Bleeding tendency in dual antiplatelet therapy with aspirin/clopidogrel: rescue of the template bleeding time in a single-center prospective study

Background

Patients with heightened platelet reactivity in response to antiplatelet agents are at an increased risk of recurrent ischemic events. However, there is a lack of diagnostic criteria for increased response to combined aspirin/clopidogrel therapy. The challenge is to identify patients at risk of bleeding. This study sought to characterize bleeding tendency in patients treated with aspirin and clopidogrel.

Patients/methods

In a single-center prospective study, 100 patients under long-term aspirin/clopidogrel treatment, the effect of therapy was assayed by template bleeding time (BT) and the inhibition of platelet aggregation (IPA) by light transmission aggregometry (LTA). Arachidonic acid (0.625 mmol/L) and adenosine diphosphate (ADP; 2, 4, and 8 ??mol/L) were used as platelet agonists.

Results

Bleeding episodes (28 nuisance, 2 hematuria [1 severe], 1 severe proctorrhagia, 1 severe epistaxis) were significantly more frequent in patients with longer BT. Template BT ?? 24 min was associated with bleeding episodes (28 of 32). Risk of bleeding increased 17.4% for each 1 min increase in BT. Correlation was found between BT and IPAmax in response to ADP 2 ??mol/L but not to ADP 4 or 8 ??mol/L.

Conclusion

In patients treated with dual aspirin/clopidogrel therapy, nuisance and internal bleeding were significantly associated with template BT and with IPAmax in response to ADP 2 ??mol/L but not in response to ADP 4 ??mol/L or 8 ??mol/L.     

A data-driven approach to optimized medication dosing: a focus on heparin

Purpose

To demonstrate a novel method that utilizes retrospective data to develop statistically optimal dosing strategies for medications with sensitive therapeutic windows. We illustrate our approach on intravenous unfractionated heparin, a medication which typically considers only patient weight and is frequently misdosed.

Methods

We identified available clinical features which impact patient response to heparin and extracted 1,511 patients from the multi-parameter intelligent monitoring in intensive care II database which met our inclusion criteria. These were used to develop two multivariate logistic regressions, modeling sub- and supra-therapeutic activated partial thromboplastin time (aPTT) as a function of clinical features. We combined information from these models to estimate an initial heparin dose that would, on a per-patient basis, maximize the probability of a therapeutic aPTT within 4–8 h of the initial infusion. We tested our model’s ability to classifying therapeutic outcomes on a withheld dataset and compared performance to a weight-alone alternative using volume under surface (VUS) (a multiclass version of AUC).

Results

We observed statistically significant associations between sub- and supra-therapeutic aPTT, race, ICU type, gender, heparin dose, age and Sequential Organ Failure Assessment scores with mean validation AUC of 0.78 and 0.79 respectively. Our final model improved outcome classification over the weight-alone alternative, with VUS values of 0.48 vs. 0.42.

Conclusions

This work represents an important step in the secondary use of health data in developing models to optimize drug dosing. The next step would be evaluating whether this approach indeed achieves target aPTT more reliably than the current weight-based heparin dosing in a randomized controlled trial.     

Risk factors and impact of major bleeding in critically ill patients receiving heparin thromboprophylaxis

Purpose

Bleeding frequently complicates critical illness and may have serious consequences. Our objectives are to describe the predictors of major bleeding and the association between bleeding and mortality in medical–surgical critically ill patients receiving heparin thromboprophylaxis.

Methods

We prospectively studied patients from 67 intensive care units and six countries enrolled in a thromboprophylaxis trial (NCT00182143) comparing dalteparin with unfractionated heparin. Patients with trauma, orthopedic surgery or neurosurgery were excluded. Trained research coordinators used a validated tool to document bleeding, which underwent duplicate independent blinded adjudication. Major bleeding was defined as hypovolemic shock, bleeding into critical sites, requiring an invasive intervention or transfusion of at least two units of red blood cells, or associated with hypotension or tachycardia in the absence of other causes. Adjusted Cox proportional hazard regression analysis was used to identify major bleeding predictors and the association between bleeding and mortality.

