstracts)
   
Trials excluded (abstracts)AT III mortality n/NControl mortality n/N
Balk 19954/172/17
Palareti 19956/309/29
Muntean 19899/458/53
Korninger 19870/50/5
Schuster 19979/2210/23
Paternoster 20000/180/21
Subgroup and sensitivity analyses

We did not find any statistically significant differences in subgroups: with adequate and inadequate components of risk of bias; and with and without adjuvant heparin (see Additional Table 2; Table 3).

Table 2. Refers to table of 'Comparisons and data' 01.01 to 01.06
  1. (a/A) PO2: ratio of arterial to alveolar oxygen pressure; ABG: arterial blood gas; AIDS: acquired immune deficiency syndrome; APACHE: acute physiology and chronic health evaluation; APTT: activated partial thromboplastin time; ARDS: acute respiratory distress syndrome; AT III: antithrombin III; BP: blood pressure

    bid: bis in die, which means twice-daily; CNS: central nerve system; COPD: chronic obstructive pulmonary disease; CPP: cerebral perfusion pressure; CRP: C-reactive protein; CT: computer tomography; DIC: disseminated intravascular coagulation; FDP: fibriongen degradation products; FFP: fresh frozen plasma; FFS: fresh frozen serum; FHF: fulminant hepatic failure; g/l: gram per litre; GCS: Glasgow coma score; GI: gestosis index; h: hour; HELLP syndrome: haemolysis, elevated liver enzymes, low platelet count; HSCT: haematopoietic stem cell transplantation; ICP: intracranial pressure; ICU: Intensive care unit; ISS: injury severity score;ITT: Intention to treat; IU: international unit; IV: intravenous; IVH: intra ventricular haemorrhage; Kg: kilogram; LMWH: low molecular weight heparin; Min: minutes; ml: millilitre; mm Hg: millimetre mercury; MODS: multiorgan dysfunction syndrome; MOFS: multiorgan failure score; MPI: Mannheimer peritonitis index; n: number; NSAID: nonsteroid anti-inflammatory drugs; NYHA: New York Heart Association classification; OSFS: organ system failure score; PC: platelet concentration; PK: prothrombin complex; Plg: plasminogen; PPIC: plasmin-plasmin inhibitor complexes.

    
Risk of bias analysisWeight
low-risk trials
RR (fixed) 95% CI, low risk of bias and
adequate quality
RR (fixed) 95% CI,
high risk of bias, inadequate or unclear
Overall mortality (quality)88.87%0.97 (0.88 to1.03)1.00 (0.78 to 1.27)
Overall mortality (random sequence generation)88.33%0.95 (0.88 to 1.02)0.99 (0.78 to 1.25)
Overall mortality (allocation concealment)90.22%0.96 (0.88 to 1.04)0.94 (0.72 to 1.21)
Overall mortality (blinding)90.67%0.95 (0.88 to 1.03)0.99 (0.76 to 1.28)
Overall mortality (completeness of follow up)88.85%0.97 (0.88 to 1.04)0.97 (0.77 to 1.23)
Overall mortality (Intention to treat)13.49%0.96 (0.77 to 1.19)0.96 (0.88 to 1.04)
Key: mortality n/N AT III 667/1708 (39.1%); n/N control 699/1750 (39.9%)RR (fixed) 0.96, 95% CI 0.89 to 1.03, Heterogeneity I² = 0 %, P = 0.81Test of interaction P = 0.17 
Table 3. Refers to tables of 'Comparisons and data': 01.07; 01.08; 01.12; 01.13; 01.14.
    
Subgroup analysisMortality
n/N AT III
Mortality
n/N Control
RR (fixed) (95% CI)
Follow up less than median of all trials87/319 (27.3%)92/360 (25.6%)0.96 (0.76 to 1.20)
Follow up greater than median of all trials508/1389 (36.6%)607/1390 (43.7%)0.97 (0.88 to 1.04)
Duration of Intervention less than/equal to 1 week647/1620 (39.9%)677/1630 (41.5%)0.96 (0.89 to 1.04)
Duration of Intervention greater than 1 week20/88 (25%)22/120 (18.3%)0.89 (0.59 to 1.34)
No adjuvant heparin *42/211 (19.9%)47/214 (22.0%)0.92 (0.67 to 1.27)
No adjuvant heparin §578/1368 (42.3%)608/1371 (44.3%)0.95 (0.88 to 1.04)
No adjuvant heparin §§200/563 (35.5%)229/560 (40.7%)0.89 (0.77 to 1.02)
Key: heterogeneity I2 = 0 %, P > 0.55*: Warren 2001 considered as a trial with adjuvant heparin therapy§: Warren 2001 considered as a trial without adjuvant heparin therapy§§: Data from Warren 2001 split based on heparin administration

Due to the ongoing debate about the interaction between AT III and heparin, we decided to make three separate subgroup analyses to examine the trial intervention based on interaction with heparin. The only difference between these subgroup analyses was the way in which the data from Warren 2001 were incorporated. Only in one subgroup analysis, splitting data from Warren 2001, did the subgroup without heparin show a statistically significant effect of AT III (RR (fixed) 0.87, 95% CI 0.75 to 0.99). As there was some heterogeneity (I² = 1.1%, P = 0.41), we applied the random-effects model as defined in our protocol and the effect was no longer significant (RR (random) 0.89, 95% CI 0.77 to 1.02) (see Analysis 1.14). Similarly, there was no statistically significant interaction with and without adjuvant heparin if all patients from Warren 2001 were analysed as participating in either a trial with (P > 0.3) or without (P > 0.3) concomitant use of heparin (see Analysis 1.12; Analysis 1.13; Analysis 1.14; Additional Table 3).

We did not find any statistically significant difference when examining the effects in subgroups according to: duration of intervention (equal or less than one week versus longer than one week); follow up less than or longer than the median of all trials; intervention among different populations (paediatrics, trauma, sepsis); or the effect of degree of follow-up completeness (see Analysis 1.5; Analysis 1.8; Analysis 1.9; Analysis 1.10; Analysis 1.11; and Additional Table 3; Table 4).

Table 4. Refers to tables of ' Comparison and data' 01.09 to 01.11 and 01.32
    
Subgroup analysisMortality: AT IIIMortality: controlRR (fixed) (95% CI)
Trauma9/33 (27.3%)4/35 (11.4%)2.15 (0.81 to 5.72)
Obstetrics (maternal)0/880/87 
Obstetrics (fetal & neonatal)5/78 (6.4%)5/80 (6.3%)1.03 (0.33 to 3.21)
Paediatrics *8/116 (6.9%)5/151 (3.3%1.49 (0.38 to 5.87)
Septic population590/1298 (45.5%)622/1303 (4.7%)0.95 (0.88 to 1.03)
Key: heterogeneity I2 = 0 %, P > 0.13*: RR (random) since I2 = 20.9 %, P = 0.26  

The funnel plot on overall mortality regardless of follow up (Figure 1) showed a symmetrical distribution that indicated no publication bias.

Adverse events, complications, and surgical intervention

Six trials with low risk of bias (Baudo 1998; Fulia 2003; Kobayashi 2003; Maki 2000; Schmidt 1998; Warren 2001) and three with high risk of bias (Langely 1993; Grenander 2001; Mitchell 2003) demonstrated a statistically significant increase in bleeding events in the intervention group compared to the control group (RR (random) 1.52, 95% CI 1.30 to 1.78). Heterogeneity was insignificant (I² = 0.3%, P = 0.43). No other outcome examining adverse events was statistically significant (see Analysis 1.15 to Analysis 1.20; Analysis 1.23; Additional Table 5; Table 6).

Table 5. Refers to tables of ' Comparison and data' 01.15 to 01.19, 01.23, 01.28
      
Secondary outcomesAT III n/NControl n/NLow risk of bias trials RR (95% CI)High risk of bias trials RR (95% CI)Overall RR (95% CI)
Intracranial bleeding (1)36/122626/12281.62 (0.96 to 2.73)0.92 (0.51 to 1.66)1.26 (0.83 to 1.92)
Renal failure (2)2/333/33No trial0.71 (0.08 to 6.11)0.71 (0.08 to 6.11)
Pneumothorax (3)2/303/300.67 (0.12 to 3.71)No trial0.67 (0.12 to 3.71)
Complications other than bleeding (4)14/7533/1120.75 (0.18 to 3.07)0.72 (0.40 to 1.30)0.72 (0.42 to 1.25)
Bleeding events (5)312/1447199/14821.37 (1.04 to 1.82)1.23 (0.48 to 3.20)1.52 (1.30 to 1.78)
Incidence of surgical intervention (6)31/5130/520.93 (0.63 to 1.36)1.12 (0.91 to 1.38)1.04 (0.85 to 1.27)
Respiratory failure not present at admission (7)115/1293137/12980.96 (0.69 to 1.32)0.83 (0.58 to 1.20)0.93 (0.76 to 1.14)
Key: RR (fixed) in analysis 3, 4, 6 since I2 = 0%, P > 0.33RR (random) in analysis 1, since I2 = 9.2 %, P = 0.33RR (random) in analysis 2, since I2 = 28.2 %, P = 0.24RR (random) in analysis 5, since I2 = 0.3 %, P = 0.43RR (random) in analysis 7, since I2 = 31.6%, P = 0.22 
Table 6. Refers to tables of ' Comparison and data' 01.20 to 01.22, 01.24 to 01.27, 01.2
      
Secondary outcomesAT III NControl NLow risk of bias trials MD (95% CI)High risk of bias trials MD (95% CI)Overall MD (95% CI)
Amount of red blood cell transfused (1)5053-600.00 (-899.18 to -300.82)150.89 (-396.18 to 697.96)-111.74 (-594.13 to 370.65)
Subjective overall quality of life assessment (2)460437-2.00 (-5.01 to 1.01)No trial-2.00 (-5.01 to 1.01)
Objective assessment of physical performance and dependency (3)460437-2.00 (-4.49 to 0.49)No trial-2.00 (-4.49 to 0.49)
Severity of sepsis (MOF score) (4)8076-0.70 (-1.22 to -0.18)-1.92 (-3.05 to -0.78)-1.24 (-2.18 to -0.29)
Severity of sepsis (APACHE I and II) (5)5250No trial-2.18 (-4.37 to 0.00)-2.18 (-4.37 to 0.00)
Severity of sepsis (OSF score) (6)1513No trial-0.20 (-0.66 to 0.26)-0.20 (-0.66 to 0.26)
Severity of illness score (7)2425-10.00 (-20.40 to 0.40)No trial-10.00 (-20.40 to 0.40)
Duration of mechanical ventilation (8)1081113.00 (-1.97 to 7.97)1.49 (-3.18 to 6.15)2.20 (-1.21 to 5.60)
Length of stay in hospital (9)8785-10.80 [-20.49 to -1.11]2.97 (-4.01 to 9.94)-1.86 (-11.38 to 7.67)
Mean length of stay in ICU (10)176170-1.70 [-5.07 to 1.69]0.63 (-1.42 to 2.69)0.01 (-1.75 to 1.76)
Key: Mean difference (MD) (fixed) in analysis 2, 3, 5, 6, 7, 8, 10, since I2 = 0%, P > 0.63MD (random) in analysis 1, since I2 = 87.7 %, P = 0.0003MD (random) in analysis 4, since I2 = 47.8 %, P = 0.15MD (random) in analysis 9, since I2 = 64.3%, P = 0.06  

Quality of life

Only one trial examined the intervention's effect on quality of life (Rublee 2003: based on data from Warren 2001). There was an objective assessment of physical performance and dependency, and a subjective overall quality of life assessment analysis. Neither assessment supported intervention with AT III (MD -2.00, 95% CI -4.49 to 0.49; MD -2.00, 95% CI -5.01 to 1.01 respectively) (Additional Table 6).

Severity of sepsis

Only one analysis, multiorgan failure score (MOFS) (MD (random) -1.24, 95% CI -2.18 to -0.29), of the four different analyses reached statistical significance when examining the effect of AT III on various illness scores. Six trials provided data (Baudo 1998; Diaz-Cremades 1994; Eisele 1998; Haire 1998; Inthorn 1997; Schorr 2000) (see Analysis 1.24 to Analysis 1.27; Additional Table 6).

Respiratory outcomes

Six trials examined the effect of AT III on the incidence of respiratory failure (not present at admission) (Eisele 1998; Fourrier 1993; Kobayashi 2003; Maki 2000; Warren 2001; Waydhas 1998). There was no statistically significant difference with AT III (RR (random) 0.93, 95% CI 0.76 to 1.14). Heterogeneity was present (I² = 31.6%, P = 0.22). Three trials examined the effect of the trial intervention on duration of mechanical ventilation (Grenander 2001; Schmidt 1998; Waydhas 1998). There was no statistically significant difference (MD 2.20, 95% CI -1.21 to 5.60). Heterogeneity was absent (see Analysis 1.28; Analysis 1.29; Additional Table 5; Table 6).

Length of stay in the ICU and in hospital

Three trials examined the intervention effect on the length of stay in hospital (Haire 1998; Smith-Erichsen 1996; Waydhas 1998) with a MD (random) of -1.86 (95% -11.38 to 7.67). Heterogeneity was significant (I² = 64.3%, P = 0.06).
One trial with low risk of bias (Baudo 1998) and five trials with high risk of bias (Albert 1992; Diaz-Cremades 1994; Fourrier 1993; Smith-Erichsen 1996; Waydhas 1998) examined the intervention effect on length of stay in the ICU. There was insufficient evidence to support any beneficial effect of the intervention (MD 0.01, 95% CI -1.75 to 1.76). Heterogeneity was absent (see Analysis 1.30; Analysis 1.31; Additional Table 6).

Discussion

In this systematic review of 20 trials with 3458 patients we found no significant beneficial effect of AT III on mortality. The analyses on mortality showed no heterogeneity and were robust when performing different subgroup analyses. Conversely, AT III increased the risk of bleeding and it appeared to improve only one of the reported severity of sepsis scores (MOFS). None of the other secondary outcomes reached statistical significance.

Neither the meta-analysis nor the subgroup analyses demonstrated a statistically significant effect of AT III on mortality. However, this is not evidence of the absence of a beneficial effect; but the data suggest that a potentially beneficial effect of AT III must be modest compared to what had been expected. The point estimate of the potential intervention effect as suggested by the low bias trials is a 5% relative risk reduction (RRR) (see Analysis 1.1). In order to demonstrate or reject a beneficial effect on mortality in a single trial, assuming a RRR of 5% (an absolute risk reduction of 2.3%, from 48.5% to 46.2%) at least 14,294 patients should be randomized (Additional Figure 3) (with 80% power and alpha 0.05, assuming a double-sided type I risk of 5% and a type II risk of 20%). However, solid evidence may be obtained with a lesser number of patients if eventually the cumulative meta-analysis z-curve crosses the trial sequential monitoring boundary constructed for a required information size of 14,294 randomized patients. On the other hand to demonstrate or reject an a priori anticipated intervention effect of a RRR of 10%, 3317 patients should be randomized. As 3458 patients have already been included in the meta-analysis, without becoming statistically significant, a RRR of 10% or more on mortality is unlikely (Additional Figure 4).

Figure 3.

Trial sequential analysis of all trials of the effect of ATIII on mortality. Cumulative z-curve in blue does not cross the trial sequential monitoring boundary (full red line with open diamonds) constructed for a low bias heterogeneity adjusted information size of 14,294 patients corresponding to a RRR of 5% with an alfa=0.05 and a power of 80% (beta = 0.20). Only 24% of the required information size has been reached so far.

