Dosing of thromboprophylaxis and mortality in critically ill COVID-19 patients

Abstract Background A substantial proportion of critically ill COVID-19 patients develop thromboembolic complications, but it is unclear whether higher doses of thromboprophylaxis are associated with lower mortality rates. The purpose of the study was to evaluate the association between initial dosing strategy of thromboprophylaxis in critically ill COVID-19 patients and the risk of death, thromboembolism, and bleeding. Method In this retrospective study, all critically ill COVID-19 patients admitted to two intensive care units in March and April 2020 were eligible. Patients were categorized into three groups according to initial daily dose of thromboprophylaxis: low (2500–4500 IU tinzaparin or 2500–5000 IU dalteparin), medium (> 4500 IU but < 175 IU/kilogram, kg, of body weight tinzaparin or > 5000 IU but < 200 IU/kg of body weight dalteparin), and high dose (≥ 175 IU/kg of body weight tinzaparin or ≥ 200 IU/kg of body weight dalteparin). Thromboprophylaxis dosage was based on local standardized recommendations, not on degree of critical illness or risk of thrombosis. Cox proportional hazards regression was used to estimate hazard ratios with corresponding 95% confidence intervals of death within 28 days from ICU admission. Multivariable models were adjusted for sex, age, body mass index, Simplified Acute Physiology Score III, invasive respiratory support, and initial dosing strategy of thromboprophylaxis. Results A total of 152 patients were included: 67 received low-, 48 medium-, and 37 high-dose thromboprophylaxis. Baseline characteristics did not differ between groups. For patients who received high-dose prophylaxis, mortality was lower (13.5%) compared to those who received medium dose (25.0%) or low dose (38.8%), p = 0.02. The hazard ratio of death was 0.33 (95% confidence intervals 0.13–0.87) among those who received high dose, and 0.88 (95% confidence intervals 0.43–1.83) among those who received medium dose, as compared to those who received low-dose thromboprophylaxis. There were fewer thromboembolic events in the high (2.7%) vs medium (18.8%) and low-dose thromboprophylaxis (17.9%) groups, p = 0.04. Conclusions Among critically ill COVID-19 patients with respiratory failure, high-dose thromboprophylaxis was associated with a lower risk of death and a lower cumulative incidence of thromboembolic events compared with lower doses. Trial registration Clinicaltrials.gov NCT04412304 June 2, 2020, retrospectively registered.

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DOSING OF THROMBOPROPHYLAXIS AND MORTALITY IN CRITICALLY ILL COVID-19 PATIENTS

10.1101/2020.09.17.20195867 ◽

2020 ◽

Author(s):

Sandra Jonmarker ◽

Jacob Hollenberg ◽

Martin Dahlberg ◽

Otto Stackelberg ◽

Jacob Litorell ◽

...

Keyword(s):

Body Weight ◽

Confidence Intervals ◽

Critically Ill ◽

Low Dose ◽

Cox Proportional Hazards ◽

High Dose ◽

Thromboembolic Events ◽

Bleeding Events ◽

Risk Of Death ◽

Dosing Strategy

Background: A substantial proportion of critically ill COVID-19 patients develop thromboembolic complications, but it is unclear whether higher doses of thromboprophylaxis are associated with lower mortality rates. The purpose of the study was to evaluate the association of initial dosing strategy of thromboprophylaxis in critically ill COVID-19 patients and the risk of death, thromboembolism, and bleeding. Method: All critically ill COVID-19 patients admitted to two intensive care units in March and April 2020 were eligible. Patients were categorized into three groups according to initial daily dose of thromboprophylaxis: low (2500−4500 IU tinzaparin or 2500−5000 IU dalteparin), medium (>4500 IU but <175 IU/kilogram, kg, of body weight tinzaparin or >5000 IU but <200 IU/kg of body weight dalteparin), and high dose (≥ 175 IU/kg of body weight tinzaparin or ≥200 IU/kg of body weight dalteparin). Thromboprophylaxis dosage was based on local standardized recommendations, not on degree of critical illness or risk of thrombosis. Cox proportional hazards regression was used to estimate hazard ratios with corresponding 95% confidence intervals of death within 28 days from ICU admission. Multivariable models were adjusted for sex, age, body-mass index, Simplified Acute Physiology Score III, invasive respiratory support, and initial dosing strategy of thromboprophylaxis. Results: A total of 152 patients were included; 67 received low, 48 medium, and 37 high dose thromboprophylaxis. Baseline characteristics did not differ between groups. Mortality was lower in high (13.5%) vs medium (25.0%) and low dose thromboprophylaxis (38.8%) groups, p≡0.02. The hazard ratio of death was 0.33 (95% confidence intervals 0.13 − 0.87) among those who received high dose, respectively 0.88 (95% confidence intervals 0.43 − 1.83) among those who received medium dose, as compared with those who received low dose thromboprophylaxis. There were fewer thromboembolic events in the high (2.7%) vs medium (18.8%) and low dose thromboprophylaxis (17.9%) groups, p≡0.04, but no difference in the proportion of bleeding events, p≡0.16. Conclusions: Among critically ill COVID-19 patients with respiratory failure, high dose thromboprophylaxis was associated with a lower risk of death and a lower cumulative incidence of thromboembolic events compared with lower doses.

