The Effect of 12-Week Treatment with Intermittent Negative Pressure on Blood Flow Velocity and Flowmotion, Measured with a Novel Doppler Device (Earlybird). Secondary Outcomes from a Randomized Sham-Controlled Trial in Patients with Peripheral Arterial Disease.

BACKGROUND: Treatment with intermittent negative pressure (INP) is proposed as an adjunct to standard care in patients with peripheral arterial disease (PAD). The aims of this study were to evaluate the applicability of a novel ultrasound Dopplerdevice (earlybird) to assess blood flow characteristics in patients with PAD during a treatment session with INP, and whether certain flowproperties could determine who could benefit from INP treatment. METHODS: Secondary outcomes of data from a randomized sham-controlled trial were explored. Patients were randomized to 12 weeks of treatment with 40 mm Hg or 10 mm Hg INP, for one hour twice daily. Earlybird blood flow velocity recordings were made before and after the 12-week treatmentperiod and consists of a 5-min recording in rest, 3-min during INP treatment and 5-min recording after ended INP test-treatment. Mean blood flow velocity (vmean), relative changes in flow and frequency spectrum by Fourier-transform of the respective bandwidths of endothelial, sympathetic, and myogenic functions, were analyzed for the different series of blood flow measurements. RESULTS: In total, 62 patients were eligible for analysis, where 32 patients were treated with 40 mm Hg INP. The acquired recordings were of good quality and were used for descriptive analyses of flow characteristics. An immediate increase in vmean during the negative pressure periods of the INP test-treatment was observed in the 40 mm Hg INP treatment group at both pre- and post-test. There was a significant difference between the treatment groups, with a difference between the medians of 13.7 (P < 0.001) at pre-test and 10.7 (P < 0.001) at posttest. This finding was confirmed with spectrum analysis by Fourier-transform of the bandwidth corresponding to INP treatment. The change in amplitude corresponding to myogenic function after 12-weeks of treatment, was significantly different in favor of the 40 mm Hg INP treatment group. We were not able to detect the specific flow characteristics indicating who would benefit INP-treatment. CONCLUSIONS: Earlybird is an applicable tool for assessing blood flow velocity in patients with PAD. Analysis of the flow velocity recordings shows that INP induces an immediate increase in blood flow velocities during INP. The positive effects of INP may be attributed to recruitment of arterioles, and thereby, increasing blood flow. In these analyses, no flow characteristics were determined which could predict who would benefit INP treatment.

Effects of intermittent negative pressure treatment on circulating vascular biomarkers in patients with intermittent claudication.

The aim of this study was to investigate the effects of lower extremity intermittent negative pressure (INP) treatment for 1 hour twice daily for 12 weeks, on circulating vascular biomarkers in patients with intermittent claudication. Patients were randomized to treatment with -40 mmHg INP (treatment group), or -10 mmHg INP (sham control group). Venous blood samples were collected at baseline and after 12 weeks, and concentrations of vascular adhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM-1), E-selectin, P-selectin, von Willebrand factor (vWF), l-arginine, asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA) were analyzed. A larger proportion of the patients in the treatment group (25/31) had a reduction in vWF levels after 12 weeks, compared to the sham control group (17/30) (p = 0.043). Within the treatment group there was a significant mean (SEM) reduction in the concentration of vWF of -11% (4) (p = 0.019), whereas there was no significant change in the levels of vWF in the sham control group (1% (6); p = 0.85). There were no significant differences in the change of any of the biomarker levels between the groups after 12 weeks of treatment. In conclusion, there were no differences in the change of the circulating levels of the measured biomarkers between the treatment group and the sham control group after 12 weeks of INP treatment. However, the observed changes in vWF might indicate a beneficial effect of INP treatment on endothelial activation and endothelial injury. Clinicaltrials.gov Identifier: NCT03640676.

A randomized controlled trial of treatment with intermittent negative pressure for intermittent claudication.

