What Is the Patient-reported Outcome and Complication Incidence After Operative Versus Nonoperative Treatment of Minimally Displaced Tibial Plateau Fractures?

BACKGROUND: Much controversy remains about whether minimally displaced tibial plateau fractures should be treated operatively or nonoperatively. It is generally accepted that gaps and stepoffs up to 2 mm can be tolerated, but this assumption is based on older studies using plain radiographs instead of CT to assess the degree of initial fracture displacement. Knowledge regarding the relationship between the degree of fracture displacement and expected functional outcome is crucial for patient counseling and shared decision-making, specifically in terms of whether to perform surgery. QUESTIONS/PURPOSES: (1) Is operative treatment associated with improved patient-reported outcomes compared with nonoperative treatment in minimally displaced tibial plateau fractures (fractures with up to 4 mm of displacement)? (2) What is the difference in the risk of complications after operative versus nonoperative treatment in minimally displaced tibial plateau fractures? METHODS: A multicenter, cross-sectional study was performed in patients treated for tibial plateau fractures between 2003 and 2019 at six hospitals. Between January 2003 and December 2019, a total of 2241 patients were treated for tibial plateau fractures at six different trauma centers. During that time, the general indication for open reduction and internal fixation (ORIF) was intra-articular displacement of > 2 mm. Patients treated with ORIF and those treated nonoperatively were potentially eligible; 0.2% (4) were excluded because they were treated with amputation because of severe soft tissue damage, whereas 4% (89) were excluded because of coexisting conditions that complicated outcome measurement including Parkinson disease, cerebrovascular accident, or paralysis (conditions causing an inability to walk). A further 2.7% (60) were excluded because their address was unknown, and 1.4% (31) were excluded because they spoke a language other than Dutch. Based on that, 1328 patients were potentially eligible for analysis in the operative group and 729 were potentially eligible in the nonoperative group. At least 1 year after injury, all patients were approached and asked to complete the Knee injury and Osteoarthritis Outcome Scale (KOOS) questionnaire. A total of 813 operatively treated patients (response percentage: 61%) and 345 nonoperatively treated patients (response percentage: 47%) responded to the questionnaire. Patient characteristics including age, gender, BMI, smoking, and diabetes were retrieved from electronic patient records, and imaging data were shared with the initiating center. Displacement (gap and stepoff) was measured for all participating patients, and all patients with minimally displaced fractures (gap or stepoff ≤ 4 mm) were included, leaving 195 and 300 in the operative and nonoperative groups, respectively, for analysis here. Multivariate linear regression was performed to assess the association of treatment choice (nonoperative or operative) with patient-reported outcomes in minimally displaced fractures. In the multivariate analysis, we accounted for nine potential confounders (age, gender, BMI, smoking, diabetes, gap, stepoff, AO/OTA classification, and number of involved segments). In addition, differences in complications after operative and nonoperative treatment were assessed. The minimum clinically important differences for the five subscales of the KOOS are 11 for symptoms, 17 for pain, 18 for activities of daily living, 13 for sports, and 16 for quality of life. RESULTS: After controlling for potentially confounding variables such as age, gender, BMI, and AO/OTA classification, we found that operative treatment was not associated with an improvement in patient-reported outcomes. Operative treatment resulted in poorer KOOS in terms of pain (-4.7 points; p = 0.03), sports (-7.6 points; p = 0.04), and quality of life (-7.8 points; p = 0.01) compared with nonoperative treatment, but those differences were small enough that they were likely not clinically important. Patients treated operatively had more complications (4% [7 of 195] versus 0% [0 of 300]; p = 0.01) and reoperations (39% [76 of 195] versus 6% [18 of 300]; p < 0.001) than patients treated nonoperatively. After operative treatment, most reoperations (36% [70 of 195]) consisted of elective removal of osteosynthesis material. CONCLUSION: No differences in patient-reported outcomes were observed at midterm follow-up between patients treated surgically and those treated nonsurgically for tibial plateau fractures with displacement up to 4 mm. Therefore, nonoperative treatment should be the preferred treatment option in minimally displaced fractures. Patients who opt for nonoperative treatment should be told that complications are rare, and only 6% of patients might undergo surgery by midterm follow-up. Patients who opt for surgery of a minimally displaced tibial plateau fracture should be told that complications may occur in up to 4% of patients, and 39% of patients may undergo a secondary intervention (most of which are elective implant removal). LEVEL OF EVIDENCE: Level III, therapeutic study.

