Biomechanical Comparison of Anterior Cruciate Ligament Reconstruction Using a Single-Bundle Round or Ribbon-like Hamstring Tendon Graft.

BACKGROUND: Persistent instability of the knee is reported in up to 30% of patients after anterior cruciate ligament (ACL) reconstruction. Based on anatomic findings showing that ACL is a flat ribbon-like structure that twists during knee flexion, a new surgical ACL reconstruction technique using a ribbon-like graft has been developed. However the effect of this surgical technique on knee kinematics has not yet been evaluated. PURPOSE: To compare the anteroposterior and rotational stability of the knee after ACL reconstruction using single-bundle (SB) round and ribbon-like grafts in anterolateral-intact/deficient knees. STUDY DESIGN: Controlled laboratory study. METHODS: Twelve human fresh-frozen cadaveric knees were tested with a 6 degrees of freedom robotic system. Internal rotation and anterior translation of the knee were recorded from 0° to 90° of flexion. A full kinematic assessment was performed in each of the following conditions: (1) intact knee, (2) after sectioning of the ACL, (3) after ACL reconstruction using a SB hamstring tendon graft in a round configuration and a ribbon-like configuration, and (4) after sectioning of the anterolateral structures. One-way analysis of variance and post hoc Tukey tests were used for statistical analyses. RESULTS: When compared with the intact knee, the ACL-deficient knee demonstrated a mean ± SD increase in anterior translation and internal rotation of 6.3 ± 2.5 mm (P < .01) and 5.8°± 2.3° (P < .01), respectively. After ACL reconstruction using a SB ribbon-like graft, the mean difference in anterior translation and internal rotation as compared with the intact knee was -0.1 ± 1.5 mm (P = .842) and 0.0°± 1.1° (P = .999). These differences from the intact knee were also not significant after ACL reconstruction using a round graft (-0.1 ± 1.3 mm, P = .999; -0.5°± 1.5°, P = .401). In the ACL-reconstructed knee using either a ribbon-like or round graft, sectioning of the anterolateral structures did not induce a significant increase of anterior translation and internal rotation of the knee. CONCLUSION: ACL reconstruction using a SB ribbon-like or round graft restored the kinematics of the intact knee at time zero. Secondary sectioning of the anterolateral structures in the ACL-reconstructed knee using both types of graft did not significantly affect the anterior translation and internal rotation of the knee. CLINICAL RELEVANCE: This is the first biomechanical study on the new ACL reconstruction technique using a ribbon-like graft.

Editorial Commentary: Lateral Extra-articular Procedures Concomitant to Anterior Cruciate Ligament Reconstruction Must Balance Clinical Efficacy and the Risk of Kinematic Restraint.

Lateral extra-articular procedures (LEAPs) performed concomitant to anterior cruciate ligament reconstruction improve clinical outcomes and can restore normal knee kinematics. However, some LEAPs may result in overconstraint depending on technique. When using an iliotibial band based technique, passing the graft deep to the lateral collateral ligament and fixing it on the lateral cortex (rather than in a tunnel with an interference screw) minimizes the risk of tunnel collision and may also reduce the risk of overconstraint. Although several laboratory studies report overconstraint with iliotibial band based procedures, clinical reports of overconstraint are rare. This may be due to lack of a clear definition of clinical overconstraint and resultant underdiagnosis. However, long term randomised controlled study has demonstrated significantly higher rates of osteoarthritis when a modified Lemaire is added to an anterior cruciate ligament reconstruction. There is clearly a need for further study and in the meantime clinical efficacy must be balanced with the risk of kinematic restriction.

On the durability of surgical masks after simulated handling and wear.