Results

Among 3,746 patients, bleeding occurred in 208 [5.6 %, 95 % confidence interval (CI) 4.9–6.3 %]. Time-dependent predictors were prolonged activated partial thromboplastin time [hazard ratio (HR) 1.10, 1.05–1.14 per 10 s increase], lower platelet count (HR 1.16, 1.09–1.24 per 50 × 10⁹/L decrease), therapeutic heparin (HR 3.26, 1.72–6.17), antiplatelet agents (HR 1.38, 1.02–1.88), renal replacement therapy (HR 1.75, 1.20–2.56), and recent surgery (HR 1.64, 1.01–2.65). Type of pharmacologic thromboprophylaxis was not associated with bleeding. Patients with bleeding had a higher risk of in-hospital death (HR 2.09, 1.69–2.57).

Conclusions

As major bleeding has modifiable risk factors and is associated with in-hospital mortality, strategies to mitigate these factors should be evaluated in critically ill patients.     

Proximally delivered dilute heparin does not improve circuit life in continuous venovenous haemodiafiltration

Objective

To assess the effect on circuit life in continuous venovenous haemodiafiltration (CVVHD) by manipulating heparin dilution and point of administration.

Design

Repeated crossover design. Cases were randomised for first circuit and heparin dilution, after which crossovers occurred until treatment was stopped.

Setting

A 24-bed combined general and surgical intensive care unit admitting 1900 patients a year. On average, 54 cases a year receive CVVHD.

Patients

26 critically ill adult patients requiring CVVHD were enrolled, 18 of whom used at least one standard circuit and one modified circuit.

Interventions

Two circuit configurations and heparin dilutions were compared. In combination A, standard CVVHD blood lines and heparin concentration (100 units/ml) were used. In combination B, heparin was delivered in a more dilute volume (10 units/ml) via a modified circuit design with an administration port immediately adjacent to the venous access.

Measurements and results

18 randomised crossovers of circuits A and B occurred. Mean/median circuit life for the standard heparin/circuit combination A was 20.1/17.5 (SD 14.6) and for the modified combination B 21.4/15.4 (SD 19.2). There was no significant difference between circuits (pairedt-test,p=0.8175). To identify other factors which could have influenced circuit life (platelet count, heparin dose and pre- and post-filter activated partial thromboplastin time, APTT) all circuits terminated for the reasons identified (n=105) were analysed using linear modelling. Survival analysis was used to determine the survival function of the circuit. Pre-heparin APTT was the only factor associated with an increase in filter life (p=0.0325). The hazard rate for filter failure was 0.049/h (95% confidence interval 0.04 to 0.06), the range of time until filters failed was 1.8 to 78.5 h.

Conclusions

Proximally administered dilute heparin is not associated with a significant increase in circuit life.     

Inhaled nitric oxide reverses cell-free hemoglobin-induced pulmonary hypertension and decreased lung compliance. Preliminary results

Background

In order to test the hypothesis that inhaled nitric oxide (NO) reverses the pulmonary hypertension induced by αα-diaspirin crosslinked hemoglobin (ααHb), were studied anesthetized pigs that were administered with a total dose of 200 mg/kg of 10% ααHb. Inhaled NO (5 ppm) was administered for 10 min, and then discontinued for 10 min. This cycle was then repeated with 10 ppm inhaled NO.

Results

ααHb caused pulmonary arterial pressure (PAP) to increase from 27 ± 1.7 to 40 ± 3.0 mmHg (P<0.05) and dynamic lung compliance to decrease from 29± 1.5 to 23± 1.6 ml/cmH₂O (P < 0.05). After both doses of inhaled NO, but particularly 10 ppm, PAP was reduced (P < 0.05) and lung compliance increased (P < 0.05) from the ααHb levels. When inhaled NO was discontinued PAP again increased and lung compliance decreased to levels significantly different from baseline (P < 0.05).

Conclusion

We conclude that cell-free hemoglobin-induced pulmonary hypertension and decreased lung compliance can be selectively counteracted by inhaled NO.     

