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PubMed2000

Do we know which patients with the antiphospholipid syndrome should receive long-term high dose anti-coagulation?

The standard treatment of thrombosis related to antiphospholipid antibodies is lifelong high-intensity oral anticoagulation. This standard is primarily based on retrospective evaluations of such patients. In this paper we give a summary of current treatment of deep leg vein thrombosis, pulmonary embolism, ischaemic stroke and transient ischaemic events in the general population and relate this to studies performed in patients with the anti-phospholipid syndrome (APS). It is concluded that many patients with APS can be treated with conventional doses of oral anticoagulants, and that anti-platelet drugs may have a role in the prevention of cerebral ischaemic events. Data from large scale prospective studies, which are underway, will ultimately identify the optimal treatment in individual patients.

Administration, Oral↗
PubMed1994

Perioperative morbidity of intracavitary gynecologic brachytherapy.

PURPOSE: To define the incidence and severity of perioperative morbidity and its subsequent management with standard tandem and ovoid insertions and to evaluate pretreatment and treatment factors associated with an increased risk of perioperative morbidity. METHODS AND MATERIALS: Ninety-five tandem and ovoid insertions were performed at the Fox Chase Cancer Center between 1985 and 1992 for cervical (n = 91) and endometrial (n = 4) cancer. Patients were placed on antibiotics in 19%, usually for a positive routine preoperative urine culture, but no patient was given prophylactic antibiotic therapy. Deep-vein thrombosis prophylaxis was practiced for 70% of implants and included subcutaneous heparin (40%), graduated compression elastic stockings (16%), and external pneumatic calf compression (14%). All patients were placed on prophylactic diphenoxylate hydrochloride, with doses ranging from three to eight tablets/day. RESULTS: Intraoperative complications were seen in 3% of implants and included two perforations and a vaginal laceration in two patients. Twenty-four percent of implants (16 patients) developed temperatures of > 100.5 (range 100.6 to 103), although only one patient required implant removal because of fever. Management of fever included antibiotics in 35% and acetaminophen only in 65%. Five implants (5%) were removed emergently secondary to presumed sepsis (n = 1), exacerbation of chronic obstructive pulmonary disease, hypotension, change in mental status (n = 3), and myocardial infarction/congestive heart failure (n = 1). No patient developed a deep-vein thrombosis, pulmonary embolism, gastrointestinal obstruction, or died of a postoperative complication. Univariate analysis of pretreatment and treatment factors revealed older age (p < 0.005) and spinal/epidural anesthesia (p < 0.02) to be associated with increased perioperative morbidity, and older age (p < 0.05) and higher ASA classification (p < 0.02) to be associated with severe complications requiring removal of implant. Multivariate analysis revealed only older age (p < 0.01) to be significantly related to perioperative morbidity. CONCLUSIONS: Fever of > 100.5 was seen in 24% of implants and can be managed successfully without removal of the implant in 96% of cases. Use of antibiotics preoperatively and intraoperatively did not reduce the risk of perioperative temperature elevation. Use of routine diphenoxylate hydrochloride prophylaxis was tolerated without ileus or gastrointestinal obstruction clinically. Although routine deep-vein thrombosis prophylaxis is reasonable, our data would support a low risk of deep-vein thrombosis for untreated patients. Severe perioperative morbidity necessitated premature implant removal in only 5% of cases and was related to older age in multivariate analysis.

Adult↗
PubMed1997

[Study of hemostatic molecular marker].

We examined hemostatic molecular markers in various thrombotic disorders. The efficacy of treatment in relation to the disseminated intravascular coagulation (DIC) score when the treatment was begun showed that greater efficacy was achieved in Pre-DIC than in DIC patients. The outcome was poorer with increasing DIC score, suggesting that early treatment is important. The sensitivity in some of molecular markers was high for both DIC and Pre-DIC. Receiver operating characteristic analysis suggest that soluble fibrin monomer level could be the most useful marker for the diagnosis of DIC. In examination of these markers in deep vein thrombosis, pulmonary embolism, acute myocardial infarction, and cerebral infarction, plasminogen activator inhibitor-1 and activated protein C-protein C inhibitor complex were useful marker for the diagnosis. Increased plasma GMP-140 was suggested to be the activation of platelets. The patients with high levels of plasma thrombomodulin (TM) considered to be a marker of vascular endothelial injuries became poor outcome. We will term these patients with high TM as systemic vascular endothelium injuries syndrome, and treat those by protecting the vascular endothelium.