Functional Outcome After Nonoperative Management of Tibial Plateau Fractures in Skeletally Mature Patients: What Sizes of Gaps and Stepoffs Can be Accepted?

BACKGROUND: Gap and stepoff measurements provide information about fracture displacement and are used for clinical decision-making when choosing either operative or nonoperative management of tibial plateau fractures. However, there is no consensus about the maximum size of gaps and stepoffs on CT images and their relation to functional outcome in skeletally mature patients with tibial plateau fractures who were treated without surgery. Because this is important for patient counseling regarding treatment and prognosis, it is critical to identify the limits of gaps and stepoffs that are well tolerated. QUESTIONS/PURPOSES: (1) In patients treated nonoperatively for tibial plateau fractures, what is the association between initial fracture displacement, as measured by gaps and stepoffs at the articular surface on a CT image, and functional outcome? (2) What is the survivorship of the native joint, free from conversion to a total knee prosthesis, among patients with tibial plateau fractures who were treated without surgery? METHODS: A multicenter cross-sectional study was performed in all patients who were treated nonoperatively for a tibial plateau fracture between 2003 and 2018 in four trauma centers. All patients had a diagnostic CT scan, and a gap and/or stepoff more than 2 mm was an indication for recommending surgery. Some patients with gaps and/or stepoffs exceeding 2 mm might not have had surgery based on shared decision-making. Between 2003 and 2018, 530 patients were treated nonoperatively for tibial plateau fractures, of which 45 had died at follow-up, 30 were younger than 18 years at the time of injury, and 10 had isolated tibial eminence avulsions, leaving 445 patients for follow-up analysis. All patients were asked to complete the validated Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire consisting of five subscales: symptoms, pain, activities of daily living (ADL), function in sports and recreation, and knee-related quality of life (QOL). The score for each subscale ranged from 0 to 100, with higher scores indicating better function. A total of 46% (203 of 445) of patients participated at a mean follow-up of 6 ± 3 years since injury. All knee radiographs and CT images were reassessed, fractures were classified, and gap and stepoff measurements were taken. Nonresponders did not differ much from responders in terms of age (53 ± 16 years versus 54 ± 20 years; p = 0.89), gender (70% [142 of 203] women versus 59% [142 of 242] women; p = 0.01), fracture classifications (Schatzker types and three-column concept), gaps (2.1 ± 1.3 mm versus 1.7 ± 1.6 mm; p = 0.02), and stepoffs (2.1 ± 2.2 mm versus 1.9 ± 1.7 mm; p = 0.13). In our study population, the mean gap was 2.1 ± 1.3 mm and stepoff was 2.1 ± 2.2 mm. The participating patients divided into groups with increasing fracture displacement based on gap and/or stepoff (< 2 mm, 2 to 4 mm, or > 4 mm), as measured on CT images. ANOVA was used to assess whether an increase in the initial fracture displacement was associated with poorer functional outcome. We estimated the survivorship of the knee free from conversion to total knee prosthesis at a mean follow-up of 5 years using a Kaplan-Meier survivorship estimator. RESULTS: KOOS scores in patients with a less than 2 mm, 2 to 4 mm, or greater than 4 mm gap did not differ (symptoms: 83 versus 83 versus 82; p = 0.98, pain: 85 versus 83 versus 86; p = 0.69, ADL: 87 versus 84 versus 89; p = 0.44, sport: 65 versus 64 versus 66; p = 0.95, QOL: 70 versus 71 versus 74; p = 0.85). The KOOS scores in patients with a less than 2 mm, 2 to 4 mm, or greater than 4 mm stepoff did not differ (symptoms: 84 versus 83 versus 77; p = 0.32, pain: 85 versus 85 versus 81; p = 0.66, ADL: 86 versus 87 versus 82; p = 0.54, sport: 65 versus 68 versus 56; p = 0.43, QOL: 71 versus 73 versus 61; p = 0.19). Survivorship of the knee free from conversion to total knee prosthesis at mean follow-up of 5 years was 97% (95% CI 94% to 99%). CONCLUSION: Patients with minimally displaced tibial plateau fractures who opt for nonoperative fracture treatment should be told that fracture gaps or stepoffs up to 4 mm, as measured on CT images, could result in good functional outcome. Therefore, the arbitrary 2-mm limit of gaps and stepoffs for tibial plateau fractures could be revisited. The survivorship of the native knee free from conversion to a total knee prosthesis was high. Large prospective cohort studies with high response rates are needed to learn more about the relationship between the degree of fracture displacement and functional recovery after tibial plateau fractures. LEVEL OF EVIDENCE: Level III, prognostic study.

