Compresor intermitente TVP

7/29/2019 Compresor intermitente TVP

1/9

Philippe VignonPierre-Francois DequinAnne RenaultArmelle MathonnetNicolas PaleironAudrey ImbertDelphine ChatellierValerie GissotGwenaelle LheritierVictor AboyansGwenael PratDenis GarotThierry BoulainJean-Luc DiehlLuc BressolletteAurelien DellucKarine Lacut

The Clinical Research in Intensive Careand Sepsis Group (CRICS Group)

Intermittent pneumatic compression to prevent

venous thromboembolism in patients with high

risk of bleeding hospitalized in intensive careunits: the CIREA1 randomized trial

Received: 20 July 2012Accepted: 6 January 2013Published online: 31 January 2013 Springer-Verlag Berlin Heidelberg andESICM 2013

P. Vignon

G. LheritierReanimation Polyvalente, CHU Dupuytren,87042 Limoges, France

P. Vignon G. LheritierINSERM, CIC-P 0801, CHU Dupuytren,87042 Limoges, France

P. Vignon G. LheritierUniversite de Limoges,87000 Limoges, France

P.-F. Dequin D. GarotUniversite Francois Rabelais et servicede Reanimation Medicale,

CHU de ToursHopital Bretonneau,Tours, France

A. Renault G. PratService de Reanimation Medicale,CHU de la Cavale Blanche, Brest, France

A. Mathonnet T. BoulainReanimation, CHRHopital de la Source,Orleans, France

N. PaleironService des maladies respiratoires,HIA Clermont-Tonnerre, Brest, France

A. Imbert J.-L. DiehlReanimation Medicale,HEGP AP-HP, Paris, France

D. ChatellierService de Reanimation Medicale,CHU de Poitiers, Poitiers, France

V. GissotService de Reanimation Polyvalente,CH DAngouleme, Saint-Michel, France

V. AboyansService de Cardiologie, CHU de Limoges,Limoges, France

J.-L. DiehlINSERM U765, Universite Paris Descartes,Sorbonne Paris Cite, France

L. Bressollette A. Delluc K. LacutEA3878, Universite de Bretagne

Occidentale, 29200 Brest, France

L. BressolletteUnite de Medecine Vasculaire,CHU Brest, 29609 Brest, France

A. DellucDepartement de Medecine Interneet Pneumologie, CHU Brest,29609 Brest, France

K. LacutINSERM, CIC 0502, Brest, France

K. Lacut ())CIC 0502, Hopital de la Cavale Blanche,Bd Tanguy Prigent, F-29609 Brest Cedex,Francee-mail: [email protected].: ?33-29-8145007Fax: ?33-29-8145008

Abstract Purpose: Venousthromboembolism (VTE) is a fre-quent and serious problem inintensive care units (ICU). Anticoag-ulant treatments have demonstratedtheir efficacy in preventing VTE.However, when the bleeding risk ishigh, they are contraindicated, andmechanical devices are recom-mended. To date, mechanicalprophylaxis has not been rigorouslyevaluated in any trials in ICUpatients. Methods: In this multi-center, open-label, randomized trialwith blinded evaluation of endpoints,we randomly assigned 407 patientswith a high risk of bleeding to receiveintermittent pneumatic compression(IPC) associated with graduatedcompression stockings (GCS) or GCSalone for 6 days during their ICU

Intensive Care Med (2013) 39:872880DOI 10.1007/s00134-013-2814-2 O R I G I N A L


2/9

stay. The primary endpoint was theoccurrence of a VTE between days 1and 6, including nonfatal symptom-atic documented VTE, or death due toa pulmonary embolism, or asymp-tomatic deep vein thrombosis

detected by ultrasonography system-atically performed on day 6.Results: The primary outcome wasassessed in 363 patients (89.2 %). Byday 6, the incidence of the primaryoutcome was 5.6 % (10 of 179

patients) in the IPC ? GCS groupand 9.2 % (17 of 184 patients) in theGCS group (relative risk 0.60; 95 %confidence interval 0.281.28;p = 0.19). Tolerance of IPC was poorin only 12 patients (6.0 %). No

intergroup difference in mortality ratewas observed. Conclusions: Withthe limitation of a low statisticalpower, our results do not support thesuperiority of the combination ofIPC ? GCS compared to GCS alone

to prevent VTE in ICU patients athigh risk of bleeding.