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Evaluation of Recombinant Factor VIIa Utilization and Development of a Cost-Effective Dose Minimization Protocol in Adult Cardiac Surgery Patients at an Academic Medical Center

Blood ◽

10.1182/blood-2018-99-119908 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5039-5039

Author(s):

Kathryn Dane ◽

John Lindsley ◽

Satish Shanbhag ◽

Michael B. Streiff ◽

Glenn Whitman ◽

...

Keyword(s):

Cardiac Surgery ◽

Low Dose ◽

Recombinant Factor Viia ◽

Factor Viia ◽

High Dose ◽

Thromboembolic Events ◽

Potential Cost ◽

Critical Bleeding ◽

Dosing Strategy ◽

Adult Cardiac Surgery

Abstract Background: Although recombinant factor VIIa is often utilized to mitigate critical bleeding following cardiac surgery, the optimal dosing strategy in this population is not well-established. At our institution, hospital guidelines recommend administration of recombinant factor VIIa 60 mcg/kg for all off-label indications. However, available data suggest doses as low as 17 mcg/kg have been efficacious in cardiac surgery patients with critical bleeding. Additionally, although low-dose recombinant factor VIIa (< 40 mcg/kg) and high-dose (50-109 mcg/kg) dosing strategies have been reported equally efficacious according to retrospective, observational studies, higher doses may be associated with increased incidence of adverse events. Therefore, we aimed to evaluate the safety of recombinant factor VIIa in cardiac surgery patients with critical bleeding, and estimate potential cost-savings associated with implementation of a low-dose recombinant factor VIIa protocol in this population. Methods: All adult cardiac surgery patients who received one or more doses of recombinant factor VIIa during a 1-year period (July 1, 2016 to June 30, 2017) were included. Thromboembolic event rates documented within 14 days following recombinant factor VIIa administration were evaluated in patients alive at discharge. An average wholesale price of 2.59 USD per mcg was utilized for recombinant factor VIIa cost calculations. Results: A total of 16 patients received 24 doses of recombinant factor VIIa during the study period. The median weight-based dose administered was 55 mcg/kg (utilizing actual body weight), and the median dose was 5 mg. The median cost per recombinant factor VIIa dose was 12,950 USD, resulting in a total expenditure of 277,174 USD. Nine of sixteen patients (56%) survived to hospital discharge. Five of nine (56%) patients alive at discharge experienced thromboembolic complications following recombinant factor VIIa administration, three (60%) of which were central nervous system (CNS) thromboembolic events. Based on data supporting low-dose strategies, a proposed weight-based recombinant factor VIIa dose-minimization protocol was developed by leadership in the departments of pharmacy, hematology, cardiac surgery, and cardiac anesthesia (Table 1). Implementation of this protocol would result in an estimated annual cost-avoidance of 168,376 USD. Conclusions: Recombinant factor VIIa administration at a dose of 55 mcg/kg in adult cardiac surgery patients with critical bleeding is associated with a high rate of thromboembolic events, including CNS thromboembolism. Additionally, this recombinant factor VIIa dosing strategy is associated with significant cost, which can be substantially reduced with implementation of a low-dose recombinant factor VIIa protocol in the cardiac surgery population. Disclosures No relevant conflicts of interest to declare.

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Renoprotective effects of a novel Nox1/4 inhibitor in a mouse model of Type 2 diabetes

Clinical Science ◽

10.1042/cs20120330 ◽

2012 ◽

Vol 124 (3) ◽

pp. 191-202 ◽

Cited By ~ 111

Author(s):

Mona Sedeek ◽

Alex Gutsol ◽

Augusto C. Montezano ◽

Dylan Burger ◽

Aurelie Nguyen Dinh Cat ◽

...