3D assessment of initial fracture displacement of tibial plateau fractures is predictive for risk on conversion to total knee arthroplasty at long-term follow-up.

PURPOSE: Currently used classification systems and measurement methods are insufficient to assess fracture displacement. In this study, a novel 3D measure for fracture displacement is introduced and associated with risk on conversion to total knee arthroplasty (TKA). METHODS: A multicenter cross-sectional study was performed including 997 patients treated for a tibial plateau fracture between 2003 and 2018. All patients were contacted for follow-up and 534 (54%) responded. For all patients, the 3D gap area was determined in order to quantify the degree of initial fracture displacement. A cut-off value was determined using ROC curves. Multivariate analysis was performed to assess the association of 3D gap area with conversion to TKA. Subgroups with increasing levels of 3D gap area were identified, and Kaplan-Meier survival curves were plotted to assess survivorship of the knee free from conversion to TKA. RESULTS: A total of 58 (11%) patients underwent conversation to TKA. An initial 3D gap area ≥ 550 mm2 was independently associated with conversion to TKA (HR 8.4; p = 0.001). Four prognostic groups with different ranges of the 3D gap area were identified: excellent (0-150 mm2), good (151-550 mm2), moderate (551-1000 mm2), and poor (> 1000 mm2). Native knee survival at 10-years follow-up was 96%, 95%, 76%, and 59%, respectively, in the excellent, good, moderate, and poor group. CONCLUSION: A novel 3D measurement method was developed to quantify initial fracture displacement of tibial plateau fractures. 3D fracture assessment adds to current classification methods, identifies patients at risk for conversion to TKA at follow-up, and could be used for patient counselling about prognosis. LEVEL OF EVIDENCE: Prognostic Level III.

Initial and Residual 3D Fracture Displacement Is Predictive for Patient-Reported Functional Outcome at Mid-Term Follow-Up in Surgically Treated Tibial Plateau Fractures.

BACKGROUND: Conventional measures of fracture displacement have low interobserver reliability. This study introduced a novel 3D method to measure tibial plateau fracture displacement and its impact on functional outcome. METHODS: A multicentre study was conducted on patients who had tibial plateau fracture surgery between 2003 and 2018. Eligible patients had a preoperative CT scan (slice thickness ≤ 1 mm) and received a Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire. A total of 362 patients responded (57%), and assessment of initial and residual fracture displacement was performed via measurement using the 3D gap area (mm2). Patients were divided into four groups based on the 3D gap area size. Differences in functional outcome between these groups were assessed using analysis of variance (ANOVA). Multiple linear regression was used to determine the association between fracture displacement and patient-reported outcome. RESULTS: Functional outcome appeared significantly worse when initial or residual fracture displacement increased. Multivariate linear regression showed that initial 3D gap area (per 100 mm2) was significantly negatively associated with all KOOS subscales: symptoms (-0.9, p < 0.001), pain (-0.0, p < 0.001), ADL (-0.8, p = 0.002), sport (-1.4, p < 0.001), and QoL (-1.1, p < 0.001). In addition, residual gap area was significantly negatively associated with the subscales symptoms (-2.2, p = 0.011), ADL (-2.2, p = 0.014), sport (-2.6, p = 0.033), and QoL (-2.4, p = 0.023). CONCLUSION: A novel 3D measurement method was applied to quantify initial and residual displacement. This is the first study which can reliably classify the degree of displacement and indicates that increasing displacement results in poorer patient-reported functional outcomes.

Radiographic Predictors of Conversion to Total Knee Arthroplasty After Tibial Plateau Fracture Surgery: Results in a Large Multicenter Cohort.