After the spread of COVID-19, surgical masks became highly recommended to the public. They tend to be handled and used multiple times, which may impact their performance. To evaluate this risk, surgical masks of Type IIR were submitted to four simulated treatments: folding, ageing with artificial saliva or sweat and washing cycles. The air permeability, mechanical integrity, electrostatic potential, and filtration efficiency (FE) of the masks were measured to quantify possible degradation. Overall, air permeability and mechanical integrity were not affected, except after washing, which slightly degraded the filtering layers. Electrostatic potential and FE showed a strong correlation, highlighting the role of electrostatic charges on small particle filtration. A slight decrease in FE for 100 nm particles was found, from 74.4% for the reference masks to 70.6% for the mask treated in saliva for 8 h. A strong effect was observed for washed masks, resulting in FE of 46.9% (± 9.5%), comparable to that of a control group with no electrostatic charges. A dry store and reuse strategy could thus be envisaged for the public if safety in terms of viral and bacterial charge is ensured, whereas washing strongly impacts FE and is not recommended.

Isolated Meniscotibial Ligament Rupture: The Medial Meniscus "Belt Lesion".

Ramp lesions play a major role in both anteroposterior and rotational instability following anterior cruciate ligament rupture. The meniscotibial ligament (MTL) is the most important structure to repair and is the primary stabilizer of the posterior horn of the medial meniscus. The posteroinferior insertion of the MTL on the posterior horn of the medial has been described, forming a posterior "belt." Isolated MTL lesion diagnosis can be challenging, as the absence of a meniscocapsular ligament lesion prevents its correct visualization through transnotch vision. This article details a technique to diagnose and repair the "belt lesion" of the medial meniscus.

Distribution of low quality filtering facepiece respirators during the COVID-19 pandemic: an independent analysis of the situation in Switzerland.

BACKGROUND: SARS-CoV-2 is a respiratory virus. Transmission occurs by droplets, contact and aerosols. In medical settings, filtering facepiece (FFP) respirators are recommended for use by personnel exposed to aerosol-generating procedures. During the COVID-19 pandemic, the demand for FFP respirators exceeded their supply worldwide and low-quality products appeared on the market, potentially putting healthcare workers at risk. AIMS: To raise awareness about variations in quality of imported FFP respirators in Switzerland during the COVID-19 pandemic, to draw attention to the current directives regulating the market launch of FFP respirators in Switzerland, to provide practical support in identifying suspicious products or documents and, finally, to offer strategies aimed at reducing the distribution of low-quality FFP respirators in the future. METHODS: Three Swiss laboratories, Spiez Laboratory and Unisanté in partnership with TOXpro SA individually set up testing procedures to evaluate aerosol penetration and fit testing of FFP respirators imported into Switzerland during COVID-19 pandemic. Additionally, Spiez Laboratory visually inspected the products, examined the certification documents and crosschecked the product information with international databases. RESULTS: Between 31 March and 15 June 2020, 151 FFP respirators were analysed. The initial assessment performed before testing allowed a reduction of up to 35% in the number of FFP respirators sent to Spiez Laboratory for evaluation, for which product information found to be faulty. After filtration efficiency evaluation and fit testing, 52% and 60% of all products tested by Spiez Laboratory and Unisanté-TOXpro SA, respectively, did not meet the minimum performance requirements established independently by the three Swiss laboratories. CONCLUSION: The demand for FFP respirators exceeded the supply capacity from established suppliers of the Swiss market. New production and import channels emerged, as did the number of poor-quality FFP respirators. FFP respirators remaining in stocks should be checked for conformity before being used, or eliminated and replaced if quality does not meet standards.

Anterolateral Ligament Reconstruction and Modified Lemaire Lateral Extra-Articular Tenodesis Similarly Improve Knee Stability After Anterior Cruciate Ligament Reconstruction: A Biomechanical Study.