Hyperglycemia-Induced Platelet Activation in Type 2 Diabetes Is Resistant to Aspirin but Not to a Nitric Oxide�CDonating Agent

OBJECTIVE

Acute, short-term hyperglycemia enhances high shear stress–induced platelet activation in type 2 diabetes. Several observations suggest that platelets in type 2 diabetes are resistant to inhibition by aspirin. Our aim was to assess comparatively the effect of aspirin, a nitric oxide–donating agent (NCX 4016), their combination, or placebo on platelet activation induced by acute hyperglycemia in type 2 diabetes.

RESEARCH DESIGN AND METHODS

In a double-blind, placebo-controlled, randomized trial, 40 type 2 diabetic patients were allocated to 100 mg aspirin once daily, 800 mg NCX 4016 b.i.d., both of them, or placebo for 15 days. On day 15, 1 h after the morning dose, a 4-h hyperglycemic clamp (plasma glucose 13.9 mmol/l) was performed, and blood samples were collected before and immediately after it for platelet activation and cyclooxygenase-1 (COX-1) inhibition studies.

RESULTS

Acute hyperglycemia enhanced shear stress–induced platelet activation in placebo-treated patients (basal closure time 63 ± 7.1 s, after hyperglycemia 49.5 ± 1.4 s, −13.5 ± 6.3 s, P < 0.048). Pretreatment with aspirin, despite full inhibition of platelet COX-1, did not prevent it (−12.7 ± 6.9 s, NS vs. placebo). On the contrary, pretreatment with the NO donor NCX 4016, alone or in combination with aspirin, suppressed platelet activation induced by acute hyperglycemia (NCX 4016 +10.5 ± 8.3 s; NCX 4016 plus aspirin: +12.0 ± 10.7 s, P < 0.05 vs. placebo for both). Other parameters of shear stress–dependent platelet activation were also more inhibited by NCX 4016 than by aspirin, despite lesser inhibition of COX-1.

CONCLUSIONS

Acute hyperglycemia-induced enhancement of platelet activation is resistant to aspirin; a NO-donating agent suppresses it. Therapeutic approaches aiming at a wider platelet inhibitory action than that exerted by aspirin may prove useful in patients with type 2 diabetes.Type 2 diabetes is associated with a two- to fourfold increased incidence of ischemic cardiovascular events and markedly enhances the risk of stroke, amputation, and death (1). Not only long-term, continuous hyperglycemia but also transient, acute hyperglycemic spikes may contribute to the poor cardiovascular prognosis of patients with type 2 diabetes (2).Platelet hyperreactivity has been identified as one of the mechanisms of enhanced arterial thrombosis in type 2 diabetes (3). We have previously shown that in type 2 diabetes an acute, short-term hyperglycemia enhances platelet activation, and, in particular, high-shear stress–induced activation, which is considered an important mechanism triggering arterial thrombosis (4). This phenomenon is partly due to acute enhancement of the circulating levels of von Willebrand factor (vWF) (4) and indeed platelet-plasma interactions involving vWF have been previously suggested to cause increased platelet aggregability (5), and recent epidemiological data show that plasma vWF predicts cardiovascular events in patients with type 2 diabetes (6). High shear stress–induced platelet activation is hardly sensitive to inhibition by aspirin, and this has been advocated as one of the reasons for the high residual incidence of ischemic events in patients with acute coronary syndromes treated with aspirin (7). The effectiveness of aspirin as an antiplatelet agent in patients with type 2 diabetes is being increasingly questioned and aspirin nonresponsiveness, i.e., the incomplete inhibition of platelet aggregation upon chronic aspirin intake, has been documented in type 2 diabetes (3,8). In the antithrombotic trialists'' collaboration overview in patients at risk of ischemic cardiovascular events, antiplatelet therapy did not reduce the odds of a vascular event in diabetes (−7%), different from the highly significant reduction produced in the overall population at risk (−25%) (9).Nitric oxide (NO), a naturally occurring antiatherothrombotic mediator, inhibits the aggregation of platelets induced by all agonists, also suppressing aspirin-resistant pathways. The production of NO is defective in patients with type 2 diabetes (5). It seems thus logical to test NO-donating agents for their effect on platelet activation in type 2 diabetes.NCX 4016 (2-(acetyloxy)benzoic acid-3-[(nitrooxy)methyl]phenyl ester), a NO-donating moiety linked to an acetylsalicylic acid backbone, is a prototype of a series of NO-donating hybrid drugs of potential use for cardiovascular disorders (10). NCX 4016 was shown to display a wide range of antiplatelet activities in vitro and in vivo (11) and to release biologically relevant amounts of NO after oral administration to humans (12,13).Based on the above considerations, we have compared aspirin with the NO-donating agent NCX 4016 for their effects on the platelet hyperreactivity induced by acute, short-term hyperglycemia in patients with type 2 diabetes.     

