Anne Marie Sørensen

Heterozygosity for a deletion in the CKR-5 gene leads to prolonged AIDS-free survival and slower CD4 T-cell decline in a cohort of HIV-seropositive individuals.

Objective:Recently, it has been shown that a homozygous 32 base-pair deletion in the gene encoding CKR-5, a major coreceptor for HIV-1, leads to resistance to infection with HIV-1. We have investigated whether HIV-seropositive individuals who were heterozygous for the CKR-5 deletion had a different course of the disease. Design:Thirty-five high-risk HIV-seronegative and 99 HIV-seropositive Danish homosexual men followed from 1985 to 1996 and 37 blood donors were analysed for their CKR-5 genotype by polymerase chain reaction. Results:Two (6%) of the 35 HIV-seronegative subjects at high-risk of infection were homozygous and seven (20%) were heterozygous for the CKR-5 deletion. This was not significantly different from the distribution in normal donors. Twenty-two (22%) of the 99 HIV-seropositive subjects were heterozygous and none was homozygous. Two subgroups of patients who had an opposite course of the HIV disease were identified. Of nine long-term non-progressors, six (66%) were heterozygous for the deletion. This frequency is significantly higher than in nine rapid progressors of whom none was heterozygous. The frequency of heterozygotes in long-term nonprogressors was also significantly higher than in the cohort as a whole. A Kaplan-Meier plot of the HIV-seropositive subjects, of whom 57 developed AIDS, showed a significantly better prognosis within the first 7 years of follow-up for those who were heterozygous for the deletion. Heterozygous individuals also had a significantly slower decrease in CD4 T-cell count per year. Conclusion:Individuals who are heterozygous for the 32-base-pair deletion in the CKR-5 gene have a slower decrease in their CD4 T-cell count and a longer AIDS-free survival than individuals with the wild-type gene for up to 11 years of follow-up.

Disseminated intravascular coagulation or acute coagulopathy of trauma shock early after trauma? An observational study

IntroductionIt is debated whether early trauma-induced coagulopathy (TIC) in severely injured patients reflects disseminated intravascular coagulation (DIC) with a fibrinolytic phenotype, acute coagulopathy of trauma shock (ACoTS) or yet other entities. This study investigated the prevalence of overt DIC and ACoTS in trauma patients and characterized these conditions based on their biomarker profiles.MethodsAn observational study was carried out at a single Level I Trauma Center. Eighty adult trauma patients (≥18 years) who met criteria for full trauma team activation and had an arterial cannula inserted were included. Blood was sampled a median of 68 minutes (IQR 48 to 88) post-injury. Data on demography, biochemistry, injury severity score (ISS) and mortality were recorded. Plasma/serum was analyzed for biomarkers reflecting tissue/endothelial cell/glycocalyx damage (histone-complexed DNA fragments, Annexin V, thrombomodulin, syndecan-1), coagulation activation/inhibition (prothrombinfragment 1+2, thrombin/antithrombin-complexes, antithrombin, protein C, activated protein C, endothelial protein C receptor, protein S, tissue factor pathway inhibitor, vWF), factor consumption (fibrinogen, FXIII), fibrinolysis (D-dimer, tissue-type plasminogen activator, plasminogen activator inhibitor-1) and inflammation (interleukin (IL)-6, terminal complement complex (sC5b-9)). Comparison of patients stratified according to the presence or absence of overt DIC (International Society of Thrombosis and Hemostasis (ISTH) criteria) or ACoTS (activated partial thromboplastin time (APTT) and/or international normalized ratio (INR) above normal reference).ResultsNo patients had overt DIC whereas 15% had ACoTS. ACoTS patients had higher ISS, transfusion requirements and mortality (all P < 0.01) and a biomarker profile suggestive of enhanced tissue, endothelial cell and glycocalyx damage and consumption coagulopathy with low protein C, antithrombin, fibrinogen and FXIII levels, hyperfibrinolysis and inflammation (all P < 0.05). Importantly, in non-ACoTS patients, apart from APTT/INR, higher ISS correlated with biomarkers of enhanced tissue, endothelial cell and glycocalyx damage, protein C activation, coagulation factor consumption, hyperfibrinolysis and inflammation, that is, resembling that observed in patients with ACoTS.ConclusionsACoTS and non-ACoTS may represent a continuum of coagulopathy reflecting a progressive early evolutionarily adapted hemostatic response to the trauma hit and both are parts of TIC whereas DIC does not appear to be part of this early response.