PURPOSE: To determine the stabilizing role of anterolateral ligament reconstruction (ALLR) and modified Lemaire lateral extra-articular tenodesis (LET) performed in combination with anterior cruciate ligament reconstruction (ACLR) and to determine whether either procedure was superior to the other. METHODS: Six nonpaired, human, fresh-frozen cadaveric knees were tested with a 6-df robotic system. Internal rotation and anterior translation of the knee were recorded from 0° to 90° of flexion after application of a 5-Nm internal rotation torque and a 134-N anterior load, respectively. A full kinematic assessment was performed in each of the following conditions: (1) intact knee, (2) after sectioning of the anterior cruciate ligament (ACL), (3) after sectioning of the ACL and anterolateral ligament, (4) after isolated ACLR, and (5) after combined ACLR and Lemaire LET and combined ACLR and ALLR. ALLR was performed using the gracilis tendon, whereas the modified Lemaire procedure was performed using the central strip of the iliotibial band. The different states were compared using a Tukey paired comparison test. RESULTS: In knees with combined deficiency of the ACL and anterolateral structures, anterior translation and internal rotation remained significantly increased after isolated ACLR compared with the intact knee (+2.33 ± 1.44 mm and +1.98° ± 1.06°, respectively; P < .01). On the other hand, the addition of ALLR or modified Lemaire LET to ACLR restored anterior translation and internal rotation to values similar to those in the intact knee. The 2 anterolateral procedures did not show statistically significantly different values for both tests. This difference was 0.67 ± 1.46 mm for anterior translation (P = .79) and 0.11° ± 1.11° for internal rotation (P = .99). CONCLUSIONS: In knees with ACL and anterolateral deficiency, combined ACLR and anterolateral reconstruction restored the native knee stability in anterior translation and internal rotation contrary to isolated ACLR. In addition, both types of extra-articular reconstruction-ALLR and modified Lemaire LET-were similar in terms of restoring knee kinematics, and neither overconstrained the knee. CLINICAL RELEVANCE: In knees with deficiency of the ACL and anterolateral structures, combined ACLR and anterolateral reconstruction increased knee stability at time zero after surgery. This biomechanical improvement could be responsible for the protective effect on ACL graft and meniscal repair reported in the literature after the combined procedure.

Knee Extension Deficit in the Early Postoperative Period Predisposes to Cyclops Syndrome After Anterior Cruciate Ligament Reconstruction: A Risk Factor Analysis in 3633 Patients From the SANTI Study Group Database.

BACKGROUND: Cyclops syndrome is characterized by a symptomatic extension deficit attributed to impingement of a cyclops lesion within the intercondylar notch. The syndrome is an important cause of reoperation after anterior cruciate ligament reconstruction (ACLR). It has been suggested that remnant-preserving ACLR techniques may predispose to cyclops syndrome, but there is very limited evidence to support this. In general terms, risk factors for cyclops syndrome are not well-understood. PURPOSE: To determine the frequency of and risk factors for reoperation for cyclops syndrome in a large series of patients after ACLR. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: A retrospective analysis of prospectively collected data was performed, including all patients who underwent primary ACLR between January 2011 to December 2017. Patients undergoing major concomitant procedures were excluded. Demographic data, intraoperative findings (including the size of preserved remnants), and postoperative outcomes were recorded. Those patients who underwent reoperation for cyclops syndrome were identified, and potential risk factors were evaluated in multivariate analysis. RESULTS: A total of 3633 patients were included in the study, among whom 65 (1.8%) underwent reoperation for cyclops syndrome. Multivariate analysis demonstrated that preservation of large remnants did not predispose to cyclops lesions (odds ratio [OR], 1.11; 95% CI, 0.63-1.93). The most important risk factor was extension deficit in the early postoperative period. If present at 3 weeks postoperatively, it was associated with a >2-fold increased risk of cyclops syndrome (OR, 2.302; 95% CI, 1.268-4.239; P < .01), which was increased to 8-fold if present 6 weeks after ACLR (OR, 7.959; 95% CI, 4.442-14.405; P < .0001). None of the other potential risk factors evaluated were found to be significantly associated with an increased frequency of cyclops syndrome. CONCLUSION: Failure to regain full extension in the early postoperative period was the only significant risk factor for cyclops syndrome after ACLR in a large cohort of patients. Other previously hypothesized risk factors, such as preservation of a large anterior cruciate ligament remnant, did not predispose to the development of this debilitating postoperative complication.