Comparison of different laboratory tests in the evaluation of hemorrhagic risk of patients using rivaroxaban in the critical care setting: diagnostic accuracy study

Background

Rivaroxaban is a direct oral anticoagulant designed to dispense with the necessity of laboratory monitoring. However, monitoring rivaroxaban levels is necessary in certain clinical conditions, especially in the critical care setting.

Methods

This is a diagnostic accuracy study evaluating sensitivity and specificity of prothrombin time (PT), activated partial thromboplastin time (aPTT), and Dilute Russell viper venom time (dRVVT), to evaluate the hemorrhagic risk in patients taking rivaroxaban. The study used a convenience sample of 40 clinically stable patients using rivaroxaban to treat deep vein thrombosis or atrial fibrillation admitted in a private hospital in Brazil, compared to a group of 60 healthy controls. The samples from patients were collected two hours after the use of the medication (peak) and two hours before the next dose (trough).

Results

The correlation with the plasmatic concentration measured by anti-FXa assay was higher for PT and dRVVTS. The PT and aPTT tests presented higher specificity, while dRVVT was 100% sensible.

Conclusions

There was a strong correlation between the tests and the plasma concentration of the drug. Additionally, our results demonstrated the potential use of dRVVT as a screening test in the emergency room and the need of a second test to improve specificity.

     

Resistance to aspirin is increased by ST-elevation myocardial infarction and correlates with adenosine diphosphate levels

Background

To be fully activated platelets are dependent on two positive feedback loops; the formation of thromboxane A₂ by cyclooxygenase in the platelets and the release of ADP. We wanted to evaluate the effect of aspirin on platelet function in patients with acute coronary syndromes and we hypothesized that increased levels of ADP in patients with acute coronary syndromes could contribute to aspirin resistance.

Methods

Platelet activity in 135 patients admitted for chest pain was assessed with PFA-100. An epinephrine-collagen cartridge (EPI-COLL) was used for the detection of aspirin resistance together with an ADP-collagen cartridge (ADP-COLL). ADP was measured with hplc from antecubital vein samples. Three subgroups were compared: chest pain with no sign of cardiac disease (NCD), NonST-elevation myocardial infarction (NSTEMI) and STEMI.

Results

Platelet activation was increased for the STEMI group compared NCD. Aspirin resistance defined as <193 sec in EPI-COLL was 9.7 % in NCD, and increased to 26.0 % (n.s.) in NSTEMI and 83.3 % (p < 0.001) in STEMI. Chronic aspirin treatment significantly reduced platelet aggregation in NCD and NSTEMI, but it had no effect in STEMI. Plasma levels of ADP were markedly increased in STEMI (905 ± 721 nmol/l, p < 0.01), but not in NSTEMI (317 ± 245), compared to NCD (334 ± 271, mean ± SD). ADP levels correlated with increased platelet activity measured with ADP-COLL (r = -0.30, p < 0.05). Aspirin resistant patients (EPI-COLL < 193 sec) had higher ADP levels compared to aspirin responders (734 ± 807 vs. 282 ± 187 nmol/l, mean ± SD, p < 0.05).

Conclusion

Platelets are activated and aspirin resistance is more frequent in STEMI, probably due to a general activation of platelets. ADP levels are increased in STEMI and correlates with platelet activation. Increased levels of ADP could be one reason for increased platelet activity and aspirin resistance.     