Keywords Intermittentpneumatic compression devices Elastic stockings Venous

thromboembolism

Venousthrombosis Intensive care units

Introduction

Venous thromboembolism (VTE), that occurs as eitherdeep vein thrombosis (DVT) or pulmonary embolism(PE), is a major cause of morbidity and mortality in

patients admitted to intensive care units (ICU) [1]. Criti-cally ill patients have often multiple risk factors for VTE[2, 3]. Most of these risk factors are related to age or comorbidities (e.g., cancer, obesity), or are acquired duringthe ICU stay (e.g., central venous catheters, mechanicalventilation, or vasopressor use) [24]. The reported inci-dence rates of VTE in hospitalized patients range between20 % and 80 % depending to the studied population, thetype of thromboprophylaxis and the screening test used[5]. In the ICU setting, PE may account for acute episodesof hemodynamic instability or hypoxia and may contrib-ute to failure of weaning from mechanical ventilation[6, 7]. Since VTE is frequently silent and clinically

unsuspected in ICU patients [810], PE remains one ofthe most common unexpected autopsy findings in thecritically ill [11], and is found at autopsy in 7 % to 27 %of ICU fatalities [12, 13].

Surprisingly, little information is yet available on VTEprophylaxis in the ICU. Randomized trials including ICUpatients have indicated a benefit of unfractionated or lowmolecular weight heparin over placebo, without signifi-cant risk of hemorrhage [1416]. In ICU patients who areat high risk of bleeding, anticoagulant treatments arecontraindicated, and current guidelines recommend theoptimal use of mechanical thromboprophylaxis withgraduated compression stockings (GCS) and/or intermit-

tent pneumatic compression (IPC) at least until thebleeding risk decreases [17]. IPC has been shown to beeffective in preventing VTE in neurosurgical patientsundergoing craniotomy [18]. A randomized trial con-ducted in patients with intracerebral hemorrhage hasshown that IPC is more efficient in preventing asymp-tomatic DVT than GCS alone [19]. However, the efficacyand safety of mechanical prophylaxis of VTE have not yetbeen specifically evaluated in ICU patients. Accordingly,we carried out an open-label randomized parallel-group

trial to determine the efficacy and safety of IPC associatedwith GCS versus GCS alone for the prevention of VTE inICU patients with a high risk of bleeding.

Materials and methods

Trial design

CIREA 1 (Compression pneumatique Intermittente enREAnimation) was a multicenter, open-label, random-ized, outcome-blinded trial conducted at nine ICUs inFrance (see Appendix). The trial protocol was approvedby the local institutional review board. The sponsorplayed no role in the analysis or drafting of themanuscript.

Study population

Patients aged 18 years or older who were at high risk ofbleeding on ICU admission were eligible for the trial. Ahigh risk of bleeding was defined as symptomatic bleed-ing or the presence of organic lesions likely to bleed,hemophilic diseases, hemostatic abnormalities (plateletcount\50,000/mm3, aPTT ratio[2, prothrombin time\40 %), or the presence of severe anemia (hemoglobin\7 g/dl) due to bleeding or unexplained. Prolongedclotting times can be the result of the use of anticoagu-lants. These parameters alone when not associated withbleeding or a high risk of bleeding could not be consid-

ered as inclusion criteria. Other requirements forinclusion were a willingness to participate for the durationof the trial, and the provision of written informed consentgiven by the patients next of kin.

Exclusion criteria were patient refusal, the absence ofa high risk of bleeding as previously defined, the presenceof a documented VTE at screening or a recent DVT(\3 months), ICU stay of more than 36 h or likely to be\72 h, a life-support limitation, a contraindication formechanical prophylaxis (i.e., severe lower limb

873


3/9

arteriopathy, any arterial graft of the legs, a wound in thelower limb related to either vascular disease or trauma),and the presence of a mechanical prosthetic heart valve.

Study procedures

Patients were randomly assigned at ratio of 1:1 to receiveeither IPC associated with GCS or GCS alone. The ran-domization was centralized with internet access (Clininfo,Lyon, France), and stratified by center and age group(1850 years, 5170 years, and[70 years).

GCS consisted of thigh-length GCS (T.E.D.TM anti-embolism stockings; Covidien, Mansfield, MA) and IPCwas achieved with the SCD EXPRESSTM compressionsystem with adapted tubing sets and thigh sleeves (Co-vidien). Nurses were trained in the use of mechanicaldevices to apply optimal compression (proper sizing ofboth GCS and sleeves for IPC, and their proper applica-tion). GCS and IPC were applied to both legs as soon aspossible after randomization and maintained continuouslyuntil compression ultrasonography (CUS) was performedon day 6. After that day, the decision to maintain VTEprophylaxis and its modality were left at the discretion ofthe investigators. Anticoagulation was not permittedduring the first 6 days of the study. The use of GCS andIPC was recorded to monitor compliance and tolerance.Compliance was considered poor if the mechanicaldevices were used less than 80 % of the time. The GCSand IPC removal date and reasons were recorded whenapplicable. The use of procoagulant treatments (pro-thrombin complex concentrate, fresh frozen plasma,platelet transfusion, vitamin K, coagulation factors, prot-amine sulfate) between admission and day 6 wasrecorded.

Prior to randomization, CUS was recommended inpatients transferred to the ICU from another hospital oranother unit after hospitalization of at least 48 h. Thisbaseline CUS was performed to exclude prevalent DVT(exclusion criterion). We assumed that patients admitteddirectly to the ICU for an acute event had no prevalentDVT but those who were already hospitalized beforeadmission to the ICU could have developed DVT duringthe first days of hospitalization.