Figure 4.

Trial sequential analysis (TSA) of all trials of the effect of ATIII on mortality. Cumulative z-curve in blue does not cross the boundary constructed for an information size of 3317 patients in the meta-analysis (full red line with open diamonds) with a RRR of 10% (alfa = 0.05) and a power of 80% (beta = 0.20). With the total number of accrued participants in randomized trials being 3458 we are able to reject a RRR of 10% with a power of 80%.

Subgroup analysis of duration of intervention and length of follow up

Based on follow up less than or longer than the median of all trials, we undertook a subgroup analysis to examine the intervention effect on mortality. However, there was no statistically significant association between follow up and mortality (see Analysis 1.7). The median follow-up time was 32 days.

We also examined intervention effect based on the median duration of intervention being less than or longer than one week. Only two trials with a total of 125 participants had a median duration of intervention longer than one week. The current evidence does not support a longer duration of intervention.

Subgroup analyses on paediatric, obstetric and trauma populations

Based on the existing data, we have to conclude that there is insufficient data to help us support or refute the use of AT III intervention among trauma, obstetric, or paediatric populations.

Subgroup analyses regarding septic populations

Very few trials met our requirements in terms of trial intervention effect on various illness scores. We accepted the various definitions provided by the authors and undertook four different meta-analyses. The range of participant numbers in these analyses ranged from 28 to 156 and only one meta-analysis reached statistical significance. The meta-analyses examining the overall mortality in the septic population, based on 2601 participants, also failed to demonstrate a statistically significant reduction of mortality.

The heparin issue

A detrimental interaction between AT III and heparin was suspected before the Warren 2001 trial, and use of ATIII with and without heparin was predefined in the protocol for secondary analyses. However, the patients were not stratified according to heparin administration and the protocol allowed concomitant use of heparin by indication, after randomization to AT III or placebo. Even if the baseline comparison of patients allocated to AT III and placebo, in the subgroup without heparin, showed similar characteristics the randomization is violated in the subgroup analysis.

Pooling all trials with and without concomitant use of heparin, with the Warren 2001 trial as either a trial with concomitant use of heparin or as a trial without use of heparin, does not provide evidence of a statistically significant intervention effect of AT III. Splitting the Warren 2001 trial into two 'separate trials', with and without concomitant use of heparin, and pooling these results with the other trials does not provide a statistically significant intervention effect of AT III in the subgroup of trials without adjuvant heparin administration (RR 0.89, 95% CI 0.71 to 1.02; using a random-effects model (I² = 1.1%)). However, splitting the Warren 2001 trial violates the randomization procedure.

Trial sequential analysis

In a single trial, interim analysis increases the risk of type I errors. To avoid type I errors, group sequential monitoring boundaries (Lan 1983) are applied to decide whether a trial could be terminated early because of a sufficiently small P value, that is the cumulative z-curve crosses the monitoring boundaries. Sequential monitoring boundaries can be applied to meta-analysis as well, called trial sequential monitoring boundaries. In trial sequential analysis the addition of each trial in a cumulative meta-analysis is regarded as an interim meta-analysis and helps to decide whether additional trials are needed.

The idea in trial sequential analysis is that if the cumulative z-curve crosses the boundary a sufficient level of evidence is reached and no further trials are needed. If the z-curve does not cross the boundary then there is insufficient evidence to reach a conclusion. To construct the trial sequential monitoring boundaries the information size is needed and is calculated as the least number of participants needed in a single trial (Pogue 1997; Pogue 1998; Wetterslev 2007). The intervention effect suggested by the low-level of bias trials in the meta-analysis of the effect of AT III on mortality is a relative risk reduction (RRR) of 5% (Additional Figure 3) and the low-bias heterogeneity adjusted information size (LBHIS) calculated based on this intervention effect is 14,294 participants (Additional Figure 3). With an accrued information size of 3458 patients and no boundaries crossed so far, only 24% of the required information size is actually available to reject or accept a 5% RRR of overall mortality. To demonstrate or reject an a priori anticipated intervention effect of a RRR of 10% 3317 should be randomized. As 3458 patients are included in the present review without the meta-analysis becoming statistically significant an RRR of 10% or more on mortality is unlikely (Additional Figure 4).

Strengths and limitations

Our systematic review has several potential limitations. As for all systematic reviews our findings and interpretations are limited by the quality and quantity of available evidence on the effects of AT III on mortality. The risk of bias of the included trials was assessed by using the published data, which ultimately may not reflect the truth. All authors were contacted but only a few responded and provided further information. Three trials with 260 participants reported zero mortality in both study groups (Kobayashi 2003; Maki 2000; Mitchell 2003). Exploratory analysis adding an imagined trial with one death and 130 participants in each study group had no noticeable effect on the result.

We excluded six trials reporting mortality data from 285 participants since they were only published as abstracts (Balk 1995; Korninger 1987; Muntean 1989; Palareti 1995; Paternoster 2000; Schuster 1997). Data from these trials showed a 20% mortality in both the AT III and control groups (Additional Table 1). This is not in contrast to data provided by the included trials. When performing a sensitivity analysis combining the mortality data of these trials with the included trials any difference did not reach statistical significance (RR 0.96, 95% CI 0.89 to 1.04; using a fixed-effect model).

There was variation in the patient population; the type, dose, and duration of AT III treatment; and length of follow up. We observed the most beneficial effects of AT III on mortality in two trials with high risk of bias (Baudo 1992; Eisele 1998) and in two trials with low risk of bias (Fulia 2003; Haire 1998), with a total population of 180 patients.

Our decision to perform trial sequential analyses was taken after the protocol for this review was published. Despite the risk of being accused of performing post-hoc analyses, it is important to mention that this method was, in the main part, developed only after publication of our protocol (Deveraux 2005; Wetterslev 2007). Due to lack of convincing evidence in favour of AT III in settings without heparin, we chose to implement trial sequential analysis results since the hypothesis of a beneficial effect of AT III in critically ill patients still generates much attention.

Although there was minimal heterogeneity among trial results on mortality, we are aware that we pooled very heterogeneous trials in terms of patients, settings, and treatment regimens. Thus, the validity of our meta-analysis may be criticised for mixing apples and oranges. However, all included conditions cause low levels of AT III, can result in DIC, and have similar inflammatory pathways. Therefore, we think that there is a good biologic reason to perform a broad meta-analysis, which also considerably increases the generalizability and usefulness of the review. Further, a broad meta-analysis increases power, reduces the risk of erroneous conclusions, and facilitates exploratory analyses which can generate hypotheses for future research (for example adjuvant heparin) (Gotzsche 2000).

Authors' conclusions

Implications for practice

There is insufficient evidence to support the use of AT III in any category of critically ill patients. We did not find a statistically significant effect of AT III on mortality; and AT III increased the risk of bleeding events. Subgroup analyses performed according to duration of intervention, length of follow up, different patient groups, and use of adjuvant heparin did not show differences in the estimates of intervention effects. Thus. based on this finding, we cannot recommend the routine use of AT III. Trial sequential analysis shows that there is sufficient evidence to reject a beneficial effect of more than 10% RRR (5% absolute risk reduction) on mortality and there is still the possibility that use of AT III may be harmful.

Implications for research

There is a need for a randomized trial with low risk of bias to evaluate the effectiveness of AT III without heparin before this intervention can be used routinely in critically ill patients. We recognize the heterogeneity in the patient population in the included trials and, as a consequence of the high mortality rate in the septic population, we believe that a new trial should address the effect of AT III in septic patients.

Acknowledgements

We would like to thank Dr John Carlisle, Prof Marcus Müllner, Dr Francois Fourrier, Dr Geoffrey Playford, Dr Christian Josef Wiedermann, Kathie Godfrey, and Nete Villebro for their help and editorial advice during the preparation of the protocol for the review.

We thank Dr John Carlisle (content editor), Dr Marialena Trivella (statistical editor), Dr Mark Simmonds (statistical comments), Prof Fourrier François; Dr Geoffrey Playford and Dr Christian J. Wiedermann (peer reviewers), and Kathie Godfrey (consumer representative) for their help and editorial advice during the preparation of this review.

We would also like to thank our local librarians for their assistance in developing the search strategy process and Dr Roberto S Oliveri for his support and advice during the preparation of this review.

We would also like to thank the authors of the following articles for providing additional data: Albert 1992; Fourrier 1993; Kobayashi 2003; Maki 2000; Warren 2001; Waydhas 1998.

Data and analyses

Download statistical data

Comparison 1. AT III versus control
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Mortality (subgroup analysis on bias risk)203458Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.89, 1.03]
1.1 Trials with low bias risk82875Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.88, 1.03]
1.2 Trials with high bias risk12583Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.78, 1.27]
2 Overall mortality (subgroup analysis on random sequence generation)203458Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.89, 1.03]
2.1 adequate random sequence generation92957Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.88, 1.03]
2.2 Inadequate or unclear random sequence generation11501Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.78, 1.25]
3 Overall mortality (subgroup analysis on allocation concealment)203458Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.89, 1.03]
3.1 adequate allocation concealment123060Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.88, 1.04]
3.2 Inadequate or unclear allocation concealment8398Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.72, 1.21]
4 Overall mortality (subgroup analysis on blinding)203458Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.89, 1.03]
4.1 blinded102957Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.88, 1.03]
4.2 Not blinded unclear blinding10501Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.76, 1.28]
5 Overall mortality (subgroup analysis on completeness of follow up)203458Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.89, 1.03]
5.1 Absence of complete follow up82855Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.88, 1.04]
5.2 Complete follow up12603Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.77, 1.23]
6 Overall mortality (subgroup analysis on ITT)203458Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.89, 1.03]
6.1 ITT13814Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.77, 1.19]
6.2 No ITT72644Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.88, 1.04]
7 Overall mortality (subgroup analysis on median follow up)203458Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.89, 1.03]
7.1 Mortality in trials with follow up less than median of all trials11679Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.76, 1.20]
7.2 Mortality in trials with follow up longer than median of all trials92779Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.88, 1.04]
8 Overall mortality (subgroup analysis on duration of intervention)203458Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.89, 1.03]
8.1 Median duration of AT III intervention equal to or less than one week173250Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.89, 1.04]
8.2 Median duration of AT III intervention longer than one week3208Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.59, 1.34]
9 Overall mortality (trauma)268Risk Ratio (M-H, Fixed, 95% CI)2.15 [0.81, 5.72]
9.1 Trials with high bias risk268Risk Ratio (M-H, Fixed, 95% CI)2.15 [0.81, 5.72]
10 Overall mortality (obstetrics)2333Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.33, 3.21]
10.1 Overall maternal mortality, trials with low bias risk2175Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
10.2 Overall fetal and neonatal mortality, trials with low bias risk2158Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.33, 3.21]
11 Overall mortality (paediatrics)3267Risk Ratio (M-H, Random, 95% CI)1.49 [0.38, 5.87]
11.1 Trials with low bias risk2182Risk Ratio (M-H, Random, 95% CI)1.49 [0.38, 5.87]
11.2 Trials with high bias risk185Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
12 Overall mortality (heparin; Warren 2001 as a trial with adjuvant heparin therapy)203458Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.89, 1.03]
12.1 Trials with complete or partially adjuvant heparin therapy143033Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.89, 1.04]
12.2 Trials without adjuvant heparin6425Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.67, 1.27]
13 Overall mortality (heparin; Warren 2001 as a trial without adjuvant heparin therapy)203458Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.89, 1.03]
13.1 Trials with complete or partially adjuvant heparin therapy13719Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.79, 1.22]
13.2 Trials without adjuvant heparin72739Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.88, 1.04]
14 Overall mortality (heparin; Warren 2001 data split based on Heparin administration)203458Risk Ratio (M-H, Random, 95% CI)0.95 [0.88, 1.03]
14.1 Trials with complete or partially adjuvant heparin therapy142335Risk Ratio (M-H, Random, 95% CI)0.99 [0.90, 1.09]
14.2 Trials without adjuvant heparin71123Risk Ratio (M-H, Random, 95% CI)0.89 [0.77, 1.02]
15 Complications during the in-patient stay specific to the trial intervention (intracranial bleeding)32454Risk Ratio (M-H, Random, 95% CI)1.26 [0.83, 1.92]
15.1 Trials with low bias risk22429Risk Ratio (M-H, Random, 95% CI)1.62 [0.96, 2.73]
15.2 Trials with high bias risk125Risk Ratio (M-H, Random, 95% CI)0.92 [0.51, 1.66]
16 Complications during the in-patient stay not specific to the trial intervention (renal failure)265Risk Ratio (M-H, Random, 95% CI)0.71 [0.08, 6.11]
16.1 Trials with high bias risk265Risk Ratio (M-H, Random, 95% CI)0.71 [0.08, 6.11]
17 Complications during the in-patient stay not specific to the trial intervention (pneumothorax)160Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.12, 3.71]
17.1 Trials with low bias risk160Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.12, 3.71]
18 Complication specific to the trial intervention other than bleeding3187Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.42, 1.25]
18.1 Trials with low bias risk160Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.18, 3.07]
18.2 Trials with high bias risk2127Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.40, 1.30]
19 Bleeding events92929Risk Ratio (M-H, Random, 95% CI)1.52 [1.30, 1.78]
19.1 Trials with low bias risk62791Risk Ratio (M-H, Random, 95% CI)1.37 [1.04, 1.82]
19.2 Trials with high bias risk3138Risk Ratio (M-H, Random, 95% CI)1.23 [0.48, 3.20]
20 Amount of red blood cells administered3103Mean Difference (IV, Random, 95% CI)-111.74 [-594.13, 370.65]
20.1 Trials with low bias risk135Mean Difference (IV, Random, 95% CI)-600.0 [-899.18, -300.82]
20.2 Trials with high bias risk268Mean Difference (IV, Random, 95% CI)150.89 [-396.18, 697.96]
21 Subjective overall quality of life assessment1897Mean Difference (IV, Fixed, 95% CI)-2.0 [-5.01, 1.01]
22 Objective assessment of physical performance and dependency (Karnofsky)1897Mean Difference (IV, Fixed, 95% CI)-2.0 [-4.49, 0.49]
23 Incidence of surgical intervention3103Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.85, 1.27]
23.1 Trials with low bias risk263Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.63, 1.36]
23.2 Trials with high bias risk140Risk Ratio (M-H, Fixed, 95% CI)1.12 [0.91, 1.38]
24 Severity of sepsis I3156Mean Difference (IV, Random, 95% CI)-1.24 [-2.18, -0.29]
24.1 Final MOF score among survivors, trials with low bias risk188Mean Difference (IV, Random, 95% CI)-0.70 [-1.22, -0.18]
24.2 Final MOF score among survivors, trials with high bias risk268Mean Difference (IV, Random, 95% CI)-1.92 [-3.05, -0.78]
25 Severity of sepsis II3102Mean Difference (IV, Fixed, 95% CI)-2.18 [-4.36, -0.00]
25.1 Final APACHE I & II scores among survivors, trials with high bias risk3102Mean Difference (IV, Fixed, 95% CI)-2.18 [-4.36, -0.00]
26 Severity of sepsis III128Mean Difference (IV, Fixed, 95% CI)-0.2 [-0.66, 0.26]
26.1 Final OSF score among survivors, trials with high bias risk128Mean Difference (IV, Fixed, 95% CI)-0.2 [-0.66, 0.26]
27 Severity of Ilness score149Mean Difference (IV, Fixed, 95% CI)-10.0 [-20.40, 0.40]
27.1 Trials with low bias risk149Mean Difference (IV, Fixed, 95% CI)-10.0 [-20.40, 0.40]
28 Incidence of respiratory failure not present at admission62591Risk Ratio (M-H, Random, 95% CI)0.93 [0.76, 1.14]
28.1 Trials with low bias risk42524Risk Ratio (M-H, Random, 95% CI)0.96 [0.69, 1.32]
28.2 Trials with high bias risk267Risk Ratio (M-H, Random, 95% CI)0.83 [0.58, 1.20]
29 Duration of mechanical ventilation3190Mean Difference (IV, Fixed, 95% CI)2.20 [-1.21, 5.60]
29.1 Trials with low bias risk1122Mean Difference (IV, Fixed, 95% CI)3.0 [-1.97, 7.97]
29.2 Trials with high bias risk268Mean Difference (IV, Fixed, 95% CI)1.49 [-3.18, 6.15]
30 Length of stay in hospital3172Mean Difference (IV, Random, 95% CI)-1.86 [-11.38, 7.67]
30.1 Trials with low bias risk149Mean Difference (IV, Random, 95% CI)-10.80 [-20.49, -1.11]
30.2 Trials with high bias risk2123Mean Difference (IV, Random, 95% CI)2.97 [-4.01, 9.94]
31 Mean length of stay in ICU6346Mean Difference (IV, Fixed, 95% CI)0.01 [-1.75, 1.76]
31.1 Trials with low bias risk1120Mean Difference (IV, Fixed, 95% CI)-1.70 [-5.09, 1.69]
31.2 Trials with high bias risk5226Mean Difference (IV, Fixed, 95% CI)0.63 [-1.42, 2.69]
32 Overall mortality among septic population62601Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.88, 1.03]
32.1 Trials with low bias risk32469Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.88, 1.03]
32.2 Trials with high bias risk3132Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.52, 1.57]
Analysis 1.1.