OBJECTIVE: We investigated the effects of lower extremity intermittent negative pressure (INP) treatment for 1 hour two times daily for 12 weeks on the walking distance of patients with intermittent claudication (IC). METHODS: Patients with IC were randomized to treatment with -40 mm Hg INP (treatment group) or -10 mm Hg INP (sham control group). Pain-free walking distance (PWD) and maximal walking distance (MWD) on a treadmill, resting and postexercise ankle-brachial index, resting and postischemic blood flow (plethysmography), and quality of life (EQ-5D-5L and Vascuqol-6) were measured at baseline and after 12 weeks of treatment. RESULTS: A total of 72 patients were randomized, and 63 had data available for the intention-to-treat analyses. The between-group comparisons showed a significant change in the PWD, favoring the treatment group over the sham control group (estimated treatment effect, 50 m; 95% confidence interval [CI], 11-89; P = .014). The PWD had increased by 68 m (P < .001) in the treatment group and 18 m (P = .064) in the sham control group. No significant difference was found in the change in the MWD between the two groups (estimated treatment effect, 42 m; 95% CI, -14 to 97; P = .139). The MWD had increased by 62 m (P = .006) in the treatment group and 20 m (P = .265) in the sham control group. For patients with a baseline PWD of <200 m (n = 56), significant changes had occurred in both PWD and MWD between the two groups, favoring the treatment group (estimated treatment effect, 42 m; 95% CI, 2-83; P = .042; and estimated treatment effect, 62 m; 95% CI, 5-118; P = .032; respectively). Both overall and for the group of patients with a PWD <200 m, no significant differences were found in the changes in the resting and postexercise ankle-brachial index, resting and postischemic blood flow, or quality of life parameters between the two groups. CONCLUSIONS: Treatment with -40 mm Hg INP increased the PWD compared with sham treatment in patients with IC. For the patients with a baseline PWD of <200 m, an increase was found in both PWD and MWD compared with sham treatment.

Lower Extremity Intermittent Negative Pressure for Intermittent Claudication. Follow-Up after 24 Weeks of Treatment.

BACKGROUND: Treatment with lower extremity intermittent negative pressure (INP) of -40 mm Hg for one hour twice daily for 12 weeks, increases walking capacity in patients with intermittent claudication (IC). However, the effects of INP treatment beyond 12 weeks have not been elucidated. The aim of the present study was to investigate the clinical effects of INP treatment after 24 weeks in patients with IC. METHODS: This was a follow-up study after a randomized sham-controlled trial, where patients randomized to the active treatment group were offered to continue treatment for 12 additional weeks (24 weeks in total). Treatment with -40 mm Hg INP was applied in a pressure chamber sealed around the lower leg, and the patients were instructed to treat themselves at home one hour in the morning and one hour in the evening. Pain free walking distance (PWD), maximal walking distance (MWD), resting ankle-brachial index (ABI) and post exercise ABI were measured at baseline, after 12 and 24 weeks. RESULTS: Ten out of 32 patients (31%) from the active treatment group in the initial trial were included in this follow-up study. At baseline, PWD was (mean ±SD) 151 ± 91 m and MWD was 362 ±159 m. There was a significant increase in both PWD and MWD after 24 weeks of treatment, compared to baseline (ANOVA; P= 0.006 and P= 0.012, respectively). Post hoc tests revealed that PWD increased significantly from baseline to 12 weeks (mean 81 m; 95% CI [6, 156]; P = 0.032), and that MWD increased significantly from 12 to 24 weeks (mean 145 m; 95% CI [22, 268]; P = 0.018). There were no significant changes in resting ABI or post exercise ABI during the 24-week treatment period (ANOVA; P= 0.157 and P= 0.450, respectively). CONCLUSION: Both PWD and MWD improved after treatment with - 40 mm Hg INP for one hour twice daily for 24 weeks, compared to baseline. The main improvement in PWD occurred during the first 12 weeks of treatment, whereas the main improvement in MWD occurred between 12 and 24 weeks of treatment.

Economic model to examine the cost-effectiveness of FlowOx home therapy compared to standard care in patients with peripheral artery disease.

