Distinguishing characteristics of pediatric patients with primary hyperoxaluria type 1 in PEDSnet.

BACKGROUND: Primary hyperoxaluria type 1 (PH1) is an autosomal recessive inborn error of metabolism that causes oxalate deposition, leading to recurrent calcium oxalate kidney stones, chronic kidney disease and systemic oxalosis, which produces a broad range of serious life-threatening complications. Patients with PH1 have delayed diagnosis due to the rarity of the disease and the overlap with early-onset kidney stone disease not due to primary hyperoxaluria. OBJECTIVE: The objective of this study was to determine the clinical features of individuals <21 years of age with PH1 that precede its diagnosis. We hypothesized that a parsimonious set of features could be identified that differentiate patients with PH1 from patients with non-primary hyperoxaluria-associated causes of early-onset kidney stone disease. STUDY DESIGN: We determined the association between clinical characteristics and PH1 diagnosis in a case-control study conducted between 2009 and 2021 in PEDSnet, a clinical research network of eight US pediatric health systems. Each patient with genetically confirmed PH1 was matched by sex and PEDSnet institution to up to 4 control patients with kidney stones without PH of any type. We obtained patient characteristics and diagnostic test results occurring before to less than 6 months after study entrance from a centralized database query and from manual chart review. Differences were examined using standardized differences and multivariable regression. RESULTS: The study sample included 37 patients with PH1 and 147 controls. Patients with PH1 were younger at diagnosis (median age of 3 vs 13.5 years); 75 % of children with PH1 were less than 8 years-old. Patients with PH1 were more likely to have combinations of nephrocalcinosis on ultrasound or CT (43 % vs 3 %), lower eGFR at diagnosis (median = 52 mL/min/1.73 m2 vs 114 mL/min/1.73 m2), and have normal mobility. Patients with PH1 had higher proportion of calcium oxalate monohydrate kidney stones than controls (median = 100 % vs 10 %). There were no differences in diagnosis of failure to thrive, stone size, or echocardiography results. CONCLUSIONS: Children with PH1 are characterized by presentation before adolescence, nephrocalcinosis, decreased eGFR at diagnosis, and calcium oxalate monohydrate stone composition. If externally validated, these characteristics could facilitate earlier diagnosis and treatment of children with PH1.

Prospective Study of the Multisite Spread of a Medication Safety Intervention: Factors Common to Hospitals With Improved Outcomes.

Context and implementation approaches can impede the spread of patient safety interventions. The objective of this article is to characterize factors associated with improved outcomes among 9 hospitals implementing a medication safety intervention. Nephrotoxic Injury Negated by Just-in-Time Action (NINJA) is a pharmacist-driven intervention that led to a sustained reduction in nephrotoxic medication-associated acute kidney injury (NTMx-AKI) at 1 hospital. Using qualitative comparative analysis, the team prospectively assessed the association between context and implementation factors and NTMx-AKI reduction during NINJA spread to 9 hospitals. Five hospitals reduced NTMx-AKI. These 5 had either (1) a pharmacist champion and >2 pharmacists working on NINJA (Scon 1.0, Scov 0.8) or (2) a nephrologist-implementing NINJA with minimal competing organizational priorities (Scon 1.0, Scov 0.2). Interviews identified ways NINJA team leaders obtained pharmacist support or successfully implemented without that support. In conclusion, these findings have implications for future spread of NINJA and suggest an approach to study spread of safety interventions more broadly.

The real world experience of pediatric primary hyperoxaluria patients in the PEDSnet clinical research network.

The rarity of primary hyperoxaluria (PH) challenges our understanding of the disease. The purpose of our study was to describe the course of clinical care in a United States cohort of PH pediatric patients, highlighting health service utilization. We performed a retrospective cohort study of PH patients < 18 years old in the PEDSnet clinical research network from 2009 to 2021. Outcomes queried included diagnostic imaging and testing related to known organ involvement of PH, surgical and medical interventions specific to PH-related renal disease, and select PH-related hospital service utilization. Outcomes were evaluated relative to cohort entrance date (CED), defined as date of first PH-related diagnostic code. Thirty-three patients were identified: 23 with PH type 1; 4 with PH type 2; 6 with PH type 3. Median age at CED was 5.0 years (IQR 1.4, 9.3 years) with the majority being non-Hispanic white (73%) males (70%). Median follow-up between CED and most recent encounter was 5.1 years (IQR 1.2, 6.8). Nephrology and Urology were the most common specialties involved in care, with low utilization of other sub-specialties (12%-36%). Most patients (82%) had diagnostic imaging used to evaluate kidney stones; 11 (33%) had studies of extra-renal involvement. Stone surgery was performed in 15 (46%) patients. Four patients (12%) required dialysis, begun in all prior to CED; four patients required renal or renal/liver transplant.    Conclusion: In this large cohort of U.S. PH children, patients required heavy health care utilization with room for improvement in involving multi-disciplinary specialists. What is Known: • Primary hyperoxaluria (PH) is rare with significant implications on patient health. Typical involvement includes the kidneys; however, extra-renal manifestations occur. • Most large population studies describe clinical manifestations and involve registries. What is New: • We report the clinical journey, particularly related to diagnostic studies, interventions, multispecialty involvement, and hospital utilization, of a large cohort of PH pediatric patients in the PEDSnet clinical research network. • There are missed opportunities, particularly in that of specialty care, that could help in the diagnosis, treatment, and even prevention of known clinical manifestations.