Combined Anterior Cruciate Ligament Repair and Anterolateral Ligament Reconstruction.

There has been a renewed interest in anterior cruciate ligament (ACL) repairs over the last decade with some early promising results in the right patient population. Additionally, the anterolateral ligament has been extensively studied and has recently been shown to have a protective effect on standard ACL reconstructions in a clinical trial. Given its protective effect on ACL reconstructions, we believe this phenomenon is also relevant to ACL repairs and can decrease rerupture rates. In this publication, we demonstrate a surgical technique for ACL repair using an internal brace combined with an anterolateral ligament reconstruction using a gracilis autograft.

Clinical Outcomes After Combined Anterior Cruciate Ligament and Anterolateral Ligament Reconstruction.

BACKGROUND: Graft rupture rate, return to sport and persistent rotational instability remain a concern postoperatively following anterior cruciate ligament (ACL) reconstruction. The anterolateral ligament (ALL) has recently been shown to act as a lateral knee stabilizer that helps improve rotational stability. To improve functional and clinical outcomes, a combined ACL reconstruction with an associated ALL reconstruction has been proposed. PURPOSE: The main purpose of this study was to evaluate the clinical outcomes of the combined ACL and ALL reconstruction. METHODS: A literature search in PubMed was performed and papers reporting on clinical outcomes after combined ACL and ALL reconstruction were identified. The inclusion criteria was a minimum 2-year follow-up. RESULTS: Five studies were included in the review. The overall graft failure rate in patients with ACL and ALL reconstruction was <3% at 2 years minimum after surgery. Comparison analysis in a high-risk population demonstrated that the graft failure rate in combined ACL and ALL reconstruction was 2.5 times lower than with isolated bone-patella tendon-bone graft and 3.1 times lower than with isolated hamstring graft. The medial meniscal repair failure rate was also 2 times lower in the combined ACL and ALL reconstruction group compared with isolated ACL reconstruction. Return to sport and functional outcomes did not show any significant difference between the groups. The rate of reoperations was not increased in patients with combined ACL and ALL reconstruction. CONCLUSIONS: Overall, combined ACL and ALL reconstruction provides promising results that may improve graft rupture rates and meniscal repair failure rates, while maintaining excellent functional outcomes.

Combined ACL and Anterolateral Ligament Reconstruction.

BACKGROUND: Clinical results of combined anterior cruciate ligament (ACL) and anterolateral ligament (ALL) reconstruction have demonstrated a significant reduction in ACL graft rupture rates and improved rates of return to sports compared with isolated ACL reconstruction1. This finding is supported by laboratory studies that have demonstrated that combined ACL reconstruction and lateral extra-articular tenodesis procedures protect the ACL graft by load-sharing with it and by more reliably restoring normal knee kinematics compared with isolated ACL reconstruction. DESCRIPTION: The ACL graft is formed from a tripled semitendinosus tendon and a single strand of gracilis tendon. The femoral tunnel is drilled to provide an anatomic location intra-articularly and to exit the femur just posterior and proximal to the lateral epicondyle. The additional length of gracilis therefore exits the femoral tunnel at the anatomic origin of the ALL and is then routed (under the iliotibial band [ITB]) through a tibial tunnel, and back to the femoral origin, to reconstruct the ALL. ALTERNATIVES: Many different types of nonanatomic lateral extra-articular tenodesis procedures have been reported. The most frequently performed were the Lemaire and MacIntosh procedures; however, these, and others, were widely abandoned after poor results were reported in the 1980s. RATIONALE: ALL reconstruction differs from other lateral extra-articular tenodesis-type procedures because the procedure is anatomically based and can be percutaneously performed. Nonanatomic procedures (typically with a strand of ITB passed under the lateral collateral ligament [LCL]) have been reported to be associated with overconstraint, early arthritis, and an increased risk of infection2-5. In contrast, ALL reconstruction has been shown to restore normal knee kinematics and to avoid overconstraint when correctly fixed in full extension and neutral rotation6. The main concern with any type of lateral extra-articular tenodesis is based on historical reports of poor outcomes2,3. However, a recent study has demonstrated that combined ACL and ALL reconstruction is associated with a reoperation rate that is comparable with the rate seen after isolated ACL reconstruction, and it has a very low rate of complications7. This makes a compelling argument for anatomic ALL and ACL reconstruction being the procedure of choice when considering an extra-articular procedure. This is further supported by the fact that, even though previous studies have demonstrated a trend toward reduced ACL graft rupture with nonanatomic lateral extra-articular tenodesis procedures, they have not shown a significant improvement in outcomes8. Combined ACL and ALL reconstruction is currently the only type of lateral extra-articular procedure that has been demonstrated to significantly reduce the risk of ACL graft rupture and improve the rate of return to sports1.