Comparison 1 AT III versus control, Outcome 1 Mortality (subgroup analysis on bias risk).

Analysis 1.2.

Comparison 1 AT III versus control, Outcome 2 Overall mortality (subgroup analysis on random sequence generation).

Analysis 1.3.

Comparison 1 AT III versus control, Outcome 3 Overall mortality (subgroup analysis on allocation concealment).

Analysis 1.4.

Comparison 1 AT III versus control, Outcome 4 Overall mortality (subgroup analysis on blinding).

Analysis 1.5.

Comparison 1 AT III versus control, Outcome 5 Overall mortality (subgroup analysis on completeness of follow up).

Analysis 1.6.

Comparison 1 AT III versus control, Outcome 6 Overall mortality (subgroup analysis on ITT).

Analysis 1.7.

Comparison 1 AT III versus control, Outcome 7 Overall mortality (subgroup analysis on median follow up).

Analysis 1.8.

Comparison 1 AT III versus control, Outcome 8 Overall mortality (subgroup analysis on duration of intervention).

Analysis 1.9.

Comparison 1 AT III versus control, Outcome 9 Overall mortality (trauma).

Analysis 1.10.

Comparison 1 AT III versus control, Outcome 10 Overall mortality (obstetrics).

Analysis 1.11.

Comparison 1 AT III versus control, Outcome 11 Overall mortality (paediatrics).

Analysis 1.12.

Comparison 1 AT III versus control, Outcome 12 Overall mortality (heparin; Warren 2001 as a trial with adjuvant heparin therapy).

Analysis 1.13.

Comparison 1 AT III versus control, Outcome 13 Overall mortality (heparin; Warren 2001 as a trial without adjuvant heparin therapy).

Analysis 1.14.

Comparison 1 AT III versus control, Outcome 14 Overall mortality (heparin; Warren 2001 data split based on Heparin administration).

Analysis 1.15.

Comparison 1 AT III versus control, Outcome 15 Complications during the in-patient stay specific to the trial intervention (intracranial bleeding).

Analysis 1.16.

Comparison 1 AT III versus control, Outcome 16 Complications during the in-patient stay not specific to the trial intervention (renal failure).

Analysis 1.17.

Comparison 1 AT III versus control, Outcome 17 Complications during the in-patient stay not specific to the trial intervention (pneumothorax).

Analysis 1.18.

Comparison 1 AT III versus control, Outcome 18 Complication specific to the trial intervention other than bleeding.

Analysis 1.19.

Comparison 1 AT III versus control, Outcome 19 Bleeding events.

Analysis 1.20.

Comparison 1 AT III versus control, Outcome 20 Amount of red blood cells administered.

Analysis 1.21.

Comparison 1 AT III versus control, Outcome 21 Subjective overall quality of life assessment.

Analysis 1.22.

Comparison 1 AT III versus control, Outcome 22 Objective assessment of physical performance and dependency (Karnofsky).

Analysis 1.23.

Comparison 1 AT III versus control, Outcome 23 Incidence of surgical intervention.

Analysis 1.24.

Comparison 1 AT III versus control, Outcome 24 Severity of sepsis I.

Analysis 1.25.

Comparison 1 AT III versus control, Outcome 25 Severity of sepsis II.

Analysis 1.26.

Comparison 1 AT III versus control, Outcome 26 Severity of sepsis III.

Analysis 1.27.

Comparison 1 AT III versus control, Outcome 27 Severity of Ilness score.

Analysis 1.28.

Comparison 1 AT III versus control, Outcome 28 Incidence of respiratory failure not present at admission.

Analysis 1.29.

Comparison 1 AT III versus control, Outcome 29 Duration of mechanical ventilation.

Analysis 1.30.

Comparison 1 AT III versus control, Outcome 30 Length of stay in hospital.

Analysis 1.31.

Comparison 1 AT III versus control, Outcome 31 Mean length of stay in ICU.

Analysis 1.32.

Comparison 1 AT III versus control, Outcome 32 Overall mortality among septic population.

Appendices

Appendix 1. Search strategies

DatabaseDates searchedSearch termsResults found
The Cochrane Central Register of Controlled Trials on the Cochrane LibraryIssue 4, 2006#1: (Antithrombin):ti,ab,kw: 1020
#2: (Antithrombin III):ti,ab,kw: 765
#3: (AT III):ti,ab,kw: 7333
#4: (ATIII ):ti,ab,kw: 60
#5: antithrombi*:ti,ab,kw: 0
#6: #1 OR #2 OR # 3 OR #4 OR #5: 1367
1367
MEDLINE1950 to November 2006#1: Antithrombins [ MeSH ]: 10415
#2: Antithrombin III [ MeSH ]: 5671
#3: antithrombin*: 14084
#4: AT III OR ATIII OR antithrombin III: 9319
#5: #1 OR #2 OR #3 OR #4: 16088
#6: random* OR controlled OR blind* OR placebo OR "controlled ? trial": 798029
#7: #6 AND #5 Limits: Humans: 1479
1479
EMBASE1980 to November 2006#1: random*: 350123
#2: controlled: 2424554
#3: blind*: 148036
#4: placebo: 139240
#5: antithrombi*: 13149
#6: antithrombin III: 8514
#7: ATIII: 543
#8: AT III: 2452
#9: (antithrombi*) or (AT III) or (ATIII) or (antithrombin III): 14294
#10: (placebo) or (blind*) or (controlled) or (random*): 2620035
# 11: ((placebo) or (blind*) or (controlled) or (random*)) and ((antithrombi*) or (AT III) or (ATIII) or (antithrombin III)): 4801
4801
Science Citation Index EXPANDED1945 to November 2006#1: TS=(antithrombin*): 11,277
#2: TS=(antithrombin III): 7,264
#3: TS=(ATIII): 489
#4: #3 OR #2 OR #1: 11,375
#5: TS=(random*) >100,000
#6: TS=(controlled) >100,000
#7: TS=(placebo): 96,007
#8: TS=(blind*) >100,000
#9: #8 OR #7 OR #6 OR #5 >100,000
#10: #9 AND #4: 1,128
 
Latin American Caribbean Health Sciences Literature (LILACS), the Chinese Biomedical Literature Database, and CINHALMarch 2005#1: Antithrombins
#2: Antithrombin III
#3: antithrombin*
#4: AT III OR ATIII OR antithrombin III
#5: ((((#1)) OR (#2)) OR (#3)) OR (#4)
#6: random* OR controlled OR blind* OR placebo OR "controlled ? trial"
#7: ((#6)) AND (#5) Limits: Humans
No randomized trials of relevance

What's new

Last assessed as up-to-date: 4 November 2006.

DateEventDescription
11 February 2013AmendedContact details updated; order of tables corrected

History

Protocol first published: Issue 3, 2005
Review first published: Issue 3, 2008

DateEventDescription
12 October 2010AmendedContact details updated.
11 May 2010AmendedContact details updated.
7 August 2008AmendedMinor edits to text
12 May 2008Amendedconverted to new Review format

Contributions of authors

Conceiving the review: Arash Afshari (AFSH), Ann Merete Møller (AMM)
Co-ordinating the review: AFSH
Undertaking manual searches: AFSH
Screening search results: AFSH, Jørn Wetterslev (JW)
Organizing retrieval of papers: AFSH
Screening retrieved papers against inclusion criteria: AFSH, JW, AMM
Appraising quality of papers: AFSH, JW, AMM
Abstracting data from papers: AFSH, JW
Writing to authors of papers for additional information: AFSH, JW
Providing additional data about papers: AFSH
Obtaining and screening data on unpublished studies: AFSH
Data management for the review: AFSH, JW
Entering data into Review Manager (RevMan 5.0): AFSH, JW
RevMan statistical data: JW, AFSH
Other statistical analysis not using RevMan: JW
Double entry of data: (data entered by person one: AFSH; data entered by person two: JW)
Interpretation of data: AFSH, JW, AMM, Jesper Brok (JB)
Statistical analysis: JW, AFSH
Writing the review: AFSH. JW, AMM, JB
Securing funding for the review: AMM
Performing previous work that was the foundation of the present study: AMM
Guarantor for the review (one author): AFSH
Person responsible for reading and checking review before submission: AFSH

Declarations of interest

None known

Sources of support

Internal sources

  • Cochrane Anaesthesia Review Group (CARG), Denmark.

External sources

  • No sources of support supplied

Differences between protocol and review

We decided after publication of our protocol for this review to also include randomized trials examining the effect of ATIII on malignant diseases and cirrhosis. The decision was based on the desire to increase precision and power without confounding our data. The generalisability and usefulness of meta-analyses are increased considerably if the individual trials cover different patient populations, settings, and treatment regimen. Further, a broad (lumping) meta-analysis increases power, reduces the risk of erroneous conclusions, and facilitates exploratory analyses, which can generate hypotheses for future research. Usually it is also recommended to pool a broad range of studies (Gotzsche 2000).

We chose to exclude trials with AT III in patients with cardiovascular diseases, since ATIII in this field has been used to compare various simultaneous active interventions. For instance, AT III has been used in cardiovascular by-pass procedures in order to evaluate graft function versus conventional anti-coagulant therapy and in ischaemic patients, AT III has been compared to other anticoagulants in invasive trans-cutaneous-interventions as an adjunctive therapy to stent procedures. We believe it would be appropriate to examine its role in cardiovascular diseases in a separate systematic review.

We did not include trials reported only as abstracts unless they were part of ongoing and current studies. The reason for exclusion of 10 studies only published as abstracts in this review was due to serious shortcomings in reporting and design. The latest of these trials are over 10 years old and are still not published. These abstracts do not provide us with valid and sufficient data to examine mortality, bias, design, follow-up and intention-to-treat analysis. We anticipated that it would be impossible to contact the investigators and the authors. However, we do provide the limited mortality data that we were able to retrieve from these trials and have also conducted a sensitivity analysis examining the role of these data in the overall mortality of the included trials.

We also extended our search strategy to include the following additional databases: Latin American Caribbean Health Sciences Literature (LILACS); the Chinese Biomedical Literature Database; and CINHAL (Cumulative Index to Nursing & Allied Health Literature).

We decided to employ trial sequential analyses as a way of estimating the level of evidence of the experimental intervention.

In our protocol we defined the secondary outcome "Bleeding events within 14 days". However, we changed this to "Bleeding events" since we found it more relevant to look at the overall bleeding without applying any time constraint. Additionally, we found very few trials reporting bleeding events within the first 14 days.

We defined bleeding events as noted by the authors (requiring transfusions) and related to the intervention.

In our protocol we stated that in cases of heterogeneity (I2 >0) the results would be presented using both fixed-effect and random-effects models. However, in our review we have chosen to present these results using a random-effects model only to make the review more readable. This does not alter the conclusion of the subgroup analyses. We felt that there was little value in using a fixed-effects model cases of substantial heterogeneity.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Albert 1992

MethodsTwo-group parallel randomized clinical trial
Generation of allocation sequence: adequate
Allocation concealment: adequate
Blinding: unclear
Follow up: adequate
ITT: no
Overall study quality: high risk of bias
No sample size calculation was reported
Participants

32 patients in the ICU with plasma AT III levels less than 70%. All patients included in the study within 2 days after admission to the ICU.

AT III group: 16 patients, 8 men, median age: 63.5 years. Median APACHE II score on inclusion: 14, TISS (therapeutic intervention scoring system): 34. Reason for admission: surgery 7 patients, trauma 4 patients, infection 3 patients, and other causes: 2 patients.

Control group: 16 patients, 9 men, median age: 66 years. Median APACHE II score on inclusion: 15, TISS (therapeutic intervention scoring system): 39. Reason for admission: surgery 5 patients, trauma 4 patients, infection 5 patients, and other causes: 2 patients.

Exclusion criteria: under 18 years old, liver disease, human immunodeficiency virus (HIV) infection, severe brain damage, patients admitted for post-operative pain relief only, anorexia nervosa, and pregnancy.

Interventions

AT III: concentrate by intravenous infusion for 20-30 minutes twice daily as long as AT III < 90%, in a dose intended to raise the level above 100% until the patients were discharged from the ICU. First dose: 2000-4000 IU, total amount: 3500-17000 IU.

Control: no placebo.

Unfractionated heparin 2500 or 5000 IU x 2 or x 3 daily was given subcutaneously to all patients for thromboprophylaxis. If continuous arteriovenous haemofiltration for acute anuria, then 20000-40000 IU Heparin per 24 hours was administered as continuous infusion. Blood samples from each patient were taken daily for 7 days or until discharge. Standard intensive care treatments were administered to all patients in both groups.

Outcomes

Primary: mortality.

Secondary: days in ICU, bleeding and transfusion, AT III, CRP, tissue plasminogen activator inhibitor (PAI-1), partial thromboplastin time, prothrombin complex (prothrombin time), fibrinogen degradation products (FDP), lactoferrin/serum, lactoferrin/plasma, lysozyme, side effects, APACHE II score and TISS (during the first 24 hours).

Notes

Country: Sweden
Letter sent to authors in November 2005. Reply received in December 2005.
2 patients randomized but not evaluated: 1 transferred to another hospital, the other had received AT III although randomized to the non-AT III group. There were 3 cases of cross over: these patients received AT III despite being allocated to the control group. These patients were evaluated up to the day when they received AT III. No side effects were reported.