All included patients were visited on day 6, and sub-sequently followed up on day 30 and day 90 (visit or

phone call). Patients or their relatives were questionedabout VTE events after ICU discharge. If a patient died,the date and the most probable cause of death wererecorded.

Endpoints

The primary endpoint with respect to efficacy was theincidence of VTE on day 6 assessed by a composite

criterion: (1) symptomatic DVT of a lower limb (objec-tively confirmed by CUS) or symptomatic, nonfatal andobjectively confirmed PE, (2) death between day 1 andday 6 related to a PE, and (3) asymptomatic DVT (eitherdistal or proximal) of a lower limb detected by CUSsystematically performed on day 6. All reported symp-

tomatic VTE and all deaths that occurred between day 1and day 6 were judged on the basis of standardized cri-teria by an independent adjudication committee unawareof the randomized treatment assignments. Only confirmedVTE and deaths considered as definitely related to PEwere included in the analysis of the primary endpoint. TheCUS performed on day 6 by trained ultrasonographerswas standardized [20] and was done blindly, i.e., thepatients had bare legs, and mechanical devices wereremoved and hidden before the procedure. All examina-tions were videotaped and sent to the coordination centerfor validation by an expert ultrasonographer who wasunaware of the treatment group. DVT of the upper limbwas not considered as a primary endpoint. Secondaryendpoints were the occurrence of a symptomatic VTEbetween day 6 and day 90, and death from any cause up today 30 or day 90.

Adverse events were recorded during the use ofmechanical devices and the tolerability of GCS and IPCwas assessed using a specific chart.

Statistical analysis

Primary analysis was performed on an intention-to-treatbasis. Randomized patients who had a documented clin-ical endpoint or a CUS examination by day 6 wereincluded in the efficacy endpoint analysis. The incidenceof the composite primary endpoint on day 6 was com-pared between groups using an exact two-sided Fishertest. Relative risk and absolute risk reduction were com-puted with their 95 % confidence intervals.

Assuming an incidence of VTE of 15 % in the GCSgroup [6, 19], we calculated that 356 patients wererequired for the study to detect a 60 % reduction in theincidence of VTE with the combination IPC ? GCS, witha power of 80 % and a two-sided alpha level of 5 %.Because approximately 20 % of patients were expected todie during the first days of their ICU stay, we decided toenroll 400 patients.

Results

Between 21 November 2007 and 20 December 2010 atotal of 407 patients underwent randomization in the CI-REA1 study, 205 in the IPC ? GCS group and 202 in theGCS group (Fig. 1). The systematic CUS was performed5.8 1.6 days after ICU admission in the IPC ? GCS

874


4/9

group and after 6.0 1.4 days in the GCS group. Threepatients in the GCS group and one in the IPC ? GCSgroup received at least one dose of curative anticoagulanttreatment before the CUS evaluation for symptomaticDVT of an upper limb (n = 2), atrial fibrillation (n = 1)and unspecified reason (n = 1). Six patients in the GCS

group and one in the IPC?

GCS group received at leastone dose of preventive anticoagulation treatment beforethe CUS evaluation.

Baseline characteristics were well balanced betweenthe two groups (Table 1). About half of the patients had aspontaneous or traumatic intracranial hemorrhage. In 29patients (7.1 %), anticoagulant treatment was adminis-tered at a therapeutic dose before ICU admission (atrialfibrillation in 16, previous VTE[3 months in 7, throm-bolysis for myocardial infarction in 2, antiphospholipidsyndrome in 1, coronary disease in 1 and unknown reason

in 2) and 29 patients (7.1 %) received thromboprophy-laxis, mainly mechanical thromboprophylaxis with GCS.More than 70 % of the patients had a central venouscatheter at inclusion, but less than 10 % in the femoralsite. Nearly 30 % of patients had had recent surgerywhich was predominantly related to the reason for ICU

admission. Mean biological values were within normalranges (Table 1). In 96 of 341 patients for whom theinformation was available, procoagulant treatment wasadministered between admission and day 6, 42 in theIPC ? GCS group and 54 in the GCS group (p = 0.12).