Biomarkers↗
PubMedDate not supplied

Effect of postoperative epidural analgesia on morbidity and mortality after total hip replacement surgery in medicare patients.

BACKGROUND AND OBJECTIVES: The effect of postoperative epidural analgesia (vs. systemic analgesia) on patient outcomes is unclear. Available randomized controlled trials (RCTs) have focused on the intraoperative period and not properly examined the effect of postoperative epidural analgesia (EA) on outcomes. METHODS: A 5% nationally random sample of Medicare beneficiaries from 1994 to 1999 was analyzed to identify patients undergoing total hip arthroplasty (Common Procedural Terminology [CPT] code 27130, 27132, 27134, 27137, 27138). Patients were divided into 2 groups depending on the presence or absence of postoperative EA based on the CPT coding (01996). The rate of major morbidity (acute myocardial infarction, deep venous thrombosis, pulmonary embolism, angina, respiratory failure, heart failure, cardiac dysrhythmias, pneumonia, pulmonary edema, sepsis, acute renal failure, paralytic ileus, acute cerebrovascular event) and death at 7 and 30 days after the procedure were compared. Multivariate regression analysis was performed to determine if the presence of postoperative (EA) had an independent effect on mortality or major morbidity. Data were reported as an odds ratio with 95% confidence intervals (CI) when appropriate. RESULTS: The unadjusted 7- and 30-day death rate was significantly lower for EA versus no EA (1.9/1000 [95% CI: 0.2-3.6] vs. 3.9/1000 [95% CI: 3.0-6.2] at 7 days [P =.04] and 5.8/1000 [95% CI: 2.9-8.7] vs. 9.9/1000 [95% CI: 8.6-11.3] at 30 days [P = 0.01]). However, multivariate regression analysis revealed that there was no difference between the groups with regard to mortality or major morbidity with the exception of an increase in deep venous thrombosis in patients who received EA. CONCLUSIONS: The use of postoperative EA was not associated a lower incidence of mortality and major morbidity in Medicare patients undergoing total hip arthroplasty. However, the results should be interpreted with caution because of limitations in using the Medicare claims data for analysis. Further trials using other properly conducted and designed studies (e.g., RCTs) would be ideal to validate these results.

Aged↗
PubMed2002

Upper extremity deep venous thrombosis.

Upper extremity deep venous thrombosis (UEDVT) makes up approximately 1-4% of all episodes of deep venous thrombosis (DVT). Risk factors for UEDVT include central venous catheterization, strenuous upper extremity exercise or anatomic abnormalities causing venous compression, inherited thrombophilia, and acquired hypercoagulable states including pregnancy, oral contraceptive use, and cancer. Unexplained or recurrent UEDVT should prompt a search for inherited hypercoagulable states or underlying malignancy. Clinical presentations include arm, neck, and shoulder pain; edema; skin discoloration; tenderness; and venous distension. Because UEDVT is frequently asymptomatic until complications ensue, a high index of suspicion is required for patients with one or more risk factors for thrombosis. Pulmonary embolism and post-thrombotic syndrome are the most common sequelae of UEDVT. Early detection and treatment of UEDVT decrease complications, morbidity, and mortality. Compressive ultrasonography is an effective and economical means of confirming the clinical diagnosis in most patients. Traditional anticoagulant therapy of UEDVT is giving way to a multimodal approach involving transcatheter thrombolytic therapy followed by a minimum of 3 months of warfarin sodium anticoagulant therapy, venous decompression as needed, and balloon angioplasty with stenting for treatment of residual stricture. Low-dose anticoagulant therapy can safely and effectively mitigate the increased risk of UEDVT associated with the use of central venous catheters.

Arm↗
PubMed2004

Thromboembolic prophylaxis as a risk factor for postoperative complications after breast cancer surgery.