Authors' conclusions: AT therapy appears to reduce hypercoagulation, fibrinolysis and the inflammatory response in seriously ill patients with acquired AT III deficiency.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskYes
Allocation concealment (selection bias)Low riskA - Adequate

Baudo 1992

MethodsTwo-group randomized clinical trial
Generation of allocation sequence: unclear.
Allocation concealment: unclear
Blinding: unclear
Follow up: adequate
ITT: yes
Overall study quality: high risk of bias
No sample size calculation was reported
Participants

29 patients with post necrotic cirrhosis undergoing liver transplantation were randomized to receive AT III (13 patients) or to control group (no placebo, 16 patients) - before the induction of anaesthesia and during surgery.

AT III group: 13 men, 4 patients with cryptogenetic cirrhosis, 4 with post-necrotic cirrhosis, 5 with alcoholic cirrhosis, average age 44±9 years, duration of surgery (min): 625±68.
Control group: 16 men, 5 patients with cryptogenetic cirrhosis, 7 with post necrotic cirrhosis, 4 with alcoholic cirrhosis, average age 42±9 years, duration of surgery (min): 642±113.

Interventions

AT III: administered by bolus infusion before the induction of anaesthesia in order to obtain a pre-operative activity of 100%. Thereafter 1,000 units per hour were given by continuous infusion until the end of surgery. No systemic heparinization.

Control: no placebo.

OutcomesMortality. Blood loss, transfusion requirements, activation of coagulation and fibrinolysis (thrombin-antithrombin complexes), activated partial thromboplastin time (aPTT), prothrombin time (PT), thrombin time (TT), reptilase time (RT), expressed as ratio (R), fibrinogen g/l), plasminogen (plg), alfa2-antiplasmin, AT III, platelet count, thrombin-antithrombin complexes (TAT), total fibrinogen, fibrinogen and fibrin degradation products.
Notes

Country: Italy
Letter sent to authors in January 2006, no reply received.

Authors' conclusion: AT III therapy did not support the working hypothesis; AT III replacement therapy did not modify total blood loss and total transfusion requirements.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskUnclear
Allocation concealment (selection bias)Unclear riskB - Unclear

Baudo 1998

MethodsTwo-group parallel randomized clinical trial
Generation of allocation sequence: adequate
Allocation concealment: adequate
Blinding: adequate
Follow up: adequate
Overall study quality: low risk of bias
ITT: no
Sample size calculation reported
Participants

Multicentre trial, 120 patients admitted to the ICU with an AT III concentration of < 70%.

AT III group: 60 patients, 42 were men, age distribution: 58.6±13.8 years, multiorgan failure score (MOFS) 5.6±2.5, simplified acute physiology score (SAPS): 15.6±4.4, 49% sepsis, 33% septic shock, 51% respiratory support, 53% haemodynamic support, haemorrhages: 5%, surgery 47%, surgery with sepsis 43%, AT III: 52.8±15.5%.

Control group: 60 patients, 41 were men, age distribution 62±12.2 years, MOFS: 4.8 ±2.3, SAPS:16.5±5.5, 51% sepsis, 23% septic shock, 48% respiratory support, 42% haemodynamic support, haemorrhages: 6%, surgery 45%, surgery with sepsis 41%, AT III: 52.9±14.5%.

Inclusion criteria: 1) respiratory and/or haemodynamic support, 2) sepsis: systemic response to infection manifested by 2 or more of a) tp > 38.5 ºC, b) heart rate > 90/min, c) respiratory rate > 20/min, d) leukocytosis > 15 x 109/l or leukopenia < 4 x 109/l, e) septic shock with sepsis-induced hypotension requiring vasoactive drugs for more than 24 h persisting despite adequate fluid replacement along with presence of hypoperfusion abnormalities that may include but are not limited to lactic acidosis, oliguria, or an acute alteration of mental status, f) postsurgical complications requiring respiratory and/or haemodynamic support, g) respiratory support with assisted or controlled ventilation > 24 h, h) haemodynamic support inotropic (dopamine/dobutamine = / >5 mg/kg /min) and/or vasoactive (epinephrine or norepinephrine), 3) 18-75 years, 4) AT III activity < 70%.

Exclusion criteria: 1) Multiple trauma, 2) liver cirrhosis/acute liver failure, 3) Cancer in a terminal phase, 4) Immunodeficiency, 5) leukaemia, 6) pregnancy, 7) Heparin therapy (except prophylaxis heparin, 5000 units b.i.d., subcut.)

Interventions

AT III: total dose 24000 units, fixed dose of 4000 AT III and 2000 IU every 12 hours, 5 days, infusion by pump.

Control: human albumin, 50 g/l, 4 g albumin bolus in 30 min, 1 bottle containing 2 g albumin every 12 h for 5 days, pump-driven.

Standard intensive care treatment, fresh frozen plasma (FFP) infused when bleeding and/or prothrombin time ratio > 2, platelet concentration (PC) infused when </= 50 (1 unit/10 kg weight).

Outcomes

Primary: mortality, survival for 30 days, multiorgan failure score (MOF) for 7 days, FFP and PC requirements.

Secondary: days in ICU, bleeding and transfusion, MOFS, septic shock survival, AT III plasma concentration.

Notes

Country: Italy
Letter sent to authors in December 2005, no reply received.
Balanced randomization within each center, post hoc analysis of septic shock subgroup. The distribution of patients with septic shock on haemodynamic support were unbalanced in the two groups at admission. Simplified acute physiology score (SAPS) and MOF score recorded for each patient at admission.

Four patients received therapy for less than 24 h; 1 patient in the placebo group was transferred to another hospital after the bolus infusion and was considered not evaluable; 3 patients with septic shock (2 AT III and 1 placebo) died within 24 h. A total of 119 were included in the analysis. No adverse reaction was recorded.

Authors' conclusion: The results showed a non-significant reduction in mortality (50% in AT group vs 54% in the placebo group). AT III only reduces 30-day mortality significantly in the subgroup of septic shock patients (70% in the AT group vs 87% in the placebo, P<0.04). Because at inclusion, septic shock and haemodynamic support were unbalanced between the placebo and the treated groups, a post hoc analysis was done and showed that AT decreased the risk of death with OR of 0.56. Probability of survival was 30% in AT group vs 17% in placebo ( P<.05).

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskAdequate
Allocation concealment (selection bias)Low riskA - Adequate

Diaz-Cremades 1994

MethodsTwo-group parallel randomized clinical trial
Generation of allocation sequence: inadequate
Allocation concealment: inadequate
Blinding: inadequate
Follow up: unclear
ITT: no
Overall study quality: high risk of bias
No sample size calculation was reported
Participants

195 critically ill patients admitted to ICU, without previous history of hepatic disease, 36 patients were chosen with AT III levels below 70% as inclusion criteria. None of the patients had manifest DIC.

AT III: 20 patients (10 with sepsis, 6 with trauma, 1 with sepsis + trauma, 3 with shock), 12 patients were men, mean age 46.25±11.79 years.

Control group: 16 patients (8 with sepsis, 4 with trauma, 2 with sepsis + trauma and 2 with shock), 10 patients were men, mean age 56.37±25.78 years.

Inclusion or exclusion criteria were not provided.

Interventions

AT III group: initial dose 60 U/kg of body weight, then 10 U/kg every 6 h, without dose adjustment depending on the AT III levels. The mean AT III dose received was 11.17±5.98 U. Treatment interrupted when the patients were discharged from ICU, or if they achieved AT III levels equal or superior to 90% during at least 48 h. Mean length of treatment: 5.8±4.2 days.

Control: human albumin 0.6%.

Standard intensive care treatment in both groups. All patients received 7500 IU of prophylactic subcutaneous calcium heparin every 12 h.

Outcomes

Primary: mortality.

Secondary: 1) platelet count, 2) side effects, 3) prothrombin time (PT), 4) activated thromboplastin time (APTT), 5) fibrinogen, 6) fibrinogen degradation products, 7) AT III, 8) protein C, 9) APACHE II score.

Notes

Country: Spain
Letter sent to authors in December 2005, no reply received.

No adverse effects reported. The only detectable alterations in the haemostasis were a mild thrombocytopenia and low levels of AT III and protein C. Manifest DIC was not reported in any patient.

Authors' conclusion: administration of AT III to critical patients with acquired low levels but without manifest DIC neither contributes to alterations in haemostasis nor the clinical evolution.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskInadequate
Allocation concealment (selection bias)High riskC - Inadequate

Eisele 1998

MethodsRandomized clinical trial
Generation of allocation sequence: unclear
Allocation concealment: unclear
Blinding: unclear
Follow up: yes, 30 days or until death
Overall study quality: high risk of bias
ITT: yes
No sample size calculation was reported
Participants

Multicentre, multinational trial of patients admitted to ICU.

AT III group: 20 patients, 11 were men, mean age: 57±16 y, weight (kg): 71±14, height (cm): 171±9. Underlying disease: peritonitis 2, mediastinitis 1, neoplasia (non-hematologic) 4, others: 12. Severity of sepsis at study entry (mean ± SD): APACHE II: 13.5 ± 5.1, MOF: 6.1±2.1, OFS:1.2±0.9, AT III activity: 45.7±14.4%. Coagulation failure: 3, acute hepatic dysfunction: 5, acute renal dysfunction: 8, acute respiratory dysfunction: 8, acute neurological dysfunction: 6.

Control group: 22 patients, 10 were men, mean age: 58±14 y, weight (kg): 73±15, height (cm): 169±8. Underlying disease: peritonitis 3, mediastinitis 1, adult respiratory distress syndrome 1, acute pancreatitis 3, neoplasia (non-haematologic) 3, other: 11. Severity of sepsis at study enter (mean ± SD): APACHE II: 15.5 ± 5.7, MOF: 6.7±2.0, OFS: 0.9±0.8, AT III activity: 49.0±19.1%. Coagulation failure: 2, acute hepatic dysfunction: 8, acute renal dysfunction: 8, acute respiratory dysfunction: 6, acute neurological dysfunction: 10.

Inclusion criteria: less than 80 and above 18 years old; fulfilled the following criteria within 6 h window prior to initiation of treatment: 1) clinical evidence of sepsis with a suspected source of infection; 2) temperature rectally > 38.5 ºC or < 35.5 ºC; 3) leukocyte count >10000/mm3 or <3500. Furthermore 3 of the following had to be fulfilled: a) heart rate >100/min; b) breath rate >24/min or mechanical ventilation because of septic indication; c) hypotension, sys BP <90 mm Hg when no vasoactive agent or fluid replacement; d) platelet count <100000/mm3; e) lactate >1.6 mmol/l; f) urine output <20ml/h.

Exclusion criteria: a) heparin (except sc low-dose), b) malignancies (incurable with metastases); c) haematologic neoplasia (except complete remission); d) chronic treatment with high dose immunosuppressive drugs; e) high dose NSAID within previous 2 days; f) known bleeding disorder; g) ongoing massive surgical bleeding, h) multiple organ failure, at least 4 organs involved existing for over 24 h; i) acute myocardial Infarction; j) chronic compensated organ dysfunction (chronic liver disease, dialysis, NYHA 3-4); k) complicated pre-existing diabetes mellitus; l) severe obstructive pulmonary disease; m) burn; n) AIDS; o) transplant, p) severe cranial trauma and/or pathologic changes on CT and GCS < 6; q) pregnancy; r) treatment with plasma expanders (Haes); s) prior enrolment in the trial or another clinical trial within the last 30 days.

Interventions

Experimental: AT III iv loading dose: 3000 units AT III, maintenance 1500 IU every 12 hours, 5 days treatment, cumulative dose: 18000 IU.

Control: placebo equivalent amounts, unknown agent.

Standard intensive care treatment in both groups.

Outcomes

Primary: 30-day all-cause mortality.

Secondary: survival days, days in ICU, safety (bleeding and transfusion), MOFS, APACHE II, OSFS, AT III activity, AT III plasma concentration, resolution of acute pre-existing organ dysfunction (neurological, respiratory, renal, hepatic and coagulation) and incidence of organ dysfunction.

Notes

Country: Germany, Belgium, the Netherlands
A letter sent to authors in December 2005, no answer received.

Acute physiology and chronic health evaluation (APACHE II), multiple organ failure (MOF) and organ system failure (OSF) scores were calculated on days 1, 2, 3, 7, 10, 20 and 30.
No adverse events reported.

Authors' conclusion: AT III administration was safe and well tolerated. 39% reduction in 30 day all-cause mortality. Shorter stay in ICU. Better performance in overall severity of illness and organ failure scores (APACHE II, MOFS, OSF score) noticeable soon after initiation of treatment. Trend towards better resolution of pre-existing organ failures and lower incidence of new organ failures. From day 4: AT III within normal range in treatment group. Survival benefit appeared to occur late in the septic process (second week after initiation of treatment, most pronounced during the third week). No advantage in regard to coagulation.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskUnclear
Allocation concealment (selection bias)Unclear riskB - Unclear

Fourrier 1993

MethodsTwo-group parallel randomized clinical trial
Generation of allocation sequence: adequate
Allocation concealment: adequate
Blinding: adequate
Follow up: yes, 28 days or until death
Overall study quality: low risk of bias
ITT: yes
Sample size was calculated to detect a 50% reduction in mortality in ICU
Participants

Critically ill patients with septic shock and DIC and MOF with at least 1 organ failure added to circulatory and hematologic failures.

AT III group: 17 patients, 10 were men, mean age (SD): 52±22 y. Underlying disease: alcoholism 5; chronic cardiac failure 8; COPD 2. No underlying disease 3; recent surgery 6. SAPS: 20±7. Organ failures: 2.8±1.0, renal failure: 57%, respiratory failure: 93%.

Control group: 18 patients, 10 were men, mean age (SD): 52±18 y. Underlying disease: alcoholism 3; chronic cardiac failure 9; COPD 3. No underlying disease 4; recent surgery 6. SAPS: 19±6. Organ failures: 2.8±0.9, renal failure: 56%, respiratory failure: 89%.

Inclusion criteria: A) mandatory criteria for septic shock: 1) bacteremia or evidence of septic focus, 2) fever >38.5 ºC, 3) leukocyte count >15x109/L or <4x109; 4) hypotension, sys BP <90 mmHg despite adequate vascular filling; 5) requirement of vasoactive agent (dopamine >15 µg/kg/min, dobutamine, epinephrine or norepinephrine) during more than 12 h.
B) Mandatory DIC-criteria: 1) platelet counts <100x109/L or a decrease of >100x109 over the last 24 hours; 2) decrease in factor V level <70%; 3) presence of soluble complexes of fibrin monomers.

Exclusion criteria: a) younger than 16 years old; b) suspected pregnancy; c) sepsis or DIC within 8 days after delivery; d) chronically immunocompromised; e) bone marrow aplasia or acute leukaemia; f) chronic liver failure with cirrhosis, recent hepatic surgery or transplant; g) multiple trauma or uncontrolled haemorrhage that required massive blood transfusion or undergone plasma exchange (< 5 days).

Interventions

Experimental: 90-120 IU/kg, loading dose over 3 h (3 ml/kg) + 3 ml/kg over 21 h, then 90-120 IU/kg/day for 3 days by continuous infusion. The aim: supranormal AT III levels. Average of 6000 IU/day.

Control: human albumin 0.6%, equivalent amount in ml.