By day 6, no death was considered by the adjudicationcommittee as due to fatal PE. PE occurred in one patientin the GCS group. No symptomatic DVT was observed.The systematic CUS detected 18 distal DVT and 8proximal DVT. The incidence of the primary endpointwas 5.6 % (10 of 179 patients) in the IPC ? GCS group

IPC + GCS

(n = 205)

GCS

(n = 202)

Randomized patients

(n = 407)

Evaluable for efficacy

endpoint at day 6

( n= 179)

Evaluable for efficacy

endpoint at day 6

(n = 184)

Excluded n = 1

Nonevaluable for

ultrasonography at day6 n = 25

- Death n = 21

- Transfer to another site before

ultrasonography n = 3

- Withdrawal of consent n = 1

Nonevaluable for

ultrasonography at

day6 n = 18- Death n = 17

- Transfer to another site

before ultrasonography n = 1

Followed-up until day 30(n= 142)

Death n = 40

Followed-up until day 90

(n = 133)

Death n = 8

Lost to follow-up n = 1

Followed-up until day 30(n= 144)

Death n = 41

Followed-up until day 90

(n = 133)

Death n = 10

Lost to follow-up n = 1

Screened patients

(n = 954)Non included n = 547- Admission > 36 hours n = 107

- Expected stay < 72 hours n = 141

- Contraindication to GCS and/or IPC n =55

- Life support limitation n = 156

- Refusal n = 53

- Mechanical heart valve n= 14

- Logistical reason n= 13

Fig. 1 Flow of patientsthrough the trial

875


5/9

and 9.2 % (17 of 184 patients) in the GCS group, leadingto a nonsignificant risk reduction of 40.0 % (relative risk,RR, 0.60; 95 % CI 0.281.28; p = 0.19; Table 2).

The incidence of VTE was 10.3 % (3 of 29 patients) inpatients previously treated with anticoagulant and 6.4 %(24 of 377 patients) in patients without previous antico-

agulant treatment (p=

0.41). Among the 96 patientstreated with procoagulant treatments between admissionand day 6, 7 (7.3 %) had VTE on day 6, and among the245 patients without procoagulant treatment, 18 (7.3 %)had VTE on day 6 (p = 0.98).

The effect of IPC ? GCS on the primary endpointwas globally homogeneous among subgroups (Fig. 2).Anticoagulation was resumed during the ICU stay in

53 % of survivors, after a median delay of 2 days(interquartile range 027 days) following the day-6CUS.

Between day 6 and day 90, no additional VTEoccurred in the GCS group but four symptomatic VTEevents occurred in the IPC ? GCS group (two proximal

DVT, one distal DVT and one PE). The incidence ofsymptomatic VTE on day 90 was 2.0 % (4/203 patients)in the IPC ? GCS group and 0.5 % (1/202 patients) in theGCS group (RR 4.0; 95 % CI 0.535.3; p = 0.4). Theincidence of all VTE events (symptomatic and asymp-tomatic) on day 90 was 7.8 % (14/179 patients) in theIPC ? GCS group and 9.2 % (17/184 patients) in theGCS group (RR 0.9; 95 % CI 0.41.7; p = 0.63).

Table 1 Baseline characteristics of patients

Characteristics All patients(n = 406)

IPC ? GCS group(n = 204)

GCS group(n = 202)

p value

Age (years), mean SD 55.4 17 56.3 16.5 54.6 17.5 0.32Female gender, n (%) 137 (33.5 %) 72 (35.3 %) 65 (32.2 %) 0.51BMI (kg/m2), mean SD 25.5 5.2 25.6 4.9 25.4 5.5 0.72SAPS II score, mean SD 42.7 18.1 41.6 18.3 43.7 17.8 0.24Primary admission diagnostic category, n (%)Spontaneous intracranial hemorrhage 146 (36.0) 81 (39.7) 65 (32.2) 0.12Traumatic intracranial hemorrhage 87 (21.4) 41 (20.1) 46 (22.8) 0.51Multisystem trauma 44 (10.8) 21 (10.3) 23 (11.4) 0.72Other hemorrhage 40 (9.9) 19 (9.3) 21 (10.4) 0.71Severe sepsis or septic shock 39 (9.6) 18 (8.8) 21 (10.4) 0.59Acute respiratory distress syndrome

with biological abnormalities24 (5.9) 14 (6.8) 10 (5.0) 0.41

Other diagnoses 26 (6.4) 10 (4.9) 16 (7.9) 0.22On ICU admission, n (%)Hospitalization more than 48 h prior

to ICU admission68 (16.7) 35 (17.2) 33 (16.3) 0.83

Therapeutic anticoagulation 29 (7.1) 13 (6.4) 16 (7.9) 0.54Thromboprophylaxis 29 (7.1) 17 (8.3) 12 (5.9) 0.35

At inclusion, n (%)Sepsis 46 (11.3) 20 (9.8) 26 (12.9) 0.33Central venous catheter 295 (72.6) 148 (72.5) 147 (72.8) 0.96Mechanical ventilation 336 (82.8) 169 (82.8) 167 (82.7) 0.96Sedation 317 (78.1) 159 (77.9) 158 (78.2) 0.95