BACKGROUND: Radiographic measurements of initial displacement of tibial plateau fractures and of postoperative reduction are used to determine treatment strategy and prognosis. We assessed the association between radiographic measurements and the risk of conversion to total knee arthroplasty (TKA) at the time of follow-up. METHODS: A total of 862 patients surgically treated for tibial plateau fractures between 2003 and 2018 were eligible for this multicenter cross-sectional study. Patients were approached for follow-up, and 477 (55%) responded. The initial gap and step-off were measured on the preoperative computed tomography (CT) scans of the responders. Condylar widening, residual incongruity, and coronal and sagittal alignment were measured on postoperative radiographs. Critical cutoff values for gap and step-off were determined using receiver operating characteristic curves. Postoperative reduction measurements were categorized as adequate or inadequate on the basis of cutoff values in international guidelines. Multivariable analysis was performed to assess the association between each radiographic measurement and conversion to TKA. RESULTS: Sixty-seven (14%) of the patients had conversion to TKA after a mean follow-up of 6.5 ± 4.1 years. Assessment of the preoperative CT scans revealed that a gap of >8.5 mm (hazard ratio [HR] = 2.6, p < 0.001) and step-off of >6.0 mm (HR = 3.0, p < 0.001) were independently associated with conversion to TKA. Assessment of the postoperative radiographs demonstrated that residual incongruity of 2 to 4 mm was not associated with increased risk of TKA compared with adequate fracture reduction of <2 mm (HR = 0.6, p = 0.176). Articular incongruity of >4 mm resulted in increased risk of TKA. Coronal (HR = 1.6, p = 0.05) and sagittal malalignment (HR = 3.7 p < 0.001) of the tibia were strongly associated with conversion to TKA. CONCLUSIONS: Substantial preoperative fracture displacement was a strong predictor of conversion to TKA. Postoperative gaps or step-offs of >4 mm as well as inadequate alignment of the tibia were strongly associated with an increased risk of TKA. LEVEL OF EVIDENCE: Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.

Role of the human erythrocyte in generation and storage of asymmetric dimethylarginine.

Proteolytic activity in whole blood may lead to release of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA). We investigated the role of the human erythrocyte in storage and generation of ADMA in healthy controls (n = 36) and critically ill patients (n = 38). Both free and total (sum of free and protein-incorporated) ADMA were measured. Upon incubation of intact erythrocytes with extracellular ADMA (0 to 40 µmol/l), equilibrium between intra- and extracellular ADMA was reached within 3 h. Compared with controls, patients had significantly higher basal concentrations of ADMA in plasma (0.88 ± 0.75 vs. 0.41 ± 0.07 µmol/l) and erythrocytes (1.28 ± 0.55 vs. 0.57 ± 0.14 µmol/l). Intracellular and plasma ADMA were significantly correlated in the patient group only (r = 0.834). Upon lysis, followed by incubation at 37°C for 2 h, free ADMA increased sevenfold (to 8.60 ± 3.61 µmol/l in patients and 3.90 ± 0.78 µmol/l in controls). In lysates of controls, free ADMA increased further to 9.85 ± 1.35 µmol/l after 18 h. Total ADMA was 15.43 ± 2.44 µmol/l and did not change during incubation. The increase of free ADMA during incubation corresponded to substantial release of ADMA from the erythrocytic protein-incorporated pool (21.9 ± 4.6% at 2 h and 60.8 ± 7.6% at 18 h). ADMA was released from proteins other than hemoglobin, which only occurred after complete lysis and was blocked by combined inhibition of proteasomal and protease activity. Neither intact nor lysed erythrocytes mediated degradation of free ADMA. We conclude that intact erythrocytes play an important role in storage of ADMA, whereas upon erythrocyte lysis large amounts of free ADMA are generated by proteolysis of methylated proteins, which may affect plasma levels in hemolysis-associated diseases.

Positive predictive value of ultrasound in correctly identifying an inguinal hernia: a single-centered retrospective pilot study.

OBJECTIVES: To determine the clinical utility of preoperative ultrasound imaging for predicting an inguinal hernia in need of surgery. In addition, we aimed to identify factors associated with false positive (FP) ultrasound examinations. METHODS: In this retrospective pilot study, we included all 175 patients who underwent inguinal hernia surgery in our hospital in 2019 and of whom a positive preoperative ultrasound examination of the groin area was available. The positive predictive value (PPV) of the ultrasound examination was determined using inguinal hernia detected during surgery (yes/no) as golden standard. To identify possible predictive factors, we compared the characteristics of patients with a FP ultrasound with patients with a true positive (TP) ultrasound. RESULTS: PPV of ultrasound examinations to identify an inguinal hernia in need of surgery correctly was 90.9% (159/175). The patients with a FP ultrasound examination had a significantly higher body mass index (BMI) than the patients with a TP ultrasound examination (27.6 ± 4.2 vs 25.8 ± 2.3, p = 0.043). CONCLUSIONS: With a false positive percentage of 9.1%, there is still room for improvement of preoperative diagnostic imaging. Studies with larger cohorts are necessary to establish prediction models that have the potential to reduce FP ultrasound results.