Standard intensive care treatment to all patients. FFP, PC, and fibrinogen concentrates restricted to haemorrhages and severe decreases in prothrombin time to <30%, platelet count to <50x109/L (1/10 kg of body weight), and fibrinogen levels to <1 g/L. LMWH 0.5 mg/kg of body weight when used in lines and filters of haemodialysis or haemofiltration.

Outcomes

Primary: 28-day mortality.

Secondary: recovery of DIC, side effects, length of stay, transfusion and vascular requirements, bleeding, numbers and types of organ failure, organ function scores, protein C+S activity, fibrinogen and AT III activity, fibrin degradation products, factor V and VII, cardiac index, systemic vascular resistances, blood lactate, total bilirubin, blood creatinine, omega score, surgery during treatment.

Notes

Country: France
Letter sent to authors in November 2005, authors replied in December 2005.

Heparin therapy was not used as control to avoid haemorrhagic hazards and discrepancies related to heparin-induced AT III consumption. Since FFP contains significant amount of AT III, infusion was restricted. No side effects reported.

Authors' conclusion: mortality reduced by 44% but it did not reach statistical significance. AT III levels were rapidly corrected and remained normal until day 10. Circulating protein C and S levels were not modified by AT III supplementation. Duration of DIC was reduced significantly (64% after day 2; 71% at the end of treatment vs placebo 11% (P<0.01) and 33 (P< 0.05)).

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskAdequate
Allocation concealment (selection bias)Low riskA - Adequate

Fulia 2003

MethodsTwo-group parallel randomized clinical trial
Generation of allocation sequence: adequate
Allocation concealment: adequate
Blinding: adequate
Follow up: yes
Overall study quality: low risk of bias
ITT: yes
No sample size calculation was reported
Participants

60 infants born before 30 weeks of gestation randomized to a loading dose of AT III or placebo.

AT III: 30 infants, 16 were male, gestational age (weeks): 28.5±1.5, birth weight (g): 1060±218, vaginal delivery: 12, elective caesarean: 18, antenatal steroids: 16, APGAR score at 1 min: 5.83±0.75, APGAR score at 5 min: 7±0.64, cord ABG pH: 7.28±0.07.

Control: 30 infants, 17 were male, gestational age (weeks): 28.5±1.3, birth weight (g): 1054±233, vaginal delivery: 11, elective caesarean: 19, antenatal steroids: 17, APGAR score at 1 min: 5.63±0.82, APGAR score at 5 min: 6.88±0.76, umbilical cord arterial blood gas pH: 7.31±0.08.

Inclusion criteria: gestational age <30 weeks, postnatal age <12 h, AT III activity <40% (normal value 20-72%).

Exclusion criteria: sepsis, congenital malformations, cerebral haemorrhage, bleeding disorders, thrombocytopenia (platelet count of 50 x 109 or less).

Interventions

AT III group: loading dose of 2 ml/kg equivalent to 100 U/kg of AT III followed by 1 ml/kg equivalent to 50 U/kg every 8 h for 48 h.

Control: 5% glucose in equivalent amounts (ml).

Arterial catheters were perfused with 1 ml/h of 5% glucose containing I U/ml of unfractionated heparin. No other anticoagulants were administered. All newborns received the same exogenous surfactant.

Outcomes

Primary: death and intraventricular haemorrhage (grade 0-IV).

Secondary: partial thromboplastin time, quick prothrombin time, platelet count, surfactant need, pneumothorax, pulmonary haemorrhage, patent ductus arteriousus, inotropes, bronchoplumonary dysplasia, level of AT III, degree of IVH measured by ultrasonography.

Notes

Country: Italy
Letter sent to authors in January 2006, no answer received.

Authors' conclusion: administration of AT III during the first 2 days of life does not decrease incidence of intraventricular haemorrhage.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskAdequate
Allocation concealment (selection bias)Low riskA - Adequate

Grenander 2001

MethodsTwo-group parallel prospective randomized trial
Generation of allocation sequence: unclear
Allocation concealment: adequate
Blinding: no
Follow up: adequate, evaluation at discharge and at 3 months post injury
Overall study quality: high risk of bias
ITT: no
No sample size calculation was provided
Participants

28 patients with purely traumatic brain injury and no other major trauma

AT III group: 13 patients, 10 were men, mean age: 48 years. Mean APACHE II score: 14.2, mean GCS: 7.7, median: 7.0; 50% had positive blood alcohol detection.

Control group: 15 patients, 10 were men, mean age: 44 years. Mean APACHE II score: 14.8, mean GCS: 7.5, median: 7.0; 50% had positive blood alcohol detection.

Inclusion criteria: 1) 14-70 years old, 2) brain injury was CT-verified and assessed by Glasgow coma scale (GCS), 3) only GCS between 4-12 included, 4) inclusion within 12 h from the time of injury.

Exclusion criteria: 1) ongoing dialysis-dependent renal disorder, 2) bleeding or coagulation disorder such as haemophilia or von Willebrand's disease, 3) anticoagulant therapy.

Interventions

AT III: 60 IU/kg body weight initially. 8 and 16 hours later an additional 20 IU/kg body weight was given - a total of 100 IU/kg body weight during 24 h. The doses were adjusted to the nearest 500 IU. Duration: 24 h. Average total dose of AT given was 8269±1562 IU.

Control: no placebo.

Both groups received additional treatment according to local standards for brain injury including surgery, ventricular drain, or intraparenchymatous intracranial pressure (ICP) device, moderate hyperventilation (pCO2 4-4.5 kPa), sedation, drainage of cerebrospinal fluid, low-dose barbiturates, mannitol infusion, inotropic drugs, clonidine and dihydroergotamine. Treatment goals were ICP<20 mm Hg and CPP>60 mm Hg.
Low molecular weight heparin 2500 IU sc only to a random group of patients in few events (1 patient in AT group and 3 patients in control group). 3 patients in each group received fresh frozen plasma for volume replacement.

Outcomes

Primary outcome: time of coagulopathy in patients with brain contusion and with or without intracranial haemorrhage, coagulation parameters improvement: soluble fibrin (SF), AT III-activity, D-dimer, thrombin-antithrombin complex (TAT), platelet count, prothrombin complex (PK) and fibrinogen, mortality at 3 months.

Secondary: duration of mechanical ventilation, APACHE II score (slightly modified in order to estimate the severity of illness), improved outcome assessed by GCS (once daily and at 3 months), brain injury progress monitored by CT, bleeding events, days with mechanical ventilation, need for intensive care, and evaluation of severe disability.

Notes

Country: Sweden
Letter sent to authors in December 2005, no answer received.

Two withdrawals (late presentation of exclusion criteria and a revoked consent), one late exclusion resulting from the revelation of improper dosage of antithrombin because of incorrect information regarding body weight. One case of cross over. One patient in the control group was given AT III by the attending physician as part of the treatment for a septic reaction. Partially missing data on this patient.

Authors' conclusion: AT III administration to patients with severe traumatic brain injury resulted in a marginal reduction of hypercoagulation. No obvious influence by AT III on brain injury progress, CT, or on outcome or time needed for intensive care could be detected.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskUnclear
Allocation concealment (selection bias)Low riskA - Adequate

Haire 1998

MethodsTwo-group parallel randomized clinical trial
Generation of allocation sequence: adequate
Allocation concealment: adequate
Blinding: adequate
Follow up: adequate, until hospital discharge or death
Overall study quality: low risk of bias
ITT: yes
Sample size calculation reported
Participants

49 patients undergoing haematopoietic stem cell transplantation (HSCT).

AT III group: 24 patients, 10 were men. Mean age (SD): 46.1±10.3 y. Underlying disease: acute myeloid leukaemia 5, breast carcinoma 8, chronic myeloid leukaemia 1, multiple myeloma 3, lymphoma 7.

Control group: 25 patients, 11 were men. Mean age (SD): 46.0±10.5 y. Underlying disease: acute lymphocytic leukaemia 1, acute myeloid leukaemia 4, breast carcinoma 4, chronic lymphocytic leukaemia 2, chronic myeloid leukaemia 4, Hodgkin's disease 1, multiple myeloma 3, lymphoma 6.

Inclusion criteria: malignant disease admitted for haematopoietic stem cell transplantation (HSCT), not committed to other confounding clinical trials, English their first language (to allow reliable use of the mini mental status examination).

Interventions

AT III: 70 U/kg within 24 h of organ dysfunction detection, followed by 50 U/kg 8,16, 48 and 72 hours later. Total dose of AT III: 270 U/kg. Estimated to provide an increment of about 250% activity above pretreatment levels after the 3rd dose. Mean total dose: 20,520 U/patient based on the mean weight of the randomized patients (76 kg).

Control: 5% human albumin, volume equal to the calculated volume of AT III concentrate.

Outcomes

Primary: mortality, severity-of-illness score, length of hospital stay.

Secondary: daily screening for pulmonary, hepatic or CNS dysfunction, MODS (multiorgan dysfunction syndrome). Correlation between AT III, number of organ failure and MODS. Number of patients progressing from single through multiple organ dysfunction.

Notes

Country: USA
Letter sent to authors in December 2005, no answer received.
One patient was randomized and received the first dose of the study drug based on an erroneous laboratory report. This patient was not included in the final analysis.
Organ dysfunction defined as: 1 CNS - a drop in the score of standardized mini mental status examination of at least 4 points from the pre-chemotherapy score; 2) pulmonary - finger oximetry reading of SpO2 <90% on two occasions on the same day separated by at least 2 hours; 3) pepatic - a combination of bilirubin >2.0 mg%, a weight gain of >5% over pre-chemotherapy weight, and abdominal pain of possible hepatic origin.
Patients with single-organ dysfunction with a concomitant AT III activity of <84% of normal were defined as having MODS.

Authors' conclusion: the AT III group had a lower severity-of-illness score, shorter duration of hospitalization and lower hospital charges. AT III concentrate was associated with improved morbidity of MODS in patients undergoing HSCT when given early in the evolution of the syndrome.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskAdequate
Allocation concealment (selection bias)Low riskA - Adequate

Harper 1991

MethodsTwo-group parallel randomized controlled trial
Generation of allocation sequence: unclear
Allocation concealment: inadequate
Blinding: inadequate
Follow up: inadequate
Overall study quality: high risk of bias
ITT: yes
No sample size calculation was provided
Participants

Patients with AT III activity of <70% admitted to the ICU. Patients with an initial AT activity above 70% monitored daily and were randomized into the study if their AT activity at any time during their stay fell below 70%.

AT III group: 44 patients, median age: 49 (range 19-78) y. Admission AT III activity: 51% (range 12-68); APACHE II score median: 16 (range 6-33).

Control group: 49 patients, median age: 49 (range 16-77) y. Admission AT III activity: 50% (range 12-64); APACHE II score median: 14 (range 4-26).

Exclusion criteria: acute or chronic renal failure prior to admission to the ICU. If readmitted to ICU, the patients were allocated to the same randomization as on their previous admission. Patients were excluded if they stayed less than 4 days on ICU.
10 liver transplant recipients and 15 patients with septicaemia, major trauma, or following major surgery in each group.

Interventions

Treatment: AT III, aiming at 120%. Loading dose was calculated from the initial AT III activity and the patient's weight ((120-AT III activity (%)) x weight (kg)). Maintenance doses were given iv over 10 min. Treatment was continued until the patient was discharged from the ICU, twice daily.

Control: no placebo.

Standard intensive care treatment to all patients.

Outcomes

Primary: mortality, coagulation parameters (AT III activity, AT-antigen concentration, fibrinogen concentration, platelet count). Renal function impaired if creatinine clearance <20 ml/min at any time during their stay on the ICU.

Secondary: days in ICU, side effects, APACHE II.

Notes

Country: UK
Letter sent to authors in November 2005, no answer received. No reported side-effects.

81 patients had an AT III activity below 70% on admission to the ICU and in a further 12 patients the plasma AT III fell below 70% whilst on the ICU. Thus a total of 93 patients were randomized: 44 to the treatment arm and 49 in the no-treatment arm. 9 patients in the AT III arm did not receive AT III replacement; 3 died before treatment was commenced; and 6 were transferred from the ICU within a few hours of randomization. A total of 35 patients received AT III replacement. Of these 25 remained on the ICU for at least 4 days. 32 patients in the control arm remained on the ICU for at least 4 days. 25 of these were selected by diagnosis to act as controls. The authors provided mortality data on all patients randomized, and we have chosen to include these in our analysis.

Authors' conclusion: AT III neither reduced mortality nor shortened the intensive care stay. AT III did not appear to reduce the incidence of impaired renal function in sepsis, trauma and post-operative patients. The study does not demonstrate a clear role for the use of AT III supplementation in intensive care.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskUnclear
Allocation concealment (selection bias)High riskC - Inadequate

Inthorn 1997

MethodsTwo-group parallel randomized clinical trial
Generation of allocation sequence: unclear
Allocation concealment: unclear
Blinding: unclear
Follow up: yes
Overall study quality: high risk of bias
ITT: yes
Sample size calculation reported
Participants

40 surgical patients with severe sepsis, post-traumatic or post-operative admitted to surgical ICU.

AT III group: 20 patients. Demographic characteristics only provided for the 14 patients included: 13/14 were men. Source of sepsis: peritonitis (10), pneumonia (2), catheter-related infection (1), late abscess (1). Age: 62.3± 3.8 y, MOF score: 4.1± 0.5.

Control group: 20 patients. Demographic characteristics only provided for the 15 patients included: 11/15 were men. Source of sepsis: peritonitis (12), pneumonia (2), Mediastinitis (1). Age: 61.5± 3.6 y, MOF score: 3.9± 0.4.

Inclusion criteria: a) one or more blood cultures positive for gram positive or negative bacteria or evidence of septic focus; b) temperature above 38.5 ºC, c) leukocyte count >15 g/L or <5 or >20% of immature (band) forms; d) thrombocyte count <100 g/L or a decrease of >20% during the last 24 hours; e) at least one organ dysfunction.

Exclusion criteria: 1) <18 years old; 2) received AT within 21 days prior to the study.

Interventions

AT III: continuous AT III infusion over 14 days in order to obtain plasma AT III > 120%. Average of 6000 IU AT III was administered on 1st day and 4000 IU on the subsequent days.

Control: no placebo treatment.

All patients received standard relevant intensive care treatment that was comparable between groups and continuous low-dose heparinization (4 IU/kg bodyweight/h). FFP was only given to patients with severe haemorrhage and markedly impaired plasmatic coagulation (contains AT III); prothrombin complex given only during excessive clinical bleeding; platelets given only when <50 g/L; packed red blood given when <10 g/dL.

Outcomes

Primary: 14 and 90-day mortality; mortality between days 7 to14, hospital discharge.

Secondary: transfusions, MOF Score, frequency of surgical interventions, frequency of DIC, AT III plasma activity, severity of organ dysfunction, effect of AT III on clotting system and MOF, haemodynamic and respiratory profile.

Notes

Country: Germany
Letter sent to authors in November 2005, no answer received.
The results of this study were also published in two additional articles (Inthorn 1998 and Hoffmann 2004 under the excluded articles section). Comparable patients in both groups and no significant baseline differences in measured outcomes. Peritonitis most frequent source of sepsis (70%).

Due to the presumed mechanisms of AT III action, only long-term supplementation was assumed to affect parameters of organ function. Thus, 11 patients were prospectively excluded from the final evaluation since they died during the 14-day period. However their data were included in an intention-to-treat analysis. No side effects were reported.