Risk factors for VTE before ICU admission, n (%)Previous VTE 12 (3.0) 5 (2.5) 7 (3.4) 0.55Cancer 52 (12.8) 27 (13.2) 25 (12.4) 0.80Recent surgery or trauma 118 (29.1) 58 (28.4) 60 (29.7) 0.78Pregnancy or post-partum 4 (1.0) 2 (1.0) 2 (1.0) 1.0Estrogen use 6 (1.5) 2 (1.0) 4 (2.0) 0.45Known thrombophilia 2 (0.5) 2 (1.0) 0 (0) 0.15Plaster cast immobilization 0 (0) 0 (0) 0 (0) Previous stroke 13 (3.2) 6 (3.0) 7 (3.5) 0.76

Cardiac insufficiency 20 (4.9) 6 (3.0) 14 (6.9) 0.07Respiratory insufficiency 64 (15.8) 32 (15.7) 32 (15.8) 0.96

Biological dataPlatelet count (G/l), mean SD 187.5 108.0 192.3 109.2 182.7 107.0 0.37Platelet count\50,000/mm3, n (%) 47 (11.6) 22 (10.8) 25 (12.4) 0.62Hemoglobin (g/dl), mean SD 12.3 7.5 11.6 2.4 12.9 10.4 0.08Hemoglobin\7 g/dl, n (%) 12 (3.0) 9 (4.4) 3 (1.5) 0.09aPTT ratio, mean SD 1.16 0.40 1.16 0.50 1.15 0.40 0.96aPTT ratio[2, n (%) 8 (2.0) 5 (2.5) 3 (1.5) 0.49Prothrombin time (%), mean SD 71.9 21.1 73.5 20.5 70.2 21.8 0.13Prothrombin time\40 %, n (%) 42 (10.3) 22 (10.8) 20 (9.9) 0.77Creatinine (lmol/l), mean SD 101.6 104.7 100.6 103.4 102.5 106.2 0.12

876


6/9

Compliance with GCS was poor in eight patients(2.0 %, one in the GCS group and seven in theIPC ? GCS group). Tolerance of GCS was poor in 13patients (3.3 %) in both groups with no differencebetween groups. The reported adverse effects (noneserious) were mild cutaneous injuries (n = 8) or dis-comfort (sweating, warmth, and tight GCS).Compliance with IPC was poor in 14 patients (7.0 %)

in the IPC ? GCS group. Tolerance of IPC was poor in12 patients (6.0 %) and early removal of IPC wasnecessary in seven patients. The most frequent reasonsfor discontinuation of IPC were discomfort, noise andrestlessness. No serious adverse event was reportedwith IPC. By day 6, 15 deaths were related to fatalhemorrhage with no difference between the groups: 7(3.4 %) in the IPC ? GCS group and 8 (4 %) in theGCS group (p = 0.78). Nonfatal major hemorrhage wasobserved in 22 patients: 10 (4.9 %) in the IPC ? GCSgroup and 12 (5.9 %) in the GCS group (p = 0.65). Byday 30, 58 patients (29 %) in the GCS group and 61patients (30 %) in the IPC ? GCS group had died

(p = 0.79). By day 90, 68 patients (34 %) in the GCSgroup and 69 patients (34 %) in the IPC ? GCS grouphad died (p = 0.97).

Discussion

In this first randomized trial specifically designed toevaluate the potential benefit of two distinct mechanicaldevices in ICU patients with a high risk of bleeding, wefound no significant difference in the incidence of VTEbetween those receiving IPC together with GCS and those

receiving GCS alone.For critically ill patients who are at high risk ofbleeding, current guidelines recommend the optimal useof mechanical thromboprophylaxis with GCS and/or IPCto prevent VTE at least until the bleeding risk decreases[17]. However, little is known about the efficacy andsafety of mechanical prophylaxis methods in ICU patients[21]. From a physiological point of view, the dynamiccompression produced by IPC is assumed to be more

efficient than the static compression produced by theGCS. In addition, IPC is thought to have a fibrinolyticaction, primarily by increasing tissue plasminogen acti-vator and decreasing plasminogen activator inhibitor [22].Despite these theoretical advantages, the addition of IPCprovided no additional benefit compared to GCS alone inour ICU patients with a high risk of bleeding. Neverthe-less, the lack of statistical power of the present study

(54 % when calculated a posteriori) did not allow us toconfidently rule out a potential beneficial effect of IPC forthe prevention of VTE in this specific clinical setting.

This low statistical power may be explained by thelow incidence of VTE observed in the GCS group(9.2 %), when compared to an expected 15 % rate. In aprevious randomized clinical trial that evaluatedIPC ? GCS versus GCS alone in patients with intrace-rebral hemorrhage, we found a 15.9 % incidence of VTEin the GCS group using systematic CUS on day 10 [19].In the present trial, the incidence of VTE in a similarpopulation subset (patients with intracranial hemorrhagein the GCS group, n = 103) was 12.6 %. In an observa-

tional study performed in 100 medical ICU patients,lower limb Doppler ultrasonography performed twice-weekly and 1 week after ICU discharge detected a DVTin 33 % of patients who were receiving a mechanicalprophylaxis [6]. A prospective study using twice-weeklyleg ultrasonography identified a proximal DVT in 25 of261 patients (10 %) during their ICU stay [3]. Takentogether, these results led us to initially expect a 15 %incidence of VTE in the GCS group, including asymp-tomatic distal and proximal DVT. The lower incidence ofVTE observed in the control group of the present studymay be related to a lower risk of thrombosis in criticallyill patients at high risk of bleeding when compared to that

of the general ICU population.Early CUS evaluation on day 6 presumably con-tributed to the fairly low incidence of observed VTE inthe present study. In previous trials, VTE endpointswere generally evaluated on day 10 or later. Never-theless, in studies that screened regularly for DVT inICU patients, DVT were identified in the first days ofICU stay. In a study by Hirsch et al., 23 of 33 DVT(70 %) were detected during the first CUS [6].