Hematoma and bruising (sugillation) are frequent problems after operations for primary breast cancer. In the present study we evaluated the influence of various methods of perioperative thromboembolic prophylaxis on the postoperative incidence of hematoma and suggilation. From June 1994 through August 1996, a series of 425 patients consecutively operated on for primary breast cancer were included. Thromboembolic prophylaxis was low-molecular-weight heparin (LMWH) in 310 patients and thigh-long graded compression (TED) stockings in 102 patients. Postoperative complications including deep vein thrombosis, pulmonary embolism, wound hematoma, and sugillation were recorded, and 17 variables with a potential influence on complications were analyzed by logistic regression analysis. Heparin prophylaxis compared to prophylaxis with TED stockings was significantly and independently associated with postoperative hematoma [odds ratio (OR) 3, 13; 95% confidence interval (CI) 1.38-7.13] or sugillation (OR 3.34; 95% CI 1.93-5.78). No clinically overt thromboembolic complications were diagnosed. After operations for breast cancer we found that LMWH was significantly associated with postoperative hematoma and sugillation compared to TED stockings for perioperative thromboembolic prophylaxis.

Anticoagulants↗
PubMed1983

Relationship of oral contraceptive estrogen dose to age.

The authors analyzed extracts of the computerized Medicaid records of 81,968 patients with prescription billing claims for oral contraceptives from the states of Michigan and Minnesota in 1980. It was found that women aged 35-39 years were more than twice as likely to be recipients of high dose (over 50 micrograms) estrogen oral contraceptive preparations than women aged 15-19. There was an increase in the proportion of high dose estrogen recipients among oral contraceptive recipients for each successive five-year age group from 15-19 to 35-39 years in both states. These findings were similar to those from National Disease and Therapeutic Index data for the United States for 1980, and appear to indicate changing patterns of use in the past decade. The independent contributions of age and estrogen dose or their combined effect with respect to the risk for venous thrombosis, pulmonary embolism, or related diseases has not been assessed in prior studies. To the extent that current use of oral contraceptives with higher estrogen doses contributes to the age-related trend of morbidity and mortality rates among women aged 15-44 years, an opportunity for prevention exists by altering this pattern of use.

Adolescent↗
PubMed2006

Major bleedings in the comparisons between low-molecular weight heparin versus oral anticoagulant therapy for venous thromboembolism.

To evaluate the safety (major bleedings) of long-term treatment of symptomatic venous thromboembolism (VTE) using low molecular weight heparin (LMWH) compared with oral anticoagulant therapy (OAT) given for at least 3 months, we analyzed 10 randomized clinical trials enrolling a total of 2817 patients with objectively diagnosed symptomatic deep vein thrombosis, pulmonary embolism or both. The relative risk (RR, incidence of recurrent symptomatic VTE) was combined across the studies, using the inverse variance and the Mantel-Haenszel method. During treatment, major bleeding complications occurred in 2.8% of the patients in the LMWH arm versus 4% in the OAT arm: no statistically significant difference was observed (p=0.31). No differences in major bleeding were registered in the additional 3-9 months of follow-up (p=0.98). Long-term treatment with LMWH does not seem to be significantly safer than OAT. However, no conclusive interpretation from different studies with different designs is possible.

Administration, Oral↗
PubMed1989

Antibody to phosphatidylethanolamine in a patient with lupus anticoagulant and thrombosis.

Most patients with lupus anticoagulant (LA) activity have coincident antibodies to a group of negatively charged phospholipids, and its is suggested that LA and anticardiolipin tests detect antibodies with overlapping specificities. Some discordance between the two assays has been described, however. One patient presenting with severe thrombotic disease (recurrent deep vein thrombosis, pulmonary embolism, inferior venocaval obstruction, myocardial infarction, and digital gangrene) showed strong LA activity in February 1987. An enzyme linked immunosorbent assay (ELISA) showed no binding to the negatively charged phospholipids cardiolipin, phosphatidylserine, and phosphatidic acid, but binding to zwitterionic phosphatidylethanolamine (PE) was demonstrated. Inhibition studies and affinity purification confirmed this finding. Interestingly, the serum did not bind to the kaolin cephalin clotting time reagent when used as antigen in an ELISA. The pathogenic significance of anti-PE antibodies and their relation to LA remains to be clarified. Further studies of the occurrence of anti-PE antibodies in patients with LA activity who have negative anticardiolipin tests are suggested.

Autoantibodies↗
PubMed2002

Enoxaparin vs heparin for prevention of deep-vein thrombosis in acute ischaemic stroke: a randomized, double-blind study.