The patients in both groups were comparable with no significant baseline differences in measured outcomes. Peritonitis was the most frequent source of sepsis (70%).

Authors' conclusion: long-term supplementation with AT III may improve lung function and prevent development of septic liver and kidney failure in patients with severe sepsis.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskUnclear
Allocation concealment (selection bias)Unclear riskB - Unclear

Kobayashi 2003

MethodsTwo-group parallel randomized clinical trial
Generation of allocation sequence: adequate
Allocation concealment: adequate
Blinding: adequate
Follow up: adequate
Overall study quality: low risk of bias
ITT: yes
Sample size calculation reported
Participants

29 severe pre-eclamptic patients (24 to 36 weeks of gestation, gestosis index (GI = or >6). Severe pre-eclampsia was defined by the presence of hypertension plus proteinuria.

AT III: 14 women; age: 30±6 y; pregnancy weight (kg): 51±7 SD; systolic BP (mm Hg): 163 ± 21, diastolic BP (mmHg): 104±15; gestosis index: 7.2±1.6; gestational age (weeks): 32.3±3.1; biophysical profile score: 7.0±2.0; primigravida (%): 71.4.

Control: 15 women; age: 30±4 y; pregnancy weight (kg): 53±9; systolic BP (mm Hg): 165 ± 12, diastolic BP (mmHg): 100±14; gestosis index: 6.6±1.8; gestational age (weeks): 29.8±3.7; biophysical profile score: 7.4±1.9; primigravida (%): 60.0.

Inclusion criteria: systolic BP = or >160 mm Hg and/or diastolic BP > or = 110 mm Hg on 2 occasions 6 hours or more apart; and/or proteinuria > or = 2 g/L in a 24-hour urine collection; and a GI = or >6 points on 2 occasions at least 6 hours apart at bed rest.

Gestosis index score was calculated as: A) edema after bed rest: 0 (none), 1 (tibia), 2 (generalized); B) proteinuria (g protein/L) 0 (<0.5), 1 (> or = 0.5-1.99), 2 ( > or = 2.0-4.99), 3 (> or = 5.0); C) systolic BP (mm Hg) 0 (<140), 1 (140-159), 2 (160-179), 3 (>180); D) diastolic (BP mm Hg) 0 (<90), 1 (90-99), 2 (100-109), 3 (110).

Exclusion criteria: patients with chronic hypertension, renal disease, diabetics mellitus, systemic lupus erythematosus, multiple pregnancies, patients with AT deficiency and other severe medical conditions.

Interventions

AT III: 1500 U/day once daily for 7 consecutive days.

Control group: unknown placebo.

5000 U/day of unfractionated heparin was given simultaneously in both groups. Heparin was infused by 24-hour intravenous drip with saline.
Concomitant therapy with other anticoagulants, antiplatelet agents, and blood preparations except albumin was not permitted during the study. Only hydralazine hydrochloride at a 30 mg/day was allowed in both groups.

Outcomes

Neonatal and fetal outcomes: mortality (neonatal and fetal), bleeding disorder, weeks of gestation at delivery, birth weight (g), APGAR score at 1 minute, neonatal distress (%), response on the biophysical profile score.

Maternal outcomes: gestosis index improvement, improvement of coagulation index, adverse events, blood loss.

Notes

Country: Japan
Letter sent to authors in December 2005, reply received in January 2006.
No adverse event related to AT III was reported.

The criteria used to initiate a preterm delivery were based on sustained severe hypertension (> or =180/110 mm Hg), thrombocytopenia (< or = 100 x (109/L), markedly worsened liver or renal function (serum aspartate aminotransferase or serum alanine amino transferase > or = 100 IU/L, serum creatinine > or = 15 mg/L, blood urea nitrogen > or = 200 mg/L), severe maternal symptoms (eclampsia, HELLP syndrome, placental abruption, pulmonary edema, etc) or impaired fetal status evidenced by intrauterine growth retardation (< or = -2 standard deviations) and oligohydramnios (amniotic pocket > or = 1 cm), or persistently severe abnormal fetal heart rates or worsened biophysical profile test results (based on fetal breathing movements, fetal tone, reactive fetal heart rate, gross body movements, qualitative amniotic fluid volume).

Authors' conclusion: Given that AT plus heparin was significantly better than treatment with heparin alone for improvement of both gestosis Index and biophysical profile of infant, it is suggested that therapy with AT alone might be effective enough for severe pre-eclampsia.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskAdequate
Allocation concealment (selection bias)Low riskA - Adequate

Langely 1993

MethodsTwo-group parallel randomized clinical trial
Generation of allocation sequence: unclear
Allocation concealment: unclear
Blinding: unclear
Follow up: adequate
Overall study quality: high risk of bias
ITT: yes
Sample size calculation was not reported
Participants

25 patients in grade III or IV coma were selected on the basis of evidence of sepsis, intravascular coagulation, and a high risk of developing multiorgan failure.

AT III: 13 patients, 7 were men, 12 with severe hepatic dysfunction on entry of which 9 also had further complications of fulminant hepatic failure (FHF). Underlying etiology: paracetamol overdose (9), hepatotoxicity to phenytoin (1), hepatitis B (1), non-A non-B hepatitis (2). Time from the onset of illness to entry into the trial: median 3 (2-28) hours.

Control: 12 patients, 4 were men, all with severe hepatic dysfunction on entry of which 6 also had further complications of FHF. Underlying etiology: paracetamol overdose (8), (1), hepatitis B (2), non-A non-B hepatitis (1), halothane hepatitis (1). Time from the onset of illness to entry into the trial: median 3 (2-37) hours.

No statistically significant differences between the two groups on admission with respect to age, sex, prothrombin ratio, and initial AT III level.

Inclusion criteria: 1) severe hepatic dysfunction, prothrombin ratio expressed as an international normalized ratio (INR) >6.7 for paracetamol overdose or INR >3.3 for other etiologies; 2) evidence of sepsis with temperature higher than 39 ºC, white cell count >15 x 109/L, or microbiologically proven sepsis; 3) presence of disseminated intravascular coagulation with spontaneous bleeding and a platelet count of less than 50 x 109/L; 4) multiorgan failure with systemic blood pressure <80 mm Hg, requiring inotropic support to maintain blood pressure and blood pH equal to or less than 7.3.

Exclusion criteria: not provided.

Interventions

AT III group: 13 patients received 3000 units of AT III on entry into the trial followed by a further 1000 units every 6 hours unless AT III levels were within the normal range. Total amount of AT III given to the patients during the course of their illness ranged from 3000 units to 23,000 U (mean 7000± 5000 U).

Control: no placebo.

All patients received standard supportive therapy for FHF witch included haemodynamic monitoring, haemodialysis or haemofiltration for renal failure, and continuous intracranial monitoring with treatment for raised intracranial pressure where necessary. Mechanical ventilation was used to treat respiratory dysfunction or pulmonary complications.

Outcomes

Primary: mortality, plasma levels of AT III.

Secondary: renal failure, cerebral edema, incidence of infection, liver transplantation, coma grade, effect of AT III on bleeding and coagulation parameters, transfusion requirements.

Notes

Country: United Kingdom
Letter sent to authors in December 2005, no reply received.

Authors conclusion: AT III activity increased from 0.26±0.04 SE U/ml to 0.82±0.07 U/ml at 3 hours post-infusion and remained greater than 0.80 U/ml throughout the study without any apparent increase in the frequency of bleeding. Survival was not improved and markers of intravascular coagulation remained similar between the groups.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskUnclear
Allocation concealment (selection bias)Unclear riskB - Unclear

Maki 2000

MethodsTwo-group parallel randomized clinical trial
Generation of allocation sequence: adequate
Allocation concealment: adequate
Blinding: adequate
Follow up: adequate, 14 day period including the time of drug administration, and until delivery to assess the birth and the status of the neonate
Overall study quality: low risk of bias
ITT: yes
No sample size calculation was reported
Participants

Severe pre-eclamptic patients (24 to 35 weeks of gestation).

AT III: 74 women, age: 30±5 y; pregnancy weight (kg): 66±12; systolic BP (mm Hg): 170±16, diastolic BP (mmHg): 103±12; gestosis index: 7.7±1.4; gestational age (weeks): 31.8±3.2; biophysical profile score: 8.6±2.0; primigravida (%): 34.8.

Control: 72 women, age: 30±5 y; pregnancy weight (kg): 65±12; systolic BP (mm Hg): 169±17, diastolic BP (mmHg): 105±12; gestosis index: 7.7±1.6; gestational age (weeks): 31.7±2.7; biophysical profile score: 8.7±1.7; primigravida (%): 37.3.

Inclusion criteria: systolic blood pressure (BP) >= 160 mm Hg and/or diastolic BP >= 110 mm Hg on 2 occasions 6 h or more apart; and/or proteinuria =>2 g/L of protein in a 24-h urine collection; gestosis Index, GI =/>6 points on 2 occasions at least 6 h apart despite bedrest. GI is calculated based on edema, proteinuria, systolic BP and diastolic BP.

Exclusion criteria: chronic hypertension, multiple pregnancy, renal disease, diabetics mellitus, systemic lupus erythematosus, other severe medical conditions and patients with AT deficiency.

Similar baseline characteristics, proportion of severe early onset pre-eclampsia was equally distributed within the study groups.
For definitions of gestosis index and bio-profile scoring technique, please see Kobayashi 2003 characteristics.

Interventions

Treatment: 3000 IU intravenous AT III once daily for 7 consecutive days.

Control: 582 mg albumin intravenously, once daily for 7 consecutive days as placebo.

Concomitant therapy with other anticoagulants, antiplatelet agents and blood preparations except albumin was not permitted during the study. Other relevant treatment such as antihypertensive agents, magnesium sulfate allowed in both groups. No heparin was used.

Outcomes

Primary endpoints: improvement of gestosis index, improvement fetal findings (biophysical profile score, and the estimated fetal weight gain), duration of pregnancy, birth weight, gestational age at delivery, improvement of coagulation parameters (TAT-complexes, plasmin-plasmin inhibitor complexes (PPIC), PC, D-dimer, AT activity, AT antigen), stillbirth or neonatal death ascribed to pre-eclampsia, maternal death from any cause, or death of neonate at any time attributed to pre-eclampsia or associated with intra-uterine growth retardation.

Secondary: adverse events related to AT.
Stillbirth included all intrauterine deaths at or after 24 weeks, and neonatal death included all deaths after birth up to the age of 28 days.

Notes

Country: Japan
Letter sent to authors in December 2005, reply received in January 2006.
Intervention had to be stopped in 23 patients in the AT III group and 29 patients in the control group prematurely due to worsening of maternal and fetal findings.

Authors' conclusion: AT therapy for pre-eclampsia is effective and safe, leading to an improved perinatal and maternal outcome. Significant improvement in GI (P=0.020) and estimated fetal weight gain (P=0.029) in AT group. D-dimer increased significantly in the placebo group (P=0.026) but did not change in the AT group. Gestation was significantly prolonged (P=0.007) and the number of low-birth weight infants was significantly smaller (P=0.011) in the AT-group. No adverse events related to AT. No significant difference was noted in Apgar score, neonatal distress, endotracheal intubation, fetal death, neonatal death, bleeding disorder, or maternal outcome.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskAdequate
Allocation concealment (selection bias)Low riskA - Adequate

Mitchell 2003

MethodsTwo-group parallel randomized clinical trial
Generation of allocation sequence: adequate
Allocation concealment: adequate
Blinding: no blinding
Follow up: inadequate.
Overall study quality: high risk of bias
ITT: no
Sample size calculation reported
Participants

Paediatric acute lymphoblastic leukaemia (ALL) patients.

AT III: 25 patients, 10 female, median age 3.8 (1.6-17.2) years, weight 18.3 (9.7-76.7) kg.

Control: 60 patients, 23 female, median age 5.9 (1.9-16.7) years, weight 20.6 (10.8-83.4) kg.

Inclusion criteria: age >6 months and <18 years, newly diagnosed with ALL at the beginning of the induction of chemotherapy, a functioning central venous line placed within 2 weeks of initiating induction chemotherapy and obtaining informed consent.

Exclusion criteria: previous treatment with L-asparaginase (ASP), a known hypersensitivity to any of the ingredients in antithrombin concentrate, medical conditions that could have interfered with participation or assessment of the study drug, received other investigational drugs within 30 days of enrolment, or required treatment with therapeutic anticoagulation.

All patients received unfractionated heparin for prophylaxis of central venous line-blockage either by continuous infusion (1-3 units/mL) or intermittent flushes (50-100 units/mL up to 4 times per day). The decision to use additional anticoagulants was left to the patient's physician.

Interventions

AT III: infusions once weekly for 4 weeks (days 1, 8, 15, 22) to increase plasma concentrations of AT to approximately 3.0 units/mL but no more than 4.0 units/mL.

Control: no placebo.

Outcomes

Primary: prevalence of thrombotic events.

Secondary: bleeding events, plasma markers, efficacy and safety.

Notes

Letter sent to authors in December 2005, no answer received.
Country: Canada and USA
No data were provided on mortality. Based on the detailed follow up, we concluded that there was no mortality in both groups.

The study was not powered to prove efficacy or safety of AT III supplementation but rather look for trends. Outcome measures were assessed blinded.

24 patients excluded from analysis (12 in each group). The reasons for exclusion in the AT III group were: 3 patients due to withdrawal of consent, 2 patients categorised as noncompliant due to an under-dosing with AT concentrate, 7 patients due to the absence of an exit venogram. In the control group: 3 patients due to withdrawal of consent, 1 patient had an adverse event, and 8 patients were excluded due to the absence of an exit venogram.

Authors' conclusion: treatment with AT III shows a trend to efficacy and safety. In contrast, there was no difference in surrogate markers for thrombosis.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskAdequate
Allocation concealment (selection bias)Low riskA - Adequate

Schmidt 1998

MethodsTwo-group parallel randomized clinical trial
Generation of allocation sequence: adequate
Allocation concealment: adequate
Blinding: adequate
Follow up: complete
Overall study quality: low risk of bias
ITT: yes
Sample size calculation reported
Participants

Premature infants with respiratory distress syndrome (RDS) in the neonatal ICU, 942 screened with birth weights 750-1900 grams.

AT III: 61 patients. 33 male, gestational age (weeks) 28.3 ±2.03, birth weight: 1.198±300.9 g, venous cord blood pH: 7.31±0.10, APGAR score at 1 min: 5.4±1.95, APGAR score at 5 min: 7.6±1.24, AT III, U/mL: 0.33± 0.08, maternal age: 28.1± 6.68, maternal steroids: 40 (65.6%).

Control: 61 patients. 31 male, gestational age (weeks) 28.8 ±2.25, birth weight: 1.201±314.4 g, venous cord blood pH: 7.28±0.15, APGAR score at 1 min: 5.3±2.22, APGAR score at 5 min: 7.7±1.16, AT III, U/mL: 0.32± 0.08, maternal age: 28.9± 5.16, maternal steroids: 35 (57.4%).

Inclusion criteria: 224 met inclusion criteria; (1) age between 2-12 h, 2) endotracheal intubation and positive pressure ventilation for RDS, 3) indwelling arterial catheter, 4) ratio of arterial to alveolar oxygen pressure (a/A) PO2 <0.3 after the first dose of exogenous surfactant).

Exclusion criteria: 1) congenital infection, 2) congenital malformation(s), 3) hydrops, 4) pulmonary hypoplasia, 5) clinically apparent bleeding disorder, 6) thrombocytopenia (platelets =/< 50 x 109/L), 7) moribund.