Table 2 Venous thromboembolic events by day 6

Outcome IPC ? GCS group,n/N (%)

GCS group,n/N (%)

Relative risk 95 % confidence interval p value

Fatal pulmonary embolism 0/204 0/202 Symptomatic pulmonary embolism 0/204 1/202 Symptomatic deep vein thrombosis 0/204 0/202 Asymptomatic distal deep vein thrombosis 6/179 (3.4) 12/183 (6.6) 0 .51 0.21.33 0.17

Asymptomatic proximal deep vein thrombosis 4/179 (2.2) 4/183 (2.2) 1.02 0.264.03 0.975Primary endpoint on day 6 10/179 (5.6) 17/184 (9.2) 0.60 0.281.28 0.191

877


7/9

Similarly, Cook et al. [3] reported that 50 % of DVTwere detected before day 8 (median day 8; interquartilerange day 414). We also chose to perform the CUSevaluation early because in patients admitted to an ICUwith a high bleeding risk, the American Collegeof Chest Physicians guidelines recommend that

pharmacological thromboprophylaxis be substituted foror added to the mechanical thromboprophylaxis as soonas the high bleeding risk decreases [17]. In the presentstudy, anticoagulation was resumed during the ICU stayin the majority of the survivors early after the sys-tematic CUS on day 6.

Fig. 2 Rates of the primaryefficacy outcome on day 6 insubgroups. The primaryefficacy endpoint was acomposite, combining fatal PE,symptomatic PE, symptomaticDVT, or asymptomatic DVTdetected by systematic CUS on

day 6. The size of each square isin proportion to the number ofpatients in the comparison. Noadjustment for multiplecomparisons was made, sincesubgroup analyses wereperformed for exploratorypurposes only. BMI is bodyweight in kilograms divided bythe square of the height inmeters

878


8/9

Since VTE is often silent and clinically unsuspectedin ICU patients [10, 11], PE is one of the most com-mon unexpected autopsy findings in this specificpopulation [11]. The recent PROTECT study showed asignificantly reduced incidence of PE in ICU patientstreated with dalteparin when compared with the group

treated with unfractionated heparin, but no reduction inasymptomatic DVT [16]. This result questions thevalidity of asymptomatic DVT as a surrogate primaryendpoint in prophylaxis trials in VTE. In the presenttrial, we failed to detect any intergroup difference inclinically relevant events, such as symptomatic VTE ordeath.

The compliance with IPC was fairly good in thepresent study. The high proportion of sedated patients atinclusion (78 %) presumably accounts for this result.Nevertheless, a few patients without sedation poorly tol-erated the inflation or the noise of IPC. No serious adverseevent was related to the use of IPC.

The present trial had substantial limitations. First, asdiscussed above, the study was underpowered to dem-onstrate a significant 60 % reduction in incidence in theIPC ? GCS group. Second, autopsy was not performedfor all fatalities, especially when death occurred in theICU. This may have led to underestimation of the PE-related death rate. Third, this study was not blinded, butday 6 CUS was performed without knowledge of themechanical device used for VTE prophylaxis andvalidation of CUS was performed by an expert ultraso-nographer who was unaware of the patients assignment.

In conclusion, the current trial was not able to showthe superiority of the combination of IPC ? GCS overGCS alone in preventing VTE in ICU patients at high riskof bleeding. However, an additional preventing effect ofIPC cannot be confidently ruled out based on the results ofthis study which lacked power, mainly because of a lowincidence of VTE in the control group. Nevertheless, thisstudy provides the basis for performing new large clinicaltrials to evaluate mechanical devices to prevent VTE invarious subsets of ICU patients with a high risk ofbleeding.

Acknowledgments This study was supported by a grant from theFrench Ministry of Health (PHRCN 2005 no. 08-13). COVIDIENsupplied the GCS (T.E.D.TM anti-embolism stockings) and the IPC(SCD EXPRESSTM compression systems with tubing sets and

sleeves). The sponsor had no role in the study. We thank theresearch coordinator I. Pichon, the members of the CIC-P 0502 andthe CIC-P 0801, the study nurses of the Clinical Research inIntensive Care and Sepsis Group (CRICS group), the Direction dela Recherche Clinique et Innovation (DRCI) of Brest UniversityHospital for their invaluable work, as well as Z. Alavi for herpertinent advice.