Atypical clinical presentation and management of urinary stone disease in non-verbal non-ambulatory children.

INTRODUCTION: Management of kidney stones primarily depends on various factors such as the presence of urinary tract obstruction, pain, stone size, location, impact on renal function, and the existence of infection. Renal colic is the classic presentation of an obstructive kidney stone. However, in this study, we present a cohort of non-verbal non-ambulatory (NVNA) patients who exhibit a distinct and uncommon presentation of kidney stones due to their medical conditions. Information about kidney stone disease in this gropup of complex pediatric patients is, scarce and their associated risk factors are not well understood. Therefore, we aim to summarize the clinical presentation, and management challenges in this unique group of NVNA patients to identify potential variables for prospective studies. METHODS: A retrospective chart review was completed for all NVNA patients seen at the pediatric multidisciplinary kidney stone clinic between July 2020 to August 2022. Demographic variables, clinical presentation data, metabolic evaluation, radiological imaging, and surgical management was included for analysis. RESULTS: A total of 224 pediatric patients were referred to the multidisciplinary stone clinic. Of those, 27 were identified to be NVNA. The most common primary diagnosis was Cerebral Palsy followed by Lennox-Gastaut syndrome. Average age at first kidney stone presentation was 11.5 years ± 5.7 years. An obstructing stone was diagnosed in 18 (66%) patients, 4 (22.2%) of these presented with sepsis. Average stone burden was 9.2 mm ( ± 5.8 mm). Of the obstructing stones, 13 (72%) were in the kidney. All patients with an obstructing stone underwent surgical management with retrograde endoscopic approach. Metabolic 24-h-urine analysis was completed in 24 (89%) patients. 17 (62%) had an elevated urine density, 15 (55%) demonstrated calcium oxalate supersaturation, 12 (44%) met criteria for acidosis, and 7 (26%) had significant hypocitraturia. DISCUSSION: NVNA patients represent a unique cohort whose clinical presentation is atypical. Limited ability to express symptoms makes early detection difficult to recognize. Twenty two percent of patients present with sepsis as their first manifestation of an acutely obstructing kidney stone. Pain is subjectively interpreted by caregivers and is an uncommon symptom. Our cohort demonstrates common risk factors for stones including propensity for chronic dehydration, slow urinary tract transit, ineffective bladder emptying, G-tube feeding, and lithogenic medications. CONCLUSION: NVNA pediatric patients have atypical kidney stone clinical presentation. Awareness of this unique group of patients should support future collaborative studies to focus on understanding these atypical presentations and reflect on improving management.

Diagnostic Code-Based Screening for Identifying Children with Primary Hyperoxaluria.

PURPOSE: We evaluated the utility of diagnostic codes to screen for patients with primary hyperoxaluria (PH) and evaluate their positive predictive value (PPV) in identifying children with this rare condition in PEDSnet, a clinical research network of pediatric health systems that shares electronic health records data. MATERIALS AND METHODS: We conducted a cross-sectional study of children who received care at 7 PEDSnet institutions from January 2009 through January 2021. We developed and applied screening criteria using diagnostic codes that generated 3 categories of the hypothesized probability of PH. Tier 1 had specific diagnostic codes for PH; tier 2 had codes for hyperoxaluria, oxalate nephropathy, or oxalosis; and tier 3 had a combination of ≥2 codes for disorder of carbohydrate metabolism and ≥1 code for kidney stones. We reviewed the electronic health records of patients with possible PH to confirm PH diagnosis and evaluate the accuracy and timing of diagnostic codes. The PPV of the codes was compared across tiers, time, PH type, and site. RESULTS: We identified 341 patients in the screen; 33 had confirmed PH (9.7%). Tier 1 had the highest proportion of PH; however, the PPV was only 20%. The degree to which an institution accurately represented point of care diagnoses in the data extraction process was predictive of higher PPV. The PPV of diagnostic codes was highest for PH3 (100%) and lowest for PH1 (22.8%). CONCLUSIONS: Diagnostic codes for PH have poor PPV. Findings suggest that one should be careful in research using large databases in which source validation is not possible.