Interventions

AT III: loading dose 100 U/kg followed by 50 U/kg every 6 h for 48 h.

Control: human albumin 1%, equivalent dose.

All participants received the same standard intensive care treatment and the same exogenous surfactant. Arterial catheters were perfused with 1 ml/h of 5% dextrose containing 1 IU/ml of unfractionated heparin. No additional administration of anticoagulants.

Outcomes

Primary: mortality.

Secondary: days in ICU, plasma AT activity, TAT-complex (thrombin-AT), prothrombin fragment (F1+2), ratio of arterial to alveolar oxygen pressure (a/A) PO2 and ventilator efficiency index (VEI), thrombin formation, Improved gas exchange, duration of mechanical ventilation, duration of supplemental oxygen therapy, safety of AT therapy evaluated primarily by comparing the incidence of severe (Grade 3) intraventricular haemorrhage and of periventricular echodensities in the 2 groups, bleeding events.

Notes

Country: Canada
Letter sent to authors in November 2005, no answer received.
AT levels in healthy preterm infants are about 40% of normal adult values, and even lower levels have been reported in sick premature infants with RDS. The therapy was initiated on average 7.2 h after delivery in each group.
Having observed for some time an apparent imbalance in deaths between the treatment groups, the external safety and efficacy monitoring committee decided to break the code and make its recommendation because 7 deaths had occurred in patients receiving AT and two with placebo.

Authors' conclusion: AT III therapy cannot be recommended in premature infants with RDS. AT III did not improve gas exchange in premature infants with RDS. It may even be harmful. The durations of mechanical ventilation and oxygen therapy were significantly prolonged, whereas deaths, periventricular and intraventricular haemorrhages and clinically apparent bleeding episodes all tended to be more common in infants randomized to AT concentrate.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskAdequate
Allocation concealment (selection bias)Low riskA - Adequate

Schorr 2000

MethodsTwo-group parallel randomized clinical trial
Generation of allocation sequence: unclear
Allocation concealment: unclear
Blinding: no blinding
Follow up: adequate
Overall study quality: high risk of bias
ITT: yes
Sample size calculation was not reported
Participants

Patients with secondary peritonitis, surgical population in ICU.

AT III: 24 patients, 12 men, median age 60 (33-86) y, APACHE II 14.4 (6-30), MOF 4.6 (0-10), SOFA 7.7 (0-18), Mannheimer peritonitis index (MPI) 26.7 (12-38), malignant diseases (%) 33. Origin of peritonitis: a) large bowel 14, b) small bowel 7, c) gastric 3, d) biliary system 1, uterus 0.

Control: 26 patients, 12 men, median age: 62 (28-85) y, APACHE II 14.6 (4-28), MOF 4.9 (0-11), SOFA 8.7 (0-16), MPI 27.8 (16-38), malignant diseases (%) 35. Origin of peritonitis: a) large bowel 13, b) small bowel 6, c) gastric 4, d) biliary system 1, uterus 1.

Inclusion criteria: 1) > 18 years, 2) diffuse secondary peritonitis affecting two or more quadrants after perforation of an intraperitoneal organ or failed anastomosis, 3) focus of infection had to be surgically eliminated.

Exclusion criteria: 1) acute pancreatitis, 2) peritonitis due to peritoneal dialysis, 3) primary peritonitis, 4) ascites due to cirrhosis of the liver or due to malignant underlying disease, 5) pregnancy, 6) incapacitated persons, 7) prisoners.

Interventions

AT III: continuous IV AT III and 2 intraperitoneal installations of fresh frozen serum (FFS). The aim was to achieve AT III level of at least 140% of the normal plasma value for 4 days. A calculated bolus was given in 1 hour followed by a continuous infusion of AT III (200 IU-800 IU per hour) depending on the 6-hourly measurements of plasma AT III. 300 ml of blood group compatible FFS was applied intraperitoneally after the operation and 6 hours post-operatively through especially installed drains. The first FFS was supplemented with 1500 IU AT III to equalize the lack of AT III in FFS. Mean AT III administered was 26196 (±299 SEM) IU.

Control: no placebo.

All patients: routine intensive care treatment. If no risk of postoperative bleeding, heparin iv 200-400 IU/h 6 hours after operation until discharge from ICU.

Outcomes

Primary: 90 day mortality.

Secondary: number of days at ICU, mechanical ventilation, organ function scores, side effects, organ failure and function, bleeding and transfusions, AT III activity, prothrombin concentrations in exudate, TAT-complex in exudate, opsonic capacity and opsonin concentration in exudate.

Notes

Country: Germany
Letter sent to authors in November 2005, no reply received.

Authors' conclusion: the chosen therapeutic approach was feasible and showed no side effects. Mortality nor multiple organ failure were significantly improved by the applied short-term adjuvant therapy.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskUnclear
Allocation concealment (selection bias)Unclear riskB - Unclear

Smith-Erichsen 1996

MethodsTwo-group parallel randomized clinical trial
Generation of allocation sequence: unclear
Allocation concealment: unclear
Blinding: unclear
Follow up: adequate, until discharge from hospital or death
ITT: no
Overall study quality: high risk of bias
No sample size calculation was reported
Participants

Critically ill and trauma patients in ICU.
83 patients allocated to intervention and control groups. Within each of these groups, the patients again were allocated to 2 groups (group 1 and group 2) according to the type of surgery or trauma.

Group 1: multiple trauma defined as injury of at least 2 body regions, but without abdominal injury.

Group 2: abdominal operations and multiple trauma with abdominal injury; 2.1) total gastrectomy, oesophageal resection, rectal resection/amputation in patients over 70 years old, 2.2) pancreatic resection, 2.3) liver resection, 2.4) secondary gastro-intestinal interventions due to post-operative complications, 2.5) multiple trauma with abdominal injury. The patients were randomized in blocks with 4 patients in each block.

AT III group: 43 patients, 30 men, age: 60.1±16.3 y. 5 patients allocated to group 1 (trauma). Number of patients in group 2 as defined above; Group 2.1=17, Group 2.2=9, Group 2.3=5, Group 2.4=6, Group 2.5=1.

Control group: 40 patients, 25 men, age: 59.0±16.2 y. 5 patients allocated to group 1 (trauma). Number of patients in group 2 as defined above; Group 2.1=17, Group 2.2=8, Group 2.3=4, Group 2.4=5, Group 2.5=1.

Inclusion criteria: AT III plasma level less than 80% measured the day after trauma or major abdominal surgery.

Exclusion criteria: trauma patients with head injury and patients below the age of 18 years.

Interventions

AT III: the aim was to maintain plasma AT III activity in the range of 100%±10%. No data were provided on average or total dose. Based on daily samples, the substitution dose was calculated. A maintenance dose of 500 IU was given at midnight and 10 hours the following day. Treatment was continued until the plasma AT III activity was maintained within the normal range for 3 consecutive days without AT III substitution but was discontinued after 14 days, irrespective of the plasma activity.

Control: no placebo.

All patients were treated according to the standard management routines of each hospital.

500 ml of dextran-70 was given every 2nd day during the 1st week as antithrombotic prophylaxis. No patient received heparin or low-molecular weight heparin during the observations period

OutcomesPrimary: plasma protease changes, mortality, days in ICU, days in hospital
Secondary: AT III level, prothrombin, prekallikrein, functional kallikrein inhibition, plasma kallikrein-like activity, plasminogen, functional antiplasmin activity and plasmin-like activity, proenzyme functional inhibition index and adverse effects.
Notes

Country: Norway
No adverse effects were reported.
Letter sent to authors in December 2006, no answer received.

Authors' conclusion: In this study both major surgery and trauma induced changes in components of the plasma protease systems. Substitution therapy with AT III concentrate to normalise plasma levels of this antiprotease did not modify these changes.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskUnclear
Allocation concealment (selection bias)Unclear riskB - Unclear

Warren 2001

MethodsTwo-group parallel randomized multicenter clinical trial
Generation of allocation sequence: adequate
Allocation concealment: adequate
Blinding: adequate
Follow up: inadequate
Overall study quality: low risk of bias
ITT: yes
Sample size calculation reported
Participants

Critically ill population of ICU patients with severe sepsis and septic shock.

AT III: 1157 patients, men 62%; age mean (SD) = 57 (17) years; SAPS II (SD) = 49 (17); body weight mean (SD) = 77 (19) kg. Underlying problem or site of infection: 1) respiratory system 35%, 2) intra-abdominal infection 27%, 3) genitourinary system 6%, 4) injury 7%, 5) other 24%. Surgical status: A) no 54%, yes 46%. Circulatory shock: 49%; blood culture results: a) gram-negative 15%, b) gram-positive 15%, c) other/mixed 4%, d) not done/not verified 66%.

Control: 1157 patients, men 61%; age mean (SD) = 58 (17) years; SAPS II (SD) = 49 (16); body weight mean (SD) = 77 (20) kg. Underlying problem or site of infection: 1) respiratory system 34%, 2) intra-abdominal infection 28%, 3) genitourinary system 8%, 4) injury 6%, 5) other 24%. Surgical status: A) no 53%, yes 47%. Circulatory shock: 47%; blood culture results: a) gram-negative 16%, b) gram-positive 17%, c) other/mixed 2%, d) not done/not verified 64%.

Inclusion criteria: 18 years or above, and met following criteria within 6 hours: 1) clinical evidence of sepsis with a suspected source of infection, 2) body temperature (rectal or core) >38.5 ºC or <35.5 ºC, 3) leukocyte count >10,000/µL or <3500/µL. Additionally, 3 of the following 6 signs had to be met within the same 6-hour period: A) heart rate >100/min, B) tachypnoea >24/min or mechanical ventilation because of septic indication, C) hypotension, systolic BP <90 mm Hg despite sufficient fluid replacement or the need of vasoactive agents to maintain systolic BP of 90 mm Hg or greater, D) platelet count <100,000/µL, E) elevated lactate above upper limits of normal range or metabolic acidosis (pH <7.3 or BE</= -10 mmol/L) not secondary to respiratory alkalosis, F) oliguria (<20ml/h despite sufficient fluid replacement).

Exclusion criteria: a) advanced directive to withhold life-sustaining treatment (except cardiopulmonary resuscitation), b) condition other than sepsis anticipated to be fatal within 28 days, c) pregnancy or breast feeding, d) history of hypersensitivity to study medication, e) treatment with other investigational drugs within the last 30 days, f) treatment with an AT III concentrate within the last 48 hours, g) treatment with heparin (except sc low dose or iv line flushing) or coumarin derivatives, h) NSAID treatment within previous 2 days, i) known bleeding disorder or ongoing massive surgical bleeding, j) platelet count <30x1000/µL, k) immunocompromised status, l) acute myocardial infarction (within previous 7 days), m) third-degree burns =/ >20% of total body area, n) incurable malignancy with metastases and life expectancy of <3 months, o) haematologic neoplasia during cytostatic treatment, p) bone marrow aplasia, q) pre-existing dialysis-dependent renal failure, r) end-stage liver disease, s) transplantation (post-operative state), t) history of stroke within the last year, u) severe cranial or spinal trauma within the last year, v) planned cranial or spinal surgery (except nontraumatic lumbar puncture) within the next 48 hours.

Interventions

AT III: loading dose of 6000 IU given over 30 minutes, followed by a continuous iv infusion of 6000 IU per day for 4 days, total of 30000 IU.

Control: equivalent volume of placebo solution (1% of human albumin).

Heparin was permitted to be used in prophylactic doses as an adjunct to standard therapy. Administration of heparin was left to the attending physicians. Not all patients received heparin (698 patients received no heparin while receiving AT). Heparin dosage: unfractionated or low molecular weight heparin for venous thrombosis prophylaxis (</= 1000 IU subcutaneous per day) and heparin flushes for vascular catheter patency (iv of </= 2I U/kg body weight/h).

Outcomes

Primary: all-cause mortality at 28 days (subgroup 28 and 90-day survival for patients not receiving heparin).

Secondary: mortality at 56 and 90 days, survival time, length of ICU stay, occurrence of new organ dysfunction within 7 days (according to logistic organ dysfunction score), severity of sepsis (SAPSII), circulatory shock index (ie ratio of heart rate (beats/minute) and systolic BP (mm Hg) exceeded the value of 1.5); surgical interventions and bleeding events for 28 days, major bleeding if intracranial or required transfusion of >3 units of blood, other serious adverse events, AT III plasma concentration, activated partial thromboplastin time and prothrombin time.

Notes

Country: KyberSept Trial Study Group, 211 contributing centres in 19 countries including USA, Germany

Letter sent to authors November 2005, reply by authors in December 2005 and January 2006.

Authors' conclusion: high-dose AT III therapy had no effect on 28-day all-cause mortality in adult patients with severe sepsis and septic shock when administered within 6 hours after the onset. There was no statistically significant difference either in the 56 or 90-day mortality. High-dose AT III was associated with an increased risk of haemorrhage when administered with heparin. Treatment benefit became evident in the subgroup of patients not receiving concomitant heparin and the longer the observation period, the greater was the difference (on day 90 it reached statistical significance).

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskAdequate
Allocation concealment (selection bias)Low riskA - Adequate

Waydhas 1998

MethodsTwo-group parallel randomized clinical trial
Generation of allocation sequence: inadequate
Allocation concealment: adequate
Blinding: adequate
Follow up: adequate
Overall study quality: high risk of bias
ITT: yes
Sample size calculation not reported
Participants

Trauma patients in ICU.

AT III: 20 patients, 13 men, age 32 (26-42) y, systolic blood pressure (SBP) on the scene 120 mm Hg (90-130), 2 patients with SBP <80 mm Hg, Glasgow coma score 13 (6-15), use of catecholamines on the scene in 2 cases, intubation on the scene 15 (75%), fluids on the scene 1.5 L (1.0-3.0), time from accident until admission 53 min (33-75), lactate 3.2 mmol/L (2.7-8.0), haemoglobin 8.9 g/100 mL (7.0-12-0), PH 7.30 (7.27-7.36), base deficit 6.2 (8.3-3.7).

Control: 20 patients, 13 men, age 35 (27-47) y, SBP on the scene 100 mm Hg (93-120), 2 patients on the scene with SBP <80 mm Hg, Glasgow coma score 13 (4-15), use of catecholamines on the scene in 2 cases, intubation on the scene 10 (50%), fluids on the scene 2.0 L (1.0-3.0), time from accident until admission 58 min (30-105), lactate 3.7 mmol/L (2.1-6.0), haemoglobin 9.5 g/100 mL (8.0-11-0), PH 7.29 (7.10-7.32), base deficit 7.6 (13.1-4.2).

Inclusion criteria: 1) injury severity score (ISS) of 29 or greater (because an ISS of 29 or greater was associated with an organ failure rate of more than 60%), 2) admission within 6 h after injury, 3) 18-70 years, 4) blunt trauma, 5) if the head region contributed to calculation of the ISS, the sum of squared abbreviated ISS of the 2 other regions that were included in the calculation had to be equal or greater than 20 points in order to rule out predominant head injury and ensure severe multiple injuries.

Exclusion criteria: a) resuscitation with epinephrine, (b) if closed chest compression performed, c) severe brain injury with uncertain outcome (both pupils unresponsive to light for more than 30 minutes, midline shift >1 cm, or extensive intracerebral haemorrhage on the initial computed tomographic scan).
The only post hoc exclusion criterion was survival of less than 24 hours after trauma.

