Cerebral blood flow velocity during simultaneous changes in mean arterial pressure and cardiac output in healthy volunteers

Abstract Purpose Cerebral blood flow (CBF) needs to be precisely controlled to maintain brain functions. While previously believed to be autoregulated and near constant over a wide blood pressure range, CBF is now understood as more pressure passive. However, there are still questions regarding the integrated nature of CBF regulation and more specifically the role of cardiac output. Our aim was, therefore, to explore the effects of MAP and cardiac output on CBF in a combined model of reduced preload and increased afterload. Method 16 healthy volunteers were exposed to combinations of different levels of simultaneous lower body negative pressure and isometric hand grip. We measured blood velocity in the middle cerebral artery (MCAV) and internal carotid artery (ICAV) by Doppler ultrasound, and cerebral oxygen saturation (ScO 2 ) by near-infrared spectroscopy, as surrogates for CBF. The effect of changes in MAP and cardiac output on CBF was estimated with mixed multiple regression. Result Both MAP and cardiac output had independent effects on MCAV, ICAV and ScO 2 . For ICAV and ScO 2 there was also a statistically significant interaction effect between MAP and cardiac output. The estimated effect of a change of 10 mmHg in MAP on MCAV was 3.11 cm/s (95% CI 2.51–3.71, P  < 0.001), and the effect of a change of 1 L/min in cardiac output was 3.41 cm/s (95% CI 2.82–4.00, P  < 0.001). Conclusion The present study indicates that during reductions in cardiac output, both MAP and cardiac output have independent effects on CBF

Determination of equi-analgesic doses of inhaled methoxyflurane versus intravenous fentanyl using the cold pressor test in volunteers: a randomised, double-blinded, placebo-controlled crossover study

Background Inhaled methoxyflurane for acute pain relief has demonstrated an analgesic effect superior to placebo. Data comparing methoxyflurane to an opioid are needed. The aim of this study was to determine the equi-analgesic doses of inhaled methoxyflurane vs i.v. fentanyl. Both drugs have an onset within minutes and an analgesic effect of 20–30 min. Methods Twelve subjects were included in a randomised, double-blinded, placebo-controlled crossover study with four treatments: placebo (NaCl 0.9%), fentanyl 25 μg i.v., fentanyl 50 μg i.v., or inhaled methoxyflurane 3 ml. The subjects reported pain intensity using the verbal numeric rating scale (VNRS) from 0 to 10 during the cold pressor test (CPT). The CPT was performed before (CPT 1), 5 min (CPT 2), and 20 min (CPT 3) after drug administration. Results Inhaled methoxyflurane and fentanyl 25 μg reduced VNRS scores significantly compared with placebo at CPT 2 (–1.14 [estimated difference in VNRS between treatment groups with 95% confidence interval {CI}: –1.50 to –0.78]; –1.15 [95% CI: –1.51 to –0.79]; both P<0.001) and CPT 3 (–0.60 [95% CI: –0.96 to –0.24]; –0.84 [95% CI: –1.20 to –0.47]; both P<0.001). There were no significant differences between the two drugs. Methoxyflurane had significantly higher VNRS scores than fentanyl 50 μg at CPT 2 (0.90 [95% CI: 0.54–1.26]; P<0.001) and CPT 3 (0.57 [95% CI: 0.21–0.94]; P<0.001). Conclusions Inhaled methoxyflurane 3 ml was equi-analgesic to fentanyl 25 μg i.v. at CPT 2. Both resulted in significantly less pain than placebo. Fentanyl 50 μg i.v. demonstrated analgesia superior to methoxyflurane. Clinical trial registration NCT0389480

Haemodynamic effects of methoxyflurane versus fentanyl and placebo in hypovolaemia: a randomised, double-blind crossover study in healthy volunteers

Background: Methoxyflurane is approved for relief of moderate to severe pain in conscious adult trauma patients: it may be self-administrated and is well suited for use in austere environments. Trauma patients may sustain injuries causing occult haemorrhage compromising haemodynamic stability, and it is therefore important to elucidate whether methoxyflurane may adversely affect the haemodynamic response to hypovolaemia. Methods: In this randomised, double-blinded, placebo-controlled, three-period crossover study, inhaled methoxyflurane 3 ml, i.v. fentanyl 25 μg, and placebo were administered to 15 healthy volunteers exposed to experimental hypovolaemia in the lower body negative pressure model. The primary endpoint was the effect of treatment on changes in cardiac output, while secondary endpoints were changes in stroke volume and mean arterial pressure and time to haemodynamic decompensation during lower body negative pressure. Results: There were no statistically significant effects of treatment on the changes in cardiac output, stroke volume, or mean arterial pressure during lower body negative pressure. The time to decompensation was longer for methoxyflurane compared with fentanyl (hazard ratio 1.9; 95% confidence interval 0.4–3.4; P=0.010), whereas there was no significant difference to placebo (hazard ratio −1.3; 95% confidence interval −2.8 to 0.23; P=0.117). Conclusions: The present study does not indicate that methoxyflurane has significant adverse haemodynamic effects in conscious adults experiencing hypovolaemia. Clinical trial registration: ClinicalTrials.gov (NCT04641949) and EudraCT (2019-004144-29) https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-004144-29/NO