OBJECTIVES: To compare the efficacy, safety, and overall risk-benefit profile of enoxaparin and unfractionated heparin (UFH) prophylaxis of venous thromboembolic complications in patients with acute ischaemic stroke. METHODS: Patients with ischaemic stroke resulting in lower-limb paralysis lasting for at least 24 h and necessitating bedrest, were randomized within 48 h of the onset of stroke, and treated with enoxaparin (40 mg subcutaneously once daily) or UFH (5000 IU subcutaneously thrice daily) for 10 +/- 2 days. Main outcome measures were deep-vein thrombosis, pulmonary embolism (PE), death from any cause, intracranial haemorrhage including haemorrhagic infarction, or any other major bleeding. RESULTS: Outcome events occurred within 3 months of stroke in 40/106 patients treated with enoxaparin (37.7%) and 52/106 patients treated with UFH (49.1%, P=0.127). Fewer patients treated with enoxaparin (14, 13.2%) than with UFH (20, 18.9%) had evidence of haemorrhagic transformation of ischaemic stroke. CONCLUSIONS: Enoxaparin administered subcutaneously once daily was as safe and effective as subcutaneous UFH given thrice daily in the prevention of thromboembolic events in patients with lower limb paralysis caused by acute ischaemic stroke.

Acute Disease↗
PubMed2001

Thrombophilia and pregnancy: review of the literature and some original data.

The association of thrombophilia with pregnancy complications has received increasing attention. It is now apparent that thrombophilia is responsible for a large number of the serious complications of pregnancy such as venous thrombosis, pulmonary embolism, fetal loss, pregnancy loss, intrauterine fetal demise, and preeclampsia. The inherited thrombophilia abnormalities, factor V Leiden mutation, prothrombin gene mutation 20210A, and antithrombin III, protein C, and protein S deficiency, and the acquired disorders, the anticardiolipin syndrome and lupus inhibitor, are responsible for a large share of the incidences of premature termination of pregnancy and many of the above complications. The normal physiology of pregnancy may be prothrombotic, with evidence for increased markers of activated coagulation and coagulation factors. There is a decrease in protein S and resistance to activated protein C occurs in a significant number of pregnancies in the absence of the factor V Leiden mutation. In the following article, we review some of the major studies that have correlated the thrombophilia and other acquired disorders that adversely impact pregnancies.

Antiphospholipid Syndrome↗
PubMed1986

Review and current status of thrombolytic therapy with streptokinase.

In 1933 Streptokinase (SK) was isolated from bacterial strains of haemolytic Streptococci. Since then it has become the widest spread drug for fibrinolysis. SK, a protein, consists of 415 aminoacids and has a molecular weight of 47,000u. Together with the plasminogen (PLG) of the blood it forms activator complexes, which then convert other PLG molecules of the blood to plasmin. Plasmin attacks and dissolves fibrin deposits. As a substance produced by bacteria SK stimulates antibody formation in the body, the titer will increase during therapy, and SK lysis should be terminated after 6 days of treatment. Usually SK is administered intravascularly to treat a wide range of diseases, associated with pathological activation of hemostasis, like deep vein thrombosis, pulmonary embolism, myocardial infarction etc.. Contraindications can be traced back to the effects of SK on coagulation and the immune system. Bleeding is the most common side effect, but also a few anaphylactic reactions, caused by massive antigen-antibody precipitation have been observed. The rate of lethality of the treatment was established at 0.7% of the cases. To reduce the incidence of side effects modifications of the drug have been proposed, such as activator complex, light B chain SK, and acylated activator therapy. Compared with Urokinase, SK shows a higher rate of side effects, especially in the field of the immune system. Therapy with Urokinase can be controlled more easily. Nevertheless because of considerable price differences and logistics, SK is preferred in Europe and the USA. If strict guidelines in therapeutic use are followed, the rate of side effects of the drug can be curtailed and will be comparable to those of Urokinase.

Humans↗
PubMed1993

Accuracy of a first-order model for estimating initial heparin dosage.