Impact of integrated clinical decision support systems in the management of pediatric acute kidney injury: a pilot study.

BACKGROUND: Acute kidney injury (AKI) is common but not often recognized. Early recognition and management may improve patient outcomes. METHODS: This is a prospective, nonrandomized study of clinical decision support (CDS) system [combining electronic alert and standardized care pathway (SCP)] to evaluate AKI detection and progression in hospitalized children. The study was done in three phases: pre-, intervention (CDS) and post. During CDS, text-page with AKI stage and link to SCP was sent to patient's contact provider at diagnosis of AKI using creatinine. The SCP provided guidelines on AKI management [AEIOU: Assess cause of AKI, Evaluate drug doses, Intake-Output charting, Optimize volume status, Urine dipstick]. RESULTS: In all, 239 episodes of AKI in 225 patients (97 females, 43.1%) were analyzed. Proportion of patients with decrease in the stage of AKI after onset was 71.4% for CDS vs. 64.4% for pre- and 55% for post-CDS phases (p = 0.3). Documentation of AKI was higher during CDS (74.3% CDS vs. 47.5% pre- and 57.5% post-, p < 0.001). Significantly greater proportion of patients had nephrotoxic medications adjusted, or fluid plan changed during CDS. Patients from CDS phase had higher eGFR at discharge and at follow-up. CONCLUSIONS: AKI remains under-recognized. CDS (electronic alerts and SCP) improve recognition and allow early intervention. This may improve long-term outcomes, but larger studies are needed. IMPACT: Acute kidney injury can cause significant morbidity and mortality. It is under-recognized in children. Clinical decision support can be used to leverage existing data in the electronic health record to improve AKI recognition. This study demonstrates the use of a novel, electronic health record-linked, clinical decision support tool to improve the recognition of AKI and guideline-adherent clinical care.

A prospective multi-center quality improvement initiative (NINJA) indicates a reduction in nephrotoxic acute kidney injury in hospitalized children.

Nephrotoxic medication (NTMx) exposure is a common cause of acute kidney injury (AKI) in hospitalized children. The Nephrotoxic Injury Negated by Just-in time Action (NINJA) program decreased NTMx associated AKI (NTMx-AKI) by 62% at one center. To further test the program, we incorporated NINJA across nine centers with the goal of reducing NTMx exposure and, consequently, AKI rates across these centers. NINJA screens all non-critically ill hospitalized patients for high NTMx exposure (over three medications on the same day or an intravenous aminoglycoside over three consecutive days), and then recommends obtaining a daily serum creatinine level in exposed patients for the duration of, and two days after, exposure ending. Additionally, substitution of equally efficacious but less nephrotoxic medications for exposed patients starting the day of exposure was recommended when possible. The main outcome was AKI as defined by the Kidney Disease Improving Global Outcomes (KDIGO) serum creatinine criteria (increase of 50% or 0.3 mg/dl over baseline). The primary outcome measure was AKI episodes per 1000 patient-days. Improvement was defined by statistical process control methodology and confirmed by Autoregressive Integrated Moving Average (ARIMA) modeling. Eight consecutive bi-weekly measure rates in the same direction from the established baseline qualified as special cause change for special process control. We observed a significant and sustained 23.8% decrease in NTMx-AKI rates by statistical process control analysis and by ARIMA modeling; similar to those of the pilot single center. Thus, we have successfully applied the NINJA program to multiple pediatric institutions yielding decreased AKI rates.

Evidence-based development of a nephrotoxic medication list to screen for acute kidney injury risk in hospitalized children.