Keyword(s):

Body Weight ◽

Low Dose ◽

Transforming Growth Factor ◽

Disease Process ◽

Thiobarbituric Acid ◽

Transforming Growth Factor Β ◽

Mitogen Activated Protein Kinase ◽

High Dose ◽

Diabetic Mice ◽

Mitogen Activated Protein

Nox (NADPH oxidase)-derived ROS (reactive oxygen species) have been implicated in the development of diabetic nephropathy. Of the Nox isoforms in the kidney, Nox4 is important because of its renal abundance. In the present study, we tested the hypothesis that GKT136901, a Nox1/4 inhibitor, prevents the development of nephropathy in db/db (diabetic) mice. Six groups of male mice (8-week-old) were studied: (i) untreated control db/m, (ii) low-dose GKT136901-treated db/m (30 mg/kg of body weight per day), (iii) high-dose GKT136901-treated db/m (90 mg/kg of body weight per day), (iv) untreated db/db; (v) low dose GKT136901-treated db/db; and (vi) high-dose GKT136901-treated db/db. GKT136901, in chow, was administered for 16 weeks. db/db mice developed diabetes and nephropathy as evidenced by hyperglycaemia, albuminuria and renal injury (mesangial expansion, tubular dystrophy and glomerulosclerosis). GKT136901 treatment had no effect on plasma glucose or BP (blood pressure) in any of the groups. Plasma and urine TBARSs (thiobarbituric acid-reacting substances) levels, markers of systemic and renal oxidative stress, respectively, were increased in diabetic mice. Renal mRNA expression of Nox4, but not of Nox2, increased, Nox1 was barely detectable in db/db. Expression of the antioxidant enzyme SOD-1 (superoxide dismutase 1) decreased in db/db mice. Renal content of fibronectin, pro-collagen, TGFβ (transforming growth factor β) and VCAM-1 (vascular cell adhesion molecule 1) and phosphorylation of ERK1/2 (extracellular-signal-regulated kinase 1/2) were augmented in db/db kidneys, with no change in p38 MAPK (mitogen-activated protein kinase) and JNK (c-Jun N-terminal kinase). Treatment reduced albuminuria, TBARS and renal ERK1/2 phosphorylation and preserved renal structure in diabetic mice. Our findings suggest a renoprotective effect of the Nox1/4 inhibitor, possibly through reduced oxidative damage and decreased ERK1/2 activation. These phenomena occur independently of improved glucose control, suggesting GKT136901-sensitive targets are involved in complications of diabetes rather than in the disease process.

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Exacerbated febrile responses to LPS, but not turpentine, in TNF double receptor-knockout mice

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1997.272.2.r563 ◽

1997 ◽

Vol 272 (2) ◽

pp. R563-R569 ◽

Cited By ~ 19

Author(s):

L. R. Leon ◽

W. Kozak ◽

J. Peschon ◽

M. J. Kluger

Keyword(s):

Body Weight ◽

Food Intake ◽

Motor Activity ◽

Knockout Mice ◽

Low Dose ◽

Late Phase ◽

High Dose ◽

Wild Type ◽

Inflammatory Stimuli ◽

Necrosis Factor

We examined the effects of injections of systemic [lipopolysaccharide (LPS), 2.5 mg/kg or 50 pg/kg ip] or local (turpentine, 100 microl sc) inflammatory stimuli on fever, motor activity, body weight, and food intake in tumor necrosis factor (TNF) double receptor (TNFR)-knockout mice. A high dose of LPS resulted in exacerbated fevers in TNFR-knockout mice compared with wild-type mice for the early phase of fever (3-15 h); the late phase of fever (16-24 h) and fevers to a low dose of LPS were similar in both groups. Motor activity, body weight, and food intake were similarly reduced in both groups of mice after LPS administration. In response to turpentine, TNFR-knockout and wild-type mice developed virtually identical responses to all variables monitored. These results suggest that 1) TNF modulates fevers to LPS dose dependently, 2) TNF does not modulate fevers to a subcutaneous injection of turpentine, and 3) knockout mice may develop cytokine redundancy in the regulation of the acute phase response to intraperitoneally injected LPS or subcutaneously injected turpentine.