Interventions

AT III: a total of 20.000 IU (16.125-22.875), vials containing 500 IU diluted in 8 mL of water. Infusion-rate of 96mL/h via a pump. AT III levels assessed every 6 h during the first 48 h. Additional AT III or placebo was substituted to keep the AT III concentration at 140% of normal. In addition, on the next 2 days the test substance was administered once daily in the morning.

Control: placebo, 20% human albumin in corresponding doses and volume.

For prophylaxis of DVT and pulmonary embolism: standard sodium heparin iv at a rate of 400 IU/h, started within the first 24 h after trauma unless contraindications (active bleeding, intracranial haemorrhage, or others). Patients with traumatic intracranial bleeding were started on heparin on day 5, when the acute phase of brain swelling had subsided and there were no signs of ongoing haemorrhage.

Outcomes

Primary: incidence and severity of multiple organ dysfunction, mortality, incidence of respiratory failure, severity of organ failure, duration of mechanical ventilation and length of stay in the ICU and hospital.

Secondary: plasma concentration of indicators of DIC and systemic inflammatory response (prothrombin, prothrombin fragment F1+F2, TAT-complex lower, partial thromboplastin time, prothrombin time, PC, plasminogen activator inhibitor I, soluble TNF receptor II, IL1 receptor antagonist, IL6, IL8, neutrophil elastase), transfusions, respiratory dysfunction, ARDS, renal and liver dysfunction, incidence of DIC.

Notes

Country: Germany
Letters sent to authors in November and December 2005, authors replied both times.

Authors' conclusion: the early and high-dose administration of AT III to patients with severe blunt trauma appears not to extenuate the posttraumatic inflammatory response or to significantly improve outcome.

8 patients were excluded due to survival less than 24 hours; 3 in control group and 5 in AT group due to severe brain injury (n = 5) and uncontrollable haemorrhage (n = 3). During the first 48 hours after trauma, 12 and 9 patients in the control and AT III groups, respectively, received heparin prophylaxis. At day 6, all but one patient in each group was receiving heparin. The sample size was too small for a reliable subgroup analysis bases on heparin administration.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskInadequate
Allocation concealment (selection bias)High riskC - Inadequate

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Balk 1995Septic patients randomized to receive either AT III or placebo in a double-blind treatment protocol. 34 patients followed for 28 days with organ dysfunction/failure evaluation. The overall mortality was 22.2% in AT III group and 12.5% in placebo. Reason for exclusion: published only as an abstract.
Banfi 1996An observational study on the use of AT III in 16 ICUs in Italy with no reported reduction in mortality or in the length of stay in hospital. Reason for exclusion: no randomization.
Blauhut 19853-group parallel randomized clinical trial comparing effects of AT III and heparin, AT III without heparin and heparin alone. Heparin concentration was different in the AT III + heparin group than the heparin group. Reason for exclusion: multiple treatments.
Brangenberg 1997103 preterm infants at a gestational age of 25-32 weeks (mean 28.9 weeks; birth weight 600-2170 g, mean 1285 g) received AT III at a single dosage of 50-200 IU/kg on the day of birth and subsequently only in case of a new fall in AT III activity below 50%. Coagulation parameters, incidence of intraventricular haemorrhage (IVH) and other clinical outcomes were reported. Reason for exclusion: observational study, no control group, no randomization.
Danielsson 1997The study was divided into 2 parts with a total of 14 consecutive patients (per cent total body surface area after burn injury > or = 20%). The first 6 patients were given AT III when AT III fell below 50%. The second part examined the restitution of the coagulation parameters when the patients (n = 8) obtained AT III substitution only at extremely low values of AT III. Reason for exclusion: observational study with no randomization or control group.
du Cheyron 2006Observational study evaluating the effect of AT III supplementation on filter lifespan compared with heparin in critically ill patients with septic shock requiring continuous renal replacement therapy (CRRT). AT III supplementation was independently associated with a decrease in clotting rate. Mortality did not differ. Reason for exclusion: retrospective case-control analysis based on a 4-year observational study. No randomization.
Fertmann 2006This study examined prophylactic high-dose AT III application in patients with first pancreas-kidney (SPK) transplantation. 53 consecutive patients with SPK were studied. In AT III group (n=24) 3000 IU of AT III was given intravenously before pancreatic reperfusion, while the control group (n=29) received standard therapy including post-operative AT III supplementation. Reason for exclusion: no randomization, retrospective analysis.
Fourrier 1990Effect of early infusion of AT III among 5 adult patients with meningococcaemia (type B) and purpura fulminans. Designed to measure the levels of AT III, protein C, protein S and survival. Reason for exclusion: no randomization, case report.
Hanada 1985Effect of AT III bolus injections (250 U/8hours) and/or continuous heparin infusion (400 U/kg/day) in 6 children with DIC (1 month to 5 years old). Reason for exclusion: no randomization, case report.
Haussmann 2006This trial comprised of two phases: 1) 71 children did not receive any specific veno-occlusive disease (VOD) prophylaxis or therapy (controls); 2) 91 children were given pre-emptive AT III replacement in case of decreased AT III activity (< or =70%). If VOD was diagnosed clinically, high-dose defibrotide (60 mg/day) and AT III replacement therapy were combined.
Reason for exclusion: no randomization, case series.
Hellgren 1984A study of AT III supplementation in 9 severely ill patients with DIC. Reason for exclusion: no randomization, no control group.
Hoffmann 2004This paper reports the effects of AT III supplementation on septic coagulatory response in patients with severe sepsis when given over 14 days. Reason for exclusion: based on the same trial as Inthorn 1997, post hoc analysis.
Hoffmann 2006This paper analyses heparin-AT III interactions in terms of long-term mortality, adverse events, and thromboembolic events. Reason for exclusion: based on the same trial as Warren 2001, post hoc analysis.
Ilias 2000An open randomized clinical trial, evaluating the safety, pharmacokinetics and practicability of two different regimens of AT III treatment (intermittent bolus infusions vs continuous infusion), both aiming at a total dose of 30,000 IU AT III with concomitant heparin during a 4-day period. Reason for exclusion: two different regimens of AT III treatment.
Inthorn 1998This paper reports the effects of long-term AT III supplementation on the inflammatory response in a septic population. Reason for exclusion: based on the same trial as Inthorn 1997.
Jochum 1995This review includes one unpublished, not double-blinded trial of AT III supplementation in a septic population aiming at AT III activity > 120%. AT III group (n = 20) received 2000-8000 U/d AT III over 21 days and heparin (4 U/kg body weight/hour). Control group (n=20) received no placebo. Outcome measures were various organ dysfunction analyses, inflammatory and coagulatory parameters and mortality (control: 80%, AT III: 65%). The results were not statistically significant. Reason for exclusion: review and data from an unpublished trial.
Kienast 2006This paper examines the treatment effects of high-dose AT III in patients with severe sepsis with or without DIC. 563 patients from Warren 2001 were identified (placebo 277; AT III 286) who did not receive concomitant heparin and had sufficient data for DIC determination. Reason for exclusion: based on the same trial as Warren 2001, post hoc analysis.
Korninger 1987A randomized trial of AT III in patients undergoing peritoneo-venous shunt operation because of intractable ascites. 10 patients with alcoholic liver cirrhosis were randomized according to the stage of liver disease and pre-operative AT III levels. AT III was infused in 5 patients, twice daily for 4 days, at a dose of 20 U/kg body weight starting 12 hours prior to operation. 5 patients were allocated to placebo. Coagulatory parameters were examined. Reason for exclusion: only published as abstract, no data on mortality.
Kowal-Vern 2000In this trial 17 patients with thermal injuries of a second or third-degree burn covering more than 20% of body surface either received AT III supplementation or standard therapy. Outcome measures were wound healing, estimated blood loss, scarring, level of contractures, and length of stay. Reason for exclusion: allocation to the groups at the patients choice, no randomization.
Leitner 2006This randomized, double-blinded, placebo-controlled study examined 30 healthy male volunteers. The active treatment groups received infusions of AT III to achieve levels of 200% and 500% before infusion of 2 ng/kg endotoxin (LPS). Reason for exclusion: experimental trial among healthy volunteers.
Maki 1987This randomized controlled trial compared two active interventions, being AT III with FOY (injectable protease inhibitor: gabexate mesilate) in patients with obstetric complications. Reason for exclusion: two different active interventions.
Messori 2002Observational retrospective study of 216 critically ill patients treated with AT III at 20 Italian hospitals. Reason for exclusion: retrospective, no randomization, no control group.
Mitchell 2003bIn this study children with ALL were screened for thrombotic events. Reason for exclusion: part of the PARKAA study (Mitchell 2003); only data on children without AT III treatment were provided.
Moriss 1997An observational study of 10 patients with severe post-bone marrow transplantation organ dysfunction (single or multiorgan) and AT III levels < 88% were treated with AT III concentrate. All patients were loaded with 50 units/kg AT III every 8 h for 3 doses followed by 50 units/kg/day each day for 3-12 days. Reason for exclusion: no randomization, no control group.
Muntean 1989This open, controlled, randomized trial examined a single administration of AT III concentrate in 103 premature infants (gestational age 26-34 weeks, mean 31). No placebo. No benefit of AT III administration was found. Trend towards more frequent deaths in the AT III group (9/45) compared with control group (8/53). Reason for exclusion: only published as an abstract.
Nishiyama 2006This randomized, unblinded trial investigated the effects of AT III on coagulation, fibrinolysis, production of cytokines and adhesion molecules in abdominal aortic aneurysm repair surgery. 16 patients for Y-shaped graft replacement of abdominal aortic aneurysm were divided into an AT III group and a control group. In the AT III group, 3000 U AT III was infused over 30 min before heparin administration and 24 h later. Reason for exclusion: no data on mortality, nor any data relevant for our review.
Palareti 1995In this trial, 119 patients (age 18-75 y, ATIII < 70% with sepsis and/or post-surgical complications requiring haemodynamic or respiratory support) were randomized to receive AT III (4000 U as bolus + 2000 U/12 hours by continuous infusion for 5 days) or placebo. Laboratory effects of AT III replacement were examined. Reason for exclusion: only published as an abstract.
Paternoster 2000This prospective study evaluated the modifications of clotting and clinical parameters before and immediately after delivery amongst a pre-eclamptic population either treated with AT III (n=18) or acting as control (n=21). Reason for exclusion: only published as a brief communication, no data on randomization or blinding.
Paternoster 2004In this study, 23 pre-eclamptic women were randomly subdivided into 2 groups: first group (n=10) were treated with 3000 units AT III once daily for 5 days or until delivery, while the second group (n=13) were treated with doses of AT III sufficient to maintain at least 80% of the activity. The end points were the prolongation of pregnancy, assessment of the maternal bleeding and haemostasis, and inflammatory markers. Reason for exclusion: comparison of 2 different regimens of AT III.
Scherer 1994In this trial, 51 adult patients scheduled for orthotopic liver transplantation were divided into 2 groups. In 37 patients with AT III activity < 70%, AT III was given pre-operatively (mean dose 2616 +/- 207 IU) in order to increase AT III activity to 80%. In the other group,14 patients with prothrombin time (PT) < 40%, and with a pre-corrected AT III during the clinical course (AT III activity > 70%), prothrombin complex was substituted (mean dose 2304 +/- 289 IU) aiming at a PT > 60%. Reason for exclusion: no randomization, 2 different interventions.
Scherer 1997A randomized prospective study examining the effects of AT III substitution in order to achieve supranormal values in patients with liver cirrhosis scheduled for liver transplantation.
19 patients were given AT III aiming at either 100% (n = 10) or 175% (n = 9) AT III activity. Control group (n = 5) received saline 0.9%. The end points were various coagulatory variables measured prior to AT III infusion and 60 min thereafter. Reason for exclusion: no data on mortality, 3 groups.
Schuster 1997A study of 45 patients with sepsis without DIC, allocated to AT III supplementation (loading dose of 3000 IU followed by 500 IU every 4 hrs for 7 days, total dose 17,000 IU) or placebo (albumin). Both groups received iv heparin (6 IU/kg/h). Reported mortality was: AT III 9/22, control 10/23. Reason for exclusion: only submitted as an abstract.
Seitz 1989An open pilot study of 42 patients with septic shock. AT III group (n= 29) treated with AT III, fresh-frozen plasma, and continuous heparin infusion at an average dose of 300 U/h. Control group (n = 13) received similar heparin regimen. Reason for exclusion: no randomization.
Shimada 1994A randomized prospective trial of AT III efficacy in hepatic resection among 24 patients with hepatocellular carcinoma. 13 patients were given 1500 IU AT III immediately before operation, during hepatectomy, and immediately after operation. Control group (n = 11) received no placebo. Coagulant and fibrinolytic profiles were determined. Reason for exclusion: no data on mortality, different population than defined in our review.
Terao 1989A randomized trial of 40 patients with pre-eclampsia comparing AT III intervention with no treatment on coagulatory findings, gestosis Index, abortion times, and incidence of newborn asphyxia. Reason for exclusion: no data on mortality.
van Beek 1994A study of adults with sepsis and AT III levels < 0.45 IU/ml. AT III group (n= 21) received AT III bolus of 20 IU/kg followed by continuous infusion of 20 IU/g per 24 h. Control (n= 21) received no placebo. Mortality: AT III group 12/21 (95% CI 34-78%), control 16/21 (95% CI 53-92%). Reason for exclusion: retrospective, no randomization.
van Leeuwen 2003This paper examined the changes in lipoprotein levels in patients with severe sepsis. Reason for exclusion: different objective, based on the same trial as Warren 2001, post hoc analysis.
Vinazzer 1995This review mentioned one unpublished trial of patients with DIC due to sepsis or septic shock in which 170 patients were evenly allocated to two groups (heparin versus AT III). This uncontrolled open clinical trial showed positive outcome of AT III substitution. Reason for exclusion: review and data from an unpublished trial.
Von Kries 1985A trial of AT III infusion after prior activation with heparin among 10 newborns with DIC. Primary outcome: AT III activity. Reason for exclusion: no randomization, case report.
Wiedermann 2006Re-analysis of prospectively defined populations from the KyberSept trial. Reason for exclusion: based on the same trial as Warren 2001, post hoc analysis.

Characteristics of ongoing studies [ordered by study ID]

D'angelo 2005

Trial name or titleEPAS (Early Preeclampsia Antithrombin Study)
Methods 
ParticipantsWomen with pre-eclampsia occurring before the 30th week of gestation.
Interventions7-day course of antithrombin 3000 IU/day. No heparin prophylaxis will be permitted during the time of AT III administration.
OutcomesPrimary outcome: reduction of the combined end point of fetoneonatal mortality and severe neonatal morbidity.
Secondary outcomes: reduction in maternal complications and stay in neonatal intensive care unit and the evaluation of the changes in coagulation and inflammation parameters.
Starting dateDecember 2004
Contact informationD'angelo A (1),Valsecchi L (2)
1): Coagulation Service and Thrombosis Research Unit
2): Department of Obstetrics and Gynecology, Irccs
H S. Raffaele Milano, Italy
NotesD'angelo A,Valsecchi L; A double-blind study of high-dose Antithrombin supplementation in early preeclampsia. Thrombosis Research. 2005; 115 Suppl 1:117

Ancillary