The effects of lower limb intermittent negative pressure on foot circulation and wound healing - Experimental and prospective studies exploring the acute circulatory and clinical effects of intermittent mild ambient subatmospheric pressure to the lower leg and foot

Sundby and co-workers have in this thesis studied the isolated effects of applying mild negative pressure (-40 mrnHg) to the limb on foot macro- and microcirculation in healthy volunteers, patients with peripheral arterial disease, and in people with spinal cord injuries. The main objectives of this thesis were (i) to explore the acute effects oflower limb intermittent negative pressure (INP) on foot arterial and cutaneous blood flow, and (ii) to explore the use of an INP device for home use for patients with poor foot circulation and chronic leg and foot ulcers. The results of this PhD thesis demonstrated an immediate and significant effect of negative pressure on foot macro- and microcirculation. Further, constant negative pressure applied to the lower limb decreased foot circulation. The same negative pressure applied intermittently increased arterial and skin blood flow of the foot in healthy volunteers. A randomized controlled pilot study on patients with spinal cord injuries and chronic leg and foot ulcers demonstrated that INP can be used as a home-based treatment for patients with spinal cord injuries. Lastly, the pilot study indicated that INP combined with standard wound care improves ulcer healing compared to standard wound care alone. Similar effects were also observed on wound healing in a case study of four patients with critical limb ischemia and chronic leg and foot ulcers who were treated with INP for eight weeks. The efficacy of INP should be tested in an adequately sized, preferably multicenter, randomized superiority trial

Correction: The effects of sympathetic activity induced by ice water on blood flow and brachial artery flow-mediated dilatation response in healthy volunteers.

[This corrects the article DOI: 10.1371/journal.pone.0219814.]

The effects of sympathetic activity induced by ice water on blood flow and brachial artery flow-mediated dilatation response in healthy volunteers

Objective To investigate the association between sympathetic activity, reactive hyperemia and brachial artery flow-mediated dilation (FMD). Background It is claimed that major surgery has an impact on endothelial function, as observed by post-operative reduced brachial artery FMD response. However, another explanation for the observed reduced FMD response post-operatively may be sympathetic stress-induced reduction in blood flow. Methods Seventeen healthy volunteers with a median age (25th-75th percentiles) of 23.5 (23–24.8) years were recruited. Participants’ brachial blood flow and FMD response were measured (i) during normal non-stress conditions (Normal1); (ii) during exposure to ice water; and (iii) afterwards, under normal non-stress conditions (Normal2). We continuously measured arterial blood pressure (Finometer), heart rate (ECG), skin blood flow of the index finger (laser Doppler), and brachial artery blood flow and diameter (Ultrasound Doppler). Measurements were taken at baseline; before a 5-min suprasystolic forearm occlusion; and following a 3-min post-occlusion, to measure reactive hyperemia and FMD. Results Median (25th-75th percentiles) FMD response after exposure to ice water was reduced compared to non-stress conditions [4.9 (2.9–8.4) % during ice water vs. 9.7 (7.6–12.2) % Normal1 and 9.7 (6.4–10.3) % Normal2, P 0.05). Heart rate significantly increased during ice water exposure [67 (59–69) beats/min)] compared to 55 (49–60) beats/min during Normal1 and 54 (47–60) beats/min during Normal2 (both P 0.05), but increased to 86 (75–98) mm Hg during ice water exposure (P < 0.05). Conclusions Increased sympathetic activity resulted in decreased blood flow and brachial artery FMD response in healthy volunteers, independent of endothelial dysfunction. Future studies should adjust for blood flow when interpreting the FMD response

The effects of intermittent negative pressure on the lower extremities' peripheral circulation and wound healing in four patients with lower limb ischemia and hard-to-heal leg ulcers: a case report

Peripheral circulation is severely compromised in the advanced stages of peripheral arterial disease. Recently, it was shown that the application of −40 mmHg intermittent negative pressure (INP) to the lower leg and foot enhances macro‐ and microcirculation in healthy volunteers. In this case report, we describe the effects of INP treatment on four patients with lower limb ischemia and hard‐to‐heal leg and foot ulcers. We hypothesized that INP therapy may have beneficial hemodynamic and clinical effects in the patients. Four patients (age range: 61–79 years) with hard‐to‐heal leg and foot ulcers (6–24 months) and ankle‐brachial pressure indices of ≤0.60 on the affected side were included. They were treated with an 8‐week intervention period of −40 mmHg INP (10 sec negative pressure and 7 sec atmospheric pressure) on the lower limbs. A custom‐made vacuum chamber was used to apply INP to the affected lower leg and foot for 2 h per day. After 8 weeks of INP therapy, one ulcer healed completely, while the other three ulcers were almost completely healed. These cases suggest that INP may facilitate wound healing. The theoretical foundation is that INP assists wound healing by improving blood flow to the small blood vessels in the affected limb, increasing the flow of oxygen and nutrients to the cells

Application of intermittent negative pressure on the lower extremity and its effect on macro- and microcirculation in the foot of healthy volunteers