PURPOSE: Medications are commonly associated with acute kidney injury (AKI). However, in both clinical practice and research, consideration of specific medications as nephrotoxic varies widely. The Nephrotoxic Injury Negated by Just-in-time Action quality improvement collaborative was formed to focus on prevention or reduction of nephrotoxic medication-associated AKI in noncritically ill hospitalized children. However, there were discrepancies among institutions as to which medications should be considered nephrotoxic. The collaborative convened a Nephrotoxic Medication (NTMx) Subcommittee to develop a consensus for the classification of nephrotoxic medications. SUMMARY: The NTMx Subcommittee initially included pediatric nephrologists, a pharmacist, and a pediatric intensivist. The committee reviewed NTMx lists from the collaborative and identified changes from the initial NTMx list. The NTMx Subcommittee conducted a literature review of the disputed medications and assigned an evidence grade based on the reported association with nephrotoxicity and the quality of the data. The association between medication exposure and AKI was also determined using administrative data from the Pediatric Health Information Systems database. The NTMx Subcommittee then came to a majority consensus regarding which medications should be included on the list. The subcommittee's recommendations were presented to the larger collaborative for approval, and consensus was achieved. The list continues to be reviewed and updated annually. CONCLUSION: Formation of a multicenter quality-improvement initiative exposed current limitations as to which medications are considered nephrotoxic in clinical and research settings and presented an opportunity to approach this problem using an evidence-based process. A consensus definition of nephrotoxic-medication exposure was achieved.

Nephrotoxin-Related Acute Kidney Injury and Predicting High-Risk Medication Combinations in the Hospitalized Child.

BACKGROUND: In the hospitalized patient, nephrotoxin exposure is one potentially modifiable risk factor for acute kidney injury (AKI). Clinical decision support based on nephrotoxin ordering was developed at our hospital to assist inpatient providers with the prevention or mitigation of nephrotoxin-related AKI. The initial decision support algorithm (Algorithm 1) was modified in order to align with a national AKI collaborative (Algorithm 2). OBJECTIVE: Our first aim was to determine the impact of this alignment on the sensitivity and specificity of our nephrotoxin-related AKI detection system. Second, if the system efficacy was found to be suboptimal, we then sought to develop an improved model. DESIGN: A retrospective cohort study in hospitalized patients between December 1, 2013 and November 30, 2015 (N = 14,779) was conducted. INTERVENTIONS: With the goal of increasing nephrotoxin-related AKI detection sensitivity, a novel model based on the identification of combinations of high-risk medications was developed. RESULTS: Application of the algorithms to our nephrotoxin use and AKI data resulted in sensitivities of 46.9% (Algorithm 1) and 43.3% (Algorithm 2, P = .22) and specificities of 73.6% and 89.3%, respectively (P < .001). Our novel AKI detection model was able to deliver a sensitivity of 74% and a specificity of 70%. CONCLUSIONS: Modifications to our AKI detection system by adopting Algorithm 2, which included an expanded list of nephrotoxins and equally weighting each medication, did not improve our nephrotoxin-related AKI detection. It did improve our system's specificity. Sensitivity increased by >50% when we applied a novel algorithm based on observed data with identification of key medication combinations.

Changing outpatient referral patterns in a small pediatric nephrology practice.

BACKGROUND: We have noted a large number of referrals for abnormal kidney imaging and laboratory tests and postulated that such referrals have increased significantly over time. Understanding changes in referral patterns is helpful in tailoring education and communication between specialists and primary providers. METHODS: We performed a retrospective chart review of new patient referrals to Mary Bridge Children's Nephrology clinic for early (2002 to 2004) and late (2011 to 2013) cohorts. The overall and individual frequencies of referrals for various indications were compared. RESULTS: The overall number of new visits was similar for early (511) and late (509) cohorts. The frequency of referrals for solitary kidneys and multi-cystic dysplastic kidneys, microalbuminuria and abnormal laboratory results increased significantly (Odds Ratio (OR) and 95% Confidence Interval of OR: 1.920 [1.079, 3.390], 2.862 [1.023, 8.006], 2.006 [1.083, 3.716], respectively) over the time interval while the proportion of referrals for urinary tract infections (UTIs) and vesicoureteral reflux (VUR) decreased by half (OR: 0.472, 95% CI: 0.288, 0.633). Similarly, referrals for urinary tract dilation and hydronephrosis occurred significantly less often (8% versus 6%, OR: 0.737, 95% CI: 0.452, 1.204) with similar changes in referrals for voiding issues (OR: 0.281, 95% CI: 0.137, 0.575). However, these changes were not statistically significant. Frequencies for other indications showed little variation. CONCLUSIONS: Changes in indications for referral likely reflect evolution of practice in management of UTIs and VUR and increased use of imaging and laboratory testing by pediatric providers. These findings have relevance for ongoing education of pediatricians and support the need for collaboration between primary providers and nephrologists to assure the judicious use of resources.