BACKGROUND: Critical limb ischaemia is a severe stage of lower limb peripheral artery disease which can lead to tissue loss, gangrene, amputation and death. FlowOx™ therapy is a novel negative-pressure chamber system intended for home use to increase blood flow, reduce pain and improve wound healing for patients with peripheral artery disease and critical limb ischaemia. METHODS: A Markov model was constructed to assess the relative cost-effectiveness of FlowOx™ therapy compared to standard care in lower limb peripheral artery disease patients with intermittent claudication or critical limb ischaemia. The model used data from two European trials of FlowOx™ therapy and published evidence on disease progression. From an NHS analysis perspective, various FlowOx™ therapy scenarios were modelled by adjusting the dose of FlowOx™ therapy and the amount of other care received alongside FlowOx™ therapy, in comparison to standard care. RESULTS: In the base case analysis, consisting of FlowOx™ therapy plus nominal care, the cost estimates were £12,704 for a single dose of FlowOx™ therapy per annum as compared with £15,523 for standard care. FlowOx™ therapy patients gained 0.27 additional quality adjusted life years compared to standard care patients. This equated to a dominant incremental cost-effectiveness ratio per QALY gained. At the NICE threshold WTP of £20,000 and £30,000 per QALY gained, FlowOx™ therapy in addition to standard care had a 0.80 and 1.00 probability of being cost-effectiveness respectively. CONCLUSIONS: FlowOx™ therapy delivered as a single annual dose may be a cost-effective treatment for peripheral artery disease. FlowOx™ therapy improved health outcomes and reduced treatment costs in this modelled cohort. The effectiveness and cost-effectiveness of FlowOx™ therapy is susceptible to disease severity, adherence, dose and treatment cost. Research assessing the impact of FlowOx™ therapy on NHS resource use is needed in order to provide a definitive economic evaluation.

Risk factors for symptomatic venous thromboembolism following surgery for closed ankle fractures: A case-control study.

BACKGROUND: We analyzed risk factors for venous thromboembolism (VTE) within 6 months after surgery for closed ankle fractures. METHODS: This was a case-control study based on data from chart review in a cohort of patients having open reduction and internal fixation (ORIF) for closed ankle fractures in two large general hospitals 2009-2011. Cases with symptomatic VTE (pulmonary embolism or deep venous thrombosis) were identified in the cohort, and additional cases of VTE were identified by computerized search of discharge diagnoses in the same hospitals in 2004-2008 and 2012-2016. In total, we identified 60 cases with VTE and compared with 240 randomly selected controls among 998 patients without VTE in the cohort. Risk factors were assessed using logistic regression analysis. RESULTS: Among cases, 27 (45%) had pulmonary embolism, 33 (55%) deep venous thrombosis. Those with VTE were older, had higher BMI, had more often a family history of VTE, and more often had antibiotic prophylaxis during surgery than controls. In multivariable logistic regression analysis age/10 (OR 25.75, 95%CI 3.52-188.44, p=0.001), (age/10)2 (OR 0.77, 95%CI 0.65-0.93, p=0.005), BMI (1.15 per kg/m2, 95%CI 1.07-1.24, p<0.001) and Charlson comorbidity index ≥2 vs.0 (OR 0.27, 95%CI 0.08-0.92, p=0.036) and 1 vs. 0 (OR 0.27, 95%CI 0.09-0.86, p=0.026) were associated with VTE within 6 months of surgery. CONCLUSIONS: The odds of symptomatic VTE within 6 months of ORIF increased with increasing age and BMI, but were lower with increasing comorbidity.

The acute effects of different levels of intermittent negative pressure on peripheral circulation in patients with peripheral artery disease.

Intermittent negative pressure (INP) applied to the lower leg induces acute increase in arterial and skin blood flow. The aim of this study was to identify the optimal level of INP to increase blood flow in patients with lower extremity peripheral artery disease (PAD). We investigated the acute effects of different levels of INP in 16 subjects (7 women and 9 men, mean (SD) age 71(8) years) diagnosed with PAD. During application of INP in a pressure chamber sealed below the knee, arterial blood flow was continuously recorded in the dorsalis pedis artery or tibialis posterior artery (ultrasound Doppler), and skin blood flow was continuously recorded at the pulp of the first toe (laser Doppler). Different pressure levels (0, -10, -20, -40, and -60 mmHg) were tested in randomized order. Maximal arterial blood flow relative to baseline (median [25th, 75th percentiles]) was: 0 mmHg; 1.08 (1.02, 1.13), -10 mmHg; 1.11 (1.07, 1.17), -20 mmHg; 1.18 (1.11, 1.32), -40 mmHg; 1.39 (1.27, 1.91) and -60 mmHg; 1.48 (1.37, 1.78). Maximal laser Doppler flux (LDF) relative to baseline was: 0 mmHg; 1.06 (1.02, 1.12), -10 mmHg; 1.08 (1.05, 1.16) -20 mmHg; 1.12 (1.06, 1.27), -40 mmHg; 1.24 (1.14, 1.50) and -60 mmHg; 1.35 (1.10, 1.70). There were significantly higher maximal arterial blood flow and maximal LDF at -40 mmHg compared with -10 mmHg (P = 0.001 and P = 0.025, respectively). There were no significant differences in maximal arterial blood flow and maximal LDF between 0 and -10 mmHg (both P = 1.0), or between -40 and -60 mmHg (both P = 1.0). INP of -40 mmHg was the lowest negative pressure level that increased blood flow.