Conflicts of interest The authors state that they have no conflictof interest.

Appendix

CIREA1 collaborators:Steering Committee: Pr Jean-Luc Diehl, Pr Philippe

Vignon, Dr Anne Renault, Pr Karine LacutAdjudication Committee: Pr L. Bressollette (expert

ultrasonographer), Pr Erwan LHerData manager and Biostatistician: Elise Poulhazan,Emmanuel Nowak

Investigators:Service de Reanimation Polyvalente, CH dAngouleme,Saint-Michel: Dr Thierry Baudin-Jacquemin, Dr SylvieNicole Calvat, Dr Arnaud Desachy, Dr Florence Hospital

Service de Reanimation Medicale, CHU de la CavaleBlanche, Brest: Dr Montaine Lefevre, Dr Jean-MarieTonnelier, Dr Alexandre Tonnelier

Federation dAnesthesie, Reanimation Urgences, HIAClermont-Tonnerre, Brest : Dr Christophe Giarcardi,Dr Bruno Ralec, Dr Mehdi Ould-Ahmed, Dr Didier

Fourel, Dr Ba Vinh N Guyen, Dr Diane Commandeur.Reanimation Polyvalente, CHU de Limoges, Limoges:Dr Jean-Bernard Amiel, Dr Marc Clavel, Dr AnthonyDugard, Dr Caroline Etchecopar-Chevreuil, Dr BrunoFrancois, Dr Nicolas Pichon, Dr Jean-Claude Voultoury.

Service de Reanimation Medicale, CHU Hotel Dieu,Nantes: Dr Olivier Zambon

Reanimation, CHRHopital de la Source, Orleans:Dr Isabelle Runge, Dr Christian Fleury, Dr MarieSkarzynski, Dr Dalila Benzekri-Lefevre, Dr Anne Bre-tagnol, Dr Nicolas Bercault

Reanimation Medicale, HEGP, AP-HP Paris: Dr Em-manuel Guerot, Dr Ana Novara, Dr Christophe Faisy,Dr Iris Pelieu, Pr Nicolas Lerolle

Service de Reanimation Medicale, CHU de Poitiers,Poitiers: Pr Olivier Pourrat, Dr Julien Voultoury, DrMichel Pinsard, Dr Anne Veinstein, Dr Jean-Pierre Frat,Dr Julie Badin, Pr Rene Robert

Service de Reanimation Medicale, CHU de ToursHopital Bretonneau, Tours: Dr Annick Legras, Dr Em-manuelle Mercier, Dr Laure Batias-Moreau, Dr StephaneEhrmann, Dr Stephanie Benardeau, Dr Maud Jonas,Dr Antoine Guillon, Dr Jennifer Buret, Dr ElodieMasseret

Vascular Ultrasonography Collaborators:Imagerie Medicale, CH dAngouleme, Saint-Michel:Dr Florence Hospital, Dr Daniele Colin, Dr Thierry Landois

Radiologie, HIA, Clermont-Tonnerre, Brest : Dr JeanRousset, Dr Marc Garetier, Dr Diouf, Dr Sandra Chinel-lato, Dr Valentin Tissot

Unite Vasculaire du service de Chirurgie Thoraciqueet Cardiovasculaire, CHU de Limoges, Limoges: Pr Phi-lippe Lacroix, Dr Tiphaine Bonnafy

Service dexplorations vasculaires, CHU Hotel Dieu,Nantes: Dr Jerome Connault

879


9/9

Angiologie, CHRHopital de la Source, Orleans:Dr Carole Bazzi

Medecine vasculaire et hypertension arterielle,HEGP, AP-HP Paris: Pr Joseph Emmerich, Dr Emman-uel Messas

Radiologie, Echographie-Doppler, CHU de Poitiers,Poitiers: Dr Elisabeth Escure, Dr Cecile Thollot, Dr Jer-ome Roumy

Pole imagerie medicale, CHU de ToursHopitalBretonneau, Tours: Dr Nicole Ferreira, Pr Frederic Patat

References

1. Attia J, Ray JG, Cook DJ, Douketis J,Ginsberg JS, Geerts WH (2001) Deepvein thrombosis and its prevention incritically ill adults. Arch Intern Med161:12681279

2. Shorr AF, Williams MD (2009) Venousthromboembolism in critically illpatients. Observations from arandomized trial in sepsis. ThrombHaemost 101:139144

3. Cook D, Crowther M, Meade M,Rabbat C, Griffith L, Schiff D, Geerts

W, Guyatt G (2005) Deep venousthrombosis in medical-surgicalcritically ill patients: prevalence,incidence, and risk factors. Crit CareMed 33:15651571