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Glucocorticoid Receptor Agonists to Improve the Productivity and Health of Early-Weaned Pigs: What Is the Best Method of Delivery?

Animals ◽

10.3390/ani10071124 ◽

2020 ◽

Vol 10 (7) ◽

pp. 1124

Author(s):

Hailey Wooten ◽

Hwanhee Kim ◽

Amanda R. Rakhshandeh ◽

Anoosh Rakhshandeh

Keyword(s):

Body Weight ◽

Glucocorticoid Receptor ◽

Low Dose ◽

Average Daily Gain ◽

Feed Ratio ◽

High Dose ◽

Suitable Alternative ◽

Treatment Groups ◽

Daily Gain ◽

All Treatment

The purpose of the current study was to determine the best method of delivery for glucocorticoid receptor agonist (GRA) treatment. A total of 167 Pig Improvement Company (PIC) piglets (body weight (BW) 7.35 ± 1.24 kg) were weaned at 25.0 ± 0.81 days of age and randomly assigned to 14 treatment groups based on a 2 × 7 factorial arrangement with sex (gilts vs. barrows), in-feed antibiotic (ANT; 110 mg/kg in-feed tylosin), repeated intramuscular (I.M.) injection of GRA (two injections, 0.2 mg/kg BW dexamethasone (DEX)), low dose in-feed GRA (LF, 2.5 mg/kg diet DEX ), high dose in-feed GRA (HF, 5 mg/kg diet DEX), low dose in-water GRA (LW, 0.8 mg/L DEX ), high dose in-water GRA (HW, 1.6 mg/L DEX ), and no treatment control (CON) as the main factors. Body weight and feed intake were measured daily from days 0 to 7 and weekly from days 7 to 28 post-weaning. The interaction effect for average daily gain (ADG) was significant with gilts performing better in the I.M., ANT, and LF groups (p = 0.05). All treatment groups, with the exception of the HW group, had a higher ADG than the CON group. Gilts in the I.M., LF, and HF groups had the highest ADG compared to other treatment groups (p ≤ 0.05). Sex and the interaction between sex and treatments had no effect on the gain-to-feed ratio (G:F; p ≥ 0.21). All treatment groups had a higher G:F than the CON group (p ≥ 0.04). These results suggest that the low-dose, in-feed GRA treatment is the best GRA delivery method and is a suitable alternative to in-feed sub-therapeutic antibiotics.

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M211. NEUROPROTECTIVE EFFECT OF SHI-ZHEN-AN-SHEN-TANG, A CHINESE HERB FORMULA ON MICE EXPOSED TO CUPRIZONE

Schizophrenia Bulletin ◽

10.1093/schbul/sbaa030.523 ◽

2020 ◽

Vol 46 (Supplement_1) ◽

pp. S216-S217

Author(s):

Chao Ma ◽

Yan Wu ◽

Pei Chen ◽

Yuan Jia ◽

Dongqing Yin ◽

...

Keyword(s):

Low Dose ◽

Neuroprotective Effect ◽

Chinese Herb ◽

Large Body ◽

High Dose ◽

Neuregulin 1 ◽

The Brain ◽

Different Doses ◽

Medium Dose

Abstract Background Our previous study indicated a therapeutic effect of Shi-Zhen-An-Shen-Tang (SZAST), a Chinese herb formula, on schizophrenia, but the related mechanism is unknown(citation). A large body of evidence suggests the important role of white matter of the brain in the pathophysiology of schizophrenia. This study was designed to evaluate the effect of SZAST on schizophrenia with demyelinated mice. Methods Male C57BL/6 mice were given mixed cuprizone (CPZ, a copper chelator, 0.2 %, w/w) rodent chow for six successive weeks to induce demyelination. During the last two weeks, mice were given an oral gavage of saline, or SZAST of three different doses (a low dose of 5.5g·kg-1·d-1, a medium dose of 8.24g·kg-1·d-1, or a high dose of 10.98 g·kg-1·d-1), or quetiapine, respectively. Behavioral tests were conducted after the last treatment. Meanwhile, the expression of myelin basic protein (MBP) and neuregulin-1(NRG1) in the brain was tested by immunohistochemistry staining or Western Blot. Results Mice exposed to CPZ for six weeks showed obvious schizophrenia-like behaviors, including lower nest-building activity, sensory gating activity, and higher locomotor activity. CPZ-fed mice also displayed a lower myelin density in the corpus callosum, hippocampus, and cerebral cortex and a reduction of MBP and NRG1 protein in the hippocampus compared with controls. Both quetiapine and SZAST significantly alleviated the abnormal schizophrenia-like behaviors and the impairment of myelin sheath in CPZ-fed mice, however, SZAST with medium dose showed better neuroprotective effect than the low dose or the high dose of SZAST. Furthermore, the expression of NRG1protein in the hippocampus was slightly, but not significantly increased in all SZAST-treated and quetiapine-treated groups. Discussion These results indicate that the neuroprotective effect of SZAST in demyelinated mice might partially relate to remyelination in the hippocampus in CPZ-fed mice.