Influence of oral antiplatelet therapy on hemorrhagic complications of pacemaker implantation

Objective

We retrospectively assessed the incidence of hemorrhagic complications associated with pacemaker implantation in patients receiving one or more antiplatelet agents.

Design and setting

Retrospective multicenter case–control study. Data were collected from three cardiac units in Germany from 2006 to 2010.

Methods

A total of 495 pacemaker patients were enrolled. 99 patients received dual antiplatelet therapy (aspirin and clopidogrel), 198 were given only aspirin and 198 had no antiplatelet therapy (control). Patients were matched for age and sex. Implant-related bleeding complications were defined as major bleeding, if surgical pocket exploration or blood transfusion were needed. Minor bleeding complications were defined as one or more of the following conditions: fall of hemoglobin content >1.5 g/dl not requiring blood transfusion; pocket hematoma; pocket effusion not requiring surgical revision.

Measurements and results

Hemorrhagic complications were seen in 4/198 control patients and 6/198 aspirin-only patients [2 vs. 3 %, p = 0.5, OR = 1.52 (0.42–5.46)]. Patients undergoing dual antiplatelet therapy had significantly more bleeding complications than patients in the aspirin-only group [11/99: 11.1 vs. 3 %, p = 0.005, OR = 3.95 (1.43–11.16)]. Major complications occurred in 1/198 control patients and 2/198 aspirin-only patients [0.5 vs. 1 %, p = 0.6, OR = 2.01 (0.18–22.35)]. In contrast, 7/99 patients undergoing dual antiplatelet therapy exhibited major complications [7.1 vs. 1 %, p = 0.004, OR = 7.46 (1.52–36.50)].

Conclusions

Although in patients undergoing pacemaker implantation dual antiplatelet therapy with aspirin and clopidogrel caused a significant increase of bleeding complications, the use of aspirin alone was not associated with a significant increase in bleeding complications.     

Safety and Feasibility of Rehabilitation Interventions in Children Undergoing Hematopoietic Stem Cell Transplant With Thrombocytopenia

Objective

To analyze the relation between platelet counts, intensities of physical therapy (PT) and occupational therapy (OT) services received, and frequencies of bleeding complications in children undergoing hematopoietic stem cell transplant (HSCT) during a period of severe thrombocytopenia.

Épidémiologie des hémorragies digestives hautes en Tunisie

Background

Acute upper gastrointestinal bleeding (UGIB) continues to be a common cause of hospital admission and morbidity and mortality. Epidemiological studies are still limited in our country.

Aim and objectives

The aim of this study is to determine the causes and outcome of patients with UGIB presenting at the teaching hospital of Monastir.

Materials and methods

The study was carried out at the teaching hospital of Monastir. The records of 874 patients who underwent endoscopy for UGIB over a period of 10 years (1997–2007) were retrospectively analysed.

Results

The acute UGIB represented 5.3% of all high digestive endoscopy. Male predominance (63.1%) was noted with an average age of 54 ± 12 years. A bleeding site could be detected in 75.6% of the patients. Diagnostic accuracy was greater within the first 24 hours of the bleeding onset and in the presence of hematemesis. Peptic ulcer was the main cause of UGIB (50.5%) followed by erosive mucosal disease (24%). The prevalence of variceal bleeding was 9.49%. Endoscopic treatment was used in 103 cases (11.7%). Operations were performed in 51 cases (9.9%), including 9.9% of ulcers. There were 36 deaths (4.1%).

Conclusion

Peptic ulcer was the most common cause of gastrointestinal bleeding in our country. Mortalitywas raised in variceal group. Most cases of UGIB can be treated with endoscopic hemostasis, when diagnostic endoscopy establishes the source.     

Standard subcutaneous dosing of unfractionated heparin for venous thromboembolism prophylaxis in surgical ICU patients leads to subtherapeutic factor Xa inhibition

Purpose

To assess coagulation status and factor Xa inhibition in surgical intensive care unit (ICU) patients administered prophylactic unfractionated heparin for venous thromboembolism (VTE) prophylaxis.