Are Sarcopenia and Myosteatosis in Elderly Patients with Pelvic Ring Injury Related to Mortality, Physical Functioning and Quality of Life?

The purpose of this study was to evaluate the prevalence of sarcopenia and/or myosteatosis in elderly patients with pelvic ring injuries and their influence on mortality, patient-perceived physical functioning and quality of life (QoL). A multicenter retrospective cohort study was conducted including elderly patients aged ≥ 65 treated for a pelvic ring injury. Cross-sectional computed tomography (CT) muscle measurements were obtained to determine the presence of sarcopenia and/or myosteatosis. Kaplan-Meier analysis was used for survival analysis, and Cox proportional hazards regression analysis was used to determine risk factors for mortality. Patient-reported outcome measures for physical functioning (SMFA) and QoL (EQ-5D) were used. Multivariable linear regression analyses were used to determine the effect of sarcopenia and myosteatosis on patient-perceived physical functioning and QoL. Data to determine sarcopenia and myosteatosis were available for 199 patients, with a mean follow-up of 2.4 ± 2.2 years: 66 patients (33%) were diagnosed with sarcopenia and 65 (32%) with myosteatosis, while 30 of them (15%) had both. Mortality rates in patients at 1 and 3 years without sarcopenia and myosteatosis were 13% and 21%, compared to 11% and 36% in patients with sarcopenia, 17% and 31% in patients with myosteatosis and 27% and 43% in patients with both. Higher age at the time of injury and a higher Charlson Comorbidity Index (CCI) were independent risk factors for mortality. Patient-reported mental and emotional problems were significantly increased in patients with sarcopenia.

Effects of preoperative flavonoid supplementation on different organ functions in rats.

BACKGROUND: Previously it has been reported that preoperative feeding preserves heart function in rats after intestinal ischemia-reperfusion. To further improve postoperative organ function, bioactive nutrition compounds were selected in vitro against the xanthine oxidase radical cascade, an enzyme suggested to play a key role in the induction of single- or multiple-organ dysfunction. METHODS: Flavonoids were selected in vitro for their capacity to (1) inhibit xanthine oxidase, (2) scavenge superoxide, and (3) scavenge peroxylradicals. The most bioactive flavonoids were added to the preoperative nutrition to study their effect on postintestinal ischemia-reperfusion organ function. RESULTS: A combination of flavonoids selected on basis of effective flavonoid xanthine oxidase inhibition and superoxide scavenging resulted in increased superoxide scavenging. In vivo, the selected flavonoid mixture significantly lowered postischemic intestinal apoptosis and intestinal oxidative stress indicated by malondialdehyde concentration when compared with ischemia-reperfusion fasted and sham-fasted animals. Moreover, this flavonoid mixture significantly lowered plasma creatinine and urea concentration, both indicating a better postoperative kidney function. Furthermore, oxidative stress measured as this flavonoid mixture when compared with control significantly lowered plasma malondialdehyde concentration in fed rats. CONCLUSIONS: Coadministration of bioactive flavonoid mixture to preoperative nutrition, in contrast to fasting, attenuates ischemia-reperfusion injury by preserving kidney function in the rat and decreasing apoptosis in the intestine.

Preoperative feeding preserves heart function and decreases oxidative injury in rats.

OBJECTIVE: The nutritional status of a patient has been implicated as an important factor in the development of postoperative complications. Fasting before an operation may have detrimental effects on the metabolic state. We hypothesized that there was a positive correlation between preoperative nutritional status and postoperative organ function. METHODS: Preoperative feeding was compared with fasting with respect to effects on organ function and biochemical parameters in an animal model of extensive large abdominal surgery. Male Wistar rats were fed ad libitum or fasted for 16 h, after which the arteria mesenterica superior was clamped for 60 min followed by 180 min of reperfusion. RESULTS: After the ischemic period, heart function was significantly better in animals that were fed ad libitum than in fasted animals. Moreover, after intestinal ischemia and reperfusion, fed rats showed significantly higher levels of intestinal adenosine triphosphate and a significantly higher malondialdehyde concentration in the intestine and lung than did fasted rats. The ratio of adenosine triphosphate to adenosine diphosphate in the liver, an indicator of energy status, in fed rats was similar to that in a sham group, whereas fasted animals showed a significantly lower value. CONCLUSIONS: Preoperative nutrition in contrast to fasting may attenuate ischemia/reperfusion-induced injury and preserve organ function in the rat.