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Intravenous administration of sodium propionate induces antidepressant or prodepressant effect in a dose dependent manner

Scientific Reports ◽

10.1038/s41598-020-77085-z ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Chunyan Hao ◽

Zefeng Gao ◽

XianJun Liu ◽

Zhijiang Rong ◽

Jingjing Jia ◽

...

Keyword(s):

Body Weight ◽

Low Dose ◽

Antidepressant Effect ◽

High Dose ◽

Mild Stress ◽

Dependent Manner ◽

Reward Seeking ◽

Metabolomic Profiling ◽

Hydroxyanthranilic Acid ◽

Dose Dependent

AbstractPropionate has been reported to exert antidepressant effects, but high-dose propionate may induce autism-like symptoms in experimental animals through induction of dysbiosis of neurotransmitters. The bi-directional effects of propionate seem to be dose-dependent. However, due to the pathological discrepancies between depression and autism, conclusions drawn from autism may not be simply transferable to depression. The effect and underlying action mechanisms of high-dose propionate on depression remains undetermined. To investigate the effects of propionate on depression, propionate dose gradients were intravenously administrated to rats exposed to chronic unpredictable mild stress (CUMS) for 1 week. Results of these behavioral tests demonstrate that low-dose propionate (2 mg/kg body weight/day) induces antidepressant effect through bodyweight recovery, elevated reward-seeking behaviors, and reduced depression-like behaviors, while high-dose propionate (200 mg/kg body weight/day) induces prodepressant effects opposite of those of low-dose propionate. A comprehensive profiling of neurotransmitters in the hippocampus demonstrated that CUMS induces reduction of NE (Norepinephrine), DA (Dopamine). GABA (γ-aminobutyric acid) was recovered by low-dose propionate, while high-dose propionate exerted more complicated effects on neurotransmitters, including reduction of NE, DA, 5-Hydroxytryptamine and Tryptophan, and increase of GABA, Kynurenine, Homovanillic acid, 3-hydroxyanthranilic acid, 3-hydroxykynurenine, 3,4-dihydroxyphenylacetic acid, and 3-methoxytyramine. The neurotransmitters disturbed by high-dose propionate suggest metabolic disorders in the hippocampus, which were confirmed by the clear group separation in PCA of metabolomic profiling. The results of this study demonstrate the double-edged dose-dependent effects of propionate on depression and suggest potential cumulative toxicity of propionate as a food additive to mood disorders.

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A Double-Blind, Randomized Study of Extended-Release Molindone for Impulsive Aggression in ADHD

Journal of Attention Disorders ◽

10.1177/1087054720909084 ◽

2020 ◽

pp. 108705472090908 ◽

Cited By ~ 1

Author(s):

Gianpiera Ceresoli-Borroni ◽

Azmi Nasser ◽

Toyin Adewole ◽

Tesfaye Liranso ◽

Jiahong Xu ◽

...

Keyword(s):

Extended Release ◽

Low Dose ◽

Behavioral Therapy ◽

Randomized Study ◽

High Dose ◽

Double Blind ◽

Impulsive Aggression ◽

Pediatric Populations ◽

Dose Ranging ◽

Medium Dose

Objective: To evaluate efficacy and safety of SPN-810 (extended-release molindone) in a Phase-2b, randomized, double-blind, placebo-controlled, dose-ranging study of children (6–12 years) with ADHD and persistent impulsive aggression (IA). Method: After lead-in, children were randomized to (a) placebo ( N = 31); (b) low-dose ( N = 29, 12/18 mg/day); (c) medium-dose ( N = 30, 24/36 mg/day); and (4) high-dose ( N = 31, 36/54 mg/day) groups. Treatment included ~2.5-week titration, 3-week maintenance, and 1-week tapering/conversion, alongside existing monotherapy (stimulants/nonstimulants) and behavioral therapy. The primary endpoint was change in Retrospective-Modified Overt Aggression Scale (R-MOAS) score at end of study, with safety monitored. Results: A total of 95 (78.5%) children completed the study. Aggression (R-MOAS) improved with low and medium doses (low dose: p = .031; medium dose: p = .024; high dose: p = .740). The most common adverse events were headache (10.0%), sedation (8.9%), and increased appetite (7.8%). Conclusion: These results suggest SPN-810 may be effective in reducing residual IA behaviors in children with ADHD. Research is still needed to support the benefit–risk profile of SPN-810 in pediatric populations.