Methods

We conducted a randomized, single-blind study at a tertiary academic medical center. Included were patients 18?years and older admitted to the surgical ICU directly after major abdominal surgery. Exclusion criteria included significant bleeding risk, preoperative anticoagulation, or history of heparin-induced thrombocytopenia. Patients were randomized to two regimens for VTE prophylaxis: standard of care unfractionated heparin, 5,000?units subcutaneously three times daily (SQH) versus unfractionated heparin via intravenous infusion, titrated to an activated partial thromboplastin time of 40–45?s (IVH). Blood samples were taken prior to surgical incision on day 0 and daily for 5?days after surgery. Samples were analyzed for factor Xa inhibition and viscoelastic whole blood clotting parameters (Sonoclot analyzer).

Results

A total of 50 patients were randomized to either SQH or IVH. The majority of patients had cancer. Patients in the SQH group had no detectable peak anti-factor Xa (aFXa) activity for 5 days after surgery, while patients in the IVH group had statistically elevated levels compared to the SQH group on days 3–5. SQH patients demonstrated a hypercoagulable profile on Sonoclot, while IVH patients displayed a normal profile.

Conclusions

Standard of care subcutaneous dosing of unfractionated heparin for VTE prophylaxis in surgical ICU patients leads to subtherapeutic levels of factor Xa inhibition.     

Reliability of sensor-based real-time workflow recognition in laparoscopic cholecystectomy

Purpose

Laparoscopic cholecystectomy is a very common minimally invasive surgical procedure that may be improved by autonomous or cooperative assistance support systems. Model-based surgery with a precise definition of distinct procedural tasks (PT) of the operation was implemented and tested to depict and analyze the process of this procedure.

Methods

Reliability of real-time workflow recognition in laparoscopic cholecystectomy ( \(n=10\) cases) was evaluated by continuous sensor-based data acquisition. Ten PTs were defined including begin/end preparation calots’ triangle, clipping/cutting cystic artery and duct, begin/end gallbladder dissection, begin/end hemostasis, gallbladder removal, and end of operation. Data acquisition was achieved with continuous instrument detection, room/table light status, intra-abdominal pressure, table tilt, irrigation/aspiration volume and coagulation/cutting current application. Two independent observers recorded start and endpoint of each step by analysis of the sensor data. The data were cross-checked with laparoscopic video recordings serving as gold standard for PT identification.

Results

Bland–Altman analysis revealed for 95 % of cases a difference of annotation results within the limits of agreement ranging from \(-\) 309 s (PT 7) to +368 s (PT 5). Laparoscopic video and sensor data matched to a greater or lesser extent within the different procedural tasks. In the majority of cases, the observer results exceeded those obtained from the laparoscopic video. Empirical knowledge was required to detect phase transit.

Conclusions

A set of sensors used to monitor laparoscopic cholecystectomy procedures was sufficient to enable expert observers to reliably identify each PT. In the future, computer systems may automate the task identification process provided a more robust data inflow is available.     

Persistent hypocoagulability in patients with septic shock predicts greater hospital mortality: impact of impaired thrombin generation

Purpose

Sepsis induces hypercoagulability, hypofibrinolysis, microthrombosis, and endothelial dysfunction leading to multiple organ failure. However, not all studies reported benefit from anticoagulation for patients with severe sepsis, and time courses of coagulation abnormalities in septic shock are poorly documented. Therefore, the aim of this prospective observational cohort study was to describe the coagulation profile of patients with septic shock and to determine whether alterations of the profile are associated with hospital mortality.

Methods

Thirty-nine patients with septic shock on ICU admission were prospectively included in the study. From admission to day 7, analytical coagulation tests, thrombin generation (TG) assays, and thromboelastometric analyses were performed and tested for association with survival.

Results

Patients with septic shock presented on admission prolongation of prothrombin time, activated partial thromboplastin time (aPTT), increased consumption of most procoagulant factors as well as both delay and deficit in TG, all compatible with a hypocoagulable state compared with reference values (P?P?=?0.007) and persistence of TG deficit (P?=?0.024) on day 3 were strong predictors of mortality, independently from disease severity scores, disseminated intravascular coagulation score, and standard coagulation tests on admission.