Utility of ambulatory blood pressure monitoring in the evaluation of elevated clinic blood pressures in children.

Although ambulatory blood pressure monitoring (ABPM) is recognized for its role in assessing white coat hypertension, other uses include evaluation of treatment adequacy, nocturnal hypertension, dipping status, and hypertension severity. We performed a retrospective study of ABPMs completed at a single center from November 2007 to October 2011 to determine the frequency of white coat hypertension, prehypertension, and hypertension in children and the correlation of these findings with office BPs. A total of 247 ABPMs were performed in 206 children, ages 4-20 years, including 48 recordings in 39 diabetic patients and 64 recordings in treated hypertensive patients. We found a poor correlation between hypertensive status based on clinic BP and diagnosis on ABPM, and evidence for a white coat effect. Among treated patients, ABPM results resulted in medication changes in 63%. We conclude that ABPM is a useful tool for characterizing hypertensive status and treatment adequacy in children.

Utility of citrate dialysate in management of acute kidney injury in children.

Dialysis concentrate acidified with citrate as opposed to acetate has been reported to prevent clotting in hemodialysis circuits, and improve dialysis efficiency in adults. There is no information on its use in children. The purpose of the study was to evaluate the utility of citrate dialysate for renal replacement therapy in a pediatric population with acute kidney injury. We performed a retrospective review of our experience using Citrasate(®) concentrate from December 2007 to August 2009. All treatments were provided using the Fresenius 2008 dialysis machine. Citrasate(®) was utilized in 7 children aged 60.3±51.0 months (mean±SD), range 13 months to 12 years. The number of treatments varied from 4 to 31 (mean 12±8 treatments) for a total of 89 treatments. Rare sporadic mild hypocalcemia was noted but could not be definitively linked with the use of Citrasate(®). Four children also required low-dose heparin (3.6-15 U/kg/h) due to clotting. Activated clotting times (when checked) were not affected by this low-dose heparin therapy. Some degree of clotting occurred in 21 of 89 (23.5%) treatments. Early termination of treatment due to thrombosis was required in 7 of 89 (7.8%) treatments. In summary, use of Citrasate(®) dialysis concentrate was well tolerated in critically ill children with acute kidney injury. Citrasate(®) reduced but did not completely eliminate the need for heparin in our population. Further study in a more diverse population would be helpful.

Cyclin-dependent kinase inhibitors block leukocyte adhesion and migration.

Leukocyte trafficking is a tightly regulated process essential for an appropriate inflammatory response. We now report a new adhesion pathway that allows unstimulated leukocytes to adhere to and migrate through exposed endothelial matrix or high-density ligand, a process we have termed ligand-induced adhesion. This ligand-induced adhesion is integrin mediated, but in contrast to phorbol ester-stimulated adhesion, it is not dependent on the small GTPase Rap-1 activity. Instead, we show a critical role for cyclin-dependent kinase (Cdk) 4 in ligand-induced adhesion by three independent lines of evidence: inhibition by pharmacological inhibitors of Cdk, inhibition by dominant-negative construct of Cdk4, and inhibition by Cdk4 small interfering RNA. The major substrate of Cdk4, Rb, is not required for ligand-induced adhesion, suggesting the involvement of a novel Cdk4 substrate. We also demonstrate that Cdk4(-/-) mice have impaired recruitment of lymphocytes to the lung following injury. The finding that Cdk inhibitors can block leukocyte adhesion and migration may expand the clinical indications for this emerging class of therapeutics.

Recombinant activated factor VII effectively reverses the anticoagulant effects of heparin, enoxaparin, fondaparinux, argatroban, and bivalirudin ex vivo as measured using thromboelastography.