4. Cook D, Douketis J, Meade M, GuyattG, Zytaruk N, Granton J, Skrobik Y,Albert M, Fowler R, Hebert P,Pagliarello G, Friedrich J, Freitag A,Karachi T, Rabbat C, Heels-Ansdell D,Geerts W, Crowther M; CanadianCritical Care Trials Group (2008)Venous thromboembolism and bleedingin critically ill patients with severe renalinsufficiency receiving dalteparinthromboprophylaxis: prevalence,

incidence and risk factors. Crit Care12:R32

5. Geerts WH, Heit JA, Clagett GP, PineoGF, Colwell CW, Anderson FA Jr,Wheeler HB (2001) Prevention ofvenous thromboembolism. Chest119:132S175S

6. Hirsch DR, Ingenito EP, Goldhaber SZ(1995) Prevalence of deep venousthrombosis among patients in medicalintensive care. JAMA 274:335337

7. McKelvie PA (1994) Autopsy evidenceof pulmonary thromboembolism. Med JAust 160:127128

8. Moser KM, Fedullo PF, LitteJohn JK,Crawford R (1994) Frequent

asymptomatic pulmonary embolism inpatients with deep venous thrombosis.JAMA 271:223225

9. Stein PD, Henry JW (1995) Prevalenceof acute pulmonary embolism amongpatients in a general hospital and atautopsy. Chest 108:978981

10. Karwinski B, Svendsen E (1989)Comparison of clinical and postmortemdiagnosis of pulmonary embolism.J Clin Pathol 42:135139

11. Twigg SJ, McCrirrick A, Sanderson PM(2001) A comparison of post mortemfindings with post hoc estimated clinicaldiagnoses of patients who die in a

United Kingdom intensive care unit.Intensive Care Med 27:706710

12. Blosser SA, Zimmerman HE, StaufferJL (1998) Do autopsies of critically illpatients reveal important findings thatwere clinically undetected? Crit CareMed 26:13321336

13. Mort TC, Yeston NS (1999) Therelationship of pre-mortem diagnosesand post-mortem findings in a surgicalintensive care unit. Crit Care Med27:299303

14. Cade JF (1982) High risk of thecritically ill for venousthromboembolism. Crit Care Med10:448450

15. Fraisse F, Holzapfel L, Couland JM,Simonneau G, Bedock B, Feissel M,Herbecq P, Pordes R, Poussel JF, RouxL (2000) Nadroparin in the preventionof deep vein thrombosis in acutedecompensated COPD. Am J RespirCrit Care Med 161:11091114

16. PROTECT Investigators for theCanadian Critical Care Trials Groupand the Australian and New ZealandIntensive Care Society Clinical TrialsGroup, Cook D, Meade M, Guyatt G,Walter S, Heels-Ansdell D, WarkentinTE, Zytaruk N, Crowther M, Geerts W,Cooper DJ, Vallance S, Qushmaq I,Rocha M, Berwanger O, Vlahakis NE

(2011) Dalteparin versus unfractionatedheparin in critically ill patients. N EnglJ Med 364:13051314

17. Kahn SR, Lim W, Dunn AS, CushmanM, Dentali F, Akl EA, Cook DJ,Balekian AA,Klein RC,Le H, SchulmanS, Murad MH; American College ofChest Physicians (2012) Prevention ofVTE in nonsurgical patients:Antithrombotic Therapy and Preventionof Thrombosis, 9th ed: AmericanCollege of Chest Physicians Evidence-Based Clinical Practice Guidelines.Chest 141(2 Suppl):e195Se226S

18. Turpie AGG, Hirsh J, Gent M, Julian D,

Johnson J (1989) Prevention of deepvein thrombosis in potentialneurosurgical patients. A randomizedtrial comparing graduated compressionstockings alone or graduatedcompression stockings plus intermittentpneumatic compression with control.Arch Intern Med 149:679681

19. Lacut K, Bressollette L, Le Gal G,Etienne E, De Tinteniac A, Renault A,Rouhart F, Besson G, Garcia JF,Mottier D, Oger E, VICTORIAh(Venous Intermittent Compression andThrombosis Occurrence Related toIntra-cerebral Acute hemorrhage)Investigators (2005) Prevention of

venous thrombosis in patients withacute intra-cerebral hemorrhage.Neurology 65:865869

20. Goodacre S, Sampson F, Thomas S, vanBeek E, Sutton A (2005) Systematicreview and meta-analysis of thediagnostic accuracy of ultrasonographyfor deep vein thrombosis. BMC MedImaging 5:6

21. Limpus A, Chaboyer W, McDonald E,Thalib L (2006) Mechanicalthromboprophylaxis in critically illpatients: a systematic review and meta-analysis. Am J Crit Care 15:402410

22. Jacobs DG, Piotrowski JJ,Hoppensteadt DA, Salvator AE, Fareed

J (1996) Hemodynamic and fibrinolyticconsequences of intermittent pneumaticcompression: preliminary results.J Trauma 40:710716

880

Documents

Compresor intermitente TVP