Conclusions

Patients with septic shock present with hypocoagulability at the time of ICU admission. Persistence of hypocoagulability assessed by prolonged aPTT and unresolving deficit in TG on day 3 after onset of septic shock is associated with greater hospital mortality.     

The aPTT assay as a monitor of heparin anticoagulation efficacy in clinical settings

Activated partial thromboplastin time (aPTT) and prothrombin time (PT) are 2 major methods of screening patients for bleeding tendency. Heparin is an anticoagulant commonly used for various clinical conditions and will thus affect the coagulation profile. The influence of heparin on PT vs aPTT, seldom addressed in the past, should be carefully investigated. Prospective data on 35 patients who were heparinized for clinically indicated conditions were collected and analyzed for the change in PT (dPT) and aPTT (daPTT) at 3 time points after treatment, all of which were compared with baseline data checked before therapy. Age, sex, and the results of a complete blood count and liver and renal function tests were also evaluated for each patient to determine their effects on dPT and daPTT. The therapeutic goal of keeping the aPTT within a desirable range was achieved in ∼75% of patients by the last day of heparin therapy. Within this range, dPTs were not statistically significant, nor was the effect of age, sex, hemoglobin level, serum albumin level, white cell count, platelet count, or renal or hepatic function. In patients with thrombosis, dPT was not significantly influenced by heparin dose. During an overlap in the periods of coumadin and heparin administration, PT was used as a guide for adjusting the coumadin dose. The anticoagulant effect, indicated by a PT in the target range, would occur primarily secondary to coumadin administration and would make it relatively easy to decide when to discontinue heparin.     

Correlation between activated clotting time and activated partial thromboplastin times

OBJECTIVE: To evaluate the correlation between clotting time tests and heparin concentration, the correlation between activated clotting time (ACT) and activated partial thromboplastin time (aPTT) results, and to compare the clinical decisions based on ACT results with those based on aPTT results. METHODS: Retrospective evaluation of a large database containing heparin concentrations, ACT results (1 device), and aPTT results (3 different instruments: 2 bedside, 1 laboratory-based). Correlations between heparin concentrations and clotting time tests and between ACT results and aPTT results were determined. Clinical decisions regarding heparin dosage adjustments based on ACT results were compared with those based on aPTT results. RESULTS: Correlations between clotting time tests and heparin concentrations were r = 0.72 for ACT and r = 0.74-0.86 for the aPTT instruments. The laboratory-based aPTT had the highest correlation to heparin concentrations. The correlation between ACT and aPTT results ranged from r = 0.64-0.67. Heparin dosage adjustment decisions based on ACT results agreed with decisions based on aPTT results 59-63% of the time. CONCLUSIONS: The laboratory-based aPTT has a stronger correlation to heparin concentration than the bedside-based aPTT and ACT. The correlation between ACT and aPTT was similar among 3 different aPTT instruments. Decisions to adjust heparin therapy based on ACT results differed from decisions based on aPTT results more than one-third of the time.     

Respiratory dialysis with an active-mixing extracorporeal carbon dioxide removal system in a chronic sheep study

Purpose

The objective of this study was to demonstrate the safety and performance of a unique extracorporeal carbon dioxide removal system (Hemolung, ALung Technologies, Pittsburgh, PA) which incorporates active mixing to improve gas exchange efficiency, reduce exposure of blood to the circuit, and provide partial respiratory support at dialysis-like settings.

Methods

An animal study was conducted using eight domestic crossbred sheep, 6–18?months of age and 49–115?kg in weight. The sheep were sedated and intubated, and a 15.5-Fr dual lumen catheter was inserted into the right jugular vein. The catheter was connected to the extracorporeal circuit primed with heparinized saline, and flow immediately initiated. The animals were then awakened and encouraged to stand. The animals were supported in a stanchion and monitored around the clock. Anticoagulation was maintained with heparin to achieve an aPTT of 46–70?s.