The role of Kupffer cells after major liver surgery.

BACKGROUND: Kupffer cells (KCs) are the resident macrophages of the liver. KCs have an enormous endotoxin eliminating capacity. Endotoxins play an important role in the development of systemic complications after partial hepatectomy by activating KCs. The role of KCs and endotoxins after partial hepatectomy is investigated. METHODS: Wistar rats (n = 16, 250-275 g) were randomly assigned to have 1 mL dichloromethylene-diphosphonate (CL2MDP) or 1 mL NaCl 0.9% i.v. Forty-eight hours later, all rats received a two-thirds liver resection. Twenty-four hours later, rats received at random 50 microg/kg endotoxin (LPS) in 1 mL or 1 mL of NaCl 0.9% IV. The rats were killed 4 hours after LPS or SAL infusion. RESULTS: CL2MDP infusion resulted in a complete KC elimination. KC-depleted rats had the lowest mean arterial pressure, the highest heart and ventilatory rate after endotoxemia. All rats were able to maintain pH in normal ranges. The KC-depleted rats after partial hepatectomy had the lowest CO2 levels and the highest levels of lactate during endotoxemia. Oxygen levels were similar in all groups. Hepatic, pulmonary, and renal mRNA expression of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta were decreased in KC-depleted rats. Plasma levels of TNF-alpha were significantly decreased in KC-depleted rats. Furthermore, the highest influx of macrophages and polymorphonuclear cells in the lung and kidney were measured in KC-depleted rats during endotoxemia. CONCLUSIONS: Partial hepatectomy in KC-depleted rats result in a more pronounced endotoxin-mediated systemic inflammation and decreased synthesis of cytokines.

Accurate prediction of xanthine oxidase inhibition based on the structure of flavonoids.

The flavonoid family shows a high potential for inhibition of xanthine oxidase. Currently, more than 4,000 flavonoids are known. The data of this study indicate that a planar structure is necessary for high inhibitory activity towards xanthine oxidase. Moreover, the contribution of a hydroxyl conjugate turns out to be a constant factor when the natural logarithm of IC(50) values is taken. This finding allows us to accurately predict the IC(50) value of any given hydroxyl group added to the basic flavone structure towards xanthine oxidase. This new method may provide an important research tool for elucidating the role that flavonoids may have in radical related diseases.

Elevation of asymmetric dimethylarginine (ADMA) in patients developing hepatic failure after major hepatectomy.

BACKGROUND: Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of the arginine-nitric oxide pathway. It is conceivable that its concentration is tightly regulated by urinary excretion and degradation by the enzyme dimethylarginine dimethylaminohydrolase, which is highly expressed in the liver. In rats, we showed a high net hepatic uptake of ADMA. Therefore, we aimed to confirm the role of the liver in humans and hypothesized elevated ADMA levels after major liver resection by a reduction of functional liver mass and injury to the remnant liver. METHODS: Patients undergoing a major hepatic resection (HEP, n = 17) or major abdominal surgery (MAS, n = 12) were included and followed in time. In addition, ADMA levels were measured in 4 patients having severe hepatic failure after a liver resection. Plasma ADMA concentration was measured by high-performance liquid chromatography. RESULTS: Preoperatively and on days 1, 3, and 5, plasma levels of ADMA were higher in HEP patients when compared with MAS patients. In HEP patients with prolonged (>7 days) hepatic injury, ADMA levels were especially elevated. On the first postoperative day, ADMA significantly correlated to bilirubin concentration (r = .528, p < .05) as a marker of postoperative hepatic function. Besides, in patients with severe hepatic failure, ADMA levels were highly elevated. CONCLUSIONS: In the present study, evidence was found for the role of the liver in the elimination of ADMA in humans. Increased levels of ADMA occur in the postoperative course after a major hepatic resection, especially when liver function is severely impaired. Further studies need to assess the role of ADMA in the development of complications after liver surgery.

Low plasma concentrations of arginine and asymmetric dimethylarginine in premature infants with necrotizing enterocolitis.