How to Rapidly Abolish Knee Extension Deficit After Injury or Surgery: A Practice-Changing Video Pearl From the Scientific Anterior Cruciate Ligament Network International (SANTI) Study Group.

Knee extension deficit is frequently observed after anterior cruciate ligament reconstruction or rupture and other acute knee injuries. Loss of terminal extension often occurs because of hamstring contracture and quadriceps inactivation rather than mechanical intra-articular pathology. Failure to regain full extension in the first few weeks after anterior cruciate ligament reconstruction is a recognized risk factor for adverse long-term outcomes, and therefore, it is important to try to address it. In this Technical Note, a simple, rapid, and effective technique to help regain full knee extension and abolish quadriceps activation failure is described.

Anterolateral Ligament Reconstruction Protects the Repaired Medial Meniscus: A Comparative Study of 383 Anterior Cruciate Ligament Reconstructions From the SANTI Study Group With a Minimum Follow-up of 2 Years.

BACKGROUND: The prevalence of osteoarthritis after successful meniscal repair is significantly less than that after failed meniscal repair. PURPOSE: To determine whether the addition of anterolateral ligament reconstruction (ALLR) confers a protective effect on medial meniscal repair performed at the time of anterior cruciate ligament reconstruction (ACLR). STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Retrospective analysis of prospectively collected data was performed to include all patients who had undergone primary ACLR with concomitant posterior horn medial meniscal repair through a posteromedial portal between January 2013 and August 2015. ACLR autograft choice was bone-patellar tendon-bone, hamstring tendons (or quadrupled hamstring tendons), or quadrupled semitendinosus tendon graft with or without ALLR. At the end of the study period, all patients were contacted to determine if they had undergone reoperation. A Kaplan-Meier survival curve was plotted, and a Cox proportional hazards regression model was used to perform multivariate analysis. RESULTS: A total of 383 patients (mean ± SD age, 27.4 ± 9.2 years) were included with a mean follow-up of 37.4 months (range, 24-54.9 months): 194 patients underwent an isolated ACLR, and 189 underwent a combined ACLR + ALLR. At final follow-up, there was no significant difference between groups in postoperative side-to-side laxity (isolated ACLR group, 0.9 ± 0.9 mm [min to max, -1 to 3]; ACLR + ALLR group, 0.8 ± 1.0 mm [min to max, -2 to 3]; P = .2120) or Lysholm score (isolated ACLR group, 93.0 [95% CI, 91.3-94.7]; ACLR + ALLR group, 93.7 [95% CI, 92.3-95.1]; P = .556). Forty-three patients (11.2%) underwent reoperation for failure of the medial meniscal repair or a new tear. The survival rates of meniscal repair at 36 months were 91.2% (95% CI, 85.4%-94.8) in the ACLR + ALLR group and 83.8% (95% CI, 77.1%-88.7%; P = .033) in the ACLR group. The probability of failure of medial meniscal repair was >2 times lower in patients with ACLR + ALLR as compared with patients with isolated ACLR (hazard ratio, 0.443; 95% CI, 0.218-0.866). No other prognosticators of meniscal repair failure were identified. CONCLUSION: Combined ACLR and ALLR is associated with a significantly lower rate of failure of medial meniscal repairs when compared with those performed at the time of isolated ACLR.