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Enhanced intestinal 2-deoxy-2-[18F]fluoro-D-glucose uptake under metformin is not fully suppressed by loperamide

Endocrine Regulations ◽

10.2478/enr-2018-0023 ◽

2018 ◽

Vol 52 (4) ◽

pp. 185-191

Author(s):

Tomomi Nobashi ◽

Tsuneo Saga ◽

Yuji Nakamoto ◽

Yoichi Shimizu ◽

Sho Koyasu ◽

...

Keyword(s):

Body Weight ◽

Small Intestine ◽

Low Dose ◽

Control Group ◽

High Dose ◽

Fdg Uptake ◽

Significant Difference ◽

Mouse Small Intestine ◽

Long Acting ◽

And Control

AbstractObjective. This study investigated whether the metformin (Met)-induced enhanced intestinal uptake of 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG) is reduced by loperamide, a long-acting anti-diarrheal agent. Methods. Mean18F-FDG uptake in the mouse small intestine and colon with Met exposure was compared with that in control mice. In the Met group, high-dose (1.0 mg/kg body weight) and low-dose (0.1 mg/kg body weight) loperamide were introduced, and18F-FDG uptake in the small intestine and colon was compared with that of control mice administered high-dose loperamide. The percent injected dose of18F-FDG per gram of tissue (%ID/g) in the extracted tissues was then determined. Results.18F-FDG uptake increased significantly in the small intestine (0.64±0.06 vs. 1.01±0.15, p=0.040) and, especially, the colon (0.46±0.13 vs. 2.16±0.51, p<0.001) after Met exposure. Neither high-dose nor low-dose loperamide significantly reduced18F-FDG uptake in the small intestine (0.82±0.31 vs. 0.84±0.22, p=0.93 and 0.78±0.25 vs. 0.70±0.15, p=0.13, respectively) or colon (2.13±0.41 vs. 1.67±0.55, p=0.063 and 1.77±0.39 vs. 1.80±0.25, p=0.56, respectively). The colonic %ID/g was significantly higher in Met groups irrespective of loperamide introduction than in control group, whereas the significant difference in the small intestine was observed only between Met and control groups. Conclusion. Metformin increased18F-FDG uptake in intestines especially in colon. Loperamide administration partially, but not sufficiently, suppresses the Met-induced increased colonic uptake of18F-FDG.

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Simulation of Transient Enhanced Diffusion in Silicon Taking into Account Ostwald Ripening of Defects

MRS Proceedings ◽

10.1557/proc-717-c5.1 ◽

2002 ◽

Vol 717 ◽

Cited By ~ 1

Author(s):

Masashi Uematsu

Keyword(s):

Time Dependence ◽

Diffusion Model ◽

Low Dose ◽

Ostwald Ripening ◽

High Dose ◽

Enhanced Diffusion ◽

Annealing Conditions ◽

Transient Enhanced Diffusion ◽

High Dose Implantation ◽

Medium Dose

AbstractThe transient enhanced diffusion (TED) of high-dose implanted P is simulated taking into account Ostwald ripening of end-of-range (EOR) defects. First, we integrated a basic diffusion model based on the simulation of in-diffusion, where no implanted damages are involved. Second, from low-dose implantation, we developed a model for TED due to {311} self-interstitial (I) clusters involving Ostwald ripening and the dissolution of {311} clusters. Third, from medium-dose implantation, we showed that P-I clusters should be taken into account, and during the diffusion, the clusters are dissolved to emit self-interstitials that also contribute to TED. Finally, from high-dose implantation, EOR defects are modeled and we derived a formula to describe the time-dependence for Ostwald ripening of EOR defects, which is more significant at higher temperatures and longer annealing times. The simulation satisfactorily predicts the TED for annealing conditions, where the calculations overestimate the diffusion without taking Ostwald ripening into account.

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