Several studies have described reduced plasma concentrations of arginine, the substrate for nitric oxide synthase (NOS) in infants with necrotizing enterocolitis (NEC). No information on the plasma concentrations of the endogenous NOS inhibitor asymmetric dimethylarginine (ADMA) in patients with NEC is currently available. We investigated whether plasma concentrations of arginine, ADMA, and their ratio differ between premature infants with and without NEC, and between survivors and non-survivors within the NEC group. In a prospective case-control study, arginine and ADMA concentrations were measured in ten premature infants with NEC (median gestational age 193 d, birth weight 968 g), and ten matched control infants (median gestational age 201 d, birth weight 1102 g), who were admitted to the Neonatal Intensive Care Unit. In the premature infants with NEC, median arginine and ADMA concentrations (micromol/l), and the arginine:ADMA ratio were lower compared to the infants without NEC: 21.4 v. 55.9, P= 0.001; 0.59 v. 0.85, P=0.009 and 36.6 v. 72.3, P=0.023 respectively. In the NEC group, median arginine (micromol/l) and the arginine:ADMA ratio were lower in non-surviving infants than in surviving infants: 14.7 v. 33.8, P=0.01 and 32.0 v. 47.5, P=0.038 respectively. In premature infants with NEC not only the NOS substrate arginine, but also the endogenous NOS inhibitor ADMA and the arginine:ADMA ratio were lower than in infants without NEC. In addition, low arginine and arginine:ADMA were associated with mortality in infants with NEC. Overall, these data suggest that a diminished nitric oxide production may be involved in the pathophysiology of NEC, but this needs further investigation.

The clinical significance of asymmetric dimethylarginine.

In 1992, asymmetrical dimethylarginine (ADMA) was first described as an endogenous inhibitor of the arginine-nitric oxide (NO) pathway. From then, its role in regulating NO production has attracted increasing attention. Nowadays, ADMA is regarded as a novel cardiovascular risk factor. The role of the kidney and the liver in the metabolism of ADMA has been extensively studied and both organs have proven to play a key role in the elimination of ADMA. Although the liver removes ADMA exclusively via degradation by the enzyme dimethylarginine dimethylaminohydrolase (DDAH), the kidney uses both metabolic degradation via DDAH and urinary excretion to eliminate ADMA. Modulating activity and/or expression of DDAH is still under research and may be a potential therapeutic approach to influence ADMA plasma levels. Interestingly, next to its association with cardiovascular disease, ADMA also seems to play a role in other clinical conditions, such as critical illness, hepatic failure, and preeclampsia. To elucidate the clinical significance of ADMA in these conditions, the field of research must be enlarged.

No compensatory upregulation of placental dimethylarginine dimethylaminohydrolase activity in preeclampsia.

BACKGROUND/AIMS: Placental dysfunction of the asymmetric dimethylarginine (ADMA) degrading enzyme dimethylarginine dimethylaminohydrolase (DDAH) has been suggested as one of the initiating events in the development of preeclampsia (PE). Our primary aim was to investigate the role of the placenta in the metabolism of ADMA during normal pregnancy and PE. METHODS: We studied 27 nonpregnant healthy women (C), 15 normotensive pregnant females (P), 16 patients with PE, and 7 patients with the 'hemolysis, elevated liver enzymes and low platelets' syndrome (H). RESULTS: There were no significant differences between P and PE with respect to fetomaternal gradient of ADMA, placental DDAH activity and placental ADMA content. During the first stage of labour, mean (+/-SD) plasma ADMA (micromol/l) was higher in H (0.69 +/- 0.22; p < 0.05) compared with C (0.44 +/- 0.07), P (0.37 +/- 0.06), and PE (0.40 +/- 0.06). ADMA was significantly associated with laboratory parameters of hepatic and renal function and with clinical parameters, including systolic and diastolic blood pressure, gestational age, birth weight, and placenta weight. CONCLUSIONS: A compensatory upregulation of placental DDAH activity is absent in patients suffering from PE and levels of ADMA in plasma and placenta are normal in patients suffering from PE. However, when the course of PE deteriorates and organ dysfunction (especially liver and kidney) becomes involved, such as during the hemolysis, elevated liver enzymes and low platelets syndrome, ADMA levels increase.

The human liver clears both asymmetric and symmetric dimethylarginine.