The popliteus tendon provides a safe and reliable location for all-inside meniscal repair device placement.

PURPOSE: Repairs of the posterior horn of the lateral meniscus can be technically challenging. In contrast to medial meniscus repairs, the capsule around the posterior segment attachment of the lateral meniscus is quite thin. This study evaluates the clinical results of an arthroscopic all-inside repair technique for unstable, vertical, lateral meniscus tears, using a suture repair placed directly into the popliteus tendon. METHODS: A retrospective analysis of prospectively collected data from the SANTI database was performed. All patients who had undergone combined ACL reconstruction with lateral meniscus all-inside repair, using sutures placed in the popliteus tendon, between 2011 and 2015, were included. Patients were reviewed clinically at 1 and 2 years' follow-up. At final follow-up, all patients were contacted to identify if they underwent further surgery or had knee pain, locking or effusion. Symptomatic patients were recalled for clinical evaluation by a physician and Magnetic Resonance Imaging of the knee. Operative notes for those undergoing further surgery were reviewed and rates and type of re-operation, including for failed lateral meniscal repair were recorded. RESULTS: Two hundred patients (mean age 28.6 ± 10.2 years) with a mean follow-up of 45.5 ± 12.8 months (range 24.7-75.2) were included. The mean Subjective International Knee Documentation Committee (IKDC) at final follow-up was 85.0 ± 11.3. The post-operative mean side-to-side laxity measured at 1 year was 0.6 ± 1.0 mm. Twenty-six patients underwent re-operation (13%) at a mean follow-up of 14.8 ± 7.8 months. The ACL graft rupture rate was 5.0%. Other causes for re-operation included medial meniscus tear (2.5%), cyclops lesion (1.5%) and septic arthritis (0.5%). The lateral meniscus repair failure rate was 3.5%. No specific complications relating to placement of sutures in the popliteus tendon were identified. CONCLUSION: Arthroscopic all-inside repair of unstable, vertical, lateral meniscus tears using a suture placed in the popliteus tendon is a safe technique. It is associated with a very low failure rate with no specific complications. LEVEL OF EVIDENCE: Level IV.

Knee Implant Loosening Detection: A Vibration Analysis Investigation.

Knee implant loosening is mainly caused by the weakness of the prosthesis-bone interface and is the main reason for surgical revisions. However, pre-operative diagnosis is difficult due to lack of accurate tests. In this study, we developed a vibration-based system to detect the loosening of the tibial implant of an instrumented knee prosthesis. The proposed system includes an instrumented vibrator for transcutaneous stimulation of the bone in a repeatable manner, and accelerometer sensors integrated into the implants to measure the propagated vibration. A coherence-based detection technique was proposed to distinguish the loosened implants from the secure ones. Fourteen ex vivo lower limbs were used, on which the knee prosthesis was implanted, and harmonic-forced vibration was applied on the tibia. The input-output coherence measure provided 92.26% accuracy, a high sensitivity (91.67%) and specificity (92.86%). This technique was benchmarked against power spectrum based analysis of the propagated vibration to the implant. In particular, loosening detection based on new peak appearance, peak shift, and peak flattening in power spectra showed inferior performance to the proposed coherence-based technique. As such, application of vibration on our instrumented knee prosthesis together with input-output coherence analysis enabled us to distinguish the secure from loose implants.

Population pharmacokinetics and Bayesian estimation of tacrolimus exposure in paediatric liver transplant recipients.