The accuracy of a first-order pharmacokinetic model for determining initial heparin infusion rates was studied, and factors that could affect the accuracy of the method were investigated. Patients who received an i.v. infusion of heparin for at least 24 hours for treatment of deep-vein thrombosis, pulmonary embolism (PE), or myocardial infarction were identified by retrospective chart review. A therapeutic dosage of heparin was defined by an activated partial thromboplastin time of 45-75 seconds. Heparin dosages were calculated by using estimated blood volume as the heparin volume of distribution, a desired steady-state heparin concentration of 0.30 units/mL, and an elimination rate constant of 0.832 hr-1. The difference between the calculated dosage and the actual therapeutic dosage was calculated. The differences for various patient subgroups were compared, and the estimated dosages were regressed against the actual dosages to determine their predictive value. Data for 49 patients were analyzed. The mean +/- S.E. difference between the actual and calculated dosages was 29.2 +/- 37.1 units/hr. No significant differences were evident according to sex or indication for therapy. Smokers and nonsmokers differed, as did obese and lean patients. The equation appeared to be more accurate in nonsmokers than smokers. The addition of 200 units/hr to the calculated dosage for patients with PE resulted in minor improvement in the predictive capacity of the equation. Moderate agreement was observed between the actual and calculated heparin dosages in non-smokers of various body weights.

Adult↗
PubMed2003

D-dimer and its relationship to fibrinogen/fibrin degradation products (FDPs) in disorders associated with activation of coagulation or fibrinolytic systems.

Levels of D-dimer and fibrinogen/fibrin degradation products (FDPs) are significantly elevated in patients with deep venous thrombosis, pulmonary embolism, disseminated intravascular coagulation, or other complications. The diagnosis of these disorders can be difficult, time-consuming, and expensive. Assays for the detection of FDPs and D-dimer are used in many laboratories to investigate these disorders. The aim of this study was to compare plasma D-dimer levels obtained by the immuno-turdimetric method (Liatest D-Dimer Diagnostica Stago, Asnières, France) with plasma FDPs were measured by latex agglutination to investigate the relationship between these parameters. These immunoassays were tested in 144 blood samples from patients with suspected disorders associated with activation of coagulation or fibrinolytic systems. D-dimer and FDPs assays were performed in plasma samples by the use of Liatest D-dimer and plasma FDPs (Diagnostica Stago), respectively. Patients were divided into four groups according to plasma D-dimer levels. In group 1, 47.4% had negative FDPs and 52.6% had positive FDPs. In group 2, 15.4% had negative FDPs and 84.6% had positive FDPs. In group 3, 10.3% had negative FDPs and 89.7% had positive FDPs. All of the patients in group 4 had positive FDPs. It was shown that plasma D-dimer levels measured by Liatest D-dimer have a relation to FDP levels measured by latex agglutination.

Biomarkers↗
PubMed2005

Melagatran and ximelagatran: new drug. No real simplification of anticoagulant therapy.

(1) The reference drug for prophylaxis against venous thromboembolism after hip or knee replacement surgery is a low-molecular-weight heparin (LMWH), given subcutaneously for 1 to 5 weeks. Vitamin K antagonists, including warfarin, have similar risk-benefit balances. (2) Subcutaneous melagatran and its oral metabolic precursor ximelagatran have recently been granted marketing authorisation in France for use as prophylaxis after hip or knee replacement surgery. Melagatran, unlike LMWH, is a specific thrombin inhibitor. (3) There are four randomised double-blind trials in more than 9000 patients comparing these agents with a LMWH (enoxaparin in three trials, dalteparin in one). Melagatran was given subcutaneously for one or two days before being replaced with ximelagatran (as soon as oral feeding was possible) for 6 to 9 days. These trials showed no advantage of melagatran-ximelagatran in terms of clinical endpoints such as symptomatic deep venous thrombosis, pulmonary embolism, and death from all causes. (4) Three randomised double-blind trials have compared ximelagatran with warfarin in more than 5000 patients. Treatment lasted 7 to 12 days. Ximelagatran was no better than warfarin when assessed using clinical endpoints. (5) In these trials melagatran-ximelagatran did not increase the risk of bleeding compared with LMWH or warfarin. (6) Melagatran-ximelagatran can cause an increase in serum transaminase activity, and is contraindicated if pretreatment serum transaminase activity is more than twice the upper limit of normal. (7) Trials versus warfarin showed a higher risk of myocardial infarction in patients taking ximelagatran (0.7% versus 0.16%). (8) There are few data on the patient subgroups most likely to receive melagatran-ximelagatran, namely patients over 75, underweight and overweight patients, and patients with renal failure. (9) There is currently no clotting test that allows the melagatran-ximelagatran dose regimen to be adjusted in patients who have an increased risk of adverse effects due to overdosing. There is no available antidote if overdose occurs. (10) Erythromycin increases melagatran bioavailability, thereby increasing the bleeding risk. Melagatran and ximelagatran must not be combined with other anticoagulants, thrombolytic agents or antiplatelet drugs because of a increased bleeding risk. (11) In practice, low-molecular-weight heparin remains the reference prophylactic treatment for venous thromboembolism after hip or knee replacement surgery.