Rapid sequence induction and intubation with rocuronium–sugammadex compared with succinylcholine: a randomized trial

BACKGROUND An unanticipated difficult airway may arise during rapid sequence induction and intubation (RSII). The aim of the trial was to assess how rapidly spontaneous ventilation could be re-established after RSII. We hypothesized that the time period from tracheal intubation to spontaneous ventilation would be shorter with rocuronium-sugammadex than with succinylcholine. METHODS This randomized and patient- and observer-blinded trial was approved by the regional Ethics Committee and the Danish Medicines Agency. We included elective surgical patients undergoing general anaesthesia for RSII using alfentanil (10 µg kg(-1)), propofol (2 mg kg(-1)), and either succinylcholine (1 mg kg(-1)) or rocuronium (1 mg kg(-1)). Sugammadex (16 mg kg(-1)) was given in the rocuronium group after tracheal intubation. The primary endpoint was the time from correct placement of the tracheal tube to spontaneous ventilation, defined as a respiratory rate of more than 8 bpm and a tidal volume of at least 3 ml kg(-1) for 30 s. RESULTS We included 61 patients; of whom, 55 were evaluated for the primary endpoint. The median time from tracheal intubation to spontaneous ventilation was 406 s with succinylcholine and 216 s with rocuronium-sugammadex (P = 0.002). The median time from tracheal intubation to 90% recovery of the first twitch in train-of-four (T(1) 90%) was 518 s with succinylcholine and 168 s with rocuronium-sugammadex (P < 0.0001). Intubation conditions and time to tracheal intubation were not significantly different. CONCLUSIONS RSII with rocuronium followed by reversal with sugammadex allowed earlier re-establishment of spontaneous ventilation than with succinylcholine.

Low hemorrhage‐related mortality in trauma patients in a Level I trauma center employing transfusion packages and early thromboelastography‐directed hemostatic resuscitation with plasma and platelets

Hemorrhage accounts for most preventable trauma deaths, but still the optimal strategy for hemostatic resuscitation remains debated.

Thrombelastography and biomarker profiles in acute coagulopathy of trauma: a prospective study

BackgroundSevere injury induces an acute coagulopathy associated with increased mortality. This study compared the Thrombelastography (TEG) and biomarker profiles upon admission in trauma patients.MethodsProspective observational study of 80 trauma patients admitted to a Level I Trauma Centre. Data on demography, biochemistry including standard coagulation tests, hematology, transfusions, Injury Severity Score (ISS) and TEG were recorded. Retrospective analysis of thawed plasma/serum for biomarkers reflecting tissue injury (histone-complexed DNA fragments), sympathoadrenal activation (adrenaline, noradrenaline), coagulation activation/inhibition and fibrinolysis (sCD40L, protein C, activated Protein C, tissue-type plasminogen activator, plasminogen activator inhibitor-1, D-dimer, prothrombinfragment 1+2, plasmin/α2-antiplasmin complex, thrombin/antithrombin complex, tissue factor pathway inhibitor, antithrombin, von willebrand factor, factor XIII). Comparison of patients stratified according to ISS/TEG maximum clot strength. Linear regression analysis of variables associated with clot strength.ResultsTrauma patients had normal (86%), hypercoagulable (11%) or hypocoagulable (1%) TEG clot strength; one had primary hyperfibrinolysis. Hypercoagulable patients had higher age, fibrinogen and platelet count (all p < 0.05), none had increased activated partial thromboplastin time (APTT) or international normalized ratio (INR) and none required massive transfusion (> 10 red blood cells the initial 24 h). Patients with normal or hypercoagulable TEG clot strength had comparable biomarker profiles, but the few patients with hypocoagulable TEG clot strength and/or hyperfibrinolysis had very different biomarker profiles.Increasing ISS was associated with higher levels of catecholamines, histone-complexed DNA fragments, sCD40L, activated protein C and D-dimer and reduced levels of non-activated protein C, antithrombin, fibrinogen and factor XIII (all p < 0.05). Fibrinogen and platelet count were associated independently with clot strength in patients with ISS ≤ 26 whereas only fibrinogen was associated independently with clot strength in patients with ISS > 26. In patients with ISS > 26, adrenaline and sCD40L were independently negatively associated with clot strength.ConclusionsTrauma patients displayed different coagulopathies by TEG and variables independently associated with clot strength changed with ISS. In the highest ISS group, adrenaline and sCD40L were independently negatively associated with clot strength indicating that these may contribute to acute coagulopathy.