Intermittent negative pressure (INP) applied to the lower leg and foot may increase peripheral circulation. However, it is not clear how different patterns of INP affect macro‐ and microcirculation in the foot. The aim of this study was therefore to determine the effect of different patterns of negative pressure on foot perfusion in healthy volunteers. We hypothesized that short periods with INP would elicit an increase in foot perfusion compared to no negative pressure. In 23 healthy volunteers, we continuously recorded blood flow velocity in a distal foot artery, skin blood flow, heart rate, and blood pressure during application of different patterns of negative pressure (−40 mmHg) to the lower leg. Each participant had their right leg inside an airtight chamber connected to an INP generator. After a baseline period at atmospheric pressure, we applied four different 120 sec sequences with either constant negative pressure or different INP patterns, in a randomized order. The results showed corresponding fluctuations in blood flow velocity and skin blood flow throughout the INP sequences. Blood flow velocity reached a maximum at 4 sec after the onset of negative pressure (average 44% increase above baseline, P < 0.001). Skin blood flow and skin temperature increased during all INP sequences (P < 0.001). During constant negative pressure, average blood flow velocity, skin blood flow, and skin temperature decreased (P < 0.001). In conclusion, we observed increased foot perfusion in healthy volunteers after the application of INP on the lower limb

The effects of time for the first 17s (one pressure cycle) after onset of negative pressure.

<p>Effect estimates are for all the INP-cycles aggregated within and between subjects relative to each subject′s mean baseline value. Blood flow velocity (cm/s), Laser Doppler Flux, LDF (AU) measured in test leg and control leg (shown as dashed line); Vacuum chamber pressure (mmHg, right y-axis).</p

The acute effects of lower limb intermittent negative pressure on foot macro- and microcirculation in patients with peripheral arterial disease

<div><p>Background</p><p>Intermittent negative pressure (INP) applied to the lower leg and foot increases foot perfusion in healthy volunteers. The aim of the present study was to describe the effects of INP to the lower leg and foot on foot macro- and microcirculation in patients with lower extremity peripheral arterial disease (PAD).</p><p>Methods</p><p>In this experimental study, we analyzed foot circulation during INP in 20 patients [median (range): 75 (63-84yrs)] with PAD. One leg was placed inside an air-tight vacuum chamber connected to an INP-generator. During application of INP (alternating 10s of -40mmHg/7s of atmospheric pressure), we continuously recorded blood flow velocity in a distal foot artery (ultrasound Doppler), skin blood flow on the pulp of the first toes (laser Doppler), heart rate (ECG), and systemic blood pressure (Finometer). After a 5-min baseline sequence (no pressure), a 10-min INP sequence was applied, followed by 5-min post-INP (no pressure). To compare and quantify blood flow fluctuations between sequences, we calculated cumulative up-and-down fluctuations in arterial blood flow velocity per minute.</p><p>Results</p><p>Onset of INP induced an increase in arterial flow velocity and skin blood flow. Peak blood flow velocity was reached 3s after the onset of negative pressure, and increased 46% [(95% CI 36–57), <i>P</i><0.001] above baseline. Peak skin blood flow was reached 2s after the onset of negative pressure, and increased 89% (95% CI 48–130), <i>P</i><0.001) above baseline. Cumulative fluctuations per minute were significantly higher during INP-sequences compared to baseline [21 (95% CI 12–30)cm/s/min to 41 (95% CI 32–51)cm/s/min, <i>P</i><0.001]. Mean INP blood flow velocity increased significantly ~12% above mean baseline blood flow velocity [(6.7 (95% CI 5.2–8.3)cm/s to 7.5 (95% CI 5.9–9.1)cm/s, <i>P</i> = 0.03)].</p><p>Conclusion</p><p>INP increases foot macro- and microcirculatory flow pulsatility in patients with PAD. Additionally, application of INP resulted in increased mean arterial blood flow velocity.</p></div

Physiological parameters for all the PAD patients (n = 20) during baseline, INP, and post-INP.

<p>Estimates are mean and 95% CI.</p

An example of blood flow velocity and laser Doppler flux responses in one of the patients (age: 64 years; Fontaine stage IIB; ABPI test leg: 0.21, ABPI control leg: 0.29, PVR test leg: 1mm, PVR control leg: 4mm) during the 20 minute experiment: 5 min baseline (atmospheric pressure), 10 min INP, and 5 min post-INP (atmospheric pressure) sequences.

<p>Panel A: Pressure within the vacuum chamber; Panel B: Blood flow velocity (ultrasound Doppler); Panel C: Laser Doppler flux in the test foot; Panel D: Laser Doppler flux in the control foot not exposed to INP. All panels’ timelines are from 0 to 1200s (x-axis).</p

Arterial blood flow velocities (cm/s) for each second relative to each subject′s mean baseline value.

<p>Black lines are mean values with 95% confidence intervals for each second as grey lines. Panel A shows the whole 20-min experiment. Panel B shows a section at the end of baseline and beginning of INP.</p