Asymmetric (ADMA) and symmetric dimethylarginine (SDMA) inhibit production of nitric oxide. The concentration of both dimethylarginines is regulated by urinary excretion, although ADMA, but not SDMA, is also subject to degradation by dimethylarginine dimethylaminohydrolase, which is highly expressed in the liver but also present in the kidney. The exact roles of the human liver and kidney in the metabolism of dimethylarginines are currently unknown. Therefore, we aimed to investigate renal and hepatic handling of ADMA and SDMA in detail in 24 patients undergoing hepatic surgery. To calculate net organ fluxes and fractional extraction (FE) rates, blood was collected from an arterial line, the portal vein, hepatic vein, and renal vein, and blood flow of the hepatic artery, portal vein, and renal vein was determined using Doppler ultrasound techniques. Results showed a significant net uptake (median [IQR]) of ADMA in both the liver (9.6 nmol/min [5.6-13.2]) and the kidney (12.1 nmol/min [1.3-17.1]). SDMA uptake was present not only in the kidney (12.7 nmol/min [3.5-25.4]), but also in the liver (7.7 nmol/min [2.8-16.4]). FE rates of ADMA for the liver and kidney were 5.0% (3.5%-7.4%) and 8.4% (1.3%-13.9%), respectively. For SDMA, hepatic and renal FE rates were 3.4% (2.1%-7.5%) and 12.5% (3.6%-16.2%), respectively. In conclusion, this study gives a detailed description of the hepatic and renal elimination of dimethylarginines and shows that the clearing of SDMA is not only confined to the kidney, but the human liver also takes up substantial amounts of SDMA from the portal and systemic circulation.

Modulation of asymmetric dimethylarginine in critically ill patients receiving intensive insulin treatment: a possible explanation of reduced morbidity and mortality?

OBJECTIVE: Asymmetric dimethylarginine, which inhibits production of nitric oxide, has been shown to be a strong and independent predictor of mortality in critically ill patients with clinical evidence of organ dysfunction. Interestingly, intensive insulin therapy in critically ill patients improved morbidity and mortality, but the exact mechanisms by which these beneficial effects are brought about remain unknown. Therefore, we aimed to investigate whether modulation of asymmetric dimethylarginine concentrations by intensive insulin therapy is involved in these effects. DESIGN: A prospective, randomized, controlled trial. SETTING: A 56-bed predominantly surgical intensive care unit in a tertiary teaching hospital. PATIENTS: From a study of 1,548 critically ill patients who were randomized to receive either conventional or intensive insulin therapy, we included 79 patients who were admitted to the intensive care unit after complicated pulmonary and esophageal surgery and required prolonged (>/=7 days) intensive care. INTERVENTIONS: Determination of asymmetric dimethylarginine concentrations. MEASUREMENTS AND MAIN RESULTS: Asymmetric dimethylarginine concentrations were determined with high-performance liquid chromatography on the day of admission, on day 2, on day 7, and on the last day at the intensive care unit. Although the asymmetric dimethylarginine levels did not change between day 0 and day 2 in patients receiving intensive insulin treatment, there was a significant increase during this period in the conventionally treated patients (p = .043). Interestingly, the mean daily insulin dose was inversely associated with the asymmetric dimethylarginine concentration on the last day (r = -.23, p = .042), and the asymmetric dimethylarginine concentration on the last day at the intensive care unit was significantly lower in the intensive insulin treatment group (p = .048). Furthermore, asymmetric dimethylarginine was positively associated with duration of intensive care unit stay, duration of ventilatory support, duration of inotropic and vasopressor treatment, number of red cell transfusions, duration of antibiotic treatment, presence of critical illness polyneuropathy, mean Acute Physiology and Chronic Health Evaluation II score, and cumulative Therapeutic Intervention Scoring System-28 score. In addition, asymmetric dimethylarginine levels in patients who died were significantly higher compared with survivors, and changes in the course of asymmetric dimethylarginine plasma concentrations were predictive for adverse intensive care unit outcome. CONCLUSIONS: Modulation of asymmetric dimethylarginine concentration by insulin at least partly explains the beneficial effects found in critically ill patients receiving intensive insulin therapy.

Elimination of asymmetric dimethylarginine by the kidney and the liver: a link to the development of multiple organ failure?

Asymmetric dimethylarginine (ADMA) is a recently recognized endogenous inhibitor of nitric oxide production. Its role in cardiovascular disease is emerging, and ADMA appears to be an important causal factor in dysfunction of the vascular system. Several studies show that ADMA accumulates during renal failure, and ADMA has been identified as causing the cardiovascular complications accompanying renal failure. In addition to the kidney, we recently suggested an important role for the liver as an ADMA-eliminating organ. In a population of critically ill patients, hepatic failure was the most prominent determinant of ADMA concentration, and, notably, high ADMA concentration proved to be a strong and independent risk factor for intensive care unit mortality in these patients. We here summarize the role of both the kidney and the liver in the regulation of ADMA levels. In addition, the potential central role of ADMA as a causative factor in the development of multiple organ failure is discussed.