Should Dosing of Rocuronium in Obese Patients Be Based on Ideal or Corrected Body Weight

BACKGROUND:Pharmacokinetic studies in obese patients suggest that dosing of rocuronium should be based on ideal body weight (IBW). This may, however, result in a prolonged onset time or compromised conditions for tracheal intubation. In this study, we compared onset time, conditions for tracheal intubation, and duration of action in obese patients when the intubation dose of rocuronium was based on three different weight corrections. METHODS:Fifty-one obese patients, with a median (range) body mass index of 44 (34–72) kg/m2, scheduled for laparoscopic gastric banding or gastric bypass under propofol-remifentanil anesthesia were randomized into three groups. The patients received rocuronium (0.6 mg/kg) based on IBW (IBW group, n = 17), IBW plus 20% of excess weight (corrected body weight [CBW]20% group, n = 17), or IBW plus 40% of excess weight (CBW40% group, n = 17). Propofol was administered as a bolus of 200 mg and an infusion at 5 mg · kg−1 · h−1 and remifentanil was administered at 1.0 &mgr;g · kg−1 · min−1, both according to CBW40%. Neuromuscular function was monitored with train-of-four nerve stimulation and acceleromyography. The primary end point was duration of action, defined as time to reappearance of the fourth twitch in train-of-four. RESULTS:The median (range) duration of action was 32 (18–49), 38 (25–66), and 42 (24–66) min in the IBW, CBW20%, and CBW40% groups, respectively (P = 0.001 for comparison of the IBW and CBW40% group). There were no significant differences in onset time (85 vs 84 vs 80 s) or in intubation conditions 90 s after administration of rocuronium. CONCLUSIONS:In obese patients undergoing gastric banding or gastric bypass, rocuronium dosed according to IBW provided a shorter duration of action without a significantly prolonged onset time or compromised conditions for tracheal intubation.

Thrombelastography and rotational thromboelastometry early amplitudes in 182 trauma patients with clinical suspicion of severe injury.

BACKGROUND Viscoelastic hemostatic assays may provide means for earlier detection of trauma-induced coagulopathy (TIC). METHODS This is a prospective observational study of 182 trauma patients admitted to a Level 1 trauma center. Clinical data, thrombelastography (TEG), and rotational thromboelastometry (ROTEM) parameters were recorded upon arrival. Citrated kaolin (CK), rapid TEG (rTEG), and functional fibrinogen curves were extracted, and early amplitudes A5 and A10 were registered. Patients were stratified according to international normalized ratio of 1.2 or less and international normalized ratio greater than 1.2 (TIC patients) as well as transfusion needs (no red blood cells [RBCs], 1–9 RBCs, and ≥10 RBC in 6 hours). Correlations were analyzed by Spearman’s correlation. RESULTS TIC patients had lower amplitudes than non-TIC patients in ROTEM/TEG as follows: EXTEM, INTEM, and FIBTEM: A5, A10, and maximum clot firmness (MCF); rTEG: A10; CK: maximum amplitude (MA); and functional fibrinogen: A5, A10, and MA (p < 0.05). Furthermore, A5 and A10 had a strong correlation with MA/MCF (&rgr; > 0.7 and p < 0.01). The A10 amplitudes were significantly lower in patients transfused with 10 or more units of RBC compared with nontransfused patients (p < 0.02). Fibrinogen concentration and platelet count had moderate correlation with A10 compared with A5 and MA/MCF (0.3 < &rgr; < 0.7 and p < 0.01). Time (median [interquartile range], in minutes) to obtain a reading was faster for A10 than MA/MCF (p < 0.001) (CK, 16 [15–17] vs. 27 [25–30]; rTEG, 11 [11–11] vs. 18 [17–20]; EXTEM, 11 [11–11] vs. 29 [26–31]; and INTEM 13[12–13] vs. 25 [22–29]). CONCLUSION Early amplitudes were lower in TIC patients, had significant correlations with MA/MCF, and differentiated between nontransfused and patients receiving one to nine RBC units or 10 or more RBC units within 6 hours. A10’s superior correlation with platelet count and fibrinogen concentration suggests that A10 reflects a more dynamic part of the hemostatic process rather than MA/MCF. Early amplitudes may translate into earlier goal-directed transfusion therapy and may allow refinement of existing transfusion algorithms. LEVEL OF EVIDENCE Prognostic and diagnostic study, level III.

HIV-infected individuals with the CCR delta32/CCR5 genotype have lower HIV RNA levels and higher CD4 cell counts in the early years of the infection than do patients with the wild type. Copenhagen AIDS Cohort Study Group.

The relations among serum HIV RNA levels, CD4 cell counts, presence of the mutant CCR5-allele in heterozygous form, and clinical outcome was analyzed in 96 patients from the Copenhagen AIDS Cohort. In the early years of the infection, patients with the CCR5 delta32/CCR5 genotype had significantly lower HIV RNA levels (p = 0.005) and higher CD4 cell counts (p < 0.005) than did patients homozygous for the normal allele. The long-term clinical benefit of being heterozygous is small and cannot solely explain the large interpatient variation in progression rates. The beneficial effect of being heterozygous seems to be mediated by events in the early stages of the HIV infection.