Factors associated with life-sustaining treatment restriction in a general intensive care unit.

PURPOSE: Few previous studies have investigated associations between clinical variables available after 24 hours in the intensive care unit (ICU), including the Charlson Comorbidity Index (CCI), and decisions to restrict life-sustaining treatment. The aim of this study was to identify factors associated with the life-sustaining treatment restriction and to explore if CCI contributes to explaining decisions to restrict life-sustaining treatment in the ICU at a university hospital in Norway from 2007 to 2009. METHODS: Patients' Simplified Acute Physiology Score II (SAPS II), age, sex, type of admission, and length of hospital stay prior to being admitted to the unit were recorded. We retrospectively registered the CCI for all patients based on the medical records prior to the index stay. A multivariable logistic regression analysis was used to assess factors associated with treatment restriction during the ICU stay. RESULTS: We included 936 patients, comprising 685 (73%) medical, 204 (22%) unscheduled and 47 (5%) scheduled surgical patients. Treatment restriction was experienced by 241 (26%) patients during their ICU stay. The variables that were significantly associated with treatment restriction in multivariable analysis were older age (odds ratio [OR] = 1.48 per 10 years, 95% confidence interval [CI] = 1.28-1.72 per 10 years), higher SAPS II (OR = 1.05, 95% CI = 1.04-1.07) and CCI values relative to the reference of CCI = 0: CCI = 2 (OR = 2.08, 95% CI = 1.20-3.61) and CCI≥3 (OR = 2.72, 95% CI = 1.65-4.47). CONCLUSIONS: In multivariable analysis, older age, greater illness severity after 24 h in the ICU and greater comorbidity at hospital admission were independently associated with subsequent life-sustaining treatment restriction. The CCI score contributed additional information independent of the SAPS II illness severity rating.

Charlson comorbidity index derived from chart review or administrative data: agreement and prediction of mortality in intensive care patients.

PURPOSE: This study compared the Charlson comorbidity index (CCI) information derived from chart review and administrative systems to assess the completeness and agreement between scores, evaluate the capacity to predict 30-day and 1-year mortality in intensive care unit (ICU) patients, and compare the predictive capacity with that of the Simplified Acute Physiology Score (SAPS) II model. PATIENTS AND METHODS: Using data from 959 patients admitted to a general ICU in a Norwegian university hospital from 2007 to 2009, we compared the CCI score derived from chart review and administrative systems. Agreement was assessed using % agreement, kappa, and weighted kappa. The capacity to predict 30-day and 1-year mortality was assessed using logistic regression, model discrimination with the c-statistic, and calibration with a goodness-of-fit statistic. RESULTS: The CCI was complete (n=959) when calculated from chart review, but less complete from administrative data (n=839). Agreement was good, with a weighted kappa of 0.667 (95% confidence interval: 0.596-0.714). The c-statistics for categorized CCI scores from charts and administrative data were similar in the model that included age, sex, and type of admission: 0.755 and 0.743 for 30-day mortality, respectively, and 0.783 and 0.775, respectively, for 1-year mortality. Goodness-of-fit statistics supported the model fit. CONCLUSION: The CCI scores from chart review and administrative data showed good agreement and predicted 30-day and 1-year mortality in ICU patients. CCI combined with age, sex, and type of admission predicted mortality almost as well as the physiology-based SAPS II.