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

Volumetric and end-tidal capnography for the detection of cardiac output changes in mechanically ventilated patients early after open heart surgery

Background. Exhaled carbon dioxide (CO2) reflects cardiac output (CO) provided stable ventilation and metabolism. Detecting CO changes may help distinguish hypovolemia or cardiac dysfunction from other causes of haemodynamic instability. We investigated whether CO2 measured as end-tidal concentration (EtCO2) and eliminated volume per breath (VtCO2) reflect sudden changes in cardiac output (CO). Methods. We measured changes in CO, VtCO2, and EtCO2 during right ventricular pacing and passive leg raise in 33 ventilated patients after open heart surgery. CO was measured with oesophageal Doppler. Results. During right ventricular pacing, CO was reduced by 21% (CI 18–24; p < 0.001), VtCO2 by 11% (CI 7.9–13; p < 0.001), and EtCO2 by 4.9% (CI 3.6–6.1; p < 0.001). During passive leg raise, CO increased by 21% (CI 17–24; p < 0.001), VtCO2 by 10% (CI 7.8–12; p < 0.001), and EtCO2 by 4.2% (CI 3.2–5.1; p < 0.001). Changes in VtCO2 were significantly larger than changes in EtCO2 (ventricular pacing: 11% vs. 4.9% (p < 0.001); passive leg raise: 10% vs. 4.2% (p < 0.001)). Relative changes in CO correlated with changes in VtCO2 (p = 0.53; p = 0.002) and EtCO2 (p = 0.47; p = 0.006) only during reductions in CO. When dichotomising CO changes at 15%, only EtCO2 detected a CO change as judged by area under the receiver operating characteristic curve. Conclusion. VtCO2 and EtCO2 reflected reductions in cardiac output, although correlations were modest. The changes in VtCO2 were larger than the changes in EtCO2, but only EtCO2 detected CO reduction as judged by receiver operating characteristic curves. The predictive ability of EtCO2 in this setting was fair. This trial is registered with NCT02070861

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

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

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: NCT0364067

Core temperature during cold-water triathlon swimming

Triathlon and other endurance races have grown in popularity. Although participants are generally fit and presumably healthy, there is measurable morbidity and mortality associated with participation. In triathlon, most deaths occur during the swim leg, and more insight into risk factors, such as hypothermia, is warranted. In this study, we measured the core temperature of 51 participants who ingested temperature sensor capsules before the swim leg of a full-distance triathlon. The water temperature was 14.4–16.4 °C, and the subjects wore wetsuits. One subject with a low body mass index and a long swim time experienced hypothermia (<35 °C). Among the remaining subjects, we found no association between core temperature and swim time, body mass index, or sex. To conclude, the present study indicates that during the swim leg of a full-distance triathlon in water temperatures ≈ 15–16 °C, subjects with a low body mass index and long swim times may be at risk of hypothermia even when wearing wetsuits

Respiratory Variations in Pulse Pressure Reflect Central Hypovolemia during Noninvasive Positive Pressure Ventilation

Background. Correct volume management is essential in patients with respiratory failure. We investigated the ability of respiratory variations in noninvasive pulse pressure (ΔPP), photoplethysmographic waveform amplitude (ΔPOP), and pleth variability index (PVI) to reflect hypovolemia during noninvasive positive pressure ventilation by inducing hypovolemia with progressive lower body negative pressure (LBNP). Methods. Fourteen volunteers underwent LBNP of 0, −20, −40, −60, and −80 mmHg for 4.5 min at each level or until presyncope. The procedure was repeated with noninvasive positive pressure ventilation. We measured stroke volume (suprasternal Doppler), ΔPP (Finapres), ΔPOP, and PVI and assessed their association with LBNP-level using linear mixed model regression analyses. Results. Stroke volume decreased with each pressure level (−11.2 mL, 95% CI −11.8, −9.6, P<0.001), with an additional effect of noninvasive positive pressure ventilation (−3.0 mL, 95% CI −8.5, −1.3, P=0.009). ΔPP increased for each LBNP-level (1.2%, 95% CI 0.5, 1.8, P<0.001) and almost doubled during noninvasive positive pressure ventilation (additional increase 1.0%, 95% CI 0.1, 1.9, P=0.003). Neither ΔPOP nor PVI was significantly associated with LBNP-level. Conclusions. During noninvasive positive pressure ventilation, preload changes were reflected by ΔPP but not by ΔPOP or PVI. This implies that ΔPP may be used to assess volume status during noninvasive positive pressure ventilation