Bleeding is the major adverse reaction to anticoagulants, leading to significant morbidity and even mortality. Protamine is a specific antidote for heparin yet is only partially effective for enoxaparin, and the activated factor X inhibitor fondaparinux and the direct thrombin inhibitors argatroban and bivalirudin lack specific antidotes. We evaluated the ability of recombinant activated factor VII (rFVIIa), a general hemostatic agent, to reverse the anticoagulant effects of heparin, enoxaparin, fondaparinux, argatroban, and bivalirudin, as measured by thromboelastography. Whole-blood samples containing each test anticoagulant, with or without rFVIIa 1.5-4.5 microg/ml, were prepared ex vivo (n >or= 48, each anticoagulant) and analyzed by thromboelastography. The thromboelastography parameters of clot initiation, propagation, rigidity and elasticity were compared for the ex-vivo samples for each anticoagulant. The reversal ability of rFVIIa was also assessed using the standard clinical assay used to monitor each anticoagulant. Thromboelastography was performed on blood from eight stably anticoagulated patients, with and without exogenous rFVIIa. For each anticoagulant, rFVIIa significantly improved and, in some cases, completely normalized all thromboelastography parameters (P < 0.001). rFVIIa significantly (P < 0.01) decreased the activated partial thromboplastin time for argatroban-containing, bivalirudin-containing, or heparin-containing blood yet did not affect the anti-activated factor X levels for enoxaparin-containing or fondaparinux-containing blood. By thromboelastography, rFVIIa exerted generally similar reversal effects on the anticoagulated patient samples as on the ex-vivo samples. In conclusion, rFVIIa effectively reverses the anticoagulant effects of heparin, enoxaparin, fondaparinux, argatroban, and bivalirudin, and should be considered for patients with excessive bleeding associated with these anticoagulants.

Differential effects of direct thrombin inhibitors and antithrombin-dependent anticoagulants on the dynamics of clot formation.

New anticoagulants, including the direct thrombin inhibitors (DTIs) and fondaparinux, are increasingly replacing unfractionated heparin and enoxaparin. We examined the effects of argatroban (n = 60), bivalirudin (n = 44), heparin (n = 14), enoxaparin (n = 22), and fondaparinux (n = 24) on clot formation utilizing thromboelastography. Blood samples containing anticoagulants at clinically relevant concentrations were prepared ex vivo and analyzed using kaolin or tissue factor activation. Thromboelastography parameters of clot initiation (R), clot propagation (K and angle), clot rigidity (maximum amplitude) and clot elasticity (G) were compared between anticoagulants. Thromboelastography was also performed on blood from eight patients receiving anticoagulants. Each anticoagulant exerted significant concentration-dependent effects on R, K and angle. Only heparin, enoxaparin, and fondaparinux significantly affected maximum amplitude and G. Significant differences existed for all parameters between heparin and each anticoagulant and between fondaparinux and each DTI (P < 0.001), and for angle, maximum amplitude, and G between enoxaparin and each DTI (P < 0.008). Thromboelastography responses in ex-vivo samples and patient samples were comparable. In conclusion, whereas argatroban, bivalirudin, heparin, enoxaparin and fondaparinux each delay clot formation, the DTIs do not alter clot rigidity or elasticity. The reduced bleeding reported with DTIs versus heparin may relate to the fact that clots form with normal rigidity and elasticity.

Targeting leukocyte integrins in human diseases.

As our understanding of integrins as multifunctional adhesion and signaling molecules has grown, so has their recognition as potential therapeutic targets in human diseases. Leukocyte integrins are of particular interest in this regard, as they are key molecules in immune-mediated and inflammatory processes and are thus critically involved in diverse clinical disorders, ranging from asthma to atherosclerosis. Antagonists that interfere with integrin-dependent leukocyte trafficking and/or post-trafficking events have shown efficacy in multiple preclinical models, but these have not always predicted success in subsequent clinical trials (e.g., ischemia-reperfusion disorders and transplantation). However, recent successes of integrin antagonists in psoriasis, inflammatory bowel disease, and multiple sclerosis demonstrate the tremendous potential of antiadhesion therapy directed at leukocyte integrins. This article will review the role of the leukocyte integrins in the inflammatory process, approaches to targeting leukocyte integrins and their ligands, and the results of completed clinical trials.

Argatroban as an alternative to heparin in extracorporeal membrane oxygenation circuits.

We investigated the anticoagulant effects of argatroban, a direct thrombin inhibitor, versus heparin in extracorporeal membrane oxygenation (ECMO) circuits. Three sham circuits were prepared according to our hospital's standard practice and run for six hours simultaneously. Two circuits were anticoagulated with argatroban (one with heparin in the wet prime and one without). One circuit had heparin in the initial prime and was then anticoagulated with heparin. We measured thrombin generation (prothrombin fragment 1+2, D-dimer and thrombin-antithrombin complexes), activated clotting times (ACTs) and partial thromboplastin times (aPTTs), and monitored thrombus formation using thromboelastography. ACTs were >1000 s in each circuit throughout assessment. No clot initiation was detected by thromboelastography. Thrombin generation was decreased in circuits anticoagulated with argatroban versus heparin, despite aPTTs being less prolonged. These results suggest that argatroban may be more efficacious than heparin for anticoagulation in ECMO. Additional studies are warranted to further evaluate argatroban in this setting.