AIMS: The objectives of this study were to develop a population pharmacokinetic (PopPK) model for tacrolimus in paediatric liver transplant patients and determine optimal sampling strategies to estimate tacrolimus exposure accurately. METHODS: Twelve hour intensive pharmacokinetic profiles from 30 patients (age 0.4-18.4 years) receiving tacrolimus orally were analysed. The PopPK model explored the following covariates: weight, age, sex, type of transplant, age of liver donor, liver function tests, albumin, haematocrit, drug interactions, drug formulation and time post-transplantation. Optimal sampling strategies were developed and validated with jackknife. RESULTS: A two-compartment model with first-order absorption and elimination and lag time described the data. Weight was included on all pharmacokinetic parameters. Typical apparent clearance and central volume of distribution were 12.1 l h(-1) and 31.3 l, respectively. The PopPK approach led to the development of optimal sampling strategies, which allowed estimation of tacrolimus pharmacokinetics and area under the concentration­time curve (AUC) on the basis of practical sampling schedules (three or four sampling times within 4 h) with clinically acceptable prediction error limit. The mean bias and precision of the Bayesian vs. reference (trapezoidal) AUCs ranged from -2.8 to -1.9% and from 7.4 to 12.5%, respectively. CONCLUSIONS: The PopPK of tacrolimus and empirical Bayesian estimates represent an accurate and convenient method to predict tacrolimus AUC(0-12) in paediatric liver transplant recipients, despite high between-subject variability in pharmacokinetics and patient demographics. The developed optimal sampling strategies will allow the undertaking of prospective trials to define the tacrolimus AUC-based therapeutic window and dosing guidelines in this population.

[Ten errors to avoid while dealing with infected total joint arthroplasties]. / Dix erreurs a ne pas commettre lors de la prise en charge d'une prothèse articulaire infectée en orthopédie.

Infections after total joint arthroplasty are rare but come with severe consequences. Timely, adequate and standardized treatment beginning at the onset of symptoms will have a major impact on the handling of this dreaded complication. In absences of clear guidelines, errors are often committed, with occasionally severe consequences for the patient. In this article, the 10 most frequent errors starting with diagnostics till antibiotic and surgical treatment will be discussed.

Limited sampling strategies for monitoring tacrolimus in pediatric liver transplant recipients.

OBJECTIVE: To develop and validate limited sampling strategies (LSSs) for tacrolimus in pediatric liver transplant recipients. METHODS: Thirty-six 12-hour pharmacokinetic profiles from 28 pediatric liver transplant recipients (0.4-18.5 years) were collected. Tacrolimus concentrations were measured by immunoassay and area under the curve (AUC0-12) was determined by trapezoidal rule. LSSs consisting of 1, 2, 3, or 4 concentration-time points were developed using multiple regression analysis. Eight promising models (2 per category) were selected based on the following criteria: r2 ≥ 0.90, inclusion of trough concentration (C0), and time points within 4 hours postdose. The predictive performance of these LSSs was evaluated in an independent set of data by measuring the mean prediction error and the root mean squared prediction error. RESULTS: Five models including 2-4 time points predicted AUC0-12 with a ±15% error limit. Bias (mean prediction error) and precision (root mean squared prediction error) of LSS involving C0, C1, and C4 (AUCpredicted = 9.30 + 3.69 × C0 + 2.19 × C1 + 4.69 × C4) were -4.98% and 8.29%, respectively. Among single time point LSSs, the model using C0 had a poor correlation with AUC0-12 (r2 = 0.53), whereas the one with C4 had the highest correlation with tacrolimus exposure (r2 = 0.84). CONCLUSIONS: Trough concentration is a poor predictor of tacrolimus AUC0-12 in pediatric liver transplant recipients. However, LSSs using 2-4 concentration-time points obtained within 4 hours postdose provide a reliable and convenient method to predict tacrolimus exposure in this population. The proposed LSSs represent an important step that will allow the undertaking of prospective trials aiming to better define tacrolimus target AUC in pediatric liver transplant recipients and to determine whether AUC-guided monitoring is superior to C0-based monitoring in terms of efficacy and safety.