Anticoagulants↗
PubMed1997

IgG anticardiolipin antibody titer > 40 GPL and the risk of subsequent thrombo-occlusive events and death. A prospective cohort study.

BACKGROUND: Anticardiolipin antibodies (aCL) have been associated with an increased risk of stroke and thrombo-occlusive events. Little is known about the influence of aCL on recurrent thrombo-occlusive events. METHODS: Consecutively identified patients (n = 132) with focal cerebral ischemia [stroke = 112, transient ischemic attack (TIA) = 20] harboring aCL of at least 10 GPL units at the time of their index event were prospectively followed to estimate the effect of aCL titer on time to and risk of subsequent thrombo-occlusive events (stroke, TIA, deep venous thrombosis, pulmonary embolism, myocardial infarction) and death. On the basis of prior literature, we divided patients into those with aCL < or = 40 GPL (n = 111; mean age, 63 +/- 14 years; mean follow-up, 1.95 years) and those with aCL > 40 GPL (n = 21; mean age, 54 +/- 20 years; mean follow-up, 1.50 years). RESULTS: There was no difference between groups for prevalence of hypertension, diabetes mellitus, cigarette smoking, atrial fibrillation, prior TIA, or sex. The GPL > 40 group was younger (54 +/- 20 versus 63 +/- 14 years; P = .055), had more prior strokes [9/21 (48%) versus 27/111 (20%); P = .030], more frequent subsequent thrombo-occlusive events and death [15/21 (71%) versus 51/111 (48%); P = .030], and a shorter median time (years) to event (0.15 versus 0.61, log rank P = .005). The risk ratio for recurrent event and death with GPL > 40 obtained from Cox proportional hazards models, adjusted for prior strokes, prior TIAs, hypertension, diabetes mellitus, atrial fibrillation, and cigarette smoking was 1.9 (95% confidence interval, 1.0 to 3.5; P = .051). CONCLUSIONS: Our data suggest that subsequent thrombo-occlusive events and death after focal cerebral ischemia associated with IgG aCL may occur sooner and more frequently with GPL > 40.

Adult↗
PubMed2005

Venous thromboembolism and mortality after hip fracture surgery: the ESCORTE study.

BACKGROUND: Recent changes in the management of hip fracture surgery patients may have modified the epidemiology of postoperative complications. OBJECTIVES: We performed an observational study of a cohort of patients undergoing hip fracture surgery to update the epidemiological data on this population. The primary study outcome was the incidence of confirmed symptomatic venous thromboembolism (VTE) [defined as deep vein thrombosis, pulmonary embolism (PE), or both] at 3 months. Overall mortality at 1, 3 and 6 months was also evaluated. PATIENTS/METHODS: Consecutive patients aged at least 18 years hospitalized in French public or private hospitals (531 centers) undergoing hip fracture surgery were recruited prospectively during 2 months in 2002 and a follow-up at 6 months. Predictive factors for VTE at 3 months and for death at 6 months were also analyzed. RESULTS: Data from 6860 (97.3%) of the 7019 recruited patients were included in the analysis. The median age was 82 years. Low molecular weight heparins were administered perioperatively in 97.6% of patients; 69.5% received this treatment for at least 4 weeks. The actuarial rate of confirmed symptomatic VTE at 3 months was 1.34% (85 events, 95% CI: 1.04-1.64). There were 16 PEs (actuarial rate: 0.25%), three of which were fatal. Overall, 1006 (14.7%) patients were dead at 6 months. Cardiovascular disease was the most frequent cause of death (270 patients; 26.8%). CONCLUSIONS: The current rate of postoperative VTE is low, but overall mortality remains high. Indeed, hip fracture patients belong to a vulnerable group of old people with comorbid diseases and a high risk of postoperative morbidity and mortality. An interdisciplinary approach could be the challenge to improve short and long-term outcome.

Adolescent↗