Results

Measurements included blood flow rate through the device, carbon dioxide exchange rate, pump speed and sweep gas flow rate. Safety and biocompatibility measurements included but were not limited to plasma-free hemoglobin, hematocrit, white blood cell count, platelet count and fibrinogen. The Hemolung removed clinically significant amounts of carbon dioxide, more than 50?ml/min, at low blood flows of 350–450?ml/min, with minimal adverse effects.

Conclusions

The results of 8-day trials in awake and standing sheep supported by the Hemolung demonstrated that this device can consistently achieve clinically relevant levels of carbon dioxide removal without failure and without significant risk of adverse reactions.     

Heparin clearance during continuous veno-venous haemofiltration

Objective

To determine whether premature clotting of haemofiltration circuits could be related to heparin removal across the filter membrane into the ultrafiltrate.

Design

Randomised study using either unfractionated (n=8) or low molecular weight (n=7) heparin for anticoagulation of the haemofiltration circuit at 1000 and 600U/h respectively. Samples were drawn at 1 and 2 h from arterial and venous limbs of the haemofilter circuit for measurement of plasma heparin (as anti-Factor Xa activity), antithrombin III and haematocrit. Ultrafiltrate samples were collected at the same time for measurement of anti-Xa activity.

Setting

Intensive care unit.

Patients

Patients in acute renal failure requiring haemofiltration.

Results

Both unfractionated and low molecular weight heparin plasma levels were within the range required for therapeutic anticoaguation in all but one patient at 2 h. Ultrafiltrate anti-Xa levels were insignificant. Antithrombin III levels in these critically ill patients were subnormal in 11 of the 15 studies.

Conclusions

Despite their small sizes, neither unfractionated nor low molecular weight heparins cross the haemofilter membrane into the ultrafiltrate in any measurable quantity. Both heparins were present in plasma at a level suitable for therapeutic anticoagulation. Subnormal levels of antithrombin III may be an important factor in determining filter longevity.     

Heparin–protamine balance after neonatal cardiopulmonary bypass surgery

Essentials

• Heparin‐protamine balance (HPB) modulates bleeding after neonatal cardiopulmonary bypass (CPB).
• HPB was examined in 44 neonates undergoing CPB.
• Post‐operative bleeding occurred in 36% and heparin rebound in 73%.
• Thrombin‐initiated fibrin clot kinetic assay and partial thromboplastin time best assessed HPB.

Summary

Background

Neonates undergoing cardiopulmonary bypass (CPB) are at risk of excessive bleeding. Blood is anticoagulated with heparin during CPB. Heparin activity is reversed with protamine at the end of CPB. Paradoxically, protamine also inhibits blood coagulation when it is dosed in excess of heparin.

Objectives

To evaluate heparin–protamine balance in neonates undergoing CPB by using research and clinical assays, and to determine its association with postoperative bleeding.

Patients/Methods

Neonates undergoing CPB in the first 30 days of life were studied. Blood samples were obtained during and after surgery. Heparin–protamine balance was assessed with calibrated automated thrombography, thrombin‐initiated fibrin clot kinetic assay (TFCK), activated partial thromboplastin time (APTT), anti‐FXa activity, and thromboelastometry. Excessive postoperative bleeding was determined by measurement of chest tube output or the development of cardiac tamponade.

Results and Conclusions

Of 44 neonates enrolled, 16 (36%) had excessive postoperative bleeding. The TFCK value was increased. By heparin in neonatal blood samples, but was only minimally altered by excess protamine. Therefore, it reliably measured heparin in samples containing a wide range of heparin and protamine concentrations. The APTT most closely correlated with TFCK results, whereas anti‐FXa and thromboelastometry assays were less correlative. The TFCK and APTT assay also consistently detected postoperative heparin rebound, providing an important continued role for these long‐established coagulation tests in the management of postoperative bleeding in neonates requiring cardiac surgical repair. None of the coagulation tests predicted the neonates who experienced postoperative bleeding, reflecting the multifactorial causes of bleeding in this population.