Trauma-Induced Coagulopathy: Standard Coagulation Tests, Biomarkers of Coagulopathy, and Endothelial Damage in Patients with Traumatic Brain Injury

It remains to be debated whether traumatic brain injury (TBI) induces a different coagulopathy than does non-TBI. This study investigated traditional coagulation tests, biomarkers of coagulopathy, and endothelial damage in trauma patients with and without TBI. Blood from 80 adult trauma patients was sampled (median of 68 min [IQR 48-88] post-injury) upon admission to our trauma center. Plasma/serum were retrospectively analyzed for biomarkers reflecting sympathoadrenal activation (adrenaline, noradrenaline), coagulation activation/inhibition and fibrinolysis (protein C, activated protein C, tissue factor pathway inhibitor, antithrombin, prothrombin fragment 1+2, thrombin/antithrombin complex, von Willebrand factor, factor XIII, d-dimer, tissue-type plasminogen activator, plasminogen activator inhibitor-1), immunology (interleukin [IL]6), endothelial cell/glycocalyx damage (soluble thrombomodulin, syndecan-1), and vasculogenesis (angiopoietin-1, -2). Patients were stratified according to: (1) isolated severe head/neck injuries (Abbreviated injury score [AIS]-head/neck ≥ 3, AIS-other<3) (isoTBI); (2) severe head/neck and extracranial injuries (AIS-head/neck ≥ 3, AIS-other>3) (sTBI+other); and (3) injuries without significant head/neck injuries (AIS-head/neck<3, including all AIS-other scores) (non-TBI). Twenty-three patients presented with isoTBI, 15 with sTBI+other and 42 with non-TBI. Acute coagulopathy of trauma shock, defined as activated partial thromboplastin time (APTT) and/or international normalized ratio (INR)>35 sec and>1.2, was found in 13%, 47%, and 5%, respectively (p=0.000). sTBI+other had significantly higher plasma levels of adrenaline, noradrenaline, annexin V, d-dimer, IL-6, syndecan-1, soluble thrombomodulin, and reduced protein C and factor XIII levels (all p<0.05). No significant biomarker differences were found between isoTBI and non-TBI patients. Injury severity scale (ISS) rather than the presence or absence of head/neck injuries determined the hemostatic and biomarker response to the injury. The coagulopathy identified thus reflected the severity of injury rather than its localization.

High sCD40L levels early after trauma are associated with enhanced shock, sympathoadrenal activation, tissue and endothelial damage, coagulopathy and mortality

Summary.  Background: Severe injury activates the sympathoadrenal, hemostatic and inflammatory systems, but a maladapted response may contribute to a poor outcome. Soluble CD40L is a platelet‐derived mediator that links inflammation, hemostasis and vascular dysfunction. Objectives: To investigate the association between the sCD40L level and tissue injury, shock, coagulopathy and mortality in trauma patients. Methods: A prospective, observational study of 80 trauma patients admitted to a Level I Trauma Center. Data on demography, biochemistry, Injury Severity Score (ISS) and 30‐day mortality were recorded and admission plasma/serum analyzed for sCD40L and biomarkers reflecting sympathoadrenal activation (adrenaline, noradrenaline), tissue/endothelial cell/glycocalyx damage (histone‐complexed DNA fragments [hcDNA], Annexin V, thrombomodulin and syndecan‐1), coagulation activation/inhibition (PF1.2, TAT‐complex, antithrombin, protein C, activated protein C, sEPCR, TFPI, von Willebrand factor [VWF], fibrinogen and factor [F] XIII), fibrinolysis (D‐dimer, tissue plasminogen activator [tPA] and plasminogen activator inhibitor‐1 [PAI‐1]) and inflammation (interleukin‐6 [IL‐6] and sC5b‐9). We compared patients stratified by median sCD40L level and investigated predictive values of sCD40L for mortality. Results: High circulating sCD40L was associated with enhanced tissue and endothelial damage (ISS, hcDNA, Annexin V, syndecan‐1 and sTM), shock (pH, standard base excess), sympathoadrenal activation (adrenaline) and coagulopathy evidenced by reduced thrombin generation (PF1.2), hyperfibrinolysis (D‐dimer), increased activated partial thromboplastin time (APTT) and inflammation (IL‐6) (all P < 0.05). A higher ISS (P = 0.017), adrenaline (P = 0.049) and platelet count (P = 0.012) and lower pH (P = 0.002) were associated with higher sCD40L by multivariate linear regression analysis. High circulating sCD40L (odds ratio [OR] 1.84 [95% CI 1.05–3.23], P = 0.034), high age (P = 0.002) and low Glasgow Coma Score (GCS) pre‐hospital (P = 0.002) were independent predictors of increased mortality. Conclusions: High early sCD40L levels in trauma patients reflect tissue injury, shock, coagulopathy and sympathoadrenal activation and predict mortality. As sCD40L has pro‐inflammatory activity and activates the endothelium, sCD40L may be involved in trauma‐induced endothelial